METHOD FOR PRODUCING POLYOXYETHYLENE DERIVATIVE, METHOD FOR QUANTITATING POLYOXYETHYLENE COMPOUND, AND LABELING REAGENT FOR ANALYSIS USE

Abstract

A method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxyl group is disclosed. The method includes labeling an unreacted high molecular weight polyoxyethylene compound having a hydroxy group using a labeling reagent in a deuterated solvent, and quantitating a labeled solution by a pre-saturation method and a proton nuclear magnetic resonance spectroscopy using inverse gated decoupling. The method allows a prompt quantitation of unreacted high molecular weight polyoxyethylene compound having a hydroxy group with a high accuracy.

Claims

1. A method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxy group by derivatizing a hydroxy group in a high molecular weight polyoxyethylene compound having the hydroxy group, the method comprising: labeling the high molecular weight polyoxyethylene compound having the hydroxy group, which is unreacted, using a labeling reagent in a deuterated solvent; and quantitating a labeled solution by a pre-saturation method and a proton nuclear magnetic resonance spectroscopy using inverse gated decoupling.

2. The method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxy group according to claim 1, wherein the high molecular weight polyoxyethylene compound having the hydroxy group is represented by the following formula (1): ##STR00029## wherein, in the formula (1), OA.sup.1 and OA.sup.2 are an oxyethylene group, a and b are each independently 0 to 2,500, and a+b is 200 or more, L.sup.1 and L.sup.2 are each independently an alkylene group which may have a bond selected from an ester bond, a urethane bond, an amide bond, a urea bond, an ether bond, and a thioether bond in an alkylene chain or at an end thereof, and the alkylene groups may be same as or different from each other in one molecule, p and q are each independently 0 or 1, s and t are each independently 0 to 8, and 2s+t8, X.sup.1 is a hydroxy group, an alkoxy group, an azide group, an oxycarbonyl group, an oxycarbonyloxy group, an oxycarbamoyl group, a cyano group, a silyl group, an acyloxy group, a sulfonyl group, or an imido group, and when t is 0, X.sup.1 is a hydroxy group, X.sup.2 is a hydroxy group, and Z is a residue obtained by removing all hydroxy groups from a compound having 2 to 8 hydroxy groups and 2 to 21 carbon atoms.

3. The method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxy group according to claim 1, wherein the high molecular weight polyoxyethylene derivative having a derivatized hydroxy group is represented by the following formula (2): ##STR00030## wherein, in the formula (2), OA.sup.1 and OA.sup.2 are an oxyethylene group, a and b are each independently 0 to 2,500, and a+b is 200 or more, L.sup.1 and L.sup.2 are each independently an alkylene group which may have a bond selected from an ester bond, a urethane bond, an amide bond, a urea bond, an ether bond, and a thioether bond in an alkylene chain or at an end thereof, and the alkylene groups may be same as or different from each other in one molecule, p and q are each independently 0 or 1, s and t are each independently 0 to 8, and 2s+t8, X.sup.3 and X.sup.4 are each independently an alkoxy group, an azide group, an oxycarbonyl group, an oxycarbonyloxy group, an oxycarbamoyl group, a cyano group, a silyl group, an acyloxy group, a sulfonyl group, or an imido group, and Z is a residue obtained by removing all hydroxy groups from a compound having 2 to 8 hydroxy groups and 2 to 21 carbon atoms.

4. The method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxy group according to claim 1, wherein the labeling reagent is an isocyanate reagent represented by the following formula (3): ##STR00031## wherein, in the formula (3), R represents an organic group having an electron-withdrawing group.

5. A labeling reagent for analysis use for a high molecular weight polyoxyethylene compound having a hydroxy group, which is represented by a formula (3): ##STR00032## wherein, in the formula (3), R represents an organic group having an electron-withdrawing group.

6. A method for quantitating a high molecular weight polyoxyethylene compound having a hydroxy group contained in a high molecular weight polyoxyethylene derivative, the method comprising: labeling the high molecular weight polyoxyethylene compound having a hydroxy group using a labeling reagent in a deuterated solvent; and quantitating a labeled solution by a pre-saturation method and a proton nuclear magnetic resonance spectroscopy using inverse gated decoupling.

