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【结 构 式】 
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【分子编号】15809 【品名】4-nitrobenzenesulfonyl chloride 【CA登记号】98-74-8 |
【 分 子 式 】C6H4ClNO4S 【 分 子 量 】221.6208 【元素组成】C 32.52% H 1.82% Cl 16% N 6.32% O 28.88% S 14.47% |
合成路线1
该中间体在本合成路线中的序号：(XXX)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 |
合成路线2
该中间体在本合成路线中的序号：The sulfonation of the 8(R)-hydroxy group of (XV) with 4-nitrophenylsulfonyl chloride, Et3N and DMAP provides the sulfonate (XVI), which is treated with Tes-OTf and Et3N in dichloromethane to protect the 6-hydroxy group yielding the silyl ether (XVII). The reaction of (XVII) with Cs-OAc and 18-crown-6 in hot benzene gives the 8(S)-acetoxy derivative (XVIII) with inversion of the configuration at the C(8). The reaction of (XVIII) with K2CO3 in methanol gives the corresponding 8(S)-hydroxy compound (XIX), which is treated with diisopropylaminophosphinic acid dibenzyl ester (XX) and tetrazole, and oxidized with tert-butyl hydroperoxide yielding the dibenzyl phosphate ester (XXI). The desilylation of (XXI) with tetrabutylammonium fluoride (TBAF) in THF affords the benzyl protected intermediate (XXII), which is finally debenzylated with H2 over Pd/C in methanol.
| 【1】 Snider, B.B.; et al.; Total synthesis of (-)-FR901483. J Am Chem Soc 1999, 121, 34, 7778. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 | |
| (XV) | 32464 | benzyl (1S,3S,6S,7S,8R,9R)-7,9-dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C28H36N2O5 | 详情 | 详情 | |
| (XVI) | 32465 | (1S,3S,6S,7S,8S,9R)-3-[[(benzyloxy)carbonyl](methyl)amino]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-9-yl 4-nitrobenzenesulfonate | C34H39N3O9S | 详情 | 详情 | |
| (XVII) | 32466 | (1S,3S,6S,7S,8S,9R)-3-[[(benzyloxy)carbonyl](methyl)amino]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-9-yl 4-nitrobenzenesulfonate | C40H53N3O9SSi | 详情 | 详情 | |
| (XVIII) | 32467 | (1S,3S,6S,7S,8R,9S)-3-[[(benzyloxy)carbonyl](methyl)amino]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-9-yl acetate | C36H52N2O6Si | 详情 | 详情 | |
| (XIX) | 32468 | benzyl (1S,3S,6S,7S,8R,9S)-9-hydroxy-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C34H50N2O5Si | 详情 | 详情 | |
| (XX) | 32469 | Diisopropylamidophosphoric acid dibenzyl ester | C20H28NO3P | 详情 | 详情 | |
| (XXI) | 32470 | benzyl (1S,3S,6S,7S,8S,9S)-9-[[bis(benzyloxy)phosphoryl]oxy]-6-(4-methoxybenzyl)-7-[(triethylsilyl)oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C48H63N2O8PSi | 详情 | 详情 | |
| (XXII) | 32471 | benzyl (1S,3S,6S,7S,8S,9S)-9-[[bis(benzyloxy)phosphoryl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-3-yl(methyl)carbamate | C42H49N2O8P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)The condensation of 2,2-dimethyl-1,3-dioxan-5-one (I) with aminoacetaldehyde dimethyl acetal (II) followed by acetylation with Ac2O/Et3N afforded the amido dioxin (III). Retro Diels-Alder reaction of dioxin (III) in warm benzonitrile generated the amidoacrolein (V), which was trapped in situ with the silyloxydiene (IV) to yield the cycloadduct (VI). Aldol cyclization between the acetamide and aldehyde functionalities of (VI) in the presence of t-BuOK produced the spiro lactam (VII). Subsequent aldol condensation between the acetal and silyl enolate functions of (VII) under acidic conditions furnished the tricyclic hydroxy ketone (VIII). Reduction of the keto group of (VIII) with NaBH(OAc)3 produced the C-4 axial alcohol (IX). Silylation of both hydroxyl groups of (IX) followed by selective cleavage of the C-2 silyl ether provided the C-4 mono silylated derivative (X). The free C-2 hydroxyl group of (X) was then oxidized to the corresponding ketone (XI) under Swern conditions. The potassium enolate of (XI) was stereoselectively alkylated with p-methoxybenzyl bromide (XII) to yield (XIII). Reduction of the keto group of (XIII) with Red-Al gave rise to the alcohol (XIV) in the undesired equatorial configuration. Inversion of the C-2 stereogenic center of (XIV) was achieved via formation of the sulfonate ester (XVI) with 4-nitrobenzenesulfonyl chloride (XV).
