CN104629045B - The method of epsilon-polylysine is prepared in a kind of ring-opening polymerisation - Google Patents
The method of epsilon-polylysine is prepared in a kind of ring-opening polymerisation Download PDFInfo
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Abstract
The present invention relates to a kind of method that ε polylysine is prepared in ring-opening polymerisation, belong to synthetic method of polymers field.Solving existing ε polylysine mainly to be prepared by biological fermentation process, production cost is higher, and less than 4,000 and molecular weight cannot regulate the polymer molecular weight simultaneously obtained by biological fermentation process, greatly limit the technical problem of the application of ε polylysine.The method is the heptatomic ring shape lactams by lysine monomer cyclization obtains band α amino, then prepares ε polylysine by the ring-opening polymerisation of heptatomic ring shape lactam monomers.The preparation method that the present invention provides uses cheap Renewable resource L lysine to be initiation material, the ε polylysine with the adjustable molecular weight of very high added value can be obtained efficiently, the molecular weight of gained ε polylysine is 3,000 100000, and the method low cost.
Description
Technical field
The present invention relates to synthetic method of polymers field, be specifically related to a kind of ring-opening polymerisation and prepare epsilon-polylysine
Method.
Background technology
In the polymer of lysine, due to different from the position of the amino that carboxyl is condensed, polymer has α and ε
Two kinds of forms (Fig. 1).α-polylysine (α-PL) is by N-carboxylic acid anhydrides (NCA) monomer of lysine,
Prepared by ring-opening polymerisation.The lysine NCA monomer ring-opening polymerisation that transition metal causes, can synthesize and obtain
Molecular weight and be distributed controlled α-polylysine, but the cytotoxicity of α-polylysine, limit its application
Field.The epsilon-polylysine (ε-PL) prepared by microbe fermentation method, safety non-toxic, biodegradable and have
There is the anti-microbial property of excellence, protected for the anticorrosion of food by U.S. food drug surveilance office (FDA) approval
Fresh and the additive of cosmetics.But the microbe fermentation method epsilon-polylysine molecular weight that obtains of synthesis less than
4000, limit its a lot of application.Accordingly, it would be desirable to explore the new way of chemical method synthesis epsilon-polylysine.
Ring-opening polymerisation products therefrom and monomer have same composition, and side reaction is fewer than polycondensation reaction, not existence etc.
The problem of equivalent proportioning, it is easy to obtain heavy polymer.Therefore, be widely used in poly(propylene oxide),
The commercial production of polycaprolactam, polysiloxanes, polylactic acid etc..
Summary of the invention
The invention solves the problems that in prior art, epsilon-polylysine is mainly prepared by biological fermentation process, production cost is relatively
Height, less than 4,000 and molecular weight cannot regulate, significantly the polymer molecular weight simultaneously obtained by biological fermentation process
Limit the technical problem of the application of epsilon-polylysine, it is provided that epsilon-polylysine is prepared in a kind of ring-opening polymerisation
Method, the method low cost, prepared epsilon-polylysine adjustable molecular weight save.
In order to solve above-mentioned technical problem, technical scheme is specific as follows:
The method of epsilon-polylysine is prepared in a kind of ring-opening polymerisation, comprises the following steps:
(1) preparation of 1B methyl ester dihydrochloride:
With L-lysine hydrochloride as raw material, methanol, as solvent and methyl esterification reagent, drips chlorination reagent,
React 2～24 hours, sucking filtration, i.e. can get 1B methyl ester dihydrochloride；
(2) preparation of (S)-alpha-amido caprolactam:
1B methyl ester dihydrochloride step (1) prepared is dissolved in methanol solvate, adds alkali,
React 6～24 hours, sucking filtration, concentrate, after recrystallization, obtain (S)-alpha-amido caprolactam；
(3) preparation of (S)-α-protection mino-caprolactam:
(S)-alpha-amido caprolactam step (2) prepared, is carried out amino by blocking group
Protection, i.e. obtains (S)-α-protection mino-caprolactam；
(4) preparation of poly-(S)-α-protection amino-lysine:
After adding catalyst in (S)-α-protection mino-caprolactam that step (3) prepares,
Polymerase 10 .5～10 hours at 120 DEG C～300 DEG C, i.e. can obtain poly-(S)-α-protection amino-lysine；
(5) preparation of epsilon-polylysine:
After poly-(S)-α-protection amino-lysine step (4) prepared sloughs blocking group, obtain
Epsilon-polylysine.
In technique scheme, the chlorination reagent described in step (1) is Benzenecarbonyl chloride., sulfonic acid chloride, second
One or more in acyl chlorides and thionyl chloride.
In technique scheme, the dropping temperature dripping chlorination reagent described in step (1) is-78 DEG C～10 DEG C,
After dropping, reaction temperature is 10 DEG C～100 DEG C.
In technique scheme, the alkali described in step (2) is triethylamine, ammonia, strong aqua ammonia, hydrogen-oxygen
Change sodium, one or more in pyridine and potassium carbonate.
In technique scheme, 1B methyl ester dihydrochloride described in step (2) and the throwing of described alkali
Material ratio is 1:2～5.
In technique scheme, reaction described in step (2) is carried out at temperature is 10 DEG C～50 DEG C.
In technique scheme, described in step (3), blocking group is benzyloxycarbonyl group, tertbutyloxycarbonyl,
Tablet held before the breast by officials methoxycarbonyl group, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, pyrrole radicals, methoxycarbonyl group, carbethoxyl group,
Phthalyl, p-toluenesulfonyl, trifluoroacetyl group, adjacent (to) nitrobenzenesulfonyl, pivaloyl
Base, benzoyl, trityl, 2,4-dimethoxy-benzyls, to the one in methoxy-benzyl and benzyl or
Multiple.
