Synthesis process of pyrithiol hydrochloride
By using one-pot cooking technology in the pyrithiol hydrochloride synthesis process, chlorination, hydrolysis-sulfation, salt formation and refining reactions, the problems of low product yield and high production cost in the existing process are solved, and product yield improvement and It has improved purity and is suitable for large-scale industrial production.
Patent Information
- Application Number
- CN202411387613.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-05
- Publication Date
- 2025-01-07
AI Technical Summary
The existing pyrameryl hydrochloride synthesis process products have low yields, high production costs, and are not suitable for large-scale production.
Using one-pot cooking technology, through chlorination, hydrolysis-sulfurization, salt formation and purification reaction, the product yield and purity are improved, the process flow is simplified, and the cost is reduced.
The product yield of pyrameryl hydrochloride has been increased from 60% to 72-76%, reducing production costs, and suitable for large-scale industrial production.
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Figure CN119264041A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical synthesis and relates to a pyritinol medicinal salt, in particular to pyritinol hydrochloride and a synthesis process thereof. Background Art
[0002] Pyritinol dihydrochloride monohydrate, also known as Brain Refresh, is a derivative of vitamin B6 that can promote the metabolism of glucose and amino acids in the brain, increase blood flow in the brain, and promote brain function. Its chemical name is 3,3-(dithiomethylene)bis(5-hydroxy-6-methyl-pyridinemethane) dihydrochloride monohydrate, and its structural formula is shown in Formula I. Pyritinol hydrochloride is suitable for the treatment of headache, dizziness, insomnia, and memory loss in concussion syndrome, sequelae of brain trauma, encephalitis, and sequelae of meningitis. It can also be used to improve cerebral arteriosclerosis and Alzheimer's disease.
[0003]
[0004] At present, the synthesis process of pyritinol hydrochloride is generally obtained by chlorination, hydrolysis, condensation and salt formation with hydrochloric acid. The yield of the synthesis process product is low and the production cost is high. Summary of the invention
[0005] The purpose of the present invention is to solve the problems in the background technology and to provide an improved method for the synthesis of pyrithione hydrochloride. The method adopts a one-pot process to obtain pyrithione hydrochloride through chlorination, hydrolysis-sulfurization, salt formation and refining reactions. The process improves the product yield from the traditional 60% to 72-76%, and the product purity is also improved. The process is also suitable for large-scale production.
[0006] To achieve the above object, the present invention adopts the following technical solutions:
[0007] Step 1: Chlorination: Use vitamin B6 as raw material, add thionyl chloride and N,N-dimethylformamide (DMF) into the reaction kettle. After the reaction is completed, reduce the pressure to concentrate the thionyl chloride and pump in dichloromethane to mix well. Pump in purified water and hydrochloric acid and stir for 30 minutes. Filter and dry to obtain intermediate 1.
[0008] Step 2: Hydrolysis-sulfurization: The intermediate 1 is heated and hydrolyzed by stirring in a hydrolysis reactor, and after cooling, anhydrous sodium sulfate is added for sulfidation, and the intermediate 2 is obtained by filtering, drying, and weighing.
[0009] Step 3: Salt formation (crude product) The intermediate 3 is added to hydrochloric acid, heated to dissolve, and then activated carbon is added for decolorization, and filtered while hot. The filtrate is cooled to 0-5°C, crystallized, filtered, dried, and weighed to obtain the intermediate 3.
[0010] Step 4: Refining Weigh acetone, purified water, and intermediate 3, add them to the reactor and heat them, add activated carbon for decolorization, press them into the crystallization kettle and stir, open the chilled water, lower the internal temperature to 0-5°C, and keep warm and stir for 2 hours. After the crystallization is completed, put the liquid into the centrifuge for filtering, drying, and weighing to obtain the finished product.
[0011] The synthetic process route is as follows:
[0012]
[0013] Preferably, the first step reaction is
[0014] (1) Add vitamin B6 and DMF into a reactor, start stirring, and add chilled water to cool down.
[0015] (2) Sulfoxide chloride is pumped into a high-level tank.
[0016] (3) Turn off the chilled water, turn on the steam, increase the temperature, and keep the reaction warm for a while.
[0017] (4) After the reaction is completed, turn off the steam, start circulating water cooling, and recover the thionyl chloride by decompression and concentration until it becomes viscous. During this period, pay attention to the change in the resistance of the stirring paddle. If the stirring is seriously obstructed, stop stirring in time and switch to dry steam to prevent damage to the motor. When there is no obvious dripping in the recovery mirror, turn off the steam and start circulating water cooling, turn off the vacuum and start emptying.
