Liquid Polyethylene Glycol

Abstract

A method of producing polyethylene glycol includes combining a tetra(ethylene glycol) initiator with one or more catalysts selected from the group consisting of MOH and MH, where M is selected from the group consisting of alkali metals and alkaline earth metals, to form a reaction mixture, wherein the reaction mixture further contains 1200 ppm or less of water as measured by Karl Fischer titration; adding ethylene oxide to the reaction mixture; and reacting the reaction mixture to form polyethylene glycol having a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography with mass spectrometry detection.

Description

[Technical Field]

[0001] The present disclosure relates to methods for producing polyethylene glycol, and more particularly to methods for producing liquid polyethylene glycol compositions having low tri(ethylene glycol) concentrations.

[0002] (Introduction) Polyethylene glycols having a weight average molecular weight of 200 grams / mole ("g / mol") to 1000 g / mol are useful in pharmaceuticals and in forming products intended for human consumption. Such low molecular weight polyethylene glycols are traditionally formed by combining ethylene oxide, an initiator, and a catalyst in a reactor until the product polymerizes to form polyethylene glycol. Given their applications, certain jurisdictions have begun to impose regulatory standards for residual substances in polyethylene glycol. For example, China has implemented a regulatory requirement that residual tri(ethylene glycol) ("TEG") in polyethylene glycol be less than 1000 parts per million ("ppm") as measured by gas chromatography with flame ionization detection.

[0003] The source of residual TEG in low-molecular-weight polyethylene glycols is not fully understood, and there are several conflicting hypotheses regarding its origin. One hypothesis regarding the residual TEG concentration relates to the use of TEG as an initiator for polyethylene glycols. For example, it has been estimated that a portion of the TEG remains unreacted, resulting in residual TEG exceeding regulatory targets. The explanation for residual TEG is particularly problematic in low-molecular-weight polyethylene glycols because TEG has a relatively similar size to the final product and is therefore expected to be present in a larger proportion in the final product. In other words, in low-molecular-weight polyethylene glycols, there is a high probability that initiators such as TEG remain unreacted. Various attempts have been made to use other initiators. U.S. Patent No. 4,946,939(A) describes the production of high-purity polyether polyols using different initiators, such as diethylene glycol, triethylene glycol, tetra(ethylene glycol), etc., together with water, followed by membrane filtration to filter out undesired low-molecular-weight components (i.e., TEG). Similarly, Chinese Patent Publication No. 106905522(A) describes the use of diethylene glycol, triethylene glycol and tetraethylene glycol in the production of polyethylene glycol having a molecular weight of 8,000 g / mol or more using a complex calcium-based catalyst.

[0004] Because TEG levels in low molecular weight polyethylene glycol remain a problem, manufacturers have resorted to removing TEG after the formation of polyethylene glycol. Conventional methods for removing TEG from polyethylene glycol include separate distillation and / or separation steps. Although effective, the introduction of additional steps not only complicates the production of polyethylene glycol, but also increases the final cost and time required to produce polyethylene glycol. Therefore, there is a need in the art for a method for directly forming polyethylene glycol with a reduced TEG concentration without additional purification steps.

[0005] In view of the above, it would be surprising to discover a method of producing polyethylene glycol having a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography with mass spectrometry detection, and 1000 ppm or less of TEG as measured by gas chromatography using flame ionization detection. Summary of the Invention

[0006] The inventors of the present application have discovered a method for producing polyethylene glycol having a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography with mass spectrometry detection, and 1000 ppm or less of TEG as measured by gas chromatography with flame ionization detection.

[0007] This disclosure is the result of the discovery that while the selection of an initiator (i.e., tetra(ethylene glycol)) with a molecular weight greater than TEG is important, the removal of water during the production of polyethylene glycol is also important. Without being bound by theory, it is believed that the presence of water tends to act as an initiator for ring-opening ethylene oxide to form ethylene glycol. Due to the relatively low molecular weight of polyethylene glycol (i.e., 200 g / mol to 1000 g / mol), some of the ethylene glycol formed during ring-opening ultimately polymerizes to TEG, causing the resulting product to exceed its regulatory target. It has been discovered that by limiting the water concentration in the combined ethylene oxide, initiator, and catalyst reaction mixture to 1200 ppm or less, the resulting polyethylene glycol exhibits a TEG concentration of 1000 ppm or less, as measured by gas chromatography with flame ionization detection.

[0008] The present disclosure is particularly advantageous in forming glycol compositions.

