CN1491948A - Spliting method for DL-pantoyl internal ester - Google Patents
Spliting method for DL-pantoyl internal ester Download PDFInfo
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- CN1491948A CN1491948A CNA021375895A CN02137589A CN1491948A CN 1491948 A CN1491948 A CN 1491948A CN A021375895 A CNA021375895 A CN A021375895A CN 02137589 A CN02137589 A CN 02137589A CN 1491948 A CN1491948 A CN 1491948A
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- internal ester
- pantoyl internal
- splitting
- resolving agent
- pantoyl
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Abstract
The present invention relates to one splitting method for DL-pantoyl internal ester. Splitting agent of the present invention is organic base R-NH2, where R is C15H15. The splitting process includes the following steps: reacting purified splitting agent with acid, dissolving in water while heating, dropping digest of DL-pantoyl internal ester, with the molar ratio between the splitting agent and DL-pantoyl internal ester being 0.5-0.7; suction filtering the reacted liquid, racemizing the filter cake, recovering the splitting agent; adding organic solvent to the filtrate for azeotropic dewatering, evaporating to eliminate excessive organic solvent and crystallization. The present invention has splitting agent with high selectivity to DL-pantoyl internal ester, high total utilization of DL-pantoyl internal ester, high splitting yield, reusing of the splitting agent and low DL-pantoyl internal ester producing cost.
Description
Technical field
The present invention relates to a kind of method for splitting of intermediate DL-pantoyl internal ester of the D-of production calcium pantothenate.
Background technology
The synthesis technique of D-calcium pantothenate great majority adopt at first synthetic DL-calcium pantothenate at present, split and generate D-calcium pantothenate and L-calcium pantothenate, and the L-calcium pantothenate becomes the DL-calcium pantothenate by the catalysis racemization, split repeatedly and are converted into the D-calcium pantothenate.The shortcoming of this method is that the resolution yield of L-calcium pantothenate is low, and then the effective rate of utilization of L-calcium pantothenate is low, and production cost is higher.Existing improving one's methods is at first the main intermediate DL-pantoyl internal ester of DL-calcium pantothenate to be split with resolving agent; get L-pantoyl internal ester and D-pantoyl internal ester; utilize the acylation reaction chirality of L-pantoyl internal ester and Beta-alanine make the transition the D-calcium pantothenate; the D-pantoyl internal ester splits after the heating racemization more again; reduced the production cost of D-calcium pantothenate; existing resolving agent is mainly organic basess such as dextrorotation interomycetine (a kind of synthesising by-product) and natural product quinine; its shortcoming is that resolving agent generally all can react with D-pantoyl internal ester and L-pantoyl internal ester simultaneously; selectivity when splitting the DL-pantoyl internal ester is low; thereby make the overall utilization of DL-pantoyl internal ester low; used resolving agent is when splitting the DL-pantoyl internal ester; general difficult recycling of large usage quantity that resolving agent is required and resolving agent, thus the production cost that splits the DL-pantoyl internal ester improved.In addition, the L-pantoyl internal ester that is used to purify adopts chloroform extraction mostly, and yield has only 12-14%, thereby the resolution yield of aforesaid method is lower.
Summary of the invention
Technical problem to be solved by this invention is the defective that overcomes above-mentioned prior art, a kind of method for splitting of DL-pantoyl internal ester is provided, the resolution yield height, the resolving agent selectivity is high and can reuse, improve the overall utilization of DL-pantoyl internal ester, reduce the production cost that splits the DL-pantoyl internal ester.
The technical solution adopted in the present invention is: the method for splitting of DL-pantoyl internal ester, used resolving agent are organic bases R-NH
2, wherein R is C
15H
15, the chemical name of resolving agent is that d-1-phenyl ground-to toluene ethamine, structural formula is:
The method for splitting of DL-pantoyl internal ester may further comprise the steps:
A) with resolving agent behind the purifying and acid-respons, resultant adds water, be heated to 80-85 ℃ of dissolving, under agitation drip DL-pantoyl internal ester hydrolyzed solution, resolving agent: the mol ratio=0.5-0.7 of DL-pantoyl internal ester: 1, temperature of reaction is controlled at 45-55 ℃, dropwises the back and continues to stir 0.5-1.5 hour, at room temperature naturally cools to 20-30 ℃ then;
B) reaction solution that obtained by a of vacuum filtration, filter cake carry out racemization, reclaim resolving agent handles, and the filtrate decompression distillation is anhydrated, add organic solvent then and carry out azeotropic dehydration, after residual moisture is sloughed, boil off excessive organic solvent and carry out crystallisation by cooling, filter the L-pantoyl internal ester.
