Crystallization method of chloral hydrate

Abstract

The invention discloses a crystallization method of chloral hydrate, which belongs to the technical field of organic compound synthesis, and comprises the following steps: carrying out hydration reaction according to the mass ratio of trichloroacetaldehyde to water of 1: (0.2-0.25), adding inorganic alkali to adjust the pH value to 4-6, adding an anti-caking agent, cooling, standing, crystallizing, filtering, pulping a filter cake with an organic solvent, filtering, and continuously carrying out vacuum drying on the filter cake to obtain the chloral hydrate. The colorless and transparent chloral hydrate crystal is prepared. The chloral hydrate prepared by the method provided by the invention meets medicinal requirements, and has the advantages of low solvent residue, no hardening phenomenon in post-treatment and good product quality stability.

Description

Technical Field

[0001] The invention discloses a chloral hydrate crystallization method, in particular to a method for preparing chloral hydrate by using trichloroacetaldehyde as a raw material through hydration reaction and crystallization, and belongs to the technical field of organic compound synthesis. Background Art

[0002] Chloral hydrate Chloral hydrate is also called chloral hydrate. Its chemical name is 2,2,2-trichloro-1,1-ethylene glycol. It is a colorless transparent crystal with a slightly bitter taste and a pungent smell. Chloral hydrate can induce physiological sleep by inhibiting the ascending activation system of the brainstem reticular formation. It is a sedative hypnotic with fast onset, good effect and few side effects. In clinical practice, chloral hydrate is mainly used for pediatric examination and treatment. It has anticonvulsant effects at higher doses and can be used for the treatment of status epilepticus and convulsions caused by high fever in children.

[0003] Upon inquiry, there are few reports on the crystallization process of chloral hydrate. Chinese patent CN112374966B reports a method for preparing chloral hydrate, using dichloromethane or chloroform as a solvent, chloroacetaldehyde and water undergo hydration reaction, and then a poor organic solvent such as n-hexane or n-heptane is added to crystallize and precipitate a white solid. The appearance of the chloral hydrate crystals prepared by this method does not meet the requirements for pharmaceutical use. In addition, when chloroform is used as a reaction solvent, since chloroform usually contains 0.6-1% ethanol as a stabilizer, ethanol and chloroacetaldehyde undergo a hemiacetal reaction to generate hemiacetal impurities of chloroacetaldehyde. The preparation method is reproduced to obtain white chloral hydrate particles, and the results of the solvent residue test show that the residual n-hexane or n-heptane in the chloral hydrate prepared by this method exceeds the standard; more importantly, the clarity of the product is unqualified.

[0004] Shi Junxiong reported a chloral hydrate crystallization process in “Research on the Crystallization Process of Chloral Hydrate” (Hunan Chemical Industry, 2000, 30(4):34-35) and Liu Yizhi reported a chloral hydrate crystallization process in “Research on the Crystallization Process of Chloral Hydrate” (Chemical Engineer, 2001, 84(3):22-23). ​​The method is to add chloroform after chloroacetaldehyde reacts with water, then add crystal modifier HS, centrifuge after static crystallization, and dry at low temperature to obtain colorless and transparent chloral hydrate particles. In this method, chloroform is added after chloroacetaldehyde is completely converted into chloral hydrate. Although chloroform can avoid the reaction of chloroacetaldehyde with ethanol in chloroform to produce by-products, due to the high boiling point of chloroform (61°C), it is difficult to ensure that the residual chloroform meets the residual limit requirement (60ppm) of the ICH guidelines by low temperature drying. The method also reported that the use of crystal modifier HS greatly improved the looseness of chloral hydrate crystals and avoided agglomeration; but the specific information of modifier HS was not disclosed.

