CN108586291A - A kind of N, N- are bis-（Carboxymethyl）The production technology of L-lysine - Google Patents
A kind of N, N- are bis-（Carboxymethyl）The production technology of L-lysine Download PDFInfo
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- CN108586291A CN108586291A CN201810002539.9A CN201810002539A CN108586291A CN 108586291 A CN108586291 A CN 108586291A CN 201810002539 A CN201810002539 A CN 201810002539A CN 108586291 A CN108586291 A CN 108586291A
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- bis
- carboxymethyl
- lysines
- lysine
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 23
- 229910052757 nitrogen Inorganic materials 0.000 title claims abstract description 20
- 238000005516 engineering process Methods 0.000 title claims abstract description 18
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 title claims 3
- 235000019766 L-Lysine Nutrition 0.000 title claims 2
- 239000004472 Lysine Substances 0.000 title claims 2
- 235000018977 lysine Nutrition 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims abstract description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 150000002669 lysines Chemical class 0.000 claims abstract description 10
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 7
- 239000007787 solid Substances 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000005119 centrifugation Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000047 product Substances 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- CKGCFBNYQJDIGS-LBPRGKRZSA-N (2s)-2-azaniumyl-6-(phenylmethoxycarbonylamino)hexanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])CCCCNC(=O)OCC1=CC=CC=C1 CKGCFBNYQJDIGS-LBPRGKRZSA-N 0.000 claims description 3
- 230000033228 biological regulation Effects 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 238000010792 warming Methods 0.000 claims description 2
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 claims 8
- SYFQYGMJENQVQT-ZETCQYMHSA-N (2s)-6-amino-2-[bis(carboxymethyl)amino]hexanoic acid Chemical compound NCCCC[C@@H](C(O)=O)N(CC(O)=O)CC(O)=O SYFQYGMJENQVQT-ZETCQYMHSA-N 0.000 claims 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 2
- 239000000706 filtrate Substances 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 230000006837 decompression Effects 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 1
- -1 bis- carboxymethyl Chemical group 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 238000001953 recrystallisation Methods 0.000 abstract 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 13
- 239000003937 drug carrier Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000002082 metal nanoparticle Substances 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000013522 chelant Substances 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000020313 Cell-Penetrating Peptides Human genes 0.000 description 1
- 108010051109 Cell-Penetrating Peptides Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002041 carbon nanotube Substances 0.000 description 1
- 229910021393 carbon nanotube Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000000412 dendrimer Substances 0.000 description 1
- 229920000736 dendritic polymer Polymers 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of N, N is bis-（Carboxymethyl）The production technology of L lysines, includes the following steps：Step A：N6 Cbz L lysines and bromoacetic acid are added in inorganic base weak solution, and under conditions of keeping pH value to be more than 9,6 ~ 12h of heating reaction；Step B：Filtering, centrifugation, drying, obtain N, the bis- carboxymethyl N6 Cbz L lysines of N；Step C：Using palladium carbon as catalyst, hydrogen catalysis reaction；Step D：Solid is precipitated in recrystallization, is dried to obtain N, N is bis-（Carboxymethyl）L lysines.A kind of N disclosed by the invention, N are bis-（Carboxymethyl）The production technology of L lysines is fed intake using trans-, is first dropped in input N6 Cbz L lysines in inorganic base weak solution, is added bromoacetic acid, is reduced the consumption that bromoacetic acid decomposes, is kept its reaction condition milder, improve the yield of product, reduce cost.The present invention also uses crystallisation to extract product, improves the purity of product, obtains the lower product of purity higher, moisture.
Description
Technical field
The invention belongs to the production technical fields of NTA intermediates, and in particular to bis- (the carboxymethyl)-L-lysines of a kind of N, N-
Production technology.
Background technology
Bis- (the carboxymethyl)-L-lysines of N, N- and its derivative be pharmaceutical carrier, nano target technology main intermediate,
It is the primary raw material for producing NTA, product is the research hotspot of domestic and international pharmaceutical carrier at present downstream.
