AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

What is SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem

 diabetes, Uncategorized  Comments Off on What is SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem
Jul 152015
 

A new “flozin” seems to me appearing on the horizon in form of SBM-TFC-039 an SGLT Inhibitor from Sirona Biochem, picked up a list from WO 2012160218,  from TFChem…….see link , Sirona Biochem Announces SGLT2 Inhibitor and Skin Lightening Patent Granted, 29 Jun 2015, Patent entitled “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”

This led me to search, “Family of aryl, heteroaryl, o-aryl and o-heteroaryl carbasugars”
WO 2012160218 A1, IN 2013-DN10635, CN 103649033Tf化学公司

Applicant Tfchem

 

Figure imgf000110_0001

List above as in http://www.google.com/patents/WO2012160218A1?cl=en

FROM THE ABOVE LIST, SBM-TFC-039 MAY BE PREDICTED/OR AS SHOWN BELOW

COMPD 16 as in/WO2012160218

 

 

COMPD 16

COMPD 16, PREDICTED/LIKELY SBM-TFC-039 has CAS 1413373-30-4, name D-​myo-​Inositol, 1-​[4-​chloro-​3-​[(4-​ethoxyphenyl)​methyl]​phenyl]​-​1,​2,​3-​trideoxy-​2,​2-​difluoro-​3-​(hydroxymethyl)​-

Just scrolling through the patent gave me more insight

MORE EVIDENCE….http://www.google.com/patents/WO2012160218A1?cl=en, this patent descibes compd 16 as follows

Compound 16 according to the invention has been compared to Dapaglifozin to underline the improvement of the duration of action, i.e. the longer duration of glucosuria, of the compound when the intracyclic oxygen atom of the glucose moiety is replaced by a CF2 moiety.

 

Figure imgf000091_0001

This assay has been carried out at a dose of 3 mg/ kg.

The results obtained are presented on Figure 5. It appears thus that 16 (3 mg/kg) triggered glucosuria that lasted beyond 24 hours compared to Dapagliflozin.

• Compound 16 according to the invention has been compared to the compound 9 of WO 2009/1076550 to underline the improvement of the duration of action of the compound when a mimic of glucose bearing a CH-OH moiety instead of the intracyclic oxygen atom is replaced by a mimic of glucose bearing a CF2 in place of the CH-OH moiet .

 

Figure imgf000092_0001
NOTE=COMPD 9 OF WO 2009/1076550 has  CAS 1161430-16-5, D-​scyllo– ​Inositol, 1-​[4-​chloro-​3-​[(4-​ethoxyphenyl)​methyl]​phenyl]​-​1,​3-​dideoxy-​3- ​(hydroxymethyl)​-  and  is very similar to the compd under discussion

 

Company Sirona Biochem Corp.
Description Sodium-glucose cotransporter 2 (SGLT2) inhibitor
Molecular Target Sodium-glucose cotransporter 2 (SGLT2)
Mechanism of Action Sodium-glucose cotransporter 2 (SGLT2) inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Preclinical
Standard Indication Diabetes
Indication Details Treat Type II diabetes
Regulatory Designation
Partner Shanghai Fosun Pharmaceutical Group Co. Ltd.

SBM-TFC-039

PATENT

WO 2012160218

http://www.google.com/patents/WO2012160218A1?cl=en

Examples within this first subclass include but are not limited to:

 

Figure imgf000019_0001

Synthesis of compound 8

C35H34O5 M = 534.64 g.mol

Mass: (ESI ): 535.00 (M + H); 552.00 (M + H20); 785.87; 1086.67 (2M + H20)

Figure imgf000053_0001

A.

 

Figure imgf000053_0002

Procedure A:

To a solution of 4 (10.5g, 15.89mmol, leq) in toluene (400mL) were added 18-crown-6 (168mg, 0.64mmol, 0.04eq) and potassium carbonate (6.69g, 48.5mmol, 3.05eq.). The mixture was stirred overnight at room temperature, and then the remising insoluble material was filtered off and washed with toluene. The filtrate and the washings were combined, washed with 2N hydrochloric acid aqueous solution followed by saturated sodium hydrogencarbonate aqueous solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford cyclohexenone 8 (4.07g; 48% yield) as yellowish oil.

Procedure B:

A solution of 7 (3.27g, 5.92mmol, leq) in pyridine (14mL) was cooled to 0°C before POCl3 (2.75mL, 29.6mmol, 5eq) was added dropwise. The mixture was stirred at this temperature for 10 min before the cooling bath was removed. The reaction mixture was stirred overnight at room temperature before being re-cooled to 0°C. POCI3 (2.75mL, 29.6mmol, 5eq) was added once again trying to complete the reaction. The mixture was stirred for an additional 20h at room temperature before being diluted with Et20 (20mL) and poured onto crushed ice. 1M HC1 aqueous solution (lOOmL) was added, and the mixture was extracted with Et20 (200mL & l OOmL). The combined organic extracts were washed with brine (lOOmL), dried over sodium sulphate, filtered and concentrated before being purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 80:20) to afford compound 8 (1.46g, 46% yield) as an orange oil. Synthesis of compound 9

C15H12BrC102 M = 339.61 g.moF1

Mass: (GC-MS): 338-340

 

Figure imgf000054_0001

The synthesis of this product is described in J. Med. Chem. 2008, 51, 1 145—1149.Synthesis of compound 10

C15H14B1CIO M = 325.63 g.mof1

 

Figure imgf000054_0002

10 The synthesis of this product is described in J. Med. Chem. 2008, 51, 1145-1 149.

Synthesis of compound 11

C50H49CIO6 M = 781.37 g.moF1

Mass: ESI+): 798.20 (M + H20)

 

Figure imgf000054_0003

Under inert atmosphere, Mg powder (265mg, 10.9mmol, 2.4eq) was charged into a three necked flask, followed by addition of a portion of 1/3 of a solution of the 4- bromo-l-chloro-2-(4-ethylbenzyl)benzene (2.95g, 9.1mmol; 2eq) in dry THF (25mL) and 1 ,2-dibromoethane (10 mol % of Mg; 85mg; 0.45mmol). The mixture was heated to reflux. After the reaction was initiated (exothermic and consuming of Mg), the remaining solution of 2-(4-ethylbenzyl)-4-bromo-l-chlorobenzene in dry TFIF was added dropwise. The mixture was then allowed to react for another one hour under gentle reflux until most of the Mg was consumed.

The above Grignard reagent was added dropwise into the solution of cyclohexenone 8 (2.42g, 4.53mmol, leq) in dry THF (25mL) under inert atmosphere at room temperature (about 25°C), then allowed to react for 3h. A saturated aqueous solution of ammonium chloride was added into the mixture to quench the reaction. The mixture was extracted with Et20, washed with brine, dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 100:0 to 80:20) to afford the target compound 11 as a yellow oil (3.01g, 86%).

Synthesis of compound 12

C5oH49C105 M = 765.37 g.mol“1

+): 782.13 (M + H20)

 

Figure imgf000055_0001

Triethylsilane (0.210mL, 1.30mmol, 3eq) and boron-trifluoride etherate (48% BF3, O. l lOmL, 0.866mmol, 2eq) were successively added into a solution of alcohol 1 1 (338mg, 0.433mmol, leq) in dichloromethane (5mL) under inert atmosphere at -20°C. After stirring for 2.5h, a saturated aqueous solution of sodium chloride was added to quench the reaction. The mixture was extracted with CH2C12 (10mLx3) and the organic layer was washed with brine, dried over Na2S04, filtrated and concentrated. The residue was purified on silica gel chromatography (cyclohexane/ethyl acetate 9.8:0.2 to 8:2) to afford the target compound 12 as a white powder (278 mg, 0.363mmol, 84%).

Synthesis of compound 13

C5oH5tC106 M = 783.39g.moF1

Mass: (ESI+): 800 (M + H20); 1581 (2M + H20)

Figure imgf000056_0001

Under inert atmosphere, borane-dimethyl sulfide complex (2M in THF, 16.7mL, 33mmol, 10.5eq) was added to a solution of 12 (2.41g; 3.15mmol, leq) in dry THF (lOOmL) cooled to 0°C. The reaction mixture was then refluxed for lh,cooled to 0°C and treated carefully with sodium hydroxide (3M in H20, 10.5mL, 31.5mmol, lOeq), followed by hydrogen peroxide (30% in H20, 3.2mL, 31.5mmol, l Oeq) at room temperature (above 30°C). The mixture was allowed to react overnight at room temperature (~25°C) before a saturated aqueous solution of ammonium chloride was added to quench the reaction. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 97:3 to 73:27) to afford the desired compound 13 (1.05g; 43%) as a yellowish oil.

Synthesis of compound 14

C50H49CIO6 M = 781.37g.mol“1

Mass: (ESI+): 798 (M + H20); 1471; 1579 (2M + H20)

 

Figure imgf000056_0002

13 14

Dess-Martin periodinane (81mg; 1.91mmol; 1.5eq) was added portion wise to a solution of alcohol 13 (l .Og; 1.28mmol, leq) in anhydrous dichloromethane (20mL) at 0°C. The reaction was then stirred overnight at room temperature before being quenched with IN aqueous solution of sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and concentrated. The residue was purified on silica gel chromatography (cyclohexane / ethyl acetate 98:2 to 82: 18), to afford the target ketone 14 (783mg, 79% yield) as a colorless oil. Synthesis of compound 15

C5oH49ClF206 M = 803.37g.moF1

19 F NMR (CDCU, 282.5MHz): -100.3 (d, J=254Hz, IF, CFF); -1 13.3 (td, Jl=254Hz, J2=29Hz, IF, CFF).

Mass: (ESI+): 820.00 (M+H20)

 

Figure imgf000057_0001

14 15

A solution of ketone 14 (421mg, 0.539mmol, leq) in DAST (2mL, 16.3mmol, 30eq.) was stirred under inert atmosphere at 70°C for 12h. The mixture was then cooled to room temperature and dichloromethane was added. The solution was poured on a mixture of water, ice and solid NaHC03. Agitation was maintained for 30min while reaching room temperature. The aqueous layer was extracted with dichloromethane and the organic phase was dried over Na2S04, filtered and concentrated. The crude product was purified on silica gel chromatography (cyclohexane/ethyl acetate 98:2 to 80:20) to afford the desired compound 15 as a yellowish oil ( 182mg, 42% yield).

Synthesis of compound 16

C22H25CIF2O5 M = 442.88g.mor1

19 F NMR (MeOD, 282.5MHz): -96.7 (d, J=254Hz, IF, CFF); 12.2 (td,

Jl=254Hz, J2=28Hz, IF, CFF).

Mass: (ESI+): 465.3 (M+Na)

 

Figure imgf000057_0002

o-Dichlorobenzene (0.320mL, 2.82mol, lOeq) followed by Pd/C 10% (0.342g, 0.32mol, l .leq) were added to a solution of 15 (228mg, 0.28mmol, leq) in a mixture of THF and MeOH (2: 1, v/v, 160mL). The reaction was placed under hydrogen atmosphere and stirred at room temperature for 2h. The reaction mixture was filtered and concentrated before being purified on silica gel chromatography (dichloromethane/methanol 100: 1 to 90: 10) to afford compound 16 (105mg, 83% yield).

