AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

GALDANSETRON

 Uncategorized  1 Response »
Jan 022014
 

cas no 116684-92-5

(3R)-9-methyl-3-[(5-methyl-1H-imidazol-4-yl)methyl]-2,3-dihydro-1H-carbazol-4-one

Molecular Formula: C18H19N3O   Molecular Weight: 293.36296

GR-81225X
GR-82115C (hydrochloride)

GSK

PRECLINICAL

Nausea and Vomiting, Treatment of

 CA 2081709     EP 0542364     US 4859662

 

 

GALDANSETRON HYDROCHLORIDE

CAS NO 156712-35-5 (HCl)

Molecular Formula: C18H20ClN3O   Molecular Weight: 329.8239

  • Galdansetron HCl
  • Galdansetron hydrochloride
  • GR 81225C
  • GR 81225X [as the base]
  • UNII-E3M2R8Q947

 

Mona Lisa Painting animation

GALDANSETRON RACEMIC

GR 67330
CAS NO 116684-93-6

2D image of a chemical structure

………………………………………………………………

Patents

  • US 20050209293 A
  • US 20060024365
  •  US 4859662 A
  • DE 3740352 A1
  • WO 2001095902 A1
  •  WO 2009146537 A1
  •  US 20100226943 A1

picture animation

DE3740352A1

Example 1

(E) -1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methylene]-4H-carbazol-4-one maleate

A solution of 1,2,3,9-tetrahydro-3-[hydroxy [5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl] methyl]-9-methyl-4H-carbazol-4-one (2.70 g) in glacial acetic acid (100 ml) was treated with p-toluenesulfonic acid monohydrate (10.80 g) and the stirred solution was heated to reflux for 4 hours. The cool dark liquid was evaporated, treated with aqueous saturated sodium bicarbonate solution (250 ml) and extracted into ethyl acetate (4 × 250 ml). The combined, dried organic extracts were evaporated and purified by SPCC. The eluting with System A (978: 20: 2 → 945: 50: 5) afforded the free base of the title compound as a light yellow-brown solid (488 mg). A hot solution of the free base (87 mg) in ethanol, about 16 ml) was treated with a hot solution of maleic acid (38 mg) in ethanol (1 ml). After cooling, the precipitate was collected to give the title compound (81 mg), mp 205-209 ° was obtained.

Analysis found: C: 65.1, H 5.2, N 10.2; C ₁ ₈ H ₁ ₇ N ₃ O · C ₄ H ₄ O ₄
theoretical values: C: 64.9, H 5.2, N 10.3%.

 

Example 7 1,2,3,9-tetrahydro-9-methyl-3-[(1H-imidazol-4-yl) methylene] – 4H-carbazol-4-one

A solution of diisopropylamine (1.54 ml) in dry THF (20 ml) of -78 ° was treated dropwise with n-butyllithium (1.32 M in hexane, 8.3 ml). The mixture was allowed to warm to 0 ° and cooled to -78 ° again. It was then in the course of 3 minutes to a stirred suspension of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (2.0 g) in dry THF (80 ml) of -78 optionally °. The resulting suspension was stirred at -78 ° on this for 2 hours and then treated with 1 – treated (triphenylmethyl)-1H-imida zol-4-carboxaldehyde (3.72 g). The mixture was stirred for a further 2 hours, during which time it was allowed to warm slowly to room temperature. Then it was cooled to -78 ° and quenched with acetic acid (2 ml). The resulting solution was allowed to warm to room temperature and 8% aqueous sodium bicarbonate solution (600 ml) was poured.

The mixture was extracted with dichloromethane (3 x 150 ml) and the combined, dried organic extracts were evaporated to give a foam. A solution of this foam and p-toluenesulfonic acid monohydrate (18 g) in a mixture of glacial acetic acid (25 ml) and dry THF (150 ml) was heated for 5 hours under reflux. The cooled mixture was carefully added to an 8% aqueous sodium bicarbonate solution (650 ml) and extracted with dichloromethane (3 x 150 ml). The combined, dried organic extracts were evaporated to give a solid which was obtained by FCC eluting with System A (100: 1: 10) was purified. In this way the title compound (1.42 g), mp 225-232 ° was obtained.

Analysis found: C: 73.3, H 5.6, N 14.7; C ₁ ₇ H ₁ ₅ N ₃ O
theoretical values: C: 73.6, H 5.5, N 15.1%

 

 

Example 8

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one maleate

A solution of 1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methylene]-4H-carbazol-4-one (3.50 g) in DMF (85 ml) and ethanol (50 ml) was added to a prereduced suspension of 10% palladium on carbon added (3.4 g) in ethanol (50 ml) and hydrogenated at room temperature and atmospheric pressure until hydrogen uptake ceased (270 ml). The catalyst was filtered off and the filtrate was evaporated. The residue was adsorbed from methanol (170 ml) of SPCC-FCC silica and applied to a column. A gradient elution system A (967: 30: 3 → 912: 80: 8) afforded the free base of the title compound as a solid (2.32 g). A portion of this solid (500 mg) in hot ethanol (15 ml) was treated with a hot solution of maleic acid (224 mg) in ethanol (2 ml). Upon cooling, a precipitate was collected, the title compound (415 mg), mp 130.5-137 ° revealed. tlc (system A 200: 10: 1) 0.30.

Analysis found: C: 63.2, H 5.5, N 9.7; C ₁ ₈ H ₁ ₉ N ₃ O · C ₄ H ₄ O ₄ · 0.33 H ₂ O
theoretical values: C: 63.6, H 5.7, N 10.1%. Water sample found: 1.55% wt. / Wt. 0.33 mol H ₂ O ≡

¹ H-NMR (d ⁶-DMSO) δ 1.8-1.98 (1H, m), 2.1-2.25 (1H, m), 2.25 (3H, s), 2.68 to 2, 84 (2H, m), 2.85 to 3.3 (3H, m), 3.75 (3H, s), 6.0 (2H, s-maleate), 7.18-7.32 (2H, m), 7.57 (1H, brd), 8.03 (1H, brd), 8.88 (1H, s).

 

+FORM

Example 31

(+) -1,2,3,9-Tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one

A solution of (±) -1,2,3,9-tetrahydro-9-methyl-3-[(5-me thyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one (500 mg) in warm methanol (30 ml) was treated with a solution of (+) -2,3-bis [[(4-methylphenyl) carbonyl] oxy] butanedioic acid (690 mg) in methanol (10 ml), and The solution was allowed to stand for 3 days at 0 °. It was then filtered to give a solid remained which was recrystallized from methanol to give the desired salt (195 mg), mp 146-148 ° was obtained. A part of this salt (186 mg) was suspended (10 ml) in water and treated with potassium carbonate (79.2 mg) and the mixture was extracted with dichloromethane (2 x 40 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (79.2 mg) as a solid, mp 230-232 ° stayed behind. [Α] = 49.7 ° (c = 0.41%, CHCl ₃).

 

– FORM

Example 32

(-) -1,2,3,9-Tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one

A solution of (±) -1,2,3,9-tetrahydro-9-methyl-3-[(5-me thyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one (500 mg) in warm methanol (30 ml) was added a solution of (- treated) -2,3-bis [[(4-methylphenyl) carbonyl] oxy] butanedioic acid (690 mg) in methanol (10 ml), and The solution was allowed to stand at 0 ° for 3 days. It was filtered, producing a solid remained which was recrystallized from methanol to give the desired salt (162 mg), mp 147-148 ° was obtained. This was suspended in water (15 ml) and treated with a solution of potassium carbonate (1 g in 10 ml water). The mixture was extracted with dichloromethane (2 x 30 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (72.5 mg) as a solid, mp 230-232 ° stayed behind. [Α] = 48.4 ° (c = 0.44%, CHCl ₃).

Example 33

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) – methyl]-4H-carbazol-4-one

A solution of Intermediate 7 (190 mg) in dry DMF (1 ml) was added dropwise to a stirred suspension of sodium hydride, under nitrogen (52% dispersion in oil, 20 mg) in dry DMF (0.4 ml). After 15 minutes, iodomethane (0.027 ml) was added and the mixture was stirred for 1.5 hours. Water (20 ml) was added and the suspension was extracted with dichloromethane (3 x 10 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 300 mg) in a mixture of THF (4 ml), acetic acid (4 ml) and water (4 ml) was dissolved. The mixture was heated at reflux for 1.5 hours. It was poured (20 ml) in saturated potassium carbonate solution and extracted with dichloromethane (3 x 10 ml). The combined, dried organic extracts were evaporated to give a semi-solid (ca 255 mg) was obtained by SPCC eluting with System A (200: 1: 10) was purified. In this way the title compound (7 mg) was obtained. The ¹ H NMR and tlc of this material were values ​​with the corresponding values ​​of the product of Example 8 in line.

Example 34

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) – methyl]-4H-carbazol-4-one

n-Butyllithium (1.45M in hexane; 2.07 ml) was added dropwise to a cold (-70 (20 ml) under nitrogen. The solution was allowed to reach 0 30 min, cooled to -70 solution of) 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (500 mg) in dry THF (10 ml under nitrogen. Hexamethylphosphoramide (0.44 ml) was added and the mixture was allowed to reach 0 cooled to -70 4-(chloromethyl)-5-methyl-1-(triphenylmethyl) -1H-imidazole (936 mg) in dry THF (15 ml) was added and the mixture was allowed to reach ca. 20 sodium bicarbonate solution (100 ml) and extracted with dichloromethane (3 give a semi-solid which was treated with a mixture of acetic acid (10 ml), water (10 ml) and THF (10 ml) and heated at reflux for 1.5 h. The solution was poured into saturated potassium carbonate solution (100 mml) and extracted with dichloromethane (3 organic extracts were evaporated to give a solid (ca. 1.8 g) which was purified by SPCC eluting with System A (200:10:1) to give the title compound (17 mg). The .sup.1 H-n.m.r. and t.l.c. of this material were consistent with those obtained from the product of Example 8.

 

BREAKING OF MALEATE SALT

Example 35

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one

1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4-yl) – methyl]-4H-carbazol-maleate (37 mg) was partitioned between 2 N sodium bicarbonate solution (10 ml) and chloroform (3 x 15 ml) separated. The combined, dried organic layers were evaporated to give the free base (26 mg) was obtained, which was dissolved at -10 ° under nitrogen in 10% aqueous THF (4 ml). To this stirred solution, a solution of 2,3-dichloro-5 ,6-dicyano-1 ,4-benzoquinone (49 mg) was added in dry THF (1.6 ml) was added dropwise, and the reaction mixture was added over 3 hours allowed to warm to 0 °. The solution was evaporated in vacuo and purified by FCC eluting with System A (94.5: 5: 0.5) to give the title compound (10 mg) was obtained as a solid.The ¹ H NMR and tlc values ​​of this material were consistent with the corresponding values ​​of the product of Example 8

INTERMEDIATE 7

Intermediate 7

1,2,3,9-Tetrahydro-3-[(5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl) methyl]-4H-carbazol-4-one

A solution of triphenylchloromethane (4.2 g) in dry DMF (40 ml) was added dropwise to a solution of 1,2,3,9 – tetrahydro-3-[(5-methyl-1H-imidazol-4-yl) methyl ]-4H-carbazol-4-one (3.5 g) and triethylamine (1.75 ml) in dry DMF (35 ml) under nitrogen.After stirring for 4 hours the mixture was poured (300 ml) in water and extracted with dichloromethane (3 x 100 ml). The combined extracts were washed with water (200 ml), dried and evaporated to give an oil (about 9 g) was obtained. This was purified by FCC eluting with System A (200: 1: 10) to give the title compound (4.57 g) as a foam, tlc (system A 200: 10: 1), Rf 0.32 was obtained.

 

Intermediate 8

4 – (chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole

A solution of thionyl chloride (1.3 ml) in dry dichloromethane (10 ml) was added over 5 minutes to a stirred suspension of 5-methyl-1-(triphenylmethyl) – 1H-imidazol-4-methanol (5.0 g ) in a mixture of dichloromethane (100 ml) and dry DMF (2 ml) at 0 °. The mixture was stirred at 0 ° for 30 minutes and washed successively with 8% sodium bicarbonate (2 x 50 ml), water (50 ml), dried and evaporated in vacuo below 40 ° to give an oil (5 g) was obtained. This was dissolved in ether (100 ml), and the resulting solution was filtered through a silica pad which was eluted with ether (2 x 100 ml) further. The combined filtrates were evaporated below 40 °, whereby a foam was obtained which was triturated with cold hexane and filtered. There was thus obtained the title compound (4.2 g) as a solid, mp 133-135 °, was obtained

 

Intermediate 14

1,2,3,9-tetrahydro-9-methyl-3 [[5-methyl-1-(triphenylmethyl) – 1H-imidazol-4-yl] methyl]-4H-carbazol-4-one

A solution of triphenylchloromethane (286 mg) in dry DMF (10 ml) was added dropwise to a stirred solution of 1,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1H-imidazol-4 – optionally yl) methyl]-4H-carbazol-4-one (292 mg) and triethylamine (101 mg) in dry DMF (20 ml). The resulting solution was stirred for 3.5 hours at room temperature under nitrogen. The reaction mixture was then poured into water (100 ml) and the resulting suspension was extracted with dichloromethane (3 x 50 ml). The combined, dried organic extracts were adsorbed onto FCC silica, which was then applied to a column. FCC eluting with System A (150: 8: 1) afforded a solid which, by crystallization from dichloromethane: hexane (2: 1) was further purified to give the title compound (304 mg), mp 193 to 195 °, was obtained.

 

INTERMEDIATES

CAS 27387-31-1

C13 H13 N O
4H-​Carbazol-​4-​one, 1,​2,​3,​9-​tetrahydro-​9-​methyl-
Carbazol-​4(1H)​-​one, 2,​3-​dihydro-​9-​methyl-
INTERMEDIATE 2 
CAS  113140-81-1
C24 H20 N2 O
1H-​Imidazole-​4-​carboxaldehyde, 5-​methyl-​1-​(triphenylmethyl)​
INTERMEDIATE 3
CAS : 116684-96-9
C37 H33 N3 O2
4H-​Carbazol-​4-​one, 1,​2,​3,​9-​tetrahydro-​3-​[hydroxy[5-​methyl-​1-​(triphenymethyl)​-​1H-​imidazol-​4-​yl]​methyl]​-​9-​methyl-
4H-Carbazol-4-one, 1,2,3,9-tetrahydro-3-[hydroxy[5-methyl-1-(triphenylmethyl)-1H-imidazol- 4-yl]methyl]-9-methyl-
INTEMEDIATE 4
triphenylchloromethane
ChemSpider 2D Image | Triphenylchloromethane | C19H15Cl
CAS 76-83-5
INTERMEDIATE 5
4-(chloromethyl)-5-methyl-1-(triphenylmethyl) -1H-imidazole
……………………………………………………………………………………….
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ANTHONY MELVIN CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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ALOSETRON HYDROCHLORIDE

 Uncategorized  1 Response »
Jan 012014
 

ALOSETRON

5-methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one

132414-02-9, Hydrochloride
122852-42-0 (free base)

122852-69-1 CHECK…..

GR-68755C

  • Alosetron HCl
  • Alosetron hydrochloride
  • GR 68755c
  • HSDB 7055
  • Lotronex
  • UNII-2F5R1A46YW

GSK

LAUNCHED 2002

United States  PATENT  US5360800 APPROVED1993-01-13  EXPIRY 2013-01-13

Alosetron is a 5-HT3 antagonist used only for the management of severe diarrhoea-predominant irritable bowel syndrome (IBS) in women. Alosetron has an antagonist action on the 5-HT3 receptors and thus may modulate serotonin-sensitive gastrointestinal (GI) processes. Alosetron was voluntarily withdrawn from the US market in November 2000 by the manufacturer due to numerous reports of severe adverse effects including ischemic colitis, severely obstructed or ruptured bowel, and death. In June 2002, the FDA approved a supplemental new drug application allowing the remarketing of the drug under restricted conditions of use.

Alosetron hydrochloride (initial brand name: Lotronex; originator: GSK) is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome (IBS) in women only. It is currently marketed by Prometheus Laboratories Inc. (San Diego), also under the trade name Lotronex. Alosetron was withdrawn from the market in 2000 owing to the occurrence of serious life-threatening gastrointestinal adverse effects, but was reintroduced in 2002 with availability and use restricted.

Alosetron hydrochloride is a potent and selective 5-HT3 antagonist marketed by GlaxoSmithKline for the oral treatment of irritable bowel syndrome (IBS) in female patients whose predominant bowel symptom is diarrhea. It is currently marketed in a tablet formulation. In 2000, the drug was withdrawn from several markets based on adverse reactions, however, was reintroduced on the U.S. market in 2002 following a recommendation of a joint FDA advisory panel comprising members of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Subcommittee of the Pharmaceutical Science Committee which stipulated reintroduction of the drug in conjunction with a risk management plan.

Alosetron was originally approved by the U.S. Food and Drug Administration (FDA) on February 9, 2000,[1] after a seven month review.[2] At the time of the initial approval U.S. Food and Drug Administration (FDA) reviewers found that alosetron improved symptoms in 10% to 20% of patients.[3]

Shipment to pharmacies started in March, 2000. On July 17, a health professional filed a report with the FDA on the death of a 50-year-old woman who suffered mesenteric ischemia. The report identified alosetron as the “primary suspect” in the death.[4]

Alosetron was withdrawn from the market voluntarily by GlaxoWellcome on November 28, 2000 owing to the occurrence of serious life-threateninggastrointestinal adverse effects, including 5 deaths and additional bowel surgeries.[2] The FDA said it had reports of 49 cases of ischemic colitis and 21 cases of “severe constipation” and that ten of the 70 patients underwent surgeries and 34 others were examined at hospitals and released without surgery. Through November 17, 2000, pharmacists had filled 474,115 prescriptions for Alosetron.[2] Severe adverse events continued to be reported, with a final total of 84 instances of ischaemic colitis, 113 of severe constipation, 143 admissions to hospital, and 7 deaths.[5]

Patient advocacy groups, most notably the Lotronex Action Group and the International Foundation for Functional Gastrointestinal Disorders (IFFGD) lobbied for the drug’s return. Public Citizen Health Research Group, another patient advocacy group, opposed the reintroduction.[6][7]

On June 7, 2002, the FDA announced the approval of a supplemental New Drug Application (sNDA) that allows restricted marketing of Lotronex (alosetron hydrochloride), to treat only women with severe diarrhea-predominant irritable bowel syndrome (IBS).[8] It was the first drug ever returned to the U.S. market after withdrawal for safety concerns.[9][10]

It is not known whether alosetron has been filed for registration in the EU.

GSK sold Lotronex to the Californian corporation Prometheus in late 2007.[11]

Alosetron hydrochloride works through antagonism of the serotonin 5-HT3 receptor, distributed extensively on visceral neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of 5-HT3 channels results in neuronal depolarization and affects the regulation of visceral pain, colonic transit and gastrointestinal secretions. Alosetron inhibits activation of non-selective cation channels and modulates the enteric nervous system. In previous clinical trials, the drug increased colonic transit time without affecting orocecal transit time, increased basal jejunal water and sodium absorption and significantly increased colonic compliance. In 2007, the compound was licensed to Prometheus Laboratories by GlaxoSmithKline in the U.S. for the treatment of IBS in patients whose predominant bowel symptom is diarrhea.

 

Criticism of the FDA

In 2001, the editor of the renowned medical journal The Lancet, Richard Horton, criticized the FDA’s handling of alosetron in an unusually sharp language.[12] Horton argued that the treatment of a non-fatal condition did not justify the use of a drug with potentially lethal side effects, and that the FDA should have revoked the approval for alosetron sooner when postmarketing surveillance revealed that many patients had suffered constipation necessitating surgical intervention and ischaemic colitis. He asserted that FDA officials were improperly motivated to maintain and reinstate the approval for alosetron because of the extent to which the FDA’s Center for Drug Evaluation and Research is funded by user fees paid by pharmaceutical manufacturers, and that the reinstatement of alosetron was negotiated in confidential meetings with representatives ofGlaxoSmithKline.

