|
【结 构 式】 
|
【分子编号】43955 【品名】tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-[2-(3-hydroxy-2-methylpropyl)-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate 【CA登记号】 |
【 分 子 式 】C31H33F2NO6 【 分 子 量 】553.6029664 【元素组成】C 67.26% H 6.01% F 6.86% N 2.53% O 17.34% |
合成路线1
该中间体在本合成路线中的序号：(XII)Addition of the organozinc reagent (II) to the cyclic anhydride (I) produced keto acid (III). After activation of the carboxyl group of (III) with carbonyl diimidazole, condensation with the lithium enolate of tert-butyl acetate furnished keto ester (IV). This was subsequently cyclized to the cyclopentapyridine system (V) upon treatment with silica in CHCl3. Addition of 2,2-difluoro-1,3-benzodioxol-5-ylmagnesium bromide (VI) to the keto group of (V) gave carbinol (VII). After hydroxyl group acetylation, hydrogenation of the olefin and simultaneous hydrogenolysis of the O-benzyl groups of (VII) over Pd/C yielded (VIII). Further epimerization of the carboxylate group of (VIII) in the presence of potassium tert-butoxide afforded isomer (IX). After conversion of (IX) to the aryl triflate (X), palladium-catalyzed coupling of (X) with allylic alcohol (XI) produced (XII).
| 【1】 Hayama, T.; Ohtake, N.; Niiyama, K.; et al.; New cyclopentenopyridine derivatives. A potent, orally active, selective endothelin ETA receptor antagonist. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-78. |
| 【2】 Nishikibe, M.; Hayama, T.; Otake, N. (Banyu Pharmaceutical Co., Ltd.); Substd. 5-(2,2-difluoro-1,3-benzodioxol-5-yl) cyclopentenopyridine deriv.. EP 1049691; WO 9937639 . |
| 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) | 17247 | furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride | 699-98-9 | C7H3NO3 | 详情 | 详情 |
| (II) | 27599 | [2-(benzyloxy)-4-methoxyphenyl](chloro)zinc | C14H13ClO2Zn | 详情 | 详情 | |
| (III) | 43947 | 2-[2-(benzyloxy)-4-methoxybenzoyl]nicotinic acid | C21H17NO5 | 详情 | 详情 | |
| (IV) | 43948 | tert-butyl 3-[2-[2-(benzyloxy)-4-methoxybenzoyl]-3-pyridinyl]-3-oxopropanoate | C27H27NO6 | 详情 | 详情 | |
| (V) | 43949 | tert-butyl 7-[2-(benzyloxy)-4-methoxyphenyl]-5-oxo-5H-cyclopenta[b]pyridine-6-carboxylate | C27H25NO5 | 详情 | 详情 | |
| (VI) | 43950 | bromo(2,2-difluoro-1,3-benzodioxol-5-yl)magnesium | C7H3BrF2MgO2 | 详情 | 详情 | |
| (VII) | 43951 | tert-butyl 7-[2-(benzyloxy)-4-methoxyphenyl]-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-hydroxy-5H-cyclopenta[b]pyridine-6-carboxylate | C34H29F2NO7 | 详情 | 详情 | |
| (VIII) | 43952 | tert-butyl (5S,6S,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(2-hydroxy-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C27H25F2NO6 | 详情 | 详情 | |
| (IX) | 43953 | tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(2-hydroxy-4-methoxyphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C27H25F2NO6 | 详情 | 详情 | |
| (X) | 43954 | tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-(4-methoxy-2-[[(trifluoromethyl)sulfonyl]oxy]phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C28H24F5NO8S | 详情 | 详情 | |
| (XI) | 43956 | 2-methyl-2-propen-1-ol | 513-42-8 | C4H8O | 详情 | 详情 |
| (XII) | 43955 | tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-[2-(3-hydroxy-2-methylpropyl)-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C31H33F2NO6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)Resolution of (XII) by chiral HPLC and then acetylation of the hydroxyl group gave the chiral acetate (XIII). The pyridine ring of (XIII) was converted to the corresponding N-oxide (XIV) by means of meta-chloroperbenzoic acid. Subsequent displacement of the N-oxide of (XIV) with N-isopropyl-benzimidoyl chloride (XV) introduced the N-benzoyl-N-isopropylamino group into the pyridine to afford (XVI). After tert-butyl ester cleavage with trifluoroacetic acid, yielding (XVIII), basic hydrolysis of the benzamido group provided the title compound.
| 【1】 Hayama, T.; Ohtake, N.; Niiyama, K.; et al.; New cyclopentenopyridine derivatives. A potent, orally active, selective endothelin ETA receptor antagonist. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PA-78. |
| 【2】 Nishikibe, M.; Hayama, T.; Otake, N. (Banyu Pharmaceutical Co., Ltd.); Substd. 5-(2,2-difluoro-1,3-benzodioxol-5-yl) cyclopentenopyridine deriv.. EP 1049691; WO 9937639 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 43955 | tert-butyl (5S,6R,7R)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-[2-(3-hydroxy-2-methylpropyl)-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C31H33F2NO6 | 详情 | 详情 | |
| (XIII) | 43957 | tert-butyl (5S,6R,7R)-7-[2-[3-(acetoxy)-2-methylpropyl]-4-methoxyphenyl]-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C33H35F2NO7 | 详情 | 详情 | |
| (XIV) | 43958 | (5S,6R,7R)-7-[2-[3-(acetoxy)-2-methylpropyl]-4-methoxyphenyl]-6-(tert-butoxycarbonyl)-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-6,7-dihydro-5H-cyclopenta[b]pyridinium-1-olate | C33H35F2NO8 | 详情 | 详情 | |
| (XV) | 43959 | N-isopropylbenzenecarboximidoyl chloride | C10H12ClN | 详情 | 详情 | |
| (XVI) | 43960 | tert-butyl (5S,6R,7R)-2-[benzoyl(isopropyl)amino]-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-[2-(3-hydroxy-2-methylpropyl)-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylate | C41H44F2N2O7 | 详情 | 详情 | |
| (XVII) | 43961 | (5S,6R,7R)-2-[benzoyl(isopropyl)amino]-5-(2,2-difluoro-1,3-benzodioxol-5-yl)-7-[2-(3-hydroxy-2-methylpropyl)-4-methoxyphenyl]-6,7-dihydro-5H-cyclopenta[b]pyridine-6-carboxylic acid | C37H36F2N2O7 | 详情 | 详情 |