In technique scheme, catalyst described in step (4) is Cabbeen class reagent, alkali metal, alkali gold
Belong to oxide, alkali metal hydroxide, alkali metal hydride, alkali metal alcoholates, alkaline-earth metal, alkaline earth gold
Belong to oxide, alkaline earth metal hydroxide, alkaline earth metal hydride or alkaline-earth alkoxides.
In technique scheme, catalyst described in step (4) account for described (S)-α-protection amino-oneself in
Amide molar fraction ratio is 0.02%～6%.
In technique scheme, poly-(the S)-α described in step (5), step (4) prepared-
It is oxolane that protection amino-lysine sloughs blocking group solvent for use, DMF, DMSO, methanol, second
One or more in alcohol, glycol dimethyl ether, chloroform, dichloromethane and water, reaction temperature is
20 DEG C～130 DEG C.
The invention has the beneficial effects as follows:
The method that epsilon-polylysine is prepared in the ring-opening polymerisation that the present invention provides, the method is by by lysine monomer
Cyclization obtains the heptatomic ring shape lactams of band α amino, then by the ring-opening polymerisation system of heptatomic ring shape lactam monomers
Standby epsilon-polylysine (seeing Fig. 2).
The preparation method that the present invention provides uses cheap Renewable resource 1B to be initiation material, it is possible to
Obtain the epsilon-polylysine with the very adjustable molecular weight of high added value efficiently, dividing of gained epsilon-polylysine
Son amount is 3000-100000, and the method low cost.
Accompanying drawing explanation
With detailed description of the invention, the present invention is described in further detail below in conjunction with the accompanying drawings.
Fig. 1 is the structural representation of α-polylysine and epsilon-polylysine.
Fig. 2 is the procedure chart that ring-opening polymerisation method prepares epsilon-polylysine.
Detailed description of the invention
Below in conjunction with the accompanying drawings the present invention is described in detail.
See the ring-opening polymerisation that Fig. 2 illustrates the present invention and provide and prepare the concrete steps of method of epsilon-polylysine
As follows:
(1) preparation of formula II 1B methyl ester dihydrochloride:
With L-lysine hydrochloride as raw material, methanol is as solvent and methyl esterification reagent, at-78 DEG C～10 DEG C
Dropping chlorination reagent, reacts 2～24 hours, sucking filtration at temperature is 10 DEG C～100 DEG C, i.e. can get L-and relies
Propylhomoserin methyl ester dihydrochloride；Chlorination reagent used is (1.5～20) with L-lysine hydrochloride ratio: 1；
Described chlorination reagent is one or more in Benzenecarbonyl chloride., sulfonic acid chloride, chloroacetic chloride and thionyl chloride；
(2) preparation of formula III (S)-alpha-amido caprolactam:
1B methyl ester dihydrochloride step (1) prepared is dissolved in methanol solvate, adds alkali,
React 6～24 hours at temperature is 10 DEG C～50 DEG C, sucking filtration, concentrate, after recrystallization, obtain (S)-α-ammonia
Base caprolactam；Described 1B methyl ester dihydrochloride is 1:2～5 with the rate of charge of described alkali；
Described alkali be the one in triethylamine, ammonia, strong aqua ammonia, sodium hydroxide, pyridine and potassium carbonate or
Multiple；
(3) preparation of formula IV (S)-α-protection mino-caprolactam:
(S)-alpha-amido caprolactam step (2) prepared, is carried out amino by blocking group
Protection, reacts 2～20 hours at reaction temperature is 20～100 DEG C, i.e. obtains that (S)-α-protection amino-oneself is interior
Amide；Blocking group used is (1～5) with (S)-alpha-amido caprolactam ratio: 1；
Described blocking group is benzyloxycarbonyl group, tertbutyloxycarbonyl, tablet held before the breast by officials methoxycarbonyl group, allyloxycarbonyl, front three
Base silicon carbethoxyl group, pyrrole radicals, methoxycarbonyl group, carbethoxyl group, phthalyl, p-toluenesulfonyl,
Trifluoroacetyl group, adjacent (to) nitrobenzenesulfonyl, pivaloyl group, benzoyl, trityl, 2,4-bis-
Methoxy-benzyl, to one or more in methoxy-benzyl and benzyl；It is preferably benzyl, pyrrole radicals and neighbour
One or more in phenyl-diformyl base.
(4) preparation of formula (V) poly-(S)-α-protection amino-lysine:
After adding catalyst in (S)-α-protection mino-caprolactam that step (3) prepares, displacement
Become nitrogen atmosphere, polymerase 10 .5～10 hours at 120 DEG C～300 DEG C, i.e. can obtain poly-(S)-α-protection amino-
Lysine；Described catalyst account for described (S)-α-protection mino-caprolactam molar fraction ratio be 0.02%～
6%；
Described catalyst is Cabbeen class reagent, alkali metal, alkali metal oxide, alkali metal hydroxide, alkali
Metal hydride, alkali metal alcoholates, alkaline-earth metal, alkaline earth oxide, alkaline earth metal hydroxide,
Alkaline earth metal hydride or alkaline-earth alkoxides；It is preferably potassium hydroxide, potassium tert-butoxide, sodium hydroxide, sodium
Simple substance, one or more in potassium simple substance, Cabbeen class reagent is five yuan or the hexa-atomic i.e. imidazoles of nitrogen heterocyclic ring Cabbeen
Class or tetrahydropyrimidine class Cabbeen；Described imidazoles or tetrahydropyrimidine class Cabbeen agent structure are as follows:
(5) preparation of formula VI epsilon-polylysine:
Poly-(S)-α-protection amino-lysine step (4) prepared sloughs blocking group, reaction temperature
Degree is 20 DEG C～130 DEG C, and the time is 1～30 day, obtains epsilon-polylysine；
Deprotection solvent used is oxolane, DMF, DMSO, methanol, ethanol, glycol dimethyl ether,
One or more in chloroform, dichloromethane and water.
