An imidazole derivative, its preparation method and application

Abstract

The present invention discloses an imidazole derivative, a preparation method thereof, and an application, belonging to the field of organic chemistry. The preparation method of the imidazole derivative of the present invention includes: adding compound 2a and dimethyl sulfate into an organic solvent, heating and reacting to obtain compound 3a; wherein, compound 2a is prepared by adding compound 1a, TrtCl, and a base reagent into a solvent, controlling the temperature at 0-10 °C, mixing evenly and reacting. The present invention also further prepares 2-(1-methylimidazol-5-yl)ethylamine (4a) by using the imidazole derivative. The present invention selects dimethyl sulfate as a methylation reagent and cooperates with a specific protecting group design to achieve the efficient preparation of 2-(1-methylimidazol-5-yl)ethylamine, with a total yield of 82.4%.

Description

Technical Field

[0001] The present invention relates to the field of organic chemistry, and particularly to an imidazole derivative, a preparation method thereof, and an application thereof. Background Art

[0002] PD-1 inhibitors have good curative effects in the immunotherapy of various cancers and other immune-related diseases. CN114650993A discloses a class of novel PD-1 inhibitors, and one of the chemical formulas is as follows:

[0003]

[0004] 2-(1-Methylimidazol-5-yl)ethylamine is an important intermediate for synthesizing the above novel PD-1 inhibitor.

[0005] In the prior art, there are multiple literatures reporting the synthesis methods of 2-(1-methylimidazol-5-yl)ethylamine or its analogs. For example, Collman et al. (The selective synthesis of 1-methyl-1H-histamines. J. Chem. Research (S), 2001, 195–197) reported a preparation method of 2-(1-methylimidazol-5-yl)ethylamine. This preparation method uses 2-(1-imidazol-5-yl)ethylamine as the starting material and obtains 2-(1-methylimidazol-5-yl)ethylamine through 7 steps. However, this method not only has many reaction steps but also has a low total yield, only 20.2%.

[0006] Therefore, it is necessary to develop a method for efficiently preparing 2-(1-methylimidazol-5-yl)ethylamine with high yield to meet the broad market demand. Summary of the Invention

[0007] The present invention is made to solve the above problems, and aims to provide an imidazole derivative, a preparation method thereof, and an application thereof. This imidazole derivative can be used for efficiently preparing 2-(1-methylimidazol-5-yl)ethylamine with high yield.

[0008] The present invention provides an imidazole derivative for efficiently synthesizing 2-(1-methylimidazol-5-yl)ethylamine, and its structure is as follows:

[0009]

[0010] The present invention provides a preparation method of an imidazole derivative, comprising the following steps:

[0011]

[0012] The obtained compound 2a and dimethyl sulfate were added to an organic solvent, and the mixture was heated to 50 - 60 °C for reaction to obtain the imidazole derivative 3a.

[0013] In one embodiment of the present invention, the molar ratio of compound 2a to dimethyl sulfate is 1:(1 - 3); specifically, 1:1.5 can be selected.

[0014] In one embodiment of the present invention, the concentration condition of compound 2a relative to the solvent is 0.3 - 0.6 mmol / mL.

[0015] In one embodiment of the present invention, the organic solvent is selected from any one or more of the following: toluene, ethyl acetate.

[0016] In one embodiment of the present invention, the reaction time is 2 - 8 h; preferably 3 h.

[0017] In one embodiment of the present invention, the preparation method of the imidazole derivative further includes: after the reaction is completed, the reaction solution is cooled to 20 ± 5 °C, filtered by suction, and then the filter cake is rinsed with toluene, and the filter cake is dried by suction to obtain compound 3a.

[0018] In one embodiment of the present invention, compound 2a is prepared through the following process:

[0019]

[0020] Compound 1a or its salt, trityl chloride (TrtCl), and a base reagent were added to a solvent, and the temperature was controlled at 0 - 10 °C and mixed evenly, and then the temperature was raised to room temperature for reaction to obtain compound 2a.