 …………………….
CN 103649033

Sirona Biochem’s SGLT Inhibitor Performs Better Than Johnson and Johnson’s SGLT Inhibitor, According to Study

Vancouver, British Columbia – December 7, 2012 – Sirona Biochem Corp. (TSX-V: SBM), announced its sodium glucose transporter (SGLT) inhibitor for Type 2 diabetes reduced blood glucose more effectively than Johnson and Johnson’s canagliflozin, an advanced SGLT inhibitor being considered for market approval in Europe and the U.S.  Studies compared Sirona Biochem’s SGLT Inhibitor, SBM-TFC-039, with canagliflozin and were conducted on Zucker Diabetic Fatty (ZDF) rats.

In the study, SBM-TFC-039 significantly and rapidly reduced blood glucose levels at a dose of 1.0 mg/kg.  Six (6) hours after administration, SBM-TFC-039 reduced blood glucose by 44% compared to canagliflozin at 26%.  SBM-TFC-039 also had a longer duration of effect than canagliflozin.  At 36 and 48 hours after treatment, SBM-TFC-039, at a dose of 1.0 mg/kg, was still effective at reducing blood glucose, whereas canagliflozin lost its effect after 36 hours.  Studies were conducted at the Institut Universitaire de Cardiologie et de Pneumologie de Québec (IUCPQ) by Principal Investigator Dr. Denis Richard, Research Chair on Obesity and Professor, Faculty of Medicine, Department of Anatomy & Physiology at Laval University.

“SGLT Inhibitors are a ground-breaking new treatment for Type 2 diabetes and these results demonstrate that SBM-TFC-039 will be a significant competitor for other SGLT Inhibitors,” said Neil Belenkie, Chief Executive Officer of Sirona Biochem. “The first SGLT Inhibitor,Forxiga™, was approved last month by the European Commission.  We believe there is tremendous market potential worldwide for SGLT Inhibitors in the treatment of diabetes.”

SBM-TFC-039 is a sodium glucose transporter (SGLT) inhibitor.  SGLT inhibitors are a new class of drug candidates for the treatment of diabetes. In the kidneys, SGLT inhibitors reduce the reabsorption of glucose into the bloodstream by eliminating excess glucose into the urine.

About Sirona Biochem Corp.
Sirona Biochem is a biotechnology company developing diabetes therapeutics, skin depigmenting and anti-aging agents for cosmetic use, biological ingredients and cancer vaccine antigens.  The company utilizes a proprietary chemistry technique to improve pharmaceutical properties of carbohydrate-based molecules. For more information visit www.sironabiochem.com.

Laboratory – France
TFChem
Voie de l’innovation
Pharma Parc II
Chaussée du Vexin
27100 Val de Reuil
France

Phone:
+33(0)2.32.09.01.16
Fax:+33(0)2.32.25.07.64


 

……………………………………………………………………………….

Shanghai Fosun Pharmaceutical Group Co. Ltd.

//////

Share

ALOGLIPTIN

 diabetes  Comments Off on ALOGLIPTIN
Jul 062015
 

Alogliptin.svg

 

ALOGLIPTIN

Alogliptin is a potent, selective inhibitor of DPP-4 with IC50 of <10 nM, exhibits greater than 10,000-fold selectivity over DPP-8 and DPP-9.

Alogliptin (trade name Nesina in the US[1] and Vipidia in Europe[2]) is an orally administered anti-diabetic drug in the DPP-4 inhibitor class,[3] developed by Syrrx, a company which was acquired by Takeda Pharmaceutical Company in 2005. Like other medications for the treatment of Type 2 diabetes, alogliptin does not decrease the risk of heart attack and stroke. Like other members of the gliptin class, it causes little or no weight gain, exhibits relatively little risk of causing hypoglycemia, and exhibits relatively modest glucose-lowering activity. Alogliptin and other gliptins are commonly used in combination with metformin in patients whose diabetes cannot adequately be controlled with metformin alone.[4]

Clinical study

Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) that is designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). [5]

A randomized clinical trial reporting in 2011 aimed to determine the efficacy and safety of alogliptin versus placebo and vogliboseamong newly diagnosed Type 2 diabetes patients in Japan. The main outcome indicated that alogliptin was statistically superior to both comparitors.[6]

A randomized clinical trial reporting in 2012 aimed to demonstrate that alogliptin was “non-inferior” to a “very low fat/calorie traditional Japanese diet” among newly diagnosed Type 2 diabetes patients in Japan. The outcome indicated that both the drug and dietary treatments comparably impacted indicators of the diabetic condition, such as HbA1c levels and glycemic efficacy. The drug treatment had its impact without changing body mass index (BMI), but the dietary treatment was accompanied by a significant reduction in the BMI.[7]

A randomized clinical trial reporting in 2011 aimed to demonstrate the efficacy of alogliptin as an add-on agent in combination withmetformin and pioglitazone versus simply increasing the dosage of pioglitazone in combination with metformin; in other words, this was a study to look at a three-agent therapy versus a two-agent therapy. The outcome of this study suggested that the addition of alogliptin to metformin and pioglitazone provided superior impact on diabetes biomarkers (e.g. HbA1c) than increasing the dose of pioglitazone in a two agent therapy with metformin.[8]

Reported adverse events

Adverse events appear to be restricted to mild hypoglycemia based on clinical studies.[6][7][8]

Alogliptin is not associated with increased weight, increased risk of cardiovasular events, or heart failure.[9][10]

Market access

In December 2007, Takeda submitted a New Drug Application (NDA) for alogliptin to the United States Food and Drug Adminiistration (USFDA),[11] after positive results from Phase III clinical trials.[1] In September of 2008, the company also filed for approval in Japan,[12] winning approval in April 2010.[11] The company also filed a Marketing Authorization Application (MAA) elsewhere outside the United States, which was withdrawn in June 2009 needing more data.[12] The first USFDA NDA failed to gain approval and was followed by a pair of NDAs (one for alogliptin and a second for a combination of alogliptin and pioglitazone) in July 2011.[11] In 2012, Takeda received a negative response from the USFDA on both of these NDAs, citing a need for additional data.[11]

In 2013 the FDA approved the drug in three formulations: As a stand-alone with the brand-name Nesina. Combined with metforminusing the name Kazano, and when combined with pioglitazone as Oseni.

Diabetes affects millions of people worldwide and is considered one of the main threats to human health in the 21st century. In 2006, the World Health Organization (WHO) estimated that over 180 million people worldwide had diabetes, and the number is projected to double by 2030. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. According to the WHO, approximately 1.1 million people died from diabetes in 2005, and it is estimated that diabetes-related deaths will increase by more than 50% in the next decade. Globally, the socioeconomic burden of diabetes is substantial.

There are two main types of diabetes, designated type 1 and type 2, with type 2 diabetes accounting for over 90% of all diabetes cases globally. Type 1 diabetes is characterized by insulin deficiency, primarily caused by autoimmune-mediated destruction of pancreatic islet β-cells, and type 2 diabetes is characterized by abnormal insulin secretion and concomitant insulin resistance. To prevent the development of ketoacidosis, people with type 1 diabetes must take exogenous insulin for survival. Although those with type 2 diabetes are not dependent on exogenous insulin as much as subjects with type 1 diabetes, they may require exogenous insulin to control blood glucose levels.

As diabetes has become a global health concern, research interest in the condition has rapidly increased. In addition to studies on prevention, many studies with the aim of developing new interventions for the treatment of diabetes, especially type 2 diabetes, have been conducted. Currently available medications for the treatment and management of type 2 diabetes include metformin, sulfonylureas, thiazolidinediones and insulin. However, these therapies are commonly associated with secondary failure and may cause hypoglycemia. Insulin resistance and progressively worsening hyperglycemia caused by reduced β-cell function are major challenges in managing type 2 diabetes. Evidence suggests that patients with insulin resistance do not develop hyperglycemia until their β-cells are unable to produce enough insulin. New agents that can enhance insulin secretion from islet β-cells in a sustained glucose-dependent manner could therefore hold promise for the treatment of type 2 diabetes.

One promising approach is based on inhibition of the serine protease dipeptidyl- peptidase IV (DPP IV), a postproline dipeptidyl aminopeptidase that belongs to the S9b peptidase family of proteolytic enzymes. It is known that DPP IV plays a key role in maintaining glucose homeostasis by controlling the incretin activity of glucagon-like peptide 1 (GLP-I) and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide). Inhibition of DPP IV is therefore recognized as a novel therapeutic approach for the treatment of type 2 diabetes.

Recently, a series of DPP IV inhibitors were developed. Among these highly potent compounds, alogliptin benzoate (SYR-322) and its analogs demonstrated encouraging antidiabetic efficacy (EP 1586571 (WO 2005/095381); WO 2008/067465; WO 2007/035379, and US 2004/097510).

Alogliptin benzoate can be prepared as described in EP 1586571 (WO 2005/095381) according to the process set forth in Scheme 1 :

Figure imgf000004_0001

Scheme 1

In accordance with this process, 6-Chlorouracil (1) is alkylated with 2- (bromomethyl)benzonitrile in the presence of NaH and LiBr in a mixture of DMF- DMSO to produce the TV-benzyluracil derivative (2) in 54% yield. Compound (2) is further alkylated with iodomethane and NaH in DMF/THF to give the 1 ,3 disubstituted uracil (3) in 72% yield. Subsequent displacement of chlorouracil (IV) with 3(R)- aminopiperidine dihydrochloride in the presence of either NaHCO3 in hot methanol or K2CO3 in aqueous isopropanol provides alogliptin (4), which is isolated as the corresponding benzoate salt by treatment with benzoic acid in ethanol. The overall yield of this three-stage process is -20-25%. One of the disadvantages of above described process is the difficulty to separate and purify mixtures of solvents with high boiling point (for example, DMF/DMSO) for recycling. Another disadvantage is the usage of hazardous materials such as sodium hydride, which requires anhydrous solvents as a reaction media.

Intermediate 2-((6-chloro-3-methyl-2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)methyl) benzonitrile (3) is alternatively obtained by alkylation of 6-chloro-3 methyluracil with 2-(bromomethyl)benzonitrile by means of diisopropylethylamine in hot NMP (WO 2007/035629). Although this process is more technological than the previously described process (EP 1586571), the overall yield is still moderate (50-55%). The problem of mixed solvents (toluene, NMP, diisopropylethylamine) separation persists for this process as well.

