A kind of preparation method of L-serine

Abstract

The invention discloses a method for preparing L-serine, which belongs to the field of pharmaceutical technology. The method for preparing L-serine comprises the following steps: a. Compound (II) reacts with compound (III) to obtain compound (IV); b. Compound (IV) reacts with paraformaldehyde under the action of a base to obtain compound (V); c. Compound (V) is salified with a chiral acid to obtain compound (VI); d. Compound (VI) is acid-displaced to obtain compound (VII); e. Compound (VII) is hydrolyzed to obtain compound (I). The invention has the advantages of short synthetic route, simple operation, high yield, high product purity, etc., and is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more specifically, to a method for preparing L-serine. Background Art

[0002] L-serine is a non-essential amino acid and a glycogenic amino acid. It can be biosynthesized in vivo from D-glyceric acid as a precursor. Threonine and glycine can also be converted into serine. Serine participates in the transformation of -SH and -OH and the biosynthesis of purine pyrimidine in the body, and can be converted into choline phospholipid components. The phosphate ester of L-serine can relieve fatigue and restore physical strength. L-serine is an important biochemical reagent and pharmaceutical agent. It is not only used in biochemical research, but is also used as a component of the third-generation amino acid infusion. For example, the content of L-serine in the amino acid mixture suitable for general nutritional therapy is 1.68g / L, and the content of L-serine in the mixed amino acid solution suitable for patients with liver damage is 5.00g / L. At the same time, it can also be used as a food and feed additive. In addition, L-serine is used in vanishing cream and cosmetics industries due to its special wettability. With the continuous development of the cosmetics industry and people's in-depth understanding of the physiological effects of amino acids, the amount of L-serine will continue to increase.

[0003] At present, the chemical synthesis methods of L-serine can be roughly divided into three categories: ① Synthesis method using hydroxyacetaldehyde as raw material; ② Synthesis method using various condensation reactions; ③ Synthesis method using vinyl compounds as raw materials.

[0004] (1) Synthesis method using hydroxyacetaldehyde as raw material:

[0005] Fischer et al. used the amino nitrile obtained by the reaction of hydroxyacetaldehyde with hydrocyanic acid and ammonia to hydrolyze and synthesize DL-serine, with an overall yield of only 9%.

[0006]

[0007] Leuchs et al. used ethoxyacetaldehyde instead of hydroxyacetaldehyde to improve its yield. The synthesis of ethoxyacetaldehyde can be synthesized by using chloroacetal, or by directly synthesizing by oxidation of easily available ethylene glycol ethyl ether. Ethoxyacetaldehyde is reacted with hydrocyanic acid and ammonia to form aminonitrile, which is then hydrolyzed with hydrobromic acid to prepare DL-serine. The total yield of chloroacetal is 14%, and the total yield of ethylene glycol ethyl ether is 51%.

[0008]

[0009] The above synthesis methods all require the use of highly toxic hydrocyanic acid and have low yields.

[0010] (2) Synthesis method using condensation reaction:

[0011] Erlenmeyer et al. conducted a condensation reaction between ethyl hippurate and ethyl formate in the presence of sodium ethoxide to obtain hydroxymethylene hippurate, which was then reduced with Na / Hg to obtain ethyl benzoylserine, which was then hydrolyzed with acid to synthesize DL-serine with a total yield of 48%.

[0012]

[0013] The above synthesis method requires the use of dangerous goods Na / Hg.

[0014] (3) Synthesis method using vinyl compounds as raw materials:

[0015] Carter et al. converted methyl acrylate into α-acetoxymercury-β-methoxypropionate, which was then reacted with bromine to produce α-bromo-β-methoxypropionate. This was then subjected to saponification and amination to obtain β-methoxyserine, which was then demethylated with hydrobromic acid to synthesize DL-serine, with a total yield of about 40%.

[0016]

[0017] Mitsui Toatsu Co., Ltd. of Japan uses acrylonitrile as raw material, and obtains DL-serine through chlorine addition, ammonia substitution, ring closure, and ion resin purification, with a total yield of about 70%.

