Novel crystal form of (S)-2-aminobutanamide hydrochloride and preparation method and application thereof

Abstract

The invention relates to a crystal form B of (S)-2-aminobutanamide hydrochloride, a preparation method of the crystal form B and a method for preparing levetiracetam by using the novel crystal form. The novel crystal form can improve the reaction yield and product purity of subsequent levetiracetam.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical and chemical engineering, and relates to a new crystal form of (S)-2-aminobutyramide hydrochloride, its preparation method and application. Background Technology

[0002] Levetiracetam, as a first-line drug in the treatment of epilepsy, is now widely regarded as the gold standard for epilepsy treatment. Its structural formula is shown below:

[0003]

[0004] US4943639A and IN2006MUM1414 disclose a synthetic method for levetiracetam, which involves the condensation and cyclization reaction of (S)-2-aminobutyramide hydrochloride with 4-chlorobutyryl chloride in dichloromethane under the action of potassium hydroxide to prepare levetiracetam. The synthetic route of this method is shown below:

[0005]

[0006] (S)-(+)-2-aminobutyramide hydrochloride is a key intermediate for levetiracetam. One route involves using L-2-aminobutyric acid as a starting material, followed by esterification with thionyl chloride, and then ammonolysis with ammonia to obtain the target compound. The reaction route is as follows:

[0007]

[0008] CN118221541A discloses an improved method for preparing 2-aminobutyramide hydrochloride, comprising reacting a mixture of the compound shown in Formula II and the compound shown in Formula IV with an aqueous ammonia solution.

[0009]

[0010] In Formulas II and IV, R is methyl or ethyl; water and ammonia in the system are removed by distillation; the distilled substrate is then dissolved in ethanol, and the pH is adjusted to ≤3 by adding ethanol hydrochloric acid. The system is then heated and stirred to disperse, and filtered to obtain (S)-(+)-2-aminobutyramide hydrochloride as shown in Formula III. Summary of the Invention

[0011] The purpose of this invention is to provide a novel crystal form of (S)-2-aminobutyramide hydrochloride, its preparation method, and its application.

[0012] In a first aspect, the present invention provides a crystal form B of (S)-2-aminobutyramide hydrochloride, which has characteristic peaks at the following 2θ values ​​in its X-ray powder diffraction pattern measured using Cu-Ka radiation: 9.0±0.2°, 18.1±0.2°, 27.3±0.2°, 36.8±0.2°.

[0013] Furthermore, the (S)-2-aminobutyramide hydrochloride crystal form B has characteristic peaks at the following 2θ values ​​in the X-ray powder diffraction pattern measured using Cu-Ka radiation: 9.0±0.2°, 14.6±0.2°, 18.1±0.2°, 27.3±0.2°, 32.6±0.2°, 34.1±0.2°, 36.8±0.2°.

[0014] Furthermore, the X-ray powder diffraction pattern of the (S)-2-aminobutyramide hydrochloride crystal form B, measured using Cu-Ka radiation, has characteristic peaks at the following 2θ values: 8.1±0.2°, 9.0±0.2°, 14.6±0.2°, 18.1±0.2°, 21.5±0.2°, 27.3±0.2°, 32.6±0.2°, 34.1±0.2°, 36.8±0.2°, 39.9±0.2°, and 46.4±0.2°.

[0015] Furthermore, the (S)-2-aminobutyramide hydrochloride crystal form B, as shown in Table 1, exhibits characteristic peaks with 2θ values ​​and relative intensities as determined by Cu-Ka radiation in its X-ray powder diffraction pattern:

[0016] Table 1

[0017]

[0018]

[0019] According to one embodiment of the present invention, the (S)-2-aminobutyramide hydrochloride crystal form B has essentially the following properties: Figure 1 The X-ray powder diffraction pattern shown is shown.

[0020] According to one embodiment of the present invention, the (S)-2-aminobutyramide hydrochloride crystal form B has essentially the following properties: Figure 2 The infrared spectrum shown.

[0021] According to one embodiment of the invention, the (S)-2-aminobutyramide hydrochloride is present in crystal form B with a content greater than 50%, preferably greater than 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. The balance is other crystal forms.

