RWJ-415667, -Drug Synthesis Database

【结构式】

【药物名称】RWJ-415667

【化学名称】11-Amino-13-deethyl-11-deoxy-3-des(hexopyranosyloxy)-3-oxo-13-propyl-6-O-[3-(6-quinoxalinyl)-2(E)-propenyl]erythromycin A 11-N,12-O-cyclic carbamate

【CA登记号】

【分子式】C₄₂H₆₀N₄O₁₀

【分子量】780.9673

【开发单位】Kosan (Originator), R.W. Johnson (Originator)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Ketolides

合成路线1 合成路线2

合成路线1

The reaction of 15-methylerythromycin A (I) with hydroxylamine, cyclohexanone di-isopropylacetal (II) and PPTS gives the substituted oxime (III), which is regioselectively silylated with Tms-Cl and imidazole to yield the disilylated compound (IV). The alkylation of (IV) with allyl bromide (V) and tBu-OK affords the 6-O-allyl derivative (VI),which is treated with HOAc and HCOOH to cleave the oxime group and furnish the 6-O-allyl-15-methylerythromycin A (VII). The cleavage of the 3-O-carbohydrate moiety of (VII) by means of aq. HCl, followed by benzoylation with Bz2O, gives the benzoyl intermediate (VIII), which is oxidized with NCS and Me2S and dehydrated with Ms-Cl, pyridine and DBU to yield the ketolide (IX). The fluorination of (IX) by means of (PhSO2)2N-F and tBu-OK affords the 2-fluoro derivative (X).

参考文献中间体

【1】 Macielag, M.; et al.; Structure-antibacterial activty relationships of ketolides derived from 15-methylerythromycin A. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1174.

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)	54474	(3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione		C₃₈H₆₉NO₁₃	详情	详情
(II)	45909	1-isopropoxycyclohexyl isopropyl ether; 1,1-diisopropoxycyclohexane	1132-95-2	C₁₂H₂₄O₂	详情	详情
(III)	54475	(3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime]		C₄₇H₈₆N₂O₁₄	详情	详情
(IV)	54476	(3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7,12,13-trihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime]		C₅₃H₁₀₂N₂O₁₄Si₂	详情	详情
(V)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(VI)	54477	(3R,4S,5R,6R,7S,9R,11S,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-({(2S,3S,6R)-4-isopropyl-6-methyl-3-[(trimethylsilyl)oxy]morpholinyl}oxy)-4-({(2R,4R,5S,6S)-4-methoxy-4,6-dimethyl-5-[(trimethylsilyl)oxy]tetrahydro-2H-pyran-2-yl}oxy)-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione 10-[O-(1-isopropoxycyclohexyl)oxime]		C₅₆H₁₀₆N₂O₁₄Si₂	详情	详情
(VII)	54478	(3R,4S,5R,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-12,13-dihydroxy-6-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-4-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyltetrahydro-2H-pyran-2-yl]oxy}-3,5,7,9,11,13-hexamethyl-14-propyl-2,10-oxacyclotetradecanedione		C₄₁H₇₃NO₁₃	详情	详情
(VIII)	54479	(2S,3S,6R)-2-{[(3R,4S,5S,6R,7S,9R,11R,12R,13S,14R)-7-(allyloxy)-4,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxacyclotetradecanyl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate		C₄₀H₆₃NO₁₁	详情	详情
(IX)	54480	(2S,3S,6R)-2-{[(3R,5R,6R,7S,9R,13S,14R)-7-(allyloxy)-13-hydroxy-3,5,7,9,11,13-hexamethyl-2,4,10-trioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate		C₄₀H₅₉NO₁₀	详情	详情
(X)	54481	(2S,3S,6R)-2-{[(3S,5S,6R,7S,9R,13S,14R)-7-(allyloxy)-3-fluoro-4,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate		C₄₀H₆₀FNO₁₀	详情	详情

合成路线2

The reaction of (X) with NaH and CDI, and then with hydroxylamine gives the cyclic carbamate (XI), which is finally condensed with 6-bromoquinoxaline (XII) by means of Pd2(dba)2 and P(o-tolyl)3 to yield the target 6-O-[3-(6-quinoxalyl)allyl] derivative.

参考文献中间体

【1】 Macielag, M.; et al.; Structure-antibacterial activty relationships of ketolides derived from 15-methylerythromycin A. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1174.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	54481	(2S,3S,6R)-2-{[(3S,5S,6R,7S,9R,13S,14R)-7-(allyloxy)-3-fluoro-4,13-dihydroxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-14-propyloxa-11-cyclotetradecen-6-yl]oxy}-4-isopropyl-6-methylmorpholinyl benzoate	C₄₀H₆₀FNO₁₀	详情	详情
(XI)	54482	(3aS,4R,7S,9S,10R,11S,13R,15R,15aR)-11-(allyloxy)-7-fluoro-8-hydroxy-10-{[(2S,3S,6R)-3-hydroxy-4-isopropyl-6-methylmorpholinyl]oxy}-3a,7,9,11,13,15-hexamethyl-4-propyldecahydro-2H-oxacyclotetradecino[4,3-d][1,3]oxazole-2,6,14(1H,7H)-trione	C₃₄H₅₇FN₂O₁₀	详情	详情
(XII)	54483	6-bromoquinoxaline	C₈H₅BrN₂	详情	详情

Extended Information