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【结 构 式】

【分子编号】56406

【品名】(2S)-1-[3-(methoxymethyl)phenyl]-3-butyn-2-ol

【CA登记号】

【 分 子 式 】C12H14O2

【 分 子 量 】190.24196

【元素组成】C 75.76% H 7.42% O 16.82%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

The tetrahydropyranyl protecting group of (XII) is removed under acidic conditions, and the resultant alcohol (XIII) is then reprotected as the silyl ether (XIV) by treatment with tert-butyldimethylsilyl chloride and imidazole. Alkyne (XIV) is converted into the vinyl iodide (XV) employing zirconocene chloride hydride and iodine. Metalation of (XV) with tert-butyllithium and 2-(thienyl)cyanocuprate, followed by Michael addition to cyclopentenone (XVI) produces the intermediate enol adduct (XVII), which is further condensed with aldehyde (XVIII) to furnish the hydroxy ketone (XIX). Dehydration of (XIX) to enone (XX) is accomplished by treatment with methanesulfonyl chloride and 4-(dimethylamino)pyridine. Selective reduction of the conjugated olefin of (XX) with tributyltin hydride and tert-butyl peroxide leads to the saturated ketone (XXI). Then, desilylation of (XXI) with HF in pyridine produces diol (XXII). The methyl ester group of (XXII) is finally hydrolyzed to the target carboxylic acid by using pig liver esterase (PLE) in a buffered medium.

2 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 .
1 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743.
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) 56405 (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran C17H22O3 详情 详情
(XIII) 56406 (2S)-1-[3-(methoxymethyl)phenyl]-3-butyn-2-ol C12H14O2 详情 详情
(XIV) 56407 tert-butyl(dimethyl)silyl (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl ether; tert-butyl({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)dimethylsilane C18H28O2Si 详情 详情
(XV) 56408 tert-butyl(dimethyl)silyl (1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl ether; tert-butyl({(1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)dimethylsilane C18H29IO2Si 详情 详情
(XVI) 13805 (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one C11H20O2Si 详情 详情
(XVII) 56986 lithium (3R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-1-cyclopenten-1-olate C29H49LiO4Si2 详情 详情
(XVIII) 56410 methyl 4-[(2-oxoethyl)sulfanyl]butanoate C7H12O3S 详情 详情
(XIX) 56411 methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)-2-hydroxyethyl]sulfanyl}butanoate C36H62O7SSi2 详情 详情
(XX) 56412 methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentylidene)ethyl]sulfanyl}butanoate C36H60O6SSi2 详情 详情
(XXI) 56413 methyl 4-{[2-((1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate C36H62O6SSi2 详情 详情
(XXII) 56987 methyl 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate C24H34O6S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XII)

After acidic cleavage of the tetrahydropyranyl group of (XI), the resultant alcohol (XII) is reprotected as the silyl ether (XIII). Hydroiodination of acetylene (XIII) is effected by treatment with iodine and zirconocene chloride hydride, yielding vinyl iodide (XIV). The organolithium derivative generated from iodide (XIV) undergoes conjugate addition to cyclopentenone (XV), producing the intermediate lithium enolate (XVI) which, upon quenching with aldehyde (XVII), leads to the substituted cyclopentanone adduct (XVIII). Dehydration of aldol (XVIII) to dienone (XIX) is performed by treatment with mesyl chloride and DMAP. The conjugated double bond of (XIX) is selectively reduced to (XX) by means of tributyltin hydride and t-butyl hydroperoxide. Finally, desilylation of (XX) with HF in pyridine affords the title prostaglandin derivative.

1 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743.
2 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 56405 (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran C17H22O3 详情 详情
(XII) 56406 (2S)-1-[3-(methoxymethyl)phenyl]-3-butyn-2-ol C12H14O2 详情 详情
(XIII) 56407 tert-butyl(dimethyl)silyl (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl ether; tert-butyl({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)dimethylsilane C18H28O2Si 详情 详情
(XIV) 56408 tert-butyl(dimethyl)silyl (1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl ether; tert-butyl({(1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)dimethylsilane C18H29IO2Si 详情 详情
(XV) 13805 (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one C11H20O2Si 详情 详情
(XVI) 56409 lithium (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-1-cyclopenten-1-olate C29H49LiO4Si2 详情 详情
(XVII) 56410 methyl 4-[(2-oxoethyl)sulfanyl]butanoate C7H12O3S 详情 详情
(XVIII) 56411 methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)-2-hydroxyethyl]sulfanyl}butanoate C36H62O7SSi2 详情 详情
(XIX) 56412 methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentylidene)ethyl]sulfanyl}butanoate C36H60O6SSi2 详情 详情
(XX) 56413 methyl 4-{[2-((1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate C36H62O6SSi2 详情 详情
Extended Information