CN108558705B - Aryl carbamate monomer containing phenolic hydroxyl amino acid, preparation method and application - Google Patents
Aryl carbamate monomer containing phenolic hydroxyl amino acid, preparation method and application Download PDFInfo
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Abstract
The invention discloses an Aryl Carbamate (AC) monomer containing phenolic hydroxyl amino acid, which is called phenolic hydroxyl amino acid-AC monomer for short, and the structural formula of the monomer is shown as a formula I or a formula II; the invention also provides a preparation method of the phenolic hydroxyl-containing amino acid-AC monomer, which comprises the following steps: the preparation method of the monomer has the advantages that the phenolic hydroxyl-containing amino acid and the aryl haloformate are dissolved in an organic solvent, the reaction is carried out for 12-48 hours at the temperature of 20-60 ℃, and the phenolic hydroxyl-containing amino acid-AC monomer is obtained through post-treatment. The invention also provides application of the phenolic hydroxyl-containing amino acid-AC monomer in the field of polyamino acid synthesis. The polyamino acid synthesized by the phenolic hydroxyl-containing amino acid-AC monomer provided by the invention has controllable molecular weight, narrow molecular weight distribution which is lower than 1.3, and yield of 90-99%; the side chain of the synthesized polyamino acid has a phenolic hydroxyl functional group, and has post-functionalization potential, and meanwhile, the synthesized polyamino acid has good biocompatibility, biodegradability and nontoxicity, and is an excellent biological material.
Description
Technical Field
The invention belongs to the field of polymer synthesis, and particularly relates to an Aryl Carbamate (AC) monomer containing phenolic hydroxyl amino acid, namely a phenolic hydroxyl amino acid-AC monomer, and a preparation method and application thereof.
Background
Polyamino acids are polymers whose main chains are linked by amide bonds and whose repeating units are amino acids. Because of having a structure similar to that of proteins and polypeptides, the polypeptide has good biocompatibility and degradability, and has wide research and application values in the fields of biomedicine and the like (Angew. chem. int. Ed.2006,45, 5752-.
Currently, polyamino acids are prepared mainly by controlled ring-opening polymerization of N-carboxyanhydrides (NCAs) of amino acids.
The phenolic hydroxyl group has proton donating ability and nucleophilic ability and stronger reaction activity, thus being a good functionalizable platform. However, due to its high reactivity, in the prior art, an amino acid-NCA monomer with a phenolic hydroxyl group needs to protect the phenolic hydroxyl group during synthesis and polymerization, and needs to be deprotected after polymerization, and needs to consider the stability of the protective group of the monomer during NCA synthesis and polymerization, and can remove the protective group relatively easily during deprotection after polymerization is completed, and benzyl ether protective groups are the most common choices. The reaction for protecting the phenolic hydroxyl group by benzyl ether needs to be carried out under the reflux condition, and catalytic hydrocracking needs to be carried out by using a Pd catalyst during deprotection. Low atom economy, high reaction difficulty and poor compatibility of reaction conditions with other monomers. In addition, highly toxic reagents such as phosgene derivatives and the like are needed in the NCA synthesis process, the reaction is required to be highly anhydrous and anaerobic, and the synthesis difficulty is very high.
In recent years, studies on the synthesis of polyamino acids using amino acid-AC (AC) have been made (Macromolecular,2008,41, 7913-. The variety of amino acid monomers suitable for synthesizing polyamino acid is expanded properly, especially amino acid with side chain containing functionalizable group.
However, the phenolic hydroxyl group-containing amino acid-AC monomer has strong reactivity because of containing a phenolic hydroxyl group functional group, and the phenolic hydroxyl group is required to be protected in the traditional method for synthesizing polyamino acid by NCA. No report is available at present for the direct polymerization of phenolic hydroxyl group-containing amino acid-AC monomers.
