CN102503850B - Hydroxyl-contained N-acylamino acid and preparation method thereof - Google Patents

Hydroxyl-contained N-acylamino acid and preparation method thereof Download PDF

Info

Publication number
CN102503850B
CN102503850B CN201110325737.7A CN201110325737A CN102503850B CN 102503850 B CN102503850 B CN 102503850B CN 201110325737 A CN201110325737 A CN 201110325737A CN 102503850 B CN102503850 B CN 102503850B
Authority
CN
China
Prior art keywords
amino acid
hydroxyl
acyl
salt
generation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201110325737.7A
Other languages
Chinese (zh)
Other versions
CN102503850A (en
Inventor
冯亚凯
曹宏飞
张利
郭锦堂
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NANGTONG HAODI ANTICORROSION EQUIPMENT Co.,Ltd.
Original Assignee
Tianjin University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tianjin University filed Critical Tianjin University
Priority to CN201110325737.7A priority Critical patent/CN102503850B/en
Publication of CN102503850A publication Critical patent/CN102503850A/en
Application granted granted Critical
Publication of CN102503850B publication Critical patent/CN102503850B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention discloses a hydroxyl-contained N-acylamino acid and a preparation method thereof. The hydroxyl-contained N-acylamino acid has the structure as follows: the hydroxyl-contained N-acylamino acid disclosed by the invention can be used for the field of material synthesis, medicines and the like, and is an intermediate product for synthetizing a high molecular material. The synthetized high molecular material is prepared into a scaffold soaked in a phosphate buffer solution; in nine months, compared with a caprolactone homopolymer, the weight is not reduced basically, whereas the weight of a caprolactone blending polymer of the hydroxyl-contained N-acylamino acid is reduced by about 8 percent; and in 10 weeks, the weight of a dioxanone homopolymer is reduced by 26 percent, whereas the weight of a dioxanone blending polymer of the hydroxyl-contained N-acylamino acid is reduced by 35 percent. Compared with the corresponding homopolymers in the prior art, the degradation rate of the blending polymers synthetized by the intermediate products is greatly increased.

