methyl 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate -Drug Synthesis Database

【结构式】

【分子编号】56987

【品名】methyl 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate

【CA登记号】

【分子式】C₂₄H₃₄O₆S

【分子量】450.59636

【元素组成】C 63.97% H 7.61% O 21.3% S 7.12%

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：(XXII)

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：(XIII)

Methanolysis of the thioacetate and silyl ether groups of (IX), with concomitant S-alkylation by methyl 4-iodobutyrate (X) lead to thioether (XI). The deprotected alcohol function of (XI) is then oxidized to ketone (XII) under modified Swern conditions. Subsequent acidic hydrolysis of the tetrahydropyranyl ether groups of (XII) provide diol (XIII). Finally, hydrolysis of ester (XIII) to the target carboxylic acid is performed employing pig liver esterase.

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 4: Practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist. Bioorg Med Chem 2002, 10, 7, 2103.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	56996	S-(2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl) ethanethioate		C₃₄H₅₄O₇SSi	详情	详情
(X)	13816	Methyl 4-iodobutyrate; Methyl 4-iodobutanoate	14273-85-9	C₅H₉IO₂	详情	详情
(XI)	56997	methyl 4-({2-[(1R,2R,3R,5S)-5-hydroxy-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate		C₃₄H₅₂O₈S	详情	详情
(XII)	56998	methyl 4-({2-[(1R,2R,3R)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate		C₃₄H₅₀O₈S	详情	详情
(XIII)	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

Extended Information