[0018] The above-mentioned synthetic route is relatively long and requires purification by an ion resin column.

[0019] Generally speaking, the three types of synthesis methods have certain risks and purification difficulties in process amplification, and all synthesized products are DL-serine. In view of this, the present invention provides a novel method for preparing L-serine. Summary of the invention

[0020] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for preparing L-serine, which has the advantages of short synthetic route, simple operation, high yield, high product purity, etc. and is suitable for industrial production.

[0021] To achieve the above object, the present invention provides the following technical solutions:

[0022] A method for preparing L-serine comprises the following steps:

[0023] a. Compound (II) reacts with compound (III) to obtain compound (IV);

[0024] b. In the presence of a base, compound (IV) reacts with paraformaldehyde to obtain compound (V);

[0025] c. Compound (V) is reacted with a chiral acid to form a salt to obtain compound (VI);

[0026] d. Compound (VII) is prepared by acid substitution of compound (VI);

[0027] e. Compound (VII) is hydrolyzed to obtain compound (I);

[0028] The compound (I) is L-serine, and its structural formula is as follows:

[0029]

[0030] The structural formula of the compound (II) is as follows:

[0031]

[0032] The compound (III) has the following structural formula:

[0033]

[0034] The compound (IV) has the following structural formula:

[0035]

[0036] The compound (V) has the following structural formula:

[0037]

[0038] The compound (VI) has the following structural formula:

[0039]

[0040] The compound (VII) has the following structural formula:

[0041]

[0042] Wherein, R1 is C1-5 alkyl;

[0043] R2 is hydrogen, phenyl, or substituted phenyl;

[0044] R3 is phenyl or substituted phenyl;

[0045] R4 is NH or O.

[0046] Further preferably, in step a, the reaction solvent comprises one or more of dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or toluene;

[0047] In step b, the reaction solvent includes one or more of dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or toluene.

[0048] Further preferably, in step b, the base is one or more of tetramethylguanidine, diazabicyclo (DBU), potassium phosphate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide;

[0049] The molar ratio of the compound (IV) to the base is 1:(0.05-1.2).

[0050] It is further preferred that: in step b, the molar ratio of the compound (IV) to paraformaldehyde is 1:(1-2);

[0051] In step b, the reaction temperature is 0-40°C.

[0052] Further preferably, in step c, the chiral acid is D-dibenzoyltartaric acid;

[0053] The molar ratio of the compound (V) to D-dibenzoyltartaric acid is 1:(0.5-1.5).

[0054] It is further preferred that: in step c, the reaction solvent comprises one or more of methanol, ethanol, isopropanol, and water;

[0055] It is further preferred that: in step d, the acid comprises one or more of hydrochloric acid, sulfuric acid, oxalic acid or trifluoroacetic acid;

[0056] The molar ratio of the compound (VI) to the acid is 1:(1-2);

[0057] Further preferably, in step d, the reaction solvent includes one or more of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, acetonitrile and toluene.

[0058] More preferably, step e comprises a step of hydrolyzing compound VII under the catalysis of a base; or

[0059] Step e comprises the step of hydrolyzing compound (VII) under the catalysis of an acid.

[0060] More preferably, the base comprises one or more of tetramethylguanidine, diazabicyclopentane (DBU), potassium phosphate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide;

[0061] The molar ratio of the compound (VII) to the base is 1:(1-2);

[0062] When the hydrolysis is carried out under the catalysis of the base, the hydrolysis temperature is 0-30°C.

[0063] It is further preferred that: the acid comprises one or more of hydrochloric acid, sulfuric acid or trifluoroacetic acid;

[0064] The molar ratio of the compound (VII) to the acid is 1:(1-8);

[0065] When the hydrolysis is carried out under the catalysis of the acid, the hydrolysis temperature is 20-100°C.