Description

The N-acyl of hydroxyl is for amino acid and preparation method
Technical field
The invention belongs to Minute Organic Synthesis field, relate to the N-acyl of the hydroxyl that a class contains optically active or racemization for amino acid and preparation method.
Background technology
The amino acid that forms human body has kind more than 20, they are: tryptophane, methionine(Met), Threonine, α-amino-isovaleric acid, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine, Gelucystine, halfcystine, arginine, glycine, Serine, tyrosine, iodogorgoic acid, L-glutamic acid, aspartic acid and citrulline etc.These amino acid are present in occurring in nature, can synthesize, and human body can not all synthesize in plant materials.Wherein 8 kinds is that human body can not synthesize, and must, by providing in food, be called " indispensable amino acid ".These 8 kinds of indispensable amino acids are: tryptophane, Threonine, methionine(Met), α-amino-isovaleric acid, Methionin, leucine, Isoleucine and phenylalanine.Other are " non-essential amino acid ".Histidine can synthesize in human body, but its resultant velocity can not meet somagenic need, has people also it to be classified as to " indispensable amino acid ".Except glycine, the amino acid in above-mentioned protein all belongs to L-a-amino acid.
L-a-amino acid is widely used among synthesizing of medical and health and medical macromolecular materials, for example, utilizing the synthetic polyamino acid of L-a-amino acid and polyester-polyamide material to be proved and can being used as medical macromolecular materials.They can be degraded into small molecules L-a-amino acid in human body, the utilization that is absorbed by the body, and the medical macromolecular materials of therefore being prepared by L-a-amino acid are extremely important.Bibliographical information, by the chemical reaction of series of complex, synthesizes morpholine-2 based on L-a-amino acid, 5-derovatives, then obtain poly-morpholine-2,5-derovatives class medical macromolecular materials by ring-opening polymerization.The degradable macromolecular material of this class can be for medicine control release, shape memory high molecule material, tissue engineering bracket etc.In L-a-amino acid molecule, contain amino and carboxyl; functional side chain group such as hydroxyl, carboxyl, amino, the sulfydryl etc. in addition that have; functional group generally need to, after overprotection, activation, just can carry out needed chemical reaction, avoids other functional groups to participate in reaction.This just causes building-up reactions route long, and productive rate is low, and the reaction having must at high temperature, also can cause the generation of amino acid racemization.
The alkylol cpd of the amino acid structure that contains optically active or racemization is the important fine chemical material of a class, and they have important application in medicine, the synthetic field of material.Traditional method is utilized the alcohol of the synthetic amino acid structure that contains optically active or racemization of L-a-amino acid; must be through chemical reaction step such as the protection to the group of not participating in reaction, the activation that participates in reactive group, synthetic, deprotections; this must cause productive rate low, and racemization reaction also can occur sometimes.
Summary of the invention
The object of the invention is to overcome the deficiency that prior art exists, provide the N-acyl of hydroxyl for amino acid.
Second object of the present invention is to provide the N-acyl amino acid whose preparation method of generation of hydroxyl.
Technical scheme of the present invention is summarized as follows:
The N-acyl of hydroxyl, for amino acid, has following structure:
Figure BDA0000101637160000021
Wherein:
R 1for C 1-C 13sub-aliphatic group or C 7-C 16sub-aryl radical;
R 2for C 1-C 13sub-aliphatic group or C 7-C 16sub-aryl radical;
R 3for hydrogen, amino acid side chain group or the amino acid side chain group with blocking group;
X is oxygen or methylene radical;
n：1-100。
Amino acid side chain group is the side-chain radical of glycine, tryptophane, methionine(Met), Threonine, α-amino-isovaleric acid, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine, Gelucystine, halfcystine, arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or citrulline;
Blocking group is carbonyl benzyloxy, tertbutyloxycarbonyl, benzylalcohol base, diamantane alcohol radical, cycloalkanes alcohol radical, benzyl, the tertiary butyl, 2-benzyloxy oxalyl group, succinyl, to xylyl, trityl or to nitrobenzyl.
The N-acyl amino acid whose preparation method of generation of hydroxyl, comprises the steps:
Amino acid salts or the amino acid salts with blocking group (III) and cyclic lactone (IV) are reacted to the N-acyl that obtains hydroxyl for amino acid salts, be acidified with acid, the N-acyl that obtains hydroxyl for amino acid (I) or (II);
Figure BDA0000101637160000022
Figure BDA0000101637160000031
Wherein:
R 1for C 1-C 13sub-aliphatic group or C 7-C 16sub-aryl radical;
R 2for C 1-C 13sub-aliphatic group or C 7-C 16sub-aryl radical;
