A process for the preparation of valsartan

Abstract

The application provides a green and efficient preparation method of valsartan. In a non-water soluble secondary alcohol or a non-water soluble tertiary alcohol, intermediate 1 is reacted with sodium azide and zinc halide to obtain valsartan intermediate 2. After the reaction is completed, the organic phase is washed, concentrated, and then non-water soluble organic solvent is added, and saponification is carried out by adding alkali. The lower layer is collected, acid is added, non-water soluble organic solvent is extracted, and the organic phase is collected and crystallized to obtain valsartan with low isomer content and high yield. The amine catalyst is not used in the application, so that nitrosamine genetic toxic impurities are not introduced, the post-treatment reduces the generation of high-nitrogen wastewater, the alcohol can be recovered by distillation, and the energy-saving and emission-reducing goals are achieved.

Description

Technical Field

[0001] This invention relates to a method for preparing valsartan, belonging to the field of pharmaceutical chemicals. Background Technology

[0002] Valsartan (trade name: Diovan) is a hypertension medication developed by Novartis in Switzerland. It is a non-peptide angiotensin II (AT) derivative. II Type I receptor antagonists, chemically named N-valeryl-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine, have the structure shown below. They possess advantages such as sustained and stable antihypertensive effects, few side effects, and the ability to be used in combination with other angiotensin II receptor blockers (ARBs). Since their market launch, they have gained clinical favor and become a first-line drug for treating hypertension, playing a vital role in clinical treatment.

[0003]

[0004] Numerous patents have been reported on the synthesis of valsartan. The step of converting the cyano group to tetrazolium is a crucial step in the synthesis of valsartan. In industrial production, the biphenyl cyano compound is typically used in conjunction with an azide compound via a cycloaddition reaction catalyzed by a Lewis acid to synthesize the biphenyl tetrazolium ring. The reaction route is as follows:

[0005]

[0006] Currently, zinc chloride is a commonly used Lewis acid in industrial production, and aprotic polar solvents such as DMF, NMP, and diethylene glycol dimethyl ether are commonly used solvents. However, these solvents are all water-soluble. When excess inorganic salts such as azide are washed away with post-treatment water, these solvents enter the wastewater, generating a large amount of organic wastewater. Furthermore, the use of solvents such as DMF can lead to dimethylamine production due to thermal decomposition. Dimethylamine reacts with residual nitrite ions in reagents such as sodium azide, generating the toxic impurity NDMA, which can negatively impact human health.

[0007] Patent KR1020100055961 reacts intermediate 1 in n-butanol, but n-butanol readily undergoes transesterification with either intermediate 1 or intermediate 2, and isomers may exist in valsartan. Patent CN112079788A dissolves intermediate 1 in toluene and performs a tetrazolium cyclization reaction with an azide compound, a Lewis acid, and an organic amine such as tetramethylethylenediamine in the presence of two catalysts. Tetramethylethylenediamine is a potential source of genotoxic nitrosamines and can also lead to high-nitrogen wastewater problems. Summary of the Invention

[0008] The purpose of this invention is to provide a green, environmentally friendly, and highly efficient process for processing tetrazolium.

[0009] One aspect of the present invention provides a method for preparing valsartan, comprising the following steps:

[0010] (1) In non-water-soluble secondary or tertiary alcohols, intermediate 1 reacts with sodium azide and zinc halide;

[0011] (2) After the reaction is complete, wash with an aqueous solution, collect and concentrate the organic phase, add a non-water-soluble organic solvent, saponify with alkali, and collect the lower layer;

[0012] (3) Add acid to the lower aqueous layer, extract with a non-water-soluble organic solvent, collect the organic phase and crystallize to obtain valsartan.

[0013] The synthesis route is shown below:

[0014]

[0015] As a preferred option:

[0016] The secondary or tertiary alcohol in step (1) is selected from any one of the secondary or tertiary alcohols of C4 to C10 or any mixture thereof; more preferably, secondary pentanol or methyl isobutyl methanol.