[0066] In summary, the present invention has the following beneficial effects:

[0067] (1) Short synthetic route. The present invention prepares L-serine through five steps of amino protection, hydroxymethylation, salt formation and resolution, acid replacement and hydrolysis. The synthetic route is short, the operation is simple, the safety is good, the process cost is low, and it is very suitable for industrial production.

[0068] (2) High yield. The yield of existing L-serine synthesis methods is generally below 50%, while the yield of L-serine prepared by the present invention is not less than 60%, and can reach up to 65%.

[0069] (3) High purity. The chemical purity and chiral purity of the L-serine prepared by the present invention are both very high, both reaching 99.98%, which is very suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 The graph shows the chemical purity of L-serine prepared in Example 1; wherein the correction factor of the 5.813min impurity is 0.1, and the corrected liquid phase chemical purity is 99.98%. Figure 1 The peak results in are as follows:

[0071]

[0072] Figure 2 The figure shows the optical purity of L-serine prepared in Example 1. Figure 2 The peak results in are as follows:

[0073]

[0074] Figure 3 The chemical purity diagram of L-serine prepared in Example 3 is shown; wherein the correction factor of the 5.692min impurity is 0.1, and the corrected liquid phase chemical purity is 99.99%. Figure 3 The peak results in are as follows:

[0075]

[0076] Figure 4 The figure shows the optical purity of L-serine prepared in Example 3. Figure 4 The peak results in are as follows:

[0077] DETAILED DESCRIPTION

[0078] The present invention is further described in detail below.

[0079] Unless otherwise defined, all terms used hereinafter shall be interpreted according to the meanings generally understood by those skilled in the art. The terms used herein are only used for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0080] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0081] The present invention uses a commercially available compound that is easily available, and can quickly and effectively prepare compound (I), i.e., L-serine, through five steps of amino protection, hydroxymethylation, salt formation, acid substitution, and hydrolysis. The structural formula of compound (I) is as follows:

[0082]

[0083] The preparation method of compound (I) comprises the following steps:

[0084] a. Preparation of compound (IV)

[0085] Since the amino group (-NH2) in compound (II) is a strong nucleophile and is prone to react under many reaction conditions, in order to prevent the amino group from participating in unnecessary reactions, compound (III) is used to protect the amino group in compound II.

[0086] Specifically, compound (II) reacts with compound (III), and after separation, concentration, filtration and drying, compound (IV) is obtained.

[0087]

[0088] Wherein, R1 is a C1-C5 alkyl group, preferably a methyl group or an ethyl group, and more preferably a methyl group;

[0089] R2 is hydrogen, phenyl, substituted phenyl, preferably phenyl;

[0090] R3 is phenyl, substituted phenyl, preferably phenyl;

[0091] R4 is NH or O, preferably NH.

[0092] In this step:

[0093] The reaction solvent includes dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or toluene, preferably dichloromethane;

[0094] The reaction temperature is 0-60°C, preferably 20-40°C.

[0095] Specifically, the imine group (-C=N-) in compound (III) has a certain electrophilicity, while the amino group (-NH2) in compound (II) has nucleophilicity after removing hydrochloric acid. The amino group acts as a nucleophilic reagent to attack the carbon atom of the imine group, and then undergoes a proton transfer process to form a new carbon-nitrogen double bond (-C=N-), generating compound (IV). This is a condensation reaction. In this process, the amino group is "protected", reducing its activity and making it less likely to undergo other unnecessary reactions in subsequent reactions.

[0096] b. Preparation of compound (V)

[0097] The base can remove the hydrogen atom on the carbon atom of the imine structure (-N=) in compound (IV) to form a carbon anion, which acts as a nucleophile to attack polyformaldehyde to ultimately generate compound (V).

[0098] Specifically, under the action of a base, compound (IV) undergoes a nucleophilic addition reaction with paraformaldehyde, and after separation, concentration, filtration and drying, compound (V) is obtained.

