METHOD FOR PREPARING TRITYL CANDESARTAN

Abstract

The present invention uses a candesartan cyclic compound as a starting material and performs thereon a three-step reaction of forming tetrazole, hydrolysis and adding a protecting group to directly obtain trityl candesartan without separating an intermediate product via crystallization. The operating process is simple and thus is more applicable to industrial production.

Claims

1. A method for preparing trityl candesartan (V), comprising the following steps: (a) reacting candesartan cyclic compound (II) with trialkyl tin azide in an organic solvent to obtain an ester of candesartan (III); (b) extracting by adding an aqueous solution of alkali metal hydroxide directly into the reaction mixture of step (a) without separating the ester of candesartan (III) obtained in step (a), and removing the organic layer to obtain an alkaline aqueous layer; (c) heating the alkaline aqueous layer separated in step (b) to completely hydrolyze the ester of candesartan (III), and then adding an acid to adjust pH value to precipitate candesartan (IV); (d) redissolving the candesartan (IV) by adding an organic solvent and an organic base directly into the mixture of step (c) without separating the candesartan (IV), and separating the organic layer; and (e) reacting the organic layer obtained in step (d) directly with triphenyl chloromethane to obtain trityl candesartan (V); and the synthetic route is shown as follows: ##STR00004## wherein, R is methyl or ethyl.

2. The method according to claim 1, wherein the organic solvent in step (a) is selected from toluene, xylene, N,N-dimethylformamide, or N,N-dimethylacetamide.

3. The method according to claim 1, wherein the trialkyl tin azide in step (a) is tributyl tin azide.

4. The method according to claim 1, wherein the alkali metal hydroxide in step (b) is selected from potassium hydroxide or sodium hydroxide.

5. The method according to claim 1, wherein the acid in step (c) is selected from hydrochloric acid, acetic acid or a mixture of them.

6. The method according to claim 5, wherein the acid in step (c) is acetic acid.

7. The method according to claim 1, wherein pH value in step (c) is in a range of 4-7.

8. The method according to claim 7, wherein the pH value in step (c) is in a range of 5-6.

9. The method according to claim 1, wherein the organic solvent in step (d) is selected from toluene, xylene, or dichloromethane.

10. The method according to claim 9, wherein the organic solvent in step (d) is dichloromethane.

11. The method according to claim 1, wherein the organic base in step (d) is triethylamine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention is further described in detail by way of examples for better understanding of the objects, technical solution and advantages of the present invention. It is obvious that the examples described are only a part of the examples of the present invention, not all of the examples. Based on the examples of the present invention, all other examples obtained by those skilled in the art without inventive efforts are within the protection scope of the present invention.

[0030] The present invention will be further described in detail below in combination with the examples.

Example 1

[0031] 250 g of tributyl tin azide was added into 600 ml of xylene. 100 g of candesartan cyclic compound (in formula II, R is ethyl) was added, heated to 140-150 C., and refluxed to react for 20 h. After the end of the reaction, the reaction mixture was cooled to 40-50 C. 600 ml of sodium hydroxide solution (48 g of sodium hydroxide dissolved in 600 ml of water) was added, and stirred under 20-35 C.

[0032] The organic layer was removed.

[0033] The alkaline aqueous layer was heated to 70-80 C. to completely hydrolyze candesartan ethyl ester. The temperature of the mixture was controlled at 25-35 C. 400 ml of dichloromethane was added. Glacial acetic acid was added dropwise to adjust pH of the mixture to 5-6 to precipitate candesartan.

[0034] Triethylamine was added dropwise into the mixture until the candesartan solid was dissolved completely. The dichloromethane layer was separated. The aqueous layer was extracted by adding 200 ml of dichloromethane once again. The organic layers were combined. 68 g of triphenyl chloromethane was added into the organic layer. The temperature of the mixture was controlled at 25-35 C. to react until the content of candesartan was reduced to less than 1.0% monitored by HPLC. After the end of the reaction, 100 ml of water was added for washing. The aqueous layer was removed. The organic layer was dried under reduced pressure. 600 ml of anhydrous ethanol was added to crystallize. The resulting crystals were collected by filtration, and dried to provide 125.5 g of trityl candesartan, yield 78.2%, purity 97.5%.