An article published in the British Medical Journal (BMJ) noted: “By allowing the marketing of alosetron, a drug that poses a serious and significant public health concern according to its own terms, the FDA failed in its mission.”[13] Others have argued that the approval process of Lotronex was an example of regulatory capture.[7]

Alosetron has an antagonist action on the 5-HT3 receptors of the enteric nervous system of the gastrointestinal tract. While being a 5-HT3 antagonist like ondansetron, it is not classified or approved as an antiemetic. Since stimulation of 5-HT3 receptors is positively correlated with gastrointestinal motility, alosetron’s 5-HT3 antagonism slows the movement of fecal matter through the large intestine, increasing the extent to which water is absorbed, and decreasing the moisture and volume of the remaining waste products.[14]

  1. U.S. Food and Drug Administration. “Drug Details”. Retrieved 11 December 2012.
  2.  Willman, David (29 November 2000). “Drug Lotronex Pulled Over Safety Fears”. The Los Angeles Times. Retrieved 11 December 2012.
  3.  Willman, David (20 December 2000). “Officer Foresaw Deadly Effects”. The Los Angeles Times. Retrieved 11 December 2012.
  4.  Willman, David (2 November 2000). “FDA Minimized Issue of Lotronex’s Safety”. The Los Angeles Times. Retrieved 11 December 2012.
  5. CENTER FOR DRUG EVALUATION AND RESEARCH (23 April 2002). “GASTROINTESTINAL DRUGS ADVISORY COMMITTEE AND DRUG SAFETY AND RISK MANAGEMENT SUBCOMMITTEE OF THE ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE”. U.S. Food and Drug Administration. Retrieved 11 December 2012.
  6.  Grady, Denise (23 April 2002). “Appeals Prompt U.S. Agency to Consider Allowing Sales of Diarrhea Drug Linked to Deaths”. The New York Times. Retrieved 11 December 2012.
  7.  Moynihan, Ray (14 September 2002). “Alosetron: a case study in regulatory capture, or a victory for patients’ rights?”. The British Medical Journal 325 (7364): 592–595.PMC 1124108. PMID 12228140. Retrieved 11 December 2012.
  8.  U.S. Food and Drug Administration. “Lotronex (alosetron hydrochloride) Information”. U.S. Food and Drug Administration. Retrieved 11 December 2012.
  9.  Pollack, A (2006-03-09). “F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk”. The New York Times. Retrieved 2008-03-13.
  10.  Grady, Denise (8 June 2002). “U.S. Lets Drug Tied to Deaths Back on Market”. The New York Times. Retrieved 11 December 2012.
  11.  Prometheus Laboratories Inc. Press Release of 7 November 2007. Retrieved on 27 August 2008.
  12.  Horton, R. (2001). “Lotronex and the FDA: a fatal erosion of integrity”. The Lancet 357 (9268): 1544–1545. doi:10.1016/S0140-6736(00)04776-0. edit
  13.  Lièvre, Michel (14 September 2002). “Alosetron for irritable bowel syndrome”. The British Medical Journal 325 (7364): 555–556. PMC 1124090. PMID 12228116. Retrieved 11 December 2012.
  14.  “HIGHLIGHTS OF PRESCRIBING INFORMATION”. Prometheus Laboratories Inc. April 2008. Retrieved 11 December 2012.
  15.  Camilleri, M.; Northcutt A.R., Kong S., Dukes G.E., McSorley D., Mangel A.W. (25 March 2000). “Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.”. The Lancet 355 (1035): 1035–40. doi:10.1016/S0140-6736(00)02033-X. PMID 10744088.
  16.  Barbehenn, Elizabeth; Peter Lurie, Sidney M. Wolfe (9 December 2000). “Alosetron for irritable bowel syndrome”. The Lancet 356 (9246): 2009. doi:10.1016/S0140-6736(05)72978-0. Retrieved 11 December 2012.

IMPORTANT REF

Drugs Fut 1992, 17(8): 660

US 2012178937

JP 2012140415

WO 2010121038

US 200815392

WO 2006119329

JP 2005225844

WO 1999017755

WO 2001087305

WO 2001045685

US 5229407

US 5008272

9-22-2010
Pyrimidine derivatives
5-7-2010
INDOLONE MODULATORS OF 5-HT3 RECEPTOR
10-3-2003
Method for treating functional dyspepsia
7-16-2003
Methods for treating irritable bowel syndrome
8-7-2002
Methods for treating irritable bowel syndrome
9-5-2001
Medicaments for the treatment of non-constipated female irritable bowel syndrome
12-22-2000
RECEPTOR AGONISTS AND ANTAGONISTS COMPOUND FOR USE AS A MEDICAMENT FOR TREATMENT OF DISORDERS INVOLVING BRONCHOCONTRACTION COMPOUND FOR USE AS A MEDICAMENT FOR TREATMENT OF DISORDERS INVOLVING BRONCHOCONTRACTION
8-25-2000
USE OF 5-HT3 RECEPTOR ANTAGONISTS USE OF 5-HT3 RECEPTOR ANTAGONISTS FOR TREATING MUSCULOESKELETAL DISEASES
8-25-2000
SYSTEMIC USE OF 5-HT3 RECEPTOR ANTAGONISTS AGAINST RHEUMATIC INFLAMMATORY PROCESSES
7-20-2000
$g(b)2-ADRENERGIC RECEPTOR AGONISTS $g(b)2-ADRENERGIC RECEPTOR AGONISTS
5-32-2000
$g(b)2-ADRENERGIC RECEPTOR AGONISTS
12-30-1999
METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS METHODS FOR IDENTIFYING NOVEL MULTIMERIC AGENTS THAT MODULATE RECEPTORS
12-17-1999
MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5-HT3 RECEPTORS MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5-HT>3< RECEPTORS MULTIVALENT AGONISTS, PARTIAL AGONISTS, INVERSE AGONISTS AND ANTAGONISTS OF THE 5-HT3 RECEPTORS
6-25-1999
ORAL DELIVERY FORMULATION
4-16-1999
MEDICAMENTS MEDICAMENTS
8-19-1998
DHA-pharmaceutical agent conjugates of taxanes
11-28-1997
DHA-PHARMACEUTICAL AGENT CONJUGATES DHA-PHARMACEUTICAL AGENT CONJUGATES
3-28-1997
5-HT3 RECEPTOR ANTAGONISTS FOR DYSKINESIA
11-2-1994
Tetrahydro-1H-pyrido[4,3-b]indol-1-one derivatives
8-31-1994
Controlled release device
9-22-2010
Pyrimidine derivatives
5-7-2010
INDOLONE MODULATORS OF 5-HT3 RECEPTOR
10-3-2003
Method for treating functional dyspepsia
7-16-2003
Methods for treating irritable bowel syndrome
8-7-2002
Methods for treating irritable bowel syndrome
9-5-2001
Medicaments for the treatment of non-constipated female irritable bowel syndrome
12-22-2000
RECEPTOR AGONISTS AND ANTAGONISTS COMPOUND FOR USE AS A MEDICAMENT FOR TREATMENT OF DISORDERS INVOLVING BRONCHOCONTRACTION COMPOUND FOR USE AS A MEDICAMENT FOR TREATMENT OF DISORDERS INVOLVING BRONCHOCONTRACTION
8-25-2000
USE OF 5-HT3 RECEPTOR ANTAGONISTS USE OF 5-HT3 RECEPTOR ANTAGONISTS FOR TREATING MUSCULOESKELETAL DISEASES
8-25-2000
SYSTEMIC USE OF 5-HT3 RECEPTOR ANTAGONISTS AGAINST RHEUMATIC INFLAMMATORY PROCESSES
7-20-2000
$g(b)2-ADRENERGIC RECEPTOR AGONISTS $g(b)2-ADRENERGIC RECEPTOR AGONISTS

The Alosetron hydrochloride is a potent and selective antagonist of the serotonin 5-HT3 receptor type. Chemically, Alosetron is designated as 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one, monohydrochloride. This is marketed in United States under trade name of LOTRONEX®

U.S. Pat. No. 5,360,800 discloses a preparation of Alosetron by condensing 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one with 4-chloromethyl-5-methylimidazole in presence of strong base such as sodium hydride. The sodium hydride was corrosive and highly flammable. This type of reaction required extra care, special type of equipments and it is commercially not feasible. This process also provides low yield.

U.S. Pat. No. 6,175,014 patent describes a process for the process Alosetron by reacting of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one of formula (II) with 4-hydroxymethyl-5-methylimidazole of formula (IIIa) or its salt in presence of mineral acid like hydrochloric acid or sulfonic acids such as p-toluene sulfonic acid or methane sulfonic acid. The process requires purification to get pure Alosetron.

 

Figure US20120178937A1-20120712-C00003

 

Hence there is a need for a simple and commercially viable process for the preparation of Alosetron which avoids hazardous base such as sodium hydride.

The present inventors identified a new process for the preparation of Alosetron by reaction of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one of formula (II) with 4-hydroxymethyl-5-methylimidazole of formula (III) or its protected derivative. This process is simple to carryout for large scale preparation and industrially viable

medical use for compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors.

5-HT3 receptor antagonists may be identified by methods well known in the art, for example by their ability to inhibit 3-(5-methyl-1H-imidazole-4-yl)-1-[1-[3H]- methyl-1 H-indol-3-yl]-1-propanone binding in rat entorhinal cortex homogenates (following the general procedure described by G Kilpatrick et al, Nature, 1987, 330, 746-748), and/or by their effect on the 5-HT-induced Bezold-Jarisch (B-J) reflex in the cat (following the general method described by A Butler et al, Br. J. Pharmacol., 94, 397-412 (1988)).

A number of different 5-HT3 receptor antagonists have been disclosed, for example those of group A: indisetron, Ro-93777, YM-114, granisetron, talipexole, azasetron, tropisetron, mirtazapine, ramosetron, ondansetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620, lintopride, KAE- 393, itasetron, mosapride and dolasetron.

In UK Patent No. 2209335, incorporated herein by reference, there is disclosed, inter alia, the compound 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4- yl)methyl]-1H-pyrido[4,3-b]indol-1-one, now known as alosetron, which may be represented by the formula (I):

 

Figure imgf000003_0001

and pharmaceutically acceptable salts, solvates and pharmaceutically acceptable equivalents thereof, in particular its hydrochloride salt.

…………………………………………………………………………………………………………

US20120178937

Figure US20120178937A1-20120712-C00004

EXAMPLE 1 Process for the Preparation of Alosetron

To a mixture of acetic acid and dimethylformamide, 3N-BOC-(-hydroxymethyl-5-methyl imidazole (95.4 g), 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (50 g), trifluoroacetic acid were added and heated to 100-115° C. After completion of the reaction, the reaction mass was cooled to room temperature. To the reaction mass, carbon was added, stirred and filtered though hyflo bed. The bed was washed with dimethylformamide. The filtrate was distilled under vacuum. To the residue, water was added and washed the reaction mass with toluene followed by isopropyl ether. The pH of the reaction mass was adjusted to 6.8-7 using potassium carbonate solution, stirred, cooled and the obtained solid was dried.

EXAMPLE 2 Process for the Preparation of Alosetron

To trifluoroacetic acid, 3N-BOC-4-hydroxymethyl-5-methylimidazole (95.4 g), dimethylformamide (480 mL) and 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (58 g) were added and heated to 100-115° C. After completion of the reaction, the reaction mass was cooled to room temperature. To the reaction mass, carbon was added and filtered though hyflo bed. The bed was washed with dimethylformamide and the filtrate was distilled under vacuum. To the residue, water was added and washed the aqueous layer with toluene followed by isopropyl ether. The pH of the reaction mass was adjusted to 6.8-7 using potassium carbonate solution, cooled and the obtained solid was dried.

 

TABLE 1
Solvent System Reaction time Yield
TFA & DMF 6-7 hours 65%
acetic acid alone  20 hours 17%
acetic acid & DMF No reaction

The above table clearly indicates that the use trifluoroacetic acid (TFA) enhances the reaction progress and also increases the yield of the product.

 

EXAMPLE 3 Purification of Alosetron

To acetic acid, crude Alosetron containing >0.2% of compound of formula (IV) was added and heated to 60-65° C., the reaction mass maintained at same temperature and cooled to 40-45° C. To the reaction mass acetone was added and refluxed. The reaction mass was cooled to 0-5° C., the solid obtained was filtered, washed with acetone (slurry) and dried to yield pure Alosetron having less than 0.02% of Impurity of formula (IV) by HPLC. Yield: 53-50 g

Reference Example 1 Preparation of Alosetron Hydrochloride

To a methanol (50 mL), Alosetron (10 g) and of IPA.HCl (8.5 mL) were added and heated to 40-45° C. The reaction mass was cooled, stirred and filtered and washed with methanol. The reaction mass was dissolved in methanol, treated with carbon, filtered and washed with methanol. The reaction mass was distilled and isopropyl ether was added to the residue and stirred at room temperature. The reaction mass was cooled, stirred. The solid obtained was filtered and washed with chilled methanol and dried.

Yield: 7.8 g Reference Example-2 Process for the preparation of 3N-BOC-(4-hydroxymethyl)-5-methylimidazole

4-Hydroxymethyl-5-methylimidazole (100 g) was dissolved in water, to the solution was added sodium carbonate (107 g) and stirred. To the reaction mass acetonitrile (400 mL) was added and cooled to 10-15° C. followed by addition of solution of DIBOC (di-tert-butyl dicarbonate) in acetonitrile. After completion of the reaction, water was added to the reaction mass and filtered. The filtrate was washed with 1:1 acetonitrile and water and than washed with hexane. The mass was extracted with toluene and the organic layer was washed with water followed by brine. The organic layer was distilled under vacuum to get oily mass of the title compound.

……………………………………..

 

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MAROPITANT

 Uncategorized  1 Response »
Dec 312013
 

 

MAROPITANT

(7R,8S)-N-[(5-tert-Butyl-2-methoxyphenyl)methyl]-7-[di(phenyl)methyl]-1-azabicyclo[2.2.2]octan-8-amine

(2S,3S)-N-[(5-tert-butyl-2-methoxy-phenyl)methyl]-2-(diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-amine

147116-67-4

PRECLINICAL, PFIZER

Maropitant, is described in WO1992021677, US 6,222,038 and US

6,255,230,US 5340826, US 5393762, EP 0769300, WO 2000073304, WO 2005082419, WO 2005082366

…………………………………………………………………………………….
MAROPITANT CITRATE MONOHYDRATE
359875-09-5,
  • Cerenia
  • CJ-11,972
  • Maropitant citrate
  • UNII-LXN6S3999X

Maropitant (trade name Cerenia in the US and other countries), used as maropitantcitrate (USAN), is a neurokinin (NK1) receptor antagonist, which was developed by Zoetisspecifically for the treatment of motion sickness and vomiting in dogs. It was approved by the FDA in 2007 for use in dogs,[1][2] and more recently has also been approved for use in cats.[3]

MORE…………
Use of the cryopreserved human hepatocyte sandwich-culture model to measure hepatic metabolism and biliary efflux
1st Int Conf Drug Des Disc (February 4-7, Dubai) 2008, Abst P-140
Proposed international nonproprietary names (Prop. INN): List 90
WHO Drug Inf 2004, 18(1): 56
Maropitant, a NK-1 antagonist decreases the sevoflurane MAC during visceral stimulation in dogs
13th World Congr Pain (August 29-September 2, Montreal) 2010, Abst PW 320
Identification of metabolites from maropitant using a dual-pressure linear ion trap and mass frontier software
9th Int ISSX Meet (September 4-8, Istanbul) 2010, Abst P343
Effect of maropitant, a new NK-1 receptor antagonist, on the sevoflurane minimum alveolar concentration during ovarian stimulation in cats
Annu Meet Am Soc Anesthesiol (ASA) (October 15-19, Chicago) 2011, Abst A1585
5-23-2012
Antimicrobial preservatives to achieve multi-dose formulation using beta-cyclodextrins for liquid dosage forms
4-17-2009
Process for preparation of 1-(2s,3s)-2-benzhydryl-n-(5- tert-butyl-2-methoxybenzyl)quinuclidin-3-amine
7-6-2007
Nk-1 receptor antagonists anesthesia recovery
6-8-2007
Pharmaceutical compositions of neurokinin receptor antagonists and cyclodextrin and methods for improved injection site toleration
7-25-2003
Use of tachykinin antagonists, including NK-1 receptor antagonists, to modify unwanted behavior in dogs, cats and horses
7-4-2001
Polymorphs of a crystalline azo-bicyclo (2,2,2) octan-3-amine citrate and their pharmaceutical compositions
11-24-1999
NK-1 receptor antagonists for the treatment of cancer
8-28-1997
NK-1 RECEPTOR ANTAGONISTS FOR THE TREATMENT OF EYE DISORDERS
4-18-1997
NK-1 RECEPTOR ANTAGONISTS FOR PREVENTION OF NEUROGENIC INFLAMMATION IN GENE THERAPY
11-20-1996
NK-1 receptor antagonists and 5HT3 receptor antagonists for the treatment of
5-24-1996
NK-1 RECEPTOR ANTAGONISTS FOR THE TREATMENT OF EYE DISORDERS
5-22-1996
Azabicyclo derivatives for treatment of urinary incontinence
2-29-1995
Pharmaceutical agents for treatment of emesis
8-24-1994
Pharmaceutical agents for treatment of urinary incontinence
12-11-1992
bibNUCLIDINE DERIVATIVES

anhydrous (2S,3S)-N-(methoxy-5-t-butylphenylmethyl-2-diphenylmethyl-1-azobicyclo[2,2,2] octan-3-amine citrate monohydrate salt, its single crystalline polymorphic Form A, and pharmaceutical composition containing them. The invention is also directed to a CNS active NK-1 receptor antagonist for treating emesis in a mammal including humans. Treating is defined here as preventing and treating.

Figure US06255320-20010703-C00001

 

U.S. Pat. No. 5,393,762 and U.S. Ser. No. 08/816,016, both incorporated by reference, describe pharmaceutical compositions and treatment of emesis using NK-1 receptor antagonists. The citrate monohydrate has significantly enhanced stability over other salt forms such as the benzoate which was unstable even at 5° C. The mesylate form is deliquescent.

synthesis
U.S. 5,807,867, U.S. 6,222,038 and U.S. 6,255,320.
Figure US20090099364A1-20090416-C00001

The compound of Formula I, an NK1 receptor antagonist, is effective as an anti-emetic agent for mammals. The compound of Formula I is the subject of U.S. Pat. No. 6,222,038 and U.S. Pat. No. 6,255,320, and the preparation of the compound of Formula I is described therein. U.S. Pat. No. 5,393,762 also describes pharmaceutical compositions and treatment of emesis using NK-1 receptor antagonists. The multiple-use formulation of the compound of Formula I may be parenterally administrated for about five days at the same site for treatment of emesis or other indications. Intravenous or, preferably, subcutaneous administration is desirable for acute use, since retention and absorption of an oral dosage form may be problematic during bouts of emesis. The multiple-use formulation is described in a co-pending U.S. provisional application No. 60/540,897 assigned to and owned by Pfizer. Inc.

The compound of Formula I also improves anesthesia recovery in mammals. A co-pending U.S. provisional application No. 60/540,697 assigned to and owned by Pfizer Inc., describes a method of improving anesthesia recovery by administering a NK-1 antagonist prior to, during or after the administration of general anesthesia.

 

 

…………………………………….

US20090099364

Figure US20090099364A1-20090416-C00026

Figure US20090099364A1-20090416-C00027

 

Figure US20090099364A1-20090416-C00028

 

Preparation of (2S,3S)-2-benzhydryl-N-(5-tert-butyl-2-methoxybenzyl) quinuclidin-3-amine citrate monohydrate, Compound of Formula Ia Step C, Scheme II

A solution of (2S,3S)-2-benzhydryl-N-(tert-butyl-2-methoxybenzyl) quinuclidin-3-amine (33.95 kg, 72.4 moles) and anhydrous citric acid (15.3 kg, 79.7 moles) in a mixture of acetone (215 kg) and water (13.6 kg) was heated to 38-42° C. The resultant mixture was then transferred to another reactor via an in-line filter. The transfer line and filter were washed through with acetone (54 kg) and these filtered washings were added to the solution. The resultant mixture was then cooled to 20-25° C. and filtered fart-butyl methyl ether (252 kg) was added portion-wise over a period of approximately 35 minutes. The resultant suspension was then granulated at 20-25° C. for approximately 20 hours. The solid was then collected by filtration on an agitated filter-dryer and the filter cake was washed twice with filtered tert-butyl methyl ether (50 kg each). The resultant solid was then dried at 35° C. under vacuum with agitation to give the title compound (44.4 kg) as a colourless solid. The product was then milted.

1H-NMR (500 MHz, d6-methanol, 30° C.) δ: 7.46 (2H, d), 7.45 (2H, d), 7.37 (4H, m), 7.31 (1H, m), 7.29 (1H, m), 7.24 (1H, dd), 6.95 (1H, d), 6.76 (1H, d), 4.75 (1H, dd), 4.71 (1H, d), 3.76 (1H, m), 3.57 (1H, d), 3.55 (3H, s), 3.37 (1H, m), 3.31 (1H, m), 3.26 (1H, m), 3.24 (1H, d), 3.10 (1H, t), 2.83 (2H, d), 2.75 (2H, d), 2.51 (1H, m), 2.35 (1H, m), 2.11 (1H, m), 2.06 (1H, m), 1.85 (1H, m), 1.29 (9H, s).

 

13C NMR (125.7 MHz, d6-methanol, 30° C.) δ: 179.4, 175.0, 156.8, 144.0, 141.5, 141.4, 131.1, 130.6, 129.4, 128.9, 128.7, 128.3, 128.2, 127.2, 126.4, 111.0, 74.0, 64.7, 56.1, 54.2, 50.4, 48.5, 48.3, 44.9, 43.8, 34.8, 32.9, 25.3, 22.2, 18.1.

LRMS (ES+): m/z [MH+] 469.

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Fedratinib

 Uncategorized  1 Response »
Dec 302013
 

FEDRATINIB

SAR-302503; TG-101348

FLT3, JAK2

http://www.ama-assn.org//resources/doc/usan/fedratinib.pdf

USAN (AB-104) FEDRATINIB
THERAPEUTIC CLAIM Antineoplastic
CHEMICAL NAMES
1. Benzenesulfonamide, N-(1,1-dimethylethyl)-3-[[5-methyl-2-[[4-[2-(1-
pyrrolidinyl)ethoxy]phenyl]amino]-4-pyrimidinyl]amino]-
2. N-tert-butyl-3-[(5-methyl-2-{4-[2-(pyrrolidin-1-yl)ethoxy]anilino}pyrimidin-4-
yl)amino]benzenesulfonamide

MOLECULAR FORMULA C27H36N6O3S
MOLECULAR WEIGHT 524.7
SPONSOR Sanofi
CODE DESIGNATIONS SAR302503; TG101348
CAS REGISTRY NUMBER……….936091-26-8

WHO 9707

TG-101348 , a dual-acting JAK2/FLT3 small molecule kinase inhibitor, has been evaluated in phase III clinical development at Sanofi (formerly known as sanofi-aventis) for the oral treatment of intermediate-2 or high risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis with splenomegaly. However, development of the compound has been discontinued due to safety issues.

