Preparation method of oxilafluorine

Abstract

The invention discloses a preparation method of oxilafluorine, which comprises the following steps: firstly, by taking N, N-dihydroxyethyl-1, 3-propane diamine as a raw material, carrying out hydroxyethylation reaction, alkylation reaction and salt forming reaction, and preparing the oxilafluorine by adopting a one-pot method without separating and purifying an intermediate in each step. According to the method, the reaction steps are simplified, the operation complexity is reduced, the reaction treatment difficulty is reduced, and the production efficiency is improved. The separation and purification process is simple and efficient, the reaction process and equipment requirements are simple, the method is suitable for large-scale industrial production, and a new synthesis method can be provided for the long-chain aliphatic tertiary amine hydrofluoride similar compound.

Description

Technical Field

[0001] The present invention relates to the field of synthesis in fine chemicals, and particularly to a preparation method of orafluoride. Background Art

[0002] Orafluoride is a new type of organic fluoride. Different from traditional fluorides, one end of orafluoride is a hydrophilic amino group, and the other end is a hydrophobic aliphatic chain, which endows it with good surface activity. It can quickly wrap each tooth, form an anti-caries protective layer, disperse dental plaque, and can well penetrate the cell membrane of bacteria, interfere with bacterial metabolism, and inhibit the production of organic acids. Orafluoride is recommended by dentists in various countries for the re-fluorination of damaged tooth enamel, playing the roles of cleaning, preventing caries, and preventing tooth sensitivity.

[0003] The synthesis methods of orafluoride have been reported, and there are mainly the following four synthetic routes: Patent US 6464962 uses beef tallow as a raw material and obtains the target product through multiple steps of reaction. Beef tallow is a mixture of long-chain aliphatic alkanes, with more by-products in subsequent reactions, cumbersome reaction steps, difficult purification, low reaction yield, and poor product quality. Patent CN 118496111A mixes multiple raw materials for reaction to obtain the target product. In this route, the reaction raw materials have poor selectivity, many side reactions, long reaction time, and difficult product purification. Patent CN 118515573A has harsh reaction conditions and low yield. This process route is only suitable for theoretical research and cannot achieve large-scale production. Patent CN 118530128A uses acrolein and a relatively expensive phase transfer catalyst. This method uses highly toxic, flammable, and strongly irritating acrolein as a raw material, and the intermediate separation and purification method is not suitable for industrial production. Therefore, it is necessary to provide a synthesis method of orafluoride with simple operation and relatively high overall yield. Summary of the Invention

[0004] The present invention provides a new preparation method of orafluoride to solve the above technical problems. The present invention can obtain orafluoride through a one-pot method. This method has simple production process operation, relatively high total reaction yield, high product quality, mild reaction conditions, simple treatment of reaction wastewater, and broad industrialization prospects.

[0005] The technical solution adopted by the present invention to solve the above technical problems is as follows:

[0006] A preparation method of orafluoride, comprising the following steps:

[0007] S1、 N,N-Dihydroxyethyl- Using 1,3-propanediamine as a raw material and Reaction of hydroxyethyl reagent compound (II) is obtained;

[0008] S2. Directly to Into the reaction solution of compound (II), add octadecyl chloride and a base, and react to obtain compound (III);

[0009] S3. The The reaction solution undergoes a salification reaction with hydrogen fluoride, and after post-treatment, orafuor (I) is obtained. ；

[0010] Among them, the specific synthesis route is as follows in the reaction formula:

[0011]

[0012] In the above solution, in step S1, at 40 - 100 °C, a catalyst and an organic solvent are added to N,N - dihydroxyethyl - 1,3-propanediamine and the hydroxyethyl reagent, and the reaction time is 4 - 8 h.

[0013] In the above solution, in the step S1 , the molar ratio of N,N - dihydroxyethyl - 1,3-propanediamine to the hydroxyethyl reagent and the catalyst is 1:1.05 - 1.15:0.01 - 0.05.

[0014] In the above solution, in the step S1 , the hydroxyethylating reagent is one of ethylene oxide or ethylene carbonate.

[0015] In the above solution, in the step S1 , the catalyst is one of pure water, methanol, ethanol, and acetic acid.

[0016] In the above solution, in step S2, at Reaction temperature 40 - 80 °C, the reaction solution of compound (II) directly undergoes an alkylation reaction with octadecyl chloride under alkaline conditions for 4 - 8 h to obtain compound (III).

[0017] In the above solution, in step S2, at Reaction temperature 40 - 80 °C, first, a part of the base is added to the reaction solution of compound (II), and then octadecyl chloride dissolved in the remaining base and organic solvent is added to the reaction solution to undergo an alkylation reaction.

[0018] In the above solution, in the step S2 , the molar ratio of N,N - dihydroxyethyl - 1,3-propanediamine to octadecyl chloride and the base is 1:1.0 - 1.1:0.05 - 0.1.

[0019] In the above solution, in the step S2 , The base is one of 2-aminopyridine, piperidine, triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine.

[0020] In the above scheme, In the step In S3, at the reaction temperature under the condition of 10 - 40 °C,of compound (III) The reaction solution reacts with hydrogen fluoride to form a salt, and then undergoes post-treatment to obtain orafuor (I).

