A kind of synthetic method of S-3-chloro-D-alanine methyl ester hydrochloride

Abstract

The present invention relates to the technical field of cycloserine intermediate synthesis, and specifically discloses a synthetic method of S-3-chloro-D-alanine methyl ester hydrochloride. Comprise the following steps: S1, D-serine is added to methanol, cooled to 5-10 DEG C, thionyl chloride is added dropwise, after the dropwise addition is completed, the temperature is raised to 30-50 DEG C for reaction for 10-24h, then ethyl acetate is added to the reaction mixture, stirred and crystallized for 0.5-2.0h, and filtered by suction to obtain D-serine methyl ester hydrochloride; S2, the above-mentioned D-serine methyl ester hydrochloride is added to dichloromethane, then thionyl chloride is added dropwise, the temperature is raised to 30-50 DEG C for reaction for 10-24h, methanol is added, heated to reflux for 0.5-2.0h, cooled and crystallized, filtered by suction, dried, and S-3-chloro-D-alanine methyl ester hydrochloride is obtained. The present method has mild reaction conditions, high product yield and purity, simple operation, and is convenient for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of cycloserine intermediate synthesis, in particular to a method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride. Background Art

[0002] Cycloserine, chemically known as D-4-amino-3-isoxazolone, is an antibiotic drug that has a good inhibitory effect on tuberculosis bacteria and is one of the preferred drugs for the treatment of tuberculosis. Recent studies have shown that cycloserine can also regulate the excitatory amino acid NMDA receptors in the central nervous system, thereby assisting in the treatment of phobias, depression, schizophrenia and other psychological diseases, and has broad market prospects.

[0003] At present, most of the cycloserine synthesis methods reported in China use D-serine as the starting material and are prepared through three steps of esterification, chlorination and cyclization. Among them, S-3-chloro-D-alanine methyl ester hydrochloride is one of the important intermediates. How to improve its yield and purity is the key and difficulty of the cycloserine synthesis process.

[0004] In the prior art, D-serine is used as the initial material, firstly, D-serine methyl ester hydrochloride is obtained by reflux reaction of hydrochloric acid and methanol, after rotary evaporation, washing with ethyl acetate, and drying, and then S-3-chloro-D-alanine methyl ester hydrochloride is obtained by chlorination with phosphorus pentachloride. This method requires the introduction of hydrogen chloride gas and nitrogen replacement operation, and requires operations such as rotary evaporation, which is not conducive to industrial production, and phosphorus pentachloride reacts violently, with many by-products, which is not conducive to the control of the reaction. There is a study that improves the chlorination reaction, using thionyl chloride as a chlorination reagent, and obtaining S-3-chloro-D-alanine methyl ester hydrochloride in a mixed solvent of dichloromethane and acetonitrile. The improved process avoids the use of more dangerous phosphorus pentachloride, but needs to drop thionyl chloride at low temperature, and the amount of solvent used is large, and the equipment requirements are high; the product is not refined, mixed with a large amount of sulfide, which is not conducive to subsequent reactions.

[0005] Other studies have published methods for synthesizing 3-chloro-L-alanine methyl ester hydrochloride from L-serine. However, practice has shown that the different chirality of the initial materials will affect the reaction temperature, reaction rate, etc., and the solubility of the final product in aqueous solution also varies greatly, thereby affecting the yield and purity of the product. Therefore, it cannot be directly applied. Summary of the invention

[0006] In view of the above problems, the present invention provides a method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride, which has mild reaction conditions, high product yield and purity, simple operation and is convenient for industrial production.

[0007] In order to achieve the above-mentioned object of the invention, the present invention adopts the following technical solutions:

[0008] A method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride comprises the following steps:

[0009] S1. Add D-serine to methanol, cool to 5-10°C, add thionyl chloride dropwise, raise the temperature to 30-50°C after the addition is complete, react for 10-24 hours, then add ethyl acetate to the reaction mixture, stir and crystallize for 0.5-2.0 hours, and filter to obtain D-serine methyl ester hydrochloride;

[0010] S2. Add the above D-serine methyl ester hydrochloride to dichloromethane, then drop thionyl chloride, raise the temperature to 30-50°C and react for 10-24 hours, then add methanol, heat to reflux for 0.5-2.0 hours, cool and crystallize, filter and dry to obtain S-3-chloro-D-alanine methyl ester hydrochloride.

