CN116751167B - A preparation method of (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acid - Google Patents
A preparation method of (E)-4-(1-benzyl-2-methyl-1H-imidazol-5-yl)-3-(ethoxyacyl)but-3-enoic acidInfo
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- CN116751167B CN116751167B CN202310805316.7A CN202310805316A CN116751167B CN 116751167 B CN116751167 B CN 116751167B CN 202310805316 A CN202310805316 A CN 202310805316A CN 116751167 B CN116751167 B CN 116751167B
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- C07—ORGANIC CHEMISTRY
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
本发明涉及一种(E)‑4‑(1‑苄基‑2‑甲基‑1H‑咪唑‑5‑基)‑3‑(乙氧基酰基)丁‑3‑烯酸的制备方法，步骤包括：S1、通过2‑溴丙二醛与乙脒盐酸盐反应，制备2‑甲基咪唑‑4‑甲醛；S2、通过所述2‑甲基咪唑‑4‑甲醛与溴苄反应，制备1‑苄基‑2‑甲基咪唑‑4‑甲醛；S3、通过所述1‑苄基‑2‑甲基咪唑‑4‑甲醛与丁二酸二乙酯反应，制备(E)‑4‑(1‑苄基‑2‑甲基‑1H‑咪唑‑5‑基)‑3‑(乙氧基酰基)丁‑3‑烯酸。本发明的制备方法通过2‑溴丙二醛与乙脒盐酸盐反应，制备2‑甲基咪唑‑4‑甲醛，无强酸性气体生成，各步中间产物亦相对稳定，且产品收率约为53％(以2‑溴丙二醛计)，更适于工业化生产。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
The invention relates to the technical field of chemical product preparation, in particular to a preparation method of (E) -4- (1-benzyl-2-methyl-1H-imidazole-5-yl) -3- (ethoxyacyl) but-3-enoate.
Background
Imidazole compounds are generally important intermediates in the fields of medicine and chemical industry, for example, (E) -4- (1-benzyl-2-methyl-1H-imidazol-5-yl) -3- (ethoxyacyl) but-3-enoate is an important medical intermediate, and the structural formula is shown in formula I:
for the preparation of this compound, U.S. patent No. 9493425B2 discloses a process for preparing benzimidazole derivatives, and specifically discloses:
However, in the preparation method, a large amount of hydrogen chloride gas with strong corrosiveness is generated in the first reaction process, the prepared methyl acetimide hydrochloride is unstable and is easy to be heated or decomposed by moisture, and the total yield of the last two steps of reactions is only about 30 percent (calculated by 2-bromopropionaldehyde), namely the product yield is extremely low, so that the preparation method is not beneficial to industrial production;
thus, there is a need for a process for the preparation of (E) -4- (1-benzyl-2-methyl-1H-imidazol-5-yl) -3- (ethoxyacyl) but-3-enoic acid.
Disclosure of Invention
The invention aims at overcoming the defects in the prior art and provides a preparation method of (E) -4- (1-benzyl-2-methyl-1H-imidazol-5-yl) -3- (ethoxyacyl) but-3-enoate.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
provided is a method for preparing (E) -4- (1-benzyl-2-methyl-1H-imidazol-5-yl) -3- (ethoxyacyl) but-3-enoic acid, comprising the steps of:
S1, preparing 2-methylimidazole-4-formaldehyde by reacting 2-bromopropionaldehyde with acetamidine hydrochloride;
s2, preparing 1-benzyl-2-methylimidazole-4-formaldehyde by reacting the 2-methylimidazole-4-formaldehyde with bromobenzyl;
s3, preparing (E) -4- (1-benzyl-2-methyl-1H-imidazole-5-yl) -3- (ethoxyacyl) but-3-enoic acid by reacting the 1-benzyl-2-methylimidazole-4-formaldehyde with diethyl succinate.
Preferably, the reaction of the 2-bromopropionaldehyde with the acetamidine hydrochloride is performed in a first solvent, wherein,
The first solvent comprises at least one of dichloromethane, tetrahydrofuran, acetone or butanone.