[0009] According to a first aspect of the present disclosure, a method of producing polyethylene glycol includes combining a tetra(ethylene glycol) initiator with one or more catalysts selected from the group consisting of MOH and MH to form a reaction mixture, where M is selected from the group consisting of alkali metals and alkaline earth metals, and further wherein the reaction mixture contains 1200 ppm or less of water as measured by Karl Fischer titration; adding ethylene oxide to the reaction mixture; and reacting the reaction mixture to form polyethylene glycol having a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography with mass spectrometry detection.

[0010] According to a second feature of the present disclosure, the step of reacting the reaction mixture further includes reacting the reaction mixture to form polyethylene glycol having a weight average molecular weight of 300 g / mol to 600 g / mol as measured by gas chromatography.

[0011] According to a third feature of the present disclosure, the polyethylene glycol has a triethylene glycol concentration of less than 1000 ppm as measured by gas chromatography with flame ionization detection.

[0012] According to a fourth aspect of the present disclosure, the polyethylene glycol has a triethylene glycol concentration of 500 ppm or less as measured by gas chromatography with flame ionization detection.

[0013] According to a fifth aspect of the present disclosure, the step of reacting the reaction mixture further comprises heating the reaction mixture to a temperature in the range of 120°C to 150°C.

[0014] According to a sixth aspect of the present disclosure, the catalyst is KOH.

[0015] According to a seventh aspect of the present disclosure, the method further comprises the step of dehydrating the initiator before combining it with the one or more catalysts.

[0016] According to an eighth aspect of the present disclosure, the method further comprises dehydrating the combined initiator and one or more catalysts.

[0017] According to a ninth feature of the present disclosure, the reaction mixture contains 800 ppm or less of water as measured by Karl Fischer titration.

[0018] According to a tenth feature of the present disclosure, the reaction mixture contains 500 ppm or less of water as measured by Karl Fischer titration. DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, the term "and / or," when used in a list of two or more items, means that any one of the listed items can be used by itself, or any combination of two or more of the listed items can be used. For example, if a composition is described as containing components A, B, and / or C, the composition can contain A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, or A, B, and C in combination.

[0020] Unless otherwise stated, all ranges are inclusive of the endpoints.

[0021] As used herein, the term weight percent ("wt %") refers to the weight percentage of a component relative to the total weight of the glycol composition, unless otherwise specified.

[0022] As used herein, Chemical Abstract Services Registry Number ("CAS#") refers to the unique numeric identifier last assigned to a chemical compound by the Chemical Abstract Service as of the priority date of this document.

[0023] Unless otherwise specified, all molecular weight measurements herein are determined by gas chromatography with mass spectrometry detection, as described below.

[0024] method The present disclosure is directed to a method for producing polyethylene glycol. The method includes combining a tetra(ethylene glycol) initiator with one or more catalysts selected from the group consisting of MOH or MH to form a reaction mixture. M is selected from the group consisting of alkali metals and alkaline earth metals. The reaction mixture contains 1200 ppm or less of water as measured by Karl Fischer titration, as described in more detail below. The method also includes adding ethylene oxide to the reaction mixture. The method also includes reacting the reaction mixture to form polyethylene glycol having a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography with mass spectrometry detection. The method may also include dehydrating the initiator before combining with the one or more catalysts. The method may also include dehydrating the combined initiator and one or more catalysts. It will be understood that the steps of the method may be performed in any order and / or simultaneously, if practicable. The steps involving adding and mixing the initiator, catalyst, and ethylene oxide may be performed in the reactor or in separate vessels for subsequent transfer to the reactor.

[0025] Reaction mixture The reaction mixture includes tetra(ethylene glycol), one or more catalysts, and ethylene oxide. Prior to the addition of ethylene oxide, the reaction mixture contains no more than 1200 ppm water as measured by Karl Fischer titration, as described in more detail below. For example, the reaction mixture may contain 1200 ppm or less of water, or 1150 ppm or less of water, or 1100 ppm or less of water, or 1050 ppm or less of water, or 1000 ppm or less, or 950 ppm or less, or 900 ppm or less, or 850 ppm or less, or 800 ppm or less, or 750 ppm or less, or 700 ppm or less, or 650 ppm or less, or 600 ppm or less, or 550 ppm or less, or 500 ppm or less, or 450 ppm or less, or 400 ppm or less, or 350 ppm or less, or 300 ppm or less, or 250 ppm or less, or 200 ppm or less, or 150 ppm or less, or 100 ppm or less, or 50 ppm or less, as measured by Karl Fischer titration. Because ethylene oxide does not contain significant amounts of water, the reaction mixture may contain the above water concentrations either before or after the addition of ethylene oxide to the reaction mixture.

