Method for initiating ring-opening polymerization of 2-oxazoline by trimethylsilyl trifluoromethanesulfonate

Abstract

The invention relates to a method for initiating ring-opening polymerization of 2-oxazoline by using silicon trifluoromethanesulfonate. Specifically, the method provided by the invention comprises the step of carrying out polymerization reaction on one or more 2-oxazoline monomers in an organic solvent in the presence of trimethylsilyl trifluoromethanesulfonate so as to form the 2-oxazoline polymer. According to the invention, the initiation condition of the traditional 2-oxazoline polymer is improved, mass polymerization can be carried out at room temperature, and synthesis of the 2-oxazoline polymer with various side chain structures is realized.

Description

Technical Field

[0001] The present invention belongs to the technical field of polymers and in particular, relates to a method for preparing a 2-oxazoline polymer. Background Art

[0002] 2-oxazoline polymer has excellent biocompatibility and important biological function, and as polyethylene glycol substitute and functional peptide mimetic, shows wide application prospect in the field of biomedical materials, such as antibacterial materials, drugs and gene delivery, anti-tumor, tissue engineering and other fields. At present, methyl trifluoromethanesulfonate (MeOTf) is the most commonly used initiator of 2-oxazoline polymerization, with the advantages of high polymerization rate and controllability. However, MeOTf has problems such as difficult synthesis and high toxicity in practical applications; moreover, some studies have found that for some specific functional monomers, such as the side chain amino monomer (AmNHBocOx) protected by tert-butyloxycarbonyl, controlled polymerization (MacromolecularChemistry and Physics, 2006, 207: 183-192) can not be successfully initiated using MeOTf initiator. On the other hand, most of the initiators currently used are used under high temperature conditions, and room temperature conditions are difficult to polymerize. Therefore, the polymerization method of 2-oxazoline monomer is of great significance to structure and function research.

[0003] In previous studies, although Matyjaszewski et al. found that trimethylsilyl trifluoromethanesulfonate (TMSOTf) could generate low-activity intermediates when used to initiate the polymerization of 2-oxazoline monomers, TMSOTf could not initiate the polymerization of 2-oxazoline under their research conditions, and no polymerization product was obtained after two weeks (Macromolecules, 1992, 25: 2070-2075).

[0004] In summary, there is an urgent need to develop new, efficient and compatible initiation strategies for different 2-oxazoline monomers to achieve the facile synthesis of 2-oxazoline polymers. Summary of the invention

[0005] In order to overcome the disadvantages of the above-mentioned method of initiating the polymerization of 2-oxazoline monomer using methyl trifluoromethanesulfonate, the present invention provides a new method of initiating the ring-opening polymerization of 2-oxazoline using silyl trifluoromethanesulfonate.

[0006] The invention provides a method for preparing a 2-oxazoline polymer, comprising the steps of: subjecting one or more 2-oxazoline monomers to a polymerization reaction in an organic solvent in the presence of a TMSOTf initiator, thereby forming a 2-oxazoline polymer.

[0007] In another preferred embodiment, the reaction is carried out in an environment protected by an inert gas or in an environment without inert gas protection.

[0008] In another preferred embodiment, the inert gas protection is carried out at room temperature or under heating conditions.

[0009] In another preferred embodiment, the inert gas protected environment is a nitrogen protected glove box.

[0010] In another preferred embodiment, the temperature range of the heating condition is 30°C-140°C; preferably 100°C.

[0011] In another preferred embodiment, the polymerization reaction time is 2h-16h, preferably 6h.

[0012] In another preferred embodiment, the organic solvent for the polymerization reaction is selected from the following group: DMAc, DMF, MeCN or a combination thereof; preferably DMAc.

[0013] In another preferred embodiment, one, two, three or four 2-oxazoline monomers are polymerized.

[0014] In another preferred embodiment, the 2-oxazoline monomer is a homopolymer or a copolymer.

[0015] In another preferred embodiment, when there are two 2-oxazoline monomers, the method comprises the steps of: mixing the two 2-oxazoline monomers in an organic solvent, and then performing a polymerization reaction in the presence of an initiator to form a 2-oxazoline copolymer.

[0016] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. DETAILED DESCRIPTION

[0017] The inventors have unexpectedly discovered through long-term and in-depth exploration and continuous research that by increasing the temperature and concentration, using TMSOTf as an initiator under optimized conditions, active controllable polymerization of various types of 2-oxazoline monomers can be achieved, and homopolymers of different chain lengths and controllable polymers of different structures, including homopolymers and random copolymers, can be prepared within 1-12 hours. Based on the above findings, the inventors have completed the present invention.

