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:

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

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

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

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

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

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

DOI: 10.1021/op900226j

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

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

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

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

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

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

1H NMR PREDICT

13C NMR PREDICT

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