Disclosure of Invention
The invention provides an aryl carbamate (containing phenolic hydroxyl amino acid-AC) monomer containing phenolic hydroxyl amino acid, which has stable property and can be stored for a long time; the invention also provides a preparation method of the monomer, which has the advantages of simple synthetic route, simple and feasible synthetic process, cheap and easily-obtained raw materials and suitability for industrial production; the invention also provides a method for synthesizing polyamino acid by using the phenolic hydroxyl-containing amino acid-AC monomer, the polymerization method has mild reaction conditions, the phenolic hydroxyl group does not need to be protected/deprotected, and the amino acid polymerization process is greatly simplified; the polyamino acid side chain obtained by polymerization has phenolic hydroxyl, the reaction activity is strong, and the polyamino acid side chain has post-functionalization potential.
The phenolic hydroxyl-containing amino acid-AC monomer is an aromatic carbamate monomer with polymerization activity synthesized by taking phenolic hydroxyl-containing amino acid as a raw material, is hereinafter referred to as phenolic hydroxyl-containing amino acid-AC monomer, and has a structure shown as a formula I or a formula II:
wherein n is an integer of 1 or more, R1～R5Independently selected from H, alkyl, cyano, fluoroalkyl, hydroxy, alkoxy, aryloxy, nitro or halogen, which may be the same or different, and R1～R5At least one of the substituents is hydroxyl; r6～R10Independently selected from H, alkyl, cyano, fluoroalkyl, hydroxy, alkoxy, nitro or halogen, which may be the same or different.
The polymerization activities of the phenolic hydroxyl-containing amino acid-AC monomer shown as the formula I or the formula II are not obviously different.
When n is 1, R3Is hydroxy and R1、R2、R4、R5Are each a hydrogen atom, R6～R10The amino acid-AC when all hydrogen atoms are called tyrosine-AC (Tyr-AC for short), and the structural formula is shown as formula I-I:
when n is 1, R2、R3Is hydroxy and R1、R4、R5When it is a hydrogen atom, R6～R10The amino acid-AC, when all are hydrogen atoms, is called DOPA-AC (DOPA-AC for short), and has a structural formula shown in formula I-ii:
when n is 1 in formula II, R2、R3Is hydroxy and R1、R4、R5Is a hydrogen atom, R6～R10The amino acid-AC when all hydrogen atoms are called N-dopa-AC (abbreviated as NDOPA-AC), and the structural formula is shown as formula II-i:
the invention also provides a preparation method of the phenolic hydroxyl amino acid-AC monomer, which comprises the following steps:
the synthetic route is as follows:
dissolving phenolic hydroxyl amino acid and aryl haloformate in an organic solvent A, reacting for 12-48 hours at 20-60 ℃, and performing aftertreatment to obtain a corresponding phenolic hydroxyl amino acid-AC monomer;
substituent R in synthetic route1～R10The number n of methylene groups is defined as in formula I; and X is Cl or Br.
The solvent A is one or more of ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, acetone, toluene or dioxane.
The post-treatment comprises filtration, organic phase concentration, column purification or recrystallization purification.
In the method for preparing the phenolic hydroxyl-containing amino acid-AC monomer provided by the invention, the dosage of the reaction raw materials is not strictly limited, and the reaction is generally carried out according to the stoichiometric ratio of the chemical reaction.
The preparation method of the phenolic hydroxyl amino acid-AC monomer provided by the invention has strong tolerance to water, heat and oxygen, mild reaction conditions, simple and easy operation, cheap and easily obtained raw materials, and recyclable reaction mother liquor.
The invention also provides application of the phenolic hydroxyl-containing amino acid-AC monomer in the field of polyamino acid synthesis.
The polyamino acid of the invention comprises a homopolymer of amino acid or a copolymer of several amino acids, is broadly defined as various topological structure polymers of amino acid segments containing phenolic hydroxyl side groups, and covers amino acid polymers of alternating, random, block, graft, star, branched and other types.
