Synthesis method of DIPPN

Abstract

The invention provides a synthesis method of DIPPN (diisopropylidene-1, 3-pentanedione), and particularly, the method comprises the following steps: (1) reacting acetonitrile with isopropyl bromide to form 2-isopropyl-3-methyl butyronitrile; and (2) enabling the 2-isopropyl-3-methyl butyronitrile to react with a methylation reagent, so as to form the DIPPN. The method provides a new synthesis method for synthesizing the WS-23 intermediate, and the method has the advantages of short steps, high yield and simple purification and post-treatment, and can be used for further large-scale production of WS-23.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a method for synthesizing DIPPN. Background Art

[0002] Cooling agent WS-23, also known as N,2,3-trimethyl-2-isopropylbutanamide, is a synthetic cooling agent widely used in food, beverages and oral care products. Unlike chloramine cooling agents, it does not have a minty taste, but can produce a strong cooling sensation in the mouth and throat, and is often used to enhance the taste of products and the sensory experience of consumers.

[0003] The main industrial synthesis method of WS-23 on the market (CN101823983A; CN107235855B) is to use propionitrile as raw material, liquid ammonia as solvent, sodium amide as base, and 2-bromopropane as alkylating agent to prepare 2,2-isopropylpropionitrile (DIPPN). DIPPN can be reacted with dimethyl carbonate in polyphosphoric acid to obtain WS-23, which is an important intermediate in the reaction.

[0004] The current synthesis process of DIPPN requires low-temperature reaction conditions to achieve the liquefaction of ammonia, which greatly increases the production cost.

[0005]

[0006] In view of the problems in the above process, the improved processes disclosed in the prior art mainly include the following:

[0007] (1) Chavakula et al. used propionitrile as the starting material and tetrahydrofuran instead of liquid ammonia as the solvent, and successfully prepared DIPPN at room temperature (Chavakula, R., Mutyala, NR and Chennupati, SR, Org. Prep. Proced. Int., 2014, 46(3), 277-279). Since propionitrile is a highly toxic chemical, its source is limited.

[0008] (2) Patent US4230688 uses 2,2-isopropylpropionitrile (DIPPN) as the starting material, first hydrolyzes it to generate diisopropylpropionic acid, then reacts it with thionyl chloride to generate the corresponding acyl chloride, and finally reacts it with methylamine to obtain WS-23. The disadvantages of this process are that it produces a lot of three wastes, poor safety, long synthesis steps, and complex operations, making it unsuitable for large-scale industrial production.

[0009] (3) Chinese invention patent CN107954888A discloses a synthetic route using methyl acetoacetate as the starting material. This route has a long process and a complicated process. For example, a large amount of reducing agent is required in the process of converting the ester group into the methyl group, and a large amount of strongly acidic and corrosive byproducts are produced in the step of Beckmann rearrangement to form amides, making this synthetic route difficult to industrialize.

[0010] Therefore, there is an urgent need for a method for synthesizing DIPPN that is short in steps, environmentally friendly, and uses simple reagents. Summary of the invention

[0011] The purpose of the present invention is to provide a method for synthesizing DIPPN with short steps, environmental friendliness and simple reagents.

[0012] In a first aspect of the present invention, a method for synthesizing DIPPN is provided, the method comprising the following reaction steps:

[0013] (1) Compound 1 reacts with compound 2 in an inert solvent to form compound 3;

[0014]

[0015] (2) In an inert solvent, compound 3 reacts with a methylating agent to form the intermediate DIPPN

[0016]

[0017] In another preferred embodiment, the method further comprises one or more features selected from the following group:

[0018] In step (1), the reaction is carried out in the presence of a base, preferably, the base is sodium amide;

[0019] In step (1), the molar ratio of compound 1 to compound 2 in the reaction is 1:(0.5-4);

[0020] In step (1), the inert solvent is selected from the group consisting of THF, 2-methyltetrahydrofuran, or a combination thereof.

[0021] In another preferred embodiment, in the step (1), the reaction temperature is 0-90°C; preferably 0-40°C.

[0022] In another preferred embodiment, in the step (1), the reaction time is 1-12 hours.

[0023] In another preferred embodiment, the inert solvent is THF saturated with ammonia.

[0024] In another preferred embodiment, the molar ratio of compound 1 to compound 2 in the reaction is 1:1-2.

[0025] In another preferred embodiment, the molar ratio of sodium amide to compound 1 in the reaction is 1:0.5-2.

