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

July 15, 2015 6:26 am / Leave a comment

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

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, 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.

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 .

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:

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)

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

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

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)

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)

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

C₅oH_5tC10₆ M = 783.39g.moF¹

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

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)

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)

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)

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

http://www.google.com/patents/CN103649033A?cl=en

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
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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

……………………………………………………………………………….

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www.fosunpharma.com/

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ALOGLIPTIN

July 6, 2015 10:19 am / Leave a comment

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 21^st 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 :

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):

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)

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

SOURCE APEXBT

References

“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.
Vipidia: EPAR summary for the public (European Medicines Agency)
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.
“www.aace.com” (PDF).
http://www.takeda.com/news/2013/20130618_5841.html
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
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
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
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.
White WB, Zannad F (January 2014). “Saxagliptin, alogliptin, and cardiovascular outcomes”. N. Engl. J. Med. 370 (5): 484.doi:10.1056/NEJMc1313880.PMID 24482824.
Grogan, Kevin (April 26, 2012),“FDA wants yet more data on Takeda diabetes drug alogliptin”,PharmaTimes (PharmaTimes), PharmaTimes online, retrieved April 26,2012
“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
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^BENZOATE850649-61-5 FREE BASE
ATC code	A10BH04
PubChem	CID: 11450633
IUPHAR/BPS	6319
ChemSpider	9625485
UNII	JHC049LO86
KEGG	D06553
ChEBI	CHEBI:72323
ChEMBL	CHEMBL376359
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

Alogliptin

- Synonyms:SYR-322
- ATC:A10BH04
Use:antidiabetic, DPP-4 inhibitor
Chemical name:2-[[5-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-2H-pyrimidin-1(2H)-yl]methyl]benzonitrile
Formula:C₁₈H₂₁N₅O₂

MW:339.40 g/mol
CAS-RN:850649-61-5

Derivatives

benzoate

Formula:C₁₉H₁₉NO₂
MW:293.37 g/mol
CAS-RN:850649-62-6

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
22115-41-9	C₈H₆BrN	2-(bromomethyl)benzonitril
	C₁₂H₈ClN₃O₂	2-[[6-chloro-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile
	C₁₃H₁₀ClN₃O₂	2-[[6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile
4270-27-3	C₄H₃ClN₂O₂	6-chloro-2,4(1H,3H)-pyrimidinedione
74-88-4	CH₃I	methyl iodide	Methane, iodo-
127294-73-9	C₅H₁₂N₂	(3R)-3-piperidinamine

Trade Names

Country	Trade Name	Vendor	Annotation
J	Nesina	Takeda ,2010

Formulations

tabl. 12.5 and 25 mg

References

- Feng, J. et al.: J. Med. Chem. (JMCMAR) 50, 2297-2300 (2007).
- WO 2 005 095 381 (SYRRX; 13.10.2005; appl. 15.12.2004; USA-prior. 15.3.2004).
- WO 2 010 109 468 (MAPI Pharma; 30.9.2010; appl. 25.3.2010; USA-prior. 26.3.2009).

solid preparation comprising Alogliptin and Pioglitazone:
- US 20 100 092 551 (Takeda Pharm.; 15.4.2010; appl. 30.1.2008; J-prior. 1.2.2007).

solid preparation comprising Alogliptin and Metformin:
- US 20 200 136 127 (Takeda Pharm.; 3.6.2010; appl. 16.7.2008; J-prior. 19.7.2007).

09b37-misc2b027 LIONEL 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

GEMIGLIPTIN

July 6, 2015 4:50 am / Leave a comment

GEMIGLIPTIN

1-[2(S)-Amino-4-[2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]-4-oxobutyl]-5,5-difluoropiperidin-2-one

PHASE 3, DPP-IV inhibitor, Lg Life Sciences Ltd.

CAS 911637-19-9

Mol. Formula: C18H19F8N5O2

Mol. Weight:489.36

Gemigliptin (rINN), previously identified as LC15-0444, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.^[1] It is well known that glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4.

Gemigliptin was initially developed solely by LG Life Sciences. In 2010, Double-Crane Pharmaceutical Co. (DCPC) joined with LGLS to co-develop the final compound and collaborate on the marketing of the drug in China. LGLS also announced on Nov., 2010 that NOBEL Ilac has been granted rights to develop and commercialize gemigliptin in Turkey.

Gemigliptin, a dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor, is currently undergoing phase III clinical trials at LG Life Sciences as an oral treatment for type II diabetes. The company is also testing the compound in phase II/III clinical studies for the treatment of patients with cisplatin-induced acute kidney injury.

DPP IV inhibitors have glucose-lowering effects mediated by GLP-1 incretin hormone which is inactivated by DPP IV. In 2010, gemigliptin was licensed to Beijing Double-Crane Pharmaceutical by LG Life Sciences for distribution and supply in China for the treatment of type 2 diabetes.

A New Drug Application (NDA) for gemigliptin in the treatment of type 2 diabetes was submitted to the Korea Food & Drug Administration (KFDA) in July 2011. Then on June 27, 2012, the KFDA has approved the manufacture and distribution of LG Life Sciences’ diabetes treatment, Zemiglo, the main substance of which is gemigliptin. Clinical trials for evaluating the safety and efficacy of gemigliptin in combination with metformin have been completed.

…………

Efficient synthesis of gemigliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus, has been developed. Gemigliptin were prepared from two key API starting materials, DP18 and DP57, in 75~80% yield and >99% purity over three steps under the GMP control: coupling, deprotection of N-Boc group, and final crystallization with L-tartaric acid. All steps were conducted in the same solvent system and the intermediates were isolated by simple filtration without distillation of solvent. The established process was validated obviously through the three consecutive batches for a commercial production.

………..IN CASE IMAGES NOT VISIBLE …….SEE THIS AT ………http://www.allfordrugs.com/2015/07/06/gemigliptin/

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Clinical data
(3S)-3-amino-4-(5,5-difluoro-2-oxopiperidino)-1-[2,4-di(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]butan-1-one
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	94% (rat), 73% (dog), 26% (monkey)
Biological half-life	3.6 h (rat), 5.2 h (dog), 5.4 h (monkey)
Identifiers
CAS Registry Number	911637-19-9
ATC code	A10 BH06
PubChem	CID: 11953153
ChemSpider	10127461
UNII	5DHU18M5D6
Synonyms	LC15-0444
Chemical data
Formula	C₁₈H₁₉F₈N₅O₂
Molecular mass	489.36 g/mol

……………….

History

The NDA for gemigliptin was submitted to KFDA in July, 2011 and it was approved on June 27, 2012. By the end of 2012, gemigliptin will be marketed in Korea as Zemiglo which is the fifth new DPP-4 inhibitor diabetes treatment in the world.

Mechanism of action

DPP-4 is a serine protease located on the cell surfaces throughout the body. In plasma, DPP-4 enzyme rapidly inactivates incretins including GLP-1 and GIP which are produced in the intestine depending on the blood glucose level and contribute to the physiological regulation of glucose homeostatis. Active GLP-1 and GIP increase the production and release of insulin by pancreatinc beta cells. GLP-1 also reduces the scretion of glucacon by pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However these incretins are rapidly cleaved by DPP-4 and their effects last only for a few minutes. DPP-4 inhibitors block the cleavage of the gliptins and thus lead to an increasee insulin level and a reduced glucagon level in a glucose-dependent way. This results in a decrease of fasting and postprandial glycemia, as well as HbA1c levels.^[2]

Preclinical studies

Gemigliptin is a competitive, reversible DPP-4 inhibitor (IC50 = 16 nM) with excellent selectivity over other critical human proteases such as DPP-2, DPP-8, DPP-9, elastase,trypsin, urokinase and cathepsin G. Gemigliptin was rapidly absorbed after single oral dosing and the compound was eliminated with a half-life of 3.6 h, 5.2 h, and 5.4 h in the rat, dog, and monkey, respectively.

The bioavailability of gemigliptin in the rat, dog, and monkey was species-dependent with the values of 94%, 73%, and 26%, respectively. Following the oral administration of gemigliptin in the rat, dog and monkey, about 80% inhibition of plasma DPP-4 activity were observed at the plasma levels of 18 nM, 14 nM and 4 nM, respectively.

In the diet-induced obese (DIO) mice, gemigliptin reduced glucose excursion during OGTT in a dose dependent manner with the minimum effective dose of 0.3 mg/kg and enhanced glucose-stimulated plasma GLP-1 increase in a dose dependent manner reaching the maximum effect at the dose of 1 mg/kg.

Following 4 week oral repeat dosing in the DIO mice, gemigliptin reduced significantly HbA1c with the minimum effective dose of 3 mg/kg. In the beagle dog, gemigliptin significantly enhanced active GLP-1, decreased glucagon, and reduced glucose excursion during OGTT following a single dosing.

Studies on animals suggest its positive effect on hepatic and renal fibrosis .^[3]^[4] Data on human patients are still inconclusive .^[5]

Clinical studies

The dose-range finding phase 2 study was performed and 145 patients (91men and 54 women) with type 2 diabetes mellitus were enrolled. All three doses (50,100 and 200 mg groups) of gemigliptin significantly reduced the HbA_1c from baseline compared to the placebo group without a significant difference between the doses.

Subjects with a higher baseline HbA_1c (≥8.5%) had a greater reduction in HbA_1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with gemigliptin treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment.

The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group.

The incidences of adverse events were similar in all study subjects. Gemigliptin monotherapy (50 mg for 12 weeks) improved the HbA_1c, FPG level, oral glucose tolerance testresults, β-cell function and insulin sensitivity measures, and was well tolerated in subjects with type 2 diabetes.

Results of Phase 3 clinical trials which have been finished recently will be updated near future.

…………..

WO 2006104356

http://www.google.co.in/patents/WO2006104356A1?cl=en

EXAMPLE 83: Synthesis of l-(f2SV2-amino-4-r2.4-bisftrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7f6H^‘)

-yl1-4-oxobutyll-5.5-difluoropiperidin-2-one [1960]

[1961] 21 mg of the title compound was obtained in a yield of 56% at the same manner as in EXAMPLE 1, except that 42 mg (0.071 mmol) of t-butyl

{(lS)-3-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-l-[(5,5

-difluoro-2-oxpiperidin-l-yl)methyl]-3-oxpropyl}carbamate obtained in

PREPARATION 143 was used. [1962] ¹K NMR (CD₃OD) δ 5.05-4.92 (2H, m), 3.98-3.91 (2H, m), 3.85-3.79 (2H, m),

3.70-3.59 (2H, m), 3.54-3.48 (IH, m), 3.36-3.33 (2H, m), 3.24 (IH, bra), 3.14 (IH, bra), 2.83-2.76 (IH, m), 2.72-2.53 (3H, m), 2.43-2.34 (2H, m) [1963] Mass (m/e) 490 (M+l)

[1964]

[1965] PREPARATION 144: Synthesis of t-butyl

(riSV3-r2.4-bisrtrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7r6HVyl]-l-(rr2 S)-2-methyl-5-oxomorpholin-4-yl1methyl 1 -3-oxpropyl 1 carbamate

[1966] 14 mg of the title compound was obtained in a yield of 17% at the same manner as in PREPARATION 45, except that 43.7 mg (0.138 mmol) of (3S)-3-[(t-butoxycarbonyl)amino]-4-[2(S)-2-methyl-5-oxomoφholin-4-yl]-butanoic acid obtained in PREPARATION 55 and 42.5 mg (0.138 mmol) of 2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloric acid salt (product of PREPARATION 127) were used.

[1967] ¹K NMR (CDCl₃) δ 5.85-5.83 (IH, m), 5.09-4.92 (IH, m), 4.95-4.78 (IH, m),

4.23-4.08 (3H, m), 4.04-3.76 (3H, m), 3.73-3.66 (IH, m), 3.46-3.38 (IH, m), 3.36-3.21 (2H, m), 3.18-3.10 (2H, m), 2.96-2.81 (IH, m), 2.61-2.50 (IH, m), 1.43-1.41 (9H, m), 1.28-1.24 (3H, m)

[1968] Mass (m/e) 470 (M+l-Boc)

…………..

WO 2012030106

https://www.google.com/patents/WO2012030106A2?cl=en

Reaction Scheme 1

PREPARATION 1: Synthesis of diethyl 2,2-difluoropentanedioate

To a solution of ethyl bromodifluoroacetate (33.2 g) in tetrahydrofuran (94.0 g) was added ethyl acrylate (8.2 g) and copper powder (10.9 g). After heating to 50℃, TMEDA (9.5 g) was added dropwise and the reaction mixture was then stirred for 3 hours at the same temperature. Upon disappearance of ethyl acrylate as the starting material, to the reaction solution was added methyl t-butyl ether (MTBE, 73.7 g) followed by addition of 10% aqueous ammonium chloride solution (49.8 g) dropwise, and the mixture was then stirred for 30 minutes. The remaining copper residue was removed by filtration through a celite, and methyl t-butyl ether (MTBE, 66.3 g) was added to separate the layers. The separated organic layer was washed successively with 10% aqueous NH₄Cl solution (66.3 g) and 3 N aqueous hydrochloric acid solution (99.6 g) in order and then distilled under reduced pressure to obtain 55.0 g of the desired title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, J=7.2 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 2.37-2.49 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H).

PREPARATION 2: Synthesis of ethyl 4,4-difluoro-5-hydroxypentanoate

14.8 g of the compound obtained from the above Preparation 1 was diluted with ethanol (20.4 g) and tetrahydrofuran (69.1 g) and then cooled to 0℃. To this solution was slowly added sodium borohydride (NaBH₄, 3.5 g) stepwise while keeping the internal temperature below 30℃. After confirming completion of the reaction by ¹H NMR, the reaction solution was cooled to the temperature of 10℃ and 10% aqueous ammonium chloride solution (77.7 g) was slowly added. The remaining boron compound was filtered through celite, and the filtrate was distilled under reduced pressure to remove tetrahydrofuran. Then, ethyl acetate (105.2 g) was added to separate the layers, and the organic layer was distilled under reduced pressure to obtain 10.8 g of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J=7.2 Hz, 3H), 2.15-2.29 (m, 2H), 2.49 (t, J=7.2 Hz, 2H), 3.69 (t, J=12.0 Hz, 2H), 4.12 (q, J=4.0 Hz, 2H).

EXAMPLE 1: Synthesis of ethyl 4,4-difluoro-5-{[(trifluoromethyl)sulfonyl]oxy}- pentanoate

To the solution of 10.8 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (100.2 g) was added pyridine (7.0 g), and then the mixture was cooled to -5.0℃. After completion of cooling, trifluoromethane sulfonic acid anhydride (20.1 g) was slowly added dropwise while keeping the reaction temperature below 6.3℃. After stirring the reaction solution for 30 minutes, 1.5 N hydrochloric acid solution was added dropwise at 0℃ to separate the layers. The aqueous layer as separated was back-extracted twice with dichloromethane (33.4 g), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 19.7 g of the title compound as a yellow oil.

¹H NMR (500 MHz, CDCl₃) δ 1.27 (t, J=7.2 Hz, 3H), 2.29-2.39 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 4.55 (t, J=11.6 Hz, 2H).

EXAMPLE 2-1: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

To the solution of 100.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (300.0 ml) was added pyridine (65.7 g), and the mixture was then cooled to -10.0℃. After completion of cooling, nonafluorobutanesulfonic anhydride (477.4 g) was slowly added dropwise. After stirring the reaction solution for 3 hours, 1.0 N hydrochloric acid solution (300.0 ml) was added dropwise to separate the layers. The aqueous layer as separated was back extracted once with dichloromethane (500.0 ml), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 177.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.26 (t, 3H, J=7.3 Hz), 2.30-2.36 (m, 2H), 2.58 (t, 2H, J=7.4 Hz), 4.16 (q, 2H, J=7.3 Hz), 4.57 (t, 2H, J=11 Hz).

EXAMPLE 2-2: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

To the solution of 500.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (1000.0 ml) was added triethylamine (389.0 g), and the mixture was then cooled to 0℃. After completion of cooling, perfluorobutanesulfonyl chloride (948.80 g) was slowly added dropwise. The reaction solution was stirred for 3 hours at room temperature, distilled under reduced pressure, dissolved in methyl t-butyl ether (MTBE, 3000.0 ml) and then washed three times with water. The organic layer thus obtained was dehydrated with magnesium sulfate, filtered through a celite and then distilled under reduced pressure to obtain 960.0 g of the title compound.

EXAMPLE 3: Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-oxo- pentanoate

To 25.0 g of the starting material, (3S)-3-[(t-butoxycarbonyl)amino]-4-oxo- pentanoic acid, was added t-butanol (96.9 g) followed by the addition of Boc₂O (25.4 g) and dimethylaminopyridine (DMAP, 62.0 g, 0.5 mol%) at room temperature, and the reaction mixture was then stirred for 23 hours at 40℃. Upon completion of the reaction, ethylene dichloride (62.3 g) in t-butanol was added, and the mixture was then distilled under reduced pressure to obtain 30.7 g of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.47 (s, 9H), 2.71 (dd, J=4.8, 16.4 Hz, 1H), 2.88 (dd, J=4.4, 16.4 Hz, 1H), 3.75 (s, 3H), 4.53 (m, 1H), 5.44 (br d, J=8.0 Hz, 1H).

