Method for subjecting an alcoholic hydroxyl group donor and an active hydrogen donor to a Mitsunobu reaction

Abstract

The method for subjecting an alcoholic hydroxyl group donor and an active hydrogen donor to a Mitsunobu reaction specifically includes a step of reacting the alcoholic hydroxyl group donor, the active hydrogen donor, a trihydrocarbylphosphine reagent, and an azodicarboxylic acid ester reagent in the presence of an organic solvent, wherein the organic solvent is a linear or branched alkane containing 8 to 16 carbon atoms.

Description

[Technical field]

[0001] The present application belongs to the field of organic synthesis and relates to a method for subjecting an alcoholic hydroxyl donor and an active hydrogen donor to the Mitsunobu reaction. [Background technology]

[0002] The Mitsunobu reaction is an organic reaction with important applications that was invented in 1967 by the Japanese organic chemist Mitsunobu Ohyo. It is an intramolecular or intermolecular dehydration reaction that occurs between an alcohol and an acidic nucleophile precursor in the presence of a trihydrocarbylphosphine and an azodicarboxylate. The reaction mechanism is generally as follows (taking triphenylphosphine and diethyl azodicarboxylate as reactant reagents and a chiral alcohol as the alcohol as an example): Triphenylphosphine and diethyl azodicarboxylate form an adduct, the proton of the nucleophile is abstracted, the alcohol is activated by binding with triphenylphosphine, and the nucleophile is converted to S. N Two reactions occur to obtain products, and the reaction equation is as follows: [ka]

[0003] The Mitsunobu reaction is generally carried out under mild neutral conditions. When chiral alcohols participate in the reaction, the configuration of the carbon atom connected to the alcoholic hydroxyl group is generally inverted, and various chemical bonds, such as CO, CN, CS and CC, can be formed, so the Mitsunobu reaction is widely applied to the total synthesis of various natural products or functional group transformation of compounds.

[0004] Since Mitsunobu reaction is a dehydration condensation process, the water content in the reaction system must be controlled to avoid the loss of trihydrocarbylphosphine and azodicarboxylic acid ester. In such a reaction, an anhydrous aprotic solvent is generally used as the medium, such as toluene, tetrahydrofuran, ethyl-t-butyl ether, ethyl acetate, acetonitrile, dimethylformamide, dimethylacetamide, dichloromethane, etc. Such aprotic solvents have low flash points, strong odors, are difficult to recover, and do not fit the current trend of environmentally friendly chemistry. In addition, such solvents generally have a large impact on product distribution, yield and post-treatment, so the optimization and selection of Mitsunobu reaction conditions are currently a research hotspot in the field of environmentally friendly chemistry.

[0005] As can be seen from the above reaction mechanism, in the Mitsunobu reaction, azodicarboxylate esters are finally converted into dicarboxylate hydrazines. [ka] The dicarboxylic acid hydrazine further reacts with the hydroxyl group released from the alcoholic hydroxyl donor to give the following by-product: [ka] R represents a group resulting from the hydroxyl group removal from an alcoholic hydroxyl donor.

[0006] The above by-products have high polarity and are difficult to remove using conventional post-treatment methods. This leads to high purification costs for the final product, significantly increasing the amount of waste liquid, waste gas and solid waste generated and production costs, and affecting the purity of the final product and its subsequent applications.

[0007] Therefore, there is a need in this field for an environmentally friendly method that can reduce the production of dicarboxylic acid hydrazine by-products, and achieve a high yield in the Mitsunobu reaction. Summary of the Invention [Problem to be solved by the invention]

[0008] The present application aims to provide a method for the Mitsunobu reaction of an alcoholic hydroxyl donor with an active hydrogen donor. The method of the present application can solve the problems of the Mitsunobu reaction in the prior art, such as the difficulty in removing by-products, the large amount of waste liquid, waste gas and solid waste in post-treatment, and the low purity of the product, and can effectively reduce the production of dicarboxylic acid hydrazine by-products, and the target product can be more easily separated from the reaction system, resulting in a high reaction yield, easy post-treatment, high product purity, no impact on subsequent applications, and environmentally friendly. [Means for solving the problem]

