Method for obtaining Α-amino acid poly(ester amides), poly(ester ureas), and their copolymers by interfacial polycondensation

Abstract

A method for producing α-amino acid poly(ester amides), poly(ester ureas), and copolymers thereof by interfacial polycondensation comprises the following steps: (a) preparing a first solution by mixing bis(α-amino acid)-, ω-alkylene diester di-p- toluenesulfonate salt, and anhydrous sodium carbonate in water; (b) preparing a second solution by dissolving an aliphatic dicarboxylic acid chloride, or triphosgene, or a mixture of triphosgene with aliphatic dicarboxylic acid chlorides and / or a mixture of triphosgene with aliphatic diisocyanates in methylene chloride; (c) cooling both the first and the second solutions; (d) adding the second solution to the first at a rate of 2350–2400 mL / min under stirring at 680–700 rpm; (e) adding 4.0–4.5 L of distilled water to the resulting reaction mixture in the reactor; (f) adding 10–12 L of distilled water to the polymer solution in the distillation / washing unit while simultaneously performing azeotropic distillation of methylene chloride and washing the polymer; and (g) drying the obtained polymer.

Description

[0001] METHOD FOR OBTAINING A-AMINO ACID POLY(ESTER AMIDES), POLY(ESTER UREAS), AND THEIR COPOLYMERS BY INTERFACIAL POLYCONDENSATION The present invention relates to the technology for producing biodegradable oc-amino acid poly(ester amides), poly(ester ureas), and their copolymers, as well as the apparatus used for producing these polymers. Biodegradable polymers constitute a class of high-molecular-weight compounds that undergo degradation into low-molecular-weight compounds under physiological conditions and are absorbed at the site of use. These biodegradable oc-amino acid polymers are highly promising biomaterials with a very wide spectrum of useful properties. They are used to manufacture various types of absorbable surgical implants and controlled / prolonged-release drug delivery systems. The global market for biodegradable polymers is multi-billion-dollar, which is due to their unique properties.

[0002] Currently, very little information is available on the technology for producing biodegradable oc-amino acid polymers, making it crucial to develop a new perfected technological process for these polymers.

[0003] It is known that biodegradable oc-amino acid poly(ester amides) can be obtained via activated polycondensation of bis-(oc-amino acid)-a,co-alkylenediester p-toluenesulfonate salts with di-p-nitrophenyl sebacinate in dimethylformamide (DMF) at 80 °C in the presence of triethylamine, acting as a p-toluenesulfonate acceptor, for 16 hours. The resulting polymer solution is cooled to room temperature, diluted with ethanol, and the polymer is precipitated by pouring into distilled water [US Patent 7304122], Polymers synthesized by this technology require very high purification costs because p-nitrophenol forms a complex with the polymer, and removing it requires enormous quantities of running hot distilled water. Complete removal of p-nitrophenol requires re-dissolution in DMF and methanol, precipitation, filtration, and drying to constant weight at 80 °C. This method does not allow regeneration of the solvents used and is associated with high costs. It should be noted that sebacoyl chloride cannot be used directly in the polycondensation process because it reacts with DMF. Therefore, it is necessary to synthesize a new monomer, di-p-nitrophenyl sebacinate, based on sebacoyl chloride, which further complicates the technological process and increases the cost of the target polymers.

[0004] It is known that biodegradable oc-amino acid poly(ester ureas) can be obtained by interfacial polycondensation of bis-(oc-amino acid)-a,co-alkylenediester p-toluenesulfonate salts with phosgene (US Patent #8765164 B2). In this method, the polycondensation process is carried out at positive temperatures (5-100 °C), which causes an instantaneous temperature rise upon mixing the reagents due to the exothermicity of the process. The temperature rise is accompanied by intense evaporation of phosgene gas and methylene chloride from the reaction mixture, leading to foaming and uncontrolled reaction conditions. Moreover, the use of phosgene gas is problematic in terms of both safety and precise dosing. This method does not practically specify the main technological process parameters that determine the properties of the resulting polymers. Unknown parameters include: 1. The rate of stirring of the reaction mixture;

[0005] 2. The rate of addition of the triphosgene solution to the di-tosylate solution;

[0006] 3. How the polymer is separated from methylene chloride and the regeneration of the latter;

[0007] 4. How the polymer is purified from reaction by-products — salts;

[0008] 5. What type of apparatus is used for production.

