Process for producing ethambutol hydrochloride

Abstract

The invention provides a production process of ethambutol hydrochloride, and belongs to the technical field of organic chemical synthesis. According to the process, L-threonine is taken as a raw material, L-2-aminobutyric acid is prepared through biological enzyme fermentation, then L-2-aminobutanol is generated through hydrogenation reduction under the cooperation of a composite catalyst, and finally L-2-aminobutanol reacts with 1, 2-dichloroethane in a micro-channel reactor to obtain a finished product. The method has the advantages of cost, efficiency, environmental protection and yield, low equipment requirement, high product purity and good chiral control, effectively overcomes the defects of the traditional indirect method, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a production process of ethambutol hydrochloride. Background Art

[0002] Ethambutol hydrochloride is a first-line antibacterial anti-tuberculosis drug recommended by the World Health Organization. It can penetrate into mycobacteria, interfere with RNA synthesis, inhibit bacterial reproduction, and has no cross-resistance with other anti-tuberculosis drugs. It has important clinical significance in the field of anti-tuberculosis drugs. Ethambutol has two chiral centers, so it is optically active and has three isomers: levorotatory, dextrorotatory, and meso. The dextrorotatory isomer is used clinically and is 200-500 times more active than the levorotatory isomer and 12 times more active than the meso. As an important pharmaceutical intermediate, ethambutol hydrochloride can be used to synthesize a variety of drugs such as antibiotics, analgesics, and anesthetics. With the improvement of people's health awareness and the growth of drug consumption, the demand for ethambutol hydrochloride in the pharmaceutical industry is also increasing.

[0003] Current methods for synthesizing ethambutol hydrochloride include direct and indirect methods. The direct method requires difficult-to-obtain raw materials, is complex, and produces low yields. The indirect method includes splitting and hydrogenation. The splitting method uses DL-2-aminobutanol as the starting material and uses D-tartaric acid to split it into D-2-aminobutanol. The hydrogenation method uses L-2-aminobutyric acid as the starting material and undergoes a hydrogenation-reduction reaction under a catalyst, strong acid, and high pressure to produce L-2-aminobutanol. Finally, the aminobutanol is reacted with 1,2-dichloroethane to produce ethambutol hydrochloride. However, the raw material DL-2-aminobutanol is relatively expensive, and the yield of tartaric acid splitting is low. The hydrogenation method also requires high equipment conditions due to high temperatures and pressures, which can easily trigger equipment alarms, interrupt the reaction, reduce reaction efficiency, and affect product chirality. Furthermore, the large difference in the ratio of aminobutanol to 1,2-dichloroethane, high reaction temperatures, and long reaction times make it unsuitable for industrial production.

[0004] In view of this, further in-depth research and improvement of the traditional indirect method is still needed. Summary of the Invention

[0005] In light of the background art, the present invention aims to provide a process for producing ethambutol hydrochloride. This process first uses L-threonine as a raw material, fermenting it through an enzyme to produce L-2-aminobutyric acid. This is then hydrogenated and reduced in the presence of a composite catalyst to produce L-2-aminobutanol. Finally, the product is reacted with 1,2-dichloroethane in a microchannel reactor to obtain the finished product. This overall process requires relatively low reaction conditions and equipment, resulting in a high-purity product, effectively overcoming the shortcomings of traditional indirect methods.

[0006] To achieve the above object, the present application specifically adopts the following technical solutions: The present application provides a production process of ethambutol hydrochloride, comprising the following steps: Step one: taking L-threonine as raw material, adding NAD, threonine deaminase, leucine dehydrogenase and alcohol dehydrogenase in sequence for biological enzyme fermentation to prepare L-2-amino butyric acid for standby; Step two: adding a composite catalyst to the L-2-amino butyric acid obtained in step one, and obtaining L-2-amino butanol by hydrogenation reduction for standby; Step three: reacting the L-2-amino butanol obtained in step two with 1,2-dichloroethane, and finally refining by hydrochloric acid to obtain ethambutol dihydrochloride.

[0007] Further, in step one, the adding in sequence specifically refers to constructing a reaction system by taking part of L-threonine, pure water and NAD, then continuously and slowly adding threonine deaminase to catalyze L-threonine to generate 2-ketobutyric acid, continuously and slowly adding leucine dehydrogenase to catalyze 2-ketobutyric acid to generate L-2-amino butyric acid after 4-6 h of reaction, and then adding isopropyl alcohol, alcohol dehydrogenase and the remaining L-threonine to maintain coenzyme circulation.