[0021] In the above scheme, The specific process of the post-treatment in step S3 is as follows: after the reaction is completed, the reaction solution is cooled to 0 °C, filtered to obtain crude orafuor (I), and then recrystallized to obtain pure orafuor (I).

[0022] In the above solution, the step S3 In it, the specific recrystallization process is as follows: the crude orafuor (I) is dissolved in an aqueous solution of a recrystallization solvent, heated under reflux until clear, then a first extraction solvent is added for extraction and washing, and the aqueous phase is separated; an alkali solution is added to the aqueous phase to adjust the pH to 10 - 11, then a second extraction solvent is added for extraction, the oil phase is separated, and then hydrogen fluoride gas is added. The reaction solution is cooled to 0 °C, and pure orafuor (I) is obtained by cooling and crystallization.

[0023] In the above solution, the step S3 In it, the aqueous solution of the recrystallization solvent is one of an aqueous solution of isopropanol, an aqueous solution of ethanol, an aqueous solution of methanol, an aqueous solution of acetonitrile, and an aqueous solution of tetrahydrofuran.

[0024] In the above solution, the step S3 In it, the first or second extraction solvent is the same or different, and it is one of n-hexane, n-heptane, cyclohexane, petroleum ether, toluene or ethyl acetate.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] 1. It overcomes the disadvantages of the prior art, such as cumbersome steps, poor product purity, and inapplicability to industrial production.

[0027] 2. Using N,N - dihydroxyethyl - Starting with 1,3-propanediamine The raw materials are used to synthesize orafuor by a one-pot method, and the total reaction yield reaches over 93%. The reaction yield is high, greatly simplifying the operation process and improving production efficiency.

[0028] 3. Adopting a recrystallization experimental scheme of free extraction and then acidification to form a salt overcomes the defects of the existing process technology and obtains a product with high purity.

[0029] 4. The reaction process is green and environmentally friendly, with less environmental pollution. Specific Embodiments

[0030] The present invention will be further described in detail through specific embodiments. It should be noted that all reagents selected in the following embodiments are commercially available or can be synthesized according to the methods described herein or known methods. For the reaction conditions not listed, they are also easily obtained by those skilled in the art.

[0031] The present invention provides a method for preparing orafuor. First, using N,N - dihydroxyethyl - 1,3-propanediamine as a raw material, through hydroxyethylation reaction, halo - octadecane alkylation reaction, and hydrogen fluoride salt - forming reaction, orafuor is directly prepared by a one - pot method. Among them, the specific reaction formula for synthesis is as follows:

[0032]

[0033] Example 1

[0034] This example provides a method for preparing orafuor, which includes the following steps:

[0035] Step 1: Synthesis of compound (Ⅱ)

[0036] S1: Add 3.25 kg of N,N - dihydroxyethyl - 1,3 - propanediamine (20 mol, 1.0 eq), 6.4 g of methanol (0.2 mol, 0.01 eq) and 10 kg of tetrahydrofuran to a 50 L special reactor equipped with a stirring device, a thermometer and a constant - pressure dropping funnel. Stir at 0 °C for 30 minutes. Slowly dropwise add a tetrahydrofuran solution of ethylene carbonate (1.85 kg of ethylene carbonate (21 mol, 1.05 eq) dissolved in 5 kg of tetrahydrofuran) over 3 h, and control the temperature at about 0 °C during the dropping process. After dropping, react the reaction mixture at 60 °C for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0037] Step 2: compound (III) Synthesis of

[0038] S2: Add 0.10 kg of triethylamine (1 mol, 0.05 eq) to the reaction solution of the above - mentioned Compound (Ⅱ) synthesis, and control the reaction temperature at 20 °C. Then dissolve 5.78 kg of octadecyl chloride (20 mol, 1.0 eq) in 0.10 kg of triethylamine (1 mol, 0.05 eq) and 12 kg of tetrahydrofuran solution, and dropwise add it through a constant - pressure dropping funnel for 2 h, and stir the reaction during the dropping process; after dropping, raise the temperature to 40 °C and react for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0039] Step 3: Compound ( Ⅰ ) Synthesis of orafuor

[0040] S3: Add to the above - mentioned stepcompound (III) It was added to the synthesis reaction solution, and 1.2 kg of dry hydrogen fluoride gas was slowly introduced. After the introduction was complete, the temperature was controlled at 25 °C and the reaction was carried out for 1 h. After the reaction was completed, the reaction solution was cooled to 0 °C, and 10.2 kg of crude olapfluor was obtained by filtration. ( Ⅰ )。 10.2 kg of water and 30.6 kg of isopropanol were added to the crude olapfluor (Ⅰ), and it was heated to 85 °C for reflux until it was dissolved clearly. It was stirred at 85 °C for 1 h, and then cooled to 40 - 45 °C. 10 kg of n-heptane was added to the reaction solution, and extraction and washing were carried out 2 times. Each time, extraction and washing were carried out at 40 - 45 °C with stirring for 30 min, and the aqueous phase was separated. The extracted aqueous phase was cooled to 10 °C, and then 3 kg of sodium hydroxide solution was slowly added dropwise. During the dropping process, the temperature was controlled not to exceed 25 °C at the highest, and adjusted to pH 10 - 11, and the reaction was stirred for 2 h. 25 kg of ethyl acetate was added to the reaction solution for extraction 3 times, and extraction and stirring were carried out for 30 min, and the oil phase was separated. 1.2 kg of dry hydrogen fluoride gas was slowly introduced into the ethyl acetate oil phase obtained by extraction. During the reaction process, the temperature was controlled at 20 - 25 °C. After the introduction was complete, the temperature was controlled at 25 °C and the reaction was carried out for 2 h. The reaction solution was cooled to 0 °C, and crystallization was carried out by cooling, and centrifugal filtration was carried out to obtain 9.5 kg of wet olapfluor (Ⅰ), and then vacuum drying was carried out at 60 °C for 10 h to obtain 9.14 kg of pure olapfluor (Ⅰ). The total reaction yield was 95.5%, and the purity was 99.25%.