[0022] A second aspect of the present invention provides a method for preparing crystal form B of (S)-2-aminobutyramide hydrochloride, comprising the following steps:

[0023] The compound shown in Formula II, or a mixture of the compounds shown in Formula II and Formula IV, is subjected to an ammoniation reaction with an aqueous ammonia solution; water and ammonia are removed from the system after the reaction by distillation; the distillate is then added to a C1-C3 alcohol, hydrogen chloride gas is introduced at a temperature below 30°C, the pH is adjusted to ≤3, and the system is stirred and dispersed at a temperature below 30°C (e.g., 10°C, 20°C, 25°C, 30°C or any value or range thereof), and filtered to obtain (S)-(+)-2-aminobutyramide hydrochloride crystal form B shown in Formula III; the structural formulas of the compounds shown in Formula II and Formula IV are shown below:

[0024]

[0025] In Formulas II and IV, R is methyl or ethyl.

[0026] After the amination reaction, it is necessary to adjust the distilled substrate to a lower acidity range in the alcohol solvent. This helps to form 2-aminobutyric acid salt and dissolve it in the alcohol solvent, thereby enabling separation from 2-aminobutyramide hydrochloride.

[0027] (S)-2-aminobutyramide hydrochloride crystal form B can be obtained well by introducing hydrogen chloride gas and stirring the dispersion below 30°C. Increasing the temperature, while helping to eliminate solid agglomeration, will lead to crystal transformation. For example, when hydrogen chloride gas is introduced above 40°C, mixed crystals of crystal form A and crystal form B will be produced, with crystal form A predominating. Typical (S)-2-aminobutyramide hydrochloride crystal form A has the following basic characteristics... Figure 3 The X-ray powder diffraction pattern shown and as follows Figure 4 The infrared spectrum shown is consistent with the spectrum obtained from the detection of the USP standard.

[0028] When using a mixture of the compound shown in Formula IV and the compound shown in Formula II, refer to the method of CN118221541A, wherein the molar ratio of the compound shown in Formula IV to the compound shown in Formula II is 1:25 to 1.5:1, preferably 1:15 to 1:1, and more preferably 1:9 to 1:5. CN118221541A is incorporated herein by reference in its entirety.

[0029] According to a specific embodiment of the present invention, the C1-C3 alcohols are selected from one or more of methanol, ethanol, and isopropanol, preferably anhydrous ethanol;

[0030] According to one specific embodiment of the present invention, in step 1, hydrogen chloride is introduced to adjust the pH to less than 2.0, preferably 0.5 to 1.5;

[0031] According to a specific embodiment of the present invention, the stirring and dispersion temperature in step 1 is 10-30°C.

[0032] According to one specific embodiment of the present invention, the stirring and dispersion time is 2 to 5 hours, more preferably 2 to 3 hours.

[0033] A third aspect of the present invention provides a method for preparing levetiracetam, comprising the following steps: in a dichloromethane solvent, (S)-2-aminobutyramide hydrochloride reacts with 4-chlorobutyryl chloride via a condensation and cyclization reaction under the action of an inorganic base to prepare levetiracetam. The synthetic route of this method is shown below:

[0034]

[0035] The (S)-2-aminobutyramide hydrochloride therein comprises crystal form B.

[0036] According to one embodiment of the invention, the (S)-2-aminobutyramide hydrochloride is present in crystal form B with a content greater than 50%, preferably greater than 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. The balance is other crystal forms.

[0037] According to one embodiment of the present invention, the inorganic base is potassium hydroxide or sodium hydroxide.

[0038] According to one embodiment of the present invention, the inorganic base is added in batches.

[0039] According to one embodiment of the present invention, (S)-2-aminobutyramide hydrochloride is first released with an inorganic base at room temperature, then cooled to -10 to 0°C, and then 4-chlorobutyryl chloride and an inorganic base are added to carry out the reaction, preferably at -5 to 0°C.

[0040] According to one embodiment of the present invention, the method for preparing levetiracetam specifically includes the following steps:

[0041] (a) In a mixture of dichloromethane and (S)-2-aminobutyramide hydrochloride, the mixture is freed with an inorganic base powder; preferably, the freeing is carried out at room temperature; more preferably, the amount of inorganic base added is in a molar ratio of 1 to 1.15:1 relative to (S)-2-aminobutyramide hydrochloride.

[0042] (b) At -10 to 0°C, a dichloromethane solution of 4-chlorobutyryl chloride and inorganic base powder are added to the reaction solution obtained in step a and the mixture is stirred and reacted; preferably, the molar ratio of the amount of inorganic base added to (S)-2-aminobutyramide hydrochloride is 1.4 to 1.8:1.

