CN115197150A - Preparation method of L-carnosine - Google Patents
Preparation method of L-carnosine Download PDFInfo
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- CN115197150A CN115197150A CN202210953579.8A CN202210953579A CN115197150A CN 115197150 A CN115197150 A CN 115197150A CN 202210953579 A CN202210953579 A CN 202210953579A CN 115197150 A CN115197150 A CN 115197150A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention provides a preparation method of L-carnosine, which comprises the following steps: reacting halogenated propionic acid shown in a formula I with dibenzylamine to obtain a compound INT-1, reacting the compound INT-1 with N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester to obtain a compound INT-2, carrying out deprotection reaction on the compound INT-2 to obtain a compound INT-3, and carrying out catalytic hydrogenation deprotection reaction on the compound INT-3 to obtain L-carnosine. The preparation method disclosed by the invention is mild in condition, easy in raw material obtaining, low in cost and suitable for industrial production, application and popularization.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of L-carnosine.
Background
L-Carnosine (L-Carnosine) is a natural dipeptide obtained by condensing beta-alanine and L-histidine, is called beta-alanyl-L-histidine for short, and researches show that the L-Carnosine has important physiological and pharmacological functions of resisting oxidation and aging, eliminating in-vivo free radicals, chelating transition metals, preventing ulcer and the like, has certain biological activity on various diseases such as hypertension, heart diseases, senile dementia, cataract, anti-tumor and the like, and has very wide application in the fields of medical health care, food, beauty and the like.
With regard to the chemical synthesis method of L-carnosine, there are many reports in the prior art, and there are two main categories summarized:
(1) Beta-alanine is subject to amino protection and carboxyl activation, then condensed with protected L-histidine, and finally the group is deprotected to obtain L-carnosine. The method mainly utilizes phthalic anhydride and beta-alanine to generate phthaloyl-beta-alanine protected amino, carboxyl reacts with thionyl chloride to generate phthaloyl-beta-alanyl chloride, peptide bond is formed with protected L-histidine, and L-carnosine is obtained by deaminating the protecting group. Hydrazine hydrate is needed to be used for carrying out the deprotection of hydrazinolysis phthaloyl in the preparation process, hydrazine belongs to a high-toxicity compound, hydrazine residue has large influence on the product quality, the hydrazinolysis reaction condition is harsh, and the generated by-products and impurities are complex, so that the yield is low, racemization is easy to occur in the peptide bond formation process, the product purity is influenced, the solvent consumption is large, and the environmental protection requirement is not facilitated.
(2) Different beta-alanine analogues or similar structures are used for constructing and condensing with L-histidine to form peptide bonds, and then functional group conversion is carried out to obtain the L-carnosine. The common method is that ethyl cyanoacetate and L-histidine are subjected to amidation reaction under the condition of sodium alkoxide to obtain cyanoacetyl-L-histidine, and the cyano group is subjected to catalytic hydrogenation reduction to obtain L-carnosine. The method has short steps, saves the processes of protection and deprotection of different groups, avoids racemization, but requires anhydrous operation under the condition of sodium alkoxide, increases the industrialization difficulty, and is easy to cause environmental pollution in the production process because the used ethyl cyanoacetate is a toxic substance.
Aiming at the defects and shortcomings of the existing process, the preparation technology of the L-carnosine with simple process, economy and environmental protection is developed, especially a process scheme which can be suitable for industrial production is sought, and the method has important practical significance for improving the economic and social benefits of the L-carnosine.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a preparation method of L-carnosine. The preparation method has mild conditions, easily obtained raw materials and low cost, is beneficial to embodying high efficiency, greenness and environmental protection, can meet the requirement of industrial scale-up production, and is suitable for industrial production, application and popularization.
