2,6-di(tert-butyl)-4-methoxyphenyl 4-fluorobenzoate -Drug Synthesis Database

【结构式】

【分子编号】41458

【品名】2,6-di(tert-butyl)-4-methoxyphenyl 4-fluorobenzoate

【CA登记号】

【分子式】C₂₂H₂₇FO₃

【分子量】358.4529832

【元素组成】C 73.72% H 7.59% F 5.3% O 13.39%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

Condensation of 1,3-dimethyl-4-piperidone (I) with aniline in the presence of titanium tetraisopropoxide produced imine (II). This was reduced with NaBH4 to give the corresponding amine as a mixture of geometric isomers, from which the desired cis isomer (III) was isolated by column chromatography. Coupling of (III) with 4-fluorobenzoate ester (IV) in the presence of butyllithium yielded the diaryl amine (V). Removal of the 2,6-di-tert-butyl-4-methoxyphenyl ester of (V) was accomplished by transesterification with sodium methoxide, followed by saponification of the methyl ester. The resulting carboxylic acid (VI) was then converted into diethyl amide (VII) using diethylamine and BOP reagent. N-Demethylation of (VII) with phenyl chloroformate furnished the phenyl carbamate (VIII), that was further hydrolyzed and decarboxylated to give piperidine (IX). This was finally alkylated with allyl bromide in the presence of K2CO3.

参考文献中间体

合成目标

【1】 Carroll, F.I.; Thomas, J.B.; Dersch, C.M.; Rothman, R.B.; Mascarella, S.W.; Burges, J.P.; Xu, H.; Herault, X.M.; Horel, R.B.; (±)-4-[(N-Allyl-cis-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 20, 3053.
【2】 Carroll, F.I.; Novel opiate cpds., methods of making and methods of use. WO 9945925 .

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)	16614	1,3-dimethyltetrahydro-4(1H)-pyridinone; 1,3-Dimethyl-4-piperidone	4629-80-5	C₇H₁₃NO	详情	详情
(II)	41966	N-(1,3-dimethyl-4-piperidinylidene)-N-phenylamine; N-(1,3-dimethyl-4-piperidinylidene)aniline		C₁₃H₁₈N₂	详情	详情
(III)	41968	N-[(3R,4S)-1,3-dimethylpiperidinyl]-N-phenylamine; (3R,4S)-1,3-dimethyl-N-phenyl-4-piperidinamine		C₁₃H₂₀N₂	详情	详情
(IV)	41458	2,6-di(tert-butyl)-4-methoxyphenyl 4-fluorobenzoate		C₂₂H₂₇FO₃	详情	详情
(V)	41969	2,6-di(tert-butyl)-4-methoxyphenyl 4-[[(3R,4S)-1,3-dimethylpiperidinyl]anilino]benzoate		C₃₅H₄₆N₂O₃	详情	详情
(VI)	41970	4-[[(3R,4S)-1,3-dimethylpiperidinyl]anilino]benzoic acid		C₂₀H₂₄N₂O₂	详情	详情
(VII)	41971	4-[[(3R,4S)-1,3-dimethylpiperidinyl]anilino]-N,N-diethylbenzamide		C₂₄H₃₃N₃O	详情	详情
(VIII)	41967	phenyl (3R,4S)-4-[4-[(diethylamino)carbonyl](phenyl)anilino]-3-methyl-1-piperidinecarboxylate		C₃₀H₃₅N₃O₃	详情	详情
(IX)	41972	N,N-diethyl-4-[[(3R,4S)-3-methylpiperidinyl]anilino]benzamide		C₂₃H₃₁N₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