In step (5), deprotection method used is corresponding with step (3).
Using dialysis after having reacted, the most cryodesiccated method obtains polymer.Or it is the most freezing dry
Dry, add a small amount of water and remove the inorganic salt of excess, after centrifugation, i.e. can get polymer.
Below the technical scheme in the embodiment of the present invention is carried out clear, complete description, it is clear that described
Embodiment be only a part of embodiment of the present invention rather than whole embodiments.Based on the reality in the present invention
Execute example, the every other embodiment that those of ordinary skill in the art are obtained under not having creative work premise,
Broadly fall into the protection domain of the invention.
Embodiment 1
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, at ice
Under water bath condition, dropwise drip the Benzenecarbonyl chloride. of 60ml, after being added dropwise to complete, at room temperature continue reaction 45
Minute, it is subsequently placed in 50 DEG C of oil baths heating 12 hours, then room temperature cool overnight, has crystal to separate out,
Filter, wash with ether, be vacuum dried 12 hours at 20 DEG C, obtain 1B methyl ester dihydrochloride 29.2g,
Yield 80%.1H NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H),
4.05 (t, J=6Hz, 1H), 3.73 (s, 3H), 2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m,
J=7.2Hz, 2H), 1.40-1.38 (m, J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, under room temperature, drip 16mL pyridine, react 16h at 15 DEG C, filter, be spin-dried for filtrate, after recrystallization,
Obtain white stringy solids (S)-alpha-amido caprolactam 18.6g, yield 80%.1H NMR(DMSO-d6,
300MHz) δ 7.64 (s, 1H), 4.03 (s, 2H), 3.46 (d, J=11.2Hz, 1H), 3.04 (m, J=12.3Hz, 2H),
1.80-1.65 (m, J=21.2Hz, 2H), 1.56-1.34 (m, J=11.6Hz, 2H), 1.26-1.17 (m, J=12.4Hz, 2H).
(3) preparation of (S)-α-tertbutyloxycarbonyl protection mino-caprolactam
50ml single port bottle is dried, and adds 2.56g (S)-alpha-amido caprolactam, 2.76g potassium carbonate, adds
25ml oxolane dissolves, subsequently the dropping tetrahydrofuran solution containing 4.36g bis-t-butyl carbonate at 40 DEG C.
After being added dropwise to complete, 20 DEG C are stirred 20 hours.After reaction terminates, filter, be spin-dried for, after recrystallization, obtain (S)
-α-tertbutyloxycarbonyl protection mino-caprolactam 2.32g, yield 91%.1H NMR(CDCl3,300MHz)
δ 6.02 (s, 1H), 5.90 (s, 1H), 4.30 (m, 1H), 3.28 (m, 2H), 2.10 (t, 2H), 1.85 (t, 2H),
1.65(m,2H),1.36(m,9H)。
(4) preparation of poly-(S)-α-tertbutyloxycarbonyl protection amino-lysine
Take 10ml single port flask to dry, add (S)-α-tertbutyloxycarbonyl protection mino-caprolactam 0.5g,
Adding 10mg Na simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 120 DEG C are reacted 10 hours.
After reaction terminates, question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-tertbutyloxycarbonyl protection amino-lysine 0.8g, add
Entering the dichloromethane solution of the trifluoroacetic acid (TFA) of 50%, 30 DEG C are reacted 5 days, after reaction terminates, obtain
Yellow solution is by concentrating, and lyophilization, addition 5ml water removes inorganic salt, centrifugation, again freezing
It is dried to obtain epsilon-polylysine.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H),
2.97 (m, 2H), 1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 12000.
Embodiment 2
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, at-78 DEG C
Under the conditions of, dripping 42.8ml thionyl chloride, dropping was more than 1 hour.System is muddy after first becoming clarification.Dropping
After completing, at room temperature reaction 30 minutes, are subsequently placed in 90 DEG C of oil baths be heated to reflux 2 hours, system
Become clear.Then room temperature cool overnight, has crystal to separate out, and filters, uses ether wash crystallization.20℃
Lower vacuum drying 12 hours, obtains 1B methyl ester dihydrochloride 33.6g, yield 92%.1H
NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H), 4.05 (t, J=6Hz, 1H), 3.73 (s, 3H),
2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m, J=7.2Hz, 2H), 1.40-1.38 (m,
J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, at 10 DEG C, the methanol solution 80mL of dropping 8gNaOH, there is white solid to analyse after solution elder generation bleach
Go out, react 24h under room temperature, filter, be spin-dried for filtrate, use 300ml re-crystallizing in ethyl acetate, obtain white silk
Shape solid (S)-alpha-amido caprolactam 18.2g, yield 78%.1H NMR(DMSO-d6,300MHz)
δ 7.64 (s, 1H), 4.03 (s, 2H), 3.46 (d, J=11.2Hz, 1H), 3.04 (m, J=12.3Hz, 2H),
1.80-1.65 (m, J=21.2Hz, 2H), 1.56-1.34 (m, J=11.6Hz, 2H), 1.26-1.17 (m, J=12.4Hz, 2H).
