CN103641784B - A kind of bendazac lysine synthesis technology - Google Patents
A kind of bendazac lysine synthesis technology Download PDFInfo
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- CN103641784B CN103641784B CN201310645970.2A CN201310645970A CN103641784B CN 103641784 B CN103641784 B CN 103641784B CN 201310645970 A CN201310645970 A CN 201310645970A CN 103641784 B CN103641784 B CN 103641784B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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Abstract
The present invention provides a kind of bendazac lysine synthesis technology.Bendazac lysine synthesis technology of the present invention is using Bendazac and L lysines as raw material, is dissolved in reaction after being mixed in 95% ethyl alcohol and purified water respectively and obtains bendazac lysine crude product into salt, then recrystallizes to obtain finished product.Bendazac lysine finished product produced by the present invention is white or off-white color crystalline powder, and more than 80% total recovery, content is 99%~101%, impurity A（3 hydroxyl, 1 benzyl Yin rattles away azoles）It does not detect less than 0.05% or, it is always miscellaneous to be less than 0.2%.Salt-forming reaction of the present invention and purification condition are mild, and the reaction time is short, high income, and purity is high, at low cost, are suitble to industrialized production.
Description
Technical field
The present invention relates to a kind of preparation processes of chemicals, and in particular to a kind of bendazac lysine synthesis technology.
Background technology
Today's society cataract is common complaint among the elderly, and frequently-occurring disease is not treated in time easy blinding, in addition to cataract is plucked
In addition to operation, previous medication effect is not obvious.
Bendazac lysine【English name】Bendazac Lysine, chemical name：L-lysine（1- benzyl -1H- Yin rattle away
Azoles -3- oxygroups）Acetate, molecular formula：C6H14N2O2·C16H14N2O3, molecular weight：428.49 structural formula is as follows：
Bendazac lysine is to be researched and developed by Angelini pharmacy group company as anti-cataract medicine, early in
Nineteen eighty-three just lists in Italy.Listing dosage form mainly has two kinds of tablet and eye drops, and Ye Youhen many enterprises of the current country exist
Production and sales.The product are aldose reductase (AR) inhibitor, and document report has inhibiting effect to crystalline lens AR, so with benzyl Dalai
Propylhomoserin (BDZL) eye drops inhibits the activity of AR in eyes, achievees the purpose that prevention or treatment cataract.
Bendazac lysine main ingredient is combined by Bendazac and L-lysine two parts, and wherein Bendazac is a kind of anti-inflammatory
Analgestic so clinical discovery bendazac lysine has certain anti-inflammatory efficacy, can be used as the various skin diseases of clinical treatment.In Chinese patent
The effect that the medicine shows treatment diabetic nephropathy in zoopery is referred in application CN1568976A, in Chinese patent Shen
The medicine please be referred in CN1739502A to be played the role for the treatment of diabete peripheral herve pathology.Since bendazac lysine has such work(
Effect, and have relatively good market prospects, we are necessary to do synthesis technology better improvement, accomplishes at low cost, high income,
It is high-quality, it in addition more will be from the aspect of patient safety and environmental protection.There are many synthetic method of bendazac lysine at present, generally
Four-step reaction.First step synthesis is using phenylhydrazine as starting material, is reacted with benzyl chloride through Benzylation, and α-benzyl phenylhydrazine is made.The
The synthesis of two steps is to react cyclization under the high temperature conditions with α-benzyl phenylhydrazine with urea, and obtained 3- hydroxyl -1- benzyls Yin rattles away azoles.Third
Step synthesis is to rattle away azoles and monoxone by carboxymethylation reaction with 3- hydroxyl -1- benzyls Yin, be made Bendazac, that is, α-[(1- benzyls -
1H- Yin rattle away azoles -3- bases) oxygen] acetic acid.The synthesis of 4th step is that Bendazac carries out salt-forming reaction with L-lysine in tetrahydrofuran,
Then it recrystallizes in ethanol, obtains final product bendazac lysine.
When synthesizing bendazac lysine, finally with Bendazac and L-lysine into salt crude product is made when, unavoidable meeting
3- hydroxyl -1- benzyls Yin is introduced to rattle away azoles this impurity.
