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【结 构 式】 
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【分子编号】18652 【品名】(2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid 【CA登记号】7432-21-5 |
【 分 子 式 】C19H18N2O4 【 分 子 量 】338.363 【元素组成】C 67.45% H 5.36% N 8.28% O 18.91% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Alternatively, N-(benzyloxycarbonyl)-L-Trp (VIII) was condensed with N,O-dimethylhydroxylamine in the presence of EDC and HOBt to give N-(methoxy)amide (IX). Hydrogenolytic deprotection produced amine (X), which was coupled with Z-Ile (III) to afford dipeptide (XI). Subsequent deprotection, and coupling of the resulting amine (XII) with sulfonyl chloride (VI) gave sulfonamide (XIII). Then, reduction of the N-(methoxy)amide with diisobutylaluminum hydride furnished the target aldehyde
| 【1】 Yasuma, T.; Oi, S.; Choh, N.; Nomura, T.; Furuyama, N.; Nishimura, A.; Fujisawa, Y.; Sohda, T.; Synthesis of peptide aldehyde derivatives as selective inhibitors of human cathepsin L and their inhibitory effect on bone resorption. J Med Chem 1998, 41, 22, 4301. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 23508 | (2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid | 3160-59-6 | C14H19NO4 | 详情 | 详情 |
| (VI) | 18650 | 1-naphthalenesulfonyl chloride | 85-46-1 | C10H7ClO2S | 详情 | 详情 |
| (VIII) | 18652 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid | 7432-21-5 | C19H18N2O4 | 详情 | 详情 |
| (IX) | 18653 | benzyl (1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethylcarbamate | C21H23N3O4 | 详情 | 详情 | |
| (X) | 18654 | (2S)-2-amino-3-(1H-indol-3-yl)-N-methoxy-N-methylpropanamide | C13H17N3O2 | 详情 | 详情 | |
| (XI) | 18655 | benzyl (1S,2S)-1-[([(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]amino)carbonyl]-2-methylbutylcarbamate | C27H34N4O5 | 详情 | 详情 | |
| (XII) | 18656 | (2S,3S)-2-amino-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]-3-methylpentanamide | C19H28N4O3 | 详情 | 详情 | |
| (XIII) | 18657 | (2S,3S)-N-[(1S)-1-(1H-indol-3-ylmethyl)-2-[methoxy(methyl)amino]-2-oxoethyl]-3-methyl-2-[(1-naphthylsulfonyl)amino]pentanamide | C29H34N4O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The racemic 4-methoxytryptophan amide (I) is resolved using immobilized Penicillin G acylase, to afford the desired L-aminoacid (III), while leaving unaltered the enantiomeric D-amide (II). After protection of aminoacid (III) as the N-benzyloxycarbonyl derivative (IV), coupling with glycine methyl ester (V) gives dipeptide (VI). Hydrogenolysis of the benzyloxycarbonyl protecting group of (VI) yields amine (VII), which is then coupled with N-Cbz-L-tryptophan (VIII) to produce the protected tripeptide (IX). Hydrogenolysis of (IX) in the presence of Pd/C provides the tripeptide building block (X).