[0008] Further, the mass ratio of NAD, threonine deaminase, leucine dehydrogenase and alcohol dehydrogenase is (0.5-1):(18-20):(28-32):(64-68), and the total amount of addition is 15%-20% of the mass of L-threonine.

[0009] Further, in step one, the biological enzyme fermentation adopts one-pot method, the reaction system temperature is maintained at 35±2℃, the reaction time is 30-36 h, the reaction is monitored by HPLC to end, and the obtained reaction liquid is filtered by adsorption, and the solid waste and wastewater are removed by vacuum distillation to obtain L-2-amino butyric acid.

[0010] Further, the composite catalyst in step two is composed of ruthenium-carbon catalyst and palladium-carbon catalyst in a mass ratio of (6-10):1.

[0011] Further, the preparation method of the ruthenium-carbon catalyst is as follows: taking needle coke and activated carbon, mixing and grinding, adding into sodium hydroxide solution for activation treatment, washing and drying as catalyst carrier; mixing metal ruthenium, potassium hydroxide and potassium nitrate, adding water for leaching, adding catalyst carrier to the obtained leaching solution, and reducing with a reducing agent to obtain the ruthenium-carbon catalyst.

[0012] Further, the preparation method of the palladium-carbon catalyst is as follows: dissolving palladium chloride in anhydrous ethanol as a precursor solution, adding carbon black to the precursor solution and stirring under ultrasonic waves to obtain a suspension, volatilizing the ethanol, drying and taking out the powder, grinding, and then transferring into a tube furnace, heating to 200-400 DEG C in a H2 / N2 mixed atmosphere, cooling, re-heating to 400-600 DEG C for reduction, and then obtaining the palladium-carbon catalyst.

[0013] Further, the temperature of the hydrogenation reduction in step two is 70-80 DEG C, the pressure is 5.5-7.0 MPa, and the reaction time is 36-48 h.

[0014] Further, in step three, the reaction of L-2-aminobutanol and 1,2-dichloroethane is carried out in a micro-channel reactor, L-2-aminobutanol and anhydrous ethanol are mixed as material one at a mass ratio of 9:1, 1,2-dichloroethane is used as material two, and the feeding rate of material one is controlled to be 4-6 times that of material two.

[0015] Further, the maximum flux of the micro-channel reactor is 500 T / year, the pressure is 1 MPa, the reaction temperature is 130 DEG C, and the reaction time is 2-3 h.

[0016] The beneficial effects of the present application are as follows: 1. In view of the defects and disadvantages of the resolution method, the present application uses L-threonine as a raw material, and generates L-2-aminobutanoic acid through a multi-enzyme system catalysis, in the same reaction system, the present application precisely controls the enzyme addition amount and speed, L-threonine also serves as an ammonia source, and the coenzyme cycle is realized through alcohol dehydrogenase and isopropyl alcohol, so that the multi-enzyme system is synchronously catalyzed. The present application avoids resolution by preparing chiral centers from scratch, overcomes the problem of low resolution yield, avoids the inhibition of enzyme catalytic activity by intermediate products, and influences the overall reaction, and does not need enzyme engineering technology, and takes into account cost, efficiency, environmental protection and yield.

[0017] 2. The prepared ruthenium-carbon catalyst and palladium-carbon catalyst are combined into a composite catalyst in a certain proportion, the reaction conditions of the hydrogenation reduction are effectively reduced, the pressure is reduced to about 6.4 MPa, the temperature is not more than 80 DEG C, the requirement for equipment is low, the isomerization phenomenon rarely occurs during the hydrogenation reaction, and the chiral control is good.

[0018] 3. The reaction of L-2-aminobutanol and 1,2-dichloroethane is carried out in a micro-channel reactor, the feeding rate of the materials is controlled, the proportion of the use amount of aminobutanol and 1,2-dichloroethane is effectively reduced, the reaction temperature is reduced to 130 DEG C, the reaction time is reduced to 2-3 h, the yield is improved, and the present application is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 The present application is a production process. DETAILED DESCRIPTION

[0020] In order to make the objectives, technical solutions and advantages of the present application clearer, the technical solutions of the present application will be clearly and completely described below in conjunction with examples. Unless otherwise specified, the specific conditions in the examples are carried out according to conventional conditions or the conditions recommended by the manufacturers. The reagents or instruments used are all conventional products that can be purchased on the market unless otherwise specified.

