CN103664670A - Method for extracting and separating phenylalanine by using N-alkyl-L-phenylalanine methyl ester - Google Patents
Method for extracting and separating phenylalanine by using N-alkyl-L-phenylalanine methyl ester Download PDFInfo
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- CN103664670A CN103664670A CN201210325545.0A CN201210325545A CN103664670A CN 103664670 A CN103664670 A CN 103664670A CN 201210325545 A CN201210325545 A CN 201210325545A CN 103664670 A CN103664670 A CN 103664670A
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Abstract
The invention discloses a method for extracting and separating phenylalanine by using N-alkyl-L-phenylalanine methyl ester, which solves the problem that no method for realizing preparation and mass production of d,1-phenylalanine exists at present. The method has the advantages of simple process, high product purity, favorable yield and the like. The specific method comprises the following step: based on the principle that two isomers of N-alkyl-L-phenylalanine methyl ester and phenylalanine have different stability constants under the assistance of copper ions, by selecting appropriate diluter and optimum concentration and temperature, extracting and separating the phenylalanine, thus achieving favorable separation effect.
Description
Technical field
The present invention relates to a kind of preparation method of organic compound, relate in particular to a kind of method of the N-of utilization alkyl-L-Phe methyl esters extracting and splitting phenylalanine.
Background technology
L-Phe is a kind of important amino acid, and it has biological activity, and humans and animals self can not synthesize, and must absorb from the external world, belongs to one of eight kinds of indispensable amino acids, and it is also the important source material of synthetic hydroxyphenylaminopropionic acid in organism simultaneously.Though be worth little in D-phenylalanine nutrition, but it can strengthen the immunologic function of human body, can suppress the decomposition of enkephalin (a kind of endogenous pain control material), thereby the activity that suppresses carboxypeptidase (degrading enzyme of enkephalin), thereby there is an outstanding town pain effect, energy antipyretic-antalgic, enhancing immunity, Cardiovarscular is the important intermediate of producing hiv virus inhibitor simultaneously.Due to the widespread use of phenylalanine at field of medicaments such as anti-cancer drug preparation and intravenous injections, the development that radix asparagi sweet extract Aspartame especially low in calories, high sugariness produces increases severely the demand of L-Phe in recent years.The method of suitability for industrialized production L-Phe mainly contains both at home and abroad at present: enzyme process and direct fermentation, and these two kinds of method production costs are high, and condition control ratio is stricter, and product purity and yield are low, can not meet the requirement of production in enormous quantities.(enzyme process yield is 60% left and right; yellow hat worn by a Taoist priest China waits Enzymatic Resolution D; L-Phe is prepared D-phenylalanine synthetic chemistry the 15th the 1st phase of volume in 2007; 69-72; Yan Bo etc. have studied take (dl)-phenylalanine and through D-L-Aminoacylase, prepares D-phenylalanine as raw material, and resolution yield can reach 97%. yellow hat worn by a Taoist priests China to be waited with immobilized penicillin acylated enzymes (IPA2750) selective hydrolysis of (dl)-N-phenylacetyl phenylalanine is split to (dl)-phenylalanine.D-N-phenylacetyl phenylalanine yield 63%, optical purity 99%ee.Fermentation method: L-Phe output reaches 2.5%, protorosaur, Northwest University, the research of gene recombination bacterium fermentative Production L-Phe)
Goal of the invention
Object of the present invention is effectively prepared phenylalanine in order to solve current shortage exactly, can not be for the problem of producing in enormous quantities, provide that a kind of to have technique simple, the method for product purity, yield advantages of higher, utilizes the method for N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine.
For achieving the above object, the present invention has adopted following technical scheme:
A kind of method of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine, its method is: utilize two kinds of isomer of N-alkyl-L-Phe methyl esters and phenylalanine stability constant under the assistance of cupric ion different, select suitable thinner, optimum concn and temperature, extraction realizes the fractionation of phenylalanine.That is:
(1) prepare N-alkyl-L-Phe methyl esters;
(2) take the phenylalanine that concentration is 1 grams per liter is water, methylene dichloride organic phase is thinner, concentration is that N-alkyl-L-Phe methyl esters and the cupric chloride of 2 grams per liters is mixed into extraction agent, counter-current extraction, two-phase be take volume ratio as 1: 1 mix and blend 90-120 minute, centrifugal phase-splitting, the extraction that completes phenylalanine splits, and makes D-phenylalanine and L-Phe.
The straight or branched alkyl that the alkyl of described N-alkyl-L-Phe methyl esters is C4-C12.
In described step (1), the method of preparing N-alkyl-L-Phe methyl esters is, by L-Phe methyl ester hydrochloride 15-25 part, methyl alcohol 140-200 part, n-octaldehyde 20-30 part by weight, under normal temperature and pressure, stir 2 hours, reactant is moved in autoclave, and interpolation Pd/C is catalyzer, passes into hydrogen, after pressure is constant, reaction finishes.Remove by filter Pd/C, revolve to steam and remove methyl alcohol, the methylene dichloride of take is purified as solvent.With dilute hydrochloric acid washing, remove unreacted phenylalanine methyl ester, with in dilute sodium hydroxide and excessive hydrochloric acid, then use saturated sodium-chloride washed product, organic phase is spent the night with anhydrous magnesium sulfate drying, filter, revolve steaming, column chromatography for separation purification, obtain yellow oily N-n-octyl-L-Phe methyl esters.
