(4-carboxybutyl)(triphenyl)phosphonium -Drug Synthesis Database

【结构式】

【分子编号】23582

【品名】(4-carboxybutyl)(triphenyl)phosphonium

【CA登记号】

【分子式】C₂₃H₂₄O₂P

【分子量】363.416122

【元素组成】C 76.02% H 6.66% O 8.81% P 8.52%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XIV)

1) The condensation of (IX) with 2-cyclopentyl-2-(pivaloyloxy)acetyl chloride (X) in dichloromethane gives the amide (XI), which is deprotected with p-toluenesulfonie acid in methanol to yield N-(10-hydroxymethylpinan-3-yl)-2-cyclopentyl-2-(pivaloyloxy)acetamide (XII). The oxidation of (XII) with SO3 - pyridine in DMSO affords the aldehyde (XIII), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide (XIV) by means ot NaH in DMSO to give the heptenoic acid derivative (XV). The deprotection of (XV) with NaOH yields the racemic mixture (at the 1,5-hydroxy substituent) (XVI), which is finally resolved into its two diastereomers by methylation with diazomethane, column chromatography (silica gel hexane) and hydrolysis with NaOH in methanol.

参考文献中间体

合成目标

【1】 Kawasaki, A.; Miyake, H.; Okegawa, T. (Ono Pharmaceutical Co., Ltd.); 13-Aza-14-oxo-TXA2 analogues. AU 8543495; EP 0171146; ES 8704880; ES 8705370; JP 1989151545; US 4792550 .
【2】 Castaner, J.; Prous, J.; ONO-3708. Drugs Fut 1987, 12, 5, 446.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	23577	(1S,2S,3S,5R)-6,6-dimethyl-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]bicyclo[3.1.1]heptan-3-amine; (1S,2S,3S,5R)-6,6-dimethyl-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]bicyclo[3.1.1]hept-3-ylamine	C₁₇H₃₁NO₂	详情	详情
(X)	23578	2-chloro-1-cyclopentyl-2-oxoethyl pivalate	C₁₂H₁₉ClO₃	详情	详情
(XI)	23579	1-cyclopentyl-2-([(1S,2S,3S,5R)-6,6-dimethyl-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]bicyclo[3.1.1]hept-3-yl]amino)-2-oxoethyl pivalate	C₂₉H₄₉NO₅	详情	详情
(XII)	23580	1-cyclopentyl-2-[[(1S,2S,3S,5R)-2-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]amino]-2-oxoethyl pivalate	C₂₃H₃₉NO₄	详情	详情
(XIII)	23581	1-cyclopentyl-2-[[(1S,2S,3S,5R)-6,6-dimethyl-2-(2-oxoethyl)bicyclo[3.1.1]hept-3-yl]amino]-2-oxoethyl pivalate	C₂₃H₃₇NO₄	详情	详情
(XIV)	23582	(4-carboxybutyl)(triphenyl)phosphonium	C₂₃H₂₄O₂P	详情	详情
(XV)	23583	(Z)-7-[(1S,2S,3S,5R)-3-([2-cyclopentyl-2-[(2,2-dimethylpropanoyl)oxy]acetyl]amino)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-5-heptenoic acid	C₂₈H₄₅NO₅	详情	详情
(XVI)	23584	(Z)-7-[(1S,2S,3S,5R)-3-[(2-cyclopentyl-2-hydroxyacetyl)amino]-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-5-heptenoic acid	C₂₃H₃₇NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

2) Amine (IX) is acylated with trifluoroacetic anhydride and pyridine in dichloromethane to the amide (XVII), which is hydrolyzed with p-toluenesulfonic acid in methanol yielding the alcohol (XVIII). The oxidation of (XVIII) with anhydrous H2SO4 - pyridine in DMSO triethylamine affords the aldehyde (XIX), which is submitted to a Wittig condensation with 4-carboxybutyltriphenylphosphonium bromide by means of NaH in DMSO giving the heptenoic acid (XX). Methylation of (XX) with diazomethane affords the corresponding methyl ester (XXI), which is deprotected with NaOH yielding the amino ester (XXII). The acylation of (XXII) with the acyl chloride (X) gives the protected amido ester (XXIII), which by partial hydrolysis with NaOH affords the racemic mixture (XVI), already obtained.