[0021] 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 this application belongs. The terminology used in the description of the application herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0022] Example 1 A production process of ethambutol hydrochloride, comprising: 1. Enzymatic synthesis of L-2-aminobutyric acid 650 parts of L-threonine, 350 parts of isopropanol, 2200 parts of pure water, 19.1 parts of threonine deaminase, 29.5 parts of leucine dehydrogenase, 65.4 parts of alcohol dehydrogenase, 0.65 parts of NAD and an appropriate amount of 10% sodium hydroxide solution are weighed by weight fraction. First, pure water, NAD and ¾ of the amount of L-threonine are added to the enzyme reaction kettle, and the pH of the system is adjusted to 8.8 and the temperature is maintained at 35°C with 10% sodium hydroxide solution; then threonine deaminase is added to the system (uniformly and slowly added within 10 h) to start the reaction, and after 5 h, leucine dehydrogenase is added (uniformly and slowly added within 3 h), and after 8 h of reaction, isopropanol, alcohol dehydrogenase and the remaining amount of L-threonine (uniformly and slowly added within 12 h) are added, and the reaction is continuously stirred. HPLC is used to monitor the end of the reaction (32 h).

[0023] After the reaction is completed, the reaction liquid is heated to 75°C, then 2 parts of activated carbon and 30 parts of diatomite are added, and after 1 h of incubation, plate and frame filtration is performed to obtain solid waste such as enzyme residue; the filtrate is collected in a distillation kettle, and under the condition of external temperature 75°C, distillation is carried out under reduced pressure, and the water solution is evaporated to about ¼ to produce wastewater, and the temperature is lowered to crystallize, and centrifugation is performed to obtain solid and centrifugation mother liquor, and the centrifugation mother liquor is transferred to a mother liquor treatment kettle for repeated distillation and crystallization to produce mother liquor waste liquid, and the obtained solid is collected and washed with ethanol, and the ethanol is recovered, and the product is dried to obtain L-2-aminobutyric acid (purity 99.2%, yield 95.7%, chiral ee value 99.5%).

[0024] 2. Catalytic hydrogenation reaction Needle coke and activated carbon were mixed in a 2:1 mass ratio and ground, then added to a 20% sodium hydroxide solution. The mixture was heated to 90°C and stirred for 2 hours for activation, then washed and dried to prepare the catalyst support. Ruthenium powder, potassium hydroxide, and potassium nitrate were mixed (mass ratio 1.2:7:1.8), heated to 850°C and melted for 3 hours. After cooling, 10 times the mass of water was added, and the mixture was heated to 70°C and stirred for 2 hours to obtain a leachate. To 100 parts of the leachate, 25 parts of the catalyst support were added. The mixture was then heated to 50°C and reduced with 100 parts of hydrazine hydrate dropwise. Finally, the mixture was reflux filtered, washed, and dried to obtain the ruthenium-on-carbon catalyst. Ten parts of palladium chloride were dissolved in an appropriate amount of anhydrous ethanol as a precursor solution. 160 parts of carbon black were added and ultrasonically stirred to obtain a suspension. The ethanol was evaporated, and the powder was dried and ground. After grinding, it was transferred to a tube furnace and heated to 300°C at a rate of 10°C / min in a H2 / N2 mixed atmosphere (5% H2) and held for 2 hours. After cooling, the temperature was raised again to 520°C at a rate of 10°C / min for reduction to obtain a palladium-carbon catalyst. The prepared ruthenium-carbon catalyst and palladium-carbon catalyst were then combined to form a composite catalyst at a mass ratio of 8:1.

[0025] Weigh 1700 parts pure water, 200 parts concentrated sulfuric acid, 375 parts L-2-aminobutyric acid (prepared above), and 1 part activated carbon by weight. Add pure water to a glass-lined batching kettle, slowly add concentrated sulfuric acid dropwise, then add L-2-aminobutyric acid and activated carbon. Stir for 1 hour, filter through a sealed bag filter, and transfer the filtrate to a hydrogenation reactor that has been deaerated with nitrogen. Add 10 parts of the composite catalyst and stir thoroughly. Continue to flow hydrogen into the hydrogenation reactor and slowly heat to 76°C using steam. Stop the hydrogen flow when the reactor pressure reaches 6.4 MPa. When the pressure in the kettle no longer decreases within 1 hour, it indicates that the reaction is completed (43 hours). The circulating cooling water is turned on to cool the temperature to 25°C. After the exhaust gas is discharged, the reaction liquid is vacuum filtered to remove the composite catalyst (the composite catalyst is put into the catalyst treatment kettle, treated with sodium hydroxide solution and sulfuric acid, washed to neutrality and then filtered and can be recycled). Continue to evaporate 1000 parts of water under reduced pressure, add caustic soda to adjust the pH to 12, add 1500 parts of methanol and stir for 1 hour, and filter to obtain the feed liquid.

