CN1552694A - Preparation of D-(-)-1-benzene amino acetic acid - Google Patents
Preparation of D-(-)-1-benzene amino acetic acid Download PDFInfo
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- CN1552694A CN1552694A CNA031289452A CN03128945A CN1552694A CN 1552694 A CN1552694 A CN 1552694A CN A031289452 A CNA031289452 A CN A031289452A CN 03128945 A CN03128945 A CN 03128945A CN 1552694 A CN1552694 A CN 1552694A
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Abstract
A process for preparing D-(-)-1-phenylglycine (levo-phenylglycine) includes such steps as removing levo-phenylglycine from acidic mother liquid containing dextro-phenylglycine by filter, adding arylaldehyde compound, heating to 105-110 deg.C, reflux for 3-5 hr to racemize it and change the dextro-phenylglycine to the rotation-mixed phenyglycine, mixing the resultant liquid with said mother liquid, distilling, concentrating, adding rotation-mixed phenylglycine and dextro-camphosulfonic acid and cyclic optical splitting.
Description
Technical field
The present invention relates to medicine intermediate D-(-)-1-phenylglycine is the preparation method of L-Phenylglycine, particularly relates to a kind of method that the dextrorotation phenylglycine is prepared again L-Phenylglycine through the sweet acid of racemization generation DL benzene through optical resolution.
Background technology
The present invention will prepare the compound that chemical name is D-(-)-1-phenylglycine (L-Phenylglycine), and its chemical structural formula is:
L-Phenylglycine is the important source material of synthetic ammonia penicillin G, cephalexin and left-handed pair of medicine such as hydrogen phenylglycine.It is to carry out chemical optics with synthetic DL phenylglycine to split and make.Technology in the past is to carry out asymmetric fractionation, racemization with Ltartaric acid, but exists the problem that quality product is low, cost is high, the three wastes are many.At U.S. Pat P4,215, a kind of d-camphorsulfonic acid of using is disclosed in 223 as resolving agent, in sulfuric acid medium, split the DL phenylglycine, the by product dextrorotation phenylglycine that racemization produced under alkaline condition again is the DL phenylglycine, the method that optical resolution prepares L-Phenylglycine is carried out in circulation, Chinese patent CN1030573A discloses a kind of preparation method of L-Phenylglycine, it is to make solvent with water, use chloroform, the solid ammonium salt is the synthesising racemation phenylglycine at ambient temperature, split the racemization phenylglycine respectively continuously with dextrorotation and l-camphor sulfonic acid again, obtain L-Phenylglycine.As the racemization agent, is DL phenylglycine with the racemization of by product dextrorotation phenylglycine with highly basic, and a large amount of soda acid, the technological processs of necessary use grown in reaction process, the three wastes are many, cost is high.
Summary of the invention
The purpose of this invention is to provide a kind of quality product height, production cost is low, technological process is short, the three wastes are few is the novel process of DL phenylglycine with the racemization of dextrorotation phenylglycine, proceeds optical resolution then, makes L-Phenylglycine.
The present invention realizes like this, the preparation method of this D-(-)-1-phenylglycine (L-Phenylglycine), comprise under agitation, with the raw material vitriol oil, the DL phenylglycine, d-camphorsulfonic acid adds in the entry, with above-mentioned reaction solution at 105-110 ℃ of heating reflux reaction 30-60 minute, be cooled to 35 ℃, filter the double salt of the horizontal acid of D-(-)-1-phenylglycine and gum camphor, this double salt is dissolved in the hot water, through recrystallization, filter, dry D-(-)-1-phenylglycine that gets, be characterized in: in (1) acid mother liquid that contains the dextrorotation phenylglycine behind elimination double salt, the aromatic aldehyde compound that adds 5-10 weight % is 100% in the weight of the DL phenylglycine that adds; (2) will add mother liquor behind the aromatic aldehyde at 105-110 ℃ of reflux 3-5 hour, carry out the optics racemization, and make the dextrorotation phenylglycine in the mother liquor change the DL phenylglycine into, in 2-3 hour, steam the azeotrope of water-aromatic aldehyde compound then; (3) mother liquor behind this reaction solution and elimination D-(-)-1-phenylglycine is merged, distillation is concentrated into temperature 110-120 ℃, add the DL phenylglycine again to the 105-110% of former add-on with add the d-camphorsulfonic acid of 1.3-1.9 weight %, more than be 100% all in the weight of the DL phenylglycine of former adding; (4) this reaction solution is carried out optical resolution with above-mentioned method for splitting, produce D-(-)-1-phenylglycine.