In preclinical models of myeloproliferative diseases, TG-101348, administered orally, was shown to reduce V617F-expressing cell populations in a dose-dependent manner without adversely impacting normal hematopoiesis. The reduction of V617F- expressing cell populations correlated with improved survival and reduced morbidity. Orphan drug designation was assigned in the U.S. and in Japan for the treatment of secondary and primary myelofibrosis. In July 2010, TargeGen was acquired by Sanofi. In 2013, orphan drug designation was assigned by the FDA for the treatment of polycythemia vera.

………………………………………..

PATENTS

WO 2013059548

WO 2012061833

WO 2010017122

US 2007259904

WO 2007053452

……………….

 

JAK inhibitors: pharmacology and clinical activity in chronic myeloprolipherative neoplasms.

Treliński J, Robak T.

Curr Med Chem. 2013;20(9):1147-61.

 

JAK2 inhibitors for myelofibrosis: why are they effective in patients with and without JAK2V617F mutation?

Santos FP, Verstovsek S.

Anticancer Agents Med Chem. 2012 Nov;12(9):1098-109. Review.

Octa-arginine mediated delivery of wild-type Lnk protein inhibits TPO-induced M-MOK megakaryoblastic leukemic cell growth by promoting apoptosis.

Looi CY, Imanishi M, Takaki S, Sato M, Chiba N, Sasahara Y, Futaki S, Tsuchiya S, Kumaki S.

PLoS One. 2011;6(8):e23640. doi: 10.1371/journal.pone.0023640. Epub 2011 Aug 10

………………………………………………..

us2007191405

Example 90 N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide (Compound LVII)

 

Figure US20070191405A1-20070816-C00156

 

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150° C. for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of EtOAc and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).

1H NMR (500 MHz, DMSO-d6): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 525 (M+H)+.

 

Example 76 N-tert-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-ylamino)-benzenesulfonamide (Intermediate 33)

 

Figure US20070191405A1-20070816-C00142

 

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium carbonate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was used in the next step without purification. MS (ES+): m/z 355 (M+H)+.

 

 

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Linsitinib

 cancer, Uncategorized  Comments Off on Linsitinib
Dec 302013
 

 

linsitinib

OSI 906

ASP7487

3-[8-Amino-1-(2-phenyl-7-quinolyl)imidazo[1,5-a]pyrazin-3-yl]-1-methyl-cyclobutanol

CAS:  867160-71-2

Chemical Formula: C26H23N5O

Molecular Weight: 421.5

Elemental Analysis: C, 74.09; H, 5.50; N, 16.62; O, 3.80

PHASE 2

Linsitinib (OSI-906) is  an orally bioavailable small molecule inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) with potential antineoplastic activity.  OSI-906 selectively inhibits IGF-1R, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell apoptosis. Overexpressed in a variety of human cancers, IGFR-1 stimulates cell proliferation, enables oncogenic transformation, and suppresses apoptosis

Linsitinib (OSI-906) was developed through drug-discovery efforts focused on identifying a potent and selective, small-molecule inhibitor of the IGF-1R signaling axis. The lead optimization phase utilized IR and IGF-1R co-crystal structures, with lead compounds from the imidazopyrazine series, to afford a structure-based design-driven component, which complemented ongoing empirical medicinal chemistry efforts. These combined approaches improved metabolic and pharmacokinetic liabilities of earlier lead compounds and ultimately led to the discovery of OSI-906. OSI-906 was synthesized from an advanced imidazopyrazine intermediate in two linear steps. OSI-906 potently inhibits ligand-dependent auto-phosphorylation of both human IGF-1R and IR in cells, while displaying a high degree of selectivity versus a wide panel of protein kinases.

Moreover, OSI-906, through its inhibition of both IGF-1R and IR, prevents ligand-induced activation of downstream pathways including pAKT, pERK1/2 and p-p70S6K and, therefore, inhibits proliferation in a variety of tumor cell lines. Robust anti-tumor activity was achieved in an IGF-1R-driven LISN xenograft model following once-daily oral administration of OSI-906. The anti-tumor activity obtained in this study correlated well with the degree and duration of inhibition of tumor IGF-1R phosphorylation achieved in vivo by OSI-906. OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with demonstrated in vivo efficacy in tumor models. It is currently being evaluated in clinical trials.

Furthermore, the exceptional selectivity profile of OSI-906 in conjunction with its ability to inhibit both IGF-1R and IR provides the unique opportunity to fully target the IGF-1R/IR axis. (source: Future Medicinal Chemistry September 2009, Vol. 1, No. 6, Pages 1153-1171. )

Linsitinib is an experimental drug candidate for the treatment of various types of cancer. It is an inhibitor of the insulin receptor and of the insulin-like growth factor 1 receptor (IGF-1R).[1] This prevents tumor cell proliferation and induces tumor cell apoptosis.[2]

The development of target-based anti-cancer therapies has become the focus of a large number of pharmaceutical research and development programs. Various strategies of intervention include targeting protein tyrosine kinases, including receptor tyrosine kinases believed to drive or mediate tumor growth.

Insulin-like growth factor-1 receptor (IGF-1R) is a receptor tyrosine kinase that plays a key role in tumor cell proliferation and apoptosis inhibition, and has become an attractive cancer therapy target. IGF-1R is involved in the establishment and maintenance of cellular transformation, is frequently overexpressed by human tumors, and activation or overexpression thereof mediates aspects of the malignant phenotype. IGF-1R activation increases invasion and metastasis propensity.

Inhibition of receptor activation has been an attractive method having the potential to block IGF-mediated signal transduction. Anti-IGF-1R antibodies to block the extracellular ligand-binding portion of the receptor and small molecules to target the enzyme activity of the tyrosine kinase domain have been developed. See Expert Opin. Ther. Patents, 17(1):25-35 (2007); Expert Opin. Ther. Targets, 12(5):589-603 (2008); and Am J. Transl. Res., 1:101-114 (2009).

US 2006/0235031 (published Oct. 19, 2006) describes a class of bicyclic ring substituted protein kinase inhibitors, including Example 31 thereof, which corresponds to the dual IR/IGF-1R inhibitor known as OSI-906. As of 2011, OSI-906 is in clinical development in various cancers and tumor types. The preparation and characterization of OSI-906, which can be named as cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol, is described in the aforementioned US 2006/0235031.

OSI-906 is a potent, selective, and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable drug-like properties. The selectivity profile of OSI-906 in conjunction with its ability to inhibit both IGF-1R and IR affords the special opportunity to fully target the IGF-1R/IR axis. See Future Med. Chem., 1(6), 1153-1171, (2009).

It is desirable to develop novel processes to prepare imidazopyrazine compounds, namely OSI-906, which may be practical, economical, efficient, reproducible, large scale, and meet regulatory requirements.

Linsitinib was discovered by OSI Pharmaceuticals and is currently in Phase III clinical trials for adrenocortical carcinoma and Phase II clinical trials for lung and ovarian cancers.[3][4]

  1.  Mulvihill, MJ; Cooke, A; Rosenfeld-Franklin, M; Buck, E; Foreman, K; Landfair, D; O’Connor, M; Pirritt, C et al. (2009). “Discovery of OSI-906: A selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor”. Future medicinal chemistry 1 (6): 1153–71. doi:10.4155/fmc.09.89.PMID 21425998.
  2.  “Linsitinib”. NCI Drug Dictionary. National Cancer Institute. Retrieved October 16, 2012.
  3.  “OSI Pharmaceuticals, LLC”. Astellas Pharma. Retrieved October 16, 2012.
  4.  “Linsitinib”. National Institutes of Health’s clinicaltrials.gov. Retrieved October 16, 2012.

OSI-906: A novel, potent, and selective first-in-class small molecule insulin-like growth factor 1 receptor (IGF-1R) inhibitor in phase I clinical trials
238th ACS Natl Meet (August 16-20, Washington) 2009, Abst MEDI 152

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US20130123501

EXAMPLES1

cis-3-[8-amino-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclobutanol (OSI-906) (Compound 1)

 

 

A vessel was charged with DMF (79 kg), cis-3-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (16.725 kg), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (22.4 kg), triphenylphosphine (0.586 kg), cesium carbonate (36.7 kg) and water (20.1 kg). The reaction mixture was degassed and heated to 95-105° C. and a solution of palladium acetate (0.125 kg) in DMF (9.8 kg) was added and rinsed in with DMF (5.9 kg). After the reaction was complete, water (154 kg) was added keeping the temperature above 70° C. The resultant slurry was cooled and the solid was collected by filtration. After washing with a mixture of DMF (9.4 kg) and water (23.4 kg) and then water (67 kg) the solid was suspended in water (167 kg) at 50° C. and the pH of the mixture was adjusted to 2.9 with 6N hydrochloric acid (10.9 kg). The resultant yellow slurry was filtered to remove the major impurities and the cake was washed with water (67 kg). The acid solution was stirred at 50-55° C. and polymer bound trimercaptotriazine resin (MP-TMT) (4.9 kg) was added. The mixture was stirred for 23 hours, the resin was removed by filtration and the cake was washed with water (58 kg).

The resultant acid solution was diluted with 2-propanol (82 kg), the temperature was adjusted to 35-45° C. and the pH was adjusted to 5.0 by the addition of 1N sodium hydroxide solution. The mixture was cooled, the yellow product was collected by filtration and was washed with water (33 kg). The solid was re-suspended in water (157 kg) stirred, filtered and washed with water (125 kg). The solid was dried under vacuum at 45-55° C. (the resulting material was a hemihydrate of OSI-906 designated Form C) and was then stirred in refluxing 2-propanol (157 kg) for 3 hours. The mixture was cooled and the solid was isolated by filtration. After washing with 2-propanol (26.7 kg), the product was dried at 45-55° C. under vacuum to yield 15.6 kg (65% yield) of OSI-906. The resulting material was an anhydrous crystalline form of OSI-906 designated Form A.

Example 2cis-3-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

 

 

THF (87 kg) and 3M methyl magnesium chloride (83.6 kg) were charged to a vessel. The contents were cooled to −65 to −55° C. and 3-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)-cyclobutanone (33.0 kg) in THF (253 kg) was added, maintaining the temperature at −65° C. to −45° C.

The charged vessel was rinsed with THF (41 kg) and the reaction mixture was stirred at −65 to −45° C. until reaction completion. Preferably, the level of iron present in the reaction is about 100 ppm or less, or about 20 ppm or less. These conditions are suitable to achieve the desired stereoselectivity. A 5% ammonium chloride solution (462 kg) was added slowly while maintaining the temperature below 10° C. The aqueous layer was then separated, the pH was adjusted to pH 7-8 by the addition of 6N hydrochloric acid and the mixture was extracted with methyl t-butyl ether (2×145 kg). The combined organic extracts were washed sequentially with 1N sodium hydroxide solution (330 kg) and 20% sodium chloride solution (2×330 kg). THF (767 kg) was then added and the solution was distilled to a residual volume of 165 L. Toluene (567 kg) was added and again the mixture was distilled to a volume of 165 L. The mixture was heated to 85-90° C. until complete dissolution was achieved and then cooled to 20-30° C. to crystallize the product. The solids were collected by filtration, washed with toluene (2×41 kg) and dried at 50-60° C. under vacuum. Yield was 78%. 1H NMR (300 MHz, DMSO-d6) δ 8.3 (d, 1H), 7.4 (d, 1H), 5.2 (s, 1H), 3.5 (m, 1H), 2.4 (m, 4H), 1.4 (s, 3H).

Example 3cis-3-(8-amino-1-bromo-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol

 

 

Cis-3-(1-bromo-8-chloro-imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (27.1 kg), isopropanol (65 kg) and 30% ammonia solution (165 kg) were charged to a suitable vessel. The vessel was sealed and the mixture was heated and stirred for 18 hours at 75 to 85° C. and then cooled. The vessel was vented to a scrubber and water (22 kg) was added. The mixture was concentrated under vacuum to a residual volume of 73-89 L and was then cooled to <5° C. The product was collected by filtration and washed with water (2×108 kg). The product was dried at 40-50° C. under vacuum. Yield was 88%. 1H NMR (300 MHz, DMSO-d6) δ 7.5 (d, 1H), 7.0 (d, 1H), 6.6 (br s, 2H), 5.2 (s, 1H), 3.4 (m, 1H), 2.4 (m, 4H), 1.4 (s, 3H).

Example 4cis-8-amino-3-(3-hydroxy-3-methyl-cyclobutyl)-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-7-ium chloride

 

 

This material was prepared by heating OSI-906 with an equivalent of hydrochloric acid in water and then allowing the solution to cool. The solid was filtered from the cooled mixture and dried. The XRPD and DSC suggest a semi-crystalline material. The DSC, XRPD, and 1H NMR (300 MHz, DMSO-d6) of the sample were recorded and are reproduced in FIGS. 1, 2, and 3, respectively.

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PATENTS

WO 2010107968

WO 2010129740

WO 2011109572

WO 2011112666

WO 2011163430

WO 2012016095

WO 2012129145

WO 2012149014

WO 2013152252

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WO2011163430A1

The present invention provides for methods of preparing OSI-906 Forms A-G illustrated in Scheme 1 .

 

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PFIZER

PF-868554 is an anti-hepatitis C drug candidate which had been in phase II clinical trials at Pfizer; however this research has been discontinued.

Li, H.; Tatlock, J.; Linton, A.; et al
Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor
J Med Chem 2009, 52(5): 1255

Johnson, S.; Drowns, M.; Tatlock, J.; et al.
Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation
Synlett (Stuttgart) 2010, 2010(5): 796

WO 2012016995

WO 2013101550

WO 2011072370

WO 2007023381

WO 2006018725

 

WO2003095441A1 * 7 mei 2003 20 nov 2003 Melwyn A Abreo Inhibitors of hepatitis c virus rna-dependent rna polymerase, and compositions and treatments using the same
WO2006018725A1 * 5 aug 2005 23 feb 2006 Pfizer Inhibitors of hepatitis c virus rna-dependent rna polymerase, and compositions and treatments using the same
US20050176701 * 19 nov 2003 11 aug 2005 Agouron Pharmaceuticals, Inc. Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same…

WO2007023381A1

 

Example 1 : Preparation of the glycolate salt of (5-amino-1H-1,2,4-triazol-3-yl)methanol

 

Figure imgf000055_0001

glycolate salt

Glycolic acid (1 L, 70% in water, 11.51 mol) was added to a 5 L flask. To the solution was slowly added aminoguanidine bicarbonate (783.33 g, 5.755 mol) in portions to control significant bubbling. As solids are added, the solution cools due to endothermic dissolution. The solution was gently heated to maintain an internal temp of 25 °C during addition. Ten minutes after complete addition of aminoguanidine bicarbonate, cone. Nitric acid (6.8 ml_) was carefully added. The solution was heated to an internal temperature of 104-108 0C (mild reflux) for 22 h. The heating was discontinued and the solution allowed to cool, with stirring. At an internal temp of aboutδi °C, solids began to crystallize. After the internal temperature was just below 80 0C, ethanol (absolute, 375 mL) was slowly added to the mixture. After the internal temp had cooled to aboutδδ 0C1the cooling was sped up by the use of an ice/water bath. After cooling below rt, the solution became very thick but remained stirrable at all times. The slurry was stirred for 2h at T<10 0C, then filtered and the solids rinsed with ethanol (900 mL cold, then 250 mL rt). The solids were dried overnight in a vacuum oven (about25 mmHg, 45-50 0C) to provide 815.80 g (75%) of (5-amino-1H-1 ,2,4-triazol-3-yl)methanol as the glycolate salt. 1H (300 MHz, de-DMSO): 3.90 (s, 2), 4.24 (s, 2).

Example 2: Preparation of (5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol

 

Figure imgf000056_0001

To a 2L, 3-neck flask was charged glycolate salt of (5-amino-1tf-1 ,2,4-triazol-3-yl)methanol (99.93 g, 0.526 mol), 2,4 pentanedione (0.578 mols, 60 mL), acetic acid (6.70 mL), and EtOH (550 mL). The mixture was heated to a slight reflux. One hour after adding the reagents, the resulting solution was cooled to ambient temperature, and CH2CI2 (500 mL) and Celite (25.03 g) were added. After stirring for 1 h, the mixture was filtered through a 4″ Buchner funnel packed with celite (20 g) and rinsed with EtOH (100 mL). The solution was distilled to 5 vols then cooled to 0 °C for 1-2 hours. The slurry was filtered and the cake was rinsed with cold EtOH (2×100 mL). The solids were dried to provide 76.67 g (81.7%) of the title compound.

1H NMR (300 MHz, d6-DMSO): 2.57 (s, 3), 2.71 (d, 3, J=0.8), 4.63 (uneven d, 2, J=5.7), 5.49

(t, 1 , J=6.2), 7.13 (d, 1 , J=0.8).

Example 3: Preparation of 5,7-dimethyl[1 ,2,4]triazolo[1 ,5-a]pyrimidine-2-carbaldehyde

 

Figure imgf000056_0002

To a 10 L reactor was sequentially charged CH2CI2 (5.1 L)1 (5,7- dimethyl[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methanol (680 g, 3.816 mol), and iodobenzene diacetate (1352 g, 4.197 mol). As the iodobenzene diacetate dissolves, there is a significant endotherm (typically down to 15-16 0C). The jacket was set to 23 0C. The mixture was warmed to ambient temperature and Tempo (2,2,6,6-tetramethyl-1-piperidinyloxy, free radical, 43.75 g, 0.28 mol) added in a single charge. The reaction was stirred until 5% of the starting alcohol remained by HPLC. Once the starting material is adjudged to be less than about about5%, the over-oxidized product begins to be observed. Allowing the reaction to run to further completion leads to an overall diminished yield of the desired product. For this reaction, the desired reaction completion was reached in 2.75 h. MTBE (5.1 L) was then slowly charged to the reactor, causing the product to precipitate, and the slurry stirred for an additional 30 mins. The mixture was filtered, washed twice with 1 :1 DCM/MTBE (2 x 1 L), and dried in a vacuum oven overnight at 50 0C to provide 500.3 g (74%) of 5,7- dimethyl[1,2,4]triazolo[1 ,5-a]pyrimidine-2-carbaldehyde as an off-white solid. 1H NMR (300 MHz, ds-DMSO): 2.64 (s, 3), 2.78 (d, 3, J=0.8), 7.36 (d, 1 , J=0.9), 10.13 (s, 1). Example 4: Preparation of the dibenzoyl-L-tartaric acid salt of 1-cyclopentyl-3-(2,6- diethylpyridin-4-yl)propan-1-one

 

Figure imgf000057_0001

DMAC

L-DBTA NEt3-HOTs + LiBr + NEt3-HBr THF/MTBE

 

Figure imgf000057_0002

A nitrogen-purged, 5-L, 3-neck flask containing 4-bromo-2,6-diethylpyridine (250.0 g, 0.6472 mol) was sequentially charged with LiBr (112.42 g, 1.2944 mol), 1-cyclopentyl-prop-2- en-1-ol ( 89.84 g, 0.7119 mol), DMAc (625 mL), and H2O (55.0 mL). The mixture was cooled to 5-10 0C and was then purged (subsurface) with N2 for 30 minutes. The flask was charged with Et3N (198.5 mL, 1.4242 mol) and Pd(OaC)2 (3.63 g, 0.0162 mol), followed by a careful purge of the headspace. The reaction was heated until the internal temperature reached 95 0C. After stirring at 95 °C for three hours, an aliquot was removed and analyzed by HPLC, showing >99% conversion to 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one. The reaction was then cooled to 30 0C over 20 min. The flask was charged with H2O (1500 mL), and MTBE (1500 mL). The solution was stirred well for 5 minutes before the mixture was allowed to settle and the aqueous layer was removed. To the organic layer was charged Celite (62.5Og), and Darco G-60 (6.25g). The slurry was stirred for 20 minutes at 20-25 0C. The slurry was then filtered using a Buchner funnel dressed with Celite. The filter cake was rinsed with MTBE (250 mL). The organic layer was extracted with 5% sodium bicarbonate solution (500 mL) and the phases separated. The organic layer was transferred to a 5 L, three-neck flask, and MTBE added to achieve a total reaction volume of 1750 mL. Additional MTBE (1500 mL) was added and atmospherically distilled until an internal volume of 1750 mL was reached. After cooling below 40 0C, a sample was removed for analysis of water content. After cooling to 20-25 0C, MTBE (250 mL) was added to bring the total volume to 2000 mL and the solution was seeded with crystals of the dibenzoyl-L-tartaric acid salt of 1-cyclopentyl-3-(2,6- diethylpyridin-4-yl)propan-1-one (130 mg), which were prepared according to this procedure. A solution of dibenzoyl-L-tartaric acid (231.89 g, 0.6472 mol) in THF (900 mL) was added over 25 minutes. The slurry was granulated for 1 hour, the mixture was filtered, and the cake rinsed with MTBE (450 mL). The solids were dried in a vacuum oven at 50 0C for 12 h to provide 366.70 g (92% yield) of the title compound. 1H NMR (300 MHz, d6-DMSO): 1.19 (t, 6, J=7.6), 1.47-1.81 (m, 8), 2.73 (q, 4, J=7.6), 2.73-2.98 (m, 5), 5.86 (s, 2), 7.00 (S1 2), 7.55-7.63 (m, 4), 7.68-7.75 (m, 2), 7.98-8.04 (m, 4).