[0099]

[0100] In this step:

[0101] The reaction solvent includes dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or toluene, preferably dichloromethane;

[0102] The molar ratio of compound (IV) and paraformaldehyde is 1:(1-2), preferably 1:1.2;

[0103] The base includes tetramethylguanidine, diazabicyclopentane (DBU), potassium phosphate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably tetramethylguanidine;

[0104] The molar ratio of compound (IV) to base is 1:(0.05-1.2), preferably 1:0.1;

[0105] The reaction temperature is 0-40°C, preferably 10-30°C.

[0106] Specifically, under the action of alkali, polyformaldehyde will depolymerize to produce formaldehyde molecules. The carbonyl carbon in the formaldehyde molecule is electrophilic, and the oxygen atom is electron-withdrawing, making the carbonyl carbon susceptible to attack by nucleophilic reagents. In this process, polyformaldehyde participates in the reaction, causing the structure of compound (IV) to change, and a hydroxymethylene group (-OH) is introduced to the carbon atom connected to the original imine group, thereby generating compound (V).

[0107] In particular, compared with other protecting groups, such as Boc protection or acetyl chloride acylation protection, it is impossible to use the above method to react with formaldehyde to introduce a hydroxymethylene group. In the present invention, after the amino group is protected by compound (III), the amino group is protected at the double bond, and the activity of the methylene group at the α position next to the amino group can be activated through the lone pair of electrons on the conjugated nitrogen atom (the yellow part can also be described as electron-withdrawing effect), so that it can react with cheap formaldehyde molecules (released by polyformaldehyde), thereby introducing a hydroxymethylene group to obtain a compound of formula (V).

[0108] c. Preparation of compound (VI)

[0109] Compound (V) is reacted with a chiral acid, cooled, filtered and dried to obtain compound (VI).

[0110]

[0111] In this step:

[0112] The chiral acid is D-dibenzoyltartaric acid;

[0113] The molar ratio of compound (V) and D-dibenzoyltartaric acid is 1:(0.5-1.5), preferably 1:0.5;

[0114] The reaction solvent includes one or more of methanol, ethanol, isopropanol, and water, preferably ethanol and water;

[0115] The volume ratio of water to ethanol is 1:(4-10), preferably 1:5;

[0116] The reaction temperature is 20-80°C, preferably 40-50°C.

[0117] d. Preparation of compound (VII)

[0118] After the acid substitution of compound (VI), the temperature is lowered, filtered and dried to obtain compound (VII).

[0119]

[0120] In this step:

[0121] The acid includes hydrochloric acid, sulfuric acid, oxalic acid or trifluoroacetic acid, preferably hydrochloric acid;

[0122] The molar ratio of compound (VI) and acid is 1:(1-2), preferably 1:1.1;

[0123] The reaction solvent includes one or more of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, acetonitrile, and toluene, preferably ethanol and ethyl acetate;

[0124] The volume ratio of ethanol to ethyl acetate is 1:(3-10), preferably 1:4;

[0125] The reaction temperature is 0-60°C, preferably 10-20°C.

[0126] Specifically, after acid replacement, the chiral acid in compound (VI) can be removed to obtain compound (VII) so as to carry out subsequent reactions and obtain the final target product.

[0127] e. Preparation of compound (I)

[0128] Compound (VII) is hydrolyzed to obtain compound (I).

[0129]

[0130] In this step:

[0131] hydrolyzing compound (VII) with a base or an acid;

[0132] The base includes tetramethylguanidine, diazabicyclopentane (DBU), potassium phosphate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide, preferably lithium hydroxide;

[0133] The molar ratio of compound (VII) and base is 1:(1-2), preferably 1:1.1;

[0134] When hydrolyzed under the catalysis of base, the hydrolysis temperature is 0-30°C, preferably 5-15°C;

[0135] The acid includes hydrochloric acid, sulfuric acid or trifluoroacetic acid, preferably hydrochloric acid;

[0136] The molar ratio of compound (VII) and acid is 1:(1-8), preferably 1:4;

[0137] When hydrolyzed under the catalysis of an acid, the hydrolysis temperature is 20-100°C, preferably 80-90°C.

