CN102503850A - Hydroxyl-contained N-acylamino acid and preparation method thereof - Google Patents

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

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CN102503850A
CN102503850A CN2011103257377A CN201110325737A CN102503850A CN 102503850 A CN102503850 A CN 102503850A CN 2011103257377 A CN2011103257377 A CN 2011103257377A CN 201110325737 A CN201110325737 A CN 201110325737A CN 102503850 A CN102503850 A CN 102503850A
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salt
amino acid
benzyl
hydroxyl
acyl
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CN102503850B (en
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冯亚凯
曹宏飞
张利
郭锦堂
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NANGTONG HAODI ANTICORROSION EQUIPMENT Co.,Ltd.
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Tianjin University
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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 the Minute Organic Synthesis field, the N-acyl that relates to one type of hydroxyl that contains optically active or racemization is for amino acid and preparation method.
Background technology
The amino acid that constitutes human body has kind more than 20; They are: tryptophane, methionine(Met), Threonine, Xie Ansuan, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine(Phe), Gelucystine, halfcystine, l-arginine, glycocoll, Serine, tyrosine, iodogorgoic acid, L-glutamic acid, aspartic acid and N.delta.-carbamylornithine etc.These amino acid are present in occurring in nature, in plant materials, can both synthesize, and human body can not all synthesize.Wherein 8 kinds is that human body can not synthetic, must be called " indispensable amino acid " by providing in the food.These 8 kinds of indispensable amino acids are: tryptophane, Threonine, methionine(Met), Xie Ansuan, Methionin, leucine, Isoleucine and phenylalanine(Phe).Other then are " non-essential amino acid ".Histidine can synthesize in human body, but its resultant velocity can not satisfy somagenic need, has the people also to classify it as " indispensable amino acid ".Except that glycocoll, the amino acid in the above-mentioned protein all belongs to the L-a-amino acid.
The L-a-amino acid is widely used for for example utilizing L-a-amino acid synthetic polyamino acid and polyester-polyamide material to be proved and can being used as medical macromolecular materials among synthesizing of medical and health and 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 therefore the medical macromolecular materials by the preparation of L-a-amino acid are extremely important.Bibliographical information based on the chemical reaction of L-a-amino acid through a series of complicacies, synthesizes morpholine-2, and the 5-derovatives obtains gathering morpholine-2 through ring-opening polymerization again, 5-derovatives class medical macromolecular materials.The degradable macromolecular material of this type can be used for medicine sustained release, shape memory high molecule material, tissue engineering bracket or the like.Contain amino and carboxyl in the L-a-amino acid molecule; The functional side chain group in addition that has is hydroxyl, carboxyl, amino, sulfydryl etc. for example; Functional group generally need just can carry out needed chemical reaction after overprotection, activation, avoid other functional groups to participate in reaction.This just causes the building-up reactions route long, and productive rate is low, and the reaction that has must at high temperature also can cause the generation of amino acid racemization.
The alkylol cpd that contains the amino acid structure of optically active or racemization is one type of important fine chemical material, and they have important application in medicine, the synthetic field of material.Traditional method is utilized the synthetic alcohol that contains the amino acid structure of optically active or racemization of L-a-amino acid; Must be through to chemical reaction step such as the protection of the group of not participating in reaction, the activation of participating in reactive group, synthetic, deprotections; This must cause productive rate low, also racemization reaction can take place sometimes.
Summary of the invention
The objective of the invention is to overcome the deficiency that prior art exists, the N-acyl that hydroxyl is provided is for amino acid.
Second purpose of the present invention provides 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 has following structure for amino acid:
Figure BDA0000101637160000021
Wherein:
R 1Be C 1-C 13Inferior aliphatic group or C 7-C 16Inferior aryl radical;
R 2Be C 1-C 13Inferior aliphatic group or C 7-C 16Inferior aryl radical;
R 3Amino acid side chain group for hydrogen, amino acid side chain group or band blocking group;
X is oxygen or methylene radical;
n：1-100。
The amino acid side chain group is the side-chain radical of glycocoll, tryptophane, methionine(Met), Threonine, Xie Ansuan, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine(Phe), Gelucystine, halfcystine, l-arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or N.delta.-carbamylornithine;
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:
With amino acid salts (III) and the cyclic lactone (IV) of amino acid salts or band blocking group react obtain hydroxyl the N-acyl for amino acid salts, add acidifying, the N-acyl that obtains hydroxyl for amino acid (I) or (II);
Wherein:
R 1Be C 1-C 13Inferior aliphatic group or C 7-C 16Inferior aryl radical;
R 2Be C 1-C 13Inferior aliphatic group or C 7-C 16Inferior aryl radical;
R 3Amino acid side chain group for hydrogen, amino acid side chain group or band blocking group;
R 4Be 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: is 0 ℃-190 ℃ reactions 30 minutes-7 days with the amino acid salts (III) and the cyclic lactone (IV) of amino acid salts or band blocking group in temperature; The N-acyl that obtains hydroxyl is for amino acid salts; Add acidifying, the N-acyl that obtains hydroxyl for amino acid (I) or (II).