[0018] (5) Turn on the circulating water cooling system, pump in dichloromethane, and stir for 15 minutes to mix thoroughly.
[0019] (6) Pump purified water and hydrochloric acid into a high-level tank, slowly drip them into the reactor (a large amount of gas is discharged), and stir for 30 minutes.
[0020] (7) Filter, dry and weigh to obtain intermediate 1.
[0021] Preferably, in the first step (1), the temperature of the chilled water is reduced to 10-20°C.
[0022] Preferably, in the first step (2), thionyl chloride is slowly added dropwise when thionyl chloride is pumped into the high-level tank (pay attention to the pressure in the kettle, if there is any abnormality, use the recovery kettle to reduce the pressure), during which the internal temperature is controlled not to exceed 20° C., and the mixture is stirred for 15 minutes after the addition is completed.
[0023] Preferably, in the first step (3), the temperature is raised to 55-60° C. and the reaction is kept warm for 1 hour.
[0024] Preferably, in the first step (4), the circulating water is cooled to ≤50°C and the vacuum degree is ≤-0.09Mpa.
[0025] Preferably, in the first step (5), the mixture is cooled to an internal temperature of 20°C.
[0026] Preferably, the second step reaction is:
[0027] (1) Preparation of sodium disulfide solution: weigh anhydrous sodium sulfide, sulfur and purified water and add them into a preparation kettle. Stir and start steaming. Raise the internal temperature to about 40°C and dissolve. Set aside.
[0028] (2) Weigh purified water and intermediate 1 and add them to the hydrolysis reactor, start stirring, turn on steam, and heat up for hydrolysis. After the reaction is completed, turn off the steam, turn on circulating water, and cool down to 25-30°C.
[0029] (3) Connect the sodium disulfide preparation kettle to the bag filter and press it into the hydrolysis reactor.
[0030] (4) Centrifuge, wash the filter cake with purified water at about 30°C, and spin dry to obtain a crude base.
[0031] (5) Weigh purified water and hydrochloric acid and add them to the hydrolysis kettle, add the crude base, and stir to dissolve. Add activated carbon, stir and filter to the neutralization kettle.
[0032] (6) Weigh purified water and sodium hydroxide and add them to the preparation kettle. Stir and dissolve. Transfer the sodium hydroxide solution to a high position.
[0033] (7) Filter, dry, and weigh to obtain intermediate 2.
[0034] Preferably, in the second step (2), the internal temperature is raised to 60-65° C. and the hydrolysis is carried out for 30 minutes.
[0035] Preferably, in the second step (3), the temperature of the hydrolysis kettle is controlled at 25-35°C, and the reaction is kept warm for 1 hour (preparation of hydrochloric acid and purified water) to adjust the pH to 7, and the pH remains unchanged after stirring for 30 minutes.
[0036] Preferably, in the second step (6), sodium hydroxide solution is added dropwise to adjust the pH to 6.5-7.5, and stirred for 15 minutes until the pH remains unchanged (if the pH is greater than 7.5, 10% hydrochloric acid is used to adjust the pH back to 6.5-7.5).
[0037] Preferably, the third step reaction is:
[0038] (1) Weigh purified water and hydrochloric acid and add them to the salt-forming reactor, add intermediate 2, start stirring, turn on steam, and heat. Add activated carbon, filter hot to the crystallization kettle, start stirring, turn on chilled water,
[0039] (2) The internal temperature is reduced to 0-5°C, kept warm for 2 hours, and centrifuged to obtain a salt.
[0040] (3) Weigh edible alcohol and purified water and add them to the dissolution kettle, add the salt-forming material, stir, turn on the steam, and raise the internal temperature to 60-70°C. Add activated carbon for decolorization for 30 minutes, pass through a preheated microporous precision filter, press into the crystallization kettle, and stir.
[0041] (4) Turn on the chilled water, lower the internal temperature to 0-5°C, keep warm for 2 hours, filter, dry, and weigh to obtain the intermediate 3.
[0042] Preferably, in the third step (1), the internal temperature is raised to 60-65° C. and kept warm for 30 minutes.
[0043] Preferably, the fourth step reaction is: (1) weighing acetone and adding it into a reaction kettle, pressing it into a crystallization kettle through a filter, discharging the material, and setting aside.
[0044] (2) Weigh acetone, purified water, and crude pyritinol hydrochloride into the reaction kettle, stir, open the reflux valve, turn on the steam, raise the internal temperature to 50-60°C, and dissolve. Add activated carbon for decolorization for 30 minutes, preheat the filter in advance, and after decolorization, open the bottom valve and press the liquid through the filter to the crystallization kettle.
