Preparation method of oxilafluorine

Abstract

The invention discloses a preparation method of oxilafluorine, which comprises the following steps: taking 2-(octadecyl amino)-ethanol and halogenated propylene as raw materials, and directly preparing oxilafluorine by a one-pot method through catalytic coupling reaction, addition reaction and hydrofluoric acid salifying reaction under the action of a copper catalyst. According to the synthesis method, the total reaction yield reaches up to 95%, the chemical selectivity of each step of reaction is high, no by-product is generated, and the catalyst can be repeatedly used; the separation and purification method is simple and efficient, and large-scale industrial production is realized; and a novel synthesis method is provided for the oxilafluorine and similar compounds.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing olafluanid. Background Art

[0002] Olafur, whose full name is bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl-octadecylamine dihydrofluoride, is a new type of fluoride-containing oral care product. It is a long-chain organic fluoride with a chemical "double side". One end is a polar water-soluble amino group and hydroxyl group, and the other end is a non-polar fatty chain. It is more fundamentally different from inorganic fluorides and can replace traditional fluorides such as sodium fluoride and sodium monofluorophosphate. As a new type of oral care product, Olafur is mainly added to toothpaste, oral cleaners, oral sprays, oral rinses, etc., to clean and prevent caries and tooth sensitivity.

[0003] At present, the existing publicly available methods for synthesizing olafluanid are mainly divided into the following four categories:

[0004] 1. Patent CN118496111A reported that 1,3-propylenediamine, 2-bromoethanol, bromooctadecane and alkali were used to prepare an intermediate in an organic solvent, and then reacted with hydrofluoric acid in an alcohol solvent to form a salt to obtain olaflu. The reaction raw material selectivity in this route is poor, there are many side reactions, the reaction time is long, and the product is difficult to purify. 2. Patent CN118530128A reported that phthalimide was added to acrolein, reductively aminized, hydrolyzed, epoxy-opened, and salified with hydrofluoric acid to obtain olaflu. The raw material acrolein of this method is highly toxic and flammable, and has a strong irritation. The intermediate separation and purification method is poor, and large-scale production cannot be achieved. 3. Patent CN118515573A reported that N-Boc-1,3-propylenediamine was reacted with 2-bromoethanol-D4, bromooctadecane, and ethylene oxide to prepare olaflu-D8. This process route is only suitable for theoretical research and cannot achieve large-scale production. 4. Patent US6464962 reported that octadecanoic acid was obtained by hydrolysis of beef tallow, and then subjected to amidation reaction, reduction reaction, acrylonitrile reduction and amination, cyanide reduction, and then epoxidation ring opening, and finally hydrofluoric acid was added to prepare olaflu. Beef tallow is a mixture of long-chain fatty alkanes, and there are many by-products in the subsequent reactions. The reaction steps are cumbersome, the purification is difficult, the reaction yield is low, and the product quality is poor. Summary of the invention

[0005] In order to solve the above technical problems, the purpose of the present invention is to provide a method for preparing olafluanid which has high reaction selectivity, few impurities, small amount of catalyst and can be recycled, high total reaction yield, high product quality, simple and efficient separation and purification method, and is suitable for large-scale industrial production.

[0006] To achieve the above object, the present invention provides a method for preparing olafluanid, comprising the following steps:

[0007] A method for preparing olafluanid, characterized in that it comprises the following steps:

[0008] S1, 2-(octadecylamino)-ethanol reacts with halogenated propylene to obtain Compound (Ⅱ);

[0009] S2, Directly add diethanolamine, base, and catalytic amount of Lewis acid solution to the reaction solution of step S1, After the reaction is completed, compound (III) is obtained by post-treatment;

[0010] S3, compound (III) is salified to obtain the compound olaflur represented by formula (I);

[0011] The synthetic route is as follows:

[0012]

[0013] In the above scheme, in step S1, 25～60 At ℃, a base and a copper catalyst are added to 2-(octadecylamino)-ethanol and halogenated propylene to carry out a catalytic coupling reaction, and the reaction time is 2 to 10 hours.

[0014] In the above scheme, in step S1, the molar ratio of halogenated propylene, base, copper catalyst and 2-(octadecylamino)-ethanol is 1.0-1.15:0.05-0.1:0.001-0.005:1.

[0015] In the above scheme, in step S1, the base is one of cesium carbonate, potassium fluoride, imidazole, 2-aminopyridine or tetrabutylammonium fluoride.

[0016] In the above scheme, in step S1, the copper catalyst is one of copper acetate, tetrakis(acetonitrile)copper tetrafluoroborate, copper acetylacetonate, Cu(II) / bisoxazoline or Cu(I) tris[3,4-bis(trifluoromethyl)phenyl]phosphine.