Over the past two decades, bioactive molecule is carried by pharmaceutical carrier and specific target spot is reached by different biological barriers
The development of newtype drug transport system achieves major progress.The emphasis researched and developed at present is dedicated to that the stock friend for the treatment of molecule is overcome to lack
It falls into, such as：Dissolubility (toxicity and absorption problem), stability (degradation in vivo), pharmacokinetics (tachymetabolism) and/or biology point
Cloth (non-specificity distribution) etc..Further, since hydrophobicity, the water solubility of most of anticancer drugs in water is poor, is made with reaching
Drug is more easy to cell internalizing, effect more preferably effect.But poorly water-soluble easily makes drug and pharmaceutical carrier occur being not easy to absorb, poison
Property big, metabolism poor performance the problems such as.
Currently, there are two the raising water-soluble solution of pharmaceutical carrier is main：Method one：Pass through additional hydrophilic function
Group or water soluble molecules (targeting or cell-penetrating peptides, polyethylene glycol or other hydrophilic ligands) carry out the chemistry knot of modified medicaments
Structure.But the increase of drug solubility may destroy the therapeutic activity of drug.Method two：It is specific to use based on drug-cargo system
Nano particle, micella block copolymer, liposome or dendrimer.Method two successfully improves the steady of drug and pharmaceutical carrier
Qualitative and dissolubility keeps its activity unaffected, and bioavailability is improved with the sustained release of time, reduces it
Toxicity, therefore have a good application prospect.But this kind of method is used, needs pharmaceutical carrier that there is highly-water-soluble.
In order to improve the water solubility of pharmaceutical carrier, being typically employed in chelating on metal nanoparticle has highly-water-soluble
The NTA or scion grafting NTA on micella block copolymer, to improve the water solubility of pharmaceutical carrier.
The metallo-chelate of NTA can be also used for modification ordered mesoporous silica dioxide (OMPS) simultaneously, and protein is fixed
In the nano-pore of OMPS, protein is set to be more easy to detach from reaction mixture, and be not easy to deform with environmental change, to increase
Its strong stability.The OMPS and His labels modified with NTA metallo-chelates are effectively compound, can be accurate in recombination process
It is oriented to control, His protein or enzyme is fixed selectively and reversibly, realizes the protein purification from crude cell lysate
Effect.The metallo-chelate of NTA can also build artificial enzyme with metal nanoparticle or be anchored and grow in carbon nano tube surface
Metal nanoparticle.The artificial enzyme of the metallo-chelate of NTA and metal nanoparticle structure can greatly improve antibiotic killing
The activity for closing bacterium, reaches good biomembrane eradicating efficacy, can also reduce the attachment of bacterium, prevents biomembrane in 120h
Interior formation has effectively disperseed the prefabricated biomembrane of all ages and classes.
Not yet there is high income, and be suitable at present as the primary raw material of NTA in bis- (the carboxymethyl)-L-lysines of N, N-
The production technology of industrialized production.
Chem.Eur.J. Sodium azide is used in [J] 2011,17,13059-13067 to be obtained by the reaction at 75 DEG C in DMF
Bis- (the carboxymethyl)-L-lysines of N, N-, this method severe reaction conditions, safety is poor, is not suitable for mass production.
Org.Biomol.Chem. [J] has used N6-Cbz-L- lysines and bromoacetic acid anti-in 2010,8,3902-3907
It answers, then hydrogenates to obtain N, bis- (the carboxymethyl)-L-lysines of N-, but its product yield to be 50%.Bromoacetic acid holds under basic conditions
It easily decomposes, first bromoacetic acid is added in strong base solution, will increase the usage amount of bromoacetic acid, reduce the yield of product, increase cost.
The method yield in amplifying production process can further decrease, and generate a large amount of wastes, be unfavorable for industrialized production.
Present inventor passes through many experiments, screens at different conditions, it was found that is suitble to the condition of industrialized production, effectively
Yield is improved, the method is substantially better than the method mentioned in above-mentioned document.
Invention content
The present invention is directed in the prior art, a kind of N of present invention offer, the production technology of bis- (the carboxymethyl)-L-lysines of N-,
It is fed intake using trans-, is first dropped in input N6-Cbz-L- lysines in inorganic base weak solution, adds bromoacetic acid, reduce bromine second
The consumption that acid decomposes, keeps its reaction condition milder, improves the yield of product, reduce cost.
