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Pleuromutilin derivative with thiadiazole skeleton, as well as preparation method and applications thereof

A technology of pleuromutilin and thiadiazole is applied in the field of pleuromutilin derivatives and their preparation, and can solve the problems of low activity, low antibacterial activity and the like

Active Publication Date: 2013-09-25
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

The structure-activity relationship shows that the antibacterial activity of the compound whose C-14 side chain is connected to a neutral group or an acidic group is extremely low, and the activity of the derivative connected to two basic center side chains is also low.

Method used

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  • Pleuromutilin derivative with thiadiazole skeleton, as well as preparation method and applications thereof
  • Pleuromutilin derivative with thiadiazole skeleton, as well as preparation method and applications thereof
  • Pleuromutilin derivative with thiadiazole skeleton, as well as preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: Synthesis of 22-O-(4-toluenesulfonyl)oxyacetylmpirin (2)

[0072] 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 (2), with a yield of 97.8%.

[0073] mp 147~148 oC; IR (KBr): 3446, 2924, 2863, 1732, 1633, 1597, 1456, 1371, 1297, 1233, 1117, 1035, 832, 664, 560 cm-1; 1H NMR (400 MHz, CDCl3) 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,J1=10Hz,J2=7.2 Hz), 2.01–2.08(m, 3H), 2....

Embodiment 2

[0074] Example 2: Synthesis of 14-O-(iodoacetyl) Mutilin (3)

[0075] 7.2g of 22-O-(4-toluenesulfonyl)oxyacetylmpirin (13.5mmol) was dissolved in 200mL of acetone, 2.3g of KI (14mmol) was added, and the reaction was terminated after reflux for 1h. The reaction mixture was filtered to remove insoluble salts, the filtrate was concentrated to 20-30 mL and filtered, and the filtrate was directly recrystallized at room temperature to give 5.36 g of a light yellow target compound.

[0076]Pale yellow powder, yield 81%, mp: 117-119 oC; IR (KBr): 3307, 2979, 2933, 1736, 1712, 1456, 1417, 1279, 1084, 1023, 985, 967 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 1H), 6.41 (dd, J = 17.4, 11.0 Hz, 1H), 5.70 (d, J = 8.5 Hz, 1H), 5.34 (d, J = 11.0 Hz, 1H), 5.20 (dd, J = 17.4, 1.1 Hz, 1H), 3.65 (d, J = 10.4 Hz, 1H), 3.57 (d, J = 10.5 Hz, 1H), 3.35 (s, 1H), 2.36 – 2.28 (m, 1H), 2.26 – 2.14 (m, 2H), 2.07 (dd, J = 16.0, 8.5 Hz, 2H), 1.79 – 1.60 (m, 4H), 1.57 – 1.47 (m, 2H), 1.47 – 1.42 (m, 4H), ...

Embodiment 3

[0077] Example 3: Synthesis of 14-O-[(2-amino-1,3,4,-thiadiazol-5-yl)thioacetyl]Multiline (Intermediate 3)

[0078] 2.45 g of 14-O-(iodoacetyl) Mutilin (5 mmol) was dissolved in 60 mL of THF, 0.73 g of 2-amino-5-mercapto-1,3,4,-thiadiazole (5.5 mmol) was dissolved in 5 mL of 10% NaOH and added dropwise to the above solution. mixture at 0 o C stirred for 2 h, then evaporated to dryness under reduced pressure, and added 100 mL of ethyl acetate. The resulting mixture was washed with saturated NH 4 Cl washed, and extracted 3 times with distilled water, separated the organic phase and washed with anhydrous Na 2 SO 4 After drying overnight, the filtrate was filtered and the mixture was separated on a silica gel column (petroleum ether: ethyl acetate = 1:2) to obtain 2.3 g of the target compound.

[0079] White powder, yield 92%, mp 74-75 o C.;IR (KBr): 3419, 3330, 2931, 1731, 1616, 1507, 1456, 1417, 1373, 1282, 1190, 1152, 1117, 1019, 980, 953, 938,916 cm -1 ; 1 H NMR (400...

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Abstract

The invention discloses a pleuromutilin derivative with a thiadiazole skeleton and a preparation method thereof. The preparation method comprises the following steps: 1, synthesizing 22-O-(4-tosyl)acetoxyl mutilin; 2, synthesizing 14-O-( iodoacetyl)mutilin; 3, synthesizing 14-O-[(4, 2-amino-1-thiadiazole-5yl)thioacetyl]mutilin; 4, synthesizing an end product. The compound synthesis method is easily available in raw materials, cheap in price, simple in operation, easy in product separation and purification and high in yield, wherein the total yield is 32-40%.

Description

technical field [0001] The invention relates to a pleuromutilin derivative and a preparation method thereof, belonging to the field of chemical medicine. Background technique [0002] The discovery and use of antibiotics is of great significance in human history. 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. In particular, drug-resistant bacteria such as Staphylococcus aureus, Streptococcus pneumoniae and Mycobacterium tuberculosis that cause respiratory diseases cause more than two million deaths every year, seriously endangering the human health. [0003] Pleuromutilin (chemical structural formula as follows) is a natural antibiotic discovered in the 1950s. Studies have shown that this compound and some of its derivatives have obvious antibacterial a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/135A61K31/433A61K31/454A61K31/5377A61K31/496A61P31/04A61P39/06
Inventor 梁剑平尚若锋郭文柱刘宇郝保成王学红郭志庭华兰英蒲秀英幸志君
Owner LANZHOU INST OF ANIMAL SCI & VETERINARY PHARMA OF CAAS
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