09 phase Jilin University's Master's thesis in 2009 is mentioned passing through into salt in 90% tetrahydrofuran tests three batches to this method,
The bendazac lysine fusing point that result of the test is is relatively low, and related substance is higher.
Guangdong chemical industry 2012,10（39）The research of bendazac lysine synthesis technology is reported, by series of experiment research
Although showing that yield increases, the solvent of salt-forming reaction is only made of 95% ethyl alcohol, can make L-lysine molten during the reaction
Xie Du is reduced, it is impossible to be reached complete homogeneous reaction, be needed to be heated to reflux ability dissolved clarification, and 80 DEG C of reaction temperature（Ethyl alcohol boiling point
78.5℃）, reaction is not mild enough, and the reaction time is long, and water-solubility impurity can not be effectively removed, and related substance is higher, content meeting
It reduces, the dissolubility of product is reduced, when heat filtering is easily precipitated, and is unfavorable for producing.
2006,20 are printed during chemical industry（4）A kind of synthetic method of bendazac lysine is reported, is demonstrate,proved by a series of experiment
Bright, the -1- of hydroxyl containing the 3- benzyls Yin of bendazac lysine made from this method rattles away azoles, and impurity content is both greater than 1%, seriously affects production
The quality of product.
Chinese patent CN102206185A reports a kind of process for refining of bendazac lysine and the like, passes through a system
The experiment of row proves, solvent is made using acetonitrile solution in salt-forming reaction, when acetonitrile solubility 90%~95%, impurity 3- hydroxyls
Base -1- benzyls Yin rattles away azoles more than 0.1%, and related substance is higher, is recrystallized by ethanol water, could be by impurity 3- hydroxyls -1-
Benzyl Yin azoles of rattling away accomplishes to be less than 0.1%, it is total it is miscellaneous be less than 0.2%, the dosage of acetonitrile is bigger, and when heat filtering, which is easily precipitated, to be unfavorable for giving birth to
Production, and acetonitrile is larger to the toxicity of people, can be detrimental to health for a long time, and pollution is will also result in environment.
In 2010 editions pharmacopeia, the related substance to bendazac lysine（3- hydroxyl -1- benzyls Yin rattles away azoles and other impurities）Have
Defined, it is therefore necessary to further improve the quality of product, it is ensured that the safety of patient medication.
Invention content
The present invention provides a kind of bendazac lysine synthesis technology, to solve synthesis bendazac lysine salt-forming reaction and refine
Deficiency in journey provides a kind of rational bendazac lysine synthetic method, and impurity 3- hydroxyl -1- benzyls Yin rattles away when preparing crude product
Azoles control, which is arrived, is less than 0.05%, is removed 3- hydroxyl -1- benzyls Yin azoles of rattling away completely by refined, it is total it is miscellaneous be less than 0.2%, content 99%
~101%, to meet production demand, ensure that Social Ecology bad border is not contaminated.
In the present invention primary raw material Bendazac and L-lysine be all by commercially available acquisition, wherein Bendazac by Wuxi not in
Si Te bio tech ltd produces, and the production of object Engineering Co., Ltd is far occurred by Ningbo City for L-lysine, and product all meets
2010 editions States Pharmacopoeia specifications.
The present invention provides a kind of bendazac lysine synthesis technology, is using Bendazac and L-lysine as raw material, dissolves respectively
Reaction obtains bendazac lysine crude product into salt after being mixed in 95% ethyl alcohol and purified water, then recrystallizes to obtain finished product；
The wherein described reaction is into salt, wherein the proportioning Bendazac of each material（kg）：L-lysine（kg）:95% ethyl alcohol
（L）：Water（L）It is 1:0.555:8:1.5（1）First the Bendazac of inventory is added in 95% ethyl alcohol, stirs, is heated to 60 DEG C
~70 DEG C, dissolved clarification；（2）The L-lysine of inventory is added in the purified water of corresponding proportion amount, stirs dissolved clarification, then by step
（2）Acquired solution is added to step（1）In acquired solution, stirring, at 60 DEG C~70 DEG C, insulation reaction 30min, heat filtering,
It is cooled to 20 DEG C~30 DEG C, crystallization 16~for 24 hours, filtering, 95% ethyl alcohol washing obtains bendazac lysine crude product；
The recrystallization is by crude product（kg）：95% ethyl alcohol（L）：Purified water（L）=1：5.4：1.2 proportioning feeds intake, and stirs
It mixes, is heated to 60 DEG C~70 DEG C, dissolved clarification keeps the temperature 30min, heat filtering, is cooled to 20 DEG C~30 DEG C, crystallization 16~for 24 hours, filtering,
95% ethyl alcohol washs, dry finished product.
It is of the present invention using Bendazac and L-lysine as raw material, can also be by such as when bendazac lysine crude product is obtained by the reaction
Lower step carries out, by Bendazac（kg）：L-lysine（kg）:95% ethyl alcohol (v)：Water（v）=1:0.555:8:1.5 proportioning is thrown
Material, stirring, is heated to 60 DEG C~70 DEG C, insulation reaction 30min, heat filtering, is cooled to 20 DEG C~30 DEG C, and crystallization 16~for 24 hours, mistake
Filter, 95% ethyl alcohol washing, obtains bendazac lysine crude product；Then, above-mentioned crude product is placed in 95% ethyl alcohol：Water volume ratio ranging from 3~
8:It in 1 solution, stirring, heating, dissolved clarification, keeps the temperature 30min, heat filtering is cooled to 20 DEG C~30 DEG C, crystallization 16~for 24 hours, mistake
Filter, the washing of 95% ethyl alcohol, dry finished product.
For the present invention mild into salt and subtractive process conditional, the reaction time is short, at low cost, adds in a certain amount of aqueous solvent,
Water-solubility impurity, more conducively synthesis condition milder, industrialized production can be removed.It is raw in my company's high-volume at present
Production.
The present invention completes in two steps from synthetic technology angle, and a step is anti-in the aqueous solution of polar non-solute
Crude product should be made into salt, then by polar non-solute：Water certain proportion is refining to obtain bendazac lysine finished product.
It has carried out a series of opposed polarity aprotic solvent selection in research process of the present invention to test, such as acetone, acetonitrile,
Tetrahydrofuran, methanol etc., in addition, from the proportioning of raw material, reaction temperature, the reaction time, recrystallization temperature, the crystallization time, dry temperature
The parameters such as degree have done extensive research.It is demonstrated experimentally that using polar non-solute into salt and it is refined when, select solvent do not conform to
The improper poor quality that can lead to product of ratio that is suitable or selecting polar non-solute and water, it is relatively low yield occur, melts
The low problem of point.Influence industrial mass production demand.The present invention only selects 95% medicinal alcohol as salt-forming reaction and refines
Solvent.Other solvent（Such as：Tetrahydrofuran, acetone, acetonitrile, methanol etc.）It is how many to have certain toxicity, environment can also be made
Into certain pollution.
Specific embodiment
Embodiment 1：Into the comparison of salt solvent
Experimental condition 1
Charge ratio：Bendazac（kg）: L-lysine（kg）: 90% tetrahydrofuran aqueous solution（L）=1∶0.52∶8
Inventory：Bendazac： 20g
L-lysine： 10.4g
90% tetrahydrofuran aqueous solution： 160ml
Method：90% tetrahydrofuran aqueous solution is added in by the Bendazac of inventory, is added in 60 DEG C, dissolved clarification is added and fed intake
The L-lysine of amount has solid insoluble, dissolved clarification after 5min, insulation reaction 30min, heat filtering, and filtrate is put into 20 DEG C of water and cools down
Crystallization 18h.
