Vatalanib succinate, PTK/ZK, CGP-79787D, CGP-79787(free base), ZK-222584, PTK-787, -Drug Synthesis Database

【结构式】

【药物名称】Vatalanib succinate, PTK/ZK, CGP-79787D, CGP-79787(free base), ZK-222584, PTK-787

【化学名称】N-(4-Chlorophenyl)-4-(pyridin-4-ylmethyl)phthalazin-1-amine succinate

【CA登记号】212142-18-2, 212141-51-0 (diHCl), 212141-54-3 (free base), 212141-89-4 (fumarate), 212141-52-1 (hydrochloride), 212141-90-7 (met

【分子式】C₂₄H₂₁ClN₄O₄

【分子量】464.91237

【开发单位】Novartis (Originator), Nihon Schering (Codevelopment), Schering AG (Codevelopment)

【药理作用】Brain Cancer Therapy, Colorectal Cancer Therapy, Glioblastoma MultiformeTherapy, Kaposi's Sarcoma Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Renal Cancer Therapy, Angiogenesis Inhibitors, Inhibitors of Signal Transduction Pathways, VEGFR-1 (Flt-1) Inhibitors, VEGFR-2 (FLK-1/KDR) Inhibitors

合成路线1 合成路线2

合成路线1

Condensation of phthalic anhydride (I) with 4-methylpyridine (II) and heating with NH2-NH2 hydrate yields phthalazine (III) which is converted into chloro derivative (IV) by directly heating in presence of POCl3 or alternatively by heating a solution of (IV) in CH3CN with HCl/dioxane and POCl3. Phthalazine (III) is added to a melt formed by 4-chloroaniline (V), P2O5 and Et3N.HCl to afford the desired product. Alternatively the final product is obtained by heating (V) with (IV) in EtOH or 1-butanol.

参考文献中间体

【1】 DE 1061788; GB 871753 .
【2】 Altmann, K.-H.; Mett, H.; Wood, J.; Stover, D.R.; Frei, J.; Bold, G.; Traxler, P. (Novartis AG); Phthalazines with angiogenesis inhibiting activity. EP 0970070; WO 9835958 .

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)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(II)	31150	4-methylpyridine	108-89-4	C₆H₇N	详情	详情
(III)	41366	4-(4-pyridinylmethyl)-1,2-dihydro-1-phthalazinol		C₁₄H₁₃N₃O	详情	详情
(IV)	41367	1-chloro-4-(4-pyridinylmethyl)phthalazine		C₁₄H₁₀ClN₃	详情	详情
(V)	12034	4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline	106-47-8	C₆H₆ClN	详情	详情

合成路线2

The reaction of phthalide (I) with pyridine-4-carbaldehyde (II) by means of NaOMe in methanol gives the nonisolated intermediate (III), which rearranges in the reaction medium to yield indenone (IV). The reaction of (IV) with hydrazine affords the phthalazinone (V), which is finally condensed with 4-chloroaniline (VI) by means of P2O5 and TEA at 170 C to provide the target phthalazine.

参考文献中间体

【1】 Manly, D.G.; Tilford, C.H.; Richardson, A.; Stock, A.M.; Amstutz, E.D.; A Study of the chemistry of pyrophthalone and related compounds. J Org Chem 1958, 23, 373-80.
【2】 Letourneux, Y.; Floc'h, R.; Le Baut, G.; Ploquin, J.; Sparfel, L.; beta-Dicéto énamines hétérocycliques: 1. Indanediones-1,3-disubstitutées en 2 par un hétérocycle azoté. J Heterocycl Chem 1980, 17, 961-73.
【3】 Andersen, L.; Pedersen, E.B.; Synthesis of 4-arylamino-1H-pyrazolo[3,4-d]pyrimidines. Acta Chem Scand Ser b 1988, B42, 492-3.
【4】 Manley, P.W.; Martiny-Baron, G.; Brüggen, J.; Mestan, J.; Meyer T.; Wood, J.M.; Ferrari, S.; Hofmann, F.; Bold, G.; Frei, J.; Furet, P.; Cozens, R.M.; CGP 79787D (PTK787/ZK222584), CGP 84738, NVP-AAC789, NVP-AAD777 and related 1-anilino-(4-pyridylmethyl)phthalazines as inhibitors of VEGF- and bFGF-induced angiogenesis. Drugs Fut 2002, 27, 1, 43.
【5】 Frei, J.; Bold, G.; Altmann, K.-H.; et al.; New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem 2000, 43, 12, 2310.

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)	12576	2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one	87-41-2	C₈H₆O₂	详情	详情
(II)	17203	4-Pyridinecarboxaldehyde; isonicotinaldehyde	872-85-5	C₆H₅NO	详情	详情
(III)	49917	3-[(Z)-4-pyridinylmethylidene]-2-benzofuran-1-one		C₁₄H₉NO₂	详情	详情
(IV)	49918	3-hydroxy-2-(4-pyridinyl)-1H-inden-1-one		C₁₄H₉NO₂	详情	详情
(V)	49919	4-(4-pyridinylmethyl)-1(2H)-phthalazinone		C₁₄H₁₁N₃O	详情	详情
(VI)	12034	4-Chlorophenylamine; 4-Chloroaniline; p-Chloroaniline	106-47-8	C₆H₆ClN	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)