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【结 构 式】 
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【分子编号】48828 【品名】(2S)-2-[[(benzyloxy)carbonyl]amino]-3,3-dimethylbutyric acid 【CA登记号】 |
【 分 子 式 】C14H19NO4 【 分 子 量 】265.3092 【元素组成】C 63.38% H 7.22% N 5.28% O 24.12% |
合成路线1
该中间体在本合成路线中的序号：(IV)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 3-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 3-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) | 41948 | 3-nitrobenzenesulfonyl chloride | 121-51-7 | C6H4ClNO4S | 详情 | 详情 |
| (XI) | 48833 | (2S)-N-((1S,2R)-1-benzyl-3-[isobutyl[(3-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) | 48835 | (2S)-N-((1S,2R)-1-benzyl-3-[isobutyl[(3-nitrophenyl)sulfonyl]amino]-2-methylpropyl)-2-([2-[(3-fluorobenzyl)amino]acetyl]amino)-3,3-dimethylbutanamide | C36H48FN5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |