The invention relates to diphenyl N, Napos; method for complexing and purifying-diisopropyl phosphoramidite monomer
Through a method including complexing, extraction and column processing, the problem of low purity in the purification of diphenyl N,N'-diisopropylphosphamide monomer is solved, and high purity production is achieved. Suitable for pharmaceutical, chemical and biotechnology fields.
Patent Information
- Application Number
- CN202411281761.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-13
- Publication Date
- 2024-12-13
AI Technical Summary
In the prior art, the purification method of diphenyl N,N'-diisopropylphosphamide monomer is generally low in product purity and difficult to achieve high purity of 99%, which limits its in the fields of pharmaceutical, chemical and biotechnology. application.
A complex purification method consisting of the following steps: react the crude diphenyl N,N'-diisopropylphosphamide monomer with the complexing agent at a specific temperature, followed by extraction and column treatment, using The decomplexing agent was dissociated and finally obtained a high-purity diphenyl N,N'-diisopropylphosphamide monomer by separation and concentration.
The purity of diphenyl N,N'-diisopropylphosphamide monomer is achieved by more than 99.0%, simple operation and mild reaction conditions, which reduces the purification cost and is conducive to its large-scale production.
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Figure CN119119114A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of compound synthesis, and in particular to a complexation and purification method for diphenyl N,N'-diisopropylphosphoramidite monomer. Background Art
[0002] Diphenyl N,N'-diisopropylphosphoramidite is an organic intermediate commonly used in synthetic chemistry and widely used in the fields of pharmaceutical chemistry and biotechnology. Its important application is as a precursor of phosphoramidite monomers in DNA and oligonucleotide synthesis.
[0003] Literature reports that diphenyl N, N'-diisopropyl phosphoramidite can be used to prepare phosphoinositide compounds. Phosphoinositide compounds are the main second messengers in cells and play an important role in cell signal transduction. Diphenyl N, N'-diisopropyl phosphoramidite monomer is a key raw material for synthesizing nucleic acids. Its purity control is very important. Only high-purity and high-quality raw materials can produce high-quality nucleic acids.
[0004] At present, the purification of phosphoramidite compounds usually involves the process of removing impurities and improving the purity of the product. The commonly used separation and purification methods for the purification of phosphoramidite monomers are solvent elution, crystallization method and column chromatography. However, the above methods generally have low product purity and cannot reach a high purity of 99%, thus limiting the application of diphenyl N,N'-diisopropyl phosphoramidite monomers. Summary of the invention
[0005] The present invention aims to solve at least one of the technical problems existing in the related art. To this end, the object of the present invention is to provide a diphenyl N,N'-diisopropylphosphoramidite monomer complex purification method.
[0006] In order to achieve this purpose, the technical solution adopted by the present invention is: A diphenyl N, N'-diisopropyl phosphoramidite monomer complexation purification method, the diphenyl N, N'-diisopropyl phosphoramidite monomer structural formula is as follows: The steps include: S100, adding a crude diphenyl N,N'-diisopropyl phosphoramidite monomer to a first organic solvent to dissolve, adding a complexing agent dropwise at a temperature of 15° C. to 25° C., and stirring for 0.5 h to 1 h to obtain a diphenyl N,N'-diisopropyl phosphoramidite monomer complex solution; S200, adding water to the diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution, extracting and separating to obtain a first organic phase, and concentrating the first organic phase to obtain a first concentrate containing the diphenyl N, N'-diisopropyl phosphoramidite monomer complex; S300, adding silica gel to the first concentrate and mixing the sample, then passing the sample through a column, eluting the sample with a second organic solvent, collecting the eluate, and concentrating the eluate to obtain a second concentrate of diphenyl N,N'-diisopropylphosphoramidite monomer complex; S400, dissolving the second concentrate, adding a decomplexing agent to the solution, reacting at a temperature of 50°C to 60°C for 6h to 8h, cooling, adding water to the reaction solution for extraction, separating the liquids to obtain a second organic phase, concentrating the second organic phase to obtain a purified diphenyl N,N'-diisopropyl phosphoramidite monomer.