Described in the present invention in the acid mother liquid that contains the dextrorotation phenylglycine, add aromatic aldehyde and carry out the optics racemization, be repeatedly to circulate to carry out through splitting the method for preparing D-(-)-1-phenylglycine then, cycle index is 5-15 time.
The weight proportion of the raw material that adds among the present invention is: the vitriol oil: DL phenylglycine: d-camphorsulfonic acid: water equals 0.18-0.25: 1: 1.2-1.5: 3.5-4.0.
Aromatic aldehyde compound described in the present invention is to choose any one kind of them from phenyl aldehyde, salicylic aldehyde and phenylacetic aldehyde.
The water that steams described in the present invention-aromatic aldehyde compound azeotrope is after separating, and aromatic aldehyde can be recycled.
The present invention is solvent with the aqueous sulfuric acid, add a small amount of aromatic aldehyde compound by product dextrorotation phenylglycine in the mother liquor is carried out racemization, change the DL phenylglycine into, and then this mother liquor is used for optical resolution prepares L-Phenylglycine, save DL phenylglycine raw material, reduced product cost.Owing to as the racemization agent, therefore shortened production technique without highly basic sodium hydroxide and potassium hydroxide, reduced the pollution of the three wastes.Owing to can carry out racemization, fractured operation repeatedly to dextrorotation phenylglycine in the mother liquor, maximally utilised the by product dextrorotation phenylglycine in the mother liquor, saved raw material, in sum, it is short that the present invention compared with prior art has technological process, advantages such as raw material consumption is few, and product cost is low, and three-waste pollution is few.
Embodiment
Now the present invention is further illustrated in conjunction with the embodiments, but embodiment is not a limiting the scope of the invention.
Embodiment 1
Under agitation successively 5 kilograms of the vitriol oils, 35 kilograms of d-camphorsulfonic acids, DL phenylglycine are joined in 100 kg of water for 26.6 kilograms.Reaction solution is heated to 10 ℃ of reflux temperature 105-1, refluxes after 30 minutes, be cooled to 35 ℃ at 2 hours internal reaction liquid.Filter out L-Phenylglycine and d-camphorsulfonic acid double salt with whizzer.
This double salt is under agitation joined in the water of 5 times of weight, and the gac of adding double salt amount 1% (weight), 90 ℃ were heated 30 minutes, filtered while hot, filtrate neutralizes with the ammoniacal liquor of 20% (weight), separate out the L-Phenylglycine crystallization, get 10.5 kilograms of L-Phenylglycine white crystals after filtration, washing, the drying approximately, yield is 79% (in the L-Phenylglycine in the DL phenylglycine).[α]
