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Preparation method of canagliflozin hemihydrate

A hydrate and total water technology, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of low upper limit of water content such as canagliflozin monohydrate, and achieve the effect of solving unstable product quality and reducing production process requirements

Active Publication Date: 2020-04-24
HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The object of the present invention is to overcome the defect that the upper limit of the water content of the recrystallization solution is low in the prior art, and it is easy to produce canagliflozin monohydrate, and a kind of canagliflozin hemihydrate that improves the upper limit of the water content in the recrystallization solution is provided. Preparation

Method used

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  • Preparation method of canagliflozin hemihydrate
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  • Preparation method of canagliflozin hemihydrate

Examples

Experimental program
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Effect test

Embodiment 1

[0034] Embodiment 1: Preparation of canagliflozin anhydrate

[0035] Weigh 72g of canagliflozin hemihydrate, add 1000mL of ethyl acetate and 1000mL of purified water, and stir at room temperature or properly heated at 35-40°C until completely dissolved. The layers were allowed to stand, the aqueous layer was discarded, and the organic layer was evaporated to remove the solvent. After dissolving with ethyl acetate, the solvent was evaporated by rotary evaporation at 35-40° C., and the residual water was taken away repeatedly several times. Finally, under the vacuum of the oil pump, the remaining solvent was evaporated to dryness to obtain the anhydrous compound of canagliflozin in the form of white foam.

Embodiment 2

[0037] Add 7.06g (15.88mmol) of canagliflozin anhydrous compound obtained in Example 1 and 0.46ml (7.94mmol, 0.5eq) of glacial acetic acid to 90mL of ethyl acetate previously dried with molecular sieves, and seal with a rubber stopper. When the solid is completely dissolved, its Karl's moisture is measured to be 0.02%. Add 1.13ml of water (that is, the water content is 4 molar equivalents), and stir evenly. Add 75 mL of n-heptane dropwise at room temperature, and crystallize for one hour after dropping, then lower the temperature, filter under reduced pressure, and heat the obtained solid under vacuum for two hours to obtain the final product. Its Karl's moisture is measured to be 2.03%, and it can be determined that the obtained solid is canagliflozin hemihydrate.

Embodiment 3

[0039] Referring to the method of Example 2, change the amount of glacial acetic acid and additional water, and detect the Karl's moisture in the final product. The specific data are shown in Table 1.

[0040] Table 1

[0041]

[0042] The Karl's moisture of completely dried canagliflozin hemihydrate is 1.98%, and the Karl's moisture of completely dried canagliflozin monohydrate is 3.89%. Therefore, it can be judged that the products obtained in 3-1 to 3-5 are all canagliflozin hemihydrates, and the products obtained in 3-6 to 3-8 are canagliflozin monohydrates by analyzing the Karl’s water content of the products. In order to further confirm its crystal form, the PXRD of each product was also measured, and the results were consistent with the results of Karl Fischer's moisture determination. Wherein the PXRD of the products of 3-5 and 3-8 are respectively as follows figure 1 , figure 2 shown.

[0043]The results show that when the crystallization solution contains ac...

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Abstract

The invention discloses a preparation method of a canagliflozin hemihydrate. According to the preparation method, acetic acid is added into a canagliflozin re-crystallization solution, so that the upper limit of the water content of the solution is increased, and the production requirement of canagliflozin hemihydrate is reduced. A same technical effect can be achieved by adjusting the pH value and utilizing residual acetic acid. The method is simple and efficient, facilitates the control of product quality and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of canagliflozin hemihydrate. Background technique [0002] Canagliflozin is the first sodium-glucose cotransporter 2 (SGLT-2) inhibitor approved by the US FDA. SGLT-2 inhibitors inhibit the glucose transport ability of SGLT-2, inhibit the reabsorption of glucose by renal tubules, reduce the concentration of glucose in the blood, and finally achieve the purpose of lowering blood sugar. Compared with common hypoglycemic drugs, SGLT-2 inhibitors can effectively reduce the risk of hypoglycemia and other symptoms. Canagliflozin was originally developed by Mitsubishi Tanabe Pharmaceuticals in Japan and marketed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson. [0003] As we all know, in the field of medicine, there are many hydrates or crystal forms of different drugs, and they have great differences in solubility, melting point, dissoluti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/10
CPCC07B2200/13C07D409/10
Inventor 李宏胡祖耀郑文韬鲍粤华
Owner HANGZHOU HUADONG MEDICINE GRP PHARMA RES INST
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