[0011] In the above-mentioned synthesis method, the reaction process is as follows:

[0012]

[0013] Compared with the prior art, the synthesis method of S-3-chloro-D-alanine methyl ester hydrochloride provided by the present invention adopts thionyl chloride as an esterification reagent, avoids the use of more dangerous hydrogen chloride gas, and has mild reaction conditions. After the reaction in step S1 is completed, ethyl acetate is directly added for crystallization, D-serine methyl ester hydrochloride is separated from the reaction system, and operations such as rotary evaporation are avoided, so that the production process is more conducive to industrial production; the esterification product is directly put into the chlorination reaction after suction filtration, avoiding operations such as washing and drying, and reducing the loss during the transfer of intermediates; the raw materials that have not been completely reacted continue to react with the remaining methanol in the second step until they are complete, thereby improving the yield of the final product, shortening the production time, and simplifying the process flow. In step S2, the reaction is isothermally reacted at the optimal reaction temperature, avoiding complex operations such as segmented temperature control, and shortening the reaction time; methanol is directly added after the reaction is completed, which not only extracts excess thionyl chloride, reduces the discharge of acidic waste liquid, but also can dissolve and crystallize S-3-chloro-D-alanine methyl ester hydrochloride to improve product purity. The liquid phase purity of S-3-chloro-D-alanine methyl ester hydrochloride prepared by the synthesis method is greater than 94%, and the total yield is greater than 92%. The synthesis method of S-3-chloro-D-alanine methyl ester hydrochloride provided by the invention has mild reaction conditions, high product yield and purity, simple operation, and is convenient for industrial production.

[0014] Preferably, in step S1, the volume mass ratio of the methanol to the D-serine is 1-10 L:1 kg;

[0015] The molar ratio of the thionyl chloride to the D-serine is 1 to 4:1;

[0016] The volume mass ratio of the ethyl acetate to the D-serine is 0.5-3.0 L:1 kg.

[0017] Further preferably, in step S1, the volume mass ratio of the methanol to the D-serine is 2-5 L:1 kg;

[0018] The molar ratio of the thionyl chloride to the D-serine is 1.2-2.0:1;

[0019] The volume mass ratio of the ethyl acetate to the D-serine is 1-2 L:1 kg.

[0020] By limiting the volume mass ratio of methanol to D-serine, the reaction can be fully carried out and the waste of solvent can be avoided; by limiting the molar ratio of thionyl chloride to D-serine, the reaction can be fully carried out and the occurrence of side reactions such as chlorination of α-H can be avoided; by limiting the volume mass ratio of ethyl acetate to D-serine, the reaction mixture can be fully crystallized, and the yield and purity of D-serine methyl ester hydrochloride can be improved.

[0021] Preferably, in step S1, during the process of dropwise adding thionyl chloride, the temperature of the D-serine-methanol reaction system is maintained at 5-10°C.

[0022] Preferably, in step S2, the volume mass ratio of the dichloromethane to the D-serine is 1.5-15.0 L:1 kg;

[0023] The molar ratio of the thionyl chloride to the D-serine is 1 to 4:1;

[0024] The volume mass ratio of the methanol to the D-serine is 1-10 L:1 kg.

[0025] Further preferably, in step S2, the volume mass ratio of the dichloromethane to the D-serine is 3-6 L:1 kg;

[0026] The molar ratio of the thionyl chloride to the D-serine is 1.2-2.0:1;

[0027] The volume mass ratio of the methanol to the D-serine is 3-5 L:1 kg.

[0028] By limiting the volume mass ratio of dichloromethane to D-serine, the reaction can be fully carried out, and the situation of the reaction liquid being hardened due to the insolubility of the product can be prevented; by limiting the molar ratio of thionyl chloride to D-serine, the reaction can be fully reacted at a constant temperature, the reaction time can be shortened, and the residue of raw materials and D-serine methyl ester hydrochloride can be avoided; by limiting the volume mass ratio of methanol to D-serine, the excess thionyl chloride can be fully extracted, the discharge of acidic waste liquid can be reduced, and S-3-chloro-D-alanine methyl ester hydrochloride can be dissolved and crystallized, thereby improving the purity of the product.

[0029] Preferably, in step S2, the temperature reduction and crystallization conditions are cooling to 0-10°C and crystallization for 0.5-2.0h;

[0030] The drying condition is: 30-50°C.

