Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative

A technology of pleuromutilin and derivatives, applied in the direction of organic chemistry, antibacterial drugs, etc.

Active Publication Date: 2015-07-29
山东齐发药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the overuse of antibiotics has led

Method used

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  • Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative
  • Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative
  • Pleuromutilin derivative with pyrimidine side chain and application of pleuromutilin derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1: 14-O-[(4-Amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]Multiline

[0021] Dissolve 1.65 g of 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (10 mmol) in 20 mL of methanol, add 1.1 mL of 10 M NaOH (11 mmol) and stir for 30 min. Then 20 mL of dichloromethane (DCM) solution containing 5.33 g (10 mmol) 22-O-(4-tosyl)oxyacetylmtilin was added dropwise, and stirred at room temperature for 36-40 h after the addition was complete. After evaporating the solvent under reduced pressure, the crude product was dissolved in a mixed solution of 60mL ethyl acetate and 20mL water, and 50mL saturated NaHCO 3 Afterwards, a large amount of white precipitate was produced, and after filtration, it was separated by column chromatography (ethyl acetate:ethanol=20:1) to obtain the target compound.

[0022] Due to the structural tautomerism of the hydroxyl and ketone formulas, the 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl)thioacetyl]muroline tautomer is 14-O-[(4 -Amino-6-ketone-pyrimi...

Embodiment 2

[0028] Example 2: 14-O-[(4-Amino-6-methoxy-pyrimidin-2-yl)thioacetyl]Multiline

[0029] 2.51g of 14-O-[(4-amino-6-hydroxy-pyrimidin-2-yl) thioacetyl] monoclonal (5.0mmol) and 2.07g of K 2 CO 3 (15 mmol) was dissolved in 20 mL of dimethylformamide (DMF), then 0.71 g of iodomethane (5.0 mmol) was added in portions. Stir the reaction at 80-85°C for 4h, cool the reaction system, filter the insoluble impurities, and evaporate the solvent to dryness under reduced pressure. The resulting mixture was separated by column chromatography (petroleum ether: ethyl acetate = 1:15) to obtain 1.7 g (28%) of 14-O-[(4-amino-6methoxy-pyrimidin-2-yl ) thioacetyl]Miltiline and 3.6 g (61%) of 14-O-[(1-methyl-4-amino-6-keto-pyrimidin-2-yl)thioacetyl]Miltiline.

[0030] 14-O-[(4-Amino-6-methoxy-pyrimidin-2-yl)thioacetyl]Multiline, the structural formula is as follows:

[0031]

[0032]IR(KBr)3374,2928,1732,1626,1585,1548,1390,1307,1273,1212,1152,1117,1048,1017,982,917cm -1 ; 1 H NMR (400MHz, ...

Embodiment 3

[0033] Example 3: 14-O-[(1-Methyl-4-amino-6-keto-pyrimidin-2-yl)thioacetyl]Multiline

[0034] The preparation method of 14-O-[(1-methyl-4-amino-6-keto-pyrimidin-2-yl)mercaptoyl]Multiline is the same as in Example 2, and the structural formula is as follows:

[0035]

[0036] IR (KBr) 3422, 2929, 1730, 1630, 1509, 1457, 1414, 1282, 1154, 1117, 1094, 807; 1 H NMR (400MHz, DMSO) δ6.28(s, 2H), 6.10(dd, J=17.8, 11.2Hz, 1H), 5.52(d, J=8.1Hz, 1H), 5.05(dd, J=27.5, 14.5Hz, 2H), 4.92(s, 1H), 4.52(d, J=5.9Hz, 1H), 4.34-3.68(m, 3H), 3.31(d, J=18.8Hz, 4H), 2.40(s, 1H),2.27-1.88(m,5H),1.83-1.58(m,2H),1.58-1.24(m,8H),1.18(t,J=7.1Hz,2H),1.05(s,4H),0.82 (d,J=6.8Hz,3H),0.61(d,J=6.8Hz,3H); 13 C NMR(100MHz,DMSO)δ217.55,170.79,166.83,161.88,161.51,160.51,141.22,115.85,81.23,73.13,70.83,60.22,57.65,45.43,44.63,43.90,42.04,40.56,40.30,40.14,39.83,39.62 ,39.41,36.82,34.56,30.57,29.38,29.07,27.09,24.93,21.23,16.61,14.89,14.56,11.98; LRMS(ES)calcd[M+H] + for C 27 h 39 N 3 o 5 S 518.2683, f...

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Abstract

The invention discloses a pleuromutilin derivative with a pyrimidine side chain. The structural formula of the derivative is shown in the specification, wherein R1 is C1-C4 alkoxy groups or hydroxyl groups; R2 is an amino group or an amide group; R3 is hydrogen or C1-C4 alkyl groups. The compound can be applied to preparation of antibacterial drugs, particularly to preparation of MRSA (methicillin-resistant staphylococcus aureus), MRSE (methicillin-resistant staphycoccus epidermidis) and/or antagonistic bacillus subtilis drugs, and the antibacterial effect is superior to that of tiamulin.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a pleuromutilin derivative with a pyrimidine side chain and an application thereof. Background technique [0002] The discovery of antibiotics has played an important role in human history. However, the overuse of antibiotics has led to serious drug resistance in many bacteria. Drug-resistant bacteria, especially Staphylococcus pneumoniae, Streptococcus pneumoniae, Mycobacterium tuberculosis, etc., cause more than two million deaths every year, seriously threatening human health. Therefore, it is particularly important to develop new anti-drug-resistant fungal drugs. [0003] Pleuromutilin (see formula i for chemical structure) is a diterpene compound with antibacterial activity isolated from the higher fungi Pleurotus multilus (Fr.) Sacc. and Pleurotus Passecke‐rianus Pilat for the first time in the 1950s. The compound consists of a 5‐6‐8 three-membered ring skel...

Claims

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Application Information

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IPC IPC(8): C07D239/56C07D401/12A61P31/04
CPCC07D239/56C07D401/12
Inventor 尚若锋衣云鹏梁剑平郝宝成刘宇郭志廷
Owner 山东齐发药业有限公司
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