Synthesis of tyloxapol
A controlled reaction process for tyloxapol synthesis addresses the challenge of high polymerization degrees by using alkaline conditions and aprotic solvents, achieving high purity and yield suitable for industrial applications.
Patent Information
- Application Number
- JP2024537936
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2022-12-12
- Filing Date
- 2022-12-20
- Publication Date
- 2025-01-22
- Estimated Expiration
- 2042-12-20
AI Technical Summary
Existing synthesis methods for tyloxapol produce polymers with a degree of polymerization greater than 6, requiring high temperatures and pressures, making them challenging for pilot facilities and industrial production.
A method involving controlled reactions of p-tert-octylphenol with formaldehyde under alkaline conditions, followed by reaction with ethylene oxide in aprotic solvents at specific molar ratios and pressures, to achieve a degree of polymerization of m=1.
The new method ensures high purity and yield, simplifying operations and making it suitable for industrial production.
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Abstract
Description
[Technical field]
[0001] The present disclosure is in the field of chemical synthesis, and in particular, relates to a method for the synthesis of tyloxapol. [Background technology]
[0002] Tyloxapol is a high molecular weight polymer (shown below) and a non-ionic liquid surfactant of the alkyl aromatic polyether alcohol type, where the hydrophobic aromatic groups increase the solubility of the molecule in oil, while the numerous hydrophilic groups, the ether alcohols, increase the solubility of the molecule in water. Therefore, tyloxapol is used as an emulsifier for water / oil and oil / water emulsions. [ka]
[0003] In addition to being used as an emulsifier for the preparation of emulsions, creams, and other formulations, tyloxapol is also widely used in the preparation of liquid formulations such as nasal drops, eye drops, and admixtures, and solid formulations such as tablets and pills, due to its good solubilizing and dispersing effects, which can shorten the disintegration time and improve the solubility in tablets.
[0004] As an active ingredient in antitussive and expectorant preparations, tyloxapol is used to reduce surface tension and liquefy mucus to facilitate the expulsion of phlegm. As an additive in preparations, tyloxapol also plays an emulsifying and penetration enhancing role. It has also been reported that tyloxapol is used in eye washes and has good decontamination and cleaning effects. The concentration used as a pharmaceutical additive should be determined according to the specific formulation, dosage form, and intended use. In general, the concentration when used is 0.1-0.5%.
[0005] At present, the synthesis process of tyloxapol is mainly as follows: 1) first, tert-octylphenol and ethylene oxide are reacted in the presence of sodium hydroxide at high temperature and pressure to produce polymerized phenol, and then the polymerized phenol is condensed with formaldehyde under heating conditions in the presence of an acid catalyst to prepare tyloxapol; 2) first, formaldehyde is polymerized with p-tert-octylphenol to obtain a phenolic resin with a suitable molecular weight, and then the suitable phenolic resin is reacted with ethylene oxide to synthesize tyloxapol. These two routes are prone to produce polymers with a degree of polymerization greater than 6 (pharmacopoeia standard is m<6) during phenolaldehyde polymerization, and require high temperature (greater than 160°C) vacuum distillation to keep the fraction at a certain temperature. This is a big challenge for pilot facilities and public projects.
[0006] Therefore, there is a need in the art for tyloxapol having a degree of polymerization m<6, particularly m=1, and a method for producing same. Summary of the Invention [Problem to be solved by the invention]
[0007] In view of the shortcomings of the above synthetic methods, the present disclosure proposes a new synthetic method to prepare tyloxapol with m = 1. The method disclosed herein is advantageous for industrial production because of its simple operation and the high purity of the obtained product. [Means for solving the problem]
[0008] Specifically, the present disclosure relates to the following technical solutions:
[0009] 1. A compound of formula (I), [ka] wherein n is 6, 7, 8, 9, 10, 11, or 12; alternatively, n is 8, 9, or 10; and alternatively, n is 9.
[0010] 2. A method for preparing the compound of formula (I) of embodiment 1, comprising the steps of: [ka] reacting a compound of formula (II) with ethylene oxide to obtain a compound of formula (I).
[0011] 3. The method of embodiment 2, wherein the molar ratio of the compound of formula (II) to ethylene oxide is from 1:19 to 1:37, alternatively from 1:25 to 1:32, alternatively from 1:27 to 1:29, and further alternatively 1:28.
