2,3,5,6-Tetrafluoropyridine -Drug Synthesis Database

【结构式】

【分子编号】56640

【品名】2,3,5,6-Tetrafluoropyridine

【CA登记号】2875-18-5

【分子式】C₅HF₄N

【分子量】151.0632928

【元素组成】C 39.75% H 0.67% F 50.31% N 9.27%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

Reaction of 2,3,5,6-tetrafluoropyridine (I) with benzylamine (II) in refluxing acetonitrile gives 2-(benzyl-amino)-3,5,6-trifluoropyridine (III), which is debenzylated with H2 over Pd/C in methanol to yield 3,5,6-trifluoropyridine-2-amine (IV). Reaction of amine (IV) with 4-methoxybenzylamine (V) in N-methylpyrrolidone at 140 C affords 3,5-difluoro-6-(4-methoxybenzylamino)pyridine-2-amine (VI), which is cyclized with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) obtained by condensation of 2-(3-chloro-2,4,5-trifluorobenzoyl)acetic acid ethyl ester (VIII) with triethyl orthoformate (IX) by means of acetic anhydride in hot DMF in the presence of K2CO3 to provide the N-protected aminoquinolone derivative (X). Reaction of quinolone (X) with HCl in refluxing acetic acid gives 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI), which is finally condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in refluxing acetonitrile.

参考文献中间体

合成目标

【2】 Yazaki, A.; Niino, Y.; Ohshita, Y.; Hirao, Y.; Amano, H.; Hayashi, N.; Kuramoto, Y. (Wakunaga Pharmaceutical Co., Ltd.); Novel pyridonecarboxylic acid derivs. or their salts and antibacterial agent comprising the same as the active ingredient. EP 0911327; EP 0992501; JP 1999322715; JP 2000136191; US 5998436; US 6133284; WO 9711068 .
【1】 Mealy, N.E.; Castaner, J.; ABT-492. Drugs Fut 2002, 27, 11, 1033.

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)	56640	2,3,5,6-Tetrafluoropyridine	2875-18-5	C₅HF₄N	详情	详情
(II)	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(III)	56641	N-benzyl-3,5,6-trifluoro-2-pyridinamine; N-benzyl-N-(3,5,6-trifluoro-2-pyridinyl)amine		C₁₂H₉F₃N₂	详情	详情
(IV)	56642	3,5,6-trifluoro-2-pyridinamine; 3,5,6-trifluoro-2-pyridinylamine		C₅H₃F₃N₂	详情	详情
(V)	15098	4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine	2393-23-9	C₈H₁₁NO	详情	详情
(VI)	56643	N-(6-amino-3,5-difluoro-2-pyridinyl)-N-(4-methoxybenzyl)amine; 3,5-difluoro-N~2~-(4-methoxybenzyl)-2,6-pyridinediamine		C₁₃H₁₃F₂N₃O	详情	详情
(VII)	11682	ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate		C₁₄H₁₂ClF₃O₄	详情	详情
(VIII)	11681	ethyl 3-(3-chloro-2,4,5-trifluorophenyl)-3-oxopropanoate	101987-86-4	C₁₁H₈ClF₃O₃	详情	详情
(IX)	21304	Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether	122-51-0	C₇H₁₆O₃	详情	详情
(X)	56644	ethyl 8-chloro-1-{3,5-difluoro-6-[(4-methoxybenzyl)amino]-2-pyridinyl}-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₂₅H₁₈ClF₄N₃O₄	详情	详情
(XI)	56645	1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid		C₁₅H₆ClF₄N₃O₃	详情	详情
(XII)	31397	3-azetidinol		C₃H₇NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Reaction of 2,3,5,6-tetrafluoropyridine (I) with ammonia in formamide gives the 2-aminopyridine derivative (IV), which is condensed with tert-butylamine (XIII) in N-methylpyrrolidone to yield 6-(tert-butylamino)-3,5-di- fluoropyridine-2-amine (XIV). Condensation of amine (XIV) with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) gives the adduct (XV), which is cyclized by means of K2CO3 in DMF to afford the quinolone derivative (XVI). Treatment of quinolone (XVI) with HCl in AcOH produces simultaneous ester hydrolysis and tert-butyl group removal, providing 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI). Finally, this compound is condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in DMF.

参考文献中间体

合成目标

【2】 Ohshita, Y.; Kuramoto, Y.; Niino, Y.; Yazaki, A.; Structure-activity relationships of fluoroquinolones containing various heteroaromatics at N-1; WQ-3034/ABT-492 and its derivatives. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-544.
【1】 Mealy, N.E.; Castaner, J.; ABT-492. Drugs Fut 2002, 27, 11, 1033.

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)	56640	2,3,5,6-Tetrafluoropyridine	2875-18-5	C₅HF₄N	详情	详情
(IV)	56642	3,5,6-trifluoro-2-pyridinamine; 3,5,6-trifluoro-2-pyridinylamine		C₅H₃F₃N₂	详情	详情
(VII)	11682	ethyl (Z)-2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxy-2-propenoate		C₁₄H₁₂ClF₃O₄	详情	详情
(XI)	56645	1-(6-amino-3,5-difluoro-2-pyridinyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid		C₁₅H₆ClF₄N₃O₃	详情	详情
(XII)	31397	3-azetidinol		C₃H₇NO	详情	详情
(XIII)	17895	2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine	75-64-9	C₄H₁₁N	详情	详情
(XIV)	56646	N~2~-(tert-butyl)-3,5-difluoro-2,6-pyridinediamine; N-(6-amino-3,5-difluoro-2-pyridinyl)-N-(tert-butyl)amine		C₉H₁₃F₂N₃	详情	详情
(XV)	56647	ethyl (Z)-3-{[6-(tert-butylamino)-3,5-difluoro-2-pyridinyl]amino}-2-(3-chloro-2,4,5-trifluorobenzoyl)-2-propenoate		C₂₁H₁₉ClF₅N₃O₃	详情	详情
(XVI)	56648	ethyl 1-[6-(tert-butylamino)-3,5-difluoro-2-pyridinyl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₂₁H₁₈ClF₄N₃O₃	详情	详情

Extended Information