Sitagliptin

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Jul 052015

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

A practical and economical approach to synthesize sitagliptin

Volume 43, Issue 24, 2013

DOI:: 10.1080/00397911.2013.773353

Kuaile Lin^a, Zhengyan Cai^a & Weicheng Zhou^a^*

pages 3281-3286

1Kuaile Lin, Zhengyan Cai, Weicheng Zhou*

State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of

Anti-Infectives,
Shanghai Institute of Pharmaceutical Industry, State Institute
ofPharmaceutical Industry, Shanghai 200437, China

* Corresponding author: Weicheng Zhou, profzhouwc@yahoo.com.cn, Tel./fax: +8621 35052484

http://www.tandfonline.com/doi/abs/10.1080/00397911.2013.773353?journalCode=lsyc20#.VPRLp_mUc9s

Economic syntheses of sitagliptin phosphate monohydrate, acknowledged as the first dipeptidyl peptidase 4 (DPP-4) inhibitor, have been achieved in an overall yield of 42.4% in four steps from 1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)butane-1,3-dione. The key stereoselective reduction of this process was carried out by NaBH₄/HCOOH instead of expensive and toxic catalysts or ligands.
LOOK FOR SUPPLEMENTARY INFO IN ABOVE PAPER

tga

………………………….

NMR
SEE AN ONLINE NMR BELOW

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

………………….

PAPER

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

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

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

Fen-Fen Zhang,^a
Meng-Hong Jiang,^b
Lin-Lin Sun,^a
Feng Zheng,^a
Lei Dong,^a
Vishva Shah,^c
Wen-Bin Shen*^d and

Ya Ding*^a

Hide Affiliations

Corresponding authors

State Key Laboratory of
Natural Medicines, Department of Pharmaceutical Analysis, China
Pharmaceutical University, Nanjing 210009, China E-mail:
ayanju@163.com

Shanghai Institute for Food and Drug Control, Shanghai 201203, China

Department of Chemistry
and Chemical Engineering, Royal Military College of Canada, Kingston,
Canada

Pharmaceutical Research
Institute, China Pharmaceutical University, Nanjing 210009, China E-mail:
cpunmrswb@163.com

Analyst, 2015,140, 280-286

DOI:
10.1039/C4AN01681E

Vishva Shah, Royal Military College of Canada

CHECK OUT PREDICTIONS
UNDERSTAND THE SIGNALS
PREDICTIONS 1H NMR

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

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

BELOW PAPENT DESCIBES THIS DRUG WELL IS RANDOMLY CHOSEN

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

The present invention relates to a novel method of preparing sitagliptin, and intermediates used therein. BACKGROUND OF THE INVENTION

Sitagliptin phosphate is a selective inhibitor of the second generation dipeptidyl peptidase IV (DPP-4) and used to maintain the systemic concentration of incretin hormone at an optimum level. Sitagliptin phosphate monohydrate was approved in October 2006 by the US Food and Drug Administration (FDA) as an adjuvant in dietetics or kinesiatrics for treatment of patients with type-2 diabetes and it is marketed in the United States and Korea under the trade name of JANUVIA™ (as a single agent).

Various methods for preparing sitagliptin and sitagliptin phosphate have been developed. For example, International Patent Publication WO 2003/004498 discloses a method of introducing a chiral-amine group using a chiral pyrazine derivative and to prepare sitagliptin by Arndt-Eistert Homologation using t-butoxylcarbonylamino-4-(2,4,5-trifluorophenyl)-butyric acid as a sitagliptin intermediate, as shown in Reaction Scheme 1.

Reaction Scheme 1

Wherein,

Boc is tert-butoxycarbonyl, TEA is trimethylamine, HOBt is 1- hydroxybenzotriazole, EDC is N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide, and DIPEA is N,N-diisopropylethylamine.