(3) (S)-α-pyrroles protects the preparation of mino-caprolactam
50ml single port bottle is dried, and adds 0.5g (S)-alpha-amido caprolactam, adds 25ml methanol and dissolves,
0.25ml acetic acid and 0.5ml 2,5-acetyl butyryl is dripped subsequently under room temperature.After being added dropwise to complete, under nitrogen protection,
80 DEG C are refluxed 12 hours.After reaction terminates, question response liquid is cooled to room temperature, extracts three times with dichloromethane,
Merge organic facies, and be dried 2 hours, after concentrated solvent, column chromatography for separation with anhydrous sodium sulfate, obtain (S)
-α-pyrroles protects mino-caprolactam 0.48g, yield 90%.1H NMR(CDCl3,300MHz)δ7.47(s,
1H), 5.85 (s, 2H), 4.87 (d, 1H), 3.31 (s, 2H), 2.32 (s, 6H), 2.22 (m, 3H), 1.77 (d, 1H),
1.49(m,1H)。
(4) poly-(S)-α-pyrroles protects the preparation of amino-lysine
50ml single port bottle is dried, and adds 1g (S)-α-pyrroles and protects mino-caprolactam, adds 1mg Na
Simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 300 DEG C are reacted 0.5 hour.After reaction terminates,
Question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-pyrroles and protect amino-lysine 0.75g.Add 300ml
Dioxane dissolves, and is subsequently added 5.02g oxammonium hydrochloride. 120ml aqueous solution, and evacuation replaces nitrogen 3 times,
Add 5.15ml triethylamine.It is warming up to 110 DEG C, refluxes 30 days.Obtain yellow solution by concentration, freezing
It is dried, adds 5ml water and remove inorganic salt, centrifugation, after drying, obtain yellow solid 0.33g, receive
Rate 72%.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H), 2.97 (m, 2H),
1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 79000.
Embodiment 3
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, in temperature
Degree is at 10 DEG C, drips 42.8ml sulfonic acid chloride, and dropping was more than 1 hour.System is muddy after first becoming clarification.Drip
After having added, react 30 minutes under this room temperature, be subsequently placed to reacting by heating 24 hours in 10 DEG C of oil baths,
System becomes clear.Then room temperature cool overnight, has crystal to separate out, and filters, uses ether wash crystallization.
It is vacuum dried 12 hours at 20 DEG C, obtains 1B methyl ester dihydrochloride 31.8g, yield 87%.1H
NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H), 4.05 (t, J=6Hz, 1H), 3.73 (s, 3H),
2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m, J=7.2Hz, 2H), 1.40-1.38 (m,
J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, under room temperature, the pyridine 28mL that dropping is dried, there is white solid to separate out, under room temperature after solution elder generation bleach
Reaction 6h, filters, is spin-dried for filtrate, uses 300ml re-crystallizing in ethyl acetate, obtains white stringy solids (S)
-alpha-amido caprolactam 14g, yield 60%.1H NMR(DMSO-d6, 300MHz) and δ 7.64 (s, 1H),
4.03 (s, 2H), 3.46 (d, J=11.2Hz, 1H), 3.04 (m, J=12.3Hz, 2H), 1.80-1.65 (m, J=21.2Hz, 2H),
1.56-1.34 (m, J=11.6Hz, 2H), 1.26-1.17 (m, J=12.4Hz, 2H).
(3) preparation of (S)-α-phthalyl protection mino-caprolactam
50ml single port bottle is dried, evacuation displacement nitrogen 3 times, under nitrogen protection, and addition 0.5g (S)-α-
Aminocaproic lactam, adds 25ml chloroform and dissolves, be subsequently added 0.63g phthalic anhydride, at 100 DEG C
Reflux 10 hours, after reaction terminates, column chromatography for separation, i.e. can get pure (S)-α-phthalyl
Base protection mino-caprolactam 0.45,87%.1H NMR(DMSO-d6, 300MHz) δ 7.88 (m, J=9Hz,
4H), 6.72 (s, 1H), 4.53 (t, J=7.6Hz, 1H), 3.25 (t, J=11.6Hz, 2H),
1.86-1.74 (m, J=21.2Hz, 2H), 1.56-1.46 (m, J=31.2Hz, 4H).
(4) preparation of poly-(S)-α-phthalyl protection amino-lysine
10ml single port bottle is dried, and adds 1g (S)-α-phthalyl protection mino-caprolactam, adds
5mg Na simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 300 DEG C are reacted 5 hours.Reaction
After end, question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-phthalyl protection amino-lysine 0.8g,
Adding sodium borohydride 2g, add 300ml oxolane, react 1 day at 50 DEG C, dialysis, lyophilization obtains
To epsilon-polylysine.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H), 2.97 (m, 2H),
1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 42000.
Embodiment 4
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, at ice
Under water bath condition, dripping 42.8ml sulfonic acid chloride, dropping was more than 1 hour.System is muddy after first becoming clarification.Drip
After having added, react 30 minutes at 40 DEG C, be subsequently placed in 100 DEG C of oil baths be heated to reflux 2 hours, body
System becomes clear.Then room temperature cool overnight, has crystal to separate out, and filters, uses ether wash crystallization.
It is vacuum dried 12 hours at 20 DEG C, obtains 1B methyl ester dihydrochloride 31.8g, yield 87%.1H
NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H), 4.05 (t, J=6Hz, 1H), 3.73 (s, 3H),
2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m, J=7.2Hz, 2H), 1.40-1.38 (m,
J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, at 50 DEG C, the dropping methanol solution 80mL containing 20g sodium hydroxide, react 6h at 50 DEG C, filter, rotation
Dry filtrate, after recrystallization, obtains white stringy solids (S)-alpha-amido caprolactam 18.2g, yield 78%.
(3) preparation of (S)-α-benzyloxycarbonyl group protection mino-caprolactam
50ml single port bottle is dried, evacuation displacement nitrogen 3 times, under nitrogen protection, and addition 1g (S)-α-
Aminocaproic lactam, adds 1g NaHCO3, it is subsequently added 10ml water, 4ml oxolane.Lower of ice bath
Add Carbobenzoxy Chloride.Stir 18 hours under room temperature.Reaction adds 10ml water after terminating, and filters, obtains white
Color solid ether Gossypol recrystallized from chloroform.I.e. obtain (S)-α-benzyloxycarbonyl group protection mino-caprolactam 1.4g,
83%.1H NMR(CDCl3, 300MHz) δ 7.37 (s, 5H), 6.17 (m, 2H), 5.12 (s, 2H), 4.38 (m,
1H), 3.25 (m, 2H) 2.11 (m, 2H), 1.86 (m, 2H) 1.39 (m, 2H).
