Synthesis method of 1-methyl-L-histidine

Abstract

The invention provides a synthesis method of 1-methyl-L-histidine, which comprises the following steps: firstly, carrying out methylation reaction on a compound 1 and N, N-dimethylformamide dimethyl acetal to obtain a compound 3; the compound 3 and NCS are subjected to a chlorination reaction, and a compound 4 is obtained; then reacting the compound 4 with diethyl acetamidomalonate to obtain a compound 5; then carrying out hydrolysis decarboxylation on the compound 5 to obtain a compound 6; and finally, splitting the compound 6 by using acetyl hydrolase to obtain a chiral compound 7 (namely 1-methyl-L-histidine). The synthesis route is short, the raw materials are cheap, the production cost can be reduced, the product yield and purity are high, and large-scale industrial production is facilitated.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing 1-methyl-L-histidine. Background Art

[0002] Anserine (β-alanyl-1-methyl-L-histidine) is a highly stable water-soluble dipeptide. By promoting uric acid excretion, it has the effect of alleviating hyperuricemia. It naturally exists in the skeletal muscle tissue and brain tissue of vertebrates. It has a PK value of about 7.1 and remains intact at low pH values (<3.0). In 1900, the Russian scholar Gulewitsch first discovered carnosine. Liebig isolated carnosine from an extract, and later it was confirmed that the structure of this substance is β-alanyl-L-histidine. This is the first representative bioactive peptide isolated from natural raw materials; this compound has water solubility and strong antioxidant, anti-aging and other functions, and has been used as a natural antioxidant in the food industry.

[0003] 1-Methyl-L-histidine is a key intermediate for synthesizing anserine. At present, there are relatively few synthesis methods for this compound. Chem. Pharm. Bull 42(9), 1784 - 1790(1994) reported the following synthesis method:

[0004]

[0005] The above method has a long route, high cost of using chiral sources, and not very high selectivity (the ratio of diastereoisomers is about 70:5). The product yield and purity are not good, and it is not suitable for industrial production. Summary of the Invention

[0006] In view of this, the present invention provides a method for synthesizing 1-methyl-L-histidine. The synthesis method provided by the present invention can shorten the synthesis route, reduce production costs, and can improve the yield and purity, and is suitable for industrial production.

[0007] The present invention provides a method for synthesizing 1-methyl-L-histidine, comprising the following steps:

[0008] A) The compound 1 undergoes a methylation reaction with N,N-dimethylformamide dimethyl acetal to obtain the compound 3;

[0009] B) The compound 3 undergoes a chlorination reaction with NCS to obtain the compound 4;

[0010] C) The compound 4 reacts with diethyl acetamidomalonate to obtain the compound 5;

[0011] D) Hydrolyze and decarboxylate the said compound 5 to obtain compound 6;

[0012] E) Resolve compound 6 with acetylhydrolase to obtain chiral compound 7;

[0013]

[0014] Preferably, in step A), the temperature of the methylation reaction is 60-120 °C and the time is 3-12 h.

[0015] Preferably, in step B), the temperature of the chlorination reaction is 80-110 °C and the time is 6-12 h.

[0016] Preferably, in step B), the chlorination reaction is carried out under a protective atmosphere.

[0017] Preferably, in step B), the chlorination reaction is carried out under the action of an initiator;

[0018] The initiator is AIBN.

[0019] Preferably, in step C), the temperature of the reaction is 40-70 °C.

[0020] Preferably, step C) specifically includes:

[0021] C1) Dissolve diethyl acetamidomalonate in an organic solvent, add sodium ethoxide and react;

[0022] C2) Add compound 4 to the system and continue to react to obtain compound 5.

[0023] Preferably, in step D), the hydrolysis and decarboxylation are carried out in the presence of a basic substance;

[0024] The basic substance is at least one of sodium hydroxide, lithium hydroxide and potassium hydroxide.

[0025] Preferably, step E) specifically includes:

[0026] E1) Dissolve compound 6 in water, add a basic regulator to adjust the pH value to 7-8, and then add acetylhydrolase to react;

[0027] E2) Separate and remove the acetylhydrolase, adjust the pH value to 5-6 with an acidic regulator, extract, concentrate the aqueous phase under reduced pressure, wash, dry and concentrate the obtained residue to obtain chiral compound 7.

