CN104529801A - Synthetic method for p-hydroxyphenyl glycine - Google Patents
Synthetic method for p-hydroxyphenyl glycine Download PDFInfo
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Abstract
The invention provides a synthetic method for p-hydroxyphenyl glycine. The synthetic method includes the following steps that firstly, para-hydroxyphenyl glycine and a resolving agent are mixed for a reaction, and double salt formed by the p-hydroxyphenyl glycine and the resolving agent is obtained; secondly, the double salt formed by the p-hydroxyphenyl glycine and the resolving agent is dissolved into water and mixed with alkali liquor, and the p-hydroxyphenyl glycine is obtained through stirring, devitrifying and refining, and the p-hydroxyphenyl glycine is obtained; the resolving agent is divided into de-mandelic acid or de-phenyl ethanesulfonic acid. According to the synthetic method for the p-hydroxyphenyl glycine, the de-mandelic acid or the de-phenyl ethanesulfonic acid serves as the resolving agent, the para-hydroxyphenyl glycine is resolved, and the p-hydroxyphenyl glycine is obtained. According to the synthetic method, the synthetic technology is simple, the sources of the resolving agent are wide, cost is low, and the conversion rate on the p-hydroxyphenyl glycine is high. In addition, mother liquid formed through the synthetic method can be sustainably used after racemization, the waste water generation amount is reduced, and materials and inorganic salt in the waste water are recycled.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of synthetic method of D-HPG.
Background technology
D-HPG is a kind of important medicine intermediate, is mainly used in semi-synthetic beta-lactam antibiotics.D-HPG is alpha-non-natural amino acid, must be obtained by the method for synthetic, its synthetic method is broadly divided into two classes: one is catalyzed by biological enzyme, selectivity synthesis D-HPG, this method selectivity is high, and route is short, but because of biological bacteria cultivation problem, and raw material 4-Hydroxyphenyl hydantoin production process can produce a large amount of phenolic wastewater, make its large-scale industrial production difficulty, second method is that induced crystallization splits synthesis method, as: application number is WO2009/127446, EP0530879A1, EP0450684A1, CN200810054625.0, the patent of CN92402863.6 and CN200610025197.X individually discloses chemosynthesis and the Split Method of DL-HPG, the method first prepares racemic para hydroxybenzene glycine, split through induced crystallization method again and obtain D-HPG, continue to apply mechanically by mother liquor, racemic para hydroxybenzene glycine is 83% to D-HPG transformation efficiency, above-mentioned chemosynthesis Split Method is the method that current domestic industryization production D-HPG generally adopts, but this method for splitting is produced exists a lot of drawback, as step is long, throughput is low, solid materials volume of the circular flow is large, low conversion rate etc., production cost is higher.
Application number is that the Chinese patent of CN102757156A discloses a kind of synthetic method of being synthesized D-HPG by racemic para hydroxybenzene glycine, by the fractionation of integration, racemization obtains D-HPG, racemic para hydroxybenzene glycine is 80% to the per pass conversion of D-HPG, simplify technical process, but adopt the method to produce D-HPG, racemization catalyst salicylic aldehyde is dropped into because of a large amount of in mother liquor, continue to apply mechanically and can produce in a large number because of the foreign pigment of salicylic aldehyde oxidation generation, have a strong impact on quality product, cause product light absorption value high, and its low conversion rate, cost is high.When the method mother liquid recycle is more than five times, namely product light absorption value exceeds qualified index, and mother liquor eliminates amount greatly, produces the waste water in a large number containing inorganic salt and organic impurity.
Summary of the invention
In view of this, the technical problem to be solved in the present invention is the synthetic method providing a kind of D-HPG, the D-HPG transformation efficiency that the present invention obtains is high, and resolving agent unit consumption is low, and superseded mother liquor is processed, racemic para hydroxybenzene glycine wherein, inorganic salt are reclaimed, technique environmental protection.
