UGI PRODUCT

PROCESS, spectroscopy, SYNTHESIS, Uncategorized Comments Off

Jul 052015

To synthesize a Ugi adduct from phenanthrene-9-carboxaldehyde, 1-heptylamine, tert-butylisocyanide and crotonic acid in methanol using Ugi 4CR

Procedure

To a one gram vial, charged with methanol (1mL) heptylamine, phenanthrene-9-carboxaldehyde, crotonic acid and tert-butyl isonitrile (0.5mmol each) was added in that order. After each addition, the resulting solution was vortexed for 15 seconds (or more) and confirmed that a homogeneous solution had been obtained. The vial was capped tight and left at room temperature for 3 days. The solution formed solid upon moving it to another spot. The obtained solid was washed with methanol (3 x 500uL), centrifuged each time to obtain a white residue. The wet product was set under a high vac to remove the solvent.

Characterization : White powder; M.pt~ 179-181C; H-NMR ( external image delta.gif

ppm, CDCl3) 0.30 (m, 1H), 0.54-0.95 (m, 10H), 1.05-1.2 (m, 1H ), 1.39 (s, 9H), 1.89 (d, 3H J 6.8Hz), 2.86 (bs, 1H), 3.28-3.60 (m 2H ), 5.79 (s,1H), 6.24 (d,1H J 15Hz), 6.87 (s 1H), 7.0-7.15 (m 1H), 7.56-7.76 (m 4H), 7.88 (d 1H J 7.85 Hz), 7.92-8.04 (m 2H), 8.68 (d 1H J 8.25 Hz), 8.73 (d 1H J 8.25Hz); 13C NMR ( external image delta.gif

ppm, CDCl3) 13.8, 18.2, 22.1, 26.2, 27.9, 28.6, 29.9, 31.0, 45.5, 51.7, 57.8, 122.0, 122.4, 123.1, 124.1, 126.8, 126.9, 127.43, 127.48, 128.9, 129.15, 129.16, 130.3, 130.47, 130.9, 131.0, 142.7, 166.9, 169.9; IR (KBr, 1/cm): v=3315, 3080, 2926, 2855, 1663, 1614, 1452, 1419, 748, 728; HRMS m/z calcd for C31 H40 N2 O2 : 495.298748 [M+Na]; found 495.2997.

Characterization amount: 118.5 mg

m.p. 179-181C
HNMR(50mg in 700uL CDCl3)
CNMR(50mg in 700uL CDCl3)
HRMS (FAB) [M+Na]
Nominal Mass (FAB) [M+H]
Nominal Mass (FAB) [M+Na]
IR (KBr)

Conclusion

A Ugi product was successfully synthesized in 50% yield.

Sitagliptin

diabetes, Uncategorized Comments Off

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

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

Understand NMR with simple molecules, Ethyl (E)-2-butenoate

Uncategorized Comments Off

Jul 052015

Ethyl (E)-2-butenoate

Ethyl trans-crotonate

NO BAK BAK ALL PICTURES

PICTURES IN PLENTY

1H NMR

Ethyl (E)-2-butenoate

1H NMR WITH INTEGRALS

Ethyl-2-butenoate

1H-NMR proton decoupled spectrum of Ethyl-2-butenoate in CDCl3.

1H-NMR proton coupled spectrum of Ethyl-2-butenoate in CDCl3.

13C NMR

APT

image of ethyl trans-crotonate

DEPT

13C-NMR proton decoupled spectrum of Ethyl-2-butenoate in CDCl3.

DEPT spectrum of Ethyl-2-butenoate

COSY spectra

The information on the H that are coupling with each other is obtained by looking at the peaks inside the grid. These peaks are usually shown in a contour type format, like height intervals on a map.
In order to see where this information comes from, let’s consider an example shown below, the COSY of ethyl 2-butenoate
First look at the peak marked A in the top left corner. This peak indicates a coupling interaction between the H at 6.9 ppm and the H at 1.8 ppm. This corresponds to the coupling of the CH3 group and the adjacent H on the alkene.
Similarly, the peak marked B indicates a coupling interaction between the H at 4.15 ppm and the H at 1.25 ppm. This corresponds to the coupling of the CH2 and the CH3 in the ethyl group.
Notice that there are a second set of equivalent peaks, also marked A and Bon the other side of the diagonal.

