Method for preparing monosubstituted glycolide and polymer thereof

Abstract

The invention belongs to the technical field of organic synthesis and high polymer materials, and particularly discloses a novel method for preparing monosubstituted glycolide and a polymer thereof. According to the method, a lactate derivative and glycollic acid are taken as initial raw materials, a series of mono-substituted glycolide is synthesized with high selectivity through acid catalysis ester exchange and intramolecular cyclization dehydration, and then the mono-substituted glycolide polymer with a specific structure is prepared through ring-opening polymerization. The core of the method is as follows: excessive glycollic acid is used for inhibiting ester exchange side reaction of lactate and promoting ester exchange reaction between glycollic acid and lactate to obtain a key intermediate, and finally, the monosubstituted glycolide monomer is obtained through one-step condensation cyclization by using the chemical structure stability of monosubstituted glycolide. The monomers can be prepared into corresponding degradable polyester through ring opening polymerization. The invention provides a general synthesis path for preparing cyclic lactone and functional polyester materials with regular structures and adjustable side chains on a large scale from bulk raw materials.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis and polymer materials technology, specifically relating to a novel preparation method of monosubstituted glycolide and its polymer polymonosubstituted glycolide. Background Technology

[0002] Monosubstituted glycolide is a unique class of biodegradable polymers, characterized by the introduction of a single substituent (such as methyl or phenyl) onto the glycolide ring. This side-chain structure fundamentally alters the physicochemical properties of the polymer—monosubstituted glycolide: its molecular chain regularity is tunable, resulting in variable crystallinity and glass transition temperature; simultaneously, the side chain properties regulate the hydrophilic / hydrophobic balance of the material, thus affecting its degradation rate. Based on these tunable physicochemical properties, the main applications of monosubstituted glycolide are concentrated in high-end biomedical fields, particularly suitable as a carrier for controlled drug release systems, and for constructing tissue engineering scaffolds and absorbable sutures. The key to synthesizing such regularly structured alternating copolymers lies in obtaining their corresponding cyclic monomers—monosubstituted glycolides. However, traditional synthetic methods typically involve a two-step substitution reaction between lactic acid and highly toxic, highly reactive halogenating agents such as bromoacetyl bromide. This method is not only cumbersome and inefficient but also generates a large amount of bromine-containing byproducts, which is environmentally unfriendly, and requires complex post-processing. Meanwhile, the reaction process typically requires large amounts of organic solvents and alkaline catalysts, increasing cost and process complexity, which greatly limits its large-scale production and application. Therefore, developing a simple, low-cost, environmentally friendly, and efficient synthetic route for monosubstituted glycolide and its polymers is of great significance. Summary of the Invention

[0003] I. Purpose of the Invention

[0004] To address the problems of lengthy routes, high feedstock toxicity, poor chemical selectivity (easily generating various cyclic dimer byproducts such as glycolide, lactide, and disubstituted products), difficult separation and purification, and limited large-scale preparation in existing technologies for synthesizing monosubstituted glycolides, this invention aims to provide a novel method for preparing monosubstituted glycolides and their polymers with high selectivity and atom economy. This method, through the design of a well-defined, stepwise controllable reaction sequence, starts from readily available raw materials such as lactate derivatives and glycolic acid, aiming to achieve the efficient synthesis of a series of monosubstituted glycolides with different substituents. Furthermore, it provides a pathway for their controllable ring-opening polymerization, thereby obtaining novel polyester materials with precisely customizable side-chain structures.

[0005] II. Technical Solution

[0006] To achieve the above-mentioned objective, this invention provides a method for preparing monosubstituted glycolide and its polymers, characterized in that the method comprises the following five sequentially performed steps:

[0007] Step 1: Acid-catalyzed transesterification reaction

[0008] Starting with the lactate derivative of general formula (I) and excess glycolic acid, the reaction is carried out in the temperature range of 0-100 °C for 30 minutes to 24 hours under the catalysis of an acid catalyst to generate the corresponding 2-((2-hydroxypropionyl)oxy)acetic acid intermediate.

[0009] Key raw materials: In the general formula (I), the R1 group is selected from methyl, ethyl, propyl, butyl, phenyl or benzyl; the R2 group is selected from methyl, ethyl, phenyl, benzyl or gemdimethyl.