Temperature of reaction is preferably 50 ℃-140 ℃, and the reaction times is 4 hours-2 days.
Amino acid in the said amino acid salts is L-amino acid, D-amino acid or D, L-amino acid.
Said amino acid is glycocoll, tryptophane, methionine(Met), Threonine, Xie Ansuan, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine(Phe), Gelucystine, halfcystine, l-arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or N.delta.-carbamylornithine.
The amino acid salts of said band blocking group is N (ε)-carbonyl benzyloxy-L-lysine salt, N (ε)-carbonyl benzyloxy-D-lysine salt, N (ε)-carbonyl benzyloxy-D; L-lysine salt, N (ε)-tertbutyloxycarbonyl-L-lysine salt, N (ε)-tertbutyloxycarbonyl-D-lysine salt, N (ε)-tertbutyloxycarbonyl-D; L-lysine salt, L-aspartate-β-benzyl ester, D-aspartate-β-benzyl ester, D; L-aspartate-β-benzyl ester, L-aspartate-β-diamantane ester, D-aspartate-β-diamantane ester, D; L-aspartate-β-diamantane ester, L-aspartate-β-cycloalkanes ester, D-aspartate-β-cycloalkanes ester, D; L-aspartate-β-cycloalkanes ester, L-glutaminate-γ-benzyl ester, D-glutaminate-γ-benzyl ester, D; L-glutaminate-γ-benzyl ester, L-glutaminate-γ-diamantane ester, D-glutaminate-γ-diamantane ester, D; L-glutaminate-γ-diamantane ester, L-glutaminate-γ-cycloalkanes ester, D-glutaminate-γ-cycloalkanes ester, D; L-glutaminate-γ-cycloalkanes ester, O-benzyl-L-Serine salt, O-benzyl-D-Serine salt, O-benzyl-D; L-Serine salt, the O-tertiary butyl-L-Serine salt, the O-tertiary butyl-D-Serine salt, the O-tertiary butyl-D; L-Serine salt, O-(2-benzyloxy oxalyl group)-L-Serine salt, O-(2-benzyloxy oxalyl group)-D-Serine salt, O-(2-benzyloxy oxalyl group)-D; L-Serine salt, O-succinyl-L-Serine salt, O-succinyl-D-Serine salt, O-succinyl-D; L-Serine salt, O-benzyl-L-tyrosine salt, O-benzyl-D-tyrosine salt, O-benzyl-D; L-tyrosine salt, the O-tertiary butyl-L-tyrosine salt, the O-tertiary butyl-D-tyrosine salt, the O-tertiary butyl-D; L-tyrosine salt, O-benzyl-L-Threonine salt, O-benzyl-D-Threonine salt, O-benzyl-D, L-Threonine salt, the O-tertiary butyl-L-Threonine salt, the O-tertiary butyl-D-Threonine salt, the O-tertiary butyl-D, L-Threonine salt, S-benzyl-L-cysteine salt, S-benzyl-D-cysteine salt, S-benzyl-D; L-cysteine salt, S-to xylyl-L-cysteine salt, S-to xylyl-D-cysteine salt, S-to xylyl-D; L-cysteine salt, S-to methoxybenzyl-L-cysteine salt, S-to methoxybenzyl-D-cysteine salt, S-to methoxybenzyl-D, L-cysteine salt, the S-tertiary butyl-L-cysteine salt, the S-tertiary butyl-D-cysteine salt, the S-tertiary butyl-D, L-cysteine salt, S-trityl-L-cysteine salt, S-trityl-D-cysteine salt, S-trityl-D; L-cysteine salt, S-to nitrobenzyl-L-cysteine salt, S-to nitrobenzyl-D-cysteine salt or S-to nitrobenzyl-D, the L-cysteine salt.