International Patent Publication WO 2004/087650 discloses a method for preparing sitagliptin phosphate comprising the steps of: subjecting (2,4,5- trifluorophenyl)acetic acid to two-step reactions to obtain methyl 4-(2,4,5- trifluorophenyl)-3-oxophenylbutylate; conducting a stereoselective reduction of the resulting compound in the presence of (S)-BrNAP-RuCl₂-Et₃N under a high hydrogen pressure; hydrolyzing the reduced product to obtain (3S)-3-hydroxy- 4-(2,4,5-trifluorophenyl)-butyric acid, a key sitagliptin intermediate; and subjecting (3S)-3-hydroxy-4-(2,4,5-trifluorophenyl)-butyric acid to seven-step processes to obtain sitagliptin phosphate, as shown in Reaction Scheme 2.

Reaction Scheme 2

Wherein,

BINAP is 2,2′-bis(diphenylphosphino)-l,l’-binaphthyl, EDC is N-ethyl-N’-(3- dimethylaminopropyl)carbodiimide, Bn is benzyl, DIAD is diisopropyl azodicarboxylate, NMM is N-methylmorpholine, and ACN is acetonitrile.

Further, International Patent Publication WO 2004/085661 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using a platinum catalyst, PtO₂, as shown in Reaction Scheme 3. Reaction Scheme 3

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

The document [J. Am. Chem. Soc, 2009, 131, p.l 1316-11317] discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using a ruthenium-based catalyst, Ru(OAc)₂ having a chiral diphosphine ligand, and International Patent Publication WO 2009/064476 discloses a method for preparing sitagliptin by stereoselectively reducing an enamine using Ru(OAc)₂and a chiral diphosphine ligand, or using a chiral acid together with a borohydride reducing agent (e.g., NaBH₄).

Reaction Scheme 5

Example 1: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)- oxirane

Step 1 : Preparation of (2S)-3-(2A5-trifluorophenyl)-l-chloro-2-propanol

Magnesium (Mg) (1.26 g) was suspended in tetrahydrofuran (THF) (10 ml), and a drop of 1,2-dibromoethane was added thereto. To the resulting mixture, 2,4,5-trifluorobenzene bromide (0.55 g) was added dropwise slowly and then stirred for 30 min. 2,4,5-trifluorobenzene bromide (9.0 g) dissolved in THF (50 ml) was added slowly dropwise to the resulting mixture for 30 min and then stirred at room temperature for 1 hour. Cul (0.72 g) was added to the resulting mixture and the reaction temperature was cooled to 0°C . (S)- epichlorohydrin (4.1 ml) dissolved in THF (40 ml) was added dropwise to the resulting mixture slowly over 30 min, heated to room temperature, and stirred for 2 hours. Satuated NH4CI (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with 50 ml of satuated saline, dried over MgSO₄, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound.

Step 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane

(2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in methanol (50 ml), and NaOH (2.3 g) was added dropwise thereto. The resulting mixture was stirred for 1 hour and methanol was removed therefrom under a reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with satuated saline, dried over MgSO₄, and filtered to remove MgSO₄. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (6.8 g; yield: 80%).

1H-NMR(300MHz, CDC1₃): 6 7.17-7.05 (2H, m), 6.96-6.88 (2H, m), 3.16-3.13 (1H, m) 3.14 (1H, dd, J=4.68, 14.7), 2.82-2.77 (2H, m), 2.54-2.47 (1H, m). Preparation Example 2: Preparation of (2S)-2-(2,4,5-trifIuorobenzyl)- oxirane

Step 1 : Preparation of (2S)-3-(2A5-trifluorophenyl)-l-chloro-2-propanol

2N -PrMgCl (26 ml) suspended in THF was added dripwise to the 2,4,5-trifluorobenzene bromide (9.55 g) dissolved in THF (30 ml) at -15 ^°C for 60 min. Cul (0.72 g) was added thereto at -15 ^°C , and heated to -10 ^°C . (S)- epichlorohydrin (4.1 ml) dissolved in THF (40 ml) was added slowly to the resulting mixture, and stirred at 0 ^°C for 1 hour. Satuated NH₄C1 (50 ml) and ethyl acetate (50 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed with 50 ml of satuated saline, dried over MgSO₄, and filtered to remove MgSO₄. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound.

