CN101691422B - Preparation method for diamine polydactyl acid - Google Patents
Preparation method for diamine polydactyl acid Download PDFInfo
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- CN101691422B CN101691422B CN2009101042903A CN200910104290A CN101691422B CN 101691422 B CN101691422 B CN 101691422B CN 2009101042903 A CN2009101042903 A CN 2009101042903A CN 200910104290 A CN200910104290 A CN 200910104290A CN 101691422 B CN101691422 B CN 101691422B
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Abstract
The invention discloses a preparation method for diamine polydactyl acid, comprising the steps of: reacting unsaturated amic acid having a general formula shown below (wherein R is unsaturated alkyl or aryl and n is any integer from 2 to 6) with amido protecting agent to prepare the amido-protecting unsaturated amic acid, performing free radical graft copolymerization reaction on polylactic acid, amido-protecting unsaturated amic acid and radical initiator to prepare the amido-protecting unsaturated amic polydactyl acid, and performing amido de-protection on unsaturated amic polydactyl acid to acquire the diamine polydactyl acid. Compared with the prior art, the method of the invention avoids polylactic acid directly contacting with basic amino and less polylactic acid participates in reaction, so the degradability of polylactic acid main chain is greatly decreased and the acquired diamine polydactyl acid has better mechanical property.
Description
Technical field
The present invention relates to the method for modifying of poly(lactic acid), particularly preparation method for diamine polydactyl acid.
Background technology
One of core content of organizational project is to make up the tissue engineering bracket with biocompatibility and biodegradability, makes it serve as interim supporter in vascularization and functional organization's forming process.Poly(lactic acid) is widely applied in organizational project as timbering material because of having excellent biological compatibility and biodegradability.The development of organizational engineering has in recent years proposed more requirement to timbering material, not only need to have suitable mechanical property and working properties, also need adhesion, growth and differentiation such as the special bioactive molecules of energy conjunctive tissue such as adhesion factor, somatomedin etc. with inducing cell.Poly(lactic acid) is owing to existing surface hydrophobicity strong, and is poor with cellular affinity, is unfavorable for the realization of cell physiological function, and side chain lacks reaction site, is difficult to covalency and introduces shortcomings such as bioactive molecules, and the application in organizational project is subjected to certain limitation.Therefore, the suitable polylactic acid modified method of research is significant to poly(lactic acid) applying in organizational project.
The investigator has adopted several different methods that poly(lactic acid) is carried out modification, as: (Macrolmol. such as Barrera DA, 1995,28:425-432) gather (lactic acid-co-Methionin), thereby in poly(lactic acid), introduce amino with the lactide dimer copolymerization that mixes dimer and lactic acid of lactic acid and Methionin; (Macromol., 1996,29:5233-5235 such as Hank DK; Macromol., 1997,30:6077-6083) in the presence of stannous octoate, make the end capped poly(lactic acid) of glycerine in 130 ℃ with rac-Lactide and glycerine, be converted into the acrylated lactic acid oligomers of three arms again with acrylate chloride, last and terminal hydroxy group polyoxyethylene glycol methyl acrylate reacts, thereby introduces two keys, hydroxyl and carboxyl in poly(lactic acid); John G etc. (Macromol., 1999,32:1853-1858) with behind depsipeptides and the L-rac-Lactide ring-opening copolymerization, prepare the corresponding polymkeric substance that contains the acrylate side chain, thereby in poly(lactic acid), introduce two keys and amide group with the acrylate chloride effect.Though above-mentioned method of modifying has improved the wetting ability and the cellular affinity of poly(lactic acid) to a great extent, do not consider that all the sour caused acid that polydactyl acid produces causes autoacceleration build degradation behavior in degradation process.
Chinese patent ZL01129048.X discloses the acid anhydride-grafted method that forms acid anhydride-grafted poly(lactic acid) to the side chain of poly(lactic acid) of unsaturated cyclics such as maleic anhydride, and the poly(lactic acid) after the modification has bigger reactive behavior and better mechanics and biological property.Chinese patent ZL02133814.0 discloses in acid anhydride-grafted poly(lactic acid) covalency and has introduced the method that strong basicity aliphatie diamine such as quadrol, butanediamine etc. form diamine modified poly-latic acids, poly(lactic acid) after the modification has good wetting ability, in degradation process, be neutral, do not show acid and cause autoacceleration build degradation behavior; But in the method, poly(lactic acid) and the amino ester bond generation aminolysis reaction that may cause in the poly(lactic acid) main chain that directly contacts of strong basicity, and poly(lactic acid) has participated in per step reaction, has increased the degraded possibility of poly(lactic acid) main chain greatly, and is bigger to the mechanical property influence of polydactyl acid.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of preparation method for diamine polydactyl acid, it is less that poly(lactic acid) participates in reaction, and avoided poly(lactic acid) to contact with the direct of strong basicity amino, greatly reduce the degraded possibility of poly(lactic acid) main chain, the mechanical property of gained diamine modified poly-latic acid is better.
