TK-2339, NSC-686288, -Drug Synthesis Database

【结构式】

【药物名称】TK-2339, NSC-686288

【化学名称】5-Amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one

【CA登记号】165179-35-1

【分子式】C₁₆H₁₁F₃N₂O₂

【分子量】320.27347

【开发单位】Kyowa Hakko (Originator), National Cancer Institute (Codevelopment)

【药理作用】ONCOLYTIC DRUGS, Antiestrogens

合成路线1 合成路线2

合成路线1

Synthesis of intermediate (XI): Treatment of 2,4-difluorophenol (I) with triethylamine and ethyl chloroformate (II) in dichloromethane yields O-ethoxycarbonyl-2,4-difluorophenol (III), which is then nitrated by means of HNO3/H2SO4 and hydrolyzed with Na2CO3 or NaHCO3 in MeOH/H2O to provide (IV). The nitro group of (IV) is then hydrogenated over Pd/C in EtOAc to afford 5-amino-2,4-difluorophenol (V), which is N-protected by reaction with pivaloyl chloride (VI) in pyridine to furnish pivaloylamino derivative (VII). Treatment of (VII) with 3,4-dihydro-2H pyran (VIII) and camphorsulfonic acid (CSA) in dichloromethane gives O-protected derivative (IX), which is converted into ethyl benzoate (X) by first reaction in THF with hexamethylphosphoric triamide (HMPA) and n-BuLi in hexane, followed by treatment with ethyl chloroformate (II). Finally, methylation of (X) by means of iodomethane (MeI) and LDA in THF/hexane yields intermediate (XI). Alternatively, intermediate (XI) can be also obtained by following this pathway: lithiation of derivative (IX) with LDA followed by treatment with TMSCl in THF affords trimethylsilylated compound (XII), which is converted into ethyl benzoate (XIII) by reaction with BuLi and ethyl chloroformate (II). Finally, TMS removal of (XIII) is achieved by treatment with tetrabutyl ammonium fluoride (TBAF) in THF to furnish derivative (X), which is methylated as described above.

参考文献中间体

【1】 Akama, T.; et al.; Synthesis of an ethyl 6-amino-3,5-difluorosalicylate derivative by sequential regioselective direct ortho-metalation; a practical synthesis of 4',5-diamino-3',6,8-trifluoroflavone, a potent antitumor agent. Synthesis 1997, 1446.
【2】 Saito, H.; Ishida, H.; Akama, T.; Kimura, U.; Gomi, K.; Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent. J Med Chem 1998, 41, 12, 2056.
【3】 Akama, T.; Ikeda, S.; Ishida, H.; Kimura, U.; Gomi, K.; Saito, H. (Kyowa Hakko Kogyo Co., Ltd.); 5-Aminoflavone derivs., their preparation and their use as antibacterial, anti-estrogenic and/or antitumor agent. EP 0638566; JP 1995109268 .

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)	21486	2,4-difluorophenol	367-27-1	C₆H₄F₂O	详情	详情
(II)	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(III)	46822	2,4-difluorophenyl ethyl carbonate		C₉H₈F₂O₃	详情	详情
(IV)	46823	2,4-difluoro-5-nitrophenol		C₆H₃F₂NO₃	详情	详情
(V)	46824	5-amino-2,4-difluorophenol		C₆H₅F₂NO	详情	详情
(VI)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(VII)	46825	N-(2,4-difluoro-5-hydroxyphenyl)-2,2-dimethylpropanamide		C₁₁H₁₃F₂NO₂	详情	详情
(VIII)	13684	3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran	110-87-2	C₅H₈O	详情	详情
(IX)	46826	N-[2,4-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)phenyl]-2,2-dimethylpropanamide		C₁₆H₂₁F₂NO₃	详情	详情
(X)	46827	ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-6-(tetrahydro-2H-pyran-2-yloxy)benzoate		C₁₉H₂₅F₂NO₅	详情	详情
(XI)	46828	ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)benzoate		C₂₀H₂₇F₂NO₅	详情	详情
(XII)	46829	N-[2,4-difluoro-5-(tetrahydro-2H-pyran-2-yloxy)-3-(trimethylsilyl)phenyl]-2,2-dimethylpropanamide		C₁₉H₂₉F₂NO₃Si	详情	详情
(XIII)	46830	ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-6-(tetrahydro-2H-pyran-2-yloxy)-4-(trimethylsilyl)benzoate		C₂₂H₃₃F₂NO₅Si	详情	详情

合成路线2

Synthesis of intermediate (XVII): Coupling of 4-bromo-2-fluoroaniline (XIV) with pivaloyl chloride (VI) in pyridine affords N-protected substituted aniline (XV), which is then treated with 1-ethoxyvinyltributyltin (XVI) and bis(triphenylphosphine) palladium chloride (PdCl2(PPh3)2) in toluene to provide acetophenone derivative (XVII). Coupling of intermediates (XI) and (XVII): Ethyl benzoate (XI) is treated with NaH and added to a solution of acetophenone (XVII) in refluxing toluene/dioxane to furnish benzopyranone (XVIII), which is finally deprotected with HCl in dioxane to give the desired product.

参考文献中间体

【1】 Akama, T.; et al.; Synthesis of an ethyl 6-amino-3,5-difluorosalicylate derivative by sequential regioselective direct ortho-metalation; a practical synthesis of 4',5-diamino-3',6,8-trifluoroflavone, a potent antitumor agent. Synthesis 1997, 1446.
【2】 Saito, H.; Ishida, H.; Akama, T.; Kimura, U.; Gomi, K.; Structure-activity relationships of the 7-substituents of 5,4'-diamino-6,8,3'-trifluoroflavone, a potent antitumor agent. J Med Chem 1998, 41, 12, 2056.
【3】 Akama, T.; Ikeda, S.; Ishida, H.; Kimura, U.; Gomi, K.; Saito, H. (Kyowa Hakko Kogyo Co., Ltd.); 5-Aminoflavone derivs., their preparation and their use as antibacterial, anti-estrogenic and/or antitumor agent. EP 0638566; JP 1995109268 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	13597	2,2-Dimethylpropanoyl chloride; Pivaloyl chloride	3282-30-2	C₅H₉ClO	详情	详情
(XI)	46828	ethyl 2-[(2,2-dimethylpropanoyl)amino]-3,5-difluoro-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)benzoate		C₂₀H₂₇F₂NO₅	详情	详情
(XIV)	14723	4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline	367-24-8	C₆H₅BrFN	详情	详情
(XV)	46831	N-(4-bromo-2-fluorophenyl)-2,2-dimethylpropanamide		C₁₁H₁₃BrFNO	详情	详情
(XVI)	19760	ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane	97674-02-7	C₁₆H₃₄OSn	详情	详情
(XVII)	46832	N-(4-acetyl-2-fluorophenyl)-2,2-dimethylpropanamide		C₁₃H₁₆FNO₂	详情	详情
(XVIII)	46833	N-(4-[5-[(2,2-dimethylpropanoyl)amino]-6,8-difluoro-7-methyl-4-oxo-4H-chromen-2-yl]-2-fluorophenyl)-2,2-dimethylpropanamide		C₂₆H₂₇F₃N₂O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)