[0026] In another preferred embodiment, the molar ratio of sodium amide to compound 1 in the reaction is 1:1-2.

[0027] In another preferred embodiment, in the step (1), sodium amide is first dissolved in an inert solvent to obtain a mixed solution A, and then a mixed solution of compound 1 and compound 2 is added to the mixed solution A in the second step.

[0028] In another preferred embodiment, the step (1) further comprises heating the mixed solution A to 15-80°C and maintaining the temperature for 10-60 minutes, then stopping the heating and allowing the mixed solution A to naturally recover to 15-30°C.

[0029] In another preferred embodiment, compound 1 and compound 2 are added to the mixed solution A under an ice-water bath.

[0030] In another preferred embodiment, in step (1), the mixed solution of compound 1 and compound 2 is added dropwise to the mixed solution A.

[0031] In another preferred embodiment, in step (1), the mixed solution of compound 1 and compound 2 is added to mixed solution A within 1 to 8 hours.

[0032] In another preferred embodiment, in step (1), the mixed solution of compound 1 and compound 2 is added to the mixed solution A in batches.

[0033] In another preferred embodiment, in step (1), the amount of the mixed solution of compound 1 and compound 2 added to the first batch of mixed solution A is 1 to 15%.

[0034] In another preferred embodiment, in step (1), the first batch of compound 1 and compound 2 is added at a temperature of 5-28°C, preferably 20-30°C.

[0035] In another preferred embodiment, in step (1), the addition of the mixed solution of compound 1 and compound 2 to the second batch of mixed solution A is completed at a reaction liquid temperature of 40-60°C, preferably 45-55°C.

[0036] In another preferred embodiment, in step (1), the addition of the second batch of the mixed solution of compound 1 and compound 2 also requires maintaining the external temperature of the reaction solution at 5-15°C; preferably 8-12°C.

[0037] In another preferred embodiment, in the step (1), the reaction is detected by gas chromatography to determine whether the reaction is complete.

[0038] In another preferred embodiment, in the step (1), the reaction further comprises isolating compound 3 from the reaction mixture.

[0039] In another preferred embodiment, the step (1) comprises: dissolving sodium amide in an inert solvent at room temperature, heating to 40-60° C. and maintaining for 20-40 minutes, then returning to room temperature, and adding a mixed solution of compound 1 and compound 2 dropwise to the above sodium amide solution in an ice water bath to react to obtain a reaction product.

[0040] In another preferred embodiment, the step (1) comprises: dissolving sodium amide in an inert solvent at room temperature, heating to 45-55° C. and maintaining for 20-40 minutes, stopping heating, and allowing it to naturally return to room temperature, and adding the mixed solution of compound 1 and compound 2 dropwise to the above sodium amide solution in an ice water bath, and after the dropwise addition is completed within 4-6 hours, continuing the reaction at room temperature for 1-3 hours.

[0041] In another preferred embodiment, the step (1) comprises: dissolving sodium amide in THF at room temperature. Adding the mixed solution of compound 1 and compound 2 dropwise to the sodium amide solution at room temperature (not more than 8-12%). Heating the reaction solution to 45-55°C, and continuing to add dropwise after the reaction is initiated, while maintaining the external temperature at about 8-12°C for 3-4 hours. After the addition is completed, continue to react at room temperature for 1-3 hours.

[0042] In another preferred embodiment, the step (1) further comprises: after the reaction is completed, the reaction solution is cooled to -2-2°C, and ice water is added dropwise within 55-65 minutes. After the addition is completed, the reaction solution is stirred at 30°C-35°C for 25-35 minutes. The reaction solution is heated and concentrated at normal pressure to remove THF. The upper organic phase is washed with water and 8-12% brine in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 3.

[0043] In another preferred embodiment, the method further comprises one or more features selected from the following group:

[0044] In step (2), the inert solvent is THF;

[0045] In step (2), the reaction is carried out in the presence of sodium amide;

[0046] In step (2), the methylating agent is selected from the group consisting of dimethyl sulfate, methyl p-toluenesulfonate, and methyl iodide;

[0047] In step (2), the reaction temperature is 15-75°C;

[0048] In step (2), the reaction time is 1-10h;

[0049] In step (2), the molar ratio of compound 3 to the methylating agent in the reaction is 1:(1-5).

[0050] In another preferred embodiment, the methylating agent in the reaction is methyl iodide.

