Synthesis method of tyroxapole

Abstract

The present invention provides a method for synthesizing tyloxapol of formula (I), which comprises first reacting p-tert-octylphenol of formula (III) with formaldehyde under alkaline conditions to obtain 2,5-dimethylol p-tert-octylphenol of formula (IV), then reacting 2,5-dimethylol p-tert-octylphenol with p-tert-octylphenol of formula (III) under acidic conditions to obtain a phenolic resin of formula (II), and finally reacting the phenolic resin of formula (II) with ethylene oxide to obtain tyloxapol of formula (I). TIFF2025501583000036.tif50170

Description

Technical Field

[0001] The present disclosure belongs to the field of chemical synthesis, and more particularly relates to a method for synthesizing tyloxapol.

Background Art

[0002] Tyloxapol is a high molecular polymer (shown below), an alkyl aromatic polyether alcohol type non-ionic liquid surfactant. The hydrophobic aromatic group improves the solubility of this molecule in oil, while the ether alcohols, which are a number of hydrophilic groups, enhance the solubility of this molecule in water. Therefore, tyloxapol is used as an emulsifier for water / oil type and oil / water type emulsions.

Chemical formula

[0003] In addition to being used as an emulsifier for the preparation of emulsions, creams, and other formulations, due to its good solubilization and dispersion effects, tyloxapol is also widely used in the preparation of liquid formulations such as nasal drops, eye drops, mixtures, etc., and solid formulations such as tablets and pills. It can shorten the disintegration time and improve the solubility in tablets.

[0004] As an active ingredient in cough and expectorant formulations, tyloxapol is used to reduce the surface tension and liquefy mucus to facilitate the discharge of sputum. Tyloxapol also serves as an additive in formulations, playing a role in emulsification and penetration promotion. In addition, tyloxapol has been reported to be used in eye washes (eye drops) and has good decontamination and washing effects. The concentration used as a pharmaceutical additive should be determined according to specific prescriptions, dosage forms, and purposes of use. Generally, the concentration during use is 0.1 - 0.5%.

[0005] Currently, the synthesis process for tyroxapole is mainly as follows: 1) First, tert-octylphenol and ethylene oxide are reacted at high temperature and high pressure in the presence of sodium hydroxide to produce a polymerized phenol, and then this polymerized phenol is condensed with formaldehyde under heating conditions in the presence of an acid catalyst to prepare tyroxapole; 2) First, formaldehyde is polymerized with p-tert-octylphenol to obtain a phenol resin of the appropriate molecular weight, and then this appropriate phenol resin is reacted with ethylene oxide to synthesize tyroxapole. These two routes tend to produce polymers with a degree of polymerization greater than 6 (pharmacopoeia standard m<6) during phenolaldehyde polymerization, and require high-temperature (above 160°C) vacuum distillation to retain fractions at specific temperatures. This is a major challenge for pilot facilities and public projects.

[0006] Therefore, in this technical field, there is a need for tyroxapole with a degree of polymerization m < 6, particularly m = 1, and a method for producing the same. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] In view of the shortcomings of the above synthesis method, this disclosure proposes a novel synthesis method for producing m=1 tyroxapole. The method disclosed is easy to operate and the resulting product is of high purity, making it beneficial for industrial production. [Means for solving the problem]

[0008] Specifically, this disclosure relates to the following technical solutions.

[0009] 1. It is a compound of formula (I), [ka] In the formula, n is 6, 7, 8, 9, 10, 11, or 12; another option is n is 8, 9, or 10; yet another option is n is 9.

[0010] 2. A method for producing the compound of formula (I) in Embodiment 1, [ka] The process includes a step of reacting the compound of formula (II) with ethylene oxide to obtain the compound of formula (I).

[0011] 3. The method according to Embodiment 2, wherein the molar ratio of compound (II) to ethylene oxide is 1:19 to 1:37, with alternative options being 1:25 to 1:32, another option being 1:27 to 1:29, and yet another option being 1:28.

[0012] 4. The reaction of the compound of formula (II) with ethylene oxide is carried out in an aprotic solvent, or alternatively, in an aprotic nonpolar solvent, and alternatively, the solvent is n-H The method according to Embodiment 2 or 3, wherein the alkane is xane, heptane, benzene, and toluene, and toluene is an alternative option.