[0026] Tetra(ethylene glycol) initiator The initiator used in this method is tetra(ethylene glycol) ("TTEG"). As explained above, utilizing TTEG as the initiator helps reduce TEG in the final polyethylene glycol by eliminating one of the hypothesized sources of TEG. TTEG has the CAS number 112-60-7 and C8H 1805. The reaction mixture may contain 40 wt% to 60 wt% TTEG, based on the total weight of the reaction mixture including ethylene oxide. For example, the reaction mixture may contain 40 wt% or more, or 42 wt% or more, or 44 wt% or more, or 46 wt% or more, or 48 wt% or more, or 50 wt% or more, or 52 wt% or more, or 54 wt% or more, or 56 wt% or more, or 58 wt% or more, and at the same time, 60 wt% or less, or 58 wt% or less, or 56 wt% or less, or 54 wt% or less, or 52 wt% or less, or 50 wt% or less, or 50 wt% or less, or 48 wt% or less, or 46 wt% or less, or 44 wt% or less, or 42 wt% or less TTEG, based on the total weight of the reaction mixture including ethylene oxide.

[0027] catalyst The catalyst is used to catalyze the alkoxylation reaction between the initiator and ethylene oxide, thereby producing polyethylene glycol. The catalyst is selected from the group consisting of MOH or MH, where M is selected from the group consisting of alkali metals and alkaline earth metals. For example, M may be lithium, sodium, potassium, rubidium, cesium, francium, beryllium, magnesium, calcium, strontium, barium, and combinations thereof. As indicated, the alkali metal or alkaline earth metal may be in the form of a hydride and / or hydroxide.

[0028] The catalyst can take various forms. For example, the catalyst may be in the form of an aqueous solution, a powder, and / or a pellet. In the example of an aqueous solution, the catalyst may be 30% by weight or more, or 35% by weight or more, or 40% by weight or more, or 45% by weight or more, or 50% by weight or more, or 55% by weight or more, or 60% by weight or more, or 65% by weight or more, or 70% by weight or more, or 75% by weight or more, or 80% by weight or more, or 85% by weight or more, or 90% by weight or more of catalytic base, based on the total weight of the aqueous solution.

[0029] The reaction mixture can include 0.01 wt.% to 10 wt.% of the catalyst, based on the total weight of the reaction mixture including ethylene oxide. For example, the reaction mixture can include 0.01 wt.% or more, or 0.2 wt.% or more, or 0.3 wt.% or more, or 0.4 wt.% or more, or 0.5 wt.% or more, or 1.0 wt.% or more, or 1.5 wt.% or more, or 2.0 wt.% or more, or 2.5 wt.% or more, or 3.0 wt.% or more, or 3.5 wt.% or more, or 4.0 wt.% or more, or 4.5 wt.% or more, or 5.0 wt.% or more, or 5.5 wt.% or more, or 6.0 wt.% of the catalyst, based on the total weight of the reaction mixture including ethylene oxide. or more, or 6.5 wt.% or more, or 7.0 wt.% or more, and at the same time, 7.5 wt.% or less, or 7.0 wt.% or less, or 6.5 wt.% or less, or 6.0 wt.% or less, or 5.5 wt.% or less, or 5.0 wt.% or less, or 4.5 wt.% or less, or 4.0 wt.% or less, or 3.5 wt.% or less, or 3.0 wt.% or less, or 2.5 wt.% or less, or 2.0 wt.% or less, or 1.5 wt.% or less, or 1.0 wt.% or less, or 0.5 wt.% or less, or 0.1 wt.% or less of catalyst.

[0030] Ethylene oxide Ethylene oxide has the CAS number 75-21-8 and the chemical structure CHO. In the presence of a catalyst, ethylene oxide can be polymerized onto a TTEG initiator to form polyethylene glycol. This reaction is commonly referred to as alkoxylation. The reaction mixture can contain 40% to 60% by weight of ethylene oxide, based on the total weight of the reaction mixture. For example, the reaction mixture may comprise 40% by weight or more, or 42% by weight or more, or 44% by weight or more, or 46% by weight or more, or 48% by weight or more, or 50% by weight or more, or 52% by weight or more, or 54% by weight or more, or 56% by weight or more, or 58% by weight or more, while simultaneously comprising 60% by weight or less, or 58% by weight or less, or 56% by weight or less, or 54% by weight or less, or 52% by weight or less, or 50% by weight or less, or 50% by weight or less, or 48% by weight or less, or 46% by weight or less, or 44% by weight or less, or 42% by weight or less ethylene oxide, based on the total weight of the reaction mixture.

