methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate -Drug Synthesis Database

【结构式】

【分子编号】14841

【品名】methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate

【CA登记号】

【分子式】C₂₉H₅₄O₅Si

【分子量】510.83026

【元素组成】C 68.19% H 10.65% O 15.66% Si 5.5%

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：(XXIIIb)

The reduction of the enone (I) with Red Al or NaBH4 gives the corresponding alcohol (XIV), which is mesylated with methanesulfonyl chloride to the ester (XV). The condensation of (XV) with dimethyl malonate by means of NaH in toluene/methanol yields the malonic derivative (XVI), which is submitted to hydrolysis with KOH and partial decarboxylation in refluxing toluene to afford the substituted acetic acid (XVII). This compound is then reduced with Red Al or LiAlH4 to the ethanol derivative (IV), already obtained. The condensation of (IV) with sodium chloroacetate by means of BuLi in DMSO, followed by esterification with methanol in H2SO4 gives the ethoxyacetic ester (XVIII), which is treated with H2O2 and Na2WO4 in dichloromethane/water with a phase-transfer agent in order to obtain the epoxide (XIX). The cleavage of (XIX) with HIO4 in the same solvent mixture affords the dialdehyde (XX), which is submitted to an aldol condensation by means of piperidine/acetic acid, yielding a mixture of two hydroxy aldehydes (XXIa and XXIb). This mixture is submitted to a Wittig condensation with the phosphonate (X), already used, and a mixture of two isomeric hydroxy ketones (XXIIa and XXIIb) is obtained. The free hydroxy group of (XXIIa and XXIIb) is protected with tert-butyldimethylsilyl chloride, and then the oxo group is reduced with NaBH4 and CeCl3 to obtain the mixture of unsaturated alcohols (XXIIIa and XXIIIb).

参考文献中间体

合成目标

【1】 Mealy, N.; Castaner, J.; Pimilprost. Drugs Fut 1996, 21, 4, 369.
【2】 Muraoka, M.; Nakamura, T.; Sugie, A.; Ono, K.; Yamamoto, M. (Sumitomo Pharmaceuticals Co., Ltd.); Bicyclooctane derivs. and their production and use. EP 0115954 .
【3】 Kawakami, H.; Muraoka, M.; Sugie, A.; Ono, K.; Kojima, A.; Syntheses of new 3-oxa-methano-PGI1 derivatives and their biological properties. Bioorg Med Chem Lett 1993, 3, 12, 2821-6.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	19373	dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester	108-59-8	C₅H₈O₄	详情	详情
	63845	sodium 2-chloroacetate		C₂H₂ClNaO₂	详情	详情
(XXIa)	14836	methyl 2-[2-[(2S,3aR,4S,5S,6aR)-4-formyl-5-hydroxyoctahydro-2-pentalenyl]ethoxy]acetate		C₁₄H₂₂O₅	详情	详情
(XXIb)	14837	methyl 2-[2-[(2R,3aS,4R,5R,6aS)-4-formyl-5-hydroxyoctahydro-2-pentalenyl]ethoxy]acetate		C₁₄H₂₂O₅	详情	详情
(XXIIa)	14838	methyl 2-(2-[(2S,3aR,4R,5S,6aR)-5-hydroxy-4-[(E,5S)-5-methyl-3-oxo-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate		C₂₃H₃₈O₅	详情	详情
(XXIIb)	14839	methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-hydroxy-4-[(E,5S)-5-methyl-3-oxo-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate		C₂₃H₃₈O₅	详情	详情
(XXIIIa)	14840	methyl 2-(2-[(2S,3aR,4R,5S,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3R,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate		C₂₉H₅₄O₅Si	详情	详情
(XXIIIb)	14841	methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate		C₂₉H₅₄O₅Si	详情	详情
(I)	14816	(3aR,7aS)-1,3,3a,4,7,7a-hexahydro-2H-inden-2-one		C₉H₁₂O	详情	详情
(IV)	14819	2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]-1-ethanol		C₁₁H₁₈O	详情	详情
(X)	14825	dimethyl (4S)-4-methyl-2-oxooctylphosphonate		C₁₁H₂₃O₄P	详情	详情
(XIV)	14829	(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-ol		C₉H₁₄O	详情	详情
(XV)	14830	(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl methanesulfonate		C₁₀H₁₆O₃S	详情	详情
(XVI)	14831	dimethyl 2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]malonate		C₁₄H₂₀O₄	详情	详情
(XVII)	14832	2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]acetic acid		C₁₁H₁₆O₂	详情	详情
(XVIII)	14833	methyl 2-[2-[(3aR,7aS)-2,3,3a,4,7,7a-hexahydro-1H-inden-2-yl]ethoxy]acetate		C₁₄H₂₂O₃	详情	详情
(XIX)	14834	methyl 2-[2-[(2aR,5aS)octahydro-1aH-indeno[5,6-b]oxiren-4-yl]ethoxy]acetate		C₁₄H₂₂O₄	详情	详情
(XX)	14835	methyl 2-[2-[(3R,4S)-3,4-bis(2-oxoethyl)cyclopentyl]ethoxy]acetate		C₁₄H₂₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXIVb)