[0031] Preferably, in step S2, during the dropwise addition of thionyl chloride, the temperature of the D-serine methyl ester hydrochloride-dichloromethane system is controlled at 0-30°C.

[0032] Preferably, in steps S1 and S2, the reaction is carried out in a glass-lined reactor.

[0033] The present invention also provides S-3-chloro-D-alanine methyl ester hydrochloride, which is prepared by the above method. DETAILED DESCRIPTION

[0034] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0035] In order to better illustrate the present invention, further examples are given below.

[0036] The production process of S-3-chloro-D-alanine methyl ester hydrochloride in the prior art is being continuously improved. The inventors have the following research and development goals: Under the premise that the purity of the product meets the requirements, the yield is improved, the industrialization degree of product preparation and the controllability of operation are improved, etc. For example, some production processes use rotary evaporation to separate intermediate products, which has low efficiency and low industrialization degree. Another example is that some reactions use segmented control, which is complicated to operate, has poor controllability and a long reaction time.

[0037] Example 1

[0038] (1) Add 1.0 kg of D-serine and 1 L of methanol to a glass-lined reactor, stir and cool to 5°C, add 691 mL of thionyl chloride dropwise, and after the addition is complete, raise the temperature to 30°C and react for 24 hours. After the reaction is complete, add 0.5 L of ethyl acetate to the reaction mixture and stir and crystallize for 2 hours, then filter to obtain a filter cake of D-serine methyl ester hydrochloride, and put the filter cake back into the glass-lined reactor.

[0039] (2) Add 1.5L of dichloromethane to the above-mentioned glass-lined reactor, add 2765mL of thionyl chloride dropwise at 0°C, and react at 30°C for 24h. After the reaction is completed, add 1L of methanol, heat and reflux for 2h, cool to 0°C for crystallization for 2h, filter to obtain a filter cake, and dry by cold suction to obtain 1.525kg of S-3-chloro-D-alanine methyl ester hydrochloride, with a liquid chromatography purity of 94.20% and a yield of 92.09%.

[0040] Among them, the liquid chromatography conditions are as follows: the chromatographic column is an ODS C18 reverse phase silica gel column, the chromatographic column parameters are 250mm×4.6mm×5μm, the mobile phase is buffer A (1% sodium dihydrogen phosphate aqueous solution) and mobile phase B (acetonitrile) for gradient elution, the flow rate is 1mL / min, the column temperature is 40°C, and the detection wavelength is 210nm.

[0041] Example 2

[0042] (1) Add 1.0 kg of D-serine and 10 L of methanol to a glass-lined reactor, stir and cool to 10°C, add 2765 mL of thionyl chloride dropwise, and after the addition is complete, heat to 50°C and react for 10 h. After the reaction is complete, add 3 L of ethyl acetate to the reaction mixture and stir and crystallize for 0.5 h, filter with suction to obtain a filter cake of D-serine methyl ester hydrochloride, and put the filter cake back into the glass-lined reactor.

[0043] (2) Add 15L of dichloromethane to the above-mentioned glass-lined reactor, add 691mL of thionyl chloride dropwise at 30°C, and react at 50°C for 10h. After the reaction is completed, add 10L of methanol, heat and reflux for 0.5h, cool to 10°C for crystallization for 0.5h, filter and obtain a filter cake, and dry it by cold suction to obtain 1.540kg of S-3-chloro-D-alanine methyl ester hydrochloride, with a liquid chromatography purity of 95.30% and a yield of 92.99%. The liquid chromatography conditions are the same as those in Example 1.

[0044] Example 3

[0045] (1) Add 1.0 kg of D-serine and 4 L of methanol to a glass-lined reactor, stir and cool to 8°C, add 1000 mL of thionyl chloride dropwise, and after the addition is complete, raise the temperature to 35°C and react for 16 hours. After the reaction is complete, add 1.5 L of ethyl acetate to the reaction mixture and stir and crystallize for 1 hour, then filter to obtain a filter cake of D-serine methyl ester hydrochloride, and put the filter cake back into the glass-lined reactor.