EXAMPLE 4: Synthesis of tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy- butanoate

30.7 g of the compound obtained from the above Example 3 was dissolved in ethanol (112.3 g) and, after lowering the internal temperature to 10.5℃ sodium borohydride (NaBH₄, 5.7 g) was slowly added dropwise. This reaction solution was stirred while maintaining the temperature below 22℃. After confirming completion of the reaction by ¹H NMR and TLC, to the reaction solution was slowly added 3.0 N hydrochloric acid solution (30.7 g) dropwise at the internal temperature of 10℃ followed by addition of diluted 0.2% hydrochloric acid solution (100.0 g). The reaction solution was adjusted to pH 3~4 with addition of 9.0% aqueous hydrochloric acid solution, and then back-extracted twice with ethyl acetate (100.0 g) and toluene (44.0 g). The organic layer thus obtained was distilled under reduced pressure to obtain 25.1 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.48-2.57 (m, 2H), 3.69 (d, J=4.9 Hz, 1H), 3.97 (m, 1H), 5.22 (bs, 1H).

EXAMPLE 5: tert-butyl (3S)-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]- butanoate

To 25.1 g of the compound obtained from the above Example 4 was added dichloromethane (133.0 g) and triethylamine (148.0 g), and the mixture was then cooled to 0℃. To this reaction solution was slowly added methanesulfonyl chloride (11.8 g) diluted with dichloromethane (39.9 g) dropwise for 50 minutes while maintaining the internal temperature below 12℃. After completion of the reaction, the reaction solution was washed with 0.5 N aqueous hydrochloric acid solution (120.0 g) and water (100.4 g), and then distilled under reduced pressure to obtain 31.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.46 (s, 9H), 2.62 (d, J=6.0 Hz, 2H), 3.04 (s, 3H), 4.21 (m, 1H), 4.30 (d, J=5.2 Hz, 2H), 5.16 (br d, J=7.2 Hz, 1H).

EXAMPLE 6: Synthesis of tert-butyl (3S)-4-azido-3-[(tert-butoxycarbonyl)amino]- butanoate

Sodium azide (NaN₃, 11.6 g) was diluted with dimethylacetamide (DMAc, 260.0 g). After elevating the internal temperature to 80℃, a solution of 31.5 g of the compound, as obtained from the above Example 5, diluted with dimethylacetamide (DMAc, 45.0 g) was added thereto. The reaction proceeded at 80℃ for 2 hours. To the reaction solution were added toluene (251.0 g) and water (320.0 g) to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 24.0 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.47 (s, 9H), 1.49 (s, 9H), 2.49 (d, J=6.0 Hz, 2H), 3.44-3.55 (m, 2H), 4.09 (br s, 1H), 5.14 (br s, 1H).

EXAMPLE 7: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

To 21.0 g of the compound obtained from the above Example 6 was added tetrahydrofuran (93.3 g) followed by the addition of triphenylphosphine (PPh₃, 21.0 g) at 40℃, the mixture was stirred for 2 hours at the same temperature, and water (3.8 g) was then added thereto. The reaction solution was distilled under reduced pressure, and the resulting triphenylphosphine oxide solid was diluted with toluene (26.0 g) and n-hexane (41.0 g), and then filtered off. The filtrate was adjusted to pH 2~3 with 1.0 N aqueous hydrochloric acid solution (110.0 g) and then subjected to separation of the layers. To remove any residual triphenylphosphine oxide solid, the aqueous layer obtained above was washed with dichloromethane (100.0 g) and then adjusted to pH 8~9 with 28% aqueous ammonia solution (7.6 g). The aqueous solution thus obtained was extracted with dichloromethane (100.0 g) and distilled under reduced pressure to obtain 8.5 g of the title compound as a white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

EXAMPLE 8: Synthesis of N,N-dibenzyl-L-N(Boc)-aspartamide 4-tert-butyl ester

N-Boc-L-aspartic acid 4-t-butyl ester (29.0 g, 0.10 mol) was added to THF (200 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (13.0 ml, 0.10 mol) followed by addition of N-methyl morpholine (12.0 ml, 0.10 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise dibenzylamine (21.1 ml, 0.11 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (300.0 mL) and 1 N hydrochloric acid to separate the layers, and distilled under reduced pressure to precipitate a solid. The solid was filtered and washed with ethyl acetate (100 ml), and then the washings were concentrated by distillation again under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (41.7 g, 0.89 mol).

¹H NMR (400 MHz, CDCl₃) δ: 7.32 (m, 5H), 7.20 (m, 5H), 5.39 (d, J=7.2 Hz, 1H), 5.30 (m, 1H), 4.87-4.77 (m, 2H), 4.48-4.39 (m, 2H), 2.72 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.56 (dd, J=15.8 Hz, J=6.4 Hz, 1H), 1.43 (s, 9H), 1.37 (s, 9H).

Mass (ESI, m/z): 491 (M+Na), 469 (M+H), 413 (M-55).

EXAMPLE 9: Synthesis of N, N-diallyl-L-N(Boc)-aspartamide 4-tert-butyl ester

L-N(Boc)-aspartic acid 4-t-butyl ester (5.00 g, 17.3 mol) was added to THF (50 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (2.26 ml, 17.3 mol) followed by addition of N-methyl morpholine (1.90 ml, 17.3 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise diallylamine (2.35 ml, 19.0 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (60 ml) and 1 N hydrochloric acid and, after separating the layers, concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (6.0 g, 16.3 mol).

¹H NMR (400 MHz, CDCl₃) δ: 5.78 (m, 2H), 5.30 (m, 1H), 5.23-5.11 (m, 1H), 5.30 (m, 1H), 4.93 (m, 1H), 4.11-3.84 (m, 4H), 2.68 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.51 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H).

Mass (ESI, m/z): 391 (M+Na), 369 (M+H), 313 (M-55).

EXAMPLE 10: Synthesis of N,N-dibenzyl-4-amino-3(S)-N(Boc)-aminobutanoic acid 4-tert-butyl ester

10.0 g of the compound obtained from the above Example 8, Ru₃(CO)₁₂ (136 mg, 1mol%), and diphenylsilane (19.7 ml, 106.7 mmol) were added to tetrahydrofuran (50 ml), and the reaction solution was stirred under reflux for over 40 hours. The reaction solution was extracted with ethyl acetate (200 ml) and concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (4.7 g, 10.5 mmol).

¹H NMR (400 MHz, CDCl₃) δ: 7.31-7.20 (m, 10H), 5.12 (bs, 1H), 3.90 (bs, 1H), 3.63 (d, J=12.0 Hz, 2H), 3.48 (d, J=12.0 Hz, 2H), 3.24 (m, 1H), 3.16 (bs, 1H), 2.42 (m, 2H), 1.81 (m, 1H), 1.59 (m, 9H), 1.46 (s, 9H), 1.06 (s, 9H).

Mass (ESI, m/z): 455 (M+H), 441 (M-13).

EXAMPLE 11: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- 4-oxobutanoate

360.0 g of the starting material, N-Boc-Asp(O-t-Bu)OH, together with Boc₂O (353.0 g) and ammonium bicarbonate (NH₄HCO₃, 123.9 g) was added to dimethylformamide (1174.6 g), and pyridine (61.0 g) was added dropwise thereto at room temperature, and the reaction mixture was then stirred for about 3 hours. Upon completion of the reaction, water (1440 ml) and toluene (1800 ml) were added to the reaction solution and stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to remove t-butanol and toluene to obtain the title compound, which was directly used in the next reaction.

EXAMPLE 12: Synthesis of (S)-tert-butyl 3-(tert-butoxycarbonylamino)-3-cyanopropanoate

To the compound obtained from Example 11 was added dimethylformamide (1019.5 g) followed by addition of cyanuric chloride (112.0 g) dropwise for 1.5 hours at temperature below 25℃. The reaction solution was stirred for one hour at room temperature, and then 0.1 N aqueous sodium hydroxide solution (1850.0 g) and toluene (1860 ml) were added thereto to separate the layers. The organic layer thus obtained was washed once again with water (700 ml) and then distilled under reduced pressure to obtain 318.3 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

EXAMPLE 13: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

To 212.1 g of the compound obtained from the above Example 12 was added acetic acid (4000 ml) followed by addition of 20 wt% Pd(OH)₂ (1.1 g) at 40℃. The mixture was stirred for 8 hours while keeping the internal temperature below 45℃ and 3 atmospheric pressure of hydrogen. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove acetic acid, diluted with toluene (640 L) and then filtered through a celite. To the filtrate was added 0.25 N aqueous hydrochloric acid solution (1060 ml) to separate the layers. The aqueous layer thus obtained was basified with aqueous ammonia solution (543.1 g) and then extracted with methyl t-butyl ether (MTBE, 1000 ml). The organic layer thus obtained was distilled under reduced pressure to obtain 185.0 g of the title compound.

EXAMPLE 14: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid t-butyl ester

Triethylamine (13.2 g) was added to 16.0 g of the compound obtained from the above Example 1 or 2-1 or 2-2, and 14.1 g of the compound obtained from the above Example 7 or 13, and the mixture was then stirred for 21 hours at 40℃. Then, dichloromethane (154.8 g) and acetic acid (18.3 g) were added, and the mixture was stirred for 5 hours at room temperature. To the resulting reaction solution was added 0.5 N aqueous hydrochloric acid solution (116.8 g) and then, the mixture was stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 23.6 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.42 (s, 9H), 1.46 (s, 9H), 2.27 (m, 2H), 2.40-2.64 (m, 4H), 3.20 (dd, J=4.3, 13.5 Hz, 1H), 3.56-3.70 (m, 2H), 3.76-3.91 (m, 2H), 4.16 (m, 1H), 5.20 (d, J=8.6 Hz, 1H).

EXAMPLE 15: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid

23.6 g of the compound obtained from the above Example 14 was added to dichloromethane (20.0 g) followed by addition of H₃PO₄ (30.0 g), and the mixture was stirred for 16 hours at room temperature. After confirming the detachment of all of t-butyl group and t-butyloxycarbonyl group, the reaction solution was adjusted to pH 7.0~8.0 with 10 N aqueous hydrogen peroxide, and Boc₂O (16.0 g) was added thereto. After completion of the addition, 10 N aqueous hydrogen peroxide was used to maintain the pH of the reaction solution at 8.0~9.0. After stirring for 3 hours, the resulting sodium phosphate was filtered off, and the filtrate was then adjusted to pH 2.0~3.0 with 3.0 N aqueous hydrochloric acid solution. The resulting solid was filtered and dried under nitrogen to obtain 14.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.32 (s, 9H), 2.20-2.43 (m, 6H), 3.26-3.31 (m, 2H), 3.61 (m, 1H), 3.81 (m, 1H), 4.02 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 12.16 (s, 1H).

For the title compound resulting from the above, its enantiomeric isomers―i.e. S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess of the enantiomeric isomers (S vs. R form) (enantiomeric excess; ee) was then calculated as being ee > 99%. On the other hand, in case of the Comparative Example prepared according to the prior method based on WO 06/104356, as described below, the excess (ee) of enantiomeric isomers (S vs. R form) was 80%. From this, it can be identified that the compound of formula (2) having an optically high purity could be obtained according to the method of the present invention.

COMPARATIVE EXAMPLE 1: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

COMPARATIVE EXAMPLE 1-1: Synthesis of methyl 5-amino-4,4-difluoro- pentanoate HCl

To 10.0 g of the compound obtained from Example 1 was added 40 ml of anhydrous ammonia solution (7 M solution in methanol), and the mixture was stirred for 3 hours. The reaction solution was distilled and 30 ml of hydrochloric acid solution saturated with methanol was added dropwise thereto. The reaction mixture was stirred at room temperature and then distilled to obtain 7.2 g of the title compound as a white solid.

¹H NMR (500 MHz, CD₃OD) δ: 2.35 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 3.49 (t, J=15.3 Hz, 2H), 3.68 (s, 3H).

COMPARATIVE EXAMPLE 1-2: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

To the solution of the compound (1.93 g), as obtained from the above Example 4, dissolved in dichloromethane (20.0 g) and H₂O (4.0 g) were added NaBr (0.8 g) and TEMPO (11 mg, 1 mol%). To this reaction solution was slowly added a solution of 5% NaOCl (11.5 g) and NaHCO₃ (1.7 g) dissolved in H₂O (12.0 g) dropwise for about 2 hours while maintaining the temperature below 5℃. Upon completion of dropwise addition, the reaction solution was stirred for 30 minutes to separate the layers. To the organic layer thus obtained was added the compound (1.6 g) obtained from the above Comparative Example 1-1. After stirring for 15 minutes at room temperature, NaBH(OAc)₃ (2.23 g) was added to the reaction solution. After stirring for about 19 hours, 10% aqueous NaHCO₃ solution (20.0 g) and 0.5 N aqueous hydrochloric acid solution (20.0 g) were added dropwise to the reaction solution to separate the layers. The organic layer thus obtained was dehydrated under anhydrous MgSO₄ to obtain 2.0 g (yield 73%) of the same title compound as Example 14, as a yellow solid. For the title compound resulting from the above, its enantiomeric isomers―i.e., S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess (ee) of the enantiomeric isomers (S vs. R form) was then calculated as being ee = 80%.

WO2006104356A1	Mar 30, 2006	Oct 5, 2006	Seong Cheol Bu	Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
EP0279435A2 *	Feb 18, 1988	Aug 24, 1988	BASF Aktiengesellschaft	Process for the reduction of mono- and dicarboxylic acids
US5556982 *	Jul 12, 1993	Sep 17, 1996	Neorx Corporation	Metal radionuclide labeled proteins for diagnosis and therapy
US20080039517 *	Aug 7, 2007	Feb 14, 2008	Washburn David G	Pyrrolidinone anilines as progesterone receptor modulators

Footnotes

Lim KS, Kim JR, Choi YJ, Shin KH, Kim KP, Hong JH, Cho JY, Shin HS, Yu KS, Shin SG, Kwon OH, Hwang DM, Kim JA, Jang IJ (October 2008). “Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: a dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study”. Clin Ther 30 (10): 1817–30. doi:10.1016/j.clinthera.2008.10.013. PMID 19014837.
Ábel T. “A New Therapy of Type 2 Diabetes: DPP-4 Inhibitors”. In Rigobelo EC. Hypoglycemia – Causes and Occurrences. Croatia: InTech. pp. 3–52. doi:10.5772/23604. ISBN 978-953-307-657-7.
Kaji K (Mar 2014). “Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats.”. J Gastroenterol.. 49 (3): 481–91.doi:10.1007/s00535-013-0783-4. PMID 23475323.
Min HS (Jun 2014). “Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction.”. Lab Invest. 94 (5): 598–607.doi:10.1038/labinvest.2014.50. PMID 24687121.
Gouni-Berthold I (2014). “The role of oral antidiabetic agents and incretin mimetics in type 2 diabetic patients with non-alcoholic Fatty liver disease.”. Curr Pharm Des. 20 (5): 3705–15.PMID 24040873.

External links

Official site

DAVID G. WASHBURN ET AL.: ‘Discovery or orally active, pyrrolidinone-based progesterone receptor partial agonist‘ BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 19, no. 16, 2009, pages 4664 – 4667, XP026419052
2	*	MONICA LOPEZ-GARCIA ET AL.: ‘Synthesis of (R)-3,4- diaminobutanoic acid by desymmetrization of dimethyl 3-(benzylamino)-glutarate through enzymatic ammonolysis‘ JOURNAL OF ORGANIC CHEMISTRY vol. 68, no. 2, 2003, pages 648 – 651, XP055105976

09b37-misc2b027 LIONEL MY SON

EVOGLIPTIN

July 3, 2015 3:46 am / Leave a comment

ChemSpider 2D Image | Evogliptin | C19H26F3N3O3

EVOGLIPTIN
CAS: 1222102-29-5 FREE

HCL……1246960-27-9

tartare.. 1222102 -51-3

Dong-A Pharmaceutical. Co., Ltd, 동아제약 주식회사
2-Piperazinone, 4-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl)-3-((1,1-dimethylethoxy)methyl)-, (3R)-
R)-4-((R)-3-Amino-4-(2,4,5-trifluorophenyl)-butanoyl)-3-(t-butoxymethyl)-piperazin-2-one

4-[3(R)-Amino-4-(2,4,5-trifluorophenyl)butyryl]-3(R)-(tert-butoxymethyl)piperazin-2-one hydrochloride

DA-1229

see…http://www.allfordrugs.com/2015/07/03/evogliptin/

DA-1229 is a dipeptidyl peptidase IV (CD26) inhibitor currently being developed in phase III clinical studies at Dong-A for the treatment of type 2 diabetes.

In 2014, Eurofarma aquired rights for product development and commercialization in Brazil.

Evogliptin Tartrate

If above image is not clear then see at…….http://www.allfordrugs.com/2015/07/03/evogliptin/

86…………H. J. Kim, W. Y. Kwak, J. P. Min, J. Y. Lee, T. H. Yoon, H. D. Kim, C. Y. Shin, M. K.
Kim, S. H. Choi, H. S. Kim, E. K. Yang, Y. H. Cheong, Y. N. Chae, K. J. Park, J. M.
Jang, S. J. Choi, M. H. Son, S. H. Kim, M. Yoo and B. J. Lee, Bioorg. Med. Chem. Lett.,
2011, 21 (12), 3809-3812.
[87] …………K. S. Lim, J. Y. Cho, B. H. Kim, J. R. Kim, H. S. Kim, D. K. Kim, S. H. Kim, H. J. Yim,
S. H. Lee, S. G. Shin, I. J. Jang and K. S. Yu, Br. J. Clin. Pharmacol., 2009, 68 (6), 883-
890.

