4-isopropyl-3-(methylsulfonyl)benzoic acid -Drug Synthesis Database

【结构式】

【分子编号】16853

【品名】4-isopropyl-3-(methylsulfonyl)benzoic acid

【CA登记号】

【分子式】C₁₁H₁₄O₄S

【分子量】242.29576

【元素组成】C 54.53% H 5.82% O 26.41% S 13.23%

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：(V)

Cariporide has been obtained by two similar ways: 1) The oxidation of 4-isopropylbenzaldehyde (I) with sodium perborate in hot acetic acid gives 4-isopropylbenzoic acid (II), which is sulfonated with hot chlorosufonic acid yielding 3-(chlorosulfonyl)-4-isopropylbenzoic acid (III). The reduction of (III) with sodium sulfite in hot NaOH solution affords 4-isopropyl-3-sulfinobenzoic acid (IV), which is alkylated with methyl bromide and NaOH in DMF giving 4-isopropyl-3-(methylsulfonyl)benzoic acid (V). The reaction of (V) with SOCl2 in refluxing toluene yields 4-isopropyl-3-(methylsulfonyl)benzoyl chloride (VI), which is finally condensed with guanidine (VII) in DMF. 2) The iodination of 4-isopropylbenzoic acid (II) with iodine chloride or N-iodosuccinimide (NIS) gives 3-iodo-4-isopropylbenzoic acid (VIII), which is treated first with SOCl2 to afford the corresponding acyl chloride (IX), and then with methanol yielding 4-iodo-4-isopropylbenzoic methyl ester (X). The reaction of (X) with sodium methylsulfite (XI) gives 4-isopropyl-3-(methylsulfonyl)benzoic acid methyl ester (XII), which is finally treated with guanidine (VII) in refluxing THF.

参考文献中间体

合成目标

【1】 Graul, A.; Prous, J.; Castañer, J.; Cariporide Mesylate. Drugs Fut 1997, 22, 11, 1197.
【2】 Kleemann, H.-W.; Lang, H.-J.; Weichert, A.; Crause, P.; Scholz, W.; Albus, U.; Schwark, J.-R. (Aventis SA); Diacyl substd. guanidines, process for their preparation, their use as medicament or diagnostic reagent and medicament containing them. CA 2130703; DE 4328352; EP 0640587; JP 1995082234 .
【3】 Lang, H.-J.; Weichert, A.; Kleemann, H.-W.; Englert, H.; Scholz, W.; Albus, U. (Aventis SA); Benzoylguanidines, process for their preparation and their use as antiarrhythmic agents. EP 0589336; JP 1994228082; US 5591754 .
【4】 Kleemann, H.-W. (Aventis SA); Substd. benzoic acid esters, process for their preparation and their use for the synthesis of inhibitors of the cellular Na+/H+-exchange. DE 4428480 .

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)	23109	4-isopropylbenzaldehyde	122-03-2	C₁₀H₁₂O	详情	详情
(II)	11698	4-Isopropylbenzoic acid	536-66-3	C₁₀H₁₂O₂	详情	详情
(III)	16851	3-(chlorosulfonyl)-4-isopropylbenzoic acid		C₁₀H₁₁ClO₄S	详情	详情
(IV)	16852	3-(dioxo-lambda(6)-sulfanyl)-4-isopropylbenzoic acid		C₁₀H₁₂O₄S	详情	详情
(V)	16853	4-isopropyl-3-(methylsulfonyl)benzoic acid		C₁₁H₁₄O₄S	详情	详情
(VI)	16854	4-isopropyl-3-(methylsulfonyl)benzoyl chloride		C₁₁H₁₃ClO₃S	详情	详情
(VII)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(VIII)	16856	3-iodo-4-isopropylbenzoic acid		C₁₀H₁₁IO₂	详情	详情
(IX)	16857	3-iodo-4-isopropylbenzoyl chloride		C₁₀H₁₀ClIO	详情	详情
(X)	16858	methyl 3-iodo-4-isopropylbenzoate		C₁₁H₁₃IO₂	详情	详情
(XI)	63963	sodium methanesulfinate		CH₃NaO₂S	详情	详情
(XII)	16859	methyl 4-isopropyl-3-(methylsulfonyl)benzoate		C₁₂H₁₆O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

Two new related ways for the synthesis of cariporide mesylate have been reported: 1) The reaction of 4-isopropylbenzoic acid (I) with chlorosulfonic acid gives 3-(chlorosulfonyl)-4-isopropylbenzoic acid (II), which is reduced wth sodium sulfite/NaOH to the sorresponding sulfinic acid (III). The methylation of (III) with methyl iodide/NaOH in dimethylacetamide affords 4-isopropyl-3-(methanesulfonyl)benzoic acid methyl ester (IV), which is finally condensed with gunidine (V). 2) The hydrolysis of benzoate (IV) with NaOH in methanol/water gives the corresponding free acid (VI), which is then condensed with guanidine (V) by means of dicyclohexylcarbodiimide (DCC) in THF. 3) Benzoic ester (IV) can also be obtained by alkylation of 4-bromo-3-(methanesulfonyl)benzoic acid methyl ester with isopropylmagnesium chloride by means of CuI, ZnCl2 and a PdCl2 catalyst in THF.

参考文献中间体

合成目标

【1】 Lang, H.J.; Scholz, W.; Faber, S.; Weichert, A.; Jansen, H.W.; Synthesis of the highly selective Na+/H+ exchange inhibitors cariporide mesylate and (3-methanesulfonyl-4-piperidino-benzoyl)guanidine methanesulfonate. Arzneim-Forsch Drug Res 1997, 47, 11, 1204.

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)	11698	4-Isopropylbenzoic acid	536-66-3	C₁₀H₁₂O₂	详情	详情
(II)	16851	3-(chlorosulfonyl)-4-isopropylbenzoic acid		C₁₀H₁₁ClO₄S	详情	详情
(III)	16852	3-(dioxo-lambda(6)-sulfanyl)-4-isopropylbenzoic acid		C₁₀H₁₂O₄S	详情	详情
(IV)	16859	methyl 4-isopropyl-3-(methylsulfonyl)benzoate		C₁₂H₁₆O₄S	详情	详情
(V)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(VI)	16853	4-isopropyl-3-(methylsulfonyl)benzoic acid		C₁₁H₁₄O₄S	详情	详情
(VII)	17625	methyl 4-bromo-3-(methylsulfonyl)benzoate		C₉H₉BrO₄S	详情	详情
(VIII)	17626	chloro(isobutyl)magnesium	5674-02-2	C₄H₉ClMg	详情	详情

Extended Information