Preferably, the reaction of the 2-bromopropionaldehyde with the acetamidine hydrochloride is performed under the protection of nitrogen.
Preferably, the reaction of the 2-bromopropionaldehyde with the acetamidine hydrochloride is performed under the catalysis of a strong base, wherein,
The strong base comprises at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium hydroxide or sodium hydroxide.
Further, the reaction of the 2-bromopropionaldehyde with the acetamidine hydrochloride specifically comprises:
s1-1, adding the 2-bromopropionaldehyde and the acetamidine hydrochloride to the first solvent;
s1-2, stirring and cooling to-50 ℃ to 0 ℃ under the protection of nitrogen, adding the strong base in batches, and controlling the temperature to be lower than-15 ℃;
S1-3, after the addition, stirring and naturally heating to-5 ℃ to 5 ℃, preserving heat for 1 to 3 hours, continuously heating to 15 ℃ to 25 ℃, and preserving heat for 1 to 3 hours;
s1-4, and obtaining the 2-methylimidazole-4-formaldehyde through post-treatment.
Preferably, the reaction of the 2-methylimidazole-4-carbaldehyde with the bromobenzyl is carried out in a second solvent, wherein,
The second solvent comprises tetrahydrofuran.
Preferably, the reaction of the 2-methylimidazole-4-carbaldehyde with the bromobenzyl is carried out under nitrogen.
Preferably, the reaction of the 2-methylimidazole-4-carbaldehyde with the bromobenzyl is carried out under catalysis of the strong base.
Further, the reaction of the 2-methylimidazole-4-formaldehyde with the bromobenzyl specifically includes:
S2-1, adding the 2-methylimidazole-4-formaldehyde into the second solvent;
S2-2, stirring and cooling to-5 ℃ to 5 ℃ under the protection of nitrogen, adding the strong base, and controlling the temperature to be lower than 10 ℃;
S2-3, after the addition, preserving heat for 1-3 hours at 5-15 ℃;
s2-4, dropwise adding the bromobenzyl;
s2-5, after the addition, preserving heat for 5-7 hours at 5-15 ℃;
s2-6, and obtaining the 1-benzyl-2-methylimidazole-4-formaldehyde through post-treatment.
Preferably, the reaction of the 1-benzyl-2-methylimidazole-4-carbaldehyde and the diethyl succinate is carried out in a third solvent, wherein,
The third solvent comprises at least one of methanol, ethanol or isopropanol.
Preferably, the reaction of the 1-benzyl-2-methylimidazole-4-carbaldehyde and the diethyl succinate is carried out under the catalysis of the strong base.
Further, the reaction of the 1-benzyl-2-methylimidazole-4-formaldehyde and the diethyl succinate specifically comprises:
S3-1, adding diethyl succinate into the third solvent;
S3-2, stirring and adding the strong base;
s3-3, after the addition, stirring and heating to 50-60 ℃;
s3-4, dropwise adding the 1-benzyl-2-methylimidazole-4-formaldehyde;
S3-5, after the addition, preserving heat for 1-3 hours at 50-60 ℃;
S3-6, and obtaining the (E) -4- (1-benzyl-2-methyl-1H-imidazole-5-yl) -3- (ethoxyacyl) but-3-enoate through post-treatment.
Compared with the prior art, the invention has the following technical effects:
The preparation method of the invention prepares the 2-methylimidazole-4-formaldehyde by the reaction of the 2-bromopropionaldehyde and the acetamidine hydrochloride, no strong acid gas is generated, the intermediate products of each step are relatively stable, and the product yield is about 53 percent (calculated by the 2-bromopropionaldehyde), thus being more suitable for industrial production.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail.
Unless defined otherwise, technical or scientific terms used in the claims and specification should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs.
As used in the specification and claims of this application, the word "comprise" or similar words mean that the presence of an article preceding the word "comprising" encompasses the presence of an article listed after the word "comprising" or equivalents thereof, and does not exclude other articles.