Example 5: Preparation of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid

 

Figure imgf000058_0001

A 3-L, 3-neck flask was charged with the dibenzoyl-L-tartaric acid salt of 1- cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one (174.95 g, 0.2832 mol), MTBE (875 mL), water (875 mL), and triethanolamine (113.0 mL, 0.8513 mol). After stirring for 2 h at rt, an aliquot of the aqueous phase was removed and analyzed by HPLC, showing no detectable starting material. The solution was transferred to a separatory funnel and the layers separated. The lower aqueous phase was discarded and the upper org. phase was washed with water (150 mL). The organic layer was added to a flask set up for distillation. The solution was distilled down to approx. 183 mL and an aliquot was removed and analyzed for water content. The dry solution of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one (th. Wt = 73.47 g) in MTBE was used directly in the next step.

A clean 2-L, 3-neck flask was charged with LiHMDS (1.0 M in THF, 355 mL, 0.355 mol) and purged with nitrogen. The flask was cooled to -34 0C. An addition funnel was then charged with EtOAc (35 mL, 0.3583 mol) and this reagent was slowly added to the reaction vessel at such a rate that the low temperature of the vessel could be maintained. After complete EtOAc addition another addition funnel was charged with the 1-cyclopentyl-3-(2,6- diethylpyridin-4-yl)propan-1-one solution (crude MTBE soln from prior reaction, theor. 73.47 g, 0.2832 mol) and rinsed over with THF (anhydrous, 5 ml_). The 1-cyclopentyl-3-(2,6- diethylpyridin-4-yl)propan-1-one solution was slowly added to the reaction flask at such a rate that the low internal temperature could be maintained. Five minutes after complete addition, a reaction aliquot was removed and analyzed by HPLC, showing less than 1% 1-cyclopentyl-3- (2,6-diethylpyridin-4-yl)propan-1-one. Ten minutes after complete ketone addition, the bath was switched to O 0C. Once the internal temperature had warmed to -10 0C, 1 M NaOH (510 mL) was added. After complete NaOH soln addition, the reaction was heated to 50 0C. After 21 hours the reaction solution was cooled below 30 0C and an aliquot of both layers was removed and analyzed for completion. The mixture was added to a separatory funnel with MTBE (350 mL) and the phases were mixed well and separated. An aliquot of the organic phase was analyzed by HPLC, verifying no significant product, and this layer was discarded. The aqueous phase was added to a flask with CH2CI2(350 mL). Concentrated aqueous HCI (about 100 mL) was slowly added to the aqueous phase until the pH = 5. The mixture was added back to a separatory funnel and mixed well. The phases were separated and the aqueous layer was extracted a second time with CH2CI2 (150 mL). The organic layers were combined and charged to a clean flask set up for distillation. The solution was distilled down to 370 mL then displaced with THF by addition of solvent portions followed by continued distillation down to 370 mL after each addition. When the distillation head temp, held steady at 65 °C for 30 min an aliquot was removed and analyzed by 1H NMR, showing a 12.5:1 ratio of THF:CH2CI2. The solution of 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF was used directly in the next step.

Example 6a: Preparation of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1,3-propanedioI salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid

 

Figure imgf000059_0001

A 2-L, 3-neck flask was sequentially charged with a solution of 3-cyclopentyl-5-(2,6- diethylpyridin-4-yl)-3-hydroxypentanoic acid (crude from last step, theoretical 95.28 g, 0.1792 mol, in about300 mL), (1 R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3-propanediol (38.03 g, 0.1792 moles) and THF (415 mL). A seed crystal of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3- propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid, prepared according to this procedure, was added and the mixture was stirred and heated to 65 0C, then held at this temperature for 16 h. The slurry was cooled slowly to rt and stirred for at least 1 h. The slurry was filtered and the cake rinsed with THF (100 mL). The filtrate (solution of (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid in THF) was used directly in the next procedure. The solids were dried to provide 67.09 g (42 %) of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3-propanediol salt of ®-3-cyclopentyl-5-(2,6- diethylpyridin-4-yl)-3-hydroxypentanoic acid as an off-white crystalline solid. Chiral HPLC analysis of the product showed a 92.1:7.9 ratio of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)- 1 ,3-propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid to (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid. HPLC conditions: The solid was dissolved in methanol. HPLC conditions: Chirobiotic TAG column, 4.6 x 250 mm, 40 0C column chamber, flow rate = 0.5 mL/min, mobile phase = 100% MeOH (0.05% TEA, 0.05% HOAc). Gradient: Initial flow rate = 0.5 mL/min; 10 min flow rate = 0.5 mL/min; 10.10 min flow rate = 2.00 mL/min; 35 min flow rate = 2.00 mL/min; 36 min flow rate = 0.5 mLΛnin. Percentages reported are at 265 nm. Retention times: (1 R,2R)-(-)-2- amino-1-(4-nitrophenyl)-1 ,3-propanediol = >30 min; (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4- yl)-3-hydroxypentanoic acid = 5.8 min; ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3- hydroxypentanoic acid = 7.2 min. 1H NMR (300 MHz, d6-DMSO): 1.19 (t, 6, J=7.6), 1.38-1.62 (m, 8), 1.65-1.75 (m, 2), 1.93-2.07 (m, 1), 2.23 (d, 1 , J=14.4), 2.31 (d, 1 , J=14.4), 2.56 (m, 2), 2.64 (q, 4, J=7.6), 2.91-2.99 (m, 1), 3.22 (dd, 1 , J=5.8, 11.1), 3.42 (dd, 1 , J=4.8, 11.1), 4.77 (d, 1 , J=6.2), 6.0 (br s, 6), 6.84 (s, 2), 7.62 (d, 2, J=8.7), 8.20 (d, 2, J=8.8). Example 6b: Recrystallization of the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3- propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid

A 2-L, 3-neck flask was charged with the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3- propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid (66.20 g, 0.1245 moles) and 2B EtOH (970 mL absolute EtOH + 5 mL toluene). The slurry was stirred and heated to reflux. After holding at reflux for 40 min, all the solids had dissolved and the solution was cooled to an internal temp of about 65 0C over 30 min, and the solution was then seeded with crystals of the title compound. The solution was allowed to cool to 50 0C and held for an additional 2h. The solution was then cooled slowly to room temperature over about 2 hours. The cooled solution was stirred at rt for an additional 10 h. The mixture was then filtered and the solids rinsed with 2B EtOH (75 mL). The solids were dried to provide 52.72 g (80%) of product as an off-white crystalline solid that was then dried under vacuum (30 mm Hg) with a nitrogen bleed at 50 0C for 12 h. Chiral HPLC analysis showed product with 96% ee. For determination of e.e., the solid was dissolved in MeOH. HPLC conditions: Chirobiotic TAG column, 4.6 x 250 mm, 40 0C column chamber, flow rate = 0.5 ml_/min, 100% MeOH (0.05% TEA, 0.05% HOAc). Gradient: Initial flow rate = 0.5 mL/min; 10 min flow rate = 0.5 mL/min; 10.10 min flow rate = 2.00 mL/min; 35 min flow rate = 2.00 mL/min; 36 min flow rate = 0.5 mL/min. Percentages reported are at 265 nm. Retention times: (1 R,2R)-(-)-2- amino-1-(4-nitrophenyl)-1 ,3-propanediol = >30 min, (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4- yl)-3-hydroxypentanoic acid = 5.8 min, ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3- hydroxypentanoic acid = 7.2 min.

Example 7: Preparation of 1-cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one from (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid

 

Figure imgf000061_0001

A flask was charged with a solution of (S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3- hydroxypentanoic acid (crude from last step, theoretical 15 g, 0.0470 mol, in about 200 mL THF) and ethanol (100 ml_, 1.7126 mol). To the solution, H2SO4 (5.0 ml_, 0.0938 mol) was added slowly. The solution was heated at reflux for 18 h. When the reaction was judged to be complete by HPLC, the solution was cooled and added to a separatory funnel with 0.5M NaOH (400 mL) and then extracted with MTBE (200 mL). The phases were separated and the organic layer was washed with aqueous acetic acid H2O (100 mL H2O + 3.0 mL HOAc). The phases were separated and the organic layer was washed with 0.5 M NaOH (100 mL). The phases were separated and the organic layer was washed with saturated aqueous NaCI solution (25 mL). The organic layer was distilled at atmospheric pressure down to an internal volume of 150 mL. The solvent was displaced by toluene via atmospheric distillation by adding toluene (100 mL), distilling down to 200 mL internal volume, and repeating this procedure two more times. The final solution was distilled down to an internal volume of 130 mL. An aliquot was removed and analyzed by KF titration. The solution was cooled to rt and a solution of KotBu (1.0M in THF, 4.7 mL, 0.0047 mol) was added in one portion. After 5 min, an aliquot was removed and analyzed by HPLC. The solution was added to a separatory funnel with 1M HCI (60 mL). The phases were mixed well and separated, transferring the product to the aqueous phase. The organic phase was extracted once with water (10 mL) and the aqueous phases combined. The organic phase was discarded. To the aqueous phase was added MTBE (60 mL) and 1 M NaOH (70 mL) and the phases mixed well. The phases were separated and the organic phase extracted with saturated aqueous NaCI solution (25 mL). MTBE was added to bring the volume up to 125 mL. The solution was cooled to rt and seeded with crystals of the dibenzoyl-L-tartaric acid salt of 1-cyclopentyl-3-(2,6-diethylpyridin- 4-yl)propan-1-one (prepared according to Example 4). In a separate vessel, L-DBTA (16.89 g, 0.0471 mol) was dissolved in THF (65 ml_). The solution of L-DBTA was added to the 1- cyclopentyl-3-(2,6-diethylpyridin-4-yl)propan-1-one solution over 45 min, and the slurry granulated for 1 h. The slurry was filtered and the cake washed with MTBE (50 mL). The solids were dried to provide 19.54 g of the dibenzoyl-L-tartaric acid salt of 1-cyclopentyl-3- (2,6-diethylpyridin-4-yl)propan-1-one (67 %) as an off-white solid. Example 8a: Preparation of the dibenzoyl-L-tartaric acid salt of ®-6-cyclopentyl-6-(2- (2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one

 

Figure imgf000062_0001

i. CDI, DWIAP O O

Ii. KO-^^OEt MgCI2

 

Figure imgf000062_0002

A nitrogen-purged flask containing the (1R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3- propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid (20.00 g, 0.0376 mol) was charged with CH2CI2 (200 mL) and H2O (100 mL). The pH of the mixture was adjusted to pH 4.75 with 40% aqueous citric acid (10 mL) and was stirred for 60 minutes. The layers were allowed to settle for 30 minutes and separated. The upper (aqueous) layer was charged CH2CI2 (50 mL), stirred 15 minutes, and was then allowed to settle. The organic layer was combined with the first organic layer and dried with sodium sulfate. The dried organic was concentrated under reduced pressure. The ®-3-cyclopentyl-5-(2,6-diethylpyridin- 4-yl)-3-hydroxypentanoic acid residue was dissolved in THF (47 mL) and this solution added to a slurry of carbonyl diimidazole (9.00 g, 0.0555 mol) and 4-N,N-dimethylaminopyridine (DMAP, 0.45 g, 0.0037 mol) in THF (106 mL) over 5 minutes. Upon complete acyl-imidazole formation, the solution was added to a slurry of potassium ethyl malonate (12.57 g, 0.0738 mol) and magnesium chloride (7.38 g, 0.0775 mol) in 106 mL THF over 5 minutes. The slurry was allowed to stir at 20-25 0C for 30 hours. An aliquot was removed and analyzed by HPLC, showing 96% conversion to ©-ethyl 5-cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3- oxoheptanoate. The flask was charged with H2O (64 mL), and MTBE (118 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the aqueous (lower) layer was removed. To the organic layer was charged brine (52 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the aqueous (lower) layer was removed. The organic layer was then displaced via atmospheric distillation with methanol (2 x 210 mL) until a total volume of 140 mL was achieved. MTBE (105 mL) was added followed by powdered potassium carbonate (7.65 g, 0.0554 mol), and the slurry heated to reflux for 12 hours. After cooling to 40 °C, MTBE (140 mL) and water (140 mL) were added. The mixture was stirred well for 5 minutes before it was allowed to settle and the aqueous (lower) layer was isolated. The organic layer was extracted with water (30 mL) and the aqueous layers were combined. CH2CI2 (140 mL) was added to the aqueous layer and the pH adjusted to 6.4 with 40% aqueous citric acid (29 mL). The aqueous layer was extracted a second time with CH2CI2 (25 mL). The combined organic layers were then displaced fully into MTBE (140 mL final volume) via atmospheric distillation, cooled, and added slowly to a solution of dibenzoyl-D-tartaric acid (9.92 g, 0.0277 mol) in MTBE (100 mL). The slurry was heated to reflux for 1 hour, then allowed to cool to 20-25 0C. The mixture was filtered, and the cake rinsed with MTBE (50 mL). The solids were dried in a vacuum oven at 50 0C for 12 h to provide 16.40 g (62%) of the title compound.

Example 8b: Preparation of the dibenzoyl-L-tartaric acid salt of ®-6-cyclopentyl-6-(2- (2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one

A nitrogen-purged flask containing the (1 R,2R)-(-)-2-amino-1-(4-nitrophenyl)-1 ,3-propanediol salt of ®-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid (50.00 g, 0.0940 mol) was charged with CH2CI2 (500 mL) and H2O (250 mL). The pH of the resulting suspension was adjusted to pH 4.6 to 4.8 (a measured pH of 4.75 is preferred) with 40% aqueous citric acid (21 mL) and was stirred for 30 minutes. The layers were allowed to settle for 30 minutes and separated. The upper (aqueous) layer was charged with CH2CI2 (100 mL), stirred 15 minutes, and allowed to settle. The organic layer was combined with the first organic layer. The upper (aqueous) layer was again charged with CH2CI2 (100 mL), stirred 15 minutes, and allowed to settle. This organic layer was also combined with the first organic layer. A sample of each of the combined organic layers and the aqueous layer was taken for HPLC analysis. The combined organic layers were atmospherically distilled until a total volume of 120 mL was reached. THF (100 mL) was charged and atmospheric distillation continued until a total volume of 120 mL was reached. The THF charge and displacement was repeated 3 times. A sample was removed and analyzed by NMR and KF. The resulting solution was added to a slurry of CDI (22.86 g, 0.1410 mol) and DMAP (1.15 g, 0.0094 mol) in THF (250 mL) over 15 minutes. The addition funnel was then rinsed with 10 mL THF which was then added to the CDI slurry. After stirring 15 minutes, a sample was removed and analyzed by HPLC. Upon complete acyl-imidazole formation, the solution was added to a slurry of potassium ethyl malonate (32.00 g, 0.1880 mol) and magnesium chloride (18.80 g, 0.1974 mol) in 250 mL THF at 20-25 0C over 25 minutes. The slurry was allowed to stir at 20-25 0C for 21 hours. An aliquot was removed and analyzed by HPLC, showing 96% conversion to ®- ethyl 5-cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3-oxoheptanoate. The flask was charged with H2O (162 mL), and MTBE (300 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the yellow aqueous (lower) layer was removed. To the organic layer was charged brine (100 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the aqueous (lower) layer was removed. The organic layer was then atmospherically distilled down to 350 mL total volume. MTBE (250 mL) was charged and the solution distilled to 350 mL total volume. Additional MTBE (250 mL) was charged and the solution distilled at a temperature of at least 55 0C to 350 mL total volume. A sample was removed for KF titration. Methanol (250 mL) was charged and the solution was then atmospherically distilled until a total volume of 350 mL was achieved. Methanol (250 mL) was charged and then the solution was atmospherically distilled until a total volume of 350 mL was achieved and a temperature of ~66 0C was achieved. Powdered potassium carbonate (19.49 g, 0.1410 mol) was added and the slurry heated to reflux for 4 hours. A sample was removed for HPLC analysis showing >99% completion. After cooling to 22 0C, MTBE (350 mL) and water (350 mL) were added. The mixture was stirred well for 5 minutes before it was allowed to settle and the product rich aqueous (lower) layer was isolated. The organic layer was extracted with water (100 mL) and the aqueous layers were combined. To the combined aqueous layers was charged MTBE (100 mL). The mixture was stirred well for 5 minutes before it was allowed to settle and the product rich aqueous (lower) layer was isolated. CH2CI2 (350 mL) was added to the aqueous layer and the pH adjusted to 6.0-6.4 with 40% aqueous citric acid (75 mL). The aqueous layer was extracted a second time with CH2CI2 (100 mL). The combined organic layers were then atmospherically distilled to 250 mL total volume. MTBE (400 mL) was charged and the solution was atmospherically distilled at a temperature of at least 55 0C until 250 mL final volume was reached. After cooling the solution to 20-25 0C, a prepared solution of dibenzoyl-D-tartaric acid (23.58 g, 0.0658 mol) in MTBE (125 mL) was added over 10 minutes. The resulting slurry was heated to reflux for 4 hours, then allowed to cool to 20-25 0C and stirred an additional 4 hours. The slurry was filtered, and the cake rinsed with MTBE (125 mL). The solids were dried in a vacuum oven at 50 0C for 12 h to provide 38.19 g (58%) of the title compound. HPLC conditions: aliquots were withdrawn and dissolved in CH3CN/H2O (40:60). HPLC conditions: Kromasil C4 column, 5 μm, 4.6x150mm, 40 0C column chamber, flow rate= 1.0 mL/min, 40% CHsCN/60% aqueous (1.OmL 70% HcIO4 in 1 L H2O) isocratic. Percentages reported are at 254 nm. Approximate retention times: ®-3- cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid = 3.4 min; ©-ethyl 5- cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3-oxoheptanoate = 7.3 min; ®-6-cyclopentyl- 3-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one = 3.9 min; D-DBTA = 5.5 min. Example 9a: Preparation of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7- dimethyl-ri^.^triazoloII.S-alpyrimidini-Z-yOmethylH-hydroxy-S.e-clihyclropyran^-one

 

Figure imgf000065_0001

BHe-pyridine

 

Figure imgf000065_0002

A flask was charged with the dibenzoyl-L-tartaric acid salt of ®-6-cyclopentyl-6-(2- (2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one (this material contained 1.5 eq DBTA counterion, 4.00 g, theor. 0.00454 mol), 2-MeTHF (40 ttiL), MTBE (40 mL), and water (20 mL). A solution of 5% aq NaHCO3 (about 20 mL) was added until the pH was 7.4. The solution pH was back-adjusted to pH = 7.2 with a small amount of 40% citric acid solution. The phases were separated and the aqueous layer was extracted with 2-MeTHF (25 mL). The combined organic layers were dried with Na2SO4 and concentrated to an oil. The oil was used directly in the subsequent condensation. To the crude ®-6-cyclopentyl-6-(2-(2,6- diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one was added methanol (32 mL) and the solution cooled to -40 0C. To the cold solution was added pyridine-borane complex (1.30 mL, 0.01287 mol) and 5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidine-2-carbaldehyde (1.41 g, 0.00800 mol). The solution was warmed to 0 0C over 45 min then stirred for an additional 2 h. The reaction was quenched by the addition of water (10 mL) and the mixture stirred at rt overnight. To the mixture was added 1M HCI (10 mL), and the solution was stirred for 3 h. lsopropyl acetate (57 mL) was added and the pH adjusted to 7 by the addition of 1 M NaOH. The phases were separated and the organic layer extracted with water (25 mL x 2). The aqueous phases were extracted further with CH2CI2 (100 ml, 2 x 25 mL). The combined IPAc and CH2CI2 layers were dried (Na2SO4), filtered, and concentrated to yield 3.41 g of crude ®-6- cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2- yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one. To the residue was added isopropyl acetate (46 mL) and EtOH (2.5 mL) and the mixture heated to reflux until homogeneous. The solution was allowed to cool slowly to rt and stirred overnight. The slurry was filtered, the solids rinsed with IPAc (13 mL), and dried to provide 1.74 g (76 %) of ®-6-cyclopentyl-6-(2-(2,6- diethylpyridin-4-yl)ethyl)-3-((5J-dirnethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-

5,6-dihydropyran-2-one as an off-white solid.

 

Example 9b: Preparation of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7- dimethyl-[1,2,4]triazolot1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one

A 500 mL flask was charged with the dibenzoyl-L-tartaric acid salt of ®-6-cyclopentyl-

6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one (15.00 g, 0.02137 moles), THF (75 mL), MeOH (75 mL), pyridine-borane (4.25 mL, 0.034 moles), and 5,7- dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidine-2-carbaldehyde (5.65 g, 0.03207 moles) was added last. The resulting mixture was stirred at rt and an aliquot was removed after 1.25 h and analyzed by HPLC showing 13.5% ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-4- hydroxy-5,6-dihydropyran-2-one. Stirring was continued for an additional 2 h, and HPLC analysis of an aliquot then showed 4.8% of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-

4-hydroxy-5,6-dihydropyran-2-one remaining. The reaction solution was charged with CH2CI2

(150 mL) and water (150 mL), and the phases were stirred overnight. The lower organic layer was removed and to the upper aqueous layer was charged CH2CI2 (25 mL), the phases were mixed well and separated and the aqueous layer was discarded. The organic layers were combined and charged to a flask containing water (150 mL) and triethanolamine (7.1 mL,

0.0535 mol), mixed well then separated. The lower organic layer was removed and to the upper aqueous layer was charged CH2CI2 (25 mL), the phases were mixed well, separated, and the aqueous layer was discarded. To the combined organic layers was charged water

(100 mL) and 1M NaOH (25 mL), the phases were mixed well, separated, and the lower organic layer was discarded. To the upper aqueous layer was charged CH2CI2 (75 mL) and

1N HCI was added until the pH=6.91 (~25 mL added), the phases were mixed well, separated, and the aqueous layer was discarded. The combined organic layers were extracted with water (3.2 volumes). The layers were separated and the organic layer was transferred to a

;lean flask marked with a 75 mL volume line. The organic layer was distilled atmospherically

0 75 mL. To the flask was charged isopropyl acetate (75 mL x 2) followed by distillation down

0 75 mL total volume after each addition. The flask was seeded and cooled to rt and stirred

)vemight. The reaction was filtered and the cake was washed with isopropyl acetate (25 ml).