The specific synthetic steps of the polyamino acid comprise:
under the initiation action of an initiator, one or more phenolic hydroxyl-containing amino acid-AC monomers are subjected to polymerization reaction in an organic solvent B, and after the reaction is completed, the polyamino acid with phenolic hydroxyl on the side chain is obtained through post-treatment;
the polymerization reaction temperature is 40-150 ℃; the polymerization time is 6 hours to 4 days.
The polymerization initiator in the present invention is an organic amine, and may be any of primary amine, secondary amine, tertiary amine and silyl amine, for example, polyamino compounds such as n-butylamine, benzylamine, diethylamine, hexamethyldisilazane, ethylenediamine, triethylenetetramine, spermine, tris (2-aminoethyl) amine, amino-terminated polyethylene glycol and polyethyleneimine having various topological structures. The initiating effect of the similar organic amine has no obvious difference.
The molecular weight of the amino-terminated polyethylene glycol is 200-5000; the molecular weight of the polyethyleneimine is 500-10000;
the molar ratio of the monomer to the initiator can vary within a wide range, and further, the molar ratio of the amino acid-AC monomer to the organic amine initiator is 10-200: 1, and further preferably 10-50.
Further, the organic solvent B for the polymerization reaction of the present invention is one or more selected from dioxane, Tetrahydrofuran (THF), N-Dimethylformamide (DMF), N-dimethylacetamide (DMAc), Tetramethylurea (TMU), dimethyl sulfoxide (DMSO), sulfolane, nitrobenzene, acetonitrile, benzonitrile, N-methylpyrrolidone (NMP), toluene, dichloromethane, and chloroform.
Further, the temperature of the polymerization reaction is preferably between 60 and 80 ℃.
Further, the polymerization reaction time is preferably 12-24 hours.
Tyr is only natural amino acid containing phenolic hydroxyl, the oxidation product of the Tyr is DOPA and NDOPA, the Tyr is naturally present in the secretion of organisms such as mussel and the like, the Tyr is naturally derived, and correspondingly, the polymerization monomer is preferably Tyr-AC, DOPA-AC or NDOPA-AC.
In the polymerization step, the post-treatment comprises organic solvent precipitation, filtration, drying and the like.
The molecular weight of the synthesized polyamino acid is controllable, the molecular weight distribution is narrow and is lower than 1.3, and the yield reaches 90-99%;
wherein the main chain is homopolyamino acid with a polyamino acid structure, and the polymerization degree of the homopolyamino acid can be controlled to be 1-200;
synthetic route for homopolyamino acids:
wherein R is11-NH2Is organic amine, n is an integer not less than 1, and m is an integer between 1 and 200.
The side chain of the polyamino acid synthesized by the invention has a phenolic hydroxyl functional group, has post-functionalization potential and provides a good functionalizable platform; meanwhile, the polyamino acid synthesized by the method has good biocompatibility and biodegradability and is nontoxic and is an excellent biological material.
The polymerization method of the phenolic hydroxyl-containing amino acid-AC monomer provided by the invention has the following characteristics:
(i) the initiator has cheap and easily obtained raw materials and high initiating activity; (ii) the polymerization condition is mild, the polyamino acid with higher molecular weight can be prepared, and the polymerization degree can reach 200; (iii) the molecular weight of the prepared polyamino acid can be adjusted through the molar ratio of the monomer to the initiator; (vi) can be copolymerized with various amino acid-AC monomers of different types to obtain amino acid copolymers with different structures and functions.
Compared with the prior art, the invention has the beneficial effects that:
(1) the present invention synthesizes for the first time monomers comprising phenolic hydroxy aryl carbamates (including phenolic hydroxy N-substituted glycines) reactive urethane compounds (AC), and such monomers have never been reported before.
(2) The monomer containing the phenolic hydroxyl amino acid-AC prepared by the invention has stable properties and can be stored for a long time.
(3) The preparation method of the phenolic hydroxyl amino acid-AC monomer provided by the invention has strong tolerance to water, heat and oxygen, mild reaction conditions, simple and easy operation, cheap and easily obtained raw materials, and is suitable for industrial production.
