A kind of preparation method of glutamine ethyl imidazole

Abstract

The present invention provides a method for preparing glutamidoethyl imidazole, and belongs to the technical field of organic synthesis. The method comprises the following steps: (1) condensing tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl fat with an amide condensation agent and histamine to obtain an intermediate; (2) hydrolyzing the intermediate under acidic conditions to obtain glutamidoethyl imidazole. Compared with the prior art, the preparation method of glutamidoethyl imidazole of the present invention has mild reaction conditions, adopts Boc as a protecting group, and has a simple and easy removal process.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and more specifically to a method for preparing glutamidoethylimidazole. Background Art

[0002] Glutamine ethyl imidazole, molecular formula is C 10 H 16 N4O3 is a compound formed by amide condensation of the α-carboxyl group of glutamic acid with the terminal amino group on histamine. Glutamine ethyl imidazole, as an anti-aging biorhythm synchronization peptide, is used to promote the expression of the skin's natural periodic circadian rhythm genes, thereby obtaining the best correlation between the physiological activity of skin cells and environmental constraints. It has the following effects: optimizing the natural defense of keratinocytes and fibroblasts, promoting the expression of vitamin D biotransformation enzymes, improving the renewal and regeneration capacity of corneocytes and keratinocytes, and promoting skin microcirculation through detoxification and nutrient supply. In recent years, due to the above-mentioned effects of glutamine ethyl imidazole, it has been widely used in cosmetics as an anti-aging functional raw material, and the demand has increased year by year. However, the existing synthesis process of glutamine ethyl imidazole is relatively demanding and dangerous. Summary of the invention

[0003] In view of this, the object of the present invention is to provide a method for preparing glutamidoethyl imidazole, the reaction conditions are mild, and the removal process is simple and easy.

[0004] In order to achieve the above object, the present invention adopts the following technical solutions:

[0005] A method for preparing glutamine ethyl imidazole comprises the following steps:

[0006] (1) subjecting tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester to a condensation reaction with an amide condensation agent and histamine to obtain an intermediate;

[0007] (2) hydrolyzing the intermediate under acidic conditions to obtain glutamidoethylimidazole.

[0008] The preparation route of glutamidoethylimidazole of the present invention is as follows:

[0009]

[0010] Preferably, the molar ratio of tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, amide condensation agent and histamine is 1:(2.5-3.5):(2-2.5).

[0011] Preferably, the condensation reaction is carried out in the presence of an organic amine.

[0012] Preferably, the organic amine is one or more of triethylamine, diisopropylethylamine and pyridine.

[0013] Preferably, the molar ratio of tert-butyloxycarbonyl-L-glutamate-5-tert-butyl ester to the organic amine is 1:(1.5-2.5).

[0014] Preferably, the amide condensation agent is a carbodiimide condensation agent and / or an onium salt condensation agent.

[0015] Preferably, the acidic conditions are provided by trifluoroacetic acid.

[0016] Preferably, the condensation reaction is carried out in an organic solvent; the organic solvent is acetone and / or acetonitrile.

[0017] Preferably, the reaction temperature in step (1) is 40-60°C and the reaction time is 8-12 hours; the reaction temperature in step (2) is 20-40°C and the reaction time is 3-5 hours.

[0018] Preferably, after hydrolysis, the pH of the reaction system is adjusted to 7.5-8, the organic phase is separated, and then recrystallization is performed; the solvent used for the recrystallization is ethanol, and the recrystallization temperature is 0-5°C.

[0019] The invention provides a method for preparing glutamidoethylimidazole, wherein tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester and histamine are condensed by an amide condensation agent, and then a Boc group is acid-lyzed to obtain a target compound, the reaction conditions are mild, Boc is used as a protecting group, the removal process is simple and easy, and no dangerous deprotection process is required. In addition, the reaction yield of the invention is high, which is above 62%; the subsequent purification process is simple, the purity is above 97%, and it is suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of glutamidoethylimidazole prepared in Example 2 of the present invention;

[0021] Figure 2 is the carbon nuclear magnetic resonance spectrum of glutamidoethylimidazole prepared in Example 2 of the present invention;

[0022] Figure 3 It is the mass spectrum of glutamine ethylimidazole prepared in Example 2 of the present invention. DETAILED DESCRIPTION

[0023] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0024] The present invention provides a method for preparing glutamidoethyl imidazole, comprising: (1) subjecting tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester to a condensation reaction with an amide condensation agent and histamine to obtain an intermediate; and (2) hydrolyzing the intermediate under acidic conditions to obtain glutamidoethyl imidazole.

