A purification and preparation method for a diamino phosphite compound

Abstract

This disclosure relates to a purification and preparation method for a diamino phosphite compound. The purification method for the diamino phosphite compound provided in this disclosure includes recrystallizing a solution containing a mixture of diamino phosphite compounds at least once. The recrystallization conditions for each recrystallization include: a temperature of -75°C to -15°C, a time of 2-100 hours, and a ratio of the mixture containing the diamino phosphite compound to the crystallization solvent of 1 g: 0.5-8 mL. The purification method provided in this disclosure is simple and controllable, low in cost, produces high-purity products, has a wide range of applications, and can be scaled up for mass production.

Description

Technical Field

[0001] This disclosure relates to the field of nucleotide preparation, specifically to a purification and preparation method for a diaminophosphite compound used in the synthesis of phosphorylated nucleotides. Background Technology

[0002] Diaminophosphite compounds, such as 2-cyanoethyl N,N,N',N'-tetraisopropylphosphite diamine (CAS: 102691-36-1), are important reagents for the preparation of nucleoside monomers, which are essential raw materials for the preparation of oligonucleotides. The purity of diaminophosphite compounds is crucial for the further preparation of high-purity oligonucleotides. In existing technologies, the raw materials are usually purified by washing or molecular distillation.

[0003] CN1659173A discloses a method for preparing a phosphorus diamine compound. Phosphorus trichloride is reacted with 2-cyanoethanol or trimethylsiloxypropionitrile to obtain 2-(cyanoethoxy)dichlorophosphorus (CDP). After this reaction, the solvent and excess phosphorus trichloride are removed by distillation. The crude product is further purified by vacuum distillation to obtain CDP with a purity greater than 98%. The CDP is then dissolved in tetrahydrofuran, stirred and cooled under a nitrogen layer, and then treated with diisopropylamine for 90 minutes. After stirring for 72 hours, a slurry is obtained. This slurry is filtered to remove diisopropylamine hydrochloride solids. The clarified filtrate is passed through an activated neutral alumina column and concentrated in a rotary evaporator. The distilled tetrahydrofuran is used to wash the diisopropylamine hydrochloride solids and alumina to collect additional product, which is then combined with the product from the first step. Concentration is then performed to obtain purified 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorus diamine. However, the distillation process in this purification method is prone to explosion, posing a significant safety hazard, and requires treatment with a neutral alumina column, making the operation quite difficult. Summary of the Invention

[0004] The inventors of this disclosure provide a purification method and a preparation method for diaminophosphite compounds. The purification method provided by this disclosure is simple to operate, controllable, and low in cost. The purification method can obtain diaminophosphite compounds with a purity of >99%, which can realize large-scale production.

[0005] On one hand, this disclosure provides a method for purifying diamino phosphite compounds, wherein the method includes recrystallizing a solution containing a mixture of diamino phosphite compounds at least once, wherein the conditions for each recrystallization include: a temperature of -75°C to -15°C, a time of 2-100 hours, and the ratio of the mixture containing the diamino phosphite compounds to the crystallization solvent in the solution is 1g:0.5-8mL.

[0006] On the other hand, this disclosure also provides a method for preparing a diamino phosphite compound, the method comprising providing a mixture containing a diamino phosphite compound and purifying the mixture containing the diamino phosphite compound according to the purification method provided in this disclosure.

[0007] Incorporate by reference

[0008] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent or patent application is specifically and individually incorporated herein by reference.

[0009] Beneficial effects

[0010] The purification method for diaminophosphite compounds disclosed herein is simple, controllable, and low in cost. This purification method can obtain diaminophosphite compounds such as 2-cyanoethyl N,N,N',N'-tetraisopropylphosphite diamine with a purity >99%.

