【药物名称】GW-587726X, PL-1441
化学结构式(Chemical Structure):
参考文献No.40828
标题:15-Membered lactams ketolides with antibacterial activity
作者:Kobrehel, G.; Lazarevski, G.; Kelneric, Z. (Pliva dd)
来源:EP 1070077; JP 2002510701; US 6110965; WO 9951616
合成路线图解说明:

6-O-Methylerythromycin A (I) was converted to a mixture of (E)- and (Z)-oximes upon treatment with hydroxylamine in refluxing MeOH. Beckmann rearrangement of the required (Z)-isomer (II) in the presence of tosyl chloride and NaHCO3 led to the macrocyclic lactam (III). Smooth acidic hydrolysis of (III) selectively removed the 3-cladinose moiety, yielding (IV). The 3-decladinosyl derivative (IV) was then protected as the 2' acetate (V) employing Ac2O in the presence of NaHCO3. Subsequent oxidation of the 3-hydroxyl group of (V) under modified Swern conditions furnished ketone (VI). Finally, methanolysis of the acetate ester group of (VI) provided the title compound.

合成路线图解说明:

6-O-Methylerythromycin A (I) was converted to a mixture of (E)- and (Z)-oximes upon treatment with hydroxylamine in refluxing MeOH. Beckmann rearrangement of the required (Z)-isomer (II) in the presence of tosyl chloride and NaHCO3 led to the macrocyclic lactam (III). Smooth acidic hydrolysis of (III) selectively removed the 3-cladinose moiety. The 3-decladinosyl derivative (IV) was then protected as the 2' acetate (V) employing Ac2O in the presence of NaHCO3. Subsequent acylation of the 3-hydroxyl group of (V) with the mixed anhydride prepared from 4-nitrophenylacetic acid (VI) and pivaloyl chloride furnished ester (VII). Finally, methanolysis of the acetate ester group of (VII) provided the title compound.

参考文献No.45448
标题:Novel 8a- and 9a-15-membered lactams
作者:Kobrehel, G.; Lazarevski, G.; Alihodzic, S.; Mutak, S. (Pliva dd)
来源:EP 1181298; WO 0063223
合成路线图解说明:

6-O-Methylerythromycin A (I) was converted to a mixture of (E)- and (Z)-oximes upon treatment with hydroxylamine in refluxing MeOH. Beckmann rearrangement of the required (Z)-isomer (II) in the presence of tosyl chloride and NaHCO3 led to the macrocyclic lactam (III). Smooth acidic hydrolysis of (III) selectively removed the 3-cladinose moiety. The 3-decladinosyl derivative (IV) was then protected as the 2' acetate (V) employing Ac2O in the presence of NaHCO3. Subsequent acylation of the 3-hydroxyl group of (V) with the mixed anhydride prepared from 4-nitrophenylacetic acid (VI) and pivaloyl chloride furnished ester (VII). Finally, methanolysis of the acetate ester group of (VII) provided the title compound.

参考文献No.645814
标题:Synthesis and antibacterial activity of isomeric 15-membered azalides
作者:Alihodzic, S.; et al.
来源:40th Intersci Conf Antimicrob Agents Chemother (Sept 17 2000, Toronto) 2001,Abst 1177
合成路线图解说明:

6-O-Methylerythromycin A (I) was converted to a mixture of (E)- and (Z)-oximes upon treatment with hydroxylamine in refluxing MeOH. Beckmann rearrangement of the required (Z)-isomer (II) in the presence of tosyl chloride and NaHCO3 led to the macrocyclic lactam (III). Smooth acidic hydrolysis of (III) selectively removed the 3-cladinose moiety, yielding (IV). The 3-decladinosyl derivative (IV) was then protected as the 2' acetate (V) employing Ac2O in the presence of NaHCO3. Subsequent oxidation of the 3-hydroxyl group of (V) under modified Swern conditions furnished ketone (VI). Finally, methanolysis of the acetate ester group of (VI) provided the title compound.

合成路线图解说明:

6-O-Methylerythromycin A (I) was converted to a mixture of (E)- and (Z)-oximes upon treatment with hydroxylamine in refluxing MeOH. Beckmann rearrangement of the required (Z)-isomer (II) in the presence of tosyl chloride and NaHCO3 led to the macrocyclic lactam (III). Smooth acidic hydrolysis of (III) selectively removed the 3-cladinose moiety. The 3-decladinosyl derivative (IV) was then protected as the 2' acetate (V) employing Ac2O in the presence of NaHCO3. Subsequent acylation of the 3-hydroxyl group of (V) with the mixed anhydride prepared from 4-nitrophenylacetic acid (VI) and pivaloyl chloride furnished ester (VII). Finally, methanolysis of the acetate ester group of (VII) provided the title compound.

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