CN109970543B - Method for recycling acyclovir condensation by-product and solvent - Google Patents
Method for recycling acyclovir condensation by-product and solvent Download PDFInfo
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- CN109970543B CN109970543B CN201910315230.XA CN201910315230A CN109970543B CN 109970543 B CN109970543 B CN 109970543B CN 201910315230 A CN201910315230 A CN 201910315230A CN 109970543 B CN109970543 B CN 109970543B
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/083—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid anhydrides
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
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Abstract
The invention discloses a recycling method of acyclovir condensation reaction byproducts and a solvent, which utilizes sodium hydroxide for toluene drying to neutralize and recycle acetic anhydride in the next batch of toluene and reduces the consumption of sodium hydroxide for toluene recycling treatment; the sodium acetate and impurities in the recovered toluene are thoroughly removed by adopting a mode of multiple water washing and layering, so that the quality of the finally recovered toluene is ensured, and the quality of the recovered toluene meets the requirements of process use; the water washing layered water is recycled in a gradient way to improve the concentration of the sodium acetate in the water washing layered water, the gradient recycling sleeve uses water as a solvent for sodium hydroxide alkali washing neutralization, the concentration of the sodium acetate is maximized after alkali washing, the preparation of the sodium acetate is convenient, and the preparation cost of the sodium acetate is reduced; the mother liquor generated by the preparation of sodium acetate is repeatedly used, so that the generation of waste water is reduced; acid toluene washing layering water gradient circulation is applied mechanically to eliminate the generation of high-salt and high-COD wastewater.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a method for recycling acyclovir condensation reaction byproducts and reaction solvents.
Background
Acyclovir is a broad-spectrum antiviral drug, and the main production process of the industrial production and synthesis reaction is as follows: the acetylation of guanine generates diacetyl guanine, the condensation of diacetyl guanine and side chain generates diacetyl acyclovir, and the alkaline hydrolysis of diacetyl acyclovir generates acyclovir. The method comprises the steps of using toluene as a solvent in the process of generating diacetylacyclovir by condensing diacetylguanine and a side chain, generating a diacetylacyclovir main product and an acetic anhydride byproduct by a condensation reaction, cooling reaction liquid, crystallizing the diacetylacyclovir, separating by throwing and filtering, enabling the byproduct acetic anhydride to exist in mother liquor, carrying out reduced pressure distillation and condensation to obtain a mixed solution of toluene and acetic anhydride, carrying out neutralization by sodium hydroxide in industrial production to remove the acetic anhydride in the toluene and realize toluene recycling, washing with water, and drying with sodium hydroxide, wherein the acetic anhydride and the sodium hydroxide react to produce the sodium acetate in the neutralization process of the sodium hydroxide. The sodium hydroxide consumption in the treatment processes is high, a large amount of wastewater containing 2-6% of sodium acetate and 8-12 of COD 60000-150000 mg/L, pH is generated, the wastewater containing salt and high COD needs to be treated and discharged after reaching the standard, the treatment processes of Fenton, neutralization, dilution, biochemistry and the like are required, the treatment cost is high, and the sodium acetate solution containing 2-6% needs to prepare sodium acetate, and the treatment cost is high due to the fact that the concentration is too low, a large amount of steam and electric energy is consumed.
Disclosure of Invention
Aiming at the problems existing in the process of treating the acyclovir condensation reaction by using toluene, the invention provides an effective solution and overcomes the problems existing in the prior art. Specifically, the invention adopts the following technical scheme:
the recycling method of the acyclovir condensation reaction byproduct and the solvent comprises the following steps:
(1) preparing alkali liquor: preparing a sodium hydroxide solution with the mass concentration of 15-20 wt% by using drinking water as a solvent;
(2) alkali neutralization and layering: organic solvent toluene containing reaction byproduct acetic anhydride obtained by distillation or reduced pressure distillation in the acyclovir condensation reaction process, namely acid toluene, is stirred and neutralized by using the acid toluene and sodium hydroxide solution with the volume ratio of 1: 0.1-0.4, and is kept stand for layering, and a lower layer brine phase is separated; regulating the pH value of the separated brine phase by using acetic acid or an acetic acid aqueous solution, carrying out reduced pressure concentration, crystallization and throwing filtration to obtain sodium acetate trihydrate; combining the filtrate with the brine phase separated by the next acid, toluene and alkali neutralization layer to prepare sodium acetate;
(3) first water washing and layering: adding 0.1-0.4 volume of drinking water into the toluene neutralized and layered in the step (2), stirring, washing, layering, and recovering layered water as a solvent for preparing alkali liquor for recycling the next batch of acid toluene;
(4) and (3) second water washing and layering: adding 0.1-0.4 volume of drinking water into the toluene washed and layered in the step (3), stirring, washing and layering, and recovering layered water as first water washing and layering water for recycling the next batch of acid toluene;
(5) and (3) washing and layering for the third time: adding 0.1-0.4 volume of drinking water into the toluene washed and layered in the step (4), stirring, washing, layering, and recovering layered water as secondary washing layered water for recycling the next batch of acid toluene;
(6) and (3) stirring and drying the supernatant toluene obtained in the step (5) by using sodium hydroxide, standing and settling, recycling the obtained supernatant toluene as an acyclovir condensation reaction solvent, and preparing alkali liquor for recycling the next batch of acid toluene by using the lower-layer settled sodium hydroxide.
