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【结 构 式】

【分子编号】65348

【品名】2-vinylpyridine

【CA登记号】100-69-6

【 分 子 式 】C7H7N

【 分 子 量 】105.13932

【元素组成】C 79.97% H 6.71% N 13.32%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XV)

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.

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:(XV)

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.

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