The invention provides a kind of synthetic method of D-HPG, comprise the following steps:
A) by racemic para hydroxybenzene glycine and resolving agent hybrid reaction, the double salt that D-HPG and resolving agent are formed is obtained;
B) double salt D-HPG and resolving agent formed is soluble in water, then mixes with alkali lye, through stirring and crystallizing with refining, obtains D-HPG;
Described resolving agent is R-melic acid or dextrorotation Phenyl-ethanesulfonic acid.
Preferably, described alkali lye is ammoniacal liquor, aqueous sodium hydroxide solution or potassium hydroxide aqueous solution.
Preferably, the pH value of the mixing solutions obtained after mixing with alkali lye is 4 ~ 8.
Preferably, the mass ratio of the double salt that formed of described D-HPG and resolving agent and water is 1:(1 ~ 5).
Preferably, steps A) in, described hybrid reaction is:
A1) racemic para hydroxybenzene glycine, water and sour Hybrid Heating are dissolved, obtain racemic para hydroxybenzene glycine solution;
A2) in above-mentioned racemic para hydroxybenzene glycine sulphuric acid soln, resolving agent is added, the double salt that reactive crystallization precipitation D-HPG and resolving agent are formed;
A3) the above-mentioned reaction solution containing double salt is separated, washs and dry, obtain the double salt that D-HPG and resolving agent are formed.
Preferably, in described racemic para hydroxybenzene glycine and described acid, hydrionic mol ratio is 1:(1 ~ 1.4).
Preferably, steps A 1) described in acid be sulfuric acid, hydrochloric acid or phosphoric acid.
Preferably, described step B) be:
B1) double salt D-HPG and resolving agent formed is soluble in water, then mixes with alkali lye, through stirring and crystallizing, obtains D-HPG crude product and the solution containing resolving agent;
B2) described D-HPG crude product and water and sour mixed dissolution, after decolouring, filtering, drips alkali lye to iso-electric point in the acid solution of D-HPG, and after filtration, drying obtains D-HPG.
Preferably, described alkali lye is ammoniacal liquor, aqueous sodium hydroxide solution or potassium hydroxide aqueous solution; Described acid is sulfuric acid, hydrochloric acid or phosphoric acid.
Preferably, the described solution circulated containing resolving agent is used for steps A) in react with racemic para hydroxybenzene glycine.
Compared with prior art, the invention provides a kind of synthetic method of D-HPG, comprise the following steps: A) by racemic para hydroxybenzene glycine and resolving agent hybrid reaction, obtain the double salt that D-HPG and resolving agent are formed; B) double salt D-HPG and resolving agent formed is soluble in water, then mixes with alkali lye, through stirring and crystallizing with refining, obtains D-HPG; Described resolving agent is R-melic acid or dextrorotation Phenyl-ethanesulfonic acid.Racemic para hydroxybenzene glycine for resolving agent with R-melic acid or dextrorotation Phenyl-ethanesulfonic acid, splits, obtains D-HPG by the present invention.Synthesis technique of the present invention is simple, and resolving agent used is easy to get, and D-HPG transformation efficiency is high, and resolving agent unit consumption is low.In addition, the mother liquor that synthetic method provided by the invention is formed is through the sustainable time use of racemization, and waste water generation can reduce more than one times compared with the synthetic method of prior art.
Result shows, racemic para hydroxybenzene glycine can reach 95% to D-HPG transformation efficiency, and resolving agent unit consumption can reach within 0.025.D-HPG optically-active can reach more than-158 °, and light absorption value is 0.01 ~ 0.025, and dextrorotation D-pHPG content can reach the level of not detecting.Quality index is obviously better than prior art.
Embodiment
The invention provides a kind of synthetic method of D-HPG, comprise the following steps:
A) by racemic para hydroxybenzene glycine and resolving agent hybrid reaction, the double salt that D-HPG and resolving agent are formed is obtained;
B) double salt D-HPG and resolving agent formed is soluble in water, then mixes with alkali lye, through stirring and crystallizing with refining, obtains D-HPG;
Described resolving agent is R-melic acid or dextrorotation Phenyl-ethanesulfonic acid.