“he solids were dried to provide 7.20 g (67%) of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-

‘l)ethyl)-3-((5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6- lihydropyran-2-one as an off-white powder, which was dried in a vacuum oven (~25 inHg at

0 0C) for 12 h. For HPLC monitoring, aliquots were withdrawn and dissolved in CH3CN/H2O

1-0:60). HPLC conditions: Kromasil C4 column, 5 μm, 4.6×150 mm, 40 0C column chamber, ow rate= 1.0 mL/min, 40% CH3CN/60% aqueous (1.0 mL 70% HcIO4 in 1L H2O) isocratic.

‘ercentages reported are at 254 nm. Retention times: ®-6-cyclopentyl-6-(2-(2,6- iethylpyridin-4-yl)ethyl)-4-hydroxy-5,6-dihydropyran-2-one = 3.85 min; ®-6-cyclopentyl-6-(2- (2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4- hydroxy-5,6-dihydropyran-2-one = 3.56 min; DBTA= 5.14 min; BH3 «pyr=3.36 min.

Example 10: Recrystallization of ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-

((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2- one

A 200 mL flask was charged with ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3- ((5,7-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (10.05 g, 0.01995 mol) and THF (70 mL). The mixture was stirred and heated to 30 to 35 0C to provide a homogeneous solution. The solution was filtered through a 0.45 μm Teflon filter, and rinsed with THF (10 mL). The filtrate was added to a flask set up for atmospheric distillation and isopropyl acetate (IPAC, 50 mL) was added. The solution was concentrated by distillation to an internal volume of 100 mL. Isopropyl acetate (50 mL) was added and distillation continued at atmospheric pressure until the internal volume reached 100 mL. The solution was seeded with ®-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl- [1 ,2,4]triazolo[1 ,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one and additional IPAC (30 mL) was added. The solution was again distilled to an internal volume of 100 mL and was cooled over about 1 h to 50 0C. The solution was held at 50 0C for an additional 1.5 h, cooled over about 2 h to rt, and stirred overnight. The resulting slurry was filtered and rinsed with IPAC (30 mL). The resulting solids were dried to provide 9.41 g (94%) of the title compound as an off-white powder that was vacuum dried (~25 in Hg, 50 0C) for 12 h.

CAS 877130-28-4
 FILIBUVIR
(R)-6-Cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one
Filibuvir;Pf-00868554;Unii-198J479Y2l;(6R)-6-Cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl(1,2,4)triazolo(1,5-A)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydro-2H-pyran-2-one;(R)-6-Cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-5,6-dihydro-2H-pyran-2-one;2H-Pyran-2-one, 6-cyclopentyl-6-(2-(2,6-diethyl-4-pyridinyl)ethyl)-3-((5,7-dimethyl(1,2,4)triazolo(1,5-A)pyrimidin-2-yl)methyl)-5,6-dihydro-4-hydroxy-, (6R)-
MF C29H37N5O3
MW 503.64
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NARLAPREVIR

 phase 2, Uncategorized  Comments Off on NARLAPREVIR
Dec 282013
 

NARLAPREVIR

An antiviral agent that inhibits hepatitis C virus NS3 protease.

M.Wt: 707.96
Formula: C36H61N5O7S

CAS No.: 865466-24-6

SCH 900518;SCH900518;SCH-900518

3-Azabicyclo[3.1.0]hexane-2-carboxamide, N-[(1S)-1-[2-(cyclopropylamino)-2-
oxoacetyl]pentyl]-3-[(2S)-2-[[[[1-[[(1,1-dimethylethyl)sulfonyl]methyl]cyclohexyl]
amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-, (1R,2S,5S)-

2. (1R,2S,5S)-N-{(1S)-1-[2-(cyclopropylamino)-2-oxoacetyl]pentyl}-3-[(2S)-2-{[(1-{[(1,1-
dimethylethyl)sulfonyl]methyl}cyclohexyl)carbamoyl]amino}-3,3-dimethylbutanoyl]-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide

3. (1R,2S,5S)-3-{N-[({1-[(tert-butylsulfonyl)methyl]cyclohexyl}amino)carbonyl]-3-methyl-L-
valyl}-N-{(1S)-1-[(cyclopropylamino)(oxo)acetyl]pentyl}-6,6-dimethyl-3-
azabicyco[3.1.0]hexane-2-carboxamide

Narlaprevir is a potent, Second Generation HCV NS3 Serine Protease Inhibitor.Narlaprevir is useful for Antiviral

Merck & Co. (Originator)

SCH-900518 had been in phase II clinical trials by Merck & Co. for the treatment of genotype 1 chronic hepatitis C; however, no recent development has been reported for this indication.

A potent oral inhibitor of HCV NS3 protease, SCH-900518 disrupts hepatitis C virus (HCV) polyprotein processing. When added to the current standard of care (SOC), peginterferon-alfa plus ribavirin, SCH-900518 is likely to increase the proportion of patients achieving undetectable HCV-RNA levels and sustained virologic response (SVR).

In 2012, the product was licensed by Merck & Co. to R-Pharm in Russia and the Commonwealth of Independent States (CIS) for the development and commercialization as treatment of hepatitis C (HCV)

PATENTS

WO 2011014494

WO 2010068714

 

 

(1 R,5S)-N-[1 (S)-[2-(cyclopropylamino)-1 ,2-dioxoethyl]pentyl]-3-[2(S)- [[[[1-[[1.1-dimethylethyl)sulfonyl]methyl]cyclohexyl]amino]carbonyl]amino]-3,3- dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2(S)-carboxamide.

 

Figure imgf000003_0001

 

Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.

The compound of Formula I is generically and specifically disclosed in

Published U.S. Patent No.2007/0042968, published February 22, 2007 (the ‘968 publication), incorporated herein by reference.

Processes suitable for making the compound of Formula I are generally described in the ‘968 publication. In particular, the ‘968 publication discusses preparing a sulfone carbamate compound, for example, the compound of Formula 837 comprising a cyclic sulfone substituent (paragraphs [0395] through [0403]). The following reaction scheme describes the procedure:

 

Figure imgf000004_0001

The process disclosed in the ‘968 publication produces the intermediate alcohol in step S7 as a mixture of diastereomers at the hydroxyl group; while this chiral center is lost in the final step of the disclosed process, the alcohol intermediate as a mixture of isomers cannot be crystallized and required a volumetrically inefficient precipitative isolation that did not remove any impurities

 

,………………………………………………………………………………………………………………………

WO2011014494A1

Figure imgf000048_0001

 

 

……………………………………………………………………………………………………………………

US20120178942

Preparation of Compound VIJ

 

Figure US20120178942A1-20120712-C00062

 

LDA was made by slowly charging n-butyl lithium (2.5 M, 159 kg) to diisopropyl amine (60 kg) dissolved in THF (252 kg), keeping the temperature at about −20° C., followed by agitation at this temperature for about 30 min. To this solution was charged cyclohexane carboxylic acid, methyl ester (70 kg), keeping the temperature below −10° C. The mixture was agitated at this temperature for about 2 h. To the resulting enolate was charged TMSCI (64.4 kg). The mixture was agitated at −10 to −20° C. for about 30 min, and then heated to about 25° C. and held at this temperature to allow for conversion to the silylenol ether Compound VIH. The reaction mixture was solvent exchanged to n-heptane under vacuum, keeping the temperature below 50° C., resulting in the precipitation of solids. The solids were filtered and washed with n-heptane, and the wash was combined with the n-heptane reaction mixture. The n-heptane mixture of Compound VIH was concentrated under vacuum and diluted with CH2Cl2.

In a separate reactor was charged CH2Cl2 (461 kg) and anhydrous ZnBr2 (14.5 kg). The temperature of the zinc slurry was adjusted to about 20° C. To the zinc slurry was simultaneously charged the solution of Compound VIH and 2-chloromethylsulfanyl-2-methyl-propane (63.1 kg, ref: Bioorg. Med. Chem. Lett, 1996, 6, 2053-2058), keeping the temperature below 45° C. After complete addition, the mixture was agitated for about 1.5 h at 35 to 45° C., after which the reaction mixture was cooled to 10 to 15° C. A solution of dilute aqueous HCl was then charged, keeping the temperature between 0 and 15° C., followed by a separation of the aqueous and organic layers (desired compound in organic layer). The organic layer was washed with aqueous NaHCO3 and water. The organic layer was solvent exchanged to methanol by vacuum distillation, keeping the temperature below 35° C., and kept as a solution in methanol for further processing to Compound VIK. Active Yield of Compound VIJ=69.7 kg (molar yield=57.9%).

Preparation of Compound VIK

 

Figure US20120178942A1-20120712-C00063

 

To a fresh reactor was charged Compound VIJ (99.8 kg active in a methanol solution), water (270 kg), NaOH (70 kg), and methanol (603 kg). The mixture was heated to −70° C. and agitated at this temperature for about 16 h. Upon conversion to the sodium salt of Compound VIK, the reaction mixture was concentrated under vacuum, keeping the temperature below 55° C., and then cooled to about 25° C. Water and MTBE were then charged, agitiated, and the layers were separated (product in the aqueous layer). The product-containing aqueous layer was further washed with MTBE.

CH2Cl2 was charged to the aqueous layer and the temperature was adjusted to ˜10° C. The resultant mixture was acidified to a pH of about 1.5 with HCl, agitated, settled, and separated (the compound was in the organic layer). The aqueous layer was extracted with CH2Cl2, and the combined organic layers were stored as a CH2Cl2 solution for further processing to Compound VID. Active yield of Compound VIK=92.7 kg (molar yield=98.5 kg). MS Calculated: 230.13; MS Found (ES−, M−H): 229.11.

Preparation of Compound VID

 

Figure US20120178942A1-20120712-C00064

 

To a reactor was charged water (952 kg), Oxone® (92.7 kg), and Compound VIK (92.7 kg active as a solution in CH2Cl2). The reaction mixture was agitated for about 24 h at a temperature of about 15° C., during which time Compound VIK oxidized to sulfone Compound VID. The excess Oxone® was quenched with aqueous Na2S2O5, the reaction mixture was settled and the layers separated; the aqueous layer was back-extracted with CH2Cl2, and the combined product-containing organic layers were washed with water.

The resultant solution was then concentrated under vacuum. To precipitate Compound VID, n-heptane was charged, and the resulting slurry was agitated for about 60 min at a temperature of about 30° C. The reaction mixture was filtered, and the wet cake was washed with n-heptane. The wet cake was redissolved in CH2Cl2, followed by the addition of n-heptane. The resultant solution was then concentrated under vacuum, keeping the temperature below 35° C., to allow for product precipitation. The resultant solution was cooled to about 0° C. and agitated at this temperature for about 1 h. The solution was filtered, the wet cake was washed with n-heptane, and dried under vacuum at about 45° C. to yield 68.7 kg Compound VID (molar yield=65.7%). MS Calculated: 262.37; MS Found (ES−, M−H): 261.09

Preparation of Compound VI

 

Figure US20120178942A1-20120712-C00065

 

To a reactor was charged Compound VID (68.4 kg), toluene (531 kg), and Et3N (31 kg). The reaction mixture was atmospherically refluxed under Dean-Stark conditions to remove water (target KF <0.05%). The reaction temperature was adjusted to 80° C., DPPA (73.4 kg) was charged over 7 h, and the mixture was agitated for an additional 2 h. After conversion to isocyanate Compound VIE via the azide, the reaction mixture was cooled to about 0 to 5° C. and quenched with aqueous NaHCO3. The resultant mixture was agitated, settled and the layers were separated. The aqueous layer was extracted with toluene, and the combined isocyante Compound VIE organic layers were washed with water.

In a separate vessel was charged L-tert- Leucine (L-Tle, 30.8 kg), water (270 kg), and Et3N (60 kg). While keeping the temperature at about 5° C., the toluene solution of Compound VIE was transferred to the solution of L-Tle. The reaction mixture was stirred at 0 to 5° C. for about 5 h, at which time the mixture was heated to 15 to 20° C. and agitated at this temperature for 2 h to allow for conversion to urea Compound VI.

The reaction was quenched by the addition of aqueous NaOH, keeping the temperature between 0 and 25° C. The reaction mixture was separated, and the organic layer was extracted with water. The combined Compound VI-containing aqueous layers were washed with toluene, and acidified to pH 2 by the addition of HCl, at which time the product precipitated from solution. The reaction mixture was filtered, washed with water and dried under vacuum at 65 to 70° C. to yield 79.7 kg crude Compound VI (molar yield 52.7%). MS Calculated: 390.54; MS Found (ES−, M−H): 389.20.

Compound VI is further purified by slurrying in CH3CN at reflux (about 80° C.), followed by cooling to RT. Typical recovery is 94%, with an increase in purity from about 80% to 99%.

Preparation of Compound Va

 

Figure US20120178942A1-20120712-C00066

 

To a reactor was charged Compound VI (87.6 kg), Compound VII-1 (48.2 kg), HOBt (6 kg) and CH3CN (615 kg). The reaction mixture was cooled to about 5° C., and NMM (35 kg) and EDCi (53.4 kg) were charged. The reaction was heated to 20 to 25° C. for about 1 h, and then to 35 to 40° C., at which time water was charged to crystallize Compound Va. The reaction mixture was cooled to 5° C. and held at this temperature for about 4 h. Compound Va was filtered and washed with water. XRD data for the hydrated polymorph of Va is as follows:

 

The Compound Va wet cake was charged to a fresh vessel and was dissolved in ethyl acetate at 25 to 30° C. The solution was washed with an aqueous HCl solution, aqueous K2CO3 solution, and brine. The solution was then concentrated under vacuum, keeping the temperature between 35 to 50° C. Additional ethyl acetate was charged, and the solution was heated to 65 to 70° C. While keeping the temperature at 65 to 70° C., n-heptane was charged, followed by cooling the resultant solution to 0 to 5° C. Compound Va was filtered and washed with an ethyl acetate/n-heptane mix.

The wet cake was dried under vacuum between 55 to 60° C. to yield 96.6 kg crystalline Compound Va (molar yield 79.2%). MS Calculated: 541.32; MS Found (ES+, M+H): 542.35.

 

Preparation of Compound IUB

 

Figure US20120178942A1-20120712-C00067

 

Pyridine (92 L) was charged to the reactor and was cooled to 5° C. To the cooled pyridine was slowly charged malonic acid (48.5 kg) and valeraldehyde (59 L), keeping the temperature below 25° C. The reaction was stirred between 25 to 35° C. for at least 60 h. After this time, H2SO4 was charged to acidify, keeping the temperature below 30° C. The reaction mixture was then extracted into MTBE. The organic layer was washed with water. In a separate reactor was charged water and NaOH. The MTBE solution was charged to the NaOH solution, keeping the temperature below 25° C., and the desired material was extracted into the basic layer. The basic layer was separated and the organic layer was discarded. MTBE was charged, the mixture was agitated, settled, and separated, and the organic layer was discarded. To the resultant solution (aqueous layer) was charged water and H2SO4 to acidify, keeping the temperature between 10 to 15° C. To the acidified mixture was charged MTBE, keeping the temperature below 25° C. The resultant solution was agitated, settled, and separated, and the aqueous layer was discarded. The product-containing organic layer was washed with water and was concentrated under vacuum, keeping the temperature below 70° C., to yield 45.4 kg Compound IIIB (molar yield=76.2%) as an oil. Compound Reference: Concellon, J. M.; Concellon, C J. Org. Chem., 2006, 71, 1728-1731

Preparation of Compound IIIC

 

Figure US20120178942A1-20120712-C00068

 

To a pressure vessel was charged Compound IIIB (9.1 kg), heptane (9 L), and H2SO4 (0.5 kg). The pressure vessel was sealed and isobutylene (13.7 kg) was charged, keeping the temperature between 19 to 25° C. The reaction mixture was agitated at this temperature for about 18 h. The pressure was released, and a solution of K2CO3 was charged to the reaction mixture, which was agitated and settled, and the bottom aqueous layer was then separated. The resultant organic solution was washed with water and distilled under vacuum (temp below 45° C.) to yield 13.5 kg Compound IIIC (molar yield=88.3%) as a yellow oil.

Preparation of Compound IIID

 

Figure US20120178942A1-20120712-C00069

 

To a reactor capable of maintaining a temperature of −60° C. was charged (S)-benzyl-1-phenyl ethylamine (18 kg) and THF (75 L). The reaction mixture was cooled to −60° C. To the mixture was charged n-hexyl lithium (42 L of 2.3 M in heptane) while maintaining a temperature of −65 to −55° C., followed by a 30 min agitation within this temperature range. To the in situ-formed lithium amide was charged Compound IIIC over 1 h, keeping the temperature between −65 to −55° C. . The reaction mixture was agitated at this temperature for 30 min to allow for conversion to the enolate intermediate. To the resultant reaction mixture was charged (+)-camphorsulfonyl oxaziridine (24 kg) as a solid, over a period of 2 h, keeping the temperature between −65 to −55° C. . The mixture was agitated at this temperature for 4 h.

The resultant reaction mixture was quenched by the addition of acetic acid (8 kg), keeping the temperature between −60 to −40° C. The mixture was warmed to 20 to 25° C., then charged into a separate reactor containing heptane. The resultant mixture was concentrated under vacuum, keeping the temperature below 35° C. Heptane and water were charged to the reaction mixture, and the precipitated solids were removed by filtration (the desired compound is in the supernatant). The cake was washed with heptane and this wash was combined with the supernatant. The heptane/water solution was agitated, settled, and separated to remove the aqueous layer. An aqueous solution of H2SO4 was charged, and the mixture was agitated, settled, and separated. The heptane layer was washed with a solution of K2CO3.

The heptane layer was concentrated under reduced pressure, keeping the temperature below 45° C., and the resulting oil was diluted in toluene, yielding 27.1 kg (active) of Compound IIID (molar yield=81.0%). MS Calculated: 411.28; MS Found (ES+, M+H): 412.22.

A similar procedure for this step was reported in: Beevers, R, et al, Bioorg. Med. Chem. Lett. 2002, 12, 641-643.

Preparation of Compound IDE

 

Figure US20120178942A1-20120712-C00070

 

Toluene (324 L) and a toluene solution of Compound IIID (54.2 kg active) was charged to the reactor. TFA (86.8 kg) was charged over about 1.5 h, keeping the temperature below 50° C. The reaction mixture was agitated for 24 h at 50° C. The reaction mixture was cooled to 15° C. and water was charged. NaOH was slowly charged, keeping the temperature below 20° C., to adjust the batch to a pH between 5.0 and 6.0. The reaction mixture was agitated, settled, and separated; the aqueous layer was discarded. The organic layer was concentrated under vacuum, keeping the temperature below 40° C., and the resulting acid intermediate (an oil), was dissolved in 2-MeTHF.

In a separate reactor, 2-MeTHF (250 L), HOBt (35.2 kg), and EDCi-HCl (38.0 kg) were charged and the mixture was adjusted to a temperature between 0 to 10° C. DIPEA (27.2 kg) was charged, keeping the mixture within this temperature range. The mixture was agitated for 5 min, followed by the addition of cyclopropyl amine (11.4 kg), keeping the temperature between 0 to 10° C.

To this solution was charged the 2-MeTHF/ acid intermediate solution, keeping the resultant solution between 0 to 10° C. The resultant mixture was heated to 25 to 35° C., and was agitated at this temperature for about 4 h. The reaction mixture was cooled to about 20° C., and was washed with aqueous citric acid, aqueous K2CO3, and water. The solvent was exchanged to n-heptane, and the desired compound was crystallized from a mix of n-heptane and toluene by cooling to 0° C. The crystalline product was filtered, washed with n-heptane, and dried to yield 37.1 kg Compound IIIE (molar yield=70.7%). MS Calculated: 394.26; MS Found (ES+, M+H): 395.22.

Preparation of Compound III

 

Figure US20120178942A1-20120712-C00071

 

To a pressure reactor was charged acetic acid (1.1 kg), methanol (55 kg), and Compound IIIE (10.9 kg). In a separate vessel, Pd/C (50% water wet, 0.5 kg) was suspended in methanol (5 kg). The Pd/C suspension was transferred to the solution containing Compound IIIE. The resultant mixture was pressurized to 80 psi with hydrogen, and agitated at 60° C. for 7 h. The reaction mixture was then purged with nitrogen, and the Pd/C catalyst was filtered off. The resultant solution was concentrated under vacuum and adjusted to about 20° C. MTBE was charged, and the resultant solution was brought to reflux. Concentrated HCl (3 L) was charged and the product was crystallized by cooling the reaction mixture to about 3° C. The desired compound was filtered, washed with MTBE, and dried under vacuum, keeping the temperature below 40° C. to yield 5.5 kg Compound III (molar yield=83.0%). MS Calculated (free base): 200.15; MS Found (ES+, M+H): 201.12.

