　 -Drug Synthesis Database

【结构式】

【分子编号】33989

【品名】　

【CA登记号】

【分子式】C₈H₁₃NaO₄

【分子量】196.178588

【元素组成】C 48.98% H 6.68% Na 11.72% O 32.62%

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：(B)

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

合成目标

【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

合成路线2

该中间体在本合成路线中的序号：

Camprofen has been synthesized previously by Picciola as a chemical intermediate in the preparation of an indazolylpropionic acid, but was apparently not itself evaluated for antiinflammatory activity during that study. The synthetic approach (scheme 16191901a), begins with 1-chloro-4-nitrobenzene (I), which is readily available commercially. Treatment of (I) with the carbanion derived from diethyl methylmalonate (using sodium hydride as base, in N,N-dimethylformamide) provides the intermediate diethyl ester (II), which is saponified in situ and then acidified to the acid (IIIa). Crude (IIIa) is then esterified to the methyl ester (IIIb), purified by column chromatography, the sequence being analogous to that of Hino et al. The nitrophenyl ester (IIIb) is dissolved in 95% ethanol and hydrogenated in the presence of palladium catalyst to provide the 4-aminophenyl compound (IV). Finally, an Ullmann-Jourdan condensation of (IV) with 2-chlorobenzoic acid in the presence of anhydrous potassium carbonate, activated copper powder and N,N-methylformamide provides camprofen. This synthetic scheme uses cheap and readily available reagents and provides racemic camprofen in an overall yield of 52% based on 1-chloro-4-nitrobenzene (I).

参考文献中间体

合成目标

【1】 Appleton, R.A.; Brown, K.; Conformational requirements at the prostaglandin cyclooxygenase receptor site: A template for designing non-steroidal anti-inflammatory drugs. Prostaglandins 1979, 18, 29.
【2】 Hino, K.; Nakamura, H.; Nagai, Y.; Uno, H.; Nishimura, H.; Non-steroidal anti-inflammatory agents. 2.[(heteroarylamino)phenyl]alkanoic acids. J Med Chem 1983, 26, 222.
【3】 Taraporewala, I.B.; Kauffman, J.M.; Synthesis and structure activity relationships of anti-inflammatory 9,10-dihydro-9-oxo-2-acridine-alkanoic acids and 4-(2-carboxyphenyl)aminobenzenealkanoic acids. J Pharm Sci 1990, 79, 2, 173.
【4】 Kauffman, J.M.; Taraporewala, I.B.; Synthesis of the p-nitrophenyl ester of acridine-2-acetic acid. J Heterocycl Chem 1982, 19, 1557.
【5】 Picciola, G.; Heterocyclic compounds containing 4-aminophenyl-alkanoic acid residues with potential antiinflammatory activity. III. Derivatives of 3-hydroxyindazole. Boll Chim Farm 1981, 120, 8, 458.
【6】 Taraporewala, I.B.; Kauffman, J.M.; CAMPROFEN. Drugs Fut 1990, 15, 6, 563.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10203	o-Chlorobenzoic acid; 2-Chlorobenzoic acid	118-91-2	C₇H₅ClO₂	详情	详情
	33989			C₈H₁₃NaO₄	详情	详情
(III-b)	13911	methyl 2-(4-nitrophenyl)propanoate		C₁₀H₁₁NO₄	详情	详情
(III-a)	52520	2-(4-nitrophenyl)propanoic acid		C₉H₉NO₄	详情	详情
(I)	13909	1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene	100-00-5	C₆H₄ClNO₂	详情	详情
(II)	13910	diethyl 2-methyl-2-(4-nitrophenyl)malonate		C₁₄H₁₇NO₆	详情	详情
(IV)	13912	methyl 2-(4-aminophenyl)propanoate	39718-97-3	C₁₀H₁₃NO₂	详情	详情

Extended Information