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【结 构 式】 
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【药物名称】KDI-792, FR-121070, FK-070 【化学名称】6-[4(R)-(4-Chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid monohydrochloride 【CA登记号】130047-30-2, 130047-27-7 (free base) 【 分 子 式 】C22H27Cl2N3O4S 【 分 子 量 】500.44819 |
【开发单位】Fujisawa (Originator), Kissei (Licensee) 【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Prostanoid TP (Thromboxane A2) Antagonists, Thromboxane Synthase Inhibitors |
合成路线1
1) The mesylation of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (I) with mesyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (II), which is treated with sodium benzoate in DMSO yielding the (2S,4S)-benzoate (III). The hydrolysis of (III) with K2CO3 in methanol affords (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (IV), which is mesylated with mesyl chloride and triethylamine as before giving the mesylate (V). The reaction of (V) with sodium azide in DMSO yields the corresponding (2S,4R)-azide (VI), which is reduced with H2 over Pd/C in methanol affording (2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid methyl ester (VII). The acylation of (VII) with 4-chlorobenzenesulfonyl chloride (VIII) and triethylamine in dichloromethane gives the corresponding amide (IX), which is reduced with diisobutylaluminum hydride (DIBAL) in toluene/THF yielding the aldehyde (X). The Wittig condensation of aldehyde (X) with (4-carboxybutyl)triphenylphosphonium bromide (XI) by means of lithium bis(trimethylsilyl)amide (LBSA) in HMPT affords 6-[1-(tert-butoxycarbonyl)-4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid (XII), which is esterified and deprotected with methanol/HCl to give 6-[4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XIII). The condensation of (XIII) with 3-(chloromethyl)pyridine (XIV) and triethylamine in refluxing THF yields 6-[4(R)-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XV), which is finally hydrolyzed with NaOH in methanol/water.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Setoi, H.; Sawada, A.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrrolidine derivs. AU 8943753; EP 0367130; JP 1990152960; US 5130323; US 5264453; US 5514701 . |
| 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) | 15780 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (II) | 15781 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (III) | 15782 | 1-(tert-butyl) 2-methyl (2S,4S)-4-(benzoyloxy)tetrahydro-1H-pyrrole-1,2-dicarboxylate | C18H23NO6 | 详情 | 详情 | |
| (IV) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (V) | 15784 | 1-(tert-butyl) 2-methyl (2S,4S)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (VI) | 15785 | 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (VII) | 15786 | 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VIII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IX) | 15788 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C17H23ClN2O6S | 详情 | 详情 | |
| (X) | 15789 | tert-butyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-2-formyltetrahydro-1H-pyrrole-1-carboxylate | C16H21ClN2O5S | 详情 | 详情 | |
| (XI) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XII) | 15791 | (Z)-6-((2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoic acid | C21H29ClN2O6S | 详情 | 详情 | |
| (XIII) | 15792 | methyl (Z)-6-((2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoate | C17H23ClN2O4S | 详情 | 详情 | |
| (XIV) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XV) | 15794 | methyl (Z)-6-[(2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-2-yl]-5-hexenoate | C23H28ClN3O4S | 详情 | 详情 |
合成路线2
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3
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 |