[0031] dehydration The method may include one or more dehydration steps. The dehydration steps are designed to reduce and / or eliminate water present in the reaction mixture (i.e., with or without ethylene oxide). For example, the method may include a step of dehydrating the initiator before combining it with one or more catalysts. Additionally or alternatively, the method may include a step of dehydrating the initiator before combining it with one or more catalysts. Additionally or alternatively, the method may include a step of dehydrating the combined initiator, catalyst, and ethylene oxide.

[0032] Dehydration of the reaction mixture can be accomplished by various means. For example, the reaction mixture may be heated to a temperature of 80°C or higher, or 100°C or higher, or 120°C or higher, or 140°C or higher, or 160°C or higher, or 180°C or higher, while simultaneously heating to a temperature of 200°C or lower, or 180°C or lower, or 160°C or lower, or 140°C or lower, or 120°C or lower, or 100°C or lower to aid in the removal of water. In another example, the dehydration procedure may involve reducing the pressure on the reaction mixture to 66.6 Pa or lower, or 60 Pa or lower, or 50 Pa or lower, or 40 Pa or lower, or 30 Pa or lower, or 20 Pa or lower, or 10 Pa or lower, or 7 Pa or lower (i.e., creating a vacuum) to aid in driving off water from the initiator and / or catalyst. The dehydration procedure may also include agitation with an impeller, stir bar, or the like. The dehydration procedure may include heating, reduced pressure, and / or agitation in combination with each other.

[0033] Reaction of the reaction mixture As explained above, this method produces polyethylene glycol, which is a compound having the structure (I): H-(O-CH2-CH2) n -OH structure (I) where n refers to the number of repeating units in the polyethylene glycol polymer. The n value for polyethylene glycol is 13As determined by C nuclear magnetic resonance, the molecular weight may range from 4 to 17. The polyethylene glycol has a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography with mass spectrometry detection. For example, as measured by gas chromatography with mass spectrometry detection, the weight average molecular weight of the polyethylene glycol may be 200 g / mol or more, or 250 g / mol or more, or 300 g / mol or more, or 350 g / mol or more, or 400 g / mol or more, or 450 g / mol or more, or 500 g / mol or more, or 550 g / mol or more, or 600 g / mol or more, or 650 g / mol or more, or 700 g / mol or more, or 750 g / mol or more, or 800 g / mol or more, or 850 g / mol or more, or 90 g / mol or more. The molecular weight may be 0 g / mol or more, or 950 g / mol or more, while at the same time being 1000 g / mol or less, or 950 g / mol or less, or 900 g / mol or less, or 850 g / mol or less, or 800 g / mol or less, or 750 g / mol or less, or 700 g / mol or less, or 650 g / mol or less, or 600 g / mol or less, or 550 g / mol or less, or 500 g / mol or less, or 450 g / mol or less, or 400 g / mol or less, or 350 g / mol or less, or 300 g / mol or less, or 250 g / mol or less.

[0034] The polyethylene glycol has a triethylene glycol concentration of less than 1000 ppm as measured by gas chromatography with flame ionization detection. For example, the polyethylene glycol can have a triethylene glycol concentration of 999 ppm or less, or 950 ppm or less, or 900 ppm or less, or 850 ppm or less, or 800 ppm or less, or 750 ppm or less, or 700 ppm or less, or 650 ppm or less, or 600 ppm or less, or 550 ppm or less, or 500 ppm or less, or 450 ppm or less, or 400 ppm or less, or 350 ppm or less, or 300 ppm or less as measured by gas chromatography with flame ionization detection.

[0035] Polyethylene glycol is produced by an alkoxylation reaction in a stainless steel reactor. The reactor is a vessel in which pressure can be maintained and the reaction mixture heated (either via an internal or external heating element) until the ethylene oxide present is polymerized on the TTEG initiator. The alkoxylation process can be carried out at pressures of 0.07 megapascals ("MPa") to 0.7 MPa. The process can be carried out under an inert atmosphere such as nitrogen, a noble gas, or the like. The alkoxylation process can be carried out at temperatures of 100°C or higher, or 120°C or higher, or 140°C or higher, or 160°C or higher, or 180°C or higher, or 200°C or higher, or 220°C or higher, or 240°C or higher, or 260°C or higher, or 280°C or higher, while simultaneously 300°C or lower, or 280°C or lower, or 260°C or lower, or 240°C or lower, or 220°C or lower, or 200°C or lower, or 180°C or lower, or 160°C or lower, or 140°C or lower, or 120°C or lower. Thus, the step of reacting the reaction mixture may further include heating the reaction mixture to between 120°C and 150°C. The alkoxylation process may include stirring the reaction mixture using an impeller at a speed of between 1 revolution per minute ("RPM") and 2000 RPM to agitate the reaction mixture. The alkoxylation reaction can be carried out for a period of between 30 minutes and 4 hours, depending on the amount of raw materials used in the reaction mixture. The reaction mixture may optionally have an acid (eg, phosphoric acid) added to the reaction mixture near the end of the alkoxylation process to neutralize the catalyst. [Example]

[0036] material The following materials were used in preparing the comparative examples ("CE") and inventive examples ("IE").