[0043] (c) At -10 to 0°C, inorganic base powder is added in batches and stirred until the reaction is complete; preferably, the molar ratio of the amount of inorganic base added to (S)-2-aminobutyramide hydrochloride is 2 to 3:1.

[0044] (d) Levetiracetam was obtained by isolation.

[0045] The innovation of this invention lies in the unexpected discovery of a crystal form B of (S)-(+)-2-aminobutyramide hydrochloride, which has significantly better solubility in dichloromethane than crystal form A. Using crystal form B can effectively improve the yield and purity of subsequent levetiracetam reactions, and in particular, helps to reduce the formation of levetiracetam acid impurities and 2-pyrrolidone impurities. Attached Figure Description

[0046] Figure 1 X-ray powder diffraction pattern of (S)-2-aminobutyramide hydrochloride crystal form B.

[0047] Figure 2 Infrared spectrum of (S)-2-aminobutyramide hydrochloride crystal form B.

[0048] Figure 3 X-ray powder diffraction pattern of (S)-2-aminobutyramide hydrochloride crystal form A.

[0049] Figure 4 Infrared spectrum of (S)-2-aminobutyramide hydrochloride crystal form A. Detailed Implementation

[0050] To better understand the present invention, the following specific embodiments are provided, but the present invention is not limited to the following embodiments.

[0051] Unless otherwise stated, any numerical value shall be understood to be modified in all cases by the term “about” to indicate that such a value may vary within a certain range. When no range is stated (e.g., error range or standard deviation of the average given in a chart or data table), the term “about” shall be understood to mean the larger range that includes the stated value, and the range included by rounding to that number, taking into account significant figures, and the range that includes plus or minus 10% of the stated value.

[0052] The structural formula of levetiracetam acid described in this invention is as follows:

[0053]

[0054] The structural formula of the 2-pyrrolidone described in this invention is as follows:

[0055]

[0056] In Example 8 and Comparative Example 1 of this invention, "equivalent" refers to the molar ratio relative to (S)-2-aminobutyramide hydrochloride.

[0057] The detection conditions used in this invention are as follows:

[0058] X-ray powder diffraction detection method:

[0059] Instrument: Aeris

[0060] Light tube type: Empyrean XRD tube Cu LFF HR

[0061] Voltage and current: 40kV, 7.5mA

[0062] Goniometer: radius 145mm

[0063] Detector: PIXcel1D-Medipix3 detector

[0064] Scanning mode: Continuous scan

[0065] Scan range (2θ): 3.0 -50.0°

[0066] The infrared detection instrument described in this invention is a Nicolet iS5 Fourier transform infrared spectrometer, and the detector is a DTGS-KBr.

[0067] The HPLC detection methods of Example 8 and Comparative Example 1 of this invention are based on the United States Pharmacopeia method.

[0068] Example 1

[0069] Step A: Add 100g of L-2-aminobutyric acid methyl ester hydrochloride and 60g of methanol to a reaction flask. Cool to 0-10℃ and maintain the temperature at 0-10℃. Purge with ammonia to adjust the pH to 6. Filter. Distill off the methanol from the free methyl ester at ≤30℃. Dissolve the methanol in 50g of drinking water. Add 240g of 50% ammonia water to the reaction flask and cool to 0±5℃. Add the free methyl ester hydrochloride to the ammonia water and stir the reaction at 0-10℃ for 22 hours. After the reaction is complete, heat to ≤60℃ and concentrate under reduced pressure until almost no liquid flows out to obtain the distillate substrate.

[0070] Step B: Add 150 ml of anhydrous ethanol to the distillation substrate and distill under reduced pressure at ≤80℃ until almost no liquid flows out. Add 150 ml of anhydrous ethanol, purge with hydrogen chloride gas to adjust the pH to 1.0, and disperse by stirring at 25-30℃ for 2 hours. Then slowly cool to -5-0℃ and stir for 2 hours. Filter, rinse the filter cake with 30 ml of anhydrous ethanol, and then dry under vacuum at 65±5℃ to obtain a white solid. The obtained solid was confirmed to be crystal form B as described in this invention. The X-ray powder diffraction pattern is shown below. Figure 1 As shown, the infrared spectrum is as follows Figure 2 As shown.