For reaching this purpose, the invention provides a kind of preparation method for diamine polydactyl acid, may further comprise the steps:
The amido protecting of a, unsaturated acyl amino acid: unsaturated acyl amino acid and amino protecting agent are reacted the unsaturated acyl amino acid that makes amido protecting; Described unsaturated acyl amino acid has following general formula:
Wherein, R is unsaturated alkyl or aromatic base, and n is arbitrary integer of from 2 to 6;
The unsaturated acyl amino acid of b, employing amido protecting carries out modification to poly(lactic acid): the unsaturated acyl amino acid of poly(lactic acid) and step a gained amido protecting is carried out the free radical grafting copolymerization reaction in the presence of radical initiator, make the unsaturated acyl amino acid polydactyl acid of amido protecting;
The deprotection of the unsaturated acyl amino acid polydactyl acid of c, amido protecting: the unsaturated acyl amino acid polydactyl acid of step b gained amido protecting is carried out amino deprotection, promptly get diamine modified poly-latic acid.
Further, described poly(lactic acid) is D-poly(lactic acid), L-poly(lactic acid) or D, the L-poly(lactic acid), and molecular weight is 50,000～3,000,000;
Further, described radical initiator is dibenzoyl peroxide (BPO) or tertbutyl peroxide (TBHP);
Further, the mass ratio of the unsaturated acyl amino acid of described poly(lactic acid), amido protecting and radical initiator is 100: 0.5～20: 0.1～10;
Further, fusion-grafting polymerization or solution graft copolymerization polymerization are adopted in described free radical grafting copolymerization reaction, described fusion-grafting polymerization is to carry out under vacuum tightness is the condition of 0.1～50mmHg or protection of inert gas, and temperature of reaction is higher than the fusing point of the unsaturated acyl amino acid of amido protecting; Carry out under the condition that described solution graft copolymerization polymerization is protection of inert gas in organic solvent, temperature of reaction is 50～150 ℃;
Further, organic solvent is selected from methylene dichloride, trichloromethane, ethyl acetate, dimethyl sulfoxide (DMSO) (DMSO), tetrahydrofuran (THF) (THF), N in the described solution graft copolymerization polymerization, in dinethylformamide (DMF) and the N,N-dimethylacetamide (DMAC) one or more;
Further, described amino protecting agent be benzene methoxy dicarbonyl chloride (CBZ-Cl) or tert-Butyl dicarbonate [(BOC)
2O];
Further, described unsaturated acyl amino acid can be reacted in organic solvent by unsaturated cyclic acid anhydrides and diamines and make, and temperature of reaction is 20～70 ℃, adds tertiary amine in the reaction system as the pH regulator agent; Described diamines has following general formula:
Wherein, n is arbitrary integer of from 2 to 6;
Further, the reaction solvent of described unsaturated cyclic acid anhydrides and diamines is selected from one or more among DMSO, THF, DMF and the DMAC;
Further, the R in the described unsaturated acyl amino acid general formula is a vinyl, and the unsaturated cyclic acid anhydrides is a maleic anhydride.
Beneficial effect of the present invention is: the inventive method is that the unsaturated acyl amino acid with amido protecting carries out the free radical grafting copolymerization modification to poly(lactic acid); avoided poly(lactic acid) to contact with the direct of strong basicity amino; and poly(lactic acid) has only participated in free radical grafting copolymerization and amino deprotection two-step reaction; thereby greatly reduce the degraded possibility of poly(lactic acid) main chain, the mechanical property of gained diamine modified poly-latic acid is better.
Description of drawings
In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention is described in further detail below in conjunction with accompanying drawing, wherein:
Fig. 1 for maleic anhydride and hexanediamine react the maleoyl hexanediamine acid that makes proton nmr spectra (
1HNMR) figure;
Fig. 2 reacts the maleoyl butanediamine acid that makes for maleic anhydride and butanediamine
1H NMR figure;
Fig. 3 is the maleoyl hexanediamine acid of benzene methoxycarbonyl (CBZ) protection
1H NMR figure;
Fig. 4 is the maleoyl hexanediamine acid of tertbutyloxycarbonyl (BOC) protection
1H NMR figure;
The maleoyl hexanediamine acid modification D that the CBZ that Fig. 5 makes for employing solution graft copolymerization polymerization protects, the Fourier transform infrared spectroscopy of L-poly(lactic acid) (FT-IR) figure;
The maleoyl hexanediamine acid modification D that the CBZ that Fig. 6 makes for employing fusion-grafting polymerization protects, the FT-IR figure of L-poly(lactic acid);
The maleoyl hexanediamine acid modification D that the BOC that Fig. 7 makes for employing fusion-grafting polymerization protects, the FT-IR figure of L-poly(lactic acid);
Fig. 8 is D, the FT-IR figure of L-poly(lactic acid);
Fig. 9 is the maleoyl hexanediamine acid modification D of the CBZ protection adopting solution graft copolymerization polymerization and fusion-grafting polymerization and make, the carbon-13 nmr spectra of L-poly(lactic acid) (
13C NMR) figure;
The maleoyl hexanediamine acid modification D that the BOC that Figure 10 makes for employing fusion-grafting polymerization protects, the L-poly(lactic acid)
13C NMR figure;
Figure 11 is D, the L-poly(lactic acid)
13C NMR figure.