[0011] This disclosure employs a low-temperature crystallization method to purify mixtures containing diamino phosphite compounds. Since diamino phosphite compounds are the main component of the mixture, supersaturation precipitation occurs during crystallization. Therefore, this method can be used to obtain high-purity diamino phosphite compounds, such as 2-cyanoethyl N,N,N',N'-tetraisopropylphosphite diamine, for mixtures containing different types of impurities with a purity ≥80% by weight. The purification method provided by this disclosure is simple and controllable, low-cost, produces high-purity products, has a wide range of applications, and can be scaled up for mass production. Detailed Implementation

[0012] The following provides a detailed description of specific embodiments of this disclosure. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit this disclosure.

[0013] Those skilled in the art will understand that for any group containing one or more substituents, these groups are not intended to introduce any substitution or substitution pattern that is spatially impractical, synthetically infeasible, and / or inherently unstable.

[0014] This disclosure provides a method for purifying diaminophosphite compounds, comprising recrystallizing a solution containing a mixture of diaminophosphite compounds at least once, wherein the recrystallization conditions include: a temperature of -75°C to -15°C, a time of 2-100 hours, and the ratio of the mixture containing the diaminophosphite compounds to the crystallization solvent in the solution being 1 g: 0.5-8 mL.

[0015] The purification method for diamino phosphite compounds provided in this disclosure, by controlling the conditions of each recrystallization and by reusing the recrystallization mother liquor, can purify the diamino phosphite compounds in a mixture to a purity greater than 99%. In some embodiments, the content of the diamino phosphite compounds in the mixture containing the diamino phosphite compounds in this disclosure is at least 80% by weight, optionally 80-95% by weight, and preferably at least 90% by weight or 90-95% by weight.

[0016] The purification method disclosed herein achieves the separation of diamino phosphite compounds and impurities through low-temperature crystallization of the mixture, eliminating the need for complex and hazardous procedures such as column chromatography or distillation, thus yielding diamino phosphite compounds with a purity greater than 99%. Furthermore, during crystallization, for mixtures containing ≥80% by weight of diamino phosphite compounds, since the diamino phosphite compounds are the main component and impurities are minor components, the impurities do not undergo supersaturation precipitation during crystallization; instead, the main component, the diamino phosphite compounds, will precipitate in a supersaturated manner. Therefore, the purification method disclosed herein is simple and controllable, has a wide range of applications, and produces high-purity products.

[0017] In some embodiments, the conditions for each recrystallization include: a temperature of -60°C to -40°C, a time of 6 to 48 hours, and a solution containing a mixture of diaminophosphite compounds, wherein the ratio of the mixture containing the diaminophosphite compounds to the crystallization solvent is 1 g: 1-5 mL.

[0018] In some embodiments, the conditions for each recrystallization include: a temperature of -60°C to -50°C, a time of 12-42 hours, and a solution containing a mixture of diaminophosphite compounds, wherein the ratio of the mixture containing the diaminophosphite compounds to the crystallization solvent is 1 g: 0.6-3 mL.

[0019] In some embodiments, recrystallization is performed 1-3 times. In a preferred embodiment, recrystallization is performed 1-2 times.

[0020] In some embodiments, the crystallization solvent of this disclosure is selected from one or more solvents that are capable of dissolving mixtures containing diaminophosphite compounds at room temperature and are liquid in a temperature range of -75°C to -30°C.

[0021] In some embodiments, the crystallization solvent is selected from C5-C9 alkane compounds, C7-C... 11 One or more of aromatic compounds, C4-C6 ether compounds, and C2-C6 nitrile compounds. In some embodiments, the crystallization solvent is a C2-C6 nitrile compound. In some embodiments, the crystallization solvent is one of acetonitrile, butyronitrile, and isobutyronitrile. In a specific embodiment, the crystallization solvent is acetonitrile.

[0022] In some embodiments, the diamino phosphite compound of this disclosure has the structure shown in formula (1):

[0023]

[0024] Equation (1)

[0025] R1 and R2 may be the same or different, and each is independently selected from C1-C8 alkyl or substituted C1-C8 alkyl, and R3 is a hydroxyl protecting group.

[0026] In some embodiments, R1 and R2 may be the same or different, and each is independently selected from one of C1-C4 alkyl groups. In some specific embodiments, R1 and R2 are both isopropyl.

