Pseudoerythromycin derivatives

Synthesis of de(3'-N-methyl)-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal (EM703)

##STR11##

Sodium acetate (3.9 g, 48.5 mmol) and iodine (2.5 g, 9.7 mmol) were added in this order to methanol (52.0 mL)-water (13.0 mL) solution of EM701 (6.9 g, 9.7 mmol) at room temperature, and stirred at 50.degree. C. for 3 hours. During the stirring, 1N aqueous solution of sodium hydroxide was added to maintain at pH 8-9 continuously. After confirming the completion of the reaction by TLC, the reaction mixture was diluted with aqueous ammonia (7.5 mL)-water (200 mL), and extracted with dichloromethane. After dehydrating the organic layer with sodium sulfate, the sodium sulfate was removed by filtration and distilled off the solvent to obtain crude substance. The crude substance was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01.fwdarw.10:1:0.05) to obtain EM703 (4.8 g, Yield: 70%, white powder). EM703: m. p.: 177-180.degree. C.

Example 1is a known compoun

Synthesis of bis-de(3'-N-methyl)-8,9-anhydro-pseudo erythromycin A 6,9-hemiketal (EM721)

##STR12##

Sodium (4.5 g, 1.67 mmol) was added in methanol (15 mL) to prepare methanol solution of sodium methoxide, and EM703 (195.4 mg, 0.279 mmol) and iodine (353.6 mg, 1.393 mmol) were added in this order at 0.degree. C. and stirred for 3 hours. After confirming completion of the reaction by TLC, sodium thiosulfate (0.8 g), aqueous ammonia (0.5 mL) and water (80 mL) were added and extracted with dichloromethane. The organic layer was dehydrated by adding sodium sulfate, filtered to remove the sodium sulfate, and removed the solvent to obtain crude substance. The crude substance was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01.fwdarw.10:1:0.05) to obtain EM721 (166.3 mg, Yield: 87%, white powder).

EM721: m. p.: 134-136.degree. C.

IR (KBr) .nu.: 3467.4, 2973.7, 2935.1, 2879.2. 1700.9, 1637.3, 1457.9, 1380.8. 1265.1, 1166.7, 1126.2, 1079.9, 1037.5, 1016.

Synthesis of bis-de(3'-N-methyl)-3'-N-ethyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal (EM722)

##STR13##

N,N-Diisopropylethylamine (26.6 .mu.L, 0.153 mmol) and ethyl iodide (12.2 .mu.L, 0.153 mmol) were added to dimethylformamide (1.0 mL) solution of EM721 (21.0 mg, 0.0305 mmol) and stirred at room temperature for 4 hours. After confirming completion of the reaction by TLC, the reaction mixture was diluted with water and extracted with dichloromethane. The organic layer was dehydrated by adding sodium sulfate, filtered to remove the sodium sulfate, and removed the solvent to obtain crude substance. The crude substance was purified by silica gel column chromatography (chloroform:methanol:aqueous ammonia=10:0.5:0.01.fwdarw.10:1:0.05) to obtain EM722 (7.0 mg, Yield: 32%, white powder).

EM722: m. p.: 124-126.degree. C.

IR (KBr) .nu.: 3471.6, 2933.2, 1704.8, 1457.9, 1378.9, 1263.1, 1166.7, 1128.2, 1074,2, 1037.5, 1018.2 cm.sup.-1.

HRMS (FAB)m / z: C.sub.37 H.sub.65 NO.sub.12 Na [M+Na].sup.+