[0028] Preferably, in step E1), the temperature of the reaction is 35-40 °C.

[0029] The synthesis method provided by the present invention first performs a methylation reaction on compound 1 with N,N-dimethylformamide dimethyl acetal to obtain compound 3; then performs a chlorination reaction on compound 3 with NCS to obtain compound 4; then reacts compound 4 with diethyl acetamidomalonate to obtain compound 5; then hydrolyzes and decarboxylates compound 5 to obtain compound 6; and finally resolves compound 6 with acetylhydrolase to obtain the chiral compound 7 (i.e., 1-methyl-L-histidine). The synthesis route of the present invention is short and the raw materials are cheap, which can reduce the production cost, and the product yield and purity are high, which is beneficial to large-scale industrial production.

[0030] The experimental results show that the synthesis method of the present invention can make the product yield reach more than 80% and the purity reach 99%. Detailed implementation mode

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this application belongs. The terms used in the specification of this application herein are only for the purpose of describing specific embodiments and are not intended to limit this application.

[0032] In this article, among the technical features described in an open-ended manner, it includes a closed technical solution composed of the listed features, and also includes an open technical solution containing the listed features.

[0033] The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0034] In this article, when it comes to a numerical range, unless otherwise specified, the above numerical range is considered continuous and includes the minimum and maximum values of this range, as well as each value between such minimum and maximum values. Further, when the range refers to an integer, it includes each integer between the minimum and maximum values of this range. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0035] In this article, for the unit of a data range, if only the unit is attached after the right endpoint, it means that the units of the left endpoint and the right endpoint are the same. For example, 60~120°C means that the units of the left endpoint "60" and the right endpoint "120" are both °C.

[0036] This text specifically discloses only some numerical ranges. However, any lower limit can be combined with any upper limit to form a range not explicitly recited; and any lower limit can be combined with other lower limits to form a range not explicitly recited, and similarly any upper limit can be combined with any other upper limit to form a range not explicitly recited. In addition, each individually disclosed point or single numerical value itself can be used as a lower limit or upper limit and combined with any other point or single numerical value or with other lower limits or upper limits to form a range not explicitly recited.

[0037] The present invention provides a method for synthesizing 1-methyl-L-histidine, comprising the following steps:

[0038] A) Reacting compound 1 with N,N-dimethylformamide dimethyl acetal to carry out methylation reaction to obtain compound 3;

[0039] B) Reacting the compound 3 with NCS to carry out chlorination reaction to obtain compound 4;

[0040] C) Reacting the compound 4 with diethyl acetamidomalonate to obtain compound 5;

[0041] D) Hydrolyzing and decarboxylating the compound 5 to obtain compound 6;

[0042] E) Resolving the compound 6 with acetyl hydrolase to obtain a chiral compound 7;

[0043]

[0044] Regarding step A) :

[0045] A) Reacting compound 1 with N,N-dimethylformamide dimethyl acetal to carry out methylation reaction to obtain compound 3.

[0046] In the present invention, the reaction route of step A) is as follows:

[0047]

[0048] That is, a methylation reaction occurs between compound 1 and N,N-dimethylformamide dimethyl acetal to generate compound 2 and compound 3, and then the two are separated to obtain compound 2 and compound 3 respectively, and then compound 3 is used for subsequent synthesis reactions.

[0049] In the present invention, the sources of compound 1 (i.e., dimethylimidazole) and N,N-dimethylformamide dimethyl acetal are not particularly limited, and they can be commercially available products or prepared according to conventional preparation methods in the art.

[0050] In the present invention, the mass ratio of the compound 1 to N,N-dimethylformamide dimethyl acetal is preferably 100∶(100 - 150), specifically it can be 100∶100, 100∶110, 100∶120, 100∶130, 100∶140, 100∶150, and more preferably 100∶120.