[0027] In some embodiments, R3 is selected from 2-cyanoethyl, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 alkenyl. In some specific embodiments, R3 is 2-cyanoethyl.

[0028] In some specific embodiments, the diamino phosphite compound is 2-cyanoethyl N,N,N',N'-tetraisopropylphosphite or ethoxy-N,N-di(propyl-2-yl)phosphite.

[0029] The purification method disclosed herein employs low-temperature crystallization. By controlling the crystallization conditions and selecting a suitable crystallization solvent, the purification of diaminophosphite compounds can be achieved. The operation process is simple and controllable, with low cost, wide applicability, and high product purity.

[0030] This disclosure also provides a method for preparing a diamino phosphite compound, the method comprising providing a mixture containing the diamino phosphite compound and purifying the mixture containing the diamino phosphite compound according to the purification method provided in this disclosure.

[0031] In some embodiments, the method for preparing a mixture containing a diamino phosphite compound includes the following steps:

[0032] S1: In the presence of a first solvent, under condensation reaction conditions, phosphorus trihalide is contacted with an alkylamine to obtain a first reaction mixture. The reaction temperature is -20°C to 15°C, the reaction time is 1-6 hours, and the ratio of phosphorus trihalide, alkylamine, and the first solvent is 1 mol: 2-20 mol: 0.5-10 L. Optionally, the reaction temperature is -10°C to 10°C, the reaction time is 3-5 hours, and the ratio of phosphorus trihalide, alkylamine, and the first solvent is 1 mol: 3-10 mol: 0.5-6 L.

[0033] S2: In the presence of a second solvent, under condensation reaction conditions, the first reaction mixture is contacted with a hydroxyl-containing compound to obtain a second reaction mixture. The reaction temperature is -30°C to 10°C, the reaction time is 1-6 hours, and the ratio of the first reaction mixture, the hydroxyl-containing compound, and the second solvent is 1 mol: 0.5-2 mol: 0.5-30 L. Optionally, the reaction temperature is -20°C to 0°C, the reaction time is 3-5 hours, and the ratio of the first reaction mixture, the hydroxyl-containing compound, and the second solvent is 1 mol: 0.8-1.5 mol: 0.5-20 L.

[0034] S3: Separate the solvent layer containing the mixture of diamino phosphite compounds from the second reaction mixture, remove the solvent, and obtain the mixture containing diamino phosphite compounds. The prepared mixture containing diamino phosphite compounds is usually referred to as crude diamino phosphite compound.

[0035] In this preparation process, the first solvent in step S1 is a polar solvent, and the second solvent in step S2 is a non-polar solvent. Alternatively, the first solvent in step S1 is a non-polar solvent, and the second solvent in step S2 is a polar solvent.

[0036] In some embodiments, the phosphorus trihalide is phosphorus trichloride or phosphorus tribromide.

[0037] In some embodiments, the alkylamine is selected from C2-C4. 10 At least one of the dialkylamines. In some embodiments, the alkylamine is selected from at least one of dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, or di-tert-butylamine. In some specific embodiments, the alkylamine is diisopropylamine.

[0038] In some embodiments, the hydroxyl-containing compound is selected from one of the structures shown in formulas (3) to (7):

[0039]

[0040] Equation (3) Equation (4) Equation (5)

[0041]

[0042] Equation (6) Equation (7)

[0043] Among them, R 31 R3, R4, R5, R6, and R7 are each independently selected from H or C1-C3 alkyl groups, and n3, n4, n5, n6, and n7 are integers selected from 1 to 5. In some embodiments, R... 31 R1, R2, R3, R4, R5, R6, and R7 are each independently H, and n3, n4, n5, n6, and n7 are integers selected from 2 to 3.

[0044] In some embodiments, the hydroxyl-containing compound is selected from hydroxypropionitrile, ethanol, or methoxymethanol. In some specific embodiments, the hydroxyl-containing compound is 3-hydroxypropionitrile.