In order to achieve the purpose, the invention adopts the following technical scheme:
in one aspect, the present invention provides a method for preparing L-carnosine, comprising the steps of:
(1) Reacting halogenated propionic acid shown in the formula I with dibenzylamine to obtain a compound INT-1, wherein the reaction formula is as follows:
in the formula, X is Br or Cl;
(2) Reacting the compound INT-1 with N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester to obtain a compound INT-2, wherein the reaction formula is as follows:
(3) And carrying out deprotection reaction on the compound INT-2 to obtain a compound INT-3, wherein the reaction formula is as follows:
(4) Carrying out catalytic hydrogenation deprotection reaction on the compound INT-3 to obtain the L-carnosine, wherein the reaction formula is as follows:
the synthesis route of the invention has mild conditions, avoids toxic impurities, is beneficial to the quality control of the L-carnosine raw material medicine, has easily obtained raw materials of the used reagents and a yield of 90 percent, has reasonable technical scheme, is environment-friendly, is beneficial to industrial production and popularization, and can be produced in large quantities to meet the use requirements.
In the invention, the halogenated propionic acid in the step (1) is 3-bromopropionic acid or 3-chloropropionic acid.
In the present invention, the molar ratio of the halopropionic acid to dibenzylamine in step (1) is 1:1-2, for example 1:1, 1.2, 1.4, 1.5, 1.7, 1.9 or 1:2.
In the present invention, the reaction in step (1) is carried out in the presence of a basic substance.
The alkaline substance is any one or the combination of at least two of sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or pyridine.
In the present invention, the molar ratio of the basic substance to the halopropionic acid is 1-4:1, such as 1:1, 1.5.
In the present invention, the solvent for the reaction in step (1) is any one or a combination of at least two of acetonitrile, tetrahydrofuran, methyl tert-butyl ether, toluene or N, N-dimethylformamide.
In the present invention, the reaction temperature in step (1) is 50 to 100 ℃ (e.g., 50 ℃, 55 ℃, 60 ℃,65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃ or 100 ℃) and the reaction time is 3 to 12 hours (e.g., 3 hours, 4 hours, 5 hours, 7 hours, 9 hours, 10 hours, 11 hours or 12 hours).
In the present invention, the molar ratio of compound INT-1 to N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester in step (2) is 1:1-1.2, such as 1:1, 1.05, 1.
In the present invention, the reaction in step (2) is carried out in the presence of a condensing agent.
In the invention, the condensing agent is N, N '-carbonyldiimidazole, N' -dicyclohexylcarbodiimide, N '-diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, 1,8-diazabicyclo [5.4.0] undec-7-ene, N' -carbonylbis (1,2,4-triazole), O-benzotriazol-N, any one or the combination of at least two of N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazole-N, N, N ', N' -tetramethylurea tetrafluoroborate, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate or 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea tetrafluoroborate.
In the present invention, the molar ratio of the condensing agent to compound INT-1 is 1-2:1, e.g. 1:1, 1.2, 1, 1.5, 1.8 or 2:1.
In the present invention, the reaction described in the step (2) is carried out in the presence of an alkali promoter.
In the invention, the alkali promoter is any one or a combination of at least two of triethylamine, N-diisopropylethylamine, 2,6-lutidine, 4-dimethylaminopyridine, pyridine, piperidine, tri-N-butylamine, triisopropylamine, diisopropylamine, dicyclohexylamine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine or N-ethylmorpholine.
In the present invention, the molar ratio of the alkali promoter to compound INT-1 is 1-2:1, e.g. 1:1, 1.2, 1, 1.5, 1.8 or 2:1.
In the present invention, the solvent for the reaction in step (2) is any one or a combination of at least two of toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, N-dimethylformamide or acetonitrile.
In the present invention, the reaction temperature in the step (2) is 50 to 80 ℃ (e.g., 50 ℃, 55 ℃, 60 ℃,65 ℃, 70 ℃, 75 ℃ or 80 ℃) and the reaction time is 6 to 18 hours (e.g., 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 14 hours, 16 hours or 18 hours).
In the invention, the deprotection reaction in the step (3) is hydrolysis deprotection reaction or alcoholysis deprotection reaction.
In the present invention, the hydrolysis deprotection reaction is carried out by adding water, controlling the temperature at 20 to 30 ℃ (for example, 20 ℃, 23 ℃, 25 ℃, 28 ℃ or 30 ℃), and carrying out the hydrolysis reaction for 0.5 to 1 hour (for example, 0.5 hour, 0.8 hour or 1 hour).
In the present invention, the alcoholysis deprotection reaction is carried out using any one of methanol, ethanol or isopropanol or a combination of at least two of them.