In a step reaction, by dripping while stirring, make the D of DL-pantoyl internal ester, the L body fully contacts resolving agent organic bases R-NH
2, by regulating R-NH
2With the ratio of DL-pantoyl internal ester, make preferential and R-NH
2Salt-forming reaction be the D-pantoyl internal ester, and the L-pantoyl internal ester causes sterically hindered greatly because of forming hydrogen bond, does not participate in and R-NH
2Salt-forming reaction, stay in the filtrate, operations such as the filtration by b step, underpressure distillation, azeotropic dehydration obtain the L-pantoyl internal ester then, the L-pantoyl internal ester utilizes organic solvent to carry out the azeotropic dehydration purification, its total recovery can reach more than 30%, the resolution yield height.The present invention has obviously improved the selectivity of resolving agent to the D-pantoyl internal ester, resolving agent is reacted with the L-pantoyl internal ester hardly, and react with the D-pantoyl internal ester, thereby improved the overall utilization of DL-pantoyl internal ester, the consumption of resolving agent is few and repeat recycling easily, has reduced the production cost that splits the DL-pantoyl internal ester.
The method for splitting of described DL-pantoyl internal ester, resolving agent with acid-respons before purification step as follows:
1. resolving agent is dissolved in the organic solvent, slowly drips glacial acetic acid, dropwise post-heating, react after 0.5-1.5 hour, at room temperature naturally cool to 20-30 ℃, be cooled to 0-10 ℃, filter to 80-85 ℃; 2. filter cake adds organic solvent, is heated to backflow, and backflow 0.5-1.5 hour, slowly drip glacial acetic acid, dropwise post-heating to 80-85 ℃, react after 0.5-1.5 hour, be cooled to 0-10 ℃ and get crystallisate, crystallisate is 80-85 ℃ of oven dry down; 3. crystallisate adds alkali and organic solvent, is heated to 40-50 ℃, stirs 0.5-1.5 hour, and control pH＞11 then with the reaction solution standing demix, are got organic layer and carried out underpressure distillation, get the resolving agent of purifying.After purified, the fractionation efficient of resolving agent is higher.
The method for splitting of described DL-pantoyl internal ester, filtrate described in the b has also been passed through following steps before azeotropic dehydration: the pH that regulates filtrate with alkali is 10-11, uses organic solvent extraction then, standing demix, organic layer carries out resolving agent and reclaims, water layer is with acid for adjusting pH 〉=1 and be heated to 60-65 ℃, and then regulating pH with alkali is 5-6, underpressure distillation, residue after the distillation dissolves with anhydrous methanol, then carry out heat filtering, filter cake discards, and filtrate is carried out Methanol Recovery.These steps are used for the resolving agent that recovery part is dissolved in filtrate, make the utilization ratio of resolving agent higher.
The method for splitting of described DL-pantoyl internal ester, the treatment process of filter cake described in the b is to add alkali and organic solvent in filter cake, be heated to 40-50 ℃, being stirred to filter cake dissolves fully, standing demix then, get resolving agent behind the organic layer reclaim under reduced pressure organic solvent, the water layer of gained heats racemization under the catalysis of acid or alkali, gets the DL-pantoyl internal ester that can reuse.
The method for splitting of described DL-pantoyl internal ester, organic solvent are toluene, ethylbenzene, benzene or dimethylbenzene.
The method for splitting of described DL-pantoyl internal ester, the rate of addition described in a be 4-6 drip/minute, stirring velocity is 400-500 rev/min.
The method for splitting of described DL-pantoyl internal ester, the preparation method of DL-pantoyl internal ester hydrolyzed solution is: the DL-pantoyl internal ester adds alkali, stirs, and is warming up to 75-80 ℃, and hydrolysis time is 0.5-1.5 hour, and the pH control 9-10 of solution uses acid for adjusting pH at 7.5-8 then.