The present invention is achieved through the following technical solutions, and is included the following steps：
Step A：N6-Cbz-L- lysines are added to the water dissolving, inorganic base weak solution is used in combination to adjust pH value to more than 9
In, bromoacetic acid is stirred and is slowly added dropwise, continuing stirring keeps bromoacetic acid dissolving complete, and inorganic base weak solution is added and keeps system pH
Value is warming up to 40~90 DEG C in 9 or more, then system, is stirred to react 6~12h, and system reaction is completed.
Step B：The system that reaction is completed is cooled to 0~5 DEG C, hydrochloric acid acidification is added, white solid is precipitated, waits for crystallization
Centrifugation, filter cake centrifuge after being beaten with pure water after completely, are dried to obtain N, the bis- carboxymethyl-N6-Cbz-L- lysines of N-.
Step C：Bis- carboxymethyl-N6-Cbz-L- the lysines of the N that step B is obtained, N- are dissolved with 35~50 DEG C of methanol, molten
Solution completely after solution be transferred in autoclave, palladium carbon is added, and after using nitrogen and hydrogen to convert 3 times respectively, is passed through hydrogen and protects
It holds and is stirred to react 6~8h under hydrogen environment, solution reaction is completed, and N, bis- (the carboxymethyl)-L-lysines of N- are generated.
Step D：The solution filtering that reaction is completed, filtered filter cake is eluted with methanol, adds pure water, is heated to
35~60 DEG C are stirred the N for making generation, and bis- (the carboxymethyl)-L-lysine dissolvings of N- are complete, filter again, recycle palladium carbon, filtrate drop
Temperature stirs addition acetone to 0~5 DEG C, and N, bis- (the carboxymethyl)-L-lysines of N- is made to be precipitated, and centrifugation, filtering, drying are produced
Object.
First N6-Cbz-L- lysines are dissolved into inorganic base weak solution in step A, keeps reaction environment milder, subtracts
The decomposition of bromoacetic acid is lacked；After bromoacetic acid is dissolved into inorganic base weak solution simultaneously, it can occur immediately with N6-Cbz-L- lysines
Reaction improves the product yield of step A, reduces cost.
The inorganic base weak solution is one kind in sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide aqueous solution.It is described
Inorganic base weak solution is preferably aqueous sodium carbonate or wet chemical, and alkaline environment is milder, while sodium carbonate
It is added after N6-Cbz-L- lysines, bromoacetic acid in solution or wet chemical, system pH variation range smaller, more
Stablize conducive to reaction system, step A obtains higher product yield.
In step A, the ratio of the bromoacetic acid mole and N6-Cbz-L- lysine moles is 2.5~4:1.
In step C, the addition of the methanol is the N that step B is obtained, the bis- carboxymethyl-N6-Cbz-L- lysines matter of N-
20~40 times of amount.
In step C, the palladium carbon is the palladium carbon of content 5% or 10%.The addition of the palladium carbon is N, the bis- carboxymethyls-of N-
The 5~10% of N6-Cbz-L- lysine quality.
In step C, the hydrogen environment is 0.2~0.5MPa to be continually fed into hydrogen and keeping reacting kettle inner pressure.
The mass ratio of water and saturated sodium-chloride water solution that addition is washed in the step C is 1:1；The saturated sodium-chloride
The mass ratio of aqueous solution and L-arginine is 1~3:1.
