CN106701869A - Preparation method of N (2)-L-alanyl-L-glutamine - Google Patents
Preparation method of N (2)-L-alanyl-L-glutamine Download PDFInfo
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- CN106701869A CN106701869A CN201611257271.0A CN201611257271A CN106701869A CN 106701869 A CN106701869 A CN 106701869A CN 201611257271 A CN201611257271 A CN 201611257271A CN 106701869 A CN106701869 A CN 106701869A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
Abstract
The invention discloses a preparation method of N (2)-L-alanyl-L-glutamine, and belongs to the technical field of synthesis and preparation of drugs. The preparation method comprises the following steps: preparation of N-phthaloyl-L-alanine, preparation of N-phthaloyl-L-alanyl chloride, enzymatic synthesis of N (2)-L-alanyl-L-glutamine, enzymatic inactivation and crude product refining, and finally the preparation of finished N (2)-L-alanyl-L-glutamine. The method can be used for producing N (2)-L-alanyl-L-glutamine by a enzymatic preparation process; a high temperature melting method is adopted in the synthesis process of the preparation of N-phthaloyl-L-alanine so as to reduce the use of toluene, triethylamine, hydrochloric acid and other solvents; in the enzymatic synthesis process, an adsorption method is adopted to immobilize peptidyl transferase, while sodium alginate chitosan is used for embedding the peptidyl transferase to form microencapsulated immobilized enzyme; the activity of the immobilized enzyme is investigated to prove that the immobilized enzyme has good permeability, has use efficiency greatly improved after embedding, improves the yield of N (2)-L-alanyl-L-glutamine, and reduces the production cost.
Description
Technical field
The invention belongs to the synthetically prepared technical field of medicine, and in particular to a kind of N (2)-Ala-Gln
Preparation method.
Background technology
N (2)-Ala-Gln (being commonly called as dipeptides) is a kind of amino acids drug, is of parenteral nutrition
Important component, it is adaptable to require supplementation with the patient of glutamine, including the patient in catabolism and hypermetabolism situation.
Glutamine is a kind of conditionally essential amino acid, is the important as precursors thing of organism nucleic acid, protein, purine, pyrimidine etc.
Matter, is also protein synthesis and the instrumentality for decomposing.But glutamine can not directly be made due to unstable, water-soluble low in itself
It is medicine, being translated into N (2)-Ala-Gln can give full play to effect of the glutamine to human body.
This kind of medicine main production is chemical synthesis in the market, wherein being divided into ammonolysis technique and hydrazinolysis work again
Skill, ammonolysis technique is mainly makes N- (2- chlorine)-propiono-glutamine be reacted with ammoniacal liquor, then by heating concentration, adjusting
The operations such as acid, electrodialysis desalination obtain N (2)-Ala-Gln；Hydrazinolysis technique is mainly phthalyl N (2)-L-
Alanyl-L-glutamine is decomposed and then by N (2) third ammonia of-L- of the operations such as water dissolves separation in the presence of hydrazine hydrate
Acyl-Glu.Above two technique is deposited in process of production to be had dusty gas, the short slabs such as solid waste is produced, in national ring
Protect supervision it is increasingly severe in the case of be unfavorable for large-scale production.
The content of the invention
The invention provides a kind of preparation method of N (2)-Ala-Gln, it is intended that using enzyme
Technique productions N (2)-Ala-Gln prepared by method, including the synthesis of N- phthalyl-L- alanyl chlorides
Protection group is introduced, enzyme' s catalysis N (2)-Ala-Gln is bonded to including peptide, Deprotection operation, to N- neighbour's benzene
The synthesis procedure of the preparation of two formyls-ALANINE reduces toluene, triethylamine, hydrochloric acid equal solvent using the method for high-temperature fusion
Use, enzyme' s catalysis technique is fixed using absorption method to peptidyl transferase, while with sodium alginate shitosan to peptidyl
Transferase carries out embedding and forms microencapsulation immobilised enzymes, and has investigated the activity for changing immobilised enzymes, may certify that the immobilised enzymes
Permeability is good, and service efficiency has larger lifting after embedding, improves N (2)-Ala-Gln yield, reduces life
Produce cost.
