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【结 构 式】 
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【分子编号】62435 【品名】ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate 【CA登记号】 |
【 分 子 式 】C12H14O4 【 分 子 量 】222.24076 【元素组成】C 64.85% H 6.35% O 28.8% |
合成路线1
该中间体在本合成路线中的序号：(VI)Electrophilic bromination of ethyl p-methoxycinnamate (I) by means of N-bromosuccinimide in moist acetone gave rise to the racemic erythro bromohydrin (II), which was esterified with butyric anhydride to produce the racemic bromoester (III). Kinetic resolution of (III) employing Candida cylindracea lipase caused the enantioselective hydrolysis of the (S,S)-enantiomer, yielding the chiral bromohydrin (V). Cyclization of (V) in the presence of NaOMe furnished epoxide (VI). The target thiazepinone (VIII) was then obtained by condensation between the glycidic ester (VI) and 2-aminobenzenethiol (VII)
| 【1】 McCague, R.; Wang, S.; Taylor, S.J.C. (Celltech Group plc); Chiral arylpropionates and their use. WO 9413828 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 25047 | butyric anhydride | 106-31-0 | C8H14O3 | 详情 | 详情 |
| (I) | 62431 | ethyl (E)-3-(4-methoxyphenyl)-2-propenoate | C12H14O3 | 详情 | 详情 | |
| (II) | 62432 | ethyl (2S,3S)-2-bromo-3-hydroxy-3-(4-methoxyphenyl)propanoate | C12H15BrO4 | 详情 | 详情 | |
| (III) | 62433 | (1S,2S)-2-bromo-3-ethoxy-1-(4-methoxyphenyl)-3-oxopropyl butyrate | C16H21BrO5 | 详情 | 详情 | |
| (IV) | 62434 | (1R,2R)-2-bromo-3-ethoxy-1-(4-methoxyphenyl)-3-oxopropyl butyrate | C16H21BrO5 | 详情 | 详情 | |
| (V) | 62432 | ethyl (2S,3S)-2-bromo-3-hydroxy-3-(4-methoxyphenyl)propanoate | C12H15BrO4 | 详情 | 详情 | |
| (VI) | 62435 | ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C12H14O4 | 详情 | 详情 | |
| (VII) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (VIII) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)A different method for the preparation of glycidic ester (VI) consists in the asymmetric epoxidation of ethyl 4-methoxycinnamate (I) with oxone(R) in the presence of chiral macrocyclic ketones, such as the binaphthyl ketone (IX)
| 【1】 Seki, M.; Furutani, T.; Imashiro, R.; Kuroda, T.; Yamanaka, T.; Harada, N.; Arawaka, H.; Kusama, M.; Hashiyama, T.; A novel synthesis of a key intermediate for diltiazem. Tetrahedron Lett 2001, 42, 46, 8201. |
| 【2】 Ozaki, Y.; Arakawa, H.; Harada, N.; Hashiyama, T.; Kuroda, T.; Seki, M.; Kusama, M. (Tanabe Seiyaku Co., Ltd.); Process for preparing optically active phenyloxirane cpds.. WO 9856762 . |
合成路线3
该中间体在本合成路线中的序号：(XIV)In a further process, the racemic trans glycidic ester (XII), prepared by Darzen's condensation between anisaldehyde (X) and methyl chloroacetate (XI), was resolved by enantioselective enzymatic hydrolysis, using several different enzymes and reaction conditions to produce the undesired (2S,3R) acid (XIII), while leaving intact the required (2R,3S)-glycidic ester (XIV) (4-7). Opening of the chiral epoxide (XIV) with 2-aminobenzenethiol (VII) proceeded with retention of the configuration, producing methyl (2S,3S)-2-hydroxy-3-(2-aminophenylsulfanyl)-3-(4-methoxyphenyl)propionate (XV) (8). Alternatively, the (S,S)-amino ester (XV) was obtained by resolution with tartaric acid of the racemic three-adduct resulting from epoxide (XII) and 2-aminobenzenethiol (VII) (9). Cyclization of amino ester (XV) in refluxing xylene in the presence of p-toluenesulfonic acid afforded the target lactam (VIII) (9). The cyclization of (XV) to lactam (VIII) was also accomplished by means of trichloroacetic acid or under basic conditions