[0051] In the present invention, the methylation reaction is preferably carried out in an organic solvent medium. The organic solvent is preferably at least one of DMF (i.e., N,N-dimethylformamide), DMAc (i.e., N,N-dimethylacetamide), and NMP (i.e., N-methylpyrrolidone), and more preferably DMF. In the present invention, the dosage ratio of the compound 1 to the organic solvent is preferably 100 g∶(400 - 1000) mL, specifically it can be 100 g∶400 mL, 100 g∶500 mL, 100 g∶600 mL, 100 g∶700 mL, 100 g∶800 mL, 100 g∶900 mL, 100 g∶1000 mL, and more preferably 100 g∶600 mL.

[0052] In the present invention, the temperature of the methylation reaction is preferably 60 - 120 °C, specifically it can be 60 °C, 70 °C, 80 °C, 90 °C, 100 °C, 120 °C, and more preferably 90 °C. The time of the methylation reaction is preferably 3 - 12 h, specifically it can be 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, and more preferably 4 h. Through the above reaction, compound 2 and compound 3 are generated in the system.

[0053] In the present invention, after the above methylation reaction, vacuum distillation separation is preferably carried out to obtain compound 3. Specifically, after the above methylation reaction, it is concentrated to dryness under reduced pressure, cooled, then ethyl acetate is added to dissolve the product, and then water is added for washing, drying, and concentration to obtain compound 3.

[0054] Regarding step B) :

[0055] B) React the compound 3 with NCS to carry out a chlorination reaction to obtain compound 4.

[0056] In the present invention, the reaction route of step B) is as follows:

[0057]

[0058] In the present invention, the structure of the NCS (i.e., N-chlorosuccinimide) is as follows, and its source has no special limitation, and it can be a commercially available product or prepared according to the conventional preparation methods in the art.

[0059]

[0060] In the present invention, the mass ratio of the compound 3 to NCS is preferably 50∶(50 - 80), specifically it can be 50∶50, 50∶60, 50∶70, 50∶80, and more preferably 50∶60.

[0061] In the present invention, the chlorination reaction is preferably carried out under the action of an initiator. The initiator is preferably AIBN (azobisisobutyronitrile). In the present invention, the mass ratio of the compound 3 to the initiator is preferably 50∶(5 - 20), specifically it can be 50∶5, 50∶10, 50∶15, 50∶20, and more preferably 50∶10.

[0062] In the present invention, the chlorination reaction is preferably carried out under a protective atmosphere. In the present invention, there is no special limitation on the type of gas providing the protective atmosphere, and it can be a conventional protective gas in the art, such as nitrogen, helium or argon, etc.

[0063] In the present invention, the chlorination reaction is preferably carried out in an organic solvent medium. The organic solvent medium is preferably at least one of toluene, xylene and mesitylene, and more preferably toluene. In the present invention, the dosage ratio of the compound 3 to the organic solvent is preferably 50 g∶(150 - 500) mL, specifically it can be 50 g∶150 mL, 50 g∶200 mL, 50 g∶250 mL, 50 g∶300 mL, 50 g∶350 mL, 50 g∶400 mL, 50 g∶450 mL, 50 g∶500 mL, and more preferably 50 g∶300 mL.

[0064] In the present invention, the temperature of the chlorination reaction is preferably 80 - 110 °C, specifically it can be 80 °C, 90 °C, 100 °C, 110 °C, and more preferably 100 °C. The time of the chlorination reaction is preferably 6 - 12 h, specifically it can be 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, and more preferably 8 h.

[0065] In the present invention, after the above chlorination reaction, the following post-treatment is preferably further carried out: cooling to room temperature, washing with water, drying, and concentrating to obtain the compound 4. Among them, the drying is preferably drying with sodium sulfate.

[0066] In the present invention, the operation of step B) preferably specifically includes: dissolving the compound 3 in an organic solvent, adding NCS and an initiator under a protective atmosphere, heating to the target temperature and reacting for a certain time, after the raw materials disappear, cooling to room temperature, washing with water, drying, and concentrating to obtain the compound 4.

[0067] Regarding step C) :

[0068] C) Reacting the compound 4 with diethyl acetamidomalonate to obtain the compound 5.