[0037] DEG, di(ethylene glycol) with CAS number 111-46-6, had a water concentration of 318 ppm as determined by Karl Fischer titration and was used as the initiator. DEG was obtained from The Dow Chemical Company (Midland, MI).

[0038] TEG, tri(ethylene glycol) with CAS number 111-27-6 and a water concentration of 363 ppm as determined by Karl Fischer titration, was used as the initiator. DEG was obtained from The Dow Chemical Company (Midland, MI).

[0039] TTEG, tetra(ethylene glycol) with CAS number 112-60-7, having a water concentration of 338 ppm as determined by Karl Fischer titration, was used as the initiator. DEG was obtained from The Dow Chemical Company (Midland, MI).

[0040] KOHP, potassium hydroxide pellets with CAS number 1310-58-3, was used as a catalyst. KOHP was obtained from Sigma Aldrich (St. Louis, MO).

[0041] AQKOH, a 45 wt % aqueous solution of potassium hydroxide, was used as a catalyst and was obtained from Sigma Aldrich (St. Louis, MO).

[0042] KH is potassium hydroxide with CAS number 7693-26-7 and was used as a catalyst. KH was obtained from Sigma Aldrich (St. Louis, MO).

[0043] EO is ethylene oxide available from Balchem ​​Corporation (New Hampton, New York) having a purity of 99.9% and a water content of less than 25 ppm.

[0044] CAC is a calcium-based catalyst. It was prepared according to the procedure in Chinese Patent Publication No. 106905522(A). Specifically, potassium hydroxide and calcium hydroxide were ground into a fine powder using a mortar and pestle. The powder was transferred to a 1-ounce glass scintillation vial containing a magnetic stir bar. While stirring, concentrated sulfuric acid was added dropwise to a final molar ratio of KOH:Ca(OH)2:H2SO4 of 2:7:1. The resulting solid was dried overnight at 50°C in a vacuum oven (0.1 MPa).

[0045] Phosphoric acid was 85 wt% pure in water and obtained from Sigma Aldrich (St. Louis, MO).

[0046] Water content of catalyst material To determine the amount of water introduced into the reactor by the catalyst, the known values ​​in Table 1 below were used.

[0047] [Table 1]

[0048] Gas Chromatography with Flame Ionization Detection ("GCFID") Preparation of internal standard solution: The internal standard solution was prepared by weighing 0.1 g of 1,3-butanediol into a jar and adding methanol to a total weight of 25 g. The solution was then mixed by hand to combine.

[0049] Preparation of calibration standard stock solutions: Calibration standard stock solutions were prepared by weighing 0.1 g each of ethylene glycol, diethylene glycol, and triethylene glycol into a jar and adding methanol to a total weight of 25 g, all weights recorded. The solutions were mixed by hand to combine.

[0050] Preparation of calibration standards: Calibration standards were prepared by weighing 0.1 g of the calibration standard stock solution into a 20 mL vial, followed by 0.1 g of the internal standard solution. 9.8 g of methanol was then weighed into the vial, and the solution was placed on a flat-bed shaker for 5 minutes to mix.

[0051] GCFID sample preparation: GCFID samples were prepared by weighing 0.4 g of sample into a 20 mL vial, followed by 0.1 g of the internal standard solution. 9.5 g of methanol was then weighed into the vial, and the solution was placed on a flat-bed shaker for several minutes to mix. Samples and standards were run using the instrument conditions specified in Table 2 below.

[0052] [Table 2]

[0053] Gas chromatography with mass spectrometric detection (GC / MS) The same samples from the GC / FID analysis were used for GC / MS analysis. The samples were analyzed using the conditions in Table 3.

[0054] [Table 3]

[0055] Karl Fischer titration Standard coulometric Karl Fischer titrations were performed in duplicate using a Metrohm 852 TITRANDO™ titrator equipped with a Metrohm 803 Ti stand. The coulometric cell contained 175 mL of HYDRANAL™ Coulomat E solution. A diaphragmless Metrohm indicator electrode and a Metrohm generator electrode were used. Metrohm TIAMO software was used for instrument control and data analysis. A Mettler-Toledo Model AE 240 balance, capable of weighing to 0.0001 g, was used. Prior to analysis, multiple injections of 2.0 μL of water were performed to confirm system accuracy. Following analysis, the system was also confirmed by injection of 2.0 μL of water. Recovery rates were within an acceptable range of 98–102%. A sample size of ~3500 mg was used. A range measurement to determine the appropriate injection volume consumed the entire ~20 g triethylene glycol (TEG) sample. Table 4 provides the standard coulometric Karl Fischer titration parameters.