When described resolving agent is R-melic acid, its reaction process is:
When described resolving agent is dextrorotation Phenyl-ethanesulfonic acid, reaction process is:
The present invention, first by racemic para hydroxybenzene glycine and resolving agent hybrid reaction, obtains the double salt that D-HPG and resolving agent are formed.The concrete mode of the present invention to described hybrid reaction does not have particular restriction, preferably as follows, concrete:
A1) racemic para hydroxybenzene glycine, water and sour Hybrid Heating are dissolved, obtain racemic para hydroxybenzene glycine solution;
A2) in above-mentioned racemic para hydroxybenzene glycine sulphuric acid soln, resolving agent is added, the double salt that reactive crystallization precipitation D-HPG and resolving agent are formed;
A3) the above-mentioned reaction solution containing double salt is separated, washs and dry, obtain the double salt that D-HPG and resolving agent are formed.
Racemic para hydroxybenzene glycine is placed in water by the present invention, then adds acid, and heating makes racemic para hydroxybenzene glycine dissolve, and obtains racemic para hydroxybenzene glycine solution.Wherein, the hydrionic mol ratio in described racemic para hydroxybenzene glycine and described acid is 1:(1 ~ 1.4), be preferably 1:(1.1 ~ 1.3).Described acid is preferably mineral acid, is more preferably the vitriol oil, hydrochloric acid or phosphoric acid, most preferably is the vitriol oil, and the concentration of the described vitriol oil is 98wt%.
Resolving agent is added, the double salt that reactive crystallization precipitation D-HPG and resolving agent are formed in above-mentioned racemic para hydroxybenzene glycine solution.Wherein, the feed postition of resolving agent of the present invention is preferably and drips.Described resolving agent is R-melic acid or dextrorotation Phenyl-ethanesulfonic acid, is preferably R-melic acid.The concentration of described resolving agent solution is 10wt% ~ 50wt%, is preferably 25wt% ~ 30wt%.
Be separated by the double salt reaction solution obtained, the method for the present invention to described separation does not have particular restriction, is preferably centrifugal or suction filtration separation.Double salt after centrifugal or suction filtration is carried out wash and dry, obtain the double salt that D-HPG and resolving agent are formed.After described double salt is separated from solution, obtain fractionation mother liquor, described fractionation mother liquor can replace steps A 1 after racemization) in water cycle be used for and racemic para hydroxybenzene glycine, acid heating for dissolving process, described cycle index is 10 ~ 20 times, until inorganic salt in the described mother liquor containing resolving agent saturated after, reclaim the racemic para hydroxybenzene glycine in mother liquor and inorganic salt.The present invention does not have particular restriction to described way of recycling, well known to a person skilled in the art recovery method, preferably, the way of recycling of described racemic para hydroxybenzene glycine is alkali neutralization, is separated, and described inorganic salt way of recycling is concentrated, cooling, crystallization, separation.
The double salt that D-HPG and resolving agent are formed by the present invention is soluble in water, then mixes with alkali lye, through stirring and crystallizing with refining, obtains D-HPG.Concrete:
B1) double salt D-HPG and resolving agent formed is soluble in water, then mixes with alkali lye, through stirring and crystallizing, obtains D-HPG crude product and the mother liquor containing resolving agent;
B2) described D-HPG crude product and water and sour mixed dissolution, after decolouring, filtering, drips alkali lye to iso-electric point in the aqueous sulfuric acid of D-HPG, and after filtration, drying obtains D-HPG.
The double salt that D-HPG and resolving agent are formed by the present invention is soluble in water, obtains the double salt aqueous solution that D-HPG and resolving agent are formed.Wherein, the mass ratio of the double salt that described D-HPG and resolving agent are formed and water is 1:(1 ~ 5), be preferably 1:(2 ~ 4).