[0010] Material ratio: The amount of glycolic acid used is 1 to 10 equivalents of the molar amount of the lactate derivative, preferably 3 to 5 equivalents. The use of excess glycolic acid is intended to act as both a reactant and a solvent, suppressing transesterification side reactions between lactate derivatives and driving the reaction equilibrium towards the product direction.

[0011] Catalyst system: The acid catalyst is selected from one or more of boron trifluoride (and its ether compounds), triphenylboron, copper tetrafluoroborate, ferric chloride, zinc chloride, indium chloride, aluminum trifluoromethanesulfonate, ferric trifluoromethanesulfonate, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, or ZSM-5 molecular sieve. The amount of catalyst used is 0.1% to 10% of the molar amount of the lactate derivative.

[0012] Step 2: Removal of excess glycolic acid

[0013] After the first step of the reaction is completed, excess glycolic acid in the system is removed by vacuum distillation. This step is usually carried out under a vacuum of 50–300 Pa and at a temperature of 40 °C to 60 °C, with the aim of efficiently recovering unreacted glycolic acid to obtain a concentrated crude intermediate that can be directly used in subsequent reactions.

[0014] Step 3: Intramolecular cyclization and dehydration reaction

[0015] The intermediate obtained in the second step was reacted with a cyclizing catalyst in the temperature range of 0-200 °C for 30 minutes to 24 hours to undergo intramolecular cyclization and dehydration, generating monosubstituted glycolide as shown in general formula (II).

[0016] Catalyst system: The cyclic catalyst is selected from one or more of stannous octoate, dibutyltin dilaurate, p-toluenesulfonic acid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or N,N'-dicyclohexylcarbodiimide (DCC). The amount of catalyst used is 0.1% to 10% of the molar amount of the intermediate.

[0017] Reaction promotion: This step can be carried out under reduced pressure to continuously remove the generated water and promote the cyclization reaction to completion.

[0018] Step 4: Purification of monosubstituted glycolide

[0019] The crude product obtained in the third step is purified to obtain high-purity monosubstituted glycolide. Purification methods include:

[0020] Vacuum distillation: Distillation is carried out at a temperature of 80-120 °C and a pressure of 50-300 Pa to initially separate the target product.

[0021] Recrystallization: The distillation product is recrystallized using one or more of diethyl ether, tetrahydrofuran, toluene, or dichloromethane as a solvent to obtain monosubstituted glycolide crystals of polymerizable purity.

[0022] Step 5: Ring-opening polymerization reaction

[0023] The monosubstituted glycolide purified in step four was used as a monomer and subjected to ring-opening polymerization in the presence of a polymerization catalyst at a temperature range of 0-200 °C for 30 minutes to 24 hours to obtain polymonosubstituted glycolide.

[0024] Catalyst system: The polymerization catalyst is selected from one or more of stannous octoate, dibutyltin dilaurate, diethylzinc, organic bases, or organic acids. The polymerization reaction can be carried out in the molten state or in solution.

[0025] III. Beneficial Effects

[0026] Compared with the prior art, the technical solution provided by the present invention has the following significant advantages:

[0027] 1. Excellent chemoselectivity: This invention employs a two-step sequential strategy of "first forming a linear hydroxy acid dimer intermediate, then intramolecular cyclization," fundamentally avoiding side reactions such as the self-condensation of lactate derivatives to form lactide, the self-condensation of glycolic acid to form glycolide, and random co-condensation to form other asymmetric lactides. This makes the target monosubstituted glycolide the main or even the only cyclic product, resulting in extremely high selectivity and greatly simplifying the subsequent separation and purification process.

[0028] 2. Atom economy and raw material cost advantages: Starting with bulk chemicals lactate derivatives and glycolic acid, the raw materials are widely available and inexpensive. Excess glycolic acid in the reaction design can be easily recovered and recycled, improving atom economy and conforming to the principles of green synthesis.

[0029] 3. Mild and controllable reaction conditions: The reaction temperature range for each step is wide (0-200 °C), and the time is flexible (0.5-24 hours), which can be optimized and adjusted according to the characteristics of different reactive substrates. A variety of catalyst systems are available, providing multiple options to adapt to different functional group compatibility.