[0069] In the present invention, the reaction route of step C) is as follows:

[0070]

[0071] In the present invention, the mass ratio of the compound 4 to diethyl acetamidomalonate is preferably 60∶(80 - 150), specifically it can be 60∶80, 60∶90, 60∶100, 60∶110, 60∶120, 60∶130, 60∶140, 60∶150, and more preferably 60∶120.

[0072] In the present invention, the reaction is preferably carried out in an organic solvent medium. The organic solvent is preferably at least one of absolute ethanol, absolute methanol, absolute isopropanol, absolute n-butanol and absolute tert-butanol, and more preferably absolute ethanol. In the present invention, the dosage ratio of the compound 4 to the organic solvent is preferably 60 g∶(500 - 1000) mL, specifically it can be 60 g∶500 mL, 60 g∶600 mL, 60 g∶700 mL, 60 g∶800 mL, 60 g∶900 mL, 60 g∶1000 mL, and more preferably 60 g∶800 mL.

[0073] In the present invention, the reaction is preferably carried out in the presence of sodium ethoxide. The mass ratio of the compound 4 to sodium ethoxide is preferably 60∶(40 - 70), specifically it can be 60∶40, 60∶50, 60∶60, 60∶70, and more preferably 60∶40.

[0074] In the present invention, the temperature of the reaction is preferably 40 - 70 °C, specifically it can be 40 °C, 50 °C, 60 °C, 70 °C, and more preferably 60 °C.

[0075] In the present invention, step C) preferably specifically includes:

[0076] C1) Dissolve diethyl acetamidomalonate in an organic solvent, and add sodium ethoxide for reaction;

[0077] C2) Add the compound 4 to the system and continue the reaction to obtain the compound 5.

[0078] In step C1), the reaction time is preferably 1 - 2 h, specifically it can be 1 h, 2 h. In step C2), when adding the compound 4, it is preferably added in batches. After adding, continue to heat up to reflux for reaction; the reaction time is preferably 4 - 12 h, specifically it can be 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h.

[0079] In the present invention, after the reaction is completed, the following post-treatment is preferably further carried out: Concentrate under reduced pressure to dryness, cool to room temperature, add water to precipitate solids, and filter by suction to obtain the compound 5.

[0080] Regarding step D) :

[0081] D) Hydrolyze and decarboxylate the said compound 5 to obtain compound 6.

[0082] In the present invention, the reaction route of step D) is as follows:

[0083]

[0084] In the present invention, the hydrolysis and decarboxylation are preferably carried out in the presence of a basic substance. The basic substance is preferably at least one of sodium hydroxide, lithium hydroxide and potassium hydroxide, more preferably sodium hydroxide. In the present invention, the mass ratio of the compound 5 to the basic substance is preferably 80∶(24 - 36), specifically 80∶24, 80∶25, 80∶26, 80∶27, 80∶28, 80∶29, 80∶30, 80∶31, 80∶32, 80∶33, 80∶34, 80∶35, 80∶36, more preferably 80∶24.

[0085] In the present invention, the hydrolysis and decarboxylation are preferably carried out in an organic solvent medium. The organic solvent is preferably at least one of methanol, ethanol, isopropanol, n - butanol and tert - butanol, more preferably methanol. In the present invention, the dosage ratio of the compound 5 to the organic solvent is preferably 80 g∶(300 - 600) mL, specifically 80 g∶300 mL, 80 g∶400 mL, 80 g∶500 mL, 80 g∶600 mL, more preferably 80 g∶400 mL.

[0086] In the present invention, the hydrolysis and decarboxylation are carried out by heating under reflux. The time of heating under reflux is preferably 2 - 12 h, specifically 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h.

[0087] In the present invention, the operation process of the above hydrolysis and decarboxylation preferably specifically includes: dissolving the compound 5 in an organic solvent, adding a basic substance, and carrying out hydrolysis and decarboxylation by heating under reflux.