The double salt aqueous solution that D-HPG and resolving agent are formed is mixed with alkali lye, through stirring and crystallizing, obtains D-HPG crude product and the solution containing resolving agent.
In the present invention, the hybrid mode that the double salt aqueous solution that described D-HPG and resolving agent are formed mixes with alkali lye is not particularly limited, and is preferably added dropwise in the double salt aqueous solution by alkali lye.The pH value of the mixing solutions obtained after mixing with alkali lye is 4 ~ 8, is more preferably 7.Described alkali lye is preferably inorganic alkali lye, is more preferably ammoniacal liquor, aqueous sodium hydroxide solution or potassium hydroxide aqueous solution, most preferably is ammoniacal liquor.The described solution containing resolving agent is capable of circulation for the hybrid reaction of racemic para hydroxybenzene glycine with resolving agent, the described sustainable recycled of solution containing resolving agent.
D-HPG crude product is refined, in the present invention, preferably refines in the following manner:
D-HPG crude product is placed in water, then adds acid, heating makes D-HPG dissolving crude product, obtains the acid solution of D-HPG crude product.Wherein, described acid can be mineral acid can be also organic acid, and be preferably the vitriol oil, hydrochloric acid, phosphoric acid or tosic acid, be more preferably the vitriol oil, the concentration of the described vitriol oil is 98wt%.
The acid solution of described D-HPG crude product is carried out decoloration process by the present invention, preferred employing activated carbon decolorizing, by activated carbon filtration after decolouring, obtain the acid solution of D-HPG, add alkali lye wherein to iso-electric point, through stirring and crystallizing, filtration, drying obtain D-HPG.Wherein, described alkali lye is preferably inorganic alkali lye, is more preferably ammoniacal liquor, aqueous sodium hydroxide solution or potassium hydroxide aqueous solution.
Racemic para hydroxybenzene glycine for resolving agent with R-melic acid or dextrorotation Phenyl-ethanesulfonic acid, splits, obtains D-HPG by the present invention.Synthesis technique of the present invention is simple, and resolving agent used is easy to get, and D-HPG transformation efficiency is high, and resolving agent unit consumption is low.In addition, the mother liquor that synthetic method provided by the invention is formed is through the sustainable time use of racemization, and waste water generation can reduce more than one times compared with the synthetic method of prior art.
Result shows, racemic para hydroxybenzene glycine can reach 95% to D-HPG transformation efficiency, and resolving agent unit consumption can reach within 0.025.D-HPG optically-active can reach more than-158 °, and light absorption value is 0.01 ~ 0.025, and dextrorotation D-pHPG content can reach the level of not detecting.Quality index is obviously better than prior art.
In order to understand the present invention further, be described below in conjunction with the synthetic method of embodiment to D-HPG provided by the invention, protection scope of the present invention is not limited by the following examples.
Embodiment 1
(1) hydrolysis of D-HPG and refining
Getting the double salt 500g (1.566mol) that D-HPG and resolving agent R-melic acid formed adds in pure water 2500g, slow dropping concentration is 18% ammoniacal liquor, being neutralized to pH value is 4, suction filtration, obtain D-HPG crude product, gained D-HPG crude product drops in 300g pure water, add 98% vitriol oil 78.3g (0.783mol), being heated to 85 DEG C makes it dissolve, add gac 0.5g, insulation 1h, filter, filtrate added drop-wise 18% ammoniacal liquor to pH value is 4, continue to stir 0.5h, suction filtration, drying obtains product 240g, yield 91.7%, product specific rotation-158.3 °, content 99.45%, alkali extinction 0.024, dextrorotation D-pHPG does not detect.Gained solution is the solution containing resolving agent salt, preserves split process and uses.