Next day filters, and collects white crystalline solid 25.2g, yield：83.0%
Experimental condition 2
Charge ratio：Bendazac（kg）: L-lysine（kg）: 95% acetonitrile solution（L）=1∶0.52∶8
Inventory：Bendazac： 20g
L-lysine： 10.4g
95% acetonitrile solution： 160ml
Method：95% acetonitrile solution is added in by the Bendazac of inventory, is added in 65 DEG C, dissolved clarification adds inventory
L-lysine has solid insoluble, dissolved clarification after 10min, insulation reaction 30min, heat filtering, and filtrate is put into cooling crystallization in 20 DEG C of water
16h。
Next day filters, and collects white crystalline solid 27.8g, yield：91.6%
Experimental condition 3
Charge ratio：Bendazac（kg）: L-lysine（kg）: 90% methanol aqueous solution（L）=1∶0.52∶8
Inventory：Bendazac： 20g
L-lysine： 10.4g
90% methanol aqueous solution： 160ml
Method：90% methanol aqueous solution is added in by the Bendazac of inventory, is added in 60 DEG C, dissolved clarification adds inventory
L-lysine has solid insoluble, dissolved clarification after 2min, insulation reaction 30min, heat filtering, and filtrate is put into cooling crystallization in 20 DEG C of water
17h。
Next day filters, and collects pale yellow crystals solid 25.5g, yield：84.0%
Experimental condition 4
Charge ratio：Bendazac（kg）: L-lysine（kg）: 90% aqueous acetone solution（L）=1∶0.52∶8
Inventory：Bendazac： 20g
L-lysine： 10.4g
90% aqueous acetone solution： 160ml
Method：90% aqueous acetone solution is added in by the Bendazac of inventory, is added in 65 DEG C, dissolved clarification adds inventory
L-lysine has solid insoluble, dissolved clarification after 4min, insulation reaction 30min, heat filtering, and filtrate is put into cooling crystallization in 20 DEG C of water
18h.Next day filters, and collects pale yellow crystals solid 27.1g, yield：89.3%
Relevant experimental data is shown in Table I
Table I
It summarizes：Selection more than solvent is proved into salt by a series of experiment, and fusing point is relatively low, and related substance is higher, experiment 3
Relatively low with 4 contents of experiment, appearance is bad, and experiment 1 and 3 yields of experiment are also relatively low, and major impurity 3- hydroxyl -1- benzyls Yin rattles away azoles
More than 0.2%.
Embodiment 2：Salt-forming condition compares under 95% medicinal alcohol aqueous solution
Experimental condition 1
Charge ratio：Bendazac（kg）: L-lysine（kg）: 95% ethyl alcohol（L）: purified water（L）=1∶0.555∶8∶2
Inventory：
Method：95% ethyl alcohol is added in by the Bendazac of inventory, after being heated to 50 DEG C, 20min minutes, also non-dissolved clarification continues
Heating, when T=58 DEG C, complete dissolved clarification adds in L-lysine, has solid insoluble, adds purified water, complete dissolved clarification, stirring
It after 10min, filters while hot, filtrate is put into cooling crystallization 4h in 10 DEG C of water.
It is filtered after crystallization 4h, collects white crystalline solid 25.0g, yield：82.3%.
Experimental condition 2
Charge ratio：Bendazac（kg）: L-lysine（kg）: 95% ethyl alcohol（L）: purified water（L）=1∶0.555∶8∶2
Inventory：
Method：95% ethyl alcohol is added in by the Bendazac of inventory, is heated to 60 DEG C~70 DEG C, complete dissolved clarification continues to heat,
L-lysine is added in, has solid insoluble, adds purified water, complete dissolved clarification after stirring 10min, filters, filtrate is put into 10 while hot
Cooling crystallization is stayed overnight in DEG C water.
Next day filters, altogether crystallization time 17.5h, collects white crystalline solid 27.7g, yield:91.2%.
Experimental condition 3
Charge ratio：Bendazac（kg）: L-lysine（kg）: 95% ethyl alcohol（L）: purified water（L）=1∶0.555∶8∶1.5
Inventory：
Method：（1）The Bendazac of inventory adds in 95% ethyl alcohol, is heated to 60 DEG C, complete dissolved clarification；
（2）The L-lysine of inventory adds in purified water dissolved clarification, will（2）Acquired solution is added to（1）In reaction system, after
Continuous heating, temperature control after stirring 30min, filter, filtrate is put into cooling crystallization in 20 DEG C of water and stays overnight while hot to 60 DEG C~70 DEG C.
Next day filters, altogether crystallization time 23h, collects white crystalline solid 28.6g, yield：94.2%.
Experimental condition 4
Charge ratio：Bendazac（kg）: L-lysine（kg）: 95% ethyl alcohol（L）: purified water（L）=1∶0.555∶8∶1.5
Inventory：
Method：（1）The Bendazac of inventory adds in 95% ethyl alcohol, is heated to 60 DEG C, complete dissolved clarification；
（2）The L-lysine of inventory adds in purified water dissolved clarification, will（2）Acquired solution is added to（1）In reaction system, after
Continuous heating, temperature control after stirring 30min, filter, filtrate is put into cooling crystallization in 20 DEG C of water while hot to 60 DEG C~70 DEG C.
