Liquid polyethylene glycol

Abstract

The present invention relates to a process for producing polyethylene glycol, the process comprising the steps of combining a tetra (ethylene glycol) initiator and 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, further wherein the reaction mixture comprises 1200 ppm or less of water as measured according to 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 according to gas chromatography-mass spectrometry detection.

Description

Background Art Technical Field

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

[0002] introduction

[0003] Polyethylene glycol with a weight average molecular weight of 200 grams per mole ("g / mol") to 1000 g / mol can be used in medicine and for 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 into polyethylene glycol. In view of the use, some jurisdictions have begun to impose regulatory standards on residual materials in polyethylene glycol. For example, China has implemented the following regulatory requirements: as measured by gas chromatography using flame ionization detection, the residual tri(ethylene glycol) ("TEG") in polyethylene glycol should be less than 1000 parts per million ("ppm").

[0004] The source of residual TEG in low molecular weight polyethylene glycol is not fully understood, and there are several competing hypotheses about the source. One hypothesis about the residual TEG concentration is related to the use of TEG as an initiator for polyethylene glycol. For example, it is assumed that some TEG is unreacted and causes residual TEG to exceed regulatory targets. The residual TEG explanation is particularly problematic for low molecular weight polyethylene glycol because TEG has a size quite similar to the final product, and is therefore expected to contain a larger percentage of the final product. In other words, in low molecular weight polyethylene glycol, initiators (such as TEG) are more likely to remain unreacted. Various attempts to use other initiators have been attempted. US4946939A describes the use of different initiators (such as diethylene glycol, triethylene glycol, tetraethylene glycol) in combination with water to produce high purity polyether polyols, and then use membrane filtration to filter out unwanted low molecular weight components (i.e. TEG). Similarly, CN106905522A 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 composite calcium-based catalyst.

[0005] Since TEG content in low molecular weight polyethylene glycol remains a problem, manufacturers have resorted to removing TEG after the polyethylene glycol is formed. Traditional 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 manufacture 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 of directly forming polyethylene glycol with a reduced TEG concentration without further purification steps.

[0006] In view of the above, it was surprisingly discovered a method for producing polyethylene glycol having a weight average molecular weight of 200 to 1000 g / mol as measured by Gas Chromatography with Mass Spectrometry Detection, which polyethylene glycol has 1000 ppm or less TEG as measured by gas chromatography using flame ionization detection. Summary of the invention

[0007] The inventors of the present application have discovered a method for producing polyethylene glycol having a weight average molecular weight of 200 to 1000 g / mol as measured by gas chromatograph-gas spectrometry, which has 1000 ppm or less TEG as measured by gas chromatography using flame ionization detection.

[0008] The present disclosure is the result of the discovery that, while it is important to select an initiator (i.e., tetra(ethylene glycol)) having a molecular weight greater than TEG, it is also important to remove water during the manufacture of polyethylene glycol. Without being bound by theory, it is believed that the presence of water tends to act as an initiator, causing the ethylene oxide to ring-open 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 the ring-opening eventually polymerizes into TEG and pushes the resulting product beyond its regulatory targets. It has been found 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 using flame ionization detection.

[0009] The present disclosure is particularly advantageous for the formation of diol compositions.

[0010] According to a first feature of the present disclosure, a method for producing polyethylene glycol comprises the following steps: combining a tetra(ethylene glycol) initiator and one or more catalysts selected from the group consisting of MOH and MH to form a reaction mixture, wherein M is selected from the group consisting of alkali metals and alkaline earth metals, 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 spectrometry.

[0011] 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 to 600 g / mol as measured according to gas chromatography.

[0012] According to a third feature of the present disclosure, the polyethylene glycol has a triethylene glycol concentration of less than 1000 ppm as measured according to gas chromatography using flame ionization detection.

[0013] According to a fourth feature of the present disclosure, the polyethylene glycol has a triethylene glycol concentration of 500 ppm or less as measured according to gas chromatography using flame ionization detection.

[0014] According to a fifth feature of the present disclosure, the step of reacting the reaction mixture further comprises heating the reaction mixture to a temperature in a range of 120°C to 150°C.

[0015] According to a sixth feature of the present disclosure, the catalyst is KOH.