[0025] The intermediate is obtained by condensing tert-butyloxycarbonyl-L-glutamate-5-tert-butyl ester with an amide condensation agent and histamine; the molar ratio of the tert-butyloxycarbonyl-L-glutamate-5-tert-butyl ester, the amide condensation agent and the histamine is 1:(2.5-3.5):(2-2.5); the condensation reaction is preferably carried out in the presence of an organic amine; the molar ratio of the tert-butyloxycarbonyl-L-glutamate-5-tert-butyl ester and the organic amine is 1:(1.5-2.5); the organic amine is one or more of triethylamine, diisopropylethylamine and pyridine; the organic amine is preferably triethylamine or diisopropylethylamine; the condensation reaction is also preferably carried out in an organic solvent; the organic solvent is acetone or acetonitrile, preferably acetonitrile; the amide condensation agent is a carbodiimide condensation agent and / or an onium salt Condensation agent; the amide condensation agent is preferably one or more of DCC, EDCI, HOBT, HBTU, and PyBop, more preferably one or more of EDCI, HOBT, and PyBop, and more preferably EDCI and HOBT, and the molar ratio of EDCI and HOBT is preferably (1-2):1; the temperature of the condensation reaction is 40-60°C, and the time is 8-12h; the temperature of the condensation reaction is preferably 60°C, and the time is preferably 8h; in the present invention, this step preferably first dissolves tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester in an organic solvent, adds the amide condensation agent and the organic amine, stirs for 1h, then adds histamine, heats to 60°C and continues to stir, and extracts and separates to obtain the intermediate; the stirring time is preferably 8h.

[0026] The intermediate is hydrolyzed under acidic conditions; the acidic conditions are provided by trifluoroacetic acid; the reaction temperature of the hydrolysis is 20-40°C and the time is 3-5h; the temperature of the hydrolysis is preferably room temperature and the time is preferably 3h; in the present invention, in this step, the intermediate is preferably dispersed in trifluoroacetic acid and a solvent and stirred for 3h; the volume ratio of the trifluoroacetic acid and the solvent is preferably 1:1; the solvent is preferably dichloromethane.

[0027] After hydrolysis, the pH of the reaction system is preferably adjusted to 7.5-8, the organic phase is separated, and then recrystallization is performed; the solvent used for the recrystallization is ethanol, and the temperature of the recrystallization is 0-5°C; in the present invention, after hydrolysis, distillation is preferably performed first, water is added, and then activated carbon is added to adsorb impurities, stirring, and filtering to obtain a filtrate, and the pH of the filtrate is adjusted to 7.5-8, ethanol is added after evaporating the water, and then recrystallization is performed, filtering, and drying to obtain glutamine ethyl imidazole; the stirring temperature is preferably 50°C, and the time is preferably 30min; the pH of the filtrate is preferably adjusted with an alkaline solution; the alkaline solution is preferably sodium hydroxide solution and / or potassium hydroxide solution; the concentration of the alkaline solution is preferably 2M; after the addition of ethanol, the system is preferably hot filtered and then low-temperature recrystallized; the temperature of the hot filtration is 70°C, and the recrystallization includes: cooling the filtered filtrate and stirring for crystallization; the filtrate is preferably cooled to 5°C, the temperature of the stirring crystallization is preferably 0-5°C, and the time is preferably 30min.

[0028] The reaction conditions of the present invention are mild, Boc is used as a protecting group, the removal process is simple and easy, and no dangerous deprotection process is required. In addition, the reaction yield of the present invention is high, which is above 62%; the subsequent purification process is simple, the purity is above 97%, and it is suitable for industrial large-scale production.

[0029] In order to further illustrate the present invention, the following examples are provided for detailed description. The raw materials used in the following examples of the present invention are all commercially available commodities.