[0005] Cao Lingfeng et al. reported a process similar to that reported by Shi Junxiong and Liu Yizhi in “Research on the Crystallization Process of Chloral Hydrate” (Shandong Chemical Industry, 2009, 38(6):3-4). This method is to avoid the occurrence of chloral hydrate crystal agglomeration by raising the system crystallization temperature to 50°C, but the literature does not report the chloroform residue and clarity stability. When this method is repeated, the chloroform residue of the obtained product exceeds the standard. More importantly, the clarity is unqualified after being placed at room temperature and away from light for 10 days, which is significantly lower than the clarity at 0 days; therefore, the stability of the chloral hydrate crystals prepared by this method is poor.

[0006] As described above, the existing process mainly has the following problems: first, the appearance of chloral hydrate crystals does not meet the pharmaceutical requirements; second, the existing process uses chloroform as a solvent, resulting in a side reaction between the stabilizer ethanol in the chloroform and trichloroacetaldehyde to produce hemiacetal impurities of trichloroacetaldehyde. At the same time, the limit requirement of chloroform as an ICH Class II solvent is below 60ppm, and the existing process is difficult to ensure the stable production of products with qualified solvent residues; more importantly, the prepared product has poor stability, and the clarity gradually decreases during the storage process and eventually leads to unqualified clarity. Summary of the invention

[0007] In order to solve the deficiencies of the prior art, the present invention provides a chloral hydrate crystallization method, which comprises the following steps: after chloral hydrate is generated by hydration reaction between trichloroacetaldehyde and water, an inorganic base is added to adjust the pH, an anti-caking agent is added, the temperature is lowered to allow the crystallization to stand, filtration is performed, the filter cake is pulped at low temperature with an organic solvent, centrifuged, and finally dried at low temperature and in a vacuum to obtain colorless and transparent chloral hydrate crystals. The chloral hydrate prepared by the method of the present invention meets the requirements for pharmaceutical use, has low solvent residue, no caking phenomenon in post-treatment, and good product quality stability.

[0008] The present invention is achieved by the following technical scheme: a chloral hydrate crystallization method, wherein a hydration reaction is carried out at a mass ratio of chloral to water of 1:0.2-0.25, an inorganic base is added thereto to adjust the pH to 4-6, an anti-caking agent is added, the temperature is lowered, and the filter is filtered after crystallization is allowed to stand still, the filter cake is pulped with an organic solvent and then filtered, and the filter cake is vacuum dried to obtain colorless and transparent chloral hydrate crystals. The amount of the anticaking agent is 0.1-0.5% of the weight of trichloroacetaldehyde, and the anticaking agent is selected from at least one of calcium carbonate, magnesium carbonate, magnesium sulfate, calcium phosphate, potassium phosphate, potassium silicate, sodium silicate, calcium silicate or magnesium silicate. During the static crystallization, the crystallization temperature is 20-30° C. and the crystallization time is 12-48 hours.

[0009] The hydration reaction temperature is controlled at 40-50°C.

[0010] The inorganic base is selected from at least one of potassium hydroxide, barium hydroxide, calcium hydroxide, lithium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or calcium bicarbonate.

[0011] The temperature is lowered to 20-30°C and then crystallized.

[0012] During the beating, the temperature is controlled at 0-10°C.

[0013] During the pulping, the amount of the organic solvent is controlled to be 0.2 to 0.5 times the weight of chloroacetaldehyde.

[0014] The beating time is 30 to 60 minutes.

[0015] The organic solvent is dichloromethane.

[0016] During the vacuum drying, the temperature is controlled at 20-35°C.

[0017] Compared with the prior art, the present invention has the following advantages and beneficial effects: (1) The present invention selects appropriate anti-caking agents, crystallization solvents (water) and their amounts in the crystallization method, and controls appropriate crystallization time and crystallization temperature, so that the prepared chloral hydrate crystals have a colorless and transparent appearance, meeting the requirements for clinical medication.

[0018] (2) The present invention can add an appropriate amount of anti-caking agent to prevent the crystallization system from agglomerating after the crystallization is completed, and the chloral hydrate crystals are loose and have good crystal looseness, which is conducive to subsequent unloading and centrifugation.

[0019] (3) The present invention performs low-temperature vacuum drying on the chloral hydrate crystals to reduce the residual solvent to a low level, with dichloromethane ≤50 ppm and chloroform ≤10 ppm.