Preparation of Compound II

 

Figure US20120178942A1-20120712-C00072

 

Compound Va (119.3 kg) was dissolved in 2-MeTHF (720 kg) and water (180 kg). To this solution was charged 50% NaOH (21.4 kg) while maintaining a temperature between 20 and 30° C. The reaction mixture was then agitated for about 7 h at a temperature between 50 and 60° C. The reaction mixture was cooled to a temperature between 20 and 30° C.

The pH of the reaction mixture was adjusted to 1.5-3.0 with dilute phosphoric acid, maintaining a temperature between 20 and 30° C. The resultant mixture was agitated for 10 min, settled for 30 min, and the bottom aqueous layer was separated and removed. The top organic layer was washed with water, followed by concentration by atmospheric distillation.

The concentrated solution was solvent exchanged to CH3CN by continuous atmospheric distillation, and crystallized by cooling to 0° C. The crystalline product was filtered, washed with CH3CN, and dried under vacuum at a temperature between 45 and 55° C. to yield 97.9 kg Compound II (molar yield=83.7%). MS Calculated: 527.30; MS Found (ES+, M+H): 528.29.

Preparation of Compound IV

 

Figure US20120178942A1-20120712-C00073

 

Compound II (21.1 kg), Compound III (9.9 kg), HOBt (3.2 kg) and EDCi (11.2 kg) were charged to the vessel, followed by CH3CN (63 kg), ethyl acetate (20 kg) and water (1.5 kg). The reaction mixture was agitated and the heterogeneous mixture was cooled to −5 to +5° C. DIPEA (11.2 kg) was charged to the reaction mixture, maintaining a temperature between −5 to +5° C. and the mixture was agitated at a temperature of −5 to +5° C. for 1 h. The resultant reaction mixture was warmed to 20 to 30° C. and agitated for 2 to 3 h.

The resultant product was extracted with aqueous HCl, aqueous K2CO3, and water.

The desired product was crystallized from ethyl acetate by cooling from reflux (78° C.) to about 0° C. The crystalline product was filtered and dried at 30° C. under vacuum to yield 23.1 kg Compound IV (molar yield=81.3%). MS Calculated: 709.44; MS Found (ES+, M+H): 710.47.

Preparation of Compound I

 

Figure US20120178942A1-20120712-C00074

 

Compound IV (22.5 kg), TEMPO (5 kg), NaOAc (45 kg), methyl acetate (68 L), MTBE (158 L), water (23 L) and acetic acid (22.5 L) were charged to the reactor. The reaction mixture was stirred at 20-30° C. to allow for dissolution of the solids, and was then cooled to 5-15° C. NaOCl solution (1.4 molar equivalents) was charged to the reaction mixture, keeping the temperature at about 10° C. After complete addition of NaOCl, the reaction mixture was agitated at 10° C. for 2 h.

The reaction was quenched by washing with a buffered sodium ascorbate/HCl aqueous solution, followed by a water wash.

The reaction mixture was solvent exchanged to acetone under vacuum, keeping the temperature below 20° C.; the desired product was crystallized by the addition of water, and dried under vacuum, keeping the temperature below 40° C. to yield 18.6 kg Compound I (molar yield=82.7%). MS Calculated: 707.43: MS Found (ES+, M+H): 708.44.

 

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Deldeprevir, (neceprevir)

 phase 1  Comments Off on Deldeprevir, (neceprevir)
Dec 272013
 

Figure US20100152103A1-20100617-C00127

 

deldeprevir,

ACH-0142684, ACH-2684

HCV NS3 PR

USAN (YY-152) DELDEPREVIR

THERAPEUTIC CLAIM Treatment of Hepatitis C
CHEMICAL NAMES
1. Cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide, N-
(cyclopropylsulfonyl)-6-[2-(3,3-difluoro-1-piperidinyl)-2-oxoethyl]-
1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-
methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5,16-dioxo-, (2R,6R,12Z,13aS,14aR,16aS)-
2. (2R,6R,12Z,13aS,14aR,16aS)-N-(cyclopropylsulfonyl)-6-[2-(3,3-difluoropiperidin-1-yl)-
2-oxoethyl]-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-yl}oxy)-
5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16atetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-
carboxamide

MOLECULAR FORMULA C45H56F2N6O8S2
MOLECULAR WEIGHT 911.1
SPONSOR Achillion Pharmaceuticals, Inc.
CODE DESIGNATION ACH-0142684, ACH-2684
CAS REGISTRY NUMBER 1229626-28-1
WHO NUMBER 9600
NOTE: This adoption statement replaces adoption N12/17 and the name neceprevir is hereby rescinded.

 

……………………………………………………………………………………………………….

deldeprevir-sodium

DELDEPREVIR SODIUM

USAN (yy-153) DELDEPREVIR SODIUM

THERAPEUTIC CLAIM Treatment of Hepatitis C

CHEMICAL NAMES

1. Cyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a(5H)-carboxamide, N-
(cyclopropylsulfonyl)-6-[2-(3,3-difluoro-1-piperidinyl)-2-oxoethyl]-
1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-
methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5,16-dioxo-, sodium salt (1:1),
(2R,6R,12Z,13aS,14aR,16aS)-

2. Sodium (cyclopropylsulfonyl){[(2R,6R,12Z,13aS,14aR,16aS)-6-[2-(3,3-difluoropiperidin-
1-yl)-2-oxoethyl]-2-({7-methoxy-8-methyl-2-[4-(1-methylethyl)thiazol-2-yl]quinolin-4-
yl}oxy)-5,16-dioxo-1,2,3,6,7,8,9,10,11,13a,14,15,16,16a-
tetradecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-14a(5H)-
yl]formyl]azanide

MOLECULAR FORMULA C45H55F2N6NaO8S2

MOLECULAR WEIGHT 933.1

SPONSOR Achillion Pharmaceuticals, Inc.

CODE DESIGNATION ACH-0142684.Na, ACH-2684.Na

CAS REGISTRY NUMBER 1298053-61-8

NOTE: This adoption statement replaces adoption N12/18 and the name neceprevir sodium

is hereby rescinded.

 

ACH-2684 is a HCV NS3 protease inhibitor in phase I clinical development at Achillion for the oral treatment of chronic hepatitis C genotype 1 and 3.

WO 2010068761
US 2010152103

Figure US20100152103A1-20100617-C00127

COMPD 133

(2R,6R,14aR,16aS,Z)- N-(cyclopropylsulfonyl)- 6-(2-(3,3-difluoropiperidin- 1-yl)-2-oxoethyl)-2- (2-(2-isopropylthiazol- 4-yl)-7-methoxy-8- methylquinolin-4- yloxy)-5,16-dioxo- 1,2,3,5,6,7,8,9,10,11, 13a,14,14a,15,16,16a- hexadecahydrocyclopropa [e]pyrrolo[1,2- a][1,4] diazacyclopentadecine- 14a-carboxamide

https://www.google.co.in/patents/US20100152103?pg=PA1&dq=US+2010152103&hl=en&sa=X&ei=1ma9Utq-C4mxrgeu54G4DA&ved=0CDcQ6AEwAA

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Deleobuvir

 Uncategorized  1 Response »
Dec 272013
 

DELEOBUVIR

(2E)-3-(2-{1-[2-(5-Bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido]cyclobutyl}-1-methyl-1H-benzimidazol- 6-yl)prop-2-enoic acid

1221574-24-8 CAS  please check may be sodium salt??

cas no  as per below ref ……863884-77-9 (free acid)

http://www.ama-assn.org/resources/doc/usan/deleobuvir.pdf

PHASE 3

BI-207127NA
BI-207127 (free acid)

BI-207127 is a novel HCV RNA polymerase inhibitor in phase III clinical development at Boehringer Ingelheim for the treatment of hepatitis C.

 

Company Boehringer Ingelheim GmbH
Description Oral non-structural protein 5B (NS5B) RNA-dependent polymerase inhibitor
Molecular Target HCV NS5B polymerase 
Mechanism of Action Viral polymerase inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Phase III
Indication Hepatitis C virus (HCV)
Partner

Deleobuvir (formerly BI 207127) is an experimental drug for the treatment of hepatitis C. It is being developed by Boehringer-Ingelheimand is currently in Phase II trials. It is a non-nucleoside hepatitis C virus NS5B polymerase inhibitor. Deleobuvir is being tested in combination regimens with pegylated interferon and ribavirin, and in interferon-free regimens with other direct-acting antiviral agents including faldaprevir.

Data from the SOUND-C2 study, presented at the 2012 AASLD Liver Meeting, showed that a triple combination of deleobuvir, faldaprevir, and ribavirin performed well in HCV genotype 1b patients.[1] Efficacy fell below 50%, however, for dual regimens without ribavirin and for genotype 1a patients.Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days’ deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10 (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.

These results were confirmed in the SOUND-C3 study, presented at the 2013 APASL Liver Conference, which found that 16 week triple therapy with deleobuvir + faldaprevir + ribavirin gave 95% SVR12 in HCV genotype 1b patients but poor virological response in genotype 1a.[2]

  1.  Interferon-free hepatitis C treatment with faldaprevir proves safe and effective in people with cirrhosis. Alcorn, K. Aidsmap.com. 20 November 2012.
  2.  S Zeuzem, J-F Dufour, M Buti, V Soriano, R Buynak, P Mantry, J Taunk, JO Stern, R Vinisko, J-P Gallivan, WO Bocher and FJ Mensa.“Interferon-free treatment with faldaprevir, deleobuvir (BI 207127) and ribavirin in SOUND-C3: 95% SVR12 in HCV GT-1b”. 23rd Conference of the Asian Pacific Association for the Study of the Liver (APASL) 6–9 June 2013. Retrieved 12 Sep 2013.

 

PATENTS

WO 2013147750

 WO 2013147749

WO 2012041771

WO 2012044520

WO 2012016995

WO 2005080388

……………………………………………………

PATENT
Patent Filing date Publication date Applicant Title
WO2010059667A1 Nov 18, 2009 May 27, 2010 Boehringer Ingelheim International Gmbh Pharmaceutical composition of a potent hcv inhibitor for oral administration
WO2011005646A2 Jul 1, 2010 Jan 13, 2011 Boehringer Ingelheim International Gmbh Pharmaceutical composition for a hepatitis c viral protease inhibitor
WO2012041771A1 * Sep 23, 2011 Apr 5, 2012 Boehringer Ingelheim International Gmbh Combination therapy for treating hcv infection
US4211771 Feb 13, 1978 Jul 8, 1980 Robins Ronald K Treatment of human viral diseases with 1-B-D-ribofuranosyl-1,2,4-triazole-3-carboxamide
US6063772 Jun 15, 1998 May 16, 2000 Icn Pharmaceuticals, Inc. Specific modulation of Th1/Th2 cytokine expression by ribavirin in activated T-lymphocytes
US6277830 Jul 7, 1999 Aug 21, 2001 Schering Corporation 5′-amino acid esters of ribavirin and the use of same to treat hepatitis C with interferon
US6323180 Aug 5, 1999 Nov 27, 2001 Boehringer Ingelheim (Canada) Ltd Hepatitis C inhibitor tri-peptides
US6403564 Oct 14, 1999 Jun 11, 2002 Schering Corporation Ribavirin-interferon alfa combination therapy for eradicating detectable HCV-RNA in patients having chronic hepatitis C infection
US7141574 Jul 18, 2002 Nov 28, 2006 Boehringer Ingelheim (Canada) Ltd. Viral polymerase inhibitors
US7514557 May 23, 2005 Apr 7, 2009 Boehringer Ingelheim International Gmbh Process for preparing acyclic HCV protease inhibitors
US7582770 Feb 18, 2005 Sep 1, 2009 Boehringer Ingelheim International Gmbh Viral polymerase inhibitors
US7585845 May 20, 2004 Sep 8, 2009 Boehringer Ingelheim International Gmbh Hepatitis C inhibitor compounds
US7642352 Feb 10, 2006 Jan 5, 2010 Boehringer Ingelheim International Gmbh Process for preparing 2,3-disubstituted indoles
US20090087409 Nov 26, 2008 Apr 2, 2009 Boehringer Ingelheim (Canada) Ltd. Viral Polymerase Inhibitors
US20100068182 Sep 16, 2009 Mar 18, 2010 Boehringer Ingelheim International Gmbh Combination therapy for treating hcv infection
US20100093792 Sep 15, 2009 Apr 15, 2010 Boehringer Ingelheim International Gmbh Crystalline forms of a potent hcv inhibitor
* Cited by examiner

NON-PATENT CITATIONS
Ref
1 BALAGOPAL GASTROENTEROLOGY vol. 139, 2010, pages 1865 – 1876
2 BERG ET AL. HEPATOL vol. 52, no. S1, 2010,
3 * DOMINIQUE LARREY ET AL: “Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with peginterferon alfa 2a and ribavirin“, JOURNAL OF HEPATOLOGY, vol. 57, no. 1, 7 March 2012 (2012-03-07), pages 39-46, XP55040240, ISSN: 0168-8278, DOI: 10.1016/j.jhep.2012.02.015
4 G. CAIRNS GENE VARIANT THAT HELPS HEPATITIS C TREATMENT MAY HINDER HIV TREATMENT, [Online] 2011, Retrieved from the Internet: <URL:http://www.bhiva.org/Ncws.aspx?NewsID=a7503829-94b9-4d2f-bd91-ld2fbaad6c8d>
5 GE ET AL. NATURE vol. 461, 2009, pages 399 – 401
6 GHANY; MARC ET AL.: ‘An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases‘ HEPATOLOGY vol. 54, no. 4, 2011, pages 1433 – 44
7 * LIZ HIGHLEYMAN: “AASLD: All-Oral Combination of BI 201335, BI 207127 and Ribavirin Shows Good Efficacy at 12 Weeks“, INTERNET CITATION, [Online] 1 December 2011 (2011-12-01), pages 1-3, XP002684260, Retrieved from the Internet: URL:www.hivandhepatitis.com/hepatitis-c/he patitis-c-topics/hcv-treatment/3371-aasld- all-oral-combination-of-bi-201335-bi-20712 7-and-ribavirin-shows-good-efficacy-at-12- weeks> [retrieved on 2012-09-27]
8 * POL S ET AL: “SVR AND PHARMACOKINETICS OF THE HCV PROTEASE INHIBITOR BI201335 WITH PEGIFN/RBV IN HCV GENOTYPE-1 PATIENTS WITH COMPENSATED LIVER CIRRHOSIS AND NON-RESPONSE TO PREVIOUS PEGIFN/RBV“, JOURNAL OF HEPATOLOGY, vol. 54, no. Suppl. 1, March 2011 (2011-03), page S486, XP55038942, & 46TH ANNUAL MEETING OF THE EUROPEAN-ASSOCIATION-FOR-THE-STUDY-OF-THE- LIVER (EASL); BERLIN, GERMANY; MARCH 30 -APRIL 03, 2011 ISSN: 0168-8278
9 S. M. BIRGE ET AL. J. PHARM. SCI. vol. 66, 1977, pages 1 – 19
10 * STEFAN ZEUZEM ET AL: “Efficacy of the Protease Inhibitor BI 201335, Polymerase Inhibitor BI 207127, and Ribavirin in Patients With Chronic HCV Infection“, GASTROENTEROLOGY, ELSEVIER, PHILADELPHIA, PA, vol. 141, no. 6, 1 December 2011 (2011-12-01), pages 2047-2055, XP002664706, ISSN: 0016-5085, DOI: 10.1053/J.GASTRO.2011.08.051
11 SULKOWSKI MS ET AL. HEPATOL vol. 50, 2009, page 2A
12 SULKOWSKI MS ET AL. J HEPATOL vol. 52, no. 1, 2010, pages S462 – S463
13 WHITE PW ET AL. ANTIMICROB AGENTS CHEMOTHER vol. 54, no. 11, 2010, pages 4611 – 4618
14 WHO COLLABORATIVE STUDY GROUP. VOX SANG vol. 76, 1999, pages 149 – 158
15 * ZEUZEM STEFAN ET AL: “STRONG ANTIVIRAL ACTIVITY AND SAFETY OF IFN-SPARING TREATMENT WITH THE PROTEASE INHIBITOR BI 201335, THE HCV POLYMERASE INHIBITOR BI 207127 AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C“, HEPATOLOGY, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol. 52, no. Suppl, 1 October 2010 (2010-10-01), pages 876A-877A, XP009154421, ISSN: 0270-9139
16 * ZEUZEM STEFAN ET AL: “VIROLOGIC RESPONSE TO AN INTERFERON-FREE REGIMEN OF BI201335 AND BI207127, WITH AND WITHOUT RIBAVIRIN, IN TREATMENT-NAIVE PATIENTS WITH CHRONIC GENOTYPE-1 HCV INFECTION: WEEK 12 INTERIM RESULTS OF THE SOUND-C2 STUDY“, HEPATOLOGY, WILLIAMS AND WILKINS, BALTIMORE, MD, US, vol. 54, no. Suppl. 1, 1 November 2011 (2011-11-01), page 1436A, XP009163087, ISSN: 0270-9139, DOI: 10.1002/HEP.24666 [retrieved on 2011-09-30]

…………………………………………………………

WO2013147750A1

The following……

 

Figure imgf000004_0001

having the chemical name: (E)-3-[2-(l-{ [2-(5-Bromo-pyrimidin-2-yl)-3-cyclopentyl-l- methyl-lH-indole-6-carbonyl]-amino}-cyclobutyl)-3-methyl-3H-benzimidazol-5-yl]- acrylic acid, is known as a selective and potent inhibitor of the HCV NS5B RNA- dependent RNA polymerase and useful in the treatment of HCV infection. Compound (2) falls within the scope of HCV inhibitors disclosed in U.S. Patents 7,141,574 and

7,582,770, and US Application Publication 2009/0087409. Compound (2) is disclosed specifically as Compound # 3085 in U.S. Patent 7,582,770. Compound (2), and pharmaceutical formulations thereof, can be prepared according to the general procedures found in the above-cited references, all of which are herein incorporated by reference in their entirety. Preferred forms of Compound (2) include the crystalline forms, in particular the crystalline sodium salt form which is prepared as herein described.

It is known in the art that particular HCV subtypes and patient subgenotypes may respond differently to HCV therapy. HCV Genotype la is traditionally more difficult to treat and are less responsive to antiviral therapy than Genotype lb. See, e.g., Ghany, Marc et al. “An Update on Treatment of Genotype 1 Chronic Hepatitis C Virus Infection: 2011 Practice Guideline by the American Association for the Study of Liver Diseases”, Case No.: 09-0592-PCT

Hepatology, 54(4): 1433-44 (2011)). In addition, and particularly with interferon-based therapy, specific single nucleotide polymorphisms (SNPs) located on the long arm of chromosome 19 within the gene cluster of IL-28B (Interleukin (IL) 28B, (also called lambda interferon), of the patient undergoing therapy can directly effect the

responsiveness of that patient to the antiviral therapy. In particular, patients having a non- CC genotype of SNP rsl2979860 or a non-TT genotype of rs 8099917 are traditionally more difficult to treat and are less responsive in terms of a sustained virological response (SVR) than patients having the CC or TT genotype.. The SNP that was most strongly associated with SVR in the genome-wide analysis was rs 12979860 followed by rs 8099917. See, e.g., Ge et al., Nature, 461 :399-401 (2009) and Balagopal,

Gastroenterology, 139: 1865-1876 (2010). See G. Cairns, “Gene variant that helps hepatitis C treatment may hinder HIV treatment”, 2011, at:

http://www.bhiva.org^ Thus, there is a need in the art for therapies that are effective against even the more difficult-to-treat patient subpopulations, particularly those exhibiting HCV subtype la and the non-CC IL28B subgenotype, as well as those exhibiting compensated liver disease.

Examples

I. Methods for Preparing Compound (1)

Methods for preparing amorphous Compound (1) and a general description of

pharmaceutically acceptable salt forms can be found in US Patents 6,323,180, 7,514,557 and 7,585,845. Methods for preparing additional forms of Compound (1), in particular the crystalline sodium salt form, can be found in U.S. Patent Application Publication No. 2010/0093792.

II. Formulations of Compound (1) Case No. : 09-0592-PCT

One example of a pharmaceutical formulation of Compound (1) include an oral solution formulation as disclosed in WO 2010/059667. Additional examples include capsules containing a lipid-based liquid formulation, as disclosed in WO 201 1/005646. III. Methods for Preparing Compound (2)

Methods for preparing amorphous Compound (2) can be found in U.S. Patents 7, 141 ,574 and 7,582,770, and US Application Publication 2009/0087409.

The following Example provides the method for preparing an additional form of

Compound (2), the sodium salt form, that may be used in the present invention.

Example 1 – Preparation of Compound (2) Sodium Salt

Step 1. Synthesis of Isopropyl 3-Cyclopentyl-l-methyl-lH-indole-6-carboxylate

 

Figure imgf000024_0001

Because of the instability of brominated product, methyl 3 -cyclopentyl- 1 -methyl- 1Η- indole-6-carboxylate needed to be converted into the more stable isopropyl 3-cyclopentyl- l-methyl- lH-indole-6-carboxylate via a simple and high yielding operation. The conversion worked the best with stoichiometric amounts of solid lithium isopropoxide. Use of 0.1 eq lithium isopropoxide led to longer reaction times and as a result to more hydrolysis by-product, while lithium isopropoxide solution in THF caused a problematic isolation and required distillation of THF.

