4-Methylbenzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】10161

【品名】4-Methylbenzaldehyde

【CA登记号】104-87-0

【分子式】C₈H₈O

【分子量】120.15092

【元素组成】C 79.97% H 6.71% O 13.32%

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：(III)

A synthesis of deuterium-labeled acrivastine has been published. The reaction of 2,6-dibromopyridine (I) with butyllithium in ethyl ether gives the monolithium salt (II), which is condensed with perdeuterated 4-methylbenzaldehyde (III) in the same solvent to yield the methanol (IV). The oxidation of (IV) with pyridinium chlorochromate in dichloromethane affords the corresponding ketone (V), which is condensed with ethyl acrylate (VI) by means of palladium acetate, triphenylphosphine and tributylamine at 130 C to give 3-[6-([2H]-4-methylbenzoyl)pyridin-2-yl]acrylic acid ethyl ester (VII). The Wittig condensation of (VII) with triphenyl[2-(1-pyrrolidinyl)ethyl]phosphonium bromide (VIII) by means of butyllithium in THF affords a cis:trans mixture that is submitted to chromatography yielding the (E,E)-isomer (IX), which is finally hydrolyzed with NaOH in ethanol, at room temperature.

参考文献中间体

合成目标

【1】 Thompson, J.B.; Blake, K.W.; McNutt, R.W.; Synthesis of deuterium-labeled acrivastine and an acrivastine metabolite. J Label Compd Radiopharm 1995, 36, 10, 973.

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)	10159	2,6-Dibromopyridine	626-05-1	C₅H₃Br₂N	详情	详情
(II)	10160	(6-Bromo-2-pyridinyl)lithium		C₅H₃BrLiN	详情	详情
(III)	10161	4-Methylbenzaldehyde	104-87-0	C₈H₈O	详情	详情
(III)	44590	4-methylbenzaldehyde		C₈H₈O	详情	详情
(IV)	10162	(6-Bromo-2-pyridinyl)(4-methylphenyl)methanol		C₁₃H₁₂BrNO	详情	详情
(IV)	44591	(6-bromo-2-pyridinyl)(4-methylphenyl)methanol		C₁₃H₁₂BrNO	详情	详情
(V)	10163	(6-Bromo-2-pyridinyl)(4-methylphenyl)methanone		C₁₃H₁₀BrNO	详情	详情
(V)	44592	(6-bromo-2-pyridinyl)(4-methylphenyl)methanone		C₁₃H₁₀BrNO	详情	详情
(VI)	10164	ethyl acrylate	140-88-5	C₅H₈O₂	详情	详情
(VII)	10165	ethyl (E)-3-[6-(4-methylbenzoyl)-2-pyridinyl]-2-propenoate		C₁₈H₁₇NO₃	详情	详情
(VII)	44593	ethyl (E)-3-[6-(4-methylbenzoyl)-2-pyridinyl]-2-propenoate		C₁₈H₁₇NO₃	详情	详情
(VIII)	10166	Triphenyl[2-(1-pyrrolidinyl)ethyl]phosphonium bromide		C₂₄H₂₇BrNP	详情	详情
(IX)	10167	ethyl (E)-3-[6-[(E)-1-(4-methylphenyl)-3-(1-pyrrolidinyl)-1-propenyl]-2-pyridinyl]-2-propenoate		C₂₄H₂₈N₂O₂	详情	详情
(IX)	44594	ethyl (E)-3-[6-[(E)-1-(4-methylphenyl)-3-(1-pyrrolidinyl)-1-propenyl]-2-pyridinyl]-2-propenoate		C₂₄H₂₈N₂O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Demethylation of methyl 4-(4-methoxyphenyl)butyrate (I) using boron tribromide affords phenol (II). Subsequent alkylation of (II) with t-butyl 2-bromoisobutyrate (III) yields ether (IV). The methyl ester group of (IV) is then selectively displaced with hydrazine hydrate to form hydrazide (V). This is condensed with p-methylbenzaldehyde (VI) to give hydrazone (VII), which is further reduced to (VIII) by catalytic hydrogenation over PtO2. Reaction of acyl hydrazide (VIII) with trimethylsilyl isocyanate leads to the acyl semicarbazide (IX). Finally, simultaneous t-butyl ester cleavage and cyclization to the target triazolone is accomplished by treatment of (IX) with several different sulfonic acids.