[0007] Furthermore, the crude product preparation process of diphenyl N,N'-diisopropylphosphoramidite monomer in step S100 is as follows: Under the protection of inert gas, add phosphorus trichloride to n-hexane, cool to -5°C ~ 0°C, add diisopropylamine dropwise, stir for 0.5h ~ 1h, heat to 15°C ~ 30°C, stir for 2h ~ 3h, cool to -5°C ~ 0°C, add triethylamine and benzyl alcohol dropwise in sequence, after the addition is complete, heat to 15°C ~ 30°C, react for 8h ~ 12h, add water to quench, stand and separate, wash the upper organic phase, stand and separate, dry the organic phase with anhydrous sodium sulfate, filter, rinse the filter cake with n-propane, concentrate the filtrate until there is no fraction, and obtain a crude diphenyl N,N'-diisopropyl phosphoramidite monomer.
[0008] Furthermore, the complexing agent in step S100 is a borane reagent.
[0009] Furthermore, the borane reagent in step S100 includes at least one of borane dimethyl sulfide and boron trifluoride tetrahydrofuran.
[0010] Furthermore, the decomplexing agent in step S400 is a diamine compound.
[0011] Furthermore, the diamine compound in step S400 includes at least one of triethylenediamine and triethylamine.
[0012] Furthermore, in step S100, the molar ratio of the complexing agent to the crude diphenyl N,N'-diisopropylphosphoramidite monomer added is 1:1 to 1.5:1.
[0013] Furthermore, the first organic solvent in step S100 is n-hexane.
[0014] Furthermore, the second organic solvent in step S300 includes at least one of n-hexane and petroleum ether.
[0015] Furthermore, in step S300, the first concentrate and silica gel are mixed with silica gel at a mass ratio of 1:1 to 1:2.
[0016] The above one or more technical solutions in the embodiments of the present invention have at least one of the following technical effects: The invention provides a method for complexing and purifying a crude diphenyl N,N'-diisopropyl phosphoramidite monomer. The diphenyl N,N'-diisopropyl phosphoramidite monomer with a purity greater than or equal to 99.0% can be obtained by the purification method. The purification method has simple operation, mild reaction conditions and low purification cost, and is conducive to the large-scale production of the diphenyl N,N'-diisopropyl phosphoramidite monomer.
[0017] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Figure 1 This is the GC chromatogram of the crude diphenyl N,N'-diisopropylphosphoramidite monomer provided in Example 1 of the present invention.
[0019] Figure 2 This is a GC chromatogram of the purified diphenyl N,N'-diisopropylphosphoramidite monomer provided in Example 2 of the present invention.
[0020] Figure 3 This is the HNMR chromatogram of the purified diphenyl N,N'-diisopropylphosphoramidite monomer provided in Example 2 of the present invention. DETAILED DESCRIPTION
[0021] In order to make the purpose, technical scheme and advantages of the present invention clearer, the technical scheme of the present invention will be clearly and completely described below in conjunction with the drawings in the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention. The following embodiments are used to illustrate the present invention, but cannot be used to limit the scope of the present invention.
[0022] In the following examples, the experimental methods used are conventional methods unless otherwise specified, and the materials, reagents, etc. used are all available from commercial sources unless otherwise specified.
[0023] Example 1 Preparation of crude diphenyl N,N'-diisopropylphosphoramidite monomer.
[0024] The synthetic reaction route is as follows: ; The preparation process is as follows: At room temperature, under nitrogen protection, add phosphorus trichloride (100g) to n-hexane, cool to 0℃, and control the temperature at about 0℃, add diisopropylamine (153.3g) dropwise, after the addition is complete, continue stirring for about 1h, slowly raise the temperature to 15℃, continue stirring for 2h, cool the reaction system to 0℃ again, add triethylamine (153.3g) dropwise, after the addition is complete, continue to control the temperature at about 0℃, slowly add benzyl alcohol (163.8g) dropwise, after the addition is complete, slowly raise the temperature to 15℃, the reaction system is continued for 8h, sampling and detection, GC detection intermediate residual amount ≤1%.