[0026] The feed liquid was transferred to a methanol distillation kettle, where the kettle temperature was controlled at 65°C by atmospheric pressure steam heating. The mixture was condensed and refluxed to remove methanol and 90% of the water. The remaining feed liquid in the kettle was transferred to a finished product rectification kettle, where the kettle temperature was controlled at 60°C. The mixture was refluxed for 45 minutes at a controlled flow rate of 250 L / h and a pressure of 0.015 MPa. The temperature was raised to 90°C and the mixture was subjected to total reflux for 3 hours. When the moisture content was less than 1%, the mixture was heated to 105°C under reduced pressure and distilled to obtain the finished L-2-aminobutanol (purity 98.4%, yield 92.9%, chiral ee value 99.9%).

[0027] 3. Microchannel reactor splicing reaction Take 24.3 parts of the above prepared L-2-aminobutanol, 2.7 parts of anhydrous ethanol, 5.4 parts of 1,2-dichloroethane by weight. L-2-aminobutanol is mixed with anhydrous ethanol to form material one, 1,2-dichloroethane as material two; material one is passed into the micro-channel reactor at a speed of 150 g / s, and material two is passed into the micro-channel reactor at a speed of 30 g / s (the maximum flux is 500 T / year), and the feeding lasts for 180 s. The micro-channel reactor is pressurized to 1 MPa, and the reaction temperature is 130℃; after 2.6 h of continuous reaction, the reaction liquid is collected into a concentration kettle, 45 parts of ammonia water is added (uniformly and slowly added within 2.5 h), then the ethanol is recovered by vacuum concentration (below 95℃), and then L-2-aminobutanol is recovered by vacuum concentration (below 150℃); the concentrated liquid is cooled to 60℃, 420 parts of ethanol is added, and then stirred and filtered. The mother liquor is transferred to a salt forming kettle, cooled to 0℃, and 225 parts of hydrochloric acid ethanol solution is added dropwise, then stirred for 2.5 h, centrifuged to collect the solid, put into a beating kettle, add anhydrous ethanol to beat for 4 h, then centrifuged, dried, and the product ethambutol dihydrochloride is obtained (purity 99.8%, yield 96.3%, chiral ee value 99.9%).

[0028] Example 2 A process for producing ethambutol hydrochloride, comprising: 1. Enzymatic synthesis of L-2-aminobutyric acid Take 700 parts of L-threonine, 300 parts of isopropanol, 2200 parts of pure water, 20 parts of threonine deaminase, 32 parts of leucine dehydrogenase, 64 parts of alcohol dehydrogenase, and 1 part of NAD and an appropriate amount of 10% sodium hydroxide solution by weight. First, add pure water, NAD and 3 / 4 of the amount of L-threonine to the enzyme reaction kettle, adjust the pH of the system to 8.8 with 10% sodium hydroxide solution, and maintain the temperature at 35℃; then add threonine deaminase (uniformly and slowly added within 10 h) to the system and start the reaction by stirring, add leucine dehydrogenase after 5 h of reaction (uniformly and slowly added within 3 h), add isopropanol, alcohol dehydrogenase and the remaining amount of L-threonine after 8 h of reaction (uniformly and slowly added within 12 h), and continue to stir and react, and monitor the reaction by HPLC until the reaction is completed (32 h).

[0029] After the reaction is completed, heat the reaction liquid to 75℃, then add 2 parts of activated carbon and 30 parts of diatomite, and keep warm for 1 h, then filter with a plate and frame to obtain enzyme residue and other solid waste; collect the filtrate into a distillation kettle, and distill under reduced pressure at an external temperature of 75℃, evaporate the aqueous solution to about 1 / 4 to produce wastewater, and then cool and crystallize, centrifuge to obtain solid and centrifugal mother liquor, transfer the centrifugal mother liquor to a mother liquor treatment kettle, repeat the distillation and crystallization to produce mother liquor waste liquid, collect the obtained solid, wash with ethanol to recover ethanol, and dry the product to obtain L-2-aminobutyric acid (purity 98.8%, yield 95.1%, chiral ee value 99.6%).