[0056] [Table 4]

[0057] The Karl Fischer titration procedure was performed according to the following procedure steps: First, the sample was drawn into a 5 mL BD Luer Lock syringe equipped with a 16G x 3 1 / 8" needle. Next, the balance was tared with the filled syringe. Next, the start button on the TIAMO™ software was pressed, and the sample was injected directly into the titration solution through the septum port. Next, the empty syringe was weighed to the nearest 0.0001 g. The mass value of the empty syringe was then multiplied by 1000, and the mass was entered into the Metrohm TIAMO™ software. Finally, the concentration of water in the sample, calculated as μg / g (ppm), is reported.

[0058] Sample preparation Two separate dehydration procedures were used in the preparation of the samples. If the dehydration procedure was not identified, no dehydration procedure was performed. After the dehydration procedure, Karl Fischer titration was performed to determine the water content of the reaction mixture. If a dehydration procedure was not outlined, the water concentration was calculated using the known water content of the raw material.

[0059] Dehydration Procedure A: In a nitrogen-filled glovebox, initiator (50-100 g) was weighed into a 240 mL glass jar containing a Teflon stir bar and heated to 120 °C with stirring under vacuum (i.e., less than 66.6 Pa). After 24 h of heating and stirring, the initiator was cooled to 23 °C and an aliquot was removed for Karl Fischer titration. The designated catalyst was added to the remainder of the initiator, and stirring was resumed until the mixture was visually homogeneous. The initiator / catalyst mixture was then used as indicated.

[0060] Dehydration Procedure B: Initiator (50-100 g) was weighed into a 240 mL glass jar containing a Teflon stir bar. AQKOH was added to the initiator with stirring. The jar was capped, placed in a nitrogen-filled glove box, heated to 120 °C, and stirred under vacuum (i.e., less than 66.6 Pa) for 24 hours. After 24 hours, stirring and heating were stopped, and the combined catalyst and initiator were allowed to cool to 23 °C. After cooling, an aliquot was removed for Karl Fischer titration. The remaining portion of the initiator / catalyst mixture was used as indicated.

[0061] General Alkoxylation Procedure: A 300 mL stainless steel pressure reactor equipped with an air-driven gas-entraining impeller, thermocouple, cooling water coil, baffles, a dip tube (6.35 mm outer diameter) connected to a nitrogen line, a monomer feed line and vent using a four-way Swagelok fitting, and an aluminum heating block was used. The 300 mL reactor was charged with the indicated initiator and catalyst, and the combined water concentration was measured using Karl Fischer titration. The reactor pressure was confirmed by supplying approximately 0.14 MPa of nitrogen and holding the pressure for 10 minutes. After ensuring the reactor was leak-free, the initiator and catalyst mixture was purged with nitrogen for 10 minutes without stirring. The reactor was then charged with 0.14 MPa of nitrogen and heated to the indicated reaction temperature with stirring by an impeller set at 1000 rpm. After the temperature stabilized for 5 minutes, ethylene oxide was fed to the reactor at a rate of 0.5 mL / min. After all the ethylene oxide had been fed to the reactor, the reaction temperature was maintained for an additional 2 hours with stirring to digest any remaining ethylene oxide. Finally, the reactor was cooled to 50°C, the stirring was stopped, the reactor was vented, and 0.04 g of 85 wt% phosphoric acid was added to the product. The reactor was closed and stirred at 1,000 rpm for 5 minutes to disperse the acid, after which the final product was collected.

[0062] CE1: According to the general alkoxylation procedure, 0.20 g of 45% aqueous KOH solution was added to 40.0 g of DEG. The reactor was heated to 150°C and 122.7 mL of EO was fed at a rate of 0.5 mL / min to obtain 142.0 g of a pale yellow liquid.

[0063] CE2: According to the general alkoxylation procedure, 0.20 g of 45% aqueous KOH solution was added to 56.8 g of TEG. The reactor was heated to 150°C and 104 mL of EO was fed at a rate of 0.5 mL / min to obtain 142.7 g of a pale yellow liquid.

[0064] CE3: According to the general alkoxylation procedure, 0.20 g of 45% aqueous KOH solution was added to 73.6 g of TTEG. The reactor was heated to 150° C. and 85.6 mL of EO was fed at a rate of 0.5 mL / min to obtain 144.0 g of a pale yellow liquid.