[0016] According to a seventh feature of the present disclosure, the method further comprises a step of dehydrating the initiator before combining with the one or more catalysts.

[0017] According to an eighth feature of the present disclosure, the method further comprises the step of dehydrating the combined initiator and the one or more catalysts.

[0018] According to a ninth feature of the present disclosure, the reaction mixture contains 800 ppm or less of water as measured according to Karl Fischer titration.

[0019] According to a tenth feature of the present disclosure, the reaction mixture contains 500 ppm or less of water as measured according to Karl Fischer titration. DETAILED DESCRIPTION

[0020] 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 may be used alone, or any combination of two or more of the listed items may be used. For example, if a composition is described as containing components A, B, and / or C, the composition may 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.

[0021] Unless otherwise stated, all ranges are inclusive.

[0022] As used herein, unless otherwise indicated, the term weight percent ("wt %") refers to the weight percent of a component based on the total weight of the diol composition.

[0023] As used herein, a Chemical Abstracts Services Registry Number ("CAS#") means the unique numeric identifier most recently assigned to a chemical compound by Chemical Abstracts Services as of the priority date of this document.

[0024] Unless otherwise stated, all molecular weight measurements herein are determined according to gas chromatography-mass spectrometry detection as explained below.

[0025] method

[0026] The present disclosure relates to a method for producing polyethylene glycol. The method includes the step of combining tetra(ethylene glycol) initiator and 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 1200ppm or less water as measured by Karl Fischer titration, as explained in more detail below. The method also includes the step of adding ethylene oxide to the reaction mixture. The method also includes the step of reacting the reaction mixture to form a polyethylene glycol with a weight average molecular weight of 200g / mol to 1000g / mol as measured by gas chromatography-mass spectrometry detection. The method may also include the step of dehydrating the initiator before combining with one or more catalysts. The method may also include the step of dehydrating the combined initiator and one or more catalysts. It should be understood that, where feasible, the steps of the method may be performed in any order and / or simultaneously. The steps involving adding and combining initiators, catalysts and ethylene oxide may be performed in a reactor, or in a separate container subsequently transferred to the reactor.

[0027] Reaction mixture

[0028] The reaction mixture comprises tetra(ethylene glycol), one or more catalysts and ethylene oxide. Prior to the addition of ethylene oxide, the reaction mixture comprises 1200 ppm or less of water as measured according to Karl Fischer titration, as explained 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 of water, or 950 ppm or less of water, or 900 ppm or less of water, or 850 ppm or less of water, or 800 ppm or less of water, or 750 ppm or less of water, or 700 ppm or less of water, or 650 ppm or less of water, or 600 ppm or less of water, or 550 ppm or less of water, or 500 ppm or less of water, or 450 ppm or less of water, or 400 ppm or less of water, or 350 ppm or less of water, or 300 ppm or less of water, or 250 ppm or less of water, or 200 ppm or less of water, or 150 ppm or less of water, or 100 ppm or less of water, or 50 ppm or less of water, as measured according to Karl Fischer titration. Since ethylene oxide does not contain significant amounts of water, the reaction mixture may contain the above-described water concentrations either before or after the addition of ethylene oxide to the reaction mixture.

[0029] Tetra(ethylene glycol) initiator

[0030] The initiator used in this process is tetra(ethylene glycol) ("TTEG"). As described above, using TTEG as an initiator facilitates the reduction of TEG in the final polyethylene glycol by eliminating one of the putative sources of TEG. TTEG has a CAS# of 112-60-7 and a C8H 18 The reaction mixture may contain 40% to 60% TTEG by weight based on the total weight of the reaction mixture including ethylene oxide. For example, the reaction mixture may contain 40% or more, or 42% or more, or 44% or more, or 46% or more, or 48% or more, or 50% or more, or 52% or more, or 54% or more, or 56% or more, or 58% or more, while 60% or less, or 58% or less, or 56% or less, or 54% or less, or 52% or less, or 50% or less, or 50% or less, or 48% or less, or 46% or less, or 44% or less, or 42% or less TTEG based on the total weight of the reaction mixture including ethylene oxide.

