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Preparation method of dapagliflozin intermediate

A technology for intermediates and solutions, which is applied in the field of synthesizing dapagliflozin intermediates using microreactors, can solve the problems of low production efficiency and waste of raw materials, and achieve the effects of reducing the generation of by-products, low recovery efficiency, and shortened time

Pending Publication Date: 2022-04-26
苏州正济药业有限公司
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  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Purpose of the invention: the technical problem to be solved by the present invention is to provide a method for preparing dapagliflozin intermediates using a microreactor to solve the problems of low preparation efficiency and serious waste of raw materials for dapagliflozin intermediates in the prior art

Method used

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  • Preparation method of dapagliflozin intermediate
  • Preparation method of dapagliflozin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: Determine the influence of the flow rate of n-butyllithium on the valve of microreactor equipment and its pipeline

[0033] The n-butyllithium solution is its hexane solution with a concentration of 1.6mol / L. During the test, the n-butyllithium solution is directly passed into it through a filter head. The whole operation of n-butyllithium needs to be free of oxygen and water. , operating under nitrogen protection, considering that the pump head and one-way valve of the microreactor are very prone to blockage, so the flow rate of different butyllithium is set to be consistent with the actual measurement, and the n-butyllithium is weighed at different time points by recording video Record the weight at different time points, whether the weight decreased at a uniform speed is consistent, and measure a reasonable butyllithium flow rate.

[0034] Table 1 Effect of the flow rate of n-butyllithium on the valves and pipelines of microreactor equipment

[0035] ...

Embodiment 2

[0038] Example 2: Effect of different flow rates on reaction progress.

[0039] A method for synthesizing compound 2 using a microreactor. According to the flow rate of n-butyl lithium should not be less than 20mL / min, the equivalent ratio of compound 1 and n-butyl lithium is 1:1.1; the influence of different flow rates on the reaction process is designed and optimized. Reaction flow rate.

[0040]

[0041] A component: C 化合物1 =0.8moL / L (preparation method: weigh 30g of compound 1 and dissolve in 116mL of tetrahydrofuran, dissolve and clear for later use);

[0042] B component: C 正丁基锂 =1.6moL / L (commercially available), PTFE pipe;

[0043] First examine the influence of the flow rate of components A and B on the reaction process:

[0044] Set the flow rate of component B to 20.0ml / min, 23.5ml / min, and 27.2ml / min in sequence, and the test results are shown in the table below.

[0045] Table 2 The impact of different flow rates on the reaction process

[0046]

[0047]...

Embodiment 3

[0048] Embodiment 3: investigate the influence of different precooling temperatures on the reaction.

[0049] A component: C 化合物1 =0.8moL / L, V A =49.5mL / min

[0050] B component: C 正丁基锂 =1.6moL / L, V B =27.2mL / min

[0051]

[0052] Results: The length of the reaction unit of the microreactor pipeline is 13cm, and the residence time of the reaction unit is controlled to be 18s, so the pre-cooling temperature is determined to be -20°C. From the analysis of the table data, the lower the pre-cooling temperature, the slower the reaction process, the lower the content of the main product, and the more residual raw materials; the lower the temperature, the lower the temperature of the intermediates that may exist in other unknown peaks, the slower the process of conversion into products, Therefore, from the perspective of data analysis, the pre-cooling temperature of -20°C increases the product significantly, and other unknown peaks decrease significantly. At the same time, -2...

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Abstract

The invention discloses a method for preparing a dapagliflozin intermediate by adopting a microreactor, and belongs to the field of preparation of medical intermediates. The method comprises the following steps: (1) pre-cooling a tetrahydrofuran solution and an n-butyllithium solution of 5-bromo-2-chloro-4 '-ethoxydiphenylmethane at-78 DEG C to-20 DEG C respectively, then pumping the pre-cooled tetrahydrofuran solution and n-butyllithium solution into a first reaction unit of a microreactor respectively, mixing and reacting to obtain a reaction solution; the molar ratio of the 5-bromo-2-chloro-4 '-ethoxydiphenylmethane to the n-butyllithium in the first reaction unit is 1: (0.85-1.5), and the flow velocity of the n-butyllithium solution is not lower than 20ml / min; and (2) respectively pumping the reaction liquid obtained in the step (1) and trimethylsilyl-protected glucolactone into a second reaction unit, mixing and reacting. The method has the advantages of continuous production, no dangerous process, simplicity and convenience in operation, less environmental pollution, safety, high efficiency and the like, and has a relatively high industrial application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a method for synthesizing a dapagliflozin intermediate by using a microreactor. [0002] technical background [0003] Dapagliflozin is a sodium-dependent glucose transporter SGLT2 inhibitor used to treat type 2 diabetes, and can be used as an important choice in diabetes drug treatment. About 100 million people worldwide suffer from type 2 diabetes (NIDDM - non-insulin-dependent diabetes mellitus), characterized by hyperglycemia due to excess hepatic glucose production and peripheral insulin resistance, but the underlying causes are unknown. Hyperglycemia is considered a major risk factor for the development of diabetic complications and may be directly related to the impaired insulin secretion that occurs in late NIDDM. It is expected that normalization of blood glucose in NIDDM patients will improve the action of insulin and counteract the development of...

Claims

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Application Information

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IPC IPC(8): C07F7/18
CPCC07F7/1892
Inventor 付明伟唐静
Owner 苏州正济药业有限公司
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