[0041] 1 1H NMR (400 MHz, CDCl 3 ) δ (ppm): 4.23 (s, 3H, -CH 2 -CH 2 -OH), 3.61~3.56 (dt, J= 9.8, 4.9 Hz, 6H, -CH 2 -), 2.56~2.47 (m, 10H, -CH 2 -), 2.41~2.37 (t, J=8.0 Hz, 2H, -CH 2 -), 1.65~1.58(m,2H,-CH 2 -),1.45~1.37(m,2H,-CH 2 -),1.27~1.21(m,30H,-C 15 H 30 -),0.85~ 0.83 (t, J = 8.0 Hz, 3H, -CH 3 ). 13 C NMR (400 MHz, CDCl 3 ) δ (ppm): 59.6 ppm, 59.1 ppm, 56.7 ppm, 55.8 ppm, 54.4 ppm, 52.6 ppm, 52.0 ppm, 31.9 ppm, 29.7 ppm, 29.6 ppm, 29.6 ppm, 29.5 ppm, 29.3 ppm, 27.6 ppm, 25.7 ppm, 24.3 ppm, 22.7 ppm, 14.1 ppm. HRMS(ESI) [C 27 H 58 N 2 O 3 +H] + m / z calcd for 459.4447, found 459.454

[0042] In the present invention, the purity of olapfluor was tested by this titration method: 1 g of olapfluor sample was dissolved in 100 g of pure water, stirred at 25 °C for 30 min until completely dissolved, then 5 drops of phenolphthalein indicator were added, and titrated with 0.1 mol / L sodium hydroxide solution until it turned slightly red and remained unchanged for 30 s as the end point. Then 20 ml of acetic anhydride was slowly added, shaken well, and left at room temperature for 15 min. Then 30 ml of isopropanol solution was added, a stir bar was placed, the glass electrode and calomel electrode of the calibrated pH meter were immersed in the liquid, the electromagnetic stirrer was turned on and adjusted to an appropriate speed, and potentiometric titration was carried out with 0.2 mol / L hydrochloric acid isopropanol standard solution, and the titration curve was plotted. The maximum jump of the potential value was taken as the end point, and the corresponding volume (V) was recorded. The purity of olapfluor in the sample was calculated according to the formula.

[0043]

[0044] In the formula: X - purity of olapfluor, %;

[0045] V - volume of the titrated hydrochloric acid standard solution, mL;

[0046] Concentration of C-hydrochloric acid standard solution, mo1 / L;

[0047] m - Sample weight, g;

[0048] M - Molar mass of free hydroxylamine of orafur, g / mo1.

[0049] Comparative Example 1

[0050] This comparative example provides a preparation method of orafur, including the following steps:

[0051] Step 1: Synthesis of compound (Ⅱ)

[0052] S1: Add 3.25 kg of N,N - dihydroxyethyl - 1,3 - propanediamine (20 mol, 1.0 eq) and 10 kg of tetrahydrofuran to a 50 L special reactor equipped with a stirring device, a thermometer, and a constant pressure dropping funnel, and stir at 0 °C for 30 minutes. Slowly dropwise add a tetrahydrofuran solution of ethylene oxide (0.88 kg of ethylene oxide (20 mol, 1.0 eq) dissolved in 1.5 kg of tetrahydrofuran) over 6 h, and control the temperature at about 0 °C during the dropping process. After dropping, the reaction mixture is reacted at 40 °C at room temperature for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0053] Step 2: compound (III) The synthesis and preparation process of is the same as that in Step 2 of Example 1.

[0054] Step 3: Compound ( Ⅰ ) The synthesis process of orafur is the same as that in Step 3 of Example 1, except that 7.91 kg of compound ( Ⅰ ) orafur , reaction yield: 82.6%, purity: 98.3% .

[0055] Comparative Example 2

[0056] This comparative example provides a preparation method of orafur, including the following steps:

[0057] Step 1: The synthesis and preparation process of compound (Ⅱ) is the same as that in Step 1 of Example 1.

