【结 构 式】 |
【分子编号】65335 【品名】6-Nitroindazole 【CA登记号】7597-18-4 |
【 分 子 式 】C7H5N3O2 【 分 子 量 】163.13572 【元素组成】C 51.54% H 3.09% N 25.76% O 19.61% |
合成路线1
该中间体在本合成路线中的序号:(I)Iodination of 6-nitroindazole (I) utilizing iodine in the presence of NaOH provides 3-iodo-6-nitroindazole (II). Subsequent protection of indazole (II) with 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) under phase-transfer conditions, followed by Suzuki coupling of the SEM-protected compound (III) with styrylboronic acid, gives the styryl indazole (IV). The nitro group of (IV) is reduced by means of SnCl2 to produce amine (V), which is then converted to the iodoindazole analogue (VI) by diazotization followed by reaction with I2 and KI. Ozonization of the styryl moiety of (VI) and further reductive work-up leads to the aldehyde (VII), which is subjected to Wittig reaction with 2-picolyl triphenylphosphonium chloride (VIII) to produce the pyridylvinylindazole (IX). Displacement of the iodoindazole (IX) with methyl 2-mercaptobenzoate (X) in the presence of Cs2CO3 and palladium catalyst gives the thioether (XI). After alkaline hydrolysis of the methyl ester (XI), the resulting carboxylic acid (XII) is coupled with methylamine in the presence of HATU to furnish the N-methyl amide (XIII). Axitinib is then obtained by removal of the SEM protecting group of (XIII) by means of tetrabutylammonium fluoride and ethylenediamine (1). Scheme 1.
【1】 Kania, R.S., Wallace, M.B., Borchardt, A.J. et al. (Agouron Pharmaceuticals, Inc.). Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use. EP 1614683, JP 2003503481, JP 2006348043, WO 0102369. |
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 |
(III) | 65337 | 3-Iodo-6-nitro-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C13H18IN3O3Si | 详情 | 详情 | |
(IV) | 65338 | 6-Nitro-3-styryl-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C21H25N3O3Si | 详情 | 详情 | |
(V) | 65339 | 6-Amino-3-styryl-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C21H27N3OSi | 详情 | 详情 | |
(VI) | 65340 | 6-Iodo-3-styryl-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C21H25IN2OSi | 详情 | 详情 | |
(VII) | 65341 | 3-formyl-6-iodo-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C14H19IN2O2Si | 详情 | 详情 | |
(VIII) | 35151 | triphenyl(2-pyridinylmethyl)phosphonium chloride; 2-picolyl triphenylphosphonium chloride | 73870-25-4 | C24H21ClNP | 详情 | 详情 |
(IX) | 65342 | 6-Iodo-3-(pyrid-2-ylvinyl)-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indazole | C21H24IN3OSi | 详情 | 详情 | |
(X) | 65343 | Methyl 2-mercaptobenzoate; Methyl thiosalicylate | 4892-02-8 | C8H8O2S | 详情 | 详情 |
(XI) | 65344 | C29H31N3O3SSi | 详情 | 详情 | ||
(XII) | 65345 | C28H29N3O3SSi | 详情 | 详情 | ||
(XIII) | 65346 | C29H32N4O2SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(I)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 |