[0045] In some embodiments, the polar solvent used in the preparation method of this disclosure is selected from acetonitrile, butyronitrile, isobutyronitrile, ethyl acetate, dichloromethane, and tetrahydrofuran, and the nonpolar solvent is selected from n-heptane, n-hexane, and n-pentane. In some specific embodiments, the polar solvent is acetonitrile, and the nonpolar solvent is n-heptane.

[0046] In some embodiments, step S3 includes: washing the second reaction mixture with a polar solvent, then separating the polar solvent layer and the non-polar solvent layer, and concentrating the non-polar solvent layer to obtain a crude phosphorus diamine compound. In some embodiments, the polar solvent used for washing the second reaction mixture with a polar solvent is selected from water, acetonitrile, butyronitrile, isobutyronitrile, ethyl acetate, dichloromethane, and tetrahydrofuran.

[0047] The present disclosure will be further illustrated by the following examples, but the present disclosure is not limited thereto. Unless otherwise specified, the diisopropylamine, n-heptane, n-hexane, acetonitrile, 3-hydroxypropionitrile and phosphorus trichloride reagents used in the following examples are all commercially available products and are of industrial grade purity.

[0048] Example 1

[0049] (1) Preparation of crude product: 103.4 g of diisopropylamine and 200 mL of n-heptane were mixed in a reaction vessel, cooled to -10 °C, and 20 g of phosphorus trichloride was added dropwise. The reaction was allowed to proceed for 3 hours. Then, a mixed solution of 100 mL of acetonitrile and 12.5 g of 3-hydroxypropionitrile was added to the reaction vessel, and the reaction was continued for 3.5 hours. 100 mL of purified water was added to the reaction vessel for washing. The solvent in the reaction vessel was evaporated at 35 °C until no liquid dripped from the condenser, yielding 45.8 g of crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine. The purity of the crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine was determined to be 87.1% using 31P-NMR (instrument and measurement conditions: Magnet System 400 MHz / 54 mm, Bruker Corporation).

[0050] (2) Purification: At room temperature, the crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphine diamine obtained in step (1) was placed in a reaction flask, 32 mL of acetonitrile was added and stirred to dissolve it, the temperature was lowered to -60°C with liquid nitrogen, and the crystals were allowed to stand for 36 hours to crystallize. After pouring out the upper liquid, 45 mL of acetonitrile was added to the reaction flask, the temperature was lowered to -60°C, and the crystals were allowed to stand for 24 hours to crystallize, resulting in a crystal weighing 38.6 g. The purity of the crystal was determined to be 99.2% using a 31P-NMR instrument.

[0051] Using the formula: Product yield = Crystal weight / Crude product weight * 100%, the crystal yield was calculated to be 84.3%.

[0052] Example 2

[0053] (1) Preparation of crude product: 117.9 g of diisopropylamine and 100 mL of n-hexane were mixed in a reaction vessel, cooled to -10 °C, and 20 g of phosphorus trichloride was added dropwise. The reaction was allowed to proceed for 1 hour. Then, a mixed solution of 300 mL of acetonitrile and 15.57 g of 3-hydroxypropionitrile was added to the reaction vessel, and the reaction was continued for another hour. 300 mL of purified water was added to the reaction vessel for washing. The solvent in the reaction vessel was evaporated at 35 °C until no liquid dripped from the condenser, yielding 45.0 g of crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine. The purity of the crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine was determined to be 92.3% by 31P-NMR.

[0054] (2) Purification: At room temperature, the crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphine diamine obtained in step (1) was placed in a reaction flask, 45 mL of acetonitrile was added and stirred to dissolve it, the temperature was lowered to -50°C with liquid nitrogen, and crystallization was allowed to occur for 24 hours. After the upper layer of liquid was poured off, 36 mL of acetonitrile was added to the reaction flask, the temperature was lowered to -50°C, and crystallization was allowed to occur for 12 hours to obtain crystals weighing 38.2 g. The purity of the crystals was determined to be 99.1% by 31P-NMR instrument, and the yield of the crystals was 84.9% compared with the crude product.