[0025] After the reaction was completed, purified water (400 ml) was added to the system for quenching, and the system was allowed to stand for separation. The upper organic phase was washed once with purified water (400 ml), and the system was allowed to stand for separation. The organic phase was dried with anhydrous sodium sulfate (150 g), filtered, and the filter cake was rinsed with n-hexane (200 ml). The organic phases were combined and concentrated (temperature ≤ 30 ° C) until there was no fraction to obtain a crude diphenyl N, N'-diisopropylphosphoramidite monomer with a yield of 86% and a purity of 89.4%, as shown in Table 1 and Figure 1 shown.
[0026] Table 1 Gas chromatography (GC) data results of crude diphenyl N,N'-diisopropylphosphoramidite monomer
[0027] Examples 2 to 6 are all about the purification of the crude diphenyl N,N'-diisopropylphosphoramidite monomer obtained in Example 1.
[0028] The complexation purification process routes of Examples 2 to 6 are as follows: In the following examples, BH3-Me2S is borane dimethyl sulfide, BH3-THF is borane tetrahydrofuran, and DABCO is triethylenediamine.
[0029] Example 2 The crude diphenyl N, N'-diisopropyl phosphoramidite monomer (50 g) was dissolved in n-hexane (500 ml), the temperature was controlled at about 25°C, 15.2 ml of 10 mol / L BH3-Me2S solution was slowly dripped into the reaction system, and after stirring for about 1 hour, HPLC detection was used to determine that the crude diphenyl N, N'-diisopropyl phosphoramidite monomer was ≤0.50%, and a diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution was obtained.
[0030] Purified water (250 ml) was added to the diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution reaction system to perform extraction operation, and the organic phase was washed once with purified water (250 ml). After separation, the organic phase was concentrated to obtain a first concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0031] The first concentrate was added with silica gel (75 g) and mixed, and then passed through a column. The column was loaded with silica gel (150 g). The mixture was eluted with n-hexane (20 V) (the eluent can be recycled) until no diphenyl N, N'-diisopropyl phosphoramidite monomer complex was detected in the eluent. The eluent was concentrated until no distillation occurred, thereby obtaining a second concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0032] The second concentrate was dissolved in n-hexane (300 ml), DABCO (32.5 g) was added, and the reaction was carried out at 60° C. for 6 h until the remaining amount of the diphenyl N, N'-diisopropyl phosphoramidite monomer complex was ≤0.2%. When the remaining amount of the diphenyl N, N'-diisopropyl phosphoramidite monomer complex was >0.2%, the reaction was considered incomplete, and the system could be filtered and DABCO was added to continue the reaction until the reaction was complete.
[0033] After the reaction was completed, the system was cooled to 15°C, purified water (150 ml) was added for extraction, and the organic phase was washed twice with purified water (150 ml). After separation, the organic phase was concentrated to obtain the purified diphenyl N, N'-diisopropylphosphoramidite monomer with a yield of 65% and a purity of 99.4%, as shown in Table 2. Figure 2 and Figure 3 shown.
[0034] Table 2 GC data of purified diphenyl N,N'-diisopropylphosphoramidite monomer
[0035] Example 3 The crude diphenyl N, N'-diisopropyl phosphoramidite monomer (50g) was dissolved in n-hexane (500ml), the temperature was controlled at 25°C, 15.2ml of 10ml / L BH3-Me2S solution was slowly dripped into the reaction system, and after stirring for 1h, HPLC was used for detection. The crude diphenyl N, N'-diisopropyl phosphoramidite monomer was ≤0.50%, and a diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution was obtained.
