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【结 构 式】 
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【分子编号】30621 【品名】2,4-difluoro-3-methoxybenzoic acid 【CA登记号】178974-97-5 |
【 分 子 式 】C8H6F2O3 【 分 子 量 】188.1306464 【元素组成】C 51.08% H 3.21% F 20.2% O 25.51% |
合成路线1
该中间体在本合成路线中的序号：(III)The methylation of 2,6-difluorophenol (I) with methyl iodide and K2CO3 in DMF gives 2,6-difluoroanisole (II), which by treatment with butyllithium and CO2 yields 2,4-difluoro-3-methoxybenzoic acid (III). The methylation of (III) with diazomethane in ether affords the methyl ester (IV), which by reaction with BBr3 in dichloromethane results in 2,4-difluoro-3-hydroxybenzoic acid methyl ester (V). The alkylation of (V) with chlorodifluoromethane and K2CO3 in DMF gives 3-(difluoromethoxy)-2,4-difluorobenzoic acid methyl ester (VI), which is treated with sodium azide in DMSO, yielding the azido derivative (VII). The reduction of (VII) with H2 over Pd/C in ethanol affords 3-amino-2,4-difluorobenzoic acid methyl ester (VIII), which is hydrolyzed with NaOH in ethanol, giving the free acid (IX). The reaction of (IX) with NaNO2 and HBr yields 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid (X), which is condensed with the magnesium salt of malonic acid monoethyl ester (XI) by means of CDI in THF, affording the 3-oxopropionate (XII). The reaction of (XII) with dimethylformamide dimethylacetal (XIII) and cyclopropylamine (XIV) by means of acetic anhydride in dichloromethane gives the 3-(cyclopropylamino)acrylate (XV), which is cyclized by means of K2CO3 in hot DMSO, yielding quinolone (XVI). The condensation of (XVI) with the isoindolylboronic acid derivative (XVII) - obtained by reaction of 5-bromo-1(R)-methyl-2-tritylisoindoline (XIX) with triisopropyl borate and butyllithium in THF - by means of bis(triphenylphosphine)palladium(II) chloride as catalyst in refluxing toluene affords the protected compound (XVIII), which is finally deprotected with HCl in ethanol.
| 【1】 Castañer, J.; Rabasseda, X.; Graul, A.; T-3811ME. Drugs Fut 1999, 24, 12, 1324. |
| 【2】 Todo, Y.; Hayashi, K.; Takahata, M.; Watanabe, Y.; Narita, H. (Toyama Chemical Co., Ltd.); Quinolonecarboxylic acid derivs. or salts thereof.. EP 0882725; US 6025370; WO 9729102 . |
| 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) | 30619 | 2,6-difluorophenol | 28177-48-2 | C6H4F2O | 详情 | 详情 |
| (II) | 30620 | 2,6-difluorophenyl methyl ether; 1,3-difluoro-2-methoxybenzene | C7H6F2O | 详情 | 详情 | |
| (III) | 30621 | 2,4-difluoro-3-methoxybenzoic acid | 178974-97-5 | C8H6F2O3 | 详情 | 详情 |
| (IV) | 30622 | methyl 2,4-difluoro-3-methoxybenzoate | C9H8F2O3 | 详情 | 详情 | |
| (V) | 30623 | methyl 2,4-difluoro-3-hydroxybenzoate | C8H6F2O3 | 详情 | 详情 | |
| (VI) | 30624 | methyl 3-(difluoromethoxy)-2,4-difluorobenzoate | C9H6F4O3 | 详情 | 详情 | |
| (VII) | 30625 | methyl 4-azido-3-(difluoromethoxy)-2-fluorobenzoate | C9H6F3N3O3 | 详情 | 详情 | |
| (VIII) | 30626 | methyl 4-amino-3-(difluoromethoxy)-2-fluorobenzoate | C9H8F3NO3 | 详情 | 详情 | |
| (IX) | 30627 | 4-amino-3-(difluoromethoxy)-2-fluorobenzoic acid | C8H6F3NO3 | 详情 | 详情 | |
| (X) | 30628 | 4-bromo-3-(difluoromethoxy)-2-fluorobenzoic acid | C8H4BrF3O3 | 详情 | 详情 | |
| (XI) | 14338 | potassium 3-ethoxy-3-oxopropanoate | 6148-64-7 | C5H7KO4 | 详情 | 详情 |
| (XII) | 30629 | ethyl 3-[4-bromo-3-(difluoromethoxy)-2-fluorophenyl]-3-oxopropanoate | C12H10BrF3O4 | 详情 | 详情 | |
| (XIII) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (XIV) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XV) | 30630 | ethyl (Z)-2-[4-bromo-3-(difluoromethoxy)-2-fluorobenzoyl]-3-(cyclopropylamino)-2-propenoate | C16H15BrF3NO4 | 详情 | 详情 | |
| (XVI) | 30631 | ethyl 7-bromo-1-cyclopropyl-8-(difluoromethoxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H14BrF2NO4 | 详情 | 详情 | |
| (XVII) | 30632 | (1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-ylboronic acid | C28H26BNO2 | 详情 | 详情 | |
| (XVIII) | 30633 | ethyl 1-cyclopropyl-8-(difluoromethoxy)-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-isoindol-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C44H38F2N2O4 | 详情 | 详情 | |
