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【结 构 式】

【分子编号】16834

【品名】8-[(3S)-3-[(tert-butoxycarbonyl)amino]tetrahydro-1H-pyrrol-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid

【CA登记号】

【 分 子 式 】C23H28FN3O5

【 分 子 量 】445.4909432

【元素组成】C 62.01% H 6.34% F 4.26% N 9.43% O 17.96%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XVI)

The reaction of 3-chlorotetrafluoropyridine (I) with sodium tert-butoxide in THF gives 4-tert-butoxy-3-chloro-2,5,6-trifluoropyridine (II), which is dechlorinated with H2 over Pd/C in methanol yielding 4-tert-butoxy-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and lithium diethylamide (LDA) in THF affords 4-tert-butoxy-2,3,6-trifluoro-5-methylpyridine (IV), which is selectively defluorinated with hydrazine in refluxing propanol to give 4-tert-butoxy-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with cyclopropylacetonitrile (VI) by means of LDA in THF yields 2-(4-tert-butoxy-5-fluoro-3-methyl-2-pyridyl)-2-cyclopropylacetonitrile (VII), which is treated first with trifluoroacetic acid and then with POCl3 to afford 2-(4-chloro-5-fluoro-3-methyl-2-pyridyl)-2-cyclopropylacetonitrile (VIII). The alcoholysis of (VIII) with ethanol/HCl gives the corresponding ethyl ester (IX), which is partially reduced with LiAlH4 in THF to afford the corresponding aldehyde (X). The condensation of (X) with diethyl malonate (XI) by means of piperidine in refluxing ethanol yields the ethylidenemalonate (XII), which, without isolation, is cyclized by heating at 235 C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The reaction of (XIII) with 3(S)-(tert-butoxycarbonylamino)pyrrolidine (XIV) by means of NaHCO3 in acetonitrile gives the corresponding condensation product (XV), which is hydrolyzed ith LiOH in THF/water to the corresponding free acid (XVI). Finally, this compound is deprotected with 4N HCl in dioxandichloromethane.

1 Fromtling, R.A.; Castañer, J.; ABT-719. Drugs Fut 1995, 20, 11, 1103.
2 Chu, D.T.W.; Li, Q.; Claiborne, A.; et al.; Synthesis and antibacterial activity of A-86719.1 and related 2-pyridones: A novel series of potent DNA gyrase inhibitors. 34th Intersci Conf Antimicrob Agents Chemother (Oct 4-7, Orlando) 1994, Abst F41.
3 Chu, D.T.; Li, Q.; Cooper, C.S.; Fung, A.K.L.; Lee, C.M.; Plattner, J.J. (Abbott Laboratories Inc.); Quinolizinone type cpds. JP 1997503783; WO 9510519 .
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) 16819 3-chloro-2,4,5,6-tetrafluoropyridine; Pyridine, 3-chloro-2,4,5,6-tetrafluoro- 1735-84-8 C5ClF4N 详情 详情
(II) 16820 4-(tert-butoxy)-3-chloro-2,5,6-trifluoropyridine; tert-butyl 3-chloro-2,5,6-trifluoro-4-pyridinyl ether C9H9ClF3NO 详情 详情
(III) 16821 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether C9H10F3NO 详情 详情
(IV) 16822 tert-butyl 2,3,6-trifluoro-5-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,3,6-trifluoro-5-methylpyridine C10H12F3NO 详情 详情
(V) 16823 tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine C10H13F2NO 详情 详情
(VI) 16824 2-cyclopropylacetonitrile; Cyclopropylacetonitrile 6542-60-5 C5H7N 详情 详情
(VII) 16825 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile C15H19FN2O 详情 详情
(VIII) 16826 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile C11H10ClFN2 详情 详情
(IX) 16827 ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate C13H15ClFNO2 详情 详情
(X) 16828 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde C11H11ClFNO 详情 详情
(XI) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(XII) 16830 diethyl 2-[2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylethylidene]malonate C18H21ClFNO4 详情 详情
(XIII) 16831 ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C16H15ClFNO3 详情 详情
(XIV) 11685 tert-butyl N-[(3S)tetrahydro-1H-pyrrol-3-yl]carbamate C9H18N2O2 详情 详情
(XV) 16833 ethyl 8-[(3S)-3-[(tert-butoxycarbonyl)amino]tetrahydro-1H-pyrrol-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate C25H32FN3O5 详情 详情
(XVI) 16834 8-[(3S)-3-[(tert-butoxycarbonyl)amino]tetrahydro-1H-pyrrol-1-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid C23H28FN3O5 详情 详情
Extended Information