[0088] In the present invention, after hydrolysis and decarboxylation, the following treatment is preferably further carried out: concentrating under reduced pressure to remove the organic solvent, dissolving the residue in water, adjusting the pH value to 5-7 with an acid, then, extracting, drying, and concentrating to obtain Compound 6. Among them, the acid is preferably at least one of hydrochloric acid, acetic acid, trifluoroacetic acid, and sulfuric acid, more preferably hydrochloric acid. The concentration of the acid is preferably 2-10 mol / L, specifically 2 mol / L, 3 mol / L, 4 mol / L, 5 mol / L, 6 mol / L, 7 mol / L, 8 mol / L, 9 mol / L, 10 mol / L. The pH value is specifically 5, 6, 7. The extraction is preferably carried out with ethyl acetate, and after extraction, the organic phases are combined (i.e., combining ethyl acetate), then, dried, and concentrated to obtain Compound 6.

[0089] Regarding step E) :

[0090] In the present invention, the reaction route of step E) is as follows:

[0091]

[0092] E) Resolving Compound 6 with acetyl hydrolase to obtain chiral Compound 7.

[0093] In the present invention, step E) preferably specifically includes:

[0094] E1) Dissolving Compound 6 in water, adding a basic regulator to adjust the pH value to 7-8, and then adding acetyl hydrolase for reaction;

[0095] E2) Separating and removing the acetyl hydrolase, adjusting the pH value to 5-6 with an acidic regulator, extracting, concentrating the aqueous phase under reduced pressure, washing, drying, and concentrating the obtained residue to obtain chiral Compound 7.

[0096] Regarding step E1:

[0097] The mass ratio of Compound 6 to water is preferably 100:(500-1200), specifically 100:500, 100:600, 100:700, 100:800, 100:900, 100:1000, 100:1100, 100:1200, more preferably 100:1000.

[0098] The basic regulator is preferably at least one of sodium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide and potassium hydroxide, and more preferably sodium hydroxide. In the present invention, the basic regulator is preferably introduced in the form of an aqueous solution; the concentration of the aqueous solution of the basic regulator is preferably 2-10 mol / L, specifically 2 mol / L, 3 mol / L, 4 mol / L, 5 mol / L, 6 mol / L, 7 mol / L, 8 mol / L, 9 mol / L, 10 mol / L. The pH value is adjusted to 7-8, specifically 7, 7.5, 8.

[0099] After adding the basic regulator to adjust the pH value of the system, it is preferred to keep the system temperature at 35-40 °C, specifically 35 °C, 36 °C, 37 °C, 38 °C, 39 °C, 40 °C. While maintaining at the above temperature, acetylhydrolase (also known as acetylhydrolase, abbreviated as PAF-AH) is added. After adding acetylhydrolase, the stirring reaction is carried out under the above pH conditions. The time of the stirring reaction is preferably 18-24 h, specifically 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h.

[0100] Regarding step E2:

[0101] After the reaction in step E1 is completed, the acetylhydrolase is separated and removed. The separation and removal method is preferably suction filtration. Then, an acidic regulator is added to adjust the pH value. The acidic regulator is preferably at least one of hydrochloric acid, sulfuric acid and trifluoroacetic acid, and more preferably hydrochloric acid. The concentration of the acid is preferably 2-10 mol / L, specifically 2 mol / L, 3 mol / L, 4 mol / L, 5 mol / L, 6 mol / L, 7 mol / L, 8 mol / L, 9 mol / L, 10 mol / L. The pH value is adjusted to 5-6, more preferably 6. The extraction preferably uses ethyl acetate for extraction. After extraction, the aqueous phase is concentrated to dryness under reduced pressure, and then the obtained residue is washed. In the present invention, it is preferably washed with methanol. Then, it is dried, specifically preferably dried with anhydrous sodium sulfate. Then, it is concentrated to obtain chiral compound 7 (i.e., 1-methyl-L-histidine).

[0102] The synthesis method provided by the present invention first carries out a methylation reaction on compound 1 with N,N-dimethylformamide dimethyl acetal to obtain compound 3; then carries out a chlorination reaction on compound 3 with NCS to obtain compound 4; then reacts compound 4 with diethyl acetamidomalonate to obtain compound 5; then hydrolyzes and decarboxylates compound 5 to obtain compound 6; finally, compound 6 is resolved with acetylhydrolase to obtain chiral compound 7 (i.e., 1-methyl-L-histidine). The synthesis route of the present invention is short, the raw materials are cheap, the production cost can be reduced, and the product yield and purity are high, which is beneficial to large-scale industrial production.