[0021] In one embodiment of the present invention, the molar ratio of compound 1a to trityl chloride is 1:(2 - 5); specifically, 1:2.5 can be selected.

[0022] In one embodiment of the present invention, the base reagent is selected from any one or more of the following: triethylamine, diisopropylethylamine, pyridine, DABCO, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.

[0023] In one embodiment of the present invention, the solvent is selected from any one or more of the following: dichloromethane, N,N - dimethylformamide.

[0024] In one embodiment of the present invention, the molar ratio of compound 1a to the base reagent is 1:(4 - 6); specifically, 1:5 can be selected.

[0025] In one embodiment of the present invention, the concentration condition of compound 1a relative to the solvent is 0.5 - 0.8 mmol / mL.

[0026] In one embodiment of the present invention, the preparation method of compound 2a specifically includes: adding a base reagent into a solvent and mixing evenly, then controlling the temperature at 0-10 °C under nitrogen protection, adding compound 1a, mixing evenly, controlling the temperature at 5 °C, adding triphenylmethyl chloride in three batches. After the addition is completed, raising the reaction temperature to room temperature (20-30 °C) and reacting for 15 h.

[0027] In one embodiment of the present invention, the preparation method of compound 2a further includes: after the reaction is completed, performing extraction, concentrating under reduced pressure, and filtering to obtain compound 2a.

[0028] The present invention also provides a method for preparing 2-(1-methylimidazol-5-yl)ethylamine by using the above-mentioned imidazole derivative,

[0029]

[0030] In the above formula, 0 < n ≤ 3,

[0031] Dissolve the imidazole derivative in a solvent, then slowly add concentrated hydrochloric acid, and raise the temperature to 50-60 °C for reaction to obtain 2-(1-methylimidazol-5-yl)ethylamine.

[0032] In one embodiment of the present invention, n can specifically be selected as 1 / 2, 1, 3 / 2, 2, 5 / 2, 3.

[0033] In one embodiment of the present invention, a synthesis method of 2-(1-methylimidazol-5-yl)ethylamine includes the following steps:

[0034]

[0035] (1) Add compound 1a, triphenylmethyl chloride (TrtCl), and a base reagent into a solvent, mix evenly at 0-10 °C, and then raise the temperature to room temperature for reaction to obtain compound 2a;

[0036] (2) Add the obtained compound 2a and dimethyl sulfate into an organic solvent, heat to 50-60 °C for reaction to obtain compound 3a;

[0037] (3) Dissolve the obtained compound 3a in a solvent, then slowly add concentrated hydrochloric acid, and raise the temperature to 50-60 °C for reaction to obtain the target product 4a, that is, 2-(1-methylimidazol-5-yl)ethylamine.

[0038] In one embodiment of the present invention, in step (3), the concentration condition of compound 3a relative to the solvent is 0.2-0.5 mmol / mL.

[0039] In one embodiment of the present invention, in step (3), the solvent is methanol.

[0040] In one embodiment of the present invention, in step (3), the concentration of concentrated hydrochloric acid is 36 wt% to 38 wt%.

[0041] In one embodiment of the present invention, in step (3), the dosage condition of concentrated hydrochloric acid relative to compound 3a is 0.3 - 0.5 mL / mmol.

[0042] In one embodiment of the present invention, in step (3), the reaction time is 3 h.

[0043] In one embodiment of the present invention, step (3) further includes: after the reaction is completed, the reaction solution is cooled to room temperature, toluene is added and stirred until the solid is completely dissolved, then methanol is concentrated off, extraction is carried out, the aqueous phase is left, isopropanol is added to the aqueous phase, stirred and filtered, the filter cake is rinsed with isopropanol, and after being drained, the filter cake is rotary evaporated to obtain compound 4a.