………….

http://www.google.com/patents/EP2410855A1?cl=en

EXAMPLE 1

Preparation of (R)-2-((6-(3 -aminopiperidin-l-yl)-3 -methyl-2,4-dioxo-3 ,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile (alogliptin) via 6-chloro-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (Scheme 3):

Figure imgf000025_0001

Scheme 3

Preparation of l-(2-isocyanobenzyl)-3-methylurea

2-cyanobenzylamine hydrochloride (90 g) and Dichloromethane (800 ml) were taken into a round bottomed (RB) flask. Methyl isocyanate (45.6 g) was added at 5°C. Triethylamine (81 g) in Dichloromethane (300 ml) was added at the same temperature and stirred at room temperature for 16h. Water (1 L) was added and stirred for 30 min. The obtained solid was collected by filtration and dried in oven at 50°C for 12h. The yield is 85% and the purity 99.8%.

Preparation of l-(2-isocyanobenzyl)-3-methyIpyrimidine-2,4,6(lH,3H,5H)-trione

a). To a stirred solution of 0.11 mol of sodium ethanolate in 80 ml of ethanol abs. was added 0.1 mol of l-(2-isocyanobenzyl)-3-methylurea and 0.1 mol diethyl malonate. The mixture was refluxed for 3-5 h. The cooled residue was acidified with 0.1 M hydrochloric acid (60 ml). The solid which separated was filtered off and recrystallized from ethanol or any suitable solvent. The yield is 78-85% and purity >95%.

b). In an alternate embodiment, l-(2-isocyanobenzyl)-3-methylurea (30 g), acetic acid (105 ml) and malonic acid (18 g) were mixed and heated to 60°C. Acetic anhydride (60 ml) was added at 60°C and heating was continued for two hours at 80°C. The reaction mixture was poured over ice water (300 ml) and the obtained solid was filtered, washed with water (1×500 ml) and methyl-tert-butylether (100 ml). The yield is 60% with 93.4% purity.

The compound thus prepared can be used for the next step without purification or purified by crystallization or column chromatography.

Preparation of 6-chloro-l-(2-isocyanobenzyl)-3-methylpyriinidine-2,4(lH,3H)- dione

a). l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4,6(lH,3H,5H)-trione (30 g) was mixed with phosphorus oxychloride (300 ml) and cooled to 0°C. Water (9 ml) was added slowly, stirred for 10 min. and heated to reflux at 110°C for 5h. Progress of the reaction was monitored by TLC (50% Ethyl acetate/Hexane). On completion of the reaction, phosphorus oxychloride was distilled off. The crude compound was dissolved in dichloromethane (500 ml) and poured into ice water (500 ml) by small portions. The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. The mixture of two isomers (4-chloro and 6-chloro derivatives = 1:1) was isolated and separated by column chromatography using neutral alumina and eluent – 25-50% of ethylacetate and hexane). The off-white solid was obtained, yield – 37%, purity – 99.8%. 1H NMR corresponds to literature data (J. Med. Chem. 2007, 50, 2297-2300).

b). In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2,4,6(1 H,3H,5H)-trione (18 mmol), phosphorus oxychloride (85 ml), benzyltriethylammonium chloride (16.5 g, 72 mmol) and phosphorus pentachloride (3.8 g, 18 mol) in acetonitrile (80 ml) was refluxed for 4-5 h with stirring. After evaporation under reduced pressure, the resulting oily residue was mixed with methylene chloride (or chloroform) and the mixture was poured into water and ice (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Crude product was crystallized from THF-hexanes to give desired compound in 70.5% yield.

c). In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2,4,6(1 H,3H,5H)-trione (13.1 mmol) in POCl3 (30 ml) was refluxed for 1-3 h. The solvent was concentrated and then partitioned with CH2Cl2 (100 ml) and water (100 ml). The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 6-chloro compound as a solid (-95%). Compound can be also precipitated from concentrated methylene chloride solution by hexanes and used as a crude for the next step or purified by reslurring in isopropanol, filtered off, washed with isopropanol, and dried under vacuum at 55-60° C.

Preparation of (R)-tert-butyl l-(3-(2-isocyanobenzyI)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate

a). 6-chloro- l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (13 g), Dimethylformamide (130 ml), Potassium carbonate (13 g) and tert-butyl (R)-piperidin- 3-ylcarbamate (10.4 g) were heated to 80°C for 7 hrs. The mixture was then allowed to come to room temperature and poured over ice water (500 ml). The obtained solid was filtered and washed with cold water (500 ml). The solid thus obtained was taken in Methyl-tert-butylether (50 ml) stirred for 10 min. filtered and washed with Hexane (50 ml), to give the N-tert-butyloxycarbonyl protected compound in -75% yield. b). In an alternate embodiment, a flask charged with a stir bar, 6-chloro-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (4.10 mmol), (Λ)-3- terrtnityloxycarbonylaminopiperidine (4.64 mmol), K2CO3 (1.15 g, 8.32 mmol) and DMF (12 mL) was stirred at 75 °C for 6 h. Then, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give the N-ter/butyloxycarbonyl protected compound in -93-96% yield.

Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile salts

a). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile hydrochloride

The crude (R)-tert-butyl l-(3-(2-isocyanobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate from previous procedure was dissolved in THF and acidified with 6M hydrochloric acid while maintaining the temperature below 15° C. The resultant slurry was cooled to 0-5° C, stirred at this temperature for 3-5 h and then filtered. The filter cake was washed twice with isopropanol and dried in vacuum at 45-5O0C to provide hydrochloride as a white crystalline solid.

b). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile trifluoroacetate

TFA (ImL) was added into the methylene chloride solution of (R)-tert-butyl l-(3-(2- isocyanobenzyl)- 1 -methyl-2,6-dioxo- 1 ,2,3,6-tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate from the above-mentioned procedure. The solution was stirred at room temperature for 1 h and then the mixture was concentrated in vacuo. The residue was dissolved in a small amount of MeOH or isopropanol and the desired salt was precipitated by addition of diisopropyl ether. The solids were filtered off, washed with diisopropyl ether and dried in vacuum at 45-5O0C to provide trifluoroacetate as an off- white powder. c). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile benzoate (Alogliptin)

The crude (R)-tert-butyl l-(3-(2-isocyanobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate was dissolved in ethanol. A solution of benzoic acid in ethanol was added and the mixture was slowly heated to 65-70°C. The solution was stirred at this temperature for Ih and was then crystallized by cooling to 0-5° C and stirring for 12 hrs. The solution was filtered, washed with alcohol. The wet cake was then conditioned under nitrogen for 2 hours. The cake was dried for 8 hrs at 40-50° C to provide the benzoic acid salt of alogliptin as a white crystalline solid.

EXAMPLE 2:

Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile (alogliptin) via 6-amino-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (Scheme 4)

Figure imgf000029_0001
Figure imgf000029_0002

Scheme 4 Preparation of 6-amino-l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)- dione

a). l-(2-isocyanobenzyl)-3-methylurea (0.2 mol) and cyanoacetic acid (0.22 mol) were dissolved in acetic anhydride (400 ml), and the mixture was heated at 80°C for 2 hours. Acetic anhydride was distilled off under reduced pressure and water (200 ml) was added. The mixture was cooled to 0-5 0C and 2N NaOH solution (220 ml) was added and stirring was continued for 2 hours. The obtained solids were filtered off, washed with cold methanol and dried under vacuum. The yield of 6-amino-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione was 72 %.

b). Under nitrogen atmosphere, l-(2-isocyanobenzyl)-3-methylurea (98.4 g) and cyanoacetic acid (80.0 g) was added to N,N-dimethylformamide (836 ml). The mixture was stirred at room temperature and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at this temperature. The mixture was stirred at room temperature for 4 hrs, cooled with water, and water-isopropanol [2:1 (volume ratio), 1670 ml] was added drop wise. The mixture was stirred under water-cooling for 1 hr, and the precipitated crystals were collected by filtration and dried to give 3-(2-cyano-acetyl)-3- methyl-l-(2-isocyanobenzyl)-urea with 68% yield.

To 3-(2-cyano-acetyl)-3-methyl-l-(2-isocyanobenzyl)-urea (120 g) were added water (962 ml) and 2N aqueous sodium hydroxide solution (24.9 ml), and the mixture was stirred with heating at 80° C for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give 6-amino-l-(2-isocyanobenzyl)-3- methylpyrimidine-2,4(lH,3H)-dione in 76% yield.

c). 6-amino-l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (0.1 mol) was mixed with (R)-piperidin-3-yl-carbamic acid tert.-butyl ester hydrochloride (0.1 mol) of the appropriate amine hydrochloride and (R)-piperidin-3-yl-carbamic acid tert.-butyl ester (0.1 mol). The mixture was heated at 100°C and bubbling continued for 3 hr. Water was added to the cooled mixture and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give N-tert-butyloxycarbonyl protected compound in ~93-96% yield.

d). Benzoate salt of alogliptin was prepared as described above. While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.

………………

Patent EP2410855A1

http://www.google.com/patents/EP2410855A1?cl=en

…………..

http://photo.blog.sina.com.cn/list/blogpic.php?pid=53891ebegd4e8671b28dc&bid=53891ebe0101grmv&uid=1401495230

 

NMR

Alogliptin.png

SOURCE  APEXBT

NMR

 

