|
【结 构 式】 
|
【分子编号】51208 【品名】(1R,2S)-2-phenylcyclohexanol 【CA登记号】 |
【 分 子 式 】C12H16O 【 分 子 量 】176.25844 【元素组成】C 81.77% H 9.15% O 9.08% |
合成路线1
该中间体在本合成路线中的序号：(+/-)-(XXII)Addition of phenylmagnesium bromide to cyclohexene oxide (XXI) in the presence of CuCl gave trans-2-phenylcyclohexanol (XXII), which was further esterified with chloroacetyl chloride to afford 2-phenylcyclohexyl chloroacetate (XXIII). Enantioselective hydrolysis of the racemic ester (XXIII) by means of Pseudomonas fluorescens lipase provided pure (1R,2S)-2-phenylcyclohexanol (XXIV), which was again esterified with chloroacetyl chloride, yielding the chiral ester (XXVI). Darzen's condensation of chloro ester (XXVI) with anisaldehyde (X) led to the chiral glycidic ester (XXVII). Epoxide ring opening in (XXVII) with 2-aminothiophenol (VII) furnished amino ester (XXVIII). Intermediate thiazepinone (VIII) was then obtained by cyclization of (XXVIII) using p-toluenesulfonic acid in refluxing xylene. Alternatively, amino ester (XXVIII) was first hydrolyzed to amino acid (XXIX), which was subsequently cyclized with p-toluenesulfonic acid as above (11). The final cyclization of amino acid (XXIX) to the intermediate thiazepinone (VIII) has also been carried out in the presence of trichloroacetic acid
| 【1】 Plaum, M.J.M.; Boesten, W.H.J.; Process for the preparation of a benzothiazepine. EP 0796853; JP 1998007667; US 5859241 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (+/-)-(XXII) | 51208 | (1R,2S)-2-phenylcyclohexanol | C12H16O | 详情 | 详情 | |
| (+/-)-(XXIII) | 62445 | (1S,2R)-2-phenylcyclohexyl 2-chloroacetate | C14H17ClO2 | 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 | |
| (X) | 27251 | 4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde | 123-11-5 | C8H8O2 | 详情 | 详情 |
| (XXI) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (XXIV) | 10492 | (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol | 2362-61-0 | C12H16O | 详情 | 详情 |
| (XXV) | 62445 | (1S,2R)-2-phenylcyclohexyl 2-chloroacetate | C14H17ClO2 | 详情 | 详情 | |
| (XXVI) | 62445 | (1S,2R)-2-phenylcyclohexyl 2-chloroacetate | C14H17ClO2 | 详情 | 详情 | |
| (XXVII) | 62446 | (1R,2S)-2-phenylcyclohexyl (2R,3S)-3-(4-methoxyphenyl)-2-oxiranecarboxylate | C22H24O4 | 详情 | 详情 | |
| (XXVIII) | 62447 | (1R,2S)-2-phenylcyclohexyl (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoate | C28H31NO4S | 详情 | 详情 | |
| (XXIX) | 62448 | (2S,3S)-3-[(2-aminophenyl)sulfanyl]-2-hydroxy-3-(4-methoxyphenyl)propanoic acid | C16H17NO4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(rac)-(II)Ring opening of cyclohexene oxide (I) with phenylmagnesium bromide in the presence of CuI, followed by acetylation of the resulting alcohol (II) gave the racemic trans-2-phenylcyclohexyl acetate (III). Enzymatic resolution of (III) using porcine liver acetone powder yielded the desired (-)-alcohol (II) along with unreacted (+)-acetate (III). Condensation of the sodium alkoxide of benzyl alcohol with bromoacetic acid (IV) afforded benzyloxyacetic acid (V), which was then coupled with the chiral alcohol (-)-(II) to give ester (VI). Hydrogenolysis of the O-benzyl group of (VI), followed by silylation of the resulting hydroxyacetate ester (VII) with triisopropylsilyl chloride, furnished (VIII). Imine (XI) was prepared by condensation of 3-methyl-2-butenal (IX) with p-anisidine (X). The asymmetric cyclocondensation reaction of the lithium enolate derived from ester (VIII) with imine (XI) yielded the chiral beta-lactam (XII). Oxidative removal of the p-methoxyphenyl protecting group of (XII) and then reprotection of the lactam N atom with Boc2O furnished the intermediate N-Boc lactam (XIII).
| 【1】 Strum, M.; Tynebor, R.; Pera, P.; Bernacki, R.J.; Ojima, I.; Synthesis and SAR of advanced second generation taxoids. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 132. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (rac)-(III) | 51206 | (1R,2S)-2-phenylcyclohexyl acetate | C14H18O2 | 详情 | 详情 | |
| (rac)-(II) | 51208 | (1R,2S)-2-phenylcyclohexanol | C12H16O | 详情 | 详情 | |
| (-)-(II) | 51209 | (-)-(1R,2S)-2-phenylcyclohexanol | C12H16O | 详情 | 详情 | |
| (+)-(III) | 51210 | (1S,2R)-2-phenylcyclohexyl acetate | C14H18O2 | 详情 | 详情 | |
| (I) | 17986 | 7-oxabicyclo[4.1.0]heptane; cyclohexene oxide | 286-20-4 | C6H10O | 详情 | 详情 |
| (IV) | 23660 | 2-Bromoacetic acid | 79-08-3 | C2H3BrO2 | 详情 | 详情 |
| (V) | 51207 | 2-(benzyloxy)acetic acid | C9H10O3 | 详情 | 详情 | |
| (VI) | 51211 | (1R,2S)-2-phenylcyclohexyl 2-(benzyloxy)acetate | C21H24O3 | 详情 | 详情 | |
| (VII) | 51212 | (1R,2S)-2-phenylcyclohexyl 2-hydroxyacetate | C14H18O3 | 详情 | 详情 | |
| (VIII) | 19151 | (1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate | C23H38O3Si | 详情 | 详情 | |
| (IX) | 19152 | 3-methyl-2-butenal | 107-86-8 | C5H8O | 详情 | 详情 |
| (X) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (XI) | 19154 | 4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine | C12H15NO | 详情 | 详情 | |
| (XII) | 19155 | (3R,4S)-1-(4-methoxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone | C23H37NO3Si | 详情 | 详情 | |
| (XIII) | 19157 | tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate | C21H39NO4Si | 详情 | 详情 |