| 【1】 Bhushan, L.B.; Jayachandran, B.E.; Bhushan, L.V.; Thottappillil, R. (Council of Scientific and Industrial Research); Process for preparing diltiazem. US 5869697 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (VIII) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (X) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (XI) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (XII) | 11905 | methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C11H12O4 | 详情 | 详情 | |
| (XIII) | 62438 | (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylic acid | C10H10O4 | 详情 | 详情 | |
| (XIV) | 62435 | ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C12H14O4 | 详情 | 详情 | |
| (XV) | 62439 | methyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate | C17H19NO4S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIV)A new enantioselective method for the preparation of glycidic ester (XIV) has been disclosed. Methyl trichloroacetate (XVI) was converted to the dichloroketene silyl acetal (XVII) by treatment with zinc powder and chlorotrimethylsilane. Asymmetric aldol condensation of (XVII) with anisaldehyde (X) in the presence of the chiral oxazaborolidine catalyst (XVIII) at -78 C produced methyl (S)-2,2-dichloro-3-hydroxy-3-(4-methoxyphenyl)propionate (XIX). Reductive mono-dechlorination of (XIX) furnished chlorohydrin (XX), which was then cyclized to glycidic ester (XIV) in the presence of NaOMe
| 【1】 Imashiro, R.; Kuroda, T.; Asymmetric synthesis of methyl (2R,3S)-3-(4-methoxyphenyl) glycidate, a key intermediate of diltiazem, via Mukaiyama aldol reaction. Tetrahedron Lett 2001, 42, 7, 1313. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (XIV) | 62435 | ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C12H14O4 | 详情 | 详情 | |
| (XVI) | 62440 | methyl 2,2,2-trichloroacetate | 598-99-2 | C3H3Cl3O2 | 详情 | 详情 |
| (XVII) | 62441 | C4H6Cl2O2 | 详情 | 详情 | ||
| (XVIII) | 62442 | C6H12BNO2 | 详情 | 详情 | ||
| (XIX) | 62443 | methyl (3S)-2,2-dichloro-3-hydroxy-3-(4-methoxyphenyl)propanoate | C11H12Cl2O4 | 详情 | 详情 | |
| (XX) | 62444 | methyl (3S)-2-chloro-3-hydroxy-3-(4-methoxyphenyl)propanoate | C11H13ClO4 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)In a variation of the preceding methods, the chiral glycidic amide (XLVII) was used as the synthetic precursor. Amide (XLVII) was either prepared by treatment of the chiral glycidic ester (VI) with ammonia, or by enzymatic resolution of (XII), followed by amidation. Iron-catalyzed addition of 2-aminothiophenol (VII) to the glycidamide (XLVII) in refluxing chlorobenzene yielded the desired threo adduct (XLVIII) as the major isomer. Cyclization of amino amide (XLVIII) under acidic conditions furnished thiazepinone (VIII)
| 【1】 Yamada, S.; Tsujioka, I.; Shibatini, T.; Yoshioka, R.; Efficient alterative synthetic route to diltiazem via (2R,3S)-3-(4-methoxyphenyl)glycidamide. Chem Pharm Bull 1999, 47, 2, 146. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 62435 | ethyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C12H14O4 | 详情 | 详情 | |
| (VII) | 25182 | 2-aminobenzenethiol | 137-07-5 | C6H7NS | 详情 | 详情 |
| (VIII) | 62436 | (2S,3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one | C16H15NO3S | 详情 | 详情 | |
| (XII) | 11905 | methyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C11H12O4 | 详情 | 详情 | |
| (XLVII) | 62463 | (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxamide | C10H11NO3 | 详情 | 详情 | |
| (XLVIII) | 62464 | (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanamide | C16H18N2O3S | 详情 | 详情 |