RU-79115, -Drug Synthesis Database

【结构式】

【药物名称】RU-79115

【化学名称】2-Propynyloxycarbamic acid 7(R)-[4-hydroxy-3-(N-methoxyethanimidoyl)-8-methyl-2-oxo-2H-1-benzopyran-7-yloxy]-8(R)-hydroxy-10(R)-methoxy-6-oxaspiro[4.5]dec-9(S)-yl ester

【CA登记号】229307-82-8

【分子式】C₂₇H₃₂N₂O₁₁

【分子量】560.56289

【开发单位】Aventis Pharma (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, DNA Gyrase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

Grignard reagent (II), prepared from 1,4-dibromobutane (I), was added to lactone (III) to produce the cyclopentanol derivative (IV). Oxidation of the primary alcohol of (IV) with sulfur trioxide-pyridine complex in the presence of DMSO gave rise to lactone (V), which was reduced to the corresponding lactol (VI) by means of DIBAL at low temperature. Subsequent acid hydrolysis of the ketal group of (VI) afforded triol (VII). Mitsunobu coupling with 4-(diphenylmethoxy)-7-hydroxycoumarin (VIII) furnished ether (IX). After selective hydroxyl group protection of (IX) with chlorotriethylsilane to give (X), the remaining free hydroxyl was further protected as the tetrahydropyranyl ether (XI). Then, removal of the benzhydryl protecting group of (XI) was achieved by hydrogenation over Pd/C to give (XII).

参考文献中间体

【1】 Periers, A.-M.; Laurin, P.; Klich, M.; Musicki, B.; Haesslein, J.-L. (Aventis Pharma SA); Novel aromatic amides, preparation method and application as medicines. FR 2773369; WO 9935155 .

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)	11883	1,4-Dibromobutane; 1,4-Butylene bromide	110-52-1	C₄H₈Br₂	详情	详情
(II)	38182	1,4-Bis(bromomagnesio)butane	23708-48-7	C₄H₈Br₂Mg₂	详情	详情
(III)	38183	(3aS,7R,7aR)-7-methoxy-2,2-dimethyltetrahydro-6H-[1,3]dioxolo[4,5-c]pyran-6-one		C₉H₁₄O₅	详情	详情
(IV)	38184	1-[(R)-[(4R,5S)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl](methoxy)methyl]cyclopentanol		C₁₃H₂₄O₅	详情	详情
(V)	38185			C₁₃H₂₀O₅	详情	详情
(VI)	38186			C₁₃H₂₂O₅	详情	详情
(VII)	38187	(8R,9S,10R)-10-methoxy-6-oxaspiro[4.5]decane-7,8,9-triol		C₁₀H₁₈O₅	详情	详情
(VIII)	38188	4-(benzhydryloxy)-7-hydroxy-8-methyl-2H-chromen-2-one		C₂₃H₁₈O₄	详情	详情
(IX)	38189	4-(benzhydryloxy)-7-[[(7R,8R,9S,10R)-8,9-dihydroxy-10-methoxy-6-oxaspiro[4.5]dec-7-yl]oxy]-8-methyl-2H-chromen-2-one		C₃₃H₃₄O₈	详情	详情
(X)	38190	4-(benzhydryloxy)-7-([(7R,8R,9S,10R)-8-hydroxy-10-methoxy-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one		C₃₉H₄₈O₈Si	详情	详情
(XI)	38191	4-(benzhydryloxy)-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one		C₄₄H₅₆O₉Si	详情	详情
(XII)	38192	4-hydroxy-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one		C₃₁H₄₆O₉Si	详情	详情

合成路线2

Acylation of (XII) with acetic anhydride and DMAP yielded the 3-acetyl coumarin (XIII). Following desilylation of (XIII) with tetrabutylammonium fluoride to give (XIV), condensation with O-methyl hydroxylamine gave oxime (XV). Treatment of (XV) with p-nitrophenyl chloroformate and DMAP generated carbonate (XVI), which was further coupled with O-propargyl hydroxylamine (XVII) to yield carbamate (XVIII). The tetrahydropyranyl group of (XVIII) was finally deprotected by methanolysis in the presence of p-toluenesulfonic acid.