(4) When the phenolic hydroxyl-containing amino acid-AC monomer provided by the invention is polymerized, the phenolic hydroxyl functional group of the monomer does not need to be protected, and ring-opening polymerization can be directly carried out to obtain a polyamino acid product with a phenolic hydroxyl group on the side chain. In the prior art, the amino acid-NCA monomer with the phenolic hydroxyl needs to protect the hydroxyl during synthesis and polymerization, and needs to be deprotected after polymerization, and the monomer synthesis difficulty and the polymerization difficulty are far away from those of the phenolic hydroxyl-containing amino acid-AC monomer.
(5) The molecular weight of the synthesized polyamino acid is controllable, the molecular weight distribution is narrow and is lower than 1.3, and the yield reaches 90-99%; meanwhile, the polyamino acid provided by the invention has good biocompatibility and biodegradability, is nontoxic and is an excellent biological material.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of a Tyr-AC monomer prepared in example 1 of the present invention.
FIG. 2 is a nuclear magnetic hydrogen spectrum of the DOPA-AC monomer prepared in example 5 of the present invention.
FIG. 3 is a nuclear magnetic hydrogen spectrum of a Tyr-AC homopolymerized polyamino acid product in example 1 of this invention.
FIG. 4 is a nuclear magnetic hydrogen spectrum of a polyamino acid product homo-polymerized with DOPA-AC in example 5 of the present invention.
FIG. 5 is a MALDI-ToF mass spectrum of a Tyr-AC homopolymerized polyamino acid product of example 1 of the present invention.
Detailed Description
For further understanding of the present invention, the aryl carbamate monomer containing phenolic hydroxyl amino acid and the synthesis and polymerization method thereof provided by the present invention are described in detail with reference to the following examples, but the present invention is not limited to these examples, and those skilled in the art can make insubstantial modifications and adjustments under the core teaching of the present invention and still fall within the scope of the present invention.
The description of the characterization method involved in the specific embodiment of the present invention is as follows:
the obtained polyamino acid has molecular weight and structure1H NMR and MALDI-ToF MS measurements.
Absolute molecular weight of polymer1H NMR end group calibration, nuclear magnetism in Bruker Avance DMX 400(1H:400MHz) on an instrument using deuterated dimethyl sulfoxide (DMSO-d)6) As solvent Tetramethylsilane (TMS) was used as internal standard.
The structure of the polymer was analyzed by MALDI-ToF MS and determined on a Bruker UltraFLEX MALDI-ToF mass spectrometer. The nitrogen laser wavelength was set at 337nm with a pulse interval of 3 ns. The acceleration voltage was 20kV, measured in the reflection mode. 2, 5-dihydroxy benzoic acid (DHB) is taken as a substrate.
Example 1
In a reaction flask, 18.1g (0.10mol) of tyrosine, 15.6g (0.10mol) of phenyl chloroformate and 150mL of ethyl acetate were charged, and the mixture was stirred at room temperature for 24 hours to separate 9.5g of Tyr-AC monomer (0.03mol, yield 31.6%). The resulting Tyr-AC monomer nuclear magnetism is shown in FIG. 1.
0.301g (1.00mmol) of Tyr-AC is added into a reaction bottle, 1.0mL of DMAc is used for dissolving, 0.5mL of DMAc solution of n-butylamine (0.10mol/L,0.05mmol) is added, the molar ratio of Tyr-AC to n-butylamine is 20:1, the mixture is sealed and placed in an oil bath at 80 ℃ for reaction for 12 hours, after the reaction, the mixture is poured into ether for precipitation and filtration, and the obtained polymer is dried in vacuum for 1 day to obtain the polytyrosine, wherein the yield is 94.2%. The number average absolute molecular weight of the obtained polymer was 5.9kDa, and the molecular weight distribution was 1.16. The nuclear magnetic hydrogen spectrum of the obtained polymer is shown in FIG. 3, and the MALDI-ToF mass spectrum is shown in FIG. 5.