Originator Dong-A Pharmaceutical
Developer Dong-A ST
Class Amides; Antihyperglycaemics; Fluorobenzenes; Piperazines; Small molecules
Mechanism of Action CD26 antigen inhibitors

Orphan Drug Status No
On Fast track No
New Molecular Entity Yes
Available For Licensing Yes – Type 2 diabetes mellitus

Highest Development Phases

Phase III Type 2 diabetes mellitus

Most Recent Events

01 Sep 2014 Phase-I clinical trials in Type-2 diabetes mellitus (In volunteers) in United Kingdom (PO)
31 Jul 2014 Phase-III clinical trials in Type-2 diabetes mellitus in South Korea (PO)
31 Jul 2014 Dong-A ST initiates enrolment in a phase I trial in patients with renal impairment in South Korea (NCT02214693)

Evogliptin Tartrate

…………………………………..

WO 2010114291

http://www.google.co.in/patents/WO2010114291A2?cl=en

Formula 1

Korea Patent Publication No. 2008-0094604 the call to the scheme, as indicated by A Ⅰ) of formula (II) beta-compound of formula 3 is already substituted heterocyclic compound having 1-hydroxy-benzotriazole group (HOBT) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and reacting with a tertiary amine to prepare a compound of formula (4) connected by peptide bonds; Ⅱ) beta comprises the step of reacting under acidic conditions a compound of the formula (4) – a method of manufacturing the heterocyclic compounds of the formula I having an amino group is disclosed.

– Scheme A]

(Wherein, PG is a protecting group.)

In this case, the beta of the formula (2) of Scheme A – a compound having an amino group is prepared in addition to the DPP-IV inhibitor International Publication represented by Formula 1 WO03 / 000181, WO03 / 004498, WO03 / 082817, WO04 / 007468, WO04 / 032836, WO05 / 011581, WO06 / 097175, WO07 / 077508, WO07 / 063928, WO08 / 028662 WO08 / it may be used for the production of different DPP-IV inhibitors according 087,560 and can be prepared in a number of ways.

To, the compound of Formula 2 is an example as shown in Scheme J. Med.Chem. 2005; 141, and Synthesis 1997; it can be produced by the known method described in 873.

Specifically, (2S) – (+) – 2,5- dihydro-3,6-dimethoxy-2-isopropyl-pyrazine 2,4,5-trifluoro-react with benzyl bromide and acid treatment, and then the amine an ester compound obtained by the protection reaction. Ester compounds are hydrolyzed to re-3- (2,4,5-trifluoro-phenyl) -2-amino-propionic acid tert such as isobutyl chloroformate, triethylamine or diisopropylethylamine to give the amine, and then using diazomethane to form a diazo ketone, and then may be prepared by reaction with silver benzoate. However, the reaction can be performed at low temperature (-78 ℃) or high alpha-amino acid to purchase and use, and may have a risk of problems such as the need to use large diazomethane.

To a different process for preparing a compound of Formula 2 as shown in scheme Tetrahedron: Asymmetry 2006; It is known in 2622; 205 or similarly Bioorganic & Medicinal Chemistry Letters 2007.

That is, a 1,1′-carbonyl-2,4,5 which the phenyl trifluoroacetic acid activated using the following imidazole mono-methyl words potassium carbonate is reacted with the beta-keto ester compound is prepared. This produced an enamine ester using ammonium acetate and ammonium solution, the ester compound chloro (1,5-cyclooctadiene) rhodium (I) dimer using a chiral ferrocenyl ligands I the reaction of the high-pressure hydrogen with a chiral primary amine with a beta-amino ester compound after production and can lead to hydrolysis to prepare a compound of formula (2). However, use of expensive metal catalyst has a problem that must be performed in high pressure hydrogenation.

The method for preparing a compound of Formula 2 is disclosed in International Publication No. WO 04/87650.

Specifically, 2,4,5-fluorophenyl reagent is oxalyl chloride, the acid activated acid with 2,2-dimethyl-1,3-dioxane-4,6-dione, and after the reaction of methanol and the resulting material at reflux to prepare a corresponding compound. With a selective reducing reagents which enantiomers (S) -BINAP-RuCl ₂ and hydrogen through a reaction (S) – producing a compound having coordinated to each other, it again after the decomposition, and the singer O- benzyl hydroxyl amine and the coupling reaction and the intermediate is prepared. To do this, the resulting intermediate tree azodicarboxylate and diisopropyl azodicarboxylate presence ring condensation reaction, treated with an aqueous solution of lithium hydroxide to (R) – while having the formula (II) coordinated to the amine group protected with a benzyl-O- the compound can be produced. However, the method has a problem as a whole to be prepared by the reaction yield to be low and a long processing time to perform the reaction.

Thus, the conventional known method for producing a compound of the general formula (2) has the disadvantage of using expensive reagents, or not suitable for commercial mass-production method by a long synthesis time yield is also low.

In addition, the compound represented by General Formula (3), as described in Korea Patent Publication No. 2008-0094604 call, can be prepared by way of reaction schemes.

Specifically, the starting material D- serine methyl ester is substituted by a hydroxy group when reflux again substituted by trityl chloride as methoxy groups converted to the aziridine compound.

[Scheme 3]

<Example 3> (R)-4-[(R)-3-아미노-4-(2,4,5-트리플루오로페닐)부타노일]-3-(t-부톡시메틸)피페라진-2-온(화학식 1) Preparation of the hydrochloride

Step 1: t- butyl (R)-4-[(R)-2-(t-부톡시메틸)-3-옥소피페라진-1-일]-4-옥소 – 1-(2,4,5-트리플루오로페닐)부탄-2-일카르바메이트(화학식 Preparation of 4)

2 L flask, prepared in Example 1 (R) -3-t- butoxycarbonyl-4- (2,4,5-trifluoro-phenyl) butanoate acid (Formula 2) 10.0 g of toluene was dissolved in 450 mL of bis (2,2′-benzothiazolyl) disulfide 13.0 g, was cooled and then 10.2 g triphenylphosphine was added to the reaction solution at 0 ℃. While stirring the reaction mixture was added to a solution of 0.8 mL of triethylamine in 20 mL of toluene was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0 ℃ and prepared in Example 2 (R) -3- (t- butoxymethyl) piperazin-2-one (Formula 3) was dissolved in 5.6 g of toluene and 40 mL pyridine a 2.4 mL was added slowly. After 30 minutes the reaction mixture was heated to room temperature and stirred for 1 hour. Saturated sheet to be the aqueous acid solution to a pH of 2.5 and then diluted with ethyl acetate 400 mL. Washed twice with brine and the organic layer was dehydrated with magnesium sulfate and concentrated. The residue was purified by column chromatography to give the title compound 838 mg.

¹ H NMR (400 MHz, CDCl ₃₎ δ 7.03 (m, 1H), 6.88 (m, 1H), 5.97 (m, 1H), 5.48 (m, 1H), 4.16 ~ 4.07 (m, 1H), 4.02 ~ 3.91 (m, 1H), 3.74 (m, 2H) 3.37 (m, 2H), 3.24 (m, 1H), 2.92 (m, 2H), 2.80 (m, 1H), 2.59 (m, 2H), 1.34 ( d, 9H), 1.13 (s, 9H)

Step 2: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluoro-phenyl) butane five days] -3- (t- butoxymethyl) piperazin-2- on the production of (I) hydrochloride

Prepared in Step 1 t- butyl (R)-4-[(R)-2-(t-부톡시메틸)-3-옥소피페라진-1-일]-4-옥소-1-(2,4,5-트리플루오로페닐)부탄-2-일카르바메이트 97 mg was dissolved in methanol was added 3 mL 2N- hydrochloric acid / diethyl ether 2 mL was stirred at room temperature for 3 hours. The reaction mixture was concentrated and dried under reduced pressure to give 64 mg of the title compound as a foaming solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.37 (m, 1H), 7.23 (m, 1H), 4.80 (m, 1H), 4.59 ~ 4.40 (m, 1H), 3.93 (m, 1H), 3.90 ~ 3.83 (m, 2H), 3.70 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.07 (m, 2H), 2.89 ~ 2.66 (m, 2H), 1.18 (s, 3H ), 1.11 (s, 6H)

Mass (M + 1): 402

<Example 4> (R)-4-[(R)-3-아미노-4-(2,4,5-트리플루오로페닐)부타노일]-3-(t-부톡시메틸)피페라진-2-온(화학식 1) tartaric acid salts

Step 1: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluoro-phenyl) butane five days] -3- (t- butoxymethyl) piperazin-2- Preparation of one (I)

Example 3 to give a compound of formula I in hydrochloride 60 mg 5% sodium hydrogen carbonate in dichloromethane was added to 10 mL of an aqueous solution / 2-propanol (4/1 (v / v)) was added to the mixed solution and extracted two times 10 mL The organic layer was dried under reduced pressure to give 55 mg of the title compound as a solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 (m, 1H), 7.14 (m, 1H), 4.56 ~ 4.39 (m, 1H), 3.96 ~ 3.81 (m, 3H), 3.70 (m, 1H) , 3.46 (m, 1H), 3.43 ~ 3.32 (m, 1H), 2.83 ~ 2.65 (m, 3H), 2.58 ~ 2.40 (m, 2H), 1.16 (s, 3H), 1.11 (s, 6H)

Mass (M + 1): 402

Step 2: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- (t- butoxymethyl) piperazin-2- one (I) tartaric acid salt [

Was dissolved 55 mg of the compound of step 1 in 0.56 mL of acetone, L- tartrate 26 mg ethanol / water (9/1 (v / v)) was added slowly to a solution of 0.35 mL was stirred for 30 minutes. Here was added 0.56 mL of 2-propanol was stirred for 10 minutes and re-filtered to give 77 mg of the title compound as a solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.38 (m, 1H), 7.22 (m, 1H), 4.80 (m, 1H), 4.59 ~ 4.40 (m, 1H), 4.40 (s, 2H), 3.93 (m, 1H), 3.90 ~ 3.83 (m, 2H), 3.70 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.07 (m, 2H), 2.89 ~ 2.66 (m, 2H ), 1.15 (s, 3H), 1.11 (s, 6H)

Mass (M + 1): 402

………………………………

WO 2010114292

http://www.google.com/patents/WO2010114292A2?cl=en

…………………………………

Discovery of DA-1229: a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes
Bioorg Med Chem Lett 2011, 21(12): 3809

http://www.sciencedirect.com/science/article/pii/S0960894X11004859

A series of β-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.

About evogliptin tartrate tablets

Evogliptin tartrate tablets is a dipeptidyl peptidase IV inhibitor, in tablet form. Evogliptin tartrate

tablets is expected to be approved for the treatment of type 2 diabetes mellitus. The Group holds

an exclusive intellectual property licence from Dong-A Pharmaceutical Co. Ltd. to develop

and commercialise evogliptin tartrate tablets in China, including the exclusive right to develop

evogliptin tartrate tablets for manufacturing and sale in the Group’s name. The new drug certificate

to be issued by the CFDA will be approved and registered under the Group’s name.

Evogliptin is a patented new molecular entity in the United States and other international markets.

Evogliptin tartrate tablets is being concurrently developed by Dong-A Pharmaceutical Co. Ltd.

for the Korean market. Based on information released from a multi-centre, phase II, randomised,

double-blind, placebo-controlled, therapeutic exploratory clinical trial conducted in Korea by

Dong-A Pharmaceutical Co. Ltd. to investigate the efficacy and safety of evogliptin, evogliptin

was proven to be effective in significantly lowering blood glucose levels in patients with type

2 diabetes. Data also show that the body weights of patients remain stable over the treatment

period. In addition, evogliptin was proven to be safe and well tolerated with no severe adverse

drug reactions observed during those phase II clinical trials. The Company believes evogliptin

tartrate tablets will help reduce the burden of patients with moderate-to-severe renal impairment

as pharmacokinetic study in animal model and healthy human volunteers showed low renal

elimination.

According to the statistics of IMS Health Incorporated, the market size of products for the

treatment of diabetes in China in 2013 was approximately RMB7.8 billion, and grew at a

compound annual growth rate of 23.4% from 2011 to 2013.

http://www.luye.cn/en/uploads//2014-07/21/_1405936452_zr21xh.pdf

Dong-A ST

SEOUL, SOUTH KOREA

14 April 2015 – 5:45pm

Oh Seung-mock

Dong-A ST has licensed its new diabetes drug Evogliptin to 17 Latin American countries including Mexico, Venezuela, Argentina, Chile, Colombia, Ecuador, Peru, the Dominican Republic, and Uruguay, Jung Jae-wook, Dong-A ST’s PR manager, told Business Korea.

Dong-A ST and Eurofarma, a Brazilian pharmaceutical company, concluded the licensing contract at Dong-A ST’s headquarters on April 13 in Seoul.

Eurofarma will be responsible for Evogliptin’s product development and sales in the 17 Latin American countries, Dong-A ST said. Dong-A ST will receive royalties from Eurofarma, and export the raw material of the medicine.

Dong-A ST has been developing Evogliptin with the support of the Ministry of Health & Welfare of South Korea as an innovative new medicine research project since May 2008. Evogliptin is a DPP-4 remedy based on the inhibition mechanism which is “excellent” at reducing blood sugar, whilst “less likely” to cause weight increases and hypoglycemia, the company said.

Park Chan-il, president of Dong-A ST, said that Dong-A ST will pursue further out-licensing “over the globe,” through continuous investment in research and development.

Maurizio Billi, Eurofarma’s president, wished to expand both companies’ partnership in the innovative new remedy development sector, according to Dong-A ST.

Last July, Dong-A ST and Eurofarma concluded a contract out-licensing Evogliptin to Brazil itself, the company said.

– See more at: http://www.businesskorea.co.kr/article/10115/southern-strategy-dong-st-licenses-new-diabetes-drug-evogliptin-17-latin-american#sthash.liqwFTWU.dpuf

http://www.koreaittimes.com/story/47669/%EB%8F%99%EC%95%84st-evogliptin-%EC%B6%94%EA%B0%80-%EB%9D%BC%EC%9D%B4%EC%84%BC%EC%8B%B1-%EC%95%84%EC%9B%83-%EA%B3%84%EC%95%BD-%EC%B2%B4%EA%B2%B0

//////////

see gliptins at…..http://drugsynthesisint.blogspot.in/p/gliptin-series.html

Dong-A Pharm. Co., Ltd, Yongin-si, Gyeonggi-do, Republic of Korea.

GOSOGLIPTIN

July 3, 2015 3:18 am / 1 Comment on GOSOGLIPTIN

ChemSpider 2D Image | gosogliptin | C17H24F2N6O

GOSOGLIPTIN

CAS 869490-23-3 FREE BASE

DIHYDROCHLORIDE..869490-47-1

GOSOGLIPTIN; UNII-GI718UO477; PF-00734200; PF-734200;

(3,3-difluoropyrrolidin-1-yl)-[(2S,4S)-4-(4-pyrimidin-2-ylpiperazin-1-yl)pyrrolidin-2-yl]methanone

Molecular Formula:	C17H24F2N6O
Molecular Weight:	366.408866 g/mol

Company	Pfizer Inc.
Description	Dipeptidyl peptidase-4 (DPP-4) inhibitor
Molecular Target	Dipeptidyl peptidase-4 (DPP-4) (CD26)
Mechanism of Action	Dipeptidyl peptidase-4 (DPP-4) inhibitor

Latest Stage of Development	Phase II
Standard Indication	Diabetes
Indication Details	Treat Type II diabetes

Type 2 diabetes mellitus is a chronic disorder characterized by hyperglycemia coupled with a gradual decline in insulin sensitivity and insulin secretion. The incretin hormone glucagon-like peptide-1 (GLP-1), which is released post-prandially from the L-cells of the intestine, stimulates the release of insulin from pancreatic β-cells. However, GLP-1 is rapidly degraded in vivo by peptidases, including dipeptidyl peptidase IV (DPP-4), which is a widely distributed serine protease that specifically cleaves N-terminal dipeptides from polypeptides with proline or alanine at the penultimate position.

In vivo administration of DPP-4 inhibitors to human subjects results in higher circulating concentrations of endogenous GLP-1 and subsequent decrease in plasma glucose. Long term treatment with a DPP-4 inhibitor leads to a reduction in circulating HbA1c (glycosylated hemoglobin). DPP-4 inhibition also offers the potential to improve the insulin producing function of the pancreas through either β-cell preservation or regeneration. Therefore, DPP-4 inhibition has emerged as a promising new treatment of Type 2 diabetes

PF-734200 is a potent, selective, orally active dipeptidyl peptidase IV inhibitor. It had been in phase II clinical development at Pfizer for the treatment of type 2 diabetes; however, in 2010 the company discontinued these trials. In 2012, the product was licensed to SatRx, a spin-off of the ChemRar High Tech Center, by Pfizer on an exclusive worldwide basis (with the exception of China) for the development and commercialization as monotherapy or in combination with other therapies for the treatment of type 2 diabetes. SatRx is conducting phase II clinical trials for the treatment of type 2 diabetes.

