Diflunisal, MK-647, Dolobid, -Drug Synthesis Database

【结构式】

【药物名称】Diflunisal, MK-647, Dolobid

【化学名称】2',4'-Difluoro-4-hydroxy-1,1'-biphenyl-3-carboxylic acid
　　　　　　2-Hydroxy-5-(2,4-difluorophenyl)benzoic acid

【CA登记号】22494-42-4

【分子式】C₁₃H₈F₂O₃

【分子量】250.20371

【开发单位】Merck & Co. (Originator), Merck Frosst (Originator), Merck Sharp & Dohme (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiarthritic Drugs, Non-Opioid Analgesics, Osteoarthritis, Treatment of, Rheumatoid Arthritis, Treatment of, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Non-Steroidal Antiinflammatory Drugs

合成路线1 合成路线2

合成路线1

Compound can be prepared in two different ways both starting from 2,4-difluoroaniline (I): 1) The diazotation of (I) with isoamyl nitrite (B) and condensation with anisole (A) gives 4-(2,4-difluorophenyl)anisole (II), which is hydrolyzed with HI in refluxing acetic acid yielding 4-(2,4-difluorophenyl)phenol (III). Finally, this compound is carbonated with K2CO3 and CO2 at 175 C and 1300 p.s.i. 2) The diazotation of (I) with isoamyl nitrite (B) and then condensation with benzene by means of powdered Cu gives 2,4-difluorobiphenyl (IV), which is acetylated with acetic anhydride by means of AlCl3 in CH2Cl2 yielding 4-(2,4-difluorophenyl)acetophenone (V). The oxidation of (V) with H2O2 in refluxing CH2Cl2 affords 4-(2,4-difluorophenyl)phenyl acetate (VI), which can be hydrolyzed with NaOH in refluxing water to give the phenol (III).

参考文献中间体

【1】 Ruyle, W.V.; et al. (Merck & Co., Inc.); Phenyl benzoic acid compounds in compositions and methods for treating inflammation. US 3674870 .
【2】 Howard, J.; et al. (Merck & Co., Inc.); Chemical products. DE 2532559; FR 2288729; GB 1496231; GB 1496232; JP 51034135 .
【3】 Houser, R.W.; Jones, H. (Merck & Co., Inc.); Process for preparing 4-(2,4-difluorophenyl)-salicyclic acid. US 4225730 .
【4】 Ruyle, W.V.; et al. (Merck & Co., Inc.); Halo-substituted 5-phenylbenzoic acids and their derivatives. GB 1175212 .
【5】 Arrigoni-Martelli, E.; Castaner, J.; Diflunisal. Drugs Fut 1978, 3, 4, 28.

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)	23767	Methoxybenzene; Methyl phenyl ether; Anisole	100-66-3	C₇H₈O	详情	详情
(B)	32169	3-Methyl-1-nitrobutane; Isoamyl nitrite	543-87-3	C₅H₁₁NO₂	详情	详情
(I)	19462	2,4-difluoroaniline; 2,4-difluorophenylamine；2,4-Difluoro-benzenamine;1-Amino-2,4-difluorobenzene	367-25-9	C₆H₅F₂N	详情	详情
(II)	33464	2',4'-difluoro[1,1'-biphenyl]-4-yl methyl ether; 2,4-difluoro-4'-methoxy-1,1'-biphenyl		C₁₃H₁₀F₂O	详情	详情
(III)	14631	2',4'-difluoro[1,1'-biphenyl]-4-ol		C₁₂H₈F₂O	详情	详情
(IV)	33465	2,4-difluoro-1,1'-biphenyl		C₁₂H₈F₂	详情	详情
(V)	33466	1-(2',4'-difluoro[1,1'-biphenyl]-4-yl)-1-ethanone		C₁₄H₁₀F₂O	详情	详情
(VI)	33467	2',4'-difluoro[1,1'-biphenyl]-4-yl acetate		C₁₄H₁₀F₂O₂	详情	详情

合成路线2

A facile preparation method for diflunisal has been reported: Reaction of 2,4-difluoroiodobenzene (I) with powdered Zn activated with 1,2-dibromoethane in DMF gives the 2,4-difluorophenylzinc iodide (II), which is condensed with 2-acetoxy-5-iodobenzoic acid methyl ester (III) by means of Pd(PPh3)4 in DMF to yield 4-acetoxy-2',4'-difluorobiphenyl-3-carboxylic acid methyl ester (IV). Finally, this compound is deacetylated and hydrolyzed with NaHCO3 in THF/water.

参考文献中间体

【1】 Lee, S.J.; Chung, S.; Jeong, N.; Choi, K.H.; A facile preparation of fluoroaryl zinc halides: An application to the synthesis of diflunisal. Bull Korean Chem Soc 2000, 21, 2, 165.

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)	43814	2,4-difluoro-1-iodobenzene	2265-93-2	C₆H₃F₂I	详情	详情
(II)	43815	(2,4-difluorophenyl)(iodo)zinc		C₆H₃F₂IZn	详情	详情
(III)	43816	methyl 2-(acetoxy)-5-iodobenzoate		C₁₀H₉IO₄	详情	详情
(IV)	43817	methyl 4-(acetoxy)-2',4'-difluoro[1,1'-biphenyl]-3-carboxylate		C₁₆H₁₂F₂O₄	详情	详情

Extended Information