[0058] Step 2: compound (III) Synthesis of

[0059] S2: In the previous step Compound To the synthesis reaction solution of (II), 0.28 kg of potassium carbonate (2 mol, 0.05 eq) was added, and the reaction temperature was controlled at 20 °C. 5.78 kg of octadecyl chloride (20 mol, 1.0 eq) was dissolved in 12 kg of tetrahydrofuran solution, and it was added dropwise with a constant-pressure dropping funnel over 2 h. Stirring reaction was carried out during the dropping process; after the dropping was completed, the temperature was raised to 40 °C and the reaction was carried out for 4 h. After the reaction was completed, there was no need for separation and purification, and the reaction solution was directly used for the next feeding.

[0060] Step 3: Compound ( Ⅰ ) The synthesis process of orafurane was the same as that in Step 3 of Example 1, except that 8.02 kg of compound ( Ⅰ ) orafurane , reaction yield: 83.9%, purity: 90.9% .

[0061] Comparative Example 3

[0062] This comparative example provides a preparation method of orafurane, including the following steps:

[0063] Step 1: The synthesis preparation process of compound (II) was the same as that in Step 1 of Example 1.

[0064] Step 2: compound (III) synthesis of

[0065] S2: To the Compound synthesis reaction solution of (II), 0.10 kg of triethylamine (1 mol, 0.05 eq) was added, and the reaction temperature was controlled at 20 °C. 6.66 kg of octadecyl bromide (20 mol, 1.0 eq) was dissolved in 0.10 kg of triethylamine (1 mol, 0.05 eq) and 20 kg of tetrahydrofuran solution, and it was added dropwise with a constant-pressure dropping funnel over 2 h. Stirring reaction was carried out during the dropping process; after the dropping was completed, the temperature was raised to 40 °C and the reaction was carried out for 4 h. After the reaction was completed, there was no need for separation and purification, and the reaction solution was directly used for the next feeding.

[0066] Step 3: Compound ( Ⅰ ) The synthesis process of orafurane was the same as that in Step 3 of Example 1, except that 9.24 kg of compound ( Ⅰ ) orafurane , reaction yield: 96.6%, purity: 93.9% .

[0067] Comparative Example 4

[0068] This comparative example provides a preparation method of orafurane, including the following steps:

[0069] Step 1: The synthesis preparation process of compound (II) was the same as that in Step 1 of Example 1.

[0070] Step 2: compound (III) synthesis of

[0071] S2: The previous stepCompound The synthesis reaction solution of (II) was cooled to 20 °C, and 0.20 kg of triethylamine (2 mol, 0.1 eq) was directly added at one time. 5.78 kg of octadecyl chloride (20 mol, 1.0 eq) was dissolved in 12 kg of tetrahydrofuran solution. After addition, the temperature was raised to 40 °C and the reaction was carried out for 4 h. After the reaction was completed, there was no need for separation and purification, and the reaction solution was directly used for the next feeding.

[0072] Step 3: Compound ( Ⅰ ) The synthesis process of orafurane was the same as that in Step 3 of Example 1, except that 7.74 kg of compound ( Ⅰ ) orafurane , reaction yield: 80.9%, purity: 91.3% was obtained.

[0073] Comparative Example 5

[0074] This comparative example provides a preparation method of orafurane, including the following steps:

[0075] Step 1: The synthesis preparation process of compound (II) was the same as that in Step 1 of Example 1.

[0076] Step 2: The synthesis preparation process of compound (Ⅲ) was the same as that in Step 2 of Example 1.

[0077] Step 3: Compound ( Ⅰ ) Synthesis of orafurane

[0078] S3: Add to the synthesis reaction solution of the previous step, slowly introduce 1.2 kg of dry hydrogen fluoride gas. After introduction, control the temperature at 25 °C and react for 1 h. After the reaction is completed, cool the reaction solution to 0 °C and filter to obtain 10.2 kg of crude orafurane compound (III) Ⅰ ( Ⅰ )。 10.2 kg of water were added to the crude orafurane (Ⅰ), heated to 85 °C and refluxed until clear, reacted for 2 h, cooled the reaction solution to 0 °C, cooled and crystallized, centrifuged and filtered to obtain 8.9 kg of wet orafurane (Ⅰ), and then dried in vacuum at 60 °C for 10 h to obtain 8.74 kg of pure orafurane (Ⅰ). The total reaction yield was 91.4%, and the purity was 86.7%.

[0079] Example 2

[0080] This comparative example provides a preparation method of orafurane, including the following steps:

[0081] Step 1: Synthesis of compound (II)

[0082] S1: Add 3.25 kg of N,N - dihydroxyethyl - 1,3 - propanediamine (20 mol, 1.0 eq), 6.4 g of methanol (0.2 mol, 0.01 eq) and 10 kg of tetrahydrofuran into a 50 L special reactor equipped with a stirring device, a thermometer and a constant - pressure dropping funnel. Stir at 0 °C for 30 minutes. Slowly add a tetrahydrofuran solution of ethylene oxide (0.88 kg of ethylene oxide (20 mol, 1.0 eq) dissolved in 1.5 kg of tetrahydrofuran). The material is added dropwise at 0 °C for 6 h, and the temperature is controlled at about 0 °C during the dropping process. After dropping, the reaction mixture is reacted at 40 °C at room temperature for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0083] Step 2: compound (III) The synthesis preparation process is the same as that of Step 2 in Example 1.

