A preparation method of 1H-imidazole-1-acetic acid alkyl ester

Abstract

The present invention discloses a method for preparing 1H-imidazole-1-acetic acid hydrocarbon ester, comprising the following steps: using a halogenated alkane as a solvent, reacting imidazole with an alkali metal alcoholate to obtain an imidazole alkali metal salt, and then reacting with an N-alkylating agent to obtain the 1H-imidazole-1-acetic acid hydrocarbon ester. The raw materials used are inexpensive and readily available, the experimental operation is simple and gentle, the yield and purity of the obtained product are high, production costs are significantly reduced, and the method provides good application prospects for the industrial production of zoledronic acid raw materials.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and in particular to a method for preparing 1H-imidazole-1-acetic acid alkyl ester. Background Art

[0002] Zoledronic acid is a third-generation heterocyclic bisphosphonate developed by Novartis in Switzerland. It was first approved for marketing in Canada in 2000 under the trade name Zometa. It can be used to treat hypercalcemia caused by malignant tumors, bone metastases caused by multiple myeloma and solid tumors, and osteoporosis in menopausal women. Clinical results have shown that zoledronic acid is the most effective bisphosphonate to date. Its structural formula is

[0003] 1H-imidazole-1-acetate is an important intermediate for the synthesis of zoledronic acid drugs and imidazole-type ionic liquids. 1H-imidazole-1-acetate (hydrocarbon 1H-imidazole-1-acetate), chemical name 1H-imidazole-1-acetate, chemical structure:

[0004] The Chinese journal "Chemical Intermediates," issue 8, 2011, pp. 49-50, discloses a method for synthesizing ethyl 1H-imidazole-1-acetate: ethyl imidazole-1-acetate is prepared by reacting ethyl chloroacetate and ethyl bromoacetate with imidazole. Ethyl halide acetate and anhydrous potassium carbonate are added, followed by heating under reflux and cooling to room temperature. After filtration, the mixture is dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to yield a pale yellow liquid. This process requires high-temperature reflux, resulting in high energy consumption. Furthermore, it generates a large number of impurities, making impurity removal difficult. The resulting product requires column chromatography, resulting in high production costs, low product yield, and the formation of ethyl imidazole-1-acetate as an impurity.

[0005] Chinese patent CN113979946A discloses a method for synthesizing ethyl 1H-imidazole-1-acetate: imidazole, potassium hydroxide, potassium carbonate, and tetrabutylammonium bromide are added to a reaction flask and reacted for 2-4 hours. Ethyl acetate is then added dropwise and reacted for 10-15 hours. The mixture is then filtered, washed multiple times with saturated brine, and distilled to obtain an oily liquid. This process has a long reaction time, produces many byproducts, requires multiple washings, and has a low yield of only approximately 30%. Furthermore, the use of tetrabutylammonium bromide increases the process's disposal costs, making it unsuitable for industrial production.

[0006] Huimin Luo et al. (Huimin Luo, Sheng Dai, Peter V. Bonnesen, et al. Separation of Fission Products Based on Room-Temperature Ionic Liquids [J]. American Chemical Society, 2006, 146-161.) used the hazardous reagent sodium hydride to remove the active hydrogen from imidazole and then conduct a nucleophilic substitution reaction. This method has high safety risks, and the sodium hydride sold industrially contains kerosene, which is not conducive to impurity removal and is not suitable for industrial production.

[0007] Chinese patent CN103342696A discloses a method for synthesizing ethyl 1H-imidazole-1-acetate: sodium is added to ethanol as a solvent to produce sodium ethoxide. Imidazole and ethyl bromoacetate are then added and reacted at room temperature. Ethyl 1H-imidazole-1-acetate is obtained through a series of operations, including filtration, vacuum distillation, further filtration, and column chromatography. However, this process has the following drawbacks: the use of flammable sodium metal increases production safety risks; post-processing requires column chromatography, which is cumbersome; and the use of ethanol as a solvent is costly. Furthermore, the process produces a high number of byproducts and results in a low product yield.