R 3for hydrogen, amino acid side chain group or the amino acid side chain group with blocking group;
R 4for lithium ion, sodium ion, potassium ion, rubidium ion or cesium ion;
X is oxygen or methylene radical;
n：1-100。
The N-acyl amino acid whose preparation method of generation of preferred hydroxyl; step is: be 0 DEG C-190 DEG C reactions 30 minutes-7 days by amino acid salts or the amino acid salts with blocking group (III) and cyclic lactone (IV) in temperature; obtain the N-acyl of hydroxyl for amino acid salts; be acidified with acid, the N-acyl that obtains hydroxyl for amino acid (I) or (II).
Temperature of reaction is preferably 50 DEG C-140 DEG C, and the reaction times is 4 hours-2 days.
Amino acid in described amino acid salts is L-amino acid, D-amino acid or D, L-amino acid.
Described amino acid is glycine, tryptophane, methionine(Met), Threonine, α-amino-isovaleric acid, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine, Gelucystine, halfcystine, arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or citrulline.
The described amino acid salts with blocking group is N (ε)-carbonyl benzyloxy-1B salt, N (ε)-carbonyl benzyloxy-D-Lys salt, N (ε)-carbonyl benzyloxy-D, 1B salt, N (ε)-tertbutyloxycarbonyl-1B salt, N (ε)-tertbutyloxycarbonyl-D-Lys salt, N (ε)-tertbutyloxycarbonyl-D, 1B salt, ASPARTIC ACID salt-β-benzyl ester, D-ASP salt-β-benzyl ester, D, ASPARTIC ACID salt-β-benzyl ester, ASPARTIC ACID salt-β-diamantane ester, D-ASP salt-β-diamantane ester, D, ASPARTIC ACID salt-β-diamantane ester, ASPARTIC ACID salt-β-cycloalkanes ester, D-ASP salt-β-cycloalkanes ester, D, ASPARTIC ACID salt-β-cycloalkanes ester, Pidolidone salt-γ-benzyl ester, D-Glu salt-γ-benzyl ester, D, Pidolidone salt-γ-benzyl ester, Pidolidone salt-γ-diamantane ester, D-Glu salt-γ-diamantane ester, D, Pidolidone salt-γ-diamantane ester, Pidolidone salt-γ-cycloalkanes ester, D-Glu salt-γ-cycloalkanes ester, D, Pidolidone salt-γ-cycloalkanes ester, O-benzyl-Serine salt, O-benzyl-D-Ser salt, O-benzyl-D, Serine salt, the O-tertiary butyl-Serine salt, the O-tertiary butyl-D-Ser salt, the O-tertiary butyl-D, Serine salt, O-(2-benzyloxy oxalyl group)-Serine salt, O-(2-benzyloxy oxalyl group)-D-Ser salt, O-(2-benzyloxy oxalyl group)-D, Serine salt, O-succinyl-Serine salt, O-succinyl-D-Ser salt, O-succinyl-D, Serine salt, O-benzyl-TYR salt, O-benzyl-D-Tyrosine salt, O-benzyl-D, TYR salt, the O-tertiary butyl-TYR salt, the O-tertiary butyl-D-Tyrosine salt, the O-tertiary butyl-D, TYR salt, O-benzyl-L-threonine salt, O-benzyl-D-Thr salt, O-benzyl-D, L-threonine salt, the O-tertiary butyl-L-threonine salt, the O-tertiary butyl-D-Thr salt, the O-tertiary butyl-D, L-threonine salt, S-benzyl-Cys salt, S-benzyl-D-Cys salt, S-benzyl-D, Cys salt, S-is to xylyl-Cys salt, S-is to xylyl-D-Cys salt, S-is to xylyl-D, Cys salt, S-is to methoxybenzyl-Cys salt, S-is to methoxybenzyl-D-Cys salt, S-is to methoxybenzyl-D, Cys salt, the S-tertiary butyl-Cys salt, the S-tertiary butyl-D-Cys salt, the S-tertiary butyl-D, Cys salt, S-trityl-Cys salt, S-trityl-D-Cys salt, S-trityl-D, Cys salt, S-is to nitrobenzyl-Cys salt, S-to nitrobenzyl-D-Cys salt or S-to nitrobenzyl-D, Cys salt.
Cyclic lactone (IV) is 6-caprolactone, to dioxy pimelinketone, 1,3-propiolactone, 1,4-butyrolactone, 1,5-valerolactone, 1,7-oenantholacton, Isosorbide-5-Nitrae-oenantholacton, γ-octalactone, δ-octalactone, γ-nonyl lactone, δ-nonalactone, γ-decalactone, δ-decalactone, ε-decalactone, fourth position undecalactone, fourth position dodecalactone, fourth position tridecalactone, fourth position tetradecalactone, thibetolide or dihydroambrettolide.
Advantage of the present invention:
The N-acyl of hydroxyl provided by the present invention can be used for for amino acid that material is synthetic, medicine and other fields.The synthetic N-acyl of the present invention contains hydroxyl for amino acid one end, and the other end contains carboxyl.Compound has two functionality, is the intermediate of a class synthesized polymer material.Under catalyzer existence condition, synthesize the mixed polymers of caprolactone and dioxy pimelinketone has been mixed to polymers by these intermediates.Synthetic material is made to biological support and be immersed in phosphate buffer solution, within the time of 9 months, contrast caprolactone homopolymer quality there is no minimizing, and the mixed polymers quality of caprolactone of the present invention has reduced approximately 8%; In 10 weeks, less 26% to dioxy pimelinketone homopolymer quality, and of the present invention the mixed polymers quality of dioxy pimelinketone has been reduced to 35%.The mixed polymers being synthesized by these intermediates is compared with the corresponding homopolymer of prior art, and degradation rate improves a lot.
The polymer materials synthetic by this class intermediate is degraded to hydroxycarboxylic acid and amino acid in vivo, amino acid can be utilized by organism, reduce the accumulation in vivo of Degradation of Polymer Materials product, alleviated or avoid biomaterial degraded product to cause in vivo bad reaction.Meanwhile, synthetic product of the present invention contains amino-acid residue, and has kept amino acid whose opticity.
