CN109970543A - The method of acyclovir condensation by-product and recycled solvent - Google Patents
The method of acyclovir condensation by-product and recycled solvent Download PDFInfo
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- CN109970543A CN109970543A CN201910315230.XA CN201910315230A CN109970543A CN 109970543 A CN109970543 A CN 109970543A CN 201910315230 A CN201910315230 A CN 201910315230A CN 109970543 A CN109970543 A CN 109970543A
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- toluene
- layering
- water
- acyclovir
- sodium hydroxide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- 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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- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the recoverying and utilizing method of a kind of acyclovir condensation reaction by-product and solvent, using in the desiccant sodium hydroxide of toluene and acetic anhydride present in recycling next group toluene, the consumption of toluene recovery processing sodium hydroxide is reduced；The mode for taking repeatedly washing layering, thoroughly goes out the sodium acetate and impurity in recycling toluene, guarantees the quality of final recycling toluene, the quality for recycling toluene is made to meet the requirement that technique uses；Washing layering gradation of moisture recycled, reach the concentration for improving sodium acetate in washing layering water, the solvent that gradient recycled water is neutralized as sodium hydroxide alkali cleaning has reached sodium acetate concentration maximization after alkali cleaning, convenient for preparing sodium acetate, be conducive to the reduction of sodium acetate preparation cost；The mother liquor that sodium acetate preparation generates applies the generation for reducing waste water repeatedly；Sour toluene washing layering gradation of moisture recycled eliminates with high salt, high-COD waste water generation.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, and in particular to acyclovir condensation reaction by-product and reaction dissolvent return
Receive the method utilized.
Background technique
Acyclovir is a kind of broad-spectrum antiviral drug, the main production process of industrialized production synthetic reaction are as follows: guanine
Acetylation generates diacetyl guanine, and diacetyl guanine and side chain condensation generate diacetyl acyclovir, diacetyl Ah former times Lip river
Wei alkaline hydrolysis generates acyclovir.Diacetyl guanine and side chain be condensed the process for generating diacetyl acyclovir done using toluene it is molten
Agent, condensation reaction generate diacetyl acyclovir principal product and acetic anhydride by-product, and reaction solution is through cooling, diacetyl acyclovir
Crystallization, is separated by rejection filter, and by-product acetic acid acid anhydride is present in mother liquor, and vacuum distillation condensation obtains the mixing of toluene and acetic anhydride
Solution goes out to fall the acetic anhydride in toluene in industrial production, realizes that toluene recycles, is neutralized using sodium hydroxide, washing,
Sodium hydroxide is dried, and in the N-process of sodium hydroxide, acetic anhydride reacts production sodium acetate with sodium hydroxide.At these
Reason process sodium hydroxide consumption is high, and generates largely containing sodium acetate 2~6%, containing COD60000~150000mg/L, pH value
Waste water between 8~12, by this saliferous, the wastewater treatment qualified discharge containing high COD need to carry out Fenton, neutralization, dilution,
The treatment processes such as biochemistry, processing cost is high, and the sodium acetate solution containing 2~6% is to prepare sodium acetate, because concentration is too low, largely
Steam and electric energy are consumed, processing cost is high.
Summary of the invention
The problem of for acyclovir condensation reaction toluene treatment process, the invention proposes effective solution sides
Case overcomes the above problem existing for current technology.Specifically, the present invention adopts the following technical scheme:
The recoverying and utilizing method of acyclovir condensation reaction by-product and solvent, comprising the following steps:
(1) Alkali liquid compounding: with water as solvent is drunk, the sodium hydroxide solution that mass concentration is 15~20wt% is prepared；
(2) alkali neutralization is layered: acyclovir condensation reaction distills or what vacuum distillation obtained contains byproduct of reaction
The organic solvent toluene of acetic anhydride, referred to as sour toluene, is stirred with the sour toluene that volume ratio is 1:0.1~0.4 with sodium hydroxide solution
Neutralization is mixed, stratification separates lower layer's salt water phase；It is dense that the salt water phase acetic acid or acetic acid aqueous solution that separate adjust pH value, decompression
Contracting, crystallization, rejection filter, obtain sodium acetate trihydrate；The salt water that filtrate separates with next group acid toluene alkali neutralization is mutually merged into row
Sodium acetate preparation；
(3) first wash is layered: drinking for 0.1~0.4 volume is added in the toluene after the layering of step (2) alkali neutralization
Water, agitator treating, layering, recycling layering water are used for the Alkali liquid compounding that next group acid toluene recovery utilizes as solvent；
(4) second wash is layered: the drinking water of 0.1~0.4 volume is added in the toluene of step (3) washing layering,
Agitator treating, layering, the first wash layering water that recycling layering water is utilized as next group acid toluene recovery；
(5) third time washing layering: being added the drinking water of 0.1~0.4 volume in the toluene of step (4) washing layering,
Agitator treating, layering, the second wash layering water that recycling layering water is utilized as next group acid toluene recovery；
(6) it is stirred drying with supernatant toluene of the sodium hydroxide to step (5), is then allowed to stand sedimentation, gained supernatant
Liquid toluene is used for next group acid toluene recovery as acyclovir condensation reaction solvent recycled, the sodium hydroxide of lower layer's sedimentation
The Alkali liquid compounding utilized.