[0008] Therefore, the current preparation of 1H-imidazole-1-acetic acid esters has many problems such as many by-products, low yield, and complicated post-processing. Therefore, it is necessary to develop a new method suitable for industrial production. Summary of the Invention

[0009] The present invention provides a novel method for preparing 1H-imidazole-1-acetic acid hydrocarbon ester, comprising the following steps:

[0010] (a) using a halogenated alkane as a solvent, reacting imidazole with an alkali metal alcoholate to obtain a mixture containing an imidazole alkali metal salt;

[0011] (b) cooling the mixture to -30°C to -5°C, adding a haloalkane solution containing an N-alkylating agent represented by formula (I) to react to obtain a 1H-imidazole-1-acetic acid ester represented by formula (II);

[0012] The reaction formula is as follows:

[0013]

[0014] Wherein, R1 is selected from alkyl and alkylaryl, and X is Cl, Br, I or F.

[0015] In some embodiments, R1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, n-hexyl, n-heptyl, n-octyl and benzyl; preferably, R1 is selected from methyl, ethyl, n-propyl, isopropyl and n-butyl; more preferably, R1 is selected from methyl, ethyl and n-propyl; X is Br or Cl.

[0016] The applicant has found through experiments that the halogenated alkane solvent in step (a) is crucial to the progress of the reaction. The halogenated alkane solvent can promote the progress of the reaction and improve the yield and purity. In some embodiments, the halogenated alkane solvent in steps (a) and (b) is selected from dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, preferably dichloromethane or chloroform.

[0017] The present invention uses alkali metal alcoholate to increase the reaction speed on the one hand, and on the other hand, the reaction does not require the use of a phase transfer catalyst.

[0018] In some embodiments, the alkali metal alcoholate in step (a) is selected from one or more of sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, potassium methoxide, potassium ethoxide, potassium propoxide and potassium butoxide, preferably sodium methoxide or sodium ethoxide.

[0019] In some embodiments, the molar ratio of imidazole to N-alkylating agent is 0.8 to 1.5:1; preferably 1 to 1.15:1; more preferably 1.03:1.

[0020] In some embodiments, in step (a), the volume mass ratio of the halogenated alkane solvent to imidazole is 10-30 ml:1 g; the reaction temperature is 10-50° C., preferably 20-40° C.; and the reaction time is 0.5-5 h.

[0021] In some embodiments, in step (b), the N-alkylating agent is preferably methyl chloroacetate, ethyl chloroacetate, propyl chloroacetate, butyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, propyl bromoacetate, butyl bromoacetate, methyl iodoacetate, ethyl iodoacetate, propyl iodoacetate or butyl iodoacetate, more preferably ethyl bromoacetate; the molar ratio of the alkali metal alcoholate to the N-alkylating agent is 0.8 to 1.5:1; preferably 1 to 1.15:1, more preferably 1.06:1.

[0022] The applicant has also found that step (b) needs to be carried out at a low temperature. If the temperature is too high, side reactions will increase, thereby increasing the content of impurities. In addition, the ester group of the product will decompose, reducing the yield.

[0023] In some embodiments, in step (b), the mixture is cooled to -30°C to -5°C before reacting, preferably -10°C; the reaction time is 2 to 10 hours, preferably 5 hours.

[0024] The present invention has simple post-processing and can obtain a product with a purity of up to 99% by extraction without column chromatography, thus meeting the requirements of industrial production. The main reason is that the screening of reaction conditions reduces the impurity content.

[0025] In some embodiments, in step (b), the reaction mixture is extracted, concentrated, and dried to obtain 1H-imidazole-1-acetic acid hydrocarbon ester represented by formula (II).

[0026] The extraction, concentration, drying and other post-processing operations can be carried out using conventional methods and conditions in the art. Preferably, the extraction solvent used in step (b) is a mixture of an organic solvent and water, and the organic solvent is selected from one or more of dichloromethane and chloroform.