| (XIX) | 30634 | (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole | C28H24BrN | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Aromatic hydroxylation of 1-bromo-2,4-difluorobenzene (I) using tert-butyl hydroperoxide and LDA afforded phenol (II), which was methylated with iodomethane and K2CO3 to give methyl ether (III). The required benzoic acid (IV) was then obtained from (III) by lithium-bromine exchange with n-butyllithium, followed by carboxylation with CO2 gas at -70 C. Treatment of (IV) with oxalyl chloride and DMF gave acid chloride (V). This was condensed with the lithium salt of monoethyl malonate to yield, after acid decarboxylation, ketoester (VI). Subsequent condensation of (VI) with triethyl orthoformate in refluxing Ac2O provided methoxyacrylate (VII), and further treatment with cyclopropylamine (VIII) furnished aminoacrylate (IX). Cyclization of (IX) by means of NaH in THF generated the quinolone system (X). Acid hydrolysis of the ethyl ester group of (X) gave quinolinecarboxylic acid (XI), which was converted to the boron difluoride complex (XII) by treatment with BF3-Et2O in hot THF. Displacement of the aromatic fluorine of (XII) with 3R-(1S-tert-butoxycarbonylaminoethyl)pyrrolidine (XIII) in the presence of DIEA, followed by boron complex cleavage with Et3N in EtOH provided the pyrrolidinylquinoline (XIV). Finally, the Boc protecting group of (XIV) was removed by hydrolysis with ethanolic HCl.
| 【1】 Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 | |
| (I) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (II) | 34648 | 3-bromo-2,6-difluorophenol | 221220-99-1 | C6H3BrF2O | 详情 | 详情 |
| (III) | 34649 | 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene | 221221-00-7 | C7H5BrF2O | 详情 | 详情 |
| (IV) | 30621 | 2,4-difluoro-3-methoxybenzoic acid | 178974-97-5 | C8H6F2O3 | 详情 | 详情 |
| (V) | 34650 | 2,4-difluoro-3-methoxybenzoyl chloride | C8H5ClF2O2 | 详情 | 详情 | |
| (VI) | 34651 | ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate | C12H12F2O4 | 详情 | 详情 | |
| (VII) | 34652 | ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate | C15H16F2O5 | 详情 | 详情 | |
| (VIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (IX) | 34653 | ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate | C16H17F2NO4 | 详情 | 详情 | |
| (X) | 34654 | ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H16FNO4 | 详情 | 详情 | |
| (XI) | 34655 | 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | 221221-16-5 | C14H12FNO4 | 详情 | 详情 |
| (XII) | 34656 | C14H11BF3NO4 | 详情 | 详情 | ||
| (XIII) | 34657 | tert-butyl (1S)-1-[(3R)pyrrolidinyl]ethylcarbamate | C11H22N2O2 | 详情 | 详情 | |
| (XIV) | 34658 | 7-((3R)-3-[(1S)-1-[(tert-butoxycarbonyl)amino]ethyl]pyrrolidinyl)-1-cyclopropyl-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid | C25H33N3O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Metalation of 1-bromo-2,4-difluorobenzene (I) by means of LDA, followed by treatment with tert-butyl hydroperoxide gave rise to phenol (II), which was further converted to methyl ether (III) by alkylation with iodomethane and K2CO3. Lithium halogen exchange of (III) with n-butyllithium, and subsequent quenching with CO2 produced 3-methoxy-2,4-difluorobenzoic acid (IV). After activation of (IV) as the acid chloride (V), condensation with the lithium derivative of monoethyl malonate (A) led to the benzoyl acetate ester (VI). The benzoyl ethoxyacrylate (VII), obtained by condensation of ketoester (VI) with triethyl orthoformate, was then reacted with cyclopropylamine (VIII) to afford enamine (IX). This was cyclized to the quinolone compound (X) upon treatment with NaH in THF. Acidic hydrolysis of ester (X) gave a keto acid, which was subsequently converted to the boron chelate (XI) by treatment with boron trifluoride etherate. Fluoride displacement of quinolone (XI) with the amino piperidine (XII) produced the piperidino quinolone (XIII). The boron difluoride complex of (XIII) was finally removed by means of triethylamine in boiling EtOH.