NMR

References

  1.  “Takeda Submits New Drug Application for Alogliptin (SYR-322) in the U.S.” (Press release). Takeda Pharmaceutical Company. January 4, 2008. Retrieved January 9, 2008.
  2.  Vipidia: EPAR summary for the public (European Medicines Agency)
  3. Feng, Jun; Zhang, Zhiyuan; Wallace, Michael B.; Stafford, Jeffrey A.; Kaldor, Stephen W.; Kassell, Daniel B.; Navre, Marc; Shi, Lihong; Skene, Robert J.; Asakawa, Tomoko; Takeuchi, Koji; Xu, Rongda; Webb, David R.; Gwaltney II, Stephen L. (2007). “Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV”. J. Med. Chem.50 (10): 2297–2300.doi:10.1021/jm070104l.PMID 17441705.
  4.  “www.aace.com” (PDF).
  5. http://www.takeda.com/news/2013/20130618_5841.html
  6.  Seino, Yutaka; Fujita, Tetsuya; Hiroi, Shinzo; Hirayama, Masashi; Kaku, Kohei (September 2011), “Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study (abstract only)”, Current Medical Research and Opinion 27 (9): 1781–1792,doi:10.1185/03007995.2011.599371,PMID 21806314, retrieved April 26,2012
  7.  Kutoh, Eiji; Ukai, Yasuhiro (2012),“Alogliptin as an initial therapy in patients with newly diagnosed, drug naïve type 2 diabetes: a randomized, control trial (abstract only)”, Endocrine(January 17, 2012), doi:10.1007/s12020-012-9596-0, PMID 22249941, retrieved April 26, 2012
  8. Bosi, Emanuele; Ellis, G.C.; Wilson, C.A.; Fleck, P.R. (October 2011), “Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study”, Diabetes, Obesity and Metabolism (October 27, 2011) 13 (12): 1088–1096, doi:10.1111/j.1463-1326.2011.01463.x, retrieved April 26,2012
  9.  White WB, Cannon CP, Heller SR et al. (October 2013). “Alogliptin after acute coronary syndrome in patients with type 2 diabetes”. N. Engl. J. Med. 369(14): 1327–35.doi:10.1056/NEJMoa1305889.PMID 23992602.
  10.  White WB, Zannad F (January 2014). “Saxagliptin, alogliptin, and cardiovascular outcomes”. N. Engl. J. Med. 370 (5): 484.doi:10.1056/NEJMc1313880.PMID 24482824.
  11.  Grogan, Kevin (April 26, 2012),“FDA wants yet more data on Takeda diabetes drug alogliptin”,PharmaTimes (PharmaTimes), PharmaTimes online, retrieved April 26,2012
  12. “GEN News Highlights: Takeda Pulls MAA for Type 2 Diabetes Therapy”. Genetic Engineering & Biotechnology News. June 4, 2009.
EP1083172A1 * May 26, 1998 Mar 14, 2001 Rimma Iliinichna Ashkinazi N-substituted derivatives of 5-oxyiminobarbituric acid
US2598936 * Apr 13, 1950 Jun 3, 1952 Searle & Co Disubstituted cyanoalkanoylureas and thioureas and methods for their production
US6066641 * Dec 12, 1995 May 23, 2000 Euro-Celtique S.A. Aryl thioxanthines
US6248746 * Jan 7, 1999 Jun 19, 2001 Euro-Celtique S.A. 3-(arylalkyl) xanthines
US20080194593 * Jan 11, 2008 Aug 14, 2008 Rao Kalla A2b adenosine receptor antagonists
WO1994003456A1 * Aug 5, 1993 Feb 17, 1994 Boehringer Ingelheim Kg Asymmetrically substituted xanthine with adenosine-antagonistic properties
WO2001029010A1 * Oct 18, 2000 Apr 26, 2001 Amjad Ali Gram-positive selective antibacterial compounds, compositions containing such compounds and methods of treatment
WO2007035629A2 * Sep 15, 2006 Mar 29, 2007 Takeda Pharmaceutical Process for the preparation of pyrimidinedione derivatives
WO2007150011A2 * Jun 22, 2007 Dec 27, 2007 Smithkline Beecham Corp Prolyl hydroxylase inhibitors
Alogliptin
Alogliptin.svg
Systematic (IUPAC) name
2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile
Clinical data
Trade names Nesina, Vipidia
Kazano, Vipidomet (withmetformin)
Oseni, Incresync (withpioglitazone)
Pregnancy
category
  • US: B (No risk in non-human studies)
Legal status
  • (Prescription only)
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 100%
Protein binding 20%
Metabolism Limited, hepatic (CYP2D6– and3A4-mediated)
Biological half-life 12–21 hours
Excretion Renal (major) and fecal (minor)
Identifiers
CAS Registry Number 850649-62-6 Yes BENZOATE850649-61-5 FREE BASE
ATC code A10BH04
PubChem CID: 11450633
IUPHAR/BPS 6319
ChemSpider 9625485 Yes
UNII JHC049LO86 Yes
KEGG D06553 Yes
ChEBI CHEBI:72323 
ChEMBL CHEMBL376359 Yes
Synonyms SYR-322
Chemical data
Formula C18H21N5O2
Molecular mass 339.39 g/mol

 

Alogliptin benzoate

MF: C18H21N5O2.C7H6O2
MW: 461.519
Melting Point: 185-188°C
Optical Rotation: -56.3° (c=1, MeOH)

Solubility:Soluble in MeOH; Insoluble in ACN

850649-62-6  CAS

 

 

DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK

Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

 amcrasto@gmail.com

09b37-misc2b027LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

 

Share

Sitagliptin

 diabetes, Uncategorized  Comments Off on Sitagliptin
Jul 052015
 

Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry

A practical and economical approach to synthesize sitagliptin

Volume 43, Issue 24, 2013

DOI:
10.1080/00397911.2013.773353

Kuaile Lina, Zhengyan Caia & Weicheng Zhoua*

pages 3281-3286

1Kuaile Lin, Zhengyan Cai, Weicheng Zhou*
State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of
Anti-Infectives,
Shanghai Institute of Pharmaceutical Industry, State Institute
ofPharmaceutical Industry, Shanghai 200437, China
* Corresponding author: Weicheng Zhou, profzhouwc@yahoo.com.cn, Tel./fax: +8621 35052484
Economic syntheses of sitagliptin phosphate monohydrate, acknowledged as the first dipeptidyl peptidase 4 (DPP-4) inhibitor, have been achieved in an overall yield of 42.4% in four steps from 1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)butane-1,3-dione. The key stereoselective reduction of this process was carried out by NaBH4/HCOOH instead of expensive and toxic catalysts or ligands.
 LOOK FOR SUPPLEMENTARY INFO IN ABOVE PAPER 
 

tga

.

 
………………………….

 

NMR
SEE AN ONLINE NMR BELOW




 

NMR…………http://file.selleckchem.com/downloads/nmr/S400205-Sitagliptin-phosphate-monohydrate-HNMR-Selleck.pdf





………………….

 
PAPER





Graphical abstract: Quantitative analysis of sitagliptin using the 19F-NMR method: a universal technique for fluorinated compound detection

 

http://pubs.rsc.org/en/content/articlelanding/2014/an/c4an01681e#!divAbstract

Quantitative analysis of sitagliptin using the 19F-NMR method: a universal technique for fluorinated compound detection

*
Corresponding authors
a
State Key Laboratory of
Natural Medicines, Department of Pharmaceutical Analysis, China
Pharmaceutical University, Nanjing 210009, China E-mail:
ayanju@163.com
b
Shanghai Institute for Food and Drug Control, Shanghai 201203, China
c
Department of Chemistry
and Chemical Engineering, Royal Military College of Canada, Kingston,
Canada
d
Pharmaceutical Research
Institute, China Pharmaceutical University, Nanjing 210009, China E-mail:
cpunmrswb@163.com
Analyst, 2015,140, 280-286


DOI:
10.1039/C4AN01681E

 


Vishva Shah, Royal Military College of Canada


 

CHECK OUT PREDICTIONS
UNDERSTAND THE SIGNALS
PREDICTIONS 1H NMR

Sitagliptin phosphate monohydrate NMR spectra analysis, Chemical CAS NO. 654671-77-9 NMR spectral analysis, Sitagliptin phosphate monohydrate H-NMR spectrum

PREDICTIONS 13 C NMR
LOOK FOR DELTA VALUES OF GROUPS
Sitagliptin phosphate monohydrate NMR spectra analysis, Chemical CAS NO. 654671-77-9 NMR spectral analysis, Sitagliptin phosphate monohydrate C-NMR spectrum
COSY NMR PREDICTION

BELOW PAPENT DESCIBES THIS DRUG WELL IS RANDOMLY CHOSEN


http://www.google.com/patents/EP2491040A2?cl=en

The present invention relates to a novel method of preparing sitagliptin, and intermediates used therein. BACKGROUND OF THE INVENTION
Sitagliptin phosphate is a selective inhibitor of the second generation dipeptidyl peptidase IV (DPP-4) and used to maintain the systemic concentration of incretin hormone at an optimum level. Sitagliptin phosphate monohydrate was approved in October 2006 by the US Food and Drug Administration (FDA) as an adjuvant in dietetics or kinesiatrics for treatment of patients with type-2 diabetes and it is marketed in the United States and Korea under the trade name of JANUVIA™ (as a single agent).
Various methods for preparing sitagliptin and sitagliptin phosphate have been developed. For example, International Patent Publication WO 2003/004498 discloses a method of introducing a chiral-amine group using a chiral pyrazine derivative and to prepare sitagliptin by Arndt-Eistert Homologation using t-butoxylcarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid as a sitagliptin intermediate, as shown in Reaction Scheme 1.
Reaction Scheme 1
Figure imgf000003_0001
Wherein,
Boc is tert-butoxycarbonyl, TEA is trimethylamine, HOBt is 1- hydroxybenzotriazole, EDC is N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide, and DIPEA is N,N-diisopropylethylamine.
International Patent Publication WO 2004/087650 discloses a method for preparing sitagliptin phosphate comprising the steps of: subjecting (2,4,5- trifluorophenyl)acetic acid to two-step reactions to obtain methyl 4-(2,4,5- trifluorophenyl)-3-oxophenylbutylate; conducting a stereoselective reduction of the resulting compound in the presence of (S)-BrNAP-RuCl2-Et3N under a high hydrogen pressure; hydrolyzing the reduced product to obtain (3S)-3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid, a key sitagliptin intermediate; and subjecting (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid to seven-step processes to obtain sitagliptin phosphate, as shown in Reaction Scheme 2.
Reaction Scheme 2
Figure imgf000004_0001
Wherein,
BINAP is 2,2′-bis(diphenylphosphino)-l,l’-binaphthyl, EDC is N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide, Bn is benzyl, DIAD is diisopropyl azodicarboxylate, NMM is N-methylmorpholine, and ACN is acetonitrile.
Further, International Patent Publication WO 2004/085661 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using a platinum catalyst, PtO2, as shown in Reaction Scheme 3. Reaction Scheme 3
Figure imgf000005_0001

Further, WO 2005/097733 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine employing a rhodium-based catalyst, [Rh(cod)Cl]2 having a chiral diphosphine ligand, as shown in Reaction Scheme 4.

