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【结 构 式】 
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【药物名称】Edoxaban;EDOXABAN TOSILATE;DU-176b 【化学名称】N1-(5-Chloropyridin-2-yl)-N2-[(1S,2R,4S)-4-(N,N-dimethylcarbamoyl)-2-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-ylcarboxamido)cyclohexyl]oxamide p-toluenesulfonate monohydrate 【CA登记号】912273-65-5;480448-29-1 (monohydrochloride);480449-70-5 (anhydrous, free base);480449-71-6 (anhydrous) 【 分 子 式 】C24H30ClN7O4S.C7H8O3S.H2O 【 分 子 量 】739.274 |
【开发单位】Daiichi Sankyo Co., Ltd. (JP) 【药理作用】Direct Factor Xa Inhibitor;Prevention of Post-operative Venous Thromboembolism;Treatment of Atrial Fibrillation |
合成路线1
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
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3
Alternatively, the monoprotected cyclohexanediamine (XIX) can be prepared as follows. Ring opening of N,N-dimethyl-3,4-epoxycyclohexanecarboxamide (XXII) with ammonium hydroxide at 40 °C, followed by protection of the resultant amino alcohol (XXIII) with Boc2O in aqueous NaOH provides the N-Boc-protected amino alcohol (XXIV). After conversion of alcohol (XXIV) to the corresponding mesylate (XXV) by means of methanesulfonyl chloride and Et3N in 4-methyl-2-pentanone, substitution with NaN3 in the presence of 1-dodecylpyridinium chloride in DMAc or toluene at 60 °C furnishes azide (XXVI). Finally, azide (XXVI) is reduced by transfer hydrogenation with ammonium formate and Pd/C in MeOH at 40 °C .
| 【1】 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. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 69436 | tert-butyl ((1R,2R,5S)-2-amino-5-(dimethylcarbamoyl)cyclohexyl)carbamate | C14H27N3O3 | 详情 | 详情 | |
| (XXII) | 69439 | (1R,3R,6S)-N,N-dimethyl-7-oxabicyclo[4.1.0]heptane-3-carboxamide | C9H15NO2 | 详情 | 详情 | |
| (XXIII) | 69440 | (1R,3R,4S)-3-amino-4-hydroxy-N,N-dimethylcyclohexanecarboxamide | C9H18N2O2 | 详情 | 详情 | |
| (XXIV) | 69441 | tert-butyl ((1R,2R,5S)-5-(dimethylcarbamoyl)-2-hydroxycyclohexyl)carbamate | C14H26N2O4 | 详情 | 详情 | |
| (XXV) | 69442 | (1R,2S,4S)-2-((tert-butoxycarbonyl)amino)-4-(dimethylcarbamoyl)cyclohexyl methanesulfonate | C15H28N2O6S | 详情 | 详情 | |
| (XXVI) | 69443 | tert-butyl ((1R,2S,5S)-2-azido-5-(dimethylcarbamoyl)cyclohexyl)carbamate | C14H25N5O3 | 详情 | 详情 |
合成路线4
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 |
合成路线5
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 |
合成路线6
The thiazolopyridine derivatives (II) and (III) can be obtained in several ways. Treatment of N-Boc-4-piperidinone (XXXVI) with pyrrolidine in the presence of p-TsOH·H2O in refluxing cyclohexane, followed by cyclization of the resulting enamine with cyanamide and elemental sulfur in MeOH gives 2-amino-5-Boc-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XXXVII), which by Sandmeyer reaction with CuBr2 and t-BuONO in DMF at 40 °C affords the 2-bromo compound (XXXVIII). After removal of the N-Boc-protecting group of intermediate (XXXVIII) with TFA, reductive methylation of the deprotected amine (XXXIX) with formaldehyde and NaBH(OAc)3 in the presence of AcOH and Et3N in CH2Cl2 yields 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XL) , optionally isolated as the corresponding tosylate salt (1). Alternatively, cyclization of 1-methyl-4-piperidinone (XLI) with cyanamide and sulfur in the presence of pyrrolidine in i-PrOH at 50 °C yields 2-amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XLII), which is converted to the corresponding bromide (XL) by diazotization with NaNO2 in the presence of HBr in H2O. Metalation of the bromo derivative (XL) with BuLi in THF at –78 °C, followed by quenching with CO2 affords the lithium carboxylate (II) , which is converted to the carboxylic acid (III) by treatment with HCl in EtOH. Alternatively, cyanation of bromide (XL) with NaCN/CuCN in DMAc at 150 °C yields nitrile (XLIII), which is hydrolyzed to carboxylate (II) using LiOH in EtOH . In one further method, deamination of intermediate (XXXVII) by diazotization with NaNO2 and H2SO4 in the presence of hypophosphorous acid in H2O gives 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (XLIV) , which is carboxylated to compound (II) by metalation with BuLi in THF at –78 °C and subsequent quenching with CO2 , or by acylation with trichloroacetyl chloride and Et3N in toluene, followed by haloform reaction of the resultant trichloromethyl ketone in the presence of LiOH .
