methyl 4-[(hydroxyimino)methyl]benzoate -Drug Synthesis Database

【结构式】

【分子编号】19219

【品名】methyl 4-[(hydroxyimino)methyl]benzoate

【CA登记号】

【分子式】C₉H₉NO₃

【分子量】179.1754

【元素组成】C 60.33% H 5.06% N 7.82% O 26.79%

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：(II)

The synthesis of FK-463 can be performed as follows: The enzymatic deacylation of FR-901379 with Streptomyces anulatas No. 4811, S. anulatas No. 8703, Streptomyces strain No. 6907 or A. utahensis IFO13244 gives the deacylated lipopeptide FR-179642 (1), which is then reacylated with 1-[4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoyl]benzotriazole 3-oxide (VI) by means of dimethylaminopyridine (DMAP) in DMF. The acylating compound (VI) can be obtained as follows: The cyclization of 4-pentyloxyphenylacetylene (I) with 4-(hydroxyiminomethyl)benzoic acid methyl ester (II) by means of triethylamine in hot THF gives 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid methyl ester (III), which is hydrolyzed with NaOH in hot THF/water yielding the corresponding free acid (IV). Finally, this compound is condensed with 1-hydroxybenzotriazole (V) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDMCA) in dichloromethane.

参考文献中间体

合成目标

【1】 Ueda, S.; Ezaki, M.; Tanaka, M.; et al.; Studies on a novel lipopeptide acylase from Streptomyces spp. for production of FR179642, a key intermediate of antifungal lipopeptide drug FK463. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-145.
【2】 Fromtling, R.A.; Castañer, J.; FK-463. Drugs Fut 1998, 23, 12, 1273.
【3】 Ohki, H.; Tomishima, M.; Yamada, A.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Cyclic hexapeptides having antibiotic activity. EP 0788511; JP 1998324695; JP 1998507174; US 6107458; WO 9611210 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(F- 901379)	19224	sodium (2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-20-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-23-[(1S,2S)-1,2-dihydroxy-2-[4-hydroxy-3-(sulfonatooxy)phenyl]ethyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-16-methyl-5,8,14,19,22,25-hexaoxo-9-(palmitoylamino)tetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosine		C₅₁H₈₁N₈NaO₂₁S	详情	详情
(FR-179642)	19225	(2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-9-Amino-20-(3-amino-1(R)-hydroxy-3-oxopropyl)-23-[1(S),2(S)-dihdyroxy-2-[4-hydroxy-3-(sulfooxy)phenyl]ethyl]-2,11,12,15-tetrahydroxy-6-(1(R)-hydroxyethyl)-16-methylperhydrodipyrrolo[2,1-c:2,1-f][1,4,7,10,13,16]hexaazacyclohenicosine-5,8,14,19,22,25-hexaone		C₃₅H₅₁N₈NaO₂₀S	详情	详情
(I)	19218	4-ethynylphenyl pentyl ether; 1-ethynyl-4-(pentyloxy)benzene		C₁₃H₁₆O	详情	详情
(II)	19219	methyl 4-[(hydroxyimino)methyl]benzoate		C₉H₉NO₃	详情	详情
(III)	19220	methyl 4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoate		C₂₂H₂₃NO₄	详情	详情
(IV)	19221	4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoic acid		C₂₁H₂₁NO₄	详情	详情
(V)	10184	1H-1,2,3-Benzotriazol-1-ol; 1-Hydroxybenzotriazole; 1H-Benzotriazol-1-ol; 1-Benzotriazolol	2592-95-2	C₆H₅N₃O	详情	详情
(VI)	19223	3-(4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoyl)-3H-1,2,3-benzotriazol-1-ium-1-olate		C₂₇H₂₄N₄O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Wittig reaction of aldehyde (I) with methylene triphenylphosphorane produced olefin (II). Oxime (IV) was prepared from methyl 4-formylbenzoate (III) by treatment with hydroxylamine. The nitrile oxide generated from imine (IV) by chlorination, followed by elimination under basic conditions, underwent a [3+2] regioselective cycloaddition with alkene (II) to produce isoxazoline (V). Oxidation of the isoxazoline ring of (V) to the corresponding isoxazole derivative (VI) was accomplished by treatment with N-bromosuccinimide. Finally, ester hydrolysis with LiOH furnished the title carboxylic acid.

参考文献中间体

合成目标

【1】 Simoni, D.; et al.; Heterocycle-containing retinoids. Discovery of a novel isoxazole arotinoid possessing potent apoptotic activity in multidrug and drug-induced apoptosis-resistant cells. J Med Chem 2001, 44, 14, 2308.

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)	50713	5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenecarbaldehyde		C₁₅H₂₀O	详情	详情
(II)	50714	1,1,4,4-tetramethyl-6-vinyl-1,2,3,4-tetrahydronaphthalene		C₁₆H₂₂	详情	详情
(III)	10170	methyl 4-formylbenzoate	1571-08-0	C₉H₈O₃	详情	详情
(IV)	19219	methyl 4-[(hydroxyimino)methyl]benzoate		C₉H₉NO₃	详情	详情
(V)	50715	methyl 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-4,5-dihydro-3-isoxazolyl]benzoate		C₂₅H₂₉NO₃	详情	详情
(VI)	50716	methyl 4-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-3-isoxazolyl]benzoate		C₂₅H₂₇NO₃	详情	详情

Extended Information