Figure imgf000005_0002
The document [J. Am. Chem. Soc, 2009, 131, p.l 1316-11317] discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using a ruthenium-based catalyst, Ru(OAc)2 having a chiral diphosphine ligand, and International Patent Publication WO 2009/064476 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using Ru(OAc)2and a chiral diphosphine ligand, or using a chiral acid together with a borohydride reducing agent (e.g., NaBH4).
Reaction Scheme 5
Figure imgf000009_0001
Example 1: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)- oxirane
Figure imgf000013_0001
Step 1 : Preparation of (2S)-3-(2A5-trifluorophenyl)-l-chloro-2-propanol
Magnesium (Mg) (1.26 g) was suspended in tetrahydrofuran (THF) (10 ml), and a drop of 1,2-dibromoethane was added thereto. To the resulting mixture, 2,4,5-trifluorobenzene bromide (0.55 g) was added dropwise slowly and then stirred for 30 min. 2,4,5-trifluorobenzene bromide (9.0 g) dissolved in THF (50 ml) was added slowly dropwise to the resulting mixture for 30 min and then stirred at room temperature for 1 hour. Cul (0.72 g) was added to the resulting mixture and the reaction temperature was cooled to 0°C . (S)- epichlorohydrin (4.1 ml) dissolved in THF (40 ml) was added dropwise to the resulting mixture slowly over 30 min, heated to room temperature, and stirred for 2 hours. Satuated NH4CI (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with 50 ml of satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound.
Step 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane
(2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml), and NaOH (2.3 g) was added dropwise thereto. The resulting mixture was stirred for 1 hour and methanol was removed therefrom under a reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (6.8 g; yield: 80%).
1H-NMR(300MHz, CDC13): 6 7.17-7.05 (2H, m), 6.96-6.88 (2H, m), 3.16-3.13 (1H, m) 3.14 (1H, dd, J=4.68, 14.7), 2.82-2.77 (2H, m), 2.54-2.47 (1H, m). Preparation Example 2: Preparation of (2S)-2-(2,4,5-trifIuorobenzyl)- oxirane
Figure imgf000014_0001
Step 1 : Preparation of (2S)-3-(2A5-trifluorophenyl)-l-chloro-2-propanol
2N -PrMgCl (26 ml) suspended in THF was added dripwise to the 2,4,5-trifluorobenzene bromide (9.55 g) dissolved in THF (30 ml) at -15 °C for 60 min. Cul (0.72 g) was added thereto at -15 °C , and heated to -10 °C . (S)- epichlorohydrin (4.1 ml) dissolved in THF (40 ml) was added slowly to the resulting mixture, and stirred at 0 °C for 1 hour. Satuated NH4C1 (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with 50 ml of satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound.
Step 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane (2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in 50 ml of methanol, and NaOH (2.3 g) was added dropwise thereto. A mixture was stirred for 1 hour, and methanol was removed therefrom under a reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added thereto, and the organic layer formed thereafter was separated. The separated organic layer was washed with satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (7.6 g; yield: 85%). Example 1: Preparation of Sitagliptin
Step 1: Preparation of (2R)-l-(2,4,5-trifluorophenyl -4-pentene-2-ol
Figure imgf000015_0001
CuBr(CH3)2 (3.3 g) was added to a reactor under the nitrogen atmosphere and cooled to -78 °C . Vinylmagnesium bromide (240 ml) was added slowly to the reactor and stirred for 20 min. (2S)-2-(2,4,5- trifluorobenzyl)-oxirane (30 g) dissolved in THF (90 ml) was added dropwise slowly over 30 min, stirred at -78 °C for 30 min, and heated to 0 °C . 2N aqueous HC1 (300 ml) was added slowly to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed twice with satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (34.5 g; yield: 100%).
1H-NMR(300MHz, CDC13): δ 7.15-7.06 (1H, m), 6.94-6.86 (1H, m), 5.85-5.79 (1H, m), 5.20-5.14 (2H, m), 3.90-3.85 (1H, m), 3.82 (1H, dd, J=4.6, 18.5), 2.69 (1H, dd, J=7.9, 14.0), 2.37-2.32 (1H, m), 2.24-2.17 (1H, m), 1.86(1H, Br). Step 2: Preparation of (2S)-l-(2-azido-4-pentenyl)-2A5-trifluorobenezene
Figure imgf000016_0001
Dichloromethane (300 ml) was added to the (2R)-1 -(2,4,5- trifluorophenyl)-4-pentene-2-ol obtained in step 1, and cooled to 0°C . Triethylamine (20.4 ml) and 4-dimethylaminopyridine (DMAP) (1.57 g) were added successively to the mixture, and methansulfonyl chloride (1 1.2 ml) was added dropwise thereto for 30 min. The resulting mixture was stirred for 1 hour, water (150 ml) was added, and the organic layer formed thereafter was separated. The separated organic layer was washed twice with satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure. The residue thus obtained was dissolved in DMF (300 ml), and NaN3 (9.91 g) was added thereto. The resulting mixture was heated to 70 °C , stirred for 2 hours, and cooled to room temperature. And then water (150 ml) and ethyl acetate (150 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The organic layer was washed twice with 150 ml of satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (31.5 g; yield: 94%).
1H-NMR(300MHz, CDC13): δ 7.11-7.02 (1H, m), 7.97-6.87 (1H, m), 5.89-5.80 (1H, m), 5.23-5.17 (1H, m), 3.63-3.59 (1H, m), 2.87 (1H, dd, J=4.7, 18.7), 2.68 (1H, dd, J=7.9, 13.7), 2.38-2.17 (2H, m). Step 3: Preparation of (3R)-3-azido-4-(2A5-trifluorophenyl)-butyric acid
Figure imgf000017_0001
Acetonitril (300 ml) and water (300 ml) were added to the (2S)-l-(2- azido-4-pentenyl)-2,4,5-trifluorobenezene obtained in step 2, and cooled to 0°C . RuCl3 (0.5 g) and NaIO4 (93 g) were added to the mixture successively, and stirred for 5 hours. Ethyl acetate (90 ml) was added to the resulting mixture, filtered and the organic layer formed thereafter was separated. The separated organic layer was washed with IN HC1 (300 ml), satuated aqueous Na2S2O3 (300 ml) and satuated saline (300 ml), successively, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (32.2 g; yield: 100%). 1H-NMR(300MHz, CDC13): 5 10.5 (1H, br), 7.17-7.05 (1H, m), 7.02-
6.87 (1H, m), 4.14-4.03 (1H, m), 2.94-2.78 (2H, m), 2.65-2.51 (2H, m).
Step 4: Preparation of (3R)-3-azido-l-(3-trifluoromethyl-5,6-dihydro-8H- [ 1 ,2,41triazolor4,3-alpyrazin-7-yl)-4-(2,4,5-trifluorophenyl)-butan- 1 -one
Figure imgf000017_0002
(3R)-3-azido-4-(2,4,5-trifluorophenyl)-buryric acid (5 g) obtained in step 3 and triazole derivative of formula (VI) (5.3 g) were added to DMF (40 ml) and water (20 ml), stirred for 15 min, and cooled to 10°C . N- methylmorpholine (2.4 ml) was added to the mixture, stirred for 10 min, and cooled to 0 °C . EDC (5.6 g) was added to the resulting mixture, and stirred for 1 hour. Ethyl acetate (50 ml) and water (25 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed four times with 50 ml of satuated saline, dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (7.8 g; yield: 93%).
1H-NMR(300MHz, CDC13): δ 7.20-7.11 (1H, m), 6.99-6.90 (1H, m), 5.20-4.96 (2H, m), 4.28-4.05 (5H, m), 2.98-2.67 (4H, m).
Step 5: Preparation of sitagliptin
Figure imgf000018_0001
(3R)-3-azido- 1 -(3-trifluoromethyl-5,6-dihydro-8H-[ 1 ,2,4]triazolo[4,3- a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl)-butan-l-one (6.4 g) obtained in step 4 and triphenylphosphin (4.3 g) were dissolved in THF (74 ml), heated to 50 °C , and stirred for 2 hours. An aqueous NH4OH (37 ml) was added to the resulting mixture and stirred for 10 hours. THF was removed from the resulting mixture under a reduced pressure, HCl (30 ml) and ethyl acetate (60 ml) were added threreto, and stirred. The water layer separated from the mixture was washed twice with 30 ml of n-hexane, satuated sodium bicarbonate was added to the water layer, and extracted three times with 60 ml of ethyl acetate. The resulting extracts were dried over MgSO4, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (5.2 g; yield: 86%).
1H-NMR(300MHz, CDC13): δ 7.14-7.06 (1H, m), 7.00-6.88 (1H, m), 5.13-4.88 (2H, m), 4.24-3.80 (4H, m), 3.58 (1H, m), 2.85-2.66 (2H, m), 2.61-2.46 (2H, m), 2.11 (3H, br).
ABOVE IS ONLY ONE EXAMPLE LEADING TO SITAGLIPTIN



DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK

Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

amcrasto@gmail.com

 

.

 

(S)-Sitagliptin……….Synfacts by Thieme

 

For description see at synfacts

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1340505

Contributor: Philip Kocienski

Philip Kocienski, Professor of Organic Chemistry.

https://www.thieme-connect.com/products/ejournals/html/10.1055/s-0033-1340505

 

Bao H, Bayeh L, Tambar UK * The University of Texas Southwestern Medical Center at Dallas, USA
Catalytic Enantioselective Allylic Amination of Olefins for the Synthesis of ent-Sitagliptin.

Synlett 2013;
24: 2459-2463

 

 

P. J. Kocienski
School of Chemistry
University of Leeds
Leeds LS2 9JT, UK
p.kocienski@chem.leeds.ac.uk
http://www.chem.leeds.ac.uk

Philip J. Kocienski was born in Troy, New York, in 1946. His love for organic chemsitry, amply stimulated by Alfred Viola whilst an undergraduate at Northeastern University, was further developed at Brown University, where he obtained his PhD degree in 1971 under Joseph Ciabattoni. Postdoctoral study with George Büchi at MIT and later with Basil Lythgoe at Leeds University, England, confirmed his interest in the synthesis of natural products. He was appointed Brotherton Research lecturer at Leeds in 1979 and Professor of Chemistry at Southampton University in 1985. In 1990 he was appointed Glaxo Professor of Chemistry at Southampton University. He moved to the University of Glasgow in 1997, where he was Regius Professor of Chemistry and now he is a Professor of Chemistry at Leeds University.

In addition to Prof. Kocienski’s work as an author he is also a member of the SYNTHESIS Editorial Board and contributes greatly to the development of Thieme Chemistry’s journals

Furthermore, Prof. Kocienski has also contributed to the Science of Synthesis project where he was an author for Volume 4, Compounds of Group 15 (As, Sb, Bi) and Silicon Compounds.

Prof. Kocienski is also responsible for compiling a database called Synthesis Reviews. This resource is free and contains 16,257 English review articles (from journals and books) of interest to synthetic organic chemists. It covers literature from 1970 to 2002.

SITAGLIPTIN……………..

GREENING UP DRUGS Merck process chemists redesigned and significantly shortened the original synthesis of type 2 diabetes drug candidate sitagliptin (Januvia) to include an unprecedented efficient hydrogenation of an unprotected enamine.

MERCK was selected for the award in the greener synthetic pathways category for revising the synthesis for sitagliptin, a chiral β-amino acid derivative that is the active ingredient in Januvia, the company’s pending new treatment for type 2 diabetes. The breakthrough leading to the new synthesis was the discovery that the amino group of the key enamine intermediate doesn’t need to be protected prior to enantioselective catalytic hydrogenation of the double bond.

This development has solved a long-standing problem in the synthesis of β-amino acid derivatives, which are known for their pharmacological properties and are commonly used as chiral building blocks, noted Karl B. Hansen, a Merck process chemist involved with the synthetic effort. The outcome has been to slash the number of reaction steps in the sitagliptin synthesis from eight to three, leading to an equally dramatic reduction in the amount of chemicals and solvent needed and the amount of waste generated.

Merck’s first-generation synthesis of sitagliptin involved preparing a β-hydroxy carboxylic acid, which was converted to a protected β-lactam and then coupled to a triazole building block. Deprotecting the resulting intermediate provided the β-amino acid moiety, and sitagliptin was isolated as a phosphoric acid salt.