Cyclic lactone (IV) is 6-caprolactone, to dioxy pimelinketone, 1; 3-propiolactone, 1; 4-GBL, 1; 5-valerolactone, 1,7-oenantholacton, 1,4-oenantholacton, γ-Xin Neizhi, δ-Xin Neizhi, γ-Ren Neizhi, δ-nonalactone, γ-decalactone, δ-Gui Neizhi, 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 synthetic, the medicine and other fields of material for amino acid.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 midbody of one type of synthesized polymer material.Under the catalyzer existence condition, synthesized caprolactone by these midbodys and mixed polymers and the dioxy pimelinketone is mixed polymers.The synthetic material is made biological support be immersed in the phosphate buffer solution, in 9 months time, contrast caprolactone homopolymer quality does not reduce basically, and the mixed polymers quality of caprolactone of the present invention has reduced about 8%; In 10 weeks, less 26% to dioxy pimelinketone homopolymer quality, and of the present inventionly the dioxy pimelinketone is mixed the polymers quality reduced 35%.Mix polymers by these midbody synthetic and compare with the corresponding homopolymer of prior art, degradation rate improves a lot.
Be degraded to hydroxycarboxylic acid and amino acid in vivo by this type midbody synthetic polymer materials; Amino acid can be utilized by organism; Reduced the accumulation in vivo of macromolecular material degraded product, alleviated or avoid the biomaterial degraded product to cause bad reaction in vivo.Simultaneously, 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, the product optically active depends on raw materials used optically active.Adopt the L-amino acid salts, then prepare the alkylol cpd that contains the L-amino acid structure, do not have racemization to take place.Adopt the D-amino acid salts, then prepare the alkylol cpd that contains the D-amino acid structure, do not have racemization to take place.Adopt the D of racemization, the L-amino acid salts is then prepared the D that contains racemization, the alkylol cpd of L-amino acid structure.Method raw material of the present invention is easy to get, also preparation easily.
Description of drawings
Fig. 1 is a N-caprolactone acyl generation-L-L-Ala 1The H-NMR spectrogram.
Fig. 2 is that N-polycaprolactone acyl generation-L-is leucic 1The H-NMR spectrogram.
Fig. 3 is that N-is leucic to dioxy hexamethylene keto acyl generation-L- 1The H-NMR spectrogram.
Embodiment
Below in conjunction with specific embodiment the present invention is further described.
Embodiment 1
The L-Sodium L-alaninate of 0.1mol and the 6-caprolactone of 0.4mol are mixed, 60 ℃ of reactions 4 hours, then 80 ℃ of reactions 2 hours; Obtain the white solid powder, with ether and ETHYLE ACETATE washing, drying obtains white crystal successively; Equal 2 through hcl acidifying to pH, use ethyl acetate extraction, drying; Revolve the steaming solvent and obtain colourless liquid, specific rotation is+14.5 °, and nuclear-magnetism and infared spectrum detect and be title product.Nuclear-magnetism is seen Fig. 1; δ=6.87 (c) are the charateristic avsorption bands of acid amides, and characteristic proton peak δ=4.51 (b) in conjunction with L-Ala have explained that reaction has taken place for amino group of amino acids and 6-caprolactone; Generated amido linkage, i.e. the N-caprolactone acyl generation-L-L-Ala of hydroxyl.δ=4.01 (i), δ=3.62 (j), δ=2.14 (d) are 6-caprolactone segmental characteristic proton peak, and 6-caprolactone structural unit and L-Ala structural unit are tried to achieve through the integral area of characteristic proton peak b and characteristic proton peak d.Get the structural unit that contains 3 6-caprolactones in the product molecule by integral area.
Embodiment 2
The L-L-Ala potassium of 0.1mol and the 6-caprolactone of 0.1mol are mixed, reacted 30 minutes down, obtain the white solid powder at 140 ℃; With the washing of ether and ETHYLE ACETATE, drying obtains white crystal successively, equals 2 through hcl acidifying to pH; Use ethyl acetate extraction; Drying is revolved the steaming solvent and is obtained colourless liquid, 3338cm in δ in the nuclear magnetic spectrogram=6.92 and the infared spectrum -1Be the characteristic proton peak of amido linkage, confirm that the synthetic product is the N-caprolactone acyl generation-L-L-Ala of hydroxyl.
