Pirprofen, SU-21524, Rengasil, -Drug Synthesis Database

【结构式】

【药物名称】Pirprofen, SU-21524, Rengasil

【化学名称】3-Chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)-alpha-methylbenzeneacetic acid
　　　　　　3-Chloro-4-(3-pyrrolin-1-yl)hydratropic acid

【CA登记号】31793-07-4

【分子式】C₁₃H₁₄ClNO₂

【分子量】251.71503

【开发单位】Novartis (Originator)

【药理作用】Acute Attacks of Migraine, Treatment of, ANALGESIC AND ANESTHETIC DRUGS, Antimigraine Drugs, Non-Steroidal Antiinflammatory Drugs

合成路线1 合成路线2

合成路线1

The methylation of ethyl 4-nitrophenylacetate (I) with NaH - ICH3 in DMF - toluene to ethyl 2-(4-nitrophenyl)propionate (II), which was reduced with H2 over Pd/C in EtOH - H2O to ethyl 2-(4-aminophenyl)propionate (III) (HCl deriv., m.p. 137-40 C). This product was acetylated with acetic anhydride to ethyl 2-(acetylaminophenyl) propionate (IV), m.p. 88-90 C, which was chlorinated with Cl2 in acetic acid to ethyl 2-(3-chloro-4-acetylaminophenyl)propionate (V), b.p. 155-60 C/0.7 mm; this, in turn, was hydrolyzed with HCl in EtOH to ethyl 2-(3-chloro-4-aminophenyl)propionate hydrochloride (VI), m.p. 164-8 C. The last step being the reaction of the preceding intermediate with cis-1,4-dichloro (or dibromo)-2-butene (A) in DMF and Na2CO3 to ethyl 2-(3-chloro-4-(3-pyrrolinyl)phenyl)propionate (VII), b.p. 128-33 C/0.25 mm; followed by hydrolysis with KOH in EtOH - H2O. The acetylation of ethyl 4-aminophenylacetate (VIII) with acetic anhydride to ethyl 4-acetylaminophenylacetate (IX), m.p. 75-8 C, followed by methylation with ICH3 and Na in liquid NH3 to ethyl 2-(4-acetylaminophenyl)propionate (IV), already obtained.

参考文献中间体

【1】 Carney, R.W.J.; de Stevens, G; Tertiary amino phenyl acetic acids. CH 574926; CH 577968; CH 578523; CH 581103; CH 581104; US 3641040 .
【2】 Castaner, J.; Pirprofen. Drugs Fut 1977, 1, 1, 23.

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)	32186	(E)-1,4-dichloro-2-butene	110-57-6	C₄H₆Cl₂	详情	详情
(I)	33982	ethyl 2-(4-nitrophenyl)acetate	5445-26-1	C₁₀H₁₁NO₄	详情	详情
(II)	33983	ethyl 2-(4-nitrophenyl)propanoate		C₁₁H₁₃NO₄	详情	详情
(III)	33984	ethyl 2-(4-aminophenyl)propanoate		C₁₁H₁₅NO₂	详情	详情
(IV)	33985	ethyl 2-[4-(acetamido)phenyl]propanoate		C₁₃H₁₇NO₃	详情	详情
(V)	33986	ethyl 2-[4-(acetamido)-3-chlorophenyl]propanoate		C₁₃H₁₆ClNO₃	详情	详情
(VI)	33987	ethyl 2-(4-amino-3-chlorophenyl)propanoate		C₁₁H₁₄ClNO₂	详情	详情
(VII)	33988	ethyl 2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl]propanoate		C₁₅H₁₈ClNO₂	详情	详情
(VIII)	21230	ethyl 2-(4-aminophenyl)acetate	5438-70-0	C₁₀H₁₃NO₂	详情	详情
(IX)	21231	ethyl 2-[4-(acetamido)phenyl]acetate		C₁₂H₁₅NO₃	详情	详情

合成路线2

The reaction of 2,4-dichloronitrobenzene (X) with sodium diethyl methylmalonate (B) in DMF to diethyl 2-(4-nitro-3-chlorophenyl)-2-methyl-malonate (XI), b.p. 147-8 C/0.25 mm, followed hydrolysis, decarboxylation and esterification to ethyl 2-(3-chloro-4-nitrophenyl)propionate (XII), b.p. 138-42 C /0.25 mm; which, in turn, was reduced as before to ethyl 2-(3-chloro-4-aminophenyl)propionate hydrochloride (VI). Conversely, the diethyl 2-(4-nitro-3-chlorophenyl)-2-methylmalonate (XI), already obtained before, could be hydrogenated first to diethyl 2-(4-amino-3-chlorophenyl)-2-methylmalonate (XIII), b.p. 180-5 C/0.25 mm, and then hydrolyzed, decarboxylated and esterified again to ethyl 2-(3-chloro-4-aminophenyl)propionate hydrochloride (VI).

参考文献中间体

【1】 Carney, R.W.; et al.; Potent nonsteroidal anti-inflammatory agent, 2-[3-chloro-4-(3-pyrrolin-1-yl)phenyl]propionic acid. Experientia 1973, 29, 8, 938.
【2】 Castaner, J.; Pirprofen. Drugs Fut 1977, 1, 1, 23.

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)	32186	(E)-1,4-dichloro-2-butene	110-57-6	C₄H₆Cl₂	详情	详情
(B)	33989			C₈H₁₃NaO₄	详情	详情
(VI)	33987	ethyl 2-(4-amino-3-chlorophenyl)propanoate		C₁₁H₁₄ClNO₂	详情	详情
(VII)	33988	ethyl 2-[3-chloro-4-(2,5-dihydro-1H-pyrrol-1-yl)phenyl]propanoate		C₁₅H₁₈ClNO₂	详情	详情
(X)	21787	2,4-dichloro-1-nitrobenzene	611-06-3	C₆H₃Cl₂NO₂	详情	详情
(XI)	33990	diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate		C₁₄H₁₆ClNO₆	详情	详情
(XII)	33991	ethyl 2-(3-chloro-4-nitrophenyl)propanoate		C₁₁H₁₂ClNO₄	详情	详情
(XIII)	33992	diethyl 2-(4-amino-3-chlorophenyl)-2-methylmalonate		C₁₄H₁₈ClNO₄	详情	详情

Extended Information