(2) fractionation of D-HPG and racemization
654.4g (3.915mol) racemic para hydroxybenzene glycine is added in 1000g water, add 98% vitriol oil 274.1g (2.741mol), being heated to 85 DEG C makes it dissolve, the solution containing resolving agent salt obtained in step (1) is dripped in above-mentioned nitration mixture D-pHPG sulphuric acid soln, joining day is 1h, after adding, lower the temperature centrifugal, D-HPG and resolving agent form double salt 463g, specific rotation-9.5 ° of yields 92.6%, gained double salt drops into hydrolyzing process again, the fractionation mother liquor obtained applies mechanically 10 times after racemization, until inorganic salt saturated after, reclaim resolving agent and D-pHPG.
(3) resolving agent unit consumption and salt reclaim
Mother liquor is applied mechanically and is amounted to 10 times after racemization, output D-pHPG 2338g, and resolving agent loss 51.4g, resolving agent unit consumption is 0.022.Racemic para hydroxybenzene glycine 85.6g, ammonium sulfate 780.1g.
Embodiment 2
(1) hydrolysis of D-HPG and refining
Getting the double salt 500g (1.566mol) that D-HPG and resolving agent R-melic acid formed adds in pure water 1500g, slow dropping concentration is 30% sodium hydroxide, being neutralized to pH value is 6, suction filtration, obtain D-HPG crude product, gained D-HPG crude product drops in 300g pure water, add 31% concentrated hydrochloric acid 184.38g (1.566mol), being heated to 85 DEG C makes it dissolve, add gac 0.5g, insulation 1h, filter, filtrate added drop-wise 30% sodium hydroxide to pH value is 6, continue to stir 0.5h, suction filtration, drying obtains product 243g, yield 92.8%, product specific rotation-158.1 °, content 99.52%, alkali extinction 0.020, dextrorotation D-pHPG does not detect.Gained solution is the solution containing resolving agent salt, preserves split process and uses.
(2) fractionation of D-HPG and racemization
654.4g (3.915mol) racemic para hydroxybenzene glycine is added in 1000g water, add 98% concentrated hydrochloric acid 553g (4.698mol), being heated to 85 DEG C makes it dissolve, the solution containing resolving agent salt obtained in step (1) is dripped in above-mentioned nitration mixture D-pHPG sulphuric acid soln, joining day is 1h, after adding, lower the temperature centrifugal, D-HPG and resolving agent form double salt 469g, specific rotation-9.5 ° of yields 93.8%, gained double salt drops into hydrolyzing process again, the fractionation mother liquor obtained is applied mechanically 10-12 time after racemization, until inorganic salt saturated after, reclaim resolving agent and D-pHPG.
(3) resolving agent unit consumption
Mother liquor is applied mechanically and is amounted to 10 times after racemization, output D-pHPG 2425g, and resolving agent loss 50.7g, resolving agent unit consumption is 0.021.Racemic para hydroxybenzene glycine 79.6g, ammonium chloride 630.2g.
Embodiment 3
(1) hydrolysis of D-HPG and refining
Getting the double salt 500g (1.566mol) that D-HPG and resolving agent R-melic acid formed adds in pure water 500g, slow dropping concentration is 30% potassium hydroxide aqueous solution, being neutralized to pH value is 8, suction filtration, obtain D-HPG crude product, gained D-HPG crude product drops in 300g pure water, add 85% phosphoric acid 60.2g (0.522mol), being heated to 85 DEG C makes it dissolve, add gac 0.5g, insulation 1h, filter, filtrate added drop-wise 30% potassium hydroxide aqueous solution to pH value is 8, continue to stir 0.5h, suction filtration, drying obtains product 244g, yield 93.2%, product specific rotation-158.7 °, content 99.55%, alkali extinction 0.018, dextrorotation D-pHPG does not detect.Gained solution is the solution containing resolving agent salt, preserves split process and uses.