[0030] 4. High designability of monomer and polymer structures: By selecting different R1 (ester group) and R2 (α-substituent) in general formula (I), a series of monosubstituted glycolide monomers with different side chain structures and stereochemistry can be synthesized modularly. This provides a strong material basis for preparing a library of functional polyester materials with different hydrophilicity / phobicity, degradation rate, thermal properties, and mechanical properties through ring-opening polymerization, expanding its application potential in biomedical engineering and specialty plastics. Attached Figure Description

[0031] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0032] Figure 1 The 1H NMR spectrum of the methyl glycolide prepared in Example 3.

[0033] Figure 2 The 1H NMR spectrum of the polymethyl glycolide prepared in Example 7 Detailed Implementation

[0034] Example 1: Synthesis of Methyl Glycolide In a 50 mL round-bottom flask, methyl lactate (1.04 g, 10 mmol), glycolic acid (7.6 g, 100 mmol), and ferric trifluoromethanesulfonate (40 mg, 0.08 mmol) were added. After reacting at 60 °C for 6 hours, excess glycolic acid was removed by vacuum distillation at 60 °C. Stannous octoate (25 mg, 0.062 mmol) was added to the residue, and the reaction was carried out at 100 °C and 100 Pa for 4 hours. The distillate was recrystallized from diethyl ether to give white crystals in 75% yield.

[0035] Example 2: Synthesis of methyl glycolide

[0036] In a 50 mL round-bottom flask, ethyl lactate (1.18 g, 10 mmol), glycolic acid (3.8 g, 50 mmol), and ferric chloride (162 mg, 0.1 mmol) were added. After reacting at 30 °C for 2 hours, excess glycolic acid was removed by vacuum distillation at 60 °C. Dibutyltin dilaurate (45 mg, 0.05 mmol) was added to the residue, and the reaction was carried out at 100 °C and 100 Pa for 2 hours. The distillate was recrystallized from diethyl ether to give white crystals in 78% yield.

[0037] Example 3: Synthesis of methyl glycolide

[0038] In a 50 mL round-bottom flask, methyl lactate (1.04 g, 10 mmol), glycolic acid (2.3 g, 30 mmol), and boron trifluoride diethyl ether (12.8 μL, 0.1 mmol) were added. After reacting at 20 °C for 1 hour, excess glycolic acid was removed by vacuum distillation at 60 °C. p-Toluenesulfonic acid (31 mg, 0.1 mmol) was added to the residue, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the crude product was obtained by vacuum distillation at 100 °C and 100 Pa. Finally, recrystallization from diethyl ether yielded white crystals in 80% yield.

[0039] Example 4: Synthesis of ethyl glycolide

[0040] Ethyl lactate (1.18 g, 10 mmol) was used as the starting material, along with glycolic acid (7.6 g, 100 mmol) and boron trifluoride diethyl ether (12.8 μL, 0.1 mmol). After reacting at 20 °C for 1 hour, excess glycolic acid was removed by vacuum distillation at 60 °C. Toluenesulfonic acid (31 mg, 0.1 mmol) was added to the residue, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the crude product was obtained by vacuum distillation at 120 °C and 100 Pa. Finally, recrystallization from diethyl ether yielded white crystals in 73% yield.

[0041] Example 5: Synthesis of phenyl glycolide

[0042] Methyl phenyl lactate (1.94 g, 10 mmol) was used as the starting material, along with glycolic acid (5.7 g, 75 mmol) and boron trifluoride diethyl ether (12.8 μL, 0.1 mmol). After reacting at 20 °C for 1 hour, excess glycolic acid was removed by vacuum distillation at 60 °C. Toluenesulfonic acid (31 mg, 0.1 mmol) was added to the residue, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the crude product was obtained by vacuum distillation at 160 °C and 80 Pa. Finally, recrystallization from diethyl ether yielded white crystals in 66% yield.

[0043] Example 6: Synthesis of gem-dimethyl glycolide

[0044] The reaction was carried out using tert-butyl lactate (1.46 g, 10 mmol) as a starting material, glycolic acid (9.1 g, 120 mmol), and boron trifluoride diethyl ether (12.8 μL, 0.1 mmol). After reacting at 20 °C for 1 hour, excess glycolic acid was removed by vacuum distillation at 60 °C. p-Toluenesulfonic acid (31 mg, 0.1 mmol) was added to the residue, and the reaction was carried out at 100 °C for 12 hours. After the reaction was completed, the crude product was obtained by vacuum distillation at 120 °C and 100 Pa. Finally, recrystallization from diethyl ether yielded white crystals in 88% yield.