Step 2: Preparation of (2S)-2-(2,4,5-trifluorobenzyl)-oxirane (2S)-3-(2,4,5-trifluorophenyl)-l-chloro-2-propanol obtained in step 1 was dissolved in 50 ml of methanol, and NaOH (2.3 g) was added dropwise thereto. A mixture was stirred for 1 hour, and methanol was removed therefrom under a reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added thereto, and the organic layer formed thereafter was separated. The separated organic layer was washed with satuated saline, dried over MgSO₄, and filtered to remove MgSO₄. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (7.6 g; yield: 85%). Example 1: Preparation of Sitagliptin

Step 1: Preparation of (2R)-l-(2,4,5-trifluorophenyl -4-pentene-2-ol

CuBr(CH₃)₂ (3.3 g) was added to a reactor under the nitrogen atmosphere and cooled to -78 ^°C . Vinylmagnesium bromide (240 ml) was added slowly to the reactor and stirred for 20 min. (2S)-2-(2,4,5- trifluorobenzyl)-oxirane (30 g) dissolved in THF (90 ml) was added dropwise slowly over 30 min, stirred at -78 °C for 30 min, and heated to 0 ^°C . 2N aqueous HC1 (300 ml) was added slowly to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed twice with satuated saline, dried over MgSO₄, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (34.5 g; yield: 100%).

1H-NMR(300MHz, CDC1₃): δ 7.15-7.06 (1H, m), 6.94-6.86 (1H, m), 5.85-5.79 (1H, m), 5.20-5.14 (2H, m), 3.90-3.85 (1H, m), 3.82 (1H, dd, J=4.6, 18.5), 2.69 (1H, dd, J=7.9, 14.0), 2.37-2.32 (1H, m), 2.24-2.17 (1H, m), 1.86(1H, Br). Step 2: Preparation of (2S)-l-(2-azido-4-pentenyl)-2A5-trifluorobenezene

Dichloromethane (300 ml) was added to the (2R)-1 -(2,4,5- trifluorophenyl)-4-pentene-2-ol obtained in step 1, and cooled to 0°C . Triethylamine (20.4 ml) and 4-dimethylaminopyridine (DMAP) (1.57 g) were added successively to the mixture, and methansulfonyl chloride (1 1.2 ml) was added dropwise thereto for 30 min. The resulting mixture was stirred for 1 hour, water (150 ml) was added, and the organic layer formed thereafter was separated. The separated organic layer was washed twice with satuated saline, dried over MgSO₄, and filtered. The organic solvent was removed from the filtrate under a reduced pressure. The residue thus obtained was dissolved in DMF (300 ml), and NaN₃ (9.91 g) was added thereto. The resulting mixture was heated to 70 °C , stirred for 2 hours, and cooled to room temperature. And then water (150 ml) and ethyl acetate (150 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The organic layer was washed twice with 150 ml of satuated saline, dried over MgSO₄, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (31.5 g; yield: 94%).

¹H-NMR(300MHz, CDC1₃): δ 7.11-7.02 (1H, m), 7.97-6.87 (1H, m), 5.89-5.80 (1H, m), 5.23-5.17 (1H, m), 3.63-3.59 (1H, m), 2.87 (1H, dd, J=4.7, 18.7), 2.68 (1H, dd, J=7.9, 13.7), 2.38-2.17 (2H, m). Step 3: Preparation of (3R)-3-azido-4-(2A5-trifluorophenyl)-butyric acid

