|
【结 构 式】 
|
【分子编号】15272 【品名】(2S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid; 3-hydroxy-L-tyrosine; Levodopa 【CA登记号】59-92-7 |
【 分 子 式 】C9H11NO4 【 分 子 量 】197.19068 【元素组成】C 54.82% H 5.62% N 7.1% O 32.45% |
合成路线1
该中间体在本合成路线中的序号：(I)Etilevodopa has been obtained by several different methods: (i) esterification of 3-hydroxy-L-tyrosine (I) (L-DOPA) with ethanol catalyzed by dry HCl gas; (ii) esterification of 3-hydroxy-L-tyrosine (I) (L-DOPA) by means of SOCl2 in hot ethanol; (iii) enzymatic hydroxylation of L-tyrosine ethyl ester (II) by means of mushroom tyrosinase in a phosphate buffer.
| 【1】 Sorbera, L.A.; Leeson, P.; Castaner, J.; Martin, L.; Etilevodopa. Drugs Fut 2001, 26, 3, 219. |
| 【2】 Ahmed, G.; Vulfson, E.N.; Facile synthesis of L-Dopa esters by the combined use of tyrosinase and alpha-chymotrypsin. Biotechnol Lett 1994, 16, 4, 367. |
| 【3】 Bahar, E.; Lidor, R.; Frenkel, A. (Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals USA, Inc.); Process for manufacture of L-DOPA ethyl ester. US 6218566; WO 0027801 . |
| 【4】 Atlas, D.; Veinberg, A.; Melamed, E.; Milman, I. (Teva Pharmaceutical Industries Ltd.; Yissum Research Development Co.); Process for preparing ethyl ester of L-DOPA. EP 0610595; US 5354885 . |
合成路线2
该中间体在本合成路线中的序号：(V)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3
该中间体在本合成路线中的序号：(I)L-DOPA (I) was esterified by means of MeOH and SOCl2, and the resulting aminoester (II) was protected with benzyloxycarbonyloxy succinimide to give carbamate (III). Further reaction of (III) with 1,2-dibromoethane produced the cyclic diether derivative (IV). Chlorsulfonylation of (IV), followed by basic treatment with DMAP and Et3N gave rise to the benzothiazine (V). After N-alkylation of (V) with iodoethane and K2CO3, basic hydrolysis of the resulting methyl ester (VI) provided carboxylic acid (VII). This was coupled to L-phenylalaninol (VIII) using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and 1-hydroxybenzotriazole (HOBt) to afford the corresponding amide as a diastereomeric mixture, which was separated by flash chromatography. The required (S,S)-diastereoisomer (IX) was then oxidized to the title aldehyde using Dess-Martin periodinane reagent.
| 【1】 Wells, G.J.; et al.; 1,2-Benzothiazine 1,1-dioxide P2-P3 peptide mimetic aldehyde calpain I inhibitors. J Med Chem 2001, 44, 21, 3488. |
| 【2】 Bihovsky, R.; Wells, G.J.; Tao, M. (Cephalon, Inc.); Benzothiazo and related heterocyclic group-containing cysteine and serine protease. WO 9821186 . |
| 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) | 29568 | methyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate | C10H13NO4 | 详情 | 详情 | |
| (III) | 29569 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(3,4-dihydroxyphenyl)propanoate | C18H19NO6 | 详情 | 详情 | |
| (IV) | 29570 | methyl (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanoate | C20H21NO6 | 详情 | 详情 | |
| (V) | 29571 | methyl 1,1-dioxo-1,2,3,4,7,8-hexahydro-2H-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxylate | C12H13NO6S | 详情 | 详情 | |
| (VI) | 29572 | methyl 2-ethyl-1,1-dioxo-1,2,3,4,7,8-hexahydro-2H-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxylate | C14H17NO6S | 详情 | 详情 | |
| (VII) | 29573 | 2-ethyl-1,1-dioxo-1,2,3,4,7,8-hexahydro-2H-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxylic acid | C13H15NO6S | 详情 | 详情 | |
| (VIII) | 28523 | (2S)-2-amino-3-phenyl-1-propanol; L-phenylalanilol; (S)-2-amino-3-phenyl-1-propanol | 5267-64-1 | C9H13NO | 详情 | 详情 |
| (IX) | 29574 | (3S)-N-[(1S)-1-benzyl-2-hydroxyethyl]-2-ethyl-1,1-dioxo-1,2,3,4,7,8-hexahydro-2H-[1,4]dioxino[2,3-g][1,2]benzothiazine-3-carboxamide | C22H26N2O6S | 详情 | 详情 | |
| (X) | 18845 | Dess-Martin periodinane; 1,1,1-Triacetoxy-1,2-benziodoxol-3(1H)-one | 87413-09-0 | C13H13IO8 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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 |
合成路线5
该中间体在本合成路线中的序号：(I)Esterification of L-Dopa (I) with thionyl chloride in methanol leads to the methyl ester (II). The phenolic hydroxyls of (II) are further acylated by acetyl chloride in trifluoroacetic acid to produce diacetate (III). Treatment of the protected derivative of L-Dopa (III) with diphosgene gives rise to isocyanate (IV). This is then coupled to entacapone (V) in refluxing acetonitrile to furnish carbamate (VI). The acetate ester groups of (VI) are finally removed by treatment with 3N HCl in acetone.
| 【1】 Leppanen, J.; et al.; Design and synthesis of a novel L-dopa-entacapone codrug. J Med Chem 2002, 45, 6, 1379. |
| 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) | 29568 | methyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate | C10H13NO4 | 详情 | 详情 | |
| (III) | 61955 | methyl (2S)-2-amino-3-[3,4-bis(acetyloxy)phenyl]propanoate | C14H17NO6 | 详情 | 详情 | |
| (IV) | 61956 | methyl (2S)-3-[3,4-bis(acetyloxy)phenyl]-2-isocyanatopropanoate | C15H15NO7 | 详情 | 详情 | |
| (V) | 61957 | (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide | C14H15N3O5 | 详情 | 详情 | |
| (VI) | 61958 | methyl (2S)-3-[3,4-bis(acetyloxy)phenyl]-2-[({5-[(E)-2-cyano-3-(diethylamino)-3-oxo-1-propenyl]-2-hydroxy-3-nitrophenoxy}carbonyl)amino]propanoate | C29H30N4O12 | 详情 | 详情 |