AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Feb 072018
 

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AMISELIMOD

UNII-358M5150LY; CAS 942399-20-4; 358M5150LY; MT-1303; Amiselimod, MT-1303

Molecular Formula: C19H30F3NO3
Molecular Weight: 377.448 g/mol

 

2-amino-2-[2-[4-heptoxy-3-(trifluoromethyl)phenyl]ethyl]propane-1,3-diol

Phase II Crohn’s disease; Multiple sclerosis; Plaque psoriasis

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AMISELIMOD HYDROCHLORIDE

  • Molecular FormulaC19H31ClF3NO3
  • Average mass413.902 Da
1,3-Propanediol, 2-amino-2-[2-[4-(heptyloxy)-3-(trifluoromethyl)phenyl]ethyl]-, hydrochloride (1:1)
2-Amino-2-{2-[4-(heptyloxy)-3-(trifluoromethyl)phenyl]ethyl}-1,3-propanediol hydrochloride (1:1)
942398-84-7 [RN]
MT-1303
UNII-AY898D6RU1
2-amino-2-[2-[4-(heptyloxy)-3-(trifluoromethyl)phenyl]ethyl]-1,3-propanediol, monohydrochloride
  • Originator Mitsubishi Tanabe Pharma Corporation
  • Class Propylene glycols; Small molecules
  • Mechanism of Action Immunosuppressants; Sphingosine-1-phosphate receptor antagonist

Highest Development Phases

  • Phase II Crohn’s disease; Multiple sclerosis; Plaque psoriasis
  • Phase I Autoimmune disorders; Inflammation; Systemic lupus erythematosus
  • No development reported Inflammatory bowel diseases

Most Recent Events

  • 04 Nov 2017 No recent reports of development identified for phase-I development in Autoimmune-disorders in Japan (PO, Capsule)
  • 04 Nov 2017 No recent reports of development identified for phase-I development in Autoimmune-disorders in USA (PO, Capsule)
  • 04 Nov 2017 No recent reports of development identified for phase-I development in Inflammation in Japan (PO, Capsule)
  • Image result

Amiselimod, also known as MT1303, is a potent and selective immunosuppressant and sphingosine 1 phosphate receptor modulator. Amiselimod may be potentially useful for treatment of multiple sclerosis; inflammatory diseases; autoimmune diseases; psoriasis and inflammatory bowel diseases. Amiselimod is currently being developed by Mitsubishi Tanabe Pharma Corporation

Mitsubishi Tanabe is developing amiselimod, an oral sphingosine-1-phosphate (S1P) receptor antagonist, for treating autoimmune diseases, primarily multiple sclerosis, psoriasis and inflammatory bowel diseases, including Crohn’s disease.

WO2007069712

EU states expire 2026, and

Expire in the US in June 2030 with US154 extension.

Inventors Masatoshi KiuchiKaoru MarukawaNobutaka KobayashiKunio Sugahara
Applicant Mitsubishi Tanabe Pharma Corporation

In recent years, calcineurin inhibitors such as cyclosporine FK 506 have been used to suppress rejection of patients receiving organ transplantation. While doing it, certain calcineurin inhibitors like cyclosporin can cause harmful side effects such as nephrotoxicity, hepatotoxicity, neurotoxicity, etc. For this reason, in order to suppress rejection reaction in transplant patients, development of drugs with higher safety and higher effectiveness is advanced.

[0003] Patent Documents 1 to 3 are useful as inhibitors of (acute or chronic) rejection in organ or bone marrow transplantation and also useful as therapeutic agents for various autoimmune diseases such as psoriasis and Behcet’s disease and rheumatic diseases 2 aminopropane 1, 3 dioly intermediates are disclosed.

[0004] One of these compounds, 2-amino-2- [2- (4-octylphenel) propane] 1, 3 diol hydrochloride (hereinafter sometimes referred to as FTY 720) is useful for renal transplantation It is currently under clinical development as an inhibitor of rejection reaction. FTY 720 is phosphorylated by sphingosine kinase in vivo in the form of phosphorylated FTY 720 [hereinafter sometimes referred to as FTY 720-P]. For example, 2 amino-2-phosphoryloxymethyl 4- (4-octafil-el) butanol. FTY720 – P has four types of S1 P receptors (hereinafter referred to as S1 P receptors) among five kinds of sphingosine – 1 – phosphate (hereinafter sometimes referred to as S1P) receptors It acts as an aggroove on the body (other than S1P2) (Non-Patent Document 1).

[0005] It has recently been reported that S1P1 among the S1P receptors is essential for the export of mature lymphocytes with thymus and secondary lymphoid tissue forces. FTY720 – P downregulates S1P1 on lymphocytes by acting as S1P1 ghost. As a result, the transfer of mature lymphocytes from the thymus and secondary lymphatic tissues is inhibited, and the circulating adult lymphocytes in the blood are isolated in the secondary lymphatic tissue to exert an immunosuppressive effect Has been suggested (

Non-Patent Document 2).

[0006] On the other hand, conventional 2-aminopropane 1, 3 dioly compounds are concerned as transient bradycardia expression as a side effect, and in order to solve this problem, 2-aminopropane 1, 3 diiori Many new compounds have been reported by geometrically modifying compounds. Among them, as a compound having a substituent on the benzene ring possessed by FTY 720, Patent Document 4 discloses an aminopropenol derivative as a S1P receptor modulator with a phosphate group, Patent Documents 5 and 6 are both S1P Discloses an amino-propanol derivative as a receptor modulator. However, trihaloalkyl groups such as trifluoromethyl groups are not disclosed as substituents on the benzene ring among them. In any case, it is currently the case that it has not yet reached a satisfactory level of safety as a pharmaceutical.

Patent Document 1: International Publication Pamphlet WO 94 Z 08943

Patent Document 2: International Publication Pamphlet WO 96 Z 06068

Patent Document 3: International Publication Pamphlet W 0 98 z 45 429

Patent Document 4: International Publication Pamphlet WO 02 Z 076995

Patent document 5: International public non-fret WO 2004 Z 096752

Patent Document 6: International Publication Pamphlet WO 2004 Z 110979

Non-patent document 1: Science, 2002, 296, 346-349

Non-patent document 2: Nature, 2004, 427, 355-360

Reference Example 3

5 bromo 2 heptyloxybenzonitrile

(3- 1) 5 Synthesis of bromo-2 heptyloxybenzonitrile (Reference Example Compound 3- 1)

1-Heptanol (1.55 g) was dissolved in N, N dimethylformamide (24 ml) and sodium hydride (0.321 g) was added at room temperature. After stirring for 1 hour, 5 bromo-2 fluoborosyl-tolyl (2.43 g) was added and the mixture was further stirred for 50 minutes. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After eliminating the 5 bromo 2 fluconate benzonitrile as a raw material, the reaction was carried out again under the same conditions and purification was carried out by silica gel column chromatography (hexane: ethyl acetate = 50: 1 to 5: 1) to obtain the desired product (3.10 g ) As a colorless oil.

– NMR (CDCl 3) δ (ppm): 0.89 (3H, t, J = 6.4 Hz), 1.24-1.35 (6H, m

J = 8.8 Hz), 1.48 (2H, quint, J = 7.2 Hz), 1.84 7.59 (1 H, dd, J = 8.8, 2.4 Hz), 7.65 (1 H, d, J = 2.4 Hz).

Example 1

2 Amino 2- [2- (4-heptyloxy-3 trifluoromethylph enyl) propane-1, 3-diol hydrochloride

(1 – 1) {2, 2 Dimethyl 5- [2- (4 hydroxy 3 trifluoromethylfuethyl) ethyl] 1,3 dioxane 5 mercaptothenylboronic acid t butyl ester (synthesis compound 1 1)

Reference Example Compound 2-5 (70.3 g) was dissolved in tetrahydrofuran (500 ml), t-butoxycallium (13.Og) was added, and the mixture was stirred for 1 hour. To the mixed solution was dropwise added a solution of the compound of Reference Example 1 (15.Og) in tetrahydrofuran (100 ml) under ice cooling, followed by stirring for 2 hours under ice cooling. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, washed with water, saturated brine, dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: D to obtain 31. Og of a pale yellow oily matter.) The geometric isomer ratio of the obtained product was (E : Z = 1: 6).

This pale yellow oil was dissolved in ethyl acetate (200 ml), 10% palladium carbon (3.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 7 hours. After purging the inside of the reaction vessel with nitrogen, the solution was filtered and the filtrate was concentrated. The residue was washed with diisopropyl ether to obtain the desired product (2.2 g) as a colorless powder.

1 H-NMR (CDCl 3) δ (ppm): 1. 43 (3H, s), 1.44 (3H, s), 1. 47 (9H, s), 1

(2H, m), 91- 1. 98 (2H, m), 2. 50-2.66 (2H, m), 3. 69 (2H, d, J = Il. 6 Hz), 3. 89 J = 8.2 Hz), 7. 22 (1 H, dd J = 8 Hz), 5. 02 (1 H, brs), 5. 52 . 2, 1. 7 Hz), 7. 29 (1 H, d, J = l. 7 Hz).

(1-2) {2,2 Dimethyl-5- [2- (4heptyloxy-3 trifluoromethyl) ethyl] 1,3 dioxane 5-mercaptobutyric acid t-butyl ester Synthesis (compound 1 2)

Compound 1-1 (510 mg) was dissolved in N, N dimethylformamide (10 ml), potassium carbonate (506 mg) and n-heptyl bromide (0.235 ml) were added and stirred at 80 ° C. for 2 hours. Water was added to the reaction solution, the mixture was extracted with ethyl acetate, washed with water and saturated brine, dried with anhydrous sulfuric acid

The resultant was dried with GENSCHUM and the solvent was distilled off under reduced pressure to obtain the desired product (640 mg) as a colorless oil.

– NMR (CDCl 3) δ (ppm): 0.89 (3H, t, J = 6.8 Hz), l.30-1.37 (6H, m

(2H, m), 1.91-1.98 (2H, m), 1.42-1.50 (2H, m), 1.42 (3H, s), 1.44 (3H, s), 1.47 J = 16.6 Hz), 4.00 (2H, t, J = 6.4 Hz), 4.9 8 (2H, d, J = 11.6 Hz), 3.69 1 H, brs), 6.88 (1 H, d, J = 8.5 Hz), 7.26 – 7.29 (1 H, m), 7.35 (1 H, d, J = 1.5 Hz).

(1-3) Synthesis of 2-amino-2- [2- (4heptyloxy 3 trifluoromethyl) ethyl] propane 1, 3 diol hydrochloride (Compound 1- 3)

Compound 12 (640 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (3 ml) was caught and stirred at 80 ° C. for 2 hours. The reaction solution was concentrated, and the residue was washed with ethyl ether to give the desired product (492 mg) as a white powder.

MS (ESI) m / z: 378 [M + H]

– NMR (DMSO-d) δ (ppm): 0.86 (3H,

6 t, J = 6.8 Hz), 1.24 – 1.39 (6

(4H, m), 3.51 (4H, d, J = 5. lHz), 4.06 (2H, m), 1.39-1.46 (2H, m), 1.68-1.78 (4H, m), 2.55-2.22 , 7.32 (2H, t, J = 5.1 Hz), 7.18 (1 H, d, J = 8.4 Hz), 7.42 – 7.45 (2 H, m), 7.76 (3 H, brs;).

PATENT

WO 2009119858

JP 2011136905

WO 2017188357

PATENT

WO-2018021517

Patent Document 1 discloses 2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane- 1,3 which is useful as a medicine excellent in immunosuppressive action, rejection- – diol hydrochloride is disclosed.
The production method includes the step of reducing 4-heptyloxy-3-trifluoromethylbenzoic acid (Ia) to 4-heptyloxy-3-trifluoromethylbenzyl alcohol (IIa). However, until now, there has been a problem such that the conversion is low and the by-product (IIa ‘) in which the trifluoromethyl group is reduced together with the compound (IIa) is generated in this step.

 

[Chemical formula 1]

 

 In particular, since a series of analogous substances derived from by-products (IIa ‘) are difficult to be removed in a later process, it is necessary to suppress strict production thereof in the manufacture of drug substances requiring high quality there were.

Patent Document 1: WO2007 / 069712

[Chemical formula 3]

(2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane- 1,3-diol hydrochloride) From
the compound (IIa), the following scheme Based on the route, 2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride was prepared.

 

[Chemical Formula 9]

STR1

 

Example 2
Synthesis of 4-heptyloxy-3-trifluoromethylbenzyl chloride (Step A) A
few drops of N, N-dimethylformamide was added to a solution of compound (IIa) (26.8 g) in methylene chloride (107 mL), and 0 At 0 ° C., thionyl chloride (8.09 mL) was added dropwise. The mixture was stirred at the same temperature for 2 hours, and water (50 mL) was added to the reaction solution. The organic layer was separated and extracted, washed with water (50 mL), saturated aqueous sodium bicarbonate solution (70 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 4-heptyloxy-3-trifluoromethylbenzyl Chloride (28.3 g) as white crystals.
1H-NMR (CDCl 3) δ (ppm): 0.89 (3H, t, J = 6.5 Hz), 1.26-1.54 (8H, m), 1.77-1.86 (2H, m , 4.49 (2H, t, J = 6.4 Hz), 4.56 (2H, s), 6.96 (IH, d, J = 8.6 Hz), 7.49 (IH, dd, J = 2.0 Hz, 8.5 Hz), 7.58 (1 H, d, J = 1.9 Hz)

 

Example 3
Synthesis of dimethyl (4-heptyloxy-3-trifluoromethylbenzyl) phosphonate (Step B) To
a solution of N, N (3-trifluoromethylbenzyl ) phosphonate of 4-heptyloxy-3-trifluoromethylbenzyl chloride (6.00 g, 19.4 mmol) (2.57 g, 23.3 mmol), cesium carbonate (7.60 g, 23.3 mmol) and tetrabutylammonium iodide (7.54 g, 20.4 mmol) were added to a dimethylformamide (36 mL) And the mixture was stirred at 25 ° C. for 1 day. Toluene (36 mL) and water (18 mL) were added for phase separation, and the resulting organic layer was washed twice with a mixture of N, N-dimethylformamide (18 mL) and water (18 mL). After concentration under reduced pressure, column purification using hexane and ethyl acetate gave 4.71 g of dimethyl (4-heptyloxy-3-trifluoromethylbenzyl) phosphonate.
1
H-NMR (CDCl 3) δ (ppm): 0.89 (3 H, t, J = 6.9 Hz), 1.20 – 1.41 (6 H, m) , 1.43-1.49 (2H, m), 1.72-1.83 (2H, m), 3.09 (IH, s), 3.14 (IH, s), 3.68 (3H , 7.41 – 7.44 (2 H, t, J = 6.4 Hz), 6.94 (1 H, d, J = 8.4 Hz), 3.70 (3 H, s), 4.02 (2H, m)

 

Example 4
tert-Butyl (E) – {2,2-dimethyl-5- [2- (4-heptyloxy-3-trifluoromethylphenyl) vinyl] -1, 3-dioxan-5- yl} carbamate Ester synthesis (Step C) A
solution of dimethyl (1.18 g, 3.09 mmol ) (4-heptyloxy-3-trifluoromethylbenzyl) phosphonate in 1.25 mL of N, N- dimethylformamide and (2, -dimethyl-5-formyl-1,3-dioxan-5-yl) carbamic acid tert-butyl ester (961 mg, 3.71 mmol) in tetrahydrofuran (4 mL) was treated with potassium tert-butoxide (1.28 g, 4 mmol) in tetrahydrofuran (7 mL), and the mixture was stirred at 0 ° C. for 6 hours. Heptane (7 mL) and water (3 mL) were added and the layers were separated, and the obtained organic layer was washed twice with water (3 mL) and concentrated. Heptane was added and the mixture was cooled in an ice bath. The precipitated crystals were collected by filtration and dried under reduced pressure to give (E) – {2,2-dimethyl-5- [2- (4-heptyloxy- Phenyl) vinyl] -1, 3-dioxan-5-yl} carbamic acid tert-butyl ester.
1
H-NMR (CDCl 3) δ (ppm): 0.89 (3 H, t, J = 6.9 Hz), 1.29 – 1.38 (6 H, m) , 1.44 – 1.59 (17 H, m), 1.77 – 1.83 (2 H, m), 3.83 – 3.93 (2 H, m), 3.93 – 4.08 (4 H, J = 16.5 Hz), 6.48 (1 H, d, J = 16.5 Hz), 6.91 (1 H, d, J), 5.21 (1 H, brs), 6.10 J = 8.5 Hz), 7.44 (1 H, dd, J = 8.6, 2.1 Hz), 7.55 (1 H, d, J = 2.0 Hz)

 

Example 5
Synthesis of 2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride (Step D)
(E) – {2, -dimethyl-5- [2- (4-heptyloxy-3-trifluoromethylphenyl) vinyl] -1,3-dioxan- 5-yl} carbamic acid tert-butyl ester (6.50 g, 12.6 mmol) Methanol (65 mL) solution was heated to 50 ° C., a solution of concentrated hydrochloric acid (2.55 g) in methanol (5.3 mL) was added dropwise, and the mixture was stirred at 60 ° C. for 6 hours. The mixture was cooled to around room temperature, 5% palladium carbon (0.33 g) was added thereto, and the mixture was stirred under a hydrogen gas atmosphere for 3 hours. After filtration and washing the residue with methanol (39 mL), the filtrate was concentrated and stirred at 5 ° C. for 1 hour. Water (32.5 mL) was added and the mixture was stirred at 5 ° C for 1 hour, and the precipitated crystals were collected by filtration. Washed with water (13 mL) and dried under reduced pressure to obtain 4.83 g of 2-amino-2- [2- (4-heptyloxy-3-trifluoromethylphenyl) ethyl] propane-1,3-diol hydrochloride .
MS (ESI) m / z: 378 [M + H]