The values mentioned in the present invention include all values increasing from low to high by one unit, here assuming that any lower value is separated from the higher value by at least two units. For example, if a component amount or a physical amount is from 1 to 100,10 to 90, preferably 20 to 80, and most preferably 5 to 95,14 to 76,23 to 67,32 to 58,41 to 49, etc. are all explicitly recited in this specification, 0.0001, 0.001, 0.01 or 0.1 is considered to be a suitable unit for values less than 1. The foregoing examples are for illustrative purposes only, and in fact, all numerical combinations between the lowest value and the highest value enumerated are to be considered to be expressly listed in this specification in a similar manner.
The invention provides a preparation method of (E) -4- (1-benzyl-2-methyl-1H-imidazole-5-yl) -3- (ethoxyacyl) but-3-enoate, which comprises the following steps:
S1, preparing 2-methylimidazole-4-formaldehyde by reacting 2-bromopropionaldehyde with acetamidine hydrochloride;
s2, preparing 1-benzyl-2-methylimidazole-4-formaldehyde by reacting the 2-methylimidazole-4-formaldehyde with bromobenzyl;
s3, preparing (E) -4- (1-benzyl-2-methyl-1H-imidazole-5-yl) -3- (ethoxyacyl) but-3-enoic acid by reacting the 1-benzyl-2-methylimidazole-4-formaldehyde with diethyl succinate.
In some preferred embodiments, the reaction of the 2-bromopropionaldehyde with the acetamidine hydrochloride comprises:
s1-1, adding the 2-bromopropionaldehyde and the acetamidine hydrochloride into a first solvent;
S1-2, stirring and cooling to-50 ℃ to 0 ℃ under the protection of nitrogen, adding strong base in batches, and controlling the temperature to be lower than-15 ℃;
S1-3, after the addition, stirring and naturally heating to-5 ℃ to 5 ℃, preserving heat for 1 to 3 hours, continuously heating to 15 ℃ to 25 ℃, and preserving heat for 1 to 3 hours;
s1-4, and obtaining the 2-methylimidazole-4-formaldehyde through post-treatment.
In some preferred embodiments, the reaction of the 2-methylimidazole-4-carbaldehyde with the bromobenzyl group comprises:
s2-1, adding the 2-methylimidazole-4-formaldehyde into a second solvent;
S2-2, stirring and cooling to-5 ℃ to 5 ℃ under the protection of nitrogen, adding the strong base, and controlling the temperature to be lower than 10 ℃;
S2-3, after the addition, preserving heat for 1-3 hours at 5-15 ℃;
s2-4, dropwise adding the bromobenzyl;
s2-5, after the addition, preserving heat for 5-7 hours at 5-15 ℃;
s2-6, and obtaining the 1-benzyl-2-methylimidazole-4-formaldehyde through post-treatment.
In some preferred embodiments, the reaction of the 1-benzyl-2-methylimidazole-4-carbaldehyde with the diethyl succinate comprises:
s3-1, adding the diethyl succinate into a third solvent;
S3-2, stirring and adding the strong base;
s3-3, after the addition, stirring and heating to 50-60 ℃;
s3-4, dropwise adding the 1-benzyl-2-methylimidazole-4-formaldehyde;
S3-5, after the addition, preserving heat for 1-3 hours at 50-60 ℃;
S3-6, and obtaining the (E) -4- (1-benzyl-2-methyl-1H-imidazole-5-yl) -3- (ethoxyacyl) but-3-enoate through post-treatment.
In some more preferred embodiments, the first solvent comprises at least one of methylene chloride, tetrahydrofuran, acetone, or butanone.
In some more preferred embodiments, the strong base comprises at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium hydroxide, or sodium hydroxide.
In some more preferred embodiments, the second solvent comprises tetrahydrofuran.
In some more preferred embodiments, the third solvent comprises at least one of methanol, ethanol, or isopropanol.