[0009] To achieve this objective, the present application employs the following technical means. In one embodiment, the present invention provides a method for subjecting an alcoholic hydroxyl donor and an active hydrogen donor to a Mitsunobu reaction, the method comprising the steps of: The method includes the steps of reacting an alcoholic hydroxyl donor, an active hydrogen donor, a trihydrocarbylphosphine reagent, and an azodicarboxylate reagent in the presence of an organic solvent to obtain a product obtained by dehydration condensation of the alcoholic hydroxyl donor and the active hydrogen donor, The organic solvent is a straight-chain or branched-chain alkane containing 8 to 16 carbon atoms (eg, a C8, C10, C12, C14, or C16 normal or isoalkane).

[0010] In the present application, the product obtained by dehydration condensation of the alcoholic hydroxyl donor and the active hydrogen donor may be any one of ethers, thioethers, esters, thioesters, amines, and amides.

[0011] In the present invention, by optimizing the reaction solvent system, the production of dicarboxylic acid hydrazine by-products can be effectively reduced, and the target product can be more easily separated from the reaction system, with a high reaction yield, easy post-treatment, and high product purity.

[0012] In some embodiments of the present application, the organic solvent is any one or a combination of at least two of isodecane, isododecane, dodecane, or isopentadecane. Preferably, the organic solvent is isododecane.

[0013] In some embodiments of the present application, the alcoholic hydroxyl group donor is an organic substance containing an alcoholic hydroxyl group, and the alcoholic hydroxyl group may be bonded to at least one type of group or a combination structure of groups selected from the group consisting of a substituted or unsubstituted linear alkyl group, a substituted or unsubstituted branched alkyl group, a substituted or unsubstituted cyclic alkyl group, a substituted or unsubstituted aromatic group, and the like.

[0014] In some embodiments of the present application, the active hydrogen donor is an organic substance containing an active hydrogen group, and the active hydrogen group is any one or a combination of at least two selected from -OH, -SH, -COOH, -COSH, -NH2, and -CONH2, and the active hydrogen group may be bonded to at least one group or a combination structure of groups selected from a substituted or unsubstituted C1 to C12 linear alkyl group, a substituted or unsubstituted C1 to C12 branched alkyl group, a substituted or unsubstituted C3 to C12 cyclic alkyl group, and a substituted or unsubstituted C6 to C12 aromatic group.

[0015] In some embodiments of the present application, the C1 to C12 alkyl group may be, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group, an isopentyl group, an n-hexyl group, an isohexyl group, or the like, and the C3 to C12 cyclic alkyl group may be, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or the like. Of the C1 to C12 alkyl groups and the C3 to C12 cyclic alkyl groups, one or at least two -CH2- are independently substituted with any one of -O-, -S-, -CO-, -CS-, -CH=CH- or -C≡C-; for example, one or at least two -CH2- may be independently substituted with any one of -O-, -S-, -CO-, -CS-, -CH=CH- or -C≡C-, or -CH2- may not be substituted; for example, an ethyl group in which one -CH2- is substituted with -O- is a methoxy group, and by this analogy, further explanation will be omitted. The C6-C12 aromatic cyclic hydrocarbon group may be, for example, a phenyl group, a substituted group, or a naphthyl group, and preferably, one or at least two -CH= of the C6-C12 aromatic cyclic hydrocarbon group are independently substituted with -N=, for example, one or at least two -CH= may be independently substituted with -N= (such as a pyridyl group, a pyrimidyl group), or -CH= may be unsubstituted, and preferably, one or at least two -H of the aromatic cyclic hydrocarbon group are independently substituted with a halogen, -CN, a C1-C5 alkyl group, or a C1-C5 alkoxy group, for example, one or at least two -H may be independently substituted with a halogen, -CN, a C1-C5 alkyl group, or a C1-C5 alkoxy group, or -H may be unsubstituted.