[0055] Example 3

[0056] (1) Preparation of crude product: 147.7 g of diisopropylamine and 160 mL of n-heptane were mixed in a reaction vessel, cooled to -10 °C, and 20 g of phosphorus trichloride was added dropwise. The reaction was carried out for 4 hours. Then, a mixed solution of 200 mL of acetonitrile and 10.4 g of 3-hydroxypropionitrile was added to the reaction vessel, and the reaction was continued for 5 hours. 200 mL of purified water was added to the reaction vessel for washing. The solvent in the reaction vessel was evaporated at 35 °C until no liquid dripped from the condenser, yielding 46.5 g of crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine. The purity of the crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine was determined to be 95.5% by 31P-NMR.

[0057] (2) Purification: At room temperature, the crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphine diamine obtained in step (1) was placed in a reaction flask, 100 mL of acetonitrile was added and stirred to dissolve, the temperature was lowered to -55°C with liquid nitrogen, and crystallization was allowed to occur for 18 hours. After the upper layer of liquid was poured off, 46 mL of acetonitrile was added to the reaction flask, the temperature was lowered to -55°C, and crystallization was allowed to occur for 12 hours to obtain crystals weighing 41.6 g. The purity of the crystals was determined to be 99.5% using a 31P-NMR instrument, and the yield of the crystals was 89.5% compared to the crude product.

[0058] Experiment Example 4

[0059] (1) Preparation of crude product: 106.9 g of diisopropylamine and 180 mL of n-heptane were mixed in a reaction vessel, cooled to -10 °C, and 20 g of phosphorus trichloride was added dropwise. The reaction was allowed to proceed for 3.5 hours. Then, a mixed solution of 150 mL of acetonitrile and 13.2 g of 3-hydroxypropionitrile was added to the reaction vessel, and the reaction was continued for 4 hours. 150 mL of purified water was added to the reaction vessel for washing. The solvent in the reaction vessel was evaporated at 35 °C until no liquid dripped from the condenser, yielding 45.2 g of crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine. The purity of the crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine was determined to be 86.2% by 31P-NMR.

[0060] (2) Purification: At room temperature, the crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphine diamine obtained in step (1) was placed in a reaction flask, 120 mL of acetonitrile was added and stirred to dissolve, the temperature was lowered to -65°C with liquid nitrogen, and crystallization was allowed to occur for 10 hours. After the upper layer of liquid was poured off, 65 mL of acetonitrile was added to the reaction flask, the temperature was lowered to -65°C, and crystallization was allowed to occur for 6 hours to obtain crystals weighing 35.2 g. The purity of the crystals was determined to be 99.1% by 31P-NMR instrument, and the yield of the crystals was 77.9% compared with the crude product.

[0061] Comparative Example 1

[0062] 2-Cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine crude product was prepared according to step (1) of Example 1. 200g of crude 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine crude product with a purity of 93.1% was taken and subjected to vacuum distillation at an external temperature of 110℃ and a vacuum degree of 75Pa to obtain 113g of product. The purity of the product was determined by 31P-NMR to be 98.2%, and the yield was 56.5%.

[0063] Some embodiments of this disclosure have been described in detail above. However, this disclosure is not limited to the specific details of the above embodiments. Within the scope of the technical concept of this disclosure, various simple modifications can be made to the technical solutions of this disclosure, and these simple modifications all fall within the protection scope of this disclosure.

[0064] It should also be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, this disclosure will not describe the various possible combinations separately.

[0065] Furthermore, various different embodiments of this disclosure can be combined in any way, as long as they do not violate the spirit of this disclosure, they should also be regarded as the content disclosed in this disclosure.

Claims

1. A method for purifying 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine, wherein, The method includes recrystallizing a solution containing a mixture of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine at least once, wherein the recrystallization conditions include: a temperature of -75°C to -40°C, a time of 2-100 hours, wherein the ratio of the mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine to the crystallization solvent is 1 g: 0.5-8 mL, the content of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine in the mixture is at least 80% by weight, and the crystallization solvent is selected from C5-C9 alkanes, C7-C6 alkane compounds, and C7-C6 alkane compounds. 11 One or more of aromatic compounds or C2-C6 nitrile compounds.

