CN115197150B - Preparation method of L-carnosine - Google Patents
Preparation method of L-carnosine Download PDFInfo
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- CN115197150B CN115197150B CN202210953579.8A CN202210953579A CN115197150B CN 115197150 B CN115197150 B CN 115197150B CN 202210953579 A CN202210953579 A CN 202210953579A CN 115197150 B CN115197150 B CN 115197150B
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a preparation method of L-carnosine, which comprises the following steps: the halopropionic acid shown in the formula I reacts with dibenzylamine to obtain a compound INT-1, the compound INT-1 reacts with N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester to obtain a compound INT-2, the compound INT-2 carries out deprotection reaction to obtain a compound INT-3, and the compound INT-3 carries out catalytic hydrogenation deprotection reaction to obtain L-carnosine. The preparation method disclosed by the invention is mild in condition, easy in raw material acquisition, low in cost and suitable for industrial production, application and popularization.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a preparation method of L-carnosine.
Background
L-Carnosine (L-Carnosine) is a natural dipeptide condensed by beta-alanine and L-histidine, beta-alanyl-L-histidine for short, and researches show that the L-Carnosine has important physiological and pharmacological functions of resisting oxidation, resisting aging, scavenging free radicals in vivo, chelating transition metals, preventing ulcers and the like, has certain biological activity for 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, cosmetology and the like.
The chemical synthesis method of L-carnosine has a large number of reports in the prior art, and mainly comprises two main categories:
(1) Beta-alanine is subjected to amino protection, carboxyl activation, condensation with protected L-histidine and deprotection to obtain L-carnosine. The method mainly utilizes phthalic anhydride and beta-alanine to generate phthaloyl-beta-alanine to protect amino, carboxyl reacts with thionyl chloride to generate phthaloyl-beta-alanyl chloride, then forms peptide bond with protected L-histidine, and then deaminates the protecting group to obtain L-carnosine. In the preparation process, hydrazine hydrate is needed for carrying out hydrazinolysis phthaloyl deprotection, hydrazine is a high-toxicity compound, hydrazine residue has a large influence on product quality, and the hydrazinolysis reaction condition is harsh, and byproducts and impurities are produced in a complex way, so that the yield is low, racemization is easy in the process of forming peptide bonds, the product purity is influenced, the solvent consumption is high, and the environment-friendly 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. Under the condition of sodium alkoxide, ethyl cyanoacetate and L-histidine are subjected to amidation reaction to obtain cyano acetyl-L-histidine, and the cyano group of the cyano acetyl-L-histidine is subjected to catalytic hydrogenation reduction to obtain L-carnosine. The method has the advantages that the steps of the route are shorter, the protection and deprotection processes for different groups are omitted, racemization is avoided, however, anhydrous operation is required under the condition of sodium alkoxide, the industrialization difficulty is increased, the ethyl cyanoacetate is a toxic substance, and environmental pollution is easy to cause in the production process.
Aiming at the defects and the shortcomings existing in the prior art, the preparation technology of the L-carnosine with simple process, economy and environmental protection is sought, and particularly, the technical scheme which can adapt to industrial production is sought, thus having important practical significance for improving the economic and social benefits of the variety.
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, green and environment-friendly, can meet the requirements of industrial scale-up production, and is suitable for industrial production application and popularization.
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) The halopropionic acid shown in the formula I reacts with dibenzylamine to obtain a compound INT-1, wherein the reaction formula is as follows:
wherein X is Br or Cl;
(2) The compound INT-1 reacts with N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester to obtain a compound INT-2, and the reaction formula is as follows:
；
(3) Deprotection of compound INT-2 to give compound INT-3 of the formula:
；
(4) The compound INT-3 is subjected to catalytic hydrogenation deprotection reaction to obtain L-carnosine, wherein the reaction formula is as follows:
。
the synthesis route of the invention has mild conditions, avoids the occurrence of toxic impurities, is beneficial to the quality control of the L-carnosine crude drug, has the advantages of easily obtained reagent raw materials, 90 percent of yield, reasonable technical scheme and environmental friendliness, is beneficial to industrialized production popularization, and can be produced in large quantities to meet the use requirement.
In the present invention, the halopropionic acid in step (1) is 3-bromopropionic acid or 3-chloropropionic acid.