Acetonitril (300 ml) and water (300 ml) were added to the (2S)-l-(2- azido-4-pentenyl)-2,4,5-trifluorobenezene obtained in step 2, and cooled to 0°C . RuCl₃ (0.5 g) and NaIO₄ (93 g) were added to the mixture successively, and stirred for 5 hours. Ethyl acetate (90 ml) was added to the resulting mixture, filtered and the organic layer formed thereafter was separated. The separated organic layer was washed with IN HC1 (300 ml), satuated aqueous Na₂S₂O₃ (300 ml) and satuated saline (300 ml), successively, dried over MgSO₄, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (32.2 g; yield: 100%). 1H-NMR(300MHz, CDC1₃): 5 10.5 (1H, br), 7.17-7.05 (1H, m), 7.02-

6.87 (1H, m), 4.14-4.03 (1H, m), 2.94-2.78 (2H, m), 2.65-2.51 (2H, m).

Step 4: Preparation of (3R)-3-azido-l-(3-trifluoromethyl-5,6-dihydro-8H- [ 1 ,2,41triazolor4,3-alpyrazin-7-yl)-4-(2,4,5-trifluorophenyl)-butan- 1 -one

(3R)-3-azido-4-(2,4,5-trifluorophenyl)-buryric acid (5 g) obtained in step 3 and triazole derivative of formula (VI) (5.3 g) were added to DMF (40 ml) and water (20 ml), stirred for 15 min, and cooled to 10^°C . N- methylmorpholine (2.4 ml) was added to the mixture, stirred for 10 min, and cooled to 0 ^°C . EDC (5.6 g) was added to the resulting mixture, and stirred for 1 hour. Ethyl acetate (50 ml) and water (25 ml) were added to the resulting mixture, and the organic layer formed thereafter was separated. The separated organic layer was washed four times with 50 ml of satuated saline, dried over MgSO₄, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (7.8 g; yield: 93%).

1H-NMR(300MHz, CDC1₃): δ 7.20-7.11 (1H, m), 6.99-6.90 (1H, m), 5.20-4.96 (2H, m), 4.28-4.05 (5H, m), 2.98-2.67 (4H, m).

Step 5: Preparation of sitagliptin

(3R)-3-azido- 1 -(3-trifluoromethyl-5,6-dihydro-8H-[ 1 ,2,4]triazolo[4,3- a]pyrazin-7-yl)-4-(2,4,5-trifluorophenyl)-butan-l-one (6.4 g) obtained in step 4 and triphenylphosphin (4.3 g) were dissolved in THF (74 ml), heated to 50 ^°C , and stirred for 2 hours. An aqueous NH₄OH (37 ml) was added to the resulting mixture and stirred for 10 hours. THF was removed from the resulting mixture under a reduced pressure, HCl (30 ml) and ethyl acetate (60 ml) were added threreto, and stirred. The water layer separated from the mixture was washed twice with 30 ml of n-hexane, satuated sodium bicarbonate was added to the water layer, and extracted three times with 60 ml of ethyl acetate. The resulting extracts were dried over MgSO₄, and filtered. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (5.2 g; yield: 86%).

1H-NMR(300MHz, CDC1₃): δ 7.14-7.06 (1H, m), 7.00-6.88 (1H, m), 5.13-4.88 (2H, m), 4.24-3.80 (4H, m), 3.58 (1H, m), 2.85-2.66 (2H, m), 2.61-2.46 (2H, m), 2.11 (3H, br).

ABOVE IS ONLY ONE EXAMPLE LEADING TO SITAGLIPTIN

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

(S)-Sitagliptin……….Synfacts by Thieme

For description see at synfacts

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

Contributor: Philip Kocienski

Philip Kocienski, Professor of Organic Chemistry.

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

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

Synlett 2013;
24: 2459-2463

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

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

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

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

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

SITAGLIPTIN……………..

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

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

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

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

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

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

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

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

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

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

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

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

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

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

PAPER

SITAGLIPTIN……………..

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

Karl B. Hansen ,* Jaume Balsells , Spencer Dreher , Yi Hsiao , Michele Kubryk ,Michael Palucki , Nelo Rivera ,Dietrich Steinhuebel , Joseph D. Armstrong III,David Askin , and Edward J. J. Grabowski

Department of Process Research, Merck Research Laboratories, Rahway, New Jersey 07065, U.S.A.

