A kind of synthetic method of valsartan intermediate

Abstract

The invention belongs to the field of pharmaceutical synthesis technology, and in particular to a method for synthesizing a valsartan intermediate. This method uses 4'-hydroxymethyl-2-cyanobiphenyl as a raw material and reacts with L-valine methyl ester hydrochloride under the action of a catalyst. Finally, the target product is obtained by concentration, salification, and drying. The target product obtained by this method has a higher yield and purity, and can effectively avoid the generation of dimer impurities in the prior art, has simple post-processing, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing a valsartan intermediate. Background Art

[0002] Valsartan, chemically known as (S)-N-pentanoyl-N-[4-(2-tetrazolyl)phenyl]benzylvaline, is an angiotensin II AT1 receptor antagonist. It represents a new class of antihypertensive drugs, following calcium channel blockers and angiotensin-converting enzyme inhibitors (ACEIs). Due to its minimal side effects, unique mechanism of action, good tolerability, and ease of administration, it is likely to replace the previous two classes of drugs and become the preferred antihypertensive drug of this century. Its chemical structure is shown below:

[0003]

[0004] Numerous synthetic processes for valsartan have been reported. Indian Patent 2011MU00371 describes a reaction between 2'-cyano-4-bromomethylbiphenyl and L-valine methyl ester hydrochloride in the presence of a phase transfer catalyst, 18-crown-6, to produce the key intermediate, N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester, with a yield of 87%. The product is then acylated with n-valeric acid in the presence of CoCl2·6H2O, reacted with NaN3, and finally hydrolyzed to yield the target product. The synthetic route is as follows:

[0005]

[0006] Chinese patent CN101450917A, on the other hand, reacts 2'-cyano-4-bromomethylbiphenyl with L-valine methyl ester hydrochloride to prepare the key secondary amine intermediate N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester, with a yield of approximately 90%. The acylate is then produced with n-valeraldehyde under the catalysis of dibromohydantoin and azobisisobutyronitrile. The ester group is then hydrolyzed, and finally the target product is reacted with NaN3 / ZnCl2. The synthetic route is as follows:

[0007]

[0008] As can be seen from the above, N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester can be used as a key intermediate in the preparation of valsartan, which directly affects the production, market supply and quality of the drug. Its chemical structure is as follows:

[0009]

[0010] However, the crude intermediate obtained by the above process is an oily substance, which is not easy to quantify and transfer, and has low purity. It requires column chromatography and other operations for purification, which is cumbersome. At the same time, the yield is only about 90%.

[0011] Furthermore, patent CN102417486A reacts 2'-cyano-4-bromomethylbiphenyl with L-valine methyl ester hydrochloride to prepare a key secondary amine intermediate solid form: N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester hydrochloride, with a yield of approximately 90%. This is then reacted with n-valeryl chloride for n-valerylation, followed by reaction with NaN3 / ZnCl2, and finally, the ester group is hydrolyzed to obtain the target product. The synthetic route is as follows:

[0012]

[0013] Furthermore, Chinese patent CN102911128A prepares the key intermediate N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester hydrochloride in the presence of a phase transfer catalyst, 18-crown-6, with a yield of 92%. The product is then subjected to a valerylation reaction, followed by reaction with NaN3 / Bu3SnCl, and finally ester hydrolysis to yield the target product. The synthetic route is as follows:

[0014]

[0015] As can be seen from the literature Organic Process Research & Development, 2007, 11, 892-898 and patents WO2009125416A2 and WO2012001484A2, the aforementioned processes inevitably produce related dimer impurities, which are difficult to purify and remove, affecting product quality. The structures of the related impurities are shown below:

[0016]

[0017] In addition, the literature J.Org.Chem., 2007, 72, 7473-7476 uses o-cyanobenzoic acid as the starting material, coupled with p-bromobenzaldehyde to produce 4'-formyl-2-cyanobiphenyl, which is then reacted with L-valine methyl ester and reduced with sodium borohydride to produce N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester. This is then subjected to n-valerylation, followed by reaction with NaN3 / Bu3SnCl, and finally ester hydrolysis to obtain the target product. The synthetic route is as follows:

[0018]

[0019] In addition, patent 2011MU00362 couples o-aminobenzonitrile with benzyl alcohol, followed by nitric acid oxidation to produce 4'-formyl-2-cyanobiphenyl. This is then reacted with L-valine methyl ester and reduced with sodium borohydride to produce N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester. This is then subjected to n-valerylation, followed by reaction with NaN3, and finally, ester hydrolysis to yield the target product. The synthetic route is as follows:

[0020]

[0021] While the above reaction can avoid the formation of dimers, it condenses to form a Schiff base, which is then reduced with catalytic hydrogenation or metal hydride to yield a secondary amine, which is then acylated with n-valeryl chloride to yield the final product, valsartan. While this method eliminates the potential for racemization, the use of catalytic oxidation or metal oxide reduction of the Schiff base is costly, cumbersome, involves multiple reaction steps, and results in low yield and purity.