[0046] (2) Add 5L of dichloromethane to the above-mentioned glass-lined reactor, add 1000mL of thionyl chloride at room temperature, and react at 40°C for 16h. After the reaction is completed, add 4L of methanol, heat and reflux for 1h, cool to 5°C for crystallization for 1h, filter and obtain a filter cake, and dry it by cold suction to obtain 1.565kg of S-3-chloro-D-alanine methyl ester hydrochloride, with a liquid chromatography purity of 96.50% and a yield of 94.50%. The liquid chromatography conditions are the same as those in Example 1.

[0047] Example 4

[0048] (1) Add 1.0 kg of D-serine and 1 L of methanol to a glass-lined reactor, stir and cool to 8°C, add 730 mL of thionyl chloride dropwise, and after the addition is complete, raise the temperature to 35°C and react for 16 hours. After the reaction is complete, add 1 L of ethyl acetate to the reaction mixture and stir and crystallize for 0.5 hours, filter with suction to obtain a filter cake of D-serine methyl ester hydrochloride, and put the filter cake back into the glass-lined reactor.

[0049] (2) Add 1.5L of dichloromethane to the above-mentioned glass-lined reactor, add 730mL of thionyl chloride at room temperature, and react at 40°C for 16h. After the reaction is completed, add 1L of methanol, heat and reflux for 1h, cool to 5°C for crystallization for 1h, filter and obtain a filter cake, and dry it by cold suction to obtain 1.524kg of S-3-chloro-D-alanine methyl ester hydrochloride, with a liquid chromatography purity of 95.10% and a yield of 92.03%. The liquid chromatography conditions are the same as those in Example 1.

[0050] Example 5

[0051] (1) Add 1.0 kg of D-serine and 2 L of methanol to a glass-lined reactor, stir and cool to 8°C, add 980 mL of thionyl chloride dropwise, and after the addition is complete, heat to 35°C and react for 16 h. After the reaction is complete, add 2 L of ethyl acetate to the reaction mixture and stir and crystallize for 0.5 h, filter with suction to obtain a filter cake of D-serine methyl ester hydrochloride, and put the filter cake back into the glass-lined reactor.

[0052] (2) Add 3L of dichloromethane to the above-mentioned glass-lined reactor, add 980mL of thionyl chloride at room temperature, and react at 40°C for 16h. After the reaction is completed, add 2L of methanol, heat and reflux for 1h, cool to 5°C for crystallization for 1h, filter and obtain a filter cake, and dry it by cold suction to obtain 1.631kg of S-3-chloro-D-alanine methyl ester hydrochloride, with a liquid chromatography purity of 95.9% and a yield of 98.49%. The liquid chromatography conditions are the same as those in Example 1.

[0053] Example 6

[0054] (1) Add 1.0 kg of D-serine and 3 L of methanol to a glass-lined reactor, stir and cool to 8°C, add 1450 mL of thionyl chloride dropwise, and after the addition is complete, heat to 35°C and react for 16 hours. After the reaction is complete, add 3 L of ethyl acetate to the reaction mixture and stir and crystallize for 0.5 hours, filter with suction to obtain a filter cake of D-serine methyl ester hydrochloride, and put the filter cake back into the glass-lined reactor.

[0055] (2) Add 3L of dichloromethane to the above-mentioned glass-lined reactor, add 1450mL of thionyl chloride at room temperature, and react at 40°C for 16h. After the reaction is completed, add 4L of methanol, heat and reflux for 1h, cool to 5°C for crystallization for 1h, filter and obtain a filter cake, and dry it by cold suction to obtain 1.563kg of S-3-chloro-D-alanine methyl ester hydrochloride, with a liquid chromatography purity of 94.04% and a yield of 94.38%. The liquid chromatography conditions are the same as those in Example 1.

[0056] Example 7

[0057] (1) Add 1.0 kg of D-serine and 10 L of methanol to a glass-lined reactor, stir and cool to 8°C, add 980 mL of thionyl chloride dropwise, and after the addition is complete, raise the temperature to 35°C and react for 16 hours. After the reaction is complete, add 3 L of ethyl acetate to the reaction mixture and stir and crystallize for 0.5 hours, filter with suction to obtain a filter cake of D-serine methyl ester hydrochloride, and put the filter cake back into the glass-lined reactor.