20 D=-157.20 (C=1%, 1 mole hydrochlorides).
Embodiment 2
The mother liquor that filters out among the embodiment 1 behind the double salt is added 1.86 kilograms of phenyl aldehydes, reaction solution is heated to 105-110 ℃, backflow 3-5 hour, carry out the optics racemization, make the dextrorotation phenylglycine in the mother liquor change the DL phenylglycine into, at 105-110 ℃, in 2-3 hour, steam the azeotrope of water-phenyl aldehyde then.Mother liquor behind the elimination L-Phenylglycine among reaction solution and the embodiment 1 is merged, PH=0.0 ± 0.4 that adds an amount of vitriol oil conditioned reaction liquid, the reaction solution distillation is concentrated into 110-120 ℃, add 11.5 kilograms of DL phenylglycines and 0.6-0.7 kilogram d-camphorsulfonic acid, with reaction solution at 105-110 ℃ of heating reflux reaction 30-60 minute, in 2 hours, reaction solution is cooled to 35 ℃, filter out the double salt of L-Phenylglycine and d-camphorsulfonic acid with whizzer.Following steps are operated by the method for embodiment 1, get 7.1 kilograms of L-Phenylglycines, and yield is 51.4%.
[α]
20 D=-154.20 (C=1%, 1 mole hydrochlorides).
Embodiment 3
Except the salicylic aldehyde that adds 1.86 kilograms replaced 1.86 kilograms phenyl aldehyde, all the other were all operated by prescription and the method for embodiment 2,10.7 kilograms of L-Phenylglycines, yield is 77.5%, [α]
20 D=-157.20 (C=1%, 1 mole hydrochlorides).
Embodiment 4
Except the phenylacetic aldehyde that adds 1.86 kilograms replaced 1.86 kilograms phenyl aldehyde, base is surplus all to be operated by prescription and the method for embodiment 2,7.5 kilograms of L-Phenylglycines, yield is 54.3%.[α]
20 D=-154.10 (C=1%, 1 mole hydrochlorides).
Embodiment 5
Except the phenyl aldehyde that adds 1.86 kilograms of 1.33 kilograms of salicylic aldehydes replacements, all the other are all operated by prescription and the method for embodiment 2, get 1 0.3 kilograms of L-Phenylglycines, and yield is 74.6%.[α]
20 D=-156.90 (C=1%, 1 mole hydrochlorides).
Embodiment 6
Except the phenyl aldehyde that adds 1.86 kilograms of 2.66 kilograms of salicylic aldehydes replacements, all the other are all operated according to prescription and the method for embodiment 2, get 10.6 kilograms of L-Phenylglycines, and yield is 76.8%.[α]
20 D=-157.30 (C=1%, 1 mole hydrochlorides).
Embodiment 7
Racemization, fractured operation are carried out in circulation, produce L-Phenylglycine.
To add 1.86 kilograms of salicylic aldehydes in the mother liquor that filter out among the embodiment 3 behind the double salt of L-Phenylglycine and d-camphorsulfonic acid.Reaction solution is heated to 105-110 ℃, backflow 3-5 hour, carry out the optics racemization, then at 105-110 ℃, in 2-3 hour, steam water-salicylic aldehyde azeotrope, mother liquor behind the elimination L-Phenylglycine among reaction solution and the embodiment 3 is merged, add an amount of vitriol oil, the PH=0.0 of conditioned reaction liquid ± 0.4 is concentrated into 110-120 ℃ with reaction solution, add 12 kilograms of DL phenylglycines, 0.4 kilogram of d-camphorsulfonic acid, with reaction solution at 105-110 ℃ of back flow reaction 30-60 minute, in 2 hours, reaction solution is cooled to 35 ℃, filters out the double salt of L-Phenylglycine and d-camphorsulfonic acid with whizzer.Following steps are operated by the method for embodiment 3, get 10.7 kilograms of L-Phenylglycines, [α]
20 D=-157.40 (C=1%, 1 mole hydrochlorides).
The comparative example 1
Method by embodiment 2 is operated, and does not add radially aromatic aldehyde, gets 5.5 kilograms of L-Phenylglycines, and yield is 40%, [α]