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PATENTS

Patent ID

Patent Title

Submitted Date

Granted Date

US2017029378 KINASE INHIBITOR
2016-10-12
US2014296183 AMINE COMPOUND AND USE THEREOF FOR MEDICAL PURPOSES
2014-06-17
2014-10-02
Patent ID

Patent Title

Submitted Date

Granted Date

US2017253563 KINASE INHIBITORS
2017-05-24
US9499486 Kinase inhibitor
2015-10-01
2016-11-22
US9751837 KINASE INHIBITORS
2015-10-01
2016-04-14
US8809304 Amine Compound and Use Thereof for Medical Purposes
2009-05-28
US2017209445 KINASE INHIBITORS
2015-10-01

////////////AMISELIMOD, Phase II, Crohn’s disease, Multiple sclerosis, Plaque psoriasis,  MT-1303,  MT1303,  MT 1303, Mitsubishi Tanabe Pharma Corporation, Mitsubishi , JAPAN, PHASE 2

CCCCCCCOC1=C(C=C(C=C1)CCC(CO)(CO)N)C(F)(F)F

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Ombitasvir オムビタスビル水和物 For Hepatitis C (HCV)

 cancer, phase 2, Uncategorized  Comments Off on Ombitasvir オムビタスビル水和物 For Hepatitis C (HCV)
Jul 012016
 

 

STR1

Ombitasvir Hydrate, 1456607-70-7

Ombitasvir.svg

Ombitasvir 1258226-87-7

Ombitasvir; ABT-267; ABT 267; UNII-2302768XJ8; 1258226-87-7;

C50H67N7O8
Molecular Weight: 894.10908 g/mol

Anti-Viral Compounds [US2010317568]

Methyl ((R)-1-((S)-2-((4-((2S,5S)-1-(4-(tert-butyl)phenyl)-5-(4-((R)-1-((methoxycarbonyl)-L-valyl)pyrrolidine-2-carboxamido)phenyl)pyrrolidin-2-yl)phenyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate,

Dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate, 

methyl N-[(2S)-1-[(2S)-2-[[4-[(2S,5S)-1-(4-tert-butylphenyl)-5-[4-[[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]phenyl]pyrrolidin-2-yl]phenyl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

オムビタスビル水和物
Ombitasvir Hydrate

C50H67N7O8.4 1/2H2O : 975.18
[1456607-70-7]

 

Abbvie Inc.  innovator

Phase II clinical development at AbbVie (previously Abbott) for the treatment of chronic hepatitis C infection in combination with ABT-450/ritonavir and, in combination with peginterferon alpha-2a/ribavirin (pegIFN/RBV) in treatment naïve Hepatitis C virus (HCV) genotype 1 infected patients.

Ombitasvir is Dimethyl ([(2S,5S)-1-(4-tert-butylphenyl) pyrrolidine-2,5diyl]bis{benzene-4,1-diylcarbamoyl(2S)pyrrolidine-2,1-diyl[(2S)-3-methyl-1-oxobutane-1,2diyl]})biscarbamate hydrate. The molecular formula is C50H67N7O8•4.5H2O (hydrate) and the molecular weight for the drug substance is 975.20 (hydrate).

Ombitasvir is in phase II clinical development at AbbVie (previously Abbott) for the treatment of chronic hepatitis C infection in combination with ABT-450/ritonavir and, in combination with peginterferon alpha-2a/ribavirin (pegIFN/RBV) in treatment naïve Hepatitis C virus (HCV) genotype 1 infected patients.

Ombitasvir is part of a fixed-dose formulation with ABT-450/ritonavir that is approved in the U.S. and the E.U.

In January 2013, Abbott spun-off its research-based pharmaceutical business into a newly-formed company AbbVie. In 2013, breakthrough therapy designation was assigned in the U.S. for the treatment of genotype 1 hepatitis C in combination with ABT-450, ritonavir and ABT-333, with and without ribavirin.

Ombitasvir (Viekira PakTM) (Technivie)

Ombitasvir is an antiviral drug for the treatment of hepatitis C virus (HCV) infection. In the United States, it is approved by theFood and Drug Administration for use in combination with paritaprevir, ritonavir and dasabuvir in the product Viekira Pak for the treatment of HCV genotype 1,[1][2] and with paritaprevir and ritonavir in the product Technivie for the treatment of HCV genotype 4.[3][4]

Ombitasvir acts by inhibiting the HCV protein NS5A.[5]

Ombitasvir is an orally available inhibitor of the hepatitis C virus (HCV) non-structural protein 5A (NS5A) replication complex, with potential activity against HCV. Upon oral administration and after intracellular uptake, ombitasvir binds to and blocks the activity of the NS5A protein. This results in the disruption of the viral RNA replication complex, blockage of HCV RNA production, and inhibition of viral replication. NS5A, a zinc-binding and proline-rich hydrophilic phosphoprotein, plays a crucial role in HCV RNA replication. HCV is a small, enveloped, single-stranded RNA virus belonging to the Flaviviridae family; HCV infection is associated with the development of hepatocellular carcinoma (HCC).

Ombitasvir.png
Ombitasvir hydrate is a NS5A non-nucleoside polymerase inhibitor which is approved as part of a four drug combination for the
treatment of adults with genotype 1 hepatitis C virus infection including those with compensated cirrhosis.REF 6,7

The four drug combination treatment consists of ombitasvir, paritaprevir (XXVII), ritonavir, and dasabuvir (X). This combination treatment is marketed as Viekira PakTM and was developed by Abbvie as an all oral treatment that eliminates the need for pegylated interferon-a injections.

The synthesis of ombitasvir hydrate is shown in Scheme 34.REF 8   Alkylation of 1-(4-nitrophenyl)ethanone (209)
with 2-bromo-1-(4-nitrophenyl)ethanone (208) in the presence of zinc chloride produced diketone 210 in 61% yield.

Asymmetric reduction of the diketone using N,N-diethylaniline borane with (S)-()-a,a-diphenyl-2-pyrrolidinemethanol (211) and trimethoxyborate gave diol 212 in 61% yield and 99.3% ee.

The diol was then treated with methanesulfonic anhydride to generate the corresponding bis-mesylate which was reacted with 4-tert-butylaniline to give pyrrolidine 213 in 51% yield over the two steps.

Hydrogenolysis of the nitro groups was accomplished using Raney nickel catalyst to give bis-aniline 214.

Separately, (L)-valine (216,Scheme 35) was reacted with methyl chloroformate to give the corresponding methyl carbamate in 90% yield which was coupled to L-proline benzyl ester in the presence of EDC and HOBt to give the corresponding dipeptide in 90% yield.

Hydrogenolysis of the benzyl ester group of the protected dipeptide using Pd/alumina catalyst produced dipeptide acid 215. Aniline 214 was treated with two equivalents of acid 215 in the presence of 1-propanephosphonic acid cyclic anhydride (T3P). The crude product was recrystallized from ethanol and heptane to give ombitasvir hydrate (XXV). No yields were provided to the final steps of this synthesis.

STR1

 

STR1

6 Gamal, N.; Andreone, P. Drugs Today (Barc) 2015, 51, 303.

7. DeGoey, D. A.; Randolph, J. T.; Liu, D.; Pratt, J.; Hutchins, C.; Donner, P.;Krueger, A. C.; Matulenko, M.; Patel, S.; Motter, C. E.; Nelson, L.; Keddy, R.;Tufano, M.; Caspi, D. D.; Krishnan, P.; Mistry, N.; Koev, G.; Reisch, T. J.;Mondal, R.; Pilot-Matias, T.; Gao, Y.; Beno, D. W.; Maring, C. J.; Molla, A.;Dumas, E.; Campbell, A.; Williams, L.; Collins, C.; Wagner, R.; Kati, W. M. J.
Med. Chem. 2014, 57, 2047.
8. DeGoey, D. A.; Kati, W. M.; Hutchins, C. W.; Donner, P. L.; Krueger, A. C.;Randolph, J. T.; Motter, C. E.; Nelson, L. T.; Patel, S. V.; Matulenko, M. A.;Keddy, R. G.; Jinkerson, T. K.; Soltwedel, T. N.; Liu, D.; Pratt, J. K.; Rockway, T.W.; Maring, C. J.; Hutchinson, D. K.; Flentge, C. A.; Wagner, R.; Tufano, M. D.;Betebenner, D. A.; Lavin, M. J.; Sarris, K.; Woller, K. R.; Wagaw, S. H.; Califano,
J. C.; Li, W.; Caspi, D. D.; Bellizzi, M. E. US Patent 2010317568A1, 2010.

