|
【结 构 式】 
|
【分子编号】15273 【品名】(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propionic acid 【CA登记号】 |
【 分 子 式 】C14H19NO6 【 分 子 量 】297.308 【元素组成】C 56.56% H 6.44% N 4.71% O 32.29% |
合成路线1
该中间体在本合成路线中的序号：(VI)The chiral synthesis of CL 316,243 is described: The chiral epoxide (IV) was prepared in a three-step procedure starting from 3-chloroacetophenone. Monochlorination followed by asymmetric reduction gave the chiral chlorohydrin (III), which was treated with base to give the epoxide. The chiral amine was prepared in a six step sequence starting from L-DOPA. Protection of the amine followed by permethylation and ester reduction gave the alcohol (VIII). Conversion to the mesylate followed by catalytic hydrogenation gave enantiomerically pure amine (X). Reaction of the epoxide (IV) with the amine (X) gave the phenethanolamine (XI). Protection as the oxazolidinone (XII) followed by demethylation and subsequent malonation with diethyl dibromomalonate yielded the protected diester (XIV). Basic hydrolysis followed by reverse phase chromatography gave CL 316,243.
| 【1】 Bloom, J.D.; Claus, T.H.; CL 316,243. Drugs Fut 1994, 19, 1, 23. |
| 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) | 15268 | m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone | 99-02-5 | C8H7ClO | 详情 | 详情 |
| (II) | 15269 | 2-chloro-1-(3-chlorophenyl)-1-ethanone | C8H6Cl2O | 详情 | 详情 | |
| (III) | 15270 | (1R)-2-chloro-1-(3-chlorophenyl)-1-ethanol | C8H8Cl2O | 详情 | 详情 | |
| (IV) | 15271 | (R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane | 62600-71-9 | C8H7ClO | 详情 | 详情 |
| (V) | 15272 | (2S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid; 3-hydroxy-L-tyrosine; Levodopa | 59-92-7 | C9H11NO4 | 详情 | 详情 |
| (VI) | 15273 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propionic acid | C14H19NO6 | 详情 | 详情 | |
| (VII) | 15274 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dimethoxyphenyl)propanoate | C17H25NO6 | 详情 | 详情 | |
| (VIII) | 15275 | tert-butyl N-[(1S)-1-(3,4-dimethoxybenzyl)-2-hydroxyethyl]carbamate | C16H25NO5 | 详情 | 详情 | |
| (IX) | 15276 | tert-butyl N-((1S)-1-(3,4-dimethoxybenzyl)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)carbamate | C19H31NO5S | 详情 | 详情 | |
| (X) | 15277 | (1R)-2-(3,4-dimethoxyphenyl)-1-methylethylamine; (2R)-1-(3,4-dimethoxyphenyl)-2-propanamine | C11H17NO2 | 详情 | 详情 | |
| (XI) | 15278 | (1R)-1-(3-chlorophenyl)-2-[[(1R)-2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-1-ethanol | C19H24ClNO3 | 详情 | 详情 | |
| (XII) | 15279 | (5R)-5-(3-chlorophenyl)-3-[(1R)-2-(3,4-dimethoxyphenyl)-1-methylethyl]-1,3-oxazolan-2-one | C20H22ClNO4 | 详情 | 详情 | |
| (XIII) | 15280 | (5R)-5-(3-chlorophenyl)-3-[(1R)-2-(3,4-dihydroxyphenyl)-1-methylethyl]-1,3-oxazolan-2-one | C18H18ClNO4 | 详情 | 详情 | |
| (XIV) | 15281 | diethyl 5-[(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxo-1,3-oxazolan-3-yl]propyl]-1,3-benzodioxole-2,2-dicarboxylate | C25H26ClNO8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)N-Protection of L-Dopa (I) by means of Boc2O and Et3N in H2O-dioxane yields Boc derivative (II), which is then benzylated by reaction with benzyl bromide (III) and K2CO3 in refluxing acetone to provide (IV). Benzyl ester moiety of (IV) is saponified by treatment with NaOH in H2O-dioxane to give carboxylic acid (V), and deprotection of the amino group by means of TFA in CH2Cl2 furnishes trifluoroacetate salt (VI). Acylation of the amine group of (VI) with chloroacetyl chloride (VII) in NaOH yields N-chloroacetyl derivative (VIII), which is cyclized by heating in DMF in the presence of Et3N to afford morpholinedione (IX). Hydrogenation of (IX) over Pd/C in HCl/EtOH provides debenzylated derivative (X), which is finally converted into the desired compound by selective acylation with pivaloyl chloride (XI) in TFA.
| 【1】 Gingolani, G.M.; et al.; Synthesis of L-(+)-3-(3-hydroxy-4-pivaloyloxybenzyl)-2,5-diketomorpholine as potential prodrug of L-Dopa. Bioorg Med Chem Lett 2000, 10, 12, 1385. |
| 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) | 15272 | (2S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid; 3-hydroxy-L-tyrosine; Levodopa | 59-92-7 | C9H11NO4 | 详情 | 详情 |
| (II) | 15273 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propionic acid | C14H19NO6 | 详情 | 详情 | |
| (III) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (IV) | 46700 | phenyl (3S)-4-[3,4-bis(benzyloxy)phenyl]-3-[(tert-butoxycarbonyl)amino]butanoate | C35H37NO6 | 详情 | 详情 | |
| (V) | 46701 | (2S)-3-[3,4-bis(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | C28H31NO6 | 详情 | 详情 | |
| (VI) | 46702 | (2S)-2-amino-3-[3,4-bis(benzyloxy)phenyl]propionic acid | C23H23NO4 | 详情 | 详情 | |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 46703 | (2S)-3-[3,4-bis(benzyloxy)phenyl]-2-[(2-chloroacetyl)amino]propionic acid | C25H24ClNO5 | 详情 | 详情 | |
| (IX) | 46704 | (3S)-3-[3,4-bis(benzyloxy)benzyl]-2,5-morpholinedione | C25H23NO5 | 详情 | 详情 | |
| (X) | 46705 | (3S)-3-(3,4-dihydroxybenzyl)-2,5-morpholinedione | C11H11NO5 | 详情 | 详情 | |
| (XI) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |