A process for the preparation of losartan

Abstract

The present application provides a preparation method of losartan, which comprises the following steps: reacting a nitrile intermediate shown as below with an azide reagent in a solvent, then adding an aqueous solution of an inorganic base selected from carbonates or bicarbonates to wash and separate an intermediate layer; and further separating the intermediate layer to obtain losartan. The azide ion after the reaction can be basically completely removed by using a conventional inorganic base solution, the removal effect is good, the preparation process is simple, the operation condition is mild and easy to control, and the method is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to a method for preparing losartan, belonging to the field of pharmaceutical and chemical engineering. Background Technology

[0002] Losartan is a drug developed by DuPont-Merck for the treatment of hypertension. It is a non-peptide angiotensin II (AT) derivative. II Type I receptor antagonist, chemically named 2-butyl-4-chloro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-methanol, has the following structure:

[0003]

[0004] Existing technology prepares losartan by reacting a nitrile-containing intermediate with an azide reagent in a toluene-based system. After the reaction, some azide reagent remains in the system and needs to be quenched to prevent the production of azidoic acid. The conventional quenching agent is sodium nitrite, but the introduction of sodium nitrite will generate nitrosamine impurities. The structural formula of the nitrile-containing intermediate is shown below:

[0005]

[0006] Patent CN 109748905A discloses an improved method for quenching azides. After the reaction, the method uses an alkaline aqueous solution to extract and separate the aqueous layer containing losartan, and then quenches it with hydrogen peroxide. The reaction in this quenching system is relatively violent, generating a large number of bubbles. The quenching process is difficult to control, and there may be safety hazards such as material explosion during scale-up production. In addition, hydrogen peroxide may also oxidize the hydroxyl functional groups in the losartan structure in the quenching system, producing oxidized impurities of losartan.

[0007] Patent CN 110467604A discloses a method for preparing losartan by reacting a cyano-containing intermediate with an azide reagent in toluene in the presence of a catalyst. After the reaction, azide ions are removed through the following process: water is added to separate the reaction system into three layers; the middle layer is separated and diluted with n-butanol; triphenylphosphine is added to the resulting diluted solution to remove residual azide ions. However, during the water extraction process, some losartan enters the aqueous layer, resulting in significant losartan loss.

[0008] It is evident that existing losartan production processes all require a quenching step of azide in the feed solution containing losartan products. However, under mild production conditions, the risk of impurity contamination cannot be completely eliminated to obtain high-yield losartan. Therefore, there is an urgent need to develop a high-yield losartan preparation method suitable for industrial production that does not introduce toxic impurities. Summary of the Invention

[0009] The purpose of this invention is to overcome the above-mentioned defects in the existing losartan production process and provide a convenient, safe, effective, and industrially feasible method for removing residual azide reagent from losartan reaction solution, while avoiding the generation of nitrosamine impurities in the losartan product.

[0010] The technical solution adopted in this invention includes the following steps:

[0011] a. Reaction of a nitrile-containing intermediate with an azide reagent in a water-insoluble organic solvent.

[0012] b. After the reaction is complete, add an aqueous solution of inorganic base of a certain concentration, heat and stir to wash, and separate the intermediate layer after washing. The inorganic base is selected from carbonates or bicarbonates.

[0013] c. Adding water and acid to the intermediate layer and allowing it to crystallize yields losartan.

[0014] The nitrile-containing intermediate has the following structural formula:

[0015]

[0016] The innovation of this invention lies in the addition of a certain concentration of inorganic alkaline aqueous solution after the reaction of the nitrile intermediate with the azide reagent is completed, so that the reaction system is divided into three layers: the upper layer is a water-insoluble organic solvent layer, the middle layer is a material layer, and the lower layer is a water layer. Heating and stirring are carried out to dissolve the azide ions in the water layer. By removing the water layer, the azide ions are basically completely removed, and the middle material layer is obtained without material loss.

[0017] In the method, the inorganic base in step b) is selected from: sodium bicarbonate, sodium carbonate, potassium bicarbonate, or potassium carbonate;

[0018] In the method, the inorganic alkali aqueous solution in step b) has a mass concentration of 15-30%, preferably 16-22%.

[0019] In the method, the volume of the inorganic alkali aqueous solution used in step b) is 2 to 5 times the volume of the water-insoluble organic solvent used;

[0020] In the method, the stirring and washing temperature in step b) is 50-90°C, preferably 70-80°C;

[0021] In the method, the stirring and washing time in step b) is 0.5 to 4 hours, preferably 0.5 to 2 hours;

[0022] In the method, step b) involves washing 1 to 5 times, preferably 2 to 3 times;

[0023] Step a) is preferably carried out in the presence of a catalyst, which is a Lewis acid, a weak base-strong acid salt, or a mixture of a weak base and a strong acid. The catalyst is selected from zinc chloride, tributyltin chloride, triethylamine hydrochloride, triethylamine sulfate, a mixture of triethylamine and hydrochloric acid, or a mixture of triethylamine and sulfuric acid. In some preferred embodiments, the catalyst is triethylamine hydrochloride.

[0024] In some preferred embodiments, the azide reagent may be sodium azide.

[0025] The water-insoluble organic solvent mentioned in step a) is toluene or xylene.

[0026] The acid mentioned in step c) is hydrochloric acid or sulfuric acid, preferably the pH of the system is adjusted to 4-5 by adding acid.

[0027] The losartan preparation method provided by this invention has the following advantages:

[0028] (1) There is no need to use sodium nitrite to quench azide ions in the reaction products, thus eliminating the formation of genotoxic impurities such as nitrosamines.

[0029] (2) Conventional inorganic alkaline solutions can basically completely remove azide ions after the reaction without the need for other quenching reagents. The removal effect is good, the product is not lost, and no new impurities are introduced.

[0030] (3) The obtained losartan product has good purity and high yield.

[0031] (4) The preparation process is simple, the operating conditions are mild and easy to control, it is green and environmentally friendly, economical and efficient, safe and suitable for large-scale industrial production. Detailed Implementation

[0032] The present invention will be further described below with reference to embodiments, but these examples do not constitute any limitation on the present invention.

[0033] Example 1:

[0034] In a three-necked flask, 30 g of a nitrile intermediate, 9.8 g of sodium azide, 12 g of triethylamine hydrochloride, and 120 ml of toluene were added. The reaction was carried out at 100–103 °C. After the reaction was completed, 300 ml of 20% sodium bicarbonate aqueous solution was added, and the temperature was maintained at 75 °C. The mixture was stirred and washed for 1 hour. After washing, the lower aqueous layer was separated. 300 ml of 20% sodium bicarbonate aqueous solution was added again, and the mixture was stirred and washed at 75 °C for 1 hour. After washing, the intermediate layer was separated, and the residual azide ions were approximately 80 ppm. 150 ml of drinking water was added to the separated intermediate layer, and the mixture was stirred at room temperature. Dilute hydrochloric acid was slowly added dropwise to adjust the pH to 4–5, allowing crystals to precipitate. The crystals were filtered and dried to obtain 29.9 g of losartan, with a yield of 89.6% and a purity of 98.8%. Azides were not detected (detection limit: 1 ppm); NDMA was not detected (detection limit: 0.03 ppm); and NDEA was not detected (detection limit: 0.02 ppm).

[0035] Example 2:

[0036] In a three-necked flask, 30 g of a nitrile intermediate, 9.8 g of sodium azide, 12 g of triethylamine hydrochloride, and 120 ml of toluene were added. The reaction was carried out at 100–103 °C. After the reaction was completed, 300 ml of 18% sodium carbonate aqueous solution was added, and the temperature was maintained at 75 °C. The mixture was stirred and washed for 1 hour. After washing, the lower aqueous layer was separated, and the mixture was washed again with 300 ml of 18% sodium carbonate aqueous solution for a total of three washes. After washing, the intermediate layer was separated, and the residual azide ions were approximately 50 ppm. 150 ml of drinking water was added to the separated intermediate layer, and the mixture was stirred at room temperature. Dilute hydrochloric acid was slowly added dropwise to adjust the pH to 4–5, allowing crystals to precipitate. The crystals were then filtered and dried to obtain 29.6 g of losartan, with a yield of 88.7% and a purity of 98.8%. Azides were not detected (detection limit: 1 ppm); NDMA was not detected (detection limit: 0.03 ppm); and NDEA was not detected (detection limit: 0.02 ppm).

[0037] Example 3:

[0038] In a three-necked flask, 30 g of a nitrile intermediate, 9.8 g of sodium azide, 12 g of triethylamine hydrochloride, and 120 ml of toluene were added. The reaction was carried out at 100–103 °C. After the reaction was completed, 500 ml of 20% potassium carbonate aqueous solution was added, and the temperature was maintained at 75 °C. The mixture was stirred and washed for 1.5 hours. After washing, the lower aqueous layer was separated, and the mixture was washed again with 500 ml of 20% potassium carbonate aqueous solution for a total of three washes. After washing, the intermediate layer was separated, and the residual azide ions were approximately 20 ppm. 120 ml of drinking water was added to the separated intermediate layer, and the mixture was stirred at room temperature. Dilute hydrochloric acid was slowly added dropwise to adjust the pH to 4–5, allowing crystals to precipitate. The crystals were then filtered and dried to obtain 29.5 g of losartan, with a yield of 88.4% and a purity of 98.8%. Azide (detection limit: 1 ppm): not detected; NDMA: not detected (detection limit: 0.03 ppm); NDEA: not detected (detection limit: 0.02 ppm).

[0039] Comparative Example 1:

[0040] In a three-necked flask, 30g of a nitrile intermediate, 9.8g of azide reagent, 12g of triethylamine hydrochloride, and 120ml of toluene were added. The reaction was carried out at 100–103℃. After the reaction was completed, three times the volume of water was added, and the temperature was maintained at 75℃. After stirring and washing for 1 hour, the system separated into three layers: an upper toluene layer, an oily middle layer (the material layer), and a lower water layer. The lower water layer and the upper toluene layer were removed. The water layer contained the material layer, resulting in significant material loss. Analysis of the middle layer revealed approximately 6000ppm of azide residue. Washing with water was ineffective in removing azide, and significant material loss occurred during the separation process, making it unsuitable for industrial production.

[0041] Comparative Example 2:

[0042] In a three-necked flask, 30 g of a nitrile intermediate, 9.8 g of azide reagent, 12 g of triethylamine hydrochloride, and 120 ml of toluene were added. The reaction was carried out at 100–103 °C. After the reaction was completed, three times the volume of 10% sodium hydroxide aqueous solution was added, and the temperature was maintained at 50–60 °C. The mixture was stirred and washed for 1 hour. After washing, the intermediate layer was separated. The azide in the intermediate layer was analyzed, and 3000 ppm of azide ions were found to remain. HPLC analysis of the aqueous layer showed 4.2% losartan residue. The intermediate layer was added to 120 ml of water and 20 ml of 15% sodium nitrite aqueous solution. The pH was adjusted to 4–5 with hydrochloric acid, crystallization was observed, and the crystals were filtered and dried to obtain 27.0 g of losartan, with a yield of 80.9% and a purity of 98.6%. The azide content was 23 ppm; NDMA was 0.2 ppm; and NDEA was 27.9 ppm.

Claims

1. A method for preparing losartan, comprising the following steps: a) React the nitrile-containing intermediate with an azide reagent in a water-insoluble organic solvent; b) After the reaction is complete, add an aqueous solution of inorganic base of a certain concentration, heat and stir to wash, and separate the intermediate layer after washing. The inorganic base is selected from carbonates or bicarbonates. c) Water and acid are added to the intermediate layer to induce crystallization and obtain losartan; the inorganic base mentioned in step b) is selected from sodium bicarbonate, sodium carbonate, potassium bicarbonate, or potassium carbonate, and the aqueous solution of the inorganic base has a mass concentration of 16-22%. The nitrile-containing intermediate has the following structural formula:

2. The preparation method according to claim 1, characterized in that... The volume of the inorganic alkali aqueous solution used in step b) is 2 to 5 times the volume of the water-insoluble organic solvent.

3. The preparation method according to claim 1, characterized in that... The stirring and washing temperature in step b) is 50–90°C.

4. The preparation method according to claim 1, characterized in that... The stirring and washing time in step b) is 0.5 to 4 hours.

5. The preparation method according to claim 1, characterized in that... The number of washes described in step b) is 1 to 5.

6. The preparation method according to claim 1, characterized in that... The azide reagent mentioned in step a) is sodium azide, potassium azide, or lithium azide.

7. The preparation method according to claim 1, characterized in that... Step a) is carried out in the presence of a catalyst, which is a Lewis acid, a weak base-strong acid salt, or a mixture of a weak base and a strong acid.

8. The preparation method according to claim 7, wherein the catalyst is zinc chloride, tributyltin chloride, triethylamine hydrochloride, triethylamine sulfate, a mixture of triethylamine and hydrochloric acid, or a mixture of triethylamine and sulfuric acid.

9. The preparation method according to claim 1, characterized in that... The water-insoluble organic solvent mentioned in step a) is toluene or xylene.

10. The preparation method according to claim 1, characterized in that... The acid mentioned in step c) is hydrochloric acid or sulfuric acid.

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