This synthesis involved a roundabout route involving four steps to introduce the pivotal chiral amino group of sitagliptin. The synthesis worked well to prepare more than 100 kg of the compound for clinical trials, and with modifications it was deemed to be a viable though not very green manufacturing process, Hansen pointed out. For example, the original synthesis required a number of distillations and aqueous extractions to isolate intermediates, leading to a large volume of waste to treat.

“Being environmentally friendly and economically savvy can, and does, go hand-in-hand.”

Merck process chemists recognized that a much more efficient process was possible by synthesizing the β-amino acid portion of the molecule directly from an enamine. But the protection-deprotection of the amine nitrogen with an acyl group during the hydrogenation is difficult on a large scale, and unprotected reactions generally result in lower yields and lower enantiomeric excesses, Hansen said.

Undaunted, the Merck scientists working on the revised synthesis discovered that the amino group could be efficiently introduced by an unprotected hydrogenation using a rhodium catalyst with a ferrocenyl phosphine ligand named Josiphos (C&EN, Sept. 5, 2005, page 40). Merck turned to Solvias, a Swiss company with experience in asymmetric hydrogenations that manufactures Josiphos, as a partner to help speed up the process development.

The new synthesis involves first coupling trifluorophenyl acetic acid and triazole building blocks to form a diketoamide, which in turn is converted to the enamine. This sequence is carried out without isolating intermediates. The enamine is then hydrogenated, sitagliptin is isolated and recrystallized as the phosphoric acid salt, and the rhodium Josiphos catalyst is recovered.

In sum, the revised synthesis increases the overall yield of sitagliptin by nearly 50% and reduces the amount of waste by more than 80%. A key difference is that the original synthesis produced more than 60 L of aqueous waste per kg of product, while the new synthesis completely eliminates aqueous waste. When tallied up, Merck expects these savings will prevent formation of 150,000 metric tons of solid and aqueous process waste over the lifetime of Januvia. Industry analysts speculate that regulatory approval of the drug will come by early next year and that it’s destined to become a top-selling drug.

The novel enamine hydrogenation “is arguably the most efficient means to prepare β-amino acid derivatives,” noted R. P. (Skip) Volante, Merck’s vice president of process research. The company currently is using the procedure to make several other exploratory drug candidates, he added. Overall, the redesigned synthesis of sitagliptin “is a green chemistry solution to the preparation of a challenging synthetic target and is an excellent example of a scientific innovation resulting in benefits to the environment,” Volante said.

First generation route to sitagliptin. BINAP = 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; EDC = N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride; DIAD = di-isopropyl azodicarboxylate; NMM = N-methylmorpholine……..http://www.technology.matthey.com/article/55/2/135-139/

http://pubs.rsc.org/en/content/articlelanding/2011/cc/c1cc11592h#!divAbstract

http://www.nature.com/nature/journal/v485/n7397/fig_tab/nature11117_F4.html

 

 

PAPER


SITAGLIPTIN……………..

First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin

Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, U.S.A.
Org. Process Res. Dev., 2005, 9 (5), pp 634–639
DOI: 10.1021/op0500786
Abstract Image

A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N-benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N-benzyloxy group and salt formation. The overall yield was 52% over eight steps.

Figure

Figure

Figure

The synthesis of 1 was completed using a four-step through-process (Scheme 4). Lactam 5 or ester 13 was hydrolyzed to amino acid 2bwith LiOH18 in THF/water by either stirring at room temperature or, in the case of 13, heating to 40 °C. While the benzyloxy group of 2b could be cleaved by hydrogenation and then protected with Boc2O to prevent side reactions during the coupling to triazole 3, the benzyloxy group of 2b was found to sufficiently protect the amino group to allow the desired amide to be formed. Thus, triazole 3 was coupled to2b at 0 °C using EDC−HCl and N-methylmorpholine (NMM) as base to afford 14in >99% assay yield. Following an aqueous workup, the organic extracts were distilled into ethanol and the solution was subjected to hydrogenation with 10% Pd on carbon. The presence of water in the hydrogenation was found to be crucial to the reaction success; anhydrous solutions of 14 hydrogenated with dry Pd on carbon proceeded only to low levels of conversion to 1, and addition of water to these reductions resulted in restored performance of the catalyst. Following hydrogenation, the catalyst was removed by filtration to provide an ethanol solution of 1. Sitagliptin was isolated in >99.5% purity as its anhydrous phosphoric acid salt by crystallizing from aqueous ethanol.

PATENT

http://www.google.co.in/patents/WO2003004498A1?cl=en

Scott D Edmondson, Michael H Fisher,Dooseop Kim, Malcolm Maccoss, Emma R Parmee, Ann E Weber, Jinyou Xu

MORE INFO………

Sitagliptin phosphate monohydrate, a dipeptidyl-peptidase IV inhibitor, is marketed by Merck & Co. for the once-daily oral treatment of type 2 diabetes. The product was first launched in Mexico followed by commercialization in the U.S. The compound has also been filed for approval in the U.S. as adjunct to diet and exercise and in combination with other therapies to improve glycemic control in the treatment of diabetes. In 2007, the product was approved by the European Medicines Evaluation Agency (EMEA) and is currently available in the U.K., Germany and Spain. In 2009, sitagliptin phosphate monohydrate was approved and launched in Japan. The product is also available in Japan for the treatment of type 2 diabetes in combination with alpha-glucosidase inhibitors and in combination therapy with insulin. In 2012, the company filed for approval in Japan for the treatment of type 2 diabetes in patients with severe renal dysfunction, and in 2013 obtained the approval.

Sitagliptin phosphate monohydrate boasts a much lower risk of hypoglycemia than currently available insulin-inducing products due to its novel mechanism of action. MSD KK (formed in 2010 following the merger of Banyu and Schering-Plough KK) and Ono are developing the drug candidate in Japan. In 2008, the compound was licensed to Almirall by Merck Sharp & Dohme for comarketing in Spain for the treatment of type 2 diabetes. In 2010, FAES obtained a comarketing and commercialization license from Merck Sharp & Dohme in Spain for the treatment of type 2 diabetes.

Januvia (sitagliptin phosphate) is an antihyperglycaemic drug containing an orally active inhibitor of the dipeptidyl peptidase-IV (DPP-IV) enzyme. Developed by Merck Sharp & Dohme (MSD), a UK subsidiary of Merck & Co, sitagliptin is used for treating type 2 diabetes mellitus. The drug has proved effective in lowering blood sugar levels of diabetes patients when taken alone or in combination with other oral diabetes medications such as metformin and thiazolidinedione.

Sitagliptin was approved by the US Food and Drug Administration (FDA) in October 2006 and is marketed under the brand name Januvia in the US. Sitagliptin in combination with metformin was approved by the FDA in March 2007 and is marketed as Janumet in the US. In the EU, Januvia was approved in April 2007 and Janumet was approved in July 2008.

Sitagliptin is a triazolopiperazine based inhibitor of DPP-IV, which was discovered by
Merck. It is a potent (IC50= 18 nM) and highly selective over DPP-8 (48000 nM), DPP-9
(>100000 nM) and other isozymes.[16] It enhances the pancreatic β-cell functions, fasting and
post-prandial glycemic control in type 2 diabetic patients. In the crystal structure with DPP-IV,
unlike other substrate-based DPP-IV inhibitors, the binding orientation of the amide carbonyl of
sitagliptin is reversed, i.e. the aromatic trifluorophenyl moiety occupies S1 pocket and the β-
amino amide moiety fits into S2 pockets. The amino group forms a salt bridge and hydrogen
bonding interactions with Glu205 and Glu206, and Tyr662, respectively.The triazolopiperazinemoiety occupies the S2 extended pocket and stacks against Phe357. The exhibited binding
interactions of the trifluoromethyl group with the Arg358 and Ser209 are responsible for its high
selectivity profile. The presence of the trifluoromethyl group in the triazole ring also improves
the oral bioavailability in animal models. Sitagliptin inhibited the plasma DPP-IV up to 80% and
47% at 2 and 24 h, respectively, after a single dose of 25.0 mg in a dose-dependent manner. In a
24-week study, sitagliptin significantly decreased fasting glucose levels and HbA1c levels
(0.8%) at doses of 100 mg q.d. Thus, sitagliptin is well tolerated and body weight neutral. It is
the first DPP-IV inhibitor in the class approved by USFDA in 2006 and is used as either a
monotherapy or in combination with metformin

S2

 

 

 

S1

S3

 

In the first synthetic approach, the synthesis of sitagliptin was started with the reaction of a Schollkopf reagent 6 with 2,4,5-trifluorobenzyl bromide to afford the compound 7, which was converted to compound 9 via hydrolysis of ester 8. The resulting Boc-protected amino acid 9 was converted to diazoketone 11 through mix anhydride protocol by using diazomethane. The intermediate 11 was converted to desired β-amino acid 12 by sonication in the presence of silver benzoate.[21] The sitagliptin (14) was synthesized by coupling of β-amino acid 12 with triazolopiperazine intermediate 5 followed by Boc deprotection of amino group of 13, and its corresponding hemi fumarate salt was then prepared (Scheme 1).[16]

SYN1

 

The second approach for synthesis of sitagliptinwas started from asymmetric reduction of β-ketoester 15 using the (S)-BinapRuCl2 complex with a catalytic amount of HBr in methanol followed by hydrolysis afforded the β-hydroxy acid 16. Lactam 17 was synthesized by coupling of 16 with BnONH2 •HCl using N-(3- dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDC), followed by cyclization reaction with diisopropyl azodicarboxylate (DIAD) and PPh3 . [22] Treatment of a catalytic amount of 0.1% NaOH with lactam 17 hydrolyzed and directly afforded the β-amino acid 18. This wascoupled withtriazolopiperazine 5 using EDC•HCl and N-methylmorpholine to provide the N-benzyloxy protected compound 19, which after hydrogenation using Pd/C and by consequent treatment with phosphoric acid provided the phosphate salt of sitagliptin (14) (Scheme 2).