(4) preparation of poly-(S)-α-benzyloxycarbonyl group protection amino-lysine
10ml single port bottle is dried, and adds 1g (S)-α-benzyloxycarbonyl group protection mino-caprolactam, adds 3mg
Na simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 240 DEG C are reacted 2 hours.After reaction terminates,
Question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-benzyloxycarbonyl group protection amino-lysine 1g, add 300ml
Oxolane dissolves, and reacts 1 day at 20 DEG C of logical hydrogen, obtains solution and concentrates, and dialysis, lyophilization obtains
Epsilon-polylysine.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H), 2.97 (m, 2H),
1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 65000.
Embodiment 5
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, at ice
Under water bath condition, dripping 42.8ml sulfonic acid chloride, dropping was more than 1 hour.System is muddy after first becoming clarification.Drip
After having added, react 30 minutes under this room temperature, be subsequently placed in 80 DEG C of oil baths be heated to reflux 5 hours,
System becomes clear.Then room temperature cool overnight, has crystal to separate out, and filters, uses ether wash crystallization.
It is vacuum dried 12 hours at 20 DEG C, obtains 1B methyl ester dihydrochloride 31.8g, yield 87%.1H
NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H), 4.05 (t, J=6Hz, 1H), 3.73 (s, 3H),
2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m, J=7.2Hz, 2H), 1.40-1.38 (m,
J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, under room temperature, the pyridine 28mL that dropping is dried, there is white solid to separate out after solution elder generation bleach, at 50 DEG C
Reaction 8h, filters, is spin-dried for filtrate, uses 300ml re-crystallizing in ethyl acetate, obtains white stringy solids (S)
-alpha-amido caprolactam 14g, yield 60%.1H NMR(DMSO-d6, 300MHz) and δ 7.64 (s, 1H),
4.03 (s, 2H), 3.46 (d, J=11.2Hz, 1H), 3.04 (m, J=12.3Hz, 2H), 1.80-1.65 (m, J=21.2Hz, 2H),
1.56-1.34 (m, J=11.6Hz, 2H), 1.26-1.17 (m, J=12.4Hz, 2H).
(3) preparation of (S)-α-N, N-dibenzyl protection mino-caprolactam
50ml single port bottle is dried, evacuation displacement nitrogen 3 times, under nitrogen protection, and addition 0.3g (S)-α-
Aminocaproic lactam, adds 20ml acetonitrile and dissolves, be subsequently added 10ml benzyl chloride, little 80 DEG C of backflows 4
Time, after reaction terminates, filter, be spin-dried for filtrate, i.e. be can get pure (S)-α-N by silica gel column chromatography,
N-dibenzyl protection mino-caprolactam 0.35,87%.1H NMR(CDCl3, 300MHz) and δ 7.58 (s, 1H),
7.38 (m, 10H), 4.09-4.04 (dd, 4H), 3.47 (d, 1H), 3.14-2.84 (dd, 2H), 2.02-1.30 (m,
6H)。
(4) preparation of poly-(S)-α-N, N-dibenzyl protection amino-lysine
10ml single port bottle is dried, and adds 1g (S)-α-N, N-dibenzyl protection mino-caprolactam, adds
5mg Na simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 270 DEG C are reacted 2 hours.Reaction
After end, question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-N, N-dibenzyl protection amino-lysine 1g, add
Enter 300ml oxolane to dissolve, be continually fed into hydrogen 5 hours at 25 DEG C, obtain solution and concentrate, dialysis,
Lyophilization obtains epsilon-polylysine.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H),
2.97 (m, 2H), 1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 43000.
Embodiment 6
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, at ice
Under water bath condition, dripping 42.8ml sulfonic acid chloride, dropping was more than 1 hour.System is muddy after first becoming clarification.Drip
After having added, react 30 minutes at 40 DEG C, be subsequently placed in 100 DEG C of oil baths be heated to reflux 2 hours, body
System becomes clear.Then room temperature cool overnight, has crystal to separate out, and filters, uses ether wash crystallization.
It is vacuum dried 12 hours at 20 DEG C, obtains 1B methyl ester dihydrochloride 31.8g, yield 87%.1H
NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H), 4.05 (t, J=6Hz, 1H), 3.73 (s, 3H),
2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m, J=7.2Hz, 2H), 1.40-1.38 (m,
J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, at 50 DEG C, the dropping methanol solution 80mL containing 20g sodium hydroxide, react 6h at 50 DEG C, filter, rotation
Dry filtrate, after recrystallization, obtains white stringy solids (S)-alpha-amido caprolactam 18.2g, yield 78%.
(3) preparation of (S)-α-tertbutyloxycarbonyl protection mino-caprolactam
50ml single port bottle is dried, and adds 2.56g (S)-alpha-amido caprolactam, 2.76g potassium carbonate, adds
25ml oxolane dissolves, subsequently the dropping tetrahydrofuran solution containing 4.36g bis-t-butyl carbonate at 40 DEG C.
After being added dropwise to complete, 20 DEG C are stirred 20 hours.After reaction terminates, filter, be spin-dried for, after recrystallization, obtain (S)
-α-tertbutyloxycarbonyl protection mino-caprolactam 2.32g, yield 91%.1H NMR(CDCl3,300MHz)
δ 6.02 (s, 1H), 5.90 (s, 1H), 4.30 (m, 1H), 3.28 (m, 2H), 2.10 (t, 2H), 1.85 (t, 2H),
1.65(m,2H),1.36(m,9H)。
(4) preparation of poly-(S)-α-tertbutyloxycarbonyl protection-lysine
Take 10ml single port flask to dry, add (S)-α-tertbutyloxycarbonyl protection mino-caprolactam 0.5g,
Adding 20mg Na simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 150 DEG C are reacted 5 hours.