(COSY spectra recorded by D. Fox, Dept of Chemistry, University of Calgary on a Bruker Advance DRX-400 spectrometer)

HETCOR spectra

The information on how the H are C are matched is obtained by looking at the peaks inside the grid. Again, these peaks are usually shown in a contour type format, like height intervals on a map.
In order to see where this information comes from, let’s consider an example shown below, the HETCOR of ethyl 2-butenoate.
First look at the peak marked A near the middle of the grid. This peak indicates that the H at 4.1 ppm is attached to the C at 60 ppm. This corresponds to the -OCH2- group.
Similarly, the peak marked B towards the top right in the grid indicates that the H at 1.85 ppm is attached to the C at17 ppm. Since the H is a singlet, we know that this corresponds to the CH3- group attached to the carbonyl in the acid part of the ester and not the CH3- group attached to the -CH2- in the alcohol part of the ester.
Notice that the carbonyl group from the ester has no “match” since it has no H attached in this example.

(HETCOR spectra recorded by D. Fox, Dept of Chemistry, University of Calgary on a Bruker Advance DRX-400 spectrometer)

HETCOR

COSY

HMQC

HMBC

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9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester

spectroscopy, SYNTHESIS Comments Off

Jul 042015

9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester



Name	9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester
Synonyms
Name in Chemical Abstracts	9,10-Ethanoanthracene-11,12-dicarboxylic acid, diethyl ester, trans-
CAS No	93368-53-7
EINECS No
Molecular formula	C₂₂H₂₂O₄
Molecular mass	350.42
SMILES code	c1cccc2[C@@H]3[C@H](C(=O)OCC)[C@@H](C(=O)OCC)[C@H](c12)c4ccccc43

1H NMR

¹H-NMR: 9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester
250 MHz, CDCl₃
delta [ppm]	mult.	atoms	assignment
1.23	t (³J = 7.2 Hz)	6 H	CH₃ ethyl
3.45	m	2 H	11-H, 12-H (-CH-COO-)
4.08	m	4 H	CH₂ ethyl
4.75	m	2 H	9-H, 10-H

¹³C-NMR

13C NMR

¹³C-NMR: 9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester
62.5 MHz, CDCl₃
delta [ppm]	assignment
14.2	CH₃ (ethyl ester)
46.7	C9, C10 (CH)
47.7	C11, C12 (CH-COO)
60.9	CH₂ (ethyl ester)
123.8	CH arom.
124.5	CH arom.
126.2	CH arom.
126.3	CH arom.
140.3	C quart. arom.
142.0	C quart. arom.
172.3	C(=O)O-
76.5-77.5	CDCl₃

IR: 9,10-Dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester
[KBr, T%, cm^-1]
[cm^-1]	assignment
3074, 3026	arom. C-H valence
2981	aliph. C-H valence
2935, 2897	aliph. C-H valence
1739	C=O valence, ester
1467	arom. C=C valence

; Side reactions

Synthesis of 9,10-dihydro-9,10-ethanoanthracene-11,12-trans-dicarboxylic acid diethyl ester

Reaction type:	cycloaddition, Diels-Alder reaction
Substance classes:	alkene, aromatics, carboxylic acid ester, diene, dienophile, acid catalyst
Techniques:	working with moisture exclusion, heating under reflux, stirring with magnetic stir bar, filtering, evaporating with rotary evaporator, recrystallizing, use of an ice cooling bath, heating with oil bath

Equipment

	three-necked flask 1000 mL			adapter with ground-glass joint and hose coupling
	protective gas piping			reflux condenser
	drying tube			bubble counter
	powder funnel			heatable magnetic stirrer with magnetic stir bar
	rotary evaporator			ice bath
	exsiccator with drying agent			oil bath

Operating scheme

MULTAN, PAKISTAN

Mutlan is an important city of Pakistan which is also known as the city of Saints. The history of Multan begins with the Alexander and later on Kushans, Arabs, Huns, Ghaznavi, Afghans, Mongols, Sikhs, Mughals and British ruled over the city. It is the city of Sufis and Saints who preached the Islam in this region. In the South Asia Multan is the oldest city.