The N-acyl amino acid whose preparation method of generation of hydroxyl of the present invention, product optically active depends on raw materials used optically active.Adopt L-amino acid salts, prepare the alkylol cpd containing L-amino acid structure, do not have racemization to occur.Adopt D-amino acid salts, prepare the alkylol cpd containing D-amino acid structure, do not have racemization to occur.The D that adopts racemization, L-amino acid salts, prepares the D containing racemization, the alkylol cpd of L-amino acid structure.Method raw material of the present invention is easy to get, also easily preparation.
Brief description of the drawings
Fig. 1 is N-caprolactone acyl generation-ALANINE 1h-NMR spectrogram.
Fig. 2 is N-polycaprolactone acyl generation-L-Leu 1h-NMR spectrogram.
Fig. 3 is N-to dioxy hexamethylene keto acyl generation-L-Leu 1h-NMR spectrogram.
Embodiment
Below in conjunction with specific embodiment, the present invention is further illustrated.
Embodiment 1
The ALANINE sodium of 0.1mol and the 6-caprolactone of 0.4mol are mixed, 60 DEG C of reactions 4 hours, then, 80 DEG C of reactions 2 hours, obtain white solid powder, successively with ether and ethyl acetate washing, the dry white crystal that obtains, equals 2 through hcl acidifying to pH, is extracted with ethyl acetate, dry, revolve steaming solvent and obtain colourless liquid, specific rotation is+14.5 °, and nuclear-magnetism and infared spectrum detect as target product.Nuclear-magnetism is shown in Fig. 1, δ=6.87 (c) are the charateristic avsorption bands of acid amides, in conjunction with feature proton peak δ=4.51 (b) of L-Ala, have illustrated that reaction has occurred for amino acid whose amino and 6-caprolactone, generate amido linkage, i.e. the N-caprolactone acyl generation-ALANINE of hydroxyl.δ=4.01 (i), δ=3.62 (j), δ=2.14 (d) are the feature proton peak of 6-caprolactone segment, and 6-caprolactone structural unit and L-Ala structural unit are tried to achieve by the integral area of feature proton peak b and feature proton peak d.Obtained the structural unit that contains 3 6-caprolactones in product molecule by integral area.
Embodiment 2
The ALANINE potassium of 0.1mol and the 6-caprolactone of 0.1mol are mixed, at 140 DEG C, react 30 minutes, obtain white solid powder, successively with the washing of ether and ethyl acetate, the dry white crystal that obtains, equals 2 through hcl acidifying to pH, be extracted with ethyl acetate, dry, revolve steaming solvent and obtain colourless liquid, 3338cm in δ=6.92 and infared spectrum in nuclear magnetic spectrogram -1for the feature proton peak of amido linkage, confirm that synthetic product is the N-caprolactone acyl generation-ALANINE of hydroxyl.
Embodiment 3
By 1 of the D-alanine sodium of 0.1mol and 0.1mol, 3-propiolactone mixes, 50 DEG C of reactions 24 hours, obtain white solid powder, successively with ether and ethyl acetate washing, the dry white crystal that obtains, equal 2 through hcl acidifying to pH, be extracted with ethyl acetate, dry, revolve steaming solvent and obtain colourless liquid, specific rotation is-14.5 °.δ=7.10th in nuclear magnetic spectrum, the feature proton peak of amido linkage, δ=2.30, δ=3.81 and δ=3.96 are characteristic peaks of 1,3-propiolactone structural unit.Confirm by nuclear magnetic spectrogram N-(1, the 3-propiolactone) acyl generation-D-alanine that product is hydroxyl.
Experimental results show that, with D-amino acid as the D-alanine sodium of glycine, tryptophane, methionine(Met), Threonine, α-amino-isovaleric acid, Methionin, Histidine, leucine, Isoleucine, phenylalanine, Gelucystine, halfcystine, arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or citrulline alternate embodiment 3, the other the same as in Example 3, also can prepare the N-caprolactone acyl generation-D-amino acid of corresponding hydroxyl.
Embodiment 4
By the D of 0.1mol, the 6-caprolactone of ALANINE rubidium and 0.4mol mixes, and reacts 7 days at 0 DEG C, then, 80 DEG C of reactions 24 hours, obtains white solid powder, successively with ether and ethyl acetate washing, and the dry white crystal, productive rate 100% of obtaining.Equal 2 through hcl acidifying to pH, be extracted with ethyl acetate, dry, to revolve and steam solvent and obtain colourless liquid, specific rotation is 0 °, nuclear-magnetism and infared spectrum detect the N-caprolactone acyl generation-D into hydroxyl, ALANINE.
Experimental results show that, with D, L--amino acid is as the D of glycine, tryptophane, methionine(Met), Threonine, α-amino-isovaleric acid, Methionin, Histidine, leucine, Isoleucine, phenylalanine, Gelucystine, halfcystine, arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or citrulline alternate embodiment 4, L--Sodium L-alaninate, the other the same as in Example 4, also can prepare the N-caprolactone acyl generation-D of corresponding hydroxyl, L---amino acid.
Embodiment 5
The Pidolidone sodium of 0.1mol and the 6-caprolactone of 0.4mol are mixed, at 60 DEG C, react 2 days, then, 80 DEG C of reactions 24 hours, obtain white solid powder, successively with ether and ethyl acetate washing, the dry white crystal that obtains, equals 2 through hcl acidifying to pH, is extracted with ethyl acetate, dry, revolve steaming solvent and obtain colourless liquid, nuclear-magnetism and infared spectrum, detect as hydroxyl N-caprolactone acyl generation-Pidolidone.