[0031] catalyst

[0032] The catalyst is used to catalyze the alkoxylation reaction between the initiator and ethylene oxide to produce polyethylene glycol. The catalyst is selected from the group consisting of MOH or MH, wherein M is selected from the group consisting of alkali metals and alkaline earth metals. For example, M can be lithium, sodium, potassium, rubidium, cesium, francium, beryllium, magnesium, calcium, strontium, barium, and combinations thereof. As indicated, the alkali metal or alkaline earth metal can be in the form of a hydride and / or hydroxide.

[0033] The catalyst can take a variety of forms. For example, the catalyst can be in the form of an aqueous solution, a powder form and / or a pellet form. In the aqueous solution example, the catalyst can 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 the catalyst based on the total weight of the aqueous solution.

[0034] The reaction mixture may contain 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 may contain 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 % or more, 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 while 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 the catalyst.

[0035] Ethylene oxide

[0036] Ethylene oxide has a CAS# of 75-21-8 and has a chemical structure of C2H4O. In the presence of a catalyst, ethylene oxide can be polymerized onto a TTEG initiator to form polyethylene glycol. Such reactions are generally referred to as alkoxylations. The reaction mixture may contain 40 to 60 weight percent ethylene oxide based on the total weight of the reaction mixture. 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, while 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 ethylene oxide, based on the total weight of the reaction mixture.

[0037] Dehydration

[0038] The method may include one or more dehydration steps. Design dehydration steps to reduce and / or eliminate the water (that is, with or without ethylene oxide) present in the reaction mixture. For example, the method may include the step of dehydrating the initiator before being combined with one or more catalysts. Additionally or alternatively, the method may include the step of dehydrating the initiator before being combined with one or more catalysts. Additionally or alternatively, the method may include the step of dehydrating the initiator, catalyst and ethylene oxide of the combination.

[0039] The dehydration of the reaction mixture can be accomplished in a variety of ways. For example, the reaction mixture can be heated to 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 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 temperature to help remove water. In another example, the dehydration procedure can reduce the pressure (i.e., produce vacuum) on the reaction mixture to 66.6Pa or less, or 60Pa or less, or 50Pa or less, or 40Pa or less, or 30Pa or less, or 20Pa or less, or 10Pa or less, or 7Pa or less to help drive water out of initiator and / or catalyst. The dehydration procedure may also include stirring such as from an impeller, stirring rod, etc. The dehydration procedure may include heating, decompression and / or stirring in combination with each other.

[0040] Allow the reaction mixture to react

[0041] As described above, the process produces polyethylene glycol. Polyethylene glycol is a compound having structure (I)

[0042] H—(O—CH2—CH2) n —OH structure (I)

[0043] Where n refers to the number of repeating units in the polyethylene glycol polymer. The value of n for polyethylene glycol can be determined by 13 C nuclear magnetic resonance is determined in the range of 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-mass spectrometry. For example, the weight average molecular weight of the polyethylene glycol can 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 900 g / mol or more as measured by gas chromatography-mass spectrometry. , or 950 / mol or more, and 1000g / mol or less, or 950g / mol or less, or 900g / mol or less, or 850g / mol or less, or 800g / mol or less, or 750g / mol or less, or 700g / mol or less, or 650g / mol or less, or 600g / mol or less, or 550g / mol or less, or 500g / mol or less, or 450g / mol or less, or 400g / mol or less, or 350g / mol or less, or 300g / mol or less, or 250g / mol or less.

[0044] The polyethylene glycol has a triethylene glycol concentration of less than 1000 ppm as measured according to gas chromatography using 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 according to gas chromatography using flame ionization detection.