Preferably, the stirring neutralization reaction time described in step (2) is 15~60 minutes, is neutralized to pH value >=9, pH value
It when < 9, adds sodium hydroxide and is adjusted to pH value >=9, the stratification time is 30~40 minutes, separates lower water.
Preferably, the salt water phase acetic acid or acetic acid aqueous solution that are separated described in step (2) adjust pH value control 7~
Between 8, react 15~60 minutes, be concentrated under reduced pressure 40~80 DEG C of temperature, be concentrated 22~28Be of Baume degrees, 5~30 DEG C of crystallization temperature
Rejection filter obtains sodium acetate trihydrate.
Preferably, the agitator treating time described in step (3)~(5) is 15~30 minutes, and the stratification time is 20
~30 minutes.
It preferably, is 30~40 minutes with sodium hydroxide piece alkali stirring drying time in step (6), the standing sedimentation time is
1~3 hour.
Preferably, the mass ratio of sour toluene and sodium hydroxide is 1:0.03~0.06 in step (6).
The present invention utilizes in the desiccant sodium hydroxide of toluene and recycles acetic anhydride present in next group toluene, reduces first
The consumption of benzene recovery processing sodium hydroxide；The mode for taking repeatedly washing layering, thoroughly go out sodium acetate in recycling toluene with
Impurity guarantees the quality of final recycling toluene, the quality for recycling toluene is made to meet the requirement that technique uses；Washing layering moisture ladder
Recycled is spent, reaches the concentration for improving sodium acetate in washing layering water, gradient recycled water is as in sodium hydroxide alkali cleaning
The solvent of sum has reached sodium acetate concentration maximization after alkali cleaning, convenient for preparing sodium acetate, be conducive to the drop of sodium acetate preparation cost
It is low；The mother liquor that sodium acetate preparation generates applies the generation for reducing waste water repeatedly；Sour toluene washing layering gradation of moisture circulating sleeve
With with high salt, high-COD waste water the generation of elimination.
Compared with prior art, the invention has the following advantages that the present invention is heavy using sodium hydroxide used in dry toluene
Drop object, be re-used in aceticanhydride in sour toluene neutralisation treatment reduce toluene recovery processing in sodium hydroxide consumption, simultaneously
Reduce the generation of " three wastes "；Toluene is washed layering third time ejected wash water by the present invention, and recovery to toluene recovery handles the
Toluene is washed second of ejected wash water of layering by secondary washing stratification step, and recovery washs for the first time to toluene recovery processing
Toluene is washed and is layered first time ejected wash water by stratification step, the alkali neutralization stratification step that recovery to toluene recovery is handled, and
The brine waste that last alkali cleaning layering generates is prepared into sodium acetate trihydrate product by concentration, crystallization rejection filter, eliminates toluene and returns
The waste water received in treatment process generates, and reduces sewage treatment expense, there is significant social benefit and economic benefit.
Detailed description of the invention
Fig. 1 is the process flow chart that acyclovir condensation reaction by-product and reaction dissolvent recycle.
Specific embodiment
The present invention is further described below by embodiment.
Embodiment 1
The sour toluene of a batch before 800L is added in the sodium hydroxide (containing sodium hydroxide 150kg) that bottom portion is deposited in after dry toluene
The recycle-water that first wash separates is configured to 15~20% sodium hydroxide solution, and the condensation of 3000L acyclovir is added
React recovery acid toluene, stirring neutralize 50 minutes, stratification 40 minutes, take subnatant with wide pH value test paper measure pH value be
9.5, separate lower layer salt water phase 840L.