[0020] (4) The chloral hydrate crystals prepared by the method of the present invention have good stability and their clarity does not change after long-term storage. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is the chloral hydrate product diagram of Example 1.

[0022] Figure 2 This is the chloral hydrate product diagram of Comparative Example 1.

[0023] Figure 3 This is the stirring state diagram of the crystallization process of Comparative Example 2. DETAILED DESCRIPTION

[0024] The invention objectives, technical solutions and beneficial effects of the present invention are further described in detail below.

[0025] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the claimed invention, and unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.

[0026] The present invention aims to provide a novel crystallization process for preparing chloral hydrate from chloral through a hydration reaction of chloral. The chloral hydrate produced by the process is colorless and transparent, meets the requirements of pharmaceutical appearance, and the residual solvent content of the product is less than or equal to 50 ppm for dichloromethane and less than or equal to 10 ppm for chloroform, without the risk of excessive residual solvent. The product can maintain clarity after being placed for 60 days under certain storage conditions, and has good product stability.

[0027] The specific implementation modes of the present invention are described below in conjunction with the embodiments. Of course, the protection scope of the present invention is not limited to the following embodiments.

[0028] It should be noted that in the following embodiments and comparative examples: (1) The clarity of the product shall be determined according to the first method (visual method) of the Clarity Test Method 0902 of the General Rules of Part IV of the Chinese Pharmacopoeia; (2) The residual solvent content was determined by gas chromatography (Chinese Pharmacopoeia 2020 Edition Part IV General Chapter 0521). A capillary column with 6% cyanopropylphenyl-94% methylpolysiloxane as the stationary phase (Agilent DB-624, 30m×0.32mm×1.8µm, or similar polarity) was used as the chromatographic column; an electron capture detector (ECD) was used; the initial column temperature was 70°C, maintained for 8 minutes, and then increased to 220°C at a rate of 20°C per minute and maintained for 5 minutes; the injection port temperature was 200°C; the detector temperature was 250°C; the column flow rate was 1 ml per minute; and the injection volume was 1 μl.

[0029] (3) According to the ICH residual solvents guidelines, the residual limit of dichloromethane is ≤600ppm, the residual limit of chloroform is ≤60ppm, and the residual limit of n-hexane is ≤290ppm.

[0030] Embodiment 1: Slowly add 5.00 kg of trichloroacetaldehyde to 1.25 kg of water, and control the system temperature at 40-50 ° C during the addition process. After the addition is completed, add sodium bicarbonate to adjust the pH to 6, then add 25.00 g of sodium silicate, and stop stirring; cool the system to 20-30 ° C, keep it still for crystallization for 48 hours, and the crystals in the system are loose and filtered; the filter cake is slurried with 2.5 kg of cold dichloromethane at 0-10 ° C for 30 minutes and then filtered; the filter cake is vacuum dried at 30 ° C for 8 hours to obtain colorless and transparent chloral hydrate crystals, see Figure 1 .

[0031] The clarity of this product is qualified; after testing, the solvent residue of this product is: no dichloromethane is detected, and chloroform is 5ppm.

[0032] Embodiment 2: Slowly add 5.00 kg of trichloroacetaldehyde to 1.00 kg of water, and control the temperature of the system at 40-50°C during the addition process. After the addition is completed, add calcium hydroxide to adjust the pH to 5, then add 5.00 g of calcium phosphate, and stop stirring; cool the system to 20-30°C, keep it still for crystallization for 36 hours, and the crystals of the system are loose and filtered; the filter cake is slurried with 1.0 kg of cold dichloromethane at 0-10°C for 30 minutes and then filtered, and the filter cake is vacuum dried at 20°C for 15 hours to obtain colorless and transparent chloral hydrate crystals.

[0033] The above chloral hydrate crystals were tested in the same manner as in Example 1: The clarity is acceptable; Solvent residues: dichloromethane 30ppm, chloroform 6ppm.