[0009] It is also known that biodegradable oc-amino acid poly(ester ureas) can be obtained by interfacial polycondensation of bis-(oc-amino acid)-a,co-alkylenediester p-toluenesulfonate salts with triphosgene (US Patent #10772964). In this method, the main technological parameters determining the properties of the resulting polymers are also not specified. Unknown parameters include:

[0010] 1. The temperature at which the polycondensation reaction occurs;

[0011] 2. The rate of stirring of the reaction mixture;

[0012] 3. The rate of addition of the triphosgene solution to the di-tosylate solution;

[0013] 4. How the polymer is separated from methylene chloride and the regeneration of the latter;

[0014] 5. What type of apparatus is used.

[0015] Essence of the Invention

[0016] The invention relates to a method for obtaining oc-amino acid poly (ester amides), poly(ester ureas), and their copolymers by interfacial polycondensation, comprising the following steps:

[0017] (a) Preparation of the first solution, which involves mixing bis-(oc-amino acid)-a, coalkylenediester p-toluenesulfonate salts with anhydrous sodium carbonate in water in a 20-25 L borosilicate glass reactor equipped with a cooling jacket, mechanical stirrer, temperature indicator, and spiral condenser;

[0018] (b) Preparation of the second solution, which involves dissolving an aliphatic dicarboxylic acid, triphosgene, or a mixture of triphosgene and aliphatic dicarboxylic acids or triphosgene and aliphatic diisocyanates in methylene chloride in an 8-10 L stainless steel mixer equipped with a stirrer and chiller;

[0019] (c) Cooling the first and second solutions to -8 to -10 °C;

[0020] (d) Adding the second solution to the first solution at 2350-2400 mL / min under stirring at 680-700 rpm at atmospheric pressure, followed by stirring the mixture for 25-30 min after completion of addition; (e) Adding 4.0-4.5 L of distilled water to the reaction mixture in the reactor for primary washing of the polymer from by-products (salts), with stirring at 75-80 rpm for at least 1 hour, and filtering the lower layer of the polymer solution through a 7-10 pm nylon filter directly into a 20-25 L stainless steel distillation / washing apparatus;

[0021] (f) Adding 10-12 L of distilled water to the polymer solution in the distillation / washing apparatus while simultaneously removing methylene chloride azeotropically and washing the polymer from polycondensation by-products (salts), with a gradual temperature increase from 25 to 100 °C and continuous stirring at 75-80 rpm for 8-10 hours, checking polymer purity via chloride ion content using the so-called Beilstein method;

[0022] (g) Drying the polymer by placing it in a Teflon dish and drying in an oven at 120-125 °C for 10-12 hours to constant weight. The molecular weights of the resulting polymers are in the range of 95,000-120,000 as measured by gel permeation chromatography.

[0023] The method also allows preparation of first and second solutions at 20-25 °C, with the second solution added to the first at 280-300 mL / min under stirring at 180-200 rpm, producing polymers with molecular weights in the range of 800-2,500.

[0024] The method also includes the interaction of bis-(oc-amino acid)-a,co-alkylenediester p-toluenesulfonate salts of bis(L-leucine)-l,6-hexylendiester p-toluenesulfonate (L6) and bis(L-phenyl)-l,6-hexylendiester p-toluenesulfonate (F6) in a 75 / 25 molar ratio with sebacoyl chloride to obtain poly(ester amide)-copoly(ester amide) 0.75(8L6)-0.25(8F6) with a molecular weight of 102,000;

[0025] The method also includes the reaction of L6 with triphosgene to obtain poly(ester urea)-1L6 with a molecular weight of 110,000;

[0026] The method also includes the reaction of L6 with a mixture of triphosgene and hexamethylene diisocyanate in a 0.25 / 0.25 molar ratio to obtain poly(ester urea)-copoly(ester urea) 0.75(lL6)-0.25(6i-L6) with a molecular weight of 120,000;

[0027] The method also includes the reaction of L6 with a mixture of triphosgene and sebacoyl chloride in a 0.30 / 0.10 molar ratio to obtain poly(ester amide)-copoly(ester urea) O.85(1L6)-0.15(8L6) with a molecular weight of 105,000.