Embodiment 6
The 1B sodium of 0.1mol and the 6-caprolactone of 0.4mol are mixed, at 60 DEG C, react 4 hours, then 80 DEG C of reactions 24 hours, obtain white solid powder, successively with the washing of ether and ethyl acetate, the dry white crystal that obtains, equals 2 through hcl acidifying to pH, be extracted with ethyl acetate, dry, revolve steaming solvent and obtain colourless liquid, nuclear-magnetism and infared spectrum, and mensuration to opticity, detect the N-caprolactone acyl generation-1B into hydroxyl.
Experimental results show that, with L-amino acid as the 1B sodium of glycine, tryptophane, methionine(Met), Threonine, α-amino-isovaleric acid, Histidine, Isoleucine, phenylalanine, Gelucystine, halfcystine, arginine, Serine, tyrosine, aspartic acid or citrulline alternate embodiment 6, other also can prepare the N-caprolactone acyl generation-L-amino acid of corresponding hydroxyl with embodiment 6.
Embodiment 7
The 6-caprolactone of 0.1molN (ε)-carbonyl benzyloxy-D-Lys sodium and 0.1mol is mixed, at 120 DEG C, react 6 hours, obtain white solid, successively with ether and ethyl acetate washing, the dry white solid that obtains, equals 2 through hcl acidifying to pH, is extracted with ethyl acetate, dry, revolve steaming solvent and obtain white solid, nuclear-magnetism and infrared spectra determine that product is N-caprolactone acyl generation-N (ε)-carbonyl benzyloxy-D-Lys.In infrared spectra, 3330cm -1for the stretching vibration peak of acid amides, 3036cm -1for phenyl ring C=C-H stretching vibration peak.In nuclear magnetic spectrogram, the feature proton peak that δ=8.62 are phenyl ring, the feature proton peak that δ=7.43 are amido linkage, δ=4.07, δ=3.70th, the feature proton peak of 6-caprolactone segment.Having there is reaction in amino and 6-caprolactone by nuclear-magnetism and the known N of infrared spectrogram (ε)-carbonyl benzyloxy-D-Lys sodium, has synthesized N-caprolactone acyl generation-N (ε)-carbonyl benzyloxy-D-Lys.
Experiment showed, with amino acid salts with blocking group as N (ε)-carbonyl benzyloxy-1B salt, N (ε)-carbonyl benzyloxy-D, 1B salt, N (ε)-tertbutyloxycarbonyl-1B salt, N (ε)-tertbutyloxycarbonyl-D-Lys salt, N (ε)-tertbutyloxycarbonyl-D, 1B salt, ASPARTIC ACID salt-β-benzyl ester, D-ASP salt-β-benzyl ester, D, ASPARTIC ACID salt-β-benzyl ester, ASPARTIC ACID salt-β-diamantane ester, D-ASP salt-β-diamantane ester, D, ASPARTIC ACID salt-β-diamantane ester, ASPARTIC ACID salt-β-cycloalkanes ester, D-ASP salt-β-cycloalkanes ester, D, ASPARTIC ACID salt-β-cycloalkanes ester, Pidolidone salt-γ-benzyl ester, D-Glu salt-γ-benzyl ester, D, Pidolidone salt-γ-benzyl ester, Pidolidone salt-γ-diamantane ester, D-Glu salt-γ-diamantane ester, D, Pidolidone salt-γ-diamantane ester, Pidolidone salt-γ-cycloalkanes ester, D-Glu salt-γ-cycloalkanes ester, D, Pidolidone salt-γ-cycloalkanes ester, O-benzyl-Serine salt, O-benzyl-D-Ser salt, O-benzyl-D, Serine salt, the O-tertiary butyl-Serine salt, the O-tertiary butyl-D-Ser salt, the O-tertiary butyl-D, Serine salt, O-(2-benzyloxy oxalyl group)-Serine salt, O-(2-benzyloxy oxalyl group)-D-Ser salt, O-(2-benzyloxy oxalyl group)-D, Serine salt, O-succinyl-Serine salt, O-succinyl-D-Ser salt, O-succinyl-D, Serine salt, O-benzyl-TYR salt, O-benzyl-D-Tyrosine salt, O-benzyl-D, TYR salt, the O-tertiary butyl-TYR salt, the O-tertiary butyl-D-Tyrosine salt, the O-tertiary butyl-D, TYR salt, O-benzyl-L-threonine salt, O-benzyl-D-Thr salt, O-benzyl-D, L-threonine salt, the O-tertiary butyl-L-threonine salt, the O-tertiary butyl-D-Thr salt, the O-tertiary butyl-D, L-threonine salt, S-benzyl-Cys salt, S-benzyl-D-Cys salt, S-benzyl-D, Cys salt, S-is to xylyl-Cys salt, S-is to xylyl-D-Cys salt, S-is to xylyl-D, Cys salt, S-is to methoxybenzyl-Cys salt, S-is to methoxybenzyl-D-Cys salt, S-is to methoxybenzyl-D, Cys salt, the S-tertiary butyl-Cys salt, the S-tertiary butyl-D-Cys salt, the S-tertiary butyl-D, Cys salt, S-trityl-Cys salt, S-trityl-D-Cys salt, S-trityl-D, Cys salt, S-is to nitrobenzyl-Cys salt, S-to nitrobenzyl-D-Cys salt or S-to nitrobenzyl-D, Cys salt.N (ε)-carbonyl benzyloxy-D-Lys sodium of (above-mentioned salt is sodium salt) alternate embodiment 7, other also can prepare the N-acyl of corresponding hydroxyl for amino acid with embodiment 7.
Embodiment 8
The glycine lithium of 0.1mol and the 6-caprolactone of 0.1mol are mixed, at 60 DEG C, react 4 hours, then, 80 DEG C of reactions 2 hours, obtain white solid powder, successively with ether and ethyl acetate washing, the dry white crystal that obtains, equals 2 through hcl acidifying to pH, is extracted with ethyl acetate, dry, revolve and steam solvent and obtain colourless liquid, nuclear-magnetism and infared spectrum, detect N-caprolactone acyl into hydroxyl for glycine.
Embodiment 9