| 【1】 Maeng, J.-H.; Funk, R.L.; Total synthesis of the immunosuppressant FR901483 via an amidoacrolein cycloaddition. Org Lett 2001, 3, 8, 1125. |
| 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) | 46538 | 2,2-dimethyl-1,3-dioxan-5-one | C6H10O3 | 详情 | 详情 | |
| (II) | 34158 | aminoacetaldehyde dimethylacetal; 2,2-dimethoxy-1-ethanamine; 2,2-dimethoxyethylamine | 22483-09-6 | C4H11NO2 | 详情 | 详情 |
| (III) | 48300 | N-(2,2-dimethoxyethyl)-N-(2,2-dimethyl-4H-1,3-dioxin-5-yl)acetamide | C12H21NO5 | 详情 | 详情 | |
| (IV) | 48301 | triisopropyl[(1-methylene-2-propenyl)oxy]silane; 1-methylene-2-propenyl triisopropylsilyl ether | C13H26OSi | 详情 | 详情 | |
| (V) | 48302 | N-(2,2-dimethoxyethyl)-N-(1-formylvinyl)acetamide | C9H15NO4 | 详情 | 详情 | |
| (VI) | 48303 | N-(2,2-dimethoxyethyl)-N-[1-formyl-4-[(triisopropylsilyl)oxy]-3-cyclohexen-1-yl]acetamide | C22H41NO5Si | 详情 | 详情 | |
| (VII) | 48304 | 1-(2,2-dimethoxyethyl)-8-[(triisopropylsilyl)oxy]-1-azaspiro[4.5]deca-3,7-dien-2-one | C22H39NO4Si | 详情 | 详情 | |
| (VIII) | 48305 | (1S,7R,8R)-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,9-dione | C11H13NO3 | 详情 | 详情 | |
| (IX) | 48306 | (1S,7R,8S,9S)-7,9-dihydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C11H15NO3 | 详情 | 详情 | |
| (X) | 48307 | (1S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C17H29NO3Si | 详情 | 详情 | |
| (XI) | 48308 | (1S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione | C17H27NO3Si | 详情 | 详情 | |
| (XII) | 27490 | 1-(bromomethyl)-4-methoxybenzene | C8H9BrO | 详情 | 详情 | |
| (XIII) | 48309 | (1S,6S,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-ene-4,7-dione | C25H35NO4Si | 详情 | 详情 | |
| (XIV) | 48310 | (1S,6S,7R,8R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-4-one | C25H37NO4Si | 详情 | 详情 | |
| (XV) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XVI) | 48311 | (1S,6S,7R,8S,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-(4-methoxybenzyl)-4-oxo-5-azatricyclo[6.3.1.0(1,5)]dodec-2-en-7-yl 4-nitrobenzenesulfonate | C31H40N2O8SSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding the dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) (prepared by condensation of tetrahydrofuran-3(S)-ol (VIII) with phosgene and N-hydroxysuccinimide (IX)) and DIEA in acetonitrile to provide the corresponding carbamate (X). The deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide (XIII). Finally, the nitro group of (XIII) is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.
