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【结 构 式】 
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【分子编号】24361 【品名】2-sulfanylpropionic acid; 2-mercaptopropionic acid 【CA登记号】57965-30-7 |
【 分 子 式 】C3H6O2S 【 分 子 量 】106.14544 【元素组成】C 33.95% H 5.7% O 30.15% S 30.21% |
合成路线1
该中间体在本合成路线中的序号：(I)Triethylamine is added to thiolactic acid (I) and 2-thiophencarbonyl chloride (II) in tetrahydrofuran. Mix is cooled at -5 C under agitation and thionyl chloride is added keeping the temperature between 0 and 10 C. A solution of homocysteine thiolactone hydrochloride and triethylamine in water is then added to the reaction, keeping the temperature below 10 C. The reaction is carried out for 1 h at room temperature under agitation, after which the solvent is evaporated at reduced pressure. Water is used to wash and diethyl ether to extract. The organic phase is dried on Na2SO4 anhydrous and the solvent is eliminated at reduced pressure. The raw product obtained from a mix of dichloromethane/diethyl ether (60/40) is crystallized (MR-889).
| 【1】 Quadro, G.; MR-889. Drugs Fut 1990, 15, 10, 997. |
| 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) | 24361 | 2-sulfanylpropionic acid; 2-mercaptopropionic acid | 57965-30-7 | C3H6O2S | 详情 | 详情 |
| (II) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (III) | 31190 | 2-[(2-thienylcarbonyl)sulfanyl]propionic acid | C8H8O3S2 | 详情 | 详情 | |
| (IV) | 31191 | S-(2-chloro-1-methyl-2-oxoethyl) 2-thiophenecarbothioate | C8H7ClO2S2 | 详情 | 详情 | |
| (V) | 22495 | 3-aminodihydro-2(3H)-thiophenone | 10593-85-8 | C4H7NOS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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3
该中间体在本合成路线中的序号：(II)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4
该中间体在本合成路线中的序号：(II)The cyclization of a mixture of phenylene-1,2-diamine (I), 2-sulfanylpropionic acid (II) and 2,6-difluorobenzaldehyde (III) in refluxing benzene gives a mixture of the two diastereomers of 1-(2,6-difluorophenyl)-3-methyl-1H,3H-thiazolo[3,4-a]benzimidazole, from which the trans-(racemic)-(IV) isomer has been isolated by silica gel column chromatography. The enantiomeric resolution has been performed by chiral HPLC affording the (1R, 3R)-(IV) isomer, the target compound.
| 【1】 Chimirri, A.; Grasso, S.; Monforte, A.M.; Monforte, P.; Rao, A.; Zappala, M.; Bruno, G.; Nicolo, F.; Pannecouque, C.; Witvrouw, M.; De Clercq, E.; Synthesis, structure and in vitro anti-human immunodeficiency virus activity of novel 3-methyl-1H,3H-thiazolo[3,4-a]benzimidazoles. Antivir Chem Chemother 1998, 9, 5, 431. |
| 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) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (II) | 24361 | 2-sulfanylpropionic acid; 2-mercaptopropionic acid | 57965-30-7 | C3H6O2S | 详情 | 详情 |
| (III) | 25504 | 2,6-difluorobenzaldehyde | 637-55-8 | C7H4F2O | 详情 | 详情 |
| (IV) | 25505 | (1R,3R)-1-(2,6-difluorophenyl)-3-methyl-3H-[1,3]thiazolo[3,4-a]benzimidazole | C16H12F2N2S | 详情 | 详情 |