[0012] 4. The reaction of the compound of formula (II) with ethylene oxide is carried out in an aprotic solvent, alternatively in an aprotic non-polar solvent, alternatively the solvent is n-hexane. 4. The method of embodiment 2 or 3, wherein the alkane is an alkane, such as xane, heptane, benzene, and toluene, and alternatively toluene.
[0013] 5. The method of any one of embodiments 2-4, wherein the reaction is carried out at a temperature of 60° C. or higher (such as 60-120° C.), alternatively at a temperature of 80° C. or higher (such as 80-100° C.), and alternatively at a temperature of 100° C.
[0014] 6. The method of any one of embodiments 2 to 5, wherein the reaction is carried out at a pressure of 0.2 to 0.8 MPa, alternatively at a pressure of 0.3 to 0.8 MPa, and alternatively at a pressure of 0.3 to 0.5 MPa.
[0015] 7. The method of any one of embodiments 2-6, wherein the reaction is carried out for at least 3 hours, alternatively at least 5 hours.
[0016] 8. The method of any one of embodiments 2 to 7, wherein the reaction is carried out in toluene at a temperature of 80-100° C. and a pressure of 0.3-0.5 MPa for at least 5 hours, and the molar ratio of the compound of formula (II) to ethylene oxide is 1:28.
[0017] 9. A compound of formula (II). [ka]
[0018] 10. A method for preparing a compound of formula (II), comprising the steps of: [ka] The method comprises reacting a compound of formula (III) with a compound of formula (IV) under acidic conditions to obtain a compound of formula (II).
[0019] 11. The molar ratio of the compound of formula (IV) to the compound of formula (III) is less than 1:2, alternatively The method of embodiment 10, wherein the ratio is 1:2.1 to 1:3, and alternatively 1:2.1 to 1:2.3, such as 1:2.1, 1:2.2, or 1:2.3.
[0020] 12. The method of embodiment 10 or 11, wherein the reaction is carried out in oxalic acid, acetic acid, sulfuric acid, or hydrochloric acid, alternatively in oxalic acid.
[0021] 13. The method of any one of embodiments 10-12, wherein the reaction is carried out at a temperature above 80°C, alternatively between 80 and 100°C, and still alternatively at 100°C.
[0022] 14. The method of any one of embodiments 10-13, wherein the reaction is carried out for at least 5 hours, alternatively 5-8 hours, alternatively at least 6 hours, and yet alternatively 6 hours.
[0023] 15. The method of any one of embodiments 10 to 14, wherein the reaction conditions are one of the following: 1) reacting 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, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is less than 1:2. 2) reacting in glacial acetic acid at 100° C. for at least 6 hours, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2. 3) reacting in 2 mol / L sulfuric acid at 100° C. for at least 6 hours, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2. 4) reacting in 2 mol / L oxalic acid at 100° C. for at least 6 hours, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2. 5) reacting in 32% hydrochloric acid at 100° C. for at least 6 hours, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2.
[0024] 16. A method for preparing a compound of formula (IV), comprising the steps of: [ka] The method comprises reacting a compound of formula (III) with formaldehyde under alkaline conditions to obtain a compound of formula (IV).
[0025] 17. The method of embodiment 16, wherein the molar ratio of the compound of formula (III) to formaldehyde is less than 1:2, alternatively from 1:2.1 to 1:5, and alternatively from 1:2.1 to 1:2.3, such as 1:2.1, 1:2.2, or 1:2.3.
[0026] 18. The method of embodiment 16 or 17, wherein the molar ratio of the compound of formula (III) to the base is less than 1:1, alternatively from 1:2 to 1:4, alternatively from 1:2 to 1:3, and further alternatively 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, alternatively in the presence of an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.
[0028] 20. The method of any one of embodiments 16 to 19, wherein the reaction is carried out at a temperature of 60° C. or higher, alternatively at a temperature of 80 to 100° C.
[0029] 21. The method of any one of embodiments 16-20, wherein the reaction is carried out for at least 2 hours, alternatively at least 3 hours, alternatively at least 4 hours.
[0030] 22. The method of any one of embodiments 16 to 20, wherein the reaction conditions are one of the following: 1) reacting in the presence of an inorganic base (alternatively an alkali metal hydroxide) at 60° C. or higher for at least 3 hours, wherein 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) reacting in the presence of potassium hydroxide at 80-100°C for at least 3 hours, in which 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 potassium hydroxide is 1:2.5. 3) reacting in the presence of sodium hydroxide at 80-100°C for at least 3 hours, in which 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 is 1:2.5.