Embodiment
For preventing amino in the unsaturated acyl amino acid and the ester bond generation aminolysis reaction in the poly(lactic acid) main chain; simultaneously for to prevent that the amino in the unsaturated acyl amino acid from oxidizing reaction taking place under hot conditions; the present invention carries out amido protecting to the unsaturated acyl amino acid earlier; unsaturated acyl amino acid with amido protecting carries out the free radical grafting copolymerization modification to poly(lactic acid) again, removes amino protecting group at last and obtains diamine modified poly-latic acid.In the present invention, all amido protectings and deprotection method all are suitable for.
The unsaturated acyl amino acid can directly be bought by the commercial channel, also can make by unsaturated cyclic acid anhydrides and diamine reactant with reference to the method for the invention, this reaction can be carried out in air, but, preferably under the protection of rare gas elementes such as nitrogen, argon gas, carry out in order to reduce the generation probability of side reaction; And, for prevent that the acid anhydrides open loop from generating-in COOH and the diamines-NH
2The reaction salify also adds the tertiary amine of non-activity hydrogen such as triethylamine etc. as the pH regulator agent in the reaction system.
Hereinafter with reference to accompanying drawing, the preferred embodiments of the present invention are described in detail.
The preparation of a, the acid of maleoyl hexanediamine
Hexanediamine 14.0g is dissolved among the DMSO 30mL, add triethylamine 20.2g, under 30 ℃ of temperature, agitation condition, drip the DMSO solution 15mL of maleic anhydride 9.8g again, 0.5 hour dropwise, stirring reaction is 2 hours under the room temperature, standing demix, lower floor's solution is splashed among the excessive THF, the thick solid precipitation that collection is separated out is used absolute ethanol washing, gets maleoyl hexanediamine acid crude; Crude product is splashed among the excessive THF after with a small amount of DMSO dissolving, collect the thick solid precipitation of separating out, use absolute ethanol washing, vacuum-drying under the room temperature promptly gets the sour pure product of maleoyl hexanediamine, and yield is 80%.
Fig. 1 reacts the maleoyl hexanediamine acid that makes for maleic anhydride and hexanediamine
1(heavy water is for measuring solvent for H NMR figure, TMS is interior mark, operating frequency 500MHz), as shown in the figure, δ=1.148,1.203,1.317 and the multiplet at 1.446ppm place be the proton peak of 4 methylene radical in the middle of the hexanediamine, the multiplet at δ=2.758ppm place is the proton peak of the methylene radical that links to each other with primary amino in the hexanediamine, and the multiplet at δ=3.013ppm place is the proton peak of the methylene radical that links to each other with secondary amine in the hexanediamine; The doublet at δ=5.698ppm and δ=6.101ppm place is the proton peak on two keys in the maleic anhydride; Calculated by peak area shows that the proton peak peak area ratio of maleic anhydride and hexanediamine was near 1: 1, and is consistent with the theoretical value of maleoyl hexanediamine acid.
The amido protecting of b, the acid of maleoyl hexanediamine
21.4g is dissolved among the NaOH solution 10mL that concentration is 2mol/L with the acid of maleoyl hexanediamine; at ice bath; agitation condition drips the DMSO solution 5mL of CBZ-Cl 20.5g down; 0.5 hour dropwise; stirring reaction 4 hours under the room temperature (in reaction process be that the NaOH solution of 2mol/L keep pH 12 or more with concentration); filter; filtrate is splashed in the excessive acetic acid ethyl ester; stir, standing demix is collected lower floor's solution; with concentration is that the hydrochloric acid of 1mol/L is regulated pH less than 1; the solid precipitation that collection is separated out is 6～7.5 with hot wash to washing lotion pH, vacuum-drying under the room temperature; promptly get the maleoyl hexanediamine acid of CBZ protection, yield is 65%.