The present invention has obviously improved the selectivity of resolving agent to the D-pantoyl internal ester, make resolving agent hardly with L-pantoyl internal ester reaction, and with the reaction of D-pantoyl internal ester, thereby improved the overall utilization of DL-pantoyl internal ester; The L-pantoyl internal ester utilizes organic solvent to carry out azeotropic dehydration and purifies, and dehydration is complete more, thorough, and its yield can reach more than 42%, the resolution yield height; Reduce the consumption of resolving agent and repeat easily and recycle, reduce the production cost that splits the DL-pantoyl internal ester.
Embodiment
The invention will be further described below in conjunction with embodiment.
Embodiment 1 (resolving agent R-NH
2Purifying)
Accurately take by weighing 285 gram R-NH
2Crude product (technical pure is the commercial goods) joins in 474 milliliters of dry toluenes, adds 64.8 gram glacial acetic acids in 250 milliliters of constant pressure funnels, slowly join in the toluene, dropwise the back and be heated to 80-85 ℃, reacted 0.5 hour, transfer to after finishing in 200 milliliters of large beakers with water-bath, naturally cooling at room temperature, after use ice-water bath instead and be cooled to 0～10 ℃ and carry out crystallization, crystallization finishes, and filters, filtrate is used for next batch applies mechanically, and solid is directly used in the recrystallization that carries out next step.
Above-mentioned solid is put in 1000 milliliters of there-necked flasks, added 423 milliliters of toluene again, warming-in-water, make its dissolving, and keep refluxing 0.5 hour, finishing is transferred in 1000 ml flasks, repeat above-mentioned crystallization processes, crystallisate, 80-85 ℃ of drying is 4 hours in baking oven.
With above-mentioned crystallisate (R-NH
3AcO) add in 500 milliliters of there-necked flasks, add 250 milliliters of 2 mol sodium hydroxide solutions and toluene, heat 40-50 ℃, stirred 30 minutes, the pH value of solution value makes it dissolving greater than 11, and molten finishing transferred in 1000 milliliters of funnels, standing demix, divide and get toluene layer, water layer discarded, toluene layer is transferred to 500 milliliters of underpressure distillation, reclaim under reduced pressure to the greatest extent, the R-NH behind the purifying
2256.6 gram.
Embodiment 2 (preparation of DL-pantoyl internal ester hydrolyzed solution)
70.5 gram DL-pantoyl internal esters are added in 1000 milliliters of four-hole boiling flasks, measure 210 milliliters in 2 mol sodium hydroxide, pour in the flask, the dress thermometer, reflux exchanger under agitation, is warmed up to 75-80 ℃, hydrolysis 0.5 hour in four-hole boiling flask.Finish, survey the pH value and be advisable for 9-10.Be 7.5-8 with 2 mol salt acid for adjusting pH value then.
Embodiment 3 (fractionation of DL-pantoyl internal ester)
With 61.5 gram R-NH
2Resolving agent adds 0.25 milliliter of concentrated hydrochloric acid, stir salify, add 480 ml waters, heating in water bath is to 80-85 ℃, make it dissolving, add the DL-pantoyl internal ester hydrolyzed solution in the foregoing description 2, the control dropping time is no less than 1 hour, and rate of addition is 5 ml/min, stir 450 rev/mins, bath temperature 70-75 ℃, drip and finish, continued stirring reaction 1 hour, be cooled to room temperature, vacuum filtration, filter cake are used to reclaim D-pantoyl internal ester and most resolving agent, and filtrate decompression reclaims moisture, make it volume and be original 1/3, finish the back with 2 mol sodium hydroxide adjusting 10-11, with 200 milliliters of toluene, 250 milliliters of extracting twice, extraction liquid toluene are used for reclaiming a small amount of resolving agent R-NH that is dissolved in filtrate
2, water is regulated pH 〉=1 with concentrated hydrochloric acid, uses heating in water bath at 60-65 ℃ then, kept 30 minutes, and finished with 2 mol sodium hydroxide and regulate pH5-6, reclaim under reduced pressure moisture, to almost anhydrous, residue dissolves with anhydrous methanol, heat filtering, filtrate is reclaimed methyl alcohol and is handled, and the solid salts substances discards, and treats that Methanol Recovery finishes, add 250 milliliters of toluene, heating, dissolve, and slough small amount of residual moisture, to be drained off finishing with the method for azeotropic dehydration, reclaiming toluene to toluene quantity is advisable for the 15-20 milliliter, transfer in the beaker, put into refrigerator and cooled and but filter, the vacuum decompression suction filtration, solid is the L-pantoyl internal ester, totally 30.1 restrain, yield is 42.7%, and specific rotation is-42.9 ℃.
