CN114989091A - Preparation method of glutamyl ethyl imidazole - Google Patents
Preparation method of glutamyl ethyl imidazole Download PDFInfo
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- CN114989091A CN114989091A CN202210666367.1A CN202210666367A CN114989091A CN 114989091 A CN114989091 A CN 114989091A CN 202210666367 A CN202210666367 A CN 202210666367A CN 114989091 A CN114989091 A CN 114989091A
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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
The invention provides a preparation method of glutamyl ethyl imidazole, belonging to the technical field of organic synthesis. The method comprises the following steps: (1) carrying out condensation reaction on tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, an amide condensing agent and histamine to obtain an intermediate; (2) and hydrolyzing the intermediate under an acidic condition to obtain glutaminyl ethylimidazole. Compared with the prior art, the preparation method of glutamyl amino ethyl imidazole has mild reaction conditions, adopts Boc as a protecting group, and has simple and easy removal process.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of glutamyl ethyl imidazole.
Background
Glutamylethylimidazole of the formula C 10 H 16 N 4 O 3 The compound is a compound formed by amide condensation of a terminal amino group of a carboxyl group at the alpha position of glutamic acid on histamine. Glutamylethylimidazole is used as an anti-aging biorhythm-synchronizing peptide to promote the expression of natural periodic circadian rhythm genes of the skin, thereby obtaining the best correlation between the physiological activities of skin cells and environmental constraints. It has the following effects: optimizing the natural defenses of keratinocytes and fibroblasts,Promoting the expression of vitamin D biotransformation enzyme, improving the regeneration and regeneration of horny layer cells and keratinocytes, and promoting skin microcirculation by detoxification and nutrient supply. In recent years, glutamine ethyl imidazole, which has the above-mentioned effects, is widely used as an anti-aging effect material in cosmetics, and the demand is increasing year by year. However, the existing synthesis process of glutamine ethyl imidazole is relatively strict in requirements and relatively high in danger.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing glutamyl ethyl imidazole, which has mild reaction conditions and simple and easy removal process,
in order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of glutamyl ethyl imidazole comprises the following steps:
(1) carrying out condensation reaction on tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, an amide condensing agent and histamine to obtain an intermediate;
(2) and hydrolyzing the intermediate under an acidic condition to obtain the glutaminyl ethylimidazole.
The preparation route of the glutamyl amino ethyl imidazole is shown as follows:
preferably, the molar ratio of the tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester to the amide condensing agent to the histamine is 1 (2.5-3.5) to 2-2.5.
Preferably, the condensation reaction is carried out in the presence of an organic amine.
Preferably, the organic amine is one or more of triethylamine, diisopropylethylamine and pyridine.
Preferably, the molar ratio of the tert-butoxycarbonyl-L-glutamic acid-5-tert-butyl ester to the organic amine is 1 (1.5-2.5).
Preferably, the amide condensing agent is a carbodiimide-based condensing agent and/or an onium salt-based condensing agent.
Preferably, the acidic conditions are provided by trifluoroacetic acid.
Preferably, the condensation reaction is carried out in an organic solvent; the organic solvent is acetone and/or acetonitrile.
Preferably, the reaction temperature in the step (1) is 40-60 ℃, and the time is 8-12 h; the reaction temperature in the step (2) is 20-40 ℃, and the reaction time is 3-5 h.
Preferably, after the hydrolysis, the pH of the reaction system is adjusted to 7.5 to 8, the organic phase is separated, and then recrystallization is performed; the solvent used for recrystallization is ethanol, and the temperature of recrystallization is 0-5 ℃.
The invention provides a preparation method of glutaminyl ethylimidazole, which comprises the steps of condensing tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester and histamine by an amide condensing agent, then hydrolyzing Boc groups by acid to obtain a target compound, wherein the reaction conditions are mild, the Boc is used as a protecting group, the removal process is simple and easy to implement, and a dangerous protecting group removal process is not needed. In addition, the reaction yield of the method is high and is over 62 percent; the subsequent purification process is simple, the purity is over 97 percent, and the method is suitable for industrial large-scale production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of glutamineethylimidazole prepared in example 2 of the present invention;
FIG. 2 is a NMR carbon spectrum of glutamineethylimidazole prepared in example 2 of the present invention;
FIG. 3 is a mass spectrum of glutamineethylimidazole prepared in example 2 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a preparation method of glutamyl ethyl imidazole, which comprises the following steps: (1) carrying out condensation reaction on tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, an amide condensing agent and histamine to obtain an intermediate; (2) and hydrolyzing the intermediate under an acidic condition to obtain the glutaminyl ethylimidazole.
Carrying out condensation reaction on tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, an amide condensing agent and histamine to obtain an intermediate; the molar ratio of the tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester to the amide condensing agent to the histamine is 1 (2.5-3.5) to 2-2.5; the condensation reaction is preferably carried out in the presence of an organic amine; the molar ratio of the tert-butoxycarbonyl-L-glutamic acid-5-tert-butyl ester to 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 condensing agent is a carbodiimide condensing agent and/or an onium salt condensing agent; the amide condensing agent is preferably one or more of DCC, EDCI, HOBT, HBTU and PyBop, more preferably one or more of EDCI, HOBT and PyBop, and is further preferably EDCI and HOBT, wherein the molar ratio of EDCI to HOBT is preferably (1-2): 1; the condensation reaction is carried out at the temperature of 40-60 ℃ for 8-12 h; the temperature of the condensation reaction is preferably 60 ℃, and the time is preferably 8 h; in the invention, the preferred step is that the tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester is firstly dissolved in an organic solvent, an amide condensing agent and organic amine are added, the mixture is stirred for 1 hour, then histamine is added, the temperature is raised to 60 ℃, the mixture is continuously stirred, and an intermediate is obtained through extraction separation; the time for continuing the stirring is preferably 8 hours.
Hydrolyzing the intermediate under acidic conditions; the acidic conditions are provided by trifluoroacetic acid; the hydrolysis reaction temperature is 20-40 ℃, and the hydrolysis reaction time is 3-5 h; the hydrolysis temperature is preferably room temperature, and the hydrolysis time is preferably 3 h; in the present invention, this step preferably disperses the intermediate in trifluoroacetic acid and solvent and stirs for 3 h; the volume ratio of the trifluoroacetic acid to the solvent is preferably 1: 1; the solvent is preferably dichloromethane.
After the hydrolysis, the pH of the reaction system is preferably adjusted to 7.5 to 8, the organic phase is separated, and then recrystallization is performed; the solvent used for recrystallization is ethanol, and the temperature of recrystallization is 0-5 ℃; in the invention, after hydrolysis, preferably, distillation is carried out, then water is added, then activated carbon is added to adsorb impurities, stirring and suction filtration are carried out to obtain filtrate, the pH of the filtrate is adjusted to 7.5-8, water is evaporated to dryness, then ethanol is added, recrystallization, suction filtration and drying are carried out to obtain glutamyl amino ethyl imidazole; the stirring temperature is preferably 50 ℃, and the stirring time is preferably 30 min; adjusting the pH of the filtrate preferably with an alkaline solution; the alkaline solution is preferably a sodium hydroxide solution and/or a potassium hydroxide solution; the concentration of the alkaline solution is preferably 2M; after the addition of ethanol, the system is preferably subjected to hot filtration and then to low-temperature recrystallization; the temperature of the hot filtration is 70 ℃, and the recrystallization comprises the following steps: cooling the filtered filtrate, stirring and crystallizing; preferably, the temperature of the filtrate is reduced to 5 ℃, the stirring crystallization temperature is preferably 0-5 ℃, and the time is preferably 30 min.
The method has mild reaction conditions, adopts Boc as a protecting group, has simple and easy removal process, and does not need a dangerous protecting group removal process. In addition, the reaction yield of the method is higher and is more than 62 percent; the subsequent purification process is simple, the purity is over 97 percent, and the method is suitable for industrial large-scale production.
In order to further illustrate the present invention, the following examples are provided for illustrative purposes. The starting materials used in the following examples of the present invention are all commercially available products.
Example 1
The preparation method of glutamyl amino ethyl imidazole in this embodiment includes the following steps:
(1) weighing 1g of tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, dissolving in 50ml of acetone, respectively adding 0.53g of HOBt and 0.67g of triethylamine, dropwise adding an acetone solution containing 0.95g of EDCI, stirring for 1h after dropwise adding is finished, then adding 0.9g of histamine, heating to 60 ℃, keeping stirring for 8h, and extracting and separating to obtain an intermediate.
(2) Dispersing the intermediate obtained in step (1) in 10ml TFA/CH 2 Cl 2 (volume)Stirring the solution for 3 hours in a ratio of 1:1), carrying out reduced pressure distillation, dispersing the solution in 200ml of purified water, weighing 100mg of activated carbon, adding the activated carbon into the solution, stirring the solution for 30min at 50 ℃, carrying out suction filtration, adjusting the pH of the filtrate to 7.5-8 by using a 2M NaOH aqueous solution, evaporating the aqueous solution under reduced pressure, dispersing the product obtained by the reduced pressure distillation in 30ml of anhydrous ethanol solution, heating the solution to 70 ℃ for full dissolution, filtering the solution while the solution is hot, placing the filtrate in a reaction bottle, gradually cooling the solution to 5 ℃, stirring the solution for crystallization, keeping the temperature at 0-5 ℃ after crystals are separated out, stirring the solution for 30min, carrying out suction filtration, and drying the solution to obtain the target compound, wherein the yield is 62% and the purity is 97%.
Example 2
The preparation method of glutamyl aminoethyl imidazole in this example includes the following steps:
(1) weighing 1g of tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, dissolving in 50ml of acetonitrile, respectively adding 0.53g of HOBt and 0.67g of triethylamine, dropwise adding an acetone solution containing 0.95g of EDCI, stirring for 1h after dropwise adding is finished, then adding 0.9g of histamine, heating to 60 ℃, keeping stirring for 8h, and extracting and separating to obtain an intermediate.
(2) Dispersing the intermediate obtained in step (1) in 10ml TFA/CH 2 Cl 2 Stirring the solution for 3 hours (volume ratio is 1:1), carrying out reduced pressure distillation, dispersing the solution in 200ml of purified water, weighing 100mg of activated carbon, adding the activated carbon into the solution, stirring the solution for 30min at 50 ℃, carrying out suction filtration, adjusting the pH of the filtrate to 7.5-8 by using a 2M NaOH aqueous solution, carrying out reduced pressure distillation on the aqueous solution, dispersing the product obtained by the reduced pressure distillation into 30ml of anhydrous ethanol solution, heating the solution to 70 ℃ for full dissolution, filtering the solution while the solution is hot, placing the filtrate into a reaction bottle, gradually cooling the solution to 5 ℃, carrying out stirring crystallization, keeping the temperature at 0-5 ℃ after crystals are separated out, stirring the solution for 30min, carrying out suction filtration and drying to obtain a target compound, wherein the yield is 70% and the purity is 97%, and the target compound is respectively subjected to nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and mass spectrum tests, and the experimental results are shown in figures 1-3 and the following.
1 H 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 C NMR(101MHz,D 2 O) δ 176.31,169.14,134.07,131.44,116.36,49.60,38.38,28.94,26.19,22.80 HRMS (M + H): 241.1306 the purity is 97%.
Example 3
The preparation method of glutamyl aminoethyl imidazole in this example includes the following steps:
(1) weighing 1g of tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, dissolving in 50ml of acetonitrile, respectively adding 2.57g of PyBOP and 0.67g of triethylamine, stirring for 1h, adding 0.9g of histamine, heating to 60 ℃, keeping stirring for 8h, extracting and separating to obtain an intermediate.
(2) Dispersing the intermediate obtained in step (1) in 10ml TFA/CH 2 Cl 2 Stirring the solution for 3 hours (volume ratio is 1:1), carrying out reduced pressure distillation, dispersing the solution in 200ml of purified water, weighing 100mg of activated carbon, adding the activated carbon into the solution, stirring the solution for 30min at 50 ℃, carrying out suction filtration, adjusting the pH of the filtrate to 7.5-8 by using a 2M NaOH aqueous solution, carrying out reduced pressure distillation on the aqueous solution, dispersing the product obtained by the reduced pressure distillation into 30ml of anhydrous ethanol solution, heating the solution to 70 ℃, fully dissolving the solution, filtering the solution while the solution is hot, placing the filtrate into a reaction bottle, gradually cooling the solution to 5 ℃, carrying out stirring crystallization, keeping the temperature at 0-5 ℃ after crystals are separated out, stirring the solution for 30min, carrying out suction filtration, and drying the product to obtain the target compound, wherein the yield is 70% and the purity is 97%.
Example 4
The preparation method of glutamyl amino ethyl imidazole in this embodiment includes the following steps:
(1) weighing 1g of tert-butoxycarbonyl-L-glutamic acid-5-tert-butyl ester, dissolving in 50ml of acetonitrile, respectively adding 2.57g of PyBOP and 0.85g of diisopropylethylamine, stirring for 1h, adding 0.9g of histamine, heating to 60 ℃, keeping stirring for 8h, and extracting and separating to obtain an intermediate.
(2) Dispersing the intermediate obtained in the step (1) in 10ml TFA/CH 2 Cl 2 Stirring the solution for 3h (volume ratio 1:1), distilling under reduced pressure, dispersing in 200ml purified water, weighing 100mg of activated carbon, adding into the solution, stirring at 50 ℃ for 30min, filtering, adjusting the pH of the filtrate to 7.5-8 with 2M NaOH aqueous solution, evaporating the aqueous solution under reduced pressure, dispersing the product obtained by reduced pressure distillation in 30ml absolute ethyl alcohol solution, heating to 70 ℃ for full dissolution, filtering while hot, and placing the filtrate in 200ml purified waterAnd (3) gradually cooling to 5 ℃ in a reaction bottle, stirring for crystallization, maintaining the temperature at 0-5 ℃ after crystals are separated out, stirring for 30min, performing suction filtration, and drying to obtain the target compound, wherein the yield is 70%, and the purity is 97%.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A preparation method of glutamyl ethyl imidazole is characterized by comprising the following steps:
(1) carrying out condensation reaction on tert-butyloxycarbonyl-L-glutamic acid-5-tert-butyl ester, an amide condensing agent and histamine to obtain an intermediate;
(2) and hydrolyzing the intermediate under an acidic condition to obtain the glutaminyl ethylimidazole.
2. The method for producing glutamineethylimidazole according to claim 1 wherein the molar ratio of tert-butoxycarbonyl-L-glutamic acid-5-tert-butyl ester, amide condensing agent and histamine is 1 (2.5-3.5) to (2-2.5).
3. The process for producing glutamylethylimidazole according to claim 1 or 2, characterized in that the condensation reaction is carried out in the presence of an organic amine.
4. A process for the preparation of glutamylethylimidazole according to claim 3, wherein the organic amine is one or more of triethylamine, diisopropylethylamine and pyridine.
5. A process for producing glutamineethylimidazole according to claim 3 wherein the molar ratio of tert-butoxycarbonyl-L-glutamic acid-5-tert-butyl ester to organic amine is 1 (1.5 to 2.5).
6. The method for producing glutamineethylimidazole according to claim 1 or 2, characterized in that the amide condensing agent is a carbodiimide-based condensing agent and/or an onium salt-based condensing agent.
7. The process for producing glutamylethylimidazole according to claim 1 or 2, wherein the acidic condition is provided by trifluoroacetic acid.
8. The process for producing glutamylethylimidazole according to claim 1 or 2, characterized in that the condensation reaction is carried out in an organic solvent; the organic solvent is acetone and/or acetonitrile.
9. The method for preparing glutamyl ethyl imidazole according to claim 1 or 2, wherein the reaction temperature in step (1) is 40-60 ℃ and the reaction time is 8-12 h; the reaction temperature in the step (2) is 20-40 ℃, and the reaction time is 3-5 h.
10. The process for producing glutamineethylimidazole according to claim 1 or 2, characterized in that after hydrolysis, the pH of the reaction system is adjusted to 7.5 to 8, the organic phase is separated and then recrystallization is carried out; the solvent used for recrystallization is ethanol, and the temperature of recrystallization is 0-5 ℃.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117143022A (en) * | 2023-08-30 | 2023-12-01 | 上海克琴科技有限公司 | Synthesis method of glutaminyl ethyl imidazole |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1136808A (en) * | 1993-11-05 | 1996-11-27 | 摩纳哥爱克希莫尔股份有限公司 | Pseudodipeptide product having imidazole grouping and applications |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1136808A (en) * | 1993-11-05 | 1996-11-27 | 摩纳哥爱克希莫尔股份有限公司 | Pseudodipeptide product having imidazole grouping and applications |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117143022A (en) * | 2023-08-30 | 2023-12-01 | 上海克琴科技有限公司 | Synthesis method of glutaminyl ethyl imidazole |
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