| 【1】 Hu, X.E.; Gray, J.L.; Almstead, J.-I.K.; Ledoussal, B. (The Procter & Gamble Co.); Antimicrobial quinolones, their compsns. and uses. EP 1015445; WO 9914214 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 |
| (I) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (II) | 34648 | 3-bromo-2,6-difluorophenol | 221220-99-1 | C6H3BrF2O | 详情 | 详情 |
| (III) | 34649 | 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene | 221221-00-7 | C7H5BrF2O | 详情 | 详情 |
| (IV) | 30621 | 2,4-difluoro-3-methoxybenzoic acid | 178974-97-5 | C8H6F2O3 | 详情 | 详情 |
| (V) | 34650 | 2,4-difluoro-3-methoxybenzoyl chloride | C8H5ClF2O2 | 详情 | 详情 | |
| (VI) | 34651 | ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate | C12H12F2O4 | 详情 | 详情 | |
| (VII) | 34652 | ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate | C15H16F2O5 | 详情 | 详情 | |
| (VIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (IX) | 34653 | ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate | C16H17F2NO4 | 详情 | 详情 | |
| (X) | 34654 | ethyl 1-cyclopropyl-7-fluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate | C16H16FNO4 | 详情 | 详情 | |
| (XI) | 59792 | 1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-7-fluoro-8-methoxy-4(1H)-quinolinone | C14H11BF3NO4 | 详情 | 详情 | |
| (XII) | 59793 | (3S,4R)-4-ethyl-3-piperidinamine; (3S,4R)-4-ethylpiperidinylamine | C7H16N2 | 详情 | 详情 | |
| (XIII) | 59794 | 7-[(3S,4R)-3-amino-4-ethylpiperidinyl]-1-cyclopropyl-3-{[(difluoroboryl)oxy]carbonyl}-8-methoxy-4(1H)-quinolinone | C21H26BF2N3O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXVI)In an alternative route to the quinolone precursor (XX), deprotonation of 2,4-difluorobromobenzene (XXIII) with LDA in THF followed by addition of tert-butyl hydroperoxide gives 3-bromo-2,6-difluorophenol (XXIV), which is converted to the corresponding methyl ether (XXV) by treatment with iodomethane and K2CO3. Metalation of the aryl bromide (XXV) with butyl lithium in cold diethyl ether and subsequent addition of CO2 gas leads to 3-methoxy-2,4-difluorobenzoic acid (XXVI). After chlorination of acid (XXVI) with oxalyl chloride and catalytic DMF, the obtained acid chloride (XXVII) is condensed with monoethyl malonate (XXVIII) in the presence of butyl lithium in THF at –50 °C to yield the 2-(benzoyl)acetate (XVII). Subsequent reaction of keto ester (XVII) with triethyl orthoformate in boiling Ac2O provides the enol ether (XXIX), which is then condensed with cyclopropylamine (XIX) in EtOH to give the key enamine (XX) (3). Scheme 3.
| 【3】 Ledoussal, B., Hu, X.E., Gray, J.L., Almstead, J.-I.K. (The Procter & Gamble Co.). Antimicrobial quinolones, their compositions and uses. CA 2303389, EP 1015445, JP 2001516756, US 6329391, US 6387928, WO 1999014214. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 34651 | ethyl 3-(2,4-difluoro-3-methoxyphenyl)-3-oxopropanoate | C12H12F2O4 | 详情 | 详情 | |
| (XIX) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XX) | 34653 | ethyl (Z)-3-(cyclopropylamino)-2-(2,4-difluoro-3-methoxybenzoyl)-2-propenoate | C16H17F2NO4 | 详情 | 详情 | |
| (XXIII) | 15488 | 1-bromo-2,4-difluorobenzene | 348-57-2 | C6H3BrF2 | 详情 | 详情 |
| (XXIV) | 34648 | 3-bromo-2,6-difluorophenol | 221220-99-1 | C6H3BrF2O | 详情 | 详情 |
| (XXV) | 34649 | 3-bromo-2,6-difluorophenyl methyl ether; 1-bromo-2,4-difluoro-3-methoxybenzene | 221221-00-7 | C7H5BrF2O | 详情 | 详情 |
| (XXVI) | 30621 | 2,4-difluoro-3-methoxybenzoic acid | 178974-97-5 | C8H6F2O3 | 详情 | 详情 |
| (XXVII) | 34650 | 2,4-difluoro-3-methoxybenzoyl chloride | C8H5ClF2O2 | 详情 | 详情 | |
| (XXVIII) | 15086 | 3-ethoxy-3-oxopropionic acid | 1071-46-1 | C5H8O4 | 详情 | 详情 |
| (XXIX) | 34652 | ethyl (Z)-2-(2,4-difluoro-3-methoxybenzoyl)-3-ethoxy-2-propenoate | C15H16F2O5 | 详情 | 详情 |