Example 2
The other polymerization conditions were the same as in example 1, except that benzylamine was used as an initiator to initiate polymerization of Tyr-AC in the presence of N-methylpyrrolidone (NMP) in a molar ratio of Tyr-AC to benzylamine of 60:1, and that the reaction was carried out in a thermostatic bath at 100 ℃ for 24 hours to obtain polytyrosine in a yield of 95.8%. The number average absolute molecular weight of the obtained polymer was 10.8kDa, and the molecular weight distribution was 1.20.
Example 3
Other polymerization conditions were the same as in example 1, except that amino-terminated polyethylene glycol (PEG-NH) having a molecular weight of 2000 was used2) Initiating polymerization of Tyr-AC, wherein the solvent is sulfolane, Tyr-AC and PEG-NH2The molar ratio of (A) to (B) is 100:1, and the reaction is carried out in a constant temperature bath at 60 ℃ for 2 days, so that the yield of the obtained polyamino acid is 99.0%.
Example 4
The other polymerization conditions were the same as in example 1 except that polymerization of Tyr-AC was initiated using tris (2-aminoethyl) amine as an initiator, N-methylpyrrolidone (NMP) was used as a solvent, the molar ratio of Tyr-AC to tris (2-aminoethyl) amine was 60:1, and the reaction was carried out in a 100 ℃ incubator for 24 hours to obtain a three-arm star-shaped polytyrosine with a yield of 93.8%.
Polymerization route:
example 5
19.7g (0.10mol) of DOPA, 15.6g (0.10mol) of phenyl chloroformate, and 150mL of ethyl acetate were charged in a reaction flask, and after stirring and reacting at room temperature for 24 hours, 11.2g of DOPA-AC monomer (0.035mol, yield 35.3%) was isolated. The nuclear magnetization of the resulting DOPA-AC monomer is shown in FIG. 2.
0.317g (1.0mmol) of DOPA-AC is added into a reaction bottle, the DOPA-AC is dissolved by 1.0mL of DMAc, 0.5mL of a DMAc solution (0.1mol/L,0.05mmol) of n-butylamine is added, the molar ratio of the DOPA-AC to the n-butylamine is 20:1, the mixture is sealed and then placed in an oil bath at 100 ℃ for reaction for 4 hours, after the reaction, the mixture is poured into ether for precipitation and filtration, and the obtained polymer is dried in vacuum for 1 day to obtain the polydopa, wherein the yield is 92.8%. The nuclear magnetic hydrogen spectrum of the obtained polymer is shown in FIG. 4.
Example 6
The other polymerization conditions were the same as in example 5, except that DOPA-AC polymerization was initiated using benzylamine as an initiator in the presence of N-methylpyrrolidone (NMP) as a solvent at a molar ratio of DOPA-AC to benzylamine of 60:1 and reacted in a thermostatic bath at 80 ℃ for 24 hours to obtain polydopa in a yield of 94.4%.
Example 7
Other polymerization conditions were the same as in example 5, except that amino-terminated polyethylene glycol (PEG-NH) having a molecular weight of 2000 was used2) Initiating polymerization of DOPA-AC in the presence of sulfolane, DOPA-AC and PEG-NH2The molar ratio of (A) to (B) is 100:1, and the reaction is carried out in a constant temperature bath at 60 ℃ for 2 days, so that the yield of the obtained polyamino acid is 98.4%.
Example 8
The other polymerization conditions were the same as in example 5, except that the polymerization of DOPA-AC was initiated using tris (2-aminoethyl) amine as an initiator in the presence of N-methylpyrrolidone (NMP) in a molar ratio of DOPA-AC to benzylamine of 60:1, and the reaction was carried out in a thermostatic bath at 80 ℃ for 24 hours to obtain a three-arm branched polydopa with a yield of 91.4%.