CLIP

STR1

DeGoey, DA, Discovery of ABT-267, a Pan-genotypic Inhibitor of HCV NS5A,  J. Med. Chem., 2014, 57 (5), pp 2047-2057

 http://pubs.acs.org/doi/full/10.1021/jm401398x

Abstract Image

We describe here N-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2S,5S stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2R,5Ranalogues. Furthermore, the attachment of substituents at the 4-position of the central N-phenyl group resulted in compounds with improved potency. Substitution with tert-butyl, as in compound 38 (ABT-267), provided compounds with low-picomolar EC50 values and superior pharmacokinetics. It was discovered that compound 38 was a pan-genotypic HCV inhibitor, with an EC50 range of 1.7–19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound 38 decreased HCV RNA up to 3.10 log10 IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin.

Dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate (38)…desired and Dimethyl (2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2R,5R)-1-(4-tert-Butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)dicarbamate (39)…….undesired

…………….. The resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous NaHCO3, brine (2×) and dried with Na2SO4. The drying agent was filtered off and the solution was concentrated in vacuo to give a crude product that was purified by column chromatography on silica gel, eluting with a solvent gradient of 2–8% methanol in dichloromethane to give a 1:1 mixture of trans-pyrrolidine isomers (290 mg, 96%). The mixture was separated on a Chiralpak AD-H column, eluting with a mixture of 1 part (2:1 isopropanol/ethanol) and 2 parts hexanes (0.1% TFA).

Compound 38 was the first of two stereoisomers to elute (101 mg, 99% ee by chiral HPLC). 1H NMR (400 MHz, DMSO-d6) δ 0.88 (d, J = 6.61 Hz, 6H), 0.93 (d, J = 6.72 Hz, 6H), 1.11 (s, 9H), 1.63 (d, J = 5.42 Hz, 2H), 1.80–2.04 (m, 8H), 2.09–2.19 (m, 2H), 2.44–2.47 (m, 2H), 3.52 (s, 6H), 3.59–3.66 (m, 2H), 3.77–3.84 (m, 2H), 4.02 (t, J = 8.40 Hz, 2H), 4.42 (dd, J = 7.86, 4.83 Hz, 2H), 5.14 (d, J = 6.18 Hz, 2H), 6.17 (d, J = 8.67 Hz, 2H), 6.94 (d, J = 8.78 Hz, 2H), 7.13 (d, J = 8.46 Hz, 4H), 7.31 (d, J= 8.35 Hz, 2H), 7.50 (d, J = 8.35 Hz, 4H), 9.98 (s, 2H).

MS (ESI) m/z 894.9 (M + H)+.

Compound39 was the second of two stereoisomers to elute. 1H NMR (400 MHz, DMSO-d6) δ 0.87 (d, J = 6.51 Hz, 6H), 0.92 (d, J = 6.72 Hz, 6H), 1.11 (s, 9H), 1.63 (d, J = 5.53 Hz, 2H), 1.82–2.04 (m, 8H), 2.09–2.18 (m, 2H), 2.41–2.47 (m, 2H), 3.52 (s, 6H), 3.58–3.67 (m, 2H), 3.75–3.84 (m, 2H), 4.02 (t, J = 7.26 Hz, 2H), 4.43 (dd, J = 7.92, 4.88 Hz, 2H), 5.14 (d, J = 6.18 Hz, 2H), 6.17 (d, J = 8.78 Hz, 2H), 6.94 (d, J = 8.67 Hz, 2H), 7.12 (d, J = 8.46 Hz, 4H), 7.31 (d, J = 8.35 Hz, 2H), 7.49 (d, J = 8.46 Hz, 4H), 9.98 (s, 2H). MS (ESI) m/z 895.0 (M + H)+.

PATENT

WO 2011156578

dimethyl (2S,2,S)-l,l ‘-((2S,2’S)-2,2′-(4,4’-((2S,5S)-l-(4-fert-butylphenyl)pyrrolidine- 2,5-diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3- methyl- l-oxobutane-2,l-diyl)dicarbamate

Figure imgf000003_0001

PATENT

US 20100317568

Example 34

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate and

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-ter/’-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

Figure imgf000133_0002

Example 34A l-(4-fer?-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine The product from Example 1C (3.67 g, 7.51 mmol) and 4-tert-butylaniline (11.86 ml, 75 mmol) in DMF (40 ml) was stirred under nitrogen at 50 °C for 4 h. The resulting mixture was diluted into ethyl acetate, treated with IM HCl, stirred for 10 minutes and filtered to remove solids. The filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to 30%) to give a solid. The solid was triturated in a minimal volume of 1 :9 ethyl acetate/hexane to give a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%).

Example 34B 4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline and 4,4′-((2R,5R)-1-(4-fert- butylphenyl)pyrrolidine-2,5-diyl)dianiline To a solution of the product from Example 34A (1.1 g, 2.47 mmol) in ethanol (20 ml) and

THF (20 ml) was added PtC>2 (0.22 g, 0.97 mmol) in a 50 ml pressure bottle and stirred under 30 psi hydrogen at room temperature for 1 h. The mixture was filtered through a nylon membrane and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (20% to 60%). The title compound eluted as the first of 2 stereoisomers (trans isomer, 0.51 g, 54%).

Example 34C

(2S,2’S)-tert-Butyl 2,2′-(4,4′-((2S,5S)-1-(4-fer/’-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- 1 -carboxylate and (2S,2’S)-tert-Butyl 2,2′- (4,4′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate To a mixture of the product from Example 34B (250 mg, 0.648 mmol), (S)-1-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (307 mg, 1.427 mmol) and HATU (542 mg, 1.427 mmol) in DMSO (10 ml) was added Hunig’s base (0.453 ml, 2.59 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (10% to 50%) to give the title compound (500 mg, 99%).

Example 34D

(2S,2’S)-N,N’-(4,4′-((2S,5S)-1-(4-ter/’-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))dipyrrolidine-2-carboxamide and (2S,2’S)-N,N’-(4,4′-((2R,5R)-1-(4-tert- butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-2-carboxamide To the product from Example 34C (498 mg, 0.638 mmol) in dichloromethane (4 ml) was added TFA (6 ml). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was partitioned between 3: 1 CHCl3dsopropyl alcohol and saturated aq. NaHCO3. The aqueous layer was extracted by 3: 1 CHCl3:isopropyl alcohol again. The combined organic layers were dried over

Figure imgf000135_0001

filtered and concentrated to give the title compound (345 mg, 93%).

Example 34E Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate and

Dimethyl (2S,2’S)-1, r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-fert-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

The product from Example 34D (29.0 mg, 0.050 mmol), (S)-2-(methoxycarbonylamino)-3- methylbutanoic acid (19.27 mg, 0.110 mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85 mg,

0.110 mmol) and N-methylmorpholine (0.027 ml, 0.250 mmol) were combined in DMF (2 ml). The reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (50% to 80%) to give a solid. The solid was triturated with ethyl acetate/hexane to give the title compound (13 mg, 29%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.85 – 0.95 (m, 12 H) 1.11 (s, 9 H) 1.59 – 1.65 (m, 2 H) 1.79 – 2.04 (m, 8 H) 2.10 – 2.18 (m, 2 H) 2.41-2.46 (m, 2H) 3.52 (s, 6 H)

3.57 – 3.67 (m, 2 H) 3.76 – 3.86 (m, 2 H) 4.00 (t, J=7.56 Hz, 2 H) 4.39 – 4.46 (m, 2 H) 5.15 (d, J=7.00

Hz, 2 H) 6.17 (d, J=7.70 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=7.37 Hz, 4 H) 7.30 (d, J=8.20

Hz, 2 H) 7.50 (d, J=8.24 Hz, 4 H) 9.98 (s, 2 H); (ESI+) m/z 895 (M+H)+. The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Example 35

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate

Figure imgf000135_0002………………desired

The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:1 mixture of hexane:(2: l isopropyl alcohol: EtOH). The title compound was the first of the 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 – 2.04 (m, 8 H) 2.09 – 2.19 (m, 2 H) 2.44 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 – 3.66 (m, 2 H) 3.77 – 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV Ib- Conl replicon assays in the presence of 5% FBS.

