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【结 构 式】 
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【分子编号】27563 【品名】2-bromo-6-butylnicotinaldehyde 【CA登记号】 |
【 分 子 式 】C10H12BrNO 【 分 子 量 】242.11542 【元素组成】C 49.61% H 5% Br 33% N 5.79% O 6.61% |
合成路线1
该中间体在本合成路线中的序号：(XV)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).
| 【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：(XV)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.
| 【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3
该中间体在本合成路线中的序号：(IV)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).
| 【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 |