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【结 构 式】 
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【分子编号】27558 【品名】(2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol 【CA登记号】 |
【 分 子 式 】C11H15BrO2 【 分 子 量 】259.1429 【元素组成】C 50.98% H 5.83% Br 30.83% O 12.35% |
合成路线1
该中间体在本合成路线中的序号：(XI)Preparation of the precursor alcohol (XI) is outlined in Scheme 1. Reduction of 2-bromo-5-methoxybenzoic acid (I) with borane-dimethylsulfide complex gave benzylic alcohol (II). After conversion of (II) to the corresponding mesylate, treatment with NaBr provided bromide (III). (1R,2S)-Aminoindanol (IV) was acylated with propionyl chloride to afford amide (V), which was converted to acetonide (VII) with 2-methoxypropene (VI) using pyridinium tosylate as the acid catalyst. Acetonide (VII) was then alkylated with bromide (III) in the presence of lithium hexamethyldisilazide at -35 C to give the chiral intermediate (VIII). Hydrolysis of acetonide at 10 C, followed by amide hydrolysis under reflux furnished a mixture of acid (IX) and methyl ester (X). This mixture was then reduced with LiAlH4 to provide the chiral alcohol (XI).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 17819 | 2-bromo-5-methoxybenzoic acid | 22921-68-2 | C8H7BrO3 | 详情 | 详情 |
| (II) | 27551 | (2-bromo-5-methoxyphenyl)methanol | C8H9BrO2 | 详情 | 详情 | |
| (III) | 27552 | 1-bromo-2-(bromomethyl)-4-methoxybenzene | C8H8Br2O | 详情 | 详情 | |
| (IV) | 27559 | (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol | C9H11NO | 详情 | 详情 | |
| (V) | 27553 | N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]propanamide | C12H15NO2 | 详情 | 详情 | |
| (VI) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VII) | 27554 | 1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-1-propanone | C15H19NO2 | 详情 | 详情 | |
| (VIII) | 27555 | (2S)-1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanone | C23H26BrNO3 | 详情 | 详情 | |
| (IX) | 27556 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropionic acid | C11H13BrO3 | 详情 | 详情 | |
| (X) | 27557 | methyl (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropanoate | C12H15BrO3 | 详情 | 详情 | |
| (XI) | 27558 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol | C11H15BrO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)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3
该中间体在本合成路线中的序号：(XI)Intermediate alcohol (XI) was then protected as the benzyl ether (XLII). After its conversion to the corresponding organolithium reagent, addition to pyridine ester (XLI) produced ketone (XLIII). Finally, the title compound was obtained by a similar sequence to that from above, involving cyclization of (XLIII) to (XLIV) with sodium tert-pentoxide, deoxygenation with SmI2, hydrogenolysis of benzyl ether to give (XLV), and then oxidation of (XLV) to acid followed by isopropyl ester hydrolysis.
| 【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 | |
| (XLI) | 27586 | methyl 3-[(1S)-1-(1,3-benzodioxol-5-yl)-3-isopropoxy-3-oxopropyl]-6-butyl-2-pyridinecarboxylate | C24H29NO6 | 详情 | 详情 | |
| (XLII) | 27587 | 2-[(2S)-3-(benzyloxy)-2-methylpropyl]-1-bromo-4-methoxybenzene | C18H21BrO2 | 详情 | 详情 | |
| (XLIII) | 27588 | isopropyl (3S)-3-(1,3-benzodioxol-5-yl)-3-(2-[2-[(2S)-3-(benzyloxy)-2-methylpropyl]-4-methoxybenzoyl]-6-butyl-3-pyridinyl)propanoate | C41H47NO7 | 详情 | 详情 | |
| (XLIV) | 27589 | isopropyl (6S,7R)-5-(1,3-benzodioxol-5-yl)-7-[2-[(2S)-3-(benzyloxy)-2-methylpropyl]-4-methoxyphenyl]-2-butyl-5-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C41H47NO7 | 详情 | 详情 | |
| (XLV) | 27590 | isopropyl (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 | C34H41NO6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The intermediate 3-(2-bromo-5-methoxyphenyl)-2(S)-methyl-1-propanol tert-butyldimethylsilyl ether (XIV) has been obtained as follows: the reduction of 2-bromo-5-methoxybenzoic acid (VII) with NaBH4/BF3 gives the expected benzyl alcohol (VIII), which by treatment with SOCl2 is converted into the benzyl chloride (IX). The condensation of (IX) with the chiral auxiliary (X) by means of LIHMDS provides the 2(S)-methylpropionic acid derivative (XI). Elimination of the chiral auxiliary with sulfuric acid gives 3-(2-bromo-5-methoxyphenyl)-2(S)-methylpropionic acid (XII), which is reduced with NaBH4/BF3 to the corresponding alcohol (XIII). Finally, this compound is silylated to afford the intermediate (XIV) with TBDMS-Cl and imidazole.
| 【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 |
|---|---|---|---|---|---|---|
| (VII) | 17819 | 2-bromo-5-methoxybenzoic acid | 22921-68-2 | C8H7BrO3 | 详情 | 详情 |
| (VIII) | 27551 | (2-bromo-5-methoxyphenyl)methanol | C8H9BrO2 | 详情 | 详情 | |
| (IX) | 38553 | 1-bromo-2-(chloromethyl)-4-methoxybenzene; 4-bromo-3-(chloromethyl)phenyl methyl ether | C8H8BrClO | 详情 | 详情 | |
| (X) | 27554 | 1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-1-propanone | C15H19NO2 | 详情 | 详情 | |
| (XI) | 27555 | (2S)-1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanone | C23H26BrNO3 | 详情 | 详情 | |
| (XII) | 27556 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropionic acid | C11H13BrO3 | 详情 | 详情 | |
| (XIII) | 27558 | (2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol | C11H15BrO2 | 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 |