Example 36 Dimethyl (2S,2’S)-1, r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-fert-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

Figure imgf000136_0001…….undesired

The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:1 mixture of hexane:(2: l isopropyl alcohol: EtOH). The title compound was the second of 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.87

(d, J=6.51 Hz, 6 H) 0.92 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.53 Hz, 2 H) 1.82 – 2.04 (m, 8

H) 2.09-2.18 (m, 2 H) 2.41 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.58 – 3.67 (m, 2 H) 3.75 – 3.84 (m, 2 H) 4.02

(t, J=7.26 Hz, 2 H) 4.43 (dd, J=7.92, 4.88 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.78 Hz, 2 H) 6.94 (d, J=8.67 Hz, 2 H) 7.12 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.49 (d, J=8.46 Hz, 4 H)

9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Example 37 Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate

Figure imgf000136_0002……………desired

Example 37A (S)-2,5-dioxopyrrolidin-1-yl 2-(methoxycarbonylamino)-3-methylbutanoate To a mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112 mmol) and N-hydroxysuccinimide (13.29g, 116 mmol) was added ethyl acetate (250 ml), and the mixture was cooled to 0-5 °C. Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the reaction mixture was stirred at 0-5 °C for about 1 hour. The reaction mixture was warmed to room temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the mixture was heated to about 50 °C to obtain a homogeneous solution. Upon cooling, crystalline solids formed. The solids were filtered and washed with isopropyl alcohol (3 x 20 ml) and dried to give the title compound as a white solid (23.2 g, 77% yield).

Example 37B

(S)- 1 -((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid To a mixture of L-proline (4.44g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a solution of the product from Example 37A (1Og, 36.7 mmol) in acetonitrile (20 inL) over 10 minutes. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water solution was added 6N HCl (9 ml) until pH ~ 2 .The solution was transferred to a separatory funnel and 25% NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then again with ethyl acetate (6 x 20 ml), and the combined extracts were washed with 25% NaCl (2 x 10ml). The solvent was evaporated to give a thick oil. Heptane was added and the solvent was evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the solvent was evaporated to give a foam, which was dried under high vacuum to give the title compound (10.67g) as a white solid.

The compound of Example 37B can also be prepreared according to the following procedure: To a flask was charged L- valine (35 g, 299 mmol), IN sodium hydroxide solution (526 ml,

526 mmol) and sodium carbonate (17.42 g, 164 mmol). The mixture was stirred for 15 min to dissolve solids and then cooled to 15 °C. Methyl chloroformate (29.6 g, 314 mmol) was added slowly to the reaction mixture. The mixture was then stirred at rt for 30 min. The mixture was cooled to 15 °C and pH adjusted to -5.0 with concentrated HCl solution. 100 inL of 2-methytetrahydrofuran (2- MeTHF) was added and the adjustment of pH continued until the pH reached ~ 2.0. 150 mL of 2- MeTHF was added and the mixture was stirred for 15 min. Layers were separated and the aqueous layer extracted with 100 mL of 2-MeTHF. The combined organic layer was dried over anhyd Na2SC^ and filtered, and Na2SC^ cake was washed with 50 mL of 2-MeTHF. The product solution was concentrated to ~ 100 mL, chased with 120 mL of IPAc twice. 250 mL of heptanes was charged slowly and then the volume of the mixture was concentrated to 300 mL. The mixture was heated to 45 °C and 160 mL of heptanes charged. The mixture was cooled to rt in 2h, stirred for 30 min, filtered and washed with 2-MeTHF/heptanes mixture (1:7, 80 inL). The wetcake was dried at 55 °C for 24 h to give 47.1 g of Moc-L- VaI-OH product as a white solid (90%).

Moc-L- VaI-OH (15O g, 856 mmol), HOBt hydrate (138 g, 899 mmol) and DMF (1500 ml) were charged to a flask. The mixture was stirred for 15 min to give a clear solution. EDC hydrochloride (172 g, 899 mmol) was charged and mixed for 20 min. The mixture was cooled to 13

°C and (L)-proline benzyl ester hydrochloride (207 g, 856 mmol) charged. Triethylamine (109 g,

1079 mmol) was then charged in 30 min. The resulting suspension was mixed at rt for 1.5 h. The reaction mixture was cooled to 15 °C and 1500 mL of 6.7% NaHCO3 charged in 1.5 h, followed by the addition of 1200 mL of water over 60 min. The mixture was stirred at rt for 30 min, filtered and washed with water/DMF mixture (1 :2, 250 mL) and then with water (1500 mL). The wetcake was dried at 55 °C for 24 h to give 282 g of product as a white solid (90%).

The resulting solids (40 g) and 5% Pd/ Alumina were charged to a Parr reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6 x 20 psig) followed by a hydrogen purge (6 x 30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. Heptane was added (120 mL), and the solution was stirred until solids formed. After an addition 2 – 3 hours additional heptane was added drop-wise (240 mL), the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound.

Example 37C

(lR,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate

The product from Example 32 (5.01 g, 13.39 mmol) was combined with 2- methyltetrahydrofuran (70 mL) and cooled to -5 °C, and N,N-diisopropylethylamine (6.81 g, 52.7 mmol) was added over 30 seconds. Separately, a solution of methanesulfonic anhydride (6.01 g, 34.5 mmol) in 2-methyltetrahydrofuran (30 mL) was prepared and added to the diol slurry over 3 min., maintaining the internal temperature between -15 °C and -25 °C. After mixing for 5 min at -15 °C, the cooling bath was removed and the reaction was allowed to warm slowly to 23 °C and mixed for 30 minutes. After reaction completion, the crude slurry was carried immediately into the next step.

Example 37D

(2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine

To the crude product solution from Example 37C (7.35 g, 13.39 mmol) was added 4-tert- butylaniline (13.4 g, 90 mmol) at 23 °C over 1 minute. The reaction was heated to 65 °C for 2 h. After completion, the reaction mixture was cooled to 23 °C and diluted with 2-methyltetrahydrofuran (100 mL) and 1 M HCl (150 mL). After partitioning the phases, the organic phase was treated with 1 M HCl (140 mL), 2-methyltetrahydrofuran (50 mL), and 25 wt% aq. NaCl (100 mL), and the phases were partitioned. The organic phase was washed with 25 wt% aq. NaCl (50 mL), dried over MgSO/t, filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2- methyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 2- methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspended in MeOH (46 mL) for 3 h, filtered, and the wet solid was washed with additional MeOH (18 mL). The solid was dried at 45 °C in a vacuum oven for 16 h to provide the title compound (3.08 g, 51% 2-step yield).

Example 37E

4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline

To a 160 ml Parr stirrer hydrogenation vessel was added the product from Example 37D (2 g, 4.49 mmol), followed by 60 ml of THF, and Raney Nickel Grace 2800 (1 g, 50 wt% (dry basis)) under a stream of nitrogen. The reactor was assembled and purged with nitrogen (8 x 20 psig) followed by purging with hydrogen (8 x 30 psig). The reactor was then pressurized to 30 psig with hydrogen and agitation (700 rpm) began and continued for a total of 16 h at room temperature. The slurry was filtered by vacuum filtration using a GF/F Whatman glass fiber filter. Evaporation of the filtrate to afford a slurry followed by the addition heptane and filtration gave the crude title compound, which was dried and used directly in the next step.

Example 37F dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, l- phenylene)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diy 1) die arb amate To a solution of the product from Example 37E (1.64 g, 4.25 mmol) in DMF (20 ml), the product from Example 37B (2.89 g, 10.63 mmol), and HATU (4.04 g, 10.63 mmol) in DMF (15OmL) was added triethylamine (1.07 g, 10.63 mmol), and the solution was stirred at room temperature for 90 min. To the reaction mixture was poured 20 mL of water, and the white precipitate obtained was filtered, and the solid was washed with water (3×5 mL). The solid was blow dried for Ih. The crude material was loaded on a silica gel column and eluted with a gradient starting with ethyl acetate/ heptane (3/7), and ending with pure ethyl acetate. The desired fractions were combined and solvent distilled off to give a very light yellow solid, which was dried at 45 °C in a vacuum oven with nitrogen purge for 15 h to give the title compound (2.3 g, 61% yield). 1H NMR (400 MHz, DMSO- D6) δ ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 – 2.04 (m, 8 H) 2.09 – 2.19 (m, 2 H) 2.44 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 – 3.66 (m, 2 H) 3.77 – 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H).

Alternately, the product from example 37E (11.7 g, 85 wt%, 25.8 mmol) and the product from example 37B (15.45 g, 56.7 mmol) are suspended in EtOAc (117 mL), diisopropylethylamine (18.67 g, 144 mmol) is added and the solution is cooled to 0 °C. In a separate flask, 1-propanephosphonic acid cyclic anhydride (T3P®) (46.0 g, 50 wt% in EtOAc, 72.2 mmol) was dissolved in EtOAc (58.5 mL), and charged to an addition funnel. The T3P solution is added to the reaction mixture drop-wise over 3-4 h and stirred until the reaction is complete. The reaction is warmed to room temperature,and washed with IM HCl/7.5 wt% NaCl (100 mL), then washed with 5% NaHCO3 (100 mL), then washed with 5% NaCl solution (100 mL). The solution was concentrated to approximately 60 mL, EtOH (300 mL) was added, and the solution was concentrated to 84 g solution.