[0071] Example 2

[0072] The distilled substrate obtained in step A of Example 1 was added to 150 ml of anhydrous ethanol and distilled under reduced pressure at a temperature ≤80°C until almost no liquid flowed out. 150 ml of anhydrous ethanol was added, and hydrogen chloride gas was introduced to adjust the pH to 1.0. The mixture was stirred and dispersed at 10–20°C for 2 hours, then slowly cooled to -5–0°C and stirred for 2 hours. The mixture was filtered, and the filter cake was washed with 30 ml of anhydrous ethanol. The mixture was then dried under vacuum at 65 ± 5°C to obtain a white solid. Analysis confirmed that the obtained solid was (S)-2-aminobutyramide hydrochloride crystal form B as described in this invention.

[0073] Example 3

[0074] The distilled substrate obtained in step A of Example 1 was added to 150 ml of methanol for distillation under reduced pressure at a controlled temperature of ≤80°C until almost no liquid flowed out. 150 ml of methanol was added, and hydrogen chloride gas was introduced to adjust the pH to 1.0. The mixture was stirred and dispersed at 10–20°C for 2 hours, then slowly cooled to -5–0°C and stirred for 2 hours. The mixture was filtered, and the filter cake was washed with 30 ml of methanol. The mixture was then vacuum dried at 65 ± 5°C to obtain a white solid. Analysis confirmed that the obtained solid was (S)-2-aminobutyramide hydrochloride crystal form B as described in this invention.

[0075] Example 4

[0076] Add 100g of L-2-aminobutyric acid methyl ester hydrochloride and 60g of methanol to a reaction flask. Cool to 0-10℃ and maintain the temperature at 0-10℃. Purge with ammonia to adjust the pH to 6. Filter. Distill off the free methyl ester at ≤30℃ to remove methanol. Dissolve the methanol in 50g of drinking water. Add 440g of 25% ammonia water to the reaction flask and cool to 0±5℃. Add the free methyl ester hydrochloride to the ammonia water and stir the reaction at 0-10℃ for 22 hours. After the reaction is complete, heat to ≤60℃ and concentrate under reduced pressure until almost no liquid remains to obtain the distillate.

[0077] Add 150 ml of isopropanol to the distillation substrate, and distill under reduced pressure at a temperature ≤80℃ until almost no liquid flows out. Add another 150 ml of isopropanol, and adjust the pH to 0.5 by purging with hydrogen chloride gas. Disperse the mixture at 10–20℃ for 5 hours, then slowly cool to -5–0℃ and stir for 2 hours. Filter the mixture, wash the filter cake with 30 ml of isopropanol, and then dry it under vacuum at 65±5℃ to obtain a white solid. Analysis showed that the obtained solid was (S)-2-aminobutyramide hydrochloride crystal form B as described in this invention.

[0078] Example 5

[0079] Add 100g of L-2-aminobutyric acid methyl ester hydrochloride and 100g of ethanol to a reaction flask. Cool to 0-10℃ and maintain the temperature at 0-10℃. Adjust the pH to 7 by introducing ammonia gas. Filter the mixture. Distill off the free methyl ester at ≤30℃ to remove ethanol. Dissolve the ethanol in 50g of drinking water. Add 300g of 50% ammonia water to the reaction flask and cool to 0±5℃. Add the free methyl ester hydrochloride to the ammonia water and stir the reaction at 0-10℃ for 22 hours. After the reaction is complete, raise the temperature to ≤60℃ and concentrate under reduced pressure until almost no liquid flows out.

[0080] Add 150 ml of anhydrous ethanol to the distillation substrate, and distill under reduced pressure at a temperature ≤80℃ until almost no liquid flows out. Add 150 ml of anhydrous ethanol, and adjust the pH to 1.5 by introducing hydrogen chloride gas. Disperse the mixture at 25–30℃ for 2 hours, then slowly cool to -5–0℃ and stir for 2 hours. Filter the mixture, wash the filter cake with 30 ml of anhydrous ethanol, and then dry it under vacuum at 65±5℃ to obtain a white solid. Analysis showed that the obtained solid was (S)-2-aminobutyramide hydrochloride crystal form B as described in this invention.

[0081] Example 6

[0082] Add 100g of L-2-aminobutyric acid methyl ester hydrochloride and 60g of isopropanol to a reaction flask. Cool to 0-10℃ and maintain the temperature at 0-10℃. Purge with ammonia to adjust the pH to 6. Filter. Distill off the free methyl ester at ≤50℃ to remove isopropanol. Dissolve the isopropanol in 50g of drinking water. Add 440g of 25% ammonia water to the reaction flask and cool to 0±5℃. Add the free L-2-aminobutyric acid methyl ester hydrochloride to the ammonia water and stir the reaction at 0-10℃ for 22 hours. After the reaction is complete, heat to ≤60℃ and concentrate under reduced pressure until almost no liquid flows out to obtain the distillate.