The reductocondensation of 3-methyl-4-oxopiperidine-1-carboxylic acid methyl ester (I) with aniline (II) by means of TsOH and NaBH4 in refluxing toluene gives 3-methyl-4-(phenylamino)piperidine-1-carboxylic acid methyl ester (III), which is acylated with propionyl anhydride yielding the corresponding propionamide as a mixture of cis and trans isomers, from which the racemic cis isomer (rac)-(IV) is isolated by crystallization. The optical resolution of (rac)-(IV) with d-tartaric acid followed by treatment with NaOH affords (3S.4R)-3-methyl-4-(phenylamino)piperidine (3S,4R)-(V), which is methylated with methyl iodide and K2CO3 to provide (3S,4R)-1,3-dimethyl-4-(phenylamino)piperidine (VI) (1). The condensation of (VI) with the 4-fluorobenzoate (VII) by means of BuLi in THF furnishes the corresponding tertiary amine (VIII), which is transesterified with NaOMe and hydrolyzed with ethanol/water to give the free benzoic acid (IX). The condensation of (IX) with diethylamine by means of BOP and TEA yields the corresponding diethylamide (X), which is demethylated by acylation with phenyl chloroformate and cleavage with KOH to afford the free piperidine NH compound (XI). Finally this piperidine derivative is allylated with allyl bromide (XII) and K2CO3 in ethanol.

参考文献中间体

合成目标

【1】 Niemegeers, C.J.E.; Van Bever, W.F.M.; Janssen, P.A.J.; Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide and N-[3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl]-N-phenylpropanamide. J Med Chem 1974, 17, 10, 1047-1051.
【2】 Carroll, F.I.; Thomas, J.B.; Dersch, C.M.; Rothman, R.B.; Mascarella, S.W.; Burges, J.P.; Xu, H.; Herault, X.M.; Horel, R.B.; (±)-4-[(N-Allyl-cis-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 20, 3053.
【3】 Carroll, F.I.; Horel, R.B.; Rothman, R.B.; Mascarella, S.W.; Dersch, C.M.; Atkinson, R.N.; Xu, H.; Herault, X.M.; Thomas, J.B.; Optically pure (-)-4-[(N-allyl-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide displays selective binding and full agonist activity for the delta opioid receptor. Bioorg Med Chem Lett 1999, 9, 23, 3347.

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)	41454	methyl 3-methyl-4-oxo-1-piperidinecarboxylate		C₈H₁₃NO₃	详情	详情
(II)	12294	Aniline; Phenylamine	62-53-3	C₆H₇N	详情	详情
(III)	41455	methyl 4-anilino-3-methyl-1-piperidinecarboxylate		C₁₄H₂₀N₂O₂	详情	详情
(IV)	41456	methyl (3S,4R)-3-methyl-4-(propionylanilino)-1-piperidinecarboxylate		C₁₇H₂₄N₂O₃	详情	详情
(V)	41457	N-[(3S,4R)-3-methylpiperidinyl]-N-phenylamine; (3S,4R)-3-methyl-N-phenyl-4-piperidinamine		C₁₂H₁₈N₂	详情	详情
(VI)	41459	N-[(3S,4R)-1,3-dimethylpiperidinyl]-N-phenylamine; (3S,4R)-1,3-dimethyl-N-phenyl-4-piperidinamine		C₁₃H₂₀N₂	详情	详情
(VII)	41458	2,6-di(tert-butyl)-4-methoxyphenyl 4-fluorobenzoate		C₂₂H₂₇FO₃	详情	详情
(VIII)	41460	2,6-di(tert-butyl)-4-methoxyphenyl 4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]benzoate		C₃₅H₄₆N₂O₃	详情	详情
(IX)	41461	4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]benzoic acid		C₂₀H₂₄N₂O₂	详情	详情
(X)	41462	4-[[(3S,4R)-1,3-dimethylpiperidinyl]anilino]-N,N-diethylbenzamide		C₂₄H₃₃N₃O	详情	详情
(XI)	41463	N,N-diethyl-4-[[(3S,4R)-3-methylpiperidinyl]anilino]benzamide		C₂₃H₃₁N₃O	详情	详情
(XII)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情

Extended Information