[0016] In some embodiments of the present application, the trihydrocarbylphosphine reagent is any one or a combination of at least two selected from triphenylphosphine, tributylphosphine, or trimethylphosphine.

[0017] In some embodiments of the present application, the azodicarboxylate reagent is any one or a combination of at least two selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, bis(2-methoxyethyl)azodicarboxylate, and bis(4-chlorobenzyl)azodicarboxylate.

[0018] In some embodiments of the present application, the molar ratio of the alcoholic hydroxyl donor to the active hydrogen donor is 1:1 to 1.2, for example, 1:1, 1:1.05, 1:1.1, 1:1.15, or 1:1.2.

[0019] In some embodiments of the present application, the molar ratio of the alcoholic hydroxyl donor to the trihydrocarbylphosphine reagent is 1:1.05 to 1.3, for example, 1:1.05, 1:1.08, 1:1.1, 1:1.15, 1:1.2, 1:1.25, or 1:1.3.

[0020] In some embodiments of the present application, the molar ratio of the alcoholic hydroxyl donor to the azodicarboxylate reagent is 1:1.05 to 1.3, for example, 1:1.05, 1:1.08, 1:1.1, 1:1.15, 1:1.2, 1:1.25, or 1:1.3.

[0021] In some embodiments of the present application, the reaction temperature is 30 to 120°C (e.g., 30°C, 50°C, 80°C, 100°C, 110°C, or 120°C), and the reaction time is 1 to 12 hours (e.g., 1 hour, 3 hours, 5 hours, 7 hours, 9 hours, 10 hours, 11 hours, or 12 hours).

[0022] In some embodiments of the present application, the order of addition of the raw materials for the reaction according to the present application is to slowly dropwise add the azodicarboxylate to an organic solvent containing the alcoholic hydroxyl donor, the active hydrogen donor, and the trihydrocarbyl phosphine reagent, or to mix the azodicarboxylate and the trihydrocarbyl phosphine reagent and then add the alcoholic hydroxyl donor and the active hydrogen donor to the mixture.

[0023] In some embodiments of the present application, the temperature is controlled to 30 to 120°C, for example, 30°C, 50°C, 80°C, 100°C, 110°C, or 120°C, during the dropping process.

[0024] In some embodiments of the present application, the reaction, including the raw material mixing process and the reaction process, is carried out under the protection of an inert gas.

[0025] In some embodiments of the present application, the reaction may be accelerated by adding ultrasound, microwaves or an organic base (such as triethylamine).

[0026] As a preferred technical solution of the present application, the method specifically comprises: The method includes a step of reacting an alcoholic hydroxyl donor, an active hydrogen donor, a trihydrocarbylphosphine reagent, and an azodicarboxylate reagent in the presence of an organic solvent at 30 to 120° C. for 1 to 12 hours; The organic solvent is a linear or branched alkane containing 8 to 16 carbon atoms; The molar ratio of the alcoholic hydroxyl donor to the active hydrogen donor is 1:1 to 1.2, the molar ratio of the alcoholic hydroxyl donor to the trihydrocarbylphosphine reagent is 1:1.05 to 1.3, and the molar ratio of the alcoholic hydroxyl donor to the azodicarboxylate reagent is 1:1.05 to 1.3. Effect of the Invention

[0027] Compared with the prior art, the present application has the following beneficial effects: 1. Compared with the conventional anhydrous aprotic solvent, the present application uses higher saturated alkanes, which can effectively reduce the production of reaction by-products, and the purity of the product is higher, without affecting the subsequent application of the product. 2. The product of the present invention can be more easily separated from the reaction system, reducing the economic and time costs of post-treatment; 3. The solvent used in this application has the characteristics of high flash point and no odor, which further meets the requirements of low danger and environmental friendliness.