[0013] 5. The method according to any one of Embodiments 2 to 4, wherein the reaction is carried out at a temperature of 60°C or higher (e.g., 60-120°C), or alternatively at a temperature of 80°C or higher (e.g., 80-100°C), or still alternatively at a temperature of 100°C.

[0014] 6. The method according to any one of Embodiments 2 to 5, wherein the reaction is carried out at a pressure of 0.2 to 0.8 MPa, as an alternative, at a pressure of 0.3 to 0.8 MPa, and as yet another alternative, at a pressure of 0.3 to 0.5 MPa.

[0015] 7. The method according to any one of embodiments 2 to 6, wherein the reaction is carried out for at least 3 hours, or alternatively, at least 5 hours.

[0016] 8. The reaction is carried out in toluene at a temperature of 80 to 100 °C and a pressure of 0.3 to 0.5 MPa for at least 5 hours, and the molar ratio of the compound of formula (II) to ethylene oxide is 1:28. The method according to any one of Embodiments 2 to 7.

[0017] 9. The compound of formula (II).

Chemical formula

[0018] 10. A method for producing the compound of formula (II),

Chemical formula

[0019] 11. The molar ratio of the compound of formula (IV) to the compound of formula (III) is less than 1:2, another option is 1:2.1 to 1:3, and yet another option is 1:2.1 to 1:2.3, such as 1:2.1, 1:2.2, or 1:2.3. The method according to Embodiment 10. Another option is 1:2.1 to 1:3, and yet another option is 1:2.1 to 1:2.3, such as 1:2.1, 1:2.2, or 1:2.3. The method according to Embodiment 10.

[0020] 12. The reaction is carried out in oxalic acid, acetic acid, sulfuric acid, or hydrochloric acid, and another option is in oxalic acid. The method according to Embodiment 10 or 11.

[0021] 13. The reaction is carried out at 80 °C or higher, another option is 80 to 100 °C, and yet another option is 100 °C. The method according to any one of Embodiments 10 to 12.

[0022] 14. The reaction is carried out for at least 5 hours, another option is 5 to 8 hours, another option is at least 6 hours, and yet another option is 6 hours. The method according to any one of Embodiments 10 to 13.

[0023] 15. The method according to any one of Embodiments 10 to 14, wherein the reaction conditions are one of the following. 1) The reaction is carried out under acidic conditions (such as in oxalic acid, acetic acid, sulfuric acid, or hydrochloric acid) at a temperature of 80°C or higher for at least 5 hours, in which case the molar ratio of compound (IV) to compound (III) is less than 1:2. 2) The reaction is carried out in glacial acetic acid at 100°C for at least 6 hours, in which case the molar ratio of compound (IV) to compound (III) is 1:2.2. 3) The reaction is carried out in 2 mol / L sulfuric acid at 100°C for at least 6 hours, in which case the molar ratio of compound (IV) to compound (III) is 1:2.2. 4) The reaction is carried out in 2 mol / L oxalic acid at 100°C for at least 6 hours, in which case the molar ratio of compound (IV) to compound (III) is 1:2.2. 5) The reaction is carried out in 32% hydrochloric acid at 100°C for at least 6 hours, in which case the molar ratio of compound (IV) to compound (III) is 1:2.2.

[0024] 16. A method for producing the compound of formula (IV), [ka] The process includes a step of reacting the compound of formula (III) with formaldehyde under alkaline conditions to obtain the compound of formula (IV).

[0025] 17. The method according to Embodiment 16, wherein the molar ratio of the compound of formula (III) to formaldehyde is less than 1:2, alternatively 1:2.1 to 1:5, and yet another option 1:2.1 to 1:2.3, such as 1:2.1, 1:2.2, or 1:2.3.

[0026] 18. The method according to Embodiment 16 or 17, wherein the molar ratio of compound to base in formula (III) is less than 1:1, alternatively 1:2 to 1:4, alternatively 1:2 to 1:3, and yet another alternative 1:2.5.

[0027] 19. The method according to any one of Embodiments 16 to 18, wherein the reaction is carried out in the presence of an inorganic base, or, as an alternative, in the presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.

[0028] 20. The method according to any one of embodiments 16 to 19, wherein the reaction is carried out at a temperature of 60°C or higher, or alternatively at a temperature of 80 to 100°C.

[0029] 21. The method according to any one of embodiments 16 to 20, wherein the reaction is carried out for at least 2 hours, or alternatively, at least 3 hours, or alternatively, at least 4 hours.