In the present invention, the molar ratio of halopropionic acid to dibenzylamine in step (1) is from 1:1 to 2, such as 1:1, 1:1.2, 1:1.4, 1:1.5, 1:1.7, 1:1.9, or 1:2.
In the present invention, the reaction of step (1) is carried out in the presence of an alkaline 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 halopropionic acid is 1-4:1, for example 1:1, 1.5:1, 1.8:1, 2:1, 2.5:1, 2.8:1, 3:1, 3.5:1, 3.8:1 or 4:1.
In the invention, the solvent of the reaction in the step (1) is any one or a combination of at least two of acetonitrile, tetrahydrofuran, methyl tertiary butyl ether, toluene or N, N-dimethylformamide.
In the present invention, the temperature of the reaction 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 the compound INT-1 to N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester of step (2) is 1:1-1.2, such as 1:1, 1:1.05, 1:1.08, 1:1.1, 1:1.15, 1:1.18 or 1:1.2.
In the present invention, the reaction of step (2) is carried out in the presence of a condensing agent.
In the present invention, 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 ' -tetramethylurea tetrafluoroborate.
In the present invention, the molar ratio of condensing agent to compound INT-1 is 1-2:1, for example 1:1, 1.2:1, 1.5:1, 1.8:1 or 2:1.
In the present invention, the reaction of step (2) is carried out in the presence of an alkali promoter.
In the present invention, the base accelerator 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 base promoter to the compound INT-1 is 1-2:1, for example 1:1, 1.2:1, 1.5:1, 1.8:1 or 2:1.
In the invention, the solvent of the reaction in the 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 temperature of the reaction in 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 present invention, the deprotection reaction in step (3) is a hydrolysis deprotection reaction or an alcoholysis deprotection reaction.
In the present invention, the hydrolysis deprotection reaction is carried out by adding water at a temperature of 20 to 30℃such as 20℃at 23℃at 25℃at 28℃or 30℃for 0.5 to 1 hour (e.g., 0.5 hour, 0.8 hour or 1 hour).
In the present invention, the alcoholysis deprotection reaction is carried out using any one or a combination of at least two of methanol, ethanol or isopropanol.
In the present invention, the alcoholysis deprotection reaction is carried out at a temperature of 20 to 30 ℃ (e.g., 20 ℃, 23 ℃, 25 ℃, 28 ℃ or 30 ℃) for a time of 0.5 to 1 hour (e.g., 0.5 hour, 0.8 hour or 1 hour).
In the invention, the solvent for the alcoholysis deprotection reaction is dichloromethane.
In the invention, the catalytic hydrogenation deprotection reaction in the step (4) is to react a compound INT-3 with hydrogen under the condition that palladium-carbon is used 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 and 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 a time of 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 of step (4) is performed at 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, the mol ratio of the halopropionic acid shown in the formula I to the dibenzylamine is 1:1-2, and the halopropionic acid and the dibenzylamine react for 3-12 hours at 50-100 ℃ to obtain a compound INT-1;
(2) In the presence of a condensing agent and an alkali accelerator, the molar ratio of the compound INT-1 to the N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester is 1:1-1.2, and the reaction is carried out for 6-18 hours at 50-80 ℃ to obtain the compound INT-2;
(3) Carrying out hydrolysis or alcoholysis deprotection reaction on the compound INT-2 to obtain a compound INT-3;
(4) And under the condition that palladium-carbon is used as a catalyst, carrying out catalytic hydrogenation deprotection reaction with hydrogen to obtain the L-carnosine.
Compared with the prior art, the invention has the following beneficial effects:
the preparation method disclosed by the invention has the advantages of mild process conditions, avoidance of toxic impurities, easiness in quality control of the L-carnosine raw material medicine, high yield of the used reagent raw material, reasonable technical scheme, environment friendliness, convenience in industrial production popularization and capability of realizing mass production to meet the use requirements.
Detailed Description
The technical scheme of the invention is further described by the following specific embodiments. It will be apparent to those skilled in the art that the examples are merely to aid in understanding the invention and are not to be construed as a specific limitation thereof.
HPLC purity measurements were performed using Agilent 1200 liquid chromatograph and specific rotation measurements were performed using a Perkin-Elmer PL341 automatic polarimeter in the examples below.