[0027] The present invention has achieved the following beneficial effects:

[0028] 1) The present invention uses a halogenated alkane as the reaction solvent and adds a halogenated alkane solution containing an N-alkylating agent to the reaction at low temperature. Selecting these conditions can reduce impurity formation and improve yield. Post-processing eliminates the need for column separation; a product with a yield of ≥90% and a purity of up to 99% can be obtained simply through extraction and concentration. However, when these conditions are changed, such as replacing the solvent with ethanol and operating the reaction at room temperature, side reactions increase and more impurities are generated, significantly reducing the yield and purity.

[0029] 2) The method of the present invention has readily available raw materials, simple operation, mild reaction conditions, short reaction time, low cost, good safety, conforms to the trend of green chemical industry, and has good industrial production application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the following description of the embodiments with reference to the accompanying drawings, in which:

[0031] Figure 1 HPLC chart of ethyl 1H-imidazole-1-acetate obtained in Example 1;

[0032] Figure 2 This is the H NMR spectrum of the product 1H-imidazole-1-acetic acid ethyl ester obtained in Example 1;

[0033] Figure 3 This is the NMR carbon spectrum of the product 1H-imidazole-1-acetic acid ethyl ester obtained in Example 1; DETAILED DESCRIPTION

[0034] The embodiments of the present invention are described in detail below, and examples of the embodiments are shown in the accompanying drawings. The embodiments described below with reference to the accompanying drawings are exemplary and intended to be used to explain the present invention, but should not be understood as limiting the present invention.

[0035] The endpoints and any values of the ranges described herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered to be specifically disclosed herein.

[0036] Example 1:

[0037] Imidazole (20.0 g, 0.294 mol, 1.0 eq), dichloromethane (240 mL), and sodium ethoxide (20.33 g, 0.299 mol, 1.02 eq) were added to a three-necked flask and stirred at 35°C for 2 h. After the reaction, the temperature was lowered to -10°C, and ethyl bromoacetate (47.1 g, 0.282 mol, 0.96 eq) dissolved in dichloromethane (48 ml) was added and reacted for 5 h. After the reaction was complete, the mixture was filtered and the filtrate was collected and dried. The filtrate was extracted with dichloromethane and water, and the organic layer was evaporated to dryness to obtain 1H-imidazole-1-acetic acid ethyl ester as a light yellow liquid (41.82 g, HPLC purity 99.0%, yield 96.3%).

[0038] HPLC: Rt = 13.916 min, see Figure 1 ; NMR hydrogen and carbon spectra are shown in Figure 2-Figure 3 .

[0039] MS (ESI): m / z = 155.1 [M+H] + .

[0040] 1 HNMR (500MHz, CDCl3), δ: 7.50(1H,s),7.09(1H,s),6.95(1H,s),4.68(2H,s),4.21-4.26(2H,q),1.23-1.30(3H,t).

[0041] 13 CNMR (500MHz, CDCl3), δ: 167.37, 137.96, 129.80, 119.95, 62.12, 48.13, 14.22.

[0042] Example 2

[0043] Imidazole (25 g, 0.368 mol, 1.0 eq), dichloromethane (270 mL), and sodium ethoxide (25 g, 0.368 mol, 1.0 eq) were added to a three-necked flask and stirred at 25°C for 3 h. After the reaction, the temperature was lowered to -5°C, and ethyl bromoacetate (58.45 g, 0.35 mol, 0.95 eq) dissolved in dichloromethane (75 mL) was added and allowed to react for 5 h. After the reaction was complete, the mixture was filtered and the filtrate was collected and dried by rotary evaporation. The filtrate was extracted with dichloromethane and water, and the organic layer was evaporated to dryness to obtain ethyl 1H-imidazole-1-acetate as a pale yellow liquid (51.58 g, HPLC purity 98.7%, yield 95.7%). MS (ESI): m / z = 155.1 [M+H] + .