[0030] 22. The method according to any one of Embodiments 16 to 20, wherein the reaction conditions are one of the following. 1) The reaction is carried out at a temperature of 60°C or higher for at least 3 hours in the presence of an inorganic base (another option being an alkali metal hydroxide), in which case the molar ratio of the compound of formula (III) to formaldehyde is less than 1:2, and the molar ratio of the compound of formula (III) to the inorganic base is less than 1:1. 2) The reaction is carried out in the presence of potassium hydroxide at 80-100°C for at least 3 hours, in which case the molar ratio of compound (III) to formaldehyde is 1:2.2 and the molar ratio of compound (III) to potassium hydroxide is 1:2.5. 3) The reaction is carried out in the presence of sodium hydroxide at 80-100°C for at least 3 hours, in which case the molar ratio of compound (III) to formaldehyde is 1:2.2 and the molar ratio of compound (III) to sodium hydroxide is 1:2.5.

[0031] 23. A method for producing the compound of formula (I), [ka] 1) A step of reacting the compound of formula (III) with formaldehyde in the presence of sodium hydroxide or potassium hydroxide at 80-100°C for at least 3 hours, wherein the molar ratio of the compound of formula (III) to formaldehyde is 1:2.2, and the molar ratio of the compound of formula (III) to sodium hydroxide / potassium hydroxide is 1:2.5. 2) A step of reacting a compound of formula (III) with a compound of formula (IV) in 2 mol / L oxalic acid at 100°C for at least 6 hours, wherein the molar ratio of compound of formula (IV) to compound of formula (III) is 1:2.2. 3) A step of reacting the compound of formula (II) with ethylene oxide in toluene at a temperature of 100°C and a pressure of 0.3 to 0.5 MPa for at least 5 hours, wherein the molar ratio of the compound of formula (II) to ethylene oxide is 1:28. Includes. [Effects of the Invention]

[0032] Beneficial effects of this disclosure

[0033] The novel method described herein has advantages such as ease of operation, mild reaction conditions, high purity of the reaction product, and high yield, making it beneficial for industrial production. [Modes for carrying out the invention]

[0034] definition

[0035] "Aprotic solvent" is a non-proton transfer solvent or These are also called non-protonic solvents. The autoprotonation reaction of such solvents is extremely weak, or they do not tend to undergo autoprotonation. Examples of non-protonic solvents include aprotic nonpolar solvents such as n-hexane, heptane, benzene, toluene, diethyl ether, and alkanes such as carbon tetrachloride, as well as amides, ketones, nitriles, dimethyl sulfoxide, pyridine, dichloromethane, N,N-dimethylformamide, and acetone. They can be divided into aprotic polar solvents and non-protic polar solvents.

[0036] "Acidic conditions" refer to conditions in which the pH of the system is less than 7, which are usually achieved by adding an acid. Examples of acids include organic acids and inorganic acids. Examples of organic acids include carboxylic acids (R-COOH), sulfonic acids (R-SO3H), sulfinic acids (R-SOOH), and thiocarboxylic acids (R- CO Examples include -SH), such as acetic acid, tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid, benzoic acid, and salicylic acid. Inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

[0037] "Alkaline conditions" refer to conditions in which the pH of the system is greater than 7, which are usually achieved by adding a base. Examples of bases include organic bases and inorganic bases. Examples of organic bases include amine compounds and nitrogen-containing heterocyclic compounds, as well as alkali metal salts of alcohols such as sodium methoxide, potassium ethoxide, and potassium tert-butoxide, alkyllithium compounds such as butyllithium and phenyllithium, and lithium amide compounds such as lithium diisopropylamide and lithium hexamethyldisilazide. Examples of inorganic bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, calcium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate.

[0038] The technical solutions of this disclosure are described below explicitly and completely with reference to examples. Obviously, the examples described are used only to illustrate this disclosure and do not limit it. All other examples that can be obtained by those skilled in the art without creative effort based on the examples of this disclosure are included within the scope of this disclosure.

[0039] The synthesis method for tyroxapole is as follows: [ka] In the formula, n is 6, 7, 8, 9, 10, 11, or 12; another option is n is 8, 9, or 10; yet another option is n is 9.

[0040] Step 1: Under alkaline conditions, the compound of formula (III) is reacted with formaldehyde to obtain the compound of formula (IV).