[0045] Example 7: Synthesis of poly(methyl glycolide) Methyl glycolide (1.44 g, 10 mmol) prepared in Example 3 and stannous octoate (12.5 mg, 0.031 mmol) were reacted at 140 °C for 6 hours under argon protection. After purification by methanol precipitation, the yield was 90%, the number average molecular weight Mn = 35 kDa, and the molecular weight distribution PDI = 1.80.

[0046] Example 8: Synthesis of poly(methyl glycolide) Methyl glycolide (1.44 g, 10 mmol) prepared in Example 3 and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (1.4 mg, 0.01 mmol) were reacted at 60 °C for 12 hours, purified by methanol precipitation, yield 85%, Mn = 95 kDa, PDI = 1.67.

[0047] Example 9: Synthesis of poly(methyl glycolide) Using methyl glycolide (1.44 g, 10 mmol) prepared in Example 3 and diethylzinc (1.2 mg, 0.01 mmol), the reaction was carried out at 30 °C for 2 hours, purified by methanol precipitation, yield 72%, Mn = 32 kDa, PDI = 2.31.

[0048] Example 10: Synthesis of poly(phenyl glycolide) Using phenyl glycolide (2.18 g, 10 mmol) prepared in Example 5, and 1,8-diazabicycloundec-7-ene (7.6 mg, 0.05 mmol) as a catalyst, the reaction was carried out at 100 °C for 12 hours. Yield 65%, Mn = 43 kDa, PDI = 1.26.

Claims

1. A process for the preparation of monosubstituted glycolide and polymers thereof, characterized in that, The process comprises the following steps: a) reacting the lactate derivative of general formula (I) with excess glycolic acid in the presence of an acid catalyst at 0-100 °C for 30 minutes to 24 hours to perform an ester exchange reaction to form the 2-((2-hydroxypropanoyl)oxy)acetic acid intermediate of general formula (I); b) removing the excess glycolic acid from step a) by distillation under reduced pressure; c) reacting the intermediate obtained in step b) in the presence of a ring- forming catalyst at 0-200 °C for 30 minutes to 24 hours to perform an intramolecular cyclodehydration reaction to form the monosubstituted glycolide of general formula (II); d) subjecting the crude product of c) to distillation under reduced pressure and recrystallization to obtain the pure monosubstituted glycolide e) subjecting the monosubstituted glycolide to ring-opening polymerization in the presence of a polymerization catalyst at 0-200 °C for 30 minutes to 24 hours to obtain the poly(monosubstituted glycolide). wherein the general formula (I) is: General Formula (II) is: General Formula (III) is: wherein R1 is selected from methyl, ethyl, propyl, butyl, phenyl or benzyl; and R2 is selected from methyl, ethyl, phenyl, benzyl or gem-dimethyl.

2. The method of claim 1, wherein, In step a), the amount of glycolic acid used is 1-10 equivalents, preferably 3-5 equivalents, of the lactate derivative.

3. The method of claim 1, wherein, In step a), the acid catalyst is selected from one or more of boron trifluoride, triphenylboron, copper tetrafluoroborate, iron chloride, zinc chloride, indium chloride, aluminum triflate, iron triflate, triflic acid, methanesulfonic acid, p-toluenesulfonic acid or ZSM-5 molecular sieve; and the amount of acid catalyst used is 0.1-10 mol% of the lactate derivative.

4. The method of claim 1, wherein, In step b), the excess glycolic acid is removed by distillation under reduced pressure at 50-300 Pa and 40-60 °C.

5. The method of claim 1, wherein, In step c), the ring-forming catalyst is selected from one or more of stannous octoate, dibutyltin dilaurate, p-toluenesulfonic acid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or N,N'-dicyclohexylcarbodiimide; and the amount of ring-forming catalyst used is 0.1-10 mol% of the intermediate.

6. The method of claim 1, wherein, In step d), the distillation under reduced pressure is performed at 50-300 Pa and 80-120 °C; and the recrystallization solvent is one or more of diethyl ether, tetrahydrofuran, toluene or dichloromethane.

7. The method of claim 1, wherein, In step e), the polymerization catalyst is selected from one or more of stannous octoate, dibutyltin dilaurate, diethyl zinc, an organic base or an organic acid.

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