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【结 构 式】 
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【分子编号】56574 【品名】6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-(3-methoxy-3-oxopropyl)-4-quinolinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C26H19F2NO4 【 分 子 量 】447.4380064 【元素组成】C 69.79% H 4.28% F 8.49% N 3.13% O 14.3% |
合成路线1
该中间体在本合成路线中的序号：(VI)Keto ester (III) was prepared by Friedel-Crafts acylation of 2-fluorobiphenyl (I) with methyl glutaryl chloride (II). Subsequent Pfitzinger condensation of (III) with 5-fluoroisatin (IV) furnished the quinoline derivative (V). Chlorination of diacid (V) with SOCl2, followed by treatment with methanol produced selectively the mono-ester (VI). The remaining carboxyl group of (VI) was activated with SOCl2 in the presence of DMF, and subsequently coupled with n-octyl amine to generate amide (VII). The methyl ester group of (VII) was then hydrolyzed to acid (VIII), which was further subjected to intramolecular ring closure upon heating with triflic acid to afford the tetracyclic system (IX). Keto group reduction in (IX) to give (X) was accomplished by a two-step procedure with NaBH4 and then with HI and Ac2O.
| 【1】 Chujo, I.; et al.; Synthetic study on novel immunosuppressant KF20444. Bioorg Med Chem 2001, 9, 12, 3273. |
| 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) | 31388 | 2-fluoro-1,1'-biphenyl | 321-60-8 | C12H9F | 详情 | 详情 |
| (II) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
| (III) | 56572 | methyl 5-(2'-fluoro[1,1'-biphenyl]-4-yl)-5-oxopentanoate | C18H17FO3 | 详情 | 详情 | |
| (IV) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
| (V) | 56573 | 3-(2-carboxyethyl)-6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-quinolinecarboxylic acid | C25H17F2NO4 | 详情 | 详情 | |
| (VI) | 56574 | 6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-(3-methoxy-3-oxopropyl)-4-quinolinecarboxylic acid | C26H19F2NO4 | 详情 | 详情 | |
| (VII) | 56575 | methyl 3-{6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-[(octylamino)carbonyl]-3-quinolinyl}propanoate | C34H36F2N2O3 | 详情 | 详情 | |
| (VIII) | 56576 | 3-{6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-[(octylamino)carbonyl]-3-quinolinyl}propanoic acid | C33H34F2N2O3 | 详情 | 详情 | |
| (IX) | 56577 | 10-fluoro-3-(2-fluorophenyl)-N-octyl-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide | C33H32F2N2O2 | 详情 | 详情 | |
| (X) | 56578 | 10-fluoro-3-(2-fluorophenyl)-N-octyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide | C33H34F2N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)In a different strategy for protecting the quinoline carboxyl group, acid (VI) was reduced to alcohol (XI) via chlorination with SOCl2, followed by treatment with NaBH4. Alcohol (XI) was then converted to the alkyl chloride (XII) with SOCl2 in dichloroethane. Subsequent ester group hydrolysis in (XII) under acidic conditions furnished the carboxylic acid (XIII). The tetracyclic compound (XIV) was obtained by cyclization of acid (XIII) in hot triflic acid. Displacement of the chloride group of (XIV) with sodium acetate in HOAc yielded acetate ester (XV), which was subsequently hydrolyzed to alcohol (XVI). Oxidation of (XVI) with DMSO and Ac2O provided aldehyde (XVII).
| 【1】 Chujo, I.; et al.; Synthetic study on novel immunosuppressant KF20444. Bioorg Med Chem 2001, 9, 12, 3273. |
| 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) | 56574 | 6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-(3-methoxy-3-oxopropyl)-4-quinolinecarboxylic acid | C26H19F2NO4 | 详情 | 详情 | |
| (XI) | 56579 | methyl 3-[6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-(hydroxymethyl)-3-quinolinyl]propanoate | C26H21F2NO3 | 详情 | 详情 | |
| (XII) | 56580 | methyl 3-[4-(chloromethyl)-6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-quinolinyl]propanoate | C26H20ClF2NO2 | 详情 | 详情 | |
| (XIII) | 56581 | 3-[4-(chloromethyl)-6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-quinolinyl]propanoic acid | C25H18ClF2NO2 | 详情 | 详情 | |
| (XIV) | 56582 | 8-(chloromethyl)-10-fluoro-3-(2-fluorophenyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinolin-5-one | C25H16ClF2NO | 详情 | 详情 | |
| (XV) | 56583 | [10-fluoro-3-(2-fluorophenyl)-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinolin-8-yl]methyl acetate | C27H19F2NO3 | 详情 | 详情 | |
| (XVI) | 56584 | 10-fluoro-3-(2-fluorophenyl)-8-(hydroxymethyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinolin-5-one | C25H17F2NO2 | 详情 | 详情 | |
| (XVII) | 56585 | 10-fluoro-3-(2-fluorophenyl)-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carbaldehyde | C25H15F2NO2 | 详情 | 详情 |