[0030] 2、Catalytic hydrogenation reaction Take the needle coke, activated carbon mixed and ground according to the mass ratio of 2:1, add to 20% sodium hydroxide solution, heated to 90℃ stirring 2 h for activation treatment, washing and drying as catalyst carrier; Ru powder, potassium hydroxide, potassium nitrate mixed (mass ratio 1.2:7:1.8), heated to 850℃ melt 3 h, after cooling add 10 times the mass of water, heated to 70℃ stirring 2 h to get leaching solution. To 100 parts of leaching solution, add 35 parts of catalyst carrier, then heated to 50℃ drop 100 parts of hydrazine hydrate for reduction, finally reflux filtration, water washing and drying to get Ru / C catalyst. Take 10 parts of palladium chloride dissolved in an appropriate amount of anhydrous ethanol as precursor solution, add 150 parts of carbon black to it and stir ultrasonically to get a suspension, evaporate ethanol, dry and take out the powder, grind and then transfer into a tube furnace, heated to 300℃ at 10℃ / min in H2 / N2 mixed atmosphere (H2 accounts for 5%), cool down and then reheat to 520℃ at 10℃ / min for reduction, get Pd / C catalyst. The prepared Ru / C catalyst and Pd / C catalyst are mixed according to the mass ratio of 6:1 to form a composite catalyst.

[0031] Take 1700 parts of pure water, 200 parts of concentrated sulfuric acid, 375 parts of L-2-aminobutyric acid prepared above, and 1 part of activated carbon by weight. Add pure water to the glass-lined batch kettle, slowly drop in concentrated sulfuric acid, then add L-2-aminobutyric acid and activated carbon, stir for 1 h, filter with airtight bag filter, transfer the filtrate to a hydrogenation reaction kettle which has been deaerated with nitrogen, add 10 parts of composite catalyst and stir evenly. Continuously introduce hydrogen into the hydrogenation reaction kettle, and slowly heat to 76℃ using steam, stop introducing hydrogen when the pressure in the kettle rises to 6.4 MPa. When the pressure in the kettle no longer decreases within 1 h, it indicates that the reaction is complete (46 h), open the circulating cooling water to cool to 25℃, after discharging the waste gas, vacuum filter the reaction liquid, filter out the composite catalyst (the composite catalyst is put into a catalyst treatment kettle, treated with sodium hydroxide solution and sulfuric acid, washed to neutral, and then dried by filtration, which can be recycled), continue to remove 1000 parts of water under reduced pressure, add flake alkali to adjust the pH to 12, add 1500 parts of methanol and stir for 1 h, filter to obtain the feed liquid.

[0032] Transfer the feed liquid to a methanol distillation kettle, control the kettle temperature at 65℃ by atmospheric steam heating, condense and reflux, distill to remove methanol and 90% water. Transfer the remaining liquid in the kettle to a product rectification kettle, control the kettle temperature at 60℃, reflux for 45 min, control the flow rate at 250 L / h, the kettle pressure at 0.015 MPa, heat to 90℃, and perform full reflux for 3 h, when the water content is less than 1%, distill under reduced pressure and heat to 105℃ to obtain L-2-aminobutanol product (purity 97.9%, yield 92.4%, chiral ee value 99.8%).

[0033] 3、Micro-channel reactor splicing reaction Weigh 24.3 parts of the L-2-aminobutanol prepared above, 2.7 parts of anhydrous ethanol, and 5.4 parts of 1,2-dichloroethane by weight. Mix the L-2-aminobutanol and anhydrous ethanol to form material one, and 1,2-dichloroethane to form material two. Feed material one and material two at a rate of 150 g / s and 30 g / s, respectively, into a microchannel reactor (maximum throughput 500 T / year) for 180 seconds. The microchannel reactor is pressurized to 1 MPa and the reaction temperature is 130°C. After 2.6 hours of continuous reaction, the reaction liquid is collected and transferred to a concentrator. 45 parts of aqueous ammonia is added (slowly and evenly over 2.5 hours). The reaction mixture is then concentrated under reduced pressure (below 95°C) to recover ethanol, and then concentrated under reduced pressure (below 150°C) to recover L-2-aminobutanol. The concentrated solution is cooled to 60°C, 420 parts of ethanol is added, and the mixture is stirred and filtered. The mother liquor was transferred to a salt-forming kettle, cooled to 0°C, and 225 parts of hydrochloric acid-ethanol solution was added dropwise. After stirring for 2.5 hours, the solid was collected by centrifugation, placed in a beating kettle, and beated with anhydrous ethanol for 4 hours, then centrifuged and dried to obtain the product ethambutol dihydrochloride (purity 99.5%, yield 98.4%, chiral ee value 99.8%).