Embodiment 3
With 1 of the D-Sodium L-alaninate of 0.1mol and 0.1mol, the 3-propiolactone mixed, 50 ℃ of reactions 24 hours; Obtain the white solid powder, with ether and ETHYLE ACETATE washing, drying obtains white crystal successively; Equal 2 through hcl acidifying to pH, use ethyl acetate extraction, drying; Revolve the steaming solvent and obtain colourless liquid, specific rotation is-14.5 °.δ in the nuclear magnetic spectrum=7.10th, the characteristic proton peak of amido linkage, δ=2.30, δ=3.81 and δ=3.96 are 1, the characteristic peak of 3-propiolactone structural unit.Confirm that by nuclear magnetic spectrogram product is N-(1, the 3-propiolactone) acyl generation-D-L-Ala of hydroxyl.
The experiment proof; D-Sodium L-alaninate with D-amino acid such as glycocoll, tryptophane, methionine(Met), Threonine, Xie Ansuan, Methionin, Histidine, leucine, Isoleucine, phenylalanine(Phe), Gelucystine, halfcystine, l-arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or N.delta.-carbamylornithine alternate embodiment 3; Other also can prepare the N-caprolactone acyl generation-D-amino acid of corresponding hydroxyl with embodiment 3.
Embodiment 4
With the D of 0.1mol, the 6-caprolactone of L-L-Ala rubidium and 0.4mol mixes, and reacts 7 days down at 0 ℃, 80 ℃ of reactions 24 hours, obtains the white solid powder then, and with ether and ETHYLE ACETATE washing, drying obtains white crystal, productive rate 100% successively.Equal 2 through hcl acidifying to pH, use ethyl acetate extraction, drying is revolved the steaming solvent and is obtained colourless liquid, and specific rotation is 0 °, and nuclear-magnetism and infared spectrum detect the N-caprolactone acyl generation-D into hydroxyl, the L-L-Ala.
The experiment proof; Use D; The D of L--amino acid such as glycocoll, tryptophane, methionine(Met), Threonine, Xie Ansuan, Methionin, Histidine, leucine, Isoleucine, phenylalanine(Phe), Gelucystine, halfcystine, l-arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or N.delta.-carbamylornithine alternate embodiment 4, the L--Sodium L-alaninate, other is with embodiment 4; Also can prepare the N-caprolactone acyl generation-D of corresponding hydroxyl, L---amino acid.
Embodiment 5
The L-Sodium Glutamate of 0.1mol and the 6-caprolactone of 0.4mol are mixed, reacted 2 days down, then 80 ℃ of reactions 24 hours at 60 ℃; Obtain the white solid powder, with ether and ETHYLE ACETATE washing, drying obtains white crystal successively; Equal 2 through hcl acidifying to pH, use ethyl acetate extraction, drying; Revolve the steaming solvent and obtain colourless liquid, nuclear-magnetism and infared spectrum detect the L-glutamic acid into hydroxyl N-caprolactone acyl generation-L-.
Embodiment 6
The L-Sodium lysinate of 0.1mol and the 6-caprolactone of 0.4mol are mixed, reacted 4 hours down, 80 ℃ of reactions 24 hours, obtain the white solid powder then at 60 ℃; With the washing of ether and ETHYLE ACETATE, drying obtains white crystal successively, equals 2 through hcl acidifying to pH; Use ethyl acetate extraction, drying is revolved the steaming solvent and is obtained colourless liquid; Nuclear-magnetism and infared spectrum, and, detect N-caprolactone acyl generation-L-Methionin into hydroxyl to the mensuration of opticity.
The experiment proof; L-Sodium lysinate with L-amino acid such as glycocoll, tryptophane, methionine(Met), Threonine, Xie Ansuan, Histidine, Isoleucine, phenylalanine(Phe), Gelucystine, halfcystine, l-arginine, Serine, tyrosine, aspartic acid or N.delta.-carbamylornithine 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-Sodium lysinate and 0.1mol is mixed, reacted 6 hours down, obtain white solid at 120 ℃; Successively with ether and ETHYLE ACETATE washing; Drying obtains white solid, equals 2 through hcl acidifying to pH, with ethyl acetate extraction, drying; Revolve the steaming solvent and obtain white solid, nuclear-magnetism and ir spectra confirm that product is N-caprolactone acyl generation-N (ε)-carbonyl benzyloxy-D-Methionin.In the ir spectra, 3330cm -1Be the stretching vibration peak of acid amides, 3036cm -1Be phenyl ring C=C-H stretching vibration peak.In nuclear magnetic spectrogram, δ=8.62 are the characteristic proton peak of phenyl ring, and δ=7.43 are the characteristic proton peak of amido linkage, δ=4.07, δ=3.70th, 6-caprolactone segmental characteristic proton peak.Reaction has taken place in amino and the 6-caprolactone that can be known N (ε)-carbonyl benzyloxy-D-Sodium lysinate by nuclear-magnetism and infrared spectrogram, has synthesized N-caprolactone acyl generation-N (ε)-carbonyl benzyloxy-D-Methionin.