The recycle-water 800L that the sour toluene second wash of a batch separates before being added in upper liquid toluene, agitator treating
30 minutes, stratification 30 minutes, separate lower layer's water phase.The sour toluene third time washing point of a batch before being added in upper liquid toluene
The recycle-water 800L that layer separates, agitator treating 30 minutes, stratification 30 minutes, separates lower layer's water phase.In upper liquid toluene
Drinking water 800L is added, agitator treating 30 minutes, stratification 30 minutes, separates lower layer's water phase.
150kg sodium hydroxide is added in upper liquid toluene, stirring is 40 minutes dry, and standing sedimentation 2 hours, from upper part
Supernatant toluene 2860L out, sample detection toluene level are 99.8%, and moisture content 0.1% meets acyclovir condensation reaction matter
Amount requires.
The 840L salt water phase 12L second acid for adjusting pH value separated is stirred to react 40 minutes, 60~65 DEG C of control subtracts to 7.2
Pressure is concentrated into 26Be, is cooled to 20 DEG C, and rejection filter obtains 408kg sodium acetate trihydrate, collects mother liquor 240L, takes sodium acetate trihydrate sample
Detection, meets GB/T693-1996 quality standard.
Embodiment 2
The sour toluene of a batch before 800L is added in the sodium hydroxide (containing sodium hydroxide 150kg) that bottom portion is deposited in after dry toluene
The recycle-water that first wash separates is configured to 15~20% sodium hydroxide solution, and the condensation of 3000L acyclovir is added
React recovery acid toluene, stirring neutralize 40 minutes, stratification 30 minutes, take subnatant with wide pH value test paper measure pH value be
9.5, separate lower layer salt water phase 860L.
The recycle-water 800L that the sour toluene second wash of a batch separates before being added in upper liquid toluene, agitator treating
20 minutes, stratification 20 minutes, separate lower layer's water phase.The sour toluene third time washing point of a batch before being added in upper liquid toluene
The recycle-water 800L that layer separates, agitator treating 20 minutes, stratification 20 minutes, separates lower layer's water phase.In upper liquid toluene
Drinking water 800L is added, agitator treating 20 minutes, stratification 20 minutes, separates lower layer's water phase.
150kg sodium hydroxide is added in upper liquid toluene, stirring is 30 minutes dry, and standing sedimentation 2 hours, from upper part
Supernatant toluene 2880L out, sample detection toluene level are 99.9%, and moisture content 0.1% meets acyclovir condensation reaction matter
Amount requires.
The 860L salt water phase separated batch prepares acetic acid mother liquid of sodium 240L in addition and is stirred with 14L second acid for adjusting pH value to 7.5
Reaction 30 minutes is mixed, 50~55 DEG C of control is concentrated under reduced pressure into 25Be, is cooled to 20 DEG C, and rejection filter obtains 482kg sodium acetate trihydrate, receives
Collect mother liquor 260L, takes sodium acetate trihydrate sample detection, meet GB/T693-1996 quality standard.
Embodiment 3
The sour toluene of a batch before 800L is added in the sodium hydroxide (containing sodium hydroxide 150kg) that bottom portion is deposited in after dry toluene
The recycle-water that first wash separates is configured to 15~20% sodium hydroxide solution, and the condensation of 3000L acyclovir is added
React recovery acid toluene, stirring neutralize 30 minutes, stratification 30 minutes, take subnatant with wide pH value test paper measure pH value be
10, separate lower layer salt water phase 865L.
The recycle-water 800L that the sour toluene second wash of a batch separates before being added in upper liquid toluene, agitator treating
25 minutes, stratification 25 minutes, separate lower layer's water phase.The sour toluene third time washing point of a batch before being added in upper liquid toluene
The recycle-water 800L that layer separates, agitator treating 25 minutes, stratification 25 minutes, separates lower layer's water phase.In upper liquid toluene
Drinking water 800L is added, agitator treating 25 minutes, stratification 25 minutes, separates lower layer's water phase.
150kg sodium hydroxide is added in upper liquid toluene, stirring is 30 minutes dry, and standing sedimentation 2 hours, from upper part
Supernatant toluene 2880L out, sample detection toluene level are 99.8%, and moisture content 0.1% meets acyclovir condensation reaction matter
Amount requires.
The 865L salt water phase separated batch prepares acetic acid mother liquid of sodium 260L in addition and is stirred with 14L second acid for adjusting pH value to 7.7
Reaction 30 minutes is mixed, 50~55 DEG C of control is concentrated under reduced pressure into 24Be, is cooled to 20 DEG C, and rejection filter obtains 478kg sodium acetate trihydrate, receives
Collect mother liquor 280L, takes sodium acetate trihydrate sample detection, meet GB/T693-1996 quality standard.