[0045] Polyethylene glycol is produced by an alkoxylation reaction in a stainless steel reactor. The reactor is a vessel capable of maintaining pressure and heating (by internal or external heating elements) the reaction mixture until the ethylene oxide present polymerizes on the TTEG initiator. The alkoxylation process can be carried out at a pressure of 0.07 megapascals ("MPa") to 0.7 MPa. The process can be carried out under an inert environment (such as nitrogen, a noble gas, etc.). The alkoxylation process may be carried out at a temperature of 100° C. or more, or 120° C. or more, or 140° C. or more, or 160° C. or more, or 180° C. or more, or 200° C. or more, or 220° C. or more, or 240° C. or more, or 260° C. or more, or 280° C. or more, while at a temperature of 300° C. or less, or 280° C. or less, or 260° C. or less, or 240° C. or less, or 220° C. or less, or 200° C. or less, or 180° C. or less, or 160° C. or less, or 140° C. or less, or 120° C. or less. Thus, the step of reacting the reaction mixture may further include the step of heating the reaction mixture to 120° C. to 150° C. The alkoxylation process may involve stirring the reaction mixture using an impeller at a speed of 1 revolution per minute (“RPM”) to 2000 RPM to stir the reaction mixture. The alkoxylation reaction can be carried out for a period of time lasting from 30 minutes to 4 hours, depending on the amount of raw materials used in the reaction mixture. The reaction mixture can optionally have an acid (e.g., phosphoric acid) added to the reaction mixture near the end of the alkoxylation process to neutralize the catalyst.

[0046] Example

[0047] Material

[0048] The following materials were used to prepare the Comparative Examples ("CE") and Inventive Examples ("IE").

[0049] DEG is di(ethylene glycol) with a CAS# of 111-46-6, with a water concentration of 318 ppm as measured by Karl Fischer titration and was used as an initiator. DEG was obtained from The Dow Chemical Company, Midland, MI.

[0050] TEG is tri(ethylene glycol) with a CAS# of 111-27-6, with a water concentration of 363 ppm as measured by Karl Fischer titration and was used as an initiator. DEG was obtained from The Dow Chemical Company, Midland, Michigan.

[0051] TTEG is tetra(ethylene glycol) with a CAS# of 112-60-7, with a water concentration of 338 ppm as measured by Karl Fischer titration and was used as an initiator. DEG was obtained from The Dow Chemical Company, Midland, Michigan.

[0052] KOHP is potassium hydroxide pellets with a CAS# of 1310-58-3 and was used as the catalyst. KOHP was obtained from Sigma Aldrich, St. Louis, MO.

[0053] AQKOH is a 45 wt% aqueous solution of potassium hydroxide in water and was used as a catalyst. AQKOH was obtained from Sigma-Aldrich, St. Louis, MO.

[0054] KH is potassium hydride with a CAS# of 7693-26-7 and was used as a catalyst. KH was obtained from Sigma-Aldrich, St. Louis, MO.

[0055] EO is ethylene oxide having a purity of 99.9% and a water content of less than 25 ppm, available from Balchem ​​Corporation, Newhapton, New York.

[0056] CAC is a calcium-based catalyst. CAC was prepared according to the procedure in patent CN106905522A. Specifically, potassium hydroxide and calcium hydroxide were ground into fine powder using a mortar and pestle. The powder was transferred to a 1-oz glass scintillation vial containing a magnetic stirring bar. Concentrated sulfuric acid was added dropwise with stirring so that the final molar ratio was 2:7:1 KOH:Ca(OH)2:H2SO4. The resulting solid was dried overnight in a vacuum oven (0.1 MPa) at 50°C.

[0057] Phosphoric acid had a purity of 85 wt% in water and was obtained from Sigma-Aldrich, St. Louis, MO.

[0058] Water content of catalyst materials

[0059] To determine the amount of water introduced into the reactor through the catalyst, the known values ​​in Table 1 below were used.

[0060] Table 1

[0061] Material <![CDATA[mg H2O / g catalyst]]> AQKOH 550 KOHP 125 KH 0

[0062] Gas chromatography using flame ionization detection ("GCFID" )

[0063] Preparation of internal standard solution :

[0064] An internal standard solution was prepared by weighing 0.1 g of 1,3-butanediol into a jar and adding methanol until the total weight was 25 g. The solutions were then mixed by hand to combine.

[0065] Calibration standard stock solution preparation :

[0066] Prepare calibration standard stock solutions by weighing 0.1 g each of ethylene glycol, diethylene glycol, and triethylene glycol into individual jars and adding methanol until the total weight is 25 g, recording all weights. Mix solutions by hand to combine.

[0067] Calibration Standard Preparation :

[0068] Calibration standards were prepared by weighing 0.1 g of the calibration standard stock solution into a 20-mL vial, followed by weighing 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 plate shaker for five minutes to mix.