Procedure: Case No.: 09-0592-PCT

The mixture of methyl 3 -cyclopentyl- 1 -methyl- lH-indole-6-carboxylate (50.0 g, 0.194 mol) and lithium isopropoxide (16.2 g, 95%, 0.233 mol) in 2-propanol was stirred at 65+5 °C for at least 30 min for complete trans-esterification. The batch was cooled to 40+5 °C and water (600 g) was added at a rate to maintain the batch temperature at 40+5°C. After addition, the mixture was cooled to 20-25 °C over 2+0.5 h and held at 20-25 °C for at least 1 h. The batch was filtered and rinsed with 28 wt% 2-propanol in water (186 g), and water (500 g). The wet cake was dried in vacuo (< 200 Torr) at 40-45 °C until the water content was < 0.5% to give isopropyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate (52.7 g, 95% yield) in 99.2 A% (240 nm).

The starting material methyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate can be prepared as described in Example 12 of U.S. Patent 7,141,574, and in Example 12 of U.S. Patent 7,642,352, both herein incorporated by reference.

Step 2. Synthesis of Isopropyl 2-Bromo-3-cyclopentyl-l-methyl-lH-indole-6- carboxylate

 

Figure imgf000025_0001

This process identified the optimal conditions for the synthesis of 2-bromo-3-cyclopentyl- l-methyl-lH-indole-6-carboxylate via bromination of the corresponding 3 -cyclopentyl- 1- methyl-lH-indole-6-carboxylate with bromine. It’s very important to control the reaction temperature and to quench the reaction mixture with a mixture of aqueous sodium thiosulfate and 4-methylmorpholine to minimize the formation of the dibromo- and 2- indolone impurities. Further neutralization of the crude product with NaOH in isopropanol greatly increases the stability of the isolated product. Case No.: 09-0592-PCT

Procedure:

The mixture of isopropyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate (50.0 g, 0.175 mol) and acetonitrile (393 g) was cooled to -6+3 °C. Bromine (33.6 g, 0.210 mol) was added while the batch was maintained at -6+3°C. The resulting slurry was stirred at – 6+3°C for at least 30 min. When HPLC showed > 94 % conversion (the HPLC sample must be quenched immediately with aqueous 4-methylmorpholine/sodium thiosulfate solution), the mixture was quenched with a solution of sodium thiosulfate (15.3 g) and 28.4 g 4-methylmorpholine in water (440 g) while the temperature was maintained at -5+5 °C. After it was stirred at 0+5 °C for at least 2 h, the batch was filtered and rinsed with 85 wt methanol/water solution (415 g), followed by water (500 g), and dried until water content is < 30%. The wet cake was suspended in 2-propanol (675 g), and heated to 75+5 °C. The resulting hazy solution was treated with 1.0 M aqueous sodium hydroxide solution (9.1 g) and then with 135.0 g water at a rate to maintain the batch at 75+5°C. The suspension was stirred at 75+5°C for at least 30 min, cooled to 15+2 °C over 30-40 min, and held at 15+2 °C for at least 1 h. The batch was filtered, rinsed with 75 wt% 2-propanol/water solution (161 g), and dried in vacuo (<200 Torr) at 50-60 °C until the water content was < 0.4% to give isopropyl 2-bromo-3-cyclopentyl-l -methyl- lH-indole-6-carboxylate as a solid (55.6 g, 87 % yield ) in 99.5 A% (240 nm) and 97.9 Wt%. Alternative Procedure:

The mixture of isopropyl 3-cyclopentyl-l-methyl-lH-indole-6-carboxylate (84 g, 0.294 mol) and isopropyl acetate (1074 g) was cooled to between -10-0 °C. Bromine (50 g, 0.312 mol) was added while the batch was maintained at -10 – 0 °C. The resulting slurry was stirred at the same temperature for additional 30 min and quenched with a pre-cooled solution of sodium thiosulfate pentahydrate (13 g) and triethylamine (64.5 g) in water (240 g) while the temperature was maintained at 0-10 °C. The mixture was heated to 40 – 50 °C and charged with methanol (664 g). After it was stirred at the same temperature for at least 0.5 h, the batch was cooled to 0 – 10 °C and stirred for another 1 hr. The precipitate was filtered, rinsed with 56 wt% methanol/water solution (322 g), and dried in vacuo (<200 Case No. : 09-0592-PCT

Torr) at 50-60 °C until the water content was < 0.4% to give isopropyl 2-bromo-3- cyclopentyl-l -methyl- lH-indole-6-carboxylate as a beige solid (90-95 g, 80-85 % yield ).

Step 3a,b. Preparation of compound I by one-pot Pd-catalyzed borylation- Suzuki coupling reaction

 

Figure imgf000027_0001

To a clean and dry reactor containing 20.04 g of isopropyl 2-bromo-3-cyclopentyl- l- methyl- lH-indole-6-carboxylate, 1.06 g of Pd(TFP)2Cl2(3 mol%) and 0.76 g of tri(2- furyl)phosphine (6 mol%) was charged 8.35 g of triethylamine (1.5 equivalent), 39.38 g of CH3CN at 23+10 °C under nitrogen or argon and started agitation for 10 min. 9.24 g of 4,4,5, 5-tetramethyl-l ,3,2-dioxaborolane was charged into the reactor. The mixture was heated to reflux (ca. 81 -83 °C) and stirred for 6h until the reaction completed. The batch was cooled to 30+5 °C and quenched with a mixture of 0.99 g of water in 7.86 g of

CH3CN. 17.24 g of 5-bromo-2-iodopyrimidine and 166.7 g of degassed aqueous potassium phosphate solution (pre-prepared from 46.70 g of K3PO4 and 120 g of H20) was charged subsquently under argon or nitrogen. The content was heated to reflux (ca. 76-77 °C) for 2 h until the reaction completed. 4.5 g of 1-methylimidazole was charged into the reactor at 70 °C. The batch was cooled to 20+3 °C over 0.5h and hold at 20+3 °C for at least lh. The solid was collected by filtration. The wet cake was first rinsed with 62.8 g of 2-propanol, Case No. : 09-0592-PCT

followed by 200 g of H20. The solid was dried under vacuum at the temperature below 50 °C.

Into a dry and clean reactor was charged dried I, 10 wt Norit SX Ultra and 5 V of THF. The content was heated at 60+5 °C for at least 1 h. After the content was cooled to 35+5 °C, the carbon was filtered off and rinsed with 3 V of THF. The filtrate was charged into a clean reactor containing 1-methylimidazole (10 wt % relative to I). After removal of 5 V of THF by distillation, the content was then cooled to 31 ±2 °C. After the agitation rate was adjusted to over 120 rpm, 2.5 V of water was charged over a period of at least 40 minutes while maintaining the content temperature at 31 + 2 °C. After the content was agitated at 31 + 2 °C for additional 20 min, 9.5 V of water was charged into the reactor over a period of at least 30 minutes at 31 + 2 °C. The batch was then cooled to about 25 + 3 °C and stirred for additional 30 minutes. The solid was collected and rinsed with 3 V of water. The wet product I was dried under vacuum at the temperature below 50 °C (19.5 g, 95 wt , 76% yield).

Alternative Procedure:

To a clean and dry reactor containing 40 g of isopropyl 2-bromo-3-cyclopentyl- l-methyl- lH-indole-6-carboxylate (0.1 10 mol), 0.74 g of Pd(OAc)2 (3.30 mmol, 3 mol% equiv.) and 3.2 g of tri(2-furyl)phosphine (13.78 mmol, 12.5 mol% equiv.) was charged 16.8 g of triethylamine (1.5 equivalent), 100 mL of acetonitrile at 25 °C under nitrogen or argon. 20.8 g of 4,4,5, 5-tetramethyl- l ,3,2-dioxaborolane was charged into the reactor within 30 min. The mixture was heated to reflux (ca. 81 -83 °C) and stirred for over 5 hrs until the reaction completed. The batch was cooled to 20 °C and quenched with a mixture of 2.7 g of water in 50 mL of CH3CN. The batch was warmed to 30 °C, stirred for 1 hr and transferred to a second reactor containing 34.4 g of 5-bromo-2-iodopyrimidine in 100 mL of acetonitrile. The reactor was rinsed with 90 mL of acetonitrile. To the second reactor was charged with degassed aqueous potassium phosphate solution (pre-prepared from 93.2 g of K3PO4 and 100 g of H20) under argon or nitrogen. The content was heated to reflux (ca. 80 °C) for over 3 h until the reaction completed. 9.2 g of 1 -methylimidazole was charged into the reactor at 70 °C and the mixture was stirred for at least 10 min. The aqueous phase was removed after phase separation. 257 g of isopropanol was charged at 70 Case No.: 09-0592-PCT

°C. The batch was cooled slowly to 0 °C and hold for at least 1 h. The solid was collected by filtration. The wet cake was rinsed twice with 2-propanol (2 x 164 g) and dried under vacuum at the temperature below 50 °C to give I as a yellow to brown solid (26 g, 75% yield).

Step 4. Hydrolysis of I to II

Figure imgf000029_0001

I (20 g) and l-methyl-2-pyrrolidinone (NMP) (113 g) were charged into a clean reactor under nitrogen. After the batch was heated to 50-53 °C with agitation, premixed aq. NaOH (5.4 g of 50% aq. NaOH and 14.3 g of water) was introduced into the reactor. The resulting mixture was stirred at 50-53 °C for about 10 hrs until the reaction completed. A premixed aq. HOAc (60 g of water and 9.0 g of HOAc) was added over 0.5 h at 45 ±5 °C to reach pH 5.5- 7.5. The batch was cooled to 20+5 °C and then kept for at least 1.0 h. The solid product was collected and rinsed with 80 g of NMP/water (1 :3 volume ratio) and then 60 g of water. The product was dried under vacuum at the temperature below 50 °C to give II as a pale yellow powder (19 -20 g, purity > 99.0 A% and 88.4 wt%, containing 5.4 wt% NMP). The yield is about 93-98%.

Notes: The original procedure used for the hydrolysis of I was carried out with aq. NaOH (2.5 eq) in MeOH/THF at 60 °C. Although it has been applied to the preparation of II on several hundred grams scale, one disadvantage of this method is the formation of 5-MeO pyrimidine during hydrolysis (ca. 0.4 A%), which is extremely difficult to remove in the subsequent steps. In addition, careful control has to be exerted during crystallization. Case No.: 09-0592-PCT

Otherwise, a thick slurry might form during acidification with HO Ac. The use of NMP as solvent could overcome all aforementioned issues and give the product with desired purity.

Alternative Process

To a reactor was charged I (71 g), isopropanol (332 g), aqueous NaOH (22 g, 45 wt ) and water (140 g) at ambient temperature. The mixture was heated to reflux (80 °C) and stirred for at least 3 hrs until the reaction completed. The batch was cooled to 70 °C and charged a suspension of charcoal (3.7 g) in isopropanol (31 g). The mixture was stirred at the same temperature for over 10 min and filtered. The residue was rinsed with isopropanol (154 g). Water (40 g) was charged to the filtrate at 70 – 80 °C, followed by slow addition of 36% HC1 solution (20 g) to reach pH 5- 6. The batch was stirred for over 30 min at 70 °C, then cooled to 20 °C over 1 hr and kept for at least 1.0 h. The solid product was collected and rinsed with 407 g of isopropanol/water (229 g IPA, 178 g H20). The product was dried under vacuum at 80 °C for over 5 hrs to give II as a white powder (61 g, 95% yield).

Notes on Steps 5 to 8 below:

A concise and scalable 4-step process for the preparation of the benzimidazole

intermediate V was developed. The first step was the preparation of 4-chloro-2-(methyl)- aminonitrobenzene starting from 2,4-dichloronitrobenzene using aqueous methyl amine in DMSO at 65 °C. Then, a ligandless Heck reaction with n-butyl acrylate in the presence of Pd(OAc)2, ‘PrzNEt, LiCl, and DMAc at 110 °C was discovered.

Step 5: SNAr reaction of (5-chloro-2-nitrophenyl)-methylamine

 

Figure imgf000030_0001

To a solution of (5-chloro-2-nitrophenyl)-methylamine (40 g, 208.3 mmol, 1 equiv) in DMSO (160 mL) was added 40% MeNH2solution in water (100 mL, 1145. 6 mmol, 5.5 eq) slowly keeping the temperature below 35 °C. The reaction was stirred at r.t. until the Case No.: 09-0592-PCT

complete consumption of the starting material (>10 h). Water (400 mL) was added to the resulting orange slurry and stirred at r.t. for additional 2 h. The solid was filtered, rinsed with water (200 mL) and dried under reduced pressure at 40 °C. (5-chloro-2-nitrophenyl)- methylamine (36.2 g, 93% yield, 94 A% purity) was isolated as a solid.

Step 6: Heck Reaction of (5-chloro-2-nitrophenyl)-methylamine

 

Figure imgf000031_0001

DMAc (5 vol), 1 10 °C, 7-22 h To a mixture of 4-chloro-2-methylaminonitrobenzene (50.0 g, 268.0 mmol, 1.0 eq),

Pd(OAc)2 (0.30 g, 1.3 mmol, 0.005 eq) and LiCI (11.4 g 268.0 mmol, 1.0 eq) in DMAc (250 mL) was added ‘Pr2NEt (56 mL, 321.5 mmol, 1.2 eq) followed by n-butyl acrylate (40 mL, 281.4 mmol, 1.05 eq) under nitrogen. The reaction mixture was stirred at 110 °C for 12 h, then cooled to 50 °C. 1 -methylimidazole (10.6 mL, 134.0 mmol, 0.5 eq) was added and the mixture was stirred for 30 min before filtering and adding water (250 mL). The resulting mixture was cooled to r.t. over 1 h. The resulting solid was filtered and washed with water and dried to yield n-butyl 3-methylamino-4-nitrocinnamate (71.8 g, 96 %, 99.2 A% purity).

Step 7: Reduction of n-butyl (3-methylamino-4-nitro)-cinnamate

 

Figure imgf000031_0002

III Case No.: 09-0592-PCT

To a reactor was charged n-butyl 3-methylamino-4-nitrocinnamate (70.0 g, mmol, 1.0 eq) , Raney Ni (4.9 g, ~20wt% H20), charcoal “Norit SX Ultra” (3.5 g), toluene (476 mL) and MeOH (224 mL). The reactor was charged with hydrogen (4 bar) and the mixture was stirred at 20- 25 °C for about 2 hrs until the reaction was completed. The reaction mixture was filtered and rinsed the filter residue with toluene (70 mL). To the combined filtrates were added “Norit SX Ultra” charcoal (3.5 g). The mixture was stirred at 50 °C for 1.0 hr and filtered. The filtrate was concentrated under reduced pressure to remove solvents to 50% of the original volume. The remained content was heated to 70 °C and charged slowly methyl cyclohexane (335 mL) at the same temperature. The mixture was cooled to about 30 – 40 °C and seeded with III seed crystals, then slowly cooled the suspension to— 10 °C. The solid was filtered and rinsed with methyl cyclohexane in three portions (3 x 46 mL). The wet cake was dried in vacuo at 40 °C to give III (53.3 g, 215 mmol, 86%).

Step 8: Preparation of benzimidazole V

DCC

Figure imgf000032_0001

To reactor-1 was charged III (35 g, 140.95 mmol) in toluene (140 g). The mixture was heated to 50 °C to obtain a clear solution. To a second reactor was charged IV (36.4 g, 169.10 mmol) and toluene (300 g), followed by addition of a solution of dicyclohexyl carbodimide (11.6 g, in 50% toluene, 28.11 mmol) at 0 – 10 °C. The mixture was stirred at the same temperature for 15 min, then charged parallelly with the content of reactor-1 and the solution of dicyclohexyl carbodimide (52.4 g, in 50% toluene, 126.98 mmol) within 1 hr while maintaining the batch temperature at 0 – 10 °C. The mixture was agitated at the same temperature for 3 hrs, and warmed to 25 °C for another 1 hr. Once III was consumed, toluene (-300 mL) was distilled off under reduced pressure at 70 – 80 °C. n-Butanol (200 g) was added, followed by 3 M HCI solution in n-butanol (188 g) while maintaining the Case No.: 09-0592-PCT

temperature at 70 – 80 °C (Gas evolution, product precipitates). After stirring for over 30 min. at 70 – 80 °C, the mixture was cooled to 20 – 30 °C over 1 hr. The precipitate was filtered and washed with acetone (172 g) and toluene (88 g). The wet cake was dried in vacuo at -60 °C to give V toluene solvate as off white solid (60 – 72 g, 85 – 95% yield). Compound V could be used directly for the next step or basified prior to next step to obtain the free base compound VI used in the next step.

Step 9. Synthesis of (E)-Butyl 3-(2-(l-(2-(5-Bromopyrimidin-2-yl)-3-cyclopentyl-l- hydroxy-lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[d]imidazol-6- yl)acrylate VII

 

Figure imgf000033_0001

5) MeOH/H20

Notes:

The conversion of the acid into acid chloride was achieved using inexpensive thionyl chloride in the presence of catalytic amount of NMP or DMF. An efficient crystallization was developed for the isolation of the desired product in high yield and purity.

Procedure (using free base VI):

To the suspension of 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-l-methyl-lH-indole-6- carboxylic acid II (see Step 4) (33.36 g, 90.0 wt %, containing -0.2 equiv of NMP from previous step,75.00 mmol) in THF (133.4 g) was added thionyl chloride (10.71 g). The mixture was stirred at 25+5 °C for at least 1 h. After the conversion was completed as determined by HPLC (as derivative of diethylamine), the mixture was cooled to 10+5 °C and N,N-diisopropylethylamine (378.77 g, 300 mmol) below 25 °C. A solution of (E)-butyl 3-(2-(l-aminocyclobutyl)-l-methyl-lH-benzo[if|imidazol-6-yl)acrylate VI (25.86 g, 97.8 Wt%, 77.25 mmol) dissolved in THF (106.7 g) was added at a rate to maintain the Case No.: 09-0592-PCT

temperature of the content < 25 °C. The mixture was stirred at 25+5 °C for at least 30 min for completion of the amide formation. The mixture was distilled at normal pressure to remove ca. 197 mL (171.5 g) of volatiles (Note: the distillation can also be done under reduced pressure). The batch was adjusted to 40+5 °C, and MeOH (118.6 g) was added. Water (15.0 g) was added and the mixture was stirred at 40+5 °C until crystallization occurred (typically in 30 min), and held for another 1 h. Water (90 g) was charged at 40+5 °C over 1 h, and the batch was cooled to 25+5 °C in 0.5 h, and held for at least 1 h. The solid was filtered, rinsed with a mixture of MeOH (39.5 g), water (100 g), and dried in vacuo (< 200 Torr) at 50+5 °C to give (E)-butyl 3-(2-(l-(2-(5-bromopyrimidin-2-yl)-3- cyclopentyl- 1 -methyl- lH-indole-6-carboxamido)cyclobutyl)- 1 -methyl- 1H- benzo[if|imidazol-6-yl)acrylate VII (51.82 g, 96.6 % yield) with a HPLC purity of 98.0 A% (240 nm) and 99.0 Wt%.

Alternative Process (using compound V from Step 8)

To reactor 1 was charged 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-l-methyl-lH-indole-6- carboxylic acid II (33.6 g), toluene (214 g) and N-methylpyrrolidone (1.37 g). The mixture was heated to 40 °C, then added a solution of thionyl chloride (13 g) in toluene (17 g). The mixture was stirred at 40 °C for at least 0.5 h and cooled to 30 °C. To a second reactor was charged with compound V (the bis-HCl salt toluene solvate from Step 8) (39.4 g), toluene (206 g) and N,N-diisopropylethylamine (70.8 g) at 25 °C. The content of reactor 1 was transferred to reactor 2 at 30 °C and rinsed with toluene (50 g). The mixture was stirred at 30 °C for another 0.5 h, then charged with isopropanol (84 g) and water (108 g) while maintained the temperature at 25 °C. After stirring for 10 min, remove the aqueous phase after phase cutting. To the organic phase was charged isopropanol (43 g), water (54 g) and stirred for 10 min. The aqueous phase was removed after phase cutting. The mixture was distilled under reduced pressure to remove ca.250 mL of volatiles, followed by addition of methyl tert-butyl ether (MTBE, 238 g). The batch was stirred at 65 °C for over 1 hr, then cooled to 20 C over 1 hr and held for another 1 hr at the same temperature. The solid was filtered, rinsed with MTBE (95 g), and dried in vacuo at 80 °C to give (E)-butyl 3-(2-(l-(2- Case No.: 09-0592-PCT

(5-bromopyrimidin-2-yl)-3-cyclopentyl-l-methyl-lH-indole-6-carboxamido)cyclobutyl) methyl- lH-benzo[if|imidazol-6-yl)acrylate VII as a beige solid (50 g, 90 % yield).

Step 10. Synthesis of (E)-3-(2-(l-(2-(5-Bromopyrimidin-2-yl)-3-cyclopentyl-l-methyl- lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[</]imidazol-6-yl)acrylic acid (Compound (1))

 

Figure imgf000035_0001

Notes:

In this process, hydrolysis of (E)-butyl 3-(2-(l-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl- l-methyl-lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[d]imidazol-6- yl)acrylate was carried out in mixture of THF/MeOH and aq NaOH. Controlled acidification of the corresponding sodium salt with acetic acid is very critical to obtain easy-filtering crystalline product in high yield and purity.