[0045] (3) Start stirring the crystallization kettle, turn on the chilled water, reduce the internal temperature to 0-5°C, and keep stirring for 2 hours.
[0046] (4) After the crystallization is completed, the liquid is placed in a centrifuge for filtration, drying, and weighing to obtain the finished product.
[0047] Compared with the prior art, the present invention has the following beneficial effects:
[0048] The present invention adopts thionyl chloride as the halogenating agent, which is cheaper than the traditional 56% hydrobromic acid, is easy to purchase, has a small amount of use and a high yield. The synthesis method is simple, the conditions are mild, the synthesis cycle is short, no noble metal catalyst is needed, and the cost is low. It is suitable for industrial large-scale production applications. BRIEF DESCRIPTION OF THE DRAWINGS
[0049] Figure 1 Pyritinol Hydrochloride Infrared Absorption Spectrum DETAILED DESCRIPTION
[0050] In order to make the purpose, technical scheme and advantages of the present invention more clearly understood, the present invention is described by the following specific embodiments, but is by no means limited thereto. The following are also preferred embodiments of the present invention, which are only used to describe the present invention and cannot be understood as limiting the present invention. It should be pointed out that any modification, equivalent substitution and improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
[0051] The experimental methods and detection methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified.
[0052] Example
[0053] 1. Chlorination
[0054] (1) Put 100 kg of vitamin B6 into a reactor, weigh 6.83 kg of DMF and add it to the reactor, start stirring, turn on chilled water, and cool to 10-20°C.
[0055] (2) Pump 578.53 kg of thionyl chloride into the high-level tank. Slowly add thionyl chloride dropwise (pay attention to the pressure in the kettle. If there is any abnormality, use the recovery kettle to reduce the pressure). During this period, control the internal temperature not to exceed 20°C. Stir for 15 minutes after the addition is completed.
[0056] (3) Turn off the chilled water, turn on the steam, raise the temperature to 55-60°C, and keep the temperature for 1 hour.
[0057] (4) After the reaction is completed, turn off the steam, turn on the circulating water to cool to ≤50℃, the vacuum degree ≤-0.09Mpa, and recover the thionyl chloride by decompression and concentration until it becomes viscous. During this period, pay attention to the change in the resistance of the stirring paddle. If the stirring is seriously obstructed, stop stirring in time and switch to dry steam to prevent damage to the motor. When there is no obvious dripping in the recovery mirror, turn off the steam and turn on the circulating water to cool down, turn off the vacuum and start emptying.
[0058] (5) Turn on the circulating water to cool the internal temperature to about 20°C, pump in 650 kg of dichloromethane, and stir for 15 minutes to mix well.
[0059] (6) Pump 38.46 kg of purified water and 14.24 kg of hydrochloric acid into the high-level tank, slowly drip into the reactor (a large amount of gas is discharged), and stir for 30 minutes.
[0060] (7) Filter and dry the mixture, and weigh 116 kg of intermediate 1.
[0061] 2. Hydrolysis-sulfurization
[0062] (1) Preparation of sodium disulfide solution: weigh 108 kg of anhydrous sodium sulfide, 45.88 kg of sulfur, and 2320 kg of purified water and add them into a preparation kettle. Stir and start steaming. Raise the internal temperature to about 40°C, dissolve, and set aside.
[0063] (2) Weigh 1160 kg of purified water and 116 kg of intermediate 1 into a hydrolysis reactor, start stirring, turn on steam, raise the internal temperature to 60-65°C, and hydrolyze for 30 minutes. After the reaction is completed, turn off the steam, turn on circulating water, and cool down to 25-30°C.
[0064] (3) Connect the sodium disulfide preparation kettle to a bag filter and press it into the hydrolysis reactor. The temperature of the hydrolysis reactor is controlled at 25-35°C. Keep the temperature for 1 hour (prepare hydrochloric acid and purified water) and adjust the pH to 7. Stir for 30 minutes until the pH remains unchanged.
[0065] (4) Centrifuge, wash the filter cake with purified water at about 30°C, and spin dry to obtain a crude base.
[0066] (5) Weigh 136 kg of purified water and hydrochloric acid and add them to the hydrolysis kettle, add the crude base, and stir to dissolve. Add activated carbon, stir and filter to the neutralization kettle.
[0067] (6) Weigh 1748 kg of purified water and 92.8 kg of sodium hydroxide and add them to the preparation kettle. Stir and dissolve. Transfer the sodium hydroxide solution to a high position. Add the sodium hydroxide solution dropwise to adjust the pH to 6.5-7.5. Stir for 15 minutes. If the pH does not change (if the pH is > 7.5, use 10% hydrochloric acid to adjust the pH to 6.5-7.5).
