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【结 构 式】 
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【分子编号】22189 【品名】(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid 【CA登记号】147577-61-5 |
【 分 子 式 】C19H23NO4 【 分 子 量 】329.39596 【元素组成】C 69.28% H 7.04% N 4.25% O 19.43% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Methylation of N-Boc-D-phenylalanine (VIII) with methyl iodide and NaH afforded the N-methyl amino acid (IX). After coupling with methylamine in the presence of EDC and HOBt, the Boc protecting group of the resulting amide (X) was removed by treatment with trifluoroacetic acid to give (XI). The N-methyl amino acid (XIII), prepared by methylation of N-Boc-naphthylalanine (XII), was then coupled to amine (XI) by means of EDC and HOAt to yield dipeptide amide (XIV). A further treatment of (XIV) with trifluoroacetic acid removed the Boc protecting group to yield (XV), which was then coupled with amino acid (VII) in the presence of EDC and HOAt yielding (XVI). Finally, deprotection of the Boc-tripeptide (XVI) with trifluoroacetic acid provided the title compound.
| 【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
| (VIII) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (IX) | 22185 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid | 37553-65-4 | C15H21NO4 | 详情 | 详情 |
| (X) | 27231 | tert-butyl (1R)-1-benzyl-2-(methylamino)-2-oxoethyl(methyl)carbamate | C16H24N2O3 | 详情 | 详情 | |
| (XI) | 27232 | (2R)-N-methyl-2-(methylamino)-3-phenylpropanamide | C11H16N2O | 详情 | 详情 | |
| (XII) | 23498 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid | C18H21NO4 | 详情 | 详情 | |
| (XIII) | 22189 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid | 147577-61-5 | C19H23NO4 | 详情 | 详情 |
| (XIV) | 27233 | tert-butyl (1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl(methyl)carbamate | C30H37N3O4 | 详情 | 详情 | |
| (XV) | 27234 | (2R)-N-[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide | C25H29N3O2 | 详情 | 详情 | |
| (XVI) | 27235 | tert-butyl (E)-5-[[(1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate | C37H48N4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)N-Boc-N-Methyl-D-phenylalaninol (I) was oxidized to aldehyde (II) using SO3-pyridine complex. Reductive amination of (II) with benzylamine to yield (III), followed by hydrogenolytic debenzylation then furnished the monoprotected diamine (IV). This was condensed with methanesulfonyl chloride to yield sulfonamide (V). After deprotection of the Boc group of (V) with trifluoroacetic acid, amine (VI) was coupled with N-Boc-N-methyl-D-naphthylalanine (VII) using EDC and HOAt. The resulting amide (VIII) was further deprotected with trifluoroacetic acid, and then coupled with 5-(tert-butoxycarbonyl)amino-5-methyl-2-hexenoic acid (IX) to yield (X). Finally, acid deprotection of the Boc group of (X) furnished the target compound.
| 【1】 Hansen, B.S.; Peschke, B.; New growth hormone secretagogues: C-terminal modified sulfonamide-analogues of NN703. Bioorg Med Chem Lett 1999, 9, 9, 1295. |
| 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) | 25300 | tert-butyl (1R)-1-benzyl-2-hydroxyethyl(methyl)carbamate | C15H23NO3 | 详情 | 详情 | |
| (II) | 25301 | tert-butyl (1R)-1-benzyl-2-oxoethyl(methyl)carbamate | C15H21NO3 | 详情 | 详情 | |
| (III) | 25302 | tert-butyl (1R)-1-benzyl-2-(benzylamino)ethyl(methyl)carbamate | C22H30N2O2 | 详情 | 详情 | |
| (IV) | 25303 | tert-butyl (1R)-2-amino-1-benzylethyl(methyl)carbamate | C15H24N2O2 | 详情 | 详情 | |
| (V) | 25304 | tert-butyl (1R)-1-benzyl-2-[(methylsulfonyl)amino]ethyl(methyl)carbamate | C16H26N2O4S | 详情 | 详情 | |
| (VI) | 25305 | N-[(2R)-2-(methylamino)-3-phenylpropyl]methanesulfonamide | C11H18N2O2S | 详情 | 详情 | |
| (VII) | 22189 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid | 147577-61-5 | C19H23NO4 | 详情 | 详情 |
| (VIII) | 25306 | tert-butyl (1R)-2-[[(1R)-1-benzyl-2-[(methylsulfonyl)amino]ethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl(methyl)carbamate | C30H39N3O5S | 详情 | 详情 | |
| (IX) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
| (X) | 25307 | tert-butyl (E,7R,10R)-10-benzyl-1,1,6,9-tetramethyl-7-(2-naphthylmethyl)-5,8,13,13-tetraoxo-13lambda(6)-thia-6,9,12-triaza-3-tetradecen-1-ylcarbamate | C37H50N4O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Amino acid (II) (obtained by N-alkylation of N-Boc-D-phenylalanine (I) with MeI), was coupled to (S)-1-amino-2-propanol (III) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-HCl (EDC) and 1-hydroxybenzotriazole to give amide (IV). The N-Boc group of (IV) was then deprotected with trifluoroacetic acid in CH2Cl2 to afford (V). Further coupling of (V) with D-naphthylalanine derivative (VI), followed by Boc deprotection with trifluoroacetic acid, provided dipeptide amide (VII). This dipeptide was coupled to intermediate amino acid (VIII) using EDC and 1-hydroxy-7-azabenzotriazole yielding tripeptide (IX). Finally, trifluoroacetic acid-promoted Boc-deprotection of (IX) provided the target compound. Intermediate amino acid (VIII) was prepared from 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (X) upon conversion to the mixed anhydride with ethyl chloroformate, followed by reduction to alcohol (XI) with LiBH4. Subsequent Swern oxidation of the alcohol (XI) furnished aldehyde (XII). This was condensed with triethyl phosphonoacetate, and then saponified with LiOH to produce the intermediate (VIII).