[0051] In another preferred embodiment, in the step (2), the molar ratio of compound 3 to methyl iodide in the reaction is 1:1-3.

[0052] In another preferred embodiment, in step (2), sodium amide is first dissolved in an inert solvent to obtain a mixed solution B, and a mixed solution of compound 3 and a methylating agent is added to the mixed solution B in a second step.

[0053] In another preferred embodiment, in the step (2), sodium amide is dissolved in an inert solvent at room temperature to obtain a mixed solution B.

[0054] In another preferred embodiment, in step (2), the mixed solution of compound 3 and the methylating agent is added to the mixed solution B at a temperature of 15-75°C, preferably, the temperature is 50-60°C; more preferably, the temperature is 20-30°C.

[0055] In another preferred embodiment, in step (2), the mixed solution of compound 3 and the methylating agent is added to the mixed solution B in a dropwise manner.

[0056] In another preferred embodiment, in step (2), the mixed solution of compound 3 and the methylating agent is added dropwise to the mixed solution B for 1-3 hours.

[0057] In another preferred embodiment, in the step (2), the reaction is detected by gas chromatography to determine whether the reaction is complete.

[0058] In another preferred embodiment, in the step (2), the reaction further comprises isolating the intermediate DIPPN from the reaction mixture.

[0059] In another preferred embodiment, the step (2) comprises: dissolving sodium amide in THF at room temperature, and then adding a mixed solution of compound 3 and a methylating agent dropwise to the sodium amide solution at 20-60° C.; after the dropwise addition is completed, obtaining a reaction product at 50-60° C.

[0060] In another preferred embodiment, in the step (2), the reaction comprises: dissolving sodium amide in THF at room temperature; adding a mixed solution of compound 3 and a methylating agent dropwise to the sodium amide solution at 20-60° C. for 1-3 h; after the addition is complete, continuing the reaction at 50-60° C. for 1-3 h.

[0061] In another preferred embodiment, in the step (2), the reaction further comprises: after the reaction is completed, cooling the reaction solution to -2-2°C, adding 10-20 mL of ice water within 50-70 minutes; after the addition is completed, stirring the reaction solution at 30°C-35°C for 25-35 minutes. The reaction solution is heated and concentrated at normal pressure to remove THF, and the temperature does not exceed 90-100°C; the upper organic phase is washed with 1-10 mL of water and 1-10 mL of 8-12% brine in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the intermediate DIPPN.

[0062] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 is the H NMR spectrum of compound 3.

[0064] Figure 2 This is the H NMR spectrum of the intermediate DIPPN.

[0065] Figure 3 This is the H NMR spectrum of WS-23. DETAILED DESCRIPTION

[0066] After extensive and in-depth research, a large number of screenings and tests, the inventors have provided a method for synthesizing DIPPN with short steps, environmental friendliness and simple reagents. The method has short steps, the reaction reagent is a common low-toxic reagent such as acetonitrile, the cost is low, the environment is friendly, the post-processing and purification are simple, the product yield is high, and the purity is as high as 99.9% or more. On this basis, the present invention was completed.

[0067] the term

[0068] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0069] As used herein, when used in reference to a specific recited numerical value, the term "about" means that the value may vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0070] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0071] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0072] Synthesis of DIPPN

[0073] The present invention provides a method for synthesizing DIPPN, which comprises the following reaction steps:

[0074] (1) Compound 1 reacts with compound 2 in an inert solvent to form compound 3;

[0075]

[0076] (2) In an inert solvent, compound 3 reacts with a methylating agent to form the intermediate DIPPN

[0077]

[0078] In step (1), the reaction is carried out in the presence of a base, preferably, the base is sodium amide; the applicant has found that the selection of the base in step (1) is important for the reaction, and when sodium amide is replaced by potassium tert-butoxide, the reaction yield will drop significantly.

[0079] The ratio of each reactant can be a suitable comparative example. In a preferred embodiment, the molar ratio of compound 1 to compound 2 in the reaction of step (1) is 1:(0.5-4).

[0080] The reaction solvent may be a suitable inert solvent. In a preferred embodiment, in step (1), the inert solvent is selected from the group consisting of THF, 2-methyltetrahydrofuran, or a combination thereof.

[0081] During the reaction, it was found that material collision easily occurred when Compound 1 and Compound 2 were added. Therefore, the reaction conditions were optimized. Sodium amide was dissolved in THF and heated, or THF was saturated with ammonia in advance, thereby effectively improving the collision when Compound 1 and Compound 2 were added.