The above is merely preferred embodiments of the present invention, practical range not for the purpose of limiting the invention.That is Fan Yiben
Equivalent changes and modifications made by the content of patent application the scope of the patents all should be technology scope of the invention.
Claims (6)
1. the recoverying and utilizing method of acyclovir condensation reaction by-product and solvent, which comprises the following steps:
(1) Alkali liquid compounding: with water as solvent is drunk, the sodium hydroxide solution that mass concentration is 15~20wt% is prepared；
(2) alkali neutralization is layered: acyclovir condensation reaction distills or what vacuum distillation obtained contains byproduct of reaction acetic acid
The organic solvent toluene of acid anhydride, referred to as sour toluene, in sour toluene and the sodium hydroxide solution stirring that volume ratio is 1:0.1~0.4
With stratification separates lower layer's salt water phase；The salt water phase acetic acid or acetic acid aqueous solution separated adjusts pH value, reduced pressure, knot
Brilliant, rejection filter, obtains sodium acetate trihydrate；The salt water that filtrate separates with next group acid toluene alkali neutralization is mutually merged into row sodium acetate
Preparation；
(3) first wash is layered: the drinking water of 0.1~0.4 volume is added in the toluene after the layering of step (2) alkali neutralization,
Agitator treating, layering, recycling layering water are used for the Alkali liquid compounding that next group acid toluene recovery utilizes as solvent；
(4) second wash is layered: the drinking water of 0.1~0.4 volume, stirring being added in the toluene of step (3) washing layering
Washing, layering, the first wash layering water that recycling layering water is utilized as next group acid toluene recovery；
(5) drinking water of 0.1~0.4 volume, stirring third time washing layering: are added in the toluene of step (4) washing layering
Washing, layering, the second wash layering water that recycling layering water is utilized as next group acid toluene recovery；
(6) it is stirred drying with supernatant toluene of the sodium hydroxide to step (5), is then allowed to stand sedimentation, gained supernatant first
Benzene is utilized as acyclovir condensation reaction solvent recycled, the sodium hydroxide of lower layer's sedimentation for next group acid toluene recovery
Alkali liquid compounding.
2. the recoverying and utilizing method of acyclovir condensation reaction by-product and solvent according to claim 1, feature exist
It is 15~60 minutes in, stirring neutralization reaction time described in step (2), is neutralized to pH value >=9, when pH value < 9, adds hydrogen
Sodium oxide molybdena is adjusted to pH value >=9, and the stratification time is 30~40 minutes, separates lower water.
3. the recoverying and utilizing method of acyclovir condensation reaction by-product and solvent according to claim 1, feature exist
In the salt water phase acetic acid or acetic acid aqueous solution separated described in step (2) adjusts pH value and controls between 7~8, reaction 15
~60 minutes, 40~80 DEG C of temperature are concentrated under reduced pressure, 22~28Be of Baume degrees is concentrated, 5~30 DEG C of rejection filters of crystallization temperature obtain three water
Sodium acetate.
4. the recoverying and utilizing method of acyclovir condensation reaction by-product and solvent according to claim 1, feature exist
In the agitator treating time described in step (3)~(5) is 15~30 minutes, and the stratification time is 20~30 minutes.
5. the recoverying and utilizing method of acyclovir condensation reaction by-product and solvent according to claim 1, feature exist
In using sodium hydroxide piece alkali stirring drying time in step (6) is 30~40 minutes, and the standing sedimentation time is 1~3 hour.
6. the recoverying and utilizing method of acyclovir condensation reaction by-product and solvent according to claim 1, feature exist
In the mass ratio of sour toluene and sodium hydroxide is 1:0.03~0.06 in step (6).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110902741A (en) * | 2019-12-04 | 2020-03-24 | 湖北省宏源药业科技股份有限公司 | Method and device for recovering solvent in diacetylacyclovir production |
| CN112300166A (en) * | 2020-10-06 | 2021-02-02 | 湖北益泰药业股份有限公司 | Method for separating acyclovir and sodium acetate from mother liquor |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110902741A (en) * | 2019-12-04 | 2020-03-24 | 湖北省宏源药业科技股份有限公司 | Method and device for recovering solvent in diacetylacyclovir production |
| CN112300166A (en) * | 2020-10-06 | 2021-02-02 | 湖北益泰药业股份有限公司 | Method for separating acyclovir and sodium acetate from mother liquor |
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