The preparation method of N (2)-Ala-Gln of the present invention, the technique productions N (2) prepared using enzyme process-
Ala-Gln, comprises the following steps that：
1) preparation of N- phthalyls-ALANINE：ALANINE, phthalic anhydride are added in reactor, in height
Synthetic reaction, generation N- phthalyls-ALANINE are carried out under warm molten condition；
2) preparation of N- phthalyls-L- alanyl chlorides：With toluene as solvent, N- phthalyls the third ammonia of-L- is put into
Acid, adds thionyl chloride, carries out being warming up to 45-55 DEG C, flows back 1-1.2 hours, then insulation reaction 3-3.5 hours, then carries out
Vacuum distillation 3-3.5 hours, vacuum took out band cooling, obtains N- phthalyl-L- alanyl chlorides；
3) enzyme' s catalysis N (2)-Ala-Gln：By step 2) prepare N- phthalyls the third ammonia of-L-
In acyl chlorides input water, pH to 7.5-8.0 is adjusted with NaOH, put into glutamine, immobilization peptidyl transferase is added to
In reaction, during add sodium acid carbonate regulation pH to 7.5-8.0, stirring, reaction solution through be centrifuged N (2)-L- alanyls-
Glu solution；
4) inactivation of enzyme：Above-mentioned N (the 2)-Ala-Gln solution that will be collected into is added to methanol solvate
In, it is centrifuged to obtain solid N (2)-Ala-Gln after crystallization, then by solid N (2)-Ala-Gln
In input water, 55-65 DEG C is heated to, adds charcoal absorption filtering, reuse acid cation exchange resin absorption, washing,
NaOH adjusts pH to 7.5-8.0, obtains N (2)-Ala-Gln crude product aqueous solution；
5) crude product refining：To 1.5 times of water of weight of addition in N (2)-Ala-Gln crude product aqueous solution, plus
Medical charcoal is warming up to decolouring 1-1.2 hours, is filtered using accurate filter, and filtrate adds methyl alcohol crystallization, is dried after centrifugation
Crush, obtain N (2)-Ala-Gln fine work.
Step 1) in ALANINE, phthalic anhydride mass ratio be 10:16-18.
Step 1) in reaction temperature be 140-150 DEG C.
Step 2) in the mass ratio of N- phthalyls-ALANINE and toluene solvant be 135:190-210.
Step 3) in the volume ratio of peptidyl transferase and solution be 1:30-35.
Step 3) in the peptidyl transferase enzyme that uses it is fixed using absorption method, while using sodium alginate shitosan
Embedding is carried out to it and forms microencapsulation immobilised enzymes.
Step 3) in reaction temperature be 40-45 DEG C.
Compared with prior art, beneficial effects of the present invention are：The system of N (2)-Ala-Gln of the present invention
Preparation Method, technique productions N (the 2)-Ala-Gln prepared using enzyme process, including N- phthalyls-L-
Alanyl chloride synthesis introduces protection group, and enzyme' s catalysis N (2)-Ala-Gln is bonded to including peptide, Deprotection
Operation, the method for using high-temperature fusion to the synthesis procedure of the preparation of N- phthalyls-ALANINE, reduces toluene, three second
The use of amine, hydrochloric acid equal solvent, enzyme' s catalysis technique is fixed using absorption method to peptidyl transferase, while using sodium alginate
Shitosan carries out embedding and forms microencapsulation immobilised enzymes to peptidyl transferase, and has investigated the activity for changing immobilised enzymes, can demonstrate,prove
The bright immobilised enzymes permeability is good, and service efficiency has larger lifting after embedding, improves N (2)-L- alanyl-L- glutamy
Amine yield, reduction production cost.
Specific embodiment
The present invention is further described with reference to specific embodiment, so that those skilled in the art do further
Understand, but and be not so limited the present invention.