Org. Process Res. Dev., 2005, 9 (5), pp 634–639

DOI: 10.1021/op0500786

http://pubs.acs.org/doi/full/10.1021/op0500786

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

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

PATENT

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

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

MORE INFO………

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

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

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

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

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

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

SYN1

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

SYN2

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

SYN3

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

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

REF

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

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

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

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

MELOGLIPTIN

diabetes, phase 2, Uncategorized Comments Off

Jul 032015

GRC 8200; 868771-57-7, EMD-675992

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

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

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

ALTERNATE……….

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

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

EVOGLIPTIN

diabetes, Phase 3 drug, Uncategorized 1 Response »

Jul 032015

ChemSpider 2D Image | Evogliptin | C19H26F3N3O3

EVOGLIPTIN
CAS: 1222102-29-5 FREE

HCL……

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

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

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

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

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

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

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

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

GOSOGLIPTIN

diabetes, Uncategorized 1 Response »

Jul 032015

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.

……………………….

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

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

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

TENELIGLIPTIN

diabetes, Uncategorized 1 Response »

Jul 032015

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

…………

…………………….

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

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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%

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Patent	Filing date	Publication date	Applicant	Title
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Patent	Submitted	Granted
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Proline derivatives and the use thereof as drugs [US7074794]	2004-06-03	2006-07-11
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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

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

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

http://organicsynthesisinternational.blogspot.in/p/gliptin-series-22.html

SAXAGLIPTIN

diabetes, Uncategorized Comments Off

Mar 292015

SAXAGLIPTIN

Saxagliptin
CAS No.:	361442-04-8
Synonyms:	Saxagliptin 15ND2; Onglyza;
Formula:	C18H25N3O2
Exact Mass:	315.19500
Molecular Weight:	315.41000

SMILES:

C1[C@@H]2C[C@@H]2N([C@@H]1C#N)C(=O)[C@H](C34CC5CC(C3)CC(C5)(C4)O)N13c nmr predict

Saxagliptin, (1S,3S,5S)-2-(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)-acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile of the following chemical structure:

is a dipeptidyl peptidase IV (DPP4) inhibitor. Saxagliptin is marketed under the trade name ONGLYZA® by Bristol-Myers Squibb for the treatment of type 2 diabetes.

Saxagliptin and its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Pat. No. 6,395,767. In addition, U.S. Pat. No. 7,420,079 discloses Saxagliptin and its hydrochloride, trifluoroacetic acid and benzoate salts, as well as Saxagliptin monohydrate.

U.S. 2009/054303 and the corresponding WO 2008/131149 application disclose several crystalline forms of Saxagliptin and of Saxagliptin salts. The crystalline forms of Saxagliptin reported in that patent application are a monohydrate (denoted there as form H-1), a hemihydrate (denoted there as form H0.5-2), a dihydrate (denoted form H2-1) and an anhydrous form (denoted there as N-3).

WO 2005/117841 (the ‘841 application) describes the cyclization of Saxagliptin to form the therapeutically inactive cyclic amidine. The ‘841 application reports that such cyclization can occur both in solid state and solution state.

WO 2010/115974 discloses Forms: I-S, HT-S, IV-S, and HT-IV-S of Saxagliptin hydrochloride.

Org. Process Res. Dev., 2009, 13 (6), pp 1169–1176

DOI: 10.1021/op900226j

http://pubs.acs.org/doi/abs/10.1021/op900226j

The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin (1), is described from the two unnatural amino acid derivatives 2 and 3. After the deprotection of 3, the core of 1 is formed by the amide coupling of amino acid 2 and methanoprolinamide 4. Subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin, 1. While acid salts of saxagliptin have proven to be stable in solution, synthesis of the desired free base monohydrate was challenging due to the thermodynamically favorable conversion of the free amine to the six-membered cyclic amidine 9. Significant process modifications were made late in development to enhance process robustness in preparation for the transition to commercial manufacturing. The impetus and rationale for those changes are explained herein.