| 【1】 Tung, R.D.; Murcko, M.A.; Bhisetti, G.R. (Vertex Pharmaceuticals Inc.); Sulfonamide inhibitors of HIV-aspartyl protease. EP 0659181; EP 0885887; JP 1996501299; US 5585397; WO 9405639 . |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (II) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (III) | 44417 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | 160232-08-6 | C19H32N2O3 | 详情 | 详情 |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 44418 | benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(isobutyl)carbamate | C27H38N2O5 | 详情 | 详情 | |
| (VI) | 44419 | benzyl (2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(isobutyl)carbamate | C22H30N2O3 | 详情 | 详情 | |
| (VII) | 39664 | 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C9H11NO6 | 详情 | 详情 | |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (IX) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (X) | 44421 | benzyl (2R,3S)-2-hydroxy-4-phenyl-3-([[(3S)tetrahydro-3-furanyloxy]carbonyl]amino)butyl(isobutyl)carbamate | C27H36N2O6 | 详情 | 详情 | |
| (XI) | 44422 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | C19H30N2O4 | 详情 | 详情 | |
| (XII) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XIII) | 44423 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H33N3O8S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is condensed with 4-nitrophenylsulfonyl chloride (IV) and TEA in hot toluene to yield the sulfonamide (V). Deprotection of (V) with HCl hot toluene/water affords the primary amine (VI), which is condensed with imidazole-1-carboxylic acid 3(S)-tetrahydrofuryl ester (VII) [prepared by reaction of tetrahydrofuran-3(S)-ol (VIII) with carbonyldiimidazole (CDI) in ethyl acetate] to provide the corresponding carbamate (IX). Finally, the nitro group of (IX) is reduced with H2 over Pd/C in ethyl acetate to afford the target compound.
| 【1】 Deininger, D.D.; O'Callaghan, J.; McGuie, S.; Singh, H.; Robertson, M.S.; Rodgers, K.; Tung, R.D.; Al-Farhan, E.; Rout, S.J. (Glaxo Group Ltd.); Process for the synthesis of HIV protease inhibitors. WO 9948885 . |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (II) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (III) | 44417 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | 160232-08-6 | C19H32N2O3 | 详情 | 详情 |
| (IV) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (V) | 44938 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H35N3O7S | 详情 | 详情 | |
| (VI) | 44939 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-nitrobenzenesulfonamide | 590-90-9 | C20H27N3O5S | 详情 | 详情 |
| (VII) | 44940 | (3S)tetrahydro-3-furanyl 1H-imidazole-1-carboxylate | C8H10N2O3 | 详情 | 详情 | |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (IX) | 44423 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H33N3O8S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)The reaction of N,N-dibenzyl-L-alaninal (I) with nitromethane, catalyzed by the chiral ammonium salt (II) and KF in THF gives the chiral nitroalcohol (III), which is reduced with NiCl2 and NaBH4 to yield the aminoalcohol (IV). The condensation of (IV) with isobutyraldehyde (V) affords the Schiff base (VI), which is reduced with NaBH4 to provide the secondary amine (VII). The reaction of (VII) with 4-nitrobenzenesulfonyl chloride (VIII) and TEA in dichloromethane furnishes the sulfonamide (IX), which is deprotected by hydrogenation with H2 over Pd/C in methanol, giving the diamino compound (X). Finally, this compound is condensed with 3(S)-tetrahydrofuryl (N-oxysuccinimidyl) carbonate (XI) by means of TEA in dichloromethane to afford the target carbamate.