 

SYN2

The third approach towards the synthesis of sitagliptin is outlined in scheme 3. Meldrum adduct 22 (Hunig’s base salt) was synthesized from trifluorophenylacetic acid 20 by the formation of a mixed anhydride with pivaloyl chloride in the presence of Meldrum’s acid 21, DIPEA and catalytic amount of dimethylamino pyridine (DMAP) in acetonitrile. Treatment of 22 with TFA resulted compound 23. β-keto amide 24 was formed on reaction of 23 with triazolopiperazine 5. β-keto amide 24 on treatment with ammonium acetate in methanol formed a key intermediate, dehydrositagliptin 25 (enamine amide). This intermediate contains the entire structure of sitagliptin 14 except two hydrogen atoms. Thus, sitagliptin 14 was synthesized by enantioselective hydrogenation of dehydrositagliptin 25 in the presence of [Rh(COD)2 OTf] 12,13 and t Bu JOSIPHOS in excellent yield with 95% ee.[23,24]

SYN3

http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

 

 

 

 

 REF

 

http://www.apiindia.org/medicine_update_2013/chap88.pdf

http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf

 

////////////

 


DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK

Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

amcrasto@gmail.com

Share

TRELAGLIPTIN

 diabetes  Comments Off on TRELAGLIPTIN
Jul 032015
 

1 TRELAGLIPTIN

 

Trelagliptin succinate (SYR-472)

2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2, 4-dioxopyrimidin-1-yl]methyl]-4-fluorobenzonitrile; butanedioic acid

2-[6-[3(R)-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-4-fluorobenzonitrile

2- [ [6- [ (3R) -3-amino-l-piperidinyl] -3, 4-dihydro-3- methyl-2, 4-dioxo-l (2H) -pyrimidinyl]methyl] -4-fluorobenzonitrile

succinic acid salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile

Mechanism of action: DPP-4 inhibitor

865759-25-7 cas FREE BASE

1029877-94-8 succinate

  • SYR 111472 succinate
  • SYR 472
  • Syr-472
  • Syr111472 succinate
  • Trelagliptin succinate
  • UNII-4118932Z90

Trelagliptin-succinate M. Wt: 475.47

Trelagliptin-succinate Formula: C22H26FN5O6

SYR-472 is an oral dipeptidyl peptidase IV inhibitor originated by Takeda. It is in phase III clinical trials for the treatment of type 2 diabetes.

  • Diabetes affects 25.8 million people of all ages, or roughly 8.3 percent of the U.S. population.
  • The World Health Organization predicts that there will be 366 million people worldwide affected by diabetes by the year 2030.
  • The advent of trelagliptin succinate, a unique once weekly medication for patients with type 2 Diabetes is now the focus of clinical trials and exciting research and development.
  • Phase III clinical trials of trelagliptin succinate commenced in September 2011, and are estimated to be complete by the second half of 2013.

TRELAGLIPTIN (SYR-472)

Trelagliptin is a novel DPP-4 inhibitor that is being developed by Takeda. In contrast to alogliplitin, which is once a day, trelagliptin is a once-weekly oral agent which should provide patients with a convenient therapeutic alternative and has the potential to improve compliance. Takeda has commenced Phase III trials of trelagliptin in Japan for the treatment of Type 2 diabetes.

Indication (Phase): Japan—Once-weekly oral treatment for type 2 diabetes (Phase III; study expected to be completed in second half of 2013)

trelagliptin succinate

Compound I, A, TRELAGLIPTIN which has the formula:

Figure US20080227798A1-20080918-C00002

is a DPP-IV inhibitor that is described in U.S. patent application Ser. No. 11/080,992 filed Mar. 15, 2005 (see Compound 34). Its dosing, administration and biological activities are described in U.S. patent application Ser. No. 11/531,671 filed Sep. 13, 2006. U.S. patent application Ser. No. 11/080,992 and Ser. No. 11/531,671 are incorporated herein by reference in their entirety.

Dipeptidyl peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) (referred herein as “DPP-IV”) is a type II membrane protein and a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (e.g., intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of human disease states, including, but are not limit to, diabetes, particularly type II diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; AIDS; and cancers.

DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV.

Compound (A) or a salt thereof has been reported as an inhibitor of dipeptidyl peptidase (DPP-IV) , which is an enzyme that decomposes glucagon-like peptide-1 (GLP-1) , a hormone increasing insulin secretion (patent document 1) .

In addition, a method including administering 1 – 250 mg of compound (A) or a salt thereof to a patient once per week (patent documents 2, 3), crystal polymorphs of compound (A) (patent documents 4, 5) , and a preparation of compound (A)

(patent documents 6, 7) have also been reported. Compound (A) and a salt thereof are recommended for oral administration in view of the easiness of self-administration, and a tablet, particularly a tablet in the dosage form for administration once per week, is desired. [0006]

The dosage form of once per week is expected to improve drug compliance of patients, whereas it requires supply of compound (A) or a salt thereof to patients in a high dose as compared to, for example, the dosage form of once per day. Since a solid preparation containing compound (A) or a salt thereof in a high dose increases its size, it may conversely degrade the drug compliance for patients, particularly infants and elderly patients having difficulty in swallowing

……………………..

SYNTHESIS

Compound 34 IS TRELAGLIPTIN

Figure US20090275750A1-20091105-C00078

4-Fluoro-2-methylbenzonitrile (31).

A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 31 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

2-Bromomethyl-4-fluorobenzonitrile (32).

A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

Alternatively, 32 was made as follows.

4-Fluoro-2-methylbenzonitrile (1 kg) in DCE (2 L) was treated with AIBN (122 g) and heated to 75° C. A suspension of DBH (353 g) in DCE (500 mL) was added at 75° C. portionwise over 20 minutes. This operation was repeated 5 more times over 2.5 hours. The mixture was then stirred for one additional hour and optionally monitored for completion by, for example, measuring the amount of residual benzonitrile using HPLC. Additional AIBN (e.g., 12.5 g) was optionally added to move the reaction toward completion. Heating was stopped and the mixture was allowed to cool overnight. N,N-diisopropylethylamine (1.3 L) was added (at <10° C. over 1.5 hours) and then diethyl phosphite (1.9 L) was added (at <20° C. over 30 min). The mixture was then stirred for 30 minutes or until completion. The mixture was then washed with 1% sodium metabisulfite solution (5 L) and purified with water (5 L). The organic phase was concentrated under vacuum to afford 32 as a dark brown oil (3328 g), which was used without further purification (purity was 97% (AUC)).

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (33).

A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C13H9ClFN3O2, 293.68; found 293.68.

Alternatively, 33 was made as follows.

To a solution of 6-chloro-3-methyluracil (750 g) and N,N-diisopropylethylamine (998 mL) in NMP (3 L) was added (at <30° C. over 25 min) a solution of 32 (2963 g crude material containing 1300 g of 32 in 3 L of toluene). The mixture was then heated at 60° C. for 2 hours or until completion (as determined, for example, by HPLC). Heating was then stopped and the mixture was allowed to cool overnight. Purified water (3.8 L) was added, and the resultant slurry was stirred at ambient temperature for 1 hour and at <5° C. for one hour. The mixture was then filtered under vacuum and the wet cake was washed with IPA (2×2.25 L). The material was then dried in a vacuum oven at 40±5° C. for 16 or more hours to afford 33 as a tan solid (>85% yield; purity was >99% (AUC)).

TFAsalt OF TRELAGLIPTIN

2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (34).

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.

FREE BASE OF TRELAGLIPTIN

Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 60° C. until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 60° C. and the mixture was allowed to cool to <25° C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2×3.6 L). The filtrate was concentrated at 45° C. under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.

HCL salt OF TRELAGLIPTIN

The HCl salt of 34 was prepared from the TFA salt as follows. The TFA salt (34) was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0° C. The HCl salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.

Alternatively, the HCl salt was prepared from the free base as follows. To a solution of free base in CH2Cl2 (12 L) was added (at <35° C. over 18 minutes) 2 M hydrochloric acid (3.1 L). The slurry was stirred for 1 hour and then filtered. The wet cake was washed with CH2Cl2 (3.6 L) and then THF (4.8 L). The wet cake was then slurried in THF (4.8 L) for one hour and then filtered. The filter cake was again washed with THF (4.8 L). The material was then dried in a vacuum oven at 50° C. (with a nitrogen bleed) until a constant weight (e.g., >26 hours) to afford 34 as the HCl salt as a white solid (1423 g, >85% yield).

Succinate salt OF TRELAGLIPTIN

Figure US20080227798A1-20080918-C00001

The succinate salt of 34 was prepared from the HCl salt as follows. To a mixture of the HCl salt of 34 (1414 g), CH2Cl2 (7 L) and purified water (14 L) was added 50% NaOH solution (212 mL) until the pH of the mixture was >12. The biphasic mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (5.7 L) and the combined organic layers were washed with purified water (6 L). The organic layer was then passed through an in-line filter and concentrated under vacuum at 30° C. over three hours to afford the free base as an off-white solid. The free base was slurried in prefiltered THF (15 L) and prefiltered IPA (5.5 L). The mixture was then heated at 60° C. until complete dissolution of the free base was observed. A prefiltered solution of succinic acid (446 g) in THF (7 L) was added (over 23 min) while maintaining the mixture temperature at >57° C. After stirring at 60° C. for 15 min, the heat was turned off, the material was allowed to cool, and the slurry was stirred for 12 hours at 25±5° C. The material was filtered under vacuum and the wet cake was washed with prefiltered IPA (2×4.2 L). The material was then dried in a vacuum oven at 70±5° C. (with a nitrogen bleed) for >80 hours to afford the succinate salt of 34 as a white solid (1546 g, >90% yield).

The product was also converted to a variety of corresponding acid addition salts. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of 34 were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(−)-Mandelic and benzenesulfonic. The succinate was found to be crystalline as determined by x-ray powder diffraction analysis.

Methanesulfonate salt

In addition, the methanesulfonate salt was prepared as follows. A 10.5 g aliquot of the benzonitrile product was mixed with 400 mL of isopropylacetate. The slurry was heated to 75° C. and filtered through #3 Whatman filter paper. The solution was heated back to 75° C. and a 1M solution of methanesulfonic acid (30.84 mL) was added slowly over 10 minutes while stirring. The suspension was cooled to room temperature at a rate of about 20° C./hr. After 1 hr at room temperature, the solid was filtered and dried in an oven overnight to obtain the methanesulfonate salt.

…………………………

FORMULATION

COMPD A IS TRELAGLIPTIN

Examples (Comparative Example IA)

Succinate of compound (A) (26.6 mg) was weighed in a glass bottle and used as Comparative Example IA. (Comparative Example 2A)

The succinate of compound (A) and microcrystalline cellulose were uniformly mixed in a mortar at a ratio of 1:10, and the mixture (226.6 mg) was weighed in a glass bottle and used as Comparative Example 2A. (Comparative Example 3A)

The succinate of compound (A) and corn starch were uniformly mixed in a mortar at a ratio of 1:5, and the mixture (126.6 mg) was weighed in a glass bottle and used as Comparative Example 3A. (Example IA) Succinate of compound (A) , mannitol and corn starch according to the formulation of Table IA were uniformly mixed in a fluid bed granulator (LAB-I, POWREX CORPORATION) , and the mixture was granulated by spraying an aqueous solution of dissolved hypromellose 2910, and dried therein. The obtained granules were passed through a sieve -(16M) to give milled granules. To the milled granules were added croscarmellose sodium, microcrystalline cellulose and magnesium stearate, and they were mixed in a bag to give granules for tableting. The granules were punched by a rotary tableting machine (Correct 19K, Kikusui Seisakusho, Ltd.) with a 6.5 mmφ punch to give a plain tablet weighting 121 mg. On the other hand, titanium oxide, yellow ferric oxide and talc were dispersed in a hypromellose 2910 aqueous solution to prepare a film coating liquid. The aforementioned coating liquid was sprayed onto the above-mentioned plain tablet in a film coating machine (Hicoater HCP-75, Freund Corporation), to give 2500 film- coated tablets containing 3.125 mg of compound (A) (free form) per tablet. Table IA

Figure imgf000028_0001

………………………..