It is filtered after crystallization 4h, collects white crystalline solid 28.7g, yield：94.7%.
Experimental condition 5
Charge ratio：Bendazac（kg）: L-lysine（kg）: 95% ethyl alcohol（L）: purified water（L）=1∶0.52∶8∶2
Inventory：
Method：（1）The Bendazac of inventory adds in 95% ethyl alcohol, is heated to 60 DEG C, complete dissolved clarification；
（2）The L-lysine of inventory adds in purified water dissolved clarification, will（2）Acquired solution is added to（1）In reaction system, after
Continuous heating, temperature control after stirring 10min, filter, filtrate is put into cooling crystallization in 20 DEG C of water while hot to 60 DEG C~70 DEG C.
It is filtered after crystallization 4h, collects white crystalline solid 23.6g, yield：77.8%.
Experimental condition 6
Charge ratio：Bendazac（kg）: L-lysine（kg）: 95% ethyl alcohol（L）: purified water（L）=1∶0.61∶8∶1.5
Inventory：
Method：（1）The Bendazac of inventory adds in 95% ethyl alcohol, is heated to 60 DEG C~70 DEG C, complete dissolved clarification；
（2）The L-lysine of inventory adds in purified water dissolved clarification, will（2）Acquired solution is added to（1）In reaction system, after
Continuous heating, temperature control after stirring 10min, filter, filtrate is put into cooling crystallization in 20 DEG C of water and stays overnight while hot to 60 DEG C~70 DEG C.
Next day filters, altogether crystallization time 18h, collects white crystalline solid 26.4g, yield：86.9%.
Relevant experimental data is shown in Table II
Table II
Crude product prepares test result analysis discussion
In terms of each lot number result of the test, crystallization time has an impact impurity and yield.Crystallization temperature have to related substance compared with
It is big to influence.Crystallization time is short, and impurity is more, and yield is low.L-lysine ratio reduces, and is affected, says to product fusing point and yield
Bright salt-forming reaction is incomplete.With reference to 6 experimental conditions, importance of the water during salt-forming reaction is also fully demonstrated, is not added with
Enter the water of proper ratio, lead to L-lysine at 60 DEG C~70 DEG C, it can not complete dissolved clarification, it is impossible to reach homogeneous reaction, influence
Product fusing point, influences product quality.
Embodiment 3：Bendazac lysine refines
Experimental condition 1
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:9:2
Inventory：Bendazac lysine crude product（Lot number：130301） 22.8g
95% ethyl alcohol： 205ml
Purified water： 45.6ml
Method：In 500ml there-necked flasks, bendazac lysine crude product, 95% ethyl alcohol, purified water are added in, is heated to 50 DEG C,
After 30min, the incomplete dissolved clarification of system continues to heat, and when T=58 DEG C, complete dissolved clarification keeps the temperature heat filtering after 10min, and filtrate is put
Enter cooling crystallization in 10 DEG C of water, filtered after crystallization 4h, collect white crystalline solid in vacuum degree≤- 0.08mpa, 60 DEG C of dryings
17h obtains dry product 18.9g, yield：82.9%.
Experimental condition 2
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:9:2
Inventory：Bendazac lysine crude product（Lot number：130302） 24.8g
95% ethyl alcohol： 223ml
Purified water： 49.6ml
Method：In 500ml there-necked flasks, bendazac lysine crude product, 95% ethyl alcohol, purified water are added in, is heated to 60 DEG C, it is complete
Full dissolved clarification keeps the temperature heat filtering after 30min, and filtrate is put into cooling crystallization in 10 DEG C of water, is filtered after crystallization 4h, collects white crystals and consolidates
Body obtains dry product 20.5g, yield in vacuum degree≤- 0.08mpa, 80 DEG C of dry 6h：82.7%.
