methyl 3-[(1S)-1-(1,3-benzodioxol-5-yl)-3-isopropoxy-3-oxopropyl]-6-butyl-2-pyridinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】27586

【品名】methyl 3-[(1S)-1-(1,3-benzodioxol-5-yl)-3-isopropoxy-3-oxopropyl]-6-butyl-2-pyridinecarboxylate

【CA登记号】

【分子式】C₂₄H₂₉NO₆

【分子量】427.4974

【元素组成】C 67.43% H 6.84% N 3.28% O 22.46%

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：(XLI)

In a related procedure, chiral oxazoline (XXXV) was prepared by condensation of ethyl acetimidate (XXXIII) with (S,S)-thiomicamine (XXXII), followed by O-methylation with MeI and sodium tert-pentoxide. Condensation of the lithium salt of (XXXV) with diethylchlorophosphate at -78 C provided phosphonate (XXXVI), which was submitted to a Horner-Emmons reaction with pyridine aldehyde (XV) to yield the vinyl oxazoline (XXXVII). Conjugate addition of the organolithium reagent (XXXVIII) to (XXXVII) then produced adduct (XXXIX) as the major diastereoisomer. Hydrolysis of the oxazoline of (XXXIX) upon refluxing in isopropyl alcohol with H2SO4 yielded isopropyl ester (XL). Pyridine carboxylate (XLI) was further obtained by carbonylation of (XL) under atmosphere of CO in the presence of bis(diphenylphosphino)ferrocene and palladium diacetate in MeOH.

参考文献中间体

合成目标

【1】 Frey, L.F.; Devine, P.N.; Tschaen, D.M.; Dolling, U.H.; Tillyer, R.D.; Kato, Y. (Banyu Pharmaceutical Co., Ltd.; Merck & Co., Inc.); Stereoselective deoxygenation reaction. EP 0923557; JP 1999514676; WO 9806700 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	27563	2-bromo-6-butylnicotinaldehyde		C₁₀H₁₂BrNO	详情	详情
(XXXII)	27578	(1S,2S)-2-amino-1-[4-(methylsulfanyl)phenyl]-1,3-propanediol		C₁₀H₁₅NO₂S	详情	详情
(XXXIII)	12831	ethyl ethanimidoate	1000-84-6	C₄H₉NO	详情	详情
(XXXIV)	27579	[(4S,5S)-2-methyl-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazol-4-yl]methanol		C₁₂H₁₅NO₂S	详情	详情
(XXXV)	27580	(4S,5S)-4-(methoxymethyl)-2-methyl-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazole		C₁₃H₁₇NO₂S	详情	详情
(XXXVI)	27581	diethyl [(4S,5S)-4-(methoxymethyl)-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazol-2-yl]methylphosphonate		C₁₇H₂₆NO₅PS	详情	详情
(XXXVII)	27582	2-bromo-6-butyl-3-((E)-2-[(4S,5S)-4-(methoxymethyl)-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazol-2-yl]ethenyl)pyridine		C₂₃H₂₇BrN₂O₂S	详情	详情
(XXXVIII)	27583	1,3-benzodioxol-5-yllithium		C₇H₅LiO₂	详情	详情
(XXXIX)	27584	[(4S,5S)-2-[(2S)-2-(1,3-benzodioxol-5-yl)-2-(2-bromo-6-butyl-3-pyridinyl)ethyl]-5-[4-(methylsulfanyl)phenyl]-4,5-dihydro-1,3-oxazol-4-yl]methyl methyl ether		C₃₀H₃₃BrN₂O₄S	详情	详情
(XL)	27585	isopropyl (3S)-3-(1,3-benzodioxol-5-yl)-3-(2-bromo-6-butyl-3-pyridinyl)propanoate		C₂₂H₂₆BrNO₄	详情	详情
(XLI)	27586	methyl 3-[(1S)-1-(1,3-benzodioxol-5-yl)-3-isopropoxy-3-oxopropyl]-6-butyl-2-pyridinecarboxylate		C₂₄H₂₉NO₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XLI)

Intermediate alcohol (XI) was then protected as the benzyl ether (XLII). After its conversion to the corresponding organolithium reagent, addition to pyridine ester (XLI) produced ketone (XLIII). Finally, the title compound was obtained by a similar sequence to that from above, involving cyclization of (XLIII) to (XLIV) with sodium tert-pentoxide, deoxygenation with SmI2, hydrogenolysis of benzyl ether to give (XLV), and then oxidation of (XLV) to acid followed by isopropyl ester hydrolysis.