……………………….

PAPER

New synthetic route to a dipeptidyl peptidase-4 inhibitor
Org Process Res Dev 2012, 16(3): 409

http://pubs.acs.org/doi/abs/10.1021/op200309z

A new synthetic route to a dipeptidyl peptidase-4 (DPP4) inhibitor was developed and demonstrated on a multigram scale. This approach takes advantage of the cheap and readily available Boc-trans-4-hydroxy-l-proline methyl ester as starting material which was derivatized through an SN2 reaction. Several leaving groups were studied, and the nosylate group showed superiority over other derivatives. Formation of an amide using the most costly starting material, 3,3-difluoropyrrolidine, was performed late in the synthesis to minimize its economical impact on the overall cost of the API.

(3,3-Difluoropyrrolidin-1-yl)-(2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone.FREE BASE

Mp 149 °C (decomp).

[α]d = −31.1 (T = 24 °C, c = 1, CHCl3). Specific rotation of product 4 prepared using the initial route: [α]d = −31.5 (T = 24 °C, c = 1, CHCl3).

1H NMR (400 MHz; CDCl3) δ 8.30 (d, J = 4 Hz, 2H), 6.48 (t, J = 4 Hz, 1H), 3.95–3.6 (m, 9H), 3.25–2.85 (m, 4H), 2.6–2.25 (m, 7H), 1.75–1.6 (m, 1H).

13C NMR (100 MHz; CDCl3) δ 172.28; 161.55; 157.70; 127.22 (t, 1J C–F = 248 Hz), 126.22 (t, 1J C–F = 246 Hz), 109.95; 66.54; 58.87; 57.99; 52.71 (t, 2 J C–F = 32 Hz); 52.00; 50.41; 43.03; 34.46, 34.37, 34.25; 19F NMR (377 MHz, CDCl3) δ −102.1 (m, 2F).

IR (neat): 2951w, 2864w, 2799w, 2759w, 1630s, 1585vs, 1547m, 1449m, 1172m, 1254m, 1129m, 982w, 923m, 796m, 638w.

HRMS (ES, N2) Calcd for C17H24F2N6O: 367.20524, found: 367.20592.

……………………….

PAPER

(3,3-difluoro-pyrrolidin-1-yl)-((2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl)-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor
Bioorg Med Chem Lett 2009, 19(7): 1991

http://www.sciencedirect.com/science/article/pii/S0960894X09001966?np=y

Pfizer Global Research & Development, Groton/New London Laboratories, Pfizer Inc, Groton, CT 06340, United States

doi:10.1016/j.bmcl.2009.02.041

A series of 4-substituted proline amides was evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC₅₀= 13 nM) and selective compound, with high oral bioavailability in preclinical species.

SEE………….https://docs.google.com/viewer?url=http%3A%2F%2Fwww.sciencedirect.com%2Fscience%2FMiamiMultiMediaURL%2F1-s2.0-S0960894X09001966%2F1-s2.0-S0960894X09001966-mmc1.doc%2F271398%2Fhtml%2FS0960894X09001966%2Fce1f70bd989d6d4b79b40c26570693d2%2Fmmc1.doc

………………….

PATENT

WO 2005116014

http://www.google.co.in/patents/WO2005116014A1?cl=en

Example 113 (3.3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone

Step 1 – (S)-2-(3.3-Difluoro-pyrrolidine-1-carbonyl)-4-oxo-pyrrolidine-1 -carboxylic acid tert-butyl ester

3,3-Difluoro- pyrrolidine hydrochloride (4.13 kg, 1.0 equivalent) was charged to the above mixture over 10 minutes at – 10°C to 0°C. Triethylamine (4.0 liters, 1.0 equiv) was introduced slowly over 70 minutes at -10°C to 0°C. Upon completion of triethylamine addition, the mixture was stirred for 1h at 0 to 5°C. The reaction was complete by HPLC assay (-1% starting material). The reaction was quenched with water (10 volumes) at 0°C to 5 °C. The mixture was heated to 20°C to 25 °C. The layers were separated, and the organic layer was washed with 0.5 M HCI (5 volumes). The organic layer was again washed with combined 5% NaHC0₃ (2 volumes) and half saturated brine solution (1.64 M, 3 volumes). The organic solution was concentrated atmospherically to a low stirrable volume (approximately 20 liters). Ethyl acetate (12.6 volumes, 82.8 liters) was added, the solution was concentrated atmospherically to -6 volumes. The mixture was held at 60°C to 65 °C for 2 hours and cooled to room temperature over 3 hours. The mixture was held at 20°C to 25 °C for 8 hours. Heptane (8 volumes) was added, and the mixture was granulated for a minimum of 2 hours. The solid was filtered, rinsed with 2:1 heptane/ethyl acetate (1 volume), and dried in a tray dryer at 25°C to 35°C for a minimum of 12 h. Yield: 7.26 kg, 79%. HPLC purity: 99.7%. The mother liquor (86 liters) was concentrated to 12 liters under partial vacuum at 65°C to 70°C. The mixture was cooled to 60°C to 65 °C. Ethyl acetate (4.0 liters) was added slowly over 15 minutes. The mixture was cooled to 20°C to 25 °C over 2 hours and was held at that temperature for at least 2 hours. The solid was filtered and rinsed with heptane/ethyl acetate (3:1 v/v, 1.7 liters). Drying in a tray dryer for 12 hours at 35°C to 45 °C yielded 435 grams of product. HPLC purity: 96.4%.

Step 2 – (2S.4S)-2-(3.3-Dif luoro-pyrrolidine-1 -carbonyl)-4-(4-pyrimidin-2-yl-piperazin-1 -yl)-pyrrolidine-1 – carboxylic acid tert-butyl ester A reactor was charged with THF (20 volumes), 2-piperazin-1-yl-pyrimidine (2.17 kg, 1.05 equivalents) and the product from Step 1 (4.00 kg, 1.0 equivalent). The mixture was held at 20°C to 25°C until all material was dissolved over 30 minutes. Acetic acid (0.792 kg, 1.05 equivalents) as added. The mixture was stirred for 1 hour during which the reaction mixture turned to cloudy. The reaction mixture was refluxed for 30 minutes and then concentrated at 60°C to 70°C until a steady temperature of 66.9°C was observed in the overheads indicating complete removal of water from the system. More THF was added as necessary. At the end, THF was added to bring the total volume in the reactor to 15 volumes of the limit reagent. The reaction mixture was cooled to -3°C to 7°C and sampled for complete formation of imine by HPLC (using sodium triacetoxyborohydride to reduce imine). Sodium triacetoxyborohydride (5.33 kg, 2.0 equivalents) was added portion-wise to the suspension at -5°C to 15°C. The reaction mixture was heated to 20°C to 25°C and held for 12 hours. HPLC results confirmed the reaction was complete by 99.8%. Sodium bicarbonate aqueous solution (10% w/w, 10 volumes) was added. The slurry was concentrated to remove 10 volumes of THF under partial vacuum at 30°C to 60°C. Ethyl acetate (10 volumes) was added to the suspension after it cooled to 20°C to 25^CC. The organic phase was separated and the aqueous phase was checked by HPLC. It contained less than 2% of the product. The organic phase was washed with water (5 volumes), saturated brine solution (5 volumes) and concentrated to a small volume (2 volumes) under partial vacuum at 45°C to 50°C. To the slurry was added heptane (10 volumes) at 45°C to 50°C over 30 minutes. The mixture was cooled to 20°C to 25°C and granulated for 2 hours. Solid was collected by filtration, rinsed with heptane (2 volumes). Drying in a tray dryer for 12 hours at 35°C to 45°C yield 5.35 kg (91.3%) of the product. Step 3 – (3.3-Dif luoro-pyrrolidin-1 -yl)-f(2S.4S)-4-(4-pyrimidin-2-yl-piperazin-1 -yl)-pyrrolidin-2-yll- methanone Water (19 liters, 2 volumes) was charged to a reactor followed by the product from Step 2 (9.57 kg,

1.0 equivalent). To the slurry was added concentrated HCI (37 wt% in water, 19.1 liters, 2 volumes) slowly at 20°C to 30°C over 4 hours. The slurry went into solution after 12 liters of HCI was added. After the addition completion, the reaction was complete by HPLC assay. The reaction mixture was cooled to 5°C to 15°C. To the mixture was added 50% NaOH aqueous solution slowly with agitation to pH 10 to pH 11. The pH was monitored with a pH meter closely during the neutralization. The total volume of 50% NaOH added was 12.45 liters. The mixture was warmed to 20°C to 25°C and extracted with ethyl acetate twice (115 liters, 12 volumes and 57 liters, 6 volumes, respectively). The sample from aqueous layer after second extraction was analyzed by HPLC and showed only 1% of the product in that aqueous solution.

The organic layers were combined and treated with magnesium sulfate (5 kg) for 1 hour. The mixture was filtered. The filter cake was rinsed with ethyl acetate (10 liters). The filtrate was charged back to the reactor via a 0.2 micron in-line filter for speck free operation. (The following operations were performed under speck free conditions.) The solution was concentrated to 20 liters (2 volumes) under partial vacuum at 50°C to 60°C. The mixture was cooled to 20°C to 25°C over 30 minutes. Upon cooling to room temperature, crystallization occurred. The mixture was held for 30 minutes. Hexanes (20 liters, 2 volumes) was added slowly over 1 hour. The mixture was granulated for 2 hours. The solid product was collected by filtration and rinsed with hexanes/ethyl acetate (10 liters, 1 :1 v/v). The filter was blown dry with nitrogen for a minimum of 2 hours. The product was dried in a tray dryer at 44°C for 12 hours.

Yield: 5.7 kg, 75.9%.

m.p. 156°C. MS m/z 367 (MH⁺).

FREE BASE

¹H NMR (400 MHz, D₂0): δ 8.15 (d, 2H, J = 5.0 Hz, CH of pyrimidine), 6.55 (t, 1 H, J = 4.8 Hz, CH of pyrimidine), 3.87-3.81 (dd, 1 H, H_2b of proline, rotomeric), 3.78-3.50 (m, 4H, N-CH₂ of pyrrolidide), 3.55-3.40 (m, 4H, N-CH₂ of piperazine), 2.97 (dd, 1 H, J = 10.2, 6.6 Hz, H_5a of proline), 2.85-2.75 (m, 1 H, H_4b of proline), 2.69 (dd, 1 H, J = 10.0, 9.1 Hz, H_5b of proline), 2.55-2.20 (m, 7H, overlapping N-CH₂ of piperazine, CH₂ of pyrrolidide and H_3b of proline), 1.47-1.38 (m, 1 H, H_3a of proline).

Alternatively, the dihydrochloride salt of the titled compound was prepared according to the method of Example 1.

………………

US 2005/0256310

http://www.google.com/patents/US20050256310

This approach begins with N–t-Boc-4-oxo-l-proline (1) that undergoes a mixed anhydride activation with pivaloyl chloride at 0 °C, followed by amidation with 3,3-difluoropyrrolidine to yield the intermediate 2. Reductive amination with 1-(2-pyrimidyl)piperazine using sodium triacetoxyborohydride in THF/AcOH provided the desired stereoisomer 3 in high yield and selectivity, the undesired diastereomer being completely removed by crystallization. Deprotection of 3 with 6 N HCl, followed by neutralization with 50% NaOH and extraction provided PF-734200 (4) in good yield.

EXAMPLE 113 (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)-methanone

Step 1—(S)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl

(S)-4-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (6.6 kg, 1.0 equivalent) was charged to a reactor, followed by addition of dichloromethane (15 volumes). The reaction mixture was cooled to 0° C. Triethylamine (4.82 liters, 1.2 equiv) was added over 30 minutes. The mixture turned from suspension to a clear solution at the end of triethylamine addition. The mixture was held at 0° C. to 5° C. for 10 minutes. Pivaloyl chloride (3.65 kg, 1.05 equivalents) was added slowly while keeping the reaction temperature at 0° C. to 5° C. The reaction mixture turned back to a slurry. The reaction mixture was sampled for completion by HPLC (using diethylamine to derivatize) after held for 1 hour at 0° C. to 5° C. 3,3-Difluoro-pyrrolidine hydrochloride (4.13 kg, 1.0 equivalent) was charged to the above mixture over 10 minutes at −10° C. to 0° C. Triethylamine (4.0 liters, 1.0 equiv) was introduced slowly over 70 minutes at −10° C. to 0° C. Upon completion of triethylamine addition, the mixture was stirred for 1 h at 0 to 5° C. The reaction was complete by HPLC assay (˜1% starting material). The reaction was quenched with water (10 volumes) at 0° C. to 5 ° C. The mixture was heated to 20° C. to 25 ° C. The layers were separated, organic layer was washed with 0.5 M HCl (5 volumes). The organic layer was again washed with combined 5% NaHCO₃(2 volumes) and half saturated brine solution (1.64 M, 3 volumes). The organic solution was concentrated atmospherically to a low stirrable volume (approximately 20 liters). Ethyl acetate (12.6 volumes, 82.8 liters) was added, the solution was concentrated atmospherically to ˜6 volumes. The mixture was held at 60° C. to 65° C. for 2 hours and cooled to room temperature over 3 hours. The mixture was held at 20° C. to 25 ° C. for 8 hours. Heptane (8 volumes) was added, and the mixture was granulated for a minimum of 2 hours. The solid was filtered, rinsed with 2:1 heptane/ethyl acetate (1 volume), and dried in a tray dryer at 25° C. to 35° C. for a minimum of 12 h. Yield: 7.26 kg, 79%. HPLC purity: 99.7%. The mother liquor (86 liters) was concentrated to 12 liters under partial vacuum at 65° C. to 70° C. The mixture was cooled to 60° C. to 65° C. Ethyl acetate (4.0 liters) was added slowly over 15 minutes. The mixture was cooled to 20° C. to 25° C. over 2 hours and was held at that temperature for at least 2 hours. The solid was filtered and rinsed with heptane/ethyl acetate (3:1 v/v, 1.7 liters). Drying in a tray dryer for 12 hours at 35° C. to 45° C. yielded 435 grams of product. HPLC purity: 96.4%.

Step 2—(2S,4S)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester

A reactor was charged with THF (20 volumes), 2-piperazin-1-yl-pyrimidine (2.17 kg, 1.05 equivalents) and the product from Step 1 (4.00 kg, 1.0 equivalent). The mixture was held at 20° C. to 25° C. until all material was dissolved over 30 minutes. Acetic acid (0.792 kg, 1.05 equivalents) as added. The mixture was stirred for 1 hour during which the reaction mixture turned to cloudy. The reaction mixture was refluxed for 30 minutes and then concentrated at 60° C. to 70° C. until a steady temperature of 66.9° C. was observed in the overheads indicating complete removal of water from the system. More THF was added as necessary. At the end, THF was added to bring the total volume in the reactor to 15 volumes of the limit reagent. The reaction mixture was cooled to −3° C. to 7° C. and sampled for complete formation of imine by HPLC (using sodium triacetoxyborohydride to reduce imine). Sodium triacetoxyborohydride (5.33 kg, 2.0 equivalents) was added portion-wise to the suspension at −5° C. to 15° C. The reaction mixture was heated to 20° C. to 25° C. and held for 12 hours. HPLC results confirmed the reaction was complete by 99.8%. Sodium bicarbonate aqueous solution (10% w/w, 10 volumes) was added. The slurry was concentrated to remove 10 volumes of THF under partial vacuum at 30° C. to 60° C. Ethyl acetate (10 volumes) was added to the suspension after it cooled to 20° C. to 25° C. The organic phase was separated and the aqueous phase was checked by HPLC. It contained less than 2% of the product. The organic phase was washed with water (5 volumes), saturated brine solution (5 volumes) and concentrated to a small volume (2 volumes) under partial vacuum at 45° C. to 50° C. To the slurry was added heptane (10 volumes) at 45° C. to 50° C. over 30 minutes. The mixture was cooled to 20° C. to 25° C. and granulated for 2 hours. Solid was collected by filtration, rinsed with heptane (2 volumes). Drying in a tray dryer for 12 hours at 35° C. to 45° C. yield 5.35 kg (91.3%) of the product.

Step 3—(3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone

Water (19 liters, 2 volumes) was charged to a reactor followed by the product from Step 2 (9.57 kg, 1.0 equivalent). To the slurry was added concentrated HCl (37 wt % in water, 19.1 liters, 2 volumes) slowly at 20° C. to 30° C. over 4 hours. The slurry went into solution after 12 liters of HCl was added. After the addition completion, the reaction was complete by HPLC assay. The reaction mixture was cooled to 5° C. to 15° C. To the mixture was added 50% NaOH aqueous solution slowly with agitation to pH 10 to pH 11. The pH was monitored with a pH meter closely during the neutralization. The total volume of 50% NaOH added was 12.45 liters. The mixture was warmed to 20° C. to 25° C. and extracted with ethyl acetate twice (115 liters, 12 volumes and 57 liters, 6 volumes, respectively). The sample from aqueous layer after second extraction was analyzed by HPLC and showed only 1% of the product in that aqueous solution. The organic layers were combined and treated with magnesium sulfate (5 kg) for 1 hour. The mixture was filtered. The filter cake was rinsed with ethyl acetate (10 liters). The filtrate was charged back to the reactor via a 0.2 micron in-line filter for speck free operation. (The following operations were performed under speck free conditions.) The solution was concentrated to 20 liters (2 volumes) under partial vacuum at 50° C. to 60° C. The mixture was cooled to 20° C. to 25° C. over 30 minutes. Upon cooling to room temperature, crystallization occurred. The mixture was held for 30 minutes. Hexanes (20 liters, 2 volumes) was added slowly over 1 hour. The mixture was granulated for 2 hours. The solid product was collected by filtration and rinsed with hexanes/ethyl acetate (10 liters, 1:1 v/v). The filter was blown dry with nitrogen for a minimum of 2 hours. The product was dried in a tray dryer at 44° C. for 12 hours.