[0069] GCFID sample preparation :

[0070] The GCFID samples were prepared by weighing 0.4 g of sample into a 20 mL vial, followed by weighing 0.1 g of internal standard solution. 9.5 g of methanol was then weighed into the vial and the solution was placed on a plate shaker for a few minutes to mix. The samples and standards were run using the instrument conditions identified in Table 2 below:

[0071] Table 2

[0072]

[0073] GC / MS )

[0074] The same samples from the GC / FID analysis were used for GC / MS analysis. The samples were analyzed using the conditions in Table 3:

[0075] Table 3

[0076]

[0077] Karl Fischer titration

[0078] Using the Metrohm 852TITRANDO with a Metrohm 803Ti bracket TM The titrator performs standard coulometric Karl Fischer titrations in duplicate. The coulometric cell contains 175 mL of HYDRANAL TMCoulomat E solution. Metrohm indicator electrodes and Metrohm generator electrodes without diaphragms were used. Instrument control and data analysis were performed using Metrohm TIAMO software. A Mettler-Toledo model AE 240 balance capable of weighing up to 0.0001 g was used. Prior to analysis, the accuracy of the system was checked using multiple injections of 2.0 μL of water. The system was also checked after analysis by injecting 2.0 μL of water. The recovery was within the acceptable range of 98%-102%. A sample amount of approximately 3500 mg was used. The range was determined to determine the appropriate injection amount for consuming an entire triethylene glycol (TEG) sample of approximately 20 g. Table 4 provides the standard Karl Fischer titration parameters:

[0079] Table 4

[0080]

[0081] 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 with a 16G x 31 / 8" needle. Next, the balance was tared with the filled syringe. Next, the TIAMO TM Press the start button on the software and inject the sample through the septum port directly into the titrant. Next, weigh the empty syringe to the nearest 0.0001 g. Next, multiply the empty syringe mass by 1000 and enter this mass into the Metrohm TIAMO TM Finally, the calculated concentration of water in the sample is reported in ug / g (ppm).

[0082] Sample preparation

[0083] In the preparation of the samples, two separate dehydration procedures were used. When no dehydration procedure was identified, no dehydration procedure was performed. After the dehydration procedure, a Karl Fischer titration was performed to determine the water content of the reaction mixture. When no dehydration procedure was outlined, the water concentration was calculated using the known water content of the raw materials.

[0084] Dehydration Procedure A: In a nitrogen-filled glove box, the initiator (50 g-100 g) was weighed into a 240 mL glass jar containing a Teflon stirring rod and heated to 120° C. under vacuum (i.e., less than 66.6 Pa) with stirring. After 24 hours 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 remaining portion of the initiator under continued stirring until the mixture was visually uniform. The initiator / catalyst mixture was then used as indicated.

[0085] Dehydration Procedure B: Initiator (50 g-100 g) was weighed into a 240 mL glass jar containing a Teflon stirring rod. AQKOH was added to the initiator under stirring. The jar was capped and placed in a nitrogen-filled glove box where it was heated to 120° C. and stirred for 24 hours under vacuum (i.e., less than 66.6 Pa). After 24 hours, stirring and heating were stopped, and the combined catalyst and initiator were cooled to 23° C. Once cooled, an aliquot was taken out for Karl Fischer titration. The remaining portion of the initiator / catalyst mixture was used as indicated.

[0086] General alkoxylation procedure: A 300 mL pressure stainless steel reactor equipped with a pneumatically driven gas entrainment impeller, a thermocouple, a cooling water coil, a baffle, a dip tube (6.35 mm outer diameter) and an aluminum heating block was used. The dip tube was connected to the nitrogen line, the monomer feed line and the exhaust port using a four-way Swagelok fitting. The indicated initiator and catalyst were loaded into the 300 mL reactor, the water concentration of the combined water was measured using Karl Fischer titration, and the reactor pressure was checked by feeding about 0.14 MPa of nitrogen and maintaining the pressure for 10 minutes. After confirming that the reactor did not have any leaks, the initiator and catalyst mixture was purged with nitrogen for 10 minutes without stirring. Then, the reactor was loaded with 0.14 MPa of nitrogen and heated to the indicated reaction temperature by stirring with an impeller set to 1000 rpm. Once the temperature stabilized for 5 minutes, ethylene oxide was fed into the reactor at a rate of 0.5 mL / min. Once all the ethylene oxide has been fed into the reactor, the reaction temperature is maintained for another 2 hours with stirring to digest the residual ethylene oxide. Finally, the reactor is cooled to 50°C, stirring is stopped, the reactor is vented, and 0.04 g of 85 wt% phosphoric acid is added to the product. The reactor is closed and stirred at 1,000 rpm for 5 minutes to disperse the acid, and then the final product is collected.