| 【1】 Ley, S.V.; et al.; Total synthesis of the cyclic heptapeptide argyrin B: A new potent inhibitor of T-cell independent antibody formation. Org Lett 2002, 4, 5, 711. |
| 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) | 58827 | 4-methoxy-N-(2-phenylacetyl)tryptophan | C20H20N2O4 | 详情 | 详情 | |
| (II) | 58828 | (2R)-3-(4-methoxy-1H-indol-3-yl)-2-[(2-phenylacetyl)amino]propanoic acid | C20H20N2O4 | 详情 | 详情 | |
| (III) | 58829 | (2S)-2-amino-3-(4-methoxy-1H-indol-3-yl)propanoic acid | C12H14N2O3 | 详情 | 详情 | |
| (IV) | 58830 | (2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoic acid | C20H20N2O5 | 详情 | 详情 | |
| (V) | 17568 | methyl 2-aminoacetate | C3H7NO2 | 详情 | 详情 | |
| (VI) | 58831 | methyl 2-{[(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C23H25N3O6 | 详情 | 详情 | |
| (VII) | 58832 | methyl 2-{[(2S)-2-amino-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C15H19N3O4 | 详情 | 详情 | |
| (VIII) | 18652 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid | 7432-21-5 | C19H18N2O4 | 详情 | 详情 |
| (IX) | 58833 | methyl (5S,8S)-5-(1H-indol-3-ylmethyl)-8-[(4-methoxy-1H-indol-3-yl)methyl]-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oate | C34H35N5O7 | 详情 | 详情 | |
| (X) | 58834 | methyl 2-{[(2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate | C26H29N5O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Esterification of N-benzyloxycarbonyl-(R)-tryptophan (I) with allyl alcohol (II) using DCC gave ester (III). The cyclization of (III) to afford diastereoselectively the pyrroloindole derivative (IV) was achieved in trifluoroacetic acid as the solvent. A second N-benzyloxycarbonyl protecting group was then introduced at the indoline nitrogen of (IV), yielding (V). Mannich reaction of the lithium anion of (V) with Eschenmoser's salt provided the (dimethylamino)methyl compound (VI). Ring opening of (VI) to the indole (VII) was performed with sulfuric acid in aqueous methanol. The allyl ester of (VII) was then removed by means of morpholine and palladium catalyst to produce acid (VIII), which was coupled with (S)-alpha-methylbenzylamine (IX) to give amide (X). After hydrogenolysis of the two benzyloxycarbonyl protecting groups of (X), the free amine (XI) was acylated with 2-benzofuranylmethyl chloroformate to furnish the title carbamate.
| 【1】 Ashwood, V.A.; et al.; Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK1 receptor antagonist. J Med Chem 2001, 44, 14, 2276. |
| 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) | 18652 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid | 7432-21-5 | C19H18N2O4 | 详情 | 详情 |
| (II) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (III) | 51359 | allyl (2R)-2-[[(benzyloxy)carbonyl]amino]-3-(1H-indol-3-yl)propanoate | C22H22N2O4 | 详情 | 详情 | |
| (IV) | 51360 | 2-allyl 1-benzyl (2R,3aS,8aS)-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate | C22H22N2O4 | 详情 | 详情 | |
| (V) | 51361 | 2-allyl 1,8-dibenzyl (2R,3aS,8aR)-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate | C30H28N2O6 | 详情 | 详情 | |
| (VI) | 51362 | 2-allyl 1,8-dibenzyl (2S,3aS,8aS)-2-[(dimethylamino)methyl]-2,3,3a,8a-tetrahydropyrrolo[2,3-b]indole-1,2,8-tricarboxylate | C33H35N3O6 | 详情 | 详情 | |
| (VII) | 51363 | benzyl 3-[(2S)-3-(allyloxy)-2-[[(benzyloxy)carbonyl]amino]-2-[(dimethylamino)methyl]-3-oxopropyl]-1H-indole-1-carboxylate | C33H35N3O6 | 详情 | 详情 | |
| (VIII) | 51364 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[1-[(benzyloxy)carbonyl]-1H-indol-3-yl]-2-[(dimethylamino)methyl]propionic acid | C30H31N3O6 | 详情 | 详情 | |
| (IX) | 20042 | (1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine | C8H11N | 详情 | 详情 | |
| (X) | 51365 | benzyl 3-((2S)-2-[[(benzyloxy)carbonyl]amino]-2-[(dimethylamino)methyl]-3-oxo-3-[[(1S)-1-phenylethyl]amino]propyl)-1H-indole-1-carboxylate | C38H40N4O5 | 详情 | 详情 | |
| (XI) | 51367 | (2S)-2-amino-3-(dimethylamino)-2-(1H-indol-3-ylmethyl)-N-[(1S)-1-phenylethyl]propanamide | C22H28N4O | 详情 | 详情 | |
| (XII) | 51366 | 2-[[(chlorocarbonyl)oxy]methyl]-1-benzofuran | C10H7ClO3 | 详情 | 详情 |