TWI300074B - Hyperbranched polymer and preparation method thereof - Google Patents

Description

Γ300Ό74 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a polymer and its preparation, and more particularly to a high-branched polymer and its preparation. [Prior Art] Polyester is a polymer material commonly used in pharmaceutical applications. The stability of a polyester compound depends mainly on the chemical unit of its composition and its chemical structure. In recent years, the use of dendrimers and hyperbranched polymers in drug delivery has attracted the interest of research units and the industry. Dendrimers are spherical polymers having a highly defined and branched structure which have better physical and chemical properties than simple linear polymers. However, dendrimers require complex and multi-step synthesis, and purification is not easy, so the cost is high and cannot be applied to industrial production methods for mass production. Compared with the regular branching structure of dendrimers, the branched structure of high-branched polymers is relatively irregular, but it has very similar physical properties and chemical properties to dendritic polymers, and its synthesis is simple and can be avoided. Complex synthetic steps. Most of the high-branched polymers can utilize reactive monomers having ABX (A and B are mutually reactive functional groups, and X is greater than or equal to 2) and react via a single pot (one- Pot reaction) way to synthesize. Therefore, the highly branched polymer is quite simple to prepare and mass-produced compared to the dendritic polymer. In the current pharmaceutical technology, linear polylactic acid/polyglycolide with biodegradable properties and copolymers thereof with hydrophilic monomers have been used as carriers for novel drugs and gene delivery. . Therefore, the characteristics of lactic acid/glycolic acid are further combined with the high-branched structure to develop a high-branched polymerization of 0424-A20830TWF(N2); P02930062; Pheolip 5 Ι300Ό74 which is easy and has excellent physical properties and chemical properties. It is one of the most important research goals in biology and medical technology. SUMMARY OF THE INVENTION The object of the present invention is to design a monomer having a lactic acid/glycolic acid carboxyl group and a diol group (AB2) to provide a biodegradable high-branched polymer which can be applied to living organisms and Medical technology, as a carrier of drugs and gene transmission. The high-branched polymer of the present invention has a residue of lactic acid or glycolic acid, and thus can be decomposed by organisms, and the synthesis step of the high-branched polymer is very simple, and the synthesis of the monomer is also very easily. Further, the monomer of the glycolic acid carboxyl group and the diol group (AB2) has a long A-B bond distance, thereby avoiding the disadvantage that the steric hindrance causes the branch to be too short. Further, another object of the present invention is to provide the highly branched polymer and the process for producing the lactic acid/glycolic acid carboxyl group and the diol group monomer. In order to achieve the above object, the high-branched polymer of the present invention is a polymerization product of the monomer represented by the formula (I).

0H

0H Formula (I) wherein R is a residue left by hydrogen dehydrogenation of a lactic acid or a glycolic acid. Further, the monomer represented by the formula (I), the hydrogen on any one or more of the carbon atoms, may be optionally substituted by a fluorine atom, an alkyl group having Ci_3 or a fluoroalkyl group. According to the present invention, the high-branched polymer is divided into 0424-A20830TWF(N2); P02930062; the amount of Pheolip 6 1300Ό74 can be between 1000 and 50000, preferably between 2000 and 30000, and more preferably Between 3000 and 10000, and the degree of branching of the polymer chain of the polymer is between 0.1 and 1 , preferably between 0.1 and 0.6, and more preferably between Between 0.3 and 0.5. Further, according to another preferred embodiment of the present invention, the method for preparing a highly branched polymer according to the present invention comprises a monomer represented by the polymerization formula (I)

0H

0H Formula (I) wherein R is a residue left by hydrogen radical removal of lactic acid or glycolic acid. Here, the single system having the formula (I) can be polymerized in the presence of a starter, and the initiator is an acid catalyst. Initiators for reacting alcohols with carboxylic acids are well known in the art and will not be described herein. Further, the single system having the formula (I) is obtained by reacting a 2,2-dihydroxymethyl propionic acid with a compound. The method, features, and advantages of the present invention are further illustrated by the accompanying drawings, which are set forth in the accompanying drawings. quasi. [Embodiment] Synthesis Example 1 of a reactive monomer having the formula (I): 0424-A20830TWF(N2); P02930062; Pheolip 7 Γ300074 2,2~bis-mercaptopropionic acid methyl ester (Carboxymethyl 2,2- Preparation of bis(hydroxymethyl)propionate monomer

HO compound (3)

Please refer to the following chemical reaction formula (I) for the synthesis route of 2,2~ dimethylolpropionate carboxymethyl ester monomer. The synthesis of compounds 1 to 3 will be described in detail below.

