(2S)-3-[3,4-bis(diethoxyphosphoryl)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid -Drug Synthesis Database

【结构式】

【分子编号】43268

【品名】(2S)-3-[3,4-bis(diethoxyphosphoryl)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid

【CA登记号】

【分子式】C₂₂H₃₇NO₁₀P₂

【分子量】537.484044

【元素组成】C 49.16% H 6.94% N 2.61% O 29.77% P 11.53%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(V)

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2

该中间体在本合成路线中的序号：(XXIV)

Coupling of carboxylic acid (V) with either the racemic amine (XVI) or the chiral amine (XXIV) in the presence of EDC and HOBt, followed by trifluoroacetic acid-promoted cleavage of the Boc group, furnished the diastereomeric mixture of amides (XXV) or the pure (S,S)-isomer (XXVI), respectively. Isomer (XXVI) was also obtained by separation of the diastereomeric mixture (XXV) by means of preparative reverse-phase HPLC. Acetylation of the amino group of (XXVI) with acetic anhydride gave amide (XXVII). Finally, the ethyl phosphonate esters of (XXVII) were hydrolyzed by means of trimethylsilyl iodide in acetonitrile.

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
(V)	43286	(9S)-9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide	C₁₉H₂₈N₂O₂	详情	详情
(XVI)	43278	9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide	C₁₉H₂₈N₂O₂	详情	详情
(XXIV)	43268	(2S)-3-[3,4-bis(diethoxyphosphoryl)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid	C₂₂H₃₇NO₁₀P₂	详情	详情
(XXV)	43287	diethyl 4-((2S)-2-amino-3-[[3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-yl]amino]-3-oxopropyl)-2-(diethoxyphosphoryl)phenylphosphonate	C₃₆H₅₅N₃O₉P₂	详情	详情
(XXVI)	43288	diethyl 4-((2S)-2-amino-3-[[(5S)-3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-yl]amino]-3-oxopropyl)-2-(diethoxyphosphoryl)phenylphosphonate	C₃₆H₅₅N₃O₉P₂	详情	详情
(XXVII)	43289	diethyl 4-((2S)-2-(acetamido)-3-[[(5S)-3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-yl]amino]-3-oxopropyl)-2-(diethoxyphosphoryl)phenylphosphonate	C₃₈H₅₇N₃O₁₀P₂	详情	详情

Extended Information