Fig. 3 is for the maleoyl hexanediamine acid of CBZ protection
1(deuterochloroform is a solvent to H MR figure, TMS is interior mark, operating frequency 500MHz), as shown in the figure, the multiplet at δ=7.187ppm and δ=7.334ppm place is the proton peak on the phenyl ring, δ=4.999ppm place unimodal is the proton peak of the methylene radical that links to each other with phenyl ring, and δ=9.111ppm place unimodal is the proton peak of the secondary amine that links to each other with ester group, confirms to have CBZ to exist; The multiplet at δ=2.987ppm and δ=3.180ppm place is the proton peak of the methylene radical that links to each other with secondary amine in the acid of maleoyl hexanediamine, the doublet at δ=6.218ppm and δ=6.392ppm place is the proton peak on two keys in the acid of maleoyl hexanediamine, be subjected to the influence of CBZ, above-mentioned peak all moves to low.
The maleoyl hexanediamine acid of c, employing amido protecting is carried out modification (solution graft copolymerization polymerization) to poly(lactic acid)
With D, (molecular weight is 50 to the L-poly(lactic acid), 000) the maleoyl hexanediamine acid 0.5g of 5.0g and CBZ protection is dissolved among the DMSO 30mL, logical nitrogen 8 minutes, add BPO 0.075g (D, the L-poly(lactic acid), the maleoyl hexanediamine acid of CBZ protection is 100: 10: 1.5 with the mass ratio of BPO), 110～120 ℃ of temperature, reaction is 10 hours under the nitrogen protection condition, sharply be cooled to the room temperature termination reaction, reaction solution is splashed in the excessive dehydrated alcohol, the membranaceous solid precipitation that collection is separated out, vacuum-drying under the room temperature gets the maleoyl hexanediamine acid polydactyl acid crude product of CBZ protection; Crude product is centrifugal with a small amount of THF dissolving back, get supernatant liquor and splash in the excessive distilled water, collect the membranaceous solid precipitation of separating out, use distilled water wash, repeat purifying 1 time, vacuum-drying under the room temperature promptly gets the pure product of maleoyl hexanediamine acid polydactyl acid of CBZ protection.
The maleoyl hexanediamine acid modification D that the CBZ that Fig. 5 makes for employing solution graft copolymerization polymerization protects, the FT-IR figure of L-poly(lactic acid), Fig. 8 is D; the FT-IR figure of L-poly(lactic acid), as shown in the figure, with D; the L-poly(lactic acid) is compared, and the maleoyl hexanediamine acid polydactyl acid of CBZ protection is at 1500～1650cm
-1The place increased by one wide in strong absorption peak, this peak is amide group in the maleoyl hexanediamine acid of CBZ protection and the phenyl ring absorption overlapping peaks in this zone; At 3000cm
-1Variation has taken place near C-H stretching vibration peak, is mainly caused by methylene radical, methyne and phenyl ring in the maleoyl hexanediamine acid of CBZ protection; At 3200～3700cm
-1The place occurred one wide in strong multiple absorption peak, its intensity is with respect to D, L-poly(lactic acid) absorption intensity herein improves a lot, and this peak is D, and the N substituted amide base in the maleoyl hexanediamine acid of terminal hydroxy group in the L-poly(lactic acid) and CBZ protection is at the absorption overlapping peaks in this zone; Above-mentioned information shows that the maleoyl hexanediamine acid of CBZ protection successfully is incorporated into D, in the L-poly(lactic acid).
Fig. 9 is the maleoyl hexanediamine acid modification D of the CBZ protection adopting solution graft copolymerization polymerization and fusion-grafting polymerization and make, the L-poly(lactic acid)
13C NMR figure; Figure 11 is D, the L-poly(lactic acid)
13C NMR figure, as shown in the figure, with D, the L-poly(lactic acid) is compared, and the maleoyl hexanediamine acid polydactyl acid of CBZ protection one group of new peak occurred at δ=29.744～30.375ppm section, is the absorption peak of 4 mesomethylene carbon in the middle of the hexanediamine.
The deprotection of the maleoyl hexanediamine acid polydactyl acid of d, amido protecting
With the maleoyl hexanediamine acid modification D of CBZ protection, L-poly(lactic acid) 2g is dissolved among the DMSO 20mL, adds the methanol solution 5mL of 5% palladium carbon catalyst 0.5g; logical hydrogen carries out hydrogenation, and reaction in 10 hours finishes, and filters; filtrate decompression is distilled to dried, and resistates adds ether and grinds to form powdery, filters; filter cake washs with ether; vacuum-drying under the room temperature gets maleoyl hexanediamine acid polydactyl acid, i.e. diamines modification D; the L-poly(lactic acid), heating is viscosity.