Yield: 5.7 kg, 75.9%. m.p. 156° C. MS m/z 367 (MH⁺).

¹H NMR (400 MHz, D₂O): δ 8.15 (d, 2H, J=5.0 Hz, CH of pyrimidine), 6.55 (t, 1H, J=4.8 Hz, CH of pyrimidine), 3.87-3.81 (dd, 1H, H_2bof proline, rotomeric), 3.78-3.50 (m, 4H, N—CH₂of pyrrolidide), 3.55-3.40 (m, 4H, N—CH₂of piperazine), 2.97 (dd, 1H, J=10.2, 6.6 Hz, H_5aof proline), 2.85-2.75 (m, 1H, H_4bof proline), 2.69 (dd, 1H, J=10.0, 9.1 Hz, H_5bof proline), 2.55-2.20 (m, 7H, overlapping N—CH₂of piperazine, CH₂of pyrrolidide and H_3bof proline), 1.47-1.38 (m, 1H, H_3aof proline).

Alternatively, the dihydrochloride salt of the titled compound was prepared according to the method of Example 1.

……………..

PAPER

Scheme 1.

Reagents and conditions: (a) 3,3-difluoropyrrolidine hydrochloride, EDC, HOBt, TEA, DCM, rt; (b) NaBH₄, MeOH, (c) (1) trifluoromethane-sulphonyl chloride, DIPEA, DCM; (2) 2-(1-piperazinyl)pyrimidine, DCM, −10 °C; (d) 4 N HCl in dioxane, rt; (e) 2-(1-piperazinyl)pyrimidine, NaBH(OAc)₃, AcOH, DCE; (f) R₁R₂NH hydrochloride, EDC, HOBt TEA, DCM, 0–rt; (g) N-heterocyclic piperazine, NaBH(OAc)_3, AcOH, DCE.

……………………….

if image is not clear see at………..http://www.allfordrugs.com/2015/07/03/gosogliptin/

Patent	Submitted	Granted
Therapeutic compounds [US7291618]	2005-11-17	2007-11-06
(2S,4S)-4-(piperazin-1-yl)pyrrolidine-2-methanone derivatives [US7465732]	2007-05-03	2008-12-16
THERAPEUTIC COMPOUNDS [US2007161664]	2007-07-12
Therapeutic compounds [US2006079498]	2006-04-13

//////////

see gliptins at…………http://drugsynthesisint.blogspot.in/p/gliptin-series.html

TENELIGLIPTIN

July 3, 2015 3:12 am / Leave a comment

TENELIGLIPTIN

Teneligliptin; 760937-92-6; UNII-28ZHI4CF9C; Teneligliptin (INN); 28ZHI4CF9C
MF	C22H30N6OS
MW	426.5782 g/mol

Teneligliptin (INN; trade name Tenelia) is a pharmaceutical drug for the treatment of type 2 diabetes mellitus. It is approved for use in Japan.^[1] It belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitors or “gliptins”.^[2] {(2S,4S)-4-[4-(3-Methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3-thiazolidin-3-yl)methanone

Teneligliptin was launched in Japan in 2012 by Mitsubishi Pharma and Daiichi Sankyo for the treatment of type 2 diabetes mellitus. In 2013, the indication was partially changed to include it as a combination therapy with existing oral hypoglycemic agents, such as biganides, alpha-glucosidaseinhibitors, rapid-acting insulin secretagogues, and insulin preparations, as well as sulfonylureas and thiazolidines that had been approved for the combination.

In 2014, the product was registered in KR for the treatment of type 2 diabetes mellitus.
In 2013, Mitsubishi Tanabe Pharma filed for approval in Japan for use of the compound as combination therapy for the treatment of diabetes type 2.

CAS	760937-92-6

3-{(2S,4S)-4-[4-(3-methyl-l -phenyl- 1 H- pyrazol-5-yl)- l-piperazinyl]-2-pyrrolidinylcarbonyl}-l , 3-thiazolidine is represented structurally by a compound of formula (I):

Teneligliptin (CAS 760937-92-6) is a novel, potent and long-lasting dipeptidyl peptidase-4 inhibitor in treatment of type 2 diabetes. Dipeptidyl-peptidase-4 (DPP- 4) inhibitor has been demonstrated to improve glycemic control, in particular postparandial hyperglycemic control.

Despite of their common mechanism of action, DPP-4 inhibitors show marked structural heterogeneity. DPP-4 inhibitors may be classified into peptidomimetic (i.e. sitagliptin, vildagliptin, saxagliptin, and anagliptin) and non-peptidomimetic (i.e. alogliptin and linagliptin) subtypes.

Teneligliptin, is chemically known as a 3- {((2S,4S)-4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-yl 25 carbonyl}thiazolidine hemipentahydrobromide hydrate and is peptidomimetic with the molecular formula of C22H30N6OS.2½HBr.xH2O and molecular weight of 642.88 g/mol for hemipentahydrobromide. The hydrate can be from mono to dihydrate.

U.S. Patent No. 7,074,794 B2 (the US ‘794) discloses teneligliptin as L-proline derivative and its pharmaceutically acceptable salts which exhibits a Dipeptidyl 5 peptidase IV (DPP-IV) inhibitory activity, which is useful for the treatment or prophylaxis of diabetes, obesity, HIV infection, cancer metastasis, dermopathy, prostatic hyperplasia, periodontitis, autoimmune diseases and the like.

The example-222 of the US ‘794 discloses the process for the preparation of teneligliptin as trihydrochloride salt U.S. Patent No. 8,003,790 B2 (the US ‘790) discloses salts of proline derivative, solvate thereof and production method thereof. In particular, the US ‘790 discloses 2.0 hydrochloride or 2.5 hydrochloride; 2.0 hydrobromide or 2.5 hydrobromide, and hydrates thereof teneligliptin.

The US ‘790 B2 further discloses different salts 15 of teneligliptin which are incorporated herein as reference in their entirety U.S. PG-Pub. No. 2011/0282058 A1 discloses salts of 3-{((2S,4S)-4-(4-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl}thiazolidine with mono-, di- and tri-basic acids or a solvate thereof. 20 International (PCT) publication No. WO 2012/165547 A1 discloses a process for preparation of teneligliptin and pharmaceutically acceptable salts thereof.

International (PCT) publication No. WO 2007/127635 A2 (the WO ‘635 A2) discloses a process for the preparation of diketo-piperazine and piperidine 25 derivatives. In particular, the WO ‘635 A2 discloses the process for preparation of 4-oxo-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester [herein compound (III)] by reacting piperazine with aryl halide.

International (PCT) publication No. WO 2012/099915 A1 (the WO ‘915 A1) 5 discloses the process for the preparation of deuterated thiazolidine derivatives. The WO ‘915 A1 also discloses the process for the preparation of 1-(3-methyl-1- phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) by condensation of 5- chloro-3-methyl-1-phenyl-1H-pyrazole with piperazine.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) discloses the process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) by deprotection of Boc-protected 1-(3-methyl-1-phenyl-1Hpyrazol-5-yl)piperazine with triflouroacetic acid.

U.S. Patent Nos. 7,807,676 B2 and 7,807,671 B2 discloses a process for the preparation of 1-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine by condensation of 5-chloro-3-methyl-1-phenyl-1H-pyrazole with piperazine in presence of n-BuLi in tetrahydrofuran. Bioorganic & Medicinal Chemistry, 14(11), 3662-3671 (2006),

Bioorganic & Medicinal Chemistry, 20(16), 5033-5041 (2012) and U.S. Patent Nos. 7,807,676 B2 and 7,807,671 B2 discloses a process for the preparation of (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate by reacting (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid with 25 thiazolidine in presence of HOBT and EDC.HCl in dimethylformamide solvent.

Bioorganic & Medicinal Chemistry, 15(2), 641-655 (2007) discloses a process for the preparation of (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3- carbonyl)pyrrolidine-1-carboxylate by treating (2S,4S)-tert-butyl 4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-(3-thiazolidinylcarbonyl)pyrrolidine-1- carboxylate with tetrabutylammonium fluoride in tetrahydrofuran.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) discloses the 5 process for the preparation of herein compound (II) after by reacting 1-(3-methyl- 1-phenyl-1H-pyrazol-5-yl)piperazine herein compound (V) with (2S,4R)-tert-butyl 4-hydroxy-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylate in presence of sodium triacetoxyborohydride. There is provided different alternative processes for the preparation of teneligliptin and intermediates thereof.

Bioorganic & Medicinal Chemistry, 20(19), 5705-5719 (2012) also discloses the process for the preparation of 4-[4-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-piperazin- 1-yl]-2-(thiazolidine-3-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester [herein compound (II)] after by reacting 1-(3-methyl-1-phenyl-1H-pyrazol-5- 15 yl)piperazine [herein compound (V)] with (2S,4S)-tert-butyl 4-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-2-(3-thiazolidinylcarbonyl)pyrrolidine-1- carboxylate in presence of trifluoromethylsulfonic anhydride and diisopropylethylamine. 3 – [[(2S, 4S) -4- [4- (3- methyl-1-phenyl–1H- pyrazol-5-yl) -1-piperazinyl ] -2-pyrrolidinyl] carbamoyl] thiazolidine, having the formula below, is a very novel DPP-4 inhibitor potential.

World Patent Application No. W02012099915 for Ge Lieting discloses a process for the preparation route is as follows:

Journal B10rganic & Medicinal Chemistry, 2012, 20, 5705-5719 also discloses a preparation method for Ge Lieting, the route is as follows:

[0009] 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine, was prepared for the Ge Lieting key intermediate. Journals B10rganic & Medicinal Chemistry, 2012,20,5705-5719 reported the preparation of the intermediates prepared route is as follows:

[0011] The preparative route after the N-Boc-N- acetoacetyl piperazine phenylhydrazine and methanesulfonic acid in an ethanol solution of the reaction at room temperature 14h, concentrated under reduced pressure after addition of pyridine.Was added phosphorus oxychloride in pyridine, 20h post treatment reaction at room temperature the reaction system. The compound obtained above was then added trifluoroacetic acid was dissolved in methylene chloride after, after treatment at room temperature for 1.5h to give 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine.

The reaction process requires mesylate mesylate flammable, easy-absorbent deliquescence, and has a strong corrosive and irritating, easy to cause the body burns; phosphorus oxychloride, a highly toxic substance, water violent hair in the air smoke, hydrolyzed into phosphoric acid and hydrogen chloride, is very unstable, to operate a lot of trouble; trifluoroacetic acid is highly corrosive and irritant, can cause the body burns; low yield of the reaction (10%). Seeking a simple operation, high reaction yield, low cost and suitable for industrial production production process 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine has a very important role in the field of medicine.

…………………………………….

since the capture is staggered, compd 165 is not clear in above pic see below

…………

if above section iis not clear see at ……..http://www.allfordrugs.com/2015/07/03/teneligliptin/

…………………….

CN104177295

reaction scheme in http://www.google.com/patents/CN104177295A?cl=en

Description: LR as Lawesson reagent (Lawesson Reagent), is a sulfur oxygen exchange reagent. The present invention provides a method for preparing key intermediates Ge Lieting method, comprising the steps of: (I) N-Boc-N- acetoacetyl piperazine Lawesson’s reagent in the presence of an organic solvent, with a phenylhydrazine of the formula occurs ⑴ reaction shown:

(2) the step (1) The product was dissolved in an organic solvent, the following formula (II) in concentrated hydrochloric acid to deprotected shown:

格列汀 refers to 1- (3-methyl-1-phenyl-5-pyrazolyl) piperazine

……………………………..

Bioorganic & Medicinal Chemistry

Volume 20, Issue 19, 1 October 2012, Pages 5705–5719

http://www.sciencedirect.com/science/article/pii/S0968089612006347

…………………………………..

………………………..

http://www.google.co.in/patents/WO2015019238A1?cl=en

Example 5: Preparation of {(2^^,.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -vHpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)

Activated carbon (10 g) was added to a solution of the residue (obtained in Example 4) in isopropyl alcohol (1000 mL) at 30°C to 35°C. The reaction mixture was filtered through a Hyflo^® bed. The filtrate was heated to a temperature of 70°C to 75°C. Hydrobromic acid (48%; 168 g) was slowly added to the filtrate at 70°C to 75°C over a period of 10 minutes to 15 minutes. The reaction mixture was stirred for 2.5 hours at 70°C to 77°C. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes. The reaction mixture was filtered to obtain a solid. The solid obtained was washed with isopropyl alcohol (2 x 200 mL), and dried at 50°C under reduced pressure for 15 hours to obtain crude {(25^*,45)-4-[4-(3-methyl-l-phenyl-lH- pyrazol-5 -yl)piperazin- 1 -yl]pyrrolidin-2-yl} ( 1 ,3 -thiazolidin-3 -yl)methanone

hemipentahydrobromide hydrate.

Yield: 90%

Example 6: Purification of {(2^’.4^)-4-r4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin- 1 -yllpyrrolidin-2-yl } ( 1.3 -thiazolidin-3 -vDmethanone hemipentahydrobromide hydrate (Formula II)

A reaction mixture containing {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin- 1 -yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone

hemipentahydrobromide hydrate (100 g; prepared according to the process of Example 5) in ethanol (700 mL) was heated at 70°C to 75°C to obtain a solution. The solution was filtered at the same temperature. The filtrate was allowed to cool to a temperature of 65 °C to 68°C, and deionized water (10 mL) was added at the same temperature. The solution was cooled to a temperature of 55°C to 60°C, and stirred at the same temperature for 2 hours. The solution was further cooled to a temperature of 20°C to 25 °C, and stirred at the same temperature for 60 minutes to obtain a solid. The solid was filtered, washed with ethanol (100 mL), and dried at 45°C to 50°C under reduced pressure for 18 hours to 20 hours to obtain pure {(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l- yl]pyrrolidin-2-yl } ( 1 ,3 -thiazolidin-3 -yl)methanone hemipentahydrobromide hydrate .

Yield: 90%

HPLC Purity: 99.93%

WO2012099915A1 *	18 Jan 2012	26 Jul 2012	Hongwen Zhu	Thiazolidine derivatives and their therapeutic use
WO2012165547A1 *	31 May 2012	6 Dec 2012	Mitsubishi Tanabe Pharma Corporation	Method for manufacturing pyrazole derivative
WO2014041560A2 *	28 Aug 2013	20 Mar 2014	Glenmark Pharmaceuticals Limited; Glenmark Generics Limited	Process for the preparation of teneligliptin
US7074794	10 Aug 2001	11 Jul 2006	Mitsubishi Pharma Corporation	Proline derivatives and the use thereof as drugs
US8003790	17 Feb 2006	23 Aug 2011	Mitsubishi Tanabe Pharma Corporation	Salt of proline derivative, solvate thereof, and production method thereof
US20050256310 *	12 May 2005	17 Nov 2005	Pfizer Inc	Therapeutic compounds

EP1854795A1 *	17 Feb 2006	14 Nov 2007	Mitsubishi Pharma Corporation	Salt of proline derivative, solvate thereof, and production method thereof
EP1894567A1 *	2 Jun 2006	5 Mar 2008	Mitsubishi Tanabe Pharma Corporation	Concomitant pharmaceutical agents and use thereof
US20040106655 *	10 Aug 2001	3 Jun 2004	Hiroshi Kitajima	Proline derivatives and the use thereof as drugs

Patent	Filing date	Publication date	Applicant	Title
WO2015019238A1 *	28 Jul 2014	12 Feb 2015	Ranbaxy Laboratories Limited	Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one

Patent	Submitted	Granted
Proline derivatives and use thereof as drugs [US7060722]	2005-11-03	2006-06-13
Proline derivatives and the use thereof as drugs [US7074794]	2004-06-03	2006-07-11
Proline derivatives and use thereof as drugs [US2006173056]	2006-08-03
SALT OF PROLINE DERIVATIVE, SOLVATE THEREOF, AND PRODUCTION METHOD THEREOF [US8003790]	2009-08-27	2011-08-23
METHOD OF TREATING ABNORMAL LIPID METABOLISM [US2010305139]	2010-12-02
COMBINED USE OF DIPEPTIDYL PEPTIDASE 4 INHIBITOR AND SWEETENER [US2010113382]	2010-05-06
CONCOMITANT PHARMACEUTICAL AGENTS AND USE THEREOF [US2009082256]	2009-03-26
PROPHYLACTIC/THERAPEUTIC AGENT FOR ABNORMALITIES OF SUGAR/LIPID METABOLISM [US2009088442]	2009-04-02
SALT OF PROLINE DERIVATIVE, SOLVATE THEREOF, AND PRODUCTION METHOD THEREOF [US2011282058]	2011-11-17

Joanne Bronson, Amelia Black, T. G. Murali Dhar, Bruce A. Ellsworth, and J. Robert Merritt. “Teneligliptin (Antidiabetic)”. Annual Reports in Medicinal Chemistry 48: 523–524. doi:10.1016/b978-0-12-417150-3.00028-4.
Kishimoto, M (2013). “Teneligliptin: A DPP-4 inhibitor for the treatment of type 2 diabetes”. Diabetes, metabolic syndrome and obesity : targets and therapy 6: 187–95. doi:10.2147/DMSO.S35682. PMC 3650886. PMID 23671395.

see gliptins at…………http://drugsynthesisint.blogspot.in/p/gliptin-series.html

NETOGLITAZONE

November 26, 2014 3:22 am / Leave a comment

Figure US08017633-20110913-C00025

NETOGLITAZONE, isaglitazone

161600-01-7

5-((6-((2-fluorophenyl)methoxy)-2-naphthalenyl)methyl)-2,4-thiazolidinedione
MCC 555
MCC-555
netoglitazone
RWJ-241947

Netoglitazone (MCC-555) is a hypoglycemic agent.

