【结 构 式】 |
【分子编号】32454 【品名】methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate 【CA登记号】 |
【 分 子 式 】C11H15NO3 【 分 子 量 】209.24504 【元素组成】C 63.14% H 7.23% N 6.69% O 22.94% |
合成路线1
该中间体在本合成路线中的序号:(III)The methylation of N-(tert-butoxycarbonyl)-L-tyrosine methyl ester (I) with methyl iodide and KOH gives the protected 4-O-methyl-L-tyrosine methyl ester (II), which is deprotected with TFA yielding (III). The Grundke oxidation of (III) affords the N-hydroxy derivative (IV), which is cyclocondensed with cyclohexane-1,4-dione monoethylene ketal (V) and ethyl acrylate (VI) in refluxing toluene to afford the spiroisoxazolidinone (VII). The reductive rearrangement of (VII) with H2 over Pd/C in acetic acid provides the spiropyrrolidinone (VIII), which is treated successively with tosyl chloride and with sodium azide to obtain the azido derivative (IX). The reduction of (IX) with H2 over Pd/C, protection of the resulting amine with Boc2O, and methylation of the resulting carbamate with NaH and methyl iodide affords the N-methylcarbamate (X). The reduction of the methoxycarbonyl group of (X) with LiBH4 in THF gives the carbinol (XI), which is oxidized with Dess-Martin periodinane to the aldehyde (XII). The rearrangement of (XII) by means of potassium tert-butoxide, followed by deprotection of the carbamate group yields the 7,10a-methanopyrrolo[1,2-a]azocin-8-one derivative (XIII), which is reduced at the carbonyl group with LiAlH4 in THF affords the 8(R)-hydroxy derivative (XIV). The protection of the amino group of (XIV) with benzyloxycarbonyl chloride and triethylamine yields the carbamate (XV).
【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 |
---|---|---|---|---|---|---|
10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 | |
(I) | 19875 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate | 4326-36-7 | C15H21NO5 | 详情 | 详情 |
(II) | 32453 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propanoate | C16H23NO5 | 详情 | 详情 | |
(III) | 32454 | methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 | |
(IV) | 32455 | methyl (2S)-2-(hydroxyamino)-3-(4-methoxyphenyl)propanoate | C11H15NO4 | 详情 | 详情 | |
(V) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
(VI) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
(VII) | 32456 | ethyl (3R)-1-[(1S)-2-methoxy-1-(4-methoxybenzyl)-2-oxoethyl]-2,9,12-trioxa-1-azadispiro[4.2.4.2]tetradecane-3-carboxylate | C24H33NO8 | 详情 | 详情 | |
(VIII) | 32457 | methyl (2S)-2-[(11R)-11-hydroxy-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C22H29NO7 | 详情 | 详情 | |
(IX) | 32458 | methyl (2S)-2-[(11S)-11-azido-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C22H28N4O6 | 详情 | 详情 | |
(X) | 32459 | methyl (2S)-2-[(11S)-11-[(tert-butoxycarbonyl)(methyl)amino]-10-oxo-1,4-dioxa-9-azadispiro[4.2.4.2]tetradec-9-yl]-3-(4-methoxyphenyl)propanoate | C28H40N2O8 | 详情 | 详情 | |
(XI) | 32460 | tert-butyl (3S)-1-[(1S)-2-hydroxy-1-(4-methoxybenzyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | C25H36N2O6 | 详情 | 详情 | |
(XII) | 32461 | tert-butyl (3S)-1-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]-2,8-dioxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | C25H34N2O6 | 详情 | 详情 | |
(XIII) | 32462 | (1S,3S,6S,7S,8S)-7-hydroxy-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecan-9-one | C20H28N2O3 | 详情 | 详情 | |
(XIV) | 32463 | (1S,3S,6S,7S,8R,9R)-6-(4-methoxybenzyl)-3-(methylamino)-5-azatricyclo[6.3.1.0(1,5)]dodecane-7,9-diol | C20H30N2O3 | 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 |
合成路线2
该中间体在本合成路线中的序号:(II)The condensation of protected tyrosinaldehyde (I) with 4-O-methyltyrosine methyl ester (II) by means of NaBH(OAc)3 gives the adduct (III), which is cyclized by means of Ph-I(OAc)2 to yield the spiro compound (IV). The 4-nitrophenylsulfonyl protecting group is eliminated with NaS-Ph in DMSO and substituted by Boc by means of Boc2O and pyridine to afford spiro compound (V). The reduction of the carbonyl and double bonds of (V) with H2 over Raney-Ni in ethanol/ethyl acetate provides the spirocyclohexanol derivative (VI), which is further reduced at the ester group by means of LiAlH4 in THF to give the carbinol (VII). The oxidation of (VII) with oxalyl chloride in DMSO/dichloromethane yields the keto aldehyde (VIII), which is cyclized by means of NaOMe in methanol to afford the tricyclic hydroxyketone (IX). The reduction of (IX) with H2 over Raney-Ni in ethanol/ethyl acetate affords the diol (X), which is selectively esterified with dibenzyl hydrogen phosphate (XI), DIAD, TEA and tris(4-chlorophenyl)phosphine in toluene to provide the phosphoric triester (XII). Finally, this compound is debenzylated with H2 over Pd/C in methanol and N-deprotected by means of HCl in dioxane to furnish the target FR-901483.