Compound

OH OH 0^0 H2/Pd-〇C1D^, £3丫. Η

MaHCO^, OMF rn

rTi OH OH Q

Compounding * 2 Compounding wheel 3 Chemical reaction formula (I) Compound 1: Synthesis of 2-Benzyl 2-bromoglycolate 12.12 g (60 mmol) of 2-bromoacetyl chloride (2-bromoacetyl) Chloride), 5.4 g (50 mmol) of benzyl alcohol and 300 ml of diethyl ether were added to the reaction flask, and then the solution was cooled to 〇QC, and 6.12 g was slowly added over 30 minutes under a nitrogen atmosphere ( 41 mmol) of triethylamine 0424-A20830TWF (N2); P02930062; Pheolip 8 1300074 and 80 ml of diethyl ether. After reacting for 8 hours at room temperature, the reaction solution was diluted with 100 ml of diethyl ether and extracted with water/brine. After filtration and the filtrate was evaporated, water was removed from magnesium sulfate to obtain 2-bromoglycolic acid phenyl ester (compound) i) llg, yield 96%. The spectral analysis of the compound 1 nuclear magnetic resonance is as follows: lR NMR (400 MHz, CDC13): δ 3.88 (s? 2Η)? 5.22 (s5 2Η)? 7.38 (m5 5Η). Compound 2: benzyloxymethyl thiol 2, 2~ Synthesis of Carbobenzyloxymethyl 2,2,bis(hydroxymethyl)propionate 30 ml of dimethyl acetal (DMF) and 2.50 g (10.9 mmol) of 2-bromoglycolate phenyl ester (Compound 1 ) was added to the reaction flask. Next, slowly add 2,04 g (15.28 mmol) of 2,2-dihydroxymethylpropionic acid (2,2,bis(hydroxymethyl)propionic acid and dissolved in 100 ml of dimethyl acetal (DMF) over 3 hours. 2.56 g (30.52 mmol) of sodium hydrogencarbonate (NaHC03). After reacting at 40 ° C for 3 hours, the reaction solution was drained under reduced pressure, water was added and extracted with dichloromethane (CH 2 C 12 ), then magnesium sulfate In addition to water, 2.6 g of benzyl carboxymethyl ester 2,2~ bishydroxymethylpropionate (Compound 2) was obtained in a yield of 85%. The spectral analysis of the compound 2 nuclear magnetic resonance was as follows: iHNMR (400 MHz, CDC13) : δ 1·18 (s, 3H), 2.92 (s, 2H, 2χ-ΟΗ), 3·78 (d, 2Η, J = 11·5 Ηζ), 3.84 (d, 2Η, J = 11· 5 Ηζ), 4·77 (s, 2 Η), 5·20 (s, 2 Η), 7.37 (m, 5 Η). Compound 3: 2, 2~ bis-methylpropionic acid vinegar (Carboxymethyl 2, 2 Synthesis of -bis(hydroxymethyl)propi〇nate) 0.60 g (2.13 mmol) of benzoic acid methyl ester 2,2~bis-methylpropionate (compound 2) and 20 ml of acetone were added to a reaction flask. , then added 0424-A20830TWF (N2); P02930062; Pheolip 9 1300074 0.8gPd / C (10%). At room temperature, a hydrogen gas with a pressure of 60 psi was introduced and reacted for two hours. After the reaction was completed, the reaction solution was filtered to remove Pd/C, and the filtrate was filtered with a Shixi rubber column to obtain 2, 2 to double. 0.34 g of methyl propyl acrylate (Compound 3) in a yield of 83%. The spectral analysis of the compound 3 nuclear magnetic resonance is as follows: ]H NMR (400 MHz5 CDC13): δ 1.16 (s? 3Η)? 3.81 (d 2Η? J = 11·6 Ηζ), 3.95 (d, 2Η, J = 11.6 Ηζ), 4.81 (s, 2Η)· Example 2: 2,2~Dicarboxymethylpropionic acid Weiethyl-2-yl Preparation of vinegar (Carboxyethan-2-yl 2,2-bis(hydroxymethyl)propionate) monomer