[0018] the term

[0019] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0020] When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0021] As used herein, the term "plurality" means two or more.

[0022] As described herein, the compounds of the present invention can be replaced with any number of substituents or functional groups to expand their scope of inclusion. Generally, the term "substituted" appears before or after the term "optional", and the general formula of the substituent included in the present invention refers to the use of a specified structural substituent to replace the hydrogen free radical. When multiple positions in a specific structure are replaced by multiple specific substituents, each position of the substituent can be the same or different. The term "substituted" used herein includes all allowed organic compound substitutions. In a broad sense, allowed substituents include non-cyclic, cyclic, branched non-branched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, heteroatom nitrogen can have a hydrogen substituent or any allowed organic compound described above to supplement its valence state. In addition, the present invention is not intended to limit the allowed substitution of organic compounds in any way.

[0023] Unless otherwise stated, any heteroatom with unsatisfied valence is assumed to have sufficient hydrogen atoms to complete its valence.

[0024] As used herein, the term "statistic coplymer" or "random" refers to a polymer formed by random connections obtained by simultaneous polymerization of two or more monomers.

[0025] The main advantages of the present invention are:

[0026] The invention provides a novel ring-opening polymerization method of 2-oxazoline monomers, and homopolymers of different chain lengths and controllable polymers of different structures, including random copolymers and block polymers, are prepared within 1-12 hours under preferred conditions. In addition, the initiator used in the invention realizes the controlled polymerization of 2-oxazoline monomers under room temperature. Compared with traditional initiators, the invention expands the structure of 2-oxazoline polymers and the scope of application in the field of biomedicine.

[0027] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually carried out under normal conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified.

[0028] Example 1. Preparation of oxazoline monomers with side chain amino groups

[0029] 1. Preparation of 2-isobutyl-2-oxazoline monomer (iBuOx)

[0030] Isobutyronitrile (10.0 g, 120.3 mmol) and zinc acetate (2.2 g, 12.0 mmol) were weighed into a round-bottom flask, 2-aminoethanol (8.1 g, 132.3 mmol) was added dropwise into the flask, and the mixture was reacted at 140°C for 20 h. The reaction mixture was cooled to room temperature and dissolved by adding DCM (150 mL). The mixture was washed with water (50 mL × 3) and saturated brine (50 mL × 1) in sequence, the organic phase was dried, filtered and distilled under reduced pressure, and the crude product was vacuum distilled to obtain colorless liquid iBuOx (7.0 g, yield 46%).

[0031] NMR characterization of iBuOx: 1 H NMR (400MHz, CDCl3) δ4.24(t,J=9.2Hz,2H),3.83(t,J=9.2Hz,2H),2.16(d,J=7.6Hz,2H),2.04(m,J=6.8Hz,1H),0.98(d,J=6.4Hz,2H).EI-MS:m / z calculated for C7H 13 NO[M] + :127.1;

[0032] 2. Preparation of 2-N-Boc-aminomethyl-2-oxazoline monomer (MeNHBocOx)

[0033] Weigh N-Boc-α-aminoacetic acid (10.0 g, 57.1 mmol) into a round-bottom flask and add DCM (200 mL) to dissolve. Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 16.4 g, 85.6 mmol), 1-hydroxybenzotriazole (HOBT, 11.6 g, 85.6 mmol), N,N-diisopropylethylamine (DIEA, 29 mL, 171.3 mmol) under ice bath, and stir under ice bath for 20 min before adding 2-chloroethylamine hydrochloride (8.6 g, 74.2 mmol). The reaction system was transferred to room temperature and the reaction was stopped after 7 hours. It was washed with 2% citric acid (100 mL×6) and deionized water (100 mL×1) in sequence. The organic phase was dried, filtered and distilled under reduced pressure. The crude product was recrystallized in DCM and Hexane solvents to obtain a colorless solid intermediate compound (6.2 g, yield 46%).

[0034] Weigh NaOH (1.2 g, 27.9 mmol) in a round-bottom flask, add ethanol (EtOH, 250 mL) to dissolve, then add the intermediate (6.0 g, 25.4 mmol), and reflux at 90°C for 1.5 h. The reaction mixture was distilled under reduced pressure to remove EtOH, and EA (100 mL) was added to dissolve. The organic phase was washed with deionized water (100 mL × 3), dried, filtered, and distilled under reduced pressure. It was recrystallized in EA and Hexane solvents to obtain a colorless solid 2-oxazoline monomer MeNH Boc Ox 2-3 (2.6 g, yield 52%).