The difference part of this embodiment and embodiment 1 is:
The maleoyl hexanediamine acid of c, employing amido protecting is carried out modification (solution graft copolymerization polymerization) to poly(lactic acid)
With D, (molecular weight is 50 to the L-poly(lactic acid), 000) 5.0g and the amino maleoyl hexanediamine acid 0.5g that is protected by CBZ are dissolved among the DMSO 30mL, logical nitrogen 8 minutes, add BPO 0.225g (D, the L-poly(lactic acid), the maleoyl hexanediamine acid of CBZ protection is 100: 10: 4.5 with the mass ratio of BPO), 80 ℃ of temperature, reaction is 12 hours under the nitrogen protection condition, sharply be cooled to the room temperature termination reaction, reaction solution is splashed in the excessive dehydrated alcohol, the membranaceous solid precipitation that collection is separated out, vacuum-drying under the room temperature gets the maleoyl hexanediamine acid polydactyl acid crude product of CBZ protection; Crude product is centrifugal with a small amount of THF dissolving back, get supernatant liquor and splash in the excessive distilled water, collect the membranaceous solid precipitation of separating out, use distilled water wash, repeat purifying 1 time, vacuum-drying under the room temperature promptly gets the pure product of maleoyl hexanediamine acid polydactyl acid of CBZ protection.
The difference part of this embodiment and embodiment 1 is:
The maleoyl hexanediamine acid of c, employing amido protecting is carried out modification (solution graft copolymerization polymerization) to poly(lactic acid)
With D, (molecular weight is 50 to the L-poly(lactic acid), 000) the maleoyl hexanediamine acid 1.0g of 5.0g and CBZ protection is dissolved among the DMSO 30mL, logical nitrogen 8 minutes, add BPO 0.4g (D, the maleoyl hexanediamine acid of L-poly(lactic acid), CBZ protection is 100: 20: 8 with the mass ratio of BPO), reaction is 10 hours under 120～130 ℃ of temperature, nitrogen protection condition, sharply be cooled to the room temperature termination reaction, reaction solution is splashed in the excessive dehydrated alcohol, the membranaceous solid precipitation that collection is separated out, vacuum-drying under the room temperature gets the maleoyl hexanediamine acid polydactyl acid crude product of CBZ protection; Crude product is centrifugal with a small amount of THF dissolving back, get supernatant liquor and splash in the excessive distilled water, collect the membranaceous solid precipitation of separating out, use distilled water wash, repeat purifying 1 time, vacuum-drying under the room temperature promptly gets the pure product of maleoyl hexanediamine acid polydactyl acid of CBZ protection.
The difference part of this embodiment and embodiment 1 is:
The maleoyl hexanediamine acid of c, employing amido protecting is carried out modification (fusion-grafting polymerization) to poly(lactic acid)
With D, (molecular weight is 50 to the L-poly(lactic acid), 000) 5.0g is dissolved among the methylene dichloride 30mL, the dichloromethane solution 2mL that adds the maleoyl hexanediamine acid 0.5g of CBZ protection, add BPO 0.075g (D again, the maleoyl hexanediamine acid of L-poly(lactic acid), CBZ protection is 100: 10: 1.5 with the mass ratio of BPO), stir, methylene dichloride is removed in underpressure distillation, vacuum-drying is to constant weight under the room temperature, be vacuum-sealed in that (vacuum tightness is 0.1～50mmHg), and 110～120 ℃ of melt polymerizations of temperature 10 hours sharply are cooled to the room temperature termination reaction in the round-bottomed flask; Product is centrifugal with a small amount of THF dissolving back, get supernatant liquor and splash in the excessive distilled water, collect the membranaceous solid precipitation of separating out, use distilled water wash, repeat purifying 1 time, vacuum-drying under the room temperature promptly gets the maleoyl hexanediamine acid polydactyl acid of CBZ protection.
The maleoyl hexanediamine acid modification D that the CBZ that Fig. 6 makes for employing fusion-grafting polymerization protects, the FT-IR figure of L-poly(lactic acid), Fig. 8 is D; the FT-IR figure of L-poly(lactic acid), as shown in the figure, with D; the L-poly(lactic acid) is compared, and the maleoyl hexanediamine acid polydactyl acid of CBZ protection is at 1500～1650cm
-1The place increased by one wide in strong absorption peak, this peak is amide group in the maleoyl hexanediamine acid of CBZ protection and the phenyl ring absorption overlapping peaks in this zone; At 3000cm
-1Variation has taken place near C-H stretching vibration peak, is mainly caused by methylene radical, methyne and phenyl ring in the maleoyl hexanediamine acid of CBZ protection; At 3200～3700cm
-1The place occurred one wide in strong multiple absorption peak, its intensity is with respect to D, L-poly(lactic acid) absorption intensity herein improves a lot, and this peak is D, and the N substituted amide base in the maleoyl hexanediamine acid of terminal hydroxy group in the L-poly(lactic acid) and CBZ protection is at the absorption overlapping peaks in this zone; The above results shows that the maleoyl hexanediamine acid of CBZ protection successfully is incorporated into D, in the L-poly(lactic acid).