[0044] Beneficial effects:

[0045] The present invention has developed a new reaction route, selected dimethyl sulfate as the methylation reagent, and with the cooperation of a specific protecting group design, it realizes the efficient preparation of 2-(1-methylimidazol-5-yl)ethylamine, with a total yield of 82.4%. Description of the drawings

[0046] Figure 1 It is the 1H NMR spectrum of compound 3a prepared in Example 1. Detailed implementation manners

[0047] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the present invention will be specifically described below in conjunction with the embodiments.

[0048] In the following embodiments, unless otherwise specified, each raw material is a commercially available raw material.

[0049] <Example 1>

[0050] Preparation of imidazole derivative (3a)

[0051] (1) Preparation of compound 2a:

[0052] This embodiment provides a preparation method of compound 2a, and the reaction formula is as follows:

[0053]

[0054] It includes the following reaction steps:

[0055] 184 mL of dichloromethane and 50.5 g of triethylamine (0.5 mol, 5.0 eq) were added to a reaction vessel, stirred, and the temperature was controlled at 0 - 10 °C under nitrogen protection. 18.4 g of compound 1a (0.1 mol, 1.0 eq) was added, and the temperature was controlled at 5 °C. 69.7 g of triphenylmethyl chloride (0.25 mol, 2.5 eq) was added in three portions. After the addition was complete, the reaction was raised to 25 °C and reacted for 15 h. After the reaction was completed, extraction was carried out, and the solvent was concentrated under reduced pressure. Filtration gave 58.8 g of compound 2a with a yield of 98.7%.

[0056] (2) Preparation of compound 3a:

[0057] This example provides a method for preparing compound 3a, and the reaction formula is as follows:

[0058]

[0059] It includes the following reaction steps:

[0060] 140 mL of toluene and 28.0 g of compound 2a (0.047 mol) were added to a reaction vessel, stirred, 8.9 g of dimethyl sulfate (0.07 mol, 1.5 eq) was added, and the reaction was heated to 60 °C and reacted for 3 h. After the reaction was completed, the reaction solution was cooled to 20 ± 5 °C, filtered by suction, and the filter cake was washed with toluene. The filter cake was dried by suction to obtain 32.3 g of compound 3a with a yield of 100.0%.

[0061] The hydrogen spectrum of product 3a is as Figure 1 shown below. 1 H NMR (400 MHz, Chloroform-d) δ 8.95 (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 = 6.3 Hz, 2H), 2.46 (t, J = 6.2 Hz, 2H).

[0062] <Example 2>

[0063] Screening of reaction solvents

[0064] Based on Example 1, in this example, the reaction solvent in step (1) was replaced. Except for the characteristics listed in the table, the remaining experimental operations were the same as those in Example 1 to prepare compound 2a, and the corresponding yield results are shown in Table 1.

[0065] Table 1 Results of preparing compound 2a with different reaction solvents

[0066] Serial number Reaction solvent Reaction yield (%) 1 Dichloromethane 98.7 2 N,N-Dimethylformamide 48.8

[0067] As can be seen from Table 1, when dichloromethane is selected as the reaction solvent, the reaction yield is greatly improved.

[0068] <Example 3>

[0069] Screening of reaction time

[0070] In this example, on the basis of Example 1, the reaction time in step (2) was replaced. Except for the features listed in the table, the remaining experimental operations were the same as those in Example 1 to prepare compound 3a, and the corresponding yield results are shown in Table 2.

[0071] Table 2 Results of preparing compound 3a with different reaction times

[0072] Serial number Reaction time (h) Reaction yield (%) 1 2 87.9 2 3 100.0 3 8 95.3

[0073] As can be seen from Table 2, when the reaction time is 3 h, the reaction yield is the highest, and when the reaction time is 8 h, the reaction yield decreases instead. Therefore, over-time reaction cannot improve the yield.

[0074] <Example 4>

[0075] Screening of reaction solvent

[0076] In this example, on the basis of Example 1, the reaction solvent in step (2) was replaced. Except for the features listed in the table, the remaining experimental operations were the same as those in Example 1 to prepare compound 3a, and the corresponding yield results are shown in Table 3.