[0031] 23. A method for preparing a compound of formula (I), comprising the steps of: [ka] 1) 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) reacting the compound of formula (III) with the compound of formula (IV) in 2 mol / L oxalic acid at 100° C. for at least 6 hours, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2; 3) reacting the compound of formula (II) with ethylene oxide in toluene at a temperature of 100° C. and a pressure of 0.3-0.5 MPa for at least 5 hours, the molar ratio of the compound of formula (II) to ethylene oxide being 1:28; Includes. Effect of the Invention
[0032] Beneficial Effects of the Present Disclosure
[0033] The new method disclosed herein has the advantages of simple operation, mild reaction conditions, high purity of the reaction product, high yield, etc., which is beneficial for industrial production. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0034] definition
[0035] "Aprotic solvent" means a non-proton transfer solvent or These solvents are also called aprotic solvents. The autoprotolysis reaction of such solvents is very weak or they have no tendency to autoprotolysis. Aprotic solvents are classified as aprotic nonpolar solvents such as alkanes, such as n-hexane, heptane, benzene, toluene, diethyl ether, and carbon tetrachloride, and nonpolar solvents such as amides, ketones, nitriles, dimethyl sulfoxide, pyridine, dichloromethane, N,N-dimethylformamide, and acetone. They can be divided into aprotic polar solvents and aprotic polar solvents.
[0036] "Acidic conditions" refers to conditions in which the pH of the system is less than 7, which is usually achieved by adding an acid. Acids include organic acids and inorganic acids. Organic acids include carboxylic acids (R-COOH), sulfonic acids (R-SO 3 Examples of the acid radicals include acetic acid, tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid, benzoic acid, and salicylic acid. Examples of the inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.
[0037] "Alkaline conditions" refers to conditions in which the pH of the system is greater than 7, which is usually achieved by adding a base. Examples of bases include organic bases and inorganic bases, and examples of organic bases include amine compounds and nitrogen-containing heterocyclic compounds, as well as common organic bases such as alkali metal salts of alcohols such as sodium methoxide, potassium ethoxide, and potassium tert-butoxide, alkyl lithium compounds such as butyl lithium and phenyl lithium, and lithium amide compounds such as lithium diisopropylamide and lithium hexamethyldisilazide, and 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, cesium bicarbonate, and the like.
[0038] The technical solutions of the present disclosure are clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only used to illustrate the present disclosure, and do not limit the present disclosure. Based on the embodiments of the present disclosure, all other embodiments obtained by those skilled in the art without creative efforts are included in the protection scope of the present disclosure.
[0039] The synthesis of tyloxapol is as follows: [ka] wherein n is 6, 7, 8, 9, 10, 11, or 12; alternatively, n is 8, 9, or 10; and alternatively, n is 9.
[0040] Step 1: A compound of formula (III) is reacted with formaldehyde under alkaline conditions to give a compound of formula (IV).
[0041] Step 2: The compound of formula (IV) is reacted with the compound of formula (III) under acidic conditions to give the compound of formula (II).
[0042] Step 3: The compound of formula (II) is reacted with ethylene oxide to give the compound of formula (I). EXAMPLES
[0043] Example 1 Synthesis of 2,5-dihydroxymethyl p-tert-octylphenol 103.0g of p-tert-octylphenol and 33g of formaldehyde were added to the reaction bottle. 500mL of water was added to the reaction bottle, and 50.0g of sodium hydroxide was added to the reaction bottle in several portions. After the addition was completed, the temperature was raised to 100°C, and the reaction was stirred for 3 hours. After the reaction was completed, the reaction solution was extracted with dichloromethane to obtain an organic phase. The organic phase was washed once each with clean water and saturated saline, and evaporated to dryness to obtain 117.6g of a yellow liquid with a yield of 88.4%. ESI-MS [M+H] +=267.5.
[0044] Test 1: Effect of different bases on the preparation of the compound of formula (IV)
[0045] Table 1: Study of the effect of different bases on the preparation of compound of formula (IV) [Table 1]
[0046] Table 2: Results of the effect 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, an alkali metal hydroxide, alternatively sodium hydroxide or potassium hydroxide, can be used.