Example 2-7

[0035] Trityl candesartan was prepared from candesartan cyclic compound in the similar manner as Example 1. The results are shown in the following table.

TABLE-US-00001 Group R in Organic Trialkyl tin Alkali metal Range Example formula solvent in azide in hydroxide in Acid in of pH in Organic solvent Organic base No. II step (a) step (a) step (b) step (c) step (c) in step (d) in step (d) Yield 2 methyl toluene tributyl tin sodium hydro- 4-5 toluene triethylamine 77.3% azide hydroxide chloric acid 3 ethyl xylene tributyl tin potassium glacial 5-6 xylene triethylamine 77.6% azide hydroxide acetic acid 4 methyl DMF tributyl tin sodium Hydro- 6-7 dichloromethane triethylamine 78.1% azide hydroxide chloric acid 5 ethyl DMA tributyl tin potassium glacial 4-5 toluene triethylamine 77.1% azide hydroxide acetic acid 6 methyl toluene tributyl tin sodium Hydro- 5-6 xylene triethylamine 77.9% azide hydroxide chloric acid 7 ethyl xylene tributyl tin potassium glacial 6-7 dichloromethane triethylamine 77.8% azide hydroxide acetic acid

Comparative Example 1

[0036] Trityl candesartan was prepared from candesartan cyclic compound according to the method described in Reference Example 7-9 of CN98101894.7. Since the product of the first step of the reaction in this document (corresponding to Reference Example 7) was not dried, thus the yield thereof was not calculated. The yield of the second step of the reaction was 80%, and the yield of the third step of the reaction was 89%. Therefore, the final yield of the prepared trityl candesartan from candesartan cyclic compound according to the method of this prior art was up to 73%. Besides, for example, the conversion rate of the first step of the reaction and the like were not taken into account for the above final yield. Therefore, the final yield of the method described in this document should be much less than 73%.

[0037] In contrast, the one-pot method of the present invention achieves a yield of 77% or above, which is significantly higher than that of the methods of the prior art. Meanwhile, complex processes such as crystallization, separation, and purification etc. are not required, and the waste discharge is reduced.

Comparative Example 2

[0038] 250 g of tributyl tin azide was added into 600 ml of xylene. 100 g of candesartan cyclic compound (in formula II, R is ethyl) was added, heated to 140-150 C., and refluxed to react for 20 h. After the end of the reaction, the reaction system was cooled to 40-50 C. 600 ml of sodium hydroxide solution (48 g of sodium hydroxide dissolved in 600 ml of water) was added, and stirred under 20-35 C.

[0039] The organic layer was removed.

[0040] The alkaline aqueous layer was heated to 70-80 C. to completely hydrolyze candesartan ethyl ester. The temperature of the mixture was controlled at 25-35 C. 400 ml of dichloromethane was added. Glacial acetic acid was added dropwise to adjust pH of the mixture to 5-6 to precipitate candesartan. The crystal was separated, washed with water and then with acetone, and dried to provide 77.6 g of candesartan (yield: 75%).

[0041] The candesartan obtained above was suspended in dichloromethane. Triethylamine was added dropwise into the mixture until the candesartan solid was dissolved completely. The dichloromethane layer was separated. The aqueous layer was extracted by adding 200 ml of dichloromethane once again. The organic layers were combined. 68 g of triphenyl chloromethane was added into the organic layer. The temperature of the mixture was controlled at 25-35 C. to react until the content of candesartan was reduced to less than 1.0% monitored by HPLC. After the end of the reaction, 100 ml of water was added for washing. The aqueous layer was removed. The organic layer was dried under reduced pressure. 600 ml of anhydrous ethanol was added to crystallize. The resulting crystals were collected by filtration, and dried to provide 120.3 g of trityl candesartan, yield 88.2%.

[0042] Therefore, the final yield of this comparative example is 66.15%. In contrast, using the one-pot method of the present invention achieves a yield of 77% or above, which is significantly higher than that of the method of this comparative example. Meanwhile, complex processes such as crystallization, separation, and purification, etc. are not required, and the waste discharge is reduced.

[0043] The examples described above are only preferred examples of the present invention, and are not intended to limit the invention. Any amendment, equivalent replacement, and improvement and the like made within the spirit and principle of the present invention should be included in the protection scope of the present invention.