Preferably, the stirring neutralization reaction time in the step (2) is 15-60 minutes, the neutralization is carried out until the pH value is more than or equal to 9, when the pH value is less than 9, sodium hydroxide is supplemented to adjust the pH value to be more than or equal to 9, the standing and layering time is 30-40 minutes, and the lower-layer water is separated.
Preferably, the pH value of the separated brine phase in the step (2) is adjusted by acetic acid or an acetic acid aqueous solution to Be controlled between 7 and 8, the reaction is carried out for 15 to 60 minutes, the reduced pressure concentration temperature is 40 to 80 ℃, the Baume degree is 22 to 28Be concentrated, and the crystallization temperature is 5 to 30 ℃ for filtration, so as to obtain the sodium acetate trihydrate.
Preferably, the stirring and washing time in the steps (3) to (5) is 15 to 30 minutes, and the standing and layering time is 20 to 30 minutes.
Preferably, sodium hydroxide flake caustic soda is used for stirring and drying in the step (6) for 30-40 minutes, and the standing and settling time is 1-3 hours.
Preferably, the mass ratio of acid toluene to sodium hydroxide in the step (6) is 1: 0.03-0.06.
According to the method, acetic anhydride existing in the next batch of toluene is neutralized and recovered by using the sodium hydroxide for toluene drying, so that the consumption of sodium hydroxide for toluene recovery treatment is reduced; the sodium acetate and impurities in the recovered toluene are thoroughly removed by adopting a mode of multiple water washing and layering, so that the quality of the finally recovered toluene is ensured, and the quality of the recovered toluene meets the requirements of process use; the water washing layered water is recycled in a gradient way to improve the concentration of the sodium acetate in the water washing layered water, the gradient recycling sleeve uses water as a solvent for sodium hydroxide alkali washing neutralization, the concentration of the sodium acetate is maximized after alkali washing, the preparation of the sodium acetate is convenient, and the preparation cost of the sodium acetate is reduced; the mother liquor generated by the preparation of the sodium acetate is repeatedly used, so that the generation of waste water is reduced; acid toluene washing layering water gradient is circularly used to eliminate the generation of high-salt and high-COD wastewater.
Compared with the prior art, the invention has the following advantages: the invention utilizes the sodium hydroxide sediment used for drying the toluene to be repeatedly used for neutralizing acetic anhydride in the acid toluene, thereby reducing the sodium hydroxide consumption in the toluene recovery treatment and reducing the generation of three wastes; according to the invention, the toluene is washed and layered for the third time, the third washing water is recycled and applied to the step of toluene recovery processing for the second washing and layering, the second washing water is recycled and applied to the step of toluene recovery processing for the first washing and layering, the first washing water for toluene washing and layering is recycled and applied to the step of alkali neutralization and layering for toluene recovery processing, and finally, the salt-containing wastewater generated by alkali washing and layering is concentrated, crystallized, spun and filtered to prepare the sodium acetate trihydrate product, so that the generation of wastewater in the toluene recovery processing process is eliminated, the sewage treatment cost is reduced, and the method has remarkable social benefit and economic benefit.
Drawings
Fig. 1 is a process flow diagram for recycling acyclovir condensation reaction by-products and reaction solvents.
Detailed Description
The invention is further described below by way of examples.
Example 1
Adding 800L of recovered water obtained by first washing and layering of a previous batch of acid toluene into sodium hydroxide (containing 150kg of sodium hydroxide) settled at the bottom of a kettle after toluene drying to prepare 15-20% sodium hydroxide solution, adding 3000L of acid toluene obtained by acyclovir condensation reaction, stirring for neutralization for 50 minutes, standing for layering for 40 minutes, taking a lower layer solution, measuring the pH value to be 9.5 by using a wide pH test paper, and separating a lower layer brine phase 840L.
