methyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate -Drug Synthesis Database

【结构式】

【分子编号】29568

【品名】methyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate

【CA登记号】

【分子式】C₁₀H₁₃NO₄

【分子量】211.21756

【元素组成】C 56.87% H 6.2% N 6.63% O 30.3%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(II)

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.

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(I)

After protection of (I) as the N-Boc derivative (II), sulfonylation of the phenolic hydroxyl groups using N-phenyl-bis(trifluoromethanesulfonimide) produced the bis(triflate) (III). The triflate groups of (III) were then displaced by diethyl phosphite, yielding phosphonate (IV). Hydrolysis of the methyl ester group with LiOH provided the corresponding carboxylic acid (V).

参考文献中间体

合成目标

【1】 Bohacek, R.; Yang, M.; Shakespeare, W.; et al.; Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity. Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 17, 9373.
【2】 Bohacek, R.; Sawyer, T.K.; Yang, M.G.; Eyermann, C.J.; Sundaramoorthi, R.; Shakespeare, W.C. (Ariad Pharmaceuticals Inc.); Bicyclic signal transduction inhibitors, compsns. containing them & uses thereof. WO 0027802 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	29568	methyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate	C₁₀H₁₃NO₄	详情	详情
(II)	43265	methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propanoate	C₁₅H₂₁NO₆	详情	详情
(III)	43266	methyl (2S)-3-(3,4-bis[[(trifluoromethyl)sulfonyl]oxy]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate	C₁₇H₁₉F₆NO₁₀S₂	详情	详情
(IV)	43267	methyl (2S)-3-[3,4-bis(diethoxyphosphoryl)phenyl]-2-[(tert-butoxycarbonyl)amino]propanoate	C₂₃H₃₉NO₁₀P₂	详情	详情
(V)	43268	(2S)-3-[3,4-bis(diethoxyphosphoryl)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid	C₂₂H₃₇NO₁₀P₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

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.

参考文献中间体

合成目标

【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

Extended Information