Multan Things to Do

See all 10 Things to Do in Multan

Baha-ud-din Zakariya Mazar

Sheikh Baha-ud-din Zakariya (1170-1267) was a sufi saint who for several years travelled the region from Baghdad, Iraq to India preaching Islam, and made his final abode in Multan. His offsprings and disciples travelled all over India to preach. His most famous descendant is Shah… more
Shah Rukn-e-Alam’s tomb

Situated on top of a small hillock, behind the old ruins of Multan Fort, the Mazar and its majestic dome is the first landmark visible when you enter proper Multan. Shah Rukn-e-Alam (1251-1335) was a Sufi saint in Multan. He was revered by his followers, and to this date thousands of pilgrims from all over… more
Other Saints and Sufis Mazars

Multan is known as City of Saints, and this is evident by the number of Masuleums, Mazars, Dargas, or tombs situated in this city. Some of them are listed below.1 Hazrat Baha-ud-Din Zakaria2 Shah Rukn-i-Alam3 Shah Shams Sabzwari4 Shah Gardez5 Musa Pak Shaheed6 Hazrat Hafiz Muhammad… more
Ghanta Ghar (Clock Tower house)

Ghanta Ghar whch is situated in the city center is the city government head quarter. (not a great picture, taken from a moving car)

more
Multan Fort

The Multan Fort on a high mound of earth which separated it from the old branch of the river Ravi. There are now only remnant of this old fort, which was considered as one of the best fort (defense wise) built in the sub-continent. The fort was destroyed when the British took over. During its haydays the fort walls were was almost 1.6… more
King mosque Eid Gah

This Masjid is a marvelous piece of architecture of multan.it is a very beautiful masjid and must to visit place of Multran city

more
Shrines must to visit

Given below is list of must to visit shrines in Multan1.Shrine B.B Pak Damman2.Shrine Hameed-ud-Din Hakim3.Shrine Qutab-al-quteeb’Moj Daryan’4.Shrine-Syed Pir Sakhi Shah Hasan Prwana5.Shrine-Qazi Qutab-ud-Din Kashani6.Shrine-Syed Hasan Kanjzee7.Shrine-Hazarat Shah Dana Shaheed8.Shrine-Abu… more
Shrines of the sufi hermits

Hi Awais,All the destinations in Pakistan, they’ve their own attraction or somethijng very special in that area, likewise in Hunza, you can’t find the shrines of the sufi hermits, or in Multan, the mountains like Nanga parbat or Kalash tribes in Lahore?Multan, Medina-tul-awlia, the city of saints, famous all over the… more
Visiting Historical Places

As I describe before that Multan is the city of Saints so there r so many Tombs to Visit and explore the history.

more

Multan Hotels

Ramada Multan

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TRELAGLIPTIN

diabetes Comments Off

Jul 032015

1 TRELAGLIPTIN

Trelagliptin succinate (SYR-472)

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

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

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

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

Sponsor/Developer: Takeda Pharmaceuticals and Furiex Pharmaceuticals

Mechanism of action: DPP-4 inhibitor

865759-25-7 cas FREE BASE

1029877-94-8 succinate

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

clinical trials….http://clinicaltrials.gov/search/intervention=SYR+472

Trelagliptin-succinate M. Wt: 475.47

Trelagliptin-succinate Formula: C22H26FN5O6

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

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

TRELAGLIPTIN (SYR-472)

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

http://www.amstock.com/proxyservices/Files/AR26348.pdf

https://www.takeda.com/investor-information/annual/files/ar2013_10_en.pdf

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

trelagliptin succinate

Compound I, A, TRELAGLIPTIN which has the formula:

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

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

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

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

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

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

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

……………………..

