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【结 构 式】 
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【分子编号】15268 【品名】m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone 【CA登记号】99-02-5 |
【 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：(XI)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2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(I)By condensation of 3-chloroacetophenone (I) with dimethyl oxalate (II) by means of NaOMe in methanol.
| 【1】 Hind, S.L.; Janssen, M.; Reinhard, J.F. Jr.; Drysdale, M.J.; Synthesis and SAR of 4-aryl-2-hydroxy-4-oxobut-2-enoic acids esters and 2-amino-4-aryl-4-oxobut-2-enoic acids and esters: Potent inhibitors of kynurenine-3-hydroxylase as potential neuroprotective agents. J Med Chem 2000, 43, 1, 123. |
合成路线4
该中间体在本合成路线中的序号：(XVII)The optically pure diol intermediate (VIII) can be obtained by several procedures. Aldol condensation of 3-chlorobenzaldehyde (XII) with the lithium enolate of ethyl acetate gives the hydroxy ester (XIII), which is reduced to racemic 1-(3-chlorophenyl)-1,3-propanediol (XIV) by means of LiAlH4 in Et2O. Ketalization of diol (XIV) with (-)-menthone (XV) employing trimethylsilyl triflate and hexamethyldisilazane produces the spiro ketal (XVI) as a diastereomeric mixture, from which the target (S)-diol (VIII) is obtained by fractional crystallization, followed by acidic ketal hydrolysis (1-3). In a different strategy utilizing an enantioselective reduction, 3’-chloroacetophenone (XVII) is condensed with diethyl carbonate by means of t-BuOK in THF to yield the keto ester (XVIII), which is selectively reduced to the (S)-hydroxy ester (XIX) by catalytic hydrogenation over a chiral ruthenium catalyst. After saponification of ester (XIX), the chiral hydroxy acid obtained (XX) is reduced to (VIII) with borane in THF. Similarly, the (S)-hydroxy acid (XX) can be produced by condensation of 3-chlorobenzoyl chloride (XXI) with the lithium enolate of trimethylsilyl acetate, followed by acidic desilylation to yield the keto acid (XXII), which is then reduced to (XX) utilizing (–)-B-chlorodiisopinocamphenylborane (DIP-Cl) in cold CH2Cl2 (1-5). In a further method, 3-chlorocinnamic acid (XXIII) is esterified with H2SO4/EtOH, followed by reduction with DIBAL to provide the cinnamyl alcohol (XXIV), which undergoes Sharpless asymmetric epoxidation to (XXV) with t-butyl hydroperoxide in the presence of (+)-diethyl tartrate. Reductive cleavage of the chiral epoxide obtained (XXV) by means of Red-Al then furnishes the target 1(S)-(3-chlorophenyl)-1,3-propanediol (VIII) (1, 2). Scheme 2.
| 【1】 Kopcho, J.J., Matelich, M.C., Reddy, K.R., Ugarkar, B.G. (Metabasis Therapeutics, Inc.). Process for preparation of cyclic prodrugs of PMEA and PMPA. JP 2005525422, US 2003225277, WO 2003095665. |
| 【2】 Erion, M.D., Kopcho, J.J., Matelich, M.C., Reddy, K.R. (Metabasis Therapeutics, Inc.). Novel phosphonic acid based prodrugs of PMEA and its analogues. EP 1532157, US 2003229225, WO 2004037161. |
| 【3】 Reddy, K.R., Matelich, M.C., Ugarkar, B.G. et al. HepDirect prodrugs of adefovir: Design, synthesis and optimization. 227th ACS Natl Meet (March 28-April 1, Anaheim) 2004, Abst MEDI- 27. |
| 【4】 Martin, K. (Metabasis Therapeutics, Inc.). Lewis acid mediated synthesis of cyclic esters. CA 2565966, EP 1753762, US 2005282782, WO 2005123729. |
| 【5】 Erion, M.D., Reddy, K.R., Boyer, S.H. et al. Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phospho(on)ate-based drugs to the liver. J Am Chem Soc 2004, 126(16): 5154-63. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 13660 | 3-Chlorobenzaldehyde | 587-04-2 | C7H5ClO | 详情 | 详情 |
| (XIII) | 65236 | C11H13ClO3 | 详情 | 详情 | ||
| (XIV) | 65237 | 1(RS)-(3-chlorophenyl)-1,3-propanediol | C9H11ClO2 | 详情 | 详情 | |
| (XV) | 10208 | L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone | 14073-97-3 | C10H18O | 详情 | 详情 |
| (XVI) | 65238 | C19H27ClO2 | 详情 | 详情 | ||
| (XVII) | 15268 | m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone | 99-02-5 | C8H7ClO | 详情 | 详情 |
| (XVIII) | 65239 | ethyl 3-(3-chlorophenyl)-3-oxopropanoate | C11H11ClO3 | 详情 | 详情 | |
| (XIX) | 65240 | C11H13ClO3 | 详情 | 详情 | ||
| (XX) | 65241 | C9H9ClO3 | 详情 | 详情 | ||
| (XXI) | 16687 | 3-chlorobenzoyl chloride | 618-46-2 | C7H4Cl2O | 详情 | 详情 |
| (XXII) | 65242 | C9H7ClO3 | 详情 | 详情 | ||
| (XXIII) | 65243 | 3-Chlorocinnamic acid | 14473-90-6 | C9H7ClO2 | 详情 | 详情 |
| (XXIV) | 65244 | C9H9ClO | 详情 | 详情 | ||
| (XXV) | 65245 | C9H9ClO2 | 详情 | 详情 |