| 【1】 Corey, E.J.; Zhang, F.-Y.; Re- and si-face-selective nitroaldol reactions catalyzed by a rigid chiral quaternary ammonium salt: A highly stereoselective synthesis of the HIV protease inhibitor amprenavir (Vertex 478). Angew Chem. Int Ed Engl 1999, 38, 13-14, 1931. |
| 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) | 37936 | (2S)-2-(dibenzylamino)-3-phenylpropanal | C23H23NO | 详情 | 详情 | |
| (II) | 45528 | 1-(9-anthrylmethyl)-2-[(benzyloxy)(4-quinolinyl)methyl]-5-vinyl-1-azoniabicyclo[2.2.2]octane fluoride | C41H39FN2O | 详情 | 详情 | |
| (III) | 45529 | (2R,3S)-3-(dibenzylamino)-1-nitro-4-phenyl-2-butanol | C24H26N2O3 | 详情 | 详情 | |
| (IV) | 45530 | (2R,3S)-1-amino-3-(dibenzylamino)-4-phenyl-2-butanol | C24H28N2O | 详情 | 详情 | |
| (V) | 13226 | 2-Methylpropanal; Isobutyraldehyde | 78-84-2 | C4H8O | 详情 | 详情 |
| (VI) | 45531 | (2R,3S)-3-(dibenzylamino)-1-[[(E)-2-methylpropylidene]amino]-4-phenyl-2-butanol | C28H34N2O | 详情 | 详情 | |
| (VII) | 37940 | (2R,3S)-3-(dibenzylamino)-1-(isobutylamino)-4-phenyl-2-butanol | C28H36N2O | 详情 | 详情 | |
| (VIII) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (IX) | 45532 | N-[(2R,3S)-3-(dibenzylamino)-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-nitrobenzenesulfonamide | C34H39N3O5S | 详情 | 详情 | |
| (X) | 45533 | 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutylbenzenesulfonamide | C20H29N3O3S | 详情 | 详情 | |
| (XI) | 39664 | 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C9H11NO6 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)A mixture of cis and trans 4-hydroxycyclohexanecarboxylic acids (II), obtained by basic hydrolysis of the corresponding ethyl ester (I), was alkylated with pentamethylbenzyl chloride (III) in the presence of Et3N to afford pentamethylbenzyl ester (IV). Recrystallization from methylene chloride/hexane provided pure cis isomer, which was converted to 4-nitrobenzenesulfonate (VI) with p-nitrobenzenesulfonyl chloride (V) and Et3N. Subsequent displacement of the sulfonate group of (VI) for a 18F- provided the labeled intermediate (VII). Then, cleavage of the benzyl ester of (VII) with trifluoroacetic acid, followed by treatment with dichloromethyl methyl ether gave trans 4-18fluorocyclohexanecarbonyl chloride (VIII). This was finally coupled with amine (WAY-100634)(IX) in the presence of Et3N in CH2Cl2 to produce the target amide.
| 【1】 Mitchell, M.A.; Hendges, S.K.; Jacobsen, E.J.; et al.; Synthesis of a series of stromelysin-selective thiadiazole urea matrix metalloproteinase inhibitors. J Med Chem 1999, 42, 9, 1525. |
| 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) | 24656 | ethyl 4-hydroxycyclohexanecarboxylate | C9H16O3 | 详情 | 详情 | |
| (II) | 24657 | 4-hydroxycyclohexanecarboxylic acid | 17419-81-7 | C7H12O3 | 详情 | 详情 |
| (III) | 24649 | 1-(chloromethyl)-2,3,4,5,6-pentamethylbenzene | 484-65-1 | C12H17Cl | 详情 | 详情 |
| (IV) | 24659 | 2,3,4,5,6-pentamethylbenzyl 4-hydroxycyclohexanecarboxylate | C19H28O3 | 详情 | 详情 | |
| (V) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (VI) | 24661 | 2,3,4,5,6-pentamethylbenzyl 4-[[(4-nitrophenyl)sulfonyl]oxy]cyclohexanecarboxylate | C25H31NO7S | 详情 | 详情 | |
| (VII) | 24662 | 2,3,4,5,6-pentamethylbenzyl 4-fluorocyclohexanecarboxylate | C19H27FO2 | 详情 | 详情 | |
| (VII) | 45362 | 2,3,4,5,6-pentamethylbenzyl 4-fluorocyclohexanecarboxylate | C19H27FO2 | 详情 | 详情 | |
| (VIII) | 24663 | 4-fluorocyclohexanecarbonyl chloride | C7H10ClFO | 详情 | 详情 | |
| (VIII) | 45363 | 4-fluorocyclohexanecarbonyl chloride | C7H10ClFO | 详情 | 详情 | |
| (IX) | 24655 | N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-2-pyridinamine | C18H24N4O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XII)The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is protected with benzyl chloroformate (IV) and TEA, yielding dicarbamate (V). Selective deprotection of (V) with dry HCl in ethyl acetate affords the primary amine (VI), which is treated with 3(S)-tetrahydrofuryl N-succinimidinyl carbonate (VII) -- obtained by reaction of tetrahydrofuran-3(S)-ol (VIII) first with phosgene and then with N-hydroxysuccinimide (IX) -- and DIEA in acetonitrile to provide the corresponding carbamate (X). Deprotection of (X) by hydrogenation with H2 over Pd/C in ethanol gives the secondary amine (XI), which is condensed with 4-nitrophenylsulfonyl chloride (XII) by means of NaHCO3 in dichloromethane/water to yield the sulfonamide intermediate (XIII).