[0030] Example 1

[0031] The preparation method of glutamidoethylimidazole of the present embodiment comprises the following steps:

[0032] (1) Weigh 1 g of tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester and dissolve it in 50 ml of acetone. Add 0.53 g of HOBt and 0.67 g of triethylamine respectively. Then, dropwise add an acetone solution containing 0.95 g of EDCI. After the dropwise addition is completed, stir for 1 h. Then, add 0.9 g of histamine. Heat to 60°C and maintain stirring for 8 h. After extraction and separation, obtain the intermediate.

[0033] (2) The intermediate obtained in step (1) was dispersed in 10 ml of TFA / CH2Cl2 (volume ratio 1:1) solution and stirred for 3 h. After vacuum distillation, it was dispersed in 200 ml of purified water, 100 mg of activated carbon was weighed and added thereto, stirred at 50° C. for 30 min, filtered, and the pH of the filtrate was adjusted to 7.5-8 with 2M NaOH aqueous solution. The aqueous solution was evaporated under reduced pressure, and the product obtained by vacuum distillation was dispersed in 30 ml of anhydrous ethanol solution, heated to 70° C. to fully dissolve, filtered while hot, and then the filtrate was placed in a reaction bottle, gradually cooled to 5° C. and stirred for crystallization. After crystals precipitated, the temperature was maintained at 0-5° C. and stirred for 30 min. The mixture was filtered and dried to obtain the target compound with a yield of 62% and a purity of 97%.

[0034] Example 2

[0035] The preparation method of glutamidoethylimidazole of the present embodiment comprises the following steps:

[0036] (1) Weigh 1 g of tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester and dissolve it in 50 ml of acetonitrile. Add 0.53 g of HOBt and 0.67 g of triethylamine respectively. Then, dropwise add an acetone solution containing 0.95 g of EDCI. After the dropwise addition is completed, stir for 1 h. Then, add 0.9 g of histamine. Heat to 60°C and maintain stirring for 8 h. After extraction and separation, obtain the intermediate.

[0037] (2) The intermediate obtained in step (1) was dispersed in 10 ml of TFA / CH2Cl2 (volume ratio 1:1) solution and stirred for 3 h. After vacuum distillation, it was dispersed in 200 ml of purified water, 100 mg of activated carbon was weighed and added thereto, stirred at 50° C. for 30 min, filtered, and the pH of the filtrate was adjusted to 7.5-8 with a 2M NaOH aqueous solution. The aqueous solution was evaporated under reduced pressure, and the product obtained by vacuum distillation was dispersed in 30 ml of anhydrous ethanol solution, heated to 70° C. to fully dissolve, filtered while hot, and then the filtrate was placed in a reaction bottle, gradually cooled to 5° C. and stirred for crystallization. After crystals precipitated, the temperature was maintained at 0-5° C. and stirred for 30 min. The mixture was filtered and dried to obtain the target compound with a yield of 70% and a purity of 97%. The target compound was tested by hydrogen nuclear magnetic resonance spectrum, carbon nuclear magnetic resonance spectrum and mass spectrometry. The experimental results are as follows: Figures 1 to 3 and as shown below.

[0038] 1H NMR(400MHz, Deuterium Oxide)δ8.64(d,J=1.7Hz,1H),7.33(s,1H),4.01(t,J=6.6Hz,1H),3.69(dt,J=14.0,7.0Hz,1H),3.54(dt,J=13 .6, 6.4Hz, 1H), 3.01 (td, J=6.6, 3.8Hz, 2H), 2.91 (d, J=5.8Hz, 1H), 2.43 (q, J=7.1Hz, 2H), 2.12 (q, J=7.1Hz, 2H). 13 CNMR (101MHz, D2O) δ176.31, 169.14, 134.07, 131.44, 116.36, 49.60, 38.38, 28.94, 26.19, 22.80. HRMS (M+H): 241.1306, purity 97%.

[0039] Example 3

[0040] The preparation method of glutamidoethylimidazole of the present embodiment comprises the following steps:

[0041] (1) Weigh 1 g of tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester and dissolve it in 50 ml of acetonitrile. Add 2.57 g of PyBOP and 0.67 g of triethylamine respectively. After stirring for 1 h, add 0.9 g of histamine. Heat to 60°C and maintain stirring for 8 h. After extraction and separation, obtain the intermediate.

