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【结 构 式】 
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【分子编号】69432 【品名】(1R,3R,4S)-ethyl 4-amino-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate 【CA登记号】 |
【 分 子 式 】C14H26N2O4 【 分 子 量 】286.37152 【元素组成】C 58.72% H 9.15% N 9.78% O 22.35% |
合成路线1
该中间体在本合成路线中的序号：(XV)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 |
合成路线2
该中间体在本合成路线中的序号：(XV)Aminocyclohexanecarboxylic acid ethyl ester (IV) and some synthetic precursors are prepared as follows. Acylation of 2-amino-5-chloropyridine (XXVII) with either potassium ethyl oxalate (XXVIII) by means of EDC and HOBt in DMF or with methyl oxalyl chloride (XXIX) in the presence of NaHCO3 in THF or CH2Cl2 or Et3N in CH2Cl2 provides the corresponding N-(5-chloro-2-pyridyl)-oxamic acid esters (XXI) and (XXX), respectively. The lithium oxamate (VI) has been prepared by hydrolysis of the methyl ester (XXX) with LiOH in aqueous THF . Coupling of the ehtyl pyridyloxamate (XXI) with the monoprotected diamine (XV) (previously derivatized as the corresponding malate or oxalate salt) in the presence of Et3N in acetonitrile at 65-70 ℃ yields oxamide (XXXI), which is finally deprotected to give intermediate (IV) by removing the N-Boc-protecting group by means of methanesulfonic acid in acetonitrile .
| 【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】 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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 69423 | (1S,2R,4S)-ethyl 3-amino-4-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)cyclohexanecarboxylate | C16H21ClN4O4 | 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 | |
| (XV) | 69432 | (1R,3R,4S)-ethyl 4-amino-3-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate | C14H26N2O4 | 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 | |
| (XXVII) | 18559 | 5-Chloro-2-pyridinylamine; 5-Chloro-2-pyridinamine; 2-Amino-5-chloropyridine | 1072-98-6 | C5H5ClN2 | 详情 | 详情 |
| (XXVIII) | 69444 | potassium 2-ethoxy-2-oxoacetate;potassium ethyl oxalate;Oxalic acid 1-ethyl 2-potassium salt | 1906-57-6 | C4H6KO4 | 详情 | 详情 |
| (XXIX) | 26971 | 2-methoxy-2-oxoacetyl chloride | 5781-53-3 | C3H3ClO3 | 详情 | 详情 |
| (XXX) | 69446 | methyl 2-((5-chloropyridin-2-yl)amino)-2-oxoacetate | C8H7ClN2O3 | 详情 | 详情 | |
| (XXXI) | 69445 | (1R,3S,4R)-ethyl 3-((tert-butoxycarbonyl)amino)-4-(2-((5-chloropyridin-2-yl)amino)-2-oxoacetamido)cyclohexanecarboxylate | C21H29ClN4O6 | 详情 | 详情 |