| 【1】 Hansen, T.K.; Ankersen, M.; Hansen, B.S.; Raun, K.; Nielsen, K.K.; Lau, J.; Peschke, B.; Lundt, B.F.; Thogersen, H.; Johansen, N.L.; Madsen, K.; Andersen, P.H.; Novel orally active growth hormone secretagogues. J Med Chem 1998, 41, 19, 3705. |
| 【2】 Eriksen, E.F.; Kappelgaard, A.-M. (Novo Nordisk A/S); Growth hormone component and bone anti-resorptive agent in cyclic (coherence) treatment of osteoporosis. WO 9746252 . |
| 【3】 Hansen, T.K.; Peschke, B.; Lau, J.; Lundt, B.F.; Ankersen, M.; Watson, B.; Madsen, K. (Novo Nordisk A/S); Cpds. with growth hormone releasing properties. JP 1999209336; JP 1999501054; JP 2000143613; US 6127391; WO 9723508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 | |
| (I) | 22184 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropionic acid | C14H19NO4 | 详情 | 详情 | |
| (II) | 22185 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid | 37553-65-4 | C15H21NO4 | 详情 | 详情 |
| (III) | 22186 | (S)-(+)-1-Amino-2-propanol; (2S)-1-amino-2-propanol | 2799-17-9 | C3H9NO | 详情 | 详情 |
| (IV) | 22187 | tert-butyl (1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl(methyl)carbamate | C18H28N2O4 | 详情 | 详情 | |
| (V) | 22188 | (2R)-N-[(2S)-2-hydroxypropyl]-2-(methylamino)-3-phenylpropanamide | C13H20N2O2 | 详情 | 详情 | |
| (VI) | 22189 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid | 147577-61-5 | C19H23NO4 | 详情 | 详情 |
| (VII) | 22190 | (2R)-N-((1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide | C27H33N3O3 | 详情 | 详情 | |
| (VIII) | 22191 | (E)-5-[(tert-butoxycarbonyl)amino]-5-methyl-2-hexenoic acid | C12H21NO4 | 详情 | 详情 | |
| (IX) | 22192 | tert-butyl (E)-5-[[(1R)-2-[((1R)-1-benzyl-2-[[(2S)-2-hydroxypropyl]amino]-2-oxoethyl)(methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl](methyl)amino]-1,1-dimethyl-5-oxo-3-pentenylcarbamate | C39H52N4O6 | 详情 | 详情 | |
| (X) | 22193 | 3-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XI) | 22194 | tert-butyl 3-hydroxy-1,1-dimethylpropylcarbamate | C10H21NO3 | 详情 | 详情 | |
| (XII) | 22195 | tert-butyl 1,1-dimethyl-3-oxopropylcarbamate | C10H19NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XI)The condensation of N-Boc-N-methyl-D-phenylalanine (VIII) with methylamine by means of EDC and HOBt gave the corresponding amide (IX). After acid deprotection of the Boc group of (IX), the resulting amino compound (X) was coupled with N-Boc-N-methyl-D-naphthylalanine (XI) using EDC and HOAt to provide dipeptide (XII). The Boc protecting group of (XII) was further cleaved with trifluoroacetic acid to give (XIII).
| 【1】 Hansen, T.K.; Peschke, B.; Lau, J.; Lundt, B.F.; Ankersen, M.; Watson, B.; Madsen, K. (Novo Nordisk A/S); Cpds. with growth hormone releasing properties. JP 1999209336; JP 1999501054; JP 2000143613; US 6127391; WO 9723508 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 | |
| (VIII) | 22185 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-phenylpropionic acid | 37553-65-4 | C15H21NO4 | 详情 | 详情 |
| (IX) | 27231 | tert-butyl (1R)-1-benzyl-2-(methylamino)-2-oxoethyl(methyl)carbamate | C16H24N2O3 | 详情 | 详情 | |
| (X) | 27232 | (2R)-N-methyl-2-(methylamino)-3-phenylpropanamide | C11H16N2O | 详情 | 详情 | |
| (XI) | 22189 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2-naphthyl)propionic acid | 147577-61-5 | C19H23NO4 | 详情 | 详情 |
| (XII) | 27233 | tert-butyl (1R)-2-[[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl](methyl)amino]-1-(2-naphthylmethyl)-2-oxoethyl(methyl)carbamate | C30H37N3O4 | 详情 | 详情 | |
| (XIII) | 27234 | (2R)-N-[(1R)-1-benzyl-2-(methylamino)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propanamide | C25H29N3O2 | 详情 | 详情 |