[0034] Embodiment 3: Slowly add 5.00 kg of trichloroacetaldehyde to 1.15 kg of water, and control the temperature of the system at 40-50 ° C during the addition process. After the addition is completed, add sodium hydroxide to adjust the pH to 4.5, then add 20.00 g of magnesium sulfate and stop stirring; cool the system to 20-30 ° C, keep it still for crystallization for 24 hours, the crystals of the system are loose, and filter; the filter cake is slurried with 1.5 kg of cold dichloromethane at 0-10 ° C for 45 minutes and then filtered, and the filter cake is vacuum dried at 35 ° C for 6 hours to obtain colorless and transparent chloral hydrate crystals.

[0035] The above chloral hydrate crystals were tested in the same manner as in Example 1: The clarity is acceptable; Solvent residues: dichloromethane 8ppm, chloroform 4ppm.

[0036] Embodiment 4: Slowly add 5.00 kg of trichloroacetaldehyde to 1.05 kg of water, control the system temperature at 40-50° C. during the addition process, add cesium carbonate to adjust the pH to 5 after the addition is completed, then add 5.00 g of calcium carbonate and stop stirring; cool the system to 20-30° C., keep it still for crystallization for 40 hours, the crystals of the system are loose, and filter; the filter cake is slurried with 2.0 kg of cold dichloromethane at 0-10° C. for 60 minutes and then filtered, and the filter cake is vacuum dried at 30° C. for 6 hours to obtain colorless and transparent chloral hydrate crystals.

[0037] The above chloral hydrate crystals were tested in the same manner as in Example 1: The clarity is acceptable; Solvent residues: dichloromethane 14ppm, chloroform 4ppm.

[0038] Embodiment 5: Slowly add 5.00 kg of trichloroacetaldehyde to 1.20 kg of water, and control the system temperature at 40-50 ° C during the addition process. After the addition is completed, add potassium bicarbonate to adjust the pH to 5.5, then add 15.00 g of calcium silicate, and stop stirring; cool the system to 20-30 ° C, keep it still for crystallization for 35 hours, the system crystals are loose, and filter; the filter cake is slurried with cold 2.5 kg of dichloromethane at 0-10 ° C for 40 minutes and then filtered, and the filter cake is vacuum dried at 25 ° C for 10 hours to obtain colorless and transparent chloral hydrate crystals.

[0039] The above chloral hydrate crystals were tested in the same manner as in Example 1: The clarity is acceptable; Solvent residue: dichloromethane was not detected, chloroform was 6ppm.

[0040] Embodiment 6: Slowly add 5.00 kg of trichloroacetaldehyde to 1.25 kg of water, and control the system temperature at 40-50 ° C during the addition process. After the addition is completed, add sodium bicarbonate to adjust the pH to 5.0, then add 5.00 g of calcium silicate, and stop stirring; cool the system to 20-30 ° C, keep it still for crystallization for 48 hours, and the crystals of the system are loose and filtered; the filter cake is slurried with cold 2.5 kg of dichloromethane at 0-10 ° C for 60 minutes and then filtered, and the filter cake is vacuum dried at 30 ° C for 8 hours to obtain colorless and transparent chloral hydrate crystals.

[0041] The above chloral hydrate crystals were tested in the same manner as in Example 1: The clarity is acceptable; Solvent residue: dichloromethane not detected, chloroform 5ppm.

[0042] Comparative Example 1: Referring to the method of patent CN112374966B, 1.00 kg of trichloroacetaldehyde and 2.60 kg of dichloromethane were taken, stirred and cooled to 0-10 ° C. When the internal temperature was 5 ° C, 100.00 g of water was slowly added dropwise. After the addition was completed, it was stirred for 30 minutes. When the internal temperature dropped below 5 ° C, 3.00 kg of n-hexane was added dropwise. The temperature was kept for crystallization for 2 hours, filtered, and the filter cake was washed with n-hexane and dried under reduced pressure for 12 hours to obtain white chloral hydrate particles. Figure 2 .