[0084] Step 3: Compound ( Ⅰ ) The synthesis process of orafur is the same as that of Step 2 in Example 1, except that 9.05 kg of compound ( Ⅰ ) orafur , reaction yield: 94.6%, purity: 98.9%.

[0085] Example 3

[0086] This example provides a preparation method of orafur, including the following steps:

[0087] Step 1: Synthesis of compound (Ⅱ)

[0088] S1: Add 3.25 kg of N,N - dihydroxyethyl - 1,3 - propanediamine (20 mol, 1.0 eq), 6.4 g of methanol (0.2 mol, 0.01 eq) and 10 kg of 1,4 - dioxane into a 50 L special reactor equipped with a stirring device, a thermometer and a constant - pressure dropping funnel. Stir at 0 °C for 30 minutes. Slowly add a 1,4 - dioxane solution of ethylene carbonate (1.76 kg of ethylene carbonate (20 mol, 1.0 eq) dissolved in 5 kg of 1,4 - dioxane). The dropping takes 3 h, and the temperature is controlled at about 0 °C during the dropping process. After dropping, the reaction mixture is reacted at 80 °C for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0089] Step 2: compound (III) Synthesis of

[0090] S2: In the previous step Compound 0.10 kg of triethylamine (1 mol, 0.05 eq) was added to the synthesis reaction solution of (II), and the reaction temperature was controlled at 20 °C. 5.78 kg of octadecyl chloride (20 mol, 1.0 eq) was dissolved in 0.10 kg of triethylamine (1 mol, 0.05 eq) and 12 kg of 1,4-dioxane solution, and it was added dropwise with a constant-pressure dropping funnel over 2 h. During the dropping process, the reaction was stirred; after the dropping was completed, the temperature was raised to 80 °C and the reaction was carried out for 6 h. After the reaction was completed, there was no need for separation and purification, and the reaction solution was directly used for the next feeding.

[0091] Step 3: Compound ( Ⅰ ) Synthesis of orafloxacin

[0092] S3: To the synthesis reaction solution of the previous step compound (III) was added, and 1.2 kg of dry hydrogen fluoride gas was slowly introduced. After the introduction was completed, the temperature was controlled at 25 °C and the reaction was carried out for 1 h. After the reaction was completed, the reaction solution was cooled to 15 °C, and 10.5 kg of crude orafloxacin was obtained by filtration. ( Ⅰ )。 The crude orafloxacin (Ⅰ) was added with 31 kg of ethanol and 10.5 kg of water, heated to 85 °C and refluxed until clear, stirred at 85 °C for 1 h, and then cooled to 40 - 45 °C. 9 kg of cyclohexane was added to the reaction solution, and extraction and washing were carried out 2 times. Each time, extraction and washing were carried out at 40 - 45 °C with stirring for 30 min, and the aqueous phase was separated; the extracted aqueous phase was cooled to 10 °C, and then 3 kg of sodium hydroxide solution was slowly added dropwise. During the dropping process, the temperature was controlled not to exceed 25 °C at the highest, adjusted to pH 10 - 11, and the reaction was stirred for 2 h. 25 kg of ethyl acetate was added to the reaction solution for extraction 3 times, and the extraction was stirred for 30 min, and the oil phase was separated. 1.2 kg of dry hydrogen fluoride gas was slowly introduced into the extracted ethyl acetate oil phase. During the reaction process, the temperature was controlled at 20 - 25 °C. After the introduction was completed, the temperature was controlled at 25 °C and the reaction was carried out for 2 h. The reaction solution was cooled to 0 °C, and crystallization was carried out by cooling and centrifuged and filtered to obtain 9.4 kg of wet orafloxacin (Ⅰ), and then vacuum dried at 60 °C for 10 h to obtain 9.08 kg of pure orafloxacin (Ⅰ). The total reaction yield was 94.8%, and the purity was 99.0%.

[0093] Example 4

[0094] This example provides a preparation method of orafloxacin, including the following steps:

[0095] Step 1: Synthesis of compound (II)

[0096] S1: Add 3.25 kg of N,N - dihydroxyethyl - 1,3 - propanediamine (20 mol, 1.0 eq), 6.4 g of methanol (0.2 mol, 0.01 eq) and 10 kg of tetrahydrofuran to a 50 L special reactor equipped with a stirring device, a thermometer and a constant pressure dropping funnel. Stir at 0 °C for 30 minutes. Slowly add dropwise a tetrahydrofuran solution of ethylene carbonate (1.76 kg of ethylene carbonate (20 mol, 1.0 eq) dissolved in 5 kg of tetrahydrofuran) over 3 h, controlling the temperature at about 0 °C during the addition. After the addition, the reaction mixture is reacted at 60 °C for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0097] Step 2: compound (III) Synthesis of

[0098] S2: Add N,N - diisopropylethylamine (1 mol, 0.05 eq) to the synthesis reaction solution of the previous step Compound (Ⅱ), and control the reaction temperature at 20 °C. Dissolve 5.78 kg of octadecyl chloride (20 mol, 1.0 eq) in a solution of 0.12 kg of N,N - diisopropylethylamine (1 mol, 0.05 eq) and 12 kg of 1,4 - dioxane, and add dropwise through a constant pressure dropping funnel for 2 h, stirring the reaction during the addition; after the addition, raise the temperature to 80 °C and react for 6 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0099] Step 3: Compound ( Ⅰ ) Synthesis of Olaflur

