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Method for preparing macrolides half-synthesized antibiotics telithromycin

A technology of macrolides and telithromycin, applied in the preparation of sugar derivatives, chemical instruments and methods, antibacterial drugs, etc., can solve the problems of low reaction yield, high price, high risk, etc., and achieve safety Good performance and low production cost

Inactive Publication Date: 2008-10-08
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In this route, the reagent EDC-HCl (1-[3-(dimethylamino) propyl group]-3-ethylcarbodiimide hydrochloride) used in the oxidation reaction is expensive, the consumption is large, and the reaction yield is low. Difficulty in purification. During the synthesis of branched chains, metal potassium is used, which is dangerous and difficult to operate. There are certain difficulties in industrial production.

Method used

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  • Method for preparing macrolides half-synthesized antibiotics telithromycin
  • Method for preparing macrolides half-synthesized antibiotics telithromycin
  • Method for preparing macrolides half-synthesized antibiotics telithromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] 3-Des[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy]-6-O-methylerythromycin

[0033] Disperse 60.0g (80.4mmol) of 6-O-methylerythromycin (clarithromycin) in 1000ml of 1M hydrochloric acid, stir at room temperature for about 5 hours, adjust the pH to 8-9 with concentrated ammonia water, add solid sodium chloride to make The solution was saturated, filtered and washed with water to obtain a white solid, which was recrystallized from acetone and petroleum ether (60-90°C) to obtain 40.2g, yield 84.9%, mp 236-240°C.

[0034] IR (KBr) 1690, 1734cm -1

[0035] 1 HNMR (CDCl 3 )δ5.18 (dd, 1H, C-13H, J=13.5Hz), 2.97 (s, 3H, C-6OCH 3 ), 2.25(s, 6H, N(CH 3 ) 2 )ppm

[0036] MS(ESI) m / e: 590(M+H) +

Embodiment 2

[0038] 2'-O-acetyl-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy]-6- O-methylerythromycin (II):

[0039] 3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy]-6-O-methylerythromycin ( Obtained from Example 1) 40.0g (68mmol) was dissolved in 400ml of dichloromethane and 11.6ml (80.4mmol) of triethylamine, and 13.44ml (141.12mmol) of acetic anhydride was added dropwise under ice bath, and the ice bath was removed after the addition , Reaction at room temperature for 3.5h. Add saturated NaHCO 3 150ml of aqueous solution was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was recrystallized from ethyl acetate and petroleum ether (15:1) to obtain 39g of white soft solid, yield 90.9%, mp 156- 160°C.

[0040] IR (KBr) 1690, 1734, 1741cm -1

[0041] 1 HNMR (CDCl 3 ) δ 4.85 (dd, 1H, C-2'CHOAC, J=18Hz), 3.04 (s, 3H, C-6OCH 3 ), 2.36(s, 6H, N(CH 3 ) ...

Embodiment 3

[0044] 2'-O-acetyl-3-de[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy]-6- O-methyl-11,12-carbonate erythromycin (III)

[0045] Compound (II) (obtained by Example 2) 20 grams (31.7mmol) was dissolved in 200ml toluene, added diethyl carbonate 40g (450.5mmol), anhydrous potassium carbonate 40g (290mmol), room temperature reaction 9 hours, washed three times , anhydrous MgSO 4 After drying, the solvent was removed under reduced pressure to obtain an off-white solid, which was recrystallized from acetone solution to obtain 15.6 g of pure product with a yield of 75%, m.p.92-93°C.

[0046] IR (KBr) 3540, 1814, 1741, 1715cm -1

[0047] 1 HNMR (CDCl 3 )δ5.0(dd,1H,H 13 , J=2.4, 10.2Hz), 2.64(s, 3H, 6-O-CH 3 ), 2.24(s, 6H, N(CH 3 ) 2 ), 2.04 (s, 3H, 2'OCOCH 3 )ppm

[0048] MS(ESI) m / e: 658(M+H) +

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Abstract

The invention discloses a new method for preparing macrolides semi-synthesizing antibiotic tallysomycin. The mother core part uses 6-methoxy bristacin as raw material, which is dewatered on the effect of the base after dewatering, acylating, re-etherification and oxidant, and then it reacts with the carbonyl diimidazole to obtain the intermediate (VI); the lateral chain part uses 3-acetyl pyridine as raw material and is hydrolyzed after bromide and reacting with the hexamine, then it ringed with the potassium sulfocyanide and reacts with the N-(4-bromide butyl)-phthalimide on base condition after the effect of diluted nitric acid and then it is hydrazinolysized to obtain the lateral chain (XIII); the intermediate (VI) reacts with the lateral chain (XIII) to synthesize the tallysomycin.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to a method for preparing macrolide semi-synthetic antibiotic telithromycin. Background technique [0002] Agouridas et al reported in J.Med.Chem.1998, 41:4080-4100 that the synthesis of telithromycin adopts the following route: [0003] [0004] Wherein the synthesis of the branched chain is as follows: [0005] [0006] In this route, the reagent EDC-HCl (1-[3-(dimethylamino) propyl group]-3-ethylcarbodiimide hydrochloride) used in the oxidation reaction is expensive, the consumption is large, and the reaction yield is low. Difficulty in purification. During the synthesis of branched chains, metal potassium is used, which is dangerous and difficult to operate. Industrial production has certain difficulties. Contents of the invention [0007] The purpose of the present invention is to provide a new method for preparing macrolide semi-synthetic antibiotic telithromycin aiming at the p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/08C07H1/00A61K31/7048A61P31/04
Inventor 尤启冬魏新李志裕毕晓玲郭青龙
Owner CHINA PHARM UNIV
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