2,4-dimethylaniline; 2,4-dimethylphenylamine -Drug Synthesis Database

【结构式】

【分子编号】32911

【品名】2,4-dimethylaniline; 2,4-dimethylphenylamine

【CA登记号】95-68-1

【分子式】C₈H₁₁N

【分子量】121.18208

【元素组成】C 79.29% H 9.15% N 11.56%

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：(I)

The intermediate benzyl 5,7-dimethylindole-2-carboxylate (X) was prepared by several procedures. Diazotization of 2,4-dimethylaniline (I), followed by Japp-Klingemann condensation of the diazonium salt (II) with ethyl 2-methyl-3-oxobutyrate (III) furnished hydrazone (IV). Subsequent Fischer indole synthesis in formic acid at 75 C provided ethyl 5,7-dimethylindole-2-carboxylate (V). An alternative route to indole (V) involved condensation of 3,5-dimethylbenzaldehyde (VI) with ethyl azidoacetate (VII) in ethanolic NaOEt, followed by thermal cyclization of the resulting azidocinnamate ester (VIII). Basic hydrolysis of ethyl ester (V) gave carboxylic acid (IX), which was converted to the benzyl ester (X) upon treatment with benzyl bromide and DBU.

参考文献中间体

合成目标

【1】 Brodin, R.; Boigegrain, R.; Molimard, J.-C.; Bignon, E.; Olliero, D. (Sanofi-Synthelabo ); Carboxamidothiazole derivs., preparation, pharmaceutical compsns. containing them. EP 1017693; FR 2768737; FR 2777887; WO 9915525 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(I)	32911	2,4-dimethylaniline; 2,4-dimethylphenylamine	95-68-1	C₈H₁₁N	详情	详情
(II)	32912	2,4-dimethylbenzenediazonium		C₈H₉N₂	详情	详情
(III)	10362	ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate	609-14-3	C₇H₁₂O₃	详情	详情
(IV)	32913	ethyl 2-[(Z)-2-(2,4-dimethylphenyl)hydrazono]propanoate		C₁₃H₁₈N₂O₂	详情	详情
(V)	32914	ethyl 5,7-dimethyl-1H-indole-2-carboxylate		C₁₃H₁₅NO₂	详情	详情
(VI)	32915	3,5-dimethylbenzaldehyde	5779-95-3	C₉H₁₀O	详情	详情
(VII)	32916	ethyl 2-azidoacetate	637-81-0	C₄H₇N₃O₂	详情	详情
(VIII)	32917	ethyl (Z)-2-azido-3-(3,5-dimethylphenyl)-2-propenoate		C₁₃H₁₅N₃O₂	详情	详情
(IX)	32918	5,7-dimethyl-1H-indole-2-carboxylic acid		C₁₁H₁₁NO₂	详情	详情
(X)	32919	benzyl 5,7-dimethyl-1H-indole-2-carboxylate		C₁₈H₁₇NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

5-Amino-3-methylisoxazole (I) was chlorinated with N-chlorosuccinimide to afford (II), which was condensed with 2-carbomethoxy-3-thiophenesulfonyl chloride (III) in the presence of NaH in THF to furnish sulfonamide (IV). After protection of the sulfonamide NH group of (IV) with methoxymethyl bromide, basic hydrolysis of the methyl ester function provided carboxylic acid (VI). This was then converted to acid chloride (VII) upon treatment with oxalyl chloride and pyridine. Aminoacetophenone derivative (IX) was prepared by BCl3-catalyzed acylation of 2,4-dimethylaniline (VIII) with acetonitrile. Coupling of aniline (IX) with acid chloride (VII) to give (X) was carried out either using an excess of aniline or, alternatively, in the presence of 4-(dimethylamino)benzonitrile as the base. Finally, removal of the methoxymethyl protecting group of (X) under acidic conditions furnished the title compound.

参考文献中间体

合成目标

【1】 Decker, E.R.; Blok, N.; Wu, C.; et al.; Acyl substitution at the ortho position of anilides enhances oral bioavailability of thiophene sulfonamides: TBC3214, and ETA selective endothelin antagonist. J Med Chem 2001, 44, 8, 1211.
【2】 Blok, N.; Keller, K.; Wu, C.; Kogan, T.; Woodard, P. (Texas Biotechnology Corp.); Sulfonamides for treatment of endothelin-mediated disorders. EP 0980369; US 5783705; WO 9849162 .

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)	17834	3-methyl-5-isoxazolylamine; 3-methyl-5-isoxazolamine; 5-Amino-3-methylisoxazole	14678-02-5	C₄H₆N₂O	详情	详情
(II)	17835	4-chloro-3-methyl-5-isoxazolamine; 4-chloro-3-methyl-5-isoxazolylamine		C₄H₅ClN₂O	详情	详情
(III)	17836	Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate		C₆H₅ClO₄S₂	详情	详情
(IV)	17837	methyl 3-[[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl]-2-thiophenecarboxylate		C₁₀H₉ClN₂O₅S₂	详情	详情
(V)	41320	methyl 3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylate		C₁₂H₁₃ClN₂O₆S₂	详情	详情
(VI)	47989	3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxylic acid		C₁₁H₁₁ClN₂O₆S₂	详情	详情
(VII)	41321	3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarbonyl chloride		C₁₁H₁₀Cl₂N₂O₅S₂	详情	详情
(VIII)	32911	2,4-dimethylaniline; 2,4-dimethylphenylamine	95-68-1	C₈H₁₁N	详情	详情
(IX)	47990	1-(2-amino-3,5-dimethylphenyl)-1-ethanone		C₁₀H₁₃NO	详情	详情
(X)	47991	N-(2-acetyl-4,6-dimethylphenyl)-3-[[(4-chloro-3-methyl-5-isoxazolyl)(methoxymethyl)amino]sulfonyl]-2-thiophenecarboxamide		C₂₁H₂₂ClN₃O₆S₂	详情	详情

Extended Information