7. The method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxy group according to claim 2, wherein the high molecular weight polyoxyethylene derivative having a derivatized hydroxy group is represented by the following formula (2): ##STR00033## wherein, in the formula (2), OA.sup.1 and OA.sup.2 are an oxyethylene group, a and b are each independently 0 to 2,500, and a+b is 200 or more, L.sup.1 and L.sup.2 are each independently an alkylene group which may have a bond selected from an ester bond, a urethane bond, an amide bond, a urea bond, an ether bond, and a thioether bond in an alkylene chain or at an end thereof, and the alkylene groups may be same as or different from each other in one molecule, p and q are each independently 0 or 1, s and t are each independently 0 to 8, and 2s+t8, X.sup.3 and X.sup.4 are each independently an alkoxy group, an azide group, an oxycarbonyl group, an oxycarbonyloxy group, an oxycarbamoyl group, a cyano group, a silyl group, an acyloxy group, a sulfonyl group, or an imido group, and Z is a residue obtained by removing all hydroxy groups from a compound having 2 to 8 hydroxy groups and 2 to 21 carbon atoms.

8. The method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxy group according to claim 2, wherein the labeling reagent is an isocyanate reagent represented by the following formula (3): ##STR00034## wherein, in the formula (3), R represents an organic group having an electron-withdrawing group.

9. The method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxy group according to claim 3, wherein the labeling reagent is an isocyanate reagent represented by the following formula (3): ##STR00035## wherein, in the formula (3), R represents an organic group having an electron-withdrawing group.

10. The method for producing a high molecular weight polyoxyethylene derivative having a derivatized hydroxy group according to claim 7, wherein the labeling reagent is an isocyanate reagent represented by the following formula (3): ##STR00036## wherein, in the formula (3), R represents an organic group having an electron-withdrawing group.

Description

EXAMPLES

[0132] The present invention will be described in more detail with reference to Examples. The accuracy of quantitating the amount of the high molecular weight PEG-OH contained in a high molecular weight PEG derivative is shown, and note that the present invention is not limited to the following Examples.

[0133] .sup.1H-NMR was obtained from a nuclear magnetic resonance apparatus (JNM-ECZ400 or JNM-ECA600) manufactured by JEOL Ltd. A tube having a diameter of 5 mm was used for the measurement, and CDCl.sub.3 containing tetramethylsilane (TMS) was used as an internal standard substance for a deuterated solvent.

Example 1: Evaluation on Quantitating Property of PEG-OH Contained in PEG Carboxylic Acid

##STR00024##

[0134] In an etherification reaction of obtaining PEG-O(CH.sub.2).sub.5COOH (molecular weight: 20,000) from PEG-OH (molecular weight: 20,000), as represented by the formula (10), the quantitating property of the unreacted PEG-OH (molecular weight: 20,000) was checked by a spike and recovery test in the following manner.

[0135] That is, into a screw tube into which 100 mg of SUNBRIGHT ME-200HC (number average molecular weight: 20,185) manufactured by NOF Corporation having the same structure as the PEG-O(CH.sub.2).sub.5COOH in the formula (10) was charged, MEH-20T (number average molecular weight: 19,689) manufactured by NOF Corporation having the same structure as the PEG-OH in the formula (10) was spiked at 0.1 wt % to 1.0 wt % with respect to SUNBRIGHT ME-200HC manufactured by NOF Corporation, to obtain each sample in Experiment 1 to Experiment 4. To each sample, 80 L of triphenylmethane (10 g/L) dissolved in deuterated chloroform and 620 L of deuterated chloroform were added, followed by dissolution. Thereafter, 20 L of trichloroacetyl isocyanate (TCI product) was added to each sample, followed by mixing by inversion. After the mixing by inversion, each sample was measured using a nuclear magnetic resonance apparatus by applying a pre-saturation method to a PEG chain-derived proton peak (3.56 ppm) and using inverse gated decoupling under the following conditions. [0136] Reference peak: TMS [0137] Quantitation reference peak: triphenylmethane ((C.sub.6H.sub.5).sub.3CH, 5.55 ppm) [0138] Target product peak: (OCH.sub.2CH.sub.2).sub.nOCH.sub.2CH.sub.2OCONHCOCCl.sub.3, 4.42 ppm [0139] Pulse sequence: single_pulse_irrdec [0140] Attenuator: 60 dB [0141] Measurement temperature: 25 C. [0142] Number of times for integration: 1024

[0143] When the integral value of the quantitation reference peak was set to 0.6548, a spike and recovery rate of each sample was calculated according to the following equation.