[0035] MeNH Boc NMR characterization of Ox: 1 H NMR (400MHz, CDCl3) δ5.17(br,1H),4.32(t,J=9.6Hz,2H),3.95(d,J=5.2Hz,2H),3.86(t,J=9.2Hz,2H),1.45(s,9H).EI-MS: m / z calculated for C9H 16 N2O3[M] + :200.1;Found 200.1.

[0036] 3. Preparation of 2-N-Boc-aminopropyl-2-oxazoline monomer (ProNHBocOx)

[0037] ProNH Boc Synthesis of Ox and MeNH Boc Ox was prepared similarly from N-Boc-γ-aminobutyric acid (11.6 g, 57.1 mmol), EDCI (16.4 g, 85.6 mmol), HOBT (11.6 g, 85.6 mmol), DIEA (29 mL, 171.3 mmol), and 2-chloroethylamine hydrochloride (8.6 g, 74.2 mmol) by reacting for 7 h to obtain a colorless solid intermediate compound (6.9 g, yield 46%).

[0038] The intermediate was then reacted with NaOH (1.2 g, 27.9 mmol) and EtOH under reflux to obtain a colorless solid 2-oxazoline monomer ProNH Boc Ox (3.0 g, yield 52%).

[0039] ProNH Boc NMR characterization of Ox: 1H NMR (400MHz, CDCl3): 4.26 (br, 1H), 4.23 (t, J = 9.2Hz, 2H), 3.83 (t, J = 9.2Hz, 2H), 3.18 ( dd,J=6.0Hz,2H),2.32(t,J=7.6Hz,2H),1.83(m,J=7.2Hz,2H),1.44(s,9H).EI-MS:m / z calculated for C 11 H 20 N2O3[M] + :228.1;Found 228.1.

[0040] 4.2-N-Boc-aminobutyl-2-oxazoline monomer (BuNH Boc Preparation of Ox

[0041] The synthesis method of BuNHBocOx is similar to that of MeNHBocOx. N-Boc-δ-aminovaleric acid (20.0 g, 92.1 mmol), EDCI (26.5 g, 138.2 mmol), HOBT (18.7 g, 138.2 mmol), DIEA (46.6 mL, 276.3 mmol), and 2-chloroethylamine hydrochloride (13.9 g, 110.7 mmol) were reacted for 8 h to obtain a colorless solid intermediate 2-6 (14.7 g, yield 57%).

[0042] Intermediate 2-6 (10.0 g, 35.9 mmol) and NaOH (1.6 g, 39.5 mmol) were reacted under EtOH reflux, and the resulting crude product was distilled to obtain colorless liquid 2-oxazoline monomer BuNHBocOx 2-7 (4.3 g, yield 49%).

[0043] BnB Boc NMR characterization of Ox: 1 H NMR (400MHz, CDCl3): δ4.68(br,1H),4.24(t,J=9.6Hz,2H),3.82(m,J=9.6Hz,2H),3.14(dd,J=6.8H z,2H),2.29(t,J=7.2Hz,2H),1.67(t,J=8.4Hz,2H),1.52(m,J=6.8Hz,2H),1.41(s,9H).EI-MS:m / z calculated for C 12 H 22 N2O3[M] + :242.2;Found 242.2.

[0044] 5.2-N-Boc-aminopentyl-2-oxazoline (AmNH Boc Preparation of Ox

[0045] AmNH Boc Synthesis of Ox and MeNH Boc Similarly to Ox, a colorless solid intermediate (6.8 g, 54% yield) was prepared by reacting N-Boc-aminocaproic acid (10.0 g, 43.2 mmol), EDCI (12.4 g, 64.8 mmol), HOBT (8.76 g, 64.8 mmol), DIEA (22 mL, 129.6 mmol), and 2-chloroethylamine hydrochloride (6.0 g, 51.8 mmol) for 9 h.

[0046] The intermediate (6.8 g, 23.2 mmol) and NaOH (1.0 g, 25.5 mmol) were reacted under EtOH reflux for 2 h, and the crude product was separated and purified by basic alumina column chromatography using PE and EA as eluents to obtain a white solid 2-oxazoline monomer AmNH Boc Ox (2.5 g, 42% yield).

[0047] AmNH Boc NMR characterization of Ox: 1 H NMR (400MHz, CDCl3): δ4.78(br,1H), 4.12(t,J=9.2Hz,2H), 3.71(m,J=9.6Hz,2H), 3.01(t,J=6.8Hz,2H),2.17(t,J=7.6Hz,2H),1.55(m,J=7.6Hz,2H),1.29(m,13H).