[0068] (7) Filter and dry, and weigh to obtain 60 kg of intermediate 2.
[0069] 3. Salt formation (crude product)
[0070] (1) Weigh 84 kg of purified water and 66 kg of hydrochloric acid and add them to the salt-forming reactor. Add 60 kg of base (intermediate 2), start stirring, turn on steam, raise the internal temperature to 60-65°C, and keep warm for 30 minutes. Add activated carbon, filter hot to the crystallization kettle, start stirring, turn on chilled water,
[0071] (2) The internal temperature is reduced to 0-5°C, kept warm for 2 hours, and centrifuged to obtain a salt.
[0072] (3) Weigh 140.8 kg of edible alcohol and 19.2 kg of purified water into a dissolving kettle, add the salt-forming material, stir, start steaming, and raise the internal temperature to 60-70°C. Add activated carbon for decolorization for 30 minutes, pass through a preheated microporous precision filter, press into a crystallization kettle, and stir.
[0073] (4) Turn on the chilled water and reduce the internal temperature to 0-5°C. Keep the temperature for 2 hours, filter and dry. Weigh 45 kg of intermediate 3.
[0074] 4. Refining:
[0075] (1) Weigh 180 kg of acetone and add it to the reaction kettle. Press it into the crystallization kettle through the filter and discharge it for standby use.
[0076] (2) Weigh 67.5 kg of purified water and 45 kg of crude pyritinol hydrochloride into the reaction kettle, stir, open the reflux valve, turn on the steam, raise the internal temperature to 50-60°C, and dissolve. Add activated carbon for decolorization for 30 minutes, preheat the filter in advance, open the bottom valve after decolorization, and press the liquid through the filter to the crystallization kettle.
[0077] (3) Start stirring the crystallization kettle, turn on the chilled water, reduce the internal temperature to 0-5°C, and keep stirring for 2 hours.
[0078] (4) After the crystallization is completed, the feed liquid is placed in a centrifuge for filtering, drying, and weighing to obtain the finished product. The yield is 73%.
[0079] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present invention.
Claims
1. A new synthesis process of pyritinol hydrochloride, the preparation method of which comprises the following steps: Step 1: Chlorination: Use vitamin B6 as raw material, add thionyl chloride and N,N-dimethylformamide (DMF) into the reaction kettle. After the reaction is completed, reduce the pressure to concentrate the thionyl chloride and pump in dichloromethane to mix well. Pump in purified water and hydrochloric acid and stir for 30 minutes. Filter and dry to obtain intermediate 1. Step 2: Hydrolysis-sulfurization: The intermediate 1 is heated and hydrolyzed by stirring in a hydrolysis reactor, and after cooling, anhydrous sodium sulfate is added for sulfidation, and the intermediate 2 is obtained by filtering, drying, and weighing. Step 3: Salt formation (crude product) The intermediate 3 is added to hydrochloric acid, heated to dissolve, and then activated carbon is added for decolorization, and filtered while hot. The filtrate is cooled to 0-5°C, crystallized, filtered, dried, and weighed to obtain the intermediate 3. Step 4: Refining Weigh acetone, purified water, and intermediate 3, add them to the reactor and heat them, add activated carbon for decolorization, press them into the crystallization kettle and stir, open the chilled water, lower the internal temperature to 0-5°C, and keep warm and stir for 2 hours. After the crystallization is completed, put the liquid into the centrifuge for filtering, drying, and weighing to obtain the finished product. The synthetic process route is as follows:
2. A synthesis process for pyritinol hydrochloride according to claim 1, characterized in that: The first step reaction is (1) Add vitamin B6 and DMF into a reactor, start stirring, add chilled water, and cool to 10-20°C. (2) Sulfoxide chloride is pumped into a high-level tank. (3) Turn off the chilled water, turn on the steam, raise the temperature to 55-60°C, and keep the temperature for 1 hour. (4) After the reaction is completed, turn off the steam, start circulating water cooling, and recover the thionyl chloride by decompression and concentration until it becomes viscous. During this period, pay attention to the change in the resistance of the stirring paddle. If the stirring is seriously obstructed, stop stirring in time and switch to dry steam to prevent damage to the motor. When there is no obvious dripping in the recovery mirror, turn off the steam and start circulating water cooling, turn off the vacuum and start emptying. (5) Turn on the circulating water cooling system to pump in DCM and stir for 15 minutes to mix well. (6) Pump purified water and hydrochloric acid into a high-level tank, slowly drip them into the reactor (a large amount of gas is discharged), and stir for 30 minutes. (7) Filter, dry and weigh to obtain intermediate 1.
