2-Amino-4-(trifluoromethyl)benzenethiol; 2-Amino-4-(trifluoromethyl)phenylhydrosulfide -Drug Synthesis Database

【结构式】

【分子编号】12097

【品名】2-Amino-4-(trifluoromethyl)benzenethiol; 2-Amino-4-(trifluoromethyl)phenylhydrosulfide

【CA登记号】

【分子式】C₇H₆F₃NS

【分子量】193.1925896

【元素组成】C 43.52% H 3.13% F 29.5% N 7.25% S 16.6%

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：(III)

Zopolrestat can be obtained by several different ways: 1) The reaction of 2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetic acid ethyl ester (I) with 2-chloroacetonitrile by means of potassium tert-butoxide in DMF gives 2-[3-(cyanomethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (II), which is cyclized with 2-amino-4-(trifluoromethyl)thiophenol (III) in refluxing ethanol yielding zopolrestat ethyl ester (IV). Finally, this compound is hydrolyzed with KOH in methanol/water/THF. 2) Compound (IV) can also be obtained by cyclization of (II) with 4-chloro-3-nitrobenzotrifluoride (V) in hot DMF saturated with H2S. 3) Compound (II) can also be obtained as follows: The reaction of phthalazine (I) with aqueous formaldehyde gives 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydrophthalazin-1-yl]acetic acid ethyl ester (VI), which is treated with PBr3 in ethyl ether yielding the bromomethyl derivative (VII). Finally, this compound is treated with potassium cyanide and KI in acetone/water.

参考文献中间体

合成目标

【1】 Mylari, B.L.; Zembrowski, W.J.; Synthesis of aldose reductase inhibitor, 3,4-dihydro-4-oxo-3-[[5-(trifluoromethyl)-2 14C benzothiazolyl]methyl]-1-phthalazineacetic acid. J Label Compd Radiopharm 1991, 29, 2, 143-8.
【2】 Mealy, N.; Prous, J.; Castaner, J.; Zopolrestat. Drugs Fut 1995, 20, 1, 33.
【3】 Mylari, B.L.; Zembrowski, W.J. (Pfizer Inc.); Preparation of oxophthalazinyl acetic acids having benzothiazole or other heterocyclic side chains. EP 0295051 .
【4】 Mylari, B.L.; Larson, E.R.; Zembrowski, W.J. (Pfizer Inc.); Heterocyclic oxophthalazinylacetic acids. EP 0222576; JP 1987114988; US 4939140 .
【5】 Siegel, T.W.; Aldinger, C.E.; Mylari, B.L.; Singleton, D.H.; Zembrowski, W.J.; Larson, E.R.; Beyer, T.A.; Dee, M.F.; Novel, potent aldose reductase inhibitors: 3,4-Dihydro-4-oxo-3-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-1-phthalazine-acetic acid (zopolrestat) and congeners. J Med Chem 1991, 34, 1, 108-22.

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)	12095	ethyl 2-(4-oxo-3,4-dihydro-1-phthalazinyl)acetate; Ethyl 3,4-dihydro-4-oxo-1-phthalazineacetate	25947-13-1	C₁₂H₁₂N₂O₃	详情	详情
(II)	12096	ethyl 2-[3-(2-nitriloethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate		C₁₄H₁₃N₃O₃	详情	详情
(III)	12097	2-Amino-4-(trifluoromethyl)benzenethiol; 2-Amino-4-(trifluoromethyl)phenylhydrosulfide		C₇H₆F₃NS	详情	详情
(IV)	12098	ethyl 2-(4-oxo-3-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]-3,4-dihydro-1-phthalazinyl)acetate		C₂₁H₁₆F₃N₃O₃S	详情	详情
(V)	12099	4-Chloro-3-nitro-alpha,alpha,alpha-trifluorotoluene; 1-Chloro-2-nitro-4-(trifluoromethyl)benzene	121-17-5	C₇H₃ClF₃NO₂	详情	详情
(VI)	12100	ethyl 2-[3-(hydroxymethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate		C₁₃H₁₄N₂O₄	详情	详情
(VII)	12101	ethyl 2-[3-(bromomethyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetate		C₁₃H₁₃BrN₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VII)

Reaction of chloromethylpyridine (I) with NaOH in aqueous THF afforded alcohol (II), which was oxidized to formylpyridine (III) with selenium dioxide in refluxing pyridine. Subsequent condensation of aldehyde (III) with phosphorane (IV) in THF provided enone (V), and this was hydrogenated in the presence of Pd/C in MeOH to give (VI). Finally, condensation of ketone (VI) with aminothiophenol (VII) in the presence of p-toluenesulfonic acid in refluxing benzene yielded the corresponding benzothiazolidine.

参考文献中间体

合成目标

【1】 Yoon, S.-H.; Seo, S.; Lee, Y.; Hwang, S.; Kim, D.Y.; Syntheses of 2-[(3,5-dimethyl-4-methoxypyridyl)alkyl]benzothiazolidine derivatives as a potential gstric H+/K+-ATPase inhibitor. Bioorg Med Chem Lett 1998, 8, 14, 1909.

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)	16521	2-(chloromethyl)-3,5-dimethyl-4-pyridinyl methyl ether; 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine; 2-Chloromethyl-3,5-dimethyl-4-methoxypyridine	86604-75-3	C₉H₁₂ClNO	详情	详情
(II)	18785	(4-methoxy-3,5-dimethyl-2-pyridinyl)methanol		C₉H₁₃NO₂	详情	详情
(III)	18786	4-methoxy-3,5-dimethyl-2-pyridinecarbaldehyde		C₉H₁₁NO₂	详情	详情
(IV)	18787	1-(triphenylphosphoranylidene)acetone	1439-36-7	C₂₁H₁₉OP	详情	详情
(V)	18788	(E)-4-(4-methoxy-3,5-dimethyl-2-pyridinyl)-3-buten-2-one		C₁₂H₁₅NO₂	详情	详情
(VI)	18789	4-(4-methoxy-3,5-dimethyl-2-pyridinyl)-2-butanone		C₁₂H₁₇NO₂	详情	详情
(VII)	12097	2-Amino-4-(trifluoromethyl)benzenethiol; 2-Amino-4-(trifluoromethyl)phenylhydrosulfide		C₇H₆F₃NS	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

Reduction of nitrothiophenol (I) by hydrogenation over Pd/C in THF affords substituted aniline (II), which is then cyclized with 2,4-dichloropyrimidine-5-carbonyl chloride (III) in THF in the presence of Amberlyst A-27 to yield the final product.

参考文献中间体

合成目标

【1】 Suto, M.J.; Suto, C.; Goldman, M.E.; Palanki, M.S.S.; Erdman, P.E.; Synthesis and structure-activity relationship studies of conformationally restricted analogs of 2-chloro-4-trifluoromethylpyrimidine-5-[N-(3',5'-bis(trifluoromethyl)-phenyl)]carboxamide. Med Chem Res 2000, 10, 1, 19.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	47215	2-nitro-4-(trifluoromethyl)benzenethiol; 2-nitro-4-(trifluoromethyl)phenylhydrosulfide	C₇H₄F₃NO₂S	详情	详情
(II)	12097	2-Amino-4-(trifluoromethyl)benzenethiol; 2-Amino-4-(trifluoromethyl)phenylhydrosulfide	C₇H₆F₃NS	详情	详情
(III)	47216	2,4-dichloro-5-pyrimidinecarbonyl chloride	C₅HCl₃N₂O	详情	详情

Extended Information