|
【结 构 式】 
|
【分子编号】16828 【品名】2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde 【CA登记号】 |
【 分 子 式 】C11H11ClFNO 【 分 子 量 】227.6655832 【元素组成】C 58.03% H 4.87% Cl 15.57% F 8.34% N 6.15% O 7.03% |
合成路线1
该中间体在本合成路线中的序号：(X)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 |
合成路线2
该中间体在本合成路线中的序号：(XI)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 Pearlman's catalyst 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 treated with hydrazine in refluxing propanol to give 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with 2-bromo-2-cyclopropylacetopnitrile (VI) by means of LDA in THF yields the expected condensation product (VII), which is treated with TFA to eliminate the tert-butyl protecting group and with POCl3 in DMF to afford the 4-chloropyridyl derivative (VIII). The hydrolysis of the nitrile group of (VIII) with HCl in ethanol gives the corresponding acetate ester (IX), which is reduced with LiAlH4 in THF to the alcohol (X). The oxidation of (X) with oxalyl chloride in DMSO/dichloromethane yields the aldehyde (XI), which is cyclized with diethyl malonate (XII) by means of piperidine in refluxing acetic acid, followed by heating at 220 C C in Dowtherm to afford 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (XIII). The condensation of (XIII) with 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) by means of triethylamine in DMF gives the expected condensation product (XV), which is methylated with methyl iodide and sodium hexamethyldisylazane (Na-HMDS) in THF yielding the N-methyl derivative (XVI). The hydrolysis of the ester group of (XVI) with LiOH in THF/water provides the corresponding free acid (XVII), which is finally deprotected with HCl in acetic acid. The synthesis of the intermediate 7(S)-(tert-butoxycarbonylamino)-5-azaspiro[2.4]heptane (XIV) has already been described in the first synthesis of compound no. 268134 (see scheme 26813401a).
| 【1】 Or, Y.S.; Armiger, Y.-L.; Fung, A. (Abbott Laboratories Inc.); Pyridone antibiotic with improved safety profile. US 5977133; WO 0010998 . |
| 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) | 16189 | (2R)-2-(1-benzothiophen-5-yl)-2-hydroxyethanoic acid | C10H8O3S | 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) | 31629 | 2-bromo-2-cyclopropylacetonitrile | C5H6BrN | 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) | 31627 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol | C11H13ClFNO | 详情 | 详情 | |
| (XI) | 16828 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde | C11H11ClFNO | 详情 | 详情 | |
| (XII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 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) | 15193 | tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate | C11H20N2O2 | 详情 | 详情 | |
| (XV) | 26950 | ethyl 8-[(7S)-7-[(tert-butoxycarbonyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C27H34FN3O5 | 详情 | 详情 | |
| (XVI) | 16951 | (1R)-1-[(4S,5R)-2,2-dimethyl-5-[(E)-1-tetradecenyl]-1,3-dioxolan-4-yl]-2-(trityloxy)-1-ethanol | C40H54O4 | 详情 | 详情 | |
| (XVII) | 31628 | 8-[(7S)-7-[(tert-butoxycarbonyl)(methyl)amino]-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid | C26H32FN3O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)The reaction of 3-chlorotetrafluoropyridine (I) with potassium tert-butoxide in THF gives the 4-tert-butoxypyridine (II), which is dechlorinated with H2 over Pearlman's catalyst in methanol yielding 4-tert-butoxy-2,3,6-trifluoropyridine (III). The methylation of (III) with methyl iodide and LDA in THF affords the 5-methyl derivative (IV), which is partially defluorinated with hydrazine in refluxing propanol to provide 4-tert-butoxy-2,5-difluoro-3-methylpyridine (V). The condensation of (V) with cyclopropylacetonitrile (VI) by means of LDA in THF gives the alpha substituted acetonitrile (VII), which is treated with trifluoroacetic acid yielding the phenol (VIII). The reaction of (VIII) with POCl3 in dichloromethane/DMF affords the corresponding chloro derivative (IX), which is treated with dry HCl in ethanol giving the carboxylic ester (X). The reduction of (X) with LiAlH4 in THF affords the expected aldehyde (XI), which is cyclized with diethyl malonate, piperidine and acetic acid in refluxing ethanol giving the quinolizine carboxylate (XIII). The reaction of (XIII) with (1S,6S)-2-(tert-butoxycarbonyl)-2,8-diazabicyclo[4.3.0]nonane (XIV) by means of NaHCO3 in refluxing acetonitrile yields the condensation product (XV), which is saponified with LiOH in THF/wter providing the protcted target compound (XVI). Finally, this compound is deprotected with HCl in dioxane/methylene chloride.
