RWJ-415667

Chemical Name: 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
项目整合开发状态: Preclinical
项目研究机构: Kosan (Originator), R.W. Johnson (Originator)
合成路线: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).

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

合成路线: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).

合成路线: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.