Embodiment 4
According to the preparation method of embodiment 3, the charging capacity of resolving agent is 40 grams, splits to purify to such an extent that L-pantoyl internal ester 37.6 restrains, and yield is 40%, and specific rotation is-42.7 ℃.
Embodiment 5 (treatment process of filter cake among the embodiment 3)
Filter cake is transferred in 1000 milliliters of there-necked flasks, add 250 milliliters of 0.2 mole in 2 mol sodium hydroxide and toluene, be heated to 40-50 ℃ with water-bath, stir 200 rev/mins, reacted 0.5 hour, and treated that solid filter cake dissolved fully, stop to stir, be transferred to 1000 milliliters of separating funnel standing demix, divide and get toluene layer.The toluene layer filtration under diminished pressure reclaims toluene and gets resolving agent R-NH
2, supplying following batch and apply mechanically, filtrate is used for following racemization and handles.
Above-mentioned filtrate is regulated pH value 3-4 with 2 mol hydrochloric acid solns, transfer in 0.5 liter of autoclave and heat, be warmed up to 170-180 ℃, stirring reaction, finishing to its opticity is 0.
Claims (8)
1, the method for splitting of DL-pantoyl internal ester, used resolving agent are organic bases R-NH
2, wherein R is C
15H
15, may further comprise the steps:
A) with resolving agent behind the purifying and acid-respons, resultant adds water, be heated to 80-85 ℃ of dissolving, under agitation drip DL-pantoyl internal ester hydrolyzed solution, resolving agent: the mol ratio=0.5-0.7 of DL-pantoyl internal ester: 1, temperature of reaction is controlled at 45-55 ℃, dropwises the back and continues to stir 0.5-1.5 hour, at room temperature naturally cools to 20-30 ℃ then;
B) reaction solution that obtained by a of vacuum filtration, filter cake carry out racemization, reclaim resolving agent handles, and the filtrate decompression distillation is anhydrated, add organic solvent then and carry out azeotropic dehydration, after residual moisture is sloughed, boil off excessive organic solvent and carry out crystallisation by cooling, filter the L-pantoyl internal ester.
2, the method for splitting of DL-pantoyl internal ester according to claim 1, the chemical name that it is characterized in that described resolving agent be d-1-phenyl-2-to toluene ethamine, its structural formula is:
3, the method for splitting of DL-pantoyl internal ester according to claim 1 and 2, it is characterized in that described resolving agent with acid-respons before purification step as follows: 1. resolving agent is dissolved in the organic solvent, slowly drip glacial acetic acid, dropwise post-heating to 80-85 ℃, reacted 0.5-1.5 hour, be cooled to 0-10 ℃ afterwards, filter; 2. filter cake adds organic solvent, is heated to backflow, and backflow 0.5-1.5 hour, slowly drip glacial acetic acid, dropwise post-heating to 80-85 ℃, reacted 0.5-1.5 hour, be cooled to 0-10 ℃ and get crystallisate, crystallisate is 80-85 ℃ of oven dry down; 3. crystallisate adds alkali and organic solvent, is heated to 40-50 ℃, stirs 0.5-1.5 hour, and control pH＞11 then with the reaction solution standing demix, are got organic layer and carried out underpressure distillation, get the resolving agent of purifying.
4, the method for splitting of DL-pantoyl internal ester according to claim 1, it is characterized in that the filtrate described in the b also passed through following steps before azeotropic dehydration: the pH that regulates filtrate with alkali is 10-11, use organic solvent extraction then, standing demix, organic layer carries out resolving agent and reclaims, water layer is with acid for adjusting pH 〉=1 and be heated to 60-65 ℃, then regulating pH with alkali is 5-6, underpressure distillation, residue after the distillation dissolves with anhydrous methanol, then carry out heat filtering, filter cake discards, and filtrate is carried out Methanol Recovery.