[0058] (2) Add 10L of dichloromethane to the above-mentioned glass-lined reactor, add 980mL of thionyl chloride at room temperature, and react at 40°C for 16h. After the reaction is completed, add 5L of methanol, heat and reflux for 1h, cool to 5°C for crystallization for 1h, filter and obtain a filter cake, and dry it by cold suction to obtain 1.545kg of S-3-chloro-D-alanine methyl ester hydrochloride, with a liquid chromatography purity of 97.23% and a yield of 93.30%. The liquid chromatography conditions are the same as those in Example 1.

[0059] Comparative Example 1

[0060] In this comparative example, ethyl acetate was not added in step (1), and the temperature was directly lowered for crystallization. The other operating steps were the same as those in Example 3.

[0061] Finally, 0.668 kg of S-3-chloro-D-alanine methyl ester hydrochloride was obtained, with a liquid chromatography purity of 94.21% and a yield of 40.34%. The liquid chromatography conditions were the same as those in Example 1.

[0062] Comparative Example 2

[0063] In this comparative example, in step (2), methanol is not added, but an equal volume of water is added, and then the temperature is raised and refluxed. The other operating steps are the same as those in Example 3.

[0064] Finally, 0.334 kg of S-3-chloro-D-alanine methyl ester hydrochloride was obtained, with a liquid chromatography purity of 93.56% and a yield of 20.17%. The liquid chromatography conditions were the same as those in Example 1.

[0065] Comparative Example 3

[0066] In this comparative example, step (2) is not subjected to temperature reflux, and the other operation steps are the same as those in Example 3.

[0067] Finally, 1.015 kg of S-3-chloro-D-alanine methyl ester hydrochloride was obtained, with a liquid chromatography purity of 95.12% and a yield of 61.29%. The liquid chromatography conditions were the same as those in Example 1.

[0068] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride, characterized in that: The following steps are involved: S1. Add D-serine to methanol, cool to 5-10°C, add thionyl chloride dropwise, and after the addition is complete, heat to 30-50°C to react for 10-24 hours, then add ethyl acetate to the reaction mixture, stir and crystallize for 0.5-2.0 hours, and filter to obtain D-serine methyl ester hydrochloride; S2, add the above D-serine methyl ester hydrochloride to dichloromethane, then add thionyl chloride dropwise, heat to 30-50°C for reaction for 10-24h, then add methanol, heat to reflux for 0.5-2.0h, cool to crystallize, filter, and dry to obtain S-3-chloro-D-alanine methyl ester hydrochloride; In step S1, the volume mass ratio of the methanol to the D-serine is 1-10 L:1 kg; In step S1, the molar ratio of the thionyl chloride to the D-serine is 1 to 4:1; In step S1, the volume mass ratio of the ethyl acetate to the D-serine is 0.5-3.0 L:1 kg; In step S2, the volume mass ratio of the dichloromethane to the D-serine is 1.5-15.0 L:1 kg; In step S2, the molar ratio of the thionyl chloride to the D-serine is 1 to 4:1; In step S2, the volume mass ratio of the methanol to the D-serine is 1-10 L:1 kg; In step S2, the temperature is lowered to 0-10°C for crystallization for 0.5-2h.

2. The method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride according to claim 1, characterized in that: In step S1, the volume mass ratio of the methanol to the D-serine is 2-5 L:1 kg; The molar ratio of the thionyl chloride to the D-serine is 1.2-2.0:1; The volume mass ratio of the ethyl acetate to the D-serine is 1-2 L:1 kg.

3. The method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride according to claim 1, characterized in that: In step S1, during the process of adding thionyl chloride dropwise, the temperature of the D-serine-methanol reaction system is maintained at 5-10°C.

4. The method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride according to claim 1, characterized in that: In step S2, the volume mass ratio of the dichloromethane to the D-serine is 3-6 L:1 kg; The molar ratio of the thionyl chloride to the D-serine is 1.2-2.0:1; The volume mass ratio of the methanol to the D-serine is 3-5 L:1 kg.

5. The method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride according to claim 1, characterized in that: In step S2, the drying condition is: 30-50°C.

6. The method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride according to claim 1, characterized in that: In step S2, during the dropwise addition of thionyl chloride, the temperature of the D-serine methyl ester hydrochloride-dichloromethane system is controlled at 0-30°C.

7. The method for synthesizing S-3-chloro-D-alanine methyl ester hydrochloride according to claim 1, characterized in that: In steps S1 and S2, the reaction is carried out in a glass-lined reactor.

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