[0138] Specifically, during the hydrolysis of compound (VII), the configuration of the chiral center is retained, thereby ensuring that L-serine is generated instead of its enantiomer D-serine.

[0139] The present invention will be further described in detail below in conjunction with specific embodiments.

[0140] Embodiment 1:

[0141] The preparation method of L-serine includes the following five steps:

[0142] S1. Preparation of compound 3

[0143] Add compound 1 (100 g, 0.552 mol), compound 2 (83 g, 0.661 mol) and dichloromethane (600 ml) into a three-necked flask and keep the temperature at 25-35°C for 5 h;

[0144] Add 10% sodium bicarbonate aqueous solution (400 ml), stir to separate the liquids, then add water (600 ml), stir to separate the liquids;

[0145] The organic phase was concentrated to dryness, ethyl acetate (30 ml) was added, n-heptane (180 ml) was added dropwise, crystallized, filtered, and dried in vacuo to obtain compound 3 (104.8 g, 75%).

[0146] The spectral data are:

[0147] 1H NMR (CDCl3, 400MHz): δ7.67-7.64 (m, 2H), 7.50-7.44 (m, 3H), 7.42-7.39 (m, 1H), 7.36-7.32 (m, 2H), 7.19-7.17 (m, 2H), 4.23 (s, 2H), 3.75 (s, 3H).

[0148]

[0149] S2. Preparation of Compound 4

[0150] Compound 3 (100 g, 0.395 mol), paraformaldehyde (14.2 g, 0.473 mol), tetramethylguanidine (4.55 g, 0.0395 mol), and dichloromethane (600 ml) were added to a three-necked flask and kept at 10-20°C for 10 h.

[0151] Add 5% ammonium chloride aqueous solution (400 ml), stir to separate the liquid, then add water (600 ml), stir to separate the liquid;

[0152] The organic phase was concentrated to dryness, ethyl acetate (100 ml) was added, n-heptane (600 ml) was added dropwise, crystallized, filtered, and dried in vacuo to obtain compound 4 (83.9 g, 75%).

[0153] The spectral data are:

[0154] 1H NMR (CDCl3, 400MHz): δ7.67-7.65 (m, 2H), 7.54-7.51 (m, 2H), 7.46-7.39 (m, 1H), 7.34-7.27 (m, 4H), 7.25-7.18 (m, 1H), 3.94 (s, 3H), 3.75 (s, 3H), 3.72 (s, 0.6H).

[0155]

[0156] S3. Preparation of Compound 5

[0157] Compound 4 (80 g, 0.28 mol), D-dibenzoyltartaric acid (50.2 g, 0.14 mol), anhydrous ethanol (400 ml), and water (80 ml) were added to a three-necked flask and reacted at 45-55°C for 1 h;

[0158] The mixture was cooled, filtered and dried in vacuo to obtain compound 5 (34.5 g, 41%).

[0159] The spectral data are:

[0160] 1H NMR (D2O, 400MHz): δ8.00-7.98 (m, 4H), 7.60-7.56 (m, 2H), 7.46-7.42 (m, 4H), 5.5 8 (s, 2H), 4.14-4.13 (t, 2H), 3.99-3.94 (dd, 2H), 3.88-3.84 (dd, 2H), 3.72 (s, 6H).

[0161]

[0162] S4. Preparation of Compound 6

[0163] Compound 5 (30 g, 0.10 mol), anhydrous ethanol (60 ml), and concentrated hydrochloric acid (11.8 g, 0.12 mol) were added to a three-necked flask, reacted at 20-30°C for 0.5 h, and ethyl acetate (240 ml) was added dropwise. The mixture was cooled, filtered, and dried under vacuum to obtain compound 6 (14.1 g, 90%).

