4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】19819

【品名】4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid

【CA登记号】

【分子式】C₁₇H₁₅NO₄S

【分子量】329.37644

【元素组成】C 61.99% H 4.59% N 4.25% O 19.43% S 9.74%

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：(VIII)

The reaction of ethyl pentafluorobenzoylacetate (I) with ethyl orthoformate in refluxing acetic anhydride and then with cyclopropylamine (II) in ether gives the aminomethylene derivative (III), which is cyclized by means of NaH in THF yielding ethyl 5,6,7,8-tetrafluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (IV). The reaction of (IV) with benzylamine (V) by means of K2CO3 in refluxing acetonitrile affords the benzylamino derivative (VI), which is deprotected by hydrogenation with H2 over Pd/C in ethanol giving ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (VII). The hydrolysis of (VII) with hot H2SO4 yields the free acid (VIII), which is finally condensed with cis-2,6-dimethylpiperazine (IX) in DMF.

参考文献中间体

合成目标

【1】 Matsumoto, J.; Miyamoto, T.; Egawa, H.; Nakamura, S. (Dainippon Pharm. Co.; Ltd.); Novel quinoline derivatives and processes for preparation thereof. AU 8664277; EP 0221463; JP 87277362 .
【2】 Prous, J.; Castaner, J.; AT-4140. Drugs Fut 1989, 14, 5, 413.

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)	20840	ethyl 3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate		C₁₁H₇F₅O₃	详情	详情
(II)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情
(III)	20842	ethyl 2-[(cyclopropylamino)methyl]-3-oxo-3-(2,3,4,5,6-pentafluorophenyl)propanoate		C₁₅H₁₄F₅NO₃	详情	详情
(IV)	20843	ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₁₅H₁₁F₄NO₃	详情	详情
(V)	15147	Benzylamine; Phenylmethanamine	100-46-9	C₇H₉N	详情	详情
(VI)	20845	ethyl 5-(benzylamino)-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₂₂H₁₉F₃N₂O₃	详情	详情
(VII)	20846	ethyl 5-amino-1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylate		C₁₅H₁₃F₃N₂O₃	详情	详情
(VIII)	19819	4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid		C₁₇H₁₅NO₄S	详情	详情
(IX)	20848	(2R,6S)-2,6-dimethylpiperazine		C₆H₁₄N₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Carboxilic acid (I) is converted to the correspondig acid chloride (II) and and amidated with dimethyl homoglutamate (III) to give the amide (IV). The benzyloxycarbonyl grouo of the amide (IV) is removed with H2 over Pd/C to give the amide (V), which is effectively alkylated with 6-(bromomethyl)-2,4-diaminopteridine (VI) to produce compound (VII). Finally, compound (VII) is hydrolyzed with 1N NaoH to yield MX-68.

参考文献中间体

合成目标

【1】 Maruyama, N.; et al.; Antirheumatic agents. Novel methotrexate derivatives which are resistant to polyglutamation. 213th ACS Natl Meet (April 13-17, San Francisco) 1997, Abst MEDI 090.

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)	19819	4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazine-7-carboxylic acid		C₁₇H₁₅NO₄S	详情	详情
(II)	19820	benzyl 7-(chlorocarbonyl)-2,3-dihydro-4H-1,4-benzothiazine-4-carboxylate		C₁₇H₁₄ClNO₃S	详情	详情
(III)	19821	dimethyl (2S)-2-aminohexanedioate		C₈H₁₅NO₄	详情	详情
(IV)	19822	dimethyl (2S)-2-[([4-[(benzyloxy)carbonyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate		C₂₅H₂₈N₂O₇S	详情	详情
(V)	19823	dimethyl (2S)-2-[(3,4-dihydro-2H-1,4-benzothiazin-7-ylcarbonyl)amino]hexanedioate		C₁₇H₂₂N₂O₅S	详情	详情
(VI)	11006	2-Amino-6-(bromomethyl)-4-pteridinylamine; 6-(Bromomethyl)-2,4-pteridinediamine	52853-40-4	C₇H₇BrN₆	详情	详情
(VII)	19825	dimethyl (2S)-2-[([4-[(2,4-diamino-6-pteridinyl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]carbonyl)amino]hexanedioate		C₂₄H₂₈N₈O₅S	详情	详情

Extended Information