Adding 800L of the recycled water separated by the previous batch of acid toluene for second water washing into the upper layer of the toluene, stirring and washing for 30 minutes, standing and separating for 30 minutes, and separating out the lower layer of the water phase. Adding 800L of recycled water which is obtained by washing and demixing the previous batch of acid toluene for the third time into the upper layer of the toluene, stirring and washing for 30 minutes, standing and demixing for 30 minutes, and separating out a lower layer of water phase. Adding 800L of drinking water into the upper layer of toluene, stirring and washing for 30 minutes, standing and layering for 30 minutes, and separating out the lower layer of water phase.
Adding 150kg of sodium hydroxide into the upper layer of toluene, stirring and drying for 40 minutes, standing and settling for 2 hours, separating 2860L of supernatant toluene from the upper part, and sampling and detecting that the toluene content is 99.8 percent and the water content is 0.1 percent, thereby meeting the quality requirement of acyclovir condensation reaction.
Regulating the pH value of the separated 840L salt water phase to 7.2 by using 12L acetic acid, stirring for reacting for 40 minutes, controlling the temperature to Be 60-65 ℃, decompressing and concentrating to 26Be, cooling to 20 ℃, performing spin filtration to obtain 408kg sodium acetate trihydrate, collecting 240L mother liquor, and taking a sodium acetate trihydrate sample for detection, wherein the detection accords with the GB/T693-1996 quality standard.
Example 2
Adding 800L of recovered water obtained by first washing and layering a previous batch of acid toluene with water into sodium hydroxide (containing 150kg of sodium hydroxide) settled at the bottom of a kettle after toluene is dried to prepare 15-20% sodium hydroxide solution, adding 3000L of acyclovir condensation reaction recovered acid toluene, stirring for neutralizing for 40 minutes, standing for layering for 30 minutes, taking a lower layer solution, measuring the pH value to be 9.5 by using a wide pH test paper, and separating 860L of a lower layer salt solution phase.
Adding 800L of the recycled water separated by the previous batch of acid toluene for second water washing into the upper layer of the toluene, stirring and washing for 20 minutes, standing and separating for 20 minutes, and separating out the lower layer of the water phase. Adding 800L of recycled water which is obtained by washing and demixing the previous batch of acid toluene for the third time into the upper layer of the toluene, stirring and washing for 20 minutes, standing and demixing for 20 minutes, and separating out a lower layer of water phase. Adding 800L of drinking water into the upper layer of toluene, stirring and washing for 20 minutes, standing and layering for 20 minutes, and separating out the lower layer of water phase.
Adding 150kg of sodium hydroxide into the upper layer of toluene, stirring and drying for 30 minutes, standing and settling for 2 hours, separating 2880L of supernatant toluene from the upper part, and sampling and detecting that the toluene content is 99.9 percent and the water content is 0.1 percent, thereby meeting the quality requirement of acyclovir condensation reaction.
Adding 860L of the separated salt water phase into 240L of the sodium acetate mother liquor prepared in the previous batch, adjusting the pH value to 7.5 by using 14L of acetic acid, stirring for reacting for 30 minutes, controlling the temperature to Be 50-55 ℃, carrying out reduced pressure concentration to 25Be, cooling to 20 ℃, carrying out filter throwing to obtain 482kg of sodium acetate trihydrate, collecting 260L of the mother liquor, and taking a sodium acetate trihydrate sample for detection, wherein the sodium acetate sample meets the GB/T693-1996 quality standard.
Example 3
Adding 800L of recycled water obtained by first washing and layering of a previous batch of acid toluene into sodium hydroxide (containing 150kg of sodium hydroxide) which is settled at the bottom of a kettle after toluene is dried to prepare 15-20% sodium hydroxide solution, adding 3000L of acid toluene obtained by acyclovir condensation reaction, stirring for neutralization for 30 minutes, standing for layering for 30 minutes, taking lower-layer liquid, measuring the pH value to be 10 by using a wide pH test paper, and separating a lower-layer brine phase 865L.
Adding 800L of the recycled water separated by the previous batch of acid toluene for second water washing into the upper layer of the toluene, stirring and washing for 25 minutes, standing and separating for 25 minutes, and separating out the lower layer of the water phase. Adding 800L of the recycled water which is obtained by washing and demixing the previous batch of acid toluene for the third time into the upper layer of the toluene, stirring and washing for 25 minutes, standing and demixing for 25 minutes, and separating out the lower layer of the water phase. Adding 800L of drinking water into the upper layer of toluene, stirring and washing for 25 minutes, standing and layering for 25 minutes, and separating out the lower layer of water phase.
