CN116178269A - Imidazole derivative and preparation method and application thereof - Google Patents
Imidazole derivative and preparation method and application thereof Download PDFInfo
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- CN116178269A CN116178269A CN202211572219.XA CN202211572219A CN116178269A CN 116178269 A CN116178269 A CN 116178269A CN 202211572219 A CN202211572219 A CN 202211572219A CN 116178269 A CN116178269 A CN 116178269A
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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
Abstract
The invention discloses an imidazole derivative, a preparation method and application thereof, and belongs to the field of organic chemistry. The preparation method of the imidazole derivative comprises the following steps: adding the compound 2a and dimethyl sulfate into an organic solvent, and heating for reaction to obtain a compound 3a; wherein the compound 2a is prepared by adding the compound 1a, trtCl and an alkali reagent into a solvent, and uniformly mixing and reacting at the temperature of 0-10 ℃. The invention also utilizes imidazole derivatives to further prepare 2- (1-methylimidazole-5-yl) ethylamine (4 a). According to the invention, dimethyl sulfate is selected as a methylation reagent, and a specific protecting group is matched for design, so that the efficient preparation of 2- (1-methylimidazole-5-yl) ethylamine is realized, and the total yield is 82.4%.
Description
Technical Field
The invention relates to the field of organic chemistry, in particular to an imidazole derivative, a preparation method and application thereof.
Background
PD-1 inhibitors have good therapeutic effects in the immunotherapy of a variety of cancers and other immune-related diseases. CN114650993a discloses a novel class of PD-1 inhibitors, one of which has the following chemical formula:
2- (1-methylimidazol-5-yl) ethylamine is an important intermediate for the synthesis of the novel PD-1 inhibitors.
In the prior art, there are various documents reporting a method for synthesizing 2- (1-methylimidazol-5-yl) ethylamine or its analogues, such as Collman et al (The selective synthesis of 1-methyl-1H-histamines J. Chem. Research (S), 2001, 195-197) reporting a method for preparing 2- (1-methylimidazol-5-yl) ethylamine starting from 2- (1-imidazol-5-yl) ethylamine by 7 steps, however, the method has a large number of reaction steps and a low total yield of only 20.2%.
Therefore, there is a need to develop a process for preparing 2- (1-methylimidazol-5-yl) ethylamine in high yield and high efficiency to meet the broad market demands.
Disclosure of Invention
The present invention has been made to solve the above problems, and an object of the present invention is to provide an imidazole derivative, and a method for producing the same and an application thereof. The imidazole derivative can be used for preparing 2- (1-methylimidazole-5-yl) ethylamine with high efficiency and high yield.
The invention provides an imidazole derivative for efficiently synthesizing 2- (1-methylimidazole-5-yl) ethylamine, which has the following structure:
the invention provides a preparation method of an imidazole derivative, which comprises the following steps:
adding the obtained compound 2a and dimethyl sulfate into an organic solvent, heating to 50-60 ℃ for reaction, and obtaining the imidazole derivative 3a.
In one embodiment of the invention, the molar ratio of compound 2a to dimethyl sulfate is 1: (1-3); specifically, 1:1.5.
in one embodiment of the invention, the concentration conditions of compound 2a relative to the solvent are in the range of 0.3 to 0.6mmol/mL.
In one embodiment of the invention, the organic solvent is selected from any one or more of the following: toluene, ethyl acetate.
In one embodiment of the invention, the reaction time is 2 to 8 hours; preferably 3 hours.
In one embodiment of the present invention, the method for preparing an imidazole derivative further comprises: after the reaction is finished, the temperature of the reaction solution is reduced to 20+/-5 ℃, suction filtration is carried out, toluene is used for leaching a filter cake, and the filter cake is dried by suction, thus obtaining the compound 3a.
In one embodiment of the invention, compound 2a is prepared by the process of:
adding the compound 1a or salt thereof, triphenylchloromethane TrtCl and an alkali reagent into a solvent, controlling the temperature to be 0-10 ℃ and uniformly mixing, and then heating to room temperature for reaction to obtain the compound 2a.
In one embodiment of the present invention, the molar ratio of compound 1a, triphenylchloromethane is 1: (2-5); specifically, 1:2.5.
in one embodiment of the invention, the alkaline agent is selected from any one or more of the following: triethylamine, diisopropylethylamine, pyridine, DABCO, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
In one embodiment of the invention, the solvent is selected from any one or more of the following: dichloromethane, N-dimethylformamide.
In one embodiment of the invention, the molar ratio of compound 1a to the base reagent is 1: (4-6); specifically, 1:5.
in one embodiment of the invention, the concentration conditions of compound 1a relative to the solvent are from 0.5 to 0.8mmol/mL.
