FYK-1388, -Drug Synthesis Database

【结构式】

【药物名称】FYK-1388

【化学名称】N1-[2-(4-Guanidinophenyl)-1(S)-(N-methylcarbamoyl)ethyl]-N4-hydroxy-2(R)-isobutyl-3(S)-(3-phenylpropyl)succinamide acetate

【CA登记号】184947-94-2, 184947-92-0 (diastereomer), 184947-93-1 (free base)

【分子式】C₃₀H₄₄N₆O₆

【分子量】584.72178

【开发单位】Daiichi Pharmaceutical (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Matrix Metalloproteinase Inhibitors, TNF-alpha-Converting Enzyme (TACE) Inhibitors

合成路线1 合成路线2

合成路线1

(R)-2-Bromo-4-methylpentanoic acid (I) was protected as the benzyl ester (II) and subsequently condensed with benzyl tert-butyl malonate (III) in the presence of potassium tert-butoxide to furnish the triester (IV) as an epimeric mixture. Alkylation of (IV) with cinnamyl bromide (V) produced adduct (VI). The key intermediate (VII) was then obtained by catalytic hydrogenation of the benzyl esters and olefin double bond of (VI), followed by thermal malonate decarboxylation.

参考文献中间体

【1】 Fujisawa, T.; Odake, S.; Morita, Y.; Hongo, T.; Ito, H.; Yasuda, J.; Suda, E.; Igeta, K.; Morikawa, T. (Fuji Yakuhin Kogyo Co., Ltd.); Highly water-soluble metalloproteinase inhibitor. EP 0832875; WO 9633968 .

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)	26058	(2S)-2-bromo-4-methylpentanoic acid		C₆H₁₁BrO₂	详情	详情
(II)	60695	benzyl (2R)-2-bromo-4-methylpentanoate		C₁₃H₁₇BrO₂	详情	详情
(III)	60696	1-benzyl 3-(tert-butyl) malonate		C₁₄H₁₈O₄	详情	详情
(IV)	60697	1,2-dibenzyl 1-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate		C₂₇H₃₄O₆	详情	详情
(V)	21131	1-[(E)-3-bromo-1-propenyl]benzene	4392-24-9	C₉H₉Br	详情	详情
(VI)	60698	4,5-dibenzyl 4-(tert-butyl) (E,5R)-7-methyl-1-phenyl-1-octene-4,4,5-tricarboxylate		C₃₆H₄₂O₆	详情	详情
(VII)	60699	(2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-phenylhexanoic acid		C₂₁H₃₂O₄	详情	详情

合成路线2

N-Boc-L-4'-Aminophenylalanine-N-methylamide (VIII) was converted to the guanidine derivative (X) by reaction with pyrazole-N,N'-bis(benzyloxycarbonyl)carboxamidine (IX). After acidic Boc group cleavage in (IX), the resultant amino amide (XI) was coupled with the carboxylic acid (VII) to produce a diastereomeric mixture of amides, which were separated by column chromatography. The desired isomer (XII) was then treated with 95% aqueous trifluoroacetic acid to remove the tert-butyl ester group, yielding acid (XIII). Coupling of (XIII) with O-benzyl hydroxylamine furnished the O-benzyl hydroxamate (XIV). Finally, the benzyl and benzyloxycarbonyl protecting groups of (XIV) were removed by catalytic hydrogenation over Pd/C to afford the title compound.

参考文献中间体

【1】 Fujisawa, T.; Odake, S.; Morita, Y.; Hongo, T.; Ito, H.; Yasuda, J.; Suda, E.; Igeta, K.; Morikawa, T. (Fuji Yakuhin Kogyo Co., Ltd.); Highly water-soluble metalloproteinase inhibitor. EP 0832875; WO 9633968 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	60699	(2R)-3-(tert-butoxycarbonyl)-2-isobutyl-6-phenylhexanoic acid	C₂₁H₃₂O₄	详情	详情
(VIII)	60700	tert-butyl (1S)-1-(4-aminobenzyl)-2-(methylamino)-2-oxoethylcarbamate	C₁₅H₂₃N₃O₃	详情	详情
(IX)	60787		C₆H₁₀N₄	详情	详情
(X)	60788	benzyl (Z)-{[(benzyloxy)carbonyl]amino}{4-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(methylamino)-3-oxopropyl]anilino}methylidenecarbamate	C₃₂H₃₇N₅O₇	详情	详情
(XI)	60789	benzyl (Z)-{4-[(2S)-2-amino-3-(methylamino)-3-oxopropyl]anilino}{[(benzyloxy)carbonyl]amino}methylidenecarbamate	C₂₇H₂₉N₅O₅	详情	详情
(XII)	60790	tert-butyl (2S,3R)-3-({[(1S)-1-{4-[({[(benzyloxy)carbonyl]amino}{[(benzyloxy)carbonyl]imino}methyl)amino]benzyl}-2-(methylamino)-2-oxoethyl]amino}carbonyl)-5-methyl-2-(3-phenylpropyl)hexanoate	C₄₈H₅₉N₅O₈	详情	详情
(XIII)	60791	(2S,3R)-3-({[(1S)-1-{4-[({[(benzyloxy)carbonyl]amino}{[(benzyloxy)carbonyl]imino}methyl)amino]benzyl}-2-(methylamino)-2-oxoethyl]amino}carbonyl)-5-methyl-2-(3-phenylpropyl)hexanoic acid	C₄₄H₅₁N₅O₈	详情	详情
(XIV)	60792	benzyl (Z)-{4-[(2S)-2-[((2R,3S)-3-{[(benzyloxy)amino]carbonyl}-2-isobutyl-6-phenylhexanoyl)amino]-3-(methylamino)-3-oxopropyl]anilino}{[(benzyloxy)carbonyl]amino}methylidenecarbamate	C₅₁H₅₈N₆O₈	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)