[0034] Example 3 A production process of ethambutol hydrochloride, comprising: 1. Enzymatic synthesis of L-2-aminobutyric acid Weigh 620 parts L-threonine, 380 parts isopropanol, 2200 parts pure water, 18 parts threonine deaminase, 28 parts leucine dehydrogenase, 68 parts alcohol dehydrogenase, 0.5 parts NAD, and an appropriate amount of 10% sodium hydroxide solution. First, add pure water, NAD, and 3 / 4 of the L-threonine to an enzyme reactor. Adjust the pH of the system to 8.8 and maintain the temperature at 35°C with 10% sodium hydroxide solution. Then, add threonine deaminase (slowly and evenly added over 10 hours) and stir to initiate the reaction. After 5 hours of reaction, add leucine dehydrogenase (slowly and evenly added over 3 hours). After 8 hours of reaction, add isopropanol, alcohol dehydrogenase, and the remaining L-threonine (slowly and evenly added over 12 hours). Stir continuously and monitor the reaction completion by HPLC (32 hours).

[0035] After the reaction, the reaction solution was heated to 75°C, and then 2 parts of activated carbon and 30 parts of diatomaceous earth were added. After keeping warm for 1 hour, the reaction solution was filtered on a plate and frame to obtain solid waste such as enzyme residue; the filtrate was collected and transferred to a distillation kettle, and vacuum distillation was carried out at an external temperature of 75°C. The aqueous solution was evaporated to about 1 / 4, generating wastewater. The temperature was lowered for crystallization, and the solid and the mother liquor were obtained by centrifugation. The mother liquor was transferred to a mother liquor treatment kettle for repeated distillation and crystallization to generate mother liquor waste. The obtained solids were combined and collected, washed with ethanol, ethanol was recovered, and the product was dried to obtain L-2-aminobutyric acid (purity 99.3%, yield 96.0%, chiral ee value 98.9%).

[0036] 2. Catalytic hydrogenation reaction Take needle coke, activated carbon mixed and ground according to the mass ratio of 2:1, add to 20% sodium hydroxide solution, heated to 90℃ stirring for 2 h for activation treatment, washing and drying as catalyst carrier; Ru powder, potassium hydroxide, potassium nitrate mixed (mass ratio 1.2:7:1.8), heated to 850℃ melt 3 h, after cooling add 10 times the mass of water, heated to 70℃ stirring for 2 h to get leaching solution. To 100 parts of leaching solution, add 20 parts of catalyst carrier, then heated to 50℃ drop 100 parts of hydrazine hydrate for reduction, finally reflux filtration, water washing and drying to get Ru / C catalyst. Take 10 parts of palladium chloride dissolved in an appropriate amount of anhydrous ethanol as precursor solution, add 180 parts of carbon black to it and stir ultrasonically to get a suspension, evaporate ethanol, dry and take out the powder, grind and then transfer into a tube furnace, heated to 300℃ at 10℃ / min in H2 / N2 mixed atmosphere (H2 accounts for 5%), cool down and then reheat to 520℃ at 10℃ / min for reduction, get Pd / C catalyst. The prepared Ru / C catalyst and Pd / C catalyst are mixed according to the mass ratio of 10:1 to form a composite catalyst.

[0037] Take 1700 parts of pure water, 200 parts of concentrated sulfuric acid, 375 parts of L-2-aminobutyric acid prepared above, and 1 part of activated carbon according to the weight fraction. Add pure water into the glass lining batching kettle, slowly drop in concentrated sulfuric acid, then add L-2-aminobutyric acid and activated carbon, stir for 1 h, filter with airtight bag filter, transfer the filtrate into a hydrogenation reaction kettle which has been deaerated with nitrogen in advance, add 10 parts of composite catalyst and stir evenly. Continuously introduce hydrogen into the hydrogenation reaction kettle, and slowly heat to 76℃ with steam, stop introducing hydrogen when the pressure in the kettle rises to 6.4 MPa. When the pressure in the kettle no longer decreases within 1 h, it indicates that the reaction is completed (47 h), open the circulating cooling water to cool down to 25℃, discharge the waste gas, then vacuum filter the reaction liquid, filter out the composite catalyst (the composite catalyst is put into a catalyst treatment kettle, treated with sodium hydroxide solution and sulfuric acid, washed until neutral, then filtered and dried, which can be recycled), continue to remove 1000 parts of water under reduced pressure, add flake caustic soda to adjust the pH to 12, add 1500 parts of methanol and stir for 1 h, then filter to obtain a feed liquid.