Compound (6) Please refer to the following chemical reaction formula (II) for the synthesis of 2,2~bishydroxymethylpropionic acid carboxyethyl-2-yl ester monomer. The synthesis of compounds 4 to 6 will be described in detail below. Mode: 0424-A20830TWF(N2); P02930062; Pheolip 10 1300074

TEA, Ether -3l· Compound* 4

NaHGO^, DMF

m OH OH compound wheel & ΥψΡά^ϋ〇η% As coffee ne OH OH 0

Compound* 5

Chemical Reaction Formula (II) Compound 4: Synthesis of Benzyl 2-bromopropionate 12.96 g (60 mmol) 2-bromopropionyl bromide, 5.4 g (50 Ment) benzyl alcohol and 300 ml of diethyl ether were added to the reaction flask, then the solution was cooled to 〇QC, and 6.12 g (41 mmol) of triethylamine was slowly added over 30 minutes under nitrogen atmosphere ( Triethyl amine) A solution prepared with 80 ml of diethyl ether. After reacting for 8 hours at room temperature, the reaction solution was diluted with 100 ml of diethyl ether and extracted with water/brine. After filtration and the filtrate was evaporated, water was removed from magnesium sulfate, and the filtrate was purified on a silica gel column to obtain 2-bromo. Phenyl propionate (Compound 4) 11.07 g, yield 91%. The spectral analysis of the compound 4 nuclear magnetic resonance is as follows: lR NMR (400 MHz, CDC13): δ 1.84 (d, 3H, J = 10·4 Ηζ), 4.42 (q, 1H, J = 10·4 Ηζ), 5.18 (s, 2H) ), 7·36 (m, 5H)· Compound 5: Benzene ethyl ester-2-yl 2,2~ bishydroxymethylpropionate (Carbobenzyloxyethan-2-yl 252-bis (hydroxymetliyl) propionate) 0424- A20830TWF(N2); P02930062; Pheolip 11 1300074 Synthesis 5.00 g (20.57 mmol) of 2-bromopropionic acid phenyl ester (Compound 4) of 60 ml of dimercaptoacetal (DMF) was added to the reaction flask. Next, 4.13 g (30.86 mmol) of 2,2-dimethylolpropionic acid (2?2-bis (dissolved in 250 ml) of dimethyl acetal (DMF) was slowly added over 3 hours under 40 ° C under a nitrogen atmosphere. Hydroxymethyl)propionic acid, 2,2-dihydroxymethyl propionic acid) and 5.18 g (61.72 mmol) of sodium hydrogencarbonate (NaHC03). After reacting at 40 ° C for 3 hours, the reaction solution was drained under reduced pressure, water was added and extracted with di-methane (CH 2 C 12 ), and then water was removed with magnesium sulfate to obtain benzene carboxy & The base 2,2~bishydroxydecylpropionate (Compound 5) was 4.6 g in a yield of 75%. The spectral analysis of the compound 5 nuclear magnetic resonance is as follows: ^NMR (400 MHz3 CDCI3): δ 1.16 (s? 3Η)5 1.55 (d? 3Η5 J = 7·6 Ηζ), 3.67 (d, 1 Η, J = 11.8 Ηζ), 3.74 (d,1Η, J = 11·4 Ηζ), 3·89 (d5 1 H, J = 1 1.8 Hz), 3·93 (d, 1 H, J = 1 1·4 Hz), 5.16 (d , 1 H, J = 12.1 Hz), 5.24 (d, 1H, J = 12.1 Hz), 5·29 (q, 1H, J = 7.6 Hz), 7.37 (m, 5H). i Compound 6: 2, 2 ~Carboxyethan-2-yl 2,2-bis(hydroxymethyl)propionate Synthesis of 0.70 g (2/13 mmol) phenylcarboxyethyl ester-2 The base 2,2~bishydroxydecylpropionate (Compound 5) and 20 ml of acetone were added to a reaction vial followed by 0.4 g of Pd/C (10%). Next, hydrogen gas having a pressure of 60 psi was introduced at room temperature and reacted for two hours. After the reaction was completed, the reaction solution was filtered to remove Pd/C, and the filtrate was purified by a silica gel column to obtain 0.2 g of 2,2~bishydroxymethylpropionate carboxyethyl-2-yl ester (Compound 6) in a yield of 86%. The spectral analysis of the compound 6 nuclear magnetic resonance is as follows: 'H NMR (400 MHz5 CDC13): δ 1.15 (s? 3H)? 1.56 (d5 3H)5 J = 0424-A20830TWF(N2); P02930062; Pheolip 12 B00074 6·8 Hz ), 3.72 (d, 1H, J = 11·6 Hz), 3.83 (s, 2H), 3.97 (d, 1H, J = 11.6 Hz) 5 5.28 (q? 1H5 J - 7.1 Hz). High-branched polymerization Synthesis of Example 3: Synthesis of High-branched Polymer HB-MPAG: Refer to the following chemical reaction formula (III), showing the monomer obtained in Example 1 (2,2~bishydroxymethylpropionic acid) Carboxylide ester) Synthesis route of high-branched polymer HB-MPAG obtained by polymerization:

〇

0^0 p-TSA (D.D05eq) Ηγ^ΟΗ rh 〇H OH compound*3 Chemical reaction formula (in) The polymerization method is as follows: 0.30 g (1.56 mmol) of 2,2~bishydroxymethylpropionic acid carboxylate Methyl ester (Compound 3) and p-toluenesulfonic acid monohydrate (8.9 mg 0.0078 mmol, 1-66 wt% in THF) dissolved in THF were placed in a reaction flask. Next, the heat was heated to 150 QC in an oil bath. After continuously stirring and reacting for 1 hour, the above reaction solution was cooled to room temperature, and reduced to 3 X 10-2 torr for two hours to remove water generated in the reaction. Then, it was brought back to atmospheric pressure and heated again to 15 (continuation of the reaction at TC. After 2 hours of reaction, the reaction flask was evacuated at 1 ° C for 5 hours. When the reaction was completed, the reaction product was dissolved in THF. It was precipitated in low temperature diethyl ether to obtain 240 mg of white high-branched polymer HB-MPAG in a yield of 88%, and its nuclear magnetic resonance spectrum is shown in Fig. 1. 0424-A20830TWF(N2); P02930062; Pheo! Ip 13 Ι300Ό74 The polymer chain degree of branching (DB) of the high-branched polymer is obtained by the relationship between the repeating units forming the branching point and the terminal functional group, and the calculation formula thereof As shown below: DB = (D + T) / (D + L + T) where D, L, T are the high-branched polymers respectively derived from 2,2-dimethylolpropionic acid (2, 2) -dihydroxymetliyl propionic acid) The integral value of dendritic, linear, and NMR signals on the sulfhydryl group. The 2,2-dihydroxymethyl propionic acid is δ 1.16 (s, 3H) before the polymerization. However, please refer to In Fig. 1, when the polymer HB-MPAG is formed, the signal of the three hydrogens on the methyl group is δ 1.16(s),: L2 5(s), and l_35(s), that is, dendritic, linear, and terminal. The integral area values of the three positions δ l_16(s), 1.25(s), and 1.35(s) are respectively brought into D, In L and T, the DB value was found to be 0.48. In addition, after analyzing the polymer HB-MPAG by gel permeation chromatography (GPC), the number average molecular weight (?η) was 7030, and the degree of polymerization distribution index was obtained. (PDI) was 1.69. Example 4: Synthesis of high-branched polymer HB-MPAL: Refer to the following chemical reaction formula (IV), showing the monomer obtained in Example 2 (2, 2~-hydroxyl Synthesis route of high-branched polymer HB-MPAL obtained by polymerization of carboxyethyl-2-propionate:

HB-MPJSL p-TSA (0.005 eq) 〇 Υ^ΌΗ Λ

OH OH compound* e 0424-A20830TWF(N2); P02930062; Pheolip 14 Γ300074 Chemical reaction formula (IV) The polymerization method was carried out in the same manner as described in Example 3 except that the reaction monomer 2,2~bishydroxyl The carboxymethyl propyl propionate is substituted with 2,2~bishydroxymethylpropionic acid carboxyethyl-2-yl ester. The nuclear magnetic resonance spectrum of HB-MPAL is shown in Figure 2. The DB value was calculated to be 〇·45, and its number average molecular weight (?η) was 4480, and the degree of polymerization was '1.8. * The high-branched polymer of the present invention has a residue of lactic acid or glycolic acid, and thus can be decomposed by organisms, and the synthesis step of the high-branched polymer is very simple, and the synthesis of the monomer is also It is very easy and can achieve extremely high yields. In addition, the high-branched polymer of the present invention is not only useful as a carrier for drug delivery, but also very suitable for use in bioavailable pharmaceutically acceptable absorbable sutures, thermosetting resins, The viscosity modifier of linear polymers or the application of various adhesives. While the present invention has been described in its preferred embodiments, the present invention is not intended to limit the invention, and the present invention may be modified and modified without departing from the spirit and scope of the invention. The scope of protection is subject to the definition of the scope of the patent application. 0424-A20830TWF(N2); P02930062; Pheolip 15 Ι300Ό74 [Schematic description of the drawings] Fig. 1 shows a nuclear magnetic resonance spectrum of the high-branched polymer HB-MPAG described in Example 3 of the present invention. Fig. 2 is a view showing a nuclear magnetic resonance spectrum of the high-branched polymer HB-MPAL of Example 4 of the present invention. [Main component symbol description] No 0

0424-A20830TWF(N2);P02930062;Pheolip 16

Claims (1)

1300074 X. Patent application scope: 1 · A high-branched polymer, which is a polymerization product of the monomer represented by formula (I) OH OH Formula (1) wherein R is a residue left by hydrogen radical removal of lactic acid or glycolic acid. 2. The high-branched polymer according to claim 1, wherein the monomer represented by the formula (I), any one or more of the hydrogen atoms on the carbon atom, may be optionally A fluorine atom, an alkyl group having Cw or a fluoroalkyl group of Cw is substituted. 3. The high-branched polymer of claim 1, wherein the high-branched polymer has a molecular weight of between 1,000 and 50,000. 4. The high-branched polymer of claim 1, wherein the high-branched polymer has a molecular weight of between 2,000 and 30,000. 5. The high-branched polymer of claim 1, wherein the high-branched polymer has a molecular weight of between 3,000 and 10,000. 6. The south-branched polymer according to claim 1, wherein the high-branched polymer has a polymer chain degree of branching between 0.1 and 1 between. 0424-A20830TWF(N2); P02930062;Pheolip 17 1300074 7. The high-branched polymer of claim 1, wherein the polymer branch of the hyperbranched polymer is branched. The degree of branching is between 0.1 and 0.6. 8. The high-hybranched polymer according to claim 1, wherein the high-branched polymer has a polymer chain degree of branching of 0.3. Between ~0.5. 9. The high-branched polymer of claim 1, wherein the single system having the formula (I) is composed of 2,2-dihydroxymethyl propionic acid and A compound is obtained by reaction. 10. A method for preparing a hyperbranched polymer comprising: a monomer represented by the polymerization formula (I) 0H 0H Formula (I) wherein R is a residue left by hydrogen dehydrogenation of lactic acid or glycolic acid. A method of producing a high-branched polymer according to claim 10, wherein the single system having the formula (I) is polymerized in the presence of a starting agent together. 12. The method of preparing a high-branched polymer according to claim 10, wherein the high-branched polymer has a molecular weight of between 1,000 and 50,000. 13. The method for preparing a high-branched 0424-A20830TWF (N2); P02930062; Pheolip 18 1300074 t compound according to claim 10, wherein the molecular weight of the hyperbranched polymer is Between 2000~30000. 14. The method of preparing a high-branched polymer according to the first aspect of the invention, wherein the high-branched polymer has a molecular weight of between 3,000 and 10,000. 15. The method of preparing a high-branched polymer according to claim 1, wherein the high-branched polymer has a degree of branching of the polymer chain. Between 0.1 and 1. The method of preparing a high-branched polymer according to claim 1, wherein the high-branched polymer has a degree of branching of the polymer chain. Between 0.1 and 0.6. 17. The method of preparing a high-branched polymer according to claim 1, wherein the high-branched polymer has a degree of branching of the polymer chain. 〇·3~0.5 between. 18. The method for preparing a high-branched polymer according to the first aspect of the invention, wherein the single system having the formula (I) is a 2,2-dihydroxymethyl propionic acid It is obtained by reacting with a compound. 19. A process for the preparation of a high-branched polymer as described in claim 10, which may be substituted with a fluorine atom, an alkyl group having CN3 or a fluoroalkyl group having Cw, as needed. 0424-A20830TWF(N2);P02930062;Pheolip 19