Spike and recovery rate (%)=(integral value of target product peak/2)100

[0144] An allowable range of the spike and recovery rate was set as 30%, and a range in which the spike and recovery was possible was checked.

TABLE-US-00001 TABLE 1 Experiment Experiment Experiment Experiment 1 2 3 4 Spiked amount 0.1 0.2 0.4 1.0 (wt %) Spike and (*) 67.5 121.3 93.5 recovery rate (%) (*)not calculated due to no peak detected

[0145] As listed in Table 1, it is found that the PEG-OH contained in the PEG-O(CH.sub.2).sub.5COOH in the formula (10) can be spiked and recovered in a range of at least 0.4 wt % or more, that is, it can be quantitated down to 0.4 wt %, with respect to the PEG-O(CH.sub.2).sub.5COOH.

Example 2: Evaluation on Quantitating Property of (PEG).SUB.2.-OH Contained in (PEG).SUB.2.-Phthalimide

##STR00025##

[0146] During one-pot synthesis as a two-stage reaction of obtaining (PEG).sub.2NH.sub.2 (molecular weight: 10,000) from (PEG).sub.2-OH (molecular weight: 10,000), as represented by the formula (11), in the first stage of phthalimidation reaction of obtaining (PEG).sub.2-PI from the (PEG).sub.2-OH, the quantitating property of the unreacted (PEG).sub.2-OH (molecular weight: 10,000) was checked by a spike and recovery test in the following manner.

[0147] Into a screw tube into which 100 mg of SUNBRIGHT 2AC-GL2-100EI (number average molecular weight: 10,082) manufactured by NOF Corporation having the same structure as the (PEG).sub.2-PI in the formula (11) was charged, SUNBRIGHT 2AC-GL2-100HO (number average molecular weight: 9,975) manufactured by NOF Corporation having the same structure as the (PEG).sub.2-OH in the formula (11) was spiked at 0.25 wt % to 0.50 wt % with respect to SUNBRIGHT 2AC-GL2-100EI, to obtain each sample in Experiment 5 and Experiment 6. To each sample, 80 L of triphenylmethane (10 g/L) dissolved in deuterated chloroform and 620 L of deuterated chloroform were added, followed by dissolution. Thereafter, 20 L of trichloroacetyl isocyanate (TCI product) was added to each sample, followed by mixing by inversion. After the mixing by inversion, each sample was measured using a nuclear magnetic resonance apparatus by applying a pre-saturation method to a PEG chain-derived proton peak (3.56 ppm) and using inverse gated decoupling under the following conditions. [0148] Reference peak: TMS [0149] Quantitation reference peak: triphenylmethane ((C.sub.6H.sub.5).sub.3CH, 5.55 ppm) [0150] Target product peak: CH((OCH.sub.2CH.sub.2).sub.nOCOCH.sub.3)CH.sub.2OCONHCOCCl.sub.3, 4.34 ppm [0151] Pulse sequence: single_pulse_irrdec [0152] Attenuator: 50 dB [0153] Measurement temperature: 25 C. [0154] Number of times for integration: 256

[0155] When the integral value of the quantitation reference peak was set to 0.3274, a spike and recovery rate of each sample was calculated according to the following equation.

Spike and recovery rate (%)=(integral value of target product peak/1)100

[0156] An allowable range of the spike and recovery rate was set as 30%, and a range in which the spike and recovery was possible was checked.