In the present invention, the alcoholysis deprotection reaction is carried out at a temperature of 20 to 30 ℃ such as 20 ℃, 23 ℃, 25 ℃, 28 ℃ or 30 ℃ for 0.5 to 1 hour such as 0.5 hour, 0.8 hour or 1 hour.
In the invention, the solvent for alcoholysis deprotection reaction is dichloromethane.
In the invention, the catalytic hydrogenation deprotection reaction in the step (4) is to react the compound INT-3 with hydrogen under the condition of using palladium-carbon as a catalyst to obtain the L-carnosine.
In the invention, the solvent for the catalytic hydrogenation deprotection reaction in the step (4) is any one or at least two of methanol, ethanol or isopropanol;
in the present invention, the catalytic hydrogenation deprotection reaction is carried out at a temperature of 30 to 60 ℃ (e.g., 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃, 55 ℃ or 60 ℃) for 6 to 12 hours (e.g., 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours).
In the present invention, the catalytic hydrogenation deprotection reaction in step (4) is carried out under normal pressure.
As a preferred technical scheme of the invention, the preparation method of the L-carnosine specifically comprises the following steps:
(1) In the presence of alkaline substances, reacting halogenated propionic acid shown in the formula I with dibenzylamine for 3-12 hours at 50-100 ℃ in a molar ratio of 1:1-2 to obtain a compound INT-1;
(2) In the presence of a condensing agent and an alkali promoter, the molar ratio of a compound INT-1 to N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester is 1:1-1.2, and the compound INT-2 is obtained after the reaction is carried out for 6-18 hours at the temperature of 50-80 ℃;
(3) Carrying out hydrolysis or alcoholysis deprotection reaction on the compound INT-2 to obtain a compound INT-3;
(4) Carrying out catalytic hydrogenation deprotection reaction with hydrogen under the condition that palladium-carbon is used as a catalyst to obtain the L-carnosine.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method disclosed by the invention is mild in process conditions, avoids toxic impurities, is beneficial to quality control of the L-carnosine raw material medicine, is easy to obtain the used reagent raw materials, high in yield, reasonable in technical scheme, environment-friendly, beneficial to industrial production and popularization, and capable of meeting use requirements in mass production.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
In the following examples HPLC purity measurements were carried out using an Agilent 1200 liquid chromatograph and specific rotation measurements were carried out using a Perkin-Elmer PL341 autosterometer.
Example 1
(1) Preparation of Compound INT-1:
dissolving 3-bromopropionic acid (10 g,65 mmol) and dibenzylamine (13 g,66 mmol) in acetonitrile (120 mL), cooling in an ice bath, slowly adding potassium hydroxide (4 g,71 mmol), heating to 50 ℃ to react for 12 h, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane and water for extraction and layering, separating an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing a crude product by using an ethyl acetate-n-hexane mixed solvent, and carrying out vacuum drying to obtain a compound INT-1 (16 g) with a yield of 91%;
(2) Preparation of Compound INT-2:
dissolving a compound INT-1 (15 g and 56 mmol) in toluene (300 mL), adding N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester (21 g and 56 mmol), N' -carbonyldiimidazole (9 g and 56 mmol) and triethylamine (6 g and 59 mmol), heating to 50 ℃, reacting for 18 h, cooling to room temperature, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove an organic solvent to obtain a crude product, recrystallizing by using an ethyl acetate-N-hexane mixed solvent, and drying in vacuum to obtain a compound INT-2 (28 g) with the yield of 81%;
(3) Preparation of Compound INT-3:
dissolving a compound INT-2 (27 g,43 mmol) in dichloromethane (300 mL), cooling in an ice bath, slowly dropwise adding methanol (60 mL), reacting at 20 ℃ for 1h, performing suction filtration, washing a filter cake with water, recrystallizing a crude product by using an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-3 (16 g) with the yield of 91%;
(4) Preparation of L-carnosine:
compound INT-3 (15 g,37 mmol) was dissolved in methanol (200 mL), palladium on charcoal (1 g) was added, and 12 h was reacted under hydrogen at atmospheric pressure at 30 ℃. Filtering, removing catalyst by diatomite, and rotary distilling to concentrate filtrateCondensing to dry to obtain L-carnosine (8 g) with the yield of 96 percent; HPLC purity>99.0%；1H NMR (400MHz，D 2 O) δ 7.70 (dd, 1H), 6.92 (s, 1H), 4.43 (dd, 1H), 3.20 (m, 2H), 3.13 (dd, 1H), 2.96 (dd, 1H), 2.65 (m, 2H); specific rotation degree [ alpha ], [ alpha ]
] 20 D =+21.3° (c=1.0，H 2 O) was in accordance with the standard.
Example 2
(1) Preparation of Compound INT-1:
dissolving 3-chloropropionic acid (14 g,0.13 mol) and dibenzylamine (40 g,0.2 mol) in tetrahydrofuran (500 mL), cooling in an ice bath, slowly adding potassium carbonate (45 g,0.33 mol), heating to 80 ℃ to react for 8 h, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane and water for extraction and layering, separating an organic phase, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing a crude product by using an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-1 (32 g) with a yield of 91%;
(2) Preparation of Compound INT-2:
dissolving a compound INT-1 (32 g,0.12 mol) in ethyl acetate (800 mL), adding N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester (48 g,0.13 mol), N' -dicyclohexylcarbodiimide (37 g,0.18 mol) and N, N-diisopropylethylamine (23 g,0.18 mol), heating to 70 ℃ for reaction for 12 h, cooling to room temperature, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove an organic solvent to obtain a crude product, recrystallizing by using an ethyl acetate-N-hexane mixed solvent, and drying in vacuum to obtain a compound INT-2 (60 g) with the yield of 81%;
(3) Preparation of Compound INT-3:
dissolving a compound INT-2 (60 g,96 mmol) in dichloromethane (800 mL), cooling in an ice bath, slowly dropwise adding ethanol (150 mL), reacting at 25 ℃ for 0.5 h, performing suction filtration, washing a filter cake, recrystallizing a crude product by using an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-3 (37 g) with the yield of 95%;
(4) Preparation of L-carnosine:
INT-3 (37 g,91 mmol) was dissolved in ethanol (450 mL), palladium on charcoal (2 g) was added, and hydrogen was passed through at 40 ℃ under atmospheric pressure to react at 9 h. The catalyst is removed by suction filtration through diatomite, and the filtrate is concentrated to be dry by rotary evaporation to obtain L-carnosine (20 g) with the yield of 97 percent; purity by HPLC>99.0 percent; specific rotation degree [ alpha ], [ alpha ]
] 20 D =+21.3° (c=1.0，H 2 O) was in accordance with the standard.
Example 3
(1) Preparation of Compound INT-1:
dissolving 3-bromopropionic acid (12 g,78 mmol) and dibenzylamine (30 g,0.15 mol) in N, N-dimethylformamide (500 mL), cooling in ice bath, slowly adding triethylamine (30 g,0.3 mol) dropwise, heating to 100 ℃ to react for 3 h, concentrating under reduced pressure to remove an organic solvent, adding dichloromethane and water for extraction and layering, separating an organic phase, washing with salt water, drying with anhydrous sodium sulfate, performing reduced pressure rotary evaporation to dryness, recrystallizing a crude product by using an ethyl acetate-N-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-1 (20 g) with the yield of 95%;
(2) Preparation of Compound INT-2:
dissolving a compound INT-1 (20 g,74 mmol) in acetonitrile (500 mL), adding N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester (33 g,89 mmol), N' -diisopropylcarbodiimide (18 g,0.14 mol) and 2,6-dimethylpyridine (15 g,0.14 mol), heating to 80 ℃ to react for 6 h, cooling to room temperature, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove an organic solvent to obtain a crude product, recrystallizing by using an ethyl acetate-N-hexane mixed solvent, and drying in vacuum to obtain a compound INT-2 (39 g) with the yield of 84%;
(3) Preparation of Compound INT-3:
dissolving a compound INT-2 (38 g,61 mmol) in dichloromethane (500 mL), cooling in an ice bath, slowly dropwise adding isopropanol (80 mL), reacting at 30 ℃ for 0.5 h, performing suction filtration, washing a filter cake, recrystallizing a crude product by using an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-3 (24 g) with the yield of 97%;
(4) Preparation of L-carnosine:
compound INT-3 (24 g,59 mmol) was dissolved in isopropanol (300 mL), palladium on charcoal (1.5 g) was added and reacted with 6 h under hydrogen at 60 ℃ under atmospheric pressure. The catalyst is removed by suction filtration through diatomite, and the filtrate is concentrated to be dry by rotary evaporation to obtain L-carnosine (13 g) with the yield of 97 percent; HPLC purity>99.0 percent; specific rotation degree [ alpha ], [ alpha ]
] 20 D =+21.3° (c=1.0，H 2 O) was in accordance with the standard.