The experiment proof; With the amino acid salts of band blocking group like N (ε)-carbonyl benzyloxy-L-lysine salt, N (ε)-carbonyl benzyloxy-D; L-lysine salt, N (ε)-tertbutyloxycarbonyl-L-lysine salt, N (ε)-tertbutyloxycarbonyl-D-lysine salt, N (ε)-tertbutyloxycarbonyl-D; L-lysine salt, L-aspartate-β-benzyl ester, D-aspartate-β-benzyl ester, D; L-aspartate-β-benzyl ester, L-aspartate-β-diamantane ester, D-aspartate-β-diamantane ester, D; L-aspartate-β-diamantane ester, L-aspartate-β-cycloalkanes ester, D-aspartate-β-cycloalkanes ester, D; L-aspartate-β-cycloalkanes ester, L-glutaminate-γ-benzyl ester, D-glutaminate-γ-benzyl ester, D; L-glutaminate-γ-benzyl ester, L-glutaminate-γ-diamantane ester, D-glutaminate-γ-diamantane ester, D; L-glutaminate-γ-diamantane ester, L-glutaminate-γ-cycloalkanes ester, D-glutaminate-γ-cycloalkanes ester, D; L-glutaminate-γ-cycloalkanes ester, O-benzyl-L-Serine salt, O-benzyl-D-Serine salt, O-benzyl-D; L-Serine salt, the O-tertiary butyl-L-Serine salt, the O-tertiary butyl-D-Serine salt, the O-tertiary butyl-D; L-Serine salt, O-(2-benzyloxy oxalyl group)-L-Serine salt, O-(2-benzyloxy oxalyl group)-D-Serine salt, O-(2-benzyloxy oxalyl group)-D; L-Serine salt, O-succinyl-L-Serine salt, O-succinyl-D-Serine salt, O-succinyl-D; L-Serine salt, O-benzyl-L-tyrosine salt, O-benzyl-D-tyrosine salt, O-benzyl-D, L-tyrosine salt, the O-tertiary butyl-L-tyrosine salt, the O-tertiary butyl-D-tyrosine salt, the O-tertiary butyl-D, L-tyrosine salt, O-benzyl-L-Threonine salt, O-benzyl-D-Threonine salt, O-benzyl-D; L-Threonine salt, the O-tertiary butyl-L-Threonine salt, the O-tertiary butyl-D-Threonine salt, the O-tertiary butyl-D; L-Threonine salt, S-benzyl-L-cysteine salt, S-benzyl-D-cysteine salt, S-benzyl-D, L-cysteine salt, S-to xylyl-L-cysteine salt, S-to xylyl-D-cysteine salt, S-to xylyl-D, L-cysteine salt, S-to methoxybenzyl-L-cysteine salt, S-to methoxybenzyl-D-cysteine salt, S-to methoxybenzyl-D; L-cysteine salt, the S-tertiary butyl-L-cysteine salt, the S-tertiary butyl-D-cysteine salt, the S-tertiary butyl-D; L-cysteine salt, S-trityl-L-cysteine salt, S-trityl-D-cysteine salt, S-trityl-D, L-cysteine salt, S-to nitrobenzyl-L-cysteine salt, S-to nitrobenzyl-D-cysteine salt or S-to nitrobenzyl-D, the L-cysteine salt.The N (ε) of (above-mentioned salt is sodium salt) alternate embodiment 7-carbonyl benzyloxy-D-Sodium lysinate, other is with embodiment 7, and the N-acyl that also can prepare corresponding hydroxyl is for amino acid.
Embodiment 8
The glycocoll lithium of 0.1mol and the 6-caprolactone of 0.1mol are mixed, reacted 4 hours down, then 80 ℃ of reactions 2 hours at 60 ℃; Obtain the white solid powder, with ether and ETHYLE ACETATE washing, drying obtains white crystal successively; Equal 2 through hcl acidifying to pH, use ethyl acetate extraction, drying; Revolve and steam solvent and obtain colourless liquid, nuclear-magnetism and infared spectrum detect N-caprolactone acyl into hydroxyl for glycocoll.