SYNTHESIS

US20090275750

Compound 34 IS TRELAGLIPTIN

4-Fluoro-2-methylbenzonitrile (31).

A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄and the solvent removed to give product 31 (yield 60%). 1H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

2-Bromomethyl-4-fluorobenzonitrile (32).

A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl₄was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

Alternatively, 32 was made as follows.

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

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

A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃(0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.

Alternatively, 33 was made as follows.

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

TFAsalt OF TRELAGLIPTIN

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

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

FREE BASE OF TRELAGLIPTIN

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

HCL salt OF TRELAGLIPTIN

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

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

Succinate salt OF TRELAGLIPTIN

Figure US20080227798A1-20080918-C00001

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

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

Methanesulfonate salt

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

…………………………

FORMULATION

WO2008114800A2

COMPD A IS TRELAGLIPTIN

Examples (Comparative Example IA)

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

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

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

………………………..

POLYMORPHS AND SYNTHESIS

WO2008067465A1

FORM A

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

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

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

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

Characterization Data of Form A of Compound I

8. Amorphous Form

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

Table A. Approximate Solubilities of Compound I

Compound I having the formula

POLYMORPH SCREEN

Crystallization Experiments of Compound I from Solvents

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

…………………………

SYNTHESIS

WO2008033851A2

EXAMPLES

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

4-Fluoro-2-methylbenzonitrile (3)

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

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

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

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

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

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

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

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

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

General procedure for the preparation of salts of Compound I.

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

…………………..

TABLET

US20070060530

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

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

The exemplary tablet formulations are as follows:



12.5 mg of Compound I (weight of free base form) per tablet

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

…………..

US20080227798 AND US20120197018

POLYMORPHS AND SYNTHESIS

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

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

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

Compound B was prepared by refluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄and the solvent removed to give product B (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

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

Compound C was prepared by refluxing a mixture of 4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl₄under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

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

Compound E was prepared by stirring a mixture of crude 3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃(0.5 g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.

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

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

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

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

SUCCINATE SALT OF TRELAGLIPTIN

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

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

……………

patents

1. US 2013172377

2. WO 2011013639

3. WO 2009099172

4.WO 2009099171

5. WO 2008114807

6.WO 2008114800

7. WO 2008033851

8. WO 2007074884

9WO 2007035629

patent document 1: US2005/0261271

patent document 2: US2007/0060530

patent document 3: US2008/0287476

patent document 4: US2008/0227798

patent document 5: US2008/0280931

patent document 6: WO2008/114800

patent document 7: WO2011/013639

US7906523 *	Oct 30, 2007	Mar 15, 2011	Takeda Pharmaceutical Company Limited	Dipeptidyl peptidase inhibitors
US8084605 *	Nov 29, 2007	Dec 27, 2011	Kelly Ron C	Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8188275 *	Oct 30, 2007	May 29, 2012	Takeda Pharmaceutical Company Limited	Dipeptidyl peptidase inhibitors
US8222411 *	Sep 15, 2006	Jul 17, 2012	Takeda Pharmaceutical Company Limited	Dipeptidyl peptidase inhibitors
US20090275750 *	Sep 15, 2006	Nov 5, 2009	Jun Feng	Dipeptidyl peptidase inhibitors

WO2013183784A1

Jun 4, 2013

Dec 12, 2013

Takeda Pharmaceutical Company Limited

Solid preparation

US20080227798 *	Nov 29, 2007	Sep 18, 2008	Kelly Ron C	Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US20120197018 *	Feb 15, 2012	Aug 2, 2012	Kelly Ron C	Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor

WO2007033265A1 *	Sep 13, 2006	Mar 22, 2007	Takeda Pharmaceutical	Dipeptidyl peptidase inhibitors for treating diabetis
WO2007033266A2 *	Sep 13, 2006	Mar 22, 2007	Takeda Pharmaceutical	Dipeptidyl peptidase inhibitors for treating diabetis
WO2007033350A1 *	Sep 13, 2006	Mar 22, 2007	Takeda Pharmaceutical	Dipeptidyl peptidase inhibitors for treating diabetes
EP1586571A1 *	Dec 21, 2004	Oct 19, 2005	Takeda San Diego, Inc.	Dipeptidyl peptidase inhibitors

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

…………………………………..

