methyl 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoate -Drug Synthesis Database

【结构式】

【分子编号】25813

【品名】methyl 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoate

【CA登记号】

【分子式】C₁₅H₁₂F₃NO₄S

【分子量】359.3258296

【元素组成】C 50.14% H 3.37% F 15.86% N 3.9% O 17.81% S 8.92%

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：(III)

Condensation of methyl 2-(chlorosulfonyl)benzoate (I) with 2-(trifluoromethyl)aniline (II) in the presence of DMAP and pyridine yielded sulfonamide (III), which was then cyclized in refluxing xylene to provide the saccharin derivative (IV). Further condensation with tert-butyl acetate (V) using potassium bis(trimethylsilyl)amide as the base afforded ketoester (VI). Then, bromination with NBS in CCl4 gave (VII), which was cyclized to the benzothiazine (VIII) with K2CO3 in DMF. Treatment with trifluoromethanesulfonic anhydride and pyridine in CH2Cl2 furnished the vinyl triflate (IX), and this was then coupled with boronic acid (X) in the presence of Pd(PPh3)4 and K2CO3 to produce (XI). Finally, the tert-butyl ester was cleaved with trifluoroacetic acid in CH2Cl2.

参考文献中间体

合成目标

【1】 Lee, C.; et al.; Synthetic studies toward a series of endothelin receptor antagonists. 1,1-Dioxo-2,4-diphenyl-2H-1,2-benzothiazine. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 058.
【2】 Berryman, K.A.; Bunker, A.M.; Doherty, A.M.; Edmunds, J.J. (Pfizer Inc.); Benzothiazine dioxides as endothelin antagonists. EP 0811001; JP 1999501013; WO 9626195 .

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)	25811	methyl 2-(chlorosulfonyl)benzoate	26638-43-7	C₈H₇ClO₄S	详情	详情
(II)	25812	2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline	88-17-5	C₇H₆F₃N	详情	详情
(III)	25813	methyl 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoate		C₁₅H₁₂F₃NO₄S	详情	详情
(IV)	25814	2-[2-(trifluoromethyl)phenyl]-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₁₄H₈F₃NO₃S	详情	详情
(V)	15397	tert-butyl acetate	540-88-5	C₆H₁₂O₂	详情	详情
(VI)	25815	tert-butyl 3-oxo-3-(2-[[2-(trifluoromethyl)anilino]sulfonyl]phenyl)propanoate		C₂₀H₂₀F₃NO₅S	详情	详情
(VII)	25816	tert-butyl 2-bromo-3-oxo-3-(2-[[2-(trifluoromethyl)anilino]sulfonyl]phenyl)propanoate		C₂₀H₁₉BrF₃NO₅S	详情	详情
(VIII)	25817	tert-butyl 4-hydroxy-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate		C₂₀H₁₈F₃NO₅S	详情	详情
(IX)	25818	tert-butyl 1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-4-[[(trifluoromethyl)sulfonyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate		C₂₁H₁₇F₆NO₇S₂	详情	详情
(X)	25819	7-ethyl-1,3-benzodioxol-5-ylboronic acid		C₉H₁₁BO₄	详情	详情
(XI)	25820	tert-butyl 4-(7-ethyl-1,3-benzodioxol-5-yl)-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate		C₂₉H₂₆F₃NO₆S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

A new, more efficient synthesis has been reported for the intermediate (XVIII). The saccharin derivative (IV) was prepared by two alternative routes. Thus, 2-sulfobenzoic acid cyclic anhydride (XII) was treated with two equivalents of 2-(trifluoromethyl)aniline (II) to give the anilinium salt (XIII), which was cyclized with POCl3 to produce (IV). Also, starting from benzenesulfonyl chloride (XIV), the corresponding sulfonamide (II) was obtained by reaction with aniline (II). Ortho lithiation with n-butyllithium at low temperature, followed by CO2 quenching, afforded carboxylic acid (XVI), which upon treatment with Ac2O and methanesulfonic acid cyclized to the saccharin (IV). Then, the saccharin ring was opened by treatment with NaOMe, and subsequent treatment with methyl bromoacetate furnished diester (XVII). Finally, Claisen cyclization promoted by TiCl4 formed the key intermediate (XVIII).

参考文献中间体

合成目标

【1】 Lee, C.; et al.; Synthetic studies toward a series of endothelin receptor antagonists. 1,1-Dioxo-2,4-diphenyl-2H-1,2-benzothiazine. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 058.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	12309	methyl 2-bromoacetate; methyl bromoacetate	96-32-2	C₃H₅BrO₂	详情	详情
(II)	25812	2-(trifluoromethyl)phenylamine; 2-(trifluoromethyl)aniline	88-17-5	C₇H₆F₃N	详情	详情
(III)	25813	methyl 2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoate		C₁₅H₁₂F₃NO₄S	详情	详情
(IV)	25814	2-[2-(trifluoromethyl)phenyl]-1H-1,2-benzisothiazole-1,1,3(2H)-trione		C₁₄H₈F₃NO₃S	详情	详情
(XII)	25821	2-Sulfobenzoic acid anhydride; 2,1lambda(6)-benzoxathiole-1,1,3-trione	81-08-3	C₇H₄O₄S	详情	详情
(XIII)	25822	2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoic acid		C₁₄H₁₀F₃NO₄S	详情	详情
(XIV)	14713	benzenesulfonyl chloride	98-09-9	C₆H₅ClO₂S	详情	详情
(XV)	25823	N-[2-(trifluoromethyl)phenyl]benzenesulfonamide		C₁₃H₁₀F₃NO₂S	详情	详情
(XVI)	25822	2-[[2-(trifluoromethyl)anilino]sulfonyl]benzoic acid		C₁₄H₁₀F₃NO₄S	详情	详情
(XVII)	25824	methyl 2-[[(2-methoxy-2-oxoethyl)-2-(trifluoromethyl)anilino]sulfonyl]benzoate		C₁₈H₁₆F₃NO₆S	详情	详情
(XVIII)	25825	methyl 4-hydroxy-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate		C₁₇H₁₂F₃NO₅S	详情	详情

Extended Information