(2S)-1-[3-(methoxymethyl)phenyl]-3-butyn-2-ol -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

合成目标

【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	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.

参考文献中间体

合成目标

【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	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