| 【1】 Chu, D.T.; Li, Q.; Cooper, C.S.; Fung, A.K.L.; Lee, C.M.; Plattner, J.J.; Ma, Z.; Wang, W.-B. (Abbott Laboratories Inc.); Quinolizinone type cpds.. EP 0871628; JP 1999510478; WO 9639407 . |
| 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) | 27200 | 2-cyclopropyl-2-(5-fluoro-4-hydroxy-3-methyl-2-pyridinyl)acetonitrile | C11H11FN2O | 详情 | 详情 | |
| (IX) | 16826 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile | C11H10ClFN2 | 详情 | 详情 | |
| (X) | 16827 | ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate | C13H15ClFNO2 | 详情 | 详情 | |
| (XI) | 16828 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde | C11H11ClFNO | 详情 | 详情 | |
| (XII) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 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) | 27201 | tert-butyl (4aS,7aS)octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate | C12H22N2O2 | 详情 | 详情 | |
| (XV) | 27202 | ethyl 8-[(4aS,7aS)-1-(tert-butoxycarbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C28H36FN3O5 | 详情 | 详情 | |
| (XVI) | 27203 | 8-[(4aS,7aS)-1-(tert-butoxycarbonyl)octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid | C26H32FN3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)Treatment of a commercial mixture of 4-chloro-tetrafluropyridine (I) and 3-chlorotetrafluoropyridine (II) with sodium tert-butoxide, followed by chromatographic separation, afforded 4-tert-butoxy-3-chloro-2,5,6-trifluoropyridine (III). Subsequent hydrogenolysis of the chlorine atom of (III) provided (IV), which was methylated with iodomethane in the presence of LDA yielding methylpyridine (V). Selective removal of the 6-fluorine of (V) to give (VI) was achieved by treatment with hydrazine hydrate in boiling n-propanol, followed by air oxidation of the intermediate pyridyl hydrazine. Alkylation of cyclopropaneacetonitrile (VII) with (VI) furnished the pyridinyl cyclopropaneacetonitrile (VIII). After acid cleavage of the tert-butyl group of (VIII), treatment with phosphoryl chloride in DMF gave rise to 4-chloropyridine derivative (IX). Then, alcoholysis of the cyano group of (IX) produced ethyl ester (X). Ester reduction by means of LiAlH4 and subsequent Swern oxidation of the resulting alcohol (XI) provided aldehyde (XII). The required quinolizinone system (XIII) was prepared by Knoevenagel condensation of pyridine aldehyde (XII) with diethyl malonate (1). The chiral piperidine (XV) was obtained by chiral HPLC resolution of racemic cis-N-carbobenzoxy-3-(tert-butoxycarbonylamino)-4-methylpiperidine (XIV), followed by hydrogenolytic cleavage of the carbobenzoxy group. Aromatic substitution of chloroquinolizinone (XIII) with piperidine (XV) yielded adduct (XVI). Hydrolysis of the ethyl ester of (XVI) with LiOH and further acid deprotection of the Boc group furnished the title compound.
| 【1】 Wang, S.; Ma, Z.; Flamm, R.K.; Cooper, C.S.; Li, Q.; Nilius, J.D.; Chu, D.T.W.; Sun OR, Y.; Meulbroek, J.A.; Shen, L.L.; Fung, A.K.L.; Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: Consequences of structural modification at the C-8 position. J Med Chem 1999, 42, 20, 4202. |
| 【2】 Chu, D.T.; Li, Q.; Cooper, C.S.; Fung, A.K.L.; Lee, C.M.; Plattner, J.J.; Ma, Z.; Wang, W.-B. (Abbott Laboratories Inc.); Quinolizinone type cpds.. EP 0871628; JP 1999510478; WO 9639407 . |
| 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) | 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 |
| (I) | 40621 | 4-chloro-2,3,5,6-tetrafluoropyridine | C5ClF4N | 详情 | 详情 | |
| (II) | 16819 | 3-chloro-2,4,5,6-tetrafluoropyridine; Pyridine, 3-chloro-2,4,5,6-tetrafluoro- | 1735-84-8 | C5ClF4N | 详情 | 详情 |
| (III) | 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 | |
| (IV) | 16821 | 4-(tert-butoxy)-2,3,6-trifluoropyridine; tert-butyl 2,3,6-trifluoro-4-pyridinyl ether | C9H10F3NO | 详情 | 详情 | |
| (V) | 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 | |
| (VI) | 16823 | tert-butyl 2,5-difluoro-3-methyl-4-pyridinyl ether; 4-(tert-butoxy)-2,5-difluoro-3-methylpyridine | C10H13F2NO | 详情 | 详情 | |
| (VII) | 16824 | 2-cyclopropylacetonitrile; Cyclopropylacetonitrile | 6542-60-5 | C5H7N | 详情 | 详情 |
| (VIII) | 16825 | 2-[4-(tert-butoxy)-5-fluoro-3-methyl-2-pyridinyl]-2-cyclopropylacetonitrile | C15H19FN2O | 详情 | 详情 | |
| (IX) | 16826 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetonitrile | C11H10ClFN2 | 详情 | 详情 | |
| (X) | 16827 | ethyl 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetate | C13H15ClFNO2 | 详情 | 详情 | |
| (XI) | 31627 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropyl-1-ethanol | C11H13ClFNO | 详情 | 详情 | |
| (XII) | 16828 | 2-(4-chloro-5-fluoro-3-methyl-2-pyridinyl)-2-cyclopropylacetaldehyde | C11H11ClFNO | 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) | 40623 | benzyl (3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-methyl-1-piperidinecarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (XV) | 40622 | tert-butyl (3S,4S)-4-methylpiperidinylcarbamate | C11H22N2O2 | 详情 | 详情 | |
| (XVI) | 40624 | ethyl 8-[(3S,4S)-3-[(tert-butoxycarbonyl)amino]-4-methylpiperidinyl]-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate | C27H36FN3O5 | 详情 | 详情 |