Refining method of candesartan

Abstract

The present invention provides a candesartan refining method, which comprises that a candesartan crude product is refined in a tetrahydrofuran or acetonitrile solvent by using an acid-base crystallization method, the yield is high, the cost is low, the refining effect is good, and the candesartan refining method is very suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a method for refining candesartan, an intermediate of candesartan cilexetil. Background Art

[0002] Candesartan cilexetil is a selective angiotensin II receptor (ATl) antagonist that antagonizes the vasoconstriction of angiotensin II by binding to the ATl receptor of vascular smooth muscle, thereby reducing peripheral vascular resistance. Candesartan is an important intermediate in the synthesis process of candesartan cilexetil, and its structural formula is shown in Formula I:

[0003]

[0004] At present, the synthesis of candesartan mainly uses cyclocomplex (VI) and sodium azide as raw materials, forms a tetrazole structure through a [3+2] cycloaddition reaction, and then uses sodium hydroxide solution to saponify and crystallize to obtain it.

[0005]

[0006] The crude candesartan synthesized by this route contains a large amount of candenone (II), candesartan isomer (III) and other impurities (such as impurities IV, V) and the specific structural formula is as follows:

[0007]

[0008] The known system for refining crude candesartan mainly includes dimethyl sulfoxide (DMF). This system has the problems of high usage of organic solvents, low refining yield, difficulty in filtering the feed liquid, and difficulty in drying. These problems have greatly caused problems such as high production costs, material waste and environmental pollution. Summary of the invention

[0009] The present invention provides a method for refining candesartan, comprising the following steps:

[0010] (a) adding the crude candesartan to an aqueous solution of an organic solvent and an inorganic base to completely dissolve it, wherein the organic solvent is selected from acetonitrile or tetrahydrofuran;

[0011] (b) cooling, adding acid to adjust the pH value of the system to acidic to precipitate candesartan;

[0012] (c) filtering and drying to obtain the refined candesartan.

[0013] As a preferred embodiment, the volume of the organic solvent used in step (a) is 0.5-2 mL / g, preferably 1-1.5 mL / g, relative to the weight of the crude candesartan.

[0014] The inorganic base is preferably sodium hydroxide, potassium hydroxide or a mixture thereof; the molar ratio of the inorganic base to the crude candesartan is 4-9:1; and the concentration range of the alkali solution is preferably 1 mol / L-3 mol / L.

[0015] The acid is acetic acid or hydrochloric acid, and acetic acid is preferably used.

[0016] In step b), the temperature is preferably finally lowered to 0-5°C, and the final pH value of the system is 5.0-5.5 after the acid is added.

[0017] Step b) is further preferably a step-by-step crystallization, and the specific method is: first cooling to 10-15°C, adding acid to adjust the pH value to 6.0-6.5 to start precipitation; continuing to cool to 0-5°C, adding acid to adjust the pH value to 5.0-5.5 to complete crystallization.

[0018] The crude candesartan of the present invention contains one or more of the following compounds:

[0019]

[0020] The refined candesartan obtained by the present invention can be further converted into candesartan cilexetil according to the method of the prior art.

[0021] The candesartan purification method provided by the present invention has the following advantages:

[0022] a. Good refining effect, can effectively reduce impurities such as candesartan ketone (II) and candesartan ester (IV);

[0023] b. The product is easy to filter and dry, simple to operate, and very suitable for industrial production;

[0024] c. Low solvent usage, high yield, effectively reducing production costs. DETAILED DESCRIPTION

[0025] Example 1

[0026] Take 20g of crude candesartan, add 200mL of 2mol / L sodium hydroxide and 20mL of tetrahydrofuran, stir and dissolve. After cooling to 15°C, add glacial acetic acid dropwise, adjust the pH to 6.5, stir and crystallize, continue to cool to 5°C, add glacial acetic acid dropwise, adjust the pH to 5.5, stir and crystallize for 1 hour, filter and dry to obtain 17.6g of solid white product, and the purity of candesartan (HPLC) is 97.6%.

[0027] Example 2

[0028] Take 20g of crude candesartan, add 160mL of 2mol / L sodium hydroxide and 40mL of tetrahydrofuran, stir and dissolve. After cooling to 10°C, add glacial acetic acid dropwise, adjust the pH to 6.0, stir and crystallize, continue to cool to 0°C, add glacial acetic acid dropwise, adjust the pH to 5.0, stir and crystallize for 1 hour, filter and dry to obtain 16.7g of solid white product, and the purity of candesartan (HPLC) is 98.2%.

[0029] Example 3

[0030] Take 20g of crude candesartan, add 100mL of 2mol / L potassium hydroxide and 30mL of tetrahydrofuran, stir and dissolve. After cooling to 13°C, add glacial acetic acid dropwise, adjust the pH to 6.2, stir and crystallize, continue to cool to 3°C, add glacial acetic acid dropwise, adjust the pH to 5.3, stir and crystallize for 2 hours, filter and dry to obtain 16.0g of solid white product, and the purity of candesartan (HPLC) is 97.3%.

[0031] Example 4

[0032] Take 20g of crude candesartan, add 100mL of 2mol / L sodium hydroxide and 10mL of tetrahydrofuran, stir and dissolve. After cooling to 15°C, add glacial acetic acid dropwise, adjust the pH to 6.4, stir and crystallize, continue to cool to 3°C, add glacial acetic acid dropwise, adjust the pH to 5.2, stir and crystallize for 1 hour, filter and dry to obtain 17.2g of solid white product, and the purity of candesartan (HPLC) is 97.7%.