Embodiment 1
The preparation method of N (2)-Ala-Gln of the present invention, the technique productions N (2) prepared using enzyme process-
Ala-Gln, comprises the following steps that：
1) preparation of N- phthalyls-ALANINE：
Exhaust is opened, to 850kg phthalic anhydrides are added in 5000L reactors, intensification makes 140 DEG C of reaction temperature extremely molten
Solution, opens stirring, puts into 500kgL- alanine, reacts 5.5 hours, generation N- phthalyls-ALANINE；
2) preparation of N- phthalyls-L- alanyl chlorides：
Feed intake at twice, toluene solution 1000kg added in 2000L reactors, put into N- phthalyls-ALANINE,
Vacuum is opened, thionyl chloride 300kg is added into 2000L reactors, carry out being warming up to 45 DEG C, flowed back 1 hour, then insulation reaction
3 hours, then carry out vacuum distillation 3 hours, vacuum takes out band cooling, obtains N- phthalyl-L- alanyl chloride toluene solutions；
3) enzyme' s catalysis N (2)-Ala-Gln：
To 900kg water is added in 3000L reactors, pH is adjusted to 7.5 with NaOH, 0 DEG C is cooled to, by above-mentioned preparation
N- phthalyl-L- alanyl chlorides input water in, put into glutamine 600kg, by the immobilization transpeptidation after treatment
Enzyme 60L be added to reaction in, 40 DEG C of reaction temperature, during add sodium acid carbonate regulation pH to 7.5, stirring, reaction solution warp
N (the 2)-Ala-Gln solution of centrifugation；
4) inactivation of enzyme：
To adding methyl alcohol 1660kg, the above-mentioned solution that will be collected into be added in methanol solvate in 3000L reactors, lower the temperature
0 DEG C, it is centrifuged to obtain solid N (2)-Ala-Gln after crystallization, then solid alanyl alanimamides is put into water,
55 DEG C are heated to, charcoal absorption filtering is added, acid cation exchange resin absorption, washing, NaOH regulation is reused
PH to 7.5；
5) crude product refining：
To putting into above-mentioned N (2)-Ala-Gln aqueous solution for being collected into, supplement 1.5 in 2000L reactors
The water of times weight, plus medical charcoal is heated up 40 DEG C, decolourizes 1 hour, and filtering transfer is carried out using titanium filter and accurate filter
To the D grades of 3000L reactor of clean area；Heated up 40 DEG C to addition methyl alcohol 1600L in 3000L reactors, plus medical charcoal, decolouring 1
Hour, carrying out filtering using titanium filter and accurate filter and be transferred to D grades of clean area 500L temporary storage tank, filtrate adds methyl alcohol
Crystallization is carried out, 0 DEG C of centrifugation of lowering the temperature, using heated-air circulation oven drying to constant weight, 50 DEG C of drying temperature is crushed, and obtains N (2)-L- third
Aminoacyl-Glu fine work.
Embodiment 2
The preparation method of N (2)-Ala-Gln of the present invention, the technique productions N (2) prepared using enzyme process-
Ala-Gln, comprises the following steps that：
1) preparation of N- phthalyls-ALANINE：
Exhaust is opened, to 850kg phthalic anhydrides are added in 5000L reactors, intensification makes 150 DEG C of reaction temperature extremely molten
Solution, opens stirring, puts into 500kgL- alanine, reacts 6 hours, generation N- phthalyls-ALANINE；
2) preparation of N- phthalyls-L- alanyl chlorides：
Feed intake at twice, toluene solution 1000kg added in 2000L reactors, put into N- phthalyls-ALANINE,
Vacuum is opened, thionyl chloride 350kg is added into 2000L reactors, carry out being warming up to 55 DEG C, flowed back 1 hour, then insulation reaction
3.5 hours, then carry out vacuum distillation 3 hours, vacuum takes out band cooling, obtains N- phthalyl-L- alanyl chloride toluene solutions；
3) enzyme' s catalysis N (2)-Ala-Gln：
To 900kg water is added in 3000L reactors, pH is adjusted to 8.0 with NaOH, 10 DEG C are cooled to, by above-mentioned system
In standby N- phthalyl-L- alanyl chlorides input water, input input glutamine 600kg, by the immobilization peptide after treatment
Based transferase 60L be added to reaction in, 45 DEG C of reaction temperature, during add sodium acid carbonate regulation pH to 8.0, stirring, reaction
N (2)-Ala-Gln of the solution through being centrifuged；
4) inactivation of enzyme：
To adding methyl alcohol 1660kg, the above-mentioned solution that will be collected into be added in methanol solvate in 3000L reactors, lower the temperature
10 DEG C, it is centrifuged to obtain solid N (2)-Ala-Gln after crystallization, then solid alanyl alanimamides is put into water,
65 DEG C are heated to, charcoal absorption filtering is added, acid cation exchange resin absorption, washing, NaOH regulation is reused
PH to 8.0；
5) crude product refining：
To putting into above-mentioned N (2)-Ala-Gln aqueous solution for being collected into, supplement 1.5 in 2000L reactors
The water of times weight, plus medical charcoal heats up 45 DEG C, decolourizes 1.2 hours, and carrying out filtering using titanium filter and accurate filter turns
Move to the D grades of 3000L reactor of clean area；Heated up 45 DEG C to addition absolute ethyl alcohol 1200L in 3000L reactors, plus medical charcoal,
Decolourize 1.2 hours, carry out filtering using titanium filter and accurate filter and be transferred to D grades of clean area 500L temporary storage tank, filtrate
Adding absolute ethyl alcohol carries out crystallization, 10 DEG C of centrifugations of lowering the temperature, and uses heated-air circulation oven drying to constant weight, 60 DEG C of drying temperature, powder
It is broken, obtain N (2)-Ala-Gln fine work.