[0082] The reaction temperature can be selected at a suitable temperature. In a preferred embodiment, the reaction temperature in step (1) is 0-90°C; preferably 0-40°C.

[0083] In a preferred embodiment, in the step (1), sodium amide is first dissolved in an inert solvent to obtain a mixed solution A, and a mixed solution of compound 1 and compound 2 is added to the mixed solution A in the second step. The method can be used to avoid the problem of material impact during the reaction. The remaining preferred conditions are described in detail in the embodiments, but it should be understood that the preferred conditions of the present invention can be arbitrarily combined, and those skilled in the art can also adjust them according to actual conditions.

[0084] Synthesis of WS-23

[0085] The DIPPN prepared by the present invention can be used as a synthetic intermediate of WS-23, and thus used to prepare the cooling agent WS-23. In the present invention, a preferred complete synthesis process of WS-23 includes the following reaction steps:

[0086]

[0087] (1) In an inert solvent such as THF or 2-methyltetrahydrofuran, sodium amide is first added, and then a mixed solution of compound 1 and compound 2 is added to form compound 3;

[0088] (2) In THF solvent, sodium amide is first added, and then a mixed solution of compound 3 and a methylating agent is added to form an intermediate DIPPN;

[0089] (3) The intermediate DIPPN reacts with dimethyl carbonate in an acidic solvent such as Eaton's reagent to form WS-23.

[0090] During the reaction, it was found that polyphosphoric acid is a very viscous liquid at room temperature, which makes the addition and post-processing more troublesome. For this reason, the reaction conditions were optimized and Eaton's reagent was added to the reaction to simplify the reaction processing and improve the reaction yield and product purity.

[0091] Usually, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 80°C, preferably 0°C to 50°C). The reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.

[0092] The main advantages of the present invention include:

[0093] (1) The starting materials used in the synthesis method replace the highly toxic controlled reagents in the prior art with the common reagent acetonitrile, which has lower toxicity, simpler raw materials, and greatly reduced costs;

[0094] (2) The synthesis method has simple steps, uses Eaton's reagent with good fluidity, uses a small amount of tetrahydrofuran, reduces the use of highly polluting and highly toxic reagents, and is safe to operate and environmentally friendly;

[0095] (3) The reaction conditions are mild, no strict low temperature conditions are required, the reaction time is short, and each step only takes a few hours to complete, which is suitable for scale-up and further industrial production;

[0096] (4) The purification and post-treatment of the product are simple, and conventional extraction and recrystallization can achieve high yield and high purity.

[0097] (5) During the reaction, it was found that the addition of compound 1 and compound 2 was prone to collision. Therefore, the reaction conditions were optimized. Sodium amide was dissolved in THF and heated during the reaction, or THF was saturated with ammonia in advance, thereby effectively improving the collision when adding compound 1 and compound 2, without potential risks.

[0098] The present invention will be further described below in conjunction with specific implementation. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0099] Step 1 Synthesis of intermediate 3

[0100]

[0101] Example 1

[0102] At room temperature, sodium amide (15.6 g, 0.4 mol) was dissolved in THF (75 mL). Heat to 50 ° C and keep for 30 minutes, stop heating, and wait for it to return to room temperature naturally. In an ice-water bath, a mixed solution of acetonitrile (8.22 g, 0.2 mol) and isopropyl bromide (49.2 g, 0.4 mol) was added dropwise to the above sodium amide solution. After the addition was completed within 4 hours, the reaction was continued at room temperature for 2 hours. GC monitored the reaction. After the reaction was complete, the reaction solution was cooled to 0 ° C and 150 mL of ice water was added dropwise within 60 minutes. After the addition was completed, the reaction solution was stirred at 30 ° C-35 ° C for 30 minutes. The reaction solution was heated and concentrated at normal pressure to remove THF. The upper organic phase was washed with water (40 mL) and 10% brine (40 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 23.6 g of yellow oily product 3 with a yield of 94.1%. The NMR spectrum of compound 3 is as follows Figure 1 shown.

[0103] 1H NMR (400MHz, CDCl3) δ2.14(t,J=8.0Hz,1H),2.00-1.85(m,2H),1.11(d,J=8.0Hz,6H),1.0(d,J=8.0Hz,6H)

[0104] During the reaction, it was found that acetonitrile and isopropyl bromide were prone to collision when added. Therefore, the reaction conditions were optimized. Sodium amide was dissolved in THF and heated during the reaction, which effectively improved the collision when acetonitrile and isopropyl bromide were added.