[0100] S3: Add to the synthesis reaction solution of the previous step compound (III) , and slowly introduce 1.2 kg of dry hydrogen fluoride gas. After the introduction, control the temperature at 25 °C and react for 1 h. After the reaction is completed, cool the reaction solution to 15 °C and filter to obtain 10.0 kg of crude Olaflur ( Ⅰ )。The crude olaflur (I) is added with 30 kg of isopropanol and 10 kg of water, heated to 85 °C for reflux until dissolved clearly, stirred at 85 °C for 1 h, and then cooled to 40 - 45 °C. 9 kg of cyclohexane is added to the reaction solution, and extraction and washing are carried out 2 times. Each time, extraction and washing are carried out at 40 - 45 °C, stirred for 30 min, and the aqueous phase is separated; the extracted aqueous phase is cooled to 10 °C, and then 3 kg of sodium hydroxide solution is slowly added. During the dropping process, the temperature is controlled not to exceed 25 °C at the highest, adjusted to pH 10 - 11, and reacted and stirred for 2 h. 25 kg of ethyl acetate is added to the reaction solution for extraction 3 times, extracted and stirred for 30 min, and the oil phase is separated. 1.2 kg of dry hydrogen fluoride gas is slowly introduced into the extracted ethyl acetate oil phase. During the reaction process, the temperature is controlled at 20 - 25 °C. After passing through, the temperature is controlled at 25 °C and reacted for 2 h. The reaction solution is cooled to 0 °C, cooled for crystallization, centrifuged and filtered to obtain 9.4 kg of wet olaflur (I), and then vacuum dried at 60 °C for 10 h to obtain 9.05 kg of pure olaflur (I). The total reaction yield is 94.5%, and the purity is 98.6%.

[0101] Example 5

[0102] This example provides a preparation method of olaflur, including the following steps:

[0103] Step 1: Synthesis of compound (II)

[0104] S1: Add 3.25 kg of N,N - dihydroxyethyl - 1,3 - propanediamine (20 mol, 1.0 eq), 24 g of acetic acid (0.4 mol, 0.02 eq) and 10 kg of tetrahydrofuran to a 50 L special reactor equipped with a stirring device, a thermometer and a constant pressure dropping funnel, and stir at 0 °C for 30 minutes. Slowly drop the tetrahydrofuran solution of ethylene carbonate (1.85 kg of ethylene carbonate (21 mol, 1.05 eq) dissolved in 5 kg of tetrahydrofuran), drop for 3 h, and control the temperature at about 0 °C during the dropping process. After dropping, the reaction mixture is reacted at 60 °C for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0105] Step 2: compound (III) Synthesis of

[0106] S2: Add 0.10 kg of triethylamine (1 mol, 0.05 eq) to the synthesis reaction solution of the previous step Compound (II), and control the reaction temperature at 20 °C. 6.36 kg of octadecyl chloride (22 mol, 1.1 eq) is dissolved in 0.10 kg of triethylamine (1 mol, 0.05 eq) and 12 kg of tetrahydrofuran solution, and is dropped through a constant pressure dropping funnel for 2 h. Stir and react during the dropping process; after dropping, the temperature is raised to 60 °C and reacted for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution is directly used for the next feeding.

[0107] Step 3:Compound ( Ⅰ ) Synthesis of Olafluride

[0108] S3: Go one step up compound (III) Add to the synthesis reaction solution, slowly introduce 1.2 kg of dry hydrogen fluoride gas. After completion, control the temperature at 25 °C and react for 1 h. After the reaction is completed, cool the reaction solution to 15 °C and filter to obtain 9.9 kg of crude olafluride ( Ⅰ )。 Add 29.7 kg of isopropanol and 9.9 kg of water to the crude olafluride (Ⅰ), heat to 85 °C and reflux until clear, stir at 85 °C for 1 h, and then cool to 40 - 45 °C. Add 10 kg of petroleum ether to the reaction solution and extract and wash twice. Each time, extract and wash at 40 - 45 °C and stir for 30 min to separate the aqueous phase; cool the extracted aqueous phase to 10 °C, and slowly add 3 kg of sodium hydroxide solution. During the dropping process, control the temperature not to exceed 25 °C at the highest, adjust to pH 10 - 11, and react and stir for 2 h. Add 25 kg of ethyl acetate to the reaction solution and extract 3 times. Extract and stir for 30 min to separate the oil phase. Slowly introduce 1.2 kg of dry hydrogen fluoride gas into the extracted ethyl acetate oil phase. Control the temperature at 20 - 25 °C during the reaction process. After completion, control the temperature at 25 °C and react for 2 h. Cool the reaction solution to 0 °C, cool and crystallize, centrifuge and filter to obtain 9.9 kg of wet olafluride (Ⅰ), and then dry it in vacuo at 60 °C for 10 h to obtain 8.95 kg of pure olafluride (Ⅰ). The total reaction yield is 93.5%, and the purity is 98.95%.