[0044] Example 3

[0045] Imidazole (20.4 g, 0.3 mol, 1.0 eq), dichloromethane (255 mL), and sodium ethoxide (21.08 g, 0.31 mol, 1.03 eq) were added to a three-necked flask and stirred at 30°C for 2 h. After the reaction, the temperature was lowered to -30°C, and ethyl bromoacetate (47.1 g, 0.282 mol, 0.94 eq) dissolved in dichloromethane (60 mL) was added and allowed to react for 6 h. After the reaction was complete, the mixture was filtered and the filtrate was collected and dried by rotary evaporation. The filtrate was extracted with dichloromethane and water, and the organic layer was evaporated to dryness to obtain ethyl 1H-imidazole-1-acetate as a pale yellow liquid (41.17 g, HPLC purity 98.5%, yield 94.8%). MS (ESI): m / z = 155.1 [M+H] + .

[0046] Example 4

[0047] Imidazole (24.5 g, 0.36 mol, 1.0 eq), dichloromethane (265 mL), and sodium ethoxide (25.16 g, 0.37 mol, 1.03 eq) were added to a three-necked flask and stirred at 30°C for 2 h. After the reaction, the temperature was lowered to 0°C, and ethyl bromoacetate (55.11 g, 0.33 mol, 0.92 eq) dissolved in dichloromethane (80 mL) was added and allowed to react for 4.5 h. After the reaction was complete, the mixture was filtered and the filtrate was collected and dried by rotary evaporation. The filtrate was extracted with dichloromethane and water, and the organic layer was evaporated to dryness to obtain ethyl 1H-imidazole-1-acetate as a pale yellow liquid (46.86 g, HPLC purity 94.7%, yield 92.2%). MS (ESI): m / z = 155.1 [M+H] + .

[0048] Example 5

[0049] Imidazole (23 g, 0.338 mol, 1.0 eq), dichloromethane (250 mL), and sodium ethoxide (21.14 g, 0.355 mol, 1.05 eq) were added to a three-necked flask and stirred at 32°C for 1.5 h. After the reaction, the temperature was lowered to -20°C, and ethyl bromoacetate (53.44 g, 0.32 mol, 0.95 eq) dissolved in dichloromethane (55 mL) was added and allowed to react for 5.5 h. After the reaction was complete, the mixture was filtered and the filtrate was collected and dried by rotary evaporation. The filtrate was extracted with dichloromethane and water, and the organic layer was evaporated to dryness to obtain ethyl 1H-imidazole-1-acetate as a pale yellow liquid (46.91 g, HPLC purity 98.6%, yield 95.2%). MS (ESI): m / z = 155.1 [M+H] + .

[0050] Example 6

[0051] Imidazole (24 g, 0.353 mol, 1.0 eq), dichloromethane (260 mL), and sodium ethoxide (24.48 g, 0.36 mol, 1.02 eq) were added to a three-necked flask and stirred at 35°C for 2 h. After the reaction, the temperature was lowered to 25°C, and ethyl bromoacetate (56.78 g, 0.34 mol, 0.96 eq) dissolved in dichloromethane (70 mL) was added and allowed to react for 6 h. After the reaction was complete, the mixture was filtered and the filtrate was collected and dried by rotary evaporation. The filtrate was extracted with dichloromethane and water, and the organic layer was evaporated to dryness to obtain ethyl 1H-imidazole-1-acetate as a pale yellow liquid (45.66 g, HPLC purity 92.1%, yield 87.2%). MS (ESI): m / z = 155.1 [M+H] + .

[0052] Example 7

[0053] Imidazole (27.2 g, 0.4 mol, 1.0 eq), 1,2-dichloroethane (280 mL), and sodium ethoxide (27.2 g, 0.4 mol, 1.0 eq) were added to a three-necked flask and stirred at 25°C for 2.5 hours. After the reaction, the temperature was lowered to -10°C, and ethyl bromoacetate (60.12 g, 0.36 mol, 0.9 eq) dissolved in 1,2-dichloroethane (65 mL) was added and allowed to react for 6 hours. After the reaction was complete, the mixture was filtered and the filtrate was collected and dried by rotary evaporation. The filtrate was extracted with dichloromethane and water, and the organic layer was evaporated to dryness to obtain ethyl 1H-imidazole-1-acetate as a pale yellow liquid (53.28 g, HPLC purity 98.8%, yield 96.1%). MS (ESI): m / z = 155.1 [M+H] + .

[0054] Example 8

[0055] Imidazole (23.8 g, 0.35 mol, 1.0 eq), chloroform (250 mL), and sodium methoxide (18.9 g, 0.35 mol, 1.0 eq) were added to a three-necked flask and stirred at 25°C for 2 h. After the reaction, the temperature was lowered to -10°C, and methyl chloroacetate (32.55 g, 0.3 mol, 0.86 eq) dissolved in chloroform (50 mL) was added and allowed to react for 6 h. After the reaction was complete, the mixture was filtered and the filtrate was collected and dried by rotary evaporation. The filtrate was extracted with chloroform and water, and the organic layer was evaporated to dryness to obtain 1H-imidazole-1-acetic acid methyl ester as a pale yellow liquid (39.82 g, HPLC purity 98.5%, yield 94.8%). MS (ESI): m / z = 141.3 [M+H] + .

[0056] Comparative Example 1

[0057] Referring to the method of CN103342696A, the post-treatment was changed from column chromatography to extraction and concentration operation. The specific operation is as follows:

[0058] To 250 ml of ethanol, 11.8 g (0.51 mol) of sodium was slowly added, followed by 35.0 g (0.51 mol) of imidazole and 57 ml (85.8 g, 0.51 mol) of ethyl bromoacetate, added dropwise at 25°C. The mixture was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was filtered, concentrated under reduced pressure, and then extracted with dichloromethane and water. The organic layer was evaporated to dryness to obtain ethyl 1H-imidazole-1-acetate as a pale yellow liquid (68.33 g, HPLC purity 85.6%, yield 87%). MS (ESI): m / z = 155.1 [M+H] + .

[0059] The above embodiments are merely examples for clarity of explanation and are not intended to limit the implementation methods. Those skilled in the art will readily appreciate that other variations or modifications based on the above descriptions are possible. It is not necessary and impossible to enumerate all implementation methods here. Obvious variations or modifications arising therefrom remain within the scope of protection of the present invention.

Claims

1. A method for preparing 1H-imidazole-1-acetic acid alkyl ester, characterized in that: (a) using a halogenated alkane as a solvent, reacting imidazole with an alkali metal alcoholate to obtain a mixture containing an imidazole alkali metal salt; (b) cooling the mixture to -30°C to -5°C, adding a haloalkane solution containing an N-alkylating agent represented by formula (I) to react to obtain a 1H-imidazole-1-acetic acid ester represented by formula (II); The reaction formula is as follows: R1 is selected from methyl and ethyl; X is Br or Cl; The halogenated alkane in steps (a) and (b) is selected from dichloromethane, chloroform and 1,2-dichloroethane; In step (a), the alkali metal alcoholate is selected from sodium methoxide and sodium ethoxide.

2. The method according to claim 1, wherein: The molar ratio of imidazole to N-alkylating agent is 0.8-1.5:

1.

3. The method according to claim 2, wherein: The molar ratio of imidazole to the N-alkylating agent is 1 to 1.15:

1.

4. The method according to claim 1, wherein: The volume mass ratio of the halogenated alkane solvent to imidazole in step (a) is 10-30 ml:1 g.

5. The method according to claim 1, wherein: The reaction temperature in step (a) is 10-50° C. and the reaction time is 0.5-5 h.

6. The method according to claim 1, wherein: The molar ratio of the alkali metal alcoholate to the N-alkylating agent is 0.8 to 1.5:

1.

7. The method according to claim 6, characterized in that: The molar ratio of the alkali metal alcoholate to the N-alkylating agent is 1 to 1.15:

1.

8. The method according to claim 1, wherein in step (b), the reaction mixture is cooled to -10°C and the reaction time is 2 to 10 hours.

9. The method according to claim 1, wherein: In step (b), after the reaction is completed, the 1H-imidazole-1-acetic acid hydrocarbon ester represented by formula (II) is obtained by extraction, concentration and drying.

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