[0028] Therefore, the present invention is useful for realizing industrialized production by using an environmentally friendly method of subjecting an alcoholic hydroxyl group donor and an active hydrogen donor to the Mitsunobu reaction, and has extremely high industrial utility value. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] The technical solution of the present application will be further described below through specific embodiments. Those skilled in the art should understand that the above examples are only for understanding the present application, and should not be considered as specifically limiting the present application.

[0030] In the following examples and comparative examples, all relevant reagents are commercially available, the GC tester is an Agilent 7820A gas chromatograph, the MS tester is an Agilent 7890B-5977A mass spectrometer, and the HPLC tester is a Shimadzu LC-20AB high performance liquid chromatograph.

[0031] [Example 1] [ka] In a 500mL three-neck flask, 30g of (4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 23g of 4-ethoxy-2,3-difluorophenol, 35.31g of triphenylphosphine and 180mL of isodecane were added, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 28g of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the above solution, and after the addition was completed, the temperature was raised to 80°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 38.4g of white solid was obtained, the GC was 85.4%, and the yield was 77%.

[0032] The MS data for compound A were 55 (5%), 69 (5%), 95 (5%), 146 (25%), 174 (50%), 220 (5%), and 394 (5%).

[0033] The reaction formulas in the following Examples 2 to 4 and Comparative Examples 1 and 2 are the same as those in Example 1, and only the specific reaction conditions were changed.

[0034] [Example 2] In a 500mL three-neck flask, 30g of (4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 23g of 4-ethoxy-2,3-difluorophenol, 35.31g of triphenylphosphine and 180mL of isododecane were added, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 28g of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the above solution, and after the addition was completed, the temperature was raised to 80°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 43.1g of white solid was obtained, the GC was 97.3%, and the yield was 86.8%.

[0035] [Example 3] 30g of (4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 23g of 4-ethoxy-2,3-difluorophenol, 35.31g of triphenylphosphine and 180mL of dodecane were added to a 500mL three-neck flask, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 28g of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the above solution, and after the dropwise addition was completed, the temperature was raised to 80°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 42.3g of white solid was obtained, the GC was 93.7%, and the yield was 85.2%.

[0036] [Example 4] In a 500mL three-neck flask, 30g of (4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 23g of 4-ethoxy-2,3-difluorophenol, 35.31g of triphenylphosphine and 180mL of isopentadecane were added, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 28g of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the above solution, and after the dropwise addition was completed, the temperature was raised to 80°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 41.7g of white solid was obtained, the GC was 89.7%, and the yield was 84%.

[0037] [Comparative Example 1] In a 500mL three-neck flask, add 30g of (4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 23g of 4-ethoxy-2,3-difluorophenol, 35.31g of triphenylphosphine and 180mL of toluene, replace the air with nitrogen gas three times, heat to 50°C while stirring, slowly add 28g of diisopropyl azodicarboxylate (DIAD) to the above solution, after the dropwise addition is completed, heat to 80°C, react for 5 hours, reduce pressure and evaporate by rotary evaporation to obtain a pale yellow solid, recrystallize the solid with 150mL of ethanol, reduce pressure and suction filter, dry the filter cake, obtain 36.5g of white solid, GC is 77.4%, and the yield is 73.5%.

[0038] [Comparative Example 2] Into a 500 mL three-neck flask, 30 g of (4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 23 g of 4-ethoxy-2,3-difluorophenol, 35.31 g of triphenylphosphine and 180 mL of DMF were added, the air was replaced with nitrogen gas three times, and the temperature was raised to 50°C while stirring, and 28 g of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the above solution. After the addition was completed, the temperature was raised to 80°C and the reaction was carried out for 5 hours. 200mL of water and 200mL of dichloromethane were added to the reaction liquid, stirred for 10 minutes, extracted and separated, the aqueous phase was extracted twice with 200mL of dichloromethane, the organic phase was combined, the organic phase was washed twice with 200mL of water, and the organic phase was rotary evaporated under reduced pressure to obtain a pale yellow solid. The solid was recrystallized with 150mL of ethanol, suction filtered under reduced pressure, and the filter cake was dried to obtain 39.1g of a white solid. The GC result was 80.2%, and the yield was 78.7%.