The described method of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine, is characterized in that: described composition is counted 20 parts of L-Phe methyl ester hydrochlorides, 170 parts of methyl alcohol, 25 parts of n-octaldehydes by weight.
The described method of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine, is characterized in that: the pressure while reacting with autoclave is 0.5MPa.
The described method of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine, is characterized in that: the concentration of sodium-chlor is 176 grams per liters.
The described method of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine, is characterized in that: in described extraction agent, and N-alkyl-L-Phe methyl esters and cupric chloride by weight 1: 0.02-0.2 proportional arrangement.
Utilize two kinds of isomer of N-alkyl-L-Phe methyl esters and phenylalanine stability constant under the assistance of cupric ion different, select suitable thinner, optimum concn and temperature, realize the fractionation of phenylalanine, the straight or branched alkyl that wherein alkyl of N-alkyl-L-Phe methyl esters is C4-C12.Thinner is methylene dichloride.
The invention has the beneficial effects as follows: utilize extraction process, there is the advantages such as technique is simple, cost is low, can be continuously produced with enzyme process and fermentation method ratio.Under optimum condition, the extracting and separating factor of D-phenylalanine and L-Phe is greater than 1.8, obtains purity and be 99% L-Phe.
Embodiment
Below in conjunction with embodiment, the invention will be further described.
Embodiment:
The preparation of 1N-normal-butyl-L-Phe methyl esters
By L-Phe methyl ester hydrochloride (5.00g, 0.023mol), methyl alcohol 70mL, be stirred to L-Phe methyl ester hydrochloride entirely molten, slowly drip triethylamine (5mL, 0.0345mol), vigorous stirring 30 minutes, slowly drips butyraldehyde-n (2.1mL, 0.023mol), and vigorous stirring, some plate tracks to butyraldehyde-n and reacts completely, and then under ice bath, adds NaBH4 (1.3369g in batches, 0.0345mol), vigorous stirring, some plate tracks to and reacts completely, and adds 10mL water quencher reaction.Add 150mL water, with methylene dichloride (60mL * 3) extraction product, get organic phase, with anhydrous magnesium sulfate drying, spend the night, decompress filter is removed anhydrous magnesium sulfate, and methylene dichloride is reclaimed in air distillation, and then column chromatography for separation is purified, obtain light yellow oily liquid, i.e. N-normal-butyl-L-Phe methyl esters.Productive rate is more than 97%.
The preparation of 2N-n-octyl-L-Phe methyl esters
By L-Phe methyl ester hydrochloride (5.00g, 0.028mol), methyl alcohol 70mL, n-octaldehyde (6.5mL, 0.042mol), under normal temperature and pressure, stir 2h, reactant is moved in autoclave, interpolation Pd/C is catalyzer, pass into hydrogen, after pressure is constant, pressure is not less than 0.5MPa, the system pressure for the treatment of no longer changes, and reaction finishes.Remove by filter Pd/C, revolve to steam and remove methyl alcohol, the methylene dichloride of take is purified as solvent.With dilute hydrochloric acid washing, remove unreacted phenylalanine methyl ester, with in dilute sodium hydroxide and excessive hydrochloric acid, then use saturated sodium-chloride washed product, organic phase is spent the night with anhydrous magnesium sulfate drying, filter, revolve steaming, column chromatography for separation purification, obtain yellow oily N-n-octyl-L-Phe methyl esters.Productive rate is more than 95%.
3 N-normal-butyl-L-Phe methyl esters extracting and splitting phenylalanines
The phenylalanine that the concentration of take is 1 grams per liter is water, methylene dichloride organic phase is thinner, concentration is that N-normal-butyl-L-Phe methyl esters and the cupric chloride of 2 grams per liters is mixed into extraction agent, the concentration of sodium-chlor is 176 grams per liters, two-phase be take volume ratio as 1: 1 mix and blend 120 minutes, centrifugal phase-splitting, records the partition ratio 1.40 of D-phenylalanine and the partition ratio 2.79 of L-Phe.Separation factor reaches 1.99.
4N-n-octyl-L-Phe methyl esters extracting and splitting phenylalanine
The phenylalanine that the concentration of take is 1 grams per liter is water, methylene dichloride organic phase is thinner, concentration is that N-n-octyl-L-Phe methyl esters and the cupric chloride of 2 grams per liters is mixed into extraction agent, the concentration of sodium-chlor is 176 grams per liters, two-phase be take volume ratio as 1: 1 mix and blend 120 minutes, centrifugal phase-splitting, records the partition ratio 0.041 of D-phenylalanine and the partition ratio 0.020 of L-Phe.Separation factor reaches 2.05.