The tetrahydrothiazolopyridine intermediate (XLIV) can also be prepared by a different procedure. After protection of 4-aminopyridine (XLV) as the N-Boc derivative (XLVI) with Boc2O in THF, treatment with BuLi in cold THF, followed by elemental sulfur yields the 3-sulfanylpyridine (XLVI). Cyclization of the Boc-protected amino thiol (XLVI) with formic acid at reflux, followed by KOH in H2O or Et2O leads to thiazolo[5,4-c]pyridine (XLVII), which is converted to the target intermediate (XLIV) by quaternization with iodomethane in DMF at 80 °C and then reduction with NaBH4 in MeOH .
| 【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】 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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XVIII) | 69458 | tert-butyl (3-mercaptopyridin-4-yl)carbamate | C10H14N2O2S | 详情 | 详情 | |
| (XXXVI) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (XXXVII) | 69450 | 2-amino-5-Boc-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine；tert-butyl 2-amino-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate；Thiazolo[5,4-c]pyridine-5(4H)-carboxylicacid, 2-amino-6,7-dihydro-, 1,1-dimethylethyl ester;2-Amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester;2-Amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butylester | 365996-05-0 | C11H17N3O2S | 详情 | 详情 |
| (XXXVIII) | 69451 | tert-butyl 2-bromo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate；Thiazolo[5,4-c]pyridine-5(4H)-carboxylicacid, 2-bromo-6,7-dihydro-, 1,1-dimethylethyl ester;2-Bromo-5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine；2-Bromo-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butylester;2-Bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylic acidtert-butyl ester | 365996-06-1 | C11H15BrN2O2S | 详情 | 详情 |
| (XXXIX) | 69452 | 2-bromo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine 2,2,2-trifluoroacetate | C8H8BrF3N2O2S | 详情 | 详情 | |
| (XL) | 69453 | 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine | C7H9BrN2S | 详情 | 详情 | |
| (XLI) | 10919 | 1-Methyl-4-piperidone; 1-Methyltetrahydro-4(1H)-pyridinone; N-Methyl-4-piperidone;1-methylpiperidin-4-one | 1445-73-4 | C6H11NO | 详情 | 详情 |
| (XLII) | 69454 | 2-amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine;5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine | C7H11N3S | 详情 | 详情 | |
| (XLIII) | 69455 | 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carbonitrile | C8H9N3S | 详情 | 详情 | |
| (XLIV) | 69456 | 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine | 259809-24-0 | C7H10N2S | 详情 | 详情 |
| (XLV) | 25661 | 4-pyridinamine; 4-aminopyridine | 5044-74-5 | C5H6N2 | 详情 | 详情 |
| (XLVI) | 69457 | tert-butyl pyridin-4-ylcarbamate;4-(Boc-amino)pyridine;4-(tert-Butoxycarbonylamino)pyridine | 98400-69-2 | C10H14N2O2 | 详情 | 详情 |
| (XLVII) | 69459 | 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridine | C6H8N2S | 详情 | 详情 |