Lumiracoxib, COX-189, Prexige, -Drug Synthesis Database

【结构式】

【药物名称】Lumiracoxib, COX-189, Prexige

【化学名称】2-[2-(2-Chloro-6-fluorophenylamino)-5-methylphenyl]acetic acid

【CA登记号】220991-20-8, 346670-74-4 (deleted CAS)

【分子式】C₁₅H₁₃ClFNO₂

【分子量】293.72776

【开发单位】Novartis (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiarthritic Drugs, ENDOCRINE DRUGS, Gynecological Disorders, Treatment of , Non-Opioid Analgesics, Osteoarthritis, Treatment of, Rheumatoid Arthritis, Treatment of, Treatment of Dysmenorrhea, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Cyclooxygenase-2 Inhibitors

合成路线1 合成路线2

合成路线1

The partial reduction of 4-methylanisole (I) with sodium in liquid ammonia/THF/ethanol gives the enol ether (II), which is condensed with 2-chloro-6-fluoroaniline (III) by means of TiCl4 in chlorobenzene/THF to yield the imine (IV), which, without isolation, is aromatized with I2 in AcOH/THF to provide N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V). The acylation of (V) with 2-chloroacetyl chloride (VI) at 90 C affords the 2-chloroacetamide (VII), which is cyclized by means of AlCl3 by heating at 160?C to afford 1-(2-chloro-6-fluorophenyl)-5-methylindolin-2-one (VIII). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol/water and acidified with 1N HCl. Alternatively, the intermediate N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine (V) can also be obtained by condensation of 2-chloro-N-(4-methylphenyl)acetamide (IX) with 2-chloro-6-fluorophenol (X) by means of K2CO3 in isopropanol to yield 2-(2-chloro-6-fluorophenoxy)-N-(4-methylphenyl)acetamide (XI), which is treated with MeONa in methanol to obtain the target secondary amine (V).

参考文献中间体

【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Lumiracoxib. Drugs Fut 2002, 27, 8, 740.
【2】 Xu, D.; Allmendinger, T.; Acemoglu, M.; Calienni, J.V.; Cercus, J.; Loiseleur, O.; Sedelmeier, G. (Novartis AG; Novartis-Erfindungen VmbH); Process for phenylacetic acid derivs.. WO 0123346 .

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)	53835	1-Methoxy-4-methylbenzene; 4-Methylanisole; Methyl P-Tolyl Ether; p-Cresyl methyl ether; 4-Methoxytoluene	104-93-8	C₈H₁₀O	详情	详情
(II)	53836	1-methoxy-4-methyl-1,4-cyclohexadiene; methyl 4-methyl-1,4-cyclohexadien-1-yl ether	n/a	C₈H₁₂O	详情	详情
(III)	53837	2-Chloro-6-fluoroaniline	363-51-9	C₆H₅ClFN	详情	详情
(IV)	53838	N-(2-chloro-6-fluorophenyl)-N-(4-methyl-2-cyclohexen-1-ylidene)amine; 2-chloro-6-fluoro-N-(4-methyl-2-cyclohexen-1-ylidene)aniline	n/a	C₁₃H₁₃ClFN	详情	详情
(V)	53839	2-chloro-6-fluoro-N-(4-methylphenyl)aniline; N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)amine	n/a	C₁₃H₁₁ClFN	详情	详情
(VI)	11296	2-Chloroacetyl chloride; Chloroacetic chloride	79-04-9	C₂H₂Cl₂O	详情	详情
(VII)	53840	2-chloro-N-(2-chloro-6-fluorophenyl)-N-(4-methylphenyl)acetamide	n/a	C₁₅H₁₂Cl₂FNO	详情	详情
(VIII)	53841	1-(2-chloro-6-fluorophenyl)-5-methyl-1,3-dihydro-2H-indol-2-one	n/a	C₁₅H₁₁ClFNO	详情	详情
(IX)	31229	2-chloro-N-(4-methylphenyl)acetamide		C₉H₁₀ClNO	详情	详情
(X)	53842	2-chloro-6-fluorophenol	2040-90-6	C₆H₄ClFO	详情	详情
(XI)	53843	2-(2-chloro-6-fluorophenoxy)-N-(4-methylphenyl)acetamide	n/a	C₁₅H₁₃ClFNO₂	详情	详情

合成路线2

The reduction of 2-iodo-5-methylbenzoic acid (I) with BH3/THF in THF gives 2-iodo-5-methylbenzyl alcohol (II), which is treated with refluxing 48% HBr to yield the benzyl bromide (III). Reaction of (III) with NaCN in ethanol/water afford the phenylacetonitrile (IV), which is hydrolyzed with NaOH in refluxing EtOH/water to provide the phenylacetic acid (V). Reaction of (V) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VI), which is treated with dimethylamine in diethyl ether/THF to yield 2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide (VII). Condensation of (VII) with 2-chloro-6-fluoroaniline (VIII) by means of Cu powder, Cu2I2 and K2CO3 in refluxing xylene affords 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]-N,N-dimethylacetamide (IX), which is finally hydrolyzed with NaOH in refluxing butanol/water.

参考文献中间体

【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Lumiracoxib. Drugs Fut 2002, 27, 8, 740.
【2】 Fujimoto, R.A.; Mugrage, B.B.; Van Duzer, J.H.; McQuire, L.W.; Xu, D. (Novartis AG); Certain 5-alkyl-2-arylaminophenylacetic acids and derivs.. JP 2001514244; US 6291523; WO 9911605 .

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)	34151	2-iodo-5-methylbenzoic acid	52548-14-8	C₈H₇IO₂	详情	详情
(II)	53844	(2-iodo-5-methylphenyl)methanol	n/a	C₈H₉IO	详情	详情
(III)	53845	2-(bromomethyl)-1-iodo-4-methylbenzene	n/a	C₈H₈BrI	详情	详情
(IV)	53846	2-(2-iodo-5-methylphenyl)acetonitrile	n/a	C₉H₈IN	详情	详情
(V)	53847	2-(2-iodo-5-methylphenyl)acetic acid	n/a	C₉H₉IO₂	详情	详情
(VI)	53848	2-(2-iodo-5-methylphenyl)acetyl chloride	n/a	C₉H₈ClIO	详情	详情
(VII)	53849	2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide	n/a	C₁₁H₁₄INO	详情	详情
(VIII)	53837	2-Chloro-6-fluoroaniline	363-51-9	C₆H₅ClFN	详情	详情
(IX)	53850	2-[2-(2-chloro-6-fluoroanilino)-5-methylphenyl]-N,N-dimethylacetamide	n/a	C₁₇H₁₈ClFN₂O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)