[0022] In summary, given the above problems in the prior art for synthesizing N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester hydrochloride, it is still a problem that needs to be solved to find a synthetic method for N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester hydrochloride with mild reaction conditions, simple operation process, high product yield and high purity, and no dimer impurities, which is suitable for industrial production. Summary of the Invention

[0023] To address the current problems in the synthesis of valsartan-related intermediate N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester hydrochloride, the present invention provides a new synthesis method. The method has mild reaction conditions, a simple operation process, and the obtained target product has high purity and yield.

[0024] The specific technical solutions of the present invention are as follows:

[0025] A method for synthesizing N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester hydrochloride as shown in formula (I) comprises the following steps:

[0026] At room temperature, SM-1, SM-2, catalyst SM-3, and base were added to the reaction solvent, and the temperature was controlled until the reaction was completed. The target product I was obtained by post-treatment. The reaction scheme is as follows:

[0027]

[0028] In a preferred embodiment, the structural formula of the catalyst SM-3 is as follows:

[0029]

[0030] In a preferred embodiment, the base is one of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide or a combination thereof, with sodium methoxide being particularly preferred.

[0031] In a preferred embodiment, the reaction solvent is toluene, xylene or a combination thereof, with toluene being particularly preferred.

[0032] In a preferred embodiment, the molar ratio of SM-1 to SM-2, SM-3 and alkali is 1:1.05-1.5:1%-5%:2.1-2.6, with 1:1.2:2%:2.3 being particularly preferred.

[0033] In a preferred embodiment, the reaction temperature is 60-100°C, with 70-75°C being particularly preferred.

[0034] In a preferred embodiment, the post-treatment scheme is as follows: after the reaction is completed, the reaction is filtered, the filtrate is washed with purified water, the organic phase is concentrated to dryness under reduced pressure, ethyl acetate is added to dissolve, concentrated hydrochloric acid is added to adjust the pH to 0.1-1.2 to form a salt, the reaction is filtered, and the filter cake is dried under reduced pressure to obtain the target product I.

[0035] In a preferred embodiment, concentrated hydrochloric acid is added to adjust the pH to 0.8-1.0.

[0036] Beneficial effects of the present invention:

[0037] 1. The present invention provides a simple and efficient method for synthesizing valsartan-related intermediate N-(2'-cyanobiphenyl-4-methylene)-L-valine methyl ester hydrochloride.

[0038] 2. The entire synthesis method does not require inert gas protection, is easy to operate, environmentally friendly, and suitable for industrial production.

[0039] 3. The target product obtained by this synthesis process has a high yield and purity. DETAILED DESCRIPTION

[0040] The present invention is further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0041] In the following embodiments, various processes and methods not described in detail are conventional methods well known in the art.

[0042] Example 1

[0043] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 20.12 g, 0.12 mol), SM-3 (1.06 g, 0.002 mol), and sodium methoxide (12.43 g, 0.23 mol) were added to toluene (50 ml), and the temperature was controlled to 70-75°C for reaction. After the reaction was completed, the mixture was filtered, and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure, and no dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 0.8-1.0 to form a salt. The product was filtered, and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 96.8% and an HPLC purity of 99.89%. No dimer impurity was detected.

[0044] Example 2

[0045] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 17.60 g, 0.105 mol), SM-3 (1.06 g, 0.002 mol), and potassium tert-butoxide (25.81 g, 0.23 mol) were added to toluene (50 ml), and the reaction was controlled at 85-90°C. After the reaction was completed, the mixture was filtered and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure. No dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 0.8-1.0 to form a salt. The product was filtered and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 94.5% and an HPLC purity of 99.86%. No dimer impurity was detected.

[0046] Example 3

[0047] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 16.76 g, 0.10 mol), SM-3 (1.06 g, 0.002 mol), and sodium methoxide (12.43 g, 0.23 mol) were added to toluene (50 ml), and the temperature was controlled at 90-95°C for reaction. After the reaction was completed, the mixture was filtered and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure. No dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 0.8-1.0 to form a salt. The product was filtered and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 92.4% and an HPLC purity of 99.78%. No dimer impurity was detected.

[0048] Example 4

[0049] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 25.14 g, 0.15 mol), SM-3 (1.06 g, 0.002 mol), and sodium methoxide (12.43 g, 0.23 mol) were added to xylene (50 ml), and the temperature was controlled at 65-70°C. After the reaction was completed, the mixture was filtered and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure. No dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 0.8-1.0 to form a salt. The product was filtered and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 96.3% and a purity of 99.75% by HPLC. No dimer impurity was detected.

[0050] Example 5

[0051] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 26.82 g, 0.16 mol), SM-3 (1.06 g, 0.002 mol), and sodium methoxide (12.43 g, 0.23 mol) were added to toluene (50 ml), and the temperature was controlled at 60-65°C for reaction. After the reaction was completed, the mixture was filtered and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure. No dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 0.8-1.0 to form a salt. The product was filtered and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 96.2% and an HPLC purity of 99.75%. No dimer impurity was detected.

[0052] Example 6

[0053] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 20.12 g, 0.12 mol), SM-3 (0.53 g, 0.001 mol), and sodium tert-butoxide (22.10 g, 0.23 mol) were added to toluene (50 ml), and the reaction was controlled at 80-85°C. After the reaction was completed, the mixture was filtered and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure. No dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 0.8-1.0 to form a salt. The product was filtered and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 93.5% and an HPLC purity of 99.82%. No dimer impurity was detected.

[0054] Example 7

[0055] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 20.12 g, 0.12 mol), SM-3 (2.65 g, 0.005 mol), and sodium ethoxide (15.65 g, 0.23 mol) were added to toluene (50 ml), and the reaction was controlled at 65-70°C. After the reaction was completed, the mixture was filtered, and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure, and no dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 0.8-1.0 to form a salt. The product was filtered, and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 95.6% and an HPLC purity of 99.72%. No dimer impurity was detected.

[0056] Example 8

[0057] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 20.12 g, 0.12 mol), SM-3 (1.06 g, 0.002 mol), and sodium methoxide (12.43 g, 0.23 mol) were added to toluene (50 ml), and the reaction was controlled at 85-90°C. After the reaction was completed, the mixture was filtered and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure. No dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 1.2 to form a salt. The product was filtered and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 94.3% and an HPLC purity of 99.73%. No dimer impurity was detected.

[0058] Example 9

[0059] At room temperature, SM-1 (20.93 g, 0.10 mol), L-valine methyl ester hydrochloride (SM-2, 20.12 g, 0.12 mol), SM-3 (1.06 g, 0.002 mol), and sodium methoxide (12.43 g, 0.23 mol) were added to toluene (50 ml), and the temperature was controlled at 65-70°C for reaction. After the reaction was completed, the mixture was filtered and the filtrate was washed with purified water (20 ml × 3). The organic phase was concentrated to dryness under reduced pressure. No dimer impurity was detected by HPLC. The concentrate was dissolved in ethyl acetate, and concentrated hydrochloric acid was added to adjust the pH to 0.1 to form a salt. The product was filtered and the filter cake was dried under reduced pressure to obtain the target product I with a yield of 94.8% and an HPLC purity of 99.72%. No dimer impurity was detected.

Claims

1. A method for synthesizing a valsartan intermediate, characterized in that: The process comprises the following steps: adding SM-1, SM-2, catalyst SM-3, and a base to a reaction solvent at room temperature, controlling the temperature until the reaction is complete, and performing post-treatment to obtain the target product I. The reaction scheme is as follows: ； The structural formula of the catalyst SM-3 is as follows: 。 2. The synthesis method according to claim 1, wherein The base is one of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide or a combination thereof.

3. The synthesis method according to claim 1, wherein The reaction solvent is toluene, xylene or a combination thereof.

4. The synthesis method according to claim 1, characterized in that The molar ratio of SM-1 to SM-2, SM-3 and alkali is 1:1.05-1.5:1%-5%:2.1-2.

6.

5. The synthesis method according to claim 1, characterized in that The reaction temperature is 60-100°C.

6. The synthesis method according to claim 1, characterized in that The reaction temperature is 70-75°C.

7. The synthesis method according to claim 1, characterized in that The post-treatment is as follows: after the reaction is completed, the reaction is filtered, the filtrate is washed with purified water, the organic phase is concentrated to dryness under reduced pressure, ethyl acetate is added to dissolve, concentrated hydrochloric acid is added to adjust the pH to 0.1-1.2 to form a salt, the reaction is filtered, and the filter cake is dried under reduced pressure to obtain the target product I.

Images