参考文献中间体

合成目标

【1】 Kawasaki, A.; Miyake, H.; Okegawa, T. (Ono Pharmaceutical Co., Ltd.); 13-Aza-14-oxo-TXA2 analogues. AU 8543495; EP 0171146; ES 8704880; ES 8705370; JP 1989151545; US 4792550 .
【2】 Castaner, J.; Prous, J.; ONO-3708. Drugs Fut 1987, 12, 5, 446.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IX)	23577	(1S,2S,3S,5R)-6,6-dimethyl-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]bicyclo[3.1.1]heptan-3-amine; (1S,2S,3S,5R)-6,6-dimethyl-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]bicyclo[3.1.1]hept-3-ylamine	C₁₇H₃₁NO₂	详情	详情
(X)	23578	2-chloro-1-cyclopentyl-2-oxoethyl pivalate	C₁₂H₁₉ClO₃	详情	详情
(XIV)	23582	(4-carboxybutyl)(triphenyl)phosphonium	C₂₃H₂₄O₂P	详情	详情
(XVI)	23584	(Z)-7-[(1S,2S,3S,5R)-3-[(2-cyclopentyl-2-hydroxyacetyl)amino]-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-5-heptenoic acid	C₂₃H₃₇NO₄	详情	详情
(XVII)	23585	N-[(1S,2S,3S,5R)-6,6-dimethyl-2-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]bicyclo[3.1.1]hept-3-yl]-2,2,2-trifluoroacetamide	C₁₉H₃₀F₃NO₃	详情	详情
(XVIII)	23586	2,2,2-trifluoro-N-[(1S,2S,3S,5R)-2-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetamide	C₁₃H₂₀F₃NO₂	详情	详情
(XIX)	23587	N-[(1S,2S,3S,5R)-6,6-dimethyl-2-(2-oxoethyl)bicyclo[3.1.1]hept-3-yl]-2,2,2-trifluoroacetamide	C₁₃H₁₈F₃NO₂	详情	详情
(XX)	23588	(Z)-7-[(1S,2S,3S,5R)-6,6-dimethyl-3-[(2,2,2-trifluoroacetyl)amino]bicyclo[3.1.1]hept-2-yl]-5-heptenoic acid	C₁₈H₂₆F₃NO₃	详情	详情
(XXI)	23589	(Z)-7-[(1S,2S,5R)-6,6-dimethyl-3-[(2,2,2-trifluoroacetyl)amino]bicyclo[3.1.1]hept-2-yl]-5-heptenoic acid	C₁₈H₂₆F₃NO₃	详情	详情
(XXII)	23590	(Z)-7-[(1S,2S,3S,5R)-3-amino-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-5-heptenoic acid	C₁₆H₂₇NO₂	详情	详情
(XXIII)	23591	methyl (Z)-7-[(1S,2S,3S,5R)-3-[(2-cyclopentyl-2-hydroxyacetyl)amino]-6,6-dimethylbicyclo[3.1.1]hept-2-yl]-5-heptenoate	C₂₄H₃₉NO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXXII)

Amino alcohol (XXVIII) was acylated with acid chloride (X) under Schotten-Baumann conditions to afford amide (XXX). Subsequent conversion of the primary alcohol (XXX) to aldehyde (XXXI) was accomplished by either Swern oxidation or by treatment with NaOCl in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). Wittig condensation of aldehyde (XXXI) with the ylide generated from (4-carboxybutyl)triphenylphosphonium bromide (XXXII) in the presence of potassium tert-butoxide furnished the Z-olefin (XXXIII). Finally, basic hydrolysis of the benzenesulfonyl protecting group of (XXXIII) yielded the title compound.

参考文献中间体

合成目标

【1】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 .
【2】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 .
【3】 Hiramatsu, Y.; Honma, T. (Shionogi & Co. Ltd.); Process for producing 5-hydroxybenzo[b]thiophene-3-carboxylic acid derivs.. EP 1069122; WO 9950260 .
【4】 Cai, D.; Larsen, R.; Journet, M.; Campos, K. (Merck & Co., Inc.); Process for the preparation of PGD2 antagonist. WO 0232892 .
【5】 Hiramatsu, Y.; Honma, T.; Mitsumori, S. (Shionogi & Co. Ltd.); Novel process for producing bicyclic amino alcohol. EP 1193243; WO 0102334 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	52252	3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate	C₁₅H₉ClO₄S₂	详情	详情
(XXVIII)	52250	2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol	C₁₁H₂₁NO	详情	详情
(XXX)	52253	3-({[3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate	C₂₆H₂₉NO₅S₂	详情	详情
(XXXI)	52254	3-({[6,6-dimethyl-3-(2-oxoethyl)bicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate	C₂₆H₂₇NO₅S₂	详情	详情
(XXXII)	23582	(4-carboxybutyl)(triphenyl)phosphonium	C₂₃H₂₄O₂P	详情	详情
(XXXIII)	52697	(Z)-7-{(1R,2R,3S,5R)-6,6-dimethyl-2-[({5-[(phenylsulfonyl)oxy]-1-benzothiophen-3-yl}carbonyl)amino]bicyclo[3.1.1]hept-3-yl}-5-heptenoic acid	C₃₁H₃₅NO₆S₂	详情	详情

Extended Information