[0164] The spectral data are:

[0165] 1H NMR (D2O, 400MHz): δ4.22-4.20 (t, 1H), 4.05-4.01 (dd, 1H), 3.94-3.90 (dd, 1H), 3.78 (s, 3H).

[0166]

[0167] S5. Preparation of L-serine

[0168] Compound 6 (12 g, 0.077 mol) and 4 mol / L hydrochloric acid aqueous solution (24 ml) were added to a three-necked flask and reacted at 80-90°C for 12 h. The mixture was concentrated to dryness, dissolved in water (18 ml), and ammonia water was added dropwise to adjust the pH to 5.5-6.2. Anhydrous ethanol (36 ml) was then added to crystallize, cooled, filtered, and dried in vacuo to obtain crude L-serine (6.08 g).

[0169] The crude L-serine (6.08 g) was dissolved in water (12 ml), and anhydrous ethanol (12 ml) was added for crystallization. The mixture was cooled, filtered, and dried under vacuum to obtain L-serine (4.86 g, 60%). HPLC chemical purity was 99.98%, and ee% = 100%.

[0170] The spectral data are:

[0171] 1H NMR (D2O, 400MHz): δ3.83-3.75 (m, 2H), 3.68-3.66 (m, 1H).

[0172]

[0173] Embodiment 2:

[0174] The difference from Example 1 is that step S2 is as follows: Compound 3 (5 g, 3.95 mmol), paraformaldehyde (0.14 g, 4.74 mmol), potassium phosphate (0.084 g, 0.395 mmol), and acetonitrile (30 ml) are added to a three-necked flask, and the mixture is kept at 10-20°C for 10 h. Filter and concentrate. Add dichloromethane (30 ml) and 5% aqueous ammonium chloride solution (20 ml), stir and separate the liquids, then add water (20 ml), stir and separate the liquids. Concentrate the organic phase to dryness, add ethyl acetate (5 ml), add n-heptane (30 ml) dropwise, crystallize, filter, and vacuum dry to obtain compound 4 (3.91 g, 70%).

[0175] The spectral data are the same as in Example 1.

[0176]

[0177] Embodiment 3:

[0178] The difference from Example 1 is that step S5 is as follows: Compound 6 (5 g, 32 mmol), water (10 ml), and lithium hydroxide (1.61 g, 67.2 mmol) are added to a three-necked flask, and the mixture is reacted at 10-20°C for 2 h. Anhydrous ethanol (20 ml) is added, crystallized, cooled, filtered, and vacuum dried to obtain L-serine (2.2 g, 65%). HPLC chemical purity is 99.99%, and ee%=100%.

[0179] The spectral data are the same as in Example 1.

[0180]

[0181] Embodiment 4:

[0182] The difference from Example 1 is that the reaction solvent in step S1 is acetonitrile and the reaction temperature is 0-20° C. The yield of the obtained compound 3 is 70%.

[0183] Embodiment 5:

[0184] The difference from Example 1 is that the reaction solvent in step S3 is ethanol. The yield of the obtained compound 5 is 36%.

[0185] Embodiment 6:

[0186] The difference from Example 1 is that the reaction solvent in step S3 is water. The yield of the obtained compound 5 is 35%.

[0187] Embodiment 7:

[0188] The difference from Example 1 is that in step S3, the reaction temperature is 20-40°C, the molar ratio of compound (V) to D-dibenzoyltartaric acid is 1:1, that is, D-dibenzoyltartaric acid is 0.28 mol. The yield of the obtained compound 5 is 40%.

[0189] Embodiment 8:

[0190] The difference from Example 1 is that the reaction solvent in step S4 is ethyl acetate. The yield of the obtained compound 6 is 88%.

[0191] Embodiment 9:

[0192] The difference from Example 1 is that the reaction solvent in step S4 is ethanol. The yield of the obtained compound 6 is 85%.

[0193] Embodiment 10:

[0194] The difference from Example 1 is that the acid in step S4 is sulfuric acid. The yield of the obtained compound 6 is 85%.