[0038] Transfer the feed liquid into a methanol distillation kettle, control the kettle temperature at 65℃ by atmospheric steam heating, condense and reflux, distill to remove methanol and 90% water. Transfer the remaining liquid in the kettle into a product rectification kettle, control the kettle temperature at 60℃, reflux for 45 min, control the flow rate at 250 L / h, the kettle pressure at 0.015 MPa, heat to 90℃, carry out full reflux for 3 h, when the water content is less than 1%, heat to 105℃ under reduced pressure to distill, obtain L-2-aminobutanol product (purity 98.7%, yield 93.8%, chiral ee value 99.9%).

[0039] 3. Microchannel reactor splicing reaction Weigh 24.3 parts of the L-2-aminobutanol prepared above, 2.7 parts of anhydrous ethanol, and 5.4 parts of 1,2-dichloroethane by weight. Mix the L-2-aminobutanol and anhydrous ethanol to form material one, and 1,2-dichloroethane to form material two. Feed material one and material two at a rate of 150 g / s and 30 g / s, respectively, into a microchannel reactor (maximum throughput 500 T / year) for 180 seconds. The microchannel reactor is pressurized to 1 MPa and the reaction temperature is 130°C. After 2.6 hours of continuous reaction, the reaction liquid is collected and transferred to a concentrator. 45 parts of aqueous ammonia is added (slowly and evenly over 2.5 hours). The reaction mixture is then concentrated under reduced pressure (below 95°C) to recover ethanol, and then concentrated under reduced pressure (below 150°C) to recover L-2-aminobutanol. The concentrated solution is cooled to 60°C, 420 parts of ethanol is added, and the mixture is stirred and filtered. The mother liquor was transferred to a salt-forming kettle, cooled to 0°C, and 225 parts of hydrochloric acid-ethanol solution was added dropwise. After stirring for 2.5 hours, the solid was collected by centrifugation, placed in a pulping kettle, and pulped with anhydrous ethanol for 4 hours, then centrifuged and dried to obtain the product ethambutol dihydrochloride (purity 99.6%, yield 96.1%, chiral ee value 99.9%).

[0040] Comparative Example 1 The process parameters were similar to those in Example 1, except that in step 1, during the enzymatic synthesis of L-2-aminobutyric acid, the pH of the system was adjusted to 8.8 and the temperature was maintained at 35°C using 10% sodium hydroxide solution. Threonine deaminase, leucine dehydrogenase, isopropanol, alcohol dehydrogenase, and the remaining L-threonine were then added to the system in a single step. The reaction was terminated after 32 hours. The resulting L-2-aminobutyric acid had a purity of 91.6%, a yield of 87.5%, and a chiral ee of 98.9%.

[0041] Comparative Example 2 The step parameters were similar to those in Example 1, except that only ruthenium-on-carbon catalyst was used as the subsequent catalyst during the catalytic hydrogenation reaction in Step 2. The resulting L-2-aminobutanol product had a purity of 93.5%, a yield of 90.2%, and a chiral ee value of 99.4%.

[0042] Comparative Example 3 The step parameters were similar to those in Example 1, except that only palladium-carbon catalyst was used as the subsequent catalyst during the catalytic hydrogenation reaction in Step 2. The resulting L-2-aminobutanol product had a purity of 96.1%, a yield of 91.8%, and a chiral ee value of 99.6%.

[0043] In summary, it can be seen that the ethambutol dihydrochloride products prepared in Examples 1-3 of the present invention have high chemical purity and chiral purity, both of which can reach more than 99.5%; compared with Comparative Example 1, it can be seen that the present invention effectively improves the efficiency by precisely controlling the addition amount and speed of each enzyme, and the synchronous catalysis of the multi-enzyme system, thereby avoiding the inhibition of the enzyme catalytic activity by intermediates and significantly prolonging the reaction time; compared with Comparative Examples 2 and 3, it can be seen that the composite catalyst of the present invention effectively reduces the reaction conditions of hydrogenation reduction, and at the same time, isomerization rarely occurs, the chirality is well controlled, and it is suitable for industrial production.