[0105] Example 2

[0106] At room temperature, sodium amide (7.8g, 0.2mol) was dissolved in THF (75mL). At room temperature, a mixed solution of acetonitrile (4.11g, 0.1mol) and isopropyl bromide (24.6g, 0.2mol) was added dropwise to the above sodium amide solution (no more than 10% was added). The reaction solution was heated to 50 degrees. After the reaction was initiated, the heating was stopped and the addition was continued while keeping the external temperature at about 10 degrees. The addition time was 4h. After the addition was completed, the reaction was continued at room temperature for 2h. The reaction was monitored by GC. After the reaction was complete, the reaction solution was cooled to 0℃ and 75mL of ice water was added dropwise within 60min. After the addition was completed, the reaction solution was stirred at 30℃–35℃ for 30min. The reaction solution was heated and concentrated at normal pressure to remove THF. The upper organic phase was washed with water (20 mL) and 10% brine (20 mL) in sequence, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 11.2 g of yellow oily product 3 with a yield of 89.3%.

[0107] Example 3

[0108] At room temperature, sodium amide (15.6 g, 0.4 mol) was dissolved in 2-methyltetrahydrofuran (150 mL), heated to 50 ° C and maintained for 30 minutes, and then the heating was stopped and the mixture was allowed to return to room temperature naturally. In an ice-water bath, a mixed solution of acetonitrile (8.22 g, 0.2 mol) and isopropyl bromide (49.2 g, 0.4 mol) was added dropwise to the above sodium amide solution. After the addition was completed within 4 hours, the reaction was continued at room temperature for 2 hours. The reaction was monitored by GC. After the reaction was complete, the reaction solution was cooled to 0 ° C and 150 mL of ice water was added dropwise within 30 minutes. After the addition was completed, the reaction solution was stirred at 30 ° C–35 ° C for 30 minutes. The reaction solution was heated and concentrated at normal pressure to remove THF. The upper organic phase was washed with water (40 mL) and 10% brine (40 mL) in sequence, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 22.9 g of yellow oily product 3 with a yield of 91.3%.

[0109] Example 4

[0110] Under ice-water cooling, sodium amide (15.6 g, 0.4 mol) was dissolved in ammonia-saturated THF (150 mL), and a mixed solution of acetonitrile (8.22 g, 0.2 mol) and isopropyl bromide (49.2 g, 0.4 mol) was added dropwise to the above sodium amide solution. After the addition was completed within 6 hours, the mixture was naturally restored to room temperature and stirred for 2 hours. The reaction was monitored by GC. After the reaction was completed, the reaction solution was cooled to 0°C and 150 mL of ice water was added dropwise within 30 minutes. After the addition was completed, the reaction solution was stirred at 30°C–35°C for 30 minutes. The reaction solution was heated and concentrated under normal pressure to remove THF. The upper organic phase was washed with water (40 mL) and 10% brine (40 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 23.9 g of yellow oily product 3 with a yield of 95.3%.

[0111] Example 5

[0112] At room temperature, potassium tert-butoxide (44.9 g, 0.4 mol) was dissolved in tetrahydrofuran (150 mL), heated to 50 ° C and maintained for 30 minutes. A mixed solution of acetonitrile (8.22 g, 0.2 mol) and isopropyl bromide (49.2 g, 0.4 mol) was added dropwise to the above potassium tert-butoxide solution at 60 ° C. After the addition was completed within 4 hours, the reaction was continued at room temperature for 2 hours. The reaction solution was cooled to 0 ° C and 150 mL of ice water was added dropwise within 30 minutes. After the addition was completed, the reaction solution was stirred at 30 ° C–35 ° C for 30 minutes. The reaction solution was heated and concentrated at normal pressure to remove THF. The upper organic phase was washed with water (40 mL) and 10% brine (40 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 13.4 g of yellow oily product 3 with a yield of 53.5%.

[0113] The results show that the choice of base in step (1) is important for the reaction. When sodium amine is replaced by potassium tert-butoxide, the reaction yield decreases significantly.

