MICAFUNGIN SODIUM, FK-463, -Drug Synthesis Database

【结构式】

【药物名称】MICAFUNGIN SODIUM, FK-463

【化学名称】(3S,6S,9S,11R,15S,18S,20R,21R,24S,25R,26S)-3-[3- Amino-1?-hydroxy-3-oxopropyl]-6-[1(S),2(S)-dihydroxy- 2-(4-hydroxy-3-sulfooxyphenyl)ethyl]-11,20,21,25- tetrahydroxy-15-[1?-hydroxyethyl]-26-methyl-18-[4-[5- [4-(pentyloxy)phenyl]isoxazol-3-yl]benzamido]- 1,4,7,13,16,22-hexaazatricyclo[22.3.0.09,13]heptacosane- 2,5,8,14,17,23-hexaone sodium salt

【CA登记号】208538-73-2

【分子式】C₅₆H₇₀N₉NaO₂₃S

【分子量】1292.2826

【开发单位】Fujisawa

【药理作用】ANTIINFECTIVE THERAPY, ANTIFUNGAL AGENTS

合成路线1 合成路线2

合成路线1

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

【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

The cyclization of the benzoic ester (I) with phenylacetylene (II) by means of triethylamine in THF gives the diphenyl isoxazole (III), which is hydrolyzed with NaOH in ethanol/THF yielding 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoic acid (IV). The activation of (IV) with HOBT and WSC in dichloromethane affords the benzotriazol-1-yl ester (V), which is finally condensed with the cyclic peptide (VI) by means of DMAP in DMF.

参考文献中间体

【1】 Tomishima, M.; et al.; FK463, a novel water-soluble echinocandin lipopeptide: Synthesis and antifungal activity. J Antibiot 1999, 52, 7, 674.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	27186	methyl 4-[chloro(hydroxyimino)methyl]benzoate	C₉H₈ClNO₃	详情	详情
(II)	19218	4-ethynylphenyl pentyl ether; 1-ethynyl-4-(pentyloxy)benzene	C₁₃H₁₆O	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)	27187	1-[(4-[5-[4-(pentyloxy)phenyl]-3-isoxazolyl]benzoyl)oxy]-1H-1,2,3-benzotriazole	C₂₇H₂₄N₄O₄	详情	详情
(VI)	27188	5-((1S,2S)-2-[(2R,6S,9S,11R,12R,14aS,15S,16S,20S,23S,25aS)-9-amino-20-[(1R)-3-amino-1-hydroxy-3-oxopropyl]-2,11,12,15-tetrahydroxy-6-[(1R)-1-hydroxyethyl]-16-methyl-5,8,14,19,22,25-hexaoxotetracosahydro-1H-dipyrrolo[2,1-c:2,1-l][1,4,7,10,13,16]hexaazacyclohenicosin-23-yl]-1,2-dihydroxyethyl)-2-hydroxyphenyl hydrogen sulfate	C₃₅H₅₂N₈O₂₀S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)