In one embodiment of the present invention, the preparation method of the compound 2a specifically includes: adding an alkali reagent into a solvent, uniformly mixing, then adding a compound 1a under the protection of nitrogen, uniformly mixing, controlling the temperature at 5 ℃, adding triphenylchloromethane in three batches, and after the addition, heating the reaction to room temperature (20-30 ℃), and reacting for 15h.
In one embodiment of the present invention, the method for preparing compound 2a further comprises: after the reaction, extracting, concentrating under reduced pressure, and filtering to obtain a compound 2a.
The invention also provides a method for preparing 2- (1-methylimidazole-5-yl) ethylamine by using the imidazole derivative,
in the formula, n is more than 0 and less than or equal to 3,
dissolving the imidazole derivative in a solvent, then slowly adding concentrated hydrochloric acid, and raising the temperature to 50-60 ℃ to react to obtain the 2- (1-methylimidazole-5-yl) ethylamine.
In one embodiment of the invention, n is specifically selected from 1/2, 1, 3/2, 5/2, 3.
In one embodiment of the present invention, a method for synthesizing 2- (1-methylimidazol-5-yl) ethylamine comprises the steps of:
(1) Adding the compound 1a, triphenylchloromethane (TrtCl) and an alkali reagent into a solvent, controlling the temperature to be 0-10 ℃ and uniformly mixing, and then heating to room temperature for reaction to obtain a compound 2a;
(2) Adding the obtained compound 2a and dimethyl sulfate into an organic solvent, heating to 50-60 ℃ for reaction to obtain a compound 3a;
(3) Dissolving the obtained compound 3a in a solvent, slowly adding concentrated hydrochloric acid, and raising the temperature to 50-60 ℃ for reaction to obtain a target compound 4a, namely 2- (1-methylimidazole-5-yl) ethylamine.
In one embodiment of the invention, in step (3), the concentration condition of compound 3a relative to the solvent is 0.2-0.5mmol/mL.
In one embodiment of the present invention, step (3), the solvent is methanol.
In one embodiment of the invention, step (3) has a concentration of concentrated hydrochloric acid of 36wt% to 38wt%.
In one embodiment of the present invention, in step (3), the amount of concentrated hydrochloric acid used is in the range of 0.3 to 0.5mL/mmol relative to compound 3a.
In one embodiment of the invention, step (3), the reaction time is 3 hours.
In one embodiment of the present invention, step (3) further comprises: after the reaction is finished, the reaction solution is cooled to room temperature, toluene is added and stirred, the solid is completely dissolved, then methanol is concentrated, extraction is carried out, water phase is remained, isopropanol is added into the water phase, stirring and filtration are carried out, the filter cake is leached by isopropanol, and the filter cake is dried by spin-drying after being pumped to obtain the compound 4a.
The beneficial effects are that:
the invention develops a new reaction route, dimethyl sulfate is selected as a methylation reagent, and a specific protecting group is matched for design, so that the efficient preparation of 2- (1-methylimidazole-5-yl) ethylamine is realized, and the total yield reaches 82.4%.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of the compound 3a prepared in example 1.
Detailed Description
The present invention will be described in detail with reference to the following examples, so that the technical means, the creation characteristics, the achievement of the purpose and the effect achieved by the present invention are easily understood.
In the examples below, each of the raw materials was a commercially available raw material unless otherwise specified.
Example 1 ]
Preparation of imidazole derivatives (3 a)
(1) Preparation of compound 2 a:
this example provides a method for preparing compound 2a, which has the following reaction formula:
the method comprises the following reaction steps:
184mL of dichloromethane and 50.5g of triethylamine (0.5 mol,5.0 eq) are added into a reaction vessel, stirred, the temperature is controlled to be between 0 and 10 ℃ under the protection of nitrogen, 18.4g of compound 1a (0.1 mol,1.0 eq) is added, and the temperature is controlled to be 5 ℃; 69.7g of triphenylchloromethane (0.25 mol,2.5 eq) were added in three portions and the reaction was allowed to warm to 25℃for 15h after the addition. After the reaction, extraction, concentration under reduced pressure and filtration gave 58.8g of compound 2a in 98.7% yield.
(2) Preparation of compound 3 a:
this example provides a process for the preparation of compound 3a, having the following formula:
the method comprises the following reaction steps:
140mL of toluene and 28.0g of Compound 2a (0.047 mol) were added to the reaction vessel, stirred, 8.9g of dimethyl sulfate (0.07 mol,1.5 eq) was added, and the reaction was heated to 60℃and reacted for 3 hours. After the reaction is finished, the reaction solution is cooled to 20+/-5 ℃, suction filtration is carried out, toluene is used for leaching a filter cake, and the filter cake is dried by suction, thus obtaining 32.3g of compound 3a, and the yield is 100.0%.
