phenyl(3-pyridinyl)methanone -Drug Synthesis Database

【结构式】

【分子编号】27766

【品名】phenyl(3-pyridinyl)methanone

【CA登记号】5424-19-1

【分子式】C₁₂H₉NO

【分子量】183.2096

【元素组成】C 78.67% H 4.95% N 7.65% O 8.73%

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：(IV)

The condensation of 6-bromohexanoic acid (I) with triphenylphosphine in refluxing acetonitrile gives the corresponding phosphonium salt (III), which is submitted to a Wittig condensation with phenyl 3-pyridyl ketone (IV) by means of NaH in DMSO, yielding a mixture of the title product and its (Z)-isomer (V). This mixture of isomers is separated by fractional crystallization or HPLC and the isomeric compound (V) is treated with refluxing aqueous 25% HBr to perform its isomerization to CV-415.

参考文献中间体

合成目标

【1】 Kato, K.; et al.; Thromboxane synthetase inhibitors (TXSI). Design, synthesis, and evaluation of a novel series of omega-pyridilalkenoic acids. J Med Chem 1985, 28, 3, 287-294.
【2】 Terao, S.; et al. (Takeda Chemical Industries, Ltd.); Substituted vinylcarboxylic acid derivative and its preparation. JP 58219162 .
【3】 Castaner, J.; Serradell, M.N.; CV-4151. Drugs Fut 1986, 11, 3, 183.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	27765	6-bromohexanoic acid	4224-70-8	C₆H₁₁BrO₂	详情	详情
(III)	18264	(5-Carboxypentyl)triphenylphosphonium bromide; (5-carboxypentyl)(triphenyl)phosphonium bromide	50889-29-7	C₂₄H₂₆BrO₂P	详情	详情
(IV)	27766	phenyl(3-pyridinyl)methanone	5424-19-1	C₁₂H₉NO	详情	详情
(V)	27767	(Z)-7-phenyl-7-(3-pyridinyl)-6-heptenoic acid		C₁₈H₁₉NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Alkylation of 3-benzoylpyridine (I) with methyl 2-bromopropionate (II) in refluxing acetone afforded pyridinium salt (III). The subsequent regiospecific copper-catalyzed condensation of (III) with cyclohexylmagesium chloride (IV) yielded dihydropyridine (V). Finally, ammonolysis of the methyl acetate ester of (V) provided the title amide.

参考文献中间体

合成目标

【1】 Agudoawu, S.A.; et al.; Synthesis and analgesic activity of 2-methyl-2-[1-(3-benzoyl-4-substituted-1,4-dihydropyridyl)]acetic acid methyl esters, acetic acids, and acetamides. Arch Pharm 1999, 332, 6, 213.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	27766	phenyl(3-pyridinyl)methanone	5424-19-1	C₁₂H₉NO	详情	详情
(II)	34941	methyl 2-bromopropanoate; 2-bromopropionic acid methyl ester	5445-17-0	C₄H₇BrO₂	详情	详情
(III)	34942	3-benzoyl-1-(2-methoxy-1-methyl-2-oxoethyl)pyridinium bromide		C₁₆H₁₆BrNO₃	详情	详情
(IV)	31866	chloro(cyclohexyl)magnesium		C₆H₁₁ClMg	详情	详情
(V)	34943	methyl 2-[3-benzoyl-4-cyclohexyl-1(4H)-pyridinyl]propanoate		C₂₂H₂₇NO₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Nitration of 3-benzoylpyridine (I) with KNO3 in sulfuric acid yielded the meta-nitrobenzoyl derivative (II). Wadsworth-Emmons reaction of ketone (II) with triethyl phosphonoacetate produced the unsaturated ester (IIIa-b) as a mixture of geometric isomers. Nitro group reduction in (IIIa-b) employing Fe and HCl gave aniline (IVa-b), which was condensed with 4-methoxybenzenesulfonyl chloride (V) to afford sulfonamide (VIa-b). After conversion of the pyridine ring of (VIa-b) to the corresponding N-oxide (VIIa-b) with m-chloroperbenzoic acid, the sulfonamide N atom of (VIIa-b) was alkylated with isopropyl iodide and K2CO3 to produce (VIIIa-b). Reduction of the N-oxide of (VIIIa-b) by means of Fe and HOAc, followed by basic hydrolysis of the ethyl ester, furnished acid (IXa-b). This was then coupled with O-t-butyldimethylsilyl hydroxylamine to provide, after separation of the Z/E isomeric mixture, the desired hydroxamic acid.

参考文献中间体

合成目标

【1】 Hirata, T.; et al.; Discovery of potent, highly selective, and orally active propenohydroxamate TNF-alpha converting enzyme (TACE) inhibitors. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 262.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIIa)	51303	ethyl (E)-3-(3-nitrophenyl)-3-(3-pyridinyl)-2-propenoate		C₁₆H₁₄N₂O₄	详情	详情
(IIIb)	51304	ethyl (Z)-3-(3-nitrophenyl)-3-(3-pyridinyl)-2-propenoate		C₁₆H₁₄N₂O₄	详情	详情
(IVa)	51305	ethyl (E)-3-(3-aminophenyl)-3-(3-pyridinyl)-2-propenoate		C₁₆H₁₆N₂O₂	详情	详情
(IVb)	51306	ethyl (Z)-3-(3-aminophenyl)-3-(3-pyridinyl)-2-propenoate		C₁₆H₁₆N₂O₂	详情	详情
(VIa)	51307	ethyl (E)-3-(3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-(3-pyridinyl)-2-propenoate		C₂₃H₂₂N₂O₅S	详情	详情
(VIb)	51308	ethyl (Z)-3-(3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-(3-pyridinyl)-2-propenoate		C₂₃H₂₂N₂O₅S	详情	详情
(VIIa)	51309	3-[(E)-3-ethoxy-1-(3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-oxo-1-propenyl]-1-pyridiniumolate		C₂₃H₂₂N₂O₆S	详情	详情
(VIIb)	51310	3-[(Z)-3-ethoxy-1-(3-[[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-oxo-1-propenyl]-1-pyridiniumolate		C₂₃H₂₂N₂O₆S	详情	详情
(VIIIa)	51311	3-[(Z)-3-ethoxy-1-(3-[isopropyl[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-oxo-1-propenyl]-1-pyridiniumolate		C₂₆H₂₈N₂O₆S	详情	详情
(VIIIb)	51312	3-[(E)-3-ethoxy-1-(3-[isopropyl[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-oxo-1-propenyl]-1-pyridiniumolate		C₂₆H₂₈N₂O₆S	详情	详情
(IXa)	51313	(E)-3-(3-[isopropyl[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-(3-pyridinyl)-2-propenoic acid		C₂₄H₂₄N₂O₅S	详情	详情
(IXb)	51314	(Z)-3-(3-[isopropyl[(4-methoxyphenyl)sulfonyl]amino]phenyl)-3-(3-pyridinyl)-2-propenoic acid		C₂₄H₂₄N₂O₅S	详情	详情
(I)	27766	phenyl(3-pyridinyl)methanone	5424-19-1	C₁₂H₉NO	详情	详情
(II)	51302	(3-nitrophenyl)(3-pyridinyl)methanone		C₁₂H₈N₂O₃	详情	详情
(V)	15719	4-methoxybenzenesulfonyl chloride	98-68-0	C₇H₇ClO₃S	详情	详情

Extended Information