Example 1
This example provides a process for the preparation of (E) -4- (1-benzyl-2-methyl-1H-imidazol-5-yl) -3- (ethoxyacyl) but-3-enoic acid comprising the steps of:
s1-1, 10.0g (66.2 mmol) of 2-bromopropionaldehyde, and 6.0g (63.5 mmol) of acetamidine hydrochloride were added to 100mL of dichloromethane;
S1-2, stirring and cooling to minus 25 ℃ plus or minus 5 ℃ under the protection of nitrogen, adding 15.9g (165.5 mmol) of sodium tert-butoxide in batches, and controlling the temperature to be lower than minus 15 ℃;
S1-3, after about 1 hour, stirring and naturally heating to 0 ℃, preserving heat for 2 hours, continuously heating to 20+/-5 ℃ and preserving heat for 2 hours;
s1-4, dropwise adding about 5g of glacial acetic acid to adjust the pH to 5-6, adding 100mL of water, stirring, separating an upper water phase, adding anhydrous sodium sulphate into an organic phase, drying, concentrating under negative pressure until no liquid is discharged, adding isopropyl ether, stirring for 30min, filtering to obtain 5.9g of light yellow crystalline solid which is 2-methylimidazole-4-formaldehyde, wherein the yield is 81.5%, and the NMR (DMSO-d 6): 12.74 (S, 1H), 9.61 (S, 1H), 7.84 (S, 1H) and 2.33 (S, 3H) ppm are obtained;
S2-1, adding 5.0g (45.5 mmol) of the 2-methylimidazole-4-carbaldehyde to 100mL of tetrahydrofuran;
s2-2, stirring and cooling to 0 ℃ plus or minus 5 ℃ under the protection of nitrogen, adding 5.2g (54.1 mmol) of the sodium tert-butoxide, and controlling the temperature to be lower than 10 ℃;
S2-3, after the addition, preserving the temperature for 2 hours at 10+/-5 ℃;
S2-4, 8.5g (49.7 mmol) of bromobenzyl are added dropwise;
s2-5, after the addition, preserving the temperature for 6 hours at 10+/-5 ℃;
S2-6, adding 100mL of water, adding 1 g-2 g of glacial acetic acid to adjust the pH to 5-6, separating an upper water phase, adding anhydrous sodium sulphate into an organic phase, drying, concentrating under negative pressure until no liquid is discharged, and obtaining 8.0g of tan oily matter, namely 1-benzyl-2-methylimidazole-4-formaldehyde, wherein the yield is 88%, and the NMR (DMSO-d 6) is 9.61 (S, 1H), 7.84 (S, 1H), 7.30 (m, 5H), 5.56 (S, 2H) and 2.33 (m, 3H) ppm;
S3-1, adding 8.7g (49.9 mmol) of diethyl succinate to 50mL of absolute ethyl alcohol;
s3-2, adding 6.0g (62.4 mmol) of the sodium tert-butoxide by stirring;
s3-3, after the addition, stirring and heating to 50-60 ℃;
S3-4, dropwise adding 5.0g (25.0 mmol) of the 1-benzyl-2-methylimidazole-4-formaldehyde;
s3-5, after the addition, preserving heat for 2 hours at 50-60 ℃;
S3-6, concentrating under negative pressure to remove ethanol, adding 100mL of dichloromethane, adding 100mL of water, adding 3 g-5 g of glacial acetic acid to regulate pH to 4-5, separating an upper water phase, concentrating a lower organic phase under negative pressure to prevent liquid, adding 30mL of absolute ethanol, stirring and cooling to 0 ℃ plus or minus 5 ℃, filtering, and vacuum drying at 50 ℃ to obtain 6.1g of light yellow solid, namely (E) -4- (1-benzyl-2-methyl-1H-imidazol-5-yl) -3- (ethoxyacyl) but-3-enoic acid, wherein the yield is 74.4%, and the HPLC purity is 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.
In summary, the preparation method of the invention prepares 2-methylimidazole-4-formaldehyde by the reaction of 2-bromopropionaldehyde and acetamidine hydrochloride, no strong acid gas is generated, the intermediate products in each step are relatively stable, and the product yield is about 53% (calculated by 2-bromopropionaldehyde), thus being more suitable for industrial production.
The foregoing description is only illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention, and it will be appreciated by those skilled in the art that equivalent substitutions and obvious variations may be made using the teachings of the present invention, which are intended to be included within the scope of the invention.