Embodiment 3
The preparation method of N (2)-Ala-Gln of the present invention, the technique productions N (2) prepared using enzyme process-
Ala-Gln, comprises the following steps that：
1) preparation of N- phthalyls-ALANINE：
Exhaust is opened, to 850kg phthalic anhydrides are added in 5000L reactors, intensification makes 145 DEG C of reaction temperature extremely molten
Solution, opens stirring, puts into 500kgL- alanine, reacts 5.8 hours, generation N- phthalyls-ALANINE；
2) preparation of N- phthalyls-L- alanyl chlorides：
Feed intake at twice, toluene solution 1000kg added in 2000L reactors, put into N- phthalyls-ALANINE,
Open vacuum and thionyl chloride 330kg is added into 2000L reactors, carry out temperature rising reflux 1.1 hours, reaction temperature is controlled 50
DEG C, then insulation reaction 3.3 hours, then carry out vacuum distillation 3.2 hours, vacuum takes out band cooling, obtains N- phthalyls-L-
Alanyl chloride toluene solution；
3) enzyme' s catalysis N (2)-Ala-Gln：
To 900kg water is added in 3000L reactors, pH is adjusted to 7.8 with NaOH, 5 DEG C are cooled to, by above-mentioned preparation
N- phthalyl-L- alanyl chlorides input water in, put into glutamine 600kg, by the immobilization transpeptidation after treatment
Enzyme 60L be added to reaction in, 40-45 DEG C of reaction temperature, during add sodium acid carbonate regulation pH to 7.8, stirring, reaction solution
N (2)-Ala-Gln through being centrifuged；
4) inactivation of enzyme：
To adding methyl alcohol 1660kg, the above-mentioned solution that will be collected into be added in methanol solvate in 3000L reactors, lower the temperature
5 DEG C, it is centrifuged to obtain solid N (2)-Ala-Gln after crystallization, then solid alanyl alanimamides is put into water,
60 DEG C are heated to, charcoal absorption filtering is added, acid cation exchange resin absorption, washing, NaOH regulation is reused
PH to 7.8；
5) crude product refining：
To putting into above-mentioned N (2)-Ala-Gln aqueous solution for being collected into, supplement 1.5 in 2000L reactors
The water of times weight, plus medical charcoal is heated up 42 DEG C, decolourizes 1 hour, and filtering transfer is carried out using titanium filter and accurate filter
To the D grades of 3000L reactor of clean area；To adding methyl alcohol 1800L, plus medical charcoal to heat up 43 DEG C in 3000L reactors, decolourize
1.1 hours, carry out filtering using titanium filter and accurate filter and be transferred to D grades of clean area 500L temporary storage tank, filtrate adds
Methyl alcohol carries out crystallization, 5 DEG C of centrifugations of lowering the temperature, and is dried to constant weight, vacuum 0.06Mpa, drying temperature using vacuum drying chamber
70 DEG C, crush, obtain N (2)-Ala-Gln fine work.
Claims (7)
1. a kind of preparation method of N (2)-Ala-Gln, it is characterised in that the technique life prepared using enzyme process
N (2)-Ala-Gln is produced, is comprised the following steps that：
1) preparation of N- phthalyls-ALANINE：ALANINE, phthalic anhydride are added in reactor, in high temperature melting
Melt and carry out under state synthetic reaction, generation N- phthalyls-ALANINE；
2) preparation of N- phthalyls-L- alanyl chlorides：With toluene as solvent, input N- phthalyls-ALANINE, plus
Enter thionyl chloride, carry out being warming up to 45-55 DEG C, flow back 1-1.2 hours, then insulation reaction 3-3.5 hours, then carry out decompression steaming
Evaporate 3-3.5 hours, vacuum takes out band cooling, obtains N- phthalyl-L- alanyl chlorides；
3) enzyme' s catalysis N (2)-Ala-Gln：By step 2) prepare N- phthalyl-L- alanyl chlorides
In input water, pH to 7.5-8.0 is adjusted with NaOH, put into glutamine, immobilization peptidyl transferase is added to reaction
In, during add sodium acid carbonate regulation pH to 7.5-8.0, stirring, reaction solution is through being centrifuged to obtain N (2)-L- alanyl-L- paddy
Aminoacyl amine aqueous solution；
4) inactivation of enzyme：Above-mentioned N (the 2)-Ala-Gln solution that will be collected into is added in methanol solvate, analysis
Solid N (2)-Ala-Gln is centrifuged to obtain after crystalline substance, then solid N (2)-Ala-Gln is put into water
In, 55-65 DEG C is heated to, charcoal absorption filtering is added, reuse acid cation exchange resin absorption, washing, hydroxide
Sodium adjusts pH to 7.5-8.0, obtains N (2)-Ala-Gln crude product aqueous solution；
5) crude product refining：To 1.5 times of water of weight are added in N (2)-Ala-Gln crude product aqueous solution, dosing is used
Charcoal is warming up to 40-45 DEG C, decolouring 1-1.2 hours, is filtered using accurate filter, and filtrate adds methyl alcohol crystallization, after centrifugation
Drying and crushing, obtains N (2)-Ala-Gln fine work.