[0041] Step 2: Under acidic conditions, the compound of formula (IV) is reacted with the compound of formula (III) to obtain the compound of formula (II).

[0042] Step 3: The compound of formula (II) is reacted with ethylene oxide to obtain the compound of formula (I). [Examples]

[0043] Example 1 Synthesis of 2,5-dihydroxymethyl p-tert-octylphenol 103.0 g of p-tert-octylphenol and 33 g of formaldehyde were placed in a reaction bottle. 500 mL of water was added to the reaction bottle, and 50.0 g of sodium hydroxide was added to the reaction bottle in several portions. After the addition was complete, the temperature was raised to 100°C and the reactants were stirred for 3 hours. After the reaction was complete, the reaction solution was extracted with dichloromethane to obtain the organic phase. The organic phase was washed once each with clean water and saturated brine, and evaporated to dryness to obtain 117.6 g of yellow liquid in yield 88.4%. ESI-MS[M+H]+ = 267.5.

[0044] Test 1: Effects of different bases on the preparation of the compound of formula (IV)

[0045] Table 1: Investigation of the effects of different bases on the preparation of the compound of formula (IV) [Table 1]

[0046] Table 2: Results of the effects of different bases on the preparation of the compound of formula (IV) [Table 2]

[0047] If the alkalinity of the base used is weak, the reaction cannot proceed normally. Therefore, alkali metal hydroxides are used, and sodium hydroxide or potassium hydroxide can be used as alternatives.

[0048] Test 2: Effect of different reaction temperatures on the preparation of the compound of formula (IV)

[0049] Table 3: Investigation of the effect of different reaction temperatures on the preparation of the compound of formula (IV) [Table 3]

[0050] Table 4: Results of the effect of different reaction temperatures on the preparation of the compound of formula (IV) [Table 4]

[0051] The above test results demonstrate that a higher temperature is required for this reaction to proceed, and that if the temperature is too low, the reaction cannot be completed within the same amount of time. Therefore, the temperature to be selected should be 60°C or higher, with 80-100°C as an alternative option.

[0052] Test 3: Effect of formaldehyde supply ratio on the production of compound (IV)

[0053] Table 5: Examination of the effect of formaldehyde supply ratio on the production of the compound of formula (IV) [Table 5]

[0054] Table 6: Results of the effect of formaldehyde supply ratio on the production of the compound of formula (IV) [Table 6]

[0055] The above test results demonstrate that the amount of formaldehyde required for this reaction needs to be slightly more than twice the standard amount to ensure yield stability. However, further increasing the amount of formaldehyde does not significantly improve the yield. Therefore, the amount of formaldehyde to be selected should be more than twice the standard amount, another option being 2.1 to 5 times the standard amount, and yet another option being 2.1 to 2.3 times the standard amount.

[0056] Test 4: Effect of base supply ratio on the preparation of compound (IV)

[0057] Table 7: Examination of the effect of the base supply ratio on the production of the compound of formula (IV) [Table 7]

[0058] Table 8: Results of the effect of the base supply ratio on the preparation of the compound of formula (IV) [Table 8]

[0059] The above test results indicate that differences in the amount of base have little effect on the product yield. To ensure the completion of the reaction, it is determined that the molar ratio of compound to base in formula (III) should be less than 1:1, with alternatives of 1:2 to 1:4, 1:2 to 1:3, and 1:2.5.

[0060] Example 12 Synthesis of phenolic resins 66.5 g of 2,5-dihydroxymethyl p-tert-octylphenol and 113.3 g of p-tert-octylphenol were placed in a reaction bottle. 250 mL of purified water and 54 g of oxalic acid were added to the mixture. After the addition was complete, the temperature was raised to 100°C and the reaction mixture was stirred for 6 hours. After the reaction was complete, the pH was adjusted to 7-8 with a 1 mol / L sodium hydroxide aqueous solution. This aqueous solution was extracted with dichloromethane to obtain the organic phase. The organic phase was washed once each with clean water and saturated brine, and the organic phase was evaporated to dryness to obtain 127.7 g of dark yellow liquid in yield 79.6%. 1 H NMR(400MHz,CDCl3)δ7.77(s,2H),7.25(d,J=2.5Hz,3H),7.10-6.59(m,5H),3.89(d, J=12.5Hz,3H),1.67(d,J=5.4Hz,6H),1.31(d,J=5.6Hz,18H),0.68(d,J=5.9Hz,27H).