[0109] Example 6

[0110] This example provides a preparation method of olafluride, including the following steps:

[0111] Step 1: Synthesis of compound (Ⅱ)

[0112] S1: Add 3.25 kg of N,N - dihydroxyethyl - 1,3 - propanediamine (20 mol, 1.0 eq), 3.6 g of water (0.2 mol, 0.01 eq) and 10 kg of tetrahydrofuran to a 50 L special reactor equipped with a stirring device, a thermometer and a constant pressure dropping funnel, and stir at 0 °C for 30 minutes. Slowly drop the acetonitrile solution of ethylene carbonate (1.85 kg of ethylene carbonate (21 mol, 1.05 eq) dissolved in 5 kg of acetonitrile) over 3 h, and control the temperature at about 0 °C during the dropping process. After completion, react the reaction mixture at 80 °C at room temperature for 4 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution can be directly used for the next feeding.

[0113] Step 2: compound (III) Synthesis

[0114] S2: Go one step up Compound 0.085 kg of piperidine (1 mol, 0.05 eq) was added to the synthesis reaction solution of (II), and the reaction temperature was controlled at 20 °C. 5.78 kg of octadecyl chloride (20 mol, 1.0 eq) was dissolved in 0.085 kg of piperidine (1 mol, 0.05 eq) and 12 kg of tetrahydrofuran solution, and it was added dropwise with a constant pressure dropping funnel over 4 h. Stirring reaction was carried out during the dropping process; after the dropping was completed, the temperature was raised to 70 °C and the reaction was carried out for 6 h. After the reaction was completed, there was no need for separation and purification, and the reaction solution was directly used for the next feeding.

[0115] Step 3: Compound ( Ⅰ ) Synthesis of orafur

[0116] S3: Add to the synthesis reaction solution of the previous step compound (III) 1.6 kg of dry hydrogen fluoride gas was slowly introduced. After the introduction was completed, the temperature was controlled at 25 °C and the reaction was carried out for 2.5 h. After the reaction was completed, the reaction solution was cooled to 15 °C, and 9.8 kg of crude orafur was obtained by filtration. ( Ⅰ )。 9.8 kg of crude orafur (Ⅰ) was added with 29.4 isopropanol and 9.8 kg of water, heated to 85 °C for reflux to dissolve and clarify, stirred at 85 °C for 3 h, and then cooled to 40 - 45 °C. 9 kg of cyclohexane was added to the reaction solution, and extraction and washing were carried out 2 times. Each time, extraction and washing were carried out at 40 - 45 °C with stirring for 30 min, and the aqueous phase was separated; the extracted aqueous phase was cooled to 10 °C, and then 3 kg of sodium hydroxide solution was slowly added. The temperature was controlled not to exceed 25 °C during the dropping process, adjusted to pH 10 - 11, and the reaction was stirred for 4 h. 25 kg of ethyl acetate was added to the reaction solution for extraction 3 times, and the extraction was stirred for 30 min, and the oil phase was separated. 1.6 kg of dry hydrogen fluoride gas was slowly introduced into the extracted ethyl acetate oil phase. The temperature was controlled at 20 - 25 °C during the reaction process. After the introduction was completed, the temperature was controlled at 25 °C and the reaction was carried out for 2 h. The reaction solution was cooled to 0 °C, and crystallization was carried out by cooling and centrifugally filtered to obtain 9.3 kg of wet orafur (Ⅰ), and then vacuum dried at 60 °C for 10 h to obtain 8.7 kg of pure orafur (Ⅰ). The total reaction yield was 91.5%, and the purity was 99.25%.

[0117] Example 7

[0118] This example provides a preparation method of orafur, including the following steps:

[0119] Step 1: Synthesis of compound (II)

[0120] S1: Add 3.25 kg of N,N - dihydroxyethyl - 1,3 - propanediamine (20 mol, 1.0 eq), 6.4 g of methanol (0.2 mol, 0.01 eq) and 10 kg of tetrahydrofuran into a 50 L special reactor equipped with a stirring device, a thermometer and a constant pressure dropping funnel. Stir at 0 °C for 30 minutes. Slowly add dropwise an acetonitrile solution of ethylene carbonate (1.85 kg of ethylene carbonate (21 mol, 1.05 eq) dissolved in 5 kg of acetonitrile) over 3 h, controlling the temperature at about 0 °C during the addition. After the addition, react the reaction mixture at 60 °C at room temperature for 6 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution can be directly used for the next feeding.

[0121] Step 2: compound (III) Synthesis of

[0122] S2: Add 0.10 kg of triethylamine (1 mol, 0.05 eq) to the synthesis reaction solution of the previous step Compound (Ⅱ). Control the reaction temperature at 20 °C. Dissolve 6.35 kg of octadecyl chloride (22 mol, 1.1 eq) in 0.085 kg of piperidine (1 mol, 0.05 eq) and 12.5 kg of tetrahydrofuran solution, and add dropwise with a constant pressure dropping funnel over 4 h, stirring the reaction during the addition; after the addition, raise the temperature to 60 °C and react for 6 h. After the reaction is completed, there is no need for separation and purification, and the reaction solution can be directly used for the next feeding.