The ALANINE caesium of 0.1mol and the 6-caprolactone of 0.1mol are mixed, and add 400 milliliters of Isosorbide-5-Nitrae-dioxane, at 60 DEG C, react 4 hours, obtain white solid, successively with ether and ethyl acetate washing, the dry white crystal that obtains, equal 2 through hcl acidifying to pH, be extracted with ethyl acetate, dry, revolve steaming solvent and obtain colourless liquid, nuclear-magnetism and infared spectrum, and to optical rotation determining, detect the N-caprolactone acyl generation-ALANINE into hydroxyl.
Embodiment 10
The ALANINE sodium of 0.1mol and the dihydroambrettolide of 0.4mol are mixed, and add 15 milliliters of dry toluenes, at 80 DEG C, react 7 hours, obtain white solid, wash solid with ether, then dissolved with distilled water, then with hcl acidifying to equaling 2 to pH, be extracted with ethyl acetate, dry, revolve steaming solvent and obtain solid.The feature proton peak that in nuclear magnetic spectrum, δ=7.13 are amido linkage, has confirmed that ring hexadecyl ester and the reaction of ALANINE sodium have generated N-dihydroambrettolide acyl generation-ALANINE.
Embodiment 11
The L-Leu sodium of 0.0007mol and the 6-caprolactone of 0.2872mol are mixed, add Sn (Oct) 2190 DEG C of reaction 4h, obtain white solid powder, dissolve through chloroform, and the hcl acidifying that pH equals 1, separatory, through ether and sherwood oil recrystallization, dry, obtain white solid, productive rate 32%.Nuclear-magnetism and infared spectrum detect the N-polycaprolactone acyl generation-L-leucine for hydroxyl.Nuclear-magnetism is shown in Fig. 2, δ=0.9 (a) is the feature proton peak of leucine methyl, δ=4.01 (k), δ=3.65 (l), δ=2.13 (f) are the feature proton peak of 6-caprolactone segment, and the polymerization degree can be tried to achieve by the integral area of the feature proton peak f of leucic feature proton peak a and 6-caprolactone segment.The polymerization degree of being tried to achieve polymkeric substance by integral area is 83, and the molecular weight of polymkeric substance is 9600.
Embodiment 12
By the L-Leu sodium of 0.0231mol and 0.017mol dioxy pimelinketone is mixed, and add 15 milliliters of dry toluenes, at 60 DEG C, react 4 hours, obtain white blocks of solid, then wash with chloroform.Its solid is dissolved in distilled water, equals 2 to pH, then its distilled water is revolved and evaporated through hcl acidifying, obtain solid, then use acetone solution, filter, filtrate obtains target product through overwinding evaporate to dryness again.The N-that nuclear-magnetism and infared spectrum detection are hydroxyl is to dioxy hexamethylene keto acyl generation-L-Leu.Nuclear-magnetism is shown in Fig. 3.δ=7.94 (e) are the feature proton peak of amido linkage, and δ=3.87 (f) is the proton peak to O=C-NH-in dioxy pimelinketone structural unit, and δ=0.87 (a) is in L-Leu structural unit-CH 3feature proton peak.In the known product molecule of intensity of comparative feature proton peak a and feature proton peak f, contain 1 to dioxy pimelinketone structural unit.
Embodiment 13
The N-acyl of the hydroxyl of preparing taking embodiment 1-embodiment 11 for amino acid as monomer, under condition of high vacuum degree condition, at 190 DEG C of reaction 7h, cool to room temperature, obtain white solid, white solid is taken out, be dissolved in chloroform, then chloroformic solution is added gradually to the mixing solutions (v: v=1: 1) of ether and normal hexane, obtain white precipitate, repeating to precipitate three times again, be precipitated through vacuum-drying to constant weight, is subject polymer.
Subject polymer is carried out to electrostatic spinning and be prepared into biologic bracket material.
Each biologic bracket material and corresponding homopolymer biologic bracket material are as a comparison immersed in phosphate buffer solution (pH=7.4), under 37 DEG C of conditions, soak 9 months, contrast caprolactone homopolymer quality there is no minimizing, and the mixed polymers quality of caprolactone of the present invention has reduced approximately 8%; In 10 weeks, dioxy pimelinketone homopolymer quality is reduced to 26%, the mixed polymers quality of dioxy pimelinketone has been reduced to 35%.The mixed polymers being synthesized by these intermediates is compared with the corresponding homopolymer of prior art, and degradation rate improves a lot, in table 1.
Table 1:
The biologic bracket material of polymkeric substance Soak 9 months quality reductions
Prepared for raw material by embodiment 1 ?8.10％
Prepared for raw material by embodiment 2 ?8.32％
Prepared for raw material by embodiment 4 ?7.89％
Prepared for raw material by embodiment 5 ?8.04％
Prepared for raw material by embodiment 6 ?8.30％
Prepared for raw material by embodiment 7 ?8.34％
Prepared for raw material by embodiment 8 ?8.11％
Prepared for raw material by embodiment 9 ?8.01％
Prepared for raw material by embodiment 10 ?8.50％
Prepared for raw material by embodiment 11 ?6.48％
The homopolymer 1 of directly being prepared by caprolactone monomer ?0.12％
The homopolymer 2 of directly being prepared by caprolactone monomer ?0.10％
Prepared for raw material by embodiment 3 ?12.50％
The homopolymer of directly being prepared by propiolactone monomer ?4.51％
Prepared for raw material by embodiment 12 ?35.01％*
By the homopolymer that dioxy pimelinketone monomer is directly prepared ?26.12％*
*for soak time is the quality reduction of 10 weeks.