[0087] CE1: Following the general alkoxylation procedure, 0.20 g of 45% aqueous KOH 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 give 142.0 g of a light yellow liquid.

[0088] CE2: Following the general alkoxylation procedure, 0.20 g of 45% aqueous KOH 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 give 142.7 g of a light yellow liquid.

[0089] CE3: Following the general alkoxylation procedure, 0.20 g of 45% aqueous KOH 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 give 144.0 g of a light yellow liquid.

[0090] 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 give 112.0 g of light yellow liquid.

[0091] CE5: Following the general alkoxylation procedure, 0.20 g of 45% aqueous KOH 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 give 142.4 g of a light yellow liquid.

[0092] 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 give 142.3 g of a light yellow liquid.

[0093] 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 give 142.3 g of light yellow liquid.

[0094] CE8: Following the general alkoxylation procedure, 64 mg KH was added to 57.0 g TEG. The reactor was heated to 150°C and 104 mL EO was fed at a rate of 0.5 mL / min to give 142.7 g of light yellow liquid.

[0095] CE9: Following the general alkoxylation procedure, 64 mg KH was added to 57.0 g TEG. The reactor was heated to 120°C and 104 mL EO was fed at a rate of 0.5 mL / min to give 142.7 g of light yellow liquid.

[0096] CE10: Following the general alkoxylation procedure, 64 mg KH was added to 28.5 g TEG. The reactor was heated to 120°C and 56.9 mL EO was fed at a rate of 0.5 mL / min to give 74.5 g of light yellow liquid.

[0097] CE11: Following the general alkoxylation procedure, 73 mg KH was added to 32.5 g TEG. The reactor was heated to 150°C and 59.6 mL EO was fed at a rate of 0.5 mL / min to give 73.4 g of light yellow liquid.

[0098] CE12: Following the general alkoxylation procedure, 52 mg KH was added to 30.0 g TTEG. The reactor was heated to 150°C and 38.7 mL EO was fed at a rate of 0.5 mL / min to give 55.4 g of light yellow liquid.

[0099] CE13: 32.0 g TTEG was dried according to Dehydration Procedure A. Then, 160 mg 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 EO was fed at a rate of 0.5 mL / min to obtain 59.4 g of light yellow liquid.

[0100] CE14: For this reaction, 36 μL of water was added to 36.8 g of TTEG treated with Dehydration Procedure A. The water concentration measured by Karl Fischer titration was 1,533 ppm. 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 give 70.4 g of a light yellow liquid.

[0101] IE1: 36.8 g of TTEG was dried according to Dehydration Procedure A. Then, 45 mg of ground 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 light yellow liquid.

[0102] IE2: 36.8 g TTEG was dried according to Dehydration Procedure A. Then, 32 mg 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 EO was fed at a rate of 0.5 mL / min to give 73.2 g of light yellow liquid.

[0103] IE3: Following Dehydration Procedure B, 36.8 g of TTEG containing KOH catalyst (0.42 mol%) was prepared. Then, the general alkoxylation procedure was followed. The reactor was heated to 120°C and 42.6 mL EO was fed at a rate of 0.5 mL / min to obtain 69.0 g of light yellow liquid.

[0104] IE4: Following Dehydration Procedure B, 36.8 g of TTEG containing KOH catalyst (0.42 mol%) was prepared, and 4 μL of water was added to the TTEG / KOH mixture. The total water concentration measured by Karl Fischer titration was 281 ppm. Then, the general alkoxylation procedure was 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 light yellow liquid.