Experimental condition 3
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:9:2
Inventory：Bendazac lysine crude product（Lot number：130303） 24.6g
95% ethyl alcohol： 221ml
Purified water： 49.2ml
Method：In 500ml there-necked flasks, bendazac lysine crude product, 95% ethyl alcohol, purified water are added in, is heated to 60 DEG C~70
DEG C, complete dissolved clarification keeps the temperature heat filtering after 30min, and filtrate is put into cooling crystallization in 10 DEG C of water, and next day filtering crystallizes 18h altogether,
It collects white crystalline solid and obtains dry product 19.5g, yield in vacuum degree≤- 0.08mpa, 60 DEG C of dry 18h：79.3%.
Experimental condition 4
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:9:2
Inventory：Bendazac lysine crude product（Lot number：130304） 22.7g
95% ethyl alcohol： 204ml
Purified water： 45.4ml
Method：In 500ml there-necked flasks, bendazac lysine crude product, 95% ethyl alcohol, purified water are added in, is heated to 70 DEG C, it is complete
Full dissolved clarification keeps the temperature heat filtering after 30min, and filtrate is put into cooling crystallization in 20 DEG C of water, is filtered after crystallization 4h, collects white crystals and consolidates
Body obtains dry product 19.1g, yield in vacuum degree≤- 0.08mpa, 60 DEG C of dry 18h：84.1%.
Experimental condition 5
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:9:2
Inventory：Bendazac lysine crude product（Lot number：130305） 20.9g
95% ethyl alcohol： 188ml
Purified water： 41.8ml
Method：In 500ml there-necked flasks, bendazac lysine crude product, 95% ethyl alcohol, purified water are added in, is heated to 60 DEG C~70
DEG C, complete dissolved clarification keeps the temperature heat filtering after 30min, and filtrate is put into cooling crystallization in 20 DEG C of water, is filtered after crystallization 4h, collects white
Crystalline solid for 24 hours, obtains dry product 17.0g, yield in vacuum degree≤- 0.08mpa, 50 DEG C of dryings：81.3%.
Experimental condition 6
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:9:1.5
Inventory：Bendazac lysine crude product（Lot number：130306） 24.2g
95% ethyl alcohol： 218ml
Purified water： 36.3ml
Method：In 500ml there-necked flasks, bendazac lysine crude product, 95% ethyl alcohol, purified water are added in, is heated to 60 DEG C~70
DEG C, complete dissolved clarification keeps the temperature heat filtering after 30min, and filtrate is put into cooling crystallization in 20 DEG C of water, and next day filtering crystallizes altogether
17h30min collects white crystalline solid and obtains dry product 23.0g, yield in vacuum degree≤- 0.08mpa, 60 DEG C of dry 18h：
95.0%。
Experimental condition 7
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:6.75:1.5
Inventory：Bendazac lysine crude product（Lot number：130301） 10g
95% ethyl alcohol： 67.5ml
Purified water： 15ml
Method：In 250ml there-necked flasks, bendazac lysine, 95% ethyl alcohol, purified water are added in, is dissolved by heating, after 15min, T
=60 DEG C, complete dissolved clarification, heat filtering is put into cooling crystallization in 20 DEG C of water.Next day filters, and crystallizes 19h50min altogether, collects white
Crystalline solid obtains dry product 8.8g, yield in vacuum degree≤- 0.08mpa, 60 DEG C of dry 17h：88.0%.
Experimental condition 8
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:6:1
Inventory：Bendazac lysine crude product（Lot number：130301） 10g
95% ethyl alcohol： 60ml
Purified water： 10ml
Method：In 250ml there-necked flasks, bendazac lysine, 95% ethyl alcohol, purified water are added in, is dissolved by heating, after 20min, T
=63 DEG C, complete dissolved clarification, heat filtering is put into cooling crystallization in 20 DEG C of water.Next day filters, and crystallizes 19h30min altogether, collects white
Crystalline solid obtains dry product 9.0g, yield in vacuum degree≤- 0.08mpa, 60 DEG C of dry 17h：90.0%.
Experimental condition 9
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:5.4:1.2
Inventory：Bendazac lysine crude product（Lot number：130302） 10g
95% ethyl alcohol： 54ml
Purified water： 12ml
Method：In 250ml there-necked flasks, bendazac lysine, 95% ethyl alcohol, purified water are added in, is dissolved by heating, after 20min, T
=65 DEG C, complete dissolved clarification, heat filtering is put into cooling crystallization in 20 DEG C of water.Next day filters, and crystallizes 19h25min altogether, collects white
Crystalline solid obtains dry product 9.2g, yield in vacuum degree≤- 0.08mpa, 60 DEG C of dry 20h：92.0%.