2. The method as described in claim 1, wherein, The conditions for each recrystallization include: a temperature of -60°C to -40°C, a time of 6-48 hours, and a solution containing a mixture of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine, wherein the ratio of the mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine to the crystallization solvent is 1 g: 1-5 mL.

3. The method as described in claim 1, wherein, The conditions for each recrystallization include: a temperature of -60°C to -50°C, a time of 12-42 hours, and a solution containing a mixture of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine, wherein the ratio of the mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine to the crystallization solvent is 1 g: 0.6-3 mL.

4. The method of claim 1, wherein, The recrystallization is performed 1-3 times.

5. The method of claim 1, wherein, The recrystallization is performed 1-2 times.

6. The method of claim 1, wherein, The crystallization solvent is one of acetonitrile, butyronitrile, and isobutyronitrile.

7. The method as described in any one of claims 1-6, wherein, The mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine has a content of 80-95% by weight.

8. A method for preparing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine, the method comprising providing a mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine, and purifying the mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine according to any one of claims 1-7.

9. The preparation method according to claim 8, wherein, A method for preparing a mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphonic diamine includes: S1: In the presence of a first solvent, under condensation reaction conditions, phosphorus trihalide is contacted with an alkylamine to obtain a first reaction mixture; S2: In the presence of a second solvent and under condensation reaction conditions, the first reaction mixture is contacted with a hydroxyl-containing compound to obtain a second reaction mixture; S3: Separate the solvent layer containing the mixture of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphoryldiamine from the second reaction mixture, remove the solvent, and obtain the mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphoryldiamine. The first solvent is a polar solvent, and the second solvent is a non-polar solvent; or, the first solvent is a non-polar solvent, and the second solvent is a polar solvent. Wherein, the phosphorus trihalide is phosphorus trichloride or phosphorus tribromide; the alkylamine is diisopropylamine; and the hydroxyl-containing compound is 3-hydroxypropionitrile.

10. The method of claim 9, wherein, The reaction temperature for the contact reaction of phosphorus trihalides with alkylamines is -20°C to 15°C, the reaction time is 1-6 hours, and the ratio of phosphorus trihalides, alkylamines, and the first solvent is 1 mol: 2-20 mol: 0.5-10 L; and / or The reaction temperature of the first reaction mixture in contact with the hydroxyl-containing compound is -30℃ to 10℃, and the reaction time is 1-6 hours. The ratio of the first reaction mixture, the hydroxyl-containing compound, and the second solvent is 1 mol: 0.5-2 mol: 0.5-30 L.

11. The method of claim 10, wherein, The reaction temperature for the phosphorus trihalide and alkylamine reaction is -10℃ to 10℃, the reaction time is 3-5 hours, and the ratio of phosphorus trihalide, alkylamine and first solvent is 1 mol: 3-10 mol: 0.5-6 L.

12. The method of claim 10, wherein, The reaction temperature for the first reaction mixture to react with the hydroxyl-containing compound is -20°C to 0°C, and the reaction time is 3-5 hours. The ratio of the first reaction mixture, the hydroxyl-containing compound, and the second solvent is 1 mol: 0.8-1.5 mol: 0.5-20 L.

13. The method of claim 9, wherein, The polar solvent is selected from one of acetonitrile, butyronitrile, isobutyronitrile, dichloromethane, ethyl acetate, and tetrahydrofuran, and the nonpolar solvent is selected from one of n-heptane, n-hexane, and n-pentane.

14. The method of claim 7, wherein, The mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine has a content of at least 90% by weight of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine.

15. The method of claim 7, wherein, The mixture containing 2-cyanoethyl N,N,N',N'-tetraisopropylphosphorous diamine has a content of 90-95% by weight.

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