[0105] IE5: Following Dehydration Procedure B, 36.8 g of TTEG containing KOH catalyst (0.42 mol%) was prepared, and 18 μL of water was added to the TTEG / KOH mixture. The total water concentration measured by Karl Fischer titration was 929 ppm. Then, the general alkoxylation procedure was 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 light yellow liquid.

[0106] IE6: Following Dehydration Procedure B, 36.8 g of TTEG containing KOH catalyst (0.42 mol%) was prepared, and 18 μL of water was added to the TTEG / KOH mixture. The total water concentration measured by Karl Fischer titration was 929 ppm. 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 70.4 g of a light yellow liquid.

[0107] result

[0108] Table 5 provides the residual TEG results based on the initiator used and the initial water concentration according to the standard calibrator.

[0109] Table 5

[0110]

[0111] Table 6 provides the weight average molecular weight ("Mw") of the various fractions of several polyethylene glycols produced and the associated weight percentages of each provided in Daltons ("Da"). The values ​​in Table 6 were calculated using peak area percentages by GC-MS detection and flame ionization detection.

[0112] Table 6

[0113] Mw(Da) IE3 IE6 IE5 CE14 62 0.01 0.03 0.01 0.02 106 0.02 0.04 0.05 0.08 150 0.08 0.16 0.21 0.37 194 1.73 1.78 1.75 2.08 238 5.53 6.14 6.42 6.9 282 12.57 13.54 13.68 14.3 326 23.31 23.95 24.02 24.25 370 27.34 26.55 26.38 25.82 414 20.95 19.44 19.33 18.38 458 7.43 6.95 7.04 6.5 502 1.95 1.16 1.06 1.27

[0114] Now referring to Table 5 and Table 6, CE1-CE12 cumulatively prove that the initial water content (i.e., 1200ppm or less), catalyst and initiator of reduction cannot be used independently to reduce the presence of TEG in the final polyethylene glycol. For example, CE3 and CE12 prove that TTEG used as an initiator alone cannot reach the desired low TEG level. CE1, CE2 and CE5-CE11 prove that the catalyst alone or the catalyst combined with the initial water content of reduction is not enough to achieve the target TEG concentration in the final polyethylene glycol. CE13 proves that if a calcium-based catalyst is used, TTEG as an initiator and the initial water content of reduction will still produce unacceptable levels of TEG. Similarly, CE14 proves that if the initial water content is higher than 1200ppm, TTEG as an initiator and KOH as a catalyst will still produce unacceptable levels of TEG.

[0115] Unlike the comparative examples, IE1-IE6 are all capable of producing polyethylene glycol having a weight average molecular weight of 200 g / mol to 1000 g / mol as measured by gas chromatography-mass spectrometry, and having 1000 ppm or less TEG as measured by gas chromatography using flame ionization detection. As can be seen from IE1-IE6, using TTEG as an initiator, one or more catalysts selected from MOH or MH (wherein M is one of an alkali metal or an alkaline earth metal) and ensuring that the reaction mixture contains 1200 ppm or less of water ensures that the produced polyethylene glycol has a TEG concentration of 1000 ppm or less as measured by gas chromatography using flame ionization detection.

Claims

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

2. The method of claim 1, wherein the step of reacting the reaction mixture further comprises: The reaction mixture is reacted to form polyethylene glycol having a weight average molecular weight of 300 to 600 g / mol as measured according to gas chromatography.

3. The method according to any one of claims 1 and 2, wherein the polyethylene glycol has a triethylene glycol concentration of less than 1000 ppm as measured according to gas chromatography using flame ionization detection.

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

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 process according to any one of claims 1 to 5, wherein the catalyst is KOH.

7. The method according to any one of claims 1 to 6, further comprising the following steps: The initiator is dehydrated prior to combining with the one or more catalysts.

8. The method according to any one of claims 1 to 6, further comprising the following steps: The combined initiator and the one or more catalysts are dehydrated.

9. The process according to any one of claims 1 to 8, wherein the reaction mixture comprises 800 ppm or less water as measured according to Karl Fischer titration.

10. The process according to any one of claims 1 to 8, wherein the reaction mixture comprises 500 ppm or less water as measured according to Karl Fischer titration.

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