After reaction terminates, question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-tertbutyloxycarbonyl protection-lysine 0.8g, add 50%
The dichloromethane solution of trifluoroacetic acid (TFA), 30 DEG C are reacted 10 days, after reaction terminates, obtain yellow
Solution is by concentrating, and lyophilization, addition 5ml water removes inorganic salt, centrifugation, again lyophilization
Obtain epsilon-polylysine.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H), 2.97 (m,
2H), 1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 5500.
Embodiment 7
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, at ice
Under water bath condition, dripping 42.8ml thionyl chloride, dropping was more than 1 hour.System is muddy after first becoming clarification.
After being added dropwise to complete, react 30 minutes under this room temperature, be subsequently placed in 70 DEG C of oil baths be heated to reflux 3 hours,
System becomes clear.Then room temperature cool overnight, has crystal to separate out, and filters, uses ether wash crystallization.
It is vacuum dried 12 hours at 20 DEG C, obtains 1B methyl ester dihydrochloride 33.6g, yield 92%.1H
NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H), 4.05 (t, J=6Hz, 1H), 3.73 (s, 3H),
2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m, J=7.2Hz, 2H), 1.40-1.38 (m,
J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, under room temperature, the methanol solution 80mL of dropping 10gNaOH, there is white solid to analyse after solution elder generation bleach
Go out, react 24h under room temperature, filter, be spin-dried for filtrate, use 300ml re-crystallizing in ethyl acetate, obtain white silk
Shape solid (S)-alpha-amido caprolactam 18.2g, yield 78%.1H NMR(DMSO-d6,300MHz)
δ 7.64 (s, 1H), 4.03 (s, 2H), 3.46 (d, J=11.2Hz, 1H), 3.04 (m, J=12.3Hz, 2H),
1.80-1.65 (m, J=21.2Hz, 2H), 1.56-1.34 (m, J=11.6Hz, 2H), 1.26-1.17 (m, J=12.4Hz, 2H).
(3) preparation of (S)-α-tertbutyloxycarbonyl protection mino-caprolactam
50ml single port bottle is dried, and adds 2.56g (S)-alpha-amido caprolactam, 2.76g potassium carbonate, adds
25ml oxolane dissolves, subsequently the dropping tetrahydrofuran solution containing 4.36g bis-t-butyl carbonate at 40 DEG C.
After being added dropwise to complete, it is stirred at room temperature 18 hours.After reaction terminates, filter, be spin-dried for, after recrystallization, obtain (S)
-α-tertbutyloxycarbonyl protection mino-caprolactam 2.32g, yield 91%.1H NMR(CDCl3,300MHz)
δ 6.02 (s, 1H), 5.90 (s, 1H), 4.30 (m, 1H), 3.28 (m, 2H), 2.10 (t, 2H), 1.85 (t, 2H),
1.65(m,2H),1.36(m,9H)。
(4) preparation of poly-(S)-α-tertbutyloxycarbonyl protection amino-lysine
Take 10ml single port flask to dry, add (S)-α-tertbutyloxycarbonyl protection mino-caprolactam 0.5g,
Adding 8mg Na simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 240 DEG C are reacted 2 hours.
After reaction terminates, question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-tertbutyloxycarbonyl protection amino-lysine 0.8g, add
Entering the dichloromethane solution of the trifluoroacetic acid (TFA) of 50%, 30 DEG C are reacted 3 days, after reaction terminates, obtain
Yellow solution is by concentrating, and lyophilization, addition 5ml water removes inorganic salt, centrifugation, again freezing
It is dried to obtain poly-ε-lysine.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H),
2.97 (m, 2H), 1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 11000.
Embodiment 8
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, at ice
Under water bath condition, dripping 42.8ml sulfonic acid chloride, dropping was more than 1 hour.System is muddy after first becoming clarification.Drip
After having added, at room temperature reaction 30 minutes, are subsequently placed in 70 DEG C of oil baths be heated to reflux 3 hours, body
System becomes clear.Then room temperature cool overnight, has crystal to separate out, and filters, uses ether wash crystallization.
It is vacuum dried 12 hours at 20 DEG C, obtains 1B methyl ester dihydrochloride 31.8g, yield 87%.1H
NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H), 4.05 (t, J=6Hz, 1H), 3.73 (s, 3H),
2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m, J=7.2Hz, 2H), 1.40-1.38 (m,
J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, under room temperature, the pyridine 16mL that dropping is dried, there is white solid to separate out, under room temperature after solution elder generation bleach
Reaction 24h, filters, is spin-dried for filtrate, uses 300ml re-crystallizing in ethyl acetate, obtains white stringy solids (S)
-alpha-amido caprolactam 14g, yield 60%.1H NMR(DMSO-d6, 300MHz) and δ 7.64 (s, 1H),
4.03 (s, 2H), 3.46 (d, J=11.2Hz, 1H), 3.04 (m, J=12.3Hz, 2H), 1.80-1.65 (m, J=21.2Hz, 2H),
1.56-1.34 (m, J=11.6Hz, 2H), 1.26-1.17 (m, J=12.4Hz, 2H).