Preferably, the purifying process specifically includes following steps：
Step A：N6-Cbz-L- lysines are added in a concentration of 10% sodium hydroxide solution, adjusts pH value and is more than 9,
And according to the molar ratio of bromoacetic acid and N6-Cbz-L- lysines it is 2.5~4:1 ratio is slowly added dropwise and bromoacetic acid, and stirring is simultaneously
Keep system temperature in 0~30 DEG C of range, the sodium hydroxide solution for being added 10% keeps system pH 9 or more, continues to stir
0.5~2h keeps bromoacetic acid dissolving complete, is then heated to 55~60 DEG C, is stirred to react 6~12h, and system reaction is completed；
Step B：The system that reaction is completed is cooled to 0 DEG C, the hydrochloric acid regulation system pH value for adding 10% is 1~2, analysis
Go out white solid, centrifuged after crystallization is complete, filter cake centrifuges after being beaten with pure water, and concentrate drying obtains N, the bis- carboxymethyl-N6- of N-
Cbz-L- lysines；
Step C：Bis- carboxymethyl-N6-Cbz-L- the lysines of the N that step B is obtained, N- are dissolved with 40 DEG C of methanol, wherein first
The addition of alcohol is N, and 25~35 times of the bis- carboxymethyl-N6-Cbz-L- lysines quality of N-, solution transfer is supreme after dissolving completely
It presses in kettle, the palladium carbon of addition content 5% or 10%, the 5 of the bis- carboxymethyl-N6-Cbz-L- lysines quality of addition N, N-
~10%, and after using nitrogen and hydrogen to convert 3 times respectively, be continually fed into hydrogen and keep reacting kettle inner pressure be 0.2~
0.5MPa is stirred to react 6~8h, and solution reaction is completed, and N, bis- (the carboxymethyl)-L-lysines of N- are generated；
Step D：The solution filtering that reaction is completed, filtered filter cake is eluted with methanol, adds pure water, is heated to
40~55 DEG C are stirred the N for making generation, and bis- (the carboxymethyl)-L-lysine dissolvings of N- are complete, filter again, recycle palladium carbon, filtrate subtracts
Pressure is concentrated into half, is cooled to 0 DEG C, and stir addition acetone, so that N, bis- (the carboxymethyl)-L-lysines of N- is precipitated, centrifugation, mistake
Filter, drying, obtain product.
Compared with prior art, the present invention haing the following advantages and advantageous effect：
(1) production technology of bis- (the carboxymethyl)-L-lysines of a kind of N provided by the present invention, N- is fed intake using trans-, first
Input N6-Cbz-L- lysines in inorganic base weak solution are dropped in, bromoacetic acid is added, the consumption that bromoacetic acid decomposes is reduced, makes
Its reaction condition is milder, improves the yield of product, so that the reaction conversion ratio of step A is reached 85% or more, entirely produces work
The product yield of skill reaches 85% or more, reduces cost.
(2) using crystallization in the production craft step D of bis- (the carboxymethyl)-L-lysines of a kind of N provided by the present invention, N-
Method extracts product, improves the purity of product, obtains purity higher, the lower product of moisture, purity can reach 99%
More than.
Specific implementation mode
The present invention is described in further detail with reference to embodiment, embodiments of the present invention are not limited thereto.
Chemical reaction according to the present invention is：
Embodiment 1
The production technology of bis- (the carboxymethyl)-L-lysines of a kind of N provided by the present invention, N- prepares N using following steps,
Bis- (the carboxymethyl)-L-lysines of N-：
Step A：7% sodium hydrate aqueous solution that 160kg is prepared with deionized water, cools to 5 DEG C, weighs 28kg
The N6-Cbz-L- lysines of (100mol) are added in sodium hydrate aqueous solution, and stirring makes N6-Cbz-L- lysines be completely dissolved,
Bromoacetic acid 34.5kg (250mol) is added portionwise in holding at 5 DEG C, then 10% sodium hydrate aqueous solution 160kg is added dropwise, and keeps
PH value is not less than 9 in system, adds and warms naturally to room temperature, continues to stir 1h, bromoacetic acid is made to be completely dissolved.It is to slowly warm up to 40
It DEG C is stirred to react 12h, system reaction is completed.
Step B：The system that reaction is completed is cooled to 0 DEG C, the hydrochloric acid regulation system pH value for adding 5% is 1~2, analysis
Go out a large amount of white solids, centrifuged after crystallization is complete, filter cake centrifuges after being beaten with 60kg pure water, and concentrate drying obtains N, the bis- carboxylics of N-
Methyl-N6-Cbz-L- lysine 35kg, yield 88.38%, purity 99.2%.
Step C：By the N of the obtained 35kg of step B, the bis- carboxymethyl-N6-Cbz-L- lysines of N- are with 40 DEG C of 1000kg
Hot methanol dissolves, and solution is transferred in autoclave after dissolving completely, the palladium carbon 5kg of content 5% is added, and use nitrogen and hydrogen respectively
After gas shift 3 times, it is 0.5MPa to be continually fed into hydrogen and keep reacting kettle inner pressure, is stirred to react 6h, and solution reaction is completed, raw
At N, bis- (the carboxymethyl)-L-lysines of N-；
Step D：The solution filtering that reaction is completed, filtered filter cake 20kg methanol is eluted, it is pure to add 100kg
Water is heated to 35 DEG C and stirs the N for making generation, and bis- (the carboxymethyl)-L-lysine dissolvings of N- are complete, filter again, recycle palladium carbon, filter
Liquid is concentrated under reduced pressure into half, is cooled to 0 DEG C, and stirs and 20kg acetone is added, and stands 12h, N, bis- (the carboxymethyl)-L- of N- is made to rely ammonia
Acid out goes out, and centrifuges, filters, dries, and obtains product 20kg, yield 86%, 99% or more content.