[0028] General Description of the Invention

[0029] The production of biodegradable oc-amino acid poly(ester amides), poly(ester ureas), and their copolymers involves the interaction of bis-(oc-amino acid)-a,co-alkylenediester p-toluenesulfonate salts (general formula I):

[0030] TOSOHH2N-CH-(R)-COO-D-OOC-(R)-CH-NH2TOSOH with an aliphatic acid dichloranhydride (general formula II)

[0031] C1-0C-A-C0-C1

[0032] or an aliphatic diisocyanate (general formula III)

[0033] OCN-I-NCO

[0034] or with triphosgene or their mixtures.

[0035] In general formula I, R = H, CH3, CH2C6H5, CH(CH3)2, CH2CH(CH3)2, CH3CH2CHCH3, independently representing natural or synthetic oc-amino acid monovalent radicals; D independently represents (C2-C20) alkylene, (C2-C20) alkenylene, (C2-Cs) alkoxy, (C2-C20) alkylenediols, or residues of natural or synthetic diols;

[0036] In general formula II, A = (CFkjx, where x = 4, 8, 10, 12 or other normal or branched divalent aliphatic dicarboxylic acid residues;

[0037] In general formula III, I = (CH2)4, (CH2)6, (CH2)4CH(COOC2H5), CH2C(CH3)2CH2CH(CH3)CH2, or C6H7(CH3)3CH2, independently representing divalent residues of aliphatic diisocyanates.

[0038] At the initial stage of production, two solutions of monomers are prepared: the first solution is prepared directly in the polymer reactor by dissolving bis-(oc-amino acid)-a, coalkylenediester p-toluenesulfonate salts with anhydrous sodium carbonate in distilled water, while the second solution is prepared by dissolving the electrophilic monomer in methylene chloride in an 8-10 L stainless steel mixer.

[0039] The first solution is prepared in the reactor at room temperature with stirring at 150 rpm for 40 min. The solution is then cooled to -10 °C using a chiller. The second solution is prepared by dosing the reagents in an 8-10 L stainless steel mixer under continuous stirring at 60 rpm and cooling to -10 °C. A 20-25 L borosilicate glass reactor equipped with a jacket, mechanical stirrer, temperature indicator, spiral condenser, and chiller is used for polymer production. The main stage of polymer formation occurs by adding the second solution to the first, and the main parameters at this stage determine the molecular weights of the resulting polymers. The highest molecular weight polymers are obtained when both solutions are cooled to -10 °C, with the second solution added at 40 mL / min while the first solution is stirred at 700 rpm.

[0040] The process is exothermic, and local temperature increases at the interface, causing methylene chloride to evaporate. A spiral condenser is used to condense the solvent. The next crucial stage is washing the polymer and completely removing the solvent. This involves filtration through a 7.0 pm nylon filter directly into a 20-25 L stainless steel distillation / washing apparatus equipped with a jacket, mechanical stirrer, temperature indicator, and an effective distillation system. The filtered polymer solution is mixed with 10 L of distilled water, and the polymer is washed at room temperature for 2 hours at 60rpm, followed by stepwise temperature increase from 25 °C to 100 °C with continuous stirring for 8-10 hours. Polymer purity is checked via chloride ion content using the Beilstein method.

[0041] The invention also allows production of low-molecular-weight oligomeric polymers (800-2,500 ) using the same apparatus without additives. For these, both solutions are prepared at 25 °C, with the second solution added at 300 mL / min while the first solution is stirred at 200 rpm.

[0042] Examples of the Implementation of the Invention

[0043] The following examples illustrate, but do not limit the scope of the present invention.