(3) preparation of (S)-α-phthalyl protection mino-caprolactam
50ml single port bottle is dried, evacuation displacement nitrogen 3 times, under nitrogen protection, and addition 0.5g (S)-α-
Aminocaproic lactam, adds 25ml chloroform and dissolves, be subsequently added 0.63g phthalic anhydride, return at 70 DEG C
Flow 10 hours, after reaction terminates, column chromatography for separation, i.e. can get pure (S)-α-phthalyl
Protection mino-caprolactam 0.45,87%.1H NMR(DMSO-d6, 300MHz) δ 7.88 (m, J=9Hz,
4H), 6.72 (s, 1H), 4.53 (t, J=7.6Hz, 1H), 3.25 (t, J=11.6Hz, 2H),
1.86-1.74 (m, J=21.2Hz, 2H), 1.56-1.46 (m, J=31.2Hz, 4H).
(4) preparation of poly-(S)-α-phthalyl protection amino-lysine
10ml single port bottle is dried, and adds 1g (S)-α-phthalyl protection mino-caprolactam, adds
20mg Na simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 270 DEG C are reacted 2 hours.Reaction
After end, question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-phthalyl protection amino-lysine 0.8g,
Adding hydrazine hydrate 4ml, add 300ml oxolane, react 10 days at 50 DEG C, dialysis, lyophilization obtains
To poly-ε-lysine.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H), 2.97 (m, 2H),
1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 8500.
Embodiment 9
(1) preparation of 1B methyl ester dihydrochloride
500ml single port flask is dried, and adds 36.5g L-lysine hydrochloride, adds 500ml methanol, at ice
Under water bath condition, dropwise drip the Benzenecarbonyl chloride. of 45ml, after being added dropwise to complete, at room temperature continue reaction 45
Minute, it is subsequently placed in 70 DEG C of oil baths be heated to reflux 3 hours, then room temperature cool overnight, has crystal to analyse
Go out, filter, wash with ether, be vacuum dried 12 hours at 20 DEG C, obtain 1B methyl ester dihydrochloride
29.2g, yield 80%.1H NMR(DMSO-d6, 300MHz) and δ 8.69 (s, 2H), 8.13 (s, 2H),
4.05 (t, J=6Hz, 1H), 3.73 (s, 3H), 2.89 (t, J=7.2Hz, 2H), 1.90-1.87 (m, J=6.8Hz, 2H), 1.60 (m,
J=7.2Hz, 2H), 1.40-1.38 (m, J=6.8Hz, 2H).
(2) preparation of (S)-alpha-amido caprolactam
500ml there-necked flask is dried, and weighs 23.3g 1B methyl ester dihydrochloride, is dissolved in 320ml methanol
In, under room temperature, drip 2820mL pyridine, react 16h at 10 DEG C, filter, be spin-dried for filtrate, after recrystallization,
Obtain white stringy solids (S)-alpha-amido caprolactam 18.6g, yield 80%.1H NMR(DMSO-d6,
300MHz) δ 7.64 (s, 1H), 4.03 (s, 2H), 3.46 (d, J=11.2Hz, 1H), 3.04 (m, J=12.3Hz, 2H),
1.80-1.65 (m, J=21.2Hz, 2H), 1.56-1.34 (m, J=11.6Hz, 2H), 1.26-1.17 (m, J=12.4Hz, 2H).
(3) (S)-α-pyrroles protects the preparation of mino-caprolactam
50ml single port bottle is dried, and adds 0.5g (S)-alpha-amido caprolactam, adds 25ml methanol and dissolves,
0.25ml acetic acid and 0.5ml 2,5-acetyl butyryl is dripped subsequently under room temperature.After being added dropwise to complete, under nitrogen protection,
80 DEG C are refluxed 2 hours.After reaction terminates, question response liquid is cooled to room temperature, extracts three times with dichloromethane,
Merge organic facies, and be dried 2 hours, after concentrated solvent, column chromatography for separation with anhydrous sodium sulfate, obtain (S)
-α-pyrroles protects mino-caprolactam 0.48g, yield 90%.1H NMR(CDCl3,300MHz)δ7.47(s,
1H), 5.85 (s, 2H), 4.87 (d, 1H), 3.31 (s, 2H), 2.32 (s, 6H), 2.22 (m, 3H), 1.77 (d, 1H),
1.49(m,1H)。
(4) poly-(S)-α-pyrroles protects the preparation of amino-lysine
50ml single port bottle is dried, and adds 2g (S)-α-pyrroles and protects mino-caprolactam, adds 50mg Na
Simple substance, evacuation displacement nitrogen 3 times, under nitrogen protection, 240 DEG C are reacted 2 hours.After reaction terminates,
Question response liquid is cooled to room temperature, settles with DMF and water.
(5) preparation of epsilon-polylysine
Take 500ml there-necked flask, add poly-(S)-α-pyrroles and protect amino-lysine 0.75g.Add 300ml
Dioxane dissolves, and is subsequently added 5.02g oxammonium hydrochloride. 120ml aqueous solution, and evacuation replaces nitrogen 3 times,
Add 5.15ml triethylamine.It is warming up to 110 DEG C, refluxes 10 days.Obtain yellow solution by concentration, freezing
It is dried, adds 5ml water and remove inorganic salt, centrifugation, after drying, obtain yellow solid 0.33g, receive
Rate 72%.1H NMR(D2O, 300MHz) δ 3.69 (m, 1H), 5.80 (s, 2H), 2.97 (m, 2H),
1.61 (s, 2H), 1.30 (s, 2H), 1.11 (s, 2H).Molecular weight 96000.