Fig. 9 is the maleoyl hexanediamine acid modification D of the CBZ protection adopting solution graft copolymerization polymerization and fusion-grafting polymerization and make, the L-poly(lactic acid)
13C NMR figure; Figure 11 is D, the L-poly(lactic acid)
13C NMR figure, as shown in the figure, with D, the L-poly(lactic acid) is compared, and the maleoyl hexanediamine acid polydactyl acid of CBZ protection one group of new peak occurred at δ=29.744～30.375ppm section, is the absorption peak of 4 mesomethylene carbon in the middle of the hexanediamine.
The difference part of this embodiment and embodiment 1 is:
The maleoyl hexanediamine acid of c, employing amido protecting is carried out modification (fusion-grafting polymerization) to poly(lactic acid)
With D, (molecular weight is 50 to the L-poly(lactic acid), 000) 5.0g is dissolved among the methylene dichloride 30mL, the dichloromethane solution 5mL that adds the maleoyl hexanediamine acid 0.5g of CBZ protection, add BPO 0.225g (D again, the maleoyl hexanediamine acid of L-poly(lactic acid), CBZ protection is 100: 10: 4.5 with the mass ratio of BPO), stir, methylene dichloride is removed in underpressure distillation, vacuum-drying is to constant weight under the room temperature, be vacuum-sealed in that (vacuum tightness is 0.1～50mmHg), and 80 ℃ of melt polymerizations of temperature 10 hours sharply are cooled to the room temperature termination reaction in the round-bottomed flask; Product is centrifugal with a small amount of THF dissolving back, get supernatant liquor and splash in the excessive distilled water, collect the membranaceous solid precipitation of separating out, use distilled water wash, repeat purifying 1 time, vacuum-drying under the room temperature promptly gets the maleoyl hexanediamine acid polydactyl acid of CBZ protection.
The difference part of this embodiment and embodiment 1 is:
The amido protecting of b, the acid of maleoyl hexanediamine
21.4g is dissolved in the NaHCO that concentration is 0.5mol/L with the acid of maleoyl hexanediamine
3Among the solution 10mL, under ice bath, agitation condition, drip and contain (BOC)
2The DMSO 10mL of O 19.4g dropwised in 0.5 hour, and stirring reaction 9 hours under the room temperature (is the NaHCO of 0.5mol/L with concentration in reaction process
3Solution is kept pH 8～9); reaction solution is splashed in the excessive acetic acid ethyl ester; stir, standing demix is collected lower floor's solution; with concentration is hydrochloric acid adjusting pH to 5～6 of 1mol/L; the solid precipitation that collection is separated out is 6～7.5 with hot wash to washing lotion pH, vacuum-drying under the room temperature; promptly get the maleoyl hexanediamine acid of BOC protection, yield is 60%.
Fig. 4 is for the maleoyl hexanediamine acid of BOC protection
1(deuterochloroform is a solvent to HNMR figure, TMS is interior mark, operating frequency 500MHz), as shown in the figure, δ=9.142ppm place unimodal is the proton peak of the secondary amine that links to each other with ester group, the maleoyl hexanediamine acid that the peak area at δ=1.36ppm place is obviously sour greater than the maleoyl hexanediamine and CBZ protects is at the peak area at this place, and this is the contribution at methyl proton peak among the BOC; Above-mentioned information shows that the amino of maleoyl hexanediamine acid successfully protected by BOC.
The maleoyl hexanediamine acid of c, employing amido protecting is carried out modification (fusion-grafting polymerization) to poly(lactic acid)
With D, (molecular weight is 50 to the L-poly(lactic acid), 000) 5.000g is dissolved among the methylene dichloride 30mL, the dichloromethane solution 2mL that adds the maleoyl hexanediamine acid 0.5g of BOC protection, add BPO 0.075g (D again, the maleoyl hexanediamine acid of L-poly(lactic acid), BOC protection is 100: 10: 1.5 with the mass ratio of BPO), stir, methylene dichloride is removed in underpressure distillation, vacuum-drying is to constant weight under the room temperature, be vacuum-sealed in that (vacuum tightness is 0.1～50mmHg), and 120～130 ℃ of melt polymerizations of temperature 10 hours sharply are cooled to the room temperature termination reaction in the round-bottomed flask; Product is centrifugal with a small amount of THF dissolving back, get supernatant liquor and splash in the excessive distilled water, collect the membranaceous solid precipitation of separating out, use distilled water wash, repeat purifying 1 time, vacuum-drying under the room temperature promptly gets the maleoyl hexanediamine acid polydactyl acid of BOC protection.