[0044] Example 1

[0045] Production of Poly(ester amide) -co-Poly(ester amide) - 0.75(8L6)-0.25(8F6) Polymer No. 1 in Table T):

[0046] 1550 g (2.25 mol) bis(L-leucine)-l,6-hexylendiester p-toluenesulfonate (L6), 567.7 g (0.75 mol) bis(L-phenyl)-l,6-hexylendiester p-toluenesulfonate (F6), 954 g (9.0 mol) anhydrous sodium carbonate and 10 L distilled water were loaded into a 20 L borosilicate glass reactor and the mixture was stirred at 120 rpm at room temperature. After 40 min the resulting aqueous solution (first solution) was cooled with a chiller to -10 °C. In parallel, a second solution was prepared by charging 717.4 g (3.0 mol) sebacoyl chloride (8) and 4.5 L methylene chloride into a 10 L stainless-steel mixer, stirring for 5-10 min, and cooling the obtained solution to -10 °C. The stirring speed of the first aqueous solution was increased to 700 rpm and the methylene chloride solution was added directly to the first solution at 2400 mL / min. After completion of the addition the reaction mixture was stirred at the same speed for an additional 30 min at atmospheric pressure. During polymer formation the reaction temperature rose to -5 °C due to the exothermic nature of the process. Upon completion of the reaction, 4.0 L distilled water was added to the reactor for primary washing of the polymer from reaction by-products (salts) and the mixture was stirred for 2 h at 120 rpm, during which the reaction mass temperature increased to 15 °C. The polymer solution in methylene chloride was then filtered through a 7-10 pm nylon filter directly into a stainless-steel distillation / washing unit. To the filtered polymer solution 10 L distilled water was added and the polymer was washed first at room temperature for 2 h, followed by stepwise heating from 25 °C to 100 °C under stirring at 120 rpm, during which azeotropic removal of methylene chloride occurred. The washing / azeotropic removal was continued for 8-10 h. Polymer purity was checked by the Beilstein test for chloride ions. The purified polymer was transferred onto Teflon trays and dried in an oven at 125 °C for 12 h to constant weight. The main characteristics of the obtained polymer are presented in Table 1.

[0047] Example 2

[0048] Production of poly(ester amide)-copoly(ester urea) 0.90(lL6)-0.10(8L6) (Polymer No. 2, Table 1):

[0049] 1Q67 g (3.0 mol) L6, 954 g (9.0 mol) anhydrous sodium carbonate, and 10 L distilled water are loaded into a 20 L glass reactor, and the mixture is stirred at 120 rpm at room temperature. After 40 min, the resulting aqueous solution (first solution) is cooled with a chiller to -10 °C. In parallel, a second solution is prepared by loading 267.1 g (0.90 mol) triphosgene, 71.7 g (0.30 mol) sebacoyl chloride (8), and 4.5 L methylene chloride into a 10 L stainless steel mixer and stirring for 25-30 min until the triphosgene is fully dissolved. Triphosgene is a trimer of phosgene, and for all polycondensation reactions, the moles of triphosgene are taken as 1 / 3 of the moles of phosgene. The resulting solution is cooled to -10 °C. In the reactor, the stirring speed of the aqueous solution is increased to 700 rpm, and the second solution is added to the first directly from the mixer / dosator at 2400mL / min. After addition of the methylene chloride solution, the reaction mixture is stirred at the same speed for an additional 30 min at atmospheric pressure. Washing of the copolymer, removal of methylene chloride, and drying are carried out as described in Example 1. The main characteristics of the produced copolymer are shown in Table 1. Example 3

[0050] Production of poly(ester urea) 1L6 (Polymer No. 3, Table 1).

[0051] 2066.8 g (3.0 mol) L6, 954 g (9.0 mol) anhydrous sodium carbonate, and 10 L distilled water are loaded into a 20 L glass reactor, and the mixture is stirred at 120 rpm at room temperature. After 40 min, the resulting aqueous solution (first solution) is cooled with a chiller to -10 °C. In parallel, a second solution is prepared by loading 296.7 g (1.0 mol) triphosgene (1) and 4.5 L methylene chloride into a 10 L stainless steel mixer and stirring for 25-30 min until the triphosgene is fully dissolved. The resulting solution is cooled to -10 °C. In the reactor, the stirring speed of the aqueous solution is increased to 700 rpm, and the second solution is added to the first directly from the mixer / dosator at 2400mL / min. After addition of the methylene chloride solution, the reaction mixture is stirred at the same speed for an additional 30 min at atmospheric pressure. Washing, methylene chloride removal, and drying of the polymer are carried out as described in Example 1. The main characteristics of the produced polymer are shown in Table 1.

