Axitinib, AG-013736, AG-13736, -Drug Synthesis Database

【结构式】

【药物名称】Axitinib, AG-013736, AG-13736

【化学名称】N-Methyl-2-[3-[2-(2-pyridyl)vinyl]-1H-indazol-6-ylsulfanyl]benzamide

【CA登记号】319460-85-0

【分子式】C₂₂H₁₈N₄OS

【分子量】386.4707

【开发单位】Pfizer, Inc. (US).

【药理作用】VEGFR/PDGFR tyrosine kinase inhibitor

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【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

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

【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3

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

【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

Drug NewChemical Entity Original Patent(1)