TAK-778-SR, TAK-778, -Drug Synthesis Database

【结构式】

【药物名称】TAK-778-SR, TAK-778

【化学名称】(2R,4S)-(-)-N-[4-(Diethoxyphosphorylmethyl)phenyl]-4-methyl-7,8-(methylenedioxy)-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxamide
　　　　　　(6R,8S)-(-)-N-[4-(Diethoxyphosphorylmethyl)phenyl]-8-methyl-9-oxo-5,6,8,9-tetrahydrothiepino[4,5-f]-1,3-benzodioxole-6-carboxamide

【CA登记号】180185-61-9, 139743-63-8 (trans-isomer)

【分子式】C₂₄H₂₈NO₇PS

【分子量】505.53106

【开发单位】Takeda (Originator)

【药理作用】Agents for Bone Repair, Bone Diseases, Treatment of, Bone Formation Stimulants, METABOLIC DRUGS, Treatment of Osteoporosis

合成路线1 合成路线2

合成路线1

The diazonium salt prepared from 3,4-methylenedioxyaniline (I) was coupled to methyl acrylate (II) in the presence of Cu2O and HBr to produce the 2-bromo-3-phenylpropionic ester (III). Subsequent displacement of the bromo group of (III) by alpha-mercaptopropionic acid (IV) gave sulfide (V). After conversion of (V) to the corresponding acid chloride with (COCl)2, intramolecular Friedel-Crafts cyclization in the presence of SnCl4 afforded the benzothiepinone (VI) as a mixture of cis and trans isomers. Further treatment of this mixture with sodium methoxide equilibrated the mixture to the more stable trans form (VII). Resolution of the racemic trans ester was achieved by basic hydrolysis, coupling to ethyl (R)-(-)-mandelate (VIII), and fractional crystallization of the desired diastereomer (IX) from EtOAc-hexane. Ester hydrolysis of (IX) under acidic conditions led to the chiral carboxylic acid (X), which was finally condensed with diethyl 4-aminobenzylphosphonate (XI) to furnish the title compound.

参考文献中间体

【1】 Oda, T.; et al.; Synthesis of novel 2-benzothiopyran and 3-benzothiepin derivatives and their stimulatory effect on bone formation. J Med Chem 1999, 42, 4, 751.

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)	10984	1,3-Benzodioxol-5-amine; 1,3-Benzodioxol-5-ylamine.; 3,4-(Methylenedioxy)aniline	14268-66-7	C₇H₇NO₂	详情	详情
(II)	14156	methyl acrylate	96-33-3	C₄H₆O₂	详情	详情
(III)	24360	3-(1,3-Benzodioxol-5-yl)-2-bromopropionic acid methyl ester		C₁₁H₁₁BrO₄	详情	详情
(IV)	24361	2-sulfanylpropionic acid; 2-mercaptopropionic acid	57965-30-7	C₃H₆O₂S	详情	详情
(V)	24362	2-[2-(1,3-Benzodioxol-5-yl)-1-(methoxycarbonyl)ethylsulfanyl]propionic acid		C₁₄H₁₆O₆S	详情	详情
(VI)	24363	8-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6-carboxylic acid methyl ester		C₁₄H₁₄O₅S	详情	详情
(VII)	24364	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid methyl ester		C₁₄H₁₄O₅S	详情	详情
(VIII)	24365	2-Hydroxy-2-phenylacetic acid methyl ester	4358-87-6	C₉H₁₀O₃	详情	详情
(IX)	24366	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid 1(R)-(methoxycarbonyl)-1-benzyl ester		C₂₂H₂₀O₇S	详情	详情
(X)	24367	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid		C₁₃H₁₂O₅S	详情	详情
(XI)	24368	4-Aminobenzylphosphonic acid diethyl ester	20074-79-7	C₁₁H₁₈NO₃P	详情	详情

合成路线2

Condensation of halo ester (I) with 2-mercaptopropionic acid (II) provided thioether (III). After conversion of the carboxylic acid group of (III) into acid chloride (IV), Friedel-Crafts cyclization yielded the racemic trans benzothiepinone (V). Subsequent ester hydrolysis gave carboxylic acid (VI). The required (2R,4S) enantiomer (IX) was then isolated by condensation with methyl (R)-mandelate (VII), followed by recrystallization of the diastereoisomeric ester (VIII) from ethyl acetate-hexane, and further hydrolysis with HCl in AcOH. Finally, coupling of (IX) with diethyl 4-aminobenzylphosphonate (X) by means of EDC and HOBt furnished the title compound.

参考文献中间体

【1】 Oda, T.; et al.; Synthesis of novel 2-benzothiopyran and 3-benzothiepin derivatives and their stimulatory effect on bone formation. Symp Med Chem 1998, Abst 2-P-31.
【2】 Sohda, T.; Taketomi, S.; Oda, T. (Takeda Chemical Industries, Ltd.); Optically active benzothiepine deriv., its preparation and use. CA 2166152; EP 0719782; JP 1996231569; JP 1997183784 .
【3】 Hoshino, T.; Muranishi, H.; Taketomi, S.; Iwasa, S. (Takeda Chemical Industries, Ltd.); Osteogenetic promoting pharmaceutical compsn.. JP 1997263545; WO 9639134 .

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)	25550	ethyl 3-(1,3-benzodioxol-5-yl)-2-bromopropanoate		C₁₂H₁₃BrO₄	详情	详情
(II)	24361	2-sulfanylpropionic acid; 2-mercaptopropionic acid	57965-30-7	C₃H₆O₂S	详情	详情
(III)	25552	2-[[1-(1,3-benzodioxol-5-ylmethyl)-2-ethoxy-2-oxoethyl]sulfanyl]propionic acid		C₁₅H₁₈O₆S	详情	详情
(IV)	25551	ethyl 3-(1,3-benzodioxol-5-yl)-2-[(2-chloro-1-methyl-2-oxoethyl)sulfanyl]propanoate		C₁₅H₁₇ClO₅S	详情	详情
(V)	25553	ethyl (6R,8S)-8-methyl-9-oxo-5,6,8,9-tetrahydrothiepino[4,5-f][1,3]benzodioxole-6-carboxylate		C₁₅H₁₆O₅S	详情	详情
(VI)	24367	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid		C₁₃H₁₂O₅S	详情	详情
(VII)	25554	methyl (2R)-2-hydroxy-2-phenylethanoate	20698-91-3	C₉H₁₀O₃	详情	详情
(VIII)	24366	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid 1(R)-(methoxycarbonyl)-1-benzyl ester		C₂₂H₂₀O₇S	详情	详情
(IX)	24367	8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid		C₁₃H₁₂O₅S	详情	详情
(X)	24368	4-Aminobenzylphosphonic acid diethyl ester	20074-79-7	C₁₁H₁₈NO₃P	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)