3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride -Drug Synthesis Database

【结构式】

【分子编号】59641

【品名】3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride

【CA登记号】

【分子式】C₁₁H₆Cl₂FNO₂

【分子量】274.0779832

【元素组成】C 48.21% H 2.21% Cl 25.87% F 6.93% N 5.11% O 11.68%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

Condensation of 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride (I) with methyl 3-aminophenylacetate (II) leads to amide (III). Intramolecular cyclization of (III) and simultaneous hydrolysis in the presence of NaOH in MeOH/DMF provide the isoxazoloquinoline derivative (IV). After activation of acid (IV) as the corresponding acid chloride (V), coupling with 3,4,5-trimethoxyaniline (VI) furnishes the title compound

参考文献中间体

合成目标

【1】 Norman, B.H.; et al.; Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1). Bioorg Med Chem Lett 2002, 12, 6, 883.
【2】 Kroin, J.S.; Norman, B.H.; Gruber, J.M. (Eli Lilly and Company); Methods for inhibiting MRP1. EP 1067928; JP 2002510625; US 6369070; WO 9951228 .

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)	59641	3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride		C₁₁H₆Cl₂FNO₂	详情	详情
(II)	41111	methyl 2-(3-aminophenyl)acetate		C₉H₁₁NO₂	详情	详情
(III)	62525	methyl 2-[3-({[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]carbonyl}amino)phenyl]acetate		C₂₀H₁₆ClFN₂O₄	详情	详情
(IV)	62526	2-{3-[9-chloro-3-methyl-4-oxoisoxazolo[4,3-c]quinolin-5(4H)-yl]phenyl}acetic acid		C₁₉H₁₃ClN₂O₄	详情	详情
(V)	62527	2-{3-[9-chloro-3-methyl-4-oxoisoxazolo[4,3-c]quinolin-5(4H)-yl]phenyl}acetyl chloride		C₁₉H₁₂Cl₂N₂O₃	详情	详情
(VI)	31545	3,4,5-trimethoxyaniline; 3,4,5-trimethoxyphenylamine；3,4,5-Trimethoxybenzenamine；[3,4,5-Tris(methyloxy)phenyl]amine	24313-88-0	C₉H₁₃NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

Acylation of ethyl 3-(methylamino)crotonate (IX) with 2-chloro-6-fluorobenzoyl chloride (X) provided the enamino ketoester (XI), which was cyclized to the isoxazole derivative (XII) upon treatment with hydroxylamine. Hydrolysis of ethyl ester (XII), followed by chlorination of the resultant acid (XIII), furnished acid chloride (XIV). This was condensed with amine (VIII) affording amide (XV). The isoxazoloquinoline derivative (XVI) was then obtained by cyclization of fluoro amide (XV) in the presence of potassium bis(trimethylsilyl)amide. Removal of the N-Cbz group of (XVI) using iodotrimethylsilane in CH2Cl2 yielded amine (XVII). 6-Fluoronicotinic acid (XIX) was prepared by permanganate oxidation of 2-fluoro-6-methylpyridine (XVIII). Finally, amine (XVII) was coupled with 6-fluoronicotinic acid (XIX) by means of EDC to furnish the title compound.

参考文献中间体

合成目标

【1】 Methods and cpds. for inhibiting MRP1. EP 1250340; WO 0146199 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	59635	benzyl [(1R,3S)-3-aminocyclohexyl]methylcarbamate		C₁₅H₂₂N₂O₂	详情	详情
(IX)	59636	ethyl (E)-3-(methylamino)-2-butenoate		C₇H₁₃NO₂	详情	详情
(X)	59637	2-Chloro-6-fluorobenzoyl chloride	79455-63-3	C₇H₃Cl₂FO	详情	详情
(XI)	59638	ethyl (E)-2-(2-chloro-6-fluorobenzoyl)-3-(methylamino)-2-butenoate		C₁₄H₁₅ClFNO₃	详情	详情
(XII)	59639	ethyl 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarboxylate		C₁₃H₁₁ClFNO₃	详情	详情
(XIII)	59640	3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarboxylic acid		C₁₁H₇ClFNO₃	详情	详情
(XIV)	59641	3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolecarbonyl chloride		C₁₁H₆Cl₂FNO₂	详情	详情
(XV)	59642	benzyl [(1R,3S)-3-({[3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl]carbonyl}amino)cyclohexyl]methylcarbamate		C₂₆H₂₇ClFN₃O₄	详情	详情
(XVI)	59643	benzyl {(1R,3S)-3-[9-chloro-3-methyl-4-oxoisoxazolo[4,3-c]quinolin-5(4H)-yl]cyclohexyl}methylcarbamate		C₂₆H₂₆ClN₃O₄	详情	详情
(XVII)	59644	5-[(1S,3R)-3-(aminomethyl)cyclohexyl]-9-chloro-3-methylisoxazolo[4,3-c]quinolin-4(5H)-one		C₁₈H₂₀ClN₃O₂	详情	详情
(XVIII)	59645	2-Fluoro-5-methylpyridine; 6-Fluoro-3-picoline	2369-19-9	C₆H₆FN	详情	详情
(XIX)	59646	6-fluoronicotinic acid		C₆H₄FNO₂	详情	详情

Extended Information