[0077] Table 3 Results of preparing compound 3a with different reaction solvents

[0078] Serial number Reaction solvent Reaction yield (%) 1 Toluene 100.0 2 Ethyl acetate 95.0 3 Methanol 10.5 4 Ethanol 14.7 5 Isopropanol 23.9

[0079] As can be seen from Table 3, when alcohol solvents such as methanol / ethanol are selected, the Trt protecting group will fall off during the reaction, so that the target compound cannot be obtained. When ethyl acetate and toluene are used as solvents, the reaction yields are both good. However, the product obtained using ethyl acetate is sticky in nature, while the product obtained using toluene is a solid product with good properties and is not sticky, which is more conducive to filtration and material transfer operations. Therefore, toluene is selected as the solvent.

[0080] <Example 5>

[0081] Preparation of 2-(1-methylimidazol-5-yl)ethylamine (4a):

[0082] This example provides a preparation method of compound 4a, and the reaction formula is as follows:

[0083]

[0084] It includes the following reaction steps:

[0085] 68.9 mL of methanol and 14.4 g of compound 3a (0.02 mol, 1.0 eq) obtained in Example 1 were added to a reaction vessel, stirred, and 6.9 mL of concentrated hydrochloric acid was slowly added. The temperature was raised to 60 °C and heated for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature, 51.7 mL of toluene was added, and stirred for 15 min. The solid was completely dissolved, then methanol was concentrated off, extracted, and the aqueous phase was left. 60 mL of isopropanol was added to the aqueous phase, stirred for 2 h, filtered, the filter cake was washed with isopropanol, and after being drained, the filter cake was dried by rotary evaporation to obtain 2.7 g of compound 4a with a yield of 83.5%.

[0086] 1 H NMR (500 MHz, Deuterium Oxide) δ 8.62 (s, 1H), 7.33 (s, 1H), 3.79 (s, 3H), 3.30 (t, J = 7.6 Hz, 2H), 3.09 (t, J = 7.7 Hz, 2H).

[0087] <Example 6>

[0088] Preparation of 2-(1-methylimidazol-5-yl)ethylamine (4a):

[0089]

[0090] Step (1) was the same as in Example 1 to obtain compound 2a.

[0091] 22.05 mmol of compound 2a (1.0 eq) was added to a reaction vessel, 10 mL of ethyl acetate was added, 8.34 g of dimethyl sulfate (66.15 mmol, 3.0 eq) was added, the temperature was raised to 60 °C, and stirred for 12 h. After the reaction was completed, it was cooled and filtered, the filter cake was taken, 100 mL of methanol was added, 10 mL of concentrated hydrochloric acid was added, and heated under reflux for 12 hours. Sampling and monitoring showed that the yield of the reaction product 4a was 79%.

[0092] <Comparative Example 1>

[0093] Preparation of 2-(1-methylimidazol-5-yl)ethylamine (4a):

[0094] A preparation method of compound 4a, and the reaction formula is as follows:

[0095]

[0096] It includes the following reaction steps:

[0097] Add 22.05 mmol of compound 5 (1.0 eq) to a reaction vessel, add 10 mL of ethyl acetate, add 8.34 g of dimethyl sulfate (66.15 mmol, 3.0 eq), raise the temperature to 60 °C, stir for 12 h. After the reaction is completed, cool down and filter. Take the filter cake, add 100 mL of methanol, add 10 mL of concentrated hydrochloric acid, and reflux under heating for 12 hours. Sampling and monitoring show that the main product in the reaction system is the methylation product, and the hydrolysis product 4a is in trace amounts, with a yield of less than 10%.

[0098] <Comparative Example 2>

[0099] Preparation of 2-(1-methylimidazol-5-yl)ethylamine (4a):

[0100] A preparation method of a compound 4a, the reaction formula is as follows:

[0101]

[0102] Including the following reaction steps:

[0103] Add 22.05 mmol of compound 5 (1.0 eq) to a reaction vessel, add 10 ml of ethyl acetate, add 4.7 g of methyl iodide (33.08 mmol, 1.5 eq), raise the temperature to 60 °C, stir for 12 h. After the reaction is completed, cool down and filter. Take the filter cake, add 100 mL of methanol, add 10 mL of concentrated hydrochloric acid, and reflux under heating for 12 hours. Sampling and monitoring show that the main product in the reaction system is the methylation product, and the hydrolysis product 4a is in trace amounts, with a yield of less than 10%.