[0017] In the above scheme, in step S2, diethanolamine, a base, and a catalytic amount of Lewis acid are added directly to the reaction solution of step 1) at a reaction temperature of -15 to 60°C. Solution , react for 4 to 10 hours, and post-treat to obtain compound (III).

[0018] In the above scheme, in step S2, the molar ratio of diethanolamine, base, Lewis acid and compound (II) is 1.2-2.4:1.0-1.6:0.001-0.005:1.

[0019] In the above scheme, in step S2, the Lewis acid is one of boron trifluoride etherate solution, tin tetrachloride, stannous chloride, titanium tetrachloride or titanium tetraisopropoxide.

[0020] In the above scheme, in the step 2), the specific process of post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to 0°C, ice water is slowly added to quench the reaction, and centrifuged and filtered; the filtrate is separated into an oil phase, the oil phase is washed with water, and dried, the oil phase is reduced in pressure to recover part of the solvent, the temperature is lowered and allowed to stand to obtain an oily crude compound (III), which is then purified by solvent hot extraction to obtain a pure compound (III).

[0021] In the above scheme, in step 2), the specific process of hot extraction purification is: adding a solvent to the crude compound (III) and heating it under reflux to dissolve it, then cooling it to 40-55°C, standing it to precipitate an oily substance, separating the oily substance and then cooling it to 5-15°C and standing it to crystallize, so as to obtain a pure compound (III).

[0022] The synthesis method of olafluanid provided by the present invention has the following technical effects:

[0023] 1. The present invention provides a copper catalyst for the alkylation reaction of an olafluran intermediate, which has high chemical selectivity and no side reactions, and the reaction product can be directly fed to the next reaction without treatment.

[0024] 2. The present invention provides a novel synthesis method of olaflu. 2-(octadecylamino)-ethanol and halogenated propylene are used as raw materials. Oraflu is directly prepared in one pot by catalytic coupling reaction, addition reaction and hydrofluoric acid salt formation reaction under a copper catalyst. The catalyst has high chemical selectivity, high yield, high product quality, and a total reaction yield of more than 95%. The separation and purification methods of each step of the reaction are simple and efficient.

[0025] 3. The products obtained by the existing technology have many impurities and poor purity, which cannot meet the use requirements; the hot extraction crystallization method overcomes the product quality defects of the existing technology and obtains high-purity products. DETAILED DESCRIPTION

[0026] The present invention is further described in detail below by specific examples. If not explicitly stated, all reagents selected in the following examples are commercially available, or can be synthesized according to this article or known methods, and the reaction conditions not listed are also easily available to those skilled in the art.

[0027] The present invention provides a method for synthesizing olaflu. First, 2-(octadecylamino)-ethanol and halogenated propylene are used as raw materials, and catalytic coupling reaction, addition reaction, and hydrofluoric acid salt formation reaction are carried out under a copper catalyst to directly prepare olaflu in a one-pot process. The specific synthesis reaction formula is as follows:

[0028]

[0029] Example 1

[0030] This embodiment provides a method for preparing olafluanid, comprising the following steps:

[0031] Step 1: Synthesis of compound (II)

[0032] S1: Add 1.56 kg 2-(octadecylamino)-ethanol (5 mol, 1.0 eq), 0.60 kg 3-bromopropylene (5 mol, 1.0 eq), 0.16 kg cesium carbonate (0.5 mol, 0.1 eq), 2.0 g copper acetylacetonate (0.0075 mol, 0.0015 eq) and 7.5 kg acetonitrile to a 25 L reactor equipped with a stirring device, a thermometer and a condensing device. After the addition of the materials, the reaction mixture was reacted at 40°C for 4 h. After the reaction was completed, the reaction solution was directly used for the next step without separation and purification. 1 H NMR(400MHz,CDCl 3 ) δ(ppm):6.00~5.92(ddd,1H,J=17.0Hz,10.2Hz,8.0Hz,-CH=CH 2 ,1H),5.26~3.16(m,-CH =CH 2 ,2H),3.50~3.46(t,J=8.0Hz,2H,-CH 2 -)2.86~2.82(t,J=8.0Hz,2H,-CH 2 -),2.41 ~2.37(t,J=8.0Hz,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=8.0Hz,3H,-CH 3 )。