Experimental condition 10
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:4.5:1
Inventory：Bendazac lysine crude product（Lot number：130303） 10g
95% ethyl alcohol： 45ml
Purified water： 10ml
Method：In 250ml there-necked flasks, bendazac lysine, 95% ethyl alcohol, purified water are added in, is dissolved by heating, after 23min, T
=66 DEG C, complete dissolved clarification, heat filtering is put into cooling crystallization in 20 DEG C of water.Next day filters, and crystallizes 19h5min altogether, collects white
Crystalline solid for 24 hours, obtains dry product 9.3g, yield in vacuum degree≤- 0.08mpa, 60 DEG C of dryings：93.0%.
Experimental condition 11
Charge ratio：Bendazac lysine crude product (kg)：95% ethyl alcohol (L)：Purified water (L)=1:6:1.1
Inventory：Bendazac lysine crude product（Lot number：130304） 10g
95% ethyl alcohol： 60ml
Purified water： 11ml
Method：In 250ml there-necked flasks, bendazac lysine, 95% ethyl alcohol, purified water are added in, is dissolved by heating, after 19min, T
=64 DEG C, complete dissolved clarification, heat filtering is put into cooling crystallization in 20 DEG C of water.Next day filters, and crystallizes 18h45min altogether, collects white
Crystalline solid for 24 hours, obtains dry product 9.1g, yield in vacuum degree≤- 0.08mpa, 60 DEG C of dryings：91.0%.Relevant experimental data is shown in Table
Ⅲ
Table III
Refined drying process test result analysis discussion
In terms of each lot number result of the test, the time of crystallization has a significant effect to yield, and crystallization time is long, high income；Water
Ratio has a significant effect to product fusing point, and the ratio of water is low, and fusing point is high.Different material proportions also has an impact product quality,
The ratio of water is low, and the impurity peaks number of product is fewer, and impurity is also smaller, and yield is also more stable, and fusing point is also higher.
By above-mentioned experimental study, enlarged experiment produces three batches.
Embodiment 4：Bendazac lysine crude product（Lot number：20120901）It prepares
（1）In 50L reaction kettles, 95% ethyl alcohol 24L is added in, stirring adds the Bendazac 3.00kg weighed up, is heated to
It 60 DEG C~70 DEG C, makes it completely dissolved；
（2）The L-lysine 1.675kg that will be weighed up, is added in purified water 4.5L, stirring and dissolving；
Again will（2）Acquired solution is added to（1）In reaction system, at 60 DEG C~70 DEG C, insulation reaction 30min, press filtration is dropped
Temperature is to 20 DEG C~30 DEG C, crystallization.
Next day, cocrystallization time 16h, T=25 DEG C, filtering are washed three times with 4L, 3L, 3L95% ethyl alcohol, drained respectively, are done
It is dry, collect white crystalline solid 4.08kg.
Embodiment 5：Bendazac lysine crude product（Lot number：20120902）It prepares
（1）In 50L reaction kettles, 95% ethyl alcohol 24L, stirring are added in, then the Bendazac 3.00kg weighed up is added in, heating
To 60 DEG C~70 DEG C, make it completely dissolved；
（2）The L-lysine 1.675kg that will be weighed up, is added in purified water 4.5L, stirring and dissolving；
Again will（2）Acquired solution is added to（1）In reaction system, at 60 DEG C~70 DEG C, insulation reaction 30min, press filtration is dropped
Temperature is to 20 DEG C~30 DEG C, crystallization.
Next day, cocrystallization time 20h, T=23 DEG C, filtering are washed three times with 4L, 3L, 3L95% ethyl alcohol, drained respectively, are done
It is dry, collect white crystalline solid 4.16kg.