2. the preparation method of N (2)-Ala-Gln according to claim 1, it is characterised in that：Step 1)
Middle ALANINE, the mass ratio of phthalic anhydride are 10:16-18.
3. the preparation method of N (2)-Ala-Gln according to claim 1, it is characterised in that：Step 1)
In reaction temperature be 140-150 DEG C.
4. the preparation method of N (2)-Ala-Gln according to claim 1, it is characterised in that：Step 2)
Middle N- phthalyls-ALANINE is 135 with the mass ratio of toluene solvant:190-210.
5. the preparation method of N (2)-Ala-Gln according to claim 1, it is characterised in that：Step 3)
Middle peptidyl transferase is 1 with the volume ratio of solution:30-35.
6. according to the preparation method of N (the 2)-Ala-Gln described in claim 1, it is characterised in that：Step 3) in
The peptidyl transferase enzyme for using is fixed using absorption method to it, while carrying out embedding formation to it with sodium alginate shitosan
Microencapsulation immobilised enzymes.
7. according to the preparation method of N (the 2)-Ala-Gln described in claim 1, it is characterised in that：Step 3) in
Reaction temperature be 40-45 DEG C.
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Citations (7)
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|---|---|---|---|---|
| EP0595345A1 (en) * | 1992-10-29 | 1994-05-04 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing alanylglutamine |
| US20050032187A1 (en) * | 2003-08-01 | 2005-02-10 | Ajinomoto Co., Inc. | Novel peptide-forming enzyme, microbe producing the enzyme and method for producing peptide using them |
| CN101423857A (en) * | 2008-12-10 | 2009-05-06 | 天津大学 | Enzymatic synthesis method of Z-L-alanyl-L-glutamine |
| CN103387600A (en) * | 2013-07-26 | 2013-11-13 | 重庆康施恩化工有限公司 | New preparation method of L-alanyl-L-glutamine |
| CN103626839A (en) * | 2013-12-19 | 2014-03-12 | 济南诚汇双达化工有限公司 | Preparation method of N(2)-L-alanyl-L-glutamine |
| CN104177472A (en) * | 2013-05-27 | 2014-12-03 | 枣庄兰氏化学有限公司 | Preparation method for o-phthaloyl-L-alanyl-L-glutamine |
| CN104561202A (en) * | 2015-02-06 | 2015-04-29 | 江苏诚信药业有限公司 | Preparation method and technological system for enzymatically synthesizing N(2)-L-alanyl-L-glutamine |
-
2016
- 2016-12-30 CN CN201611257271.0A patent/CN106701869A/en active Pending
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|---|---|---|---|---|
| EP0595345A1 (en) * | 1992-10-29 | 1994-05-04 | Kyowa Hakko Kogyo Co., Ltd. | Process for producing alanylglutamine |
| US20050032187A1 (en) * | 2003-08-01 | 2005-02-10 | Ajinomoto Co., Inc. | Novel peptide-forming enzyme, microbe producing the enzyme and method for producing peptide using them |
| CN101423857A (en) * | 2008-12-10 | 2009-05-06 | 天津大学 | Enzymatic synthesis method of Z-L-alanyl-L-glutamine |
| CN104177472A (en) * | 2013-05-27 | 2014-12-03 | 枣庄兰氏化学有限公司 | Preparation method for o-phthaloyl-L-alanyl-L-glutamine |
| CN103387600A (en) * | 2013-07-26 | 2013-11-13 | 重庆康施恩化工有限公司 | New preparation method of L-alanyl-L-glutamine |
| CN103626839A (en) * | 2013-12-19 | 2014-03-12 | 济南诚汇双达化工有限公司 | Preparation method of N(2)-L-alanyl-L-glutamine |
| CN104561202A (en) * | 2015-02-06 | 2015-04-29 | 江苏诚信药业有限公司 | Preparation method and technological system for enzymatically synthesizing N(2)-L-alanyl-L-glutamine |
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