[0048] Example 2. Synthesis of 2-methyloxazoline homopolymer at room temperature

[0049]

[0050] In a nitrogen-protected glove box, weigh MeOx (119 mg, 1.4 mmol) and mix it with acetonitrile (MeCN) to make it 1.4 M, add a magnetic stirrer, weigh TMSOTf (31 mg, 0.14 mmol) and mix it with MeCN to make it 0.14 M, add 1 mL of TMSOTf solution to 1 mL of MeOx solution under stirring, tighten the reaction vial with a sealing cap and stir the reaction at room temperature (30°C). Monitor the reaction progress by TLC. After the monomer is completely consumed, transfer the reaction solution to a 50 mL centrifuge tube, add MeOH (100 μL) to dilute, add methyl tert-butyl ether (MTBE, 45 mL) to precipitate, centrifuge at 4200 rpm for 3 min, pour off the supernatant and evaporate the residual solvent with an air pump. Add MeOH (200 μL) to dissolve the precipitate under shaking, add MTBE (45 mL) and centrifuge again. After repeating the dissolution-precipitation process twice, the centrifuge tube was placed in a drying dish and vacuumed overnight to remove the residual solvent to obtain the purified white solid poly(2-methyloxazoline) (PMeOx 10 ). PMeOx 10 The molecular weight of the obtained product was characterized by MALDI-TOF-MS. After 7 days of reaction, a polymer with a yield of 89.7% was obtained. The polymer with narrow dispersion (Mn=1359Da, )

[0051] Example 3. Synthesis of 2-methyloxazoline homopolymer at room temperature and in different solvents

[0052] As described in Example 2, the solvent was replaced with DMAc, DMF, DMSO, PhCN, MeCN and Sulfolane at 30°C and an initial monomer concentration of 4 M. The reaction was carried out at room temperature for 7 days in different solvents under the condition of an initial monomer:initiator concentration ratio M:I=20:1. PEtOx was successfully obtained with high yields (89.7-92.1%). 20 (Mn = 2100-3600Da, DP=21-36).

[0053] Example 4. Synthesis of 2-methyloxazoline homopolymer in DMAc solvent at different temperatures

[0054] As described in Example 2, the polymerization solvent was DMAc, and the polymerization was carried out at different temperatures of 30, 60, 100, and 140°C, and PEtOx was successfully obtained with a high yield (86.2-91.7%). 20 (Mn = 2700-3400Da, DP = 27-34). It was also found that the polymerization rate increased with increasing polymerization temperature. At 100°C, EtOx could react by more than 98% within 1 hour. At 140°C, EtOx could react completely within 0.5 hour.

[0055] Example 5. Synthesis of 2-ethyloxazoline homopolymers with different chain lengths in DMAc solvent at 100°C

[0056]

[0057] As described in Example 4, the polymerization solvent was DMAc, and the polymerization was carried out at 100°C. EtOx (119 mg, 1.2 mmol) was weighed and prepared with DMAc to a final concentration of 4 M (concentration after adding the initiator solution), TMSOTf was weighed and prepared with DMAc to a concentration of 1 M, and 120 μL, 60 μL, 30 μL, 20 μL and 12 μL of TMSOTf solution were added to the EtOx solution under stirring, respectively, and the mixture was sealed and taken out from the glove box to react at 100°C. The reaction progress was monitored by HPLC. When HPLC showed that all the monomers were consumed, the reaction solution was transferred to a 50 mL centrifuge tube for polymer post-treatment to obtain purified PEtOx n The results showed that the chain length of PEtOx ranged from 14mer (M n =1.4 kDa) gradually increased to 242mer (M n =24 kDa), with narrow dispersion And the degree of polymerization is consistent with the theoretical value.

[0058] Example 6. Synthesis of 2-phenyloxazoline homopolymer in DMAc solvent at 100°C

[0059]

[0060] As described in Example 5, the polymerization solvent was DMAc, the initial reaction concentration of PhOx monomer was 4M, and the polymerization was carried out at 100°C. The GPC characterization results of the polymerization product showed that the yield of the polymerization product was 87.5%, and the chain length was 20mer (M n =3.0 kDa, ) and the degree of polymerization are consistent with the theoretical values.

[0061] Example 7. 2-Oxazoline Homopolymer PMeNH in DMAc Solvent at 100°C Boc Synthesis of Ox

[0062]

[0063] As described in Example 5, the polymerization solvent was DMAc, MeNHBoc The initial reaction concentration of Ox monomer was 2M, and polymerization was carried out at 100°C. The GPC characterization results of the polymerization products showed that the yield of the polymerization products was 84.4%, and the chain length was 23mer (M n =4.6 kDa, ) and the degree of polymerization are consistent with the theoretical values.