[0061] Test 5: Effect of supply ratio on the production of compound (II)

[0062] Table 9: Examination of the effect of supply ratio on the production of the compound of formula (II) [Table 9]

[0063] Table 10: Results of the effect of supply ratio on the production of compound (II) [Table 10]

[0064] The above test results indicate that raw materials remain when the supply ratio is 1:2. The supply ratio required for this reaction needs to be slightly more than twice the standard amount to ensure yield stability. However, further increasing the supply ratio does not significantly improve the yield. Therefore, it is appropriate to select a supply ratio of 2.1 to 2.3 times, such as 2.1, 2.2, or 2.3 times, as alternatives to more than twice the standard amount.

[0065] Test 6: Effects of different acids on the preparation of the compound of formula (II)

[0066] Table 11: Investigation of the effects of different acids on the preparation of the compound of formula (II) [Table 11]

[0067] Table 12: Different preparations for the compound of formula (II) Acid As a result of the effects [Table 12]

[0068] The above tests demonstrate that the reaction can proceed smoothly under acidic conditions, and that oxalic acid yields the best reaction results. Therefore, oxalic acid is preferred.

[0069] Test 7: Effect of reaction time on the preparation of compound (II)

[0070] Table 13: Investigation of the effect of reaction time on the preparation of compound (II) [Table 13]

[0071] Table 14: Results of the effect of reaction time on the preparation of compound (II) [Table 14]

[0072] The above tests demonstrate that the reaction can proceed smoothly when the reaction time is 5 hours or longer. The yield did not change significantly even when the reaction time was extended. Therefore, it is confirmed that to ensure the reaction proceeds completely, the reaction time should be at least 5 hours, 5-8 hours as an alternative option, at least 6 hours as another alternative option, and 6 hours as yet another alternative option.

[0073] Example 22 Method for synthesizing tyroxapole 80.0 g of phenolic resin and 400.0 mL of toluene were placed in a pressure-resistant reaction bottle. The reaction mixture was cooled to 0°C. 153.2 g of ethylene oxide was added to the reaction mixture, and the mixture was heated to 80-100°C in a sealed reaction bottle. At this point, the pressure in the reaction bottle was approximately 0.3-0.5 MPa. The reaction was carried out for 5 hours while maintaining this temperature. After the reaction was complete, the reaction solution was cooled to 0°C. 400 mL of water was added to the reaction solution, and the pH was adjusted to 9 with a 1 mol / L sodium hydroxide aqueous solution. The liquid was separated to obtain the organic phase. The organic phase was washed once each with water and saturated brine. The organic phase was collected, and the solvent was evaporated to dryness to obtain yellow oil. The obtained yellow oil was distilled under reduced pressure to obtain 76.0 g of pale yellow oil. This was obtained with a yield of 77.3% and a purity of 99.4%. 1H NMR(400MHz,DMSO-d6)δ7.54-6.41(m,8H),4.54(t,J=5.4Hz,3H),4.28-3.78(m,4H),3.69(ddt,J=14 .5,9.3,4.1Hz,10H),3.76-3.40(m,98H),1.92-1.45(m,6H),1.36-1.04(m,18H),0.88-0.27(m,27H).

[0074] Experiment 8: Searching for the molar ratio of compound (II) to ethylene oxide.

[0075] Table 15: Example of a test to explore the molar ratio of compound (II) to ethylene oxide. [Table 15]

[0076] Table 16: Results of searching for the molar ratio of compound (II) to ethylene oxide [Table 16]

[0077] The above test results demonstrate that the degree of polymerization of the compound can be controlled by the molar ratio of the compound to ethylene oxide in formula (II). Degree of polymerization n= To obtain product 9, the supply ratio for one option is 1:27 to 1:29, and for the other option it is 1:28.

[0078] Experiment 9: Exploration of reaction temperature

[0079] Table 17: Examples of reaction temperature exploration tests [Table 17]

[0080] Table 18: Results of reaction temperature exploration [Table 18]

[0081] The above test results indicate that all reactions can proceed normally. Therefore, it is confirmed that the temperature may be above 60°C (e.g., 60-120°C), or as an alternative, above 80°C (e.g., 80-100°C), or even as yet another option, 100°C.