A portion of the EtOH solution of product (29 g) was heated to 40 °C, and added 134 g 40 w% EtOH in H2O. A slurry of seeds in 58 wt/wt% EtOH/H2O was added, allowed to stir at 40 °C for several hours, then cooled to 0 °C. The slurry is then filtered, and washed with 58wt/wt% EtOH/H2O. The product is dried at 40 – 60 °C under vacuum, and then rehydrated by placing a tray of water in the vacuum oven to give the title compound. The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

PATENT

Example 34

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate and

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-ter/’-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

Figure imgf000133_0002

Example 34A l-(4-fer?-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine The product from Example 1C (3.67 g, 7.51 mmol) and 4-tert-butylaniline (11.86 ml, 75 mmol) in DMF (40 ml) was stirred under nitrogen at 50 °C for 4 h. The resulting mixture was diluted into ethyl acetate, treated with IM HCl, stirred for 10 minutes and filtered to remove solids. The filtrate organic layer was washed twice with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (5% to 30%) to give a solid. The solid was triturated in a minimal volume of 1 :9 ethyl acetate/hexane to give a light yellow solid as a mixture of trans and cis isomers (1.21 g, 36%).

Example 34B 4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline and 4,4′-((2R,5R)-1-(4-fert- butylphenyl)pyrrolidine-2,5-diyl)dianiline To a solution of the product from Example 34A (1.1 g, 2.47 mmol) in ethanol (20 ml) and

THF (20 ml) was added PtC>2 (0.22 g, 0.97 mmol) in a 50 ml pressure bottle and stirred under 30 psi hydrogen at room temperature for 1 h. The mixture was filtered through a nylon membrane and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (20% to 60%). The title compound eluted as the first of 2 stereoisomers (trans isomer, 0.51 g, 54%).

Example 34C

(2S,2’S)-tert-Butyl 2,2′-(4,4′-((2S,5S)-1-(4-fer/’-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine- 1 -carboxylate and (2S,2’S)-tert-Butyl 2,2′- (4,4′-((2R,5R)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)dipyrrolidine-1-carboxylate To a mixture of the product from Example 34B (250 mg, 0.648 mmol), (S)-1-(tert- butoxycarbonyl)pyrrolidine-2-carboxylic acid (307 mg, 1.427 mmol) and HATU (542 mg, 1.427 mmol) in DMSO (10 ml) was added Hunig’s base (0.453 ml, 2.59 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (10% to 50%) to give the title compound (500 mg, 99%).

Example 34D

(2S,2’S)-N,N’-(4,4′-((2S,5S)-1-(4-ter/’-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))dipyrrolidine-2-carboxamide and (2S,2’S)-N,N’-(4,4′-((2R,5R)-1-(4-tert- butylphenyl)pyrrolidine-2,5-diyl)bis(4,l-phenylene))dipyrrolidine-2-carboxamide To the product from Example 34C (498 mg, 0.638 mmol) in dichloromethane (4 ml) was added TFA (6 ml). The reaction mixture was stirred at room temperature for 1 h and concentrated in vacuo. The residue was partitioned between 3: 1 CHCl3dsopropyl alcohol and saturated aq. NaHCO3. The aqueous layer was extracted by 3: 1 CHCl3:isopropyl alcohol again. The combined organic layers were dried over

Figure imgf000135_0001

filtered and concentrated to give the title compound (345 mg, 93%).

Example 34E Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate and

Dimethyl (2S,2’S)-1, r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-fert-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

The product from Example 34D (29.0 mg, 0.050 mmol), (S)-2-(methoxycarbonylamino)-3- methylbutanoic acid (19.27 mg, 0.110 mmol), EDAC (21.09 mg, 0.110 mmol), HOBT (16.85 mg,

0.110 mmol) and N-methylmorpholine (0.027 ml, 0.250 mmol) were combined in DMF (2 ml). The reaction mixture was stirred at room temperature for 3 h. The mixture was partitioned with ethyl acetate and water. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel eluting with ethyl acetate in hexane (50% to 80%) to give a solid. The solid was triturated with ethyl acetate/hexane to give the title compound (13 mg, 29%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.85 – 0.95 (m, 12 H) 1.11 (s, 9 H) 1.59 – 1.65 (m, 2 H) 1.79 – 2.04 (m, 8 H) 2.10 – 2.18 (m, 2 H) 2.41-2.46 (m, 2H) 3.52 (s, 6 H)

3.57 – 3.67 (m, 2 H) 3.76 – 3.86 (m, 2 H) 4.00 (t, J=7.56 Hz, 2 H) 4.39 – 4.46 (m, 2 H) 5.15 (d, J=7.00

Hz, 2 H) 6.17 (d, J=7.70 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=7.37 Hz, 4 H) 7.30 (d, J=8.20

Hz, 2 H) 7.50 (d, J=8.24 Hz, 4 H) 9.98 (s, 2 H); (ESI+) m/z 895 (M+H)+. The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Example 35

Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate

Figure imgf000135_0002………….desired

The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:1 mixture of hexane:(2: l isopropyl alcohol: EtOH). The title compound was the first of the 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 – 2.04 (m, 8 H) 2.09 – 2.19 (m, 2 H) 2.44 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 – 3.66 (m, 2 H) 3.77 – 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV Ib- Conl replicon assays in the presence of 5% FBS.

Example 36 Dimethyl (2S,2’S)-1, r-((2S,2’S)-2,2′-(4,4′-((2R,5R)-1-(4-fert-butylphenyl)pyrrolidine-2,5- diyl)bis(4, 1 -phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 – oxobutane-2, 1 -diyl)dicarbamate

Figure imgf000136_0001……….undesired

The product from Example 34E was purified by chiral chromatography on a Chiralpak AD-H semi-prep column eluting with a 2:1 mixture of hexane:(2: l isopropyl alcohol: EtOH). The title compound was the second of 2 diastereomers to elute. 1H NMR (400 MHz, DMSO-D6) δ ppm 0.87

(d, J=6.51 Hz, 6 H) 0.92 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.53 Hz, 2 H) 1.82 – 2.04 (m, 8

H) 2.09-2.18 (m, 2 H) 2.41 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.58 – 3.67 (m, 2 H) 3.75 – 3.84 (m, 2 H) 4.02

(t, J=7.26 Hz, 2 H) 4.43 (dd, J=7.92, 4.88 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.78 Hz, 2 H) 6.94 (d, J=8.67 Hz, 2 H) 7.12 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.49 (d, J=8.46 Hz, 4 H)

9.98 (s, 2 H). The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Example 37 Dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-fert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,l- phenylene))bis(azanediyl)bis(oxomethylene)bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diyl)dicarbamate

Figure imgf000136_0002………………desired

Example 37A (S)-2,5-dioxopyrrolidin-1-yl 2-(methoxycarbonylamino)-3-methylbutanoate To a mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112 mmol) and N-hydroxysuccinimide (13.29g, 116 mmol) was added ethyl acetate (250 ml), and the mixture was cooled to 0-5 °C. Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the reaction mixture was stirred at 0-5 °C for about 1 hour. The reaction mixture was warmed to room temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the mixture was heated to about 50 °C to obtain a homogeneous solution. Upon cooling, crystalline solids formed. The solids were filtered and washed with isopropyl alcohol (3 x 20 ml) and dried to give the title compound as a white solid (23.2 g, 77% yield).

Example 37B

(S)- 1 -((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid To a mixture of L-proline (4.44g, 38.6 mmol), water (20 ml), acetonitrile (20 ml) and DIEA (9.5 g, 73.5 mmol) was added a solution of the product from Example 37A (1Og, 36.7 mmol) in acetonitrile (20 inL) over 10 minutes. The reaction mixture was stirred overnight at room temperature. The solution was concentrated under vacuum to remove the acetonitrile. To the resulting clear water solution was added 6N HCl (9 ml) until pH ~ 2 .The solution was transferred to a separatory funnel and 25% NaCl (10 ml) was added and the mixture was extracted with ethyl acetate (75 ml), and then again with ethyl acetate (6 x 20 ml), and the combined extracts were washed with 25% NaCl (2 x 10ml). The solvent was evaporated to give a thick oil. Heptane was added and the solvent was evaporated to give a foam, which was dried under high vacuum. Diethyl ether was added and the solvent was evaporated to give a foam, which was dried under high vacuum to give the title compound (10.67g) as a white solid.