20 D=-152.40 (C=1%, 1 mole hydrochlorides).
The comparative example 2
The mother liquor that filters out among the embodiment 1 behind the double salt is slowly added chip solid sodium hydroxide 4-5 kilogram, make the pH value of filtrate be adjusted into 12.5 ± 0.4, be heated to 102 ℃, kept 4 hours, add the mother liquor that filters out the L-Phenylglycine product among the embodiment 1, steam unnecessary reaction solution volume, rise to 110 ℃ until the temperature of reaction solution.Be cooled to 25 ℃.Filter the sodium sulfate of separating out with whizzer.This filtrate is added 0.27 kilogram of d-camphorsulfonic acid, 11.5 kilograms of DL phenylglycines, slowly add the about 5-7 kilogram of the vitriol oil, the pH value of reaction solution is adjusted between 0.0 ± 0.4.Reaction solution is heated to reflux temperature (110 ℃), after 30 minutes, in 2 hours, reaction solution is cooled to 35 ℃.Filter out L-Phenylglycine and d-camphorsulfonic acid double salt with whizzer.
This double salt is under agitation added down in the water of 5 times of weight, and the gac of adding double salt amount 1%, 90 ℃ were heated 30 minutes, filtered while hot, filtrate neutralizes with 20% ammoniacal liquor, separates out the L-Phenylglycine crystallization, gets 10.7 kilograms of sweet sour white crystals of left-handed benzene after filtration, washing, the drying, yield is 77.5%, [α]
20 D=-156.50 (C=1%, 1 mole hydrochlorides).
Claims (5)
1, the preparation method of a kind of D-(-)-1-phenylglycine, comprise: under agitation, the raw material vitriol oil, DL phenylglycine, d-camphorsulfonic acid are added in the entry, with above-mentioned reaction solution at 105-110 ℃ of heating reflux reaction 30-60 minute, be cooled to 35 ℃ then, filter the double salt of D-(-)-1-phenylglycine and d-camphorsulfonic acid, this double salt is dissolved in the hot water, obtain D-(-)-1-phenylglycine through recrystallization, filtration, drying, it is characterized in that:
(1) in the acid mother liquid that contains the dextrorotation phenylglycine behind elimination double salt, adding the aromatic aldehyde compound of 5-10 weight %, is 100% in the weight of the DL phenylglycine that adds;
(2) will add mother liquor behind the aromatic aldehyde at 105-110 ℃ of reflux 3-5 hour, carry out the optics racemization, and make the dextrorotation phenylglycine in the mother liquor change the DL phenylglycine into, under said temperature, in 2-3 hour, steam water-aromatic aldehyde compound azeotrope then;
(3) mother liquor behind this reaction solution and elimination D-(-)-1-phenylglycine is merged, distillation is concentrated into 110-120 ℃, add the 105-115 weight % of DL phenylglycine to former add-on, add the d-camphorsulfonic acid of 1.3-1.9 weight %, more than be 100% all in the weight of the DL phenylglycine of former adding;
(4) this reaction solution is carried out optical resolution with above-mentioned method for splitting, produce D-(-)-1-phenylglycine.
2, the preparation method of D-according to claim 1 (-)-1-phenylglycine, it is characterized in that: described in the acid mother liquid that contains the dextrorotation phenylglycine, add aromatic aldehyde and carry out the optics racemization, be repeatedly to circulate to carry out through splitting the method for preparing D-(-)-1-phenylglycine then, cycle index is 5-15 time.
3, the preparation method of D-according to claim 1 and 2 (-)-1-phenylglycine, it is characterized in that: the weight proportion of the raw material of adding is: the vitriol oil: DL phenylglycine: d-camphorsulfonic acid: water equals 0.18-0.25: 1: 1.2-1.5: 3.5-4.0.
4, the preparation method of D-according to claim 1 and 2 (-)-1-phenylglycine is characterized in that: described aromatic aldehyde compound is from phenyl aldehyde, chooses any one kind of them in salicylic aldehyde and the phenylacetic aldehyde.
5, the preparation method of D-according to claim 1 and 2 (-)-1-phenylglycine is characterized in that: the described water that steams-aromatic aldehyde compound azeotrope is after separating, and aromatic aldehyde can be recycled.