Synthesis

US 5594016

http://www.google.co.in/patents/US5594016

Reaction of aldehyde (III) with 2-fluorobenzyl alcohol (VIII) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF furnishes 6-(2-fluorobenzyloxy)naphthalene-2-carbaldehyde (IX) , which is then reduced with NaBH4 in ethanol/THF to give the naphthalenemethanol derivative (X). Halogenation of (X) by means of iodide, triphenylphosphine and imidazole in THF yields the naphthylmethyl iodide derivative (XI), which is finally condensed with thiazolidine-2,4-dione (IV) by means of HMPA and butyl lithium in THF.

Ueno, H.; Oe, T.; Suehiro, I.; Nakamura, F. (Mitsubishi Chemical Corp.); Naphthalene derivs.. EP 0604983; JP 1994247945; US 5594016 .

http://www.google.co.in/patents/EP0604983B1?cl=en

References

Sorbera, L.A.; Castañer, J.; Del Fresno, M.; Silvestre, J. (2002). “Netoglitazone”. Drugs of the Future 27 (2): 132.doi:10.1358/dof.2002.027.02.657482.

Netoglitazone
Systematic (IUPAC) name

5-[(6-[(2-fluorophenyl)methoxy]naphthalen-2-yl)methyl]-1,3-thiazolidine-2,4-dione
Clinical data
Legal status	Uncontrolled
Identifiers
CAS number	161600-01-7
ATC code	?
PubChem	CID 204109

UNII	QOV2JZ647A
KEGG	D05150
Chemical data
Formula	C₂₁H₁₆F N O₃S
Mol. mass	381.420 g/mol

Pharmaceutical composition comprising a glitazone and a 4-oxobutanoic acid, and the use thereof for treating diabetes [US2005085489]	2005-04-21
Compositions of a cyclooxygenase-2 selective inhibitor and a peroxisome proliferator activated receptor agonist for the treatment of ischemic mediated central nervous system disorders [US2005107387]	2005-05-19
Pharmaceutical composition comprising an ACAT inhibitor and an insulin resistance reducing agent [US2005119314]	2005-06-02
Medical devices to treat or inhibit restenosis [US2005149174]	2005-07-07
Medicinal compositions containing diuretic and insulin resistance-improving agent [US2005288339]	2005-12-29
Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione [US2006149075]	2006-07-06
Concomitant drug as therapeutic agent for inflammatory bowel disease [US2006177444]	2006-08-10
Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes [US2004167178]	2004-08-26
Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione [US2003158241]	2003-08-21
Pharmacological method for treatment of neuropathic pain [US2007249561]	2007-10-25

Patent	Submitted	Granted
Medicinal composition containing diabetes remedy [US7943584]	2008-02-14	2011-05-17
Medicinal compositions containing diuretic and insulin resistance-improving agent [US7199139]	2004-03-18	2007-04-03
Crystals of 5-[{6-(2-fluorobenzyl)oxy-2-naphthyl}methyl]-2,4-thiazolidinedione [US6541493]		2003-04-01
Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes [US6756360]		2004-06-29
Roflumilast for the Treatment of Diabetes Mellitus [US8017633]	2008-09-04	2011-09-13

Combination of FBPase Inhibitors and Insulin Sensitizers for the Treatment of Diabetes [US2008004226]	2008-01-03
Pharmaceutical Composition Comprising Ppar Regulator [US2008153882]	2008-06-26
Pharmaceutical combination comprising vitamin k [US2009137614]	2009-05-28
Pharmaceutical Composition Containing PPARgamma Agonist [US2009137626]	2009-05-28
Pharmaceutical agent comprising insulin resistance improving agent [US2009124626]	2009-05-14
ROFLUMILAST FOR THE TREATMENT OF DIABETES MELLITUS [US2011269750]	2011-11-03
Combination treatment for diabetes mellitus [US2010179131]	2010-07-15
Therapeutic agent for diabetes containing insulin resistance improving agent [US2007049515]	2007-03-01
PHARMACEUTICAL COMBINATION COMPRISING VITAMIN K [US2011028499]	2011-02-03
RESPIRATORY DISEASE TREATMENT [US8236786]	2011-03-03	2012-08-07

NAVEGLITAZAR (LY519818)

November 25, 2014 8:06 am / Leave a comment

NAVEGLITAZAR

2(S)-Methoxy-3-[4-[3-(4-phenoxyphenoxy)propoxy]phenyl]propionic acid

476436-68-7

C25 H26 O6, 422.4703

CCRIS 9448
LY 519818
LY 9818
LY519818
LY9818
Naveglitazar
UNII-Y995M7GM0G

http://clinicaltrials.gov/search/intervention=NAVEGLITAZAR

Naveglitazar, a peroxisome proliferator-activated receptor (PPAR) modulator, had been in phase II clinical trials for the once-daily oral treatment of type 2 diabetes, however, no recent development for this indication has been reported. The compound was originally discovered through an ongoing research collaboration between Lilly and Ligand, but, in 2006, Lilly discontinued the development program.

Naveglitazar [LY519818; benzenepropanoic acid, alpha-methoxy-4-[3-(4-phenoxyphenoxy)propoxy], (alpha-S)-] is a nonthiozolidinedione peroxisome proliferator-activated receptor alpha-gamma dual, gamma-dominant agonist that has shown glucose-lowering potential in animal models and in the clinic.

Studies have been conducted to characterize the disposition, metabolism, and excretion of naveglitazar in mice, rats, and monkeys after oral and/or i.v. bolus administration.

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2-Alkoxydihydrocinnamates as PPAR agonists. Activity modulation by the incorporation of phenoxy substituents.

Martín JA, Brooks DA, Prieto L, González R, Torrado A, Rojo I, López de Uralde B, Lamas C, Ferritto R, Dolores Martín-Ortega M, Agejas J, Parra F, Rizzo JR, Rhodes GA, Robey RL, Alt CA, Wendel SR, Zhang TY, Reifel-Miller A, Montrose-Rafizadeh C, Brozinick JT, Hawkins E, Misener EA, Briere DA, Ardecky R, Fraser JD, Warshawsky AM.

Bioorg Med Chem Lett. 2005 Jan 3;15(1):51-5.

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http://www.google.im/patents/US20050020684?cl=un

EXAMPLE 153

′2-Methoxy-3-{3-[3-(4-phenoxy-phenoxy)-propoxy]-phenyl}-propionic acid

The title compound was prepared from 3-(3-Hydroxy-phenyl)-2-methoxy-propionic acid methyl ester from Example 152, Step D with 4-(3-bromopropoxy)1-phenoxybenzene in a manner analogous as in Example 152, Step E. MS (ES) for C₂₅H₂₆O₆[M+NH₄]⁺: 440.2, [M+Na]⁺: 445.2. ¹H-NMR (CDCl₃, 200.15 MHz): 7.33-7.17 (m, 3H), 7.07-6.78 (m, 10H), 4.15 (dt, 4H, J=1.9, 6.2), 4.03 (dd, 1H, J=7.3, 4.3), 3.40 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.98 (dd, 1H, J=14.0, 7.5), 2.25 (qui, 2H, J=5.9)ppm.

DENAGLIPTIN

November 25, 2014 7:25 am / Leave a comment

DENAGLIPTIN

(2S,4S)-1-[(2S)-2- amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile

1-[2(S)-Amino-3,3-bis(4-fluorophenyl)propionyl]-4(S)-fluoropyrrolidine-2(S)-carbonitrile

GSK-823093, 823093
811432-66-3 CAS TOSYLATE

483369-58-0 (free base)

Denagliptin (GSK-823093) having the structural formula D below is (2S,4S)-1-[(2S)-2- amino-3,3-bis(4-fluorophenyl)propionyl]-4-fluoropyrrolidine-2-carbonitrile, also named (2S,4S)-4-fluoro-1-[4-fluoro-beta-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile

(D) – A –

Denagliptin is specifically disclosed in US Patent No. 7,132,443 and in WO 03/002531. In one embodiment, denagliptin is in the form of its hydrochloride salt as disclosed in Example 2 of WO 03/002531 or its tosylate salt as disclosed in WO 2005/009956. A class of this embodiment refers to denagliptin tosylate. Crystalline anhydrous denagliptin tosylate is disclosed in WO 2005/009956.

Denagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor which entered phase III clinical trials in 2006 for the treatment of type 2 diabetes at GlaxoSmithKline. Development of this compound was put on hold due to unfavorable preliminary data from preclinical long-term toxicity trials.

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http://www.google.com/patents/US7132443

Example 2

(2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride

A. 3,3-Bis(4-fluorophenyl)-3-hydroxypropanoic acid.

To an anhydrous THF (80 mL) solution of n-butyl lithium (46 mL of 2.5 M, 115 mmol) at 0° C. was added dropwise diisopropylamine (11.13 g, 115 mmol) and the solution stirred for 10 minutes. Keeping the solution at 0° C., acetic acid (2.64 g, 44 mmol) was added dropwise and the mixture stirred for 10 min and it was then heated 50° C. After 30 min a heavy precipitate had formed and the solution was allowed to cool. A solution of 4,4′-diflurobenzophenone (9.6 g, 0.044 mol) in THF (50 mL, anhydrous) was added at 0° C., and the solution stirred at room temperature overnight. Water (100 mL) and diethyl ether (100 mL) were added and the aqueous layer was separated and acidified with 1M HCl to pH 3. The organics were extracted with ethyl acetate (3×200 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a crude white solid that could be washed with cold CHCl₃to remove trace amounts of the benzophenone. The solid was dried under high vacuum yielding 5.63 g (20.2 mmol, 46% yield) of compound A as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 12.4 (s(br), 1H), 7.48–7.39 (m, 4H), 7.19–7.02 (m, 4H), 5.91 (s(br), 1H), 3.25 (s, 2H) ppm.

B. 3,3-Bis(4-fluorophenyl)acrylic acid.

To a 20% solution of sulfuric acid in acetic acid (50 mL, V/V) was compound A (5.6 g, 20.2 mmol) and the mixture stirred for 30 minutes at RT. To this solution was added H₂O (500 mL) and the organics were extracted with ethyl acetate (3×150 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a white solid. The solid was dried under high vacuum yielding 4.97 g (19.1 mmol, 95% yield) of compound B as a white solid.

¹H NMR (CDCl₃) 400 MHz δ 7.27–7.21 (m, 2H), 7.19–7.13 (m, 2H), 7.10–6.95 (m, 4H), 6.26 (s, 1H) ppm.

C. 3,3-Bis(4-fluorophenyl)propanoic acid.

To a solution of compound B (2.5 g, 9.61 mmol) in ethyl acetate (250 mL) was added 10% palladium on carbon (50% w/w) and hydrogenated at 1 atmosphere of hydrogen for 12 hours. The heterogeneous solution was filtered through celite and concentrated in vacuo to provide a yellow oil. The oil was dried under high vacuum yielding 2.40 g (9.16 mmol, 95% yield) of compound C as a yellow oil.

¹H NMR (d₆-DMSO) 400 MHz δ 12.08 (brs, 1H), 7.40–7.30 (m, 4H), 7.15–7.05 (m, 4H), 4.45 (t, 1H, J=8.1 Hz), 3.05(d, 2H, J=8.1 Hz) ppm.

D. (4S,5R)-3-[3,3-Bis(4-fluorophenyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one.

To a THF (50 mL, anhydrous) containing compound C (2.0 g, 7.63 mmol) was added N,N-diisopropylethylamine (1.18 g, 9.16 mmol) and then the solution cooled to −78° C. To this solution was added trimethylacetyl chloride (0.97 g, 8.01 mmol) and the solution warmed to 0° C. over 1 hour. The cloudy mixture was filtered and the filtrate added slowly over 10 min to a solution of the lithiated (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone at −78° C., which was prepared by the dropwise addition of n-butyl lithium (3.0 mL of 2.5 M, 7.63 mmol) to a THF (50 mL) solution of (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone (1.35 g, 7.63 mmol) at −78° C. which had stirred for 10 min to provide the lithiated (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone. The yellow mixture was warmed to 0° C. and quenched with H₂O (50 mL) and extracted with diethyl ether (3×250 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a solid. Flash chromatography (silica gel, 20% ethyl acetate/hexanes) provided compound D. The white solid was dried under high vacuum yielding 2.31 g (5.49 mmol, 72% yield) as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 7.40–7.25 (m, 9H), 7.18–7.02 (m, 4H), 5.76 (d, 1H, J=7.6 Hz), 4.65 (m, 1H), 4.58 (t, 1H, J=7.6 Hz), 3.72 (dd, 1H, J=16.8, 7.0 Hz) 3.57 (dd, 1H, J=16.8, 7.0 Hz), 0.58 (d, 3H, J=6.7 Hz) ppm.

E. (4S,5R)-3-[(2S)-2-Azido-3,3-bis(4-fluorophenyl)propanoyl]-4-methyl-5-[(1E,3Z)-1-methylhexa-1,3,5-trienyl]-1,3-oxazolidin-2-one.

To a THF (50 mL anhydrous) solution containing compound D (2.0 g, 4.75 mmol) at −78° C. was added dropwise potassium bis(trimethylsilyl)amide (10.0 mL of 0.5 M toluene solution, 4.98 mmol). After stirring for 10 min 2,4,6-triisopropylbenzenesulfonyl azide (trisyl azide) (1.84 g, 5.94 mmol) in THF (10 mL, anhydrous) was added in one portion. After 3 minutes acetic acid was added (1.31 g, 21.8 mmol) at −78° C. and then the reaction quickly warmed to 30° C. and stirred for 1 hr at that temperature generating a light yellow solution. To this solution was added H₂O (100 mL) and the organics were extracted with ethyl acetate (500 mL). After washing with sat NaHCO₃(100 mL) and drying over MgSO₄the solvent was reomved in vacuo yielding a yellow oil. Column chromatography (ethyl acetate/hexanes 1:9) provided compound E as a white solid. HPLC showed a single diastereoisomer. The white solid was dried under high vacuum yielding 1.71 g (3.70 mmol, 78% yield) as a white solid.

¹H NMR (CDCl₃) 400 MHz δ 7.42–7.35 (m, H), 7.25–7.18 (m, H), 7.10–7.06 (m, 2H), 7.05–6.92 (m, 2H), 5.95 (d, 1H, J=10.8 Hz), 5.05 (d, 1H, J=7.1 Hz), 4.60 (d, 1H, J=10.8 Hz), 4.38 (m, 1H), 0.95 (d, 3H, J=6.8 Hz) ppm.

F. (2S)-2-Azido-3,3-bis(4-fluorophenyl)propanoic acid.

To a THF/H₂O (4:1, 50 mL) solution of compound E (1.5 g, 3.25 mmol) at 0° C. was added a solution of lithium hydroxide (0.272 g, 6.49 mmol) in hydrogen peroxide (1.50 mL of 30% soln in H₂O, 48.75 mmol). The mixture was stirred at 0° C. for 1 hr and then quenched with Na₂SO₄(6.3 g, 50 mL of 1.0 M solution in H₂O). The THF was removed in vacuo and the solution acidified to pH 1 with 6.0 M HCl at 0° C. The organics were extracted with ethyl acetate (2×200 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a clear oil. Column chromatography (EtOAc/hexanes/acetic acid 50:50:1) provided compound F as a white solid. The solid was dried under high vacuum yielding 0.78 g (2.60 mmol, 80% yield) as a white solid.

¹H NMR (CDCl₃) 400 MHz δ 9.60(s(br), 1H), 7.25–7.10 (m, 4H), 7.10–6.95 (m, 4H), 4.50 (d, 2H, J=8.6 Hz) ppm.

G. (2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoic acid.

To an ethyl acetate (250 mL) solution of compound F (1.5 g, 4.95 mmol) was added 10% palladium on carbon (10% w/w) and hydrogenated at 1 atmosphere of hydrogen for 12 hr. The heterogeneous solution was filtered through celite (1 g) and the filtrate concentrated in vacuo to provide a clear oil. The oil was dried under high vacuum yielding 1.30 g (4.70 mmol, 95% yield) of compound G as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 10.2(s(br), 1H), 7.38–7.27(m, 4H), 7.08–6.98 (m, 4H), 4.25 (d, 1H, J=8.3 Hz), 3.95 (d, 1H, J=8.3 Hz) ppm.