[0036] Purified water (250 ml) was added to the diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution reaction system to perform extraction operation, and the organic phase was washed once with purified water (250 ml). After separation, the organic phase was concentrated to obtain a first concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0037] The first concentrate was added with silica gel (75 g) and mixed, and then passed through a column. The column was loaded with silica gel (150 g). The product was eluted with n-hexane (30 V) (the eluent can be recycled) until no diphenyl N, N'-diisopropyl phosphoramidite monomer complex was detected in the eluent. The eluent was concentrated until no distillation occurred to obtain a second concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0038] The second concentrate was dissolved in n-hexane (300 ml), ethylenediamine (43.5 g) was added to the system, and the system was reacted at 50° C. for 6 h until the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was ≤0.2%. When the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was >0.2%, the reaction was considered incomplete, and the system could be filtered and ethylenediamine was added to continue the reaction until the reaction was complete.
[0039] After the reaction was completed, the system was cooled to 25° C., purified water (150 ml) was added for extraction, the organic phase was washed twice with purified water (150 ml), the organic phase was separated and concentrated to obtain the purified diphenyl N, N'-diisopropylphosphoramidite monomer with a yield of 57% and a purity of 99.1%.
[0040] Example 4 The crude diphenyl N, N'-diisopropyl phosphoramidite monomer (20 g) was dissolved in n-hexane (200 ml), the temperature was controlled at 15°C, 61 ml of 1.0 mol / L BH3-THF solution was slowly dripped into the reaction system, and after stirring for 0.5 h, HPLC was used for detection. The crude diphenyl N, N'-diisopropyl phosphoramidite monomer was ≤0.50%, and a diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution was obtained.
[0041] Purified water (100 ml) was added to the diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution reaction system to perform extraction operation, and the organic phase was washed once with purified water (150 ml). After separation, the organic phase was concentrated to obtain a first concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0042] The first concentrate was added with silica gel (30 g) and mixed, and then passed through a column. The column was loaded with silica gel (60 g). Petroleum ether (20 V) was used for elution (the eluent can be recycled) until no diphenyl N, N'-diisopropyl phosphoramidite monomer complex was detected in the eluent. The eluent was concentrated until no distillation occurred to obtain a second concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0043] The second concentrate was dissolved in n-hexane (150 ml), DABCO (13 g) was added to the system, and the system was reacted at 50° C. for 8 h until the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was ≤0.2%. When the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was >0.2%, the reaction was considered incomplete, and the system could be filtered and DABCO was added to continue the reaction until the reaction was complete.
[0044] After the reaction was completed, the reaction system was cooled to 25° C., purified water (100 ml) was added for extraction, and the organic phase was washed twice with purified water (100 ml). After separation, the organic phase was concentrated to obtain purified diphenyl N, N'-diisopropylphosphoramidite monomer with a yield of 61% and a purity of 99.1%.
[0045] Example 5 The crude diphenyl N, N'-diisopropyl phosphoramidite monomer (30 g) was dissolved in n-hexane (200 ml), the temperature was controlled at 25°C, 61 ml of 1.0 mol / L BH3-THF solution was slowly dripped into the reaction system, and after stirring for 0.5 h, HPLC was used for detection. The crude diphenyl N, N'-diisopropyl phosphoramidite monomer was ≤0.50%, and a diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution was obtained.
[0046] Purified water (100 ml) was added to the diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution reaction system to perform extraction operation, and the organic phase was washed once with purified water (100 ml). After separation, the organic phase was concentrated to obtain a first concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0047] The first concentrate was added with silica gel (30 g) for column operation, the column was loaded with silica gel (60 g), and petroleum ether (30 V) was used for elution (the eluent can be recycled) until no diphenyl N, N'-diisopropyl phosphoramidite monomer complex was detected in the eluent, and the eluent was concentrated until no distillation occurred to obtain a second concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0048] The second concentrate was dissolved in n-hexane (150 ml), DABCO (13 g) was added to the system, and the system was reacted at 50° C. for 8 h until the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was ≤0.2%. When the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was >0.2%, the reaction was considered incomplete, and the system could be filtered and DABCO was added to continue the reaction until the reaction was complete.
[0049] After the reaction was completed, the system was cooled to 25° C., purified water (75 ml) was added for extraction, and the organic phase was washed twice with purified water (75 ml). After separation, the organic phase was concentrated to obtain purified diphenyl N, N'-diisopropylphosphoramidite monomer with a yield of 62% and a purity of 99.1%.