参考文献中间体

合成目标

【1】 Frey, L.F.; Devine, P.N.; Tschaen, D.M.; Dolling, U.H.; Tillyer, R.D.; Kato, Y. (Banyu Pharmaceutical Co., Ltd.; Merck & Co., Inc.); Stereoselective deoxygenation reaction. EP 0923557; JP 1999514676; WO 9806700 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	27558	(2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol	C₁₁H₁₅BrO₂	详情	详情
(XLI)	27586	methyl 3-[(1S)-1-(1,3-benzodioxol-5-yl)-3-isopropoxy-3-oxopropyl]-6-butyl-2-pyridinecarboxylate	C₂₄H₂₉NO₆	详情	详情
(XLII)	27587	2-[(2S)-3-(benzyloxy)-2-methylpropyl]-1-bromo-4-methoxybenzene	C₁₈H₂₁BrO₂	详情	详情
(XLIII)	27588	isopropyl (3S)-3-(1,3-benzodioxol-5-yl)-3-(2-[2-[(2S)-3-(benzyloxy)-2-methylpropyl]-4-methoxybenzoyl]-6-butyl-3-pyridinyl)propanoate	C₄₁H₄₇NO₇	详情	详情
(XLIV)	27589	isopropyl (6S,7R)-5-(1,3-benzodioxol-5-yl)-7-[2-[(2S)-3-(benzyloxy)-2-methylpropyl]-4-methoxyphenyl]-2-butyl-5-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate	C₄₁H₄₇NO₇	详情	详情
(XLV)	27590	isopropyl (5S,6R,7R)-5-(1,3-benzodioxol-5-yl)-2-butyl-7-[2-[(2S)-3-hydroxy-2-methylpropyl]-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate	C₃₄H₄₁NO₆	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XLI)

Alternatively, pyridine ester (XLI) was condensed with the organolithium reagent derived from the silyl-protected intermediate (XXI) to give the corresponding ketone (XLVI). Subsequent desilylation of (XLVI) with HF to (XLVII), followed by base-catalyzed aldol cyclization afforded (XLVIII). Then, the sequence of oxidation to acid (XLIX) with Jones reagent, followed by deoxygenation with SmI2 and basic hydrolysis provided the title diacid.

参考文献中间体

合成目标

【1】 Frey, L.F.; Devine, P.N.; Tschaen, D.M.; Dolling, U.H.; Tillyer, R.D.; Kato, Y. (Banyu Pharmaceutical Co., Ltd.; Merck & Co., Inc.); Stereoselective deoxygenation reaction. EP 0923557; JP 1999514676; WO 9806700 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XXI)	27567	4-bromo-3-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)phenyl methyl ether	C₁₇H₂₉BrO₂Si	详情	详情
(XLI)	27586	methyl 3-[(1S)-1-(1,3-benzodioxol-5-yl)-3-isopropoxy-3-oxopropyl]-6-butyl-2-pyridinecarboxylate	C₂₄H₂₉NO₆	详情	详情
(XLVI)	27591	isopropyl (3S)-3-(1,3-benzodioxol-5-yl)-3-[6-butyl-2-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxybenzoyl]-3-pyridinyl]propanoate	C₄₀H₅₅NO₇Si	详情	详情
(XLVII)	27592	isopropyl (3S)-3-(1,3-benzodioxol-5-yl)-3-(6-butyl-2-[2-[(2S)-3-hydroxy-2-methylpropyl]-4-methoxybenzoyl]-3-pyridinyl)propanoate	C₃₄H₄₁NO₇	详情	详情
(XLVIII)	27593	isopropyl (5S,6R)-5-(1,3-benzodioxol-5-yl)-2-butyl-7-hydroxy-7-[2-[(2S)-3-hydroxy-2-methylpropyl]-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate	C₃₄H₄₁NO₇	详情	详情
(XLIX)	27594	(2S)-3-[2-[(5S,6R)-5-(1,3-benzodioxol-5-yl)-2-butyl-7-hydroxy-6-(isopropoxycarbonyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]-5-methoxyphenyl]-2-methylpropionic acid	C₃₄H₃₉NO₈	详情	详情

Extended Information