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【结 构 式】

【分子编号】69426

【品名】N-((1S,2R,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide

【CA登记号】

【 分 子 式 】C17H27N5O2S

【 分 子 量 】365.5

【元素组成】C 55.87% H 7.44% N 19.16% O 8.75% S 8.77%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(VII)

Edoxaban tosilate has been prepared by the following synthetic strategies:
1) By conjugation of the cyclohexanediamine (I) with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate (II) by means of EDC and HOBt in DMAc or DMF .
2) By conjugation of diamine (I) with the HCl salt of 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (III) in the presence of EDC, HOBt and Et3N .
3) By conjugation of the thiazolopyridinecarboxylic acid (III) with the aminocyclohexanecarboxylic acid ethyl ester (IV) using EDC, HOBt and Et3N to provide diamide ester (V) , which is then hydrolyzed with NaOH in H2O/DMSO, followed by coupling of the resultant carboxylic acid with dimethylamine in the presence of EDC and HOBt in aqueous acetonitrile .
4) By conjugation of the monoacylated cyclohexanediamine (VII) with N-(5-chloro-2-pyridyl)oxamic acid lithium salt (VI) by means of EDC and HOBt in DMF .
The tosilate salt has been obtained by treatment with p-toluenesulfonic acid in EtOH or H2O/EtOH/CH2Cl2 .

1 Nagasawa, Sato, K., Yagi, T., H., Kitani, Y. (Daiichi Sankyo Co., Ltd.).Process for producing thiazole derivative. CA 2545730, EP 1683800, US 7547786, US 2007135476, US 2009192313.
2 Ohta, T., Komoyira, S., Yoshimo, T. et al. (Daiichi Sankyo Co., Ltd.).Diamine derivatives. CA 2451605, CA 2456841, EP 1405852, EP 1415992, JP 2008143905, US 2005020645, US 2005119486, US 2005245565, US 2008015215, US 2009270446, US 7342014, US 7365205, WO 2003000657, WO 2003000680, WO 2003016302.
3 Ohta, T., Komoriya, S., Yoshino, T. et al. (Daiichi Sankyo Co., Ltd.). Diamine derivatives. CA 2511493, EP 1577301, JP 2007070369, JP 2008138011, US 2006252837, US 2009281074, US 7576135, WO 2004058715.
4 Sato, K., Kawanami, K., Yagi, T. (Daiichi Sankyo Co., Ltd.). Optically active diamine derivative and process for producing the same. EP 1925611, JP 2007106759, US 2009105491, WO 2007032498.
5 Schwartz, H.M., Wu, W.-S., Marr, P.W., Jones, J.B. Predicting the enantiomeric selectivity of chymotrypsin. Homologous series of ester substances. J Am Chem Soc 1978, 100(16): 5199-203.
6 Noguchi, S., Koyama, T. (Daiichi Sankyo Co., Ltd.). Process for production of diamine derivative. WO 2008156159.
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) 69420 N1-((1S,2R,4S)-2-amino-4-(dimethylcarbamoyl)cyclohexyl)-N2-(5-chloropyridin-2-yl)oxalamide C16H22ClN5O3 详情 详情
(II) 69421 lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate C8H9LiN2O2S 详情 详情
(III) 69422 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid hydrochloride C8H10N2O2S.HCl 详情 详情
(IV) 69423 (1S,2R,4S)-ethyl 3-amino-4-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)cyclohexanecarboxylate C16H21ClN4O4 详情 详情
(V) 69424 (1S,3R,4S)-ethyl 4-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-3-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamido)cyclohexanecarboxylate C24H29ClN6O5S 详情 详情
(VI) 69425 N-(5-chloro-2-pyridyl)oxamic acid lithium salt;lithium 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate C7H4ClLiN2O3 详情 详情
(VII) 69426 N-((1S,2R,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide C17H27N5O2S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(VII)

Intermediate (VII) is prepared as follows. Hydrolysis of cis-azido-carbamate (XIV) using aqueous LiOH gives the corresponding carboxylic acid (XXXII), which is converted into carboxamide (XXXIII) by reaction with dimethylamine hydrochloride in the presence of EDC, HOBt and NMM in CH2Cl2. N-deprotection of carboxamide (XXXIII) with HCl in EtOH/CH2Cl2, followed by condensation of the resultant amine (XXXIV) with the lithium thiazolopyridinecarboxylate derivative (II) by means of EDC and HOBt in DMF provides amide (XXXV), which is finally reduced at the azido moiety by catalytic hydrogenation over Pd/C in MeOH .

1 Ohta, T., Komoyira, S., Yoshimo, T. et al. (Daiichi Sankyo Co., Ltd.).Diamine derivatives. CA 2451605, CA 2456841, EP 1405852, EP 1415992, JP 2008143905, US 2005020645, US 2005119486, US 2005245565, US 2008015215, US 2009270446, US 7342014, US 7365205, WO 2003000657, WO 2003000680, WO 2003016302.
2 Ohta, T., Komoriya, S., Yoshino, T. et al. (Daiichi Sankyo Co., Ltd.). Diamine derivatives. CA 2511493, EP 1577301, JP 2007070369, JP 2008138011, US 2006252837, US 2009281074, US 7576135, WO 2004058715.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 69421 lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate C8H9LiN2O2S 详情 详情
(VII) 69426 N-((1S,2R,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide C17H27N5O2S 详情 详情
(XIV) 69431 (1R,3R,4S)-ethyl 4-azido-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate C14H24N4O4 详情 详情
(XXVI) 69443 tert-butyl ((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl)carbamate C14H25N5O3 详情 详情
(XXXII) 69447 (1R,3S,4R)-4-azido-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid C12H20N4O4 详情 详情
(XXXIV) 69448 (1S,3R,4R)-3-amino-4-azido-N,N-dimethylcyclohexanecarboxamide C9H17N5O 详情 详情
(XXXV) 69449 N-((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide C17H25N7O2S 详情 详情
Extended Information