[0050] Example 6 The crude diphenyl N, N'-diisopropyl phosphoramidite monomer (30 g) was dissolved in n-hexane (500 ml), the temperature was controlled at 20°C, 9.2 ml of 10 mol / L BH3-Me2S solution was slowly dripped into the reaction system, and after stirring for 1 h, HPLC was used to detect that the crude diphenyl N, N'-diisopropyl phosphoramidite monomer was ≤0.50%, and a diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution was obtained.
[0051] Purified water (150 ml) was added to the diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution reaction system to perform extraction operation, and the organic phase was washed once with purified water (150 ml). After separation, the organic phase was concentrated to obtain a first concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0052] The first concentrate was added with silica gel (45 g) for column operation, the column was loaded with silica gel (90 g), and petroleum ether (25 V) was used for elution (the eluent can be recycled) until no diphenyl N, N'-diisopropyl phosphoramidite monomer complex was detected in the eluent, and the eluent was concentrated until no distillation occurred to obtain a second concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0053] The second concentrate was dissolved in n-hexane (220 ml), DABCO (19.5 g) was added to the system, and the system was reacted at 60° C. for 6 h until the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was ≤0.2%. When the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was >0.2%, the reaction was considered incomplete, and the system could be filtered and DABCO was added to continue the reaction until the reaction was complete.
[0054] After the reaction was completed, the system was cooled to 20°C, purified water (100 ml) was added for extraction, the organic phase was washed twice with purified water (100 ml), and the organic phase was concentrated after separation to obtain the purified diphenyl N, N'-diisopropylphosphoramidite monomer with a yield of 64% and a purity of 99.3%.
[0055] Example 7 The crude diphenyl N, N'-diisopropyl phosphoramidite monomer (30 g) was dissolved in n-hexane (500 ml), the temperature was controlled at 25°C, 9.2 ml of 10 mol / L BH3-Me2S solution was slowly dripped into the reaction system, and after stirring for 1 h, HPLC was used to detect that the crude diphenyl N, N'-diisopropyl phosphoramidite monomer was ≤0.50%, and a diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution was obtained.
[0056] Purified water (150 ml) was added to the diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution reaction system to perform extraction operation, and the organic phase was washed once with purified water (150 ml). After separation, the organic phase was concentrated to obtain a first concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0057] The first concentrate was added with silica gel (40 g) and passed through a column. The column was loaded with silica gel (80 g). Petroleum ether (20 V) was used for elution (the eluent can be recycled) until no diphenyl N, N'-diisopropyl phosphoramidite monomer complex was detected in the eluent. The eluent was concentrated until no distillation occurred to obtain a second concentrate containing diphenyl N, N'-diisopropyl phosphoramidite monomer complex.
[0058] The second concentrate was dissolved in n-hexane (150 ml), DABCO (19.5 g) was added to the system, and the system was reacted at 60° C. for 8 h until the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was ≤0.2%. When the residual amount of diphenyl N, N'-diisopropyl phosphoramidite monomer complex was >0.2%, the reaction was considered incomplete, and the system could be filtered and DABCO was added to continue the reaction until the reaction was complete.
[0059] After the reaction was completed, the system was cooled to 25°C, purified water (150 ml) was added for extraction, the organic phase was washed twice with purified water (150 ml), and the organic phase was concentrated after separation to obtain the purified diphenyl N, N'-diisopropylphosphoramidite monomer with a yield of 56% and a purity of 99.5%.
[0060] It can be seen from the above examples that the present invention provides a method for complexing and purifying a crude diphenyl N,N'-diisopropyl phosphoramidite monomer. The purification method can obtain a diphenyl N,N'-diisopropyl phosphoramidite monomer with a purity of ≥99.0%. The purification method is simple to operate, has mild reaction conditions, and has low purification cost, which is conducive to the large-scale production of diphenyl N,N'-diisopropyl phosphoramidite monomers.