Example 4
(1) Preparation of Compound INT-1:
dissolving 3-chloropropionic acid (8.5 g,78 mmol) and dibenzylamine (30 g,0.15 mol) in toluene (500 mL), cooling in an ice bath, slowly dropwise adding pyridine (24 g,0.3 mol), heating to 90 ℃ to react for 4 h, carrying out reduced pressure concentration to remove an organic solvent, adding dichloromethane and water for extraction and layering, separating an organic phase, washing with salt water, drying with anhydrous sodium sulfate, carrying out reduced pressure rotary evaporation to dryness, recrystallizing a crude product by using an ethyl acetate-n-hexane mixed solvent, and carrying out vacuum drying to obtain a compound INT-1 (20 g) with the yield of 95%;
(2) Preparation of Compound INT-2:
dissolving a compound INT-1 (20 g,74 mmol) in isopropyl acetate (600 mL), adding N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester (33 g,89 mmol), N' -diisopropylcarbodiimide (18 g,0.14 mol) and 2,6-lutidine (15 g,0.14 mol), heating to 80 ℃ to react to obtain 6 h, cooling to room temperature, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove an organic solvent to obtain a crude product, recrystallizing by using an ethyl acetate-N-hexane mixed solvent, and drying in vacuum to obtain a compound INT-2 (39 g) with the yield of 84%;
(3) Preparation of Compound INT-3:
dissolving a compound INT-2 (38 g,61 mmol) in dichloromethane (500 mL), cooling in an ice bath, slowly dripping water (80 mL), keeping the temperature at 30 ℃ to react for 1h, performing suction filtration, washing a filter cake with water, recrystallizing a crude product by using an ethyl acetate-n-hexane mixed solvent, and performing vacuum drying to obtain a compound INT-3 (24 g) with the yield of 97%;
(4) Preparation of L-carnosine:
compound INT-3 (24 g,59 mmol) was dissolved in isopropanol (300 mL), palladium on charcoal (1.5 g) was added and reacted with hydrogen at 60 ℃ under atmospheric pressure for 6 h. The catalyst is removed by suction filtration through diatomite, and the filtrate is concentrated to be dry by rotary evaporation to obtain L-carnosine (13 g) with the yield of 97 percent; HPLC purity>99.0 percent; specific rotation degree [ alpha ], [ alpha ]
] 20 D =+21.3° (c=1.0，H 2 O) was in accordance with the standard.
The applicant states that the preparation method of the present invention is illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must rely on the above examples to be implemented. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (12)
1. A preparation method of L-carnosine, which is characterized by comprising the following steps:
(1) Reacting the halogenated propionic acid shown in the formula I with dibenzylamine to obtain a compound INT-1, wherein the reaction formula is as follows:
in the formula, X is Br or Cl;
(2) Reacting the compound INT-1 with N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester to obtain a compound INT-2, wherein the reaction formula is as follows:
(3) And carrying out deprotection reaction on the compound INT-2 to obtain a compound INT-3, wherein the reaction formula is as follows:
(4) Carrying out catalytic hydrogenation deprotection reaction on the compound INT-3 to obtain the L-carnosine, wherein the reaction formula is as follows:
2. the method according to claim 1, wherein the halopropionic acid of step (1) is 3-bromopropionic acid or 3-chloropropionic acid, and the molar ratio of the halopropionic acid to dibenzylamine is 1:1-2.