The compound of Example 37B can also be prepreared according to the following procedure: To a flask was charged L- valine (35 g, 299 mmol), IN sodium hydroxide solution (526 ml,

526 mmol) and sodium carbonate (17.42 g, 164 mmol). The mixture was stirred for 15 min to dissolve solids and then cooled to 15 °C. Methyl chloroformate (29.6 g, 314 mmol) was added slowly to the reaction mixture. The mixture was then stirred at rt for 30 min. The mixture was cooled to 15 °C and pH adjusted to -5.0 with concentrated HCl solution. 100 inL of 2-methytetrahydrofuran (2- MeTHF) was added and the adjustment of pH continued until the pH reached ~ 2.0. 150 mL of 2- MeTHF was added and the mixture was stirred for 15 min. Layers were separated and the aqueous layer extracted with 100 mL of 2-MeTHF. The combined organic layer was dried over anhyd Na2SC^ and filtered, and Na2SC^ cake was washed with 50 mL of 2-MeTHF. The product solution was concentrated to ~ 100 mL, chased with 120 mL of IPAc twice. 250 mL of heptanes was charged slowly and then the volume of the mixture was concentrated to 300 mL. The mixture was heated to 45 °C and 160 mL of heptanes charged. The mixture was cooled to rt in 2h, stirred for 30 min, filtered and washed with 2-MeTHF/heptanes mixture (1:7, 80 inL). The wetcake was dried at 55 °C for 24 h to give 47.1 g of Moc-L- VaI-OH product as a white solid (90%).

Moc-L- VaI-OH (15O g, 856 mmol), HOBt hydrate (138 g, 899 mmol) and DMF (1500 ml) were charged to a flask. The mixture was stirred for 15 min to give a clear solution. EDC hydrochloride (172 g, 899 mmol) was charged and mixed for 20 min. The mixture was cooled to 13

°C and (L)-proline benzyl ester hydrochloride (207 g, 856 mmol) charged. Triethylamine (109 g,

1079 mmol) was then charged in 30 min. The resulting suspension was mixed at rt for 1.5 h. The reaction mixture was cooled to 15 °C and 1500 mL of 6.7% NaHCO3 charged in 1.5 h, followed by the addition of 1200 mL of water over 60 min. The mixture was stirred at rt for 30 min, filtered and washed with water/DMF mixture (1 :2, 250 mL) and then with water (1500 mL). The wetcake was dried at 55 °C for 24 h to give 282 g of product as a white solid (90%).

The resulting solids (40 g) and 5% Pd/ Alumina were charged to a Parr reactor followed by THF (160 mL). The reactor was sealed and purged with nitrogen (6 x 20 psig) followed by a hydrogen purge (6 x 30 psig). The reactor was pressurized to 30 psig with hydrogen and agitated at room temperature for approximately 15 hours. The resulting slurry was filtered through a GF/F filter and concentrated to approximately 135 g solution. Heptane was added (120 mL), and the solution was stirred until solids formed. After an addition 2 – 3 hours additional heptane was added drop-wise (240 mL), the slurry was stirred for approximately 1 hour, then filtered. The solids were dried to afford the title compound.

Example 37C

(lR,4R)-1,4-bis(4-nitrophenyl)butane-1,4-diyl dimethanesulfonate

The product from Example 32 (5.01 g, 13.39 mmol) was combined with 2- methyltetrahydrofuran (70 mL) and cooled to -5 °C, and N,N-diisopropylethylamine (6.81 g, 52.7 mmol) was added over 30 seconds. Separately, a solution of methanesulfonic anhydride (6.01 g, 34.5 mmol) in 2-methyltetrahydrofuran (30 mL) was prepared and added to the diol slurry over 3 min., maintaining the internal temperature between -15 °C and -25 °C. After mixing for 5 min at -15 °C, the cooling bath was removed and the reaction was allowed to warm slowly to 23 °C and mixed for 30 minutes. After reaction completion, the crude slurry was carried immediately into the next step.

Example 37D

(2S,5S)-1-(4-tert-butylphenyl)-2,5-bis(4-nitrophenyl)pyrrolidine

To the crude product solution from Example 37C (7.35 g, 13.39 mmol) was added 4-tert- butylaniline (13.4 g, 90 mmol) at 23 °C over 1 minute. The reaction was heated to 65 °C for 2 h. After completion, the reaction mixture was cooled to 23 °C and diluted with 2-methyltetrahydrofuran (100 mL) and 1 M HCl (150 mL). After partitioning the phases, the organic phase was treated with 1 M HCl (140 mL), 2-methyltetrahydrofuran (50 mL), and 25 wt% aq. NaCl (100 mL), and the phases were partitioned. The organic phase was washed with 25 wt% aq. NaCl (50 mL), dried over MgSO/t, filtered, and concentrated in vacuo to approximately 20 mL. Heptane (30 mL) and additional 2- methyltetrahydrofuran were added in order to induce crystallization. The slurry was concentrated further, and additional heptane (40 mL) was slowly added and the slurry was filtered, washing with 2- methyltetrahydrofuran:heptane (1:4, 20 mL). The solids were suspended in MeOH (46 mL) for 3 h, filtered, and the wet solid was washed with additional MeOH (18 mL). The solid was dried at 45 °C in a vacuum oven for 16 h to provide the title compound (3.08 g, 51% 2-step yield).

Example 37E

4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)dianiline

To a 160 ml Parr stirrer hydrogenation vessel was added the product from Example 37D (2 g, 4.49 mmol), followed by 60 ml of THF, and Raney Nickel Grace 2800 (1 g, 50 wt% (dry basis)) under a stream of nitrogen. The reactor was assembled and purged with nitrogen (8 x 20 psig) followed by purging with hydrogen (8 x 30 psig). The reactor was then pressurized to 30 psig with hydrogen and agitation (700 rpm) began and continued for a total of 16 h at room temperature. The slurry was filtered by vacuum filtration using a GF/F Whatman glass fiber filter. Evaporation of the filtrate to afford a slurry followed by the addition heptane and filtration gave the crude title compound, which was dried and used directly in the next step.

Example 37F dimethyl (2S,2’S)-l,r-((2S,2’S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4, l- phenylene)bis(azanediyl)bis(oxomethylene))bis(pyrrolidine-2, 1 -diyl))bis(3-methyl- 1 -oxobutane-2, 1 – diy 1) die arb amate To a solution of the product from Example 37E (1.64 g, 4.25 mmol) in DMF (20 ml), the product from Example 37B (2.89 g, 10.63 mmol), and HATU (4.04 g, 10.63 mmol) in DMF (15OmL) was added triethylamine (1.07 g, 10.63 mmol), and the solution was stirred at room temperature for 90 min. To the reaction mixture was poured 20 mL of water, and the white precipitate obtained was filtered, and the solid was washed with water (3×5 mL). The solid was blow dried for Ih. The crude material was loaded on a silica gel column and eluted with a gradient starting with ethyl acetate/ heptane (3/7), and ending with pure ethyl acetate. The desired fractions were combined and solvent distilled off to give a very light yellow solid, which was dried at 45 °C in a vacuum oven with nitrogen purge for 15 h to give the title compound (2.3 g, 61% yield). 1H NMR (400 MHz, DMSO- D6) δ ppm 0.88 (d, J=6.61 Hz, 6 H) 0.93 (d, J=6.72 Hz, 6 H) 1.11 (s, 9 H) 1.63 (d, J=5.42 Hz, 2 H) 1.80 – 2.04 (m, 8 H) 2.09 – 2.19 (m, 2 H) 2.44 – 2.47 (m, 2 H) 3.52 (s, 6 H) 3.59 – 3.66 (m, 2 H) 3.77 – 3.84 (m, 2 H) 4.02 (t, J=8.40 Hz, 2 H) 4.42 (dd, J=7.86, 4.83 Hz, 2 H) 5.14 (d, J=6.18 Hz, 2 H) 6.17 (d, J=8.67 Hz, 2 H) 6.94 (d, J=8.78 Hz, 2 H) 7.13 (d, J=8.46 Hz, 4 H) 7.31 (d, J=8.35 Hz, 2 H) 7.50 (d, J=8.35 Hz, 4 H) 9.98 (s, 2 H).

Alternately, the product from example 37E (11.7 g, 85 wt%, 25.8 mmol) and the product from example 37B (15.45 g, 56.7 mmol) are suspended in EtOAc (117 mL), diisopropylethylamine (18.67 g, 144 mmol) is added and the solution is cooled to 0 °C. In a separate flask, 1-propanephosphonic acid cyclic anhydride (T3P®) (46.0 g, 50 wt% in EtOAc, 72.2 mmol) was dissolved in EtOAc (58.5 mL), and charged to an addition funnel. The T3P solution is added to the reaction mixture drop-wise over 3-4 h and stirred until the reaction is complete. The reaction is warmed to room temperature,and washed with IM HCl/7.5 wt% NaCl (100 mL), then washed with 5% NaHCO3 (100 mL), then washed with 5% NaCl solution (100 mL). The solution was concentrated to approximately 60 mL, EtOH (300 mL) was added, and the solution was concentrated to 84 g solution.