Chlorination reagent used in above-described embodiment can also be chloroacetic chloride or Benzenecarbonyl chloride., sulfonic acid chloride,
Multiple in chloroacetic chloride and thionyl chloride.The alkali used can also be for triethylamine, ammonia, strong aqua ammonia, carbon
Acid potassium, or triethylamine, ammonia, strong aqua ammonia, sodium hydroxide, pyridine and potassium carbonate in multiple.Made
Blocking group can also be tablet held before the breast by officials methoxycarbonyl group, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, methoxy carbonyl
Base, carbethoxyl group, p-toluenesulfonyl, trifluoroacetyl group, neighbour (to) nitrobenzenesulfonyl, pivaloyl
Base, benzoyl, trityl, 2,4-dimethoxy-benzyl, to the one in methoxy-benzyl and benzyl or
Multiple.The catalyst used can also be for Cabbeen class reagent, other alkali metal in addition to sodium simple substance, alkali
Metal-oxide, alkali metal hydroxide, alkali metal hydride, alkali metal alcoholates, alkaline-earth metal, alkaline earth
Metal-oxide, alkaline earth metal hydroxide, alkaline earth metal hydride or alkaline-earth alkoxides.Step (5)
Used in deprotection solvent can also be DMF, DMSO, methanol, ethanol, glycol dimethyl ether,
Or oxolane, DMF, DMSO, methanol, ethanol, glycol dimethyl ether, chloroform, dichloromethane
Multiple with in water.Here will not enumerate embodiment.
Obviously, above-described embodiment is only for clearly demonstrating example, and not to embodiment
Limit.For those of ordinary skill in the field, can also be made it on the basis of the above description
The change of its multi-form or variation.Here without also cannot all of embodiment be given exhaustive.And by
What this was extended out obviously changes or changes among still in the protection domain of the invention.
Claims (10)
1. the method that epsilon-polylysine is prepared in a ring-opening polymerisation, it is characterised in that comprise the following steps:
(1) preparation of 1B methyl ester dihydrochloride:
With L-lysine hydrochloride as raw material, methanol, as solvent and methyl esterification reagent, drips chlorination reagent,
React 2～24 hours, sucking filtration, i.e. can get 1B methyl ester dihydrochloride；
(2) preparation of (S)-alpha-amido caprolactam:
1B methyl ester dihydrochloride step (1) prepared is dissolved in methanol solvate, adds alkali,
React 6～24 hours, sucking filtration, concentrate, after recrystallization, obtain (S)-alpha-amido caprolactam；
(3) preparation of (S)-α-protection mino-caprolactam:
(S)-alpha-amido caprolactam step (2) prepared, is carried out amino by blocking group
Protection, i.e. obtains (S)-α-protection mino-caprolactam；
(4) preparation of poly-(S)-α-protection amino-lysine:
After adding catalyst in (S)-α-protection mino-caprolactam that step (3) prepares,
Polymerase 10 .5～10 hours at 120 DEG C～300 DEG C, i.e. can obtain poly-(S)-α-protection amino-lysine；
(5) preparation of epsilon-polylysine:
After poly-(S)-α-protection amino-lysine step (4) prepared sloughs blocking group, obtain
Epsilon-polylysine.
Method the most according to claim 1, it is characterised in that the chlorination reagent described in step (1)
For one or more in Benzenecarbonyl chloride., sulfonic acid chloride, chloroacetic chloride and thionyl chloride.
Method the most according to claim 1, it is characterised in that drip chlorination described in step (1)
The dropping temperature of reagent is-78 DEG C～10 DEG C, and after dropping, reaction temperature is 10 DEG C～100 DEG C.
Method the most according to claim 1, it is characterised in that the alkali described in step (2) is three
One or more in ethamine, ammonia, strong aqua ammonia, sodium hydroxide, pyridine and potassium carbonate.
Method the most according to claim 1, it is characterised in that 1B described in step (2)
Methyl ester dihydrochloride is 1:2～5 with the molar feed ratio of described alkali.
Method the most according to claim 5, it is characterised in that described in step (2) reaction be
Temperature is to carry out at 10 DEG C～50 DEG C.
Method the most according to claim 1, it is characterised in that blocking group described in step (3)
For benzyloxycarbonyl group, tertbutyloxycarbonyl, tablet held before the breast by officials methoxycarbonyl group, allyloxycarbonyl, trimethylsilyl ethoxycarbonyl, pyrrole
Cough up base, methoxycarbonyl group, carbethoxyl group, phthalyl, p-toluenesulfonyl, trifluoroacetyl group, neighbour
(to) nitrobenzenesulfonyl, pivaloyl group, benzoyl, trityl, 2,4-dimethoxy-benzyls, right
One or more in methoxy-benzyl and benzyl.
Method the most according to claim 1, it is characterised in that described in step (4), catalyst is
Cabbeen class reagent, alkali metal, alkali metal oxide, alkali metal hydroxide, alkali metal hydride, alkali gold
Belong to alkoxide, alkaline-earth metal, alkaline earth oxide, alkaline earth metal hydroxide, alkaline earth metal hydride or
Alkaline-earth alkoxides.
Method the most according to claim 1, it is characterised in that described in step (4), catalyst accounts for
Described (S)-α-protection mino-caprolactam molar fraction ratio is 0.02%～6%.
Method the most according to claim 1, it is characterised in that by step (4) described in step (5)
It is oxolane that poly-(S)-α-protection amino-lysine prepared sloughs blocking group solvent for use, DMF,
One or more in DMSO, methanol, ethanol, glycol dimethyl ether, chloroform, dichloromethane and water, instead
Answering temperature is 20 DEG C～130 DEG C.
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| CN108484901B (en) * | 2018-04-10 | 2020-03-06 | 中国科学院长春应用化学研究所 | Method for preparing polylysine with high content of linear epsilon-polylysine through thermal polycondensation |
| CN111116472B (en) * | 2020-01-06 | 2022-03-01 | 中国科学院长春应用化学研究所 | Seven-membered cyclic lysine derivative monomer and preparation method thereof, and antibacterial poly (epsilon-lysine) derivative and preparation method thereof |
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| CN103131006A (en) * | 2013-02-04 | 2013-06-05 | 中国科学院长春应用化学研究所 | Grafted copolymer and preparation method thereof and layer-by-layer decorative materials |
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