H. (2S)-2-[(tert-Butoxycarbonyl)amino]-3,3-bis(4-fluorophenyl)propanoic acid.

To a CH₂Cl₂(150 mL) solution containing compound G (1.30 g, 4.69 mmol) was added triethylamine (2.37 g, 23.4 mmol) and di-tert-butyl dicarbonate (1.23 g, 5.63 mmol). After stirring for 12 hr H₂O (50 mL) and CH₂Cl₂(300 mL) were added and the solution acidified to pH 3 with 1.0 M HCl. Separation of the ethyl acetate layer followed by drying over MgSO₄and removal of the solvent in vacuo yielded a clear oil. The oil was dried under high vacuum yielding 1.68 g (4.4 mmol, 95% yield) of compound H as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 12.4 (s(br), 1H), 7.35–7.22 (m, 4H), 7.15–6.95 (m, 4H), 4.78 (t, 1H, J=8.9 Hz), 4.25 (d, 1H, J=8.9 Hz), 3.05 (m, 1H), 1.20 (s, 3H), 1.15 (s, 6H) ppm.

I. (2S,4S)-1-[(2S)-2-(tert-Butoxycarbonyl)amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile.

To a DMF solution (25 mL anhydrous) was compound H (1.0 g, 2.65 mmol) and HATU (1.0 g, 2.65 mmol). To this solution was added N,N-diisopropylethylamine (0.462 mL, 2.65 mmol) and after 30 min (2S, 4S)-4-fluoro-2-pyrrolidinecarbonitrile 4-methylbenzenesulfonate (0.619 g, 2.12 mmol) and additional N,N-diisopropylethylamine (0.37 mL 2.12 mmol) were added. This solution was allowed to stir at RT for 12 hr and then saturated sodium bicarbonate (100 mL) was added. The resulting gummy mixture was extracted with ethyl acetate (3×100 mL) and the organics were washed with saturated NaCl (50 mL) followed by drying over MgSO₄. Filtration and removal of the solvent in vacuo yielded a clear oil. The oil was chromatographed on silica gel (hexanes/EtOAc 4:1) to provide a white solid. The solid was dried under high vacuum yielding 815 mg (1.72 mmol, 65% yield) of compound I as a white solid.

¹H NMR (CDCl₃) 400 MHz δ 7.38–7.32 (m, 2H), 7.21–7.15 (m, 2H), 7.12–6.98(m, 4H), 5.15 (d, 1H, J=51 Hz), 5.03 (d, 1H, J=8.9 Hz, 4.89 (d, 1H, J=11.2 Hz), 4.86 (d, 1H, J=8.9 Hz), 4.40 (d, 1H, J=11.2 Hz), 3.83 (ddd, 1H, J=36.8, 12.1, 3.7 Hz), 3.05 (d, 1H, J=12.2 Hz), 2.62 (t, 1H, J=15.3 Hz), 2.25 (m, 1H), 1.38 (s, 9H) ppm.

J. (2S,4S)-1-[(2S)-2-Amino-3,3-bis(4-fluorophenyl)propanoyl]-4-fluoropyrrolidine-2-carbonitrile hydrochloride.

To compound I (0.5 g, 1.05 mmol) was added 4.0 N HCl in 1,4-dioxane (10 mL, 40 mmol) and after 3 hr diethyl ether (100 mL) was added. The resulting precipitate was collected by filtration and after drying under high vacuum 0.41 g (1.0 mmol, 95% yield) of compound J was obtained as a white solid.

¹H NMR (d₆-DMSO) 400 MHz δ 8.42 (s(br), 3H), 7.72–7.66 (m, 2H), 7.38–7.32 (m, 2H), 7.25–7.19 (m, 2H), 7.06–7.0 (m, 2H), 5.38 (d, 1H, J=51 Hz), 4.91 (d, 2H, J=8.8 Hz), 4.82 (d, 1H, J=11.3 Hz), 4.41 (d, 1H, J=11.3 Hz), 3.86 (ddd, 1H, J=39.2, 12.4, 3.1 Hz), 3.45 (q, 1H, J=12.4 Hz), 2.38–2.20 (m, 2H) ppm.

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PAPER

Org. Process Res. Dev., 2009, 13 (5), pp 900–906

DOI: 10.1021/op900178d

http://pubs.acs.org/doi/full/10.1021/op900178d

A recent paper from workers at GSK describes improvements to the synthesis of Denagliptin (12). The final chemical step is Boc deprotection of (11) with p-toluenesulphonic acid (p-TSA) in isopropanol (IPA). Some isolated batches of final product contained impurities 12A (~1%), 12B (~1%), and 12C (~0.3%). Investigation showed that these three impurities were not produced during the reaction but were produced in the dryer if there was any excess p-TSA in the filter cake during drying. These impurities could be avoided by washing the filter cake with 2 volumes of IPA prior to drying.

D.E. Paterson,* J.D. Powers, M. LeBlanc, T. Sharkey, E. Boehler, E. Irdam, and M.H. Osterhout (GlaxoSmithKline), Org. Process. Res. Dev.,2009, 13(5), 900-906.

Denagliptin Tosylate (1)

To a mixture of 11 (110 kg, 232 mmol) in isopropanol (550 L, 5 vol) at 70 °C was added a solution of p-toluenesulfonic acid monohydrate (88.4 kg, 464 mol) in isopropanol (550 L, 5 vol) over one hour while maintaining the temperature at 70 °C. After the addition, the reaction was stirred at 70 °C for 6 h. The batch was cooled to 20 °C, held for 30 min, filtered, and washed with isopropanol (2 × 220 L, 2 vol). The solids were dried at 55 °C to give 118 kg (89%) of 1 as a white solid.

Recrystallization of Denagliptin Tosylate (1)

A mixture of denagliptin tosylate (100 kg, 183 mol) and isopropanol (500 L, 5 vol) and water (500 L, 5 vol), was heated until all the solids dissolved (approximately 72 °C). The hot solution was filtered into another vessel. The solution was cooled to approximately 5 °C, and water (300 L, 3 vol) was added. The reaction was stirred at this temperature for 30 min and was filtered. The filtercake was washed with filtered isopropanol (2 × 200 L, 2 × 2 vol), and pulled dry. The solids were dried at 55 °C to give 91.9 kg (92%) of 1 as a white solid.

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http://www.google.com.ar/patents/US7462641?cl=pt-PT

(2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt

Figure US07462641-20081209-C00001

Figure US07462641-20081209-C00003

EXAMPLE 1Preparation of (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt, Form 1a) Preparation of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide

A reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-proline (130 g, 1 wt, 1 eq.), dichloromethane (520 mL, 4 vol), pyridine (55 mL, 0.4 vol, 1.2 eq), and Boc-anhydride (145 g, 1.1 wt, 1.2 eq.). The reaction solution was stirred at approximately 20° C. for 2 hours. The reactor was charged with ammonium bicarbonate (62 g, 0.5 wt, 1.44 eq), and was stirred at approximately 20° C. overnight. The reaction was filtered over a bed of celite (130 g, 1 wt), and the filter cake was washed with dichloromethane (260 mL, 2 vol). The filtrate was concentrated to a volume of 3 volumes, heptane (520 mL, 4 vol) was added, and again concentrated to a final volume of 3 volumes. Heptane (390 mL, 3 vol) was added, and the reaction was cooled to approx. 5° C. for 30 min.

The solid was collected by filtration, washed with heptane (260 mL, 2 vol), and then dried under vacuum at approximately 50° C. to constant weight. Yield: 88-90%.

b) Preparation of (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid

The reactor was charged with (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide (116 g, 1 wt, 1 eq.), isopropyl acetate (578 mL, 5 vol), and pyridine (88 mL, 0.8 vol, 2.2 eq). The resulting slurry was stirred at approx. 20° C. Trifluoroacetic anhydride (77 mL, 1.0 wt, 1.1 eq.) was added over at least 30 minutes, maintaining the temperature at approx. 20° C. The reaction solution was stirred an additonal 1 hour at approx. 20° C. Water (578 mL, 5 vol) was added slowly, and the reaction mixture was stirred for 15 minutes. The stirring was stopped, the layers were allowed to separate, and the aqueous (lower) layer was discarded. The organic layer was concentrated under vacuum at a jacket temperature of approximately 50° C. to half volume. The reaction was diluted back up to 5 volumes with isopropyl acetate. The reactor contents were cooled to 20° C., and the reactor was charged with p-toluenesulfonic acid (94 g, 0.8 wt, 1 eq). The reaction was stirred for 2 hours, and GC analysis at this point should show complete consumption of (4S)-1-(tert-butoxycarbonyl)-4-fluoro-L-prolinamide. The reaction was concentrated to 3 volumes under full vacuum at a jacket temperature of approximately 50° C. and 2 volumes of isopropyl alcohol were added. The reaction was concentrated to a final volume of 4 volumes. The reaction was cooled to 0° C. and held for 30 minutes. The solids were collected by filtration, washed with isopropyl alcohol (1 vol), and then dried under vacuum at approx. 50° C. to constant weight. Yield: 68-71%.

c) Preparation of tert-Butyl{(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate

A reactor was charged with N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-β-(4-fluorophenyl)-L-phenylalanine (400 g, 1 wt, 1 eq.), (2S,4S)-4-fluoropyrrolidine-2-carbonitrile para-toluenesulfonic acid (307.7 g, 0.77 wt, 1.01 eq.), O-(7-Azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexaflurophosphate [i.e. HATU] (408 g, 1.02 wt, 1.01 equiv.), and DMF (2.8L, 7 vol). The mixture was cooled to approximately 0° C. Hunig’s base (376 mL, 0.94 vol, 2.04 equiv.) was added over at least 30 minutes. The mixture was heated to approximately 25° C. and was stirred at this temperature until the reaction was complete (ca. 3 hours). MTBE (2.8L mL, 7 vol) was added, followed by water (2L, 5 vol) over at least 30 minutes to quench the reaction. The aqueous phase was extracted with MTBE (1.2L, 3 vol). The combined organic phases were washed with water (2L, 5 vol). The organic phase was concentrated under vacuum to 3 volumes, and ethanol (1.6L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes, and ethanol (1.6 L, 4 vol) was added. The reaction was further concentrated under vacuum to 3 volumes. Added ethanol (2L, 5 vol). The ethanol solution of tert-Butyl {(1 S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamatewas used directly in the next step.

d) Preparation of (2S,4S)-4-fluoro-1-[4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]-2-pyrrolidinecarbonitrile p-toluenesulfonic acid salt. Form 1

A 10L reactor equipped with overhead stirring was charged with a slurry of tert-Butyl {(1S)-1-[bis(4-fluorophenyl)methyl]-2-[(2S,4S)-2-cyano-4-fluoro-1-pyrrolidinyl]-2-oxoethyl}carbamate (500 g, 1 wt, 1 eq) in ethanol (3.5L, 7 vol). To this solution was added para-toluenesulfonic acid (403g, 0.806 wt, 2 eq). This solution was heated to 60° C., and was allowed to stir at this temperature for 12 hours. The reaction mixture was cooled to 5° C. and was stirred at this temperature for 30 minutes. The solids were collected by filtration, washed with ethanol (2×1 L), and dried to constant weight in a 50° C. vacuum oven. Yield: 70-80% over 2 steps.

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Augustyns, K. et al., “The Unique Properties of Dipeptidyl-Peptidase IV (DPP IV/CD26) and the Therapeutic Potential of DPP IV Inhibitors,” Current Medicinal Chemistry, V6, N4, 1999, pp. 311-327.

US7132443 *	26 Jun 2002	7 Nov 2006	Smithklinebeecham Corporation	Fluoropyrrolidines as dipeptidyl peptidase inhibitors
WO2003002531A2	26 Jun 2002	9 Jan 2003	Curt Dale Haffner	Fluoropyrrolidines as dipeptidyl peptidase inhibitors

……………………..

DIABETES

MURAGLITAZAR(CAS-No. 331741-94-7), ROSIGLITAZONE (CAS-NO. 122320-73-4), PIOGLITAZONE (CAS-No. 111025-46-8), RAGAGLITAZAR(CAS-No. 222834-30-2), FARGLITAZAR(CAS-No. 196808-45-4), TESAGLITAZAR(CAS-No. 251565-85-2), NAVEGLITAZAR(CAS-No. 476-436-68-7), NETOGLITAZONE (CAS-NO. 161600-01-7), RIVOGLITAZONE (CAS-No. 185428-18-6), K-111 (CAS-No. 221564-97-2), GW-677954 (CAS-No. 622402-24-8), FK-614 (CAS-No 193012-35-0) and (−)-Halofenate (CAS-No. 024136-23-0).

TABLE 1

INN or Research
Code	Structure/Chemical Name

BIM-51077	L-histidyl-2-methylalanyl-L-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-
	aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-alanyl-L-
	alanyl-L-lysyl-L-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-L-
	lysyl-2-methylalanyl-L-argininamide
EXENATIDE	L-histidylglycyl-L-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L-leucyl-
	L-seryl-L-lysyl-glutaminyl-L-methionyl-L-glutamyl-L-glutamyl-L-glutamyl-L-alanyl-L-valyl-L-
	arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-
	asparaginylglyclglycyl-L-prolyl-L-seryl-L-serylglycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-
	serinamide
CJC-1131	L-histidyl-D-alanyl-L-alpha-glutamylglycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-
	aspartyl-L-valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-alpha-glutamylglycyl-L-glutaminyl-L-alanyl-L-
	alanyl-L-lysyl-L-alpha-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-L-tryptophyl-L-leucyl-L-valyl-
	L-lysylglycyl-L-arginyl-N6-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-
	yl)propionamido]ethoxy]ethoxy]acetyl]-L-lysin-amide
LIRAGLUTIDE	L-histidyl-L-alanyl-L-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-aspartyl-L-
	valyl-L-seryl-L-seryl-L-tyrosyl-L-leucyl-L-glutamyl-glycyl-L-glutaminyl-L-alanyl-L-alanyl-Nepsilon-
	(Nalpha-hexadecanoyl-gamma-L-glutamyl)-L-lysyl-L-glutamyl-L-phenylalanyl-L-isoleucyl-L-alanyl-
	L-tryptophyl-L-leucyl-L-valyl-L-arginyl-glycyl-L-arginyl-glycine
ZP-10	H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-
	Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser-Lys-Lys-Lys-Lys-Lys-Lys-NH2

TOLBUTAMIDE

TOLAZAMIDE

GLIPIZIDE

CARBUTAMIDE

GLISOXEPIDE

GLISENTIDE

GLIBORNURIDE

GLIBENCLAMIDE

GLIQUIDONE

GLIMEPIRIDE

GLICLAZIDE

METFORMIN

ACARBOSE

MIGLITOL

VOGLIBOSE

MURAGLITAZAR

ROSIGLITAZONE

PIOGLITAZONE

RAGAGLITAZAR

FARGLITAZAR

TESAGLITAZAR

NAVEGLITAZAR

NETOGLITAZONE

RIVOGLITAZONE

K-111

GW-677954

FK-614

(−)-Halofenate

REPAGLINIDE

NATEGLINIDE

MITIGLINIDE

SITAGLIPTIN

SAXAGLIPTIN

VILDAGLIPTIN

DENAGLIPTIN

P32/98

NVP-DPP-728

SILDENAFIL

VARDENAFIL

TADALAFIL

PRAMLINTIDE	L-lysyl-L-cysteinyl-L-asparaginyl-L-threonyl-L-alanyl-L-threonyl-L-cysteinyl-L-alanyl-L-threonyl-
	L-glutaminyl-L-arginyl-L-leucyl-L-alanyl-L-asparaginyl-L-phenylalanyl-L-leucyl-L-valyl-L-histidyl-
	L-seryl-L-seryl-L-asparaginyl-L-asparaginyl-L-phenylalanylglycyl-L-prolyl-L-isoleucyl-L-leucyl-L-
	prolyl-L-prolyl-L-threonyl-L-asparaginyl-L-valylglycyl-L-seryl-L-asparaginyl-L-threonyl-L-
	tyrosinamide, cyclic (2−>7)disulfide

ETOMOXIR

HMR-1426

CETILISTAT

SIBUTRAMINE

Additional information with regard to the preparation, suitable dosage forms and dose ranges of the glucagon-like-peptide-1 receptor agonists listed in Table 1 can be found in the following patents/patent applications: WO0334331, EP0981611, EP1180121, WO9808871 and WO0104156.

DUTOGLIPTIN

November 25, 2014 4:43 am / Leave a comment

Dutogliptin tartrate
Syn name: 1-[N-[3(R)-Pyrrolidinyl]glycyl]pyrrolidin-2(R)-ylboronic acid L-tartrate
Cas number: 890402-81-0
Molecular Formula: C14H26BN3O9
Molecular Weight: 391.18

DUTOGLIPTIN

[1-[2-(Pyrrolidin-3-ylamino)acetyl]pyrrolidin-2-yl]boronic Acid; [(2R)-1-[2-[[(3R)-Pyrrolidin-3-yl]amino]acetyl]pyrrolidin-2-yl]boronic acid

C₁₀H₂₀BN₃O_3, 241.0951

852329-66-9

Dutogliptin
PHX1149
UNII-38EAO245ZX

clinical trials

http://clinicaltrials.gov/search/intervention=Dutogliptin

PHX-1149 is a dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor which had been in phase III clinical trials at Phenomix and Forest for the oral, once-daily treatment of type 2 diabetes.