Embodiment 9
The L-L-Ala caesium of 0.1mol and the 6-caprolactone of 0.1mol are mixed, and add 400 milliliter 1, the 4-dioxane reacted 4 hours down at 60 ℃; Obtain white solid, with the washing of ether and ETHYLE ACETATE, drying obtains white crystal successively, equals 2 through hcl acidifying to pH; Use ethyl acetate extraction, drying is revolved the steaming solvent and is obtained colourless liquid; Nuclear-magnetism and infared spectrum, and, detect N-caprolactone acyl generation-L-L-Ala into hydroxyl to optical rotation determining.
Embodiment 10
The L-Sodium L-alaninate of 0.1mol and the dihydroambrettolide of 0.4mol are mixed, and add 15 milliliters of dry toluenes, reacted 7 hours down at 80 ℃; Obtain white solid, use the ether wash solids, with zero(ppm) water it is dissolved again; Then with hcl acidifying to equaling 2 to pH; Use ethyl acetate extraction, drying is revolved the steaming solvent and is obtained solid.δ in the nuclear magnetic spectrum=7.13 are the characteristic proton peak of amido linkage, have confirmed that the reaction of ring hexadecyl ester and L-Sodium L-alaninate has generated N-dihydroambrettolide acyl generation-L-L-Ala.
Embodiment 11
The L-Sodium L-leucine of 0.0007mol and the 6-caprolactone of 0.2872mol are mixed, add Sn (Oct) 2190 ℃ of reaction 4h obtain the white solid powder, through dissolved in chloroform, and the hcl acidifying that pH equals 1, separatory, through ether and sherwood oil recrystallization, drying gets white solid, productive rate 32%.Nuclear-magnetism and infared spectrum detect and are the N-polycaprolactone acyl generation-L-leucine of hydroxyl.Nuclear-magnetism is seen Fig. 2; δ=0.9 (a) is the characteristic proton peak of leucine methyl; δ=4.01 (k), δ=3.65 (l), δ=2.13 (f) are 6-caprolactone segmental characteristic proton peak, and the polymerization degree can be tried to achieve through the integral area of leucic characteristic proton peak a and 6-caprolactone segmental characteristic proton peak f.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
With the L-Sodium L-leucine of 0.0231mol and 0.017mol the dioxy pimelinketone is mixed, and add 15 milliliters of dry toluenes, reacted 4 hours down, obtain white blocks of solid, wash with chloroform then at 60 ℃.Its solid is dissolved in the zero(ppm) water, equals 2 through hcl acidifying to pH, its zero(ppm) water is revolved steam again, obtain solid, use acetone solution again, filter, filtrating obtains title product through the overwinding evaporate to dryness again.Nuclear-magnetism and infared spectrum detect N-for hydroxyl to dioxy hexamethylene keto acyl generation-L-leucine.Nuclear-magnetism is seen Fig. 3.δ=7.94 (e) are the characteristic proton peak of amido linkage, and δ=3.87 (f) is the proton peak to O=C-NH-in the dioxy pimelinketone structural unit, and δ=0.87 (a) is in the L-leucine structural unit-CH 3The characteristic proton peak.The intensity of comparative feature proton peak a and characteristic proton peak f can be known and contains 1 in the product molecule to dioxy pimelinketone structural unit.
Embodiment 13
N-acyl with the hydroxyl of embodiment 1-embodiment 11 preparation is a monomer for amino acid, under the condition of high vacuum degree condition, at 190 ℃ of reaction 7h; Cool to room temperature obtains white solid, and white solid is taken out; Be dissolved in the chloroform, then chloroformic solution added gradually the mixing solutions (v: v=1: 1), obtain white precipitate of ether and normal hexane; Repeat again to precipitate three times, obtain the deposition through vacuum-drying to constant weight, be subject polymer.
Subject polymer is carried out electrostatic spinning be prepared into biologic bracket material.