[0061] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A diphenyl N,N'-diisopropylphosphoramidite monomer complexation purification method, characterized in that: The diphenyl N,N'-diisopropyl phosphoramidite monomer structural formula is as follows: The steps include: S100, adding a crude diphenyl N,N'-diisopropyl phosphoramidite monomer to a first organic solvent to dissolve, adding a complexing agent dropwise at a temperature of 15° C. to 25° C., and stirring for 0.5 h to 1 h to obtain a diphenyl N,N'-diisopropyl phosphoramidite monomer complex solution; S200, adding water to the diphenyl N, N'-diisopropyl phosphoramidite monomer complex solution, extracting and separating to obtain a first organic phase, and concentrating the first organic phase to obtain a first concentrate containing the diphenyl N, N'-diisopropyl phosphoramidite monomer complex; S300, adding silica gel to the first concentrate and mixing the sample, then passing the sample through a column, eluting the sample with a second organic solvent, collecting the eluate, and concentrating the eluate to obtain a second concentrate of diphenyl N,N'-diisopropylphosphoramidite monomer complex; S400, dissolving the second concentrate, adding a decomplexing agent to the solution, reacting at a temperature of 50°C to 60°C for 6h to 8h, cooling, adding water to the reaction solution for extraction, separating the liquids to obtain a second organic phase, concentrating the second organic phase to obtain a purified diphenyl N,N'-diisopropyl phosphoramidite monomer.
2. The diphenyl N,N'-diisopropylphosphoramidite monomer complexation purification method as claimed in claim 1, characterized in that: The preparation process of the crude diphenyl N,N'-diisopropylphosphoramidite monomer in step S100 is as follows: Under the protection of inert gas, add phosphorus trichloride to n-hexane, cool to -5°C ~ 0°C, add diisopropylamine dropwise, stir for 0.5h ~ 1h, heat to 15°C ~ 30°C, stir for 2h ~ 3h, cool to -5°C ~ 0°C, add triethylamine and benzyl alcohol dropwise in sequence, after the addition is complete, heat to 15°C ~ 30°C, react for 8h ~ 12h, quench with water, stand and separate, wash the upper organic phase, stand and separate, dry the organic phase with anhydrous sodium sulfate, filter, rinse the filter cake with n-propane, concentrate the filtrate until there is no fraction, and obtain a crude diphenyl N,N'-diisopropyl phosphoramidite monomer.
3. The diphenyl N,N'-diisopropylphosphoramidite monomer complex purification method as claimed in claim 1, characterized in that: The complexing agent in step S100 is a borane reagent.
4. The diphenyl N,N'-diisopropylphosphoramidite monomer complex purification method as claimed in claim 3, characterized in that: The borane reagent in step S100 includes at least one of borane dimethyl sulfide and boron trifluoride tetrahydrofuran.
5. The diphenyl N,N'-diisopropylphosphoramidite monomer complex purification method as claimed in claim 1, characterized in that: The decomplexing agent in step S400 is a diamine compound.
6. The method for complexing and purifying diphenyl N,N'-diisopropylphosphoramidite monomer as claimed in claim 5, characterized in that: The diamine compound in step S400 includes at least one of triethylenediamine and triethylamine.
7. The diphenyl N,N'-diisopropylphosphoramidite monomer complex purification method as claimed in claim 1, characterized in that: In step S100, the molar ratio of the complexing agent to the crude diphenyl N,N'-diisopropylphosphoramidite monomer added is 1:1 to 1.5:
1.
8. The method for complexing and purifying diphenyl N,N'-diisopropylphosphoramidite monomer as claimed in claim 1, characterized in that: The first organic solvent in step S100 is n-hexane.
9. The diphenyl N,N'-diisopropylphosphoramidite monomer complex purification method as claimed in claim 1, characterized in that: The second organic solvent in step S300 includes at least one of n-hexane and petroleum ether.
10. The method for complexing and purifying diphenyl N,N'-diisopropylphosphoramidite monomer as claimed in claim 2, characterized in that: In step S300, the first concentrate and silica gel are mixed with silica gel in a mass ratio of 1:1 to 1:2.