TABLE-US-00002 TABLE 2 Experiment 5 Experiment 6 Spiked amount 0.25 0.50 (wt %) Spike and recovery 100 97.0 rate (%)

[0157] As listed in Table 2, it is found that the (PEG).sub.2-OH contained in the (PEG).sub.2-PI can be spiked and recovered in a range of 0.25 wt % or more, that is, it can be quantitated down to 0.25 wt %, with respect to the (PEG).sub.2-PI.

Example 3: Evaluation on Quantitating Property of PEG-OH Contained in PEG-OCH.SUB.2.C.SUB.6.H.SUB.5

##STR00026##

[0158] During one-pot synthesis as a two-stage reaction of obtaining (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 from (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5, as represented by the formula (12), in the second stage of methoxylation reaction of obtaining the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 from (Ms-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5, the quantitating property of the unreacted (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was checked by a spike and recovery test in the following manner.

[0159] Into a screw tube into which 100 mg of SUNBRIGHT GL2-200BZ (number average molecular weight: 19,451) manufactured by NOF Corporation having the same structure as the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 in the formula (12) was charged, SUNBRIGHT GL2-200BH (number average molecular weight: 19,859) manufactured by NOF Corporation having the same structure as the (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 in the formula (12) was spiked at 0.1 wt % to 1.0 wt % with respect to SUNBRIGHT GL2-200BZ, to obtain each sample in Experiment 7 to Experiment 10. To each sample, 700 L of deuterated chloroform was added, followed by dissolution. Thereafter, 20 L of trichloroacetyl isocyanate (TCI product) was added to each sample, followed by mixing by inversion. After the mixing by inversion, each sample was measured using a nuclear magnetic resonance apparatus by applying a pre-saturation method to a PEG chain-derived proton peak (3.56 ppm) and using inverse gated decoupling under the following conditions. [0160] Reference peak: TMS [0161] Quantitation reference peak: CH.sub.2OCH.sub.2C.sub.6H.sub.5, 4.54 ppm [0162] Target product peak: ((OCH.sub.2CH.sub.2).sub.nOCH.sub.2CH.sub.2OCONHCOCCl.sub.3).sub.2, 4.42 ppm [0163] Pulse sequence: single_pulse_irrdec [0164] Attenuator: 60 dB [0165] Measurement temperature: 25 C. [0166] Number of times for integration: 1024

[0167] When the integral value of the quantitation reference peak was set to 2.000, a spike and recovery rate of each sample was calculated according to the following equation.

Spike and recovery rate (%)=(integral value of target product peak/4)100

[0168] An allowable range of the spike and recovery rate was set as 30%, and a range in which the spike and recovery was possible was checked.

TABLE-US-00003 TABLE 3 Experiment Experiment Experiment Experiment 7 8 9 10 Spiked amount 0.1 0.2 0.4 1.0 (wt %) Spike and (*) 112.5 118.8 95.0 recovery rate (%) (*)not calculated due to no peak detected

[0169] As listed in Table 3, it is found that the (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 contained in the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 in the formula (12) can be spiked and recovered in a range of 0.2 wt % or more, that is, it can be quantitated down to 0.2 wt %, with respect to the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5.

Example 4: Evaluation on Quantitating Property of 4Arm PEG-OH Contained in 4Arm PEG-CN

##STR00027##

[0170] In a cyanoethylation reaction of obtaining 4arm PEG-CN from 4arm PEG-OH, as represented by the formula (13), the quantitating property of the unreacted 4arm PEG-OH was checked by a spike and recovery test in the following manner.