[0082] Experiment 10: Exploration of reaction pressure

[0083] Table 19: Examples of tests for exploring reaction pressure [Table 19]

[0084] Table 20: Results of reaction pressure exploration [Table 20]

[0085] The results above demonstrate that the reaction must be carried out under pressure. Under normal pressure, only one ethylene oxide reacts, and polymerization cannot occur. Therefore, the reaction needs to be carried out under pressure. However, the higher the pressure, the greater the reaction risk. Through investigation, it was ultimately confirmed that the pressure can be 0.2–0.8 MPa, an alternative option of 0.3–0.8 MPa, and yet another option of 0.3–0.5 MPa.

[0086] While preferred embodiments and alternatives have been disclosed above, these are not intended to limit the scope of this disclosure. Anyone familiar with the art may make various changes and modifications without departing from the spirit and scope of this disclosure. Therefore, the scope of protection of this disclosure should be determined by the claims.

Claims

1. A method for producing the compound of formula (I), 【Chemistry 1】 The process includes a step of reacting the compound of formula (II) with ethylene oxide to obtain the compound of formula (I), In formula (I) above, n is 6, 7, 8 or 9, A method wherein the reaction is carried out at a temperature of 80 to 100°C and a pressure of 0.2 to 0.8 MPa.

2. The method according to claim 1, wherein the method satisfies one or more of the following conditions: (1) The molar ratio of the compound in formula (II) to ethylene oxide is between 1:19 and 1:37; (2) The reaction between the compound of formula (II) and ethylene oxide is carried out in an aprotic solvent; (3) The reaction is carried out at a pressure of 0.3 to 0.8 MPa; and (4) The reaction is carried out for at least 3 hours.

3. The method according to claim 1, which satisfies one or more of the following conditions: (1) The molar ratio of the compound in formula (II) to ethylene oxide is between 1:27 and 1:29; (2) The reaction between the compound of formula (II) and ethylene oxide is carried out in an alkane; (3) The reaction is carried out at a pressure of 0.3 to 0.5 MPa; and (4) The reaction is carried out for at least 5 hours.

4. The method according to claim 1, wherein the reaction is carried out in toluene at a temperature of 80 to 100°C and a pressure of 0.3 to 0.5 MPa for at least 5 hours, and the molar ratio of the compound of formula (II) to the ethylene oxide is 1:

28.

5. A method for producing the compound of formula (II), 【Chemistry 2】 The process includes a step of reacting the compound of formula (III) with the compound of formula (IV) under acidic conditions to obtain the compound of formula (II), A method wherein the above reaction is carried out in oxalic acid.

6. The method according to claim 5, wherein the method satisfies one or more of the following conditions: (1) The molar ratio of compound (IV) to compound (III) is less than 1:2; (2) The reaction is carried out at 80°C or higher; and (3) The reaction is carried out for at least 5 hours.

7. The method according to claim 5, which satisfies one or more of the following conditions: (1) The molar ratio of compound (IV) to compound (III) is 1:2.1 to 1:2.3; (2) The reaction is carried out at 80 to 100°C; and (3) The reaction is carried out for at least 6 hours.

8. The conditions for the above reaction are, 1) The reaction is carried out in oxalic acid at a temperature of 80°C or higher for at least 5 hours, in which case the molar ratio of compound (IV) to compound (III) is less than 1:2; 2) The reaction is carried out in 2 mol / L oxalic acid at 100°C for at least 6 hours, in which case the molar ratio of compound (IV) to compound (III) is 1:2.

2. The method according to claim 5, which is one of the methods.

9. A method for producing the compound of formula (I), 【Transformation 3】 In equation (I), n is 6, 7, 8, or 9. 1) A step of reacting a compound of formula (III) with formaldehyde in the presence of sodium hydroxide or potassium hydroxide at 80 to 100°C for at least 3 hours, wherein the molar ratio of compound of formula (III) to formaldehyde is 1:2.2, and the molar ratio of compound of formula (III) to sodium hydroxide / potassium hydroxide is 1:2.

5. 2) A step of reacting a compound of formula (III) with a compound of formula (IV) in 2 mol / L oxalic acid at 100°C for at least 6 hours, wherein the molar ratio of compound of formula (IV) to compound of formula (III) is 1:2.

2. 3) A step of reacting the compound of formula (II) with ethylene oxide in toluene at a temperature of 100°C and a pressure of 0.3 to 0.5 MPa for at least 5 hours, wherein the molar ratio of the compound of formula (II) to ethylene oxide is 1:

28. Methods that include...

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