Embodiment 2
The production technology of bis- (the carboxymethyl)-L-lysines of a kind of N provided by the present invention, N- prepares N using following steps,
Bis- (the carboxymethyl)-L-lysines of N-：
Step A：350kg wet chemicals are prepared with the potassium carbonate of 50kg, after being cooled to room temperature, weigh 28kg
The N6-Cbz-L- lysines of (100mol) are added, and stirring makes N6-Cbz-L- lysines be completely dissolved, and keep slowly adding at room temperature
Entering bromoacetic acid 35kg (253mol), stirs, pH value is not less than 9 in holding system, warms naturally to room temperature, continues to stir 0.5h,
Bromoacetic acid is set to be completely dissolved.It is to slowly warm up to 60 DEG C and is stirred to react 8h, system reaction is completed.
Step B：The system that reaction is completed is cooled to 0 DEG C, the hydrochloric acid regulation system pH value for adding 10% is 1~2, analysis
Go out a large amount of white solids, centrifuged after crystallization is complete, filter cake centrifuges after being beaten with 60kg pure water, and concentrate drying obtains N, the bis- carboxylics of N-
Methyl-N6-Cbz-L- lysine 36kg, yield 90.9%, purity 99.5%.
Step C：By the N of the obtained 36kg of step B, the bis- carboxymethyl-N6-Cbz-L- lysines of N- are with 40 DEG C of 1000kg
Hot methanol dissolves, and solution is transferred in autoclave after dissolving completely, and the palladium carbon 2.5kg of content 10% is added, and uses nitrogen respectively
After being converted 3 times with hydrogen, it is 0.2MPa to be continually fed into hydrogen and keep reacting kettle inner pressure, is stirred to react 8h, pressure no longer under
Drop, solution reaction are completed, and N, bis- (the carboxymethyl)-L-lysines of N- are generated；
Step D：The solution filtering that reaction is completed, filtered filter cake 20kg methanol is eluted, it is pure to add 100kg
Water is heated to 50 DEG C and stirs the N for making generation, and bis- (the carboxymethyl)-L-lysine dissolvings of N- are complete, filter again, recycle palladium carbon, filter
Liquid is concentrated under reduced pressure into half, is cooled to 0 DEG C, and stirs and 20kg acetone is added, and stands 12h, N, bis- (the carboxymethyl)-L- of N- is made to rely ammonia
Acid out goes out, and centrifuges, filters, dries, and obtains product 21kg, yield 88%, 99% or more content.
Embodiment 3
The production technology of bis- (the carboxymethyl)-L-lysines of a kind of N provided by the present invention, N- prepares N using following steps,
Bis- (the carboxymethyl)-L-lysines of N-：
Step A：7% potassium hydroxide aqueous solution that 160kg is prepared with deionized water, cools to 5 DEG C, weighs 28kg
The N6-Cbz-L- lysines of (100mol) are added, and stirring makes N6-Cbz-L- lysines be completely dissolved, and keeps at 5 DEG C in batches
Bromoacetic acid 34.5kg (250mol) is added, then 10% sodium hydrate aqueous solution 160kg is added dropwise, pH value is not less than in holding system
9, it adds and warms naturally to room temperature, continue to stir 1h, bromoacetic acid is made to be completely dissolved.It is to slowly warm up to 80 DEG C and is stirred to react 6h, body
System's reaction is completed.
Step B：The system that reaction is completed is cooled to 0 DEG C, the hydrochloric acid regulation system pH value for adding 10% is 1~2, analysis
Go out a large amount of white solids, centrifuged after crystallization is complete, filter cake centrifuges after being beaten with 60kg pure water, and concentrate drying obtains N, the bis- carboxylics of N-
Methyl-N6-Cbz-L- lysine 36.5kg, yield 92.17%, purity 99.5%.