Monohydrate 1 was isolated as a white solid (58.2 kg, 88%).

1 H NMR (400 MHz, CD2Cl2- d6) δ 5.25 (dd, J1 ) J2 ) 1.0 Hz, 1H), 4.93 (dd, J1 ) 10.6 Hz, J2 ) 2.3 Hz, 1H), 3.55-3.50 (m, 1H), 3,35 (s, 1H), 2.45 (ddd, J1 ) 16.1 Hz, J2 ) 10.9 Hz, J3 ) 5.6 Hz, 1H), 2.25 (dd, J1 ) 13.6 Hz, J2 ) 2.5 Hz, 1H), 2.18-2.10 (m, 2H), 1.83-1.42 (m, 15H), 1.40-1.27 (m, 3H) 1.0-0.87 (m, 2H)

13C NMR (100 MHz, CD2Cl2) δ 173.43, 120.15, 68.83, 60.90, 46.57, 45.51, 45.08, 45.01, 41.62, 38.15, 37.92, 37.35, 35.88, 30.98, 30.93, 30.80, 18.00, 13.69.

MS (FAB) m/z 316 [M + H]+

1H NMR PREDICT

Saxagliptin NMR spectra analysis, Chemical CAS NO. 361442-04-8 NMR spectral analysis, Saxagliptin H-NMR spectrum

13C NMR PREDICT
Saxagliptin NMR spectra analysis, Chemical CAS NO. 361442-04-8 NMR spectral analysis, Saxagliptin C-NMR spectrum

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http://www.google.com/patents/WO2012162507A1?cl=en

two amino acid derivatives (A) and (B), described in further detail hereinbelow, coupled in the presence of a coupling reagent. The amide coupling of (S)-a[[(l,l-dimethyleethoxy)carbonyl]amino]-3- hydroxytricyclo [3.3.1.1]decane-l-acetic acid (A) and (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide (B), subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin (C).

synthetic route is disclosed as follows:

Scheme-IV

Scheme-V

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Savage, Scott A., et al., “Preparation of Saxagliptin, a Novel DPP-IV Inhibitor“, Organic Process Research & Development, 2009, vol. 13, pp. 1169-1176.

REFERENCES

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US7470810	11 Jan 2005	30 Dec 2008	Bristol-Myers Squibb Company	Such as 1-dodecane-thiotrifluoroacetate; alkyl/arylthiol is treated with trifluoroacetic anhydride in presence of pyridine, solvent (dichloromethane), and dimethylaminopyridine (DMAP) as catalyst; for protection of amino acids
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WO2001068603A2	5 Mar 2001	20 Sep 2001	Bristol Myers Squibb Co	Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use
WO2008131149A2	18 Apr 2008	30 Oct 2008	Squibb Bristol Myers Co	Crystal forms of saxagliptin and processes for preparing same
WO2010115974A1	9 Apr 2010	14 Oct 2010	Sandoz Ag	Crystal forms of saxagliptin
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Citing Patent	Filing date	Publication date	Applicant	Title
US8748631 *	24 May 2012	10 Jun 2014	Apicore, Llc	Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof
US20130023671 *	24 May 2012	24 Jan 2013	Apicore, Llc	Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof

REFERENCES

1. Scott A. Savage, Gregory S. Jones, Sergei Kolotuchin, Shelly Ann Ramrattan, Truc Vu, and Rebert E. Waltermire (2009) Preparation of Saxagliptin, a Novel DPP-IV Inhibitor, Organic Process Research & Development., 13, 1169-1176.
2. Santosh K. Sing, Narendra Manne and Manojit Pal, (2008) Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile: A key intermediate for dipeptidyl peptidase IV inhibitors. Beilstein Journal of Organic Chemistry, 4, No. 20.
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