【1】 Scheffler, G.; et al.; An enantiospecific synthesis of the potent immunosuppressant FR901483. Angew Chem. Int Ed 2000, 39, 24, 4593. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VIa) | 53437 | methyl (2R)-2-{(3S)-3-[(tert-butoxycarbonyl)(methyl)amino]-8-hydroxy-1-azaspiro[4.5]dec-1-yl}-3-(4-methoxyphenyl)propanoate | n/a | C26H40N2O6 | 详情 | 详情 |
(VIb) | 53438 | methyl (2R)-2-{(3S)-3-[(tert-butoxycarbonyl)(methyl)amino]-8-hydroxy-1-azaspiro[4.5]dec-1-yl}-3-(4-methoxyphenyl)propanoate | n/a | C26H40N2O6 | 详情 | 详情 |
(VIIa) | 53439 | tert-butyl (3S)-8-hydroxy-1-[(1R)-2-hydroxy-1-(4-methoxybenzyl)ethyl]-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | n/a | C25H40N2O5 | 详情 | 详情 |
(VIIb) | 53440 | tert-butyl (3S)-8-hydroxy-1-[(1R)-2-hydroxy-1-(4-methoxybenzyl)ethyl]-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | n/a | C25H40N2O5 | 详情 | 详情 |
(I) | 53433 | N-[(1R)-1-formyl-2-(4-hydroxyphenyl)ethyl]-N-methyl-4-nitrobenzenesulfonamide | n/a | C16H16N2O6S | 详情 | 详情 |
(II) | 32454 | methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 | |
(III) | 53434 | methyl (2R)-2-[((2R)-3-(4-hydroxyphenyl)-2-{methyl[(4-nitrophenyl)sulfonyl]amino}propyl)amino]-3-(4-methoxyphenyl)propanoate | n/a | C27H31N3O8S | 详情 | 详情 |
(IV) | 53435 | methyl (2R)-3-(4-methoxyphenyl)-2-((3S)-3-{methyl[(4-nitrophenyl)sulfonyl]amino}-8-oxo-1-azaspiro[4.5]deca-6,9-dien-1-yl)propanoate | n/a | C27H29N3O8S | 详情 | 详情 |
(V) | 53436 | methyl (2R)-2-{(3S)-3-[(tert-butoxycarbonyl)(methyl)amino]-8-oxo-1-azaspiro[4.5]deca-6,9-dien-1-yl}-3-(4-methoxyphenyl)propanoate | n/a | C26H34N2O6 | 详情 | 详情 |
(VIII) | 53441 | tert-butyl (3S)-1-[(1R)-1-formyl-2-(4-methoxyphenyl)ethyl]-8-oxo-1-azaspiro[4.5]dec-3-yl(methyl)carbamate | n/a | C25H36N2O5 | 详情 | 详情 |
(IX) | 53442 | tert-butyl (1S,3S)-7-hydroxy-6-(4-methoxybenzyl)-9-oxo-5-azatricyclo[6.3.1.0~1,5~]dodec-3-yl(methyl)carbamate | n/a | C25H36N2O5 | 详情 | 详情 |
(X) | 53443 | tert-butyl (1S,3S)-7,9-dihydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.01,5]dodec-3-yl(methyl)carbamate | n/a | C25H38N2O5 | 详情 | 详情 |
(XI) | 53444 | Dibenzyl phosphate; Phosphoric acid dibenzyl ester | 1623-08-1 | C14H15O4P | 详情 | 详情 |
(XII) | 53445 | tert-butyl (1S,3S)-9-{[bis(benzyloxy)phosphoryl]oxy}-7-hydroxy-6-(4-methoxybenzyl)-5-azatricyclo[6.3.1.0~1,5~]dodec-3-yl(methyl)carbamate | n/a | C39H51N2O8P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(II)The title compound has been synthesized by two related methods. Coupling of N-Boc-L-methylhistidine (I) with D-4-methoxyphenylalanine methyl ester (II) employing EDC/HOBt affords the protected dipeptide (III). Subsequent saponification of the methyl ester (III) leads to carboxylic acid (IV). This is then coupled to 4-butyryl-4-phenylpiperidine (V) to furnish amide (VI). Finally, acidic cleavage of the N-Boc protecting group of (VI) provides the title compound.
【1】 Poindexter, G.S.; Ruediger, E.H.; Ruel, R.; Lawrence, R.M.; Yu, G.; Macor, J.; Morton, G.C.; Thibault, C.; Herpin, T. (Bristol-Myers Squibb Co.); Cpds. useful as modulators of melanocortin receptors and pharmaceutical compsns. comprising same. EP 1363631; EP 1363898; WO 0270511; WO 0279146 . |
【2】 Macor, J.E.; Carlson, K.E. (Bristol-Myers Squibb Co.); Co-administration of melanocortin receptor agonists and phosphodiesterase inhibitor for treatment of cyclic-AMP associated disorders. WO 0269905 . |
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) | 63382 | N-{[(1,1-dimethylethyl)oxy]carbonyl}-1-methylhistidine | C12H19N3O4 | 详情 | 详情 | |
(II) | 32454 | methyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate | C11H15NO3 | 详情 | 详情 | |
(III) | 63383 | methyl 2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(1-methyl-1H-imidazol-5-yl)propanoyl]amino}-3-[4-(methyloxy)phenyl]propanoate | C23H32N4O6 | 详情 | 详情 | |
(IV) | 63384 | N-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-(1-methyl-1H-imidazol-5-yl)propanoyl]-4-(methyloxy)phenylalanine | C22H30N4O6 | 详情 | 详情 | |
(V) | 63385 | 1-(4-phenyl-4-piperidinyl)-1-butanone | C15H21NO | 详情 | 详情 | |
(VI) | 63386 | 1,1-dimethylethyl 2-[(2-(4-butanoyl-4-phenyl-1-piperidinyl)-1-{[4-(methyloxy)phenyl]methyl}-2-oxoethyl)amino]-1-[(1-methyl-1H-imidazol-5-yl)methyl]-2-oxoethylcarbamate | C37H49N5O6 | 详情 | 详情 |