[0033] Step 2: Compound (III) Synthesis

[0034] S2: Previous step CompoundThe reaction liquid of (II) was cooled to -15°C, and then 0.63kg diethanolamine (6mol, 1.20eq) and 0.64kg N,N-diisopropylethylamine (5mol, 1.0eq) were added. After the addition, the temperature was kept at -15°C for 0.5h. Then, tin tetrachloride tetrahydrofuran solution (6.96g tin tetrachloride dissolved in 100g tetrahydrofuran) was slowly added dropwise. During the addition, the temperature was kept at -15°C to -10°C. After the addition was completed, the mixture was stirred for 15min, and then the mixture was heated to 20°C for 6h. The reaction was completed. The reaction liquid was cooled to 0°C, and 2kg ice water was slowly added dropwise to quench the reaction. After the addition was completed, the mixture was stirred for 0.5h. The copper catalyst was centrifuged and filtered to obtain the copper catalyst. The catalyst can be recycled after drying. The filtrate was allowed to stand for 15min, and the upper oil phase was separated. 2kg water was added to the oil phase, and the oil phase was washed twice, each time with stirring for 0.5h. After washing, the oil phase was allowed to stand to separate the oil phase. The oil phase was dried by adding 200g of anhydrous sodium sulfate, and the oil phase was decompressed at 50°C to recover 2kg of solvent, and then cooled to 10°C, allowed to stand for 0.5h, and the upper solvent was separated to obtain 2.52kg of crude oily compound (III). The crude compound (III) was added with 6.3kg of acetonitrile solvent, heated to 80°C and refluxed to dissolve, and then 50g of activated carbon was added, stirred for 0.5h, and the activated carbon was filtered while hot, and the filtrate was cooled to 40-55°C, allowed to stand for 0.5h to precipitate an oily substance, and the separated oily substance was cooled to 5-15°C and allowed to stand for crystallization to obtain 2.22kg of pure compound (III). 1 H NMR(400MHz,CDCl 3 )δ(ppm):3.25(s,3H,-CH 2 -CH 2 -OH), 3.61~3.56(m,10H,-CH 2 -), 2.56~2.47(m,10H,-CH 2 -),2.41~2.37(t,J=8.0Hz,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=8.0Hz,3H,-CH 3 )。 13 C NMR(400MHz,CDCl 3 )δ(ppm):59.6ppm,59.1ppm, 56.7ppm,55.8ppm,54.4ppm,52.6ppm,52.0ppm,31.9ppm,29.7ppm,29.6ppm,29.6ppm, 29.5ppm,29.3ppm,27.6ppm,25.7ppm,24.3ppm,22.7ppm,14.1ppm.HRMS(ESI)[C 27 H 58 N 2 O 3 +H] + m / zcalcd for 459.4447, found 459.4548.

[0035] Step 3: Compound ( Ⅰ ) Synthesis of Olaflu

[0036] S3: Add 2.22 kg of pure compound (III) and 8.9 kg of methanol to a 25 L reactor equipped with a stirring device, a thermometer, and a condensing device, and slowly introduce 0.5 kg of dry hydrofluoric acid 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 5 ° C and filter to obtain 2.28 kg of pure olaflu ( Ⅰ )。 The total reaction yield is 95.2%, and the purity is 98.63%.

[0037] The purity of olaflu in the present invention is tested by this titration method: take 1g olaflu sample and dissolve it in 100g pure water, stir at 25 degrees for 30min until it is completely dissolved, then add 5 drops of phenolphthalein indicator, titrate with 0.1mol / L sodium hydroxide solution to a slightly reddish color, and maintain it for 30s without fading as the end point. Then slowly add 20ml acetic anhydride, shake well, and leave it at room temperature for 15min. Then add 30ml isopropanol solution, put in a stirring rod, immerse the calibrated glass electrode and calomel electrode of the acidometer in the liquid, turn on the electromagnetic stirrer and adjust the appropriate speed, perform potentiometric titration with 0.2mol / L hydrochloric acid isopropanol standard solution, draw a titration curve, take the maximum jump of the potential value as the end point, record the corresponding volume (V), and calculate the purity of olaflu in the sample according to the formula.

[0038]

[0039] Where: X-olafluor purity, %;

[0040] V- is the volume of the standard hydrochloric acid solution to be titrated, mL;

[0041] C-concentration of hydrochloric acid standard solution, mol / L;

[0042] m-sample weight, g;

[0043] M-Molar mass of free hydroxylamine of olaflurane, g / mo1.

[0044] Comparative Example 1

[0045] This comparative example provides a method for preparing olafluanid, comprising the following steps:

[0046] Step 1: Synthesis of compound (II)

[0047] S1: Add 1.56 kg 2-(octadecylamino)-ethanol (5 mol, 1.0 eq), 0.60 kg 3-bromopropylene (5 mol, 1.0 eq), 0.16 kg cesium carbonate (0.5 mol, 0.1 eq) and 7.5 kg acetonitrile. The feeding is completed. Reaction mixture 40 ℃ The reaction was completed after 4 hours of reaction without separation and purification. The liquid is directly used in the next step.