[0065] CE4: Following the general alkoxylation procedure, 0.15 g of calcium catalyst was added to 29.1 g of DEG. The reactor was heated to 150°C and 99.6 mL of EO was fed at a rate of 0.5 mL / min to yield 112.0 g of a pale yellow liquid.

[0066] CE5: According to the general alkoxylation procedure, 0.20 g of 45% aqueous KOH solution was added to 56.8 g of TEG. The reactor was heated to 120° C. and 104 mL of EO was fed at a rate of 0.5 mL / min to obtain 142.4 g of a pale yellow liquid.

[0067] CE6: Following the general alkoxylation procedure, 102 mg of KOH pellets were added to 65.0 g of TEG. The reactor was heated to 120° C. and 104 mL of EO was fed at a rate of 0.5 mL / min to yield 142.3 g of a pale yellow liquid.

[0068] CE7: ​​Following the general alkoxylation procedure, 52 mg of KOH pellets were added to 33.0 g of TEG. The reactor was heated to 120° C. and 104 mL of EO was fed at a rate of 0.5 mL / min to yield 142.3 g of a pale yellow liquid.

[0069] CE8: Following the general alkoxylation procedure, 64 mg of KH was added to 57.0 g of TEG. The reactor was heated to 150° C. and 104 mL of EO was fed at a rate of 0.5 mL / min to yield 142.7 g of a pale yellow liquid.

[0070] CE9: Following the general alkoxylation procedure, 64 mg of KH was added to 57.0 g of TEG. The reactor was heated to 120° C. and 104 mL of EO was fed at a rate of 0.5 mL / min to give 142.7 g of a pale yellow liquid.

[0071] CE10: Following the general alkoxylation procedure, 64 mg of KH was added to 28.5 g of TEG. The reactor was heated to 120° C. and 56.9 mL of EO was fed at a rate of 0.5 mL / min to give 74.5 g of a pale yellow liquid.

[0072] CE11: Following the general alkoxylation procedure, 73 mg of KH was added to 32.5 g of TEG. The reactor was heated to 150° C. and 59.6 mL of EO was fed at a rate of 0.5 mL / min to give 73.4 g of a pale yellow liquid.

[0073] CE12: Following the general alkoxylation procedure, 52 mg of KH was added to 30.0 g of TTEG. The reactor was heated to 150° C. and 38.7 mL of EO was fed at a rate of 0.5 mL / min to give 55.4 g of a pale yellow liquid.

[0074] CE13: 32.0 g of TTEG was dried according to Dehydration Procedure A. Then, 160 mg of calcium catalyst was added to the initiator, and the general alkoxylation procedure was followed. The reactor was heated to 150 °C, and 37.1 mL of EO was fed at a rate of 0.5 mL / min to obtain 59.4 g of a pale yellow liquid.

[0075] CE14: For this reaction, 36 μL of water was added to 36.8 g of TTEG treated with Dehydration Procedure A. The water concentration was determined to be 1,533 ppm by Karl Fischer titration. The general alkoxylation procedure was then followed. The reactor was heated to 120° C. and 42.6 mL of EO was fed at a rate of 0.5 mL / min to yield 70.4 g of a pale yellow liquid.

[0076] IE1: 36.8 g of TTEG was dried according to Dehydration Procedure A. Then, 45 mg of crushed KOH pellets were added to the TTEG initiator, and the mixture was stirred for 10 minutes until homogeneous. The general alkoxylation procedure was followed. The reactor was heated to 120 °C, and 42.6 mL of EO was fed at a rate of 0.5 mL / min to obtain 69.4 g of a pale yellow liquid.

[0077] IE2: 36.8 g of TTEG was dried according to Dehydration Procedure A. Then, 32 mg of KH powder was added to the initiator, and the general alkoxylation procedure was followed. The reactor was heated to 150 °C, and 47.3 mL of EO was fed at a rate of 0.5 mL / min to obtain 73.2 g of a pale yellow liquid.

[0078] IE3: 36.8 g of TTEG containing KOH catalyst (0.42 mol%) was prepared according to the dehydration procedure B. Then, the general alkoxylation procedure was followed. The reactor was heated to 120°C, and 42.6 mL of EO was fed at a rate of 0.5 mL / min to obtain 69.0 g of a pale yellow liquid.

[0079] IE4: 36.8 g of TTEG containing KOH catalyst (0.42 mol%) was prepared according to the dehydration procedure B, and 4 μL of water was added to the TTEG / KOH mixture. The total water concentration measured by Karl Fischer titration was 281 ppm. The general alkoxylation procedure was then followed. The reactor was heated to 150 °C, and 42.6 mL of EO was fed at a rate of 0.5 mL / min to obtain 70.8 g of a pale yellow liquid.