5, the method for splitting of DL-pantoyl internal ester according to claim 1, the concrete treatment process that it is characterized in that filter cake described in the b is: add alkali and organic solvent in filter cake, be heated to 40-50 ℃, being stirred to filter cake dissolves fully, standing demix then, the organic layer filtration under diminished pressure gets resolving agent, and the filtrate of gained is heated racemization under the catalysis of acid or alkali, gets the DL-pantoyl internal ester that can reuse.
6,, it is characterized in that described organic solvent is toluene, ethylbenzene, benzene or dimethylbenzene according to the method for splitting of claim 1,3,4 or 5 described DL-pantoyl internal esters.
7, the method for splitting of DL-pantoyl internal ester according to claim 1 is characterized in that the rate of addition described in a is the 4-6 ml/min, and stirring velocity is 400-500 rev/min.
8, the method for splitting of DL-pantoyl internal ester according to claim 1, the preparation method who it is characterized in that described DL-pantoyl internal ester hydrolyzed solution is: the DL-pantoyl internal ester adds alkali, stir, be warming up to 75-80 ℃, hydrolysis time is 0.5-1.5 hour, the pH control 9-10 of solution uses acid for adjusting pH at 7.5-8 then.
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|---|---|---|---|
| CN 02137589 CN1199961C (en) | 2002-10-23 | 2002-10-23 | Spliting method for DL-pantoyl internal ester |
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|---|---|---|---|
| CN 02137589 CN1199961C (en) | 2002-10-23 | 2002-10-23 | Spliting method for DL-pantoyl internal ester |
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| CN1199961C CN1199961C (en) | 2005-05-04 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229584A (en) * | 2011-04-19 | 2011-11-02 | 吴江 | Method for preparing D-(-)- or L-(+)-pantoic acid lactone by splitting pantoic acid lactone |
| CN107382697A (en) * | 2017-08-22 | 2017-11-24 | 杭州新博思生物医药有限公司 | A kind of method that efficient separating prepares the naphthoic acid of (S) tetrahydrochysene 1 |
| CN107709307A (en) * | 2015-06-19 | 2018-02-16 | 巴斯夫欧洲公司 | The preparation of pantoyl internal ester |
| CN107814708A (en) * | 2017-11-27 | 2018-03-20 | 杭州新博思生物医药有限公司 | A kind of recovery method of resolving agent quinine |
| CN109400556A (en) * | 2018-12-29 | 2019-03-01 | 上海应用技术大学 | A kind of synthetic method of D- (-)-pantoic acid lactone |
| CN111455013A (en) * | 2020-05-14 | 2020-07-28 | 吴江 | Method for auxiliary resolution of pantolactone by weak base salt |
-
2002
- 2002-10-23 CN CN 02137589 patent/CN1199961C/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229584A (en) * | 2011-04-19 | 2011-11-02 | 吴江 | Method for preparing D-(-)- or L-(+)-pantoic acid lactone by splitting pantoic acid lactone |
| CN102229584B (en) * | 2011-04-19 | 2013-03-13 | 吴江 | Method for preparing D-(-)- or L-(+)-pantoic acid lactone by splitting pantoic acid lactone |
| CN107709307A (en) * | 2015-06-19 | 2018-02-16 | 巴斯夫欧洲公司 | The preparation of pantoyl internal ester |
| CN107382697A (en) * | 2017-08-22 | 2017-11-24 | 杭州新博思生物医药有限公司 | A kind of method that efficient separating prepares the naphthoic acid of (S) tetrahydrochysene 1 |
| CN107814708A (en) * | 2017-11-27 | 2018-03-20 | 杭州新博思生物医药有限公司 | A kind of recovery method of resolving agent quinine |
| CN109400556A (en) * | 2018-12-29 | 2019-03-01 | 上海应用技术大学 | A kind of synthetic method of D- (-)-pantoic acid lactone |
| CN111455013A (en) * | 2020-05-14 | 2020-07-28 | 吴江 | Method for auxiliary resolution of pantolactone by weak base salt |
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| Publication number | Publication date |
|---|---|
| CN1199961C (en) | 2005-05-04 |
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