[0039] [Comparative Example 3] 30g of (4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 23g of 4-ethoxy-2,3-difluorophenol, 35.31g of triphenylphosphine and 180mL of n-hexane were added to a 500mL three-neck flask, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 28g of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the above solution, and after the dropwise addition was completed, the temperature was raised to 80°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 38.7g of white solid was obtained, the GC was 81.2%, and the yield was 78%.

[0040] [Comparative Example 4] 30g of (4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 23g of 4-ethoxy-2,3-difluorophenol, 35.31g of triphenylphosphine and 180mL of cyclohexane were added to a 500mL three-neck flask, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 28g of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the above solution, and after the dropwise addition was completed, the temperature was raised to 80°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 35.2g of white solid was obtained, the GC was 80.8%, and the yield was 71%.

[0041] Measurement of by-product content The content of the compound 4-((4-ethoxy-2,3-difluorophenoxy)methyl)-4'-propyl-1,1'-bis(cyclohexane) in the above Examples 1 to 4 and Comparative Examples 1 and 2 was measured by HPLC, and the results are shown in Table 1 below.

[0042] [Table 1]

[0043] As can be seen from Table 1, compared with the general aprotic solvents in the prior art, the present application uses C8-C16 linear or branched alkanes as the organic solvents for the Mitsunobu reaction, which can significantly reduce the generation of impurities and help improve the purity of the product.

[0044] [Example 5] [ka] 30g of 4-(4-ethyl-2-fluorophenyl)cyclohexanol, 30.8g of 4-(4-propylcyclohexyl)aniline, 37.17g of triphenylphosphine and 180mL of isododecane were added to a 500mL three-neck flask, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 29.2g of diisopropyl azodicarboxylate (DIAD) was slowly dropped into the above solution, and after the dropwise addition was completed, the temperature was raised to 100°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 48.6g of white solid was obtained, the GC was 91.4%, and the yield was 85.4%.

[0045] The MS data for compound B were 123 (15%), 216 (55%), 392 (10%), and 421 (20%).

[0046] [Example 6] [ka] 30g of 4-(2',3'-difluoro-4'-methyl-[1,1'-biphenyl]-4-yl)cyclohexanol, 17.11g of 4-propylbenzoic acid, 27.33g of triphenylphosphine and 180mL of isododecane were added to a 500mL three-neck flask, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 21.47g of diisopropyl azodicarboxylate (DIAD) was slowly added dropwise to the above solution, and after the dropwise addition was completed, the temperature was raised to 100°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 40.6g of white solid was obtained, the GC was 98.1%, and the yield was 91.2%.

[0047] The MS data for compound C were 163 (35%), 244 (15%), 285 (25%), 419 (10%), and 448 (15%).

[0048] [Example 7] [ka] 30g of 4-(3-fluoro-4-isopropylphenyl)cyclohexanol, 20.29g of 4-propylbenzenethiol, 34.96g of triphenylphosphine and 180mL of isododecane were added to a 500mL three-neck flask, the air was replaced with nitrogen gas three times, the temperature was raised to 50°C while stirring, 23.66g of diisopropyl azodicarboxylate (DEAD) was slowly added dropwise to the above solution, and after the addition was completed, the temperature was raised to 80°C and reacted for 5 hours. The reaction solution was filtered while hot, the filtrate was frozen at -10°C for 4 hours, and then suction filtered under reduced pressure, the filter cake was dried, and 42.8g of white solid was obtained, the GC was 97.6%, and the yield was 91%.

[0049] The MS data for compound D were 137 (10%), 151 (45%), 327 (25%), 341 (10%), and 370 (10%).

[0050] The applicant asserts that although the application describes the process method of the application through the above examples, the application is not limited to the above examples, i.e., the application cannot be implemented without relying on the above examples.