[0044] The embodiments described above merely represent several preferred embodiments of the present invention. While the descriptions are relatively specific and detailed, they are not intended to limit the present invention. It should be noted that those skilled in the art will readily appreciate that the present invention is susceptible to various variations and modifications. Any modifications, equivalent substitutions, or improvements within the scope of the present invention are intended to be included within the scope of protection of the present invention.

Claims

1. A process for producing ethambutol hydrochloride, characterized in that, The steps include: Step 1: Using L-threonine as a raw material, NAD, threonine deaminase, leucine dehydrogenase, and alcohol dehydrogenase are added step by step in sequence for enzyme fermentation to produce L-2-aminobutyric acid for later use; Step 2: adding a composite catalyst to the L-2-aminobutyric acid obtained in step 1, and reducing the mixture by hydrogenation to obtain L-2-aminobutanol for later use; Step 3: reacting the L-2-aminobutanol obtained in step 2 with 1,2-dichloroethane, and finally purifying the mixture with hydrochloric acid to obtain ethambutol dihydrochloride.

2. The process for producing ethambutol hydrochloride according to claim 1, wherein In step 1, a specific portion of L-threonine, pure water, and NAD are added step by step to construct a reaction system. Subsequently, threonine deaminase is slowly added to catalyze L-threonine to generate 2-ketobutyrate. After the reaction for 4-6 hours, leucine dehydrogenase is slowly added to catalyze 2-ketobutyrate to generate L-2-aminobutyrate. After the addition of leucine dehydrogenase, isopropanol, alcohol dehydrogenase, and the remaining L-threonine are added to maintain the coenzyme cycle.

3. The process for producing ethambutol hydrochloride according to claim 1, wherein The mass ratio of NAD, threonine deaminase, leucine dehydrogenase and alcohol dehydrogenase is (0.5-1):(18-20):(28-32):(64-68), and the total amount added is 15%-20% of the mass of L-threonine.

4. The process for producing ethambutol hydrochloride according to claim 1, wherein In step 1, the bio-enzyme fermentation adopts a one-pot method, the reaction system temperature is maintained at 35±2°C, the reaction time is 30-36 hours, and the completion of the reaction is monitored by HPLC. The obtained reaction solution is subjected to adsorption filtration and reduced-pressure distillation to remove solid waste and wastewater to obtain L-2-aminobutyric acid.

5. The process for producing ethambutol hydrochloride according to claim 1, wherein The composite catalyst in step 2 is composed of a ruthenium-carbon catalyst and a palladium-carbon catalyst in a mass ratio of (6-10):

1.

6. The process for producing ethambutol hydrochloride according to claim 5, wherein The preparation method of the ruthenium-carbon catalyst comprises the following steps: mixing needle coke and activated carbon, grinding the mixture, adding the mixture to a sodium hydroxide solution for activation treatment, washing and drying the mixture to prepare a catalyst carrier; mixing metallic ruthenium, potassium hydroxide and potassium nitrate and melting the mixture, adding water for leaching, adding the catalyst carrier to the obtained leachate, and reducing the mixture with a reducing agent to obtain the catalyst carrier.

7. The process for producing ethambutol hydrochloride according to claim 5, wherein The preparation method of the palladium-carbon catalyst comprises the following steps: dissolving palladium chloride in anhydrous ethanol as a precursor solution, adding carbon black thereto and ultrasonically stirring the solution to obtain a suspension, volatilizing the ethanol, drying and removing the powder, grinding the powder and transferring the powder into a tube furnace, heating the temperature to 200-400° C. and maintaining the temperature in a H2 / N2 mixed atmosphere, cooling the solution and then heating the temperature again to 400-600° C. for reduction to obtain the catalyst.

8. The process for producing ethambutol hydrochloride according to claim 1, wherein The temperature of the hydrogenation reduction in step 2 is 70-80° C., the pressure is 5.5-7.0 MPa, and the reaction time is 36-48 h.

9. The process for producing ethambutol hydrochloride according to claim 1, wherein In step 3, L-2-aminobutanol and 1,2-dichloroethane are reacted in a microchannel reactor. L-2-aminobutanol and anhydrous ethanol are mixed in a mass ratio of 9:1 as material one, and 1,2-dichloroethane is used as material two. The introduction rate of material one is controlled to be 4-6 times that of material two.

10. The process for producing ethambutol hydrochloride according to claim 1, wherein The maximum flux of the microchannel reactor is 500 T / year, the pressure is 1 MPa, the reaction temperature is 130℃, and the reaction time is 2-3 h.

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