Each biologic bracket material and corresponding homopolymer biologic bracket material as a comparison are immersed in the phosphate buffer solution (pH=7.4); Under 37 ℃ of conditions; Soaked 9 months; Contrast caprolactone homopolymer quality does not reduce basically, and the mixed polymers quality of caprolactone of the present invention has reduced about 8%; In 10 weeks, dioxy pimelinketone homopolymer quality is reduced 26%, the dioxy pimelinketone is mixed the polymers quality reduced 35%.Mix polymers by these midbody synthetic and compare with the corresponding homopolymer of prior art, degradation rate improves a lot, and sees table 1.
Table 1:
The biologic bracket material of polymkeric substance Soak 9 months quality reductions
By embodiment 1 is feedstock production ?8.10％
By embodiment 2 is feedstock production ?8.32％
By embodiment 4 is feedstock production ?7.89％
By embodiment 5 is feedstock production ?8.04％
By embodiment 6 is feedstock production ?8.30％
By embodiment 7 is feedstock production ?8.34％
By embodiment 8 is feedstock production ?8.11％
By embodiment 9 is feedstock production ?8.01％
By embodiment 10 is feedstock production ?8.50％
By embodiment 11 is feedstock production ?6.48％
The homopolymer 1 that directly prepares by caprolactone monomer ?0.12％
The homopolymer 2 that directly prepares by caprolactone monomer ?0.10％
By embodiment 3 is feedstock production ?12.50％
The homopolymer that directly prepares by the propiolactone monomer ?4.51％
By embodiment 12 is feedstock production ?35.01％*
By the homopolymer that dioxy pimelinketone monomer is directly prepared ?26.12％*
*For soak time is the quality reduction in 10 weeks.

Claims (9)

1. the N-acyl of hydroxyl is characterized in that having following structure for amino acid:
Figure FDA0000101637150000011
Wherein:
R 1Be C 1-C 13Inferior aliphatic group or C 7-C 16Inferior aryl radical;
R 2Be C 1-C 13Inferior aliphatic group or C 7-C 16Inferior aryl radical;
R 3Amino acid side chain group for hydrogen, amino acid side chain group or band blocking group;
X is oxygen or methylene radical;
n：1-100。
2. the N-acyl of hydroxyl according to claim 1 is characterized in that for amino acid said amino acid side chain group is the side-chain radical of glycocoll, tryptophane, methionine(Met), Threonine, Xie Ansuan, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine(Phe), Gelucystine, halfcystine, l-arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or N.delta.-carbamylornithine; Said 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.
3. the N-acyl of the hydroxyl of claim 1 amino acid whose preparation method of generation is characterized in that comprising the steps:
With amino acid salts (III) and the cyclic lactone (IV) of amino acid salts or band blocking group react obtain hydroxyl the N-acyl for amino acid salts, add acidifying, the N-acyl that obtains hydroxyl for amino acid (I) or (II);
Figure FDA0000101637150000012
Figure FDA0000101637150000021
Wherein:
R 1Be C 1-C 13Inferior aliphatic group or C 7-C 16Inferior aryl radical;
R 2Be C 1-C 13Inferior aliphatic group or C 7-C 16Inferior aryl radical;
R 3Amino acid side chain group for hydrogen, amino acid side chain group or band blocking group;
R 4Be lithium ion, sodium ion, potassium ion, rubidium ion or cesium ion;
X is oxygen or methylene radical;
n：1-100。
4. according to the N-acyl of the said hydroxyl of claim 3 amino acid whose preparation method of generation; It is characterized in that said step is: is 0 ℃-190 ℃ reactions 30 minutes-7 days with the amino acid salts (III) and the cyclic lactone (IV) of amino acid salts or band blocking group in temperature; The N-acyl that obtains hydroxyl is for amino acid salts; Add acidifying, the N-acyl that obtains hydroxyl for amino acid (I) or (II).
5. according to the N-acyl amino acid whose preparation method of generation of the said hydroxyl of claim 4, it is characterized in that said temperature of reaction is 50 ℃-140 ℃, the said reaction times is 4 hours-2 days.
6. according to the N-acyl amino acid whose preparation method of generation of claim 3,4 or 5 said hydroxyls, it is characterized in that the amino acid in the said amino acid salts is L-amino acid, D-amino acid or D, L-amino acid.
7. according to the N-acyl amino acid whose preparation method of generation of the said hydroxyl of claim 6, it is characterized in that said amino acid is glycocoll, tryptophane, methionine(Met), Threonine, Xie Ansuan, Methionin, Histidine, leucine, Isoleucine, L-Ala, phenylalanine(Phe), Gelucystine, halfcystine, l-arginine, Serine, tyrosine, L-glutamic acid, aspartic acid or N.delta.-carbamylornithine.