[0123] Step 3: Compound ( Ⅰ ) Synthesis of Olaflur

[0124] S3: Add to the synthesis reaction solution of the previous step compound (III) , and slowly introduce 1.4 kg of dry hydrogen fluoride gas. After the introduction, control the temperature at 25 °C and react for 3 h. After the reaction is completed, cool the reaction solution to 15 °C and filter to obtain 10.2 kg of crude Olaflur ( Ⅰ )。The crude orafuor (I) is added with 30.6 kg of isopropanol and 10.2 kg of water, heated to 85 °C and refluxed until dissolved clearly, stirred at 85 °C for 3 h, and then cooled to 40 - 45 °C. 9 kg of cyclohexane is added to the reaction solution, and extraction and washing are carried out 2 times. Each time of extraction and washing is carried out at 40 - 45 °C with stirring for 30 min, and the aqueous phase is separated out; the extracted aqueous phase is cooled to 10 °C, and then 3 kg of sodium hydroxide solution is slowly added. During the dropping process, the temperature control is not more than 25 °C at the highest, adjusted to pH 10 - 11, and reacted with stirring for 4 h. 25 kg of ethyl acetate is added to the reaction solution for extraction 3 times, with extraction and stirring for 30 min, and the oil phase is separated out. 1.4 kg of dry hydrogen fluoride gas is slowly introduced into the extracted ethyl acetate oil phase. During the reaction process, the temperature control is 20 - 25 °C. After passing through, the temperature is controlled at 25 °C and reacted for 2 h. The reaction solution is cooled to 0 °C, cooled for crystallization, centrifuged and filtered to obtain 9.3 kg of wet orafuor (I), and then vacuum dried at 60 °C for 10 h to obtain 8.7 kg of pure orafuor (I). The total reaction yield is 96.2%, and the purity is 97.94%.

[0125] In the specification, the present invention is described in detail through specific examples. However, those skilled in the art can make various deformations and changes to the present invention within the scope of the present invention and the scope of the technical idea, and these deformations and changes also fall within the scope of the claims of the present invention.

Claims

1. A method for preparing olafluanid, characterized in that: The following steps are involved: S1、 N,N-dihydroxyethyl- 1,3-Propylenediamine as raw material and Hydroxyethyl reagent reaction Compound (II) is obtained; S2, directly to In the reaction solution of compound (II), octadecane and a base are added to react to obtain Compound (III); S3. Compound (III) The reaction solution reacts with hydrogen fluoride to form a salt, and then post-processes to obtain olafluanid (Ⅰ) ； The specific synthesis route is as follows:

2. The method for preparing olaflurane according to claim 1, characterized in that: In the step S1, at 40 to 100°C, N,N-dihydroxyethyl- 1,3-Propylenediamine Add catalyst and organic solvent to the hydroxyethyl reagent and react for 4 to 8 hours.

3. The method for preparing olafluran according to claim 2, characterized in that: In the step S1, N,N-dihydroxyethyl- 1,3-Propylenediamine The molar ratio of the hydroxyethyl reagent to the catalyst is 1:1.05-1.15:0.01-0.

05.

4. The method for preparing olaflurane according to any one of claims 1 to 3, characterized in that: In the step S1, the hydroxyethylation agent is one of ethylene oxide or ethylene carbonate.

5. The method for preparing olafluran according to claim 2, characterized in that: In step S1, the catalyst is one of pure water, methanol, ethanol or acetic acid.

6. The method for preparing olafluran according to claim 1, characterized in that: In step S2, Reaction temperature At 40-80°C, the reaction solution of compound (II) is directly reacted with chlorooctadecane under alkaline conditions for 4-8 hours to obtain Compound (III).

7. The method for preparing olafluran according to claim 6, characterized in that: In step S2, Reaction temperature At 40-80°C, a portion of the base is first added to the reaction solution of compound (II), and then chlorooctadecane is dissolved in the remaining base and an organic solvent and then added to the reaction solution to cause an alkylation reaction.

8. The method for preparing olafluran according to claim 6, characterized in that: In step S2, N,N-dihydroxyethyl- 1,3-Propylenediamine The molar ratio of chlorooctadecane to alkali is 1:1.0~1.1:0.05~0.

1.

9. The method for preparing olaflurane according to claim 1, characterized in that: The specific process of post-treatment in step S3 is as follows: after the reaction is completed, the reaction solution is cooled to 0° C. and filtered to obtain crude olaflurane (I), and then recrystallized to obtain pure olaflurane (I).

10. The method for preparing olafluran according to claim 9, characterized in that: The recrystallization process is specifically as follows: the crude product of olaflu (I) is treated with a recrystallization solvent aqueous solution, heated to reflux and dissolved, then a first extraction solvent is added for extraction and washing, and an aqueous phase is separated; an alkaline solution is added to the aqueous phase to adjust the pH to 10-11, then a second extraction solvent is added for extraction, an oil phase is separated, and hydrogen fluoride gas is added, the reaction solution is cooled to 0°C, and the pure product of olaflu (I) is obtained by cooling and crystallization.

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