[0048] S2: Compound (III) The synthetic preparation process is the same as step 2 in Example 1, except that after the reaction is completed, the copper catalyst is not recovered by centrifugal filtration, and 1.75 kg of pure compound (III) is obtained by post-treatment.

[0049] S3: Compound ( Ⅰ ) The synthesis process of olaflu is the same as step 3 in step Example 1, except that 1.60 kg of pure olaflu is obtained. ( Ⅰ )， The total reaction yield is 66.8%, and the purity is 93.93%.

[0050] Comparative Example 2

[0051] This comparative example provides a method for preparing olafluanid, comprising the following steps:

[0052] S1: Synthesis of compound (II)

[0053] To a 25L reactor equipped with a stirrer, a thermometer, and a condenser, 1.56kg of 2-(octadecylamino)-ethanol (5mol, 1.0eq), 0.60kg of 3-bromopropylene (5mol, 1.0eq), 0.16kg of cesium carbonate (0.5mol, 0.1eq), 1.4g of cuprous iodide (0.0075mol, 0.0015eq) and 7.5 kg acetonitrile. The feeding is completed. The reaction mixture was kept at 40°C The reaction was completed after 4 h of reaction. No separation or purification was required and the reaction solution was directly used in the next step.

[0054] S2: Compound (III) The synthetic preparation process is the same as step 2 in Example 1, except that after the reaction is completed, the copper catalyst is not recovered by centrifugal filtration, and 2.15 kg of pure compound (III) is obtained by post-treatment.

[0055] S3: Compound ( Ⅰ ) The synthesis process of olaflu is the same as step 3 in step Example 1, except that 1.90 kg of pure olaflu is obtained. ( Ⅰ )， The total reaction yield is 79.3%, and the purity is 95.93%.

[0056] Comparative Example 3

[0057] This comparative example provides a method for preparing olafluanid, comprising the following steps:

[0058] S1: Synthesis of compound (II)

[0059] 1.56 kg 2-(octadecylamino)-ethanol (5 mol, 1.0 eq), 0.60 kg 3-bromopropylene (5 mol, 1.0 eq), 2.0 g copper acetylacetonate (0.0075 mol, 0.0015 eq) and 7.5 kg acetonitrile were added to a 25 L reactor equipped with a stirring device, a thermometer and a condensing device. After the addition of the materials, the reaction mixture was reacted at 40° C. for 8 h. After the reaction was completed, the reaction solution was directly used for the next step without separation and purification.

[0060] S2: Compound (III) The synthetic preparation process is the same as step 2 in step Example 1.

[0061] S3: Compound ( Ⅰ ) The synthesis process of olaflu is the same as step 3 in step Example 1, except that 1.93 kg of pure olaflu is obtained. ( Ⅰ )， The total reaction yield is 80.8%, and the purity is 96.98%.

[0062] Comparative Example 4

[0063] This comparative example provides a method for preparing olafluanid, comprising the following steps:

[0064] S1: The synthetic preparation process of compound (II) is the same as step 1 in step example 1.

[0065] S2: Compound (III) Synthesis

[0066] Previous CompoundThe reaction solution of (II) was cooled to -15°C, and then 0.63kg diethanolamine (6mol, 1.20eq) and 0.64kg N,N-diisopropylethylamine (5mol, 1.0eq) were added. After the addition, the temperature was kept at -15°C for 0.5h. Then, a tetrahydrofuran solution of trifluoromethanesulfonic acid (0.75g trifluoromethanesulfonic acid dissolved in 100g tetrahydrofuran) was slowly added dropwise. The temperature was kept at -15°C to -10°C during the addition. After the addition was completed, the mixture was stirred for 15min, and then the mixture was heated to 20°C for 6h. The reaction was completed. The reaction solution was cooled to 0°C, and 2kg ice water was slowly added dropwise to quench the reaction. After the addition was completed, the mixture was stirred for 0.5h. The copper catalyst was centrifuged and filtered to obtain the copper catalyst. The catalyst can be recycled after drying. The filtrate was allowed to stand for 15min, and the upper oil phase was separated. 2kg water was added to the oil phase, and the oil phase was washed twice, each time with stirring for 0.5h. After washing, the oil phase was allowed to stand to separate the oil phase. The oil phase was dried by adding 200g of anhydrous sodium sulfate, and the oil phase was decompressed at 50°C to recover 2kg of solvent, and then cooled to 10°C, allowed to stand for 0.5h, and the upper solvent was separated to obtain 2.52kg of crude oily compound (III). The crude compound (III) was added with 6.3kg of acetonitrile solvent, heated to 80°C and refluxed to dissolve, and then 50g of activated carbon was added, stirred for 0.5h, and the activated carbon was filtered while hot, and the filtrate was cooled to 40-55°C, allowed to stand for 0.5h to precipitate an oily substance, and the separated oily substance was cooled to 5-15°C and allowed to stand for crystallization to obtain 2.02kg of pure compound (III).

