Sunday 29 March 2015

SAXAGLIPTIN


SAXAGLIPTIN

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

SMILES:

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

13c nmr predict

Saxagliptin, (1S,3S,5S)-2-(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)-acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile of the following chemical structure:
Figure US08410288-20130402-C00001

is a dipeptidyl peptidase IV (DPP4) inhibitor. Saxagliptin is marketed under the trade name ONGLYZA® by Bristol-Myers Squibb for the treatment of type 2 diabetes.
Saxagliptin and its hydrochloride and trifluoroacetic acid salts are disclosed in U.S. Pat. No. 6,395,767. In addition, U.S. Pat. No. 7,420,079 discloses Saxagliptin and its hydrochloride, trifluoroacetic acid and benzoate salts, as well as Saxagliptin monohydrate.
U.S. 2009/054303 and the corresponding WO 2008/131149 application disclose several crystalline forms of Saxagliptin and of Saxagliptin salts. The crystalline forms of Saxagliptin reported in that patent application are a monohydrate (denoted there as form H-1), a hemihydrate (denoted there as form H0.5-2), a dihydrate (denoted form H2-1) and an anhydrous form (denoted there as N-3).
WO 2005/117841 (the '841 application) describes the cyclization of Saxagliptin to form the therapeutically inactive cyclic amidine. The '841 application reports that such cyclization can occur both in solid state and solution state.
WO 2010/115974 discloses Forms: I-S, HT-S, IV-S, and HT-IV-S of Saxagliptin hydrochloride.




Org. Process Res. Dev.200913 (6), pp 1169–1176
DOI: 10.1021/op900226j





Abstract Image
The commercial-scale synthesis of the DPP-IV inhibitor, saxagliptin (1), is described from the two unnatural amino acid derivatives 2 and 3. After the deprotection of 3, the core of 1 is formed by the amide coupling of amino acid 2 and methanoprolinamide 4. Subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin, 1. While acid salts of saxagliptin have proven to be stable in solution, synthesis of the desired free base monohydrate was challenging due to the thermodynamically favorable conversion of the free amine to the six-membered cyclic amidine 9. Significant process modifications were made late in development to enhance process robustness in preparation for the transition to commercial manufacturing. The impetus and rationale for those changes are explained herein.
Monohydrate 1 was isolated as a white solid (58.2 kg, 88%). 


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


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


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




1H NMR PREDICT

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


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


..................

http://www.google.com/patents/WO2012162507A1?cl=en
 two amino acid derivatives (A) and (B), described in further detail hereinbelow, coupled in the presence of a coupling reagent. The amide coupling of (S)-a[[(l,l-dimethyleethoxy)carbonyl]amino]-3- hydroxytricyclo [3.3.1.1]decane-l-acetic acid (A) and (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3- carboxamide (B), subsequent dehydration of the primary amide and deprotection of the amine affords saxagliptin (C).
Figure imgf000002_0001





synthetic route is disclosed as follows:
Figure imgf000011_0001


Figure imgf000012_0001

Scheme-IV
Figure imgf000015_0001


Scheme-V
Figure imgf000016_0001

Figure imgf000017_0001



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

REFERENCES
US639576716 Feb 200128 May 2002Bristol-Myers Squibb CompanyCyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US699518327 Jul 20047 Feb 2006Bristol Myers Squibb CompanyAdamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US718684628 Mar 20056 Mar 2007Bristol-Myers Squibb CompanyProcess for preparing a dipeptidyl peptidase IV inhibitor and intermediates employed therein
US721470223 May 20058 May 2007Bristol-Myers Squibb CompanyReacting the amide compound with phosphorus oxychloride in an organic solvent; treating the reaction mixture with water to form (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile-hydrochloride
US72235732 May 200529 May 2007Bristol-Myers Squibb CompanyEnzymatic ammonolysis process for the preparation of intermediates for DPP IV inhibitors
US742007918 Nov 20032 Sep 2008Bristol-Myers Squibb CompanyIntermediates for making 1(alpha-amino-1-(cyclopropyl-fused pyrrolidinylcarbonyl)methyl)-3-hydroxyadamantanes, e.g., methyl 3-hydroxy-<a-oxotricyclo[3.3.1.13,7]decane-1-acetate
US747081011 Jan 200530 Dec 2008Bristol-Myers Squibb CompanySuch as 1-dodecane-thiotrifluoroacetate; alkyl/arylthiol is treated with trifluoroacetic anhydride in presence of pyridine, solvent (dichloromethane), and dimethylaminopyridine (DMAP) as catalyst; for protection of amino acids
US774108212 Apr 200522 Jun 2010Bristol-Myers Squibb CompanyProcess for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor
US794365618 Apr 200817 May 2011Bristol-Myers Squibb CompanyCrystal forms of saxagliptin and processes for preparing same
US200600359548 Aug 200516 Feb 2006Sharma Padam NAmmonolysis process for the preparation of intermediates for DPP IV inhibitors
WO2001068603A25 Mar 200120 Sep 2001Bristol Myers Squibb CoCyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use
WO2008131149A218 Apr 200830 Oct 2008Squibb Bristol Myers CoCrystal forms of saxagliptin and processes for preparing same
WO2010115974A19 Apr 201014 Oct 2010Sandoz AgCrystal forms of saxagliptin
WO2011140328A15 May 201110 Nov 2011Teva Pharmaceutical Industries Ltd.Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof

Citing PatentFiling datePublication dateApplicantTitle
US8748631 *24 May 201210 Jun 2014Apicore, LlcProcess for preparing saxagliptin and its novel intermediates useful in the synthesis thereof
US20130023671 *24 May 201224 Jan 2013Apicore, LlcProcess for preparing saxagliptin and its novel intermediates useful in the synthesis thereof

REFERENCES
  • 1. Scott A. Savage, Gregory S. Jones, Sergei Kolotuchin, Shelly Ann Ramrattan, Truc Vu, and Rebert E. Waltermire (2009) Preparation of Saxagliptin, a Novel DPP-IV Inhibitor, Organic Process Research & Development., 13, 1169-1176.
  • 2. Santosh K. Sing, Narendra Manne and Manojit Pal, (2008) Synthesis of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile: A key intermediate for dipeptidyl peptidase IV inhibitors. Beilstein Journal of Organic Chemistry, 4, No. 20.
  • 3. U.S. Pat. No. (2010) 0274025 A1.
  • 4. U.S. Pat. No. (2006) 0035954 A1.
  • 5. U.S. Pat. No. (2005) 0090539 A1.
  • 6. Organic letters. (2001) Vol. 3, No.5, Page: 759-762
  • 7. Tetrahedron 59 (2003) 2953-2989







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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.
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.
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.

1 comment:

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