Example 1
(1) Preparation of Compound INT-1:
3-bromopropionic acid (10 g,65 mmol) and dibenzylamine (13 g,66 mmol) are dissolved in acetonitrile (120 mL), cooled in an ice bath, potassium hydroxide (4 g,71 mmol) is slowly added, the temperature is raised to 50 ℃ for reaction 12 h, the organic solvent is removed by decompression concentration, dichloromethane and water are added for extraction and delamination, the organic phase is separated out, brine is washed, anhydrous sodium sulfate is dried, decompression is carried out by spin evaporation until the organic phase is dried, the crude product is recrystallized by an ethyl acetate-n-hexane mixed solvent, and the crude product is dried in vacuum to obtain a compound INT-1 (16 g), and the yield is 91%;
(2) Preparation of Compound INT-2:
dissolving compound INT-1 (15 g,56 mmol) in toluene (300 mL), adding N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester (21 g,56 mmol), N' -carbonyldiimidazole (9 g,56 mmol) and triethylamine (6 g,59 mmol), heating to 50deg.C for reacting 18 h, cooling to room temperature, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove organic solvent to obtain crude product, recrystallizing with ethyl acetate-N-hexane mixed solvent, and vacuum drying to obtain compound INT-2 (28 g) with yield of 81%;
(3) Preparation of Compound INT-3:
dissolving compound INT-2 (27 g,43 mmol) in dichloromethane (300 mL), cooling in ice bath, slowly dropwise adding methanol (60 mL), reacting at 20deg.C for 1h, suction filtering, washing filter cake with water, recrystallizing crude product with ethyl acetate-n-hexane mixed solvent, and vacuum drying to obtain compound INT-3 (16 g), yield 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 the mixture was reacted at 30℃under normal pressure with hydrogen gas to give 12 h. The catalyst is removed by the suction filtration through diatomite, and the filtrate is concentrated to dryness by rotary evaporation to obtain L-carnosine (8 g) with the yield of 96%; HPLC purity>99.0%；1H NMR (400MHz，D 2 O) delta 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 [] 20 D =+21.3° (c=1.0，H 2 O) is consistent with standard.
Example 2
(1) Preparation of Compound INT-1:
3-Chloropropionic acid (14 g,0.13 mol), dibenzylamine (40 g,0.2 mol) are dissolved in tetrahydrofuran (500 mL), cooled in an ice bath, potassium carbonate (45 g,0.33 mol) is slowly added, the temperature is raised to 80 ℃ for reaction 8 h, the organic solvent is removed by decompression concentration, dichloromethane and water are added for extraction and delamination, the organic phase is separated, common salt is washed with water, anhydrous sodium sulfate is dried, decompression and rotary evaporation are carried out to dryness, the crude product is recrystallized by ethyl acetate-normal hexane mixed solvent, and vacuum drying is carried out, thus obtaining compound INT-1 (32 g), and the yield is 91%;
(2) Preparation of Compound INT-2:
dissolving 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 ℃ to react for 12 h, cooling to room temperature, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove organic solvent to obtain crude product, recrystallizing with ethyl acetate-N-hexane mixed solvent, and vacuum drying to obtain compound INT-2 (60 g) with yield of 81%;
(3) Preparation of Compound INT-3:
dissolving the 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, filtering, washing a filter cake with water, recrystallizing a crude product by using an ethyl acetate-n-hexane mixed solvent, and drying in vacuum to obtain the compound INT-3 (37 g), wherein the yield is 95%;
(4) Preparation of L-carnosine:
compound INT-3 (37 g,91 mmol) was dissolved in ethanol (450 mL), palladium on charcoal (2 g) was added and reacted at 40℃under normal pressure with hydrogen gas 9 h. The catalyst is removed by the suction filtration through diatomite, and the filtrate is concentrated to dryness by rotary evaporation to obtain L-carnosine (20 g) with the yield of 97%; HPLC purity>99.0%; specific rotation [] 20 D =+21.3° (c=1.0，H 2 O) is consistent with standard.