[0171] Into a screw tube into which 100 mg of SUNBRIGHT PTE-200CN (number average molecular weight: 20,086) manufactured by NOF Corporation having the same structure as the 4arm PEG-CN in the formula (13) was charged, SUNBRIGHT PTE-20000 (number average molecular weight: 20,568) manufactured by NOF Corporation having the same structure as the 4arm PEG-OH in the formula (13) was spiked at 0.1 wt % to 1.0 wt % with respect to SUNBRIGHT PTE-200CN, to obtain each sample in Experiment 11 to Experiment 14. To each sample, 80 L of triphenylmethane (10 g/L) dissolved in deuterated chloroform and 620 L of deuterated chloroform were added, followed by dissolution. Thereafter, 20 L of trichloroacetyl isocyanate (TCI product) was added to each sample, followed by mixing by inversion. After the mixing by inversion, each sample was measured using a nuclear magnetic resonance apparatus by applying a pre-saturation method to a PEG chain-derived proton peak (3.56 ppm) and using inverse gated decoupling under the following conditions. [0172] Reference peak: TMS [0173] Quantitation reference peak: triphenylmethane ((C.sub.6H.sub.5).sub.3CH, 5.55 ppm) [0174] Target product peak: [(OCH.sub.2CH.sub.2).sub.nOCH.sub.2CH.sub.2OCONHCOCCl.sub.3].sub.4, 4.42 ppm [0175] Pulse sequence: single_pulse_irrdec [0176] Attenuator: 60 dB [0177] Measurement temperature: 25 C. [0178] Number of times for integration: 1024

[0179] When the integral value of the quantitation reference peak was set to 0.6548, a spike and recovery rate of each sample was calculated according to the following equation.

Spike and recovery rate (%)=(integral value of target product peak/8)100

[0180] An allowable range of the spike and recovery rate was set as 30%, and a range in which the spike and recovery was possible was checked.

TABLE-US-00004 TABLE 4 Experiment Experiment Experiment Experiment 11 12 13 14 Spiked amount 0.1 0.2 0.4 1.0 (wt %) Spike and (*) 46.3 75.6 106.3 recovery rate (%) (*)not calculated due to no peak detected

[0181] As listed in Table 4, it is found that the 4arm PEG-OH contained in the 4arm PEG-CN can be spiked and recovered in a range of 0.4 wt % or more, that is, it can be quantitated down to 0.4 wt %, with respect to the 4arm PEG-CN.

Example 5: Evaluation on Quantitating Property of 8Arm PEG-OH Contained in 8Arm PEG-VS

##STR00028##

[0182] In a vinyl sulfonation reaction of obtaining 8arm PEG-VS from 8arm PEG-OH, as represented by the formula (14), the quantitating property of the unreacted 8arm PEG-OH was checked by a spike and recovery test in the following manner.

[0183] Into a screw tube into which 100 mg of SUNBRIGHT HGEO-400VS (number average molecular weight: 40,731) manufactured by NOF Corporation having the same structure as the 8arm PEG-VS in the formula (14) was charged, SUNBRIGHT HGEO-40000 (number average molecular weight: 43,573) manufactured by NOF Corporation having the same structure as the 8arm PEG-OH in the formula (14) was spiked at 0.1 wt % to 1.0 wt % with respect to SUNBRIGHT HGEO-400VS, to obtain each sample in Experiment 15 to Experiment 18. To each sample, 80 L of triphenylmethane (10 g/L) dissolved in deuterated chloroform and 620 L of deuterated chloroform were added, followed by dissolution. Thereafter, 20 L of trichloroacetyl isocyanate (TCI product) was added to each sample, followed by mixing by inversion. After the mixing by inversion, each sample was measured using a nuclear magnetic resonance apparatus by applying a pre-saturation method to a PEG chain-derived proton peak (3.56 ppm) and using inverse gated decoupling under the following conditions. [0184] Reference peak: TMS [0185] Quantitation reference peak: triphenylmethane ((C.sub.6H.sub.5).sub.3CH, ppm) [0186] Target product peak: [(OCH.sub.2CH.sub.2).sub.nOCH.sub.2CH.sub.2OCONHCOCCl.sub.3].sub.8, ppm [0187] Pulse sequence: single_pulse_irrdec [0188] Attenuator: 60 dB [0189] Measurement temperature: 25 C. [0190] Number of times for integration: 1024

[0191] When the integral value of the quantitation reference peak was set to 1.3096, a spike and recovery rate of each sample was calculated according to the following equation.

Spike and recovery rate (%)=(integral value of target product peak/16)100

[0192] An allowable range of the spike and recovery rate was set as 30%, and a range in which the spike and recovery was possible was checked.