(2) fractionation of D-HPG and racemization
654.4g (3.915mol) racemic para hydroxybenzene glycine is added in 1000g water, add 85% phosphatase 11 50.5g (1.305mol), being heated to 85 DEG C makes it dissolve, the solution containing resolving agent salt obtained in step (1) is dripped in above-mentioned nitration mixture D-pHPG sulphuric acid soln, joining day is 1h, after adding, lower the temperature centrifugal, D-HPG and resolving agent form double salt 462g, specific rotation-9.6 ° of yields 92.4%, gained double salt drops into hydrolyzing process again, the fractionation mother liquor obtained is applied mechanically 10-12 time after racemization, until inorganic salt saturated after, reclaim resolving agent and D-pHPG.
(3) resolving agent unit consumption
Mother liquor is applied mechanically and is amounted to 10 times after racemization, output D-pHPG 2419g, and resolving agent loss 52.3g, resolving agent unit consumption is 0.0216.Racemic para hydroxybenzene glycine 81.5g, ammonium phosphate 544.3g.
Embodiment 4
(1) hydrolysis of D-HPG and refining
Getting the double salt 500g (1.415mol) that D-HPG and resolving agent dextrorotation Phenyl-ethanesulfonic acid formed adds in pure water 2500g, slow dropping concentration is 18% ammoniacal liquor, being neutralized to pH value is 4, suction filtration, obtain D-HPG crude product, gained D-HPG crude product drops in 300g pure water, add 98% vitriol oil 70.8g (0.7075mol), being heated to 85 DEG C makes it dissolve, add gac 0.5g, insulation 1h, filter, filtrate added drop-wise 18% ammoniacal liquor to pH value is 4, continue to stir 0.5h, suction filtration, drying obtains product 210.75g, yield 89.1%, product specific rotation-156.6 °, content 99.22%, alkali extinction 0.033, dextrorotation D-pHPG content 0.32%.Gained solution is the solution containing resolving agent salt, preserves split process and uses.
(2) fractionation of D-HPG and racemization
590g (3.53mol) racemic para hydroxybenzene glycine is added in 1000g water, add 98% vitriol oil 247.1g (2.471mol), being heated to 85 DEG C makes it dissolve, the solution containing resolving agent salt obtained in step (1) is dripped in above-mentioned nitration mixture D-pHPG sulphuric acid soln, joining day is 1h, after adding, lower the temperature centrifugal, D-HPG and resolving agent form double salt 447g, specific rotation-76.2 °, yield 89.4%, gained double salt drops into hydrolyzing process again, the fractionation mother liquor obtained applies mechanically 10 times after racemization, until inorganic salt saturated after, reclaim resolving agent and D-pHPG.
(3) resolving agent unit consumption
Mother liquor is applied mechanically and is amounted to 10 times after racemization, output D-pHPG 2122.3g, and resolving agent loss 108.45g, resolving agent unit consumption is 0.0511.Racemic para hydroxybenzene glycine 63.9g, ammonium sulfate 709.2g.
Embodiment 5
(1) hydrolysis of D-HPG and refining
Getting the double salt 500g (1.415mol) that D-HPG and resolving agent dextrorotation Phenyl-ethanesulfonic acid formed adds in pure water 1500g, slow dropping concentration 30% sodium hydroxide, being neutralized to pH value is 6, suction filtration, obtain D-HPG crude product, gained D-HPG crude product drops in 300g pure water, add 31% concentrated hydrochloric acid 166.6g (1.415mol), being heated to 85 DEG C makes it dissolve, add gac 0.5g, insulation 1h, filter, filtrate added drop-wise 30% sodium hydroxide to pH value is 6, continue to stir 0.5h, suction filtration, drying obtains product 208.15g, yield 88.0%, product specific rotation-156.7 °, content 99.19%, alkali extinction 0.034, dextrorotation D-pHPG content 0.30%.Gained solution is the solution containing resolving agent salt, preserves split process and uses.