[0104] <Comparative Example 3>

[0105] Preparation of 2-(1-methylimidazol-5-yl)ethylamine (4a):

[0106] A preparation method of a compound 4a, the reaction formula is as follows:

[0107]

[0108] Including the following reaction steps:

[0109] Add 22.05 mmol of compound 2a (1.0 eq) to a reaction vessel, add 10 ml of ethyl acetate, add 4.7 g of methyl iodide (33.08 mmol, 1.5 eq), raise the temperature to 60 °C, stir for 12 h. After the reaction is completed, cool down and filter. Take the filter cake, add 100 mL of methanol, add 10 mL of concentrated hydrochloric acid, and reflux under heating for 12 hours. Sampling and monitoring show that the main product in the reaction system is the methylation product, and the hydrolysis product 4a is in trace amounts, with a yield of less than 10%.

[0110] Combined with Example 1 and the comparative example, the difficulty in synthesizing the target compound 4a lies in the hydrolysis reaction, and the hydrolysis effect is jointly influenced by the substituent and the anion.

[0111] Functions and effects of the examples

[0112] Regarding the imidazole derivative involved in the above example, since a new reaction route was developed and dimethyl sulfate was selected as the methylation reagent to synthesize a new compound, the present invention can efficiently prepare 2-(1-methylimidazol-5-yl)ethylamine.

[0113] Since the reaction time and the reaction solvent were screened, further improving the reaction yield, the present invention can prepare the required imidazole derivative in a high yield.

[0114] The above embodiments are preferred cases of the present invention and are not used to limit the protection scope of the present invention.

Claims

1. An imidazole derivative having the following structure, 2. A method for preparing the imidazole derivative according to claim 1, characterized in that, It includes the following steps: Add the obtained compound 2a and dimethyl sulfate into an organic solvent, heat to 50 - 60 °C for reaction to obtain imidazole derivative 3a; The organic solvent is selected from any one or more of the following: toluene, ethyl acetate.

3. According to the method of claim 2, characterized in that, The molar ratio of compound 2a to dimethyl sulfate is 1:(1 - 3).

4. According to the method of claim 2, characterized in that, Compound 2a is prepared through the following process: Add compound 1a or its salt, trityl chloride (TrtCl), and a base reagent into a solvent, control the temperature at 0 - 10 °C, and then raise the temperature to room temperature for reaction to obtain compound 2a.

5. According to the method of claim 4, characterized in that, The molar ratio of compound 1a to trityl chloride is 1:(2 - 5).

6. According to the method of claim 4, characterized in that, The molar ratio of compound 1a to the base reagent is 1:(4 - 6).

7. According to the method of claim 4, characterized in that, The base reagent is selected from any one or more of the following: triethylamine, diisopropylethylamine, pyridine, DABCO, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide.

8. According to the method of claim 4, characterized in that, The solvent is selected from any one or more of the following: dichloromethane, N,N - dimethylformamide.

9. A method for preparing 2-(1-methylimidazol-5-yl)ethylamine by using the imidazole derivative according to claim 1, characterized in that, In the above formula, 0 < n ≤ 3, Dissolve imidazole derivative 3a in a solvent, then slowly add hydrochloric acid, raise the temperature to 50 - 60 °C for reaction to obtain 2-(1 - methylimidazol - 5 - yl)ethylamine, The concentration condition of the imidazole derivative 3a relative to the solvent is 0.2 - 0.5 mmol / mL, The concentration of the hydrochloric acid is 36 wt% - 38 wt%, The dosage condition of the hydrochloric acid relative to compound 3a is 0.3 - 0.5 mL / mmol.

Images