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【结 构 式】 
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【分子编号】27570 【品名】1,3-benzodioxol-5-yl(bromo)magnesium 【CA登记号】 |
【 分 子 式 】C7H5BrMgO2 【 分 子 量 】225.3245 【元素组成】C 37.31% H 2.24% Br 35.46% Mg 10.79% O 14.2% |
合成路线1
该中间体在本合成路线中的序号：(XXIV)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2
该中间体在本合成路线中的序号：(XXIV)In a further procedure, pyridine-2,3-dicarboxylic acid (L) was esterified with MeOH and SOCl2 and then oxidized to the N-oxide (LI), which by treatement with POCl3 gave chloropyridine (LII). Then, substitution of the halogen atom of (LII) for a butyl group using n-BuLi in the presence of ZnCl2 and palladium catalyst provided butylpyridine (LIII). Saponification of the methyl esters, followed by reaction with Ac2O gave cyclic anhydride (LIV). This was condensed with organozinc reagent (LV) to give ketone (LVI). After activation of (LVI) with carbonyl diimidazole, condensation with the lithium enolate of ethyl acetate, followed by cyclization produced cyclopentenone (LVII). This was condensed with Grignard reagent (XXIV) to give (LVIII) and then reduced with Zn and HCl and isomerized in the presence of EtONa to provide (LIX) as a racemic mixture.
| 【1】 Niiyama, K.; et al.; A potent, orally active, most balanced ETA/ETB dual endothelin receptor antagonist. Discovery of J-104132. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.297. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 27570 | 1,3-benzodioxol-5-yl(bromo)magnesium | C7H5BrMgO2 | 详情 | 详情 | |
| (L) | 17246 | 2,3-pyridinedicarboxylic acid; Quinolinic Acid | 89-00-9 | C7H5NO4 | 详情 | 详情 |
| (LI) | 27595 | 2,3-bis(methoxycarbonyl)-1-pyridiniumolate | C9H9NO5 | 详情 | 详情 | |
| (LII) | 27596 | dimethyl 6-chloro-2,3-pyridinedicarboxylate | C9H8ClNO4 | 详情 | 详情 | |
| (LIII) | 27597 | dimethyl 6-butyl-2,3-pyridinedicarboxylate | C13H17NO4 | 详情 | 详情 | |
| (LIV) | 27598 | 2-butylfuro[3,4-b]pyridine-5,7-dione | C11H11NO3 | 详情 | 详情 | |
| (LV) | 27599 | [2-(benzyloxy)-4-methoxyphenyl](chloro)zinc | C14H13ClO2Zn | 详情 | 详情 | |
| (LVI) | 27600 | 2-[2-(benzyloxy)-4-methoxybenzoyl]-6-butylnicotinic acid | C25H25NO5 | 详情 | 详情 | |
| (LVII) | 27601 | ethyl 7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-5-oxo-5H-cyclopenta[b]pyridine-6-carboxylate | C25H25NO5 | 详情 | 详情 | |
| (LVIII) | 27602 | ethyl 5-(1,3-benzodioxol-5-yl)-7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-5-hydroxy-5H-cyclopenta[b]pyridine-6-carboxylate | C36H35NO7 | 详情 | 详情 | |
| (LIX) | 27603 | ethyl (5S,6R,7R)-5-(1,3-benzodioxol-5-yl)-7-[2-(benzyloxy)-4-methoxyphenyl]-2-butyl-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C36H37NO6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIX)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 |