Claims (8)

  1. The N of hydroxyl ?acyl for amino acid, it is characterized in that having following structure:
    Figure FDA0000490899120000011
    Wherein:
    R 1for C 1?C 13sub-aliphatic group;
    R 2for C 1?C 13sub-aliphatic group;
    R 3for hydrogen, amino acid side chain group;
    X is oxygen or methylene radical;
    n:1‐100。
  2. The N of hydroxyl according to claim 1 ?acyl for amino acid, it is characterized in that described amino acid side chain group is the side-chain radical of glycine, tryptophane, methionine(Met), Threonine, α-amino-isovaleric acid, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine, Gelucystine, halfcystine, arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or citrulline.
  3. The N of the hydroxyl of claim 1 ?amino acid whose preparation method of acyl generation, it is characterized in that comprising the steps:
    By the reaction of amino acid salts (III) and cyclic lactone (IV) obtain hydroxyl N ?acyl for amino acid salts, be acidified with acid, obtain hydroxyl N ?acyl for amino acid (I) or (II);
    Figure FDA0000490899120000012
    Figure FDA0000490899120000021
    Wherein:
    R 1for C 1?C 13sub-aliphatic group;
    R 2for C 1?C 13sub-aliphatic group;
    R 3for hydrogen, amino acid side chain group;
    R 4for lithium ion, sodium ion, potassium ion, rubidium ion or cesium ion;
    X is oxygen or methylene radical;
    n:1‐100。
  4. According to claim 3 the N of hydroxyl ?amino acid whose preparation method of acyl generation, it is characterized in that described step is: by amino acid salts (III) and cyclic lactone (IV) temperature be 0 DEG C ?190 DEG C of reaction 30 Fen Zhong ?7 days, obtain hydroxyl N ?acyl for amino acid salts, be acidified with acid, obtain hydroxyl N ?acyl for amino acid (I) or (II).
  5. According to claim 4 the N of hydroxyl ?amino acid whose preparation method of acyl generation, it is characterized in that described temperature of reaction be 50 DEG C ?140 DEG C, the described reaction times be 4 little Shi ?2 days.
  6. According to the N of hydroxyl described in claim 3,4 or 5 ?amino acid whose preparation method of acyl generation, it is characterized in that amino acid in described amino acid salts be L ?amino acid, D ?amino acid or D, L ?amino acid.
  7. According to claim 6 the N of hydroxyl ?amino acid whose preparation method of acyl generation, it is characterized in that described amino acid is glycine, tryptophane, methionine(Met), Threonine, α-amino-isovaleric acid, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine, Gelucystine, halfcystine, arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or citrulline.
  8. According to the N of hydroxyl described in claim 3,4 or 5 ?amino acid whose preparation method of acyl generation, it is characterized in that described cyclic lactone (IV) Wei ε ?caprolactone, to dioxy pimelinketone, 1,4 ?butyrolactone, 1,5 ?valerolactone, 1,7 ?oenantholacton, 1,4 ?oenantholacton, γ ?caprylolactone, δ ?caprylolactone, γ ?nonalactone, δ ?nonalactone, γ ?decalactone, δ ?decalactone, ε ?decalactone, fourth position undecalactone, fourth position dodecalactone, fourth position tridecalactone, fourth position tetradecalactone, thibetolide or dihydroambrettolide.
CN201110325737.7A 2011-10-24 2011-10-24 Hydroxyl-contained N-acylamino acid and preparation method thereof Active CN102503850B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201110325737.7A CN102503850B (en) 2011-10-24 2011-10-24 Hydroxyl-contained N-acylamino acid and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201110325737.7A CN102503850B (en) 2011-10-24 2011-10-24 Hydroxyl-contained N-acylamino acid and preparation method thereof