The hydrogen spectrum of product 3a is shown in figure 1. 1 H NMR(400MHz,Chloroform-d)δ8.95(s,1H),7.43–7.37(m,9H),7.35–7.29(m,7H),7.26–7.16(m,14H),6.75(s,1H),3.94(s,3H),3.63(s,3H),2.84(t,J＝6.3Hz,2H),2.46(t,J＝6.2Hz,2H)。
Example 2 ]
Screening of reaction solvents
This example prepared compound 2a in the same manner as in example 1 except for the features listed in the table by substituting the reaction solvent in step (1) on the basis of example 1, and the corresponding yield results are shown in table 1.
TABLE 1 results of preparation of Compound 2a from different reaction solvents
| Sequence number | Reaction solvent | Reaction yield (%) |
| 1 | Dichloromethane (dichloromethane) | 98.7 |
| 2 | N, N-dimethylformamide | 48.8 |
As is clear from Table 1, when methylene chloride was used as the reaction solvent, the reaction yield was greatly improved.
Example 3 ]
Screening of reaction time
In this example, the reaction time in step (2) was replaced on the basis of example 1. Compound 3a was prepared in the same manner as in example 1 except for the features listed in the table, and the corresponding yield results are shown in table 2.
TABLE 2 results of preparation of Compound 3a at various reaction times
| Sequence number | Reaction time (h) | Reaction yield (%) |
| 1 | 2 | 87.9 |
| 2 | 3 | 100.0 |
| 3 | 8 | 95.3 |
As is clear from Table 2, the reaction yield was the highest when the reaction time was 3 hours, and the reaction yield was rather lowered when the reaction time was 8 hours, so that the yield could not be improved by the time-lapse reaction.
Example 4 ]
Screening of reaction solvents
This example prepared compound 3a in the same manner as in example 1 except that the reaction solvent in step (2) was replaced on the basis of example 1, and the corresponding yield results are shown in table 3.
TABLE 3 results of preparation of Compound 3a from different reaction solvents
| Sequence number | Reaction solvent | Reaction yield (%) |
| 1 | Toluene (toluene) | 100.0 |
| 2 | Acetic acid ethyl ester | 95.0 |
| 3 | Methanol | 10.5 |
| 4 | Ethanol | 14.7 |
| 5 | Isopropyl alcohol | 23.9 |
As is clear from Table 3, when an alcohol solvent such as methanol/ethanol is used, the Trt protecting group is released during the reaction, and the target compound cannot be obtained. When ethyl acetate and toluene are used as solvents, the reaction yield is good, but the product prepared by using ethyl acetate is sticky in nature, and the product prepared by using toluene is a solid product, has good properties, is not sticky, and is more beneficial to filtration and material transfer operation, so toluene is used as the solvent.
Example 5 ]
Preparation of 2- (1-methylimidazol-5-yl) ethylamine (4 a):
this example provides a process for the preparation of compound 4a, having the following formula:
the method comprises the following reaction steps:
68.9mL of methanol and 14.4g of compound 3a (0.02 mol,1.0 eq) obtained in example 1 prepared in example 1 were put into a reaction vessel, stirred, 6.9mL of concentrated hydrochloric acid was slowly added, the temperature was raised to 60℃and heated for 3 hours. After the reaction, the reaction solution is cooled to room temperature, 51.7mL of toluene is added, stirring is carried out for 15min, the solid is completely dissolved, then methanol is concentrated, extraction is carried out, water phase is remained, 60mL of isopropanol is added into the water phase, stirring is carried out for 2h, filtration is carried out, the filter cake is leached by isopropanol, after pumping, 2.7g of compound 4a is obtained by spin drying the filter cake, and the yield is 83.5%.
1 H NMR(500MHz,Deuterium Oxide)δ8.62(s,1H),7.33(s,1H),3.79(s,3H),3.30(t,J＝7.6Hz,2H),3.09(t,J＝7.7Hz,2H).
Example 6 ]
Preparation of 2- (1-methylimidazol-5-yl) ethylamine (4 a):
step (1) was the same as in example 1 to obtain compound 2a.
22.05mmol of Compound 2a (1.0 eq) was added to the reaction vessel, 10mL of ethyl acetate was added, 8.34g of dimethyl sulfate (66.15 mmol,3.0 eq) was added, the temperature was raised to 60℃and stirred for 12 hours, after the reaction was completed, the temperature was lowered and filtered, 100mL of methanol was added to the filter cake, 10mL of concentrated hydrochloric acid was added, and the mixture was heated and refluxed for 12 hours. The yield of reaction product 4a was 79% as monitored by sampling.
