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【结 构 式】

【药物名称】CP-B, CMP-3

【化学名称】7-[2(S)-[3(R)-Hydroxy-4-[3-(trifluoromethyl)phenyl]butyl]-5-oxopyrrolidin-1-yl]heptanoic acid

【CA登记号】346672-61-5

【 分 子 式 】C22H30F3NO4

【 分 子 量 】429.4839

【开发单位】Pfizer (Originator)

【药理作用】Bone Diseases, Treatment of, METABOLIC DRUGS, Treatment of Osteoporosis, Prostanoid EP4 Agonists

合成路线1

Alkylation of (R)-5-(t-butyldimethylsilyloxymethyl)pyrrolidin-2-one (I) with ethyl 7-bromoheptanoate (II) affords the pyrrolidone-ester (III). After removal of the silyl protecting group of (III) with tetrabutylammonium fluoride, the resultant alcohol (IV) is oxidized to aldehyde (V) under modified Swern conditions, using DMSO/EDC

1 Cameron, K.O.; Crawford, D.T.; DaSilva-Jardine, P.; et al.; Discovery and bone anabolic activity of highly selective EP4 receptor prostaglandin E2 (PGE2) agonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 307.
2 Thompson, D.D.; Lefker, B.A.; Cameron, K.O.; Ke, H.Z. (Pfizer Products Inc.); EP4 receptor selective agonists in the treatment of osteoporosis. EP 1110949; JP 2001181210; WO 0146140 .
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) 60581 (5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-pyrrolidinone C11H23NO2Si 详情 详情
(II) 36428 ethyl 7-bromoheptanoate 29823-18-5 C9H17BrO2 详情 详情
(III) 60582 ethyl 7-[(2R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxopyrrolidinyl]heptanoate C20H39NO4Si 详情 详情
(IV) 60583 ethyl 7-[(2R)-2-(hydroxymethyl)-5-oxopyrrolidinyl]heptanoate C14H25NO4 详情 详情
(V) 60584 ethyl 7-[(2R)-2-formyl-5-oxopyrrolidinyl]heptanoate C14H23NO4 详情 详情

合成路线2

[3-(Trifluoromethyl)phenyl]acetic acid (VI) is coupled to N,O-dimethylhydroxylamine to produce the N-methoxy amide (VII). Subsequent condensation of methoxyamide (VII) with dimethyl methylphosphonate (VIII) in the presence of BuLi leads to the oxo phosphonate (IX). Horner-Emmons condensation of phosphonate (IX) with aldehyde (V) furnishes enone (X). Diastereoselective reduction of (X) by means of catecholborane in the presence of (R)-2-methyl-CBS-oxazaborolidine in cold CH2Cl2 provides the allylic alcohol (XI) as the major isomer. Subsequent catalytic hydrogenation of (XI) gives the saturated alcohol (XII). Finally, basic hydrolysis of the ethyl ester group of (XII) produces the target carboxylic acid

1 Cameron, K.O.; Crawford, D.T.; DaSilva-Jardine, P.; et al.; Discovery and bone anabolic activity of highly selective EP4 receptor prostaglandin E2 (PGE2) agonists. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 307.
2 Thompson, D.D.; Lefker, B.A.; Cameron, K.O.; Ke, H.Z. (Pfizer Products Inc.); EP4 receptor selective agonists in the treatment of osteoporosis. EP 1110949; JP 2001181210; WO 0146140 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 60584 ethyl 7-[(2R)-2-formyl-5-oxopyrrolidinyl]heptanoate C14H23NO4 详情 详情
(VI) 60585 2-[3-(trifluoromethyl)phenyl]acetic acid C9H7F3O2 详情 详情
(VII) 60586 N-methoxy-N-methyl-2-[3-(trifluoromethyl)phenyl]acetamide C11H12F3NO2 详情 详情
(VIII) 13607 dimethyl methylphosphonate 756-79-6 C3H9O3P 详情 详情
(IX) 60587 dimethyl 2-oxo-3-[3-(trifluoromethyl)phenyl]propylphosphonate C12H14F3O4P 详情 详情
(X) 60588 ethyl 7-((5R)-2-oxo-5-{(E)-3-oxo-4-[3-(trifluoromethyl)phenyl]-1-butenyl}pyrrolidinyl)heptanoate C24H30F3NO4 详情 详情
(XI) 60589 ethyl 7-((2R)-2-{(E,3S)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]-1-butenyl}-5-oxopyrrolidinyl)heptanoate C24H32F3NO4 详情 详情
(XII) 60590 ethyl 7-((2S)-2-{(3R)-3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrrolidinyl)heptanoate C24H34F3NO4 详情 详情
Extended Information