[0017] The volume of the secondary or tertiary alcohol used in step (1) is 0.5 to 10 ml per gram of intermediate 1, preferably 1 to 4 ml.

[0018] The zinc halide mentioned in step (1) is selected from: zinc chloride, zinc bromide, preferably zinc chloride;

[0019] The reaction temperature in step (1) is 80–160 °C;

[0020] The aqueous solution mentioned in step (2) is water, an aqueous solution of inorganic salts, or an aqueous solution of organic salts.

[0021] The non-water-soluble organic solvent mentioned in step (2) or step (3) is toluene, xylene, ethyl acetate, or isopropyl acetate;

[0022] The volume of the non-water-soluble organic solvent used in step (2) is 0.5 to 10 ml per gram of intermediate 1, preferably 2 to 4 ml;

[0023] In step (3), the pH range is adjusted to 1-5 during acidification.

[0024] A second aspect of the present invention provides a method for preparing valsartan intermediate 2, comprising the following steps:

[0025] In non-water-soluble secondary or tertiary alcohols, intermediate 1 reacts with sodium azide and zinc halide to give intermediate 2, as shown in the following synthetic route:

[0026]

[0027] The specific preferred embodiment of the second aspect of the present invention is the same as the conditions of step 1 of the first aspect of the present invention.

[0028] All raw materials used in this invention are commercially available.

[0029] The beneficial technical effects of this invention are as follows: The preparation method of this invention uses non-water-soluble secondary or tertiary alcohols as reaction solvents, and utilizes the steric hindrance of these alcohols to prevent the transesterification reaction of intermediate 1 or intermediate 2, resulting in valsartan with low isomer content, high purity, and high yield. This invention does not use amine catalysts, thus avoiding the introduction of nitrosamine genotoxic impurities. Post-treatment can reduce the generation of high-nitrogen wastewater, and the secondary or tertiary alcohols can be recovered by distillation, making it more environmentally friendly. Therefore, the method involved in this invention has significant practical value. Detailed Implementation

[0030] Example 1

[0031] In a three-necked flask, 41.4 g of intermediate 1 and 165 mL of sec-amyl alcohol were added sequentially, followed by 16.6 g of sodium azide and 14.6 g of zinc chloride. The mixture was heated to 110–120 °C and maintained at this temperature for 36 hours. After the reaction was complete, water was added and stirred. The mixture was then transferred and separated, the lower aqueous layer was removed, and the upper organic phase was collected. The reaction was then washed twice with water.

[0032] The organic phase was concentrated by adding 165 mL of toluene to the concentrate and stirring until dissolved. Then, 50 mL of 30% sodium hydroxide aqueous solution and 100 mL of water were added to the dissolved solution, and the mixture was stirred for 24 hours. After the reaction was complete, the mixture was transferred and separated, and the upper toluene layer was removed.

[0033] The lower layer was slowly acidified with 6N hydrochloric acid until the pH reached 1-3. Ethyl acetate was then added to the acidified solution and stirred until dissolved. The mixture was transferred and separated. The aqueous phase was extracted once with ethyl acetate. The two organic phases were combined and washed with water. The washed organic phase was dehydrated, concentrated, crystallized, filtered, and dried to obtain 35.5 g of crude valsartan. The two-step yield was 80.2%, and the HPLC purity was 99.5%. The content of the valsartan isomer (D-valsartan) was 0.49%.

[0034] Example 2

[0035] In a three-necked flask, 41.4 g of intermediate 1 and 165 mL of methyl isobutyl alcohol were added sequentially, followed by 16.6 g of sodium azide and 14.6 g of zinc chloride. The mixture was heated to 125–130 °C and maintained at this temperature for 24 hours. After the reaction was complete, water was added and stirred. The mixture was then transferred and separated, the lower aqueous layer was removed, and the upper organic phase was collected. The reaction was then washed twice with water.