[0195] Embodiment 11:

[0196] The difference from Example 1 is that the acid in step S5 is sulfuric acid and the acid hydrolysis temperature is 25-35° C. The yield of the obtained L-serine is 55%.

[0197] Embodiment 12:

[0198] The difference from Example 3 is that the base is tetramethylguanidine. The yield of L-serine obtained is 61%.

[0199] The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments. All technical solutions under the concept of the present invention belong to the protection scope of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications without departing from the principle of the present invention should also be regarded as the protection scope of the present invention.

Claims

1. A method for preparing L-serine, characterized in that: The steps include: a. Compound (II) reacts with compound (III) to obtain compound (IV); b. In the presence of a base, compound (IV) reacts with paraformaldehyde to obtain compound (V); c. Compound (V) is reacted with a chiral acid to form a salt to obtain compound (VI); d. Compound (VII) is prepared by acid substitution of compound (VI); e. Compound (VII) is hydrolyzed to obtain compound (I); The compound (I) is L-serine, and its structural formula is as follows: ； The structural formula of the compound (II) is as follows: ； The compound (III) has the following structural formula: ； The compound (IV) has the following structural formula: ； The compound (V) has the following structural formula: ； The compound (VI) has the following structural formula: ； The compound (VII) has the following structural formula: ； Wherein, R1 is a C1-C5 alkyl group; R2 is hydrogen, phenyl or substituted phenyl; R3 is phenyl or substituted phenyl; R4 is NH or O; In step c, the chiral acid is D-dibenzoyltartaric acid.

2. A method for preparing L-serine according to claim 1, characterized in that: In step a, the reaction solvent includes one or more of dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or toluene; In step b, the reaction solvent includes one or more of dichloromethane, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile or toluene.

3. A method for preparing L-serine according to claim 1, characterized in that: In step b, the base includes one or more of tetramethylguanidine, diazabicyclo (DBU), potassium phosphate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide; The molar ratio of the compound (IV) to the base is 1:(0.05-1.2).

4. A method for preparing L-serine according to claim 1, characterized in that: In step b, the molar ratio of the compound (IV) to paraformaldehyde is 1:(1-2); In step b, the reaction temperature is 0-40°C.

5. A method for preparing L-serine according to claim 1, characterized in that: The molar ratio of the compound (V) to D-dibenzoyltartaric acid is 1:(0.5-1.5).

6. A method for preparing L-serine according to claim 1, characterized in that: In step c, the reaction solvent includes one or more of methanol, ethanol, isopropanol, and water.

7. A method for preparing L-serine according to claim 1, characterized in that: In step d, the acid comprises one or more of hydrochloric acid, sulfuric acid, oxalic acid or trifluoroacetic acid; The molar ratio of the compound (VI) to the acid is 1:(1-2); In step d, the reaction solvent includes one or more of methanol, ethanol, isopropanol, ethyl acetate, dichloromethane, tetrahydrofuran, methyl tert-butyl ether, acetonitrile, and toluene.

8. A method for preparing L-serine according to claim 1, characterized in that: Step e comprises the step of hydrolyzing compound (VII) under the catalysis of a base; or Step e comprises the step of hydrolyzing compound (VII) under the catalysis of an acid.

9. A method for preparing L-serine according to claim 8, characterized in that: The base includes one or more of tetramethylguanidine, diazabicyclo (DBU), potassium phosphate, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine, lithium hydroxide, sodium hydroxide or potassium hydroxide; The molar ratio of the compound (VII) to the base is 1:(1-2); When the hydrolysis is carried out under the catalysis of the base, the hydrolysis temperature is 0-30°C.

10. A method for preparing L-serine according to claim 8, characterized in that: The acid includes one or more of hydrochloric acid, sulfuric acid or trifluoroacetic acid; The molar ratio of the compound (VII) to the acid is 1:(1-8); When the hydrolysis is carried out under the catalysis of the acid, the hydrolysis temperature is 20-100°C.

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