参考文献中间体

合成目标

【1】 Braden, T.; et al.; Novel acid-catalyzed synthesis of triazolones from acyl semicarbazides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 381.
【2】 Perixosome proliferator activated receptor alpha agonists. WO 0238553 .

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)	57580	methyl 4-(4-methoxyphenyl)butanoate		C₁₂H₁₆O₃	详情	详情
(II)	57581	methyl 4-(4-hydroxyphenyl)butanoate		C₁₁H₁₄O₃	详情	详情
(III)	34947	tert-butyl 2-bromo-2-methylpropanoate	23877-12-5	C₈H₁₅BrO₂	详情	详情
(IV)	57582	methyl 4-{4-[2-(tert-butoxy)-1,1-dimethyl-2-oxoethoxy]phenyl}butanoate		C₁₉H₂₈O₅	详情	详情
(V)	57583	tert-butyl 2-[4-(4-hydrazino-4-oxobutyl)phenoxy]-2-methylpropanoate		C₁₈H₂₈N₂O₄	详情	详情
(VI)	10161	4-Methylbenzaldehyde	104-87-0	C₈H₈O	详情	详情
(VII)	57584	tert-butyl 2-methyl-2-[4-(4-{2-[(E)-(4-methylphenyl)methylidene]hydrazino}-4-oxobutyl)phenoxy]propanoate		C₂₆H₃₄N₂O₄	详情	详情
(VIII)	57585	tert-butyl 2-methyl-2-(4-{4-[2-(4-methylbenzyl)hydrazino]-4-oxobutyl}phenoxy)propanoate		C₂₆H₃₆N₂O₄	详情	详情
(IX)	57586	tert-butyl 2-(4-{4-[2-(aminocarbonyl)-2-(4-methylbenzyl)hydrazino]-4-oxobutyl}phenoxy)-2-methylpropanoate		C₂₇H₃₇N₃O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

Reductive alkylation of tert-butyl carbazate (VI) with 4-methylbenzaldehyde (VII) under catalytic hydrogenation conditions affords the N-p-methylbenzyl carbazate (VIII). This is then condensed with trimethylsilyl isocyanate to form the semicarbazide derivative (IX). Subsequent acidic Boc group cleavage in (IX) yields (X). Semicarbazide (X) is then acylated with acid chloride (V) producing (XI). Cyclization of the acyl semicarbazide (XI) in the presence of CSA leads to triazolone (XII). Finally, alkaline hydrolysis of the ethyl ester group of (XII) furnishes the title carboxylic acid.

参考文献中间体

合成目标

【1】 Braden, T.; et al.; Novel acid-catalyzed synthesis of triazolones from acyl semicarbazides. 224th ACS Natl Meet (Aug 18 2002, Boston) 2002, Abst MEDI 381.
【2】 Perixosome proliferator activated receptor alpha agonists. WO 0238553 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	57590	ethyl 2-[4-(4-chloro-4-oxobutyl)phenoxy]-2-methylpropanoate		C₁₆H₂₁ClO₄	详情	详情
(VI)	10893	tert-butyl 1-hydrazinecarboxylate; tert-butyl carbazate	870-46-2	C₅H₁₂N₂O₂	详情	详情
(VII)	10161	4-Methylbenzaldehyde	104-87-0	C₈H₈O	详情	详情
(VIII)	57591	tert-butyl 2-(4-methylbenzyl)-1-hydrazinecarboxylate		C₁₃H₂₀N₂O₂	详情	详情
(IX)	57592	tert-butyl 2-(aminocarbonyl)-2-(4-methylbenzyl)-1-hydrazinecarboxylate		C₁₄H₂₁N₃O₃	详情	详情
(X)	57593	1-(4-methylbenzyl)-1-hydrazinecarboxamide		C₉H₁₃N₃O	详情	详情
(XI)	57594	ethyl 2-(4-{4-[2-(aminocarbonyl)-2-(4-methylbenzyl)hydrazino]-4-oxobutyl}phenoxy)-2-methylpropanoate		C₂₅H₃₃N₃O₅	详情	详情
(XII)	57595	ethyl 2-methyl-2-(4-{3-[1-(4-methylbenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]propyl}phenoxy)propanoate		C₂₅H₃₁N₃O₄	详情	详情

Extended Information