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SAXAGLIPTIN

 diabetes, Uncategorized  Comments Off on SAXAGLIPTIN
Mar 292015
 


SAXAGLIPTIN

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

SMILES:

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

 

Saxagliptin, (1S,3S,5S)-2-(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)-acetyl)-2-azabicyclo[3.1.0]hexane-3-carbonitrile of the following chemical structure:
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., 2009, 13 (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
US6395767 16 Feb 2001 28 May 2002 Bristol-Myers Squibb Company Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method
US6995183 27 Jul 2004 7 Feb 2006 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US7186846 28 Mar 2005 6 Mar 2007 Bristol-Myers Squibb Company Process for preparing a dipeptidyl peptidase IV inhibitor and intermediates employed therein
US7214702 23 May 2005 8 May 2007 Bristol-Myers Squibb Company Reacting 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
US7223573 2 May 2005 29 May 2007 Bristol-Myers Squibb Company Enzymatic ammonolysis process for the preparation of intermediates for DPP IV inhibitors
US7420079 18 Nov 2003 2 Sep 2008 Bristol-Myers Squibb Company Intermediates 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
US7470810 11 Jan 2005 30 Dec 2008 Bristol-Myers Squibb Company Such as 1-dodecane-thiotrifluoroacetate; alkyl/arylthiol is treated with trifluoroacetic anhydride in presence of pyridine, solvent (dichloromethane), and dimethylaminopyridine (DMAP) as catalyst; for protection of amino acids
US7741082 12 Apr 2005 22 Jun 2010 Bristol-Myers Squibb Company Process for preparing dipeptidyl peptidase IV inhibitors and intermediates therefor
US7943656 18 Apr 2008 17 May 2011 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
US20060035954 8 Aug 2005 16 Feb 2006 Sharma Padam N Ammonolysis process for the preparation of intermediates for DPP IV inhibitors
WO2001068603A2 5 Mar 2001 20 Sep 2001 Bristol Myers Squibb Co Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl iv, processes for their preparation, and their use
WO2008131149A2 18 Apr 2008 30 Oct 2008 Squibb Bristol Myers Co Crystal forms of saxagliptin and processes for preparing same
WO2010115974A1 9 Apr 2010 14 Oct 2010 Sandoz Ag Crystal forms of saxagliptin
WO2011140328A1 5 May 2011 10 Nov 2011 Teva Pharmaceutical Industries Ltd. Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof
Citing Patent Filing date Publication date Applicant Title
US8748631 * 24 May 2012 10 Jun 2014 Apicore, Llc Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof
US20130023671 * 24 May 2012 24 Jan 2013 Apicore, Llc Process for preparing saxagliptin and its novel intermediates useful in the synthesis thereof

REFERENCES

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