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【结 构 式】

【分子编号】69430

【品名】(1R,3R,4S)-ethyl 3-((tert-butoxycarbonyl)amino)-4-((methylsulfonyl)oxy)cyclohexanecarboxylate

【CA登记号】

【 分 子 式 】C15H27NO7S

【 分 子 量 】365.448

【元素组成】C 49.30% H 7.45% N 3.83% O 30.65% S 8.77%

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:(XIII)

Resolution of racemic 3-cyclohexene-1-carboxylic acid (VIII) with (R)-α-methylbenzylamine results in the target (S)-enantiomer, which undergoes intramolecular iodolactonization to compound (IX) by means of I2, KI and NaHCO3 in H2O/CH2Cl2. The bicyclic iodolactone (IX) then rearranges to epoxy ester (X) by treatment with NaOH in EtOH/H2O. Ring opening of epoxide (X) with NaN3 in the presence of NH4Cl in DMF at 76 °C affords the trans-azido alcohol (XI), which is converted to the tert-butyl carbamate (XII) by catalytic hydrogenation in the presence of Pd/C and Boc2O in EtOAc . Carbamate (XII) can also be obtained by reaction of epoxide (X) with ethanolic ammonia at 50 °C, followed by protection of the resultant amino alcohol with Boc2O in EtOH . After conversion of alcohol (XII) to the corresponding mesylate (XIII) by means of methanesulfonyl chloride and Et3N in CH2Cl2 or EtOAc , substitution of the mesylate group with NaN3 in the presence or the absence of phase transfer catalysts, including Aliquat 336, Hex4NCl, PhCH2NEt3Cl, Me4NCl , or Bu4NCl or Et4NCl , in NMP at 60 °C affords the cis-azido-carbamate (XIV) . Reduction of azide (XIV) by either hydrogenation with H2 and Pd/C in EtOH/EtOAc or transfer hydrogenation with ammonium formate and Pd/C in EtOH/H2O gives amine (XV), which is optionally converted to the corresponding oxalate salt . Subsequent protection of the free amine group in compound (XV) or its oxalate with benzyl chloroformate in the presence of NaHCO3 in THF/H2O or EtOAc/H2O yields the fully protected diamine (XVI), which undergoes ester hydrolysis by means of LiOH in H2O/THF or H2O/EtOH to furnish the carboxylic acid (XVII). After condensation of carboxylic acid (XVII) with dimethylamine hydrochloride by means of EDC and HOBt in CH2Cl2 or DMF , the resulting N,N-dimethylcarboxamide (XVIII) is selectively deprotected by catalytic hydrogenolysis over Pd/C in MeOH or EtOH yielding amine (XIX), which is optionally isolated as the oxalate salt by precipitation with oxalic acid in EtOAc . Coupling of the cyclohexylamine (XIX) with N-(5-chloro-2-pyridyl)oxamic acid lithium salt (VI) by means of EDC and HOBt in CH2Cl2 then leads to amide (XX) , which can be alternatively obtained by condensation of the corresponding oxalate salt of (XIX) with ethyl N-(5-chloro-2-pyridyl)oxamate (XXI) in the presence of Et3N in acetonitrile . Finally, subsequent deprotection of amide (XX) by means of HCl in ethanol or MsOH in acetonitrile provides the target cyclohexanediamine (I).

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.
3 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.
4 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.
5 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
(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
(VIII) 39146 3-cyclohexene-1-carboxylic acid;Cyclohex-3-ene-1-carboxylic acid 4771-80-6 C7H10O2 详情 详情
(IX) 11582 (1R,4R,5R)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one C7H9IO2 详情 详情
(X) 69427 (1R,3R,6S)-ethyl 7-oxabicyclo[4.1.0]heptane-3-carboxylate C9H14O3 详情 详情
(XI) 69428 (1R,3R,4S)-ethyl 3-azido-4-hydroxycyclohexanecarboxylate C9H15N3O3 详情 详情
(XII) 69429 (1R,3R,4S)-ethyl 3-((tert-butoxycarbonyl)amino)-4-hydroxycyclohexanecarboxylate C14H25NO5 详情 详情
(XIII) 69430 (1R,3R,4S)-ethyl 3-((tert-butoxycarbonyl)amino)-4-((methylsulfonyl)oxy)cyclohexanecarboxylate C15H27NO7S 详情 详情
(XIV) 69431 (1R,3R,4S)-ethyl 4-azido-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate C14H24N4O4 详情 详情
(XV) 69432 (1R,3R,4S)-ethyl 4-amino-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate C14H26N2O4 详情 详情
(XVI) 69433 (1R,3R,4S)-ethyl 4-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate C22H32N2O6 详情 详情
(XVII) 69434 (1R,3R,4S)-4-(((benzyloxy)carbonyl)amino)-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylic acid C20H28N2O6 详情 详情
(XVIII) 69435 benzyl tert-butyl ((1R,2R,4S)-4-(dimethylcarbamoyl)cyclohexane-1,2-diyl)dicarbamate C22H33N3O5 详情 详情
(XIX) 69436 tert-butyl ((1R,2R,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate C14H27N3O3 详情 详情
(XX) 69437 tert-butyl ((1R,2R,5S)-2-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)-5-(dimethylcarbamoyl)cyclohexyl)carbamate C21H30ClN5O5 详情 详情
(XXI) 69438 ethyl N-(5-chloro-2-pyridyl)oxamate;ethyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate C9H9ClN2O3 详情 详情
Extended Information