In 2008, the compound was licensed to Forest by Phenomix in North America for development and commercialization; however this license agreement was terminated in 2010. In 2009, the compound was licensed to Chiesi by Phenomix for development and commercialization for the treatment of diabetes type 2 in Europe, Brazil, the Russian Federation and all other members of the Commonwealth of Independent States, Turkey and Northern Africa. Phenomix ceased operations in 2010.

………………………….

WO2010107809A2

http://www.google.com/patents/WO2010107809A2?cl=en

http://www.google.com/patents/US20100240611?cl=en

The enzyme dipeptidyl peptidase IV (DPP-IV) is a member of the dipeptidyl peptidase family, which cleaves N-terminal dipeptide residues from proteins, particularly where the dipeptide includes an N-terminal penultimate proline or alanine residue. DPP-IV is believed to be involved in glucose control, as its peptidolytic action inactivates the insulotropic peptides glucagon-like peptide I (GLP-I) and gastric inhibitory protein (GIP).

Inhibition of DPP- IV, such as with synthetic inhibitors in vivo, can serve to increase plasma concentrations of GLP-I and GIP, and thus improve glycemic control in the body. Such synthetic inhibitors would therefore be useful in the treatment of diabetes mellitus and related conditions. Certain such selective DPP-IV inhibitors have been developed, as are disclosed in U.S. Patent 7,317,109, U.S. Patent 7,576,121, U.S. Application Publication Nos. 2007/0060547, 2007/0185061, 2007/0299036, 2008/0182995, 2008/0300413, 2006/0264400, and 2006/0264401, and in International Applications WO2008/027273 and WO2008/144730, the contents of which are incorporated herein by reference. Inhibition of DPP-IV by compounds of the structure of formula (I) is disclosed therein:

Example 1 – Synthesis of (R)-N-( 1 , 1 -Dimethylethoxycarbonyl)(pyrrolidine-2-yl)boronic Acid.

An oven dried 1 L three neck round bottom flask equipped with an overhead stirrer, addition funnel and internal thermocouple was charged with (IS, 2S)-Dimethyl-bis(3,3- dimethylbutyl)cyclohexane-l,2-diamine (approx. 50 g, 161.23 mmol, 1.2 eq), BOC-pyrrolidine (approx. 23.55 ml, 134.35 mmol, 1 eq) and dry toluene (approx. 500 ml) under inert atmosphere. The clear colorless solution was cooled to ^“ 78° C and a solution of sec-BuLi (approx. 115.16 ml of a 1.4 solution in cyclohexane, 161.23 mmol, 1.2 eq) was added slowly via dropping funnel over approx. 10 minutes (the temperature of the reaction mixture was maintained between approx. – 78⁰C and -65⁰C). The light orange colored solution was stirred for 3.5 hours at approx. -78⁰C, which was then followed by the addition of a solution of trimethylborate (approx. 45.06 ml, 403.05 mmol, 3 eq) in toluene (approx. 75 ml) via dropping funnel over 30 minutes while maintaining the temperature below -65⁰C. The reaction mixture was warmed slowly to room temperature, and stirred for 16 hours at room temperature. The reaction mixture was added into an aqueous sodium hydroxide solution (approx. 670 ml of 2.0 M solution, 1340 mmol, 10 eq) and the resulting cloudy mixture was stirred for 30 minutes before allowing layers to separate. The aqueous phase (product) was transferred to a receiver and backwashed with toluene (approx. 100 ml). The organic phases (chiral amine ligand) were transferred to a receiver for later isolation. The aqueous phase was acidified to pH 5-6 by slow addition of HCl {cone), then extracted with EtOAc (approx. 3 x 500 ml). The organic extracts were combined, dried over Na₂SO₄ and concentrated until a final volume of approximately 100 ml. Heptane (approx. 300 ml) was added and the concentrated mixture was stirred at room temperature overnight (approx. 15 hours). The resulting white precipitate was filtered and the filter cake was washed with cold heptane. The product was dried at room temperature under vacuum to yield (R)- (pyrrolidine-2-yl)boronic acid (approx. 20.31 g, 94.44 mmol, 70.27 %) as a white solid. [α]²⁵D – 72.5 (c 1, DCM); 94-95 % ee (% ee was determined through chiral HPLC); ¹H NMR (400 MHz, D₂O) δ 3.40-3.50 (IH), 3.20- 3.30 (IH), 2.90-3.00 (IH), 2.10 (IH), 2.00 (IH), 1.85 (IH), 1.72 (IH), 1.45-1.48 (9H); m/z (ES+) 216.06.

Example 2 – Isolation of the chiral ligand ((1S, 2S)-Dimethyl-bis(3,3-dimethyl butyl) cyclohexane- 1 ,2-diamine)

Water (approx. 300 ml) was added to the first organic extract from the previous workup and cooled to 0° C the mixture was acidified to pH 3 by slow addition of HCl. The resulting cloudy mixture was stirred vigorously before allowing layers to separate. The aqueous phase (product) was transferred to a receiver and backwashed with toluene (approx. 100 ml). The aqueous phase was stirred at O⁰C and the pH of the solution was adjusted to 12-13 by the addition of sodium hydroxide. The mixture was extracted with toluene (approx. 3 x 500 ml) and the combined organic phases were concentrated under reduced pressure to give the crude chiral diamine (approx. 48.32 g, 155.57 mmol, 96.5%) as light yellow oil. Further purification by vacuum distillation (approx. 120-130⁰C, house vacuum) yielded the chiral diamine as a colorless oil (approx. 45.57 g, 146.72 mmol) in 91% recovery).Example 3 – Synthesis of (R)-N-(I, l-dimethylethoxycarbonyl)-pinanediol-(Pyrrolidin-2-yl) boronate

A solution of (R)-Pyrrolidine boronic acid (approx. 300 mg, 1.39 mmol) in isopropyl acetate (approx. 10 ml) was treated with (+)-pinanediol (approx. 236.35 mg, 1.39 mmol, 1 eq) and Na₂SO₄ (approx. 203.25 mg, 1.39 mmol, 1 eq). After 24 hr, the solvent was evaporated to give crude boronic ester (approx. 475.55 mg, 1.36 mmol, 98 %) as a clear oil: 98-99 % de via chiral HPLC; ¹U NMR (400 MHz, CDCl₃) δ 4.32 (IH), 3.47 (IH), 3.41-3.31 (2H), 3.22-3.05 (IH), 2.38- 2.30 (IH), 2.20-1.75 (8H), 1.45 (9H), 1.41 (3H), 1.28 (3H), .85 (3H); m/z (ES, M+l) 350.28.Example 4 – (R)-N-(Pyrrolidine-2-yl)-pinacol boronate

To a solution of pyrrolidine boronic acid (approx. 456 mg, 2.12 mmol) in isopropyl acetate

(approx. 15 ml) was added pinacol (approx. 251 mg, 2.12 mmol, 1 eq) and Na₂SO₄ (approx. 310 mg, 2.12 mmol, 1 eq). The mixture was stirred for 24 hr and the solvent was evaporated to yield crude pinacol boronate. The residue was triturated with EtOAc/hexane (approx. 1 : 10) at RT for 1 hr then filtered to give the pinacol boronate (approx. 611 mg, 2.06 mmol, 97 %) as a white solid: . ¹H NMR (400 MHz, CDCl₃) δ 3.40-2.95 (3H), 1.95-1.50 (4H), 1.40 (9H), 1.20 (12H); m/z (ES+) 298.21. Removal of the Boc-protecting group was achieved by dissolving the white solid pinacol boronate in dry ether (approx. 15 ml), cooling to 0° C in an ice bath followed with addition of 1.5 eq of HCl in dioxane After 8 hours, the solvent was evaporated then triturated in hexane for 1 hr. The white precipitate was filtered and dried to yield the acid salt (approx. 472 mg, 2.02 mmol, 98 %): ¹HNMR (CDCl₃) δ 3.48 (IH), 3.36 (IH), 3.21 (IH), 2.21 (IH), 2.03 (2H), 1.95 (IH), 1.35 (12H); m/z (ES M+l) 198.21.

Example 5 – Synthesis of (R)-3-(Benzyloxycarbonyl-{2-oxo-2-[(R)-2-((lS,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^'”]dec-4-yl)-pyrrolidin-l-yl]-ethyl}-amino)- pyrrolidine- 1-carboxylic acid benzyl ester

A mixture of (R)-3-(benzyloxycarbonyl-carboxymethyl-amino)-pyrrolidine- 1-carboxylic acid benzyl ester dicyclohexylamine salt) (approx. 300.Og, 0.505mol), water (approx. 1.5L), 2M aqueous sulfuric acid (approx. 0.75L, 1.5mol) and toluene (approx. 2L) was stirred in a 1OL reactor at room temperature for 15 min. After settling the layers were separated. The aqueous layer was stirred with toluene (approx. 1.0L) for 15 min, and the layers were separated. The combined organic layers were washed with water (approx. 1.5L), and concentrated under vacuum at 45⁰C to 1.5L. To this solution was added N-methylmorpholine (approx. 55.4 mL, 0.505mol) and this mixture was added to a cold solution (approx. 0°-5°C) of ethyl chloroformate (approx. 48.1 mL, 0.505mol) in toluene (approx. 1.0L). The reaction mixture was stirred at 0° – 5⁰C for 15 min and solid (2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²‘⁶]dec-4-yl)-pyrrolidine hydrochloride) (approx. 144.4g, 0.505mol) was added in one portion followed by addition of N- Methylmorpholine (approx. 110.8 mL, l.Olmol). The mixture was stirred for 30 min at 0°-5°C, and allowed to warm to 20°-25°C. Stirring was continued for an additional 2.5 h. Water (approx. 2.0L) was then added, and the mixture was stirred for an additional 15 min. The layers were separated and the organic layer was subsequently washed with 0.85M aqueous sodium bicarbonate solution (approx. 1.2L), water (approx. 2.0L), and 0.065M citric acid solution (approx. 1.5L). Toluene solution was concentrated under vacuum at 45⁰C, to give 287.3 g (approx. 88.4%) of the title compound. ¹H NMR (400 MHz, CDCl₃, ppm): mixture of rotomers, 7.35-7.25 (10H,m); 5.22- 4.99 (4H,m); 4.60 (IH, d); 4.22 (IH, dd); 4.11-3.65 (3H, m); 3.60-3.00 (6H, m); 2.32-1.91 (8H, m); 1.89-1.67 (4H, m); 1.42-1.18 (6H, m); 0.84-0.72 (3H, m); m/z (M+H)=644. Example 6 – Synthesis of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9-trimethyl- 3,5-dioxa-4-bora-tricyclo[6.1.1.0 ‘ ]dec-4-yl)-pyrrolidin- 1 -yl]-ethanone

a) THF solvateA solution of (R)-3-(Benzyloxycarbonyl-{2-oxo-2-[(R)-2-((l S,2S,6R,8S)-2,9,9-trimethyl-3,5- dioxa-4-bora-tricyclo[6.1.1.0²‘”]dec-4-yl)-pyrrolidin- 1 -yl] -ethyl }-amino)-pyrrolidine- 1 – carboxylic acid benzyl ester (approx. 4.76 g, 7.4 mmol) in toluene (approx. 60 mL) was diluted with methanol (approx. 60 mL). 10% Pd/C (wet, 500 mg) was added, and the mixture was hydrogenated at 50 psi for 3 h. The mixture was filtered through celite and washed with methanol (approx. 10 mL). The solution was then concentrated under vacuum to dryness. The residue was dissolved in THF (approx. 10 mL) at 4O⁰C and crystallized overnight at -1O⁰C to -15°C. Crystals were filtered, washed with cold THF (approx. 3 mL), and dried under vacuum for 5 h to yield 1.9 g (approx. 68.5%) of the title compound. ¹H NMR (400 MHz, D₂O, 1 drop TFA), 64.18 – 4.89 (m, IH), 3.93 – 3.85 (m, IH), 3.77 (s, 2H), 3.55 (dd, IH)₅ 3.45 -3.38 (m, 4H), 3.35 – 3.25 (m, 2H), 3.24 – 3.05 (m, 3H), 2.93 (t, IH), 2.33 – 2.24 (m, IH), 2.15 – 1.42 (m, 16H), 1.09 (s, 3H), 0.94 (s, 3H), 0.78 (d, IH), 0.50 (s, 3H). m/z (ES+) = 376.30.

Thermogravimetric analysis of THF solvate of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-

((lS,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²‘⁶]dec-4-yl)-pyrrolidin-l-yl]- ethanone was performed as is shown in Figure 5.

X-Ray Diffractogram of THF solvate of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)- 2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0²‘⁶]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 6. b) Non-solvate

A solution of (3-(Benzyloxycarbonyl-{2-oxo-2-[2-(2,9,9-trimethyl-3,5-dioxa-4-bora- tricyclo[6.1.1.0²‘⁶]dec-4-yl)-pyrrolidin-l-yl]-ethyl}-amino]-pyrrolidine-l-carboxylic acid benzyl ester) (approx. 20.Og, 31.Ommol) in toluene (approx. 8OmL) was diluted with methanol (approx. 20 mL). 10% Pd/C (2g, wet) was added, and the mixture was hydrogenated at 50 psi for 3 h. The mixture was filtered through celite and the filter bed was washed with a mixture of toluene (approx. 2OmL) and methanol (approx. 4 mL). The solution was concentrated to 8OmL at 30 -35 ⁰C under vacuum (approx. 90 to 120 mBar). THF (approx. 10OmL) was added and the solution was concentrated to 12OmL at 30 -35 ⁰C under vacuum (approx. 90 to 120 mBar). The mixture was stirred at 35 ⁰C for Ih, resulting in crystallization. The mixture was cooled to 0 ⁰C and held at that temperature for 2h. Crystals were isolated by filtration, washed with a cold mixture of toluene (approx. 20 mL) and THF (approx. 5 mL), and dried under vacuum at 35 ⁰C for 16 h to yield 9.11 g (approx. 24.3 mmol, 78%) of the title compound as a white solid.¹H NMR (400 MHz, D₂0, 1 drop TFA), δ 4.34 (dd, IH, J= 9, 2 Hz), 4.08 (m, IH), 3.99 (s, 2H), 3.74 (dd, IH, J= 13, 8 Hz), 3.52 -3.29 (m, 6H), 3.12 (t, IH, J= 8 Hz), 2.47 (m, IH), 2.27 (m, IH), 2.19 – 2.06 (m, 2H), 2.02 – 1.84 (m, 6H), 1.67 (m, 2H), 1.30 (s, 3H), 1.15 (s, 3H), 1.00 (d, IH, J= 11 Hz), 0.71 (s, 3H). m/z (ES+) = 376.30.

Thermogravimetric analysis of 2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9- trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.0^'”]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 7.

X-Ray Diffractogram of2-((R)-Pyrrolidin-3-ylamino)-l-[(R)-2-((lS,2S,6R,8S)-2,9,9-trimethyl-

3,5-dioxa-4-bora-tricyclo[6.1.1.0 ‘ ]dec-4-yl)-pyrrolidin-l-yl]-ethanone was performed as is shown in Figure 8.

Example 7 – Synthesis of Dutogliptin Tartrate

A round bottom flask equipped with a magnetic stirrer was charged with 2-(Pyrrolidin-3- ylamino)- 1 -[2-(2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0]dec-4-yl)-pyrrolidin-l-yl]- ethanone (approx. l:l-Pinanediol borane / THF complex; 2.98 g, 6.67 mmol, leq), (L)-tartaric acid (approx. 1.00 g, 6.67 mmol, 1 eq), and H₂O (approx. 15 mL). The mixture was allowed to stir for 1 hour then tert-Butyl methyl ether (approx. 15 ml) and (i?)-N-(l,l- dimethylethoxycarbonyl)(pyrrolidine-2-yl)boronic acid (approx. 1.46 g, 6.80 mmol, 1.02 eq) were added. The bi-phasic mixture was allowed to stir for 20 hours at room temperature before separating the layers. The aqueous phase backwashed with tert-butyl methyl ether (approx. 15 ml) and the organic layers were combined. Lyophilization of the aqueous layer provided dutogliptin tartrate as a white solid (approx. 2.60 g, 6.65 mmol, 99.7%): ¹H NMR (400 MHz, D₂O, one drop of TFA) δ 4.48 (2H), 3.95-3.88 (IH), 3.81 (2H), 3.59-3.54 (IH), 3.37-3.28 (2H), 3.21-3.16 (2H), 3.11-3.07 (IH), 2.82-2.78 (IH), 2.37-2.28 (IH), 2.04-1.96 (IH), 1.88-1.78 (2H), 1.71-1.60 (IH), 1.50-1.42 (IH); m/z (ES+) 241.10 (-tartrate acid).

US20060069250 *	Sep 28, 2005	Mar 30, 2006	Xiaohu Deng	Synthesis by chiral diamine-mediated asymmetric alkylation
US20080182995 *	Oct 31, 2007	Jul 31, 2008	Phenomix Corporation	Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-iv
US20080300413 *	Jul 27, 2006	Dec 4, 2008	David Alan Campbell	Efficiently preparing boropyrrolidines and derivatives by coupling a (pyrrolidin3-yl-amino-)acetic acid and a 7,9,8-dioxaborotricyclic- (4,3,0,1(2,4))decane; protecting groups avert side reactions; antidiabetic agents

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