3. The production method according to claim 1, wherein the reaction of step (1) is carried out in the presence of a basic substance;
the alkaline substance is any one or the combination of at least two of sodium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, N-diisopropylethylamine or pyridine;
the molar ratio of the alkaline substance to the halogenated propionic acid is 1-4:1.
4. The process according to claim 1, wherein the solvent for the reaction in step (1) is any one or a combination of at least two of acetonitrile, tetrahydrofuran, methyl tert-butyl ether, toluene, or N, N-dimethylformamide;
the reaction temperature in the step (1) is 50-100 ℃, and the reaction time is 3-12 hours.
5. The method of claim 1, wherein the molar ratio of compound INT-1 to N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester in step (2) is 1:1-1.2.
6. The production method according to claim 1, wherein the reaction of step (2) is carried out in the presence of a condensing agent;
the condensing agent is any one or a combination of at least two of N, N '-carbonyldiimidazole, N, N' -dicyclohexylcarbodiimide, N, N '-diisopropylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole, 1,8-diazabicyclo [5.4.0] undec-7-ene, N, N' -carbonylbis (1,2,4-triazole), O-benzotriazol-N, N, N ', N' -tetramethylurea hexafluorophosphate, O-benzotriazol-N, N, N ', N' -tetramethylurea tetrafluoroborate, 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate or 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea tetrafluoroborate;
the molar ratio of the condensing agent to the compound INT-1 is 1-2:1.
7. The production method according to claim 1, wherein the reaction of step (2) is carried out in the presence of an alkali promoter;
the alkali accelerator is any one or the combination of at least two of triethylamine, N-diisopropylethylamine, 2,6-lutidine, 4-dimethylaminopyridine, pyridine, piperidine, tri-N-butylamine, triisopropylamine, diisopropylamine, dicyclohexylamine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine or N-ethylmorpholine;
the molar ratio of the alkali accelerator to the compound INT-1 is 1-2:1.
8. The preparation method according to claim 1, wherein the solvent for the reaction in step (2) is any one or a combination of at least two of toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, N-dimethylformamide, or acetonitrile;
the reaction temperature of the step (2) is 50-80 ℃, and the reaction time is 6-18 hours.
9. The production method according to claim 1, wherein the deprotection reaction in step (3) is a hydrolysis deprotection reaction or an alcoholysis deprotection reaction;
the hydrolysis deprotection reaction is to add water, control the temperature to be 20-30 ℃ and carry out hydrolysis reaction for 0.5-1 hour;
the alcoholysis deprotection reaction is carried out by using any one or the combination of at least two of methanol, ethanol or isopropanol;
the temperature of the alcoholysis deprotection reaction is 20-30 ℃, and the time is 0.5-1 hour;
the solvent for alcoholysis deprotection reaction is dichloromethane.
10. The preparation method according to claim 1, wherein the catalytic hydrogenation deprotection reaction in step (4) is a reaction of compound INT-3 with hydrogen gas in the presence of palladium-carbon as a catalyst to obtain L-carnosine.
11. The preparation method according to claim 1, wherein the solvent for the catalytic hydrogenation deprotection reaction in step (4) is any one or at least two of methanol, ethanol or isopropanol;
the temperature of the catalytic hydrogenation deprotection reaction is 30-60 ℃, and the time is 6-12 hours;
and (5) carrying out catalytic hydrogenation deprotection reaction in the step (4) under normal pressure.
12. The method of claim 1, comprising the steps of:
(1) In the presence of alkaline substances, reacting halogenated propionic acid shown in the formula I with dibenzylamine for 3-12 hours at 50-100 ℃ in a molar ratio of 1:1-2 to obtain a compound INT-1;
(2) In the presence of a condensing agent and an alkali promoter, the molar ratio of a compound INT-1 to N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester is 1:1-1.2, and the compound INT-2 is obtained after the reaction is carried out for 6-18 hours at the temperature of 50-80 ℃;
(3) Carrying out hydrolysis or alcoholysis deprotection reaction on the compound INT-2 to obtain a compound INT-3;
(4) Carrying out catalytic hydrogenation deprotection reaction with hydrogen under the condition that palladium-carbon is used as a catalyst to obtain the L-carnosine.
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