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【结 构 式】 
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【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% |
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 |