8. according to the N-acyl of claim 3,4 or 5 said hydroxyls amino acid whose preparation method of generation; The amino acid salts that it is characterized in that said band blocking group is N (ε)-carbonyl benzyloxy-L-lysine salt, N (ε)-carbonyl benzyloxy-D-lysine salt, N (ε)-carbonyl benzyloxy-D; L-lysine salt, N (ε)-tertbutyloxycarbonyl-L-lysine salt, N (ε)-tertbutyloxycarbonyl-D-lysine salt, N (ε)-tertbutyloxycarbonyl-D; L-lysine salt, L-aspartate-β-benzyl ester, D-aspartate-β-benzyl ester, D; L-aspartate-β-benzyl ester, L-aspartate-β-diamantane ester, D-aspartate-β-diamantane ester, D; L-aspartate-β-diamantane ester, L-aspartate-β-cycloalkanes ester, D-aspartate-β-cycloalkanes ester, D; L-aspartate-β-cycloalkanes ester, L-glutaminate-γ-benzyl ester, D-glutaminate-γ-benzyl ester, D; L-glutaminate-γ-benzyl ester, L-glutaminate-γ-diamantane ester, D-glutaminate-γ-diamantane ester, D; L-glutaminate-γ-diamantane ester, L-glutaminate-γ-cycloalkanes ester, D-glutaminate-γ-cycloalkanes ester, D; L-glutaminate-γ-cycloalkanes ester, O-benzyl-L-Serine salt, O-benzyl-D-Serine salt, O-benzyl-D; L-Serine salt, the O-tertiary butyl-L-Serine salt, the O-tertiary butyl-D-Serine salt, the O-tertiary butyl-D; L-Serine salt, O-(2-benzyloxy oxalyl group)-L-Serine salt, O-(2-benzyloxy oxalyl group)-D-Serine salt, O-(2-benzyloxy oxalyl group)-D; L-Serine salt, O-succinyl-L-Serine salt, O-succinyl-D-Serine salt, O-succinyl-D; L-Serine salt, O-benzyl-L-tyrosine salt, O-benzyl-D-tyrosine salt, O-benzyl-D, L-tyrosine salt, the O-tertiary butyl-L-tyrosine salt, the O-tertiary butyl-D-tyrosine salt, the O-tertiary butyl-D, L-tyrosine salt, O-benzyl-L-Threonine salt, O-benzyl-D-Threonine salt, O-benzyl-D; L-Threonine salt, the O-tertiary butyl-L-Threonine salt, the O-tertiary butyl-D-Threonine salt, the O-tertiary butyl-D; L-Threonine salt, S-benzyl-L-cysteine salt, S-benzyl-D-cysteine salt, S-benzyl-D, L-cysteine salt, S-to xylyl-L-cysteine salt, S-to xylyl-D-cysteine salt, S-to xylyl-D, L-cysteine salt, S-to methoxybenzyl-L-cysteine salt, S-to methoxybenzyl-D-cysteine salt, S-to methoxybenzyl-D; L-cysteine salt, the S-tertiary butyl-L-cysteine salt, the S-tertiary butyl-D-cysteine salt, the S-tertiary butyl-D; L-cysteine salt, S-trityl-L-cysteine salt, S-trityl-D-cysteine salt, S-trityl-D, L-cysteine salt, S-to nitrobenzyl-L-cysteine salt, S-to nitrobenzyl-D-cysteine salt or S-to nitrobenzyl-D, the L-cysteine salt.
9. according to the N-acyl of claim 3,4 or 5 said hydroxyls amino acid whose preparation method of generation; It is characterized in that said cyclic lactone (IV) is for 6-caprolactone, to dioxy pimelinketone, 1; 3-propiolactone, 1; 4-GBL, 1; 5-valerolactone, 1,7-oenantholacton, 1,4-oenantholacton, γ-Xin Neizhi, δ-Xin Neizhi, γ-Ren Neizhi, δ-nonalactone, γ-decalactone, δ-Gui Neizhi, ε-decalactone, fourth position undecalactone, fourth position dodecalactone, fourth position tridecalactone, fourth position tetradecalactone, thibetolide or dihydroambrettolide.
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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 (1)

* Cited by examiner, † Cited by third party
Title
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》, no. 4, 31 December 1984 (1984-12-31), pages 485 - 493 *

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