Publications (2)

Publication Number Publication Date
CN102503850A CN102503850A (en) 2012-06-20
CN102503850B true CN102503850B (en) 2014-06-11

Family

ID=46216001

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201110325737.7A Active CN102503850B (en) 2011-10-24 2011-10-24 Hydroxyl-contained N-acylamino acid and preparation method thereof

Country Status (1)

Country Link
CN (1) CN102503850B (en)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4818542A (en) * 1983-11-14 1989-04-04 The University Of Kentucky Research Foundation Porous microspheres for drug delivery and methods for making same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4818542A (en) * 1983-11-14 1989-04-04 The University Of Kentucky Research Foundation Porous microspheres for drug delivery and methods for making same

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
具有表面活性的螯合型缓蚀剂-N-酰代氨基酸的研究;许学文等;《华东化工学院学报》;19841231(第4期);第485-493页 *
许学文等.具有表面活性的螯合型缓蚀剂-N-酰代氨基酸的研究.《华东化工学院学报》.1984,(第4期),第485-493页.

Also Published As

Publication number Publication date
CN102503850A (en) 2012-06-20

Similar Documents

Publication Publication Date Title
US4892733A (en) Biodegradable synthesis polypeptide and its therapeutic use
Fetsch et al. Polypeptoids from N-substituted glycine N-carboxyanhydrides: Hydrophilic, hydrophobic, and amphiphilic polymers with poisson distribution
Mallakpour et al. Progress in synthetic polymers based on natural amino acids
Rodriguez-Galan et al. Degradable poly (ester amide) s for biomedical applications
Fasman et al. The Synthesis and Conformation of High Molecular Weight Poly-ε-carbobenzyloxy-L-lysine and Poly-L-lysine· HCl1, 2
Deng et al. A biodegradable triblock copolymer poly (ethylene glycol)-b-poly (l-lactide)-b-poly (l-lysine): Synthesis, self-assembly, and RGD peptide modification
Kim et al. Self‐assembly of thermally responsive amphiphilic diblock copolypeptides into spherical micellar nanoparticles
US4888398A (en) Biodegradable polypeptide and the use thereof for the gradual release of drugs
Han et al. Recent advances of poly (ester amide) s-based biomaterials
Weissbuch et al. Racemic β-sheets as templates of relevance to the origin of homochirality of peptides: Lessons from crystal chemistry
Guo et al. Synthesis, characterization, and biodegradation of novel poly (ether ester amide) s based on L-phenylalanine and oligoethylene glycol
Gkikas et al. Well-defined homopolypeptides, copolypeptides, and hybrids of poly (L-proline)
Chronopoulou et al. Biofabrication of genipin-crosslinked peptide hydrogels and their use in the controlled delivery of naproxen
Li et al. Crucial impact of residue chirality on the gelation process and biodegradability of thermoresponsive polypeptide hydrogels
CN102503850B (en) Hydroxyl-contained N-acylamino acid and preparation method thereof
Perdih et al. Post-polymerization modification of poly (L-glutamic acid) with D-(+)-glucosamine
US7018654B2 (en) Pharmaceutical composition containing an active agent in an amino acid copolymer structure
WO2012108614A1 (en) Temperature-sensitive polyethylene glycol / polyester block copolymer in which bioactive functional group is introduced into side chain thereof
Guha et al. Dipeptide nanotubes, with N-terminally located ω-amino acid residues, that are stable proteolytically, thermally, and over a wide range of pH
US8455619B2 (en) Polypeptide synthesis for drug delivery
CN1844192A (en) Synthesis of ABA polypeptide -b- polytetrahydrofuran-b-polypeptide triblock copolymer
Bai et al. Seeding Crystals, Harvesting Polypeptides: Preparing Long Chiral-Sequence Controlled Polypeptides by Interlocked Polymerization in Cocrystals (iPiC) of N-Thiocarboxyanhydride (NTA) at Room Temperature
Métro et al. Amino Acids and Peptides in Ball Milling
Enomoto et al. Synthesis of peptide-grafted comb polypeptides via polymerisation of NCA-peptides
Zavradashvili et al. Amino acid based epoxy-poly (ester amide) s—A new class of functional biodegradable polymers: Synthesis and chemical transformations

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20201120

Address after: Industrial concentration zone, Erjia Town, Tongzhou District, Nantong City, Jiangsu Province

Patentee after: NANGTONG HAODI ANTICORROSION EQUIPMENT Co.,Ltd.

Address before: 300072 Tianjin City, Nankai District Wei Jin Road No. 92

Patentee before: Tianjin University

TR01 Transfer of patent right