Claims

1. A method for subjecting an alcoholic hydroxyl donor and an active hydrogen donor to a Mitsunobu reaction, specifically, The method includes the steps of reacting an alcoholic hydroxyl donor, an active hydrogen donor, a trihydrocarbylphosphine reagent, and an azodicarboxylate reagent in the presence of an organic solvent to obtain a product obtained by dehydration condensation of the alcoholic hydroxyl donor and the active hydrogen donor, The organic solvent is any one or a combination of at least two of isodecane, isododecane, dodecane, or isopentadecane; the alcoholic hydroxyl donor is 4'-propyl-[1,1'-bis(cyclohexane)]-4-yl)methanol, 4-(4-ethyl-2-fluorophenyl)cyclohexanol, 4-(2',3'-difluoro-4'-methyl-[1,1'-biphenyl]-4-yl)cyclohexanol, or 4-(3-fluoro-4-isopropylphenyl)cyclohexanol; The method wherein the active hydrogen donor is 4-ethoxy-2,3-difluorophenol, 4-(4-propylcyclohexyl)aniline, 4-propylbenzoic acid, or 4-propylbenzenethiol.

2. The method of claim 1 , wherein the organic solvent is isododecane.

3. The method according to claim 1 or 2, wherein the trihydrocarbylphosphine reagent is any one or a combination of at least two selected from triphenylphosphine, tributylphosphine, and trimethylphosphine.

4. The method according to any one of claims 1 to 3, wherein the azodicarboxylate reagent is any one or a combination of at least two selected from diethyl azodicarboxylate, diisopropyl azodicarboxylate, bis(2-methoxyethyl)azodicarboxylate, and bis(4-chlorobenzyl)azodicarboxylate.

5. the molar ratio of the alcoholic hydroxyl donor to the active hydrogen donor is 1:1 to 1.2; Preferably, the molar ratio of the alcoholic hydroxyl donor to the trihydrocarbylphosphine reagent is 1:1.05-1.3; The method according to any one of claims 1 to 4, wherein the molar ratio of the alcoholic hydroxyl donor to the azodicarboxylic ester reagent is preferably 1:1.05-1.

3.

6. The method according to any one of claims 1 to 5, wherein in the reaction, the reaction temperature is 30 to 120°C and the reaction time is 1 to 12 hours.

7. The order of adding the raw materials for the reaction is to slowly dropwise add the azodicarboxylate to the organic solvent containing the alcoholic hydroxyl donor, the active hydrogen donor, and the trihydrocarbyl phosphine reagent, or mix the azodicarboxylate with the trihydrocarbyl phosphine reagent, and then add the alcoholic hydroxyl donor and the active hydrogen donor to the mixed solution; The method according to any one of claims 1 to 6, wherein the temperature is controlled at 30 to 120°C during the dropping step.

8. The reaction is carried out under inert gas protection, Preferably, an organic base is added during the reaction, Preferably, the organic base is triethylamine; The method according to any one of claims 1 to 7, wherein ultrasound or microwaves are preferably used in the reaction process.

9. in particular, The method includes a step of reacting an alcoholic hydroxyl donor, an active hydrogen donor, a trihydrocarbylphosphine reagent and an azodicarboxylate reagent in the presence of an organic solvent at 30 to 120° C. for 1 to 12 hours to obtain a product obtained by dehydration condensation of the alcoholic hydroxyl donor and the active hydrogen donor, The organic solvent is any one or a combination of at least two of isodecane, isododecane, dodecane, or isopentadecane; 9. The method according to claim 1, wherein the molar ratio of the alcoholic hydroxyl donor to the active hydrogen donor is 1:1-1.2, the molar ratio of the alcoholic hydroxyl donor to the trihydrocarbylphosphine reagent is 1:1.05-1.3, and the molar ratio of the alcoholic hydroxyl donor to the azodicarboxylate reagent is 1:1.05-1.3.

Images