[0033] Example 5

[0034] Take 20g of crude candesartan, add 160mL of 2mol / L sodium hydroxide and 10mL of tetrahydrofuran, stir and dissolve. After cooling to 15°C, add glacial acetic acid dropwise, adjust the pH to 6.2, stir and crystallize, continue to cool to 0°C, add glacial acetic acid dropwise, adjust the pH to 5.0, stir and crystallize for 1 hour, filter and dry to obtain 16.9g of solid white product, and the purity of candesartan (HPLC) is 97.1%.

[0035] Example 6

[0036] Take 20g of crude candesartan, add 160mL of 2mol / L sodium hydroxide and 20mL of tetrahydrofuran, stir to dissolve, cool to 15°C, add glacial acetic acid dropwise, adjust pH to 6.5, stir to crystallize, continue to cool to 2°C, add glacial acetic acid dropwise, adjust pH to 5.2, stir to crystallize for 1 hour, filter and dry to obtain 17.1g of solid white product, candesartan purity (HPLC) 98.5%.

[0037] Example 7

[0038] Take 20g of crude candesartan, add 200mL of 1mol / L sodium hydroxide and 40mL of tetrahydrofuran, stir to dissolve, cool to 10°C, add glacial acetic acid dropwise, adjust pH to 6.5, stir to crystallize, continue to cool to 0°C, add glacial acetic acid dropwise, adjust pH to 5.0, stir to crystallize for 1 hour, filter and dry to obtain 17.5g of solid white product, candesartan purity (HPLC) 98.2%.

[0039] Example 8

[0040] Take 20g of crude candesartan, add 100mL of 3mol / L sodium hydroxide and 20mL of tetrahydrofuran, stir to dissolve, cool to 15°C, add glacial acetic acid dropwise, adjust pH to 6.5, stir to crystallize, continue to cool to 0°C, add glacial acetic acid dropwise, adjust pH to 5.0, stir to crystallize for 1 hour, filter and dry to obtain 18.0g of solid white product, candesartan purity (HPLC) 97.5%.

[0041] Example 9

[0042] Take 20g of crude candesartan, add 160mL of 2mol / L sodium hydroxide and 30mL of tetrahydrofuran, stir to dissolve, cool to 10°C, add 2mol / L hydrochloric acid dropwise, adjust pH to 6.2, stir to crystallize, continue to cool to 0°C, add 2mol / L hydrochloric acid dropwise, adjust pH to 5.3, stir to crystallize for 1 hour, filter and dry to obtain 17.7g of solid white product, candesartan purity (HPLC) 97.9%.

[0043] Example 10

[0044] Take 20g of crude candesartan, add 160mL of 2mol / L sodium hydroxide and 20mL of acetonitrile, stir to dissolve, cool to 12°C, add glacial acetic acid dropwise, adjust pH to 6.0, stir to crystallize, continue to cool to 0°C, add glacial acetic acid dropwise, adjust pH to 5.0, stir to crystallize for 1 hour, filter and dry to obtain 18.5g of solid white product, candesartan purity (HPLC) 98.0%.

[0045] Embodiment 11

[0046] Take 20g of crude candesartan, add 200mL of 2mol / L sodium hydroxide and 30mL of acetonitrile. Stir to dissolve, cool to 15°C, add glacial acetic acid dropwise, adjust pH to 6.2, stir to crystallize, continue to cool to 2°C, add glacial acetic acid dropwise, adjust pH to 5.0, stir to crystallize for 1 hour, filter and dry to obtain 17.8g of solid white product, candesartan purity (HPLC) 98.3%.

[0047] Table 1 is a summary of the HPLC test results of the crude candesartan and the refined product in Experimental Examples 1-11:

[0048] Table 1

[0049]

[0050]

Claims

1. A method for refining candesartan, comprising the following steps: (a) adding the crude candesartan to an aqueous solution of an organic solvent and an inorganic base to completely dissolve it, wherein the organic solvent is selected from acetonitrile or tetrahydrofuran; (b) cooling, adding acid to adjust the pH value of the system to acidic to precipitate candesartan; (c) filtering and drying to obtain the refined candesartan.

2. The method according to claim 1, characterized in that: The volume of the organic solvent used in step (a) is 0.5-2 mL / g, preferably 1-1.5 mL / g, relative to the weight of the crude candesartan product.

3. The method according to claim 1, characterized in that: The inorganic base is selected from: sodium hydroxide, potassium hydroxide or a mixture thereof.

4. The method according to claim 1, characterized in that: The molar ratio of the amount of the inorganic base to the crude candesartan is 4-9:

1.

5. The method according to claim 4, characterized in that: The concentration range of the alkali solution is 1 mol / L-3 mol / L.

6. The method of claim 1, wherein the acid is acetic acid or hydrochloric acid, preferably acetic acid.

7. The method according to claim 1, wherein the temperature in step b) is finally lowered to 0-5°C, and the final pH value of the system is 5.0-5.5 after adding acid.

8. The method according to claim 6, wherein the specific method of step b) is: First cool down to 10-15°C, add acid to adjust pH to 6.0-6.5 to start precipitation; The temperature was continued to drop to 0-5°C, and acid was added to adjust the pH value to 5.0-5.5 to complete crystallization.

9. The method according to claim 1, wherein the crude candesartan contains one or more of the following compounds:

10. A method for preparing candesartan cilexetil, comprising further converting the candesartan prepared according to the method of claims 1 to 9 into candesartan cilexetil.

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