3. A synthesis process for pyritinol hydrochloride according to claim 2, characterized in that: In step (2), thionyl chloride is slowly added dropwise when it is pumped into the high-level tank (pay attention to the pressure in the kettle. If there is any abnormality, use the recovery kettle to reduce the pressure). During this period, the internal temperature is controlled not to exceed 20° C. After the addition is completed, stir for 15 minutes.
4. A synthesis process for pyritinol hydrochloride according to claim 2, characterized in that: In step (3).
5. A synthesis process for pyritinol hydrochloride according to claim 2, characterized in that: In step (4), the circulating water is cooled to ≤50°C and the vacuum degree is ≤-0.09Mpa.
6. A synthesis process for pyritinol hydrochloride according to claim 2, characterized in that: In step (5), the mixture is cooled to an internal temperature of 20°C.
7. A synthesis process for pyritinol hydrochloride according to claim 1, characterized in that: The second step reaction is: (1) Preparation of sodium disulfide solution: weigh anhydrous sodium sulfide, sulfur and purified water and add them into a preparation kettle. Stir and start steaming. Raise the internal temperature to about 40°C and dissolve. Set aside. (2) Weigh purified water and intermediate 1 and add them to the hydrolysis reactor. Start stirring, turn on steam, raise the internal temperature to 60-65°C, and hydrolyze for 30 minutes. After the reaction is completed, turn off the steam, turn on circulating water, and cool down to 25-30°C. (3) Connect the sodium disulfide preparation kettle to a bag filter and press it into the hydrolysis reactor. The temperature of the hydrolysis reactor is controlled at 25-35°C. Keep the temperature for 1 hour (prepare hydrochloric acid and purified water) and adjust the pH to 7. Stir for 30 minutes until the pH remains unchanged. (4) Centrifuge, wash the filter cake with purified water at about 30°C, and spin dry to obtain a crude base. (5) Weigh purified water and hydrochloric acid and add them to the hydrolysis kettle, add the crude base, and stir to dissolve. Add activated carbon, stir and filter to the neutralization kettle. (6) Weigh purified water and sodium hydroxide and add them to the preparation kettle. Stir and dissolve. Transfer the sodium hydroxide solution to a high position and add the sodium hydroxide solution dropwise. (7) Filter, dry, and weigh to obtain intermediate 2.
8. A synthesis process for pyritinol hydrochloride according to claim 7, characterized in that: In step (6), sodium hydroxide solution is added dropwise to adjust the pH to 6.5-7.5, and the mixture is stirred for 15 minutes until the pH remains unchanged (if the pH is greater than 7.5, 10% hydrochloric acid is used to adjust the pH to 6.5-7.5).
9. A synthesis process for pyritinol hydrochloride according to claim 1, characterized in that: The third step reaction is: (1) Weigh purified water and hydrochloric acid and add them to the salt-forming reactor, add intermediate 2, start stirring, turn on steam, raise the internal temperature to 60-65°C, and keep warm for 30 minutes. Add activated carbon, filter hot to the crystallization kettle, start stirring, turn on chilled water, (2) The internal temperature is reduced to 0-5°C, kept warm for 2 hours, and centrifuged to obtain a salt. (3) Weigh edible alcohol and purified water and add them to the dissolution kettle, add the salt-forming material, stir, turn on the steam, and raise the internal temperature to 60-70°C. Add activated carbon for decolorization for 30 minutes, pass through a preheated microporous precision filter, press into the crystallization kettle, and stir. (4) Turn on the chilled water, lower the internal temperature to 0-5°C, keep warm for 2 hours, filter, dry, and weigh to obtain the intermediate 3.
10. A synthesis process for pyritinol hydrochloride according to claim 1, characterized in that: The fourth step reaction is: (1) Weigh acetone and add it to the reaction kettle. Press it into the crystallization kettle through the filter. Discharge the material and set aside. (2) Weigh acetone, purified water, and crude pyritinol hydrochloride into the reaction kettle, stir, open the reflux valve, turn on the steam, raise the internal temperature to 50-60°C, and dissolve. Add activated carbon for decolorization for 30 minutes, preheat the filter in advance, and after decolorization, open the bottom valve and press the liquid through the filter to the crystallization kettle. (3) Start stirring the crystallization kettle, turn on the chilled water, reduce the internal temperature to 0-5°C, and keep stirring for 2 hours. (4) After the crystallization is completed, the liquid is placed in a centrifuge for filtration, dried, and weighed to obtain the finished product.