Claims (4)
1. A process for the preparation of (E) -4- (1-benzyl-2-methyl-1H-imidazol-5-yl) -3- (ethoxyacyl) but-3-enoic acid, comprising the steps of:
S1, preparing 2-methylimidazole-4-formaldehyde by reacting 2-bromopropionaldehyde with acetamidine hydrochloride;
s2-1, adding the 2-methylimidazole-4-formaldehyde into tetrahydrofuran;
s2-2, stirring and cooling to 0 ℃ plus or minus 5 ℃ under the protection of nitrogen, adding sodium tert-butoxide, and controlling the temperature to be lower than 10 ℃;
S2-3, after the addition, preserving the temperature for 2 hours at 10+/-5 ℃;
S2-4, dropwise adding bromobenzyl;
s2-5, after the addition, preserving the temperature for 6 hours at 10+/-5 ℃;
S2-6, adding water, adding glacial acetic acid to adjust the pH value to 5-6, and separating an upper water phase, adding anhydrous sodium sulfate into an organic phase for drying, and concentrating under negative pressure until no liquid is discharged, thus obtaining a tan oily substance, namely 1-benzyl-2-methylimidazole-4-formaldehyde;
s3-1, adding diethyl succinate into absolute ethyl alcohol;
s3-2, stirring and adding sodium tert-butoxide;
s3-3, after the addition, stirring and heating to 50-60 ℃;
s3-4, dropwise adding the 1-benzyl-2-methylimidazole-4-formaldehyde;
s3-5, after the addition, preserving heat for 2 hours at 50-60 ℃;
S3-6, concentrating under negative pressure to remove ethanol, adding dichloromethane, adding water, adding glacial acetic acid to adjust the pH value to 4-5, separating an upper water phase, concentrating a lower organic phase under negative pressure to prevent liquid, adding absolute ethanol, stirring and cooling to 0 ℃ plus or minus 5 ℃, filtering, and vacuum drying at 50 ℃ to obtain a pale yellow solid, namely (E) -4- (1-benzyl-2-methyl-1H-imidazol-5-yl) -3- (ethoxyacyl) but-3-enoic acid.
2. The process according to claim 1, wherein the reaction of 2-bromopropionaldehyde with acetamidine hydrochloride is carried out in a first solvent,
The first solvent comprises at least one of dichloromethane, tetrahydrofuran, acetone or butanone.
3. The method according to claim 1, wherein the reaction of 2-bromopropionaldehyde with acetamidine hydrochloride is performed under the protection of nitrogen.
4. The process according to claim 1, wherein the reaction of 2-bromopropionaldehyde with acetamidine hydrochloride is carried out under the catalysis of a strong base,
The strong base comprises at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium hydroxide or sodium hydroxide.
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| CN1269813C (en) * | 2000-09-05 | 2006-08-16 | 阿斯特拉曾尼卡有限公司 | Imidazolo-5-yl-2-anilino-pyrimidines as agents for inhibition of cell proliferation |
| CN114213337A (en) * | 2021-12-30 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of benzimidazole drug intermediate |
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| EP1741711A1 (en) * | 2005-07-04 | 2007-01-10 | KRKA, D.D., Novo Mesto | A process for the preparation of losartan derivatives by chlorination and reduction of the respective 1H-imidazole-5-carbaldehydes |
| KR101472686B1 (en) * | 2013-07-09 | 2014-12-16 | 씨제이헬스케어 주식회사 | Method for preparation of benzimidazole derivatives |
| CN115028587A (en) * | 2022-06-23 | 2022-09-09 | 苏州诚和医药化学有限公司 | Preparation process of benzimidazole derivative intermediate |
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| CN1269813C (en) * | 2000-09-05 | 2006-08-16 | 阿斯特拉曾尼卡有限公司 | Imidazolo-5-yl-2-anilino-pyrimidines as agents for inhibition of cell proliferation |
| CN114213337A (en) * | 2021-12-30 | 2022-03-22 | 苏州诚和医药化学有限公司 | Production process of benzimidazole drug intermediate |
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