[0048] Test 2: Effect of different reaction temperatures on the preparation of compound of formula (IV)
[0049] Table 3: Study of the effect of different reaction temperatures on the preparation of compound of formula (IV) [Table 3]
[0050] Table 4: Results of the effect of different reaction temperatures on the preparation of compound of formula (IV) [Table 4]
[0051] The above test results prove that a higher temperature is required to make this reaction proceed, and if the temperature is too low, the reaction cannot proceed completely within the same time. Therefore, the temperature selected should be above 60°C, with another option being 80-100°C.
[0052] Test 3: Effect of formaldehyde feed ratio on the production of the compound of formula (IV)
[0053] Table 5: Study of the effect of formaldehyde feed ratio on the production of compound of formula (IV) [Table 5]
[0054] Table 6: Results of the effect of the feed ratio of formaldehyde on the production of the compound of formula (IV) [Table 6]
[0055] The above test results prove that the amount of formaldehyde required for this reaction should be slightly more than twice the standard amount to ensure the stability of the yield. However, further increasing the amount of formaldehyde cannot significantly improve the yield. Therefore, the amount of formaldehyde selected should be more than twice, another option is 2.1-5 times, and yet another option is 2.1-2.3 times.
[0056] Test 4: Effect of base feed ratio on the preparation of compound of formula (IV)
[0057] Table 7: Study of the effect of base feed ratio on the production of compound of formula (IV) [Table 7]
[0058] Table 8: Results of the effect of the base feed ratio on the preparation of the compound of formula (IV) [Table 8]
[0059] The above test results show that the amount of base has little effect on the product yield. It is determined that the molar ratio of the compound of formula (III) to the base should be less than 1:1, alternatively 1:2-1:4, alternatively 1:2-1:3, and alternatively 1:2.5 to ensure the reaction is complete.
[0060] Example 12 Synthesis of phenolic resin 66.5g of 2,5-dihydroxymethyl p-tert-octylphenol and 113.3g of p-tert-octylphenol were placed in a reaction bottle. 250mL of purified water and 54g of oxalic acid were added to the mixture. After the addition was completed, the temperature was raised to 100°C and the reaction was stirred for 6 hours. After the reaction was completed, the pH was adjusted to 7-8 with 1mol / L aqueous sodium hydroxide solution. The aqueous solution was extracted with dichloromethane to obtain an organic phase. The organic phase was washed once each with clean water and saturated saline, and the organic phase was evaporated to dryness to obtain 127.7g of a dark yellow liquid with a yield of 79.6%. 1 H NMR (400 MHz, CDCl 3 )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 Feed Ratio on the Production of Compound of Formula (II)
[0062] Table 9: Study of the effect of feed ratio on the production of compound of formula (II) [Table 9]
[0063] Table 10: Results of the effect of feed ratio on the production of the compound of formula (II) [Table 10]
[0064] The above test results show that when the feed ratio is 1:2, the raw material remains. The feed ratio required for this reaction needs to be slightly more than twice the standard amount to ensure the stability of the yield. However, further increasing the feed ratio cannot improve the yield significantly. Therefore, it is appropriate to select a feed ratio of 2.1-2.3 times, such as 2.1 times, 2.2 times, or 2.3 times, which is more than 2 times, another option is 2.1-3 times, and still another option is 2.1 times, 2.2 times, or 2.3 times.
[0065] Test 6: Effect of different acids on the preparation of the compound of formula (II)
[0066] Table 11: Study of the effect of different acids on the preparation of compound of formula (II) [Table 11]
[0067] Table 12: Results of the effect of different acid ratios on the preparation of compounds of formula (II) [Table 12]
[0068] The above test proves that the reaction can proceed smoothly under acidic conditions, and the reaction result of oxalic acid is the best, therefore, oxalic acid is preferred.
[0069] Test 7: Effect of reaction time on the preparation of the compound of formula (II)
[0070] Table 13: Study of the effect of reaction time on the preparation of compound of formula (II) [Table 13]
[0071] Table 14: Results of the effect of reaction time on the preparation of compounds of formula (II) [Table 14]
[0072] The above test proves that the reaction can proceed smoothly when the reaction time is 5 hours or more. The yield does not change significantly after the reaction time is increased. Therefore, it is confirmed that the reaction time should be at least 5 hours, another option is 5-8 hours, another option is at least 6 hours, and still another option is 6 hours to ensure the reaction proceeds completely.