Claims (1)
1. a method of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine, its method is: utilize two kinds of isomer of N-alkyl-L-Phe methyl esters and phenylalanine stability constant under the assistance of cupric ion different, select suitable thinner, optimum concn and temperature, realize the fractionation of phenylalanine.That is:
(1) prepare N-alkyl-L-Phe methyl esters;
(2) take the phenylalanine that concentration is 1 grams per liter is water, methylene dichloride organic phase is thinner, concentration is that N-alkyl-L-Phe methyl esters and the cupric chloride of 2 grams per liters is mixed into extraction agent, two-phase be take volume ratio as 1: 1 mix and blend 90-120 minute, centrifugal phase-splitting, the extraction that completes phenylalanine splits, and makes D-phenylalanine and L-Phe.
2 methods of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine according to claim 1, is characterized in that: the straight or branched alkyl that the alkyl of described N-alkyl-L-Phe methyl esters is C4-C12.
3 methods of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine according to claim 1 and 2, it is characterized in that: in described step (1), the method of preparing N-alkyl-L-Phe methyl esters is, by L-Phe methyl ester hydrochloride 15-25 part, methyl alcohol 140-200 part, n-octaldehyde 20-30 part by weight, under normal temperature and pressure, stir 2h, reactant is moved in autoclave, interpolation Pd/C is catalyzer, pass into hydrogen, after pressure is constant, reaction finishes.Remove by filter Pd/C, revolve to steam and remove methyl alcohol, the methylene dichloride of take is purified as solvent.With dilute hydrochloric acid washing, remove unreacted phenylalanine methyl ester, with in dilute sodium hydroxide and excessive hydrochloric acid, then use saturated sodium-chloride washed product, organic phase is spent the night with anhydrous magnesium sulfate drying, filter, revolve steaming, column chromatography for separation purification, obtain yellow oily N-n-octyl-L-Phe methyl esters.
4 methods of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine according to claim 3, is characterized in that: described composition is counted 20 parts of L-Phe methyl ester hydrochlorides, 170 parts of methyl alcohol, 25 parts of n-octaldehydes by weight.
5 methods of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine according to claim 3, is characterized in that: the pressure while reacting with autoclave is 0.5MPa.
6 methods of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine according to claim 1, is characterized in that: the concentration of sodium-chlor is 176 grams per liters.
7 methods of utilizing N-alkyl-L-Phe methyl esters extracting and splitting phenylalanine according to claim 1, is characterized in that: in described extraction agent, and N-alkyl-L-Phe methyl esters and cupric chloride by weight 1: 0.02-0.2 proportional arrangement.
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Citations (5)
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| JPS6193145A (en) * | 1984-10-15 | 1986-05-12 | Funakoshi Yakuhin Kk | Method of separating amino acid enantiomer by chromatography |
| WO2002016406A1 (en) * | 2000-08-21 | 2002-02-28 | The Nutrasweet Company | METAL ION ASSISTED N-[N-(3,3-DIMETHYLBUTYL)-L-α-ASPARTYL]-L-PHENYLALANINE 1-METHYL ESTER ISOMER RESOLUTION |
| CN1566080A (en) * | 2003-07-08 | 2005-01-19 | 丁大为 | Resolution of DL-phenylalanine |
| CN101016251A (en) * | 2007-02-09 | 2007-08-15 | 济南大学 | Method of extracting and splitting phenylalanine by D-dialkyl tartrate |
| CN102618618A (en) * | 2012-02-27 | 2012-08-01 | 闫博 | Method for producing D-phenylalanine by using L-phenylalanine as raw material |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6193145A (en) * | 1984-10-15 | 1986-05-12 | Funakoshi Yakuhin Kk | Method of separating amino acid enantiomer by chromatography |
| WO2002016406A1 (en) * | 2000-08-21 | 2002-02-28 | The Nutrasweet Company | METAL ION ASSISTED N-[N-(3,3-DIMETHYLBUTYL)-L-α-ASPARTYL]-L-PHENYLALANINE 1-METHYL ESTER ISOMER RESOLUTION |
| CN1566080A (en) * | 2003-07-08 | 2005-01-19 | 丁大为 | Resolution of DL-phenylalanine |
| CN101016251A (en) * | 2007-02-09 | 2007-08-15 | 济南大学 | Method of extracting and splitting phenylalanine by D-dialkyl tartrate |
| CN102618618A (en) * | 2012-02-27 | 2012-08-01 | 闫博 | Method for producing D-phenylalanine by using L-phenylalanine as raw material |
Non-Patent Citations (3)
| Title |
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| 崔玉 等: "正十二烷基-L-羟基脯氨酸手性配位萃取拆分外消旋苯丙氨酸", 《无机化学学报》, vol. 28, no. 4, 30 April 2012 (2012-04-30), pages 686 - 690 * |
| 崔玉 等: "正辛基-L-羟基脯氨酸萃取苯丙氨酸的机理及性能", 《高等学校化学学报》, vol. 29, no. 5, 31 May 2008 (2008-05-31), pages 882 - 886 * |
| 游淇: "新型手性螯合萃取剂的合成及萃取拆分消旋氨基酸的研究", 《中国优秀硕士论文全文数据库 工程科技I辑》, no. 11, 15 November 2011 (2011-11-15) * |
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Application publication date: 20140326 |