Example 3
(1) Preparation of Compound INT-1:
3-bromopropionic acid (12 g,78 mmol), dibenzylamine (30 g,0.15 mol) are dissolved in N, N-dimethylformamide (500 mL), the mixture is cooled in an ice bath, triethylamine (30 g,0.3 mol) is slowly added dropwise, the temperature is raised to 100 ℃ for reaction 3 h, the organic solvent is removed by decompression concentration, dichloromethane and water are added for extraction and delamination, the organic phase is separated, common salt water is used for washing, anhydrous sodium sulfate is dried, decompression rotary evaporation is carried out until the mixture is dried, the crude product is recrystallized by an ethyl acetate-N-hexane mixed solvent, and vacuum drying is carried out, thus obtaining the compound INT-1 (20 g), and the yield is 95%;
(2) Preparation of Compound INT-2:
dissolving 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-lutidine (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 organic solvent to obtain crude product, recrystallizing with ethyl acetate-N-hexane mixed solvent, and vacuum drying to obtain compound INT-2 (39 g) with yield of 84%;
(3) Preparation of Compound INT-3:
dissolving compound INT-2 (38 g,61 mmol) in dichloromethane (500 mL), cooling in ice bath, slowly dropwise adding isopropanol (80 mL), reacting at 30deg.C for 0.5. 0.5 h, vacuum filtering, washing filter cake with water, recrystallizing crude product with ethyl acetate-n-hexane mixed solvent, and vacuum drying to obtain compound INT-3 (24 g) with 97% yield;
(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 at 60℃under normal pressure with hydrogen gas to give 6 h. The catalyst is removed by the suction filtration through diatomite, and the filtrate is concentrated to dryness by rotary evaporation to obtain L-carnosine (13) g with the yield of 97%; HPLC purity>99.0%; specific rotation [] 20 D =+21.3° (c=1.0，H 2 O) is consistent with standard.
Example 4
(1) Preparation of Compound INT-1:
3-Chloropropionic acid (8.5 g,78 mmol), dibenzylamine (30 g,0.15 mol) are dissolved in toluene (500 mL), cooled in an ice bath, pyridine (24 g,0.3 mol) is slowly added dropwise, the temperature is raised to 90 ℃ for reaction 4 h, the organic solvent is removed by decompression concentration, dichloromethane and water are added for extraction and delamination, the organic phase is separated out, common salt is washed with water, anhydrous sodium sulfate is dried, decompression rotary evaporation is carried out to dryness, the crude product is recrystallized by ethyl acetate-normal hexane mixed solvent, and vacuum drying is carried out, thus obtaining compound INT-1 (20 g), and the yield is 95%;
(2) Preparation of Compound INT-2:
dissolving 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 for 6 h, cooling to room temperature, filtering to remove insoluble substances, concentrating the filtrate under reduced pressure to remove organic solvent to obtain crude product, recrystallizing with ethyl acetate-N-hexane mixed solvent, and vacuum drying to obtain compound INT-2 (39 g) with yield of 84%;
(3) Preparation of Compound INT-3:
dissolving compound INT-2 (38 g,61 mmol) in dichloromethane (500 mL), cooling in ice bath, slowly dropwise adding water (80 mL), reacting at 30deg.C for 1h, suction filtering, washing filter cake with water, recrystallizing crude product with ethyl acetate-n-hexane mixed solvent, and vacuum drying to obtain compound INT-3 (24 g) with 97% yield;
(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 at 60℃under normal pressure with hydrogen gas to give 6 h. The catalyst is removed by the suction filtration through diatomite, and the filtrate is concentrated to dryness by rotary evaporation to obtain L-carnosine (13) g with the yield of 97%; HPLC purity>99.0%; specific rotation [] 20 D =+21.3° (c=1.0，H 2 O) is consistent with standard.
The applicant states that the present invention is illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must be practiced in dependence upon the above examples. It should be apparent to those skilled in the art that any modification of the present invention, equivalent substitution of raw materials for the product of the present invention, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present invention and the scope of disclosure.