[0073] Example 22 Method for synthesizing tyloxapol 80.0 g of phenolic resin and 400.0 mL of toluene were placed in a pressure-resistant reaction bottle. The reaction product was cooled to 0°C. 153.2 g of ethylene oxide was added to the reaction product, and the reaction product was heated to 80-100°C in a sealed reaction bottle. At this point, the pressure in the reaction bottle was about 0.3-0.5 MPa. The reaction was carried out for 5 hours while maintaining this temperature. After the reaction was completed, 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 1 mol / L aqueous sodium hydroxide solution. The liquid was separated to obtain an organic phase. The organic phase was washed once each with water and saturated saline. The organic phase was collected, and the solvent was evaporated to dryness to obtain a yellow oil. The obtained yellow oil was distilled under reduced pressure to obtain 76.0 g of a pale yellow oil. was obtained in 77.3% yield and 99.4% purity. 1 H NMR (400MHz, DMSO-d 6)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] Test 8: Search for the molar ratio of compound of formula (II) to ethylene oxide
[0075] Table 15: Test examples for exploring the molar ratio of the compound of formula (II) to ethylene oxide [Table 15]
[0076] Table 16: Results of molar ratio search of compound of formula (II) to ethylene oxide [Table 16]
[0077] The above test results prove that the degree of polymerization of the compound can be controlled by the molar ratio of the compound of formula (II) to ethylene oxide. To obtain a product with a degree of polymerization of 9, the feed ratio is optionally 1:27 to 1:29, and alternatively 1:28.
[0078] Test 9: Searching for reaction temperature
[0079] Table 17: Test examples for reaction temperature exploration [Table 17]
[0080] Table 18: Reaction temperature survey results [Table 18]
[0081] The above test results show that all reactions can proceed normally. Therefore, it is confirmed that the temperature may be higher than 60°C (e.g., 60-120°C), alternatively higher than 80°C (e.g., 80-100°C), or even alternatively 100°C.
[0082] Test 10: Search for reaction pressure
[0083] Table 19: Test examples for reaction pressure exploration [Table 19]
[0084] Table 20: Reaction pressure search results [Table 20]
[0085] The above results prove that the reaction needs to be carried out under pressure. Under normal pressure, only one ethylene oxide can react and cannot polymerize. Therefore, the reaction needs to be pressurized. However, the higher the pressure, the greater the reaction risk. Through the study, it is finally confirmed that the pressure can be 0.2-0.8MPa, another option is 0.3-0.8MPa, and yet another option is 0.3-0.5MPa.
[0086] Although the present disclosure has been disclosed above with respect to preferred embodiments and alternative examples, they are not intended to limit the present disclosure. Anyone familiar with the present technology can make various changes and modifications without departing from the spirit and scope of the present disclosure. Therefore, the protection scope of the present disclosure should be determined by the claims.
Claims
1. A compound of formula (I) 【Chemistry 1】 A compound of formula (I) wherein n is 6, 7, 8, 9, 10, 11, or 12; alternatively, n is 8, 9, or 10; and alternatively, n is 9.
2. A method for preparing a compound of formula (I) according to claim 1, comprising the steps of: 【Chemistry 2】 A process comprising the step of reacting a compound of formula (II) with ethylene oxide to obtain a compound of formula (I).
3. 3. The process of claim 2, wherein the molar ratio of the compound of formula (II) to ethylene oxide is from 1:19 to 1:37, alternatively from 1:25 to 1:32, alternatively from 1:27 to 1:29, and further alternatively 1:
28.
4. 4. The process according to claim 2 or 3, wherein the reaction of the compound of formula (II) with ethylene oxide is carried out in an aprotic solvent, alternatively in an aprotic non-polar solvent, alternatively the solvent is an alkane such as n-hexane, heptane, benzene and toluene, and yet alternatively toluene.
5. 5. The method of any one of claims 2 to 4, wherein the reaction is carried out at a temperature of 60°C or higher (such as 60-120°C), alternatively at a temperature of 80°C or higher (such as 80-100°C), yet alternatively at a temperature of 100°C.
6. 6. The method of any one of claims 2 to 5, wherein the reaction is carried out at a pressure of 0.2 to 0.8 MPa, alternatively at a pressure of 0.3 to 0.8 MPa, and alternatively at a pressure of 0.3 to 0.5 MPa.