[0042] (2) The intermediate obtained in step (1) was dispersed in 10 ml of TFA / CH2Cl2 (volume ratio 1:1) solution and stirred for 3 h. After vacuum distillation, it was dispersed in 200 ml of purified water, 100 mg of activated carbon was weighed and added thereto, stirred at 50° C. for 30 min, filtered, and the pH of the filtrate was adjusted to 7.5-8 with 2M NaOH aqueous solution. The aqueous solution was evaporated under reduced pressure, and the product obtained by vacuum distillation was dispersed in 30 ml of anhydrous ethanol solution, heated to 70° C. to fully dissolve, filtered while hot, and then the filtrate was placed in a reaction bottle, gradually cooled to 5° C. and stirred for crystallization. After crystals precipitated, the temperature was maintained at 0-5° C. and stirred for 30 min. The mixture was filtered and dried to obtain the target compound with a yield of 70% and a purity of 97%.

[0043] Example 4

[0044] The preparation method of glutamidoethylimidazole of the present embodiment comprises the following steps:

[0045] (1) Weigh 1 g of tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester and dissolve it in 50 ml of acetonitrile. Add 2.57 g of PyBOP and 0.85 g of diisopropylethylamine respectively. After stirring for 1 h, add 0.9 g of histamine. Heat to 60°C and maintain stirring for 8 h. After extraction and separation, obtain the intermediate.

[0046] (2) The intermediate obtained in step (1) was dispersed in 10 ml of TFA / CH2Cl2 (volume ratio 1:1) solution and stirred for 3 h. After vacuum distillation, it was dispersed in 200 ml of purified water, 100 mg of activated carbon was weighed and added thereto, stirred at 50° C. for 30 min, filtered, and the pH of the filtrate was adjusted to 7.5-8 with 2M NaOH aqueous solution. The aqueous solution was evaporated under reduced pressure, and the product obtained by vacuum distillation was dispersed in 30 ml of anhydrous ethanol solution, heated to 70° C. to fully dissolve, filtered while hot, and then the filtrate was placed in a reaction bottle, gradually cooled to 5° C. and stirred for crystallization. After crystals precipitated, the temperature was maintained at 0-5° C. and stirred for 30 min. The mixture was filtered and dried to obtain the target compound with a yield of 70% and a purity of 97%.

[0047] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing glutamidoethyl imidazole, characterized in that: The following steps are involved: (1) dissolving tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester in an organic solvent, adding an amide condensation agent and an organic amine, stirring for 1 hour, then adding histamine, heating to 60° C. and continuing stirring, extracting and separating to obtain an intermediate; the organic solvent is acetonitrile; the organic amine is one or more of triethylamine and diisopropylethylamine; (2) hydrolyzing the intermediate under acidic conditions to obtain glutamidoethylimidazole.

2. The method for preparing glutamidoethyl imidazole according to claim 1, characterized in that: The molar ratio of the tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, the amide condensation agent and the histamine is 1:(2.5-3.5):(2-2.5).

3. The preparation method of glutamidoethyl imidazole according to claim 1, characterized in that The molar ratio of the tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester to the organic amine is 1:(1.5-2.5).

4. The method for preparing glutamidoethyl imidazole according to claim 1 or 2, characterized in that: The amide condensation agent is a carbodiimide condensation agent and / or an onium salt condensation agent.

5. The method for preparing glutamidoethyl imidazole according to claim 1 or 2, characterized in that: The acidic conditions were provided by trifluoroacetic acid.

6. The method for preparing glutamidoethylimidazole according to claim 1 or 2, characterized in that: The reaction time in step (1) is 8 to 12 hours; the reaction temperature in step (2) is 20 to 40° C. and the reaction time is 3 to 5 hours.

7. The method for preparing glutamidoethylimidazole according to claim 1 or 2, characterized in that: After hydrolysis, the pH of the reaction system is adjusted to 7.5-8, the organic phase is separated, and then recrystallization is performed; the solvent used for the recrystallization is ethanol, and the recrystallization temperature is 0-5°C.

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