(2) fractionation of D-HPG and racemization
590g (3.53mol) racemic para hydroxybenzene glycine is added in 1000g water, add 31% concentrated hydrochloric acid 498.75g (4.236mol), being heated to 85 DEG C makes it dissolve, the solution containing resolving agent salt obtained in step (1) is dripped in above-mentioned nitration mixture D-pHPG sulphuric acid soln, joining day is 1h, after adding, lower the temperature centrifugal, D-HPG and resolving agent form double salt 439g, specific rotation-76.4 °, yield 87.8%, gained double salt drops into hydrolyzing process again, the fractionation mother liquor obtained is applied mechanically 10-12 time after racemization, until inorganic salt saturated after, reclaim resolving agent and D-pHPG.
(3) resolving agent unit consumption
Mother liquor is applied mechanically and is amounted to 10 times after racemization, output D-pHPG 2093.1g, and resolving agent loss 105.49g, resolving agent unit consumption is 0.0504.Racemic para hydroxybenzene glycine 63.5g, ammonium chloride 492.2g.
Embodiment 6
(1) hydrolysis of D-HPG and refining
Getting the double salt 500g (1.415mol) that D-HPG and resolving agent dextrorotation Phenyl-ethanesulfonic acid formed adds in pure water 500g, slow dropping concentration is 30% potassium hydroxide, being neutralized to pH value is 8, suction filtration, obtain D-HPG crude product, gained D-HPG crude product drops in 300g pure water, add 85% strong phosphoric acid 54.4g (0.472mol), being heated to 85 DEG C makes it dissolve, add gac 0.5g, insulation 1h, filter, filtrate added drop-wise 18% ammoniacal liquor to pH value is 8, continue to stir 0.5h, suction filtration, drying obtains product 214.53g, yield 90.7%, product specific rotation-156.6 °, content 99.09%, alkali extinction 0.036, dextrorotation D-pHPG content 0.33%.Gained solution is the solution containing resolving agent salt, preserves split process and uses.
(2) fractionation of D-HPG and racemization
590g (3.53mol) racemic para hydroxybenzene glycine is added in 1000g water, add 85% strong phosphoric acid 135.7g (1.177mol), being heated to 85 DEG C makes it dissolve, the solution containing resolving agent salt obtained in step (1) is dripped in above-mentioned nitration mixture D-pHPG sulphuric acid soln, joining day is 1h, after adding, lower the temperature centrifugal, D-HPG and resolving agent form double salt 446g, specific rotation-76.1 °, yield 89.2%, gained double salt drops into hydrolyzing process again, the fractionation mother liquor obtained is applied mechanically 10-12 time after racemization, until inorganic salt saturated after, reclaim resolving agent and D-pHPG.
(3) resolving agent unit consumption
Mother liquor is applied mechanically and is amounted to 10 times after racemization, output D-pHPG 2126.1g, and resolving agent loss 101.63g, resolving agent unit consumption is 0.0478.Racemic para hydroxybenzene glycine 59.2g, ammonium phosphate 382.2g.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a synthetic method for D-HPG, is characterized in that, comprises the following steps:
A) by racemic para hydroxybenzene glycine and resolving agent hybrid reaction, the double salt that D-HPG and resolving agent are formed is obtained;
B) double salt D-HPG and resolving agent formed is soluble in water, then mixes with alkali lye, through stirring and crystallizing with refining, obtains D-HPG;
Described resolving agent is R-melic acid or dextrorotation Phenyl-ethanesulfonic acid.
2. synthetic method according to claim 1, is characterized in that, described alkali lye is ammoniacal liquor, aqueous sodium hydroxide solution or potassium hydroxide aqueous solution.
3. synthetic method according to claim 1, is characterized in that, the pH value of the mixing solutions obtained after mixing with alkali lye is 4 ~ 8.
4. synthetic method according to claim 1, is characterized in that, the mass ratio of the double salt that described D-HPG and resolving agent are formed and water is 1:(1 ~ 5).