[0080] IE5: 36.8 g of TTEG containing KOH catalyst (0.42 mol%) was prepared according to the dehydration procedure B, and 18 μL of water was added to the TTEG / KOH mixture. The total water concentration measured by Karl Fischer titration was 929 ppm. The general alkoxylation procedure was then followed. The reactor was heated to 150 °C, and 42.6 mL of EO was fed at a rate of 0.5 mL / min to obtain 70.8 g of a pale yellow liquid.

[0081] IE6: 36.8 g of TTEG containing KOH catalyst (0.42 mol%) was prepared according to the dehydration procedure B, and 18 μL of water was added to the TTEG / KOH mixture. The total water concentration measured by Karl Fischer titration was 929 ppm. The general alkoxylation procedure was then followed. The reactor was heated to 120 °C, and 42.6 mL of EO was fed at a rate of 0.5 mL / min to obtain 70.4 g of a pale yellow liquid.

[0082] result Table 5 provides the residual TEG results based on the initiator used and the initial water concentration with a standard calibration.

[0083] [Table 5]

[0084] Table 6 provides the weight average molecular weights ("Mw") of the different components of some polyethylene glycols produced and their associated weight percentages, given in Daltons ("Da"). The values ​​in Table 6 were calculated by gas chromatography with mass spectrometry and flame ionization detection using peak area percentages.

[0085] [Table 6]

[0086] Referring now to Tables 5 and 6, CE1-CE12 cumulatively demonstrate that reduced initial water content (i.e., 1200 ppm or less), catalyst, and initiator cannot all be used independently to reduce the presence of TEG in the final polyethylene glycol. For example, CE3 and CE12 demonstrate that TTEG used alone as an initiator cannot achieve the desired low TEG level. CE1, CE2, and CE5-CE11 demonstrate that catalyst alone or in combination with reduced initial water content is not sufficient to achieve the target TEG concentration in the final polyethylene glycol. CE13 demonstrates that TTEG as the initiator and reduced initial water content still produces unacceptable levels of TEG when using a Ca-based catalyst. Similarly, CE14 demonstrates that TTEG as the initiator and KOH as the catalyst still produces unacceptable levels of TEG when the initial water content is greater than 1200 ppm.

[0087] Unlike the comparative examples, IE1 to IE6 all have a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography with mass spectrometry detection, and are capable of producing polyethylene glycol having 1000 ppm or less of TEG as measured by gas chromatography with flame ionization detection. As can be seen from IE1 to IE6, utilizing one or more catalysts selected from the group consisting of TTEG, MOH, or MH (wherein M is one of the alkali metals or alkaline earth metals) as the initiator and ensuring that the reaction mixture contains 1200 ppm or less of water ensures that polyethylene glycol is produced having a TEG concentration of 1000 ppm or less as measured by gas chromatography with flame ionization detection.

Claims

1. 1. A method for producing polyethylene glycol, comprising: combining a tetra(ethylene glycol) initiator with one or more catalysts selected from the group consisting of MOH and MH, where M is selected from the group consisting of alkali metals and alkaline earth metals to form a reaction mixture, wherein the reaction mixture further contains 1200 ppm or less of water as determined by Karl Fischer titration; adding ethylene oxide to the reaction mixture; reacting the reaction mixture to form polyethylene glycol having a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography with mass spectrometry detection.

2. reacting the reaction mixture 10. The method of claim 1, further comprising reacting the reaction mixture to form polyethylene glycol having a weight average molecular weight of 300 g / mol to 600 g / mol as measured by gas chromatography.

3. 3. The method of claim 1 or 2, wherein the polyethylene glycol has a triethylene glycol concentration of less than 1000 ppm as measured by gas chromatography with flame ionization detection.

4. 3. The method of claim 2, wherein the polyethylene glycol has a triethylene glycol concentration of 500 ppm or less as measured by gas chromatography with flame ionization detection.

5. 5. The method of any one of claims 1 to 4, wherein the step of reacting the reaction mixture further comprises heating the reaction mixture to a temperature in the range of 120°C to 150°C.

6. The method of any one of claims 1 to 5, wherein the catalyst is KOH.

7. 7. The method of any one of claims 1 to 6, further comprising the step of dehydrating the initiator prior to combining with the one or more catalysts.

8. 7. The method of any one of claims 1 to 6, further comprising the step of dehydrating the combined initiator and the one or more catalysts.

9. 9. The method of any one of claims 1 to 8, wherein the reaction mixture contains no more than 800 ppm of water as measured by Karl Fischer titration.

10. 9. The method of any one of claims 1 to 8, wherein the reaction mixture contains no more than 500 ppm water as measured by Karl Fischer titration.

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