2-(4-nitrophenyl)propanoic acid -Drug Synthesis Database

【结构式】

【分子编号】52520

【品名】2-(4-nitrophenyl)propanoic acid

【CA登记号】

【分子式】C₉H₉NO₄

【分子量】195.1748

【元素组成】C 55.39% H 4.65% N 7.18% O 32.79%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(VIII)

It can be obtained in two different ways, both starting from ethyl alpha-(4-aminophenyl)propionate (I): 1) The condensation of the amino compound (I) with benzaldehyde (A), followed by reduction of the Schiff base with H2 over Pt in ethanol gives ethyl alpha-(benzylaminophenyl)propionate (II), which by reaction with phosgene in toluene affords ethyl alpha-[N-chlorocarbonyl-(4-benzylaminophenyl)]propionate (III); the cyclization of this compound with AlCl3 in CH2Cl2 yields ethyl alpha-[4-(1-oxo-2-iso-indolinyl)phenyl]propionate (IV), which is finally saponified with K2CO3 in ethanol - water. 2) The cyclization of the amino compound (I) with 2-cyanobenzyl bromide (B) in refluxing ethanol affords ethyl alpha-[4-(1-imino-2-iso-indolinyl)phenyl]propionate (V). which is finally hydrolyzed and saponified with K2CO3 as before. The starting aminoester (I) is obtained as follows: The nitration of alpha-phenylpropionitrile (VI) gives alpha-(4-nitrophenyl)propionitrile (VII), which is hydrolyzed with H2SO4 to alpha-(4-nitrophenyl)propionic acid (VIII). Esterification of this acid with ethanol and H2SO4 yields ethyl alpha-(4-nitrophenyl)propionate (IX), which is finally reduced with H2 over Pd/C in ethanol giving the aminoester (I), b.p.(0.5mm) 125 C.

参考文献中间体

合成目标

【1】 Castaner, J.; Arrigoni, Martelli, E.; Indoprofen. Drugs Fut 1976, 1, 5, 242.
【2】 Nanini, G.; et al.; New analgesic-anti-inflammatory drugs. 1-oxo-2-substituted isoindoline derivatives. Arzneim-Forsch 1973, 23, Suppl. 3, 1090.

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)	10498	Benzaldehyde;Benzoic aldehyde;Phenylmethanal	100-52-7	C₇H₆O	详情	详情
(B)	33303	2-(bromomethyl)benzonitrile	22115-41-9	C₈H₆BrN	详情	详情
(I)	33984	ethyl 2-(4-aminophenyl)propanoate		C₁₁H₁₅NO₂	详情	详情
(II)	60734	ethyl 2-[4-(benzylamino)phenyl]propanoate		C₁₈H₂₁NO₂	详情	详情
(III)	60737	ethyl 2-{4-[benzyl(chlorocarbonyl)amino]phenyl}propanoate		C₁₉H₂₀ClNO₃	详情	详情
(IV)	60738	ethyl 2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]propanoate		C₁₉H₁₉NO₃	详情	详情
(V)	60739	ethyl 2-[4-(1-imino-1,3-dihydro-2H-isoindol-2-yl)phenyl]propanoate		C₁₉H₂₀N₂O₂	详情	详情
(VI)	60735	hydratroponitrile		C₉H₉N	详情	详情
(VII)	60736	2-(4-nitrophenyl)propanenitrile		C₉H₈N₂O₂	详情	详情
(VIII)	52520	2-(4-nitrophenyl)propanoic acid		C₉H₉NO₄	详情	详情
(IX)	33983	ethyl 2-(4-nitrophenyl)propanoate		C₁₁H₁₃NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III-a)

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

合成路线3

该中间体在本合成路线中的序号：(VII)

Ethyl 2-(4-nitrophenyl)propionate (VIII), obtained by acid-catalyzed esterification of carboxylic acid (VII), was alkylated by means of iodomethane and NaH to furnish the 2-methylpropionate (IX). Subsequent nitro group hydrogenation over Pd/C gave aniline (X). Diazotization of (X), followed by SnCl2 reduction of the intermediate diazonium salt, afforded the aryl hydrazine (XI). Cyclization between hydrazine (XI) and ketone (VI) under Fischer indolization conditions occurred with concomitant cyclopropyl group rearrangement to generate the racemic beta-methyl tryptamine derivative (XII), which was further separated into the enantiomers.

参考文献中间体

合成目标

【1】 Chu, L.; Wyvratt, M.J.; Ponpipom, M.M.; Lin, P.; Ashton, W.T.; Goulet, M.; Young, J.; Girotra, N.N.; Fisher, M.H. (Merck & Co., Inc.); Antagonists of gonadotropin releasing hormone. EP 1095038; WO 0004013 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	52519	(3,5-dimethylphenyl)(2-methylcyclopropyl)methanone	C₁₃H₁₆O	详情	详情
(VII)	52520	2-(4-nitrophenyl)propanoic acid	C₉H₉NO₄	详情	详情
(VIII)	33983	ethyl 2-(4-nitrophenyl)propanoate	C₁₁H₁₃NO₄	详情	详情
(IX)	52521	ethyl 2-methyl-2-(4-nitrophenyl)propanoate	C₁₂H₁₅NO₄	详情	详情
(X)	52522	ethyl 2-(4-aminophenyl)-2-methylpropanoate	C₁₂H₁₇NO₂	详情	详情
(XI)	52523	ethyl 2-(4-hydrazinophenyl)-2-methylpropanoate	C₁₂H₁₈N₂O₂	详情	详情
(XII)	52524	ethyl 2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropanoate	C₂₅H₃₂N₂O₂	详情	详情

Extended Information