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The preparation method of 3-amino-rifamycins

A rifamycin and amino technology, which is applied in the field of preparation of 3-amino-rifamycin S, can solve the problems of inability to realize industrial industrialization, increase environmental protection costs, complicated operations, etc. The effect of reducing the generation of waste liquid and the simple operation process

Active Publication Date: 2017-05-31
CHONGQING HUABANGSHENGKAI PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The first route is obtained by substituting 3-bromo-rifamycin S nitro group, and then reducing and oxidizing (such as: US4017481 and US2417277). This method has a long route and complicated operation, and needs to go through steps such as extraction, distillation, and filtration; Route 2 uses 3-bromo-rifamycin S as the raw material, after sodium iodide iodization, and then uses sodium azide as the introduction agent for amino groups (US4007169), sodium azide is highly toxic and explosive, and cannot be realized Industrialization; Route 3 is prepared by using 3-bromo-rifamycin S as a raw material and directly feeding ammonia into the gas (CN200610022509). The reaction time of this method is long, requiring 7-30 hours, and ammonia gas needs to be passed all the time. The reaction is uncontrollable, and tail gas needs to be collected at the same time, resulting in a large amount of waste liquid, which increases environmental protection costs and is not suitable for large-scale industrial production

Method used

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Examples

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Effect test

Embodiment 1

[0028] Example 1 Preparation of 3-amino-rifamycin S

[0029] Add 200g of 3-bromo-rifamycin S into a three-necked flask, add 2L of 1,4-dioxane, stir to dissolve, control the temperature at 32±3°C, and dropwise add an ammonia-methanol solution with a mass percentage of ammonia of 8%. The mixed solution of 472ml and 2L of 1,4-dioxane, after the dropwise addition, send a sample for HPLC monitoring, after the reaction is completed, concentrate the 1,4-dioxane until the flow is cut off, add ethylene glycol monomethyl ether Heat to 60°C and stir for 30 minutes, cool to about 25±5°C, then maintain the system temperature at 5±5°C and stir for 1 hour, filter, and vacuum-dry the filter cake at 40°C for 4 hours to obtain 3-amino-rifamycin S 170g, yield 92.9%, purity 99.1%, MS: M+1=718.8, M+Na=733.5.

Embodiment 2

[0030] Example 2 Preparation of 3-amino-rifamycin S

[0031] Add 20g of 3-bromo-rifamycin S into a three-necked flask, add 200ml of tetrahydrofuran, stir to dissolve, control the temperature at 32±3°C, add dropwise a mixture of 47ml of ammonia methanol solution with a mass percentage of 8% ammonia and 200ml of tetrahydrofuran After the dropwise addition is completed, send samples to HPLC for monitoring. After the reaction is completed, concentrate the tetrahydrofuran until the flow is cut off. Add ethylene glycol monomethyl ether and heat to 60°C for 30 minutes, then cool to 25±5°C, and then maintain the system Stir at 5±5°C for 1 hour, filter, and vacuum-dry the filter cake at 40°C for 4 hours to obtain 16.2 g of 3-amino-rifamycin S with a yield of 88.5% and a purity of 99.2%.

Embodiment 3

[0032] Example 3 Preparation of 3-amino-rifamycin S

[0033] Add 10g of 3-bromo-rifamycin S into a three-necked flask, add 50ml of methanol, stir to dissolve, control the temperature at 32±3°C, add dropwise 44ml of ammonia-methanol solution with a mass percentage of ammonia of 8%, after the dropwise addition , send samples to HPLC monitoring, after the reaction is completed, concentrate the tetrahydrofuran until the flow is cut off, add glycol monomethyl ether, heat to 60°C and stir for 30 minutes, cool to 25±5°C, and then keep the system temperature at 5±5°C and stir After filtering for 1 hour, the filter cake was vacuum-dried at 40° C. for 4 hours to obtain 8.5 g of 3-amino-rifamycin S with a yield of 92.4% and a purity of 98.5%.

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Abstract

The invention relates to the field of chemical synthesis, in particular to a preparation method of 3-amino-rifamycin S. The preparation method of 3-amino-rifamycin S specifically includes the steps of: dissolving 3-bromo-rifamycin S in one or more of ether solvent, hydrocarbon solvent and alcohol solvent to obtain a reaction system; adding an ammonia-methanol solution into the reaction system to conduct reaction; after full reaction, carrying out crystallization treatment, and then conducting filtering and drying to obtain 3-amino-rifamycin S. The method provided by the invention has the characteristics of controllable reaction, mild reaction process, simple operation process, and short process needing only 1-5h. The method also has high yield all over 80%, the product has good purity over 98.5%, and can be directly used for other reaction without refining. And the whole production process is environment-friendly and has small burden, thus being suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, in particular to a preparation method of 3-amino-rifamycin S. Background technique [0002] Rifamycin (rifamycins) is a complex isolated from the metabolites of Streptomyces mediterranei by Sensi et al. in 1959, and then A, B, C, D, E and so on were isolated. In 1962, rifamycin B was chemically transformed into rifamycin SV, and was first used clinically. Due to its poor oral absorption, mepirifamycin, namely rifampicin, was screened from multiple derivatives of 3-formylrifamycin SV. This product can be administered orally, and has good curative effect, but it is easy to cause bacterial strains to develop drug resistance, the effective time is short, and the infection activity of Mycobacterium avium complex (MAC) in AIDS complications is relatively low, and the toxicity is relatively high. Therefore, for a period of time, countries all over the world have been competing to develop new derivati...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/08
CPCC07D498/08
Inventor 朱强杨玉金
Owner CHONGQING HUABANGSHENGKAI PHARM
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