Polymerization route:
example 9
0.317g (1.00mmol) of NDOPA-AC was charged into a reaction flask, and dissolved in 1.0mL of DMF, and then 0.25mL of a solution of N-butylamine in DMF (0.2mol/L,0.05mmol) was added at a molar ratio of NDOPA-AC to N-butylamine of 20:1, and after sealing, the mixture was placed in an oil bath at 60 ℃ for reaction for 2 days, after the reaction, the mixture was poured into diethyl ether for precipitation, filtered, and the resulting polymer was vacuum-dried for 1 day to give poly-N-dopa in a yield of 90.2%.
Claims (8)
1. The application of the phenolic hydroxyl-containing amino acid-AC monomer in the field of polyamino acid synthesis is characterized in that under the initiation action of an initiator, one or more phenolic hydroxyl-containing amino acid-AC monomers are subjected to polymerization reaction in an organic solvent B, and after the reaction is completed, the polyamino acid with phenolic hydroxyl on the side chain is obtained through post-treatment;
the phenolic hydroxyl-containing amino acid-AC monomer has a structure shown in a formula I or a formula II:
wherein n is an integer of 1 or more, R1～R5Independently selected from H, alkyl, cyano, fluoroalkyl, hydroxy, alkoxy, aryloxy, nitro or halogen, and R1～R5At least one of the substituents is hydroxyl; r6～R10Independently selected from H, alkyl, cyano, fluoroalkyl, hydroxy, alkoxy, nitro or halogen;
the initiator is organic amine; the organic solvent B is one or more of dioxane, tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, tetramethylurea, dimethyl sulfoxide, sulfolane, nitrobenzene, acetonitrile, benzonitrile, N-methylpyrrolidone, toluene, dichloromethane or trichloromethane.
2. The use of claim 1, wherein the phenolic hydroxyl group-containing amino acid-AC monomer is a tyrosine-AC monomer of formula I-I or a dopa-AC monomer of formula I-ii:
3. the use of claim 1, wherein the phenolic hydroxyl group-containing amino acid-AC monomer is an N-dopa-AC monomer having a formula of formula II-i:
4. the use according to claim 1, wherein the preparation method of the phenolic hydroxyl group-containing amino acid-AC monomer comprises:
and dissolving the amino acid containing the phenolic hydroxyl group and aryl haloformate in an organic solvent A, reacting for 12-48 hours at 20-60 ℃, and performing post-treatment to obtain the corresponding amino acid-AC monomer containing the phenolic hydroxyl group.
5. The use according to claim 4, wherein the solvent A is one or more of ethyl acetate, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, acetone, toluene or dioxane.
6. The use according to claim 1,
the molar ratio of the phenolic hydroxyl-containing amino acid-AC monomer to the initiator is 10-200: 1;
the polymerization reaction temperature is 40-150 ℃; the polymerization time is 6 hours to 4 days.
7. Use according to claim 1, wherein the organic amine is n-butylamine, benzylamine, diethylamine, hexamethyldisilazane, ethylenediamine, triethylenetetramine, spermine, tris (2-aminoethyl) amine, amino-terminated polyethylene glycol or polyethyleneimine;
the molecular weight of the amino-terminated polyethylene glycol is 200-5000; the molecular weight of the polyethyleneimine is 500-10000.
8. The use according to claim 1, wherein the molar ratio of the phenolic hydroxyl group-containing amino acid-AC monomer to the initiator is 10-50: 1.
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| Glucuronidation as A Major Metabolic Clearance Pathway of 14C-Labeled Muraglitazar in Humans: Metabolic Profiles in Subjects With or Without Bile Collection;Lifei Wang et al.;《Drug Metabolism and Disposition》;20061231;第34卷(第3期);第427-439页 * |
| Synthesis of Polypeptides from Activated Urethane Derivatives of a-Amino Acids;YASUTAKA KAMEI et al.;《Journal of Polymer Science: Part A: Polymer Chemistry》;20081231;第46卷;第2525-2535页 * |
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