ER-34122, -Drug Synthesis Database

【结构式】

【药物名称】ER-34122

【化学名称】5-[1-[1,5-Bis(4-methoxyphenyl)pyrazol-3-yl]-1,1-dimethoxymethyl]-2-chlorobenzamide

【CA登记号】179325-62-3

【分子式】C₂₇H₂₆ClN₃O₅

【分子量】507.97837

【开发单位】Eisai (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, 5-Lipoxygenase Inhibitors, Cyclooxygenase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

Title compound has been prepared by several routes: Condensation of 4'-methoxyacetophenone (I) with diethyl oxalate in the presence of lithium hexamethyldisilazide provided lithium ethyl 4-methoxybenzoylpyruvate (II). Subsequent condensation of (II) with 4-methoxyphenylhydrazine hydrochloride (III) yielded diarylpyrazole (IV). This was coupled with bromide (V) in the presence of n-BuLi to afford ketone (VI). The oxazoline ring of (VI) was then hydrolyzed to carboxylic acid (VII) by successive treatments with HCl and with NaOH. Activation of the carboxylic acid of (VII) as the mixed anhydride with ethyl chloroformate, followed by treatment with gaseous ammonia provided amide (VIII). The required dimethyl ketal was finally introduced in (VIII) by means of trimethyl orthoformate in MeOH in the presence of p-TsOH.

参考文献中间体

【1】 Lamari, L.; Zitouni, A.; Boudjella, H.; et al.; J Heterocycl Chem 1989, 26, 8, 1389-1392.
【2】 Numata, H.; Okamoto, Y.; Shinoda, M.; Kobayashi, N.; Miyazawa, S.; Kawahara, T.; Shirota, H.; Nagakura, N.; Horizoe, T.; Abe, S.; Kobayashi, S.; Yamanaka, T. (Eisai Co., Ltd.); Pyrazole derivs. exhibiting anti-inflammatory and analgesic effects. JP 1998509140; WO 9614302 .

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)	11041	4-Methoxyacetophenone; 1-(4-Methoxyphenyl)-1-ethanone	100-06-1	C₉H₁₀O₂	详情	详情
(II)	25533	2-Hydroxy-4-(4-methoxyphenyl)-3-oxo-2(E)-butenoic acid ethyl ester lithium salt		C₁₃H₁₃LiO₅	详情	详情
(III)	12688	4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine	3471-32-7	C₇H₁₀N₂O	详情	详情
(IV)	25534	ethyl 1,5-bis(4-methoxyphenyl)-1H-pyrazole-3-carboxylate		C₂₀H₂₀N₂O₄	详情	详情
(V)	25535	2-(5-bromo-2-chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole		C₁₁H₁₁BrClNO	详情	详情
(VI)	25536	[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl][4-chloro-3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]methanone		C₂₉H₂₆ClN₃O₄	详情	详情
(VII)	25537	5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzoic acid		C₂₅H₁₉ClN₂O₅	详情	详情
(VIII)	25538	5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzamide		C₂₅H₂₀ClN₃O₄	详情	详情

合成路线2

Alternatively, pyrazole ester (IV) was hydrolyzed to carboxylic acid (IX) with NaOH in ethanol. Then, conversion of (IX) to acid chloride with SOCl2, followed by treatment with N,O-dimethylhydroxylamine provided N-methoxy amide (X). Subsequent coupling of (X) with bromide (V) in the presence of n-BuLi afforded ketone (VI). Oxazoline hydrolysis as before yielded acid (VII), which was protected as the methyl ester (XI) upon treatment with MeI and NaH. Ketalization of (XI) was carried out with trimethyl orthoformate in MeOH in the presence of p-TsOH yielding (XII), and the methyl ester function of (XII) was then hydrolyzed with NaOH to furnish acid (XIII). Finally, conversion to the target amide was effected by reaction with ammonia in the presence of EDC and HOBt.

参考文献中间体

【1】 Numata, H.; Okamoto, Y.; Shinoda, M.; Kobayashi, N.; Miyazawa, S.; Kawahara, T.; Shirota, H.; Nagakura, N.; Horizoe, T.; Abe, S.; Kobayashi, S.; Yamanaka, T. (Eisai Co., Ltd.); Pyrazole derivs. exhibiting anti-inflammatory and analgesic effects. JP 1998509140; WO 9614302 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	25534	ethyl 1,5-bis(4-methoxyphenyl)-1H-pyrazole-3-carboxylate	C₂₀H₂₀N₂O₄	详情	详情
(V)	25535	2-(5-bromo-2-chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole	C₁₁H₁₁BrClNO	详情	详情
(VI)	25536	[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl][4-chloro-3-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl]methanone	C₂₉H₂₆ClN₃O₄	详情	详情
(VII)	25537	5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzoic acid	C₂₅H₁₉ClN₂O₅	详情	详情
(IX)	25539	1,5-bis(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid	C₁₈H₁₆N₂O₄	详情	详情
(X)	25540	N-methoxy-1,5-bis(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide	C₂₀H₂₁N₃O₄	详情	详情
(XI)	25541	methyl 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzoate	C₂₆H₂₁ClN₂O₅	详情	详情
(XII)	25542	methyl 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl](dimethoxy)methyl]-2-chlorobenzoate	C₂₈H₂₇ClN₂O₆	详情	详情
(XIII)	25543	5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl](dimethoxy)methyl]-2-chlorobenzoic acid	C₂₇H₂₅ClN₂O₆	详情	详情

合成路线3

An further synthetic route to the intermediate ketoester (XI) is depicted in Scheme 23794901c. Pyrazole aldehyde (XIV) was condensed with 5-bromo-2-chlorobenzoic acid (XV) in the presence of two equivalents of n--BuLi to afford carbinol (XVI). Subsequent reaction of (XVI) with (trimethylsilyl) diazomethane provided methyl ester (XVII). Then, oxidation of (XVII) with activated MnO2 in boiling 1,2-dichloroethane led to the required ketone (XI).

参考文献中间体

【1】 Numata, H.; Okamoto, Y.; Shinoda, M.; Kobayashi, N.; Miyazawa, S.; Kawahara, T.; Shirota, H.; Nagakura, N.; Horizoe, T.; Abe, S.; Kobayashi, S.; Yamanaka, T. (Eisai Co., Ltd.); Pyrazole derivs. exhibiting anti-inflammatory and analgesic effects. JP 1998509140; WO 9614302 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	25541	methyl 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzoate		C₂₆H₂₁ClN₂O₅	详情	详情
(XIV)	25544	1,5-bis(4-methoxyphenyl)-1H-pyrazole-3-carbaldehyde		C₁₈H₁₆N₂O₃	详情	详情
(XV)	25545	5-bromo-2-chlorobenzoic acid	21739-92-4	C₇H₄BrClO₂	详情	详情
(XVI)	25546	5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl](hydroxy)methyl]-2-chlorobenzoic acid		C₂₅H₂₁ClN₂O₅	详情	详情
(XVII)	25547	methyl 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl](hydroxy)methyl]-2-chlorobenzoate		C₂₆H₂₃ClN₂O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)