【结 构 式】 |
【分子编号】24367 【品名】8(S)-Methyl-9-oxo-5,6,8,9-tetrahydro-1,3-dioxolo[4,5-h][3]benzothiepine-6(R)-carboxylic acid 【CA登记号】 |
【 分 子 式 】C13H12O5S 【 分 子 量 】280.30128 【元素组成】C 55.71% H 4.32% O 28.54% S 11.44% |
合成路线1
该中间体在本合成路线中的序号:(X)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.
【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
该中间体在本合成路线中的序号:(VI)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.
【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 |
合成路线3
该中间体在本合成路线中的序号:(IX)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.
【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 |