TABLE-US-00005 TABLE 5 Experiment Experiment Experiment Experiment 15 16 17 18 Spiked amount 0.1 0.2 0.4 1.0 (wt %) Spike and (*) 111.5 95.8 110.3 recovery rate (%) (*)not calculated due to no peak detected

[0193] As listed in Table 5, it is found that the 8arm PEG-OH contained in the 8arm PEG-VS in the formula (14) can be spiked and recovered in a range of 0.2 wt % or more, that is, it can be quantitated down to 0.2 wt %, with respect to the 8arm PEG-VS.

Comparative Example 1: Evaluation on Quantitating Property of (HO-PEG).SUB.2.-OCH.SUB.2.-C.SUB.6.H.SUB.5 .Contained in (PEG).SUB.2.-OCH.SUB.2.C.SUB.6.H.SUB.5

[0194] In the second stage of methoxylation process of obtaining the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 from the (Ms-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 as shown in Example 3, the quantitating property of the unreacted (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was checked by a spike and recovery test according to a method described in Patent Literature 1 in the following manner. The method described in Patent Literature 1 is a method using methanesulfonyl chloride as a labeling reagent.

[0195] Into a screw tube into which 100 mg of SUNBRIGHT GL2-200BZ (number average molecular weight: 19,451) manufactured by NOF Corporation as an equivalent product of the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was charged, SUNBRIGHT 2 MS-GL2-200BZ (number average molecular weight: 19,607) manufactured by NOF Corporation as an equivalent product of the (Ms-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5, obtained by labeling the (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 with methanesulfonyl chloride, was spiked at 0.1 wt % to 2.0 wt % with respect to SUNBRIGHT GL2-200BZ, to obtain each sample in Experiment 19 to Experiment 22. To each sample, 700 L of deuterated chloroform was added, followed by dissolution, and then each sample was measured using a nuclear magnetic resonance apparatus under the following conditions.

[0196] No pre-saturation method or inverse gated decoupling was applied. [0197] Reference peak: TMS [0198] Quantitation reference peak: CH.sub.2OCH.sub.2C.sub.6H.sub.5, 4.54 ppm [0199] Target product peak: ((OCH.sub.2CH.sub.2).sub.nOS(O).sub.2CH.sub.3).sub.2, 3.00 ppm [0200] Pulse sequence: single_pulse [0201] Measurement temperature: 25 C. [0202] Number of times for integration: 128

[0203] When the integral value of the quantitation reference peak was set to 2.000, a spike and recovery rate of each sample was calculated according to the following equation.

Spike and recovery rate (%)=(integral value of target product peak/6)100

[0204] An allowable range of the spike and recovery rate was set as 30%, and a range in which the spike and recovery was possible was checked.

TABLE-US-00006 TABLE 6 Experiment Experiment Experiment Experiment 19 20 21 22 Spiked amount 0.1 0.2 0.4 1.0 (wt %) Spike and (*) 91.9 75.3 102.7 recovery rate (%) (*)not calculated due to no peak detected

[0205] As listed in Table 6, it is found that the (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 contained in the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 can be quantitated down to 0.2 wt % with respect to the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5. That is, the unreacted (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 contained in the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 can be spiked and recovered in a range of 0.2 wt % or more, that is, it can be quantitated down to 0.2 wt %. This is equivalent to the quantitating property shown in Example 3, indicating that the analysis method according to the present invention has quantitative accuracy equivalent to that previously reported.

Example 6: Evaluation on Production Time in Present Invention

[0206] During one-pot synthesis as a two-stage reaction of obtaining (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 from (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5, as described Patent Literature 1, the production time required when the analysis method according to the present invention was used to check the completion of the reaction process was evaluated in the following manner.

[0207] That is, according to Example 16-4 in Patent Literature 1, the second alkyl etherification was carried out over 9 hours using (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 (200 g) as a raw material, and then the completion of the reaction process was checked using the analysis method according to the present invention, that is, in the following manner.

[0208] The reaction solution (5 mL) was sampled, and the precipitate was removed by suction filtration. To the obtained filtrate, 100 mL of ethyl acetate was added, and the mixture was stirred for 5 minutes under a nitrogen atmosphere. Thereafter, 100 mL of hexane was added, the mixture was stirred for 10 minutes to precipitate crystals, and then the crystals were collected by suction filtration.

