A-170568(free base), A-170568.1, -Drug Synthesis Database

【结构式】

【药物名称】A-170568(free base), A-170568.1

【化学名称】1-Cyclopropyl-7-fluoro-9-methyl-8-[7(S)-(methylamino)-5-azaspiro[2.4]hept-5-yl]-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride

【CA登记号】

【分子式】C₂₁H₂₅ClFN₃O₃

【分子量】421.9031

【开发单位】Abbott (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, DNA Gyrase Inhibitors, Quinolizinones

合成路线1 合成路线2

合成路线1

The cyclopropanation of ethyl acetoacetate (I) with 1,2-dibromoethane and K2CO3 in DMF, followed by hydrolysis with NaOH gives 1-acetylcyclopropane-1-carboxylic acid (II), which is condensed with 1(R)-phenylethylamine (A) by means of butyl chloroformate in dichloromethane yielding the chiral amide (III). The protection of the acetyl group with ethylene glycol and p-toluenesulfonic acid affords the cyclic acetal (IV), which is brominated with Br2 in dioxane to give the bromomethyl compound (V). The cyclization of (V) by means of NaH in THF affords the spirocyclopropane derivative (VI), which is deprotected with HCl providing the spiro pyrrolidinedione (VII). The reaction of (VII) with hydroxylamine affords the oxime (VIII), which is reduced with H2 over RaNi in methanol and crystallized with l-tartaric acid to give the desired chiral 7(R)-amino-5-(1(R)-phenylethyl)-5-azaspiro[2.4]heptan-4-one (IX). The reduction of the ketonic group of (IX) with LiAlH4 yields the chiral amine (X), which is protected with tert-butoxycarbonyl anhydride to the carbamate (XI). The hydrogenation of (XI) with H 2 over Pd/C affords the spiropyrrolidine (XII) with its NH group free, which is condensed with the quinolizine (XIII) by means of triethylamine in DMF providing intermediate (XIV). This compound is methylated by means of methyl iodide and sodium bis(trimethylsilyl)amide yielding the methylamino derivative (XV), which is finally deprotected and hydrolyzed to the target compound with LiOH in ethanol.

参考文献中间体

【1】 Armiger, Y.L.; Chu, D.T.W.; Fung, A.K.L.; et al.; The discovery of A-165753 and A-170568, two potent broad-spectrum antimicrobial agents. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-86.

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)	10039	(1R)-1-Phenylethylamine; (1R)-1-Phenyl-1-ethanamine.; L-alpha-Phenylethylamine	3886-69-9	C₈H₁₁N	详情	详情
(I)	11819	ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate	141-97-9	C₆H₁₀O₃	详情	详情
(II)	15194	1-acetylcyclopropanecarboxylic acid		C₆H₈O₃	详情	详情
(III)	15179	1-acetyl-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide		C₁₄H₁₇NO₂	详情	详情
(IV)	15180	1-(2-methyl-1,3-dioxolan-2-yl)-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide		C₁₆H₂₁NO₃	详情	详情
(V)	15181	1-[2-(bromomethyl)-1,3-dioxolan-2-yl]-N-[(1R)-1-phenylethyl]cyclopropanecarboxamide		C₁₆H₂₀BrNO₃	详情	详情
(VI)	15198	10-[(1R)-1-phenylethyl]-5,8-dioxa-10-azadispiro[2.0.4.3]undecan-11-one		C₁₆H₁₉NO₃	详情	详情
(VII)	15173	5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione		C₁₄H₁₅NO₂	详情	详情
(VIII)	15174	5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione 7-oxime		C₁₄H₁₆N₂O₂	详情	详情
(IX)	15176	(7S)-7-amino-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-4-one		C₁₄H₁₈N₂O	详情	详情
(X)	15177	(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]heptan-7-amine; (7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-ylamine		C₁₄H₂₀N₂	详情	详情
(XI)	15204	tert-butyl N-[(7S)-5-[(1R)-1-phenylethyl]-5-azaspiro[2.4]hept-7-yl]carbamate		C₁₉H₂₈N₂O₂	详情	详情
(XII)	15193	tert-butyl N-[(7S)-5-azaspiro[2.4]hept-7-yl]carbamate		C₁₁H₂₀N₂O₂	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)	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
(XV)	26951	ethyl 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-carboxylate		C₂₈H₃₆FN₃O₅	详情	详情

合成路线2

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).

参考文献中间体

【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

Extended Information

Drug NewChemical Entity Original Patent(1)