Pleuromutilin derivatives, and preparation method and application thereof

A technology for pleuromutilin and derivatives, which is applied in the field of pleuromutilin derivatives and their synthesis, and can solve the problems of low antibacterial activity and activity

Active Publication Date: 2013-02-13
LANZHOU INST OF ANIMAL SCI & VETERINARY PHARMA OF CAAS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The side chain of pleuromutilin C14 is the main site for chemical modification. The structure-activity relationship shows that the antibacterial activity of the compound

Method used

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  • Pleuromutilin derivatives, and preparation method and application thereof
  • Pleuromutilin derivatives, and preparation method and application thereof
  • Pleuromutilin derivatives, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Example 1. 22-O-(4-toluenesulfonyl)oxyacetylmpirin (A)

[0043] Dissolve 75.7g (0.2mol) of pleuromutilin and 42g (0.22mol) of p-toluenesulfonyl chloride in 200ml of methyl tert-butyl ether, stir the mixture slowly and drop into NaOH solution with a concentration of 0.01mol / ml 50ml. Then heated to reflux while vigorously stirring. After 10-20min, a large amount of white matter was formed, and then stirred for 20-40min. Filter while hot with a Buchner funnel, then rinse with methyl tert-butyl ether (MTBE) and distilled water, and dry naturally to obtain a white powder product (A), with a yield of 97.8%.

[0044] mp 147~148 o C; IR (KBr): 3446, 2924, 2863, 1732, 1633, 1597, 1456, 1371, 1297, 1233, 1117, 1035, 832, 664, 560 cm -1 ; 1 H NMR (400 MHz, CDCl 3) δ 0.63 (d, 3H, J = 6.8 Hz), 0.87 (d, 3H, J = 6.8Hz), 1.11–1.15 (m, 1H), 1.22-1.26 (s, 5H), 1.33–1.36 (m, 1H), 1.41–1.44 (m, 1H), 1.46-1.50 (m, 5H), 1.63-1.65 (dd, 2H,J 1 =10Hz,J 2 =7.2 Hz), 2.01–2.08(m, 3H), 2.21...

Embodiment 2

[0045] Example 2. 14-O-[(1-Amino-2-methylpropan-2-yl)thioacetyl]Multiline (B)

[0046] Cut 0.63g of sodium metal into small pieces and add it to 150ml of absolute ethanol, filter out impurities after the reaction to obtain a sodium ethylate ethanol solution with a mass concentration of 1 to 2%, then add 1.89g (13.5mmol) of Dimethylcysteamine hydrochloride, stirred at room temperature for about 1h, cooled to -5°C, added 7.2g (13.5mmol) of 22-O-(4-toluenesulfonyl)oxyacetylmtilin, and Stir in the bath for 2.5h, distill most of the ethanol under reduced pressure after the reaction, add ethyl acetate to extract, and wash the unreacted dimethylcysteamine hydrochloride and the p-toluenesulfonate generated with distilled water, to the separated organic The phase was dried overnight by adding anhydrous magnesium sulfate, and then separated on a silica gel column (ethyl acetate:ethanol=10:1) or recrystallized (ethyl acetate) to obtain 3.7 g of the target compound (B), with a yield of 59...

Embodiment 3

[0048] Example 3. 14-O-[(2-chloro-benzoyl-2-methylpropan-2-yl) mercaptoacetyl] Mutilin ( 4a )

[0049] Method 1: Dissolve 0.78g (5mmol) of o-chlorobenzoic acid in 30ml of SOCl 2 , heated to reflux for about 4h. Then the unreacted SOCl is reclaimed under reduced pressure 2 , the resulting oil was cooled to room temperature, and 30ml of dichloromethane (DCM) was added for use.

[0050] 1.6g (3.5mmol) of 14-O-[(1-amino-2-methylpropan-2-yl) mercaptoyl] Mutilin and 2.5g of triethylamine were dissolved in 60ml of DCM, in Add the oil obtained from the above reaction dropwise under stirring at around 0°C, and react for another 3 hours after the dropwise addition. After the reaction, the mixture was washed twice with water and washed with saturated NH 4 Cl solution was washed, and after separation, the organic phase was washed with anhydrous MgSO 4 After drying overnight, the DCM was evaporated under reduced pressure, and the resulting mixture was separated by silica gel column...

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Abstract

The invention discloses new pleuromutilin derivatives which have a structural formula (I) or a structural formula (II) shown in the specification, wherein in the formula (I), when n=0, R1 is Cl, CH3, OCH3 or NH2; and when n=1, R1=H, and R2=NH2. The compounds have favorable inhibiting action on Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Streptococcus mastitidis; the antibacterial activity of one compound having a phenyl group with ortho-substituting groups or para-substituting groups (such as Cl, CH3, OCH3 or NH2) is superior to the antibacterial activity of one compound having a phenyl group with meta-substituting groups; and part of compounds having para-substituting aryl groups or ortho-substituting aryl groups are the same with valnemulin in the antibacterial activity on Staphylococcus epidermidis or Streptococcus mastitidis, and can be used for the preparation of antibacterial drugs. The synthesis method of the compounds has the advantages that the raw materials are accessible, the price is low, the operation process is simple, the products are easy to separate and purify, the yield is high and the total yield is 35-45%.

Description

technical field [0001] The invention belongs to the field of antibiotic drugs, and in particular relates to a class of pleuromutilin derivatives whose side chain ends are aryl groups, and a synthesis method and application thereof. Background technique [0002] The discovery and use of antibiotics is of great significance in human history. Antibiotics not only prolong human life, but also improve people's quality of life. But in the past 30 years, the widespread use and even abuse of antibiotics has caused many bacteria to develop increasingly serious drug resistance. Due to the emergence of drug resistance, the curative effect of drugs with better curative effect is reduced or invalid. Especially Staphylococcus aureus ( Staphylococcus aureus ), Streptococcus pneumoniae ( Staphylococcus pneumoniae ) and Mycobacterium tuberculosis ( Mycobacterium tuberculosis ) and other drug-resistant bacteria, causing more than two million deaths every year, seriously endangering huma...

Claims

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Application Information

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IPC IPC(8): C07C323/52C07C319/14C07D209/42A61K31/22A61K31/404A61P31/04
CPCY02A50/30
Inventor 梁剑平尚若锋刘宇郭文柱陶蕾郭志廷华兰英蒲秀英幸志君郝宝成王学红
Owner LANZHOU INST OF ANIMAL SCI & VETERINARY PHARMA OF CAAS
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