5-amino-2-hydroxybenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】29932

【品名】5-amino-2-hydroxybenzoic acid

【CA登记号】89-57-6

【分子式】C₇H₇NO₃

【分子量】153.13752

【元素组成】C 54.9% H 4.61% N 9.15% O 31.34%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(C)

The reaction of beta-tetralone (I) with pyrrolidine (A) yields enamine (II), which is condensed with phenacyl bromide (B) in DMF to give the 1-phenacyl-2-tetralone (III). Finally, this diketone is cyclized with 5-aminosalycilic acid (C) in refluxing acetic acid.

参考文献中间体

合成目标

【1】 Anderson, V.B.; et al.; Carboxyarylindoles as non steroidal anti-inflammatory agents. J Med Chem 1976, 1, 7, 320.
【2】 Castaner, J.; Arrigoni-Martelli, E.; Fendosal. Drugs Fut 1976, 1, 7, 320.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	10315	2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone	70-11-1	C₈H₇BrO	详情	详情
(A)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(I)	39106	3,4-Dihydro-2(1H)-naphthalenone; beta-Tetralone	530-93-8	C₁₀H₁₀O	详情	详情
(II)	20382	1-(3,4-dihydro-2-naphthalenyl)pyrrolidine	21403-95-2	C₁₄H₁₇N	详情	详情
(III)	40460	1-(2-oxo-2-phenylethyl)-3,4-dihydro-2(1H)-naphthalenone		C₁₈H₁₆O₂	详情	详情
(C)	29932	5-amino-2-hydroxybenzoic acid	89-57-6	C₇H₇NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Acetylation of 5-aminosalicylic acid (I) with acetic anhydride in hot acetic acid gives 5-acetaminosalicylic acid (II), which is methylated with dimethyl sulfate and K2CO3 in refluxing acetone yielding methyl 2-methoxy-5-acetaminobenzoate (III). Nitration of (III) with HNO3 in acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (IV), which is deacetylated with H2SO4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (V). The diazotation of (V) with NaNO2-HCl, followed by reaction with sodium ethylmercaptide, oxidation with H2O2 and hydrolysis with NaOH in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (VI), which is condensed with N-ethyl-2-aminomethylpyrrolidine (VII) by means of ethyl chloroformate and triethylamine in dioxane affording 2-methoxy-4-nitro-N-[(1-ethyl-2-pyrrolidinyl) methyl]-5-(ethylsulfonyl)benzamide (VIII). Finally, this compound is reduced with H2 over Raney-Ni in ethanol.

参考文献中间体

合成目标

【1】 Acher, J.; Monier, J.-C. (Societe d'Etudes Scientifiques et Industrielles de L'Ile de France); Nouveaux procédé de préparation de dérivés de 4-amino-5-alkylsulfonyl-o-anisamides et nouveaux dérivés de 4-nitro-5-alkylsulfonyl-o-anisamides utiles comme intermédiaires de synthèse. FR 2460930 .
【2】 Patel, R.; Packham, T.W.; Germain, A.L.; Barras, J.R.; Milne, D.J. (GlaxoSmithKline plc); Process of preparing 2,3,5-trihalobenzaldehyde. WO 9507877 .

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)	29932	5-amino-2-hydroxybenzoic acid	89-57-6	C₇H₇NO₃	详情	详情
(II)	29933	5-(acetamido)-2-hydroxybenzoic acid		C₉H₉NO₄	详情	详情
(III)	29934	methyl 5-(acetamido)-2-methoxybenzoate	81172-89-6	C₁₁H₁₃NO₄	详情	详情
(IV)	29935	methyl 5-(acetamido)-2-methoxy-4-nitrobenzoate		C₁₁H₁₂N₂O₆	详情	详情
(V)	29936	methyl 5-amino-2-methoxy-4-nitrobenzoate		C₉H₁₀N₂O₅	详情	详情
(VI)	29937	5-(ethylsulfonyl)-2-methoxy-4-nitrobenzoic acid		C₁₀H₁₁NO₇S	详情	详情
(VII)	29943	(1-ethyl-2-pyrrolidinyl)methylamine; (1-ethyl-2-pyrrolidinyl)methanamine	26116-12-1	C₇H₁₆N₂	详情	详情
(VIII)	29938	N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxy-4-nitrobenzamide		C₁₇H₂₅N₃O₆S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Acetylation of 5-aminosalicylic acid (I) with acetic anhydride in hot acetic acid gives 5-acetaminosalicylic acid (II), which is methylated with dimethyl sulfate and K2CO3 in refluxing acetone yielding methyl 2-methoxy-5-acetaminobenzoate (III). Nitration of (III) with HNO3 in acetic acid affords methyl 2-methoxy-4-nitro-5-acetaminobenzoate (IV), which is deacetylated with H2SO4 in refluxing methanol to give methyl 2-methoxy-4-nitro-5-aminobenzoate (V). The diazotation of (V) with NaNO2-HCl, followed by reaction with sodium ethylmercaptide, oxidation with H2O2 and hydrolysis with NaOH in ethanol yields 2-methoxy-4-nitro-5-(ethylsulfonyl)benzoic acid (VI). The reaction of (VI) with refluxing SOCl2 gives the corresponding acyl chloride (IX), which is then condensed with (VII) in butannne yielding (VIII). Finally, this compound is reduced with H2 over Raney-Ni in ethanol.