Claims (11)
1. A method for preparing L-carnosine, comprising the steps of:
(1) The halopropionic acid shown in the formula I reacts with dibenzylamine to obtain a compound INT-1, wherein the reaction formula is as follows:
；
wherein X is Br or Cl;
(2) The compound INT-1 reacts with N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester to obtain a compound INT-2, and the reaction formula is as follows:
；
(3) Deprotection of compound INT-2 to give compound INT-3 of the formula:
；
(4) The compound INT-3 is subjected to catalytic hydrogenation deprotection reaction to obtain L-carnosine, wherein the reaction formula is as follows:
；
the reaction of the step (1) is carried out in the presence of an alkaline substance, and the reaction of the step (2) is carried out in the presence of a condensing agent and an alkali promoter;
the condensing agent is any one or a combination of at least two of N, N '-carbonyl diimidazole, 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 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, dicyclohexylamine, tetramethylguanidine, N-methylpyrrolidone, N-methylmorpholine or N-ethylmorpholine;
the deprotection reaction in the step (3) is a hydrolysis deprotection reaction or an alcoholysis deprotection reaction, and the catalytic hydrogenation deprotection reaction in the step (4) is a reaction of the compound INT-3 with hydrogen under the condition that palladium-carbon is used as a catalyst.
2. The process according to claim 1, wherein the halopropionic acid in step (1) is 3-bromopropionic acid or 3-chloropropionic acid, and the molar ratio of halopropionic acid to dibenzylamine is 1:1-2.
3. The process according to claim 1, wherein the reaction of step (1) is carried out in the presence of an alkaline 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 halopropionic acid is 1-4:1.
4. The process of 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 temperature of the reaction in the step (1) is 50-100 ℃, and the reaction time is 3-12 hours.
5. The process according to claim 1, wherein the molar ratio of the compound INT-1 to N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester in step (2) is 1:1-1.2.
6. The process according to claim 1, wherein the molar ratio of condensing agent to compound INT-1 is 1-2:1.
7. The process according to claim 1, wherein the molar ratio of base promoter to compound INT-1 is 1-2:1.
8. The method according to claim 1, wherein the solvent for the reaction in the step (2) is any one or a combination of at least two of toluene, xylene, ethyl acetate, isopropyl acetate, butyl acetate, N-dimethylformamide, and acetonitrile;
the temperature of the reaction in the step (2) is 50-80 ℃ and the reaction time is 6-18 hours.
9. The preparation method according to claim 1, wherein the hydrolysis deprotection reaction is carried out by adding water, controlling the temperature to 20-30 ℃ and carrying out hydrolysis reaction for 0.5-1 hour;
the alcoholysis deprotection reaction is carried out by using any one or a 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 the alcoholysis deprotection reaction is dichloromethane.
10. The 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, and isopropanol;
the temperature of the catalytic hydrogenation deprotection reaction is 30-60 ℃ and the time is 6-12 hours;
the catalytic hydrogenation deprotection reaction in the step (4) is carried out under normal pressure.
11. The method of manufacturing according to claim 1, comprising the steps of:
(1) In the presence of alkaline substances, the mol ratio of the halopropionic acid shown in the formula I to the dibenzylamine is 1:1-2, and the halopropionic acid and the dibenzylamine react for 3-12 hours at 50-100 ℃ to obtain a compound INT-1;
(2) In the presence of a condensing agent and an alkali accelerator, the molar ratio of the compound INT-1 to the N, 1-bis (trimethylsilyl) -L-histidine trimethylsilyl ester is 1:1-1.2, and the reaction is carried out for 6-18 hours at 50-80 ℃ to obtain the compound INT-2;
(3) Carrying out hydrolysis or alcoholysis deprotection reaction on the compound INT-2 to obtain a compound INT-3;
(4) And under the condition that palladium-carbon is used as a catalyst, carrying out catalytic hydrogenation deprotection reaction with hydrogen to obtain the L-carnosine.
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| CN101284862A (en) * | 2008-05-26 | 2008-10-15 | 常熟富士莱医药化工有限公司 | Synthetic method of L-carnosine |
| CN106565607A (en) * | 2016-10-11 | 2017-04-19 | 湖北泓肽生物科技有限公司 | Synthetic method of L-carnosine |
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| JP2019167317A (en) * | 2018-03-26 | 2019-10-03 | 株式会社トクヤマ | Method for producing l-carnosine derivative and l-carnosine |
| CN111051289A (en) * | 2017-09-05 | 2020-04-21 | 株式会社德山 | Protected L-carnosine derivative, L-carnosine and method for producing crystalline L-carnosine zinc complex |
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