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【结 构 式】

【分子编号】65238

【品名】 

【CA登记号】 

【 分 子 式 】C19H27ClO2

【 分 子 量 】322.87488

【元素组成】C 70.68% H 8.43% Cl 10.98% O 9.91%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XVI)

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
Extended Information