Preparation method of tulathromycin

A technology of tebramycin and compound, which is applied in the field of preparation of tebramycin and can solve problems such as difficulty in operation

Inactive Publication Date: 2020-03-24
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the synthesis route of telamycin reported in other existing patents, the preparation process of the intermediate requires ultra-low temperature reaction conditions, and requires salt formation and purification, etc., and the operation is difficult.

Method used

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  • Preparation method of tulathromycin
  • Preparation method of tulathromycin
  • Preparation method of tulathromycin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The preparation of embodiment 1 formula II compound

[0046] Add the compound of formula I (100.00g) and dichloromethane (700.00g) into the reaction flask at room temperature, stir and cool down to -5.0°C, add dropwise a mixture of phenyl chloroformate (22.36g) and dichloromethane (100.00g) The solution was kept at 0°C and stirred for 3 hours. After the reaction was completed, an aqueous solution of sodium carbonate was added, and the liquid was separated to obtain an organic phase, which was concentrated to obtain the compound of formula II, which was directly used in the next step. Yield: 92%.

[0047] MS (ESI) m / z: 855.51 [M+H] + .

[0048] The preparation of embodiment 2 formula III compound

[0049] Add the compound of formula II in Example 1, o-iodylbenzoic acid (114.32g) and DMSO (300.00g) into the reaction flask at room temperature, add trifluoroacetic acid (23.26g) dropwise, and after the dropwise completion, keep warm at 30°C and stir the reaction. After t...

Embodiment 3

[0051] The preparation of embodiment 3 formula IV compound

[0052] Add Me to the reaction flask at room temperature 3SBr (13.80g) and tetrahydrofuran (100.00g), under the protection of nitrogen, the temperature was lowered to -15°C, potassium tert-butoxide (13.13g) was added, the temperature was lowered to -70°C, and the compound of formula III (25.00g ) in dichloromethane (70.00g), control the internal temperature not to exceed -50°C, add ammonium chloride aqueous solution dropwise to quench the reaction, stir, separate liquids to obtain an organic phase, and concentrate to obtain the compound of formula IV. Yield: 92%.

[0053] MS (ESI) m / z: 867.51 [M+H] + .

Embodiment 4

[0054] The preparation of embodiment 4 formula V compound

[0055] Add the formula IV compound (25.00g) among the embodiment 3 in the reaction bottle, water (100ml) and acetic acid (1.73g), be warming up to 40 ℃ of stirring reaction, reaction is finished, the water ( 50ml) solution, the pH was adjusted to 11.0, and the compound of formula V was obtained by filtration. Yield: 90%.

[0056] MS (ESI) m / z: 747.49 [M+H] +

[0057] 1 H NMR (400MHz, CDCl 3 ), δ: 3.73 (dd, J = 7.4, 117Hz, H-11), 3.30 (s, 12-OH), 2.70 (dq, J = 6.6, 1.7Hz, H-10), 2.49 (dJ = 8.75Hz ,H-9),2.33(s,NMe),2.30(s,NMe2),2.04(t,H-9ax),2.02(m,8-H),1.16(d,J=6.5Hz,10-CH3 ), 1.09(s, 12-CH3), 1.05(d, J=7.6Hz, 4-CH3), 0.94(d, J=6.7Hz, 8-H3), 3.05(s, NH), 5.42(s, CH2), 7.19 (s, 5H).

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Abstract

The invention provides a preparation method of tulathromycin, and belongs to the field of pharmaceutical chemicals. The method comprises the following steps of: reacting azithromycin serving as a rawmaterial with phenyl chloroformate to protect hydroxyl to obtain protected nitrogen azithromycin, oxidizing the hydroxyl into a ketone group by oxidation, epoxidizing, deprotecting, and reacting withn-propylamine to obtain tulathromycin. The product produced by the method has the characteristics of high purity, high yield, low cost, simple operation and stable process.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a preparation method of telamycin. Background technique [0002] Tulathromycin (Tulathromycin), also known as tulamycin, tolamycin. The drug is a new type of erythromycin semi-synthetic veterinary antibiotic developed by Pfizer Animal Health in the late 1990s. From 1998 to 2003, Pfizer registered patent protection for its compound, synthetic process and preparation. On October 13, 2004, the EU Veterinary Medical Advisory Committee (VMAC) approved Tyramycin Injection Draxxin to be launched in the EU; on May 24, 2005, the U.S. Food and Drug Administration (FDA) approved Tyramycin Injection Ricksin is launched in the United States. The Ministry of Agriculture of my country approved the domestic use of telamycin for the first time in Announcement No. 957 in 2008. And from the Groton production plant of Pfizer of the United States and the Ambiose production plant of P...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/00C07H1/00
CPCC07H17/00C07H1/00
Inventor 徐军寇景平王仲清廖高鸿陈夷花罗忠华黄芳芳
Owner SUNSHINE LAKE PHARM CO LTD
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