参考文献中间体

【1】 Periers, A.-M.; Laurin, P.; Klich, M.; Musicki, B.; Haesslein, J.-L. (Aventis Pharma SA); Novel aromatic amides, preparation method and application as medicines. FR 2773369; WO 9935155 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	16605	4-Nitrophenyl chloroformate; 1-[(Chlorocarbonyl)oxy]-4-nitrobenzene	7693-46-1	C₇H₄ClNO₄	详情	详情
(XII)	38192	4-hydroxy-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one		C₃₁H₄₆O₉Si	详情	详情
(XIII)	38193	3-acetyl-4-hydroxy-7-([(7R,8R,9R,10R)-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-9-[(triethylsilyl)oxy]-6-oxaspiro[4.5]dec-7-yl]oxy)-8-methyl-2H-chromen-2-one		C₃₃H₄₈O₁₀Si	详情	详情
(XIV)	38194	3-acetyl-4-hydroxy-7-[[(7R,8R,9R,10R)-9-hydroxy-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-7-yl]oxy]-8-methyl-2H-chromen-2-one		C₂₇H₃₄O₁₀	详情	详情
(XV)	38195	3-ethanimidoyl-4-hydroxy-7-[[(7R,8R,9R,10R)-9-hydroxy-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-7-yl]oxy]-8-methyl-2H-chromen-2-one		C₂₈H₃₇NO₁₀	详情	详情
(XVI)	38196	(7R,8R,9R,10R)-7-[(3-ethanimidoyl-4-hydroxy-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-9-yl 4-nitrophenyl carbonate		C₃₅H₄₀N₂O₁₄	详情	详情
(XVII)	38197	O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne		C₃H₅NO	详情	详情
(XVIII)	38198	(7R,8R,9R,10R)-7-[(3-ethanimidoyl-4-hydroxy-8-methyl-2-oxo-2H-chromen-7-yl)oxy]-10-methoxy-8-(tetrahydro-2H-pyran-2-yloxy)-6-oxaspiro[4.5]dec-9-yl 2-propynyloxycarbamate		C₃₂H₄₀N₂O₁₂	详情	详情

合成路线3

The reaction of the spiro compound (I) with CDI in refluxing dichloroethane gives the cyclic carbonate (II), which is condensed with the benzopyranone (III) by means of DEAD and PPH3 in DMF, yielding the adduct (IV). Elimination of the diphenylmethyl protecting group by hydrogenation with H2 over Pd/C in THF affords compound (V), which is acylated with acetic anhydride to provide the acetyl derivative (VI). The reaction of (VI) with O-(2-propynyl)hydroxylamine (VII) by means of LiClO4 gives the propargyloxycarbamate (VIII) as a mixture of regioisomers that are separated by chromatography. The opening of the carbonate ring of (VII) is accompanied by the formation of the corresponding oxime at the acetyl group of the benzopyran. This oxime is easily exchanged for methoxy by reaction with an excess of O-methoxyhydroxylamine and K-OAc in ethanol to give rise to the target compound.

参考文献中间体

【1】 Laurin, P.; Periers, A.-M.; Musicki, B.; et al.; Improved antibacterial activities of coumarin antibiotics bearing 5',5'-dialkylnoviose: Biological activity of RU79115. Bioorg Med Chem Lett 2000, 10, 15, 1695.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	38187	(8R,9S,10R)-10-methoxy-6-oxaspiro[4.5]decane-7,8,9-triol	C₁₀H₁₈O₅	详情	详情
(II)	47153		C₁₁H₁₆O₆	详情	详情
(III)	38188	4-(benzhydryloxy)-7-hydroxy-8-methyl-2H-chromen-2-one	C₂₃H₁₈O₄	详情	详情
(IV)	47154		C₃₄H₃₂O₉	详情	详情
(V)	47155		C₂₁H₂₂O₉	详情	详情
(VI)	47156		C₂₃H₂₄O₁₀	详情	详情
(VII)	38197	O-(2-propynyl)hydroxylamine; 3-(aminooxy)-1-propyne	C₃H₅NO	详情	详情
(VIII)	47157		C₂₉H₃₂N₂O₁₁	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)