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| CNB031289452A CN1293041C (en) | 2003-05-30 | 2003-05-30 | Preparation of D-(-)-1-benzene amino acetic acid |
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| CNB031289452A CN1293041C (en) | 2003-05-30 | 2003-05-30 | Preparation of D-(-)-1-benzene amino acetic acid |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101906052A (en) * | 2009-06-05 | 2010-12-08 | 上海宝钢化工有限公司 | Method for preparing D-m-hydroxyphenylglycine |
| CN101426795B (en) * | 2006-04-21 | 2011-01-12 | Zach系统股份公司 | Process for preparing dorzolamide |
| CN101560132B (en) * | 2009-05-14 | 2011-12-14 | 浙江普洛医药科技有限公司 | Method for racemizing chiral amino acid or derivatives of chiral amino acid |
| CN106565550A (en) * | 2016-11-02 | 2017-04-19 | 河北美邦工程科技股份有限公司 | Method for concentrating and dewatering camphor sulfonic acid solution in production process of L-phenylglycine |
| CN114516811A (en) * | 2022-03-07 | 2022-05-20 | 浙江云涛生物技术股份有限公司 | Method for racemization reaction of phenylglycine in alkaline environment |
| CN115093331A (en) * | 2022-07-19 | 2022-09-23 | 浙江云涛生物技术股份有限公司 | Extraction process of benzylamine in high boiling point organic matter discharged from phenylglycine production |
Families Citing this family (2)
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| CA2828946C (en) | 2011-04-18 | 2016-06-21 | Eisai R&D Management Co., Ltd. | Therapeutic agent for tumor |
| KR20150098605A (en) | 2012-12-21 | 2015-08-28 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Amorphous form of quinoline derivative, and method for producing same |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL188407C (en) * | 1977-10-18 | 1992-06-16 | Kessels Gerard | PROCESS FOR THE PREPARATION OF D (-) - ALFA-PHENYLGLYCIN. |
| US4401820A (en) * | 1981-01-23 | 1983-08-30 | Tanabe Seiyaku Co., Ltd. | Process for racemizing optically active α-amino acids or a salt thereof |
| CN1015174B (en) * | 1988-03-02 | 1991-12-25 | 浙江医科大学 | Mfg. process for l-phenylglycine |
-
2003
- 2003-05-30 CN CNB031289452A patent/CN1293041C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101426795B (en) * | 2006-04-21 | 2011-01-12 | Zach系统股份公司 | Process for preparing dorzolamide |
| CN101560132B (en) * | 2009-05-14 | 2011-12-14 | 浙江普洛医药科技有限公司 | Method for racemizing chiral amino acid or derivatives of chiral amino acid |
| CN101906052A (en) * | 2009-06-05 | 2010-12-08 | 上海宝钢化工有限公司 | Method for preparing D-m-hydroxyphenylglycine |
| CN101906052B (en) * | 2009-06-05 | 2013-10-30 | 上海宝钢化工有限公司 | Method for preparing D-m-hydroxyphenylglycine |
| CN106565550A (en) * | 2016-11-02 | 2017-04-19 | 河北美邦工程科技股份有限公司 | Method for concentrating and dewatering camphor sulfonic acid solution in production process of L-phenylglycine |
| CN106565550B (en) * | 2016-11-02 | 2018-04-13 | 河北美邦工程科技股份有限公司 | A kind of thickening method of camphorsulfonic acid solution in L-Phenylglycine production process |
| CN114516811A (en) * | 2022-03-07 | 2022-05-20 | 浙江云涛生物技术股份有限公司 | Method for racemization reaction of phenylglycine in alkaline environment |
| CN115093331A (en) * | 2022-07-19 | 2022-09-23 | 浙江云涛生物技术股份有限公司 | Extraction process of benzylamine in high boiling point organic matter discharged from phenylglycine production |
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