| 【1】 Martin, L.; Castaner, R.M.; Sorbera, L.A.; Castaner, J.; Fosamprenavir. Drugs Fut 2001, 26, 3, 224. |
| 【2】 Tung, R.D.; Murcko, M.A.; Bhisetti, G.R. (Vertex Pharmaceuticals Inc.); Sulfonamide inhibitors of HIV-aspartyl protease. EP 0659181; EP 0885887; JP 1996501299; US 5585397; WO 9405639 . |
| 【3】 Tung, R.D. (Vertex Pharmaceuticals Inc.); THF-containing sulfonamide inhibitors of aspartyl protease. EP 0846110; WO 9633184 . |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (II) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (III) | 44417 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | 160232-08-6 | C19H32N2O3 | 详情 | 详情 |
| (IV) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 44418 | benzyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl(isobutyl)carbamate | C27H38N2O5 | 详情 | 详情 | |
| (VI) | 44419 | benzyl (2R,3S)-3-amino-2-hydroxy-4-phenylbutyl(isobutyl)carbamate | C22H30N2O3 | 详情 | 详情 | |
| (VII) | 39664 | 1-([[(3S)tetrahydro-3-furanyloxy]carbonyl]oxy)-2,5-pyrrolidinedione | C9H11NO6 | 详情 | 详情 | |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (IX) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (X) | 44421 | benzyl (2R,3S)-2-hydroxy-4-phenyl-3-([[(3S)tetrahydro-3-furanyloxy]carbonyl]amino)butyl(isobutyl)carbamate | C27H36N2O6 | 详情 | 详情 | |
| (XI) | 44422 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | C19H30N2O4 | 详情 | 详情 | |
| (XII) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XIII) | 44423 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H33N3O8S | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XII)The reaction of the chiral epoxide (I) with isobutylamine (II) in refluxing ethanol gives the secondary amine (III), which is condensed with 4-nitrophenylsulfonyl chloride (XII) and TEA in hot toluene, yielding sulfonamide (XIV). Deprotection of (XIV) with HCl in hot toluene/water affords the primary amine (XV), which is condensed with imidazole-1-carboxylic acid 3(S)-tetrahydrofuryl ester (XVI) -- prepared by reaction of tetrahydrofuran-3(S)-ol (VIII) with carbonyldiimidazole (CDI) in ethyl acetate -- to provide intermediate (XIII).
| 【1】 Martin, L.; Castaner, R.M.; Sorbera, L.A.; Castaner, J.; Fosamprenavir. Drugs Fut 2001, 26, 3, 224. |
| 【2】 Deininger, D.D.; O'Callaghan, J.; McGuie, S.; Singh, H.; Robertson, M.S.; Rodgers, K.; Tung, R.D.; Al-Farhan, E.; Rout, S.J. (Glaxo Group Ltd.); Process for the synthesis of HIV protease inhibitors. WO 9948885 . |
| 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) | 19730 | tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate | 98737-29-2 | C15H21NO3 | 详情 | 详情 |
| (II) | 13306 | 2-Methyl-1-propanamine; Isobutylamine | 78-81-9 | C4H11N | 详情 | 详情 |
| (III) | 44417 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate | 160232-08-6 | C19H32N2O3 | 详情 | 详情 |
| (VIII) | 44420 | (3S)-tetrahydro-3-furanol; (S)-3-Hydroxytetrahydrofuran | 86087-23-2 | C4H8O2 | 详情 | 详情 |
| (XII) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XIII) | 44423 | (3S)tetrahydro-3-furanyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H33N3O8S | 详情 | 详情 | |
| (XIV) | 44938 | tert-butyl (1S,2R)-1-benzyl-2-hydroxy-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]propylcarbamate | C25H35N3O7S | 详情 | 详情 | |
| (XV) | 44939 | N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-isobutyl-4-nitrobenzenesulfonamide | 590-90-9 | C20H27N3O5S | 详情 | 详情 |
| (XVI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(X)The protection of the NH group of N-[3(S)-(dibenzylamino)-2(R)-hydroxy-4-phenylbutyl]-N-isobutylamine (I) with Boc2O and TEA in THF gives the carbamate (II), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol to yield the primary amine (III). The condensation of (III) with N-(benzyloxycarbonyl)-L-tert-leucine (IV) by means of EDC, HOBT and NMM in DMF affords the leucinamide (V), which is deprotected with H2 and Pd/C in methanol, providing the intermediate (VI). The acylation of the free amino group of (VI) with chloroacetyl chloride (VII) and KHCO3 in ethyl acetate/water gives the chloroacetamide (VIII), which is treated with HCl in ethyl acetate/dioxane in order to eliminate the Boc protecting group and yield the secondary amine (IX). The reaction of (IX) with 4-nitrophenylsulfonyl chloride (X) and K2CO3 in THF/water gives the sulfonamide (XI), which is treated with 3-fluorobenzylamine (XII) in refluxing THF to afford the glycyl-tert-leucyl derivative (XIII). Finally, the reduction of the nitro group of (XIII) with H2 over Pd/C in methanol provides the target 4-aminophenylsulfonamide.