[0083] Add 150 ml of isopropanol to the distillation substrate and distill under reduced pressure at a temperature ≤80℃ until almost no liquid flows out. Add 150 ml of isopropanol, purge with hydrogen chloride gas to adjust the pH to 2.0, and disperse by stirring at 20–30℃ for 2 hours. Then slowly cool to -5–0℃ and stir for 2 hours. Filter, wash the filter cake with 30 ml of isopropanol, and then dry under vacuum at 65±5℃ to obtain a white solid. Analysis showed that the obtained solid was (S)-2-aminobutyramide hydrochloride crystal form B as described in this invention.

[0084] Comparative Example 1

[0085] Add 150 ml of anhydrous ethanol to the distilled substrate obtained in step A of Example 1, then adjust the pH to 1 with 30% ethanol-hydrochloric acid solution. Heat to 80°C and stir to disperse the system for 2 hours, then cool to 0°C and stir for 2 hours. Filter, rinse the filter cake with an appropriate amount of anhydrous ethanol, and dry to obtain (S)-(+)-2-aminobutyramide hydrochloride crystal form A. The X-ray powder diffraction pattern is shown below. Figure 3 As shown, the infrared spectrum is as follows Figure 4 As shown.

[0086] Example 7: Solubility Experiment

[0087] The (S)-2-aminobutyramide hydrochloride crystal form B prepared in Example 1 and the (S)-2-aminobutyramide hydrochloride crystal form A prepared in Control Example 1 were added to dichloromethane and equilibrated in a shaker at 25°C for 12 hours. The solubility was measured, and the results are shown in Table 2.

[0088] Table 2

[0089]

[0090] The results in Table 2 show that crystal form B has a certain solubility in dichloromethane, which is higher than that of crystal form A.

[0091] Example 8: Conversion Experiment of Levetiracetam (Crystal Form B)

[0092] Take 40 g of (S)-2-aminobutyramide hydrochloride (crystal form B) and add it to a four-necked reaction flask containing 662.5 g of dichloromethane. Heat to 25°C, add 1 equivalent of powdered potassium hydroxide, and allow to incubate for 30 minutes. Then cool to -5°C, add 1.5 equivalents of powdered potassium hydroxide, and maintain the temperature at -5°C for 30 minutes. Next, add a mixed solution of 44.8 g of 4-chlorobutyryl chloride and 75 ml of dichloromethane, maintaining the temperature at -5°C. After the addition is complete, maintain the temperature at 0–-5°C for 30 minutes, then maintain the temperature at -5°C and add 2.5 equivalents of powdered potassium hydroxide in portions. After adding the potassium hydroxide, maintain the reaction temperature for 5 hours. The mixture was filtered, and the filtrate was separated into layers. The separated organic layer was concentrated under reduced pressure at 40°C to obtain 48.5 g of white to off-white solid (yield 98.7%) with an HPLC purity of 96.3%, containing 1.1% levetiracetam acid and 0.5% 2-pyrrolidone.

[0093] Comparative Example 2: Conversion Experiment of Levetiracetam in Crystal Form A

[0094] Take 40 g of (S)-2-aminobutyramide hydrochloride (crystal form A) and add it to a four-necked reaction flask containing 662.5 g of dichloromethane. Heat to 25°C, add 1 equivalent of powdered potassium hydroxide, and allow to incubate for 30 minutes. Then cool to -5°C, add 1.5 equivalents of powdered potassium hydroxide, and maintain the temperature at -5°C for 30 minutes. Next, add a mixed solution of 44.8 g of 4-chlorobutyryl chloride and 75 ml of dichloromethane, maintaining the temperature at -5°C. After the addition is complete, maintain the temperature at 0–-5°C for 30 minutes, then maintain the temperature at -5°C and add 2.5 equivalents of powdered potassium hydroxide in portions. After adding the potassium hydroxide, maintain the reaction temperature for 5 hours. The mixture was filtered, and the filtrate was separated into layers. The separated organic layer was concentrated under reduced pressure at 40°C to obtain 46.8 g of white to off-white solid (yield 95.2%) with an HPLC purity of 93.9%, containing 2.4% levetiracetam acid and 1.5% 2-pyrrolidone.

