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【结 构 式】 
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【分子编号】48834 【品名】3-Fluorobenzylamine 【CA登记号】100-82-3 |
【 分 子 式 】C7H8FN 【 分 子 量 】125.1456632 【元素组成】C 67.18% H 6.44% F 15.18% N 11.19% |
合成路线1
该中间体在本合成路线中的序号：(IV)The alkylation of 4,4'-dihydroxybiphenyl (I) with ethyl bromoacetate (II) in the presence of sodium methoxide afforded the (biphenylyloxy)acetate (III). Heating of ester (III) with m-fluorobenzylamine (IV) at 85 C produced amide (V), which was subsequently reduced to amine (VI) by means of borane, generated in situ from NaBH4 and BF3. Finally, condensation of the secondary amine (VI) with methyl isocyanate gave rise to the title urea derivative.
| 【1】 Fex, T.; Asp, B.; Stamvik, A.; Carlsson, J.-I.; Billstrom, A. (Pharmacia AB); Novel antitumour cpds. with antimitotic activity. WO 9529155 . |
| 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) | 55986 | 4,4'-Biphenol; 4,4'-Dihydroxybiphenyl; 4,4'-Dihydroxydiphenyl; 4,4'-Diphenol | 92-88-6 | C12H10O2 | 详情 | 详情 |
| (II) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (III) | 55987 | ethyl 2-[(4'-hydroxy[1,1'-biphenyl]-4-yl)oxy]acetate | C16H16O4 | 详情 | 详情 | |
| (IV) | 48834 | 3-Fluorobenzylamine | 100-82-3 | C7H8FN | 详情 | 详情 |
| (V) | 55990 | N-(3-fluorobenzyl)-2-[(4'-hydroxy[1,1'-biphenyl]-4-yl)oxy]acetamide | C21H18FNO3 | 详情 | 详情 | |
| (VI) | 55991 | 4'-{2-[(3-fluorobenzyl)amino]ethoxy}[1,1'-biphenyl]-4-ol | C21H20FNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)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3
该中间体在本合成路线中的序号：(XII)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 |