| 【1】 Kaltenbach, R.F.; Trainor, G.L. (DuPont Pharmaceuticals Co.); Bis-amino acid sulfonamides containing N-terminally A substd. benzyl group as HIV protease inhibitors. EP 1140983; WO 0042060 . |
| 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) | 48825 | (2R,3S)-N(3),N(3)-dibenzyl-N(1)-isobutyl-2-methyl-4-phenyl-1,3-butanediamine; N,N-dibenzyl-N-[(1S,2R)-1-benzyl-3-(isobutylamino)-2-methylpropyl]amine | C29H38N2 | 详情 | 详情 | |
| (II) | 48826 | tert-butyl (2R,3S)-3-(dibenzylamino)-2-methyl-4-phenylbutyl(isobutyl)carbamate | C34H46N2O2 | 详情 | 详情 | |
| (III) | 48827 | tert-butyl (2R,3S)-3-amino-2-methyl-4-phenylbutyl(isobutyl)carbamate | C20H34N2O2 | 详情 | 详情 | |
| (IV) | 48828 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3,3-dimethylbutyric acid | C14H19NO4 | 详情 | 详情 | |
| (V) | 48829 | benzyl (1S)-1-[([(1S,2R)-1-benzyl-3-[(tert-butoxycarbonyl)(isobutyl)amino]-2-methylpropyl]amino)carbonyl]-2,2-dimethylpropylcarbamate | C34H51N3O5 | 详情 | 详情 | |
| (VI) | 48830 | tert-butyl (2R,3S)-3-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-2-methyl-4-phenylbutyl(isobutyl)carbamate | C26H45N3O3 | 详情 | 详情 | |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 48831 | tert-butyl (2R,3S)-3-([(2S)-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanoyl]amino)-2-methyl-4-phenylbutyl(isobutyl)carbamate | C28H46ClN3O4 | 详情 | 详情 | |
| (IX) | 48832 | (2S)-N-[(1S,2R)-1-benzyl-3-(isobutylamino)-2-methylpropyl]-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanamide | C23H38ClN3O2 | 详情 | 详情 | |
| (X) | 15809 | 4-nitrobenzenesulfonyl chloride | 98-74-8 | C6H4ClNO4S | 详情 | 详情 |
| (XI) | 48836 | (2S)-N-((1S,2R)-1-benzyl-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]-2-methylpropyl)-2-[(2-chloroacetyl)amino]-3,3-dimethylbutanamide | C29H41ClN4O6S | 详情 | 详情 | |
| (XII) | 48834 | 3-Fluorobenzylamine | 100-82-3 | C7H8FN | 详情 | 详情 |
| (XIII) | 48837 | (2S)-N-((1S,2R)-1-benzyl-3-[isobutyl[(4-nitrophenyl)sulfonyl]amino]-2-methylpropyl)-2-([2-[(3-fluorobenzyl)amino]acetyl]amino)-3,3-dimethylbutanamide | C36H48FN5O6S | 详情 | 详情 |