Procedure:

To the suspension of (E)-butyl 3-(2-(l-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-l- methyl-lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[(i]imidazol-6- yl)acrylate VII (489.0 g, 91.9 Wt%, 633.3 mmol) in THF (1298 g) and MeOH (387 g) was added 50% NaOH (82.7 g, 949.9 mmol), followed by rinse with water (978 g). The mixture was stirred between 65-68 C for about 1 h for complete hydrolysis. The resulting solution was cooled to 35 C, and filtered through an in-line filter (0.5 micron), and rinsed with a pre-mixed solution of water (978 g) and MeOH (387 g). The solution was heated to Case No.: 09-0592-PCT

60 +4 C, and acetic acid (41.4 g, 689 mmol) was added over 1 h while the mixture was well agitated. The resulting suspension was stirred at 60 ±4 C for 0.5 h. Another portion of acetic acid (41.4 g, 689 mmol) was charged in 0.5 h, and batch was stirred at 60 ±4 C for additional 0.5 h. The batch was cooled to 26 ±4 C over 1 h and held for 1 h. The batch was filtered, rinsed with a premixed solution of water (1956 g) and MeOH (773.6 g), dried at 50 C under vacuum to give (E)-3-(2-(l-(2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-l- methyl-lH-indole-6-carboxamido)cyclobutyl)-l-methyl-lH-benzo[(i]imidazol-6-yl)acrylic acid (1) (419.0 g, 95 % yield) with > 99.0 A% (240 nm) and 94.1 Wt% by HPLC. Step 11. Formation of Compound (1) Sodium Salt (Type A)

 

Figure imgf000036_0001

To a reactor were charged Compound (1) (150 g, mmol), THF (492 mL), H20 (51 mL) and 45% aqueous NaOH solution (20.4 g, mmol). The mixture was stirred for >1 hr at -25 °C to form a clear solution (pH = 9 -11). To the solution was charged a suspension of Charcoal (1.5 g) and H20 (27 mL). The mixture was stirred at -35 °C for >30 min and filtered. The filter was rinsed with THF (108 mL) and H20 (21 mL). The filtrate was heated to 50 °C and charged with methyl ethylketone (MEK) (300 mL). The mixture was seeded with Compound (1) sodium salt MEK solvate (Type A) seeds (0.5 g) and stirred for another 1 hr at 50 °C. To the mixture was charged additional MEK (600 mL). The resultant mixture was stirred for another 1 hr at 50 °C and then cooled to 25 °C. The precipitate was filtered and rinsed with MEK twice (2 x 300 mL). The wet cake was dried in vacuum at 80 °C to give Compound (1) sodium salt (Type A) (145.6 g, 94%). Case No.: 09-0592-PCT

The Compound (1) sodium salt (Type A) MEK solvate seeds used in the above process step can be manufactured by the above process except without using seeds and without drying of the solvate. Notes Re2ardin2 Crystallization Step 11

 

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ASUNAPREVIR

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Dec 242013
 

 

ASUNAPREVIR

630420-16-5 CAS

 

THERAPEUTIC CLAIM Treatment of hepatitis C
CHEMICAL NAMES
1. Cyclopropanecarboxamide, N-[(1,1-dimethylethoxy)carbonyl]-3-methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxy-1-isoquinolinyl)oxy]-L-prolyl-1-amino-N-(cyclopropylsulfonyl)-2-ethenyl-, (1R,2S)-
2. 1,1-dimethylethyl [(1S)-1-{[(2S,4R)-4-(7-chloro-4methoxyisoquinolin-1-yloxy)-2-({(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}carbamoyl)pyrrolidin-1-yl]carbonyl}-2,2-dimethylpropyl]carbamate

MOLECULAR FORMULA C35H46ClN5O9S
MOLECULAR WEIGHT 748.3

SPONSOR Bristol-Myers Squibb
CODE DESIGNATION ………..BMS-650032
CAS REGISTRY NUMBER 630420-16-5

ChemSpider 2D Image | asunaprevir | C35H46ClN5O9S

 

Asunaprevir (formerly BMS-650032) is an experimental drug candidate for the treatment of hepatitis C. It is undergoing development by Bristol-Myers Squibb and is currently inPhase III clinical trials.[1]

In 2013, the company Bristol-Myers Squibb received breakthrough therapy designation in the U.S. for the treatment of chronic hepatitis C in combination with daclatasvir and BMS-791325.

Asunaprevir is an inhibitor of the hepatitis C virus enzyme serine protease NS3.[2]

Asunaprevir is being tested in combination with pegylated interferon and ribavirin, as well as in interferon-free regimens with other direct-acting antiviral agents includingdaclatasvir[3][4][5]

Asunaprevir is an antiviral agent originated by Bristol-Myers Squibb undergoing the registration in Japan for the treatment of chronic hepatitis C virus infection in combination with daclatasvir in patients who are non-responsive to interferon plus ribavirin and interferon based therapy ineligible naive/intolerant

 

  1. “A Phase 3 Study in Combination With BMS-790052 and BMS-650032 in Japanese Hepatitis C Virus (HCV) Patients”. ClinicalTrials.gov.
  2. C. Reviriego (2012). Drugs of the Future 37 (4): 247–254.doi:10.1358/dof.2012.37.4.1789350.
  3.  Preliminary Study of Two Antiviral Agents for Hepatitis C Genotype 1. Lok, A et al. New England Journal of Medicine. 366(3):216-224. January 19, 2012.
  4.  “Bristol-Myers’ Daclatasvir, Asunaprevir Cured 77%: Study”. Bloomberg. Apr 19, 2012.
  5. AASLD: Daclatasvir plus Asunaprevir Rapidly Suppresses HCV in Prior Null Responders. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
  6. Bioorganic and Medicinal Chemistry Letters, 2011 ,  vol. 21,   7  pg. 2048 – 2054

patents

WO 2003099274, WO 2003099274, WO 2009085659

 

6-20-2012
Crystalline forms of N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-((7-chloro-4-methoxy-1-isoquinolinyl)oxy)-N- ((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)-L-prolinamide
4-25-2012
Hepatitis C Virus Inhibitors
3-30-2011
HEPATITIS C VIRUS INHIBITORS
11-12-2008
Hepatitis C virus inhibitors
2-8-2006
Hepatitis C virus inhibitors

……….

Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated 170 million persons worldwide—roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.

Presently, the most effective HCV therapy employs a combination of alpha-interferon and ribavirin, leading to sustained efficacy in 40 percent of patients. Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy. However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Thus, there is a clear and unmet need to develop effective therapeutics for treatment of HCV infection.

Figure US08338606-20121225-C00018
Figure US08338606-20121225-C00019
http://www.google.com/patents/US8338606

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https://www.google.co.in/patents/WO2003099274A1?dq=WO+2003099274&ei=fje5Us3WBo3JrQfcsoHgAw&cl=en

Compound 277

Compound 277 was prepared by following Scheme 2 of Example 269 except that 3- (4-chloro-phenyl)-3-methoxy-acrylic acid was used in place of 2- trifluormethoxycinnamic acid in step 1.

Step 1:

Modifications: 4.24 g 3-(4-chloro-phenyl)-3-methoxy-acrylic acid used, 130 mg product obtained (3% yield) Product:

Figure imgf000383_0002

Data: 1H NMR(400 MHz, CD3OD) δ ppm 3.96 (s, 3 H), 7.19 (dd, 7=8.80, 2.45 Hz, 1 H), 7.28 (d, 7=2.45 Hz, 1 H), 7.34 (s, 1 H), 8.25 (d, 7=9.05 Hz, 1 H); MS: (M+H)+ 210.

Step 2:

Modifications: 105 mg 7-chloro-4-methoxy-2H-isoquinolin-l-one used, 60 mg product obtained (71% yield). Product:

Figure imgf000384_0001

Data: Η NMR (400 Hz, CDC13) δ ppm 4.05 (s, 3 H), 7.67 (dd, 7=8.80, 1.96 Hz, 1 H), 7.80 (s, 1 H), 8.16 (d, 7=9.05 Hz, 1 H), 8.24 (d, 7=1.96 Hz, 1 H); MS: (M+H)+ 229.

Step 3:

Modifications: 46 mg l,7-dichloro-4-methoxy-isoquinoline and 113 mg { l-[2-(l- cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy- pyrrolidine-1 -carbon yl]-2,2-dimethyl-propyl} -carbamic acid tert-butyl ester used, 50 mg product obtained (31% yield). Product:

Figure imgf000384_0002

Compound 277

Data: 1H NMR (400 Hz, CD3OD) δ ppm 1.06 (m, 11 H), 1.16 (s, 9 H), 1.24 (m, 2 H), 1.44 (dd, 7=9.54, 5.38 Hz, 1 H), 1.88 (dd, 7=8.07, 5.62 Hz, 1 H), 2.28 (m, 2 H), 2.59 (dd, 7=13.69, 6.85 Hz, 1 H), 2.94 (m, 1 H), 4.00 (s, 3 H), 4.05 (d, 7=11.74 Hz, 1 H), 4.19 (s, 1 H), 4.43 (d, 7=11.49 Hz, 1 H), 4.56 (dd, 7=10.03, 6.85 Hz, 1 H), 5.12 (d, 7=11.49 Hz, 1 H), 5.30 (d, 7=17.12 Hz, 1 H), 5.76 (m, 2 H), 7.57 (s, 1 H), 7.67 (d, 7=8.56 Hz, 1 H), 8.04 (s, 1 H), 8.08 (d, 7=8.80 Hz, 1 H); MS: (M+H)+ 749.

 

 

 

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https://www.google.co.in/patents/US6995174?dq=WO+2003099274&ei=1DW5Uoa0C4GTrgfy84HgBQ&cl=en

Figure US06995174-20060207-C00021

 

 

Figure US06995174-20060207-C00022

 

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WO 2003099274

Figure US06995174-20060207-C00038

 

https://www.google.co.in/patents/US6995174?dq=WO+2003099274&ei=fje5Us3WBo3JrQfcsoHgAw&cl=en

…………………….

 

https://www.google.co.in/patents/US20090202476?dq=WO+2009085659&ei=dzy5UpL_LMXXrQewxYG4Dw&cl=en

 

Figure US20090202476A1-20090813-C00018

 

Figure US20090202476A1-20090813-C00019

 

Preparation of Compound C

DMSO (264 ml) was added to a mixture of Compound A (6 g, 26.31 mmol, 1.0 eq, 96.5% potency), Compound B (6.696 g, 28.96 mmol, 1.1 eq) and KOtBu (8.856 g, 78.92 mmol, 3 eq) under nitrogen and stirred at 36° C. for 1 h. After cooling the dark solution to 16° C., it was treated with water (66 ml) and EtOAc (132 ml). The resulting biphasic mixture was acidified to pH 4.82 with 1N HCl (54 ml) at 11.2-14.6° C. The phases were separated. The aqueous phase was extracted once with EtOAc (132 ml). The organic phases were combined and washed with 25% brine (2×132 ml). Rich organic phase (228 ml) was distilled at 30-40° C./50 mbar to 37.2 ml. A fresh EtOAc (37.2 ml) was added and distilled out to 37.2 ml at 30-35° C./50 nm bar. After heating the final EtOAc solution (37.2 ml) to 50° C., heptane ((37.2 ml) was added at 46-51° C. and cooled to 22.5° C. over 2 h. It was seeded with 49 mg of Compound C and held at 23° C. for 15 min to develop a thin slurry. It was cooled to 0.5° C. in 30 min and kept at 0.2-0.5° C. for 3 h. After the filtration, the cake was washed with heptane (16.7 ml) and dried at 47° C./80 mm/15.5 h to give Compound C as beige colored solids (6.3717 g, 58.9% corrected yield, 99.2% potency, 97.4 AP).

Preparation of Compound E

DIPEA (2.15 ml, 12.3 mmol, 1.3 eq followed by EDAC (2 g, 10.4 mmol, 1.1 eq) were added to a mixture of Compound C (4 g, 9.46 mmol, 97.4% potency, 98.5 AP), Compound D (4.568 g, 11.35 mmol, 1.20 eq), HOBT-H2O (0.86 g, 4.18 mmol, 0.44 eq) in CH2Cl2 (40 ml) at 23-25° C. under nitrogen. The reaction was complete after 3 h at 23-25° C. It was then washed with 1N HCl (12 ml), water (12 ml) and 25% brine (12 ml). MeOH (80 ml) was added to the rich organic solution at 25° C., which was distilled at atmospheric pressure to ˜60 ml to initiate the crystallization of the product. The crystal slurry was then cooled from 64° C. to 60° C. in 5 min and stirred at 60° C. for 1 h. It was further cooled to 24° C. over 1.5 h and held at 24° C. for 2 h. After the filtration, the cake was washed with MeOH (12 ml) and dried at 51° C./20-40 nm i/18 h to give Compound E (5.33 g, 89% yield, 97.7% potency, 99.1 AP).

Preparation of Compound F

5-6N HCl in IPA (10.08 ml, 50.5 mmol, Normality: 5N) was added in four portions in 1 h to a solution of Compound E (8 g, 12.6 mmol, 97.7% potency, 99.1 AP) in IPA (120 ml) at 75° C. After stirring for 1 h at 75° C., the resulting slurry was cooled to 21° C. in 2 h and stirred at 21° C. for 2 h. It was filtered and the cake was washed with IPA (2×24 ml). The wet cake was dried at 45° C./House vacuum/16 h to give Compound F as an off-white solid (6.03 g, 84.5% yield, 98.5% potency, 100 AP).

Preparation of Compound (I)

DIPEA (9.824 ml) followed by HATU (7.99 g) were added to a stirred mixture of Compound F (10 g, 99.2% potency, 99.6 AP) and Compound G (4.41 g) in CH2Cl2 (100 ml) at 2.7-5° C. under nitrogen. The resulting light brown solution was stirred at 0.2-3° C. for 1.5 h, at 3-20° C. in 0.5 h and at 20-23° C. for 15.5 h for a reaction completion. It was quenched with 2N HCl (50 ml) at 23° C. and stirred for 20 min at 23-24° C. The biphasic mixture was polish filtered through diatomaceous earth (Celite®) (10 g) to remove insoluble solids of HOAT and HATU. The filter cake was washed with 20 ml of CH2Cl2. After separating the organic phase from the filtrates, it was washed with 2N HCl (5×50 ml) and water (2×50 ml). The organic phase (115 ml) was concentrated to ˜50 ml, which was diluted with absolute EtOH (200 proof, 100 ml) and concentrated again to ˜50 ml. Absolute EtOH (50 ml) was added to bring the final volume to 100 ml. It was then warmed to 50° C. to form a clear solution and held at 50° C. for 35 min. The ethanolic solution was cooled from 50 to 23° C. over 15 min to form the crystal slurry. The slurry was stirred at 23 CC for 18 h, cooled to 0.3° C. over 30 min and kept at 0.2-0.3° C. for 2 h. After the filtration, the cake was washed with cold EtOH (2.7° C., 2×6 ml) and dried at 53° C./72 mm/67 h to give Compound (I) in Form T1F-1/2 as an off white solid (10.49 g, 80.7% yield, 99.6 AP).https://www.google.co.in/patents/US20090202476?dq=WO+2009085659&ei=dzy5UpL_LMXXrQewxYG4Dw&cl=en

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extra info

Hepatitis C virus (HCV) infection is the principal cause of chronic liver disease that can lead to cirrhosis, carcinoma and liver failure.1 More than 200 million people worldwide are chronically infected by this virus. Currently, the most effective treatment for HCV infection is based on a combination therapy of injectable pegylated interferon-α (PEG IFN-α) and antiviral drug ribavirin. This treatment, indirectly targeting the virus, is associated with significant side effects often leading to treatment discontinuation in certain patient populations.2 In addition, this treatment regimen cures only less than 50% of patients infected with genotype-1 which is the predominant genotype (while genotype 1a is most abundant in the US, the majority of sequences in Europe and Japan are from genotype 1b).3 Limited efficacy and adverse side effects of current treatment, and high prevalence of infection worldwide highlight an urgent need for more effective, convenient, and well-tolerated treatments.4

HCV NS3 serine protease plays a critical role in the HCV replication by cleaving downstream sites (with the assistance of the cofactor NS4A) along the HCV viral polyprotein to produce functional proteins. Recently, NS3/4A protease inhibitors have emerged as a promising treatment for HCV infection.5 There are two distinct classes of NS3 protease inhibitors in clinical development. The first class is comprised of serine-trap inhibitors, exemplified by VX-950 (telaprevir)6 and SCH-503034 (boceprevir).7 The second class is represented by reversible noncovalent inhibitors such as macrocyclic inhibitors BILN-2061 (ciluprevir),8 ITMN-191 (danoprevir),9 TMC-43535010 and MK-7009 (vaniprevir).11 Due to concern over cardiac issues in animals treated with macrocyclic BILN-2061,12 newer acyclic inhibitors have recently been developed exemplified by BI-20133513 and BMS-650032.14 However, a rapid development of viral resistance has been observed for patients treated with HCV NS3 protease inhibitors.15 Therefore, the discovery of new NS3 protease inhibitors with novel binding paradigm and thus potentially differentiated resistance profile is highly desirable.

References and notes

    • F. Zoulim, M. Chevallier, M. Maynard, C. Trepo
    • Rev. Med. Virol., 13 (2003), p. 57
    • M.W. Fried
    • Hepatology, 36 (2002), p. S237
    • B.L. Pearlman
    • Am. J. Med., 117 (2004), p. 344
    • (a) R. Flisiak, A. Parfieniuk
    • For a recent review on HCV anti-viral agents, see: Expert Opin. Invest. Drugs, 19 (2010), p. 63
    • (b) A.D. Kwong, L. McNair, I. Jacobson, S. George
    • Curr. Opin. Pharmacol., 8 (2008), p. 522
    • (a) K.X. Chen, F.G. Njoroge
    • For a recent review on HCV NS3/4A protease inhibitors, see: Curr. Opin. Invest. Drugs, 10 (2009), p. 821
    • (b) M. Reiser, J. Timm
    • Expert Rev. Anti. Infect. Ther., 7 (2009), p. 537
    • C. Lin, A.D. Kwong, R.B. Perni
    • Infect. Disord. Drug Targets, 6 (2006), p. 3
    • F.G. Njoroge, K.X. Chen, N.Y. Shih, J.J. Piwinski
    • Acc. Chem. Res., 41 (2008), p. 50
    • M. Llinàs-Brunet, M.D. Bailey, G. Bolger, C. Brochu, A.M. Faucher, J.M. Ferland, M. Garneau, E. Ghiro, V. Gorys, C. Grand-Maître, T. Halmos, N. Lapeyre-Paquette, F. Liard, M. Poirier, M. Rhéaume, Y.S. Tsantrizos, D. Lamarre
    • J. Med. Chem., 47 (2004), p. 1605
    • S.D. Seiwert, S.W. Andrews, Y. Jiang, V. Serebryany, H. Tan, K. Kossen, P.T. Rajagopalan, S. Misialek, S.K. Stevens, A. Stoycheva, J. Hong, S.R. Lim, X. Qin, R. Rieger, K.R. Condroski, H. Zhang, M.G. Do, C. Lemieux, G.P. Hingorani, D.P. Hartley, J.A. Josey, L. Pan, L. Beigelman, L.M. Blatt
    • Antimicrob. Agents Chemother., 52 (2008), p. 4432
    • P. Raboisson, H. de Kock, A. Rosenquist, M. Nilsson, L. Salvador-Oden, T.I. Lin, N. Roue, V. Ivanov, H. Wähling, K. Wickström, E. Hamelink, M. Edlund, L. Vrang, S. Vendeville, W. Van de Vreken, D. McGowan, A. Tahri, L. Hu, C. Boutton, O. Lenz, F. Delouvroy, G. Pille, D. Surleraux, P. Wigerinck, B. Samuelsson, K. Simmen
    • Bioorg. Med. Chem. Lett., 18 (2008), p. 4853
    • J.A. McCauley, C.J. McIntyre, M.T. Rudd, K.T. Nguyen, J.J. Romano, J.W. Butcher, K.F. Gilbert, K.J. Bush, M.K. Holloway, J. Swestock, B.L. Wan, S.S. Carroll, J.M. Dimuzio, D.J. Graham, S.W. Ludmerer, S.S. Mao, M.W. Stahlhut, C.M. Fandozzi, N. Trainor, D.B. Olsen, J.P. Vacca, N.J. Liverton
    • J. Med. Chem., 53 (2010), p. 2443
    • H. Hinrichsen, Y. Benhamou, H. Wedemeyer, M. Reiser, R.E. Sentjens, J.L. Calleja, X. Forns, A. Erhardt, J. Crönlein, R.L. Chaves, C.L. Yong, G. Nehmiz, G.G. Steinmann
    • Gastroenterology, 127 (2004), p. 1347
    • M. Llinàs-Brunet, M.D. Bailey, N. Goudreau, P.K. Bhardwaj, J. Bordeleau, M. Bös, Y. Bousquet, M.G. Cordingley, J. Duan, P. Forgione, M. Garneau, E. Ghiro, V. Gorys, S. Goulet, T. Halmos, S.H. Kawai, J. Naud, M.A. Poupart, P.W. White
    • J. Med. Chem., 53 (2010), p. 6466
    • (a)Chemical and Engineering News (April 12, 2010 issue), 88, pp 30–33.
    • (b)Perrone, R.K.; Wang, C.; Ying, W.; Song, A.I. WO 2009085659
    • L. Rong, H. Dahari, R.M. Ribeiro, A.S. Perelson
    • Sci. Transl. Med., 2 (2010), p. 30ra32

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