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【结 构 式】 
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【分子编号】15800 【品名】methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate 【CA登记号】 |
【 分 子 式 】C13H18N2O5S 【 分 子 量 】314.3624 【元素组成】C 49.67% H 5.77% N 8.91% O 25.45% S 10.2% |
合成路线1
该中间体在本合成路线中的序号：(XXI)2) The esterification of trans-4-hydroxy-L-proline (XVI) with SOCl2 and methanol gives the methyl ester (XVII), which is condensed with 3-(methanesulfonyloxymethyl)pyridine (XVIII), obtained by treatment of 3-(hydroxymethyl)pyridine (XIX) with methanesulfonyl chloride, by means of triethylamine yielding trans-N-(3-pyridylmethyl)-4-hydroxy-L-proline methyl ester (XX). The treatment of (XX) with methanesulfonyl chloride affords the corresponding mesylate (XXI), which by reaction with LiCl in hot polyethylene glycol gives cis-4-chloro-N-(3-pyridylmethyl)-L-proline methyl ester (XXII). The reaction of (XXII) with sodium azide in DMSO yields the trans-4-azido derivative (XXIII), which is reduced with triphenylphosphine in hot ethyl acetate to the corresponding trans-4-amino compound (XXIV). The treatment of (XXIV) with 4-chlorophenylsulfonyl chloride (VIII) and triethylamine in ethyl acetate affords the sulfonamide (XXV), which is reduced with diisobutylaluminum hydride in toluene/dichloromethane giving (2S,4R)-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidine-2-carbaldehyde (XXVI). Finally, this compound is submitted to a Wittig condensation with (4-carboxybutyl)triphenylphosphonium chloride (XXVII) and potassium tert-butoxide in THF.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Kagara, K.; Goto, S.; Yonishi, S.; Ikushima, M.; Baba, Y.; Horiai, H. (Fujisawa Pharmaceutical Co., Ltd.); Process for producing pyrrolidine deriv. and salt thereof. WO 9401400 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (XVI) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
| (XVII) | 15796 | methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate | C6H11NO3 | 详情 | 详情 | |
| (XVIII) | 15797 | 3-pyridinylmethyl methanesulfonate | C7H9NO3S | 详情 | 详情 | |
| (XIX) | 15798 | 3-Pyridinemethanol; 3-pyridinylmethanol | 100-55-0 | C6H7NO | 详情 | 详情 |
| (XX) | 15799 | methyl (2S,4R)-4-hydroxy-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H16N2O3 | 详情 | 详情 | |
| (XXI) | 15800 | methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C13H18N2O5S | 详情 | 详情 | |
| (XXII) | 15801 | methyl (2S,4S)-4-chloro-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H15ClN2O2 | 详情 | 详情 | |
| (XXIII) | 15802 | methyl (2S,4R)-4-azido-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H15N5O2 | 详情 | 详情 | |
| (XXIV) | 15803 | methyl (2S,4R)-4-amino-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H17N3O2 | 详情 | 详情 | |
| (XXV) | 15804 | methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C18H20ClN3O4S | 详情 | 详情 | |
| (XXVI) | 15805 | 4-chloro-N-[(3R,5S)-5-formyl-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-3-yl]benzenesulfonamide | C17H18ClN3O3S | 详情 | 详情 | |
| (XXVII) | 28718 | (4-carboxybutyl)(triphenyl)phosphonium chloride | C23H24ClO2P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)3) The cyclization of the previously described trans-4-(methanesulfonyloxy)-1-(3-pyridylmethyl)-L-prolinemethyl ester (XXI) with NaOH in acetonitrile gives the expected lactone (XXVIII), which by methanolysis with K2CO3 in methanol yields cis-4-hydroxy-1-(3-pyridylmethyl)-L-proline methyl ester (XXIX). The acylation of (XXIX) with 4-nitrophenylsulfonyl chloride (XXX) and triethylamine in dichloromethane affords the corresponding cis-sulfonyloxyproline derivative (XXXI), which is treated with the sodium salt of 4-chlorophenylsulfonamide (XXXII) in DMSO to give trans-4-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)-L-proline methyl ester (XXV) already obtained. The reduction of (XXV) with NaBH4 in THF yields the corresponding hydroxymethyl derivative (XXXIII), which is oxidized with SO3/pyridine to the previously described aldehyde (XXVI). 4) The condensation of the previously described cis-4-hydroxyproline derivative (XXIX) with N-(4-chlorophenylsulfonyl)carbamic acid methyl ester (XXXIV) by means of triphenylphosphine and diethyl azodicarboxylate (DEAD) in THF gives (2S,4R)-trans-4-[4-chloro-N-(methoxycarbonyl)phenylsulfonamido]-1-(3-pyridylmethyl)pyrrolidine-2-carboxylic acid methyl ester (XXXV), which is reduced with NaBH4 to the trans-hydroxymethyl derivative (XXXIII), already described.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Kamijo, T.; Hokari, H.; Hirata, K.; Yanagi, T.; Oda, Y. (Kissei Pharmaceutical Co., Ltd.); Novel pyrrolidine derivs. JP 1995291965 . |
| 【3】 Kamijo, T.; Hokari, H.; Hirata, K.; Yanagi, T.; Oda, Y. (Kissei Pharmaceutical Co., Ltd.); Novel pyrrolidine derivs. JP 1996012670 . |
| 【4】 Kamijo, T.; Hokari, H.; Hirata, K.; Yanagi, T.; Oda, Y. (Kissei Pharmaceutical Co., Ltd.); Manufacturing method of (5Z)-6-[(2S,4R)-4-(4-chlorophenylsulfonylamino)-1-(3-pyridylmethyl)-2-pyrrolidinyl-5-hexenoic acid and its intermediates. JP 1995291966 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 15800 | methyl (2S,4R)-4-[(methylsulfonyl)oxy]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C13H18N2O5S | 详情 | 详情 | |
| (XXV) | 15804 | methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C18H20ClN3O4S | 详情 | 详情 | |
| (XXVI) | 15805 | 4-chloro-N-[(3R,5S)-5-formyl-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-3-yl]benzenesulfonamide | C17H18ClN3O3S | 详情 | 详情 | |
| (XXVIII) | 15807 | (1S,4S)-5-(3-pyridinylmethyl)-2-oxa-5-azabicyclo[2.2.1]heptan-3-one | C11H12N2O2 | 详情 | 详情 | |
| (XXIX) | 15808 | methyl (2S,4S)-4-hydroxy-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C12H16N2O3 | 详情 | 详情 | |
| (XXX) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XXXI) | 15810 | methyl (2S,4S)-4-[[(4-nitrophenyl)sulfonyl]oxy]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C18H19N3O7S | 详情 | 详情 | |
| (XXXII) | 15811 | 4-Chlorobenzenesulfonamide sodium salt | C6H5ClNNaO2S | 详情 | 详情 | |
| (XXXIII) | 15812 | 4-chloro-N-[(3R,5S)-5-(hydroxymethyl)-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-3-yl]benzenesulfonamide | C17H20ClN3O3S | 详情 | 详情 | |
| (XXXIV) | 15813 | methyl N-[(4-chlorophenyl)sulfonyl]carbamate | C8H8ClNO4S | 详情 | 详情 | |
| (XXXV) | 15814 | methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl](methoxycarbonyl)amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrole-2-carboxylate | C20H22ClN3O6S | 详情 | 详情 |