diethyl 2-methyl-2-(4-nitrophenyl)malonate -Drug Synthesis Database

【结构式】

【分子编号】13910

【品名】diethyl 2-methyl-2-(4-nitrophenyl)malonate

【CA登记号】

【分子式】C₁₄H₁₇NO₆

【分子量】295.29212

【元素组成】C 56.94% H 5.8% N 4.74% O 32.51%

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：(X)

The malonic synthesis of 4-nitrochlorobenzene (VIII) with sodium diethyl methylmalonate (IX) (prepared with the corresponding malonic ester and NaH) in hot DMF gives diethyl (4-nitrophenyl)methylmalonate (X), which is reduced with H2 over Pd/C as before yielding diethyl (4-aminophenyl)methylmalonate (XI). The alkylation of (XI) with (VI) by means of NaHCO3 in refluxing ethanol affords diethyl [4-(2-methylallyl)aminophenyl]methylmalonate (XII), which is treated with sodium ethoxide in refluxing ethanol to yield ethyl 2-(4-[2-methylallylamino)phenyl]propionate (XIV). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol. Partial hydrolysis of (XII) with NaOH in refluxing ethanol gives 2-[4-(2-methylallylamino)phenyl]methylmalonic acid (XIII), which is finally decarboxylated by treatment with refluxing aqueous HCl. The simultaneous hydrolysis and decarboxylation of (XII) with NaOH in refluxing ethanol also gives the title product.

参考文献中间体

合成目标

【1】 Dumaitre, B.; et al.; Synthesis of some analgesic and antiinflammatory 4-aminophenylacetic and 4-aminophenylacetic and 2-(4-aminophenyl)propionic acid derivatives. Eur J Med Chem - Chim Ther 1979, 14, 3, 207-214.
【2】 Serradell, M.N.; Castaner, J.; Alminoprofen. Drugs Fut 1984, 9, 3, 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
(VI)	12127	3-Chloro-2-methyl-1-propene; Isobutenyl chloride	563-47-3	C₄H₇Cl	详情	详情
(VIII)	13909	1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene	100-00-5	C₆H₄ClNO₂	详情	详情
(IX)	30310	diethyl 2-methylmalonate	609-08-5	C₈H₁₄O₄	详情	详情
(X)	13910	diethyl 2-methyl-2-(4-nitrophenyl)malonate		C₁₄H₁₇NO₆	详情	详情
(XI)	30311	diethyl 2-(4-aminophenyl)-2-methylmalonate		C₁₄H₁₉NO₄	详情	详情
(XII)	30312	diethyl 2-methyl-2-[4-[(2-methyl-2-propenyl)amino]phenyl]malonate		C₁₈H₂₅NO₄	详情	详情
(XIII)	30313	2-methyl-2-[4-[(2-methyl-2-propenyl)amino]phenyl]malonic acid		C₁₄H₁₇NO₄	详情	详情
(XIV)	30314	ethyl 2-[4-[(2-methyl-2-propenyl)amino]phenyl]propanoate		C₁₅H₂₁NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

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