2-bromo-6-butylnicotinonitrile -Drug Synthesis Database

【结构式】

【分子编号】27562

【品名】2-bromo-6-butylnicotinonitrile

【CA登记号】

【分子式】C₁₀H₁₁BrN₂

【分子量】239.11482

【元素组成】C 50.23% H 4.64% Br 33.42% N 11.72%

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：(XIV)

Pyridone (XII) was converted to its dianion with LDA and then alkylated with propyl bromide to give the butyl pyridone (XIII). This was converted into bromopyridine (XIV) by subsequent treatment with PBr3. The nitrile group of (XIV) was then reduced to aldehyde (XV) using diisobutylaluminum hydride. The aldehye (XV) underwent a Heck reaction with tert-butyl acrylate (XVI) using tri-o-tolylphosphine and a palladium catalyst to provide unsaturated ester (XVII). Further condensation of the aldehyde group of (XVII) with (S,S)-pseudoephedrine (XVIII) produced the chiral oxazolidine (XIX). Alcohol (XI) was then protected as the silyl ether (XXI) using tert-butyldimethylsilyl chloride. After its conversion to the organolithium reagent with tert-butyllithium, addition to pyridyl acrylate (XIX) gave intermediate (XXII), and further acidic work-up removed the chiral auxiliary to afford aldehyde (XXIII).

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
(XI)	27558	(2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol		C₁₁H₁₅BrO₂	详情	详情
(XII)	27560	6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile	4241-27-4	C₇H₆N₂O	详情	详情
(XIII)	27561	6-butyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile		C₁₀H₁₂N₂O	详情	详情
(XIV)	27562	2-bromo-6-butylnicotinonitrile		C₁₀H₁₁BrN₂	详情	详情
(XV)	27563	2-bromo-6-butylnicotinaldehyde		C₁₀H₁₂BrNO	详情	详情
(XVI)	12760	tert-butyl acrylate	1663-39-4	C₇H₁₂O₂	详情	详情
(XVII)	27564	tert-butyl (E)-3-(6-butyl-3-formyl-2-pyridinyl)-2-propenoate		C₁₇H₂₃NO₃	详情	详情
(XVIII)	27565	(1S,2S)-2-amino-1-phenyl-1-propanol		C₉H₁₃NO	详情	详情
(XIX)	27566	tert-butyl (E)-3-[6-butyl-3-[(4S,5S)-3,4-dimethyl-5-phenyl-1,3-oxazolidin-2-yl]-2-pyridinyl]-2-propenoate		C₂₇H₃₆N₂O₃	详情	详情
(XX)	10255	Imidazole; 1H-Imidazole	288-32-4	C₃H₄N₂	详情	详情
(XXI)	27567	4-bromo-3-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)phenyl methyl ether		C₁₇H₂₉BrO₂Si	详情	详情
(XXII)	27568	tert-butyl (3R)-3-[6-butyl-3-[(4S,5S)-3,4-dimethyl-5-phenyl-1,3-oxazolidin-2-yl]-2-pyridinyl]-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate		C₄₄H₆₆N₂O₅Si	详情	详情
(XXIII)	27569	tert-butyl (3R)-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]-3-(6-butyl-3-formyl-2-pyridinyl)propanoate		C₃₄H₅₃NO₅Si	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The intermediate 3-(6-butyl-3-formylpyridin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) has been obtained as follows: the alhylation of 2-hydroxy-6-methylpyridine-3-carbonitrile (I) with propyl bromide and LDA gives 6-butyl-2-hydroxypyridine-3-carbonitrile (II), which is brominated with tetrabutylammonium bromide and P2O5 yielding the 2-bromo-6-butylpyridine-3-carbonitrile (III). The reduction of (III) with DIBAL affords the corresponding aldehyde (IV), which is finally condensed with tert-butyl acrylate (V) by means of allyl palladium chloride dimer to furnich the target intermediate (VI).

参考文献中间体

合成目标

【1】 Song, Z.J.; et al.; Practical asymetric synthesis of an endothelin receptor antagonist. J Org Chem 1999, 64, 26, 9658.

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)	38551	2-hydroxy-6-methylnicotinonitrile		C₇H₆N₂O	详情	详情
(II)	38552	6-butyl-2-hydroxynicotinonitrile		C₁₀H₁₂N₂O	详情	详情
(III)	27562	2-bromo-6-butylnicotinonitrile		C₁₀H₁₁BrN₂	详情	详情
(IV)	27563	2-bromo-6-butylnicotinaldehyde		C₁₀H₁₂BrNO	详情	详情
(V)	12760	tert-butyl acrylate	1663-39-4	C₇H₁₂O₂	详情	详情
(VI)	27564	tert-butyl (E)-3-(6-butyl-3-formyl-2-pyridinyl)-2-propenoate		C₁₇H₂₃NO₃	详情	详情

Extended Information