[0114] Step 2: Preparation of intermediate DIPPN

[0115]

[0116] Example 6

[0117] At room temperature, sodium amide (11.7 g, 0.3 mol) was dissolved in THF (200 mL). At 55 degrees, a mixed solution of intermediate 3 (12.5 g, 0.1 mol) and dimethyl sulfate (18.9 g, 0.15 mol) was added dropwise to the above sodium amide solution for 2 hours. After the addition was complete, the reaction was continued at 55 degrees for 2 hours. The reaction was monitored by GC. After the reaction was complete, the reaction solution was cooled to 0°C and 150 mL of ice water was added dropwise within 60 minutes. After the addition was complete, the reaction solution was stirred at 30°C-35°C for 30 minutes. The reaction solution was heated and concentrated at normal pressure to remove THF, and the temperature did not exceed 95°C. The upper organic phase was washed with water (50 mL) and 10% brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 11.8 g of a yellow oily product with a yield of 84.9%. The NMR spectrum of DIPPN is as follows Figure 2 shown.

[0118] Gas chromatography was used to detect the purity of DIPPN. The specific chromatographic conditions are shown in Table 1 below:

[0119] Table 1 Gas chromatography analysis conditions of DIPPN

[0120]

[0121] The analysis results are shown in Table 2 below, and the purity of DIPPN is 99.8328%.

[0122] Table 2 Gas chromatography purity results of DIPPN

[0123]

[0124] 1 H NMR (400MHz, CDCl3) δ2.05-1.85 (m, 2H), 1.16 (s, 3H), 1.09 (d, J = 8.0Hz, 6H), 0.97 (d, J = 8.0Hz, 6H).

[0125] Example 7

[0126] At room temperature, sodium amide (11.7 g, 0.3 mol) was dissolved in THF (200 mL). At 55 degrees, a mixed solution of 3 (12.5 g, 0.1 mol) and methyl p-toluenesulfonate (55.9 g, 0.3 mol) was added dropwise to the above sodium amide solution for 2 hours. After the addition was completed, the reaction was continued at 55 degrees for 2 hours. GC monitored the reaction. After the reaction was complete, the reaction solution was cooled to 0°C and 150 mL of ice water was added dropwise within 60 minutes. After the addition was completed, the reaction solution was stirred at 30°C-35°C for 30 minutes. The reaction solution was heated and concentrated at normal pressure to remove THF, and the temperature did not exceed 95°C. The upper organic phase was washed with water (50 mL) and 10% brine (50 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 10.6 g of yellow oily product DIPPN with a yield of 76.3%.

[0127] Example 8

[0128] At room temperature, sodium amide (7.8 g, 0.2 mol) was dissolved in THF (200 mL). At room temperature, a mixed solution of intermediate 3 (12.5 g, 0.1 mol) and iodomethane (28.4 g, 0.2 mol) was added dropwise to the above sodium amide solution for 2 h. After the addition was complete, the reaction was continued at 55 degrees for 2 h. The reaction was monitored by GC. After the reaction was complete, the reaction solution was cooled to 0 ° C and 15 mL of ice water was added dropwise within 60 min. After the addition was complete, the reaction solution was stirred at 30 ° C–35 ° C for 30 min. The reaction solution was heated and concentrated at normal pressure to remove THF, and the temperature did not exceed 95 ° C. The upper organic phase was washed with water (5 mL) and 10% brine (5 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 12.9 g of a yellow oily product DIPPN with a yield of 92.8%.

[0129] The results show that the best methylation effect can be achieved when methyl iodide is used as the methylation agent here.

[0130] Step 3: Synthesis of target product WS-23

[0131]

[0132] Example 9

[0133] Place Eaton's reagent (80.0 g) in a 250 mL eggplant-shaped bottle, dissolve DIPPN (20 g, 0.14 mol) and dimethyl carbonate (12.9 g, 0.14 mol) in Eaton's reagent, and place the reaction device in a 135 ° C oil bath and heat and stir for about 7 hours. Cool the reaction solution, dilute with deionized water (100 mL), and a large amount of light yellow solid precipitates under ice-water cooling. Filter to obtain 25.8 g of WS-23 crude product. The crude product is recrystallized with n-heptane to obtain 23.5 g of crystalline white solid, which is pure WS-23, with a yield of 95.5% and a gas chromatographic purity of 99.97%. The NMR spectrum of WS-23 is as follows Figure 3 shown.

[0134] Gas chromatography was used to detect the purity of WS-23. The specific chromatographic conditions are shown in Table 3 below:

[0135] Table 3 Gas chromatography analysis conditions of WS-23

[0136]

[0137] The analysis results are shown in Table 4 below, and the purity of WS-23 is 99.9701%.