Adding 150kg of sodium hydroxide into the upper layer of toluene, stirring and drying for 30 minutes, standing and settling for 2 hours, separating 2880L of supernatant toluene from the upper part, and sampling and detecting that the toluene content is 99.8 percent and the water content is 0.1 percent, thereby meeting the quality requirement of acyclovir condensation reaction.
Adding 260L of sodium acetate mother liquor prepared in the previous batch into the separated 865L of salt water phase, adjusting the pH value to 7.7 by using 14L of acetic acid, stirring and reacting for 30 minutes, controlling the temperature to Be 50-55 ℃, concentrating under reduced pressure to 24Be, cooling to 20 ℃, performing filter spinning to obtain 478kg of sodium acetate trihydrate, collecting 280L of mother liquor, taking a sodium acetate trihydrate sample, and detecting the sodium acetate sample to meet the GB/T693-1996 quality standard.
The above description is only for the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. That is, all equivalent changes and modifications made according to the content of the claims of the present invention should be within the technical scope of the present invention.
Claims (5)
1. The recycling method of the acyclovir condensation reaction byproduct and the solvent is characterized by comprising the following steps of:
(1) preparing alkali liquor: preparing a sodium hydroxide solution with the mass concentration of 15-20 wt% by using drinking water as a solvent;
(2) alkali neutralization and layering: organic solvent toluene containing reaction byproduct acetic anhydride obtained by distillation or reduced pressure distillation in the acyclovir condensation reaction process, namely acid toluene, is stirred with sodium hydroxide solution by the volume ratio of 1: 0.1-0.4, is subjected to neutralization reaction for 15-60 minutes until the pH value is more than or equal to 9, and is kept stand for layering to separate out a lower layer brine phase; adjusting the pH value of the separated brine phase to 7-8 by using acetic acid or an acetic acid aqueous solution, reacting for 15-60 minutes, concentrating under reduced pressure at the temperature of 40-80 ℃, concentrating at the Baume degree of 22-28 Be, and performing filter spinning at the crystallization temperature of 5-30 ℃ to obtain sodium acetate trihydrate; combining the filtrate with the brine phase separated by the next acid, toluene and alkali neutralization layer to prepare sodium acetate;
(3) first water washing and layering: adding 0.1-0.4 volume of drinking water into the toluene neutralized and layered in the step (2), stirring, washing, layering, and recovering layered water as a solvent for preparing alkali liquor for recycling the next batch of acid toluene;
(4) and (3) second water washing and layering: adding 0.1-0.4 volume of drinking water into the toluene washed and layered in the step (3), stirring, washing and layering, and recovering layered water as first water washing and layering water for recycling the next batch of acid toluene;
(5) and (3) water washing and layering for the third time: adding 0.1-0.4 volume of drinking water into the toluene subjected to water washing and layering in the step (4), stirring, washing and layering, and recovering layered water to be used as secondary water washing and layering water for recycling the next batch of acid toluene;
(6) and (3) stirring and drying the supernatant toluene obtained in the step (5) by using sodium hydroxide, standing and settling, recycling the obtained supernatant toluene as an acyclovir condensation reaction solvent, and preparing alkali liquor for recycling the next batch of acid toluene by using the lower-layer settled sodium hydroxide.
2. The method for recycling acyclovir condensation reaction byproducts and the solvent as claimed in claim 1, wherein in the step (2), when the pH value of neutralization is less than 9, sodium hydroxide is added to adjust the pH value to be more than or equal to 9, standing and layering time is 30-40 minutes, and lower water is separated.
3. The method for recycling acyclovir condensation reaction byproducts and the solvent according to claim 1, wherein the stirring and washing time in the steps (3) to (5) is 15 to 30 minutes, and the standing and layering time is 20 to 30 minutes.
4. The method for recycling acyclovir condensation reaction byproducts and the solvent as claimed in claim 1, wherein sodium hydroxide flake caustic soda is used in the step (6) for stirring and drying for 30-40 minutes, and the standing and settling time is 1-3 hours.
5. The method for recycling acyclovir condensation reaction byproducts and the solvent according to claim 1, wherein the mass ratio of the acid toluene to the sodium hydroxide in the step (6) is 1: 0.03-0.06.
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| 阿昔洛韦的合成;赖焜民;《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》;20130115(第01期);第29页 * |
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