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【结 构 式】 
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【分子编号】27569 【品名】tert-butyl (3R)-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]-3-(6-butyl-3-formyl-2-pyridinyl)propanoate 【CA登记号】 |
【 分 子 式 】C34H53NO5Si 【 分 子 量 】583.88406 【元素组成】C 69.94% H 9.15% N 2.4% O 13.7% Si 4.81% |
合成路线1
该中间体在本合成路线中的序号：(XXIII)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：(XXIII)Addition of Grignard reagent (XXIV) to this aldehyde (XXIII) at -78 C produced the diastereomeric mixture of alcohols (XXV), which was oxidized to ketone (XXVI) with tetrapropylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide. The tert-butyl ester group of (XXVI) was then transesterified with n-butanol and Ti(OBu)4 to ester (XXVII). Cyclization of ketoester (XXVII) was performed in the presence of lithium hexamethyldisilazide to produce the cyclopentapyridine system (XXVIII). This mixture of tertiary alcohols was deoxygenated with triethylsilane and a Lewis acid to yield (XXIX) as the major diastereoisomer.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XXIV) | 27570 | 1,3-benzodioxol-5-yl(bromo)magnesium | C7H5BrMgO2 | 详情 | 详情 | |
| (XXV) | 27571 | tert-butyl (3R)-3-[3-[1,3-benzodioxol-5-yl(hydroxy)methyl]-6-butyl-2-pyridinyl]-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate | C41H59NO7Si | 详情 | 详情 | |
| (XXVI) | 27572 | tert-butyl (3R)-3-[3-(1,3-benzodioxol-5-ylcarbonyl)-6-butyl-2-pyridinyl]-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate | C41H57NO7Si | 详情 | 详情 | |
| (XXVII) | 27573 | butyl (3R)-3-[3-(1,3-benzodioxol-5-ylcarbonyl)-6-butyl-2-pyridinyl]-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate | C41H57NO7Si | 详情 | 详情 | |
| (XXVIII) | 27574 | butyl (6S,7R)-5-(1,3-benzodioxol-5-yl)-2-butyl-7-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]-5-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C41H57NO7Si | 详情 | 详情 | |
| (XXIX) | 27575 | butyl (5S,6R,7R)-5-(1,3-benzodioxol-5-yl)-2-butyl-7-[2-[(2S)-3-hydroxy-2-methylpropyl]-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C35H43NO6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)The cyclization of the intermediate 3-(6-butyl-3-formylpyridin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) with the chiral auxiliary (XV) by means of AcOH gives the chiral oxazolidine (XVI), which is enantioselectively condensed with the intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) by means of n-BuLi to yield the adduct (XVII). Elimination of the chiral auxiliary with citric acid affords the aldehyde (XVIII), which is treated with 1,3-benzodioxol-5-ylmagnesium bromide (XIX) to provide the corresponding secondary alcohol (XX). Alternatively, the cyclization of the intermediate 3-(6-butyl-3-formylpyidin-2-yl)-2(E)-propenoic acid tert-butyl ester (VI) with the chiral auxiliary (XXI) by means of AcOH gives the chiral oxazolidine (XXII), which is enantioselectively condensed with the intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) by means of n-BuLi to yield the adduct (XXIII). Elimination of the chiral auxiliary with citric acid affords the previously reported aldehyde (XVIII).
| 【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 |
|---|---|---|---|---|---|---|
| (VI) | 27564 | tert-butyl (E)-3-(6-butyl-3-formyl-2-pyridinyl)-2-propenoate | C17H23NO3 | 详情 | 详情 | |
| (XIV) | 27567 | 4-bromo-3-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)phenyl methyl ether | C17H29BrO2Si | 详情 | 详情 | |
| (XV) | 38554 | (1S,2R)-1-(methylamino)-2,3-dihydro-1H-inden-2-ol | C10H13NO | 详情 | 详情 | |
| (XVI) | 38555 | tert-butyl (E)-3-[6-butyl-3-(3-methyl-2,3-dihydro-1,3-benzoxazol-2-yl)-2-pyridinyl]-2-propenoate | C24H30N2O3 | 详情 | 详情 | |
| (XVII) | 38556 | tert-butyl (3R)-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]-3-[6-butyl-3-(3-methyl-2,3-dihydro-1,3-benzoxazol-2-yl)-2-pyridinyl]propanoate | C41H60N2O5Si | 详情 | 详情 | |
| (XVIII) | 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 | |
| (XIX) | 27570 | 1,3-benzodioxol-5-yl(bromo)magnesium | C7H5BrMgO2 | 详情 | 详情 | |
| (XX) | 38557 | tert-butyl (3R)-3-[3-[(R)-1,3-benzodioxol-5-yl(hydroxy)methyl]-6-butyl-2-pyridinyl]-3-[2-((2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropyl)-4-methoxyphenyl]propanoate | C41H59NO7Si | 详情 | 详情 | |
| (XXI) | 34409 | (1S,2S)-2-(methylamino)-1-phenyl-1-propanol | 90-82-4 | C10H15NO | 详情 | 详情 |
| (XXII) | 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 | |
| (XXIII) | 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 |