[0103] The experimental results show that the synthesis method of the present invention can achieve a product yield of over 80% and a purity of 99%.

[0104] To further understand the present invention, the preferred embodiments of the present invention will be described below in conjunction with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

[0105] Example 1

[0106] The synthesis route is as follows:

[0107]

[0108] The synthesis process is as follows:

[0109] A) Take 100 g of Compound 1 and dissolve it in 600 mL of DMF. Add 120 g of N,N-dimethylformamide dimethyl acetal and heat to 90 °C for reaction for 4 h. Then concentrate to dryness under reduced pressure. After cooling, add 500 mL of ethyl acetate to dissolve the product, add 200 mL of water for washing twice, dry, and concentrate to obtain Compound 3 (yield 80%, purity > 98%).

[0110] B) Take 50 g of Compound 3 and dissolve it in 300 mL of toluene. Under nitrogen protection, add 60 g of NCS and 10 g of AIBN, heat to 100 °C for reaction for 8 h. After the raw materials disappear, cool to room temperature, add 100 mL of water for washing, dry with sodium sulfate, and concentrate to obtain Compound 4 (yield 90%).

[0111] C) Take 120 g of diethyl acetamidomalonate and dissolve it in 800 mL of absolute ethanol. Add 40 g of sodium ethoxide and heat to 60 °C for reaction for 2 h. Then, add 60 g of Compound 4 in batches. After adding, continue to heat to reflux for reaction for 6 h. After the raw materials disappear, concentrate to dryness under reduced pressure. Cool to room temperature and add 200 mL of water to precipitate a solid. Filter by suction to obtain Compound 5 (yield 95%).

[0112] D) Take 80 g of Compound 5 and dissolve it in 400 mL of methanol. Add 24 g of sodium hydroxide and heat to reflux for 2 h until the raw materials disappear. Concentrate under reduced pressure to remove methanol. The residue is dissolved in 20 mL of water, and the pH is adjusted to 6 with 6 mol / L hydrochloric acid. Extract with 400 mL of ethyl acetate twice. Combine the ethyl acetate phases, dry, and concentrate to obtain Compound 6 (yield 95%).

[0113] E) Dissolve 100 g of Compound 6 in 1000 g of water, adjust the pH value to 8 with an aqueous sodium hydroxide solution (concentration 5 mol / L), keep the temperature at 37 °C, add 5 g of acetylated hydrolase, control the pH value to remain unchanged under stirring, continue stirring for 24 h, and the reaction is completed. Filter off the enzyme by suction, adjust the pH value to 6 with hydrochloric acid (concentration 6 mol / L), extract twice with 200 mL of ethyl acetate, concentrate the aqueous phase to dryness under reduced pressure, wash the residue twice with methanol (500 mL), and then dry with anhydrous sodium sulfate and concentrate to obtain Compound 7 (i.e., 1-methyl-L-histidine, yield 90%, purity 99%).

[0114] Example 2

[0115] The synthesis route is as follows: the same as Example 1.

[0116] The synthesis process is as follows:

[0117] A) Dissolve 100 g of Compound 1 in 600 mL of DMF, add 150 g of N,N-dimethylformamide dimethyl acetal, heat to 120 °C and react for 3 h; then concentrate to dryness under reduced pressure, cool, dissolve the product in 500 mL of ethyl acetate, add 200 mL of water and wash twice, dry and concentrate to obtain Compound 3.

[0118] B) Dissolve 50 g of Compound 3 in 500 mL of toluene, add 80 g of NCS and 20 g of AIBN under nitrogen protection, heat to 110 °C and react for 12 h. After the raw materials disappear, cool to room temperature, add 100 mL of water and wash, dry with sodium sulfate and concentrate to obtain Compound 4.

[0119] C) Dissolve 150 g of diethyl acetamidomalonate in 1000 mL of absolute ethanol, add 70 g of sodium ethoxide, heat to 70 °C and react for 2 h; then, add 60 g of Compound 4 in batches. After adding, continue to heat to reflux and react for 6 h. After the raw materials disappear, concentrate to dryness under reduced pressure, cool to room temperature, add 200 mL of water, precipitate a solid, filter by suction to obtain Compound 5.

