2-Mercapto-N-methylbenzamide -Drug Synthesis Database

【结构式】

【分子编号】65352

【品名】2-Mercapto-N-methylbenzamide

【CA登记号】20054-45-9

【分子式】C₈H₉NOS

【分子量】167.2316

【元素组成】C 57.46% H 5.42% N 8.38% O 9.57% S 19.17%

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：(XXI)

In an alternative method, reaction of 6-nitroindazole (I) with iodine and K2CO3 gives the 3-iodo derivative (II), which is protected as the 1-tetrahydropyranyl indazole (XIV) with dihydropyran and methanesulfonic acid. Palladium-catalyzed coupling of iodoindazole (XIV) with 2-vinylpyridine (XV), followed by reduction of the resulting adduct (XVI) with iron and NH4Cl, provides the THP-protected 6-amino-3-(pyridylvinyl)indazole (XVII). After diazotization of aminoindazole (XVII) with NaNO2/HCl in AcOH, treatment of the intermediate diazonium salt with I2/KI yields the 6-iodoindazole (XVIII). The intermediate 2-mercapto-N-methylbenzamide (XXI) is prepared as follows. 2,2’-Dithiosalicylic acid (XIX) is chlorinated with SOCl2, followed by condensation with methylamine, to give the dithiosalicylamide (XX), which is reductively cleaved to the mercaptobenzamide (XXI) employing NaBH4. Then, coupling between iodoindazole (XVIII) and 2-mercapto-N-methylbenzamide (XXI) by means of PdCl2(dppf)2 and Cs2CO3 affords the tetrahydropyranyl-protected axitinib (XXII), which is finally deprotected by treatment with p-toluenesulfonic acid in hot MeOH (2). Scheme 2.

参考文献中间体

合成目标

【2】 Babu, S., Dagnino, R. Jr., Ouellette, M.A., Shi, B., Tian, Q., Zook, S.E. (Pfizer, Inc.). Methods for preparing indazole compounds. WO 2006048745.

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)	65335	6-Nitroindazole	7597-18-4	C₇H₅N₃O₂	详情	详情
(II)	65336	3-Iodo-6-nitroindazole; 3-Iodo-6-nitro-1H-indazole	70315-70-7	C₇H₄IN₃O₂	详情	详情
(XIV)	65347	3-Iodo-6-nitro-1-tetrahydropyranyl-1H-indazole		C₁₃H₁₂IN₃O₃	详情	详情
(XV)	65348	2-vinylpyridine	100-69-6	C₇H₇N	详情	详情
(XVI)	65349	6-Nitro-3-(pyrid-2-ylvinyl)-1-tetrahydropyranyl-1H-indazole		C₁₉H₁₈N₄O₃	详情	详情
(XVII)	65350	6-Amino-3-(pyrid-2-ylvinyl)-1-tetrahydropyranyl-1H-indazole		C₁₉H₂₀N₄O	详情	详情
(XVIII)	65351	6-Iodo-3-(pyrid-2-ylvinyl)-1-tetrahydropyranyl-1H-indazole		C₁₉H₁₈IN₃O	详情	详情
(XIX)	20404	2-[(2-carboxyphenyl)disulfanyl]benzoic acid; 2,2'-Dithiodibenzoic acid	119-80-2	C₁₄H₁₀O₄S₂	详情	详情
(XX)	31248	N-methyl-2-([2-[(methylamino)carbonyl]phenyl]disulfanyl)benzamide	2527-58-4	C₁₆H₁₆N₂O₂S₂	详情	详情
(XXI)	65352	2-Mercapto-N-methylbenzamide	20054-45-9	C₈H₉NOS	详情	详情
(XXII)	65353			C₂₇H₂₆N₃O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXI)

A related procedure consists of the iodination of 6-iodoindazole (XXIII) with I2 and KOH to give 3,6-diiodoindazole (XXIV), which is coupled with 2-mercapto-N-methylbenzamide (XXI) in the presence of Pd2(dba)3 and Xantphos diphosphine ligand to yield the diaryl thioether (XXV). Alternatively, intermediate (XXV) can be prepared by coupling of 6-iodoindazole (XXIII) with mercaptobenzamide (XXI), followed by iodination of the resulting indazolyl thioether (XXVI). Optionally, the indazolyl derivative (XXV) is protected as the N-Boc (XXVIIa) or the N-tetrahydropyranyl derivative (XXVIIb) by treatment with Boc2O and DMAP or with dihydropyran and p-TsOH, respectively. Palladium-catalyzed coupling of the protected iodoindazoles (XXVIIa) and (XXVIIb) with 2-vinylpyridine (XV) then leads to the respective N-protected axitinib derivatives (XXII) and (XXVIII), which are finally deprotected utilizing p-TsOH in MeOH or TFA, respectively. Alternatively, axitinib can be obtained by direct coupling of unprotected iodoindazole (XXV) with 2-vinylpyridine (XV) in the presence of palladium diacetate, tri-o-tolylphosphine, LiBr and 1,8-bis(dimethylamino)naphthalene (proton sponge) in hot NMP (3). Scheme 3.

参考文献中间体

合成目标

【3】 Ewanicki, B.L., Flahive, E.J., Kasparian, A.J. et al. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Methods of preparing indazole compounds. US 2006094881, WO 2006048744.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXVIIa)	65358			C₂₀H₂₀IN₃O₃S	详情	详情
(XXVIIb)	65359			C₂₀H₂₀IN₃O₂S	详情	详情
(XV)	65348	2-vinylpyridine	100-69-6	C₇H₇N	详情	详情
(XXI)	65352	2-Mercapto-N-methylbenzamide	20054-45-9	C₈H₉NOS	详情	详情
(XXII)	65353			C₂₇H₂₆N₃O₂S	详情	详情
(XXIII)	65354	6-Iodo-1H-indazole	261953-36-0	C₇H₅IN₂	详情	详情
(XXIV)	65355	3,6-Diiodo-1H-indazole	319472-78-1	C₇H₄I₂N₂	详情	详情
(XXV)	65356	2-[(3-Iodo-1H-indazol-6-yl)thio]-N-methylbenzamide	885126-34-1	C₁₅H₁₂IN₃OS	详情	详情
(XXVI)	65357	2-[(1H-indazol-6-yl)thio]-N-methylbenzamide		C₁₅H₁₃N₃OS	详情	详情
(XXVIII)	65360			C₂₇H₂₆N₄O₃S	详情	详情

Extended Information