[0138] Table 4 Gas chromatography purity results of WS-23

[0139]

[0140] 1 H NMR (400MHz, CDCl3) δ5.62 (brs, 1H), 2.81 (d, J = 6.0Hz, 3H), 2.05-1.95 (m, 2H), 1.00 (s, 3H), 0.93 (d, J = 8.0Hz, 8H), 0.86 (d, J = 8.0Hz, 8H).

[0141] Example 10

[0142] Eaton's reagent (65.0 g) was placed in a 250 mL eggplant-shaped bottle, DIPPN (20 g, 0.144 mol) and dimethyl carbonate (7.6 g, 0.084 mol) were dissolved in Eaton's reagent, and the reaction device was placed in a 135°C oil bath and heated and stirred for about 7 hours. The reaction solution was cooled, diluted with deionized water (100 mL), and a large amount of light yellow solid precipitated under ice-water cooling. The crude product was filtered and recrystallized with n-heptane to obtain 23.1 g of crystalline white solid, with a yield of 93.9% and a gas chromatographic purity of 99.97%.

[0143] Embodiment 11

[0144] Put polyphosphoric acid (80.0 g) in a 250 mL eggplant-shaped bottle, dissolve DIPPN (20 g, 0.14 mol) and dimethyl carbonate (12.9 g, 0.14 mol) in Eaton's reagent, and place the reaction device in a 135°C oil bath for heating and stirring for about 7 hours. Cool the reaction solution, dilute it with deionized water (100 mL), and a large amount of light yellow solid precipitates under ice-water cooling. Filter and recrystallize the crude product with n-heptane to obtain 22.6 g of crystalline white solid, with a yield of 91.9% and a gas chromatographic purity of 98.7%.

[0145] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for synthesizing DIPPN, characterized in that: The method comprises the following reaction steps: (1) Compound 1 reacts with compound 2 in an inert solvent to form compound 3; (2) In an inert solvent, compound 3 reacts with a methylating agent to form an intermediate DIPPN:

2. The method according to claim 1, characterized in that The method further comprises one or more features selected from the group consisting of: In step (1), the reaction is carried out in the presence of a base, preferably, the base is sodium amide; In step (1), the molar ratio of compound 1 to compound 2 in the reaction is 1:(0.5-4); In step (1), the inert solvent is selected from the group consisting of THF, THF saturated with ammonia, 2-methyltetrahydrofuran, or a combination thereof.

3. The method according to claim 2, characterized in that In the step (1), the reaction temperature is 0-90°C; preferably 0-40°C.

4. The method according to claim 2, characterized in that The inert solvent is THF or THF saturated with ammonia.

5. The method according to claim 2, characterized in that In the step (1), sodium amide is firstly dissolved in an inert solvent to obtain a mixed solution A, and then a mixed solution of compound 1 and compound 2 is added to the mixed solution A in the second step.

6. The method according to claim 5, characterized in that The step (1) further comprises heating the mixed solution A to 15-80° C. and maintaining the temperature for 10-60 minutes, then stopping the heating and allowing the mixed solution A to naturally recover to 15-30° C.

7. The method according to claim 1, characterized in that The step (1) comprises: dissolving sodium amide in an inert solvent at room temperature, heating to 40-60° C. and maintaining for 20-40 minutes, then returning to room temperature, and adding a mixed solution of compound 1 and compound 2 dropwise to the sodium amide solution in an ice water bath to react and obtain a reaction product.

8. The method according to claim 1, characterized in that The method further comprises one or more features selected from the group consisting of: In step (2), the inert solvent is THF; In step (2), the reaction is carried out in the presence of sodium amide; In step (2), the methylating agent is selected from the group consisting of dimethyl sulfate, methyl p-toluenesulfonate, and methyl iodide; In step (2), the reaction temperature is 15-75°C; In step (2), the reaction time is 1-10h; In step (2), the molar ratio of compound 3 to the methylating agent in the reaction is 1:(1-5).

9. The method according to claim 8, characterized in that The methylating agent in the reaction is methyl iodide.

10. The method according to claim 1, characterized in that The step (2) comprises: dissolving sodium amide in THF at room temperature, and then adding a mixed solution of compound 3 and a methylating agent dropwise into the sodium amide solution at 20-60° C.; and obtaining a reaction product at 50-60° C. after the dropwise addition is completed.

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