………………………..

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

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

NMR, 3-[3-(benzoylamino)-4-hydroxylphenyl] propanoic acid

spectroscopy Comments Off

Jul 022015

http://www.google.com/patents/WO2008022462A1?cl=en

1 H-NMR Spectrum of Compound 35…………3-[3-(benzoylamino)-4-hydroxylphenyl] propanoic acid

¹H-NMR (Acetone-D₆) δ: 2.60 (t, 2H, J = 7.4, H- 3), 2.84 (t, 2H, J = 7.9, H-2), 6.89 (d, IH, J = 8.2, H-8), 7.00 (dd, IH, J = 2.1 , 8.25, H- 9), 7.57 (m, 4H, H-5, H-4′, H-5′, H-6¹), 8.05 (d, 2H, J = 8.2, H-3′, H-7′), 9.07 (broad s, IH, NH), 9.54 (broad s, IH, OH), 10.58 (broad s, IH, CO₂H).

¹³C-NMR Spectrum of Compound 35

¹³C-NMR (Acetone- D₆) δ: 30.87 (C- 3), 36.21 (C- 2), 118.69 (C- 8), 123.31 (C-5), 123.41 (C- 6), 126.88 (C- 9), 127.37 (C- 4), 128.54 (C-4¹, C-6¹), 129.61 (C-3¹, C-7′), 132.99 (C-5¹), 134.99 (C-2¹), 148.03 (C-7), 167.34 (C-I¹), 173.94 (C-I ).

¹³C-NMR Spectrum of Compound 35

COSY-NMR Spectrum of Compound 35

COSY-NMR Spectrum of Compound 35

HETCOR-NMR Spectrum of Compound 35

3-[3-(benzoylamino)-4-hydroxylphenyl] propanoic acid 35:

To a solution of 32 (222 mg, 1.06 mmol, leq.) dissolved in THF (20 mL) was added the catalyst 10 % palladium-on-charcoal (15 % by mass, 33 mg). The resulting mixture was then placed on a hydrogenator, flushed (5 times) with hydrogen and left to agitate under pressure (36 psi.) overnight (12 hrs) while recharging hydrogen pressure twice (36 psi.) until hydrogen up-take by reaction mixture stopped (pressure did not decrease for 1-2 hrs.). The reaction mixture was vacuum filtered through Celite ‘ rinsing with THF. To the filtered solution containing 33 was directly added BzCl (154 mg, 1.1 mmol, 1 eq.) and left to stir at room temperature for 30 min. Then 10 % HCl (25 mL) was added and stirring continued an additional 5 min. followed by extraction with CIT₂Cl₂ (2 x 35 mL). The organic fractions were combined, dried (MgSO₄), and evaporated off solvent. The resulting mixture was re-crystallized with Hexane/ Acetone to afford an off white solid (250 mg) with an 83 % yield from compound 32. Molecular Formula – C₁₆Hi₅NO₄. Formula Weight – 285.295 g mole^“1.

FT-IR (KBR disk) cm^{” 1} : 3201 (NH, OH), 1692 (CO₂H), 1636 (NHAc).

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¹H-NMR Spectrum of Compound (+/-V36