[0064] Example 8. 2-Oxazoline Homopolymer PProNH in DMAc Solvent at 100°C Boc Synthesis of Ox

[0065]

[0066] As described in Example 5, the polymerization solvent was DMAc, ProNH Boc The initial reaction concentration of Ox monomer was 2M, and polymerization was carried out at 100°C. The GPC characterization results of the polymerization products showed that the yield of the polymerization products was 91.7%, and the chain length was 24mer (M n =5.5 kDa, ) and the degree of polymerization are consistent with the theoretical values.

[0067] Example 9. 2-Oxazoline Homopolymer PBuNH in DMAc Solvent at 100°C Boc Synthesis of Ox

[0068]

[0069] As described in Example 5, the polymerization solvent was DMAc, BuNH Boc The initial reaction concentration of Ox monomer was 2M, and polymerization was carried out at 100°C. The GPC characterization results of the polymerization products showed that the yield of the polymerization products was 95.0%, and the chain length was 22mer (M n =5.4 kDa, ) and the degree of polymerization are consistent with the theoretical values.

[0070] Example 10. Synthesis of 2-oxazoline copolymers in DMAc solvent at 100°C

[0071]

[0072] The operation of random copolymerization is as follows: in a nitrogen circulating glove box, 4M EtOx (119.0 mg, 1.2 mmol) DMAc solution and 4M PhOx (176.6 mg, 1.2 mmol) DMAc solution are mixed under stirring conditions, and 60 μL 1M TMSOTf DMAc solution is added dropwise. The reaction vial is tightened with a sealing cap and taken out of the glove box, and placed on a heated stirrer at 100°C for stirring reaction. The reaction progress is monitored by TLC plates and HPLC. When HPLC shows that all the monomers are consumed, the reaction solution is transferred to a 50 mL centrifuge tube for polymer post-treatment and GPC characterization. The GPC characterization results of the polymerization product show that the yield of the polymerization product is 89.3%, and the chain length is 43mer (M n =4.9 kDa, ) and the degree of polymerization are consistent with the theoretical values.

[0073] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing a 2-oxazoline polymer, characterized in that, The method comprises the following steps: in an organic solvent, in the presence of trimethylsilyl trifluoromethanesulfonate, polymerizing one or more 2-oxazoline monomers to form a 2-oxazoline polymer.

2. The preparation method according to claim 1, characterized in that The 2-oxazoline polymer comprises one or more of the repeating units shown in formula I, Wherein, R is selected from the following substituted or unsubstituted groups: C1-C 15 Alkyl, C1-C 15 Alkylamino, C2-C 15 Alkenyl, C2-C 15 Alkynyl, C1-C 15 Alkyl hydroxyl, C1-C 15 Alkyl aldehyde, C1-C 15 Alkylsulfonyl, -Rc-COO-Rc", -Rc-CO-Rc", -Rc-O-Rc"-, -Rc-S-Rc", C3-C 12 Cycloalkyl, C4-C 12 Cycloalkenyl, 5-12 membered heterocyclic group, C6-C 12 Aryl, 5-12 membered heteroaryl; Wherein, the substitution refers to substitution by one or more groups selected from the following groups: halogen, hydroxyl, amino, guanidine, -CO-NH2, -COOH, -SH, C1-C6 alkyl S-, Ph-, -PhOH, glucose, C1-C 15 Alkyl, C1-C 15 Halogenated alkyl, C1-C 15 Alkoxy, C1-C 15 Halogenated alkoxy, C3-C 15 Cycloalkyl, C4-C 12 Cycloalkenyl, 5-10 membered heteroaryl, 5-12 membered heterocyclyl.

3. The preparation method according to claim 2, characterized in that: Includes steps: In a heated organic solvent, in the presence of trimethylsilyl trifluoromethanesulfonate initiator, polymerizing the 2-oxazoline monomer represented by formula A to obtain a 2-oxazoline polymer; Wherein, the R structure is as described in claim 2; and the temperature range of the heating condition is 60-140°C.

4. The preparation method according to claim 3, characterized in that: The polymerization reaction was carried out at room temperature.

5. The preparation method according to claim 3, characterized in that: The organic solvent is selected from the group consisting of acetonitrile (MeCN), benzonitrile (PhCN), sulfolane, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), and N,N-dimethylformamide (DMAc).

6. The preparation method according to claim 2, characterized in that: The chain length of the 2-oxazoline polymer is 10-500.

7. The preparation method according to claim 2, characterized in that: The 2-oxazoline polymer is a homopolymer or / and a blended polymer.

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