A portion of the EtOH solution of product (29 g) was heated to 40 °C, and added 134 g 40 w% EtOH in H2O. A slurry of seeds in 58 wt/wt% EtOH/H2O was added, allowed to stir at 40 °C for several hours, then cooled to 0 °C. The slurry is then filtered, and washed with 58wt/wt% EtOH/H2O. The product is dried at 40 – 60 °C under vacuum, and then rehydrated by placing a tray of water in the vacuum oven to give the title compound. The title compound showed an EC50 value of less than about 0.1 nM in HCV lb-Conl replicon assays in the presence of 5% FBS.

Intermediates

Example 32

( 1 R,4R)- 1 ,4-bis(4-mtrophenyl)butane- 1 ,4-diol

Figure imgf000132_0002

To (S)-(-)-α,α-diphenyl-2-pyrrohdinemethanol (2 71 g, 10 70 mmol) was added THF (80 mL) at 23 °C The very thin suspension was treated with t11methyl borate (1 44 g, 13 86 mmol) over 30 seconds, and the resulting solution was mixed at 23 °C for 1 h The solution was cooled to 16-19 °C, and N,N-diethylanilme borane (21 45 g, 132 mmol) was added dropwise via syringe over 3-5 mm (caution vigorous H2 evolution), while the internal temperature was maintained at 16-19 °C After 15 mm, the H2 evolution had ceased To a separate vessel was added the product from Example IA (22 04 g, 95 wt%, 63 8 mmol), followed by THF (80 mL), to form an orange slurry After cooling the slurry to 11 °C, the borane solution was transferred via cannula into the dione slurry over 3-5 min During this period, the internal temperature of the slurry rose to 16 °C After the addition was complete, the reaction was maintained at 20-27 °C for an additional 2 5 h After reaction completion, the mixture was cooled to 5 °C and methanol (16 7 g, 521 mmol) was added dropwise over 5-10 mm, maintaining an internal temperature <20 °C (note vigorous H2 evolution) After the exotherm had ceased (ca 10 mm), the temperature was adjusted to 23 °C, and the reaction was mixed until complete dissolution of the solids had occurred Ethyl acetate (300 mL) and 1 M HCl (120 mL) were added, and the phases were partitioned The organic phase was then washed successively with 1 M HCl (2 x 120 mL), H2O (65 mL), and 10% aq NaCl (65 mL) The orgamcs were dried over MgSO4, filtered, and concentrated in vacuo Crystallization of the product occurred during the concentration The slurry was warmed to 50 °C, and heptane (250 inL) was added over 15 min. The slurry was then allowed to mix at 23 °C for 30 min and filtered. The wet cake was washed with 3: 1 heptane:ethyl acetate (75 mL), and the orange, crystalline solids were dried at 45 °C for 24 h to provide the title compound (15.35 g, 99.3% ee, 61% yield), which was contaminated with 11% of the meso isomer (vs. dl isomer).

References

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  2. “FDA approves Viekira Pak to treat hepatitis C”. Food and Drug Administration. December 19, 2014.
  3. “TECHNIVIE™ (ombitasvir, paritaprevir and ritonavir) Tablets, for Oral Use. Full Prescribing Information” (PDF). AbbVie Inc., North Chicago, IL 60064. Retrieved 28 July 2015.
  4. “FDA approves Technivie for treatment of chronic hepatitis C genotype 4”. Food and Drug Administration. July 24, 2015.
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Ombitasvir
Ombitasvir.svg
Systematic (IUPAC) name
Methyl ((R)-1-((S)-2-((4-((2S,5S)-1-(4-(tert-butyl)phenyl)-5-(4-((R)-1-((methoxycarbonyl)-L-valyl)pyrrolidine-2-carboxamido)phenyl)pyrrolidin-2-yl)phenyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate
Clinical data
Trade names Viekira Pak (with ombitasvir, paritaprevir, ritonavir and dasabuvir), Technivie (with ombitasvir, paritaprevir, and ritonavir)
Routes of
administration
Oral
Legal status
Legal status
Pharmacokinetic data
Bioavailability not determined
Protein binding ~99.9%
Metabolism amide hydrolysis followed by oxidation
Onset of action ~4 to 5 hours
Biological half-life 21 to 25 hours
Excretion mostly with feces (90.2%)
Identifiers
CAS Number 1258226-87-7
PubChem CID 54767916
ChemSpider 31136214
ChEBI CHEBI:85183 Yes
Synonyms ABT-267
Chemical data
Formula C50H67N7O8
Molar mass 894.11 g/mol

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 19
Patent 8268349
Expiration Aug 25, 2024. 8268349*PED expiration date: Feb 25, 2025
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 2 of 19
Patent 8466159
Expiration Sep 4, 2032
Applicant ABBVIE INC
Drug Application N206619 (Prescription Drug: VIEKIRA PAK (COPACKAGED). Ingredients: DASABUVIR SODIUM ; OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 3 of 19
Patent 9139536
Expiration Nov 9, 2028
Applicant ABBVIE INC
Drug Application N206619 (Prescription Drug: VIEKIRA PAK (COPACKAGED). Ingredients: DASABUVIR SODIUM ; OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 4 of 19
Patent 9044480
Expiration Apr 10, 2031
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 5 of 19
Patent 9006387
Expiration Jun 10, 2030
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 6 of 19
Patent 8691938
Expiration Apr 13, 2032
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 7 of 19
Patent 8686026
Expiration Jun 9, 2031
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 8 of 19
Patent 8685984
Expiration Sep 4, 2032
Applicant ABBVIE INC
Drug Application N206619 (Prescription Drug: VIEKIRA PAK (COPACKAGED). Ingredients: DASABUVIR SODIUM ; OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 9 of 19
Patent 8680106
Expiration Sep 4, 2032
Applicant ABBVIE INC
Drug Application N206619 (Prescription Drug: VIEKIRA PAK (COPACKAGED). Ingredients: DASABUVIR SODIUM ; OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 10 of 19
Patent 8642538
Expiration Sep 10, 2029
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 11 of 19
Patent 8501238
Expiration Sep 17, 2028
Applicant ABBVIE INC
Drug Application N206619 (Prescription Drug: VIEKIRA PAK (COPACKAGED). Ingredients: DASABUVIR SODIUM ; OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 12 of 19
Patent 8492386
Expiration Sep 4, 2032
Applicant ABBVIE INC
Drug Application N206619 (Prescription Drug: VIEKIRA PAK (COPACKAGED). Ingredients: DASABUVIR SODIUM ; OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 13 of 19
Patent 8420596
Expiration Apr 10, 2031. 8420596*PED expiration date: Oct 10, 2031
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 14 of 19
Patent 8399015
Expiration Aug 25, 2024. 8399015*PED expiration date: Feb 25, 2025
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 15 of 19
Patent 8188104
Expiration May 17, 2029
Applicant ABBVIE INC
Drug Application N206619 (Prescription Drug: VIEKIRA PAK (COPACKAGED). Ingredients: DASABUVIR SODIUM ; OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 16 of 19
Patent 7364752
Expiration Nov 10, 2020. 7364752*PED expiration date: May 10, 2021
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 17 of 19
Patent 7148359
Expiration Jul 19, 2019. 7148359*PED expiration date: Jan 19, 2020
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 18 of 19
Patent 6703403
Expiration Jun 26, 2016. 6703403*PED expiration date: Dec 26, 2016
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)
FDA Orange Book Patents: 19 of 19
Patent 6037157
Expiration Jun 26, 2016. 6037157*PED expiration date: Dec 26, 2016
Applicant ABBVIE INC
Drug Application N207931 (Prescription Drug: TECHNIVIE. Ingredients: OMBITASVIR; PARITAPREVIR; RITONAVIR)

/////Ombitasvir Hydrate, 1456607-70-7, Ombitasvir,  1258226-87-7, Viekira PakTM, Technivie, ABT-267, ABT 267, UNII-2302768XJ8, オムビタスビル 水和物 , phase II,  clinical development ,  AbbVie, Abbott,  chronic hepatitis C infection,  combination with ABT-450/ritonavir,  peginterferon alpha-2a/ribavirin (pegIFN/RBV), naïve Hepatitis C virus (HCV) genotype 1 infected patients.

O=C(Nc1ccc(cc1)[C@@H]5CC[C@@H](c3ccc(NC(=O)[C@@H]2CCCN2C(=O)[C@@H](NC(=O)OC)C(C)C)cc3)N5c4ccc(cc4)C(C)(C)C)[C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C

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