Claims

1. Crystal form B of (S)-2-aminobutyramide hydrochloride, characterized in that... The characteristic peaks in the X-ray powder diffraction pattern measured using Cu-Ka radiation have the following 2θ values: 9.0±0.2°, 18.1±0.2°, 27.3±0.2°, and 36.8±0.2°.

2. (S)-2-aminobutyramide hydrochloride crystal form B, characterized in that... The characteristic peaks in the X-ray powder diffraction pattern measured using Cu-Ka radiation have the following 2θ values: 9.0±0.2°, 14.6±0.2°, 18.1±0.2°, 27.3±0.2°, 32.6±0.2°, 34.1±0.2°, 36.8±0.2°; preferably, the characteristic peaks in the X-ray powder diffraction pattern measured using Cu-Ka radiation have the following 2θ values: 8.1±0.2°. °, 9.0±0.2°, 14.6±0.2°, 18.1±0.2°, 21.5±0.2°, 27.3±0.2°, 32.6±0.2°, 34.1±0.2°, 36.8±0.2°, 39.9±0.2°, 46.4±0.2°; further preferred are the characteristic peaks with 2θ values ​​and relative intensities shown in Table 1 in the X-ray powder diffraction pattern determined by Cu-Ka radiation: Table 1 3. (S)-2-aminobutyramide hydrochloride crystal form B, characterized by having an X-ray powder diffraction pattern as shown in Figure 1.

4. (S)-2-aminobutyramide hydrochloride crystal form B, characterized in that... It has a basic infrared spectrum as shown in Figure 2.

5. (S)-2-aminobutyramide hydrochloride, characterized in that... It exists in the form of crystal form B with a content greater than 50%, preferably in the form of crystal form B with a content greater than 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%. The crystal form B is as described in any one of claims 1 to 4.

6. A method for preparing crystal form B of (S)-2-aminobutyramide hydrochloride according to any one of claims 1 to 4, characterized in that... Includes the following steps: The compound shown in Formula II, or a mixture of the compounds shown in Formula II and Formula IV, is subjected to an ammoniation reaction with an aqueous ammonia solution; water and ammonia are removed from the system by distillation after the reaction; the distillate is then added to a C1-C3 alcohol, and the pH is adjusted to ≤3 by passing hydrogen chloride gas through it at a temperature below 30°C. The system is then stirred and dispersed at a temperature below 30°C, and filtered to obtain (S)-(+)-2-aminobutyramide hydrochloride crystal form B shown in Formula III; the structural formulas of the compounds shown in Formula II and Formula IV are shown below: In Formulas II and IV, R is methyl or ethyl. Preferably, the molar ratio of the compound represented by Formula IV to the compound represented by Formula II is 1:25-1.5:1, more preferably 1:15-1:1, and even more preferably 1:9-1:

5.

7. The method according to claim 6, characterized in that... The C1-C3 alcohols are selected from one or more of methanol, ethanol, and isopropanol.

8. The method according to claim 6, characterized in that... In step 1, hydrogen chloride is introduced to adjust the pH to less than 2.0, preferably 0.5 to 1.5; further, in step 1, the stirring and dispersion temperature is 10 to 30°C, and the stirring and dispersion time is 2 to 5 hours, more preferably 2 to 3 hours.

9. A method for preparing levetiracetam, comprising the following steps: Levetiracetam was prepared by condensation and cyclization of (S)-2-aminobutyramide hydrochloride with 4-chlorobutyryl chloride in dichloromethane solvent under the action of an inorganic base. The synthetic route of this method is shown below: The (S)-2-aminobutyramide hydrochloride comprises crystal form B, as described in any one of claims 1 to 4; the preferred inorganic base is potassium hydroxide or sodium hydroxide; preferably, the (S)-2-aminobutyramide hydrochloride crystal form B is prepared by the method described in any one of claims 6 to 8.

10. The method according to claim 9, wherein the (S)-2-aminobutyramide hydrochloride is present in a crystal form B of greater than 50%, preferably in a crystal form B of greater than 55%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%.

11. The method according to claim 9, characterized in that... First, (S)-2-aminobutyramide hydrochloride is released at room temperature with an inorganic base, then cooled to -10 to 0°C, and then 4-chlorobutyryl chloride and an inorganic base are added to carry out the reaction.

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