Step C：By the N of the obtained 36.5kg of step B, the bis- carboxymethyl-N6-Cbz-L- lysines of N- are with 40 DEG C of 1000kg
Hot methanol dissolving, dissolve completely after solution be transferred in autoclave, be added content 5% palladium carbon 5kg, and respectively use nitrogen and
After hydrogen is converted 3 times, it is 0.2MPa to be continually fed into hydrogen and keep reacting kettle inner pressure, is stirred to react 8h, and pressure no longer declines,
Solution reaction is completed, and N, bis- (the carboxymethyl)-L-lysines of N- are generated；
Step D：The solution filtering that reaction is completed, filtered filter cake 20kg methanol is eluted, it is pure to add 100kg
Water is heated to 50 DEG C and stirs the N for making generation, and bis- (the carboxymethyl)-L-lysine dissolvings of N- are complete, filter again, recycle palladium carbon, filter
Liquid is concentrated under reduced pressure into half, is cooled to 0 DEG C, and stirs and 20kg acetone is added, and stands 12h, N, bis- (the carboxymethyl)-L- of N- is made to rely ammonia
Acid out goes out, and centrifuges, filters, dries, and obtains product 22kg, yield 91%, 99% or more content.
The product that Examples 1 to 3 obtains is detected using nuclear-magnetism (hydrogen spectrum) and mass spectrum (MS), the nuclear-magnetism (hydrogen spectrum)
In with D2For O as solvent, spectrometer frequency is 400MHz.The detection data that its nuclear-magnetism (hydrogen spectrum) obtains is：3.90-4.00 (m,
5H)；3.02-3.05 (t, 2H)；1.65-2.05(m；6H)；The detection data that its mass spectrum obtains is：m/z：263[M+ H]+, 285
[M+ Na]+, consistent with target product, it can be seen that, product prepared by production technology provided by the invention is N, bis- (the carboxylic first of N-
Base)-L-lysine.
| Data name | Fusing point (DEG C) | Moisture (%) |
| Embodiment one | 205.6-206.0 | 0.46 |
| Embodiment two | 205.4-205.9 | 0.48 |
| Embodiment three | 205.5-205.9 | 0.45 |
Table 1
The present invention also uses the fusing point and moisture of thermal analyzer measurement product, testing result as shown in table 1.
The above is only presently preferred embodiments of the present invention, not does limitation in any form to the present invention, it is every according to
According to the technical spirit of the present invention to any simple modification, equivalent variations made by above example, the protection of the present invention is each fallen within
Within the scope of.
Claims (8)
1. a kind of N, N- are bis-（Carboxymethyl）The production technology of L-lysine, which is characterized in that include the following steps：
Step A：N6-Cbz-L- lysines are added to the water dissolving, inorganic base weak solution is used in combination to adjust pH value to more than 9, stirring
And bromoacetic acid is slowly added dropwise, continuing stirring keeps bromoacetic acid dissolving complete, and be added inorganic base weak solution keep system pH 9 with
On, then system is warming up to 40 ~ 90 DEG C, is stirred to react 6 ~ 12h, and system reaction is completed；
Step B：The system that reaction is completed is cooled to 0 ~ 5 DEG C, hydrochloric acid acidification is added, white solid is precipitated, waits for that crystallization is complete
After centrifuge, filter cake centrifuges after being beaten with pure water, is dried to obtain N, the bis- carboxymethyl-N6-Cbz-L- lysines of N-；
Step C：Bis- carboxymethyl-N6-Cbz-L- the lysines of the N that step B is obtained, N- are dissolved with 35 ~ 50 DEG C of methanol, have been dissolved
Solution is transferred in autoclave after complete, and palladium carbon is added, and after using nitrogen and hydrogen to convert respectively 3 times, is passed through hydrogen and is maintained at
It is stirred to react 6 ~ 8h reactions under hydrogen environment to complete, generates N, N- is bis-（Carboxymethyl）L-lysine；
Step D：The solution filtering that reaction is completed, filtered filter cake is eluted with methanol, adds pure water, it is heated to 35 ~
60 DEG C are stirred the N for making generation, and N- is bis-（Carboxymethyl）L-lysine dissolving is complete, filters again, recycles palladium carbon, and filtrate is cooled to 0
~ 5 DEG C, and addition acetone is stirred, keep N, N- bis-（Carboxymethyl）L-lysine is precipitated, and centrifugation, filtering, drying obtain product.
