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【结 构 式】

【分子编号】65679

【品名】N-Boc-(S)-adamantylglycine

【CA登记号】 

【 分 子 式 】C17H28NO4

【 分 子 量 】310.41366

【元素组成】C 65.78% H 9.09% N 4.51% O 20.62%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(II)

After protection of (S)-adamantylglycine (I) as the tert-butyl carbamate (II) with Boc2O and K2CO3, hydroxylation of the adamantane ring using KMnO4 in hot aqueous KOH gives the alcohol (III) (1). Alternatively, the Boc-protected amino acid (III) can be prepared by treatment of (3-hydroxyadamantyl)glycine (IV) with Boc2O and NaOH. Subsequent coupling of N-Boc-(S)-(3-hydroxyadamantyl)glycine (III) with (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide (V) using either EDC/HOBt or methanesulfonyl chloride and Hunig’s base produces amide (VI) (1-6). After protection of the hydroxyl group of (VI) with triethylsilyl triflate, the silylated carboxamide (VII) is dehydrated to the corresponding nitrile (VIII) by treatment with POCl3 and imidazole in pyridine. Deprotection of (VIII) employing trifluoroacetic acid in CH2Cl2 then gives saxagliptin (1). Scheme 1.
Alternatively, direct dehydration of unsilylated carboxamide (VI) with trifluoroacetic anhydride in the presence of pyridine or NaOH produces nitrile (IX), which undergoes acidic Boc group cleavage to furnish saxagliptin (2-6). Scheme 1.
In a related strategy, (3-hydroxyadamantyl)glycine (IV) is protected with either ethyl trifluoroacetate and potassium methoxide or dodecyl trifluorothioacetate and NaOH to give the trifluoroacetamide (X), which is further esterified with trifluoroacetic anhydride in isopropyl acetate to yield the N,O-bis(trifluoroacetyl) derivative (XI). After conversion of (XI) to the corresponding acid chloride (XII) by means of Vilsmeier reagent, condensation with the bicyclic carbonitrile (XIII) leads to amide (XIV). Hydrolysis of the trifluoroacetate ester (XIV) with NaHCO3 in MeOH provides (XV), from which the N-trifluoroacetyl group is reductively removed by means of NaBH4 to yield saxagliptin. Alternatively, the title compound is directly produced by treatment of the bis(trifluoroacetyl)-protected precursor (XIV) with NaBH4 in EtOH (7). Scheme 1.

1 Robl, J.A., Sulsky, R.B., Betebenner, D.A., Magnin, D.R., Hamann, L.G., Augeri, D.J. (Bristol-Myers Squibb Co.). Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method. EP 1261586, JP 2003531118, US 6395767, WO 0168603.
2 u, T.C., Hamann, L.G., Fox, R. et al. (Bristol-Myers Squibb Co.). Methods and compounds producing dipeptidyl peptidase IV inhibitors and intermediates thereof. JP 200651621, US 2005090539, WO 2004052850.
3 Politino, M., Cadin, M.M., Skonezny, P.M., Chen, J.G. (Bristol-Myers Squibb Co.). EP 1737970, JP 2007532137, WO 2005106011.
4 Sharma, P.N., Galvin, G.M., Boettger, S.D., Racha, S., Zhu, J., Melton, J., Mudryk, B. (Bristol-Myers Squibb Co.). Ammonolysis process for the preparation of intermediates for DPP IV inhibitors. US 2006035954, WO 2006020664.
5 Sharma, P.N. (Bristol-Myers Squibb Co.). Process for producing a dipeptidyl peptidase IV inhibitor. EP 1751102, US 2005267191, US 7214702, WO 2005115982.
6 Augeri, D.J., Robl, J.A., Betebenner, D.A. et al. Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005, 48(15): 5025-37.
7 Sharma, P.N., Gublo, E.J., Galvin, G.M., Boettger, S.D., Racha, S. (Bristol-Myers Squibb Co.). Process for preparing a dipeptidyl peptidase IV inhibitor and intermediates employed therein. WO 2005094323.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 65678 (S)-adamantylglycine 60256-21-5 C12H19NO2 详情 详情
(II) 65679 N-Boc-(S)-adamantylglycine   C17H28NO4 详情 详情
(III) 65680 N-Boc-(S)-(3-hydroxyadamantyl)glycine   C17H28NO5 详情 详情
(IV) 65681 (S)-(3-hydroxyadamantyl)glycine   C12H19NO3 详情 详情
(V) 65682 (1S,3S,5S)-2-Azabicyclo[3.1.0]hexane-3-carboxamide 361440-68-8 C6H10N2O 详情 详情
(VI) 65683     C23H36N3O5 详情 详情
(VII) 65684     C29H50N3O5Si 详情 详情
(VIII) 65685     C29H48N3O4Si 详情 详情
(IX) 65686     C22H34N3O5 详情 详情
(X) 65687     C14H18F3NO4 详情 详情
(XI) 65688     C16H17F6NO5 详情 详情
(XII) 65689     C16H16ClF6NO4 详情 详情
(XIII) 65690 (1S,3S,5S)-2-Azabicyclo[3.1.0]hexane-3-carbonitrile 866083-42-3 C6H8N2 详情 详情
(XIV) 65691     C22H23F6N3O4 详情 详情
(XV) 65692     C20H24F3N3O3 详情 详情
Extended Information