Comparative example 1 ]
Preparation of 2- (1-methylimidazol-5-yl) ethylamine (4 a):
a process for the preparation of compound 4a, the reaction formula is as follows:
the method comprises the following reaction steps:
22.05mmol of Compound 5 (1.0 eq) was added to the reaction vessel, 10mL of ethyl acetate was added, 8.34g of dimethyl sulfate (66.15 mmol,3.0 eq) was added, the temperature was raised to 60℃and stirred for 12 hours, after the reaction was completed, the temperature was lowered and filtered, a cake was taken, 100mL of methanol was added, 10mL of concentrated hydrochloric acid was added, and the mixture was heated and refluxed for 12 hours. Sampling and monitoring, wherein the main product in the reaction system is a methylation product, the trace amount of hydrolysate 4a is produced, and the yield is less than 10%.
Comparative example 2 ]
Preparation of 2- (1-methylimidazol-5-yl) ethylamine (4 a):
a process for the preparation of compound 4a, the reaction formula is as follows:
the method comprises the following reaction steps:
22.05mmol of Compound 5 (1.0 eq) was added to the reaction vessel, 10mL of ethyl acetate was added, 4.7g of methyl iodide (33.08 mmol,1.5 eq) was added, the temperature was raised to 60℃and stirred for 12 hours, after the reaction was completed, the temperature was lowered and filtration was carried out, a cake was taken, 100mL of methanol was added, 10mL of concentrated hydrochloric acid was added, and the mixture was heated and refluxed for 12 hours. Sampling and monitoring, wherein the main product in the reaction system is a methylation product, the hydrolysis product is 4a trace, and the yield is lower than 10%.
Comparative example 3 ]
Preparation of 2- (1-methylimidazol-5-yl) ethylamine (4 a):
a process for the preparation of compound 4a, the reaction formula is as follows:
the method comprises the following reaction steps:
22.05mmol of Compound 2a (1.0 eq) was added to the reaction vessel, 10mL of ethyl acetate was added, 4.7g of methyl iodide (33.08 mmol,1.5 eq) was added, the temperature was raised to 60℃and stirred for 12 hours, after the reaction was completed, the temperature was lowered and filtration was performed, a cake was taken, 100mL of methanol was added, 10mL of concentrated hydrochloric acid was added, and the mixture was heated and refluxed for 12 hours. Sampling and monitoring, wherein the main product in the reaction system is a methylation product, the hydrolysis product is 4a trace, and the yield is lower than 10%.
From the point of view of example 1 and comparative example, the difficulty in synthesizing the target 4a is that the hydrolysis reaction, the substituent and the anion together affect the hydrolysis effect.
Effects and effects of the examples
According to the imidazole derivatives according to the above examples, since a new reaction scheme was developed and dimethyl sulfate was selected as a methylating agent to synthesize a new compound, the present invention can efficiently produce 2- (1-methylimidazol-5-yl) ethylamine.
The present invention can produce the desired imidazole derivative in high yield because the reaction time and the reaction solvent are selected and the reaction yield is further improved.
The above embodiments are preferred examples of the present invention, and are not intended to limit the scope of the present invention.
Claims (10)
1. An imidazole derivative having a structure as shown in the specification,
2. the process for producing an imidazole derivative according to claim 1, comprising the steps of:
adding the obtained compound 2a and dimethyl sulfate into an organic solvent, heating to 50-60 ℃ for reaction, and obtaining the imidazole derivative 3a.
3. The method according to claim 1, wherein the organic solvent is selected from any one or more of the following: toluene, ethyl acetate.
4. The method according to claim 1, wherein the molar ratio of compound 2a to dimethyl sulfate is 1: (1-3).
5. The method according to claim 1, wherein compound 2a is prepared by the process of:
adding the compound 1a or salt thereof, triphenylchloromethane TrtCl and an alkali reagent into a solvent, controlling the temperature to be 0-10 ℃, and then heating to room temperature for reaction to obtain the compound 2a.
6. The method according to claim 5, wherein the molar ratio of the compound 1a to the triphenylchloromethane is 1: (2-5).
7. The method according to claim 5, wherein the molar ratio of compound 1a to the base reagent is 1: (4-6).
8. The method of claim 5, wherein the alkaline reagent is selected from any one or more of the following: triethylamine, diisopropylethylamine, pyridine, DABCO, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.
9. The method of claim 5, wherein the solvent is selected from any one or more of the following: dichloromethane, N-dimethylformamide.
10. A process for preparing 2- (1-methylimidazol-5-yl) ethylamine by using the imidazole derivative according to claim 1, characterized in that,
in the formula, n is more than 0 and less than or equal to 3,
the imidazole derivative 3a is dissolved in a solvent, hydrochloric acid is slowly added, and the temperature is raised to 50-60 ℃ to react, so that 2- (1-methylimidazole-5-yl) ethylamine is obtained.
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