[0052] Example 4 Production of poly(ester urea)-copoly(ester urea) 0.75(lL6)-0.25(6i-L6) (Polymer No. 4, Table 1):

[0053] 2066.8 g (3.0 mol) L6, 954 g (9.0 mol) anhydrous sodium carbonate, and 10 L distilled water are loaded into a 20 L glass reactor and the mixture is stirred at 120 rpm at room temperature. After 40 min, the resulting aqueous solution (first solution) is cooled with a chiller to -10 °C. In parallel, a second solution is prepared by loading 222.6 g (0.75 mol) triphosgene (1), 126.2 g (0.75 mol) hexamethylene diisocyanate, and 4.5 L methylene chloride into an 8 L stainless steel mixer and stirring for 35 min until the triphosgene is fully dissolved. The resulting solution is cooled to -10 °C. In the reactor, the stirring speed of the aqueous solution is increased to 700 rpm, and the second solution is added to the first directly from the mixer / dosator at 2400 mL / min. After addition of the methylene chloride solution, the reaction mixture is stirred at the same speed for an additional 30 min at atmospheric pressure. Washing, methylene chloride removal, and drying of the polymer are carried out as described in Example 1. The main characteristics of the produced copolymer are shown in Table 1.

[0054] Example 5

[0055] Production of poly (ester amide) 8L6 Polymer No. 5, Table T): 2067 g (3.0 mol) L6, 954 g (9.0 mol) anhydrous sodium carbonate, and 10 L distilled water are loaded into a 20 L glass reactor, and the mixture is stirred at 120 rpm at room temperature. After 40 min, the resulting aqueous solution (first solution) is cooled with a chiller to -10 °C. In parallel, a second solution is prepared by loading 717.4 g (3.0 mol) sebacoyl chloride (8) and 4.5 L methylene chloride into a 10 L stainless steel mixer and stirring for 5-10 min. The resulting solution is cooled to -10 °C. In the reactor, the stirring speed of the aqueous solution is increased to 700 rpm, and the second solution is added to the first directly from the mixer at 2400 mL / min. After addition of the methylene chloride solution, the reaction mixture is stirred at the same speed for 25-30 min at atmospheric pressure. Washing, methylene chloride removal, and drying are carried out as described in Example 1. The main characteristics of the produced polymer are shown in Table 1.

[0056] Example 6

[0057] Production of poly (ester amide) 8F6 Polymer No. 6, Table 1): 2270.8 g (3.0 mol) F6, 954 g (9.0 mol) anhydrous sodium carbonate, and 10 L distilled water are loaded into a 20 L glass reactor, and the mixture is stirred at 120 rpm at 25 °C for 40 min. In parallel, a second solution is prepared by loading 717.4 g (3.0 mol) sebacoyl chloride (8) and 5.0 L methylene chloride into a 10 L stainless steel mixer and stirring for 5-10 min at room temperature. In the reactor, the stirring speed of the aqueous solution is increased to 200 rpm, and the second solution is added to the first at 25 °C directly from the mixer at 300 mL / min. After addition of the methylene chloride solution, the reaction mixture is stirred at the same speed for 25-30 min at atmospheric pressure. Washing, methylene chloride removal, and drying of the polymer are carried out as described in Example 1. Drying is performed in Teflon dishes at 80 °C to constant weight. The main characteristics of the produced polymer are shown in Table 1.

[0058] Table 1

[0059] Main Characteristics of Biodegradable oc- Amino Acid-Based Polymers

[0060] „ , Yield, Intrinsic Viscosity, ,r,r,r n rTg, Tm, # PolymeryMw Mn Mw / Mno®

[0061] % dl / g C C 1 0.75(8L6)-0.25(8F6) 96 0.96 102,00052,000 1.96 27 80 2 0.85(lL6)-0.15(8L6) 95 1.12 105,00054,700 1.92 51 110 3 1L6 95 1.05 110,00058,800 1.87 64 126 4 0.75(lL6)-0.25(6i-L6) 96 1.12 120,00063,000 1.90 48 104 5 8L6 96 0.90 95,000 47,0002.01 22 78 6 8F6 87 0.09 1,600 600 2.7 2 31

[0062] Notes:

[0063] • L = L-leucine residue, F = L-phenylalanine residue, 1 = triphosgene residue, 6i = 1,6- hexamethylene diisocyanate residue, 8 = sebacic acid residue, 6 = 1,6-hexanediol residue;

[0064] • Intrinsic viscosity determined in DMF at 25 °C, solution concentration 0.5 g / dL; • Mw and Mn determined by GPC in DMF (standard: PMMA);

[0065] • Tg and Tm determined by DSC with heating rate 10 °C / min.