The maleoyl hexanediamine acid modification D that the BOC that Fig. 7 makes for employing fusion-grafting polymerization protects, the FT-IR figure of L-poly(lactic acid), Fig. 8 is D; the FT-IR figure of L-poly(lactic acid), as shown in the figure, with D; the L-poly(lactic acid) is compared, and the maleoyl hexanediamine acid polydactyl acid of BOC protection is at 1500～1650cm
-1The place increased by one wide in strong absorption peak, this peak is the absorption peak of the amide group in the maleoyl hexanediamine acid of BOC protection; Other no considerable change.
The maleoyl hexanediamine acid modification D that the BOC that Figure 10 makes for employing fusion-grafting polymerization protects, the L-poly(lactic acid)
13C NMR figure; Figure 11 is D, the L-poly(lactic acid)
13C NMR figure, as shown in the figure, with D, the L-poly(lactic acid) is compared, and the maleoyl hexanediamine acid polydactyl acid of BOC protection one group of new peak occurred at δ=29.744～30.375ppm section, is the absorption peak of 4 mesomethylene carbon in the middle of the hexanediamine; Other no considerable change.
The deprotection of the maleoyl hexanediamine acid polydactyl acid of d, amido protecting
Maleoyl hexanediamine acid modification D with the BOC protection; L-poly(lactic acid) 2g is dissolved among the ethyl acetate 20mL; add trifluoracetic acid 1.5mL; stirring reaction removed BOC in 12 hours under the room temperature; adopt dehydrated alcohol and ethyl acetate co-precipitation again, purifying makes maleoyl hexanediamine acid polydactyl acid, i.e. diamines modification D; the L-poly(lactic acid), heating is viscosity.
The preparation of a, the acid of maleoyl butanediamine
Butanediamine 10.5g is dissolved among the DMSO 30mL, add triethylamine 20.2g, under 30 ℃ of temperature, agitation condition, drip the DMSO solution 15mL of maleic anhydride 9.8g again, 0.5 hour dropwise, stirring reaction is 2 hours under the room temperature, standing demix, lower floor's solution is splashed among the excessive THF, the thick solid precipitation that collection is separated out is used absolute ethanol washing, gets maleoyl butanediamine acid crude; Crude product is splashed among the excessive THF after with a small amount of DMSO dissolving, collect the thick solid precipitation of separating out, use absolute ethanol washing, vacuum-drying under the room temperature promptly gets the sour pure product of maleoyl butanediamine, and yield is 86%.
Fig. 2 reacts the maleoyl butanediamine acid that makes for maleic anhydride and butanediamine
1(heavy water is for measuring solvent for H NMR figure, TMS is interior mark, operating frequency 500MHz), as shown in the figure, the multiplet at δ=1.397 and 1.506ppm place is the proton peak of 2 methylene radical in the middle of the butanediamine, the multiplet at δ=2.798ppm place is the proton peak of the methylene radical that links to each other with primary amino in the butanediamine, and the multiplet at δ=3.113ppm place is the proton peak of the methylene radical that links to each other with secondary amine in the butanediamine; The doublet at δ=5.778ppm and δ=6.200ppm place is the proton peak on two keys in the maleic anhydride; Calculated by peak area shows that the proton peak peak area ratio of maleic anhydride and butanediamine was near 1: 1, and is consistent with the theoretical value of maleoyl butanediamine acid.
The amido protecting of b, the acid of maleoyl butanediamine
18.6g is dissolved among the NaOH solution 10mL that concentration is 2mol/L with the acid of maleoyl butanediamine; at ice bath; agitation condition drips the DMSO solution 5mL of CBZ-Cl 20.5g down; 0.5 hour dropwise; stirring reaction 4 hours under the room temperature (in reaction process be that the NaOH solution of 2mol/L keep pH 12 or more with concentration); filter; filtrate is splashed in the excessive acetic acid ethyl ester; stir, standing demix is collected lower floor's solution; with concentration is that the hydrochloric acid of 1mol/L is regulated pH less than 1; the solid precipitation that collection is separated out is 6～7.5 with hot wash to washing lotion pH, vacuum-drying under the room temperature; promptly get the maleoyl butanediamine acid of CBZ protection, yield is 70%.
The maleoyl butanediamine acid of c, employing amido protecting is carried out modification (solution graft copolymerization polymerization) to poly(lactic acid)
With D, (molecular weight is 50 to the L-poly(lactic acid), 000) the maleoyl butanediamine acid 0.025g of 5.0g and CBZ protection is dissolved among the DMSO 30mL, logical nitrogen 8 minutes, add BPO 0.005g (D, the L-poly(lactic acid), the maleoyl butanediamine acid of CBZ protection is 100: 0.5: 0.1 with the mass ratio of BPO), 110～120 ℃ of temperature, reaction is 10 hours under the nitrogen protection condition, sharply be cooled to the room temperature termination reaction, reaction solution is splashed in the excessive dehydrated alcohol, the membranaceous solid precipitation that collection is separated out, vacuum-drying under the room temperature gets the maleoyl butanediamine acid polydactyl acid crude product of CBZ protection; Crude product is centrifugal with a small amount of THF dissolving back, get supernatant liquor and splash in the excessive distilled water, collect the membranaceous solid precipitation of separating out, use distilled water wash, repeat purifying 1 time, vacuum-drying under the room temperature promptly gets the pure product of maleoyl butanediamine acid polydactyl acid of CBZ protection.