7. The method of any one of claims 2 to 6, wherein the reaction is carried out for at least 3 hours, alternatively at least 5 hours.
8. 8. The process according to any one of claims 2 to 7, wherein the reaction is carried out in toluene at a temperature of 80-100°C and a pressure of 0.3-0.5 MPa for at least 5 hours, and the molar ratio of the compound of formula (II) to the ethylene oxide is 1:
28.
9. A compound of formula (II). 【Chemistry 3】
10. A process for preparing a compound of formula (II), comprising the steps of: 【Chemistry 4】 A process comprising reacting a compound of formula (III) with a compound of formula (IV) under acidic conditions to obtain a compound of formula (II).
11. 11. The method of claim 10, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is less than 1:2, alternatively from 1:2.1 to 1:3, and alternatively from 1:2.1 to 1:2.3, such as 1:2.1, 1:2.2, or 1:2.
3.
12. 12. The method of claim 10 or 11, wherein the reaction is carried out in oxalic acid, acetic acid, sulfuric acid, or hydrochloric acid, alternatively in oxalic acid.
13. The method of any one of claims 10 to 12, wherein the reaction is carried out at 80°C or above, alternatively 80-100°C, and yet alternatively 100°C.
14. 14. The method of any one of claims 10 to 13, wherein the reaction is carried out for at least 5 hours, alternatively 5 to 8 hours, alternatively at least 6 hours, and yet alternatively 6 hours.
15. The reaction conditions are 1) reacting 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, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is less than 1:2; 2) reacting in glacial acetic acid at 100° C. for at least 6 hours, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2; 3) reacting in 2 mol / L sulfuric acid at 100° C. for at least 6 hours, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2; 4) reacting in 2 mol / L oxalic acid at 100° C. for at least 6 hours, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2; 5) reacting in 32% hydrochloric acid at 100° C. for at least 6 hours, where the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2; The method according to any one of claims 10 to 14, wherein the method is one of
16. A process for preparing a compound of formula (IV), comprising the steps of: 【Chemistry 5】 A process comprising reacting a compound of formula (III) with formaldehyde under alkaline conditions to obtain a compound of formula (IV).
17. 17. The method of claim 16, wherein the molar ratio of the compound of formula (III) to formaldehyde is less than 1:2, alternatively from 1:2.1 to 1:5, and alternatively from 1:2.1 to 1:2.3, such as 1:2.1, 1:2.2, or 1:2.
3.
18. 18. The method of claim 16 or 17, wherein the molar ratio of the compound of formula (III) to the base is less than 1:1, alternatively from 1:2 to 1:4, alternatively from 1:2 to 1:3, and further alternatively 1:2.
5.
19. The reaction is carried out in the presence of an inorganic base, alternatively lithium hydroxide, sodium hydroxide, 19. The process according to any one of claims 16 to 18, wherein the process is carried out in the presence of an alkali metal hydroxide, such as ammonium hydroxide or potassium hydroxide.
20. The process according to any one of claims 16 to 19, wherein the reaction is carried out at a temperature of at least 60°C, alternatively at a temperature of 80 to 100°C.
21. The method of any one of claims 16 to 20, wherein the reaction is carried out for at least 2 hours, alternatively at least 3 hours, alternatively at least 4 hours.
22. The reaction conditions are 1) reacting in the presence of an inorganic base (alternatively an alkali metal hydroxide) at 60° C. or higher for at least 3 hours, wherein 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) reacting in the presence of potassium hydroxide at 80-100° C. for at least 3 hours, in which 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 potassium hydroxide is 1:2.5; 3) reacting in the presence of sodium hydroxide at 80-100° C. for at least 3 hours, in which 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 is 1:2.5; The method according to any one of claims 16 to 20, wherein the method is one of
23. A process for preparing a compound of formula (I), comprising the steps of: 【Chemistry 6】 1) 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, 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) reacting the compound of formula (III) with the compound of formula (IV) in 2 mol / L oxalic acid at 100° C. for at least 6 hours, wherein the molar ratio of the compound of formula (IV) to the compound of formula (III) is 1:2.2; 3) reacting the compound of formula (II) with ethylene oxide in toluene at a temperature of 100° C. and a pressure of 0.3-0.5 MPa for at least 5 hours, wherein the molar ratio of the compound of formula (II) to ethylene oxide is 1:28; A method comprising: