A preparation method of (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid

Abstract

The present invention relates to a method for preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid. The method comprises the following steps: S1, preparing 2-methylimidazole-4-carboxaldehyde by reacting 2-bromomalondialdehyde with acetamidine hydrochloride; S2, preparing 1-benzyl-2-methylimidazole-4-carboxaldehyde by reacting the 2-methylimidazole-4-carboxaldehyde with benzyl bromide; and S3, preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid by reacting the 1-benzyl-2-methylimidazole-4-carboxaldehyde with diethyl succinate. The preparation method of the present invention prepares 2-methylimidazole-4-carboxaldehyde by reacting 2-bromomalondialdehyde with acetamidine hydrochloride. No strong acidic gas is generated, and the intermediate products in each step are relatively stable. The product yield is about 53% (calculated as 2-bromomalondialdehyde), which is more suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical product preparation, and in particular to a method for preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid. Background Art

[0002] Imidazole compounds are generally important intermediates in the pharmaceutical and chemical fields. For example, (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid is an important pharmaceutical intermediate, and its structural formula is shown in Formula I:

[0003]

[0004] Regarding the preparation method of the compound, U.S. Patent No. 9493425B2 discloses a method for preparing a benzimidazole derivative, and specifically discloses:

[0005]

[0006] However, in this preparation method, a large amount of highly corrosive hydrogen chloride gas is generated during the first reaction, and the resulting methyl acetimidate hydrochloride is unstable and easily decomposed by heat or moisture. The total yield of the last two steps is only about 30% (calculated based on 2-bromomalondialdehyde), i.e., the product yield is extremely low. Therefore, this preparation method is not suitable for industrial production.

[0007] Therefore, there is an urgent need for a method for preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid. Summary of the Invention

[0008] The object of the present invention is to provide a method for preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid in view of the deficiencies in the prior art.

[0009] To achieve the above object, the technical solution adopted by the present invention is:

[0010] Provided is a method for preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid, comprising the following steps:

[0011] S1, preparing 2-methylimidazole-4-carbaldehyde by reacting 2-bromomalondialdehyde with acetamidine hydrochloride;

[0012] S2, preparing 1-benzyl-2-methylimidazole-4-carboxaldehyde by reacting the 2-methylimidazole-4-carboxaldehyde with benzyl bromide;

[0013] S3. Prepare (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid by reacting the 1-benzyl-2-methylimidazole-4-carboxaldehyde with diethyl succinate.

[0014] Preferably, the reaction of the 2-bromomalondialdehyde and the acetamidine hydrochloride is carried out in a first solvent; wherein,

[0015] The first solvent includes at least one of dichloromethane, tetrahydrofuran, acetone, or butanone.

[0016] Preferably, the reaction of the 2-bromomalondialdehyde and the acetamidine hydrochloride is carried out under the protection of nitrogen.

[0017] Preferably, the reaction of the 2-bromomalondialdehyde and the acetamidine hydrochloride is carried out under the catalysis of a strong base; wherein,

[0018] The strong base includes at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium hydroxide, or sodium hydroxide.

[0019] Furthermore, the reaction of the 2-bromomalondialdehyde and the acetamidine hydrochloride specifically includes:

[0020] S1-1, adding the 2-bromomalondialdehyde and the acetamidine hydrochloride to the first solvent;

[0021] S1-2, under the protection of nitrogen, after stirring and cooling to -50°C to 0°C, add the strong base in batches, and control the temperature below -15°C;

[0022] S1-3, after the addition is completed, stir and naturally heat to -5℃~5℃, and keep warm for 1h~3h, then continue to heat to 15℃~25℃, and keep warm for 1h~3h;

[0023] S1-4, through post-treatment, the 2-methylimidazole-4-carboxaldehyde is obtained.

[0024] Preferably, the reaction of the 2-methylimidazole-4-carboxaldehyde and the benzyl bromide is carried out in a second solvent; wherein,

[0025] The second solvent includes tetrahydrofuran.

[0026] Preferably, the reaction of the 2-methylimidazole-4-carboxaldehyde and the benzyl bromide is carried out under the protection of nitrogen.

[0027] Preferably, the reaction of the 2-methylimidazole-4-carboxaldehyde and the benzyl bromide is carried out under the catalysis of the strong base.

[0028] Furthermore, the reaction of the 2-methylimidazole-4-carboxaldehyde and the benzyl bromide specifically includes:

[0029] S2-1, adding the 2-methylimidazole-4-carboxaldehyde to the second solvent;

[0030] S2-2, under the protection of nitrogen, after stirring and cooling to -5°C to 5°C, add the strong base and control the temperature below 10°C;

[0031] S2-3, after addition, keep warm at 5℃~15℃ for 1h~3h;

[0032] S2-4, adding the benzyl bromide dropwise;

[0033] S2-5, after addition, keep warm at 5℃~15℃ for 5h~7h;

[0034] S2-6, through post-treatment, the 1-benzyl-2-methylimidazole-4-carboxaldehyde is obtained.

[0035] Preferably, the reaction of 1-benzyl-2-methylimidazole-4-carboxaldehyde and diethyl succinate is carried out in a third solvent; wherein,

[0036] The third solvent includes at least one of methanol, ethanol, or isopropanol.

[0037] Preferably, the reaction of the 1-benzyl-2-methylimidazole-4-carboxaldehyde and the diethyl succinate is carried out under the catalysis of the strong base.

[0038] Furthermore, the reaction of the 1-benzyl-2-methylimidazole-4-carboxaldehyde and the diethyl succinate specifically includes:

[0039] S3-1, adding diethyl succinate to the third solvent;

[0040] S3-2, adding the strong base with stirring;

[0041] S3-3, after adding, stir and heat to 50℃~60℃;

[0042] S3-4, adding the 1-benzyl-2-methylimidazole-4-carbaldehyde dropwise;

[0043] S3-5, after adding, keep warm at 50℃~60℃ for 1h~3h;

[0044] S3-6. After post-treatment, the (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid is obtained.

[0045] The present invention adopts the above technical solution, which has the following technical effects compared with the prior art:

[0046] The preparation method of the present invention prepares 2-methylimidazole-4-carboxaldehyde by reacting 2-bromomalondialdehyde with acetamidine hydrochloride. No strong acidic gas is generated, and the intermediate products in each step are relatively stable. The product yield is about 53% (calculated based on 2-bromomalondialdehyde), and the method is more suitable for industrial production. DETAILED DESCRIPTION

[0047] The specific embodiments of the present invention will be described in detail below.

[0048] Unless otherwise defined, technical or scientific terms used in the claims and the specification shall have the same general meaning as understood by persons having ordinary skills in the technical field to which the present invention belongs.

[0049] The words "include" or similar used in the patent application specification and claims of the present invention mean that the items before "include" include the items listed after "include" or their equivalents, and do not exclude other items.

[0050] The numerical values ​​mentioned in the present invention include all numerical values ​​that increase by one unit from the lowest to the highest, assuming that there is at least two units between any lower value and the higher value. For example, if a component or a physical quantity is said to be from 1 to 100, preferably from 10 to 90, and most preferably from 20 to 80, it is intended that values ​​such as 5 to 95, 14 to 76, 23 to 67, 32 to 58, and 41 to 49 are clearly listed in this specification; for values ​​less than 1, 0.0001, 0.001, 0.01, or 0.1 are considered to be more appropriate units. The above examples are for illustrative purposes only. In fact, all numerical combinations between the lowest value and the highest value listed are considered to be clearly listed in this specification in a similar manner.

[0051] The present invention provides a method for preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid, which comprises the following steps:

[0052]

[0053] S1, preparing 2-methylimidazole-4-carbaldehyde by reacting 2-bromomalondialdehyde with acetamidine hydrochloride;

[0054] S2, preparing 1-benzyl-2-methylimidazole-4-carboxaldehyde by reacting the 2-methylimidazole-4-carboxaldehyde with benzyl bromide;

[0055] S3. Prepare (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid by reacting the 1-benzyl-2-methylimidazole-4-carboxaldehyde with diethyl succinate.

[0056] In some preferred embodiments, the reaction of the 2-bromomalondialdehyde and the acetamidine hydrochloride comprises:

[0057] S1-1, adding the 2-bromomalondialdehyde and the acetamidine hydrochloride to the first solvent;

[0058] S1-2. Under nitrogen protection, stir and cool to -50°C to 0°C, then add strong base in batches, and control the temperature below -15°C;

[0059] S1-3, after the addition is completed, stir and naturally heat to -5℃~5℃, and keep warm for 1h~3h, then continue to heat to 15℃~25℃, and keep warm for 1h~3h;

[0060] S1-4, through post-treatment, the 2-methylimidazole-4-carboxaldehyde is obtained.

[0061] In some preferred embodiments, the reaction of the 2-methylimidazole-4-carbaldehyde and the benzyl bromide comprises:

[0062] S2-1, adding the 2-methylimidazole-4-carboxaldehyde to the second solvent;

[0063] S2-2, under the protection of nitrogen, after stirring and cooling to -5°C to 5°C, add the strong base and control the temperature below 10°C;

[0064] S2-3, after addition, keep warm at 5℃~15℃ for 1h~3h;

[0065] S2-4, adding the benzyl bromide dropwise;

[0066] S2-5, after addition, keep warm at 5℃~15℃ for 5h~7h;

[0067] S2-6, through post-treatment, the 1-benzyl-2-methylimidazole-4-carboxaldehyde is obtained.

[0068] In some preferred embodiments, the reaction of the 1-benzyl-2-methylimidazole-4-carbaldehyde and the diethyl succinate comprises:

[0069] S3-1, adding diethyl succinate to the third solvent;

[0070] S3-2, adding the strong base with stirring;

[0071] S3-3, after adding, stir and heat to 50℃~60℃;

[0072] S3-4, adding the 1-benzyl-2-methylimidazole-4-carbaldehyde dropwise;

[0073] S3-5, after adding, keep warm at 50℃~60℃ for 1h~3h;

[0074] S3-6. After post-treatment, the (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid is obtained.

[0075] In some more preferred embodiments, the first solvent includes at least one of dichloromethane, tetrahydrofuran, acetone, or butanone.

[0076] In some more preferred embodiments, the strong base includes at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium hydroxide, or sodium hydroxide.

[0077] In some more preferred embodiments, the second solvent includes: tetrahydrofuran.

[0078] In some more preferred embodiments, the third solvent includes at least one of methanol, ethanol, or isopropanol.

[0079] Example 1

[0080] This embodiment provides a method for preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid, comprising the following steps:

[0081]

[0082] S1-1. To 100 mL of dichloromethane, 10.0 g (66.2 mmol) of 2-bromomalondialdehyde and 6.0 g (63.5 mmol) of acetamidine hydrochloride were added;

[0083] S1-2. Under nitrogen protection, stir and cool to -25°C ± 5°C, then add 15.9 g (165.5 mmol) of sodium tert-butoxide in batches while controlling the temperature below -15°C;

[0084] S1-3, add after about 1 hour, stir and naturally heat to 0℃, keep warm for 2 hours, continue to heat to 20℃±5℃, and keep warm for 2 hours;

[0085] S1-4. Add about 5 g of glacial acetic acid dropwise to adjust the pH to 5-6; add 100 mL of water, stir, and separate the upper aqueous phase; add sodium sulfate to the organic phase for drying, and concentrate under reduced pressure until no liquid is discharged; add isopropyl ether, stir for 30 min, and filter to obtain 5.9 g of a light yellow crystalline solid, which is 2-methylimidazole-4-carbaldehyde; the yield is 81.5%, NMR (DMSO-d6): 12.74 (s, 1H), 9.61 (s, 1H), 7.84 (s, 1H), 2.33 (s, 3H) ppm;

[0086]

[0087] S2-1, adding 5.0 g (45.5 mmol) of the 2-methylimidazole-4-carbaldehyde to 100 mL of tetrahydrofuran;

[0088] S2-2, under the protection of nitrogen, after stirring and cooling to 0°C ± 5°C, 5.2 g (54.1 mmol) of the sodium tert-butoxide was added, and the temperature was controlled below 10°C;

[0089] S2-3, after addition, keep warm at 10℃±5℃ for 2h;

[0090] S2-4, add 8.5 g (49.7 mmol) of benzyl bromide dropwise;

[0091] S2-5, after addition, keep warm at 10℃±5℃ for 6h;

[0092] S2-6. Add 100 mL of water and 1 g to 2 g of glacial acetic acid to adjust the pH to 5 to 6, and separate the upper aqueous phase; add sodium sulfate to the organic phase for drying, and concentrate under reduced pressure until no liquid is discharged. 8.0 g of a brown oil is obtained, which is 1-benzyl-2-methylimidazole-4-carbaldehyde; the yield is 88%, NMR (DMSO-d6): 9.61 (s, 1H), 7.84 (s, 1H), 7.30 (m, 5H), 5.56 (s, 2H), 2.33 (m, 3H) ppm;

[0093]

[0094] S3-1. Add 8.7 g (49.9 mmol) of diethyl succinate to 50 mL of anhydrous ethanol;

[0095] S3-2, adding 6.0 g (62.4 mmol) of the sodium tert-butoxide with stirring;

[0096] S3-3, after adding, stir and heat to 50℃~60℃;

[0097] S3-4, adding 5.0 g (25.0 mmol) of the 1-benzyl-2-methylimidazole-4-carbaldehyde dropwise;

[0098] S3-5, after addition, keep warm at 50℃~60℃ for 2h;

[0099] S3-6, vacuum concentration to remove ethanol; add 100 mL of dichloromethane, add 100 mL of water, add 3 g to 5 g of glacial acetic acid to adjust the pH to 4 to 5, separate the upper aqueous phase; vacuum concentrate the lower organic phase until no liquid is discharged; add 30 mL of anhydrous ethanol, stir and cool to 0°C ± 5°C; filter, and vacuum dry at 50°C to obtain 6.1 g of a light yellow solid, which is (E)-4-(1-benzyl-2-methyl-1H-imidazole). oxazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid; the yield was 74.4%, the HPLC purity was 99.1%, NMR (DMSO-d6): 10.91 (s, 1H), 7.2-7.0 (m, 5H), 7.46 (s, 1H), 5.26 (m, 2H), 4.10 (q, 2H), 3.36 (s, 2H), 2.30 (s, 3H), 1.18 (t, 3H) ppm.

[0100] In summary, the preparation method of the present invention prepares 2-methylimidazole-4-carboxaldehyde by reacting 2-bromomalondialdehyde with acetamidine hydrochloride. No strong acidic gas is generated, the intermediate products in each step are relatively stable, and the product yield is approximately 53% (calculated as 2-bromomalondialdehyde), making it more suitable for industrial production.

[0101] The above description is only a preferred embodiment of the present invention and does not limit the implementation mode and protection scope of the present invention. For those skilled in the art, it should be aware that all solutions obtained by equivalent substitutions and obvious changes made using the contents of the present invention specification should be included in the protection scope of the present invention.

Claims

1. A method for preparing (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid, characterized in that the steps include: S1, preparing 2-methylimidazole-4-carbaldehyde by reacting 2-bromomalondialdehyde with acetamidine hydrochloride; S2-1, adding the 2-methylimidazole-4-carbaldehyde to tetrahydrofuran; S2-2. Under nitrogen protection, stir and cool to 0°C ± 5°C, then add sodium tert-butoxide, and control the temperature below 10°C; S2-3, after addition, keep warm at 10℃±5℃ for 2h; S2-4, add benzyl bromide dropwise; S2-5, after addition, keep warm at 10℃±5℃ for 6h; S2-6. Add water and glacial acetic acid to adjust the pH to 5-6, and separate the upper aqueous phase; add sodium sulfate to the organic phase for drying, and concentrate under negative pressure until no liquid is discharged. The resulting brown oil is 1-benzyl-2-methylimidazole-4-carboxaldehyde; S3-1, adding diethyl succinate to anhydrous ethanol; S3-2, adding sodium tert-butoxide with stirring; S3-3, after adding, stir and heat to 50℃~60℃; S3-4, adding the 1-benzyl-2-methylimidazole-4-carbaldehyde dropwise; S3-5, after addition, keep warm at 50℃~60℃ for 2h; S3-6. Concentrate under negative pressure to remove ethanol; add dichloromethane, water, and glacial acetic acid to adjust the pH to 4-5, and separate the upper aqueous phase; concentrate the lower organic phase under negative pressure until no liquid is discharged; add anhydrous ethanol, stir and cool to 0℃±5℃; filter, and vacuum dry at 50℃. The resulting light yellow solid is (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid.

2. The preparation method according to claim 1, characterized in that The reaction of 2-bromomalondialdehyde and acetamidine hydrochloride is carried out in a first solvent; wherein, The first solvent includes at least one of dichloromethane, tetrahydrofuran, acetone, or butanone.

3. The preparation method according to claim 1, characterized in that The reaction of the 2-bromomalondialdehyde and the acetamidine hydrochloride is carried out under the protection of nitrogen.

4. The preparation method according to claim 1, characterized in that The reaction of the 2-bromomalondialdehyde and the acetamidine hydrochloride is carried out under the catalysis of a strong base; wherein, The strong base includes at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium hydroxide, or sodium hydroxide.

Images