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【结 构 式】 
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【分子编号】15271 【品名】(R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane 【CA登记号】62600-71-9 |
【 分 子 式 】C8H7ClO 【 分 子 量 】154.59568 【元素组成】C 62.15% H 4.56% Cl 22.93% O 10.35% |
合成路线1
该中间体在本合成路线中的序号：(X)The reaction of 7-methoxy-2-tetralone (I) with benzamide in refluxing toluene gives N-(7-methoxy-3,4-dihydronpahthalen-2-yl)benzamide (II), which is enantioselectively hydrogenated with H2 over a chiral Ru or Rh catalyst yielding the chiral benzamide (III). The hydrolysis of (III) with methanesulfonic acid in acetic acid at 160 C affords the chiral 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) , which is treated with 48% HBr affording 7-hydroxy-1,2,3,4-tetrahydronaphthalen-2(S)-ylamine (V). The protection of the amino group of (V) with Boc2O and triethylamine gives the carbamate (VI), which is condensed with ethyl 2-bromoacetate (VII) by means of K2CO3 yielding 2-[7(S)-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yloxy]acetic acid ethyl ester (VIII). The deprotection of (VIII) with TFA affords 2-(7(S)-amino-5,6,7,8-tetrahydronaphthalen-2-yloxy]acetic acid ethyl ester (IX), which is finally condensed with the chiral 2(R)-(3-chlorophenyl)oxirane (X) in hot DMS. The chiral intermediate 7-methoxy-1,2,3,4-tetrahydronaphthalen-2(S)-amine (IV) can also by obtained by optical resolution of the racemic mixture (rac)-(IV) by means of (R)-(-)-mandelic acid.
| 【1】 Devocelle, M.; et al.; Alternative synthesis of the chiral atypical beta-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation. Tetrahedron Lett 1999, 40, 24, 4551. |
| 【2】 Cecchi, R.; et al.; Synthesis and beta-adrenergic activity of atypical beta-adrenergic phenylethanolaminotetralin stereoisomers. Eur J Med Chem 1994, 29, 4, 259. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40592 | Benzamide | 55-21-0 | C7H7NO | 详情 | 详情 | |
| (rac)-(IV) | 32818 | 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; 7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine | C11H15NO | 详情 | 详情 | |
| (I) | 24999 | 7-methoxy-3,4-dihydro-2(1H)-naphthalenone | 4133-34-0 | C11H12O2 | 详情 | 详情 |
| (II) | 32816 | N-(7-methoxy-3,4-dihydro-2-naphthalenyl)benzamide | C18H17NO2 | 详情 | 详情 | |
| (III) | 32817 | N-[(2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]benzamide | C18H19NO2 | 详情 | 详情 | |
| (IV) | 32820 | (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2S)-7-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine | C11H15NO | 详情 | 详情 | |
| (V) | 32819 | (7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenol | C10H13NO | 详情 | 详情 | |
| (VI) | 32821 | tert-butyl (2S)-7-hydroxy-1,2,3,4-tetrahydro-2-naphthalenylcarbamate | C15H21NO3 | 详情 | 详情 | |
| (VII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VIII) | 32822 | ethyl 2-([(7S)-7-[(tert-butoxycarbonyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl]oxy)acetate | C19H27NO5 | 详情 | 详情 | |
| (IX) | 32823 | ethyl 2-[[(7S)-7-amino-5,6,7,8-tetrahydro-2-naphthalenyl]oxy]acetate | C14H19NO3 | 详情 | 详情 | |
| (X) | 15271 | (R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane | 62600-71-9 | C8H7ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The chiral intermediate 2(R)-(3-chlorophenyl)oxirane (X) has been obtained as follows: The bromination of 3'-chloroacetophenone (XI) with Br2 in acetic acid gives the 3'-chlorophenacyl bromide (XII), which is treated with dimethylamine in toluene yielding 3'-chloro-2-(dimethylamino)acetophenone (XIII). The hydrogenation of (XIII) with H2 over a chiral Rh catalyst affords the (R)-alcohol (XIV), which is finally treated with NaOH in chloroform to provide the intermediate oxirane (X).
| 【1】 Devocelle, M.; et al.; Alternative synthesis of the chiral atypical beta-adrenergic phenylethanolaminotetraline agonist SR58611A using enantioselective hydrogenation. Tetrahedron Lett 1999, 40, 24, 4551. |
| 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) | 15271 | (R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane | 62600-71-9 | C8H7ClO | 详情 | 详情 |
| (XI) | 15268 | m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone | 99-02-5 | C8H7ClO | 详情 | 详情 |
| (XII) | 32824 | 2-bromo-1-(3-chlorophenyl)-1-ethanone | C8H6BrClO | 详情 | 详情 | |
| (XIII) | 32825 | 1-(3-chlorophenyl)-2-(dimethylamino)-1-ethanone | C10H12ClNO | 详情 | 详情 | |
| (XIV) | 32826 | (1R)-1-(3-chlorophenyl)-2-(dimethylamino)-1-ethanol | C10H14ClNO | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The chiral synthesis of CL 316,243 is described: The chiral epoxide (IV) was prepared in a three-step procedure starting from 3-chloroacetophenone. Monochlorination followed by asymmetric reduction gave the chiral chlorohydrin (III), which was treated with base to give the epoxide. The chiral amine was prepared in a six step sequence starting from L-DOPA. Protection of the amine followed by permethylation and ester reduction gave the alcohol (VIII). Conversion to the mesylate followed by catalytic hydrogenation gave enantiomerically pure amine (X). Reaction of the epoxide (IV) with the amine (X) gave the phenethanolamine (XI). Protection as the oxazolidinone (XII) followed by demethylation and subsequent malonation with diethyl dibromomalonate yielded the protected diester (XIV). Basic hydrolysis followed by reverse phase chromatography gave CL 316,243.