This new mixture is submitted to a selective epoxidation with (-)-DIPT, titanium tetraisopropoxide and TBHP in order to obtain a mixture of the epoxy alcohol (XXIVa) and the unsaturated alcohol (XXIVb). A chromatographic separation of the mixture followed by desilylation with acetic acid in methanol gives the desired final product.

参考文献中间体

合成目标

【1】 Mealy, N.; Castaner, J.; Pimilprost. Drugs Fut 1996, 21, 4, 369.
【2】 Shimoju. T.; Tanno, N. (Sumitomo Pharmaceuticals Co., Ltd.); Manufacturing method of optically active carbacyclin derivs. JP 1991220158 .
【3】 Muraoka, M.; Nakamura, T.; Sugie, A.; Ono, K.; Yamamoto, M. (Sumitomo Pharmaceuticals Co., Ltd.); Bicyclooctane derivs. and their production and use. EP 0115954 .
【4】 Kawakami, H.; Muraoka, M.; Sugie, A.; Ono, K.; Kojima, A.; Syntheses of new 3-oxa-methano-PGI1 derivatives and their biological properties. Bioorg Med Chem Lett 1993, 3, 12, 2821-6.
【5】 Kawakami, H.; Kojima, A.; Shimoju, T.; Shimaji, K.; Nagata, H.; Muraoka, M.; Tanno, N.; Synthesis and structure-activity relationships of SM-10902, a novel drug for the treatment of peripheral circulatory insufficiency. 111th Annu Meet Pharmaceut Soc Jpn (March 28-30, Tokyo) 1991, Abst 29V 1-036.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXIIIa)	14840	methyl 2-(2-[(2S,3aR,4R,5S,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3R,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate	C₂₉H₅₄O₅Si	详情	详情
(XXIVb)	14841	methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate	C₂₉H₅₄O₅Si	详情	详情
(XXIIIb)	14841	methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate	C₂₉H₅₄O₅Si	详情	详情
(XXIVa)	14842	methyl 2-[2-((2S,3aR,4R,5S,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2S)-3-[(1R,3S)-1-hydroxy-3-methylheptyl]oxiranyl]octahydro-2-pentalenyl)ethoxy]acetate	C₂₉H₅₄O₆Si	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXIIIb)

参考文献中间体

合成目标

【1】 Mealy, N.; Castaner, J.; Pimilprost. Drugs Fut 1996, 21, 4, 369.
【2】 Shimoju. T.; Tanno, N. (Sumitomo Pharmaceuticals Co., Ltd.); Manufacturing method of optically active carbacyclin derivs. JP 1991220158 .
【3】 Muraoka, M.; Nakamura, T.; Sugie, A.; Ono, K.; Yamamoto, M. (Sumitomo Pharmaceuticals Co., Ltd.); Bicyclooctane derivs. and their production and use. EP 0115954 .
【4】 Kawakami, H.; Muraoka, M.; Sugie, A.; Ono, K.; Kojima, A.; Syntheses of new 3-oxa-methano-PGI1 derivatives and their biological properties. Bioorg Med Chem Lett 1993, 3, 12, 2821-6.
【5】 Kawakami, H.; Kojima, A.; Shimoju, T.; Shimaji, K.; Nagata, H.; Muraoka, M.; Tanno, N.; Synthesis and structure-activity relationships of SM-10902, a novel drug for the treatment of peripheral circulatory insufficiency. 111th Annu Meet Pharmaceut Soc Jpn (March 28-30, Tokyo) 1991, Abst 29V 1-036.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXIIIa)	14840	methyl 2-(2-[(2S,3aR,4R,5S,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3R,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate	C₂₉H₅₄O₅Si	详情	详情
(XXIVb)	14841	methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate	C₂₉H₅₄O₅Si	详情	详情
(XXIIIb)	14841	methyl 2-(2-[(2R,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(E,3S,5S)-3-hydroxy-5-methyl-1-nonenyl]octahydro-2-pentalenyl]ethoxy)acetate	C₂₉H₅₄O₅Si	详情	详情
(XXIVa)	14842	methyl 2-[2-((2S,3aR,4R,5S,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-[(2S)-3-[(1R,3S)-1-hydroxy-3-methylheptyl]oxiranyl]octahydro-2-pentalenyl)ethoxy]acetate	C₂₉H₅₄O₆Si	详情	详情

Extended Information