[0120] D) Dissolve 80 g of Compound 5 in 600 mL of methanol, add 36 g of sodium hydroxide, heat to reflux for 2 h until the raw materials disappear. Concentrate under reduced pressure to remove methanol, dissolve the residue in 20 mL of water, adjust the pH to 6 with hydrochloric acid with a concentration of 6 mol / L, extract twice with 400 mL of ethyl acetate, combine the ethyl acetate phases, dry and concentrate to obtain Compound 6.

[0121] (E) Dissolve 100 g of Compound 6 in 1200 g of water, adjust the pH value to 8 with an aqueous sodium hydroxide solution (concentration 5 mol / L), maintain the temperature at 40 °C, add 5 g of acetylated hydrolase, control the pH value to remain unchanged under stirring, continue stirring for 24 h, and the reaction is completed. Filter off the enzyme by suction, adjust the pH value to 6 with hydrochloric acid (concentration 6 mol / L), extract twice with 200 mL of ethyl acetate, concentrate the aqueous phase under reduced pressure to dryness, wash the residue twice with methanol (500 mL), and then dry with anhydrous sodium sulfate and concentrate to obtain Compound 7 (i.e., 1-methyl-L-histidine, yield 80%, purity 99%).

[0122] In this article, specific examples are used to elaborate on the principles and implementation modes of the present invention. The description of the above examples is only used to help understand the method and its core idea of the present invention, including the best mode, and also enables any person skilled in the art to practice the present invention, including manufacturing and using any device or system, and implementing any combined method. It should be noted that for those of ordinary skill in the art in this technical field, without departing from the principles of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention. The protection scope of the present invention patent is defined by the claims and may include other embodiments that can be conceived by those skilled in the art. If these other embodiments have structural elements similar to the literal description of the claims, or if they include equivalent structural elements that have no substantial difference from the literal description of the claims, then these other embodiments should also be included within the scope of the claims.

Claims

1. A method for synthesizing 1-methyl-L-histidine, characterized in that, It includes the following steps: A) Methylate compound 1 with N,N-dimethylformamide dimethyl acetal to obtain compound 3; B) Chlorinate the said compound 3 with NCS to obtain compound 4; C) React the said compound 4 with diethyl acetamidomalonate to obtain compound 5; D) Hydrolyze and decarboxylate the said compound 5 to obtain compound 6; E) Resolve the said compound 6 with acetylhydrolase to obtain chiral compound 7; 2. The synthesis method according to claim 1, wherein, In step A), the temperature of the methylation reaction is 60 - 120 °C, and the time is 3 - 12 h.

3. The synthesis method according to claim 1, characterized in that, In step B), the temperature of the chlorination reaction is 80 - 110 °C, and the time is 6 - 12 h.

4. The synthesis method according to claim 1, wherein In step B), the chlorination reaction is carried out under a protective atmosphere.

5. The synthesis method according to claim 1, characterized in that, In step B), the chlorination reaction is carried out under the action of an initiator; The initiator is AIBN.

6. The synthesis method according to claim 1, characterized in that, In step C), the temperature of the reaction is 40 - 70 °C.

7. The synthesis method according to claim 1, wherein Step C) specifically includes: C1) Dissolve diethyl acetamidomalonate in an organic solvent, add sodium ethoxide and react; C2) Add compound 4 to the system and continue the reaction to obtain compound 5.

8. The synthesis method according to claim 1, characterized in that, In step D), the hydrolysis and decarboxylation are carried out in the presence of a basic substance; The basic substance is at least one of sodium hydroxide, lithium hydroxide and potassium hydroxide.

9. The synthesis method according to claim 1, wherein Step E) specifically includes: E1) Dissolve compound 6 in water, add a basic regulator to adjust the pH value to 7 - 8, then add acetylhydrolase and react; E2) Separate and remove the acetylhydrolase, adjust the pH value to 5 - 6 with an acidic regulator, extract, concentrate the aqueous phase under reduced pressure, wash, dry and concentrate the obtained residue to obtain chiral compound 7.

10. The synthesis method according to claim 9, characterized in that, In step E1), the temperature of the reaction is 35 - 40 °C.

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