[0066] The description of the invention presented herein does not cover all possible variants, but all variants can be implemented without requiring inventive skill.

Claims

The Claims1. A method for producing oc- amino acid poly(ester amides), poly(ester ureas) and their copolymers by interfacial polycondensation, the method comprising the following steps: (a) preparing a first solution by mixing a bis(oc-amino acid)-oc,co-alkylene diester di-p-toluenesulfonate salt and anhydrous sodium carbonate in water in a borosilicate glass reactor of 20-25 L capacity equipped with a cooling jacket, mechanical agitator, temperature indicator and spiral internal cooler; (b) preparing a second solution by dissolving an aliphatic dicarboxylic acid chloride, or triphosgene, or a mixture of triphosgene and an aliphatic dicarboxylic acid chloride, or a mixture of triphosgene and an aliphatic di-isocyanate in methylene chloride in an 8-10 L stainless-steel mixing vessel equipped with an agitator and a chiller; (c) cooling each of the first and second solutions to -8 °C to -10 °C; (d) adding the second solution to the first solution at a rate of 2350-2400 mL / min while stirring the first solution at 680-700 rpm at atmospheric pressure, and continuing stirring for 25-30 minutes after completion of the addition; (e) adding 4.0-4.5 L of distilled water to the reaction mass in the reactor for primary washing of the polymer from reaction by-products (salts), wherein the washing is performed at a stirring rate of 75-80 rpm for at least 1 hour; filtering the lower phase of the polymer solution through a 7-10 pm nylon filter directly into a 20-25 L stainless-steel distillation / washing unit; (f) adding 10-12 L of distilled water to the polymer solution in the distillation / washing unit and simultaneously azeotropically evaporating methylene chloride and washing the polymer from accompanying polycondensation by-products (salts), wherein the methylene chloride evaporation and polymer washing are carried out by stepwise increasing the temperature from 25 °C to 100 °C under continuous stirring at 75-80 rpm for 8-10 hours, and verifying polymer purity by chloride-ion content using the Beilstein test; (g) drying the obtained polymer by placing the polymer on Teflon trays and drying in a drying oven at 120-125 °C for 10-12 hours to constant weight, whereby the obtained polymers have molecular weights in the range of 95,000-120,000 as measured by gel permeation chromatography.2 The method of claim 1, wherein a mixture of bis(L-leucine)-l,6-hexylene diester di-p-toluenesulfonate salt and bis(L-phenylalanine)-l,6-hexylene diester di-p-toluenesulfonate salt in a molar ratio of 0.75:0.25 is reacted with sebacoyl chloride to produce a poly(ester amide)-co-poly(ester amide) having a molecular weight of about 102,000 as measured by gel permeation chromatography.3 The method of claim 1, wherein the bis(L-leucine)-l,6-hexylene diester di-p-toluenesulfonate saltis reacted with triphosgene to produce a poly(ester urea) having a molecular weight of about 110,0004. The method of claim 1, wherein the bis(L-leucine)-l,6-hexylene diester di-p-toluenesulfonate salt is reacted with a mixture of triphosgene and hexamethylene diisocyanate in a molar ratio of 0.25:0.25 to produce a poly(ester urea) -co-poly (ester urea) having a molecular weight of about 120,000 .5 The method of claim 1, wherein the bis(L-leucine)-l,6-hexylene diester di-p-toluenesulfonate salt is reacted with a mixture of triphosgene and sebacoyl chloride in a molar ratio of 0.30:0.10 to produce a poly(ester amide)-co-poly(ester urea) having a molecular weight of about 105,000.