5. synthetic method according to claim 1, is characterized in that, steps A) in, described hybrid reaction is:
A1) racemic para hydroxybenzene glycine, water and sour Hybrid Heating are dissolved, obtain racemic para hydroxybenzene glycine solution;
A2) in above-mentioned racemic para hydroxybenzene glycine sulphuric acid soln, resolving agent is added, the double salt that reactive crystallization precipitation D-HPG and resolving agent are formed;
A3) the above-mentioned reaction solution containing double salt is separated, washs and dry, obtain the double salt that D-HPG and resolving agent are formed.
6. synthetic method according to claim 5, is characterized in that, steps A 1) described in acid be sulfuric acid, hydrochloric acid or phosphoric acid.
7. synthetic method according to claim 5, is characterized in that, the hydrionic mol ratio in racemic para hydroxybenzene glycine and described acid is 1:(0.5 ~ 0.7).
8. synthetic method according to claim 1, is characterized in that, described step B) be:
B1) double salt D-HPG and resolving agent formed is soluble in water, then mixes with alkali lye, through stirring and crystallizing, obtains D-HPG crude product and the solution containing resolving agent;
B2) described D-HPG crude product and water and sour mixed dissolution, after decolouring, filtering, drips alkali lye to iso-electric point in the acid solution of D-HPG, and after filtration, drying obtains D-HPG.
9. synthetic method according to claim 8, is characterized in that, described alkali lye is ammoniacal liquor, aqueous sodium hydroxide solution or potassium hydroxide aqueous solution; Described acid is sulfuric acid, hydrochloric acid or phosphoric acid.
10. synthetic method according to claim 8, is characterized in that, the described solution circulated containing resolving agent is used for steps A) in react with racemic para hydroxybenzene glycine.
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| CN104892444A (en) * | 2015-06-16 | 2015-09-09 | 山西星火维敏制药有限公司 | Method for synthesizing D-p-hydroxyphenylglycine methyl ester |
| CN109020823A (en) * | 2018-09-12 | 2018-12-18 | 山西卓联锐科科技有限公司 | A kind of processing method of D-pHPG mother liquor waste water |
| CN113636948A (en) * | 2021-08-20 | 2021-11-12 | 湖北省宏源药业科技股份有限公司 | Treatment method of DL-p-hydroxyphenylglycine asymmetric transformation and resolution waste liquid |
| CN115850127A (en) * | 2022-11-28 | 2023-03-28 | 湖北省宏源药业科技股份有限公司 | Synthesis method of L-p-hydroxyphenylglycine phenyl ethanesulfonate |
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| CN104892444A (en) * | 2015-06-16 | 2015-09-09 | 山西星火维敏制药有限公司 | Method for synthesizing D-p-hydroxyphenylglycine methyl ester |
| CN104892444B (en) * | 2015-06-16 | 2016-05-11 | 山西新宝源制药有限公司 | A kind of method of synthetic D-pHPG methyl esters |
| WO2016202252A1 (en) * | 2015-06-16 | 2016-12-22 | 山西新宝源制药有限公司 | Method for synthesizing d-para-hydroxyphenylglycine methyl ester |
| CN109020823A (en) * | 2018-09-12 | 2018-12-18 | 山西卓联锐科科技有限公司 | A kind of processing method of D-pHPG mother liquor waste water |
| CN113636948A (en) * | 2021-08-20 | 2021-11-12 | 湖北省宏源药业科技股份有限公司 | Treatment method of DL-p-hydroxyphenylglycine asymmetric transformation and resolution waste liquid |
| CN113636948B (en) * | 2021-08-20 | 2024-04-09 | 湖北省宏源药业科技股份有限公司 | DL-p-hydroxyphenylglycine asymmetric conversion resolution waste liquid treatment method |
| CN115850127A (en) * | 2022-11-28 | 2023-03-28 | 湖北省宏源药业科技股份有限公司 | Synthesis method of L-p-hydroxyphenylglycine phenyl ethanesulfonate |
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