| 【1】 Bloom, J.D.; Claus, T.H.; CL 316,243. Drugs Fut 1994, 19, 1, 23. |
| 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) | 15268 | m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone | 99-02-5 | C8H7ClO | 详情 | 详情 |
| (II) | 15269 | 2-chloro-1-(3-chlorophenyl)-1-ethanone | C8H6Cl2O | 详情 | 详情 | |
| (III) | 15270 | (1R)-2-chloro-1-(3-chlorophenyl)-1-ethanol | C8H8Cl2O | 详情 | 详情 | |
| (IV) | 15271 | (R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane | 62600-71-9 | C8H7ClO | 详情 | 详情 |
| (V) | 15272 | (2S)-2-amino-3-(3,4-dihydroxyphenyl)propionic acid; 3-hydroxy-L-tyrosine; Levodopa | 59-92-7 | C9H11NO4 | 详情 | 详情 |
| (VI) | 15273 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propionic acid | C14H19NO6 | 详情 | 详情 | |
| (VII) | 15274 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dimethoxyphenyl)propanoate | C17H25NO6 | 详情 | 详情 | |
| (VIII) | 15275 | tert-butyl N-[(1S)-1-(3,4-dimethoxybenzyl)-2-hydroxyethyl]carbamate | C16H25NO5 | 详情 | 详情 | |
| (IX) | 15276 | tert-butyl N-((1S)-1-(3,4-dimethoxybenzyl)-2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)carbamate | C19H31NO5S | 详情 | 详情 | |
| (X) | 15277 | (1R)-2-(3,4-dimethoxyphenyl)-1-methylethylamine; (2R)-1-(3,4-dimethoxyphenyl)-2-propanamine | C11H17NO2 | 详情 | 详情 | |
| (XI) | 15278 | (1R)-1-(3-chlorophenyl)-2-[[(1R)-2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]-1-ethanol | C19H24ClNO3 | 详情 | 详情 | |
| (XII) | 15279 | (5R)-5-(3-chlorophenyl)-3-[(1R)-2-(3,4-dimethoxyphenyl)-1-methylethyl]-1,3-oxazolan-2-one | C20H22ClNO4 | 详情 | 详情 | |
| (XIII) | 15280 | (5R)-5-(3-chlorophenyl)-3-[(1R)-2-(3,4-dihydroxyphenyl)-1-methylethyl]-1,3-oxazolan-2-one | C18H18ClNO4 | 详情 | 详情 | |
| (XIV) | 15281 | diethyl 5-[(2R)-2-[(5R)-5-(3-chlorophenyl)-2-oxo-1,3-oxazolan-3-yl]propyl]-1,3-benzodioxole-2,2-dicarboxylate | C25H26ClNO8 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)Alkylation of 7-hydroxyindole (I) with methyl chloroacetate (II) provided indolyl ether (III). Conjugate addition of 2-nitropropene (IV) to indole (III) in refluxing benzene, afforded the 3-(2-nitropropyl)indole (V), which was further reduced to the corresponding amine (VI) by catalytic hydrogenation over Raney nickel. Ring opening of the chiral epoxide (VII) with the racemic amine (VI) gave rise to a diastereomeric mixture of amino alcohols (VIII). After isolation of the desired (R,R)-isomer by column chromatography, basic hydrolysis of the methyl ester function yielded the title carboxylic acid.
| 【1】 Kato, S.; Harada, H.; Hirokawa, Y.; Yoshida, N.; Kawashima, H. (Dainippon Pharmaceutical Co., Ltd.); Indole derivs.. EP 0801059; JP 1996231504; US 5817689; WO 9616938 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIIa) | 56159 | methyl 2-{[3-((2R)-2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}propyl)-1H-indol-7-yl]oxy}acetate | C22H25ClN2O4 | 详情 | 详情 | |
| (VIIIb) | 56160 | methyl 2-{[3-((2S)-2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}propyl)-1H-indol-7-yl]oxy}acetate | C22H25ClN2O4 | 详情 | 详情 | |
| (I) | 56154 | 7-Hydroxyindole; 7-Indolol | 2380-84-9 | C8H7NO | 详情 | 详情 |
| (II) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (III) | 56155 | methyl 2-(1H-indol-7-yloxy)acetate | C11H11NO3 | 详情 | 详情 | |
| (IV) | 56156 | 2-nitro-1-propene | C3H5NO2 | 详情 | 详情 | |
| (V) | 56157 | methyl 2-{[3-(2-nitropropyl)-1H-indol-7-yl]oxy}acetate | C14H16N2O5 | 详情 | 详情 | |
| (VI) | 56158 | methyl 2-{[3-(2-aminopropyl)-1H-indol-7-yl]oxy}acetate | C14H18N2O3 | 详情 | 详情 | |
| (VII) | 15271 | (R)-(+)-3-Chlorostyrene oxide; (2R)-2-(3-Chlorophenyl)oxirane | 62600-71-9 | C8H7ClO | 详情 | 详情 |