[0036] The organic phase was concentrated by adding 165 mL of toluene to the concentrate and stirring until dissolved. Then, 50 mL of 30% sodium hydroxide aqueous solution and 100 mL of water were added to the dissolved solution, and the mixture was stirred for 24 hours. After the reaction was complete, the mixture was transferred and separated, and the upper toluene layer was removed.

[0037] The lower layer was slowly acidified with 6N hydrochloric acid until the pH reached 1-3. Ethyl acetate was then added to the acidified solution and stirred until dissolved. The mixture was transferred and separated. The aqueous phase was extracted once with ethyl acetate. The two organic phases were combined and washed with water. The washed organic phase was dehydrated, concentrated, crystallized, filtered, and dried to obtain 36.1 g of crude valsartan. The two-step yield was 81.4%, the HPLC purity was 99.3%, and the content of the valsartan isomer (D-valsartan) was 0.56%.

[0038] Comparative Example 1:

[0039] In a three-necked flask, 41.4 g of intermediate 1 and 195 mL of n-butanol were added sequentially, followed by 38.0 g of sodium azide and 39.8 g of zinc chloride. The mixture was heated to 90–95 °C and reacted for 42 hours. The reaction mixture was cooled to room temperature, 2000 mL of water was added, and the mixture was stirred. The alcohol solvent was removed by vacuum distillation. The resulting solid product was filtered, washed with 200 mL of water, and dried.

[0040] Add 100 mL of 10N-NaOH and 300 mL of dichloromethane to the solid obtained above, stir for 24 hours, and then adjust the pH to below 3 using hydrochloric acid aqueous solution. Crystallize by adding 4500 mL of cyclohexane dropwise to the separated organic layer, age for 3 hours, and then filter. Wash the obtained crystals with a mixed solution of 200 mL of dichloromethane and cyclohexane, and dry to obtain 33.7 g of crude valsartan, with a two-step yield of 76.2% and a valsartan isomer (D-valsartan) content of 2.61%.

Claims

1. A method for preparing a key intermediate 2 of valsartan, comprising the following steps: In sec-pentanol or methyl isobutyl methanol, intermediate 1 reacts with sodium azide and zinc halide to give intermediate 2. The synthetic route is shown below: 。 2. A method for preparing valsartan, comprising the following steps: (1) In sec-pentanol or methyl isobutyl methanol, intermediate 1 reacts with sodium azide and zinc halide; (2) After the reaction is complete, wash with water, collect and concentrate the organic phase, add non-water-soluble organic solvent, add NaOH / H2O for saponification, and collect the lower layer; (3) Add HCl to the lower aqueous layer, extract with ethyl acetate, collect the organic phase and crystallize to obtain valsartan. The synthetic route is shown below: 。 3. According to the preparation method of claim 1 or 2, the volume of sec-pentanol or methyl isobutyl methanol used is 0.5~10 ml per gram of intermediate 1.

4. According to the preparation method of claim 3, the volume of sec-amyl alcohol or methyl isobutyl methanol used is 1-4 ml per gram of intermediate 1.

5. In the preparation method according to claim 1 or 2, the zinc halide is selected from: zinc chloride, zinc bromide.

6. The preparation method according to claim 1 or 2, wherein the reaction temperature is 80~160℃.

7. According to the preparation method of claim 2, the non-water-soluble organic solvent is toluene, xylene, ethyl acetate, or isopropyl acetate; the volume of the non-water-soluble organic solvent used in step (2) is 0.5~10 ml relative to each gram of intermediate 1.

8. According to the preparation method of claim 7, the volume of the non-water-soluble organic solvent used in step (2) is 2-4 ml relative to each gram of intermediate 1.

9. According to the preparation method of claim 2, the pH range is adjusted to 1~5 during acidification in step (3).

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