POLYMORPHS AND SYNTHESIS

FORM A

Form A may be prepared by crystallization from the various solvents and under the various crystallization conditions used during the polymorph screen (e.g., fast and slow evaporation, cooling of saturated solutions, slurries, and solvent/antisolvent additions). Tables B and C of Example 3 summarize the procedures by which Form A was prepared. For example, Form A was obtained by room temperature slurry of an excess amount of Compound I in acetone, acetonitrile, dichloromethane, 1,4-dioxane, diethyl ether, hexane, methanol, isopropanol, water, ethylacetate, tetrahydrofuran, toluene, or other like solvents on a rotating wheel for approximately 5 or 7 days. The solids were collected by vacuum filtration, and air dried in the hood. Also, Form A was precipitated from a methanol solution of Compound I by slow evaporation (SE).

[0091] Form A was characterized by XRPD, TGA, hot stage microscopy, IR, Raman spectroscopy, solution 1H-NMR, and solid state 13C-NMR.

[0092] Figure 1 shows a characteristic XRPD spectrum (CuKa, λ=1.5418A) of Form A. The XRPD pattern confirmed that Form A was crystalline. Major X-Ray diffraction lines expressed in °2Θ and their relative intensities are summarized in Table 1.

Table 1. Characteristic XRPD Peaks (CuKa) of Form A

Figure imgf000018_0001

Figure imgf000019_0001

Characterization Data of Form A of Compound I

Figure imgf000064_0001

8. Amorphous Form

[0137] The Amorphous Form of Compound I was prepared by lyophilization of an aqueous solution of Compound I (Example 10). The residue material was characterized by XRPD and the resulting XRPD spectrum displayed in Figure 26. The XRPD spectrum shows a broad halo with no specific peaks present, which confirms that the material is amorphous. The material was further characterized by TGA, DSC, hot stage microscopy, and moisture sorption analysis.

Table A. Approximate Solubilities of Compound I

Compound I having the formula

Figure imgf000076_0002

Figure imgf000052_0001

Figure imgf000053_0001

POLYMORPH SCREEN

Crystallization Experiments of Compound I from Solvents

Figure imgf000059_0001

Figure imgf000060_0001

Figure imgf000061_0001

Figure imgf000062_0001

a) FE = fast evaporation; SE = slow evaporation; RT = room temperature; SC = slow cool;CC = crash cool, MB = moisture sorption/desorption analysis b) qty = quantity; PO = preferred orientation

…………………………

SYNTHESIS

EXAMPLES

1. Preparation of 2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro- 2H-pyrimidin-l-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically acceptable salts

Figure imgf000039_0001

Figure imgf000039_0002

4-Fluoro-2-methylbenzonitrile (3)

[0166] A mixture of 2-bromo-5fluorotoluene ( 2) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was re fluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product 3 (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, IH), 6.93-7.06 (m, 2H), 2.55 (s, 3H). 2-Bromomethyl-4-fluorobenzonitrile (4)

[0167] A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl4 was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification.1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro- benzonitrile (6)

[0168] A mixture of crude 3-methyl-6-chlorouracil (5) (0.6 g, 3.8 mmol), 2- Bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO

(10 mL) was stirred at 60 C for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, 1=12, 8.4Hz, IH), 7.26 (d, J- 4.0Hz, IH), 7.11-7.17 (m, IH), 6.94 (dd, J=2.0, 9.0 Hz, IH), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for Ci3H9ClFN3O2, 293.68; found 293.68.

2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl]-4-fluoro-benzonitrile, TFA salt (1) (TFA salt of Compound I)

Figure imgf000040_0001

[0169] 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4- fluoro-benzonitrile (5) (300 mg, 1.0 mmol), (i?)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100 0C for 2 hrs. The final compound was obtained as a TFA salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, IH), 7.16-7.27 (m, 2H), 5.46 (s, IH), 5.17-5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, IH), 2.67-2.92 (m, 2H), 2.07-2.17 (m, IH), 1.82-1.92 (m, IH), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for Ci8H20FN5O2, 357.38; found, 357.38.

2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl]-4-fluoro-benzonitrile, HCl salt

Figure imgf000041_0001

[0170] The TFA salt of Compound I was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0 C. The HCl salt was obtained after removing the solvent. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, IH), 7.12-7.26 (m, 2H), 5.47 (s, IH), 5.21-5.32 (ABq, 2H, J = 32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, IH), 2.69-2.93 (m, 2H), 2.07-2.17 (m, IH), 1.83-1.93 (m, IH), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for Ci8H20FN5O2, 357.38; found, 357.38.

General procedure for the preparation of salts of Compound I.

[0171] The benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to a corresponding acid addition salt. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of Compound I were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(-)-Mandelic and benzenesulfonic. [0172] The isolation and/or purification steps of the intermediate compounds in the above described process may optionally be avoided if the intermediates from the reaction mixture are obtained as relatively pure compounds and the by-products or impurities of the reaction mixture do not interfere with the subsequent reaction steps. Where feasible, one or more isolation steps may be eliminated to provide shorter processing times, and the elimination of further processing may also afford higher overall reaction yields.

…………………..

TABLET

2. Exemplary formulations comprising succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile

Provided are examples of tablet formulations that may be used to administer succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (Succinate salt of Compound I) according to the present invention. It is noted that the formulations provided herein may be varied as is known in the art.

The exemplary tablet formulations are as follows:

12.5 mg of Compound I (weight of free base form) per tablet
Core Tablet Formulation
(1) 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4- 17.0 mg
dioxo-3,4-dihydro-2H-pyrimidin-1-
ylmethyl]-4-fluoro-benzonitrile (succinate salt)
(2) Lactose Monohydrate, NF, Ph, Eur 224.6 mg
(FOREMOST 316 FAST FLO)
(3) Microcrystalline Cellulose, NF, Ph, Eur 120.1 mg
(AVICEL PH 102)
(4) Croscarmellose Sodium, NF, Ph, Eur 32.0 mg
(AC-DO-SOL)
(5) Colloidal Silicon Dioxide, NF, Ph, Eur 3.2 mg
(CAB-O-SIL M-5P)
(6) Magnesium Stearate, NF, Ph, Eur 3.2 mg
(MALLINCKRODT, Non-bovine Hyqual)
TOTAL 400.0 mg
(per tablet)

…………..

POLYMORPHS AND SYNTHESIS

EXAMPLES Example 1 Preparation of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate (Compound I)

Figure US20080227798A1-20080918-C00004

Compound I may be prepared by the follow synthetic route (Scheme 1)

Figure US20080227798A1-20080918-C00005

A. Preparation of 4-fluoro-2-methylbenzonitrile (Compound B)

Figure US20080227798A1-20080918-C00006

Compound B was prepared by refluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO4 and the solvent removed to give product B (yield 60%). 1H-NMR (400 MHz, CDCl3): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)

Figure US20080227798A1-20080918-C00007

Compound C was prepared by refluxing a mixture of 4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl4 under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

C. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound D)

Figure US20080227798A1-20080918-C00008

Compound E was prepared by stirring a mixture of crude 3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K2CO3 (0.5 g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO4 and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). 1H-NMR (400 MHz, CDCl3): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C13H9ClFN3O2, 293.68; found 293.68.

D. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound F)

Figure US20080227798A1-20080918-C00009

Compound F was prepared by mixing and stirring 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound E) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as trifluoroacetate (TFA) salt after HPLC purification. 1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.

E. Preparation of Compound I: the succinic acid salt of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile

Figure US20080227798A1-20080918-C00010

The TFA salt prepared in the above step (Example 1, Step D) was suspended in DCM, and then washed with saturated Na2CO3. The organic layer was dried and removed in vacuo. The benzonitrile product (approximately 10 mg) was dissolved in MeOH (1 mL) and to which succinic acid in THF (1.05 equivalents) was added. The solutions were allowed to stand for three days open to the air. If a precipitate formed, the solid was collected by filtration. If no solid formed, the mixture was concentrated in vacuo, and the succinate salt was obtained after removing the solvent.

SUCCINATE SALT OF TRELAGLIPTIN

1H-NMR (400 MHz, CD3OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C18H20FN5O2, 357.38; found, 357.38.

Compound I such prepared was found to be crystalline as determined by x-ray powder diffraction analysis (FIG. 1). The crystal material was designated Form A.

……………

patents

1. US 2013172377

2. WO 2011013639

3. WO 2009099172

4.WO 2009099171

5. WO 2008114807

6.WO 2008114800

7. WO 2008033851

8. WO 2007074884

9WO 2007035629

patent document 1: US2005/0261271

patent document 2: US2007/0060530

patent document 3: US2008/0287476

patent document 4: US2008/0227798

patent document 5: US2008/0280931

patent document 6: WO2008/114800

patent document 7: WO2011/013639

US7906523 * Oct 30, 2007 Mar 15, 2011 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8084605 * Nov 29, 2007 Dec 27, 2011 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8188275 * Oct 30, 2007 May 29, 2012 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US8222411 * Sep 15, 2006 Jul 17, 2012 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US20090275750 * Sep 15, 2006 Nov 5, 2009 Jun Feng Dipeptidyl peptidase inhibitors
WO2013183784A1 Jun 4, 2013 Dec 12, 2013 Takeda Pharmaceutical Company Limited Solid preparation
US20080227798 * Nov 29, 2007 Sep 18, 2008 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US20120197018 * Feb 15, 2012 Aug 2, 2012 Kelly Ron C Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
WO2007033265A1 * Sep 13, 2006 Mar 22, 2007 Takeda Pharmaceutical Dipeptidyl peptidase inhibitors for treating diabetis
WO2007033266A2 * Sep 13, 2006 Mar 22, 2007 Takeda Pharmaceutical Dipeptidyl peptidase inhibitors for treating diabetis
WO2007033350A1 * Sep 13, 2006 Mar 22, 2007 Takeda Pharmaceutical Dipeptidyl peptidase inhibitors for treating diabetes
EP1586571A1 * Dec 21, 2004 Oct 19, 2005 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
Share

MELOGLIPTIN

 diabetes, phase 2, Uncategorized  Comments Off on MELOGLIPTIN
Jul 032015
 

 

GRC 8200; 868771-57-7, EMD-675992

4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-carbonitrile

4(S)-Fluoro-1-[2-[(1R,3S)-3-(1H-1,2,4-triazol-1-ylmethyl)cyclopentylamino]acetyl]pyrrolidine-2(S)-carbonitrile

GRC-8200, a dipeptidyl peptidase IV inhibitor (DPP-IV), is currently undergoing phase II clinical trials at Glenmark Pharmaceuticals and Merck KGaA for the treatment of type 2 diabetes. In 2006, the compound was licensed by Glenmark Pharmaceuticals to Merck KGaA in Europe, Japan and N. America for the treatment of type 2 diabetes, however, these rights were reaquired by Glenmark in 2008.

.