4-amino-2-methyl-6-quinolinylamine; 2-methyl-4,6-quinolinediamine -Drug Synthesis Database

【结构式】

【分子编号】49031

【品名】4-amino-2-methyl-6-quinolinylamine; 2-methyl-4,6-quinolinediamine

【CA登记号】

【分子式】C₁₀H₁₁N₃

【分子量】173.21756

【元素组成】C 69.34% H 6.4% N 24.26%

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：(XI)

Bromination of methyl toluate (I) with N-bromosuccinimide and benzoyl peroxide (Bz2O2) in refluxing CCl4 gives alpha-bromo-o-toluate (II), which is coupled with phenolic derivative (III) by means of K2CO3 in DMF to provide phenoxy derivative (IV). Saponification of the methyl ester group of (IV) by treatment with KOH in refluxing EtOH affords carboxylic acid (V), which is then converted into the desired compound via the corresponding acid chloride obtained by reaction with oxalyl chloride in CHCl3, followed by coupling with 4,6-diamino-2-methylquinoline (XII) by means of pyridine. Quinoline (XII) can be obtained as follows: Condensation of 4-aminoacetanilide (VII) with methyl acetoacetate (VIII) by heating in MeOH affords crotonate (IX), which is then subjected to cyclization in refluxing Dowtherm A to provide hydroxy quinoline (X). Methylation of (X) with dimethyl sulfate in refluxing toluene gives methoxy quinoline (XI), whose methoxy group is converted into an amino group with ammonium acetate and whose acetyl group is finally removed by hydrolysis with HCl.

参考文献中间体

合成目标

【1】 Kitao, Y.; Shinkai, H.; Ito, T.; Uchida, I.; Yamada, H.; Iida, T.; 4-Aminoquinolones: Novel nociceptin antagonists with analgesics activity. J Med Chem 2000, 43, 24, 4667.
【2】 Shinkai, H.; Yamada, H.; to, T. (Japan Tobacco Inc.); Amide derivs. and nociceptin antagonists. EP 1072263; JP 1999335355; WO 9948492 .

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)	49024	2-Methyl Methylbenzoate; 2-Methylbenzoic acid methyl ester; Methyl o-toluate; o-Toluic acid methyl ester	89-71-4	C₉H₁₀O₂	详情	详情
(II)	28575	methyl 2-(bromomethyl)benzoate		C₉H₉BrO₂	详情	详情
(III)	49025	p-Ethylphenol; 4-Ethylphenol	123-07-9	C₈H₁₀O	详情	详情
(IV)	49026	methyl 2-[(4-ethylphenoxy)methyl]benzoate		C₁₇H₁₈O₃	详情	详情
(V)	49027	2-[(4-ethylphenoxy)methyl]benzoic acid		C₁₆H₁₆O₃	详情	详情
(VI)	29016	N-(4-aminophenyl)acetamide	122-80-5	C₈H₁₀N₂O	详情	详情
(VII)	11791	methyl 3-oxobutanoate; Methyl acetoacetate	105-45-3	C₅H₈O₃	详情	详情
(VIII)	49028	methyl (Z)-3-[4-(acetamido)anilino]-2-butenoate		C₁₃H₁₆N₂O₃	详情	详情
(IX)	49029	N-(4-hydroxy-2-methyl-6-quinolinyl)acetamide		C₁₂H₁₂N₂O₂	详情	详情
(X)	49030	N-(4-methoxy-2-methyl-6-quinolinyl)acetamide		C₁₃H₁₄N₂O₂	详情	详情
(XI)	49031	4-amino-2-methyl-6-quinolinylamine; 2-methyl-4,6-quinolinediamine		C₁₀H₁₁N₃	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-Nitroisatin (VIII) is condensed with acetone in the presence of aqueous ammonia in an autoclave at 100 C to produce the quinolinecarboxamide (IX). Subsequent Hofmann rearrangement of (IX) with sodium hypochlorite produces the 4-amino quinoline (X). The nitro group of (X) is then reduced by catalytic hydrogenation over Pd/C to give the diaminoquinoline (VII).

参考文献中间体

合成目标

【1】 Shinkai, H.; Yamada, H.; to, T. (Japan Tobacco Inc.); Amide derivs. and nociceptin antagonists. EP 1072263; JP 1999335355; WO 9948492 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	58318	2-methyl-6-nitro-4-quinolinamine; 2-methyl-6-nitro-4-quinolinylamine		C₁₀H₉N₃O₂	详情	详情
(VIII)	49031	4-amino-2-methyl-6-quinolinylamine; 2-methyl-4,6-quinolinediamine		C₁₀H₁₁N₃	详情	详情
(IX)	58316	5-nitro-1H-indole-2,3-dione; 5-Nitroisatin	611-09-6	C₈H₄N₂O₄	详情	详情
(X)	58317	2-methyl-6-nitro-4-quinolinecarboxamide		C₁₁H₉N₃O₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

Radical bromination of methyl ortho-toluate (XI) with N-bromosuccinimide in the presence of benzoyl peroxide affords the 2-(bromomethyl)benzoate (XII). This is then condensed with 4-ethylphenol (XIII) to furnish ether (XIV). Alkaline hydrolysis of the methyl ester group of (XIV) provides acid (XV), which is further activated as the corresponding acid chloride (XVI) with oxalyl chloride in chloroform. Finally, condensation of acid chloride (XVI) with the diaminoquinoline (VII) gives rise to the title compound.

参考文献中间体

合成目标

【1】 Kitao, Y.; Shinkai, H.; Ito, T.; Uchida, I.; Yamada, H.; Iida, T.; 4-Aminoquinolones: Novel nociceptin antagonists with analgesics activity. J Med Chem 2000, 43, 24, 4667.
【2】 Shinkai, H.; Yamada, H.; to, T. (Japan Tobacco Inc.); Amide derivs. and nociceptin antagonists. EP 1072263; JP 1999335355; WO 9948492 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	49031	4-amino-2-methyl-6-quinolinylamine; 2-methyl-4,6-quinolinediamine		C₁₀H₁₁N₃	详情	详情
(XI)	49024	2-Methyl Methylbenzoate; 2-Methylbenzoic acid methyl ester; Methyl o-toluate; o-Toluic acid methyl ester	89-71-4	C₉H₁₀O₂	详情	详情
(XII)	28575	methyl 2-(bromomethyl)benzoate		C₉H₉BrO₂	详情	详情
(XIII)	49025	p-Ethylphenol; 4-Ethylphenol	123-07-9	C₈H₁₀O	详情	详情
(XIV)	49026	methyl 2-[(4-ethylphenoxy)methyl]benzoate		C₁₇H₁₈O₃	详情	详情
(XV)	49027	2-[(4-ethylphenoxy)methyl]benzoic acid		C₁₆H₁₆O₃	详情	详情
(XVI)	55816	2-[(4-ethylphenoxy)methyl]benzoyl chloride		C₁₆H₁₅ClO₂	详情	详情

Extended Information