[0043] The white chloral hydrate particles were tested in the same manner as in Example 1: The appearance does not meet the requirements for pharmaceutical use and the clarity is unqualified; Solvent residues: dichloromethane 190ppm, n-hexane 330ppm; among them, the n-hexane residue exceeds the limit (limit ≤ 290ppm).

[0044] Comparative Example 2: Referring to the preparation method of the document "Study on the Crystallization Process of Chloral Hydrate" (Chemical Engineer, 2001, 84(3):22-23), 600 g of trichloroacetaldehyde was heated to 80°C, and 90 g of distilled water was slowly added dropwise under stirring. After the addition, stirring was continued for 1 hour. The mixture was cooled to 30°C, and 170 mL of chloroform was added. After stirring for 5 minutes, a large amount of hardening occurred in the system and stirring was impossible. Figure 3 .

[0045] Comparative Example 3: With reference to the preparation method of the literature "Study on Crystallization Process of Chloral Hydrate" (Shandong Chemical Industry, 2009, 38(6):3-4), 54.50 g of water was slowly added dropwise to 500.00 g of trichloroacetaldehyde, cooled to 50°C in a water bath, and then 386 mL of chloroform was added. After stirring for 6 h, the filter was filtered, and the filter cake was washed with 5% sodium carbonate solution to a pH of 4-6. The filter cake was vacuum dried at 40°C to obtain anhydrous transparent chloral hydrate crystals.

[0046] Detection of chloral hydrate: The clarity is acceptable; Solvent residue: chloroform 390ppm, residue exceeds the limit (limit ≤ 60ppm).

[0047] The clarity stability of Example 1, Example 5, Example 6 and Comparative Example 3 among the above embodiments were randomly selected and investigated. The results are shown in Table 1 below.

[0048] Table 1: Clarity stability test results of Examples 1, 5, 6 and Comparative Example 3 (25°C + protected from light) The results show that under the same storage conditions (25°C + dark), the clarity of Comparative Example 3 has become unqualified after being placed for 10 days; while the clarity of Example 1, Example 5 and Example 6 is still qualified even after being placed for 60 days. Therefore, the stability of the chloral hydrate crystals prepared by the method provided by the present invention is significantly better than that of the existing disclosed technology.

[0049] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A crystallization method for chloral hydrate, characterized in that: The hydration reaction is carried out at a mass ratio of chloral to water of 1:0.2-0.25, an inorganic base is added thereto to adjust the pH to 4-6, an anti-caking agent is added, the temperature is lowered, and the mixture is filtered after standing and crystallizing. The filter cake is pulped with an organic solvent and then filtered, and the filter cake is vacuum dried to obtain colorless and transparent chloral hydrate crystals. The amount of the anticaking agent is 0.1-0.5% of the weight of trichloroacetaldehyde, and the anticaking agent is selected from at least one of calcium carbonate, magnesium carbonate, magnesium sulfate, calcium phosphate, potassium phosphate, potassium silicate, sodium silicate, calcium silicate or magnesium silicate. During the static crystallization, the crystallization temperature is 20-30° C. and the crystallization time is 12-48 hours.

2. The crystallization method according to claim 1, characterized in that: The hydration reaction temperature is controlled at 40-50°C.

3. The crystallization method according to claim 1, characterized in that: The inorganic base is selected from at least one of potassium hydroxide, barium hydroxide, calcium hydroxide, lithium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate or calcium bicarbonate.

4. The crystallization method according to claim 1, characterized in that: The temperature is lowered to 20-30°C and then crystallized.

5. The crystallization method according to claim 1, characterized in that: During the beating, the temperature is controlled at 0-10°C.

6. The crystallization method according to claim 1, characterized in that: During the pulping, the amount of the organic solvent is controlled to be 0.2 to 0.5 times the weight of chloroacetaldehyde.

7. The crystallization method according to claim 1, characterized in that: The beating time is 30 to 60 minutes.

8. The crystallization method according to claim 1, characterized in that: The organic solvent is dichloromethane.

9. The crystallization method according to claim 1, characterized in that: During the vacuum drying, the temperature is controlled at 20-35°C.

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