[0209] The collected crystals were dried under a reduced pressure for 1 hour, and 100 mg of the dry solid was dissolved in 0.7 mL of deuterated chloroform. 20 L of trichloroacetyl isocyanate was spiked thereto, followed by mixing by inversion. Thereafter, the amount of the unreacted (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was checked by .sup.1H-NMR analysis under the same measurement conditions as in Example 3, and it was found that the reaction was complete.

[0210] It was found by the analysis over 3 hours after sampling the reaction solution that the amount of the unreacted (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was 0.2% or less. Then, according to Example 16-4 in Patent Literature 1, washing with water, dehydration, and crystallization were carried out for 6 hours, followed by drying under a reduced pressure for 8 hours, and the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was obtained in a total production time of 26 hours.

Comparative Example 2: Evaluation on Production Time in Related-Art Method

[0211] During one-pot synthesis as a two-stage reaction of obtaining the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 from the (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5, as described Patent Literature 1, in order to check the completion of the reaction process, methanesulfonyl chloride was used as a labeling reagent, and in the case of no reaction, the production time to check the amount of the (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was evaluated in the following manner.

[0212] According to Example 16-4 in Patent Literature 1, the second alkyl etherification was carried out over 9 hours using (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 (200 g) as a raw material, and then the completion of the reaction process was checked using the method described in Example 27 in Patent Literature 1, that is, in the following manner.

[0213] The reaction solution (20 mL) was sampled, and the precipitated chloride was removed by suction filtration. To the obtained filtrate, 300 mL of ethyl acetate was added, and the mixture was stirred for 5 minutes under a nitrogen atmosphere. Thereafter, 300 mL of hexane was added, the mixture was stirred for 30 minutes to precipitate crystals, and then the crystals were collected by suction filtration.

[0214] The collected crystals were dried under a reduced pressure for 5 hours, 3.0 g of the obtained dry solid was charged into a round bottom flask, and 100 g of toluene was added thereto and heated under a reflux for 1 hour to azeotropically remove 50 g of toluene and water. After cooling to room temperature, 0.095 g of triethylamine was added, the mixture was heated to 40 C., 0.054 g of methanesulfonyl chloride was spiked, and the mixture was reacted at 40 C. for 3 hours. After the reaction was completed, the precipitated chloride was removed by suction filtration. To the obtained filtrate, 100 mL of ethyl acetate was added, and the mixture was stirred for 5 minutes under a nitrogen atmosphere. Thereafter, 100 mL of hexane was added, the mixture was stirred for 10 minutes to precipitate crystals, and then the crystals were collected by suction filtration.

[0215] The collected crystals were dried under a reduced pressure for 6 hours, and 20 mg of the obtained crystals were dissolved in 0.7 mL of deuterated chloroform. The amount of the unreacted (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was checked by .sup.1H-NMR analysis under the same measurement conditions as in Comparative Example 1, and it was found that the reaction was complete.

[0216] It was found by the analysis over 17 hours after sampling the reaction solution that the amount of the unreacted (HO-PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was 0.2% or less. Then, according to Example 16-4 in Patent Literature 1, washing with water, dehydration, and crystallization were carried out for 6 hours, followed by drying under a reduced pressure for 8 hours, and the (PEG).sub.2-OCH.sub.2C.sub.6H.sub.5 was obtained in a total production time of 40 hours.

[0217] That is, compared to Example 6, the production time was 14 hours longer.

[0218] From the above, it is indicated that the present invention can sufficiently shorten the production time compared to the related-art method.

INDUSTRIAL APPLICABILITY

[0219] According to the present invention, in the production of obtaining a high molecular weight polyoxyethylene derivative by derivatizing a hydroxy group using a high molecular weight polyoxyethylene compound having a hydroxy group as a raw material, the time required for process analysis can be shortened and the total production time can be shortened.

[0220] Although the present invention has been described in detail and with reference to specific embodiments, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.

[0221] The present application is based on a Japanese patent application (Japanese Patent Application No. 2022-35886) filed on Mar. 9, 2022, the contents which are incorporated herein by reference.