参考文献中间体

合成目标

【1】 Acher, J.; Monier, J.-C. (Societe d'Etudes Scientifiques et Industrielles de L'Ile de France); Nouveaux procédé de préparation de dérivés de 4-amino-5-alkylsulfonyl-o-anisamides et nouveaux dérivés de 4-nitro-5-alkylsulfonyl-o-anisamides utiles comme intermédiaires de synthèse. FR 2460930 .
【2】 Patel, R.; Packham, T.W.; Germain, A.L.; Barras, J.R.; Milne, D.J. (GlaxoSmithKline plc); Process of preparing 2,3,5-trihalobenzaldehyde. WO 9507877 .

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)	29932	5-amino-2-hydroxybenzoic acid	89-57-6	C₇H₇NO₃	详情	详情
(II)	29933	5-(acetamido)-2-hydroxybenzoic acid		C₉H₉NO₄	详情	详情
(III)	29934	methyl 5-(acetamido)-2-methoxybenzoate	81172-89-6	C₁₁H₁₃NO₄	详情	详情
(IV)	29935	methyl 5-(acetamido)-2-methoxy-4-nitrobenzoate		C₁₁H₁₂N₂O₆	详情	详情
(V)	29936	methyl 5-amino-2-methoxy-4-nitrobenzoate		C₉H₁₀N₂O₅	详情	详情
(VI)	29937	5-(ethylsulfonyl)-2-methoxy-4-nitrobenzoic acid		C₁₀H₁₁NO₇S	详情	详情
(VII)	29943	(1-ethyl-2-pyrrolidinyl)methylamine; (1-ethyl-2-pyrrolidinyl)methanamine	26116-12-1	C₇H₁₆N₂	详情	详情
(VIII)	29938	N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxy-4-nitrobenzamide		C₁₇H₂₅N₃O₆S	详情	详情
(IX)	29939	5-(ethylsulfonyl)-2-methoxy-4-nitrobenzoyl chloride		C₁₀H₁₀ClNO₆S	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

5-Amino-2-hydroxybenzoic acid (I) was protected as the N-Boc derivative (II) by treatment with di-tert-butyl dicarbonate and Et3N. Reaction with triphenylphosphine and carbon tetrabromide in tetrahydrofuran generated the bromobutyl ester (III). After conversion of (III) to the nitroxybutyl ester (IV) by reaction with AgNO3 in refluxing acetonitrile, acid deprotection of the Boc group furnished the title compound.

参考文献中间体

合成目标

【1】 Del Soldato, P. (NicOx SA); Medicine nitrate salts. WO 0006585 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	41419	tetrahydrofuran	109-99-9	C₄H₈O	详情	详情
(I)	29932	5-amino-2-hydroxybenzoic acid	89-57-6	C₇H₇NO₃	详情	详情
(II)	41418	5-[(tert-butoxycarbonyl)amino]-2-hydroxybenzoic acid		C₁₂H₁₅NO₅	详情	详情
(III)	41420	4-bromobutyl 5-[(tert-butoxycarbonyl)amino]-2-hydroxybenzoate		C₁₆H₂₂BrNO₅	详情	详情
(IV)	41421	4-(nitrooxy)butyl 5-[(tert-butoxycarbonyl)amino]-2-hydroxybenzoate		C₁₆H₂₂N₂O₈	详情	详情

Extended Information