2. a kind of N according to claim 1, N- are bis-（Carboxymethyl）The production technology of L-lysine, it is characterised in that：Institute
It is one kind in sodium hydroxide, sodium carbonate, potassium carbonate, potassium hydroxide aqueous solution to state inorganic base weak solution.
3. a kind of N according to claim 1, N- are bis-（Carboxymethyl）The production technology of L-lysine, it is characterised in that：Step
In rapid A, the ratio of the bromoacetic acid mole and N6-Cbz-L- lysine moles is 2.5 ~ 4:1.
4. a kind of N according to claim 1, N- are bis-（Carboxymethyl）The production technology of L-lysine, it is characterised in that：Step
In rapid C, the addition of the methanol is the N that step B is obtained, the 20 ~ 40 of the bis- carboxymethyl-N6-Cbz-L- lysines quality of N-
Times.
5. a kind of N according to claim 1, N- are bis-（Carboxymethyl）The production technology of L-lysine, it is characterised in that：Step
In rapid C, the palladium carbon is the palladium carbon of content 5% or 10%.
6. a kind of N according to claim 5, N- are bis-（Carboxymethyl）The production technology of L-lysine, it is characterised in that：Institute
State palladium carbon addition be N, the 5 ~ 10% of the bis- carboxymethyl-N6-Cbz-L- lysines quality of N-.
7. a kind of N according to claim 1, N- are bis-（Carboxymethyl）The production technology of L-lysine, it is characterised in that：Step
In rapid C, the hydrogen environment is 0.2 ~ 0.5MPa to be continually fed into hydrogen and keeping reacting kettle inner pressure.
8. according to a kind of N of claim 1 ~ 7 any one of them, N- is bis-（Carboxymethyl）The production technology of L-lysine, feature
It is：Include the following steps：
Step A：N6-Cbz-L- lysines are added in a concentration of 7% sodium hydroxide solution, adjust pH value more than 9, and according to
The molar ratio of bromoacetic acid and N6-Cbz-L- lysines is 2.5 ~ 4:1 ratio is slowly added dropwise and bromoacetic acid, stirs and keeps system
Temperature keeps system pH 9 or more, continues 0.5 ~ 2h of stirring, make bromine in 0 ~ 30 DEG C of range, the sodium hydroxide solution for being added 10%
Acetic acid is complete, is then heated to 55 ~ 60 DEG C, is stirred to react 6 ~ 12h, and system reaction is completed；
Step B：The system that reaction is completed is cooled to 0 DEG C, the hydrochloric acid regulation system pH value for adding 10% is 1 ~ 2, and white is precipitated
Solid centrifuges after crystallization is complete, and filter cake centrifuges after being beaten with pure water, and concentrate drying obtains N, the bis- carboxymethyl-N6-Cbz- of N-
L-lysine；
Step C：Bis- carboxymethyl-N6-Cbz-L- the lysines of the N that step B is obtained, N- dissolve with 40 DEG C of methanol, wherein methanol
Addition is N, and 25 ~ 35 times of the bis- carboxymethyl-N6-Cbz-L- lysines quality of N-, solution is transferred to autoclave after dissolving completely
In, the palladium carbon of addition content 5% or 10%, the 5 ~ 10% of the bis- carboxymethyl-N6-Cbz-L- lysines quality of addition N, N-,
And after using nitrogen and hydrogen to convert respectively 3 times, it is 0.2 ~ 0.5MPa to be continually fed into hydrogen and keep reacting kettle inner pressure, and stirring is anti-
It answers 6 ~ 8h, solution reaction to complete, generates N, N- is bis-（Carboxymethyl）L-lysine；
Step D：The solution filtering that reaction is completed, filtered filter cake is eluted with methanol, adds pure water, it is heated to 40 ~
55 DEG C are stirred the N for making generation, and N- is bis-（Carboxymethyl）L-lysine dissolving is complete, filters again, recycles palladium carbon, and filtrate decompression is dense
It is reduced to half, is cooled to 0 DEG C, and stirs addition acetone, keeps N, N- bis-（Carboxymethyl）L-lysine is precipitated, and centrifugation, is done filtering
It is dry, obtain product.
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