The deprotection of the maleoyl butanediamine acid polydactyl acid of d, amido protecting
With the maleoyl butanediamine acid modification D of CBZ protection, L-poly(lactic acid) 2g is dissolved among the DMSO 20mL, adds the methanol solution 5mL of 5% palladium carbon catalyst 0.5g; logical hydrogen carries out hydrogenation, and reaction in 10 hours finishes, and filters; filtrate decompression is distilled to dried, and resistates adds ether and grinds to form powdery, filters; filter cake washs with ether; vacuum-drying under the room temperature gets maleoyl butanediamine acid polydactyl acid, i.e. diamines modification D; the L-poly(lactic acid), heating is viscosity.
Explanation is at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although by invention has been described with reference to the preferred embodiments of the present invention, but those of ordinary skill in the art is to be understood that, can make various changes to it in the form and details, and the spirit and scope of the present invention that do not depart from appended claims and limited.
Claims (9)
1. preparation method for diamine polydactyl acid is characterized in that: may further comprise the steps:
The amido protecting of a, unsaturated acyl amino acid: unsaturated acyl amino acid and amino protecting agent are reacted the unsaturated acyl amino acid that makes amido protecting; Described unsaturated acyl amino acid has following general formula:
Wherein, R is a vinyl, and n is arbitrary integer of from 2 to 6;
The unsaturated acyl amino acid of b, employing amido protecting carries out modification to poly(lactic acid): the unsaturated acyl amino acid of poly(lactic acid) and step a gained amido protecting is carried out the free radical grafting copolymerization reaction in the presence of radical initiator, make the unsaturated acyl amino acid polydactyl acid of amido protecting;
The deprotection of the unsaturated acyl amino acid polydactyl acid of c, amido protecting: the unsaturated acyl amino acid polydactyl acid of step b gained amido protecting is carried out amino deprotection, promptly get diamine modified poly-latic acid.
2. preparation method for diamine polydactyl acid according to claim 1 is characterized in that: described poly(lactic acid) is D-poly(lactic acid), L-poly(lactic acid) or D, the L-poly(lactic acid), and molecular weight is 50,000～3,000,000.
3. preparation method for diamine polydactyl acid according to claim 2 is characterized in that: described radical initiator is dibenzoyl peroxide or tertbutyl peroxide.
4. preparation method for diamine polydactyl acid according to claim 3 is characterized in that: the unsaturated acyl amino acid of described poly(lactic acid), amido protecting and the mass ratio of radical initiator are 100: 0.5～20: 0.1～10.
5. preparation method for diamine polydactyl acid according to claim 4, it is characterized in that: fusion-grafting polymerization or solution graft copolymerization polymerization are adopted in described free radical grafting copolymerization reaction, described fusion-grafting polymerization is to carry out under vacuum tightness is the condition of 0.1～50mmHg or protection of inert gas, and temperature of reaction is higher than the fusing point of the unsaturated acyl amino acid of amido protecting; Carry out under the condition that described solution graft copolymerization polymerization is protection of inert gas in organic solvent, temperature of reaction is 50～150 ℃.
6. preparation method for diamine polydactyl acid according to claim 5, it is characterized in that: organic solvent is selected from methylene dichloride, trichloromethane, ethyl acetate, tetrahydrofuran (THF), N in the described solution graft copolymerization polymerization, in dinethylformamide, N,N-dimethylacetamide and the dimethyl sulfoxide (DMSO) one or more.
7. preparation method for diamine polydactyl acid according to claim 6 is characterized in that: described amino protecting agent is benzene methoxy dicarbonyl chloride or tert-Butyl dicarbonate.
8. preparation method for diamine polydactyl acid according to claim 1, it is characterized in that: described unsaturated acyl amino acid can be reacted in organic solvent by unsaturated cyclic acid anhydrides and diamines and make, the unsaturated cyclic acid anhydrides is a maleic anhydride, temperature of reaction is 20～70 ℃, adds tertiary amine in the reaction system as the pH regulator agent; Described diamines has following general formula:
Wherein, n is arbitrary integer of from 2 to 6.
9. preparation method for diamine polydactyl acid according to claim 8, it is characterized in that: the reaction solvent of described unsaturated cyclic acid anhydrides and diamines is selected from dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), N, in dinethylformamide and the N,N-dimethylacetamide one or more.
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