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Synthesis method of tulathromycin and synthesis method of tulathromycin phosphate

A technology of terramycin and a synthesis method, applied in the field of compound preparation, can solve problems such as unfavorable operation, unfavorable operation and cost saving, and achieve the effects of cost saving, low equipment requirements and mild reaction conditions

Inactive Publication Date: 2020-04-14
GUANGDONG WENS DAHUANONG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] For the preparation of tulamycin, the published preparation method of Pfizer Company is to use norazithromycin as a raw material, and at first protect 2 with benzyl chloroformate. 、 position hydroxyl group, then sequentially oxidize and epoxidize the 4-position hydroxyl group, and remove the CBZ protecting group by catalytic hydrogenation, and finally obtain telamycin (EP1253153A; US6472371; WO 0155158 A1) through ring-opening amination; but this method Ultra-low temperature and high pressure conditions are required, which is not conducive to operation, so it is not conducive to operation and cost saving when used in mass production

Method used

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  • Synthesis method of tulathromycin and synthesis method of tulathromycin phosphate
  • Synthesis method of tulathromycin and synthesis method of tulathromycin phosphate
  • Synthesis method of tulathromycin and synthesis method of tulathromycin phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Hydroxyl protection steps:

[0035] In a low-temperature reaction tank, add 20 g of demethylazithromycin shown in formula I to a three-necked flask at a temperature of -10-0°C, dissolve it in 320 mL of dichloromethane, then cool to 3°C, stir, and slowly 4.7g of CBZ-Cl was added dropwise, and after 10 minutes, 2.7g of triethylamine was slowly added dropwise. The pH of the reaction solution was slightly alkaline, and stirred at 3°C ​​for 2h. The end point of the reaction was monitored by thin-layer chromatography, and the reaction was completed. Add 150mL of distilled water, adjust the pH to 2 with 3N HCl, separate the liquids, extract the organic phase with an acidic water phase, combine the water phases, extract the water phase with petroleum ether and dichloromethane twice, add 150 mL of dichloromethane to the water phase Chloromethane, adjust pH=9 with 5N NAOH, separate the liquids, extract the aqueous phase with 50 mL of dichloromethane, combine the organic phases, d...

Embodiment 2

[0039] Hydroxyoxidation step:

[0040] Put 5 g of the product obtained in Example 1 into a three-necked flask, dissolve it in 60 mL of toluene, cool it down to 0 ° C, add a mixed solution of 2 g of aluminum tert-butoxide and 10 mL of cyclohexanone and alkali-containing chloroform, then raise the temperature to 10 ° C, and stir After 4 hours of reaction, the end point of the reaction was monitored by thin-layer chromatography, and the reaction was completed. After the reaction, it was extracted with ethyl acetate, and the extract was concentrated under reduced pressure and dried in vacuo. 4.2 g of the oxidized product was obtained, the yield was 84%, and the melting point was 197-199°C.

[0041] The detection data of this product are as follows:

[0042] 1 HNMR(400MHz,DMSO):δ7.32-7.37(m,5H),5.09-5.25(m,2H),4.75(t,2H),4.51-4.57(m,3H),4.25(s,1H), 3.98-4.03(m,1H),3.57-3.60(m,2H),3.43-3.49(m,4H),3.33(s,3H),2.98-3.05(m,2H),2.52-2.68(m,3H ),2.31(d,J=11.3Hz,1H),2.26(s,8H),2.16(t,...

Embodiment 3

[0044] Carbonyl epoxidation steps:

[0045] Dissolve 5 g of the oxidation product obtained in Example 2 with a 50 / 100 mL (THF / DMSO) mixed solvent, weigh 3 g of NaH and 3 g of trimethylsulfonium iodide in DMSO, then add the oxidation product solution, and then add 2.5 mL triethylamine, stirred at 25°C for 3h. Thin-layer chromatography monitors the end point of the reaction, and the reaction ends. Add 50 mL of water, then add 100 mL of ethyl acetate, stir, separate the water phase, extract the ethyl acetate phase with water three times, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and dry in vacuo to obtain 4 g of white solid with a yield of 79%, melting point: 189-191°C, elemental analysis: C 55.1, H 25.3, N 6.9.

[0046] The detection data of this product are as follows:

[0047] 1 HNMR (400MHz, DMSO): δ7.28-7.37(m, 5H), 5.10-5.16(m, 2H), 5.05(d, J=5.1Hz, 1H), 4.73(t, 2H), 4.65(d, J=19.2Hz, 1H), 4.50-4.53(m, 1H), 4.20(d, J=6.8Hz, 1H), 3.61(d, J=2...

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Abstract

The invention discloses a synthesis method of tulathromycin and a synthesis method of tulathromycin phosphate. The synthesis method comprises the following steps: 1, protecting a hydroxyl group: preparing a hydroxyl protection product represented by formula II from an azithromycin A intermediate represented by formula I; 2, performing hydroxyl oxidation and carbonyl epoxidation: carrying out epoxidation on the hydroxyl protection product of the formula II by using an oxidation product to obtain a product represented by formula III; 3, performing protection group removal: dissolving the productof the formula III, adding palladium on carbon, an acid and ammonium formate, and performing a reaction to obtain a product represented by formula IV; and 4, performing amination: dissolving the product of the formula IV and n-propylamine, and heating for a reaction to obtain tulathromycin. The synthesis method of tulathromycin phosphate comprises the following steps: dissolving the tulathromycin, adjusting the pH value to 6-7.5, decolorizing, crystallizing, and drying to obtain the tulathromycin phosphate. The process and reaction conditions are improved to simplify the synthesis route and steps, so the cost can be greatly saved, and the production efficiency is improved.

Description

technical field [0001] The invention relates to a synthesis method of tulamycin and tulamycin phosphate, belonging to the technical field of compound preparation. Background technique [0002] Tulathromycin is the Chinese name of Tulathromycin, the chemical name is (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[[2,6-dideoxy-3-C- Methyl-3-O-methyl-4-C-[(propylamino)methyl]–α-L-nucleo-hexapyranosyl-oxy 2-ethyl-3,4,10-trihydroxy acid -3,5,8,10,12,14-Hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)–β-D-xyl-hexypyranosyl] Oxy]-1-oxa-6-azacyclopentadecane (15-membered macrocycle). [0003] Turamycin is the latest animal-specific macrolide semi-synthetic antibiotic developed by Pfizer Animal Health. It was launched in the European Union and the United States in 2004. A single dose of tulamycin provides a full course of therapy. It is mainly used for the respiratory diseases of pigs and cattle caused by Actinobacillus, Mycoplasma, Pasteurella and Haemophilus para. The data show that...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00
CPCC07H1/00C07H17/00Y02P20/55
Inventor 陈良柱潘志坤方炳虎
Owner GUANGDONG WENS DAHUANONG BIOTECH
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