13 C-NMR Spectrum of Compound (+/-V36

N-(l-oxaspiro[4.5]deca-6,9-dien-2,8-dion-7-yl)acetamide (+/-)-36: To a solution of 34 (122 mg, .547 mmol, 1 eq.) dissolved in acetone (10 mL, 0 ⁰C) was added PIFA (306 mg, .71 1 mmol, 1.3 eq.) in one portion and stirred for 20-25 minutes (confirmed by tic: [1 : 1] EtOAc/Hexane). The reaction mixture was diluted with ethyl acetate (15 mL), washed with cold water (10 mL), dried organic fraction (MgSO₄) and evaporated off solvent to afford a Tan solid. The crude product was purified by re-dissolving with CHCI₃, filtering of the solution through Celite ^®, evaporating off the solvent and placing it under vacuum overnight to afford an off white solid (120 mg, 98 % yield). Molecular Formula – C_{1 1}Hi iNO₄. Formula Weight – 221.209 g mole^“1. FT-IR (KBR disk) cm^“1: 3333 (NH), 1777 (lactone), 1668 (amide), 1650 (ketone), 1620 (α, β-conjugation to ketone). ¹H-NMR (CDCl₃) δ: 2.17 (s, 3H, H-2′), 2.44 (m, 2H, H-4), 2.81 (m, 2H, H-3), 6.35 (d, IH, J = 10.0, H-9), 6.94 (dd, IH, J = 3.1, 10.0, H- 10), 7.75 (d, IFI, J = 3.1, H-6), 7.99 (broad s, IH, NH). ¹³C-NMR (CDCl₃) δ: 24.86 (C- 2′), 28.36 (C- 4), 32.91 (C- 3), 79.76 (C-5), 124.30 (C- 6), 127.12 (C- 9), 131.55 (C- 7), 148.37 (C-10), 169.51 (C-I’), 175.46 (C-2), 179.40 (C- 8).

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¹H-NMR Spectrum of Compound 32

(2E)-3-(4-hydroxyl-3-nitrophenyl) acrylic acid 32: To a solution of 4- hydroxyl-3-nitrobenzaldehyde (1.073 g, 6.43 mmol, 1 eq.) dissolved in pyridine (25 mL) was added piperidine (25 drops) and the resulting mixture was stirred (4-5 min.). Malonic acid (1.671 g, 16.1 mmol, 2.5 eq.) was then added in one portion and the resulting mixture was warmed (60-63 ⁰C) and stirred overnight (12-14 hrs, confirmed by tic: EtOAc, mini work up, 10 % HCl and EtOAc). The reaction was cooled and acidified (50 % HCl) until yellow precipitate formed (pH~2). This yellow precipitate was extracted with ethyl acetate (2 x 150 niL). The organic fractions were combined and washed with brine (150 mL), dried (MgSO₄), and the solvent was evaporated to afford a yellow solid. Removed excess solvent by vacuum and used without further purification (1.250 g, 93 % yield). Molecular Formula – CgH₇NO₅. Formula Weight – 209.156 g mole^“1. FT-IR (KBR disk) cm^“1: 2942 (OH), 1684 (CO₂H), 1626 (C=C), 1533,1270 (NO₂). ¹FI-NMR (Acetone-D₆) δ: 2.87 (broad s, IH, OH), 6.58 (d, IH, J= 16.0, H-2), 7.27 (d, IH, J= 8.8, H-8), 7.70 (d, IH, J= 16.4, H-3), 8.08 (d, IH, J= 2.2, 8.5, H-9), 8.40 (d, IFI, J = 2.2, FI-5), 10.67 (broad s, I H, CO₂FI). The¹³C-NMR of this compound agrees with the previously published data.⁵²

Con Dao Island, Vietnam

con dau six senses resort image

Con Dao Island, Vietnam

This 16-island archipelago is a “pocket of paradise,” says Robert Reid, a travel editor at Lonely Planet.

Getting there: Take a 45-minute flight from Ho Chi Minh City.

What to do: The diving is among the best in Vietnam. Take scuba lessons as a couple or discover the nearby secluded beaches of Bai Dat Doc and Dam Trau.

Where to stay: Six Senses resort offers luxury villas on the East Vietnam Sea. The resort has an in-house spa offering traditional Vietnamese healing practices; it also boasts outdoor treatment rooms and a yoga and meditation pavilion. Inquire for rates.

Con Dao travel guide – Wikitravel

wikitravel.org/en/Con_Dao

Con Dao is an island off the southern coast of Vietnam. … The Con Dao Islands separated from the mainland about 15,000 years ago. This has resulted in the …

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