Embodiment 6：Bendazac lysine crude product（Lot number：20120903）It prepares
（1）In 50L reaction kettles, 95% ethyl alcohol 24L, stirring are added in, then the Bendazac 3.00kg weighed up is added in, heating
To 60 DEG C~70 DEG C, make it completely dissolved；
（2）The L-lysine 1.675kg that will be weighed up, is added in purified water 4.5L, stirring and dissolving；
Again will（2）Acquired solution is added to（1）In reaction system, at 60 DEG C~70 DEG C, insulation reaction 30min, press filtration is dropped
Temperature is to 20 DEG C~30 DEG C, crystallization.
Next day, T=21 DEG C, filtering was washed three times with 4L, 3L, 3L95% ethyl alcohol, drained respectively, is done for 24 hours the cocrystallization time
It is dry, collect white crystalline solid 4.21kg.Relevant experimental data is shown in Table IV
Table IV
Embodiment 7：It is prepared by bendazac lysine finished product（Lot number：BL120901）
22.1L95% ethyl alcohol, 4.9L purified waters are added in 50L reaction kettles, stirring adds 4.07kg bendazac lysines
Crude product is heated to 60 DEG C~70 DEG C, keeps the temperature 30min, and press filtration cools to 20 DEG C~30 DEG C, crystallization.
Next day, cocrystallization time 16h, t=21 DEG C, filtering are washed three times with 4L, 3L, 3L95% ethyl alcohol, drained respectively, are received
White collection crystalline solid obtains finished product 3.64kg in vacuum degree≤- 0.08mpa, 60 DEG C of dry 16h
Embodiment 8：It is prepared by bendazac lysine finished product（Lot number：BL120902）
22.5L95% ethyl alcohol, 5.0L purified waters are added in 50L reaction kettles, stirring adds 4.15kg bendazac lysines
Crude product is heated to 60 DEG C~70 DEG C, keeps the temperature 30min, and press filtration cools to 20 DEG C~30 DEG C, crystallization.
Next day, cocrystallization time 20h, t=25 DEG C, filtering are washed three times with 4L, 3L, 3L95% ethyl alcohol, drained respectively, are received
White collection crystalline solid obtains finished product 3.67kg in vacuum degree≤- 0.08mpa, 60 DEG C of dry 20h.
Embodiment 9：It is prepared by bendazac lysine finished product（Lot number：BL120903）
22.5L95% ethyl alcohol, 5.0L purified waters are added in 50L reaction kettles, stirring adds 4.20kg bendazac lysines
Crude product is heated to 60 DEG C~70 DEG C, keeps the temperature 30min, and press filtration cools to 20 DEG C~30 DEG C, crystallization.
Next day, t=23 DEG C, filtering was washed three times with 4L, 3L, 3L95% ethyl alcohol, drained respectively, is received for 24 hours the cocrystallization time
For white collection crystalline solid in vacuum degree≤- 0.08mpa, 60 DEG C of dryings for 24 hours, obtain finished product 3.72kg.Relevant experimental data is shown in Table V.
Table V
Claims (1)
1. a kind of bendazac lysine synthesis technology, it is characterised in that using Bendazac and L-lysine as raw material, be dissolved in respectively
Reaction obtains bendazac lysine crude product into salt after being mixed in 95% ethyl alcohol and purified water, then recrystallizes to obtain finished product；
The wherein described reaction is into salt, wherein the proportioning of each material presses kg：kg：L：L counts Bendazac：L-lysine:95% ethyl alcohol：
Water is 1:0.555:8:1.5, the Bendazac of inventory is first added in 95% ethyl alcohol by (1), and stirring is heated to 60 DEG C~70
DEG C, dissolved clarification；(2) L-lysine of inventory is added in the purified water of corresponding proportion amount, stirs dissolved clarification, then by step (2)
Acquired solution is added in step (1) acquired solution, stirring, at 60 DEG C~70 DEG C, insulation reaction 30min, and heat filtering, cooling
To 20 DEG C~30 DEG C, crystallization 16~for 24 hours, filtering, 95% ethyl alcohol washing obtains bendazac lysine crude product；
The recrystallization is by kg：L：L counts crude product：95% ethyl alcohol：Purified water is 1：5.4：1.2 proportioning feeds intake, stirring,
It is heated to 60 DEG C~70 DEG C, dissolved clarification keeps the temperature 30min, heat filtering, is cooled to 20 DEG C~30 DEG C, crystallization 16~for 24 hours, and filtering, 95%
Ethyl alcohol washs, dry finished product.
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