[0067] S3: Compound ( Ⅰ ) The synthesis process of olaflu is the same as step 3 in step Example 1, except that 1.81 kg of pure olaflu is obtained. ( Ⅰ )， The total reaction yield is 75.8%, and the purity is 94.93%.

[0068] Comparative Example 5

[0069] This comparative example provides a method for preparing olafluanid, comprising the following steps:

[0070] S1: The synthetic preparation process of compound (II) is the same as step 1 in step example 1.

[0071] S2: Compound (III) Synthesis

[0072] Previous CompoundThe reaction solution of (Ⅱ) was cooled to -15℃, and then 0.63kg diethanolamine (6mol, 1.20eq) and 0.64kg N,N-diisopropylethylamine (5mol, 1.0eq) were added. After the addition, the temperature was kept at -15℃ for 0.5h, and then the temperature was raised to 20℃ for 6h. The reaction was completed. The reaction solution was cooled to 0℃, and 2kg ice water was slowly added dropwise to quench the reaction. After the addition was completed, the mixture was stirred for 0.5h, and the copper catalyst was centrifuged and filtered to obtain the copper catalyst. The catalyst can be recycled after drying. The filtrate was allowed to stand for 15min, and the upper oil phase was separated. 2kg water was added to the oil phase, and the oil phase was washed twice, each time stirred for 0.5h. After washing, the oil phase was allowed to stand to separate the oil phase. 200g anhydrous sodium sulfate was added to the oil phase for drying, and 2kg of solvent was recovered under reduced pressure at 50℃. The reaction solution was cooled to 10℃, and the mixture was allowed to stand for 0.5h. The upper solvent was separated to obtain 2.52kg of crude oil compound (Ⅲ).

[0073] S3: Compound ( Ⅰ ) The synthesis process of olaflu is the same as step 3 in step Example 1, except that 1.89 kg of pure olaflu is obtained. ( Ⅰ )， The total reaction yield is 79.0%, and the purity is 94.98%.

[0074] Comparative Example 6

[0075] This comparative example provides a method for preparing olafluanid, comprising the following steps:

[0076] S1: Synthesis of compound (II)

[0077] 0.52 kg diethanolamine (5 mol, 1.0 eq), 0.60 kg 3-bromopropylene (5 mol, 1.0 eq), 0.16 kg cesium carbonate (0.5 mol, 0.1 eq), 2.0 g copper acetylacetonate (0.0075 mol, 0.0015 eq) and 7.5 kg acetonitrile were added to a 25 L reactor equipped with a stirring device, a thermometer and a condensing device. After the addition of the materials, the reaction mixture was reacted at 40°C for 4 hours. After the reaction was completed, the reaction solution was directly used for the next step without separation and purification.

[0078] S2: Compound (III) Synthesis

[0079] Previous CompoundThe reaction solution of (II) was cooled to -15℃, and then 1.56kg 2-(octadecylamino)-ethanol (5mol, 1.0eq) and 0.64kg N,N-diisopropylethylamine (5mol, 1.0eq) were added. After the addition, the temperature was kept at -15℃ for 0.5h. Then, tin tetrachloride tetrahydrofuran solution (6.96g tin tetrachloride dissolved in 100g tetrahydrofuran) was slowly added dropwise. During the addition, the temperature was kept at -15℃ to -10℃. After the addition was completed, the mixture was stirred for 15min, and then the temperature was raised to 20℃ for 6h. The reaction was completed. The reaction solution was cooled to 0℃, and 2kg ice water was slowly added dropwise to quench the reaction. After the addition was completed, the mixture was stirred for 0.5h. The copper catalyst was centrifuged and filtered to obtain the copper catalyst. The catalyst can be recycled after drying. The filtrate was allowed to stand for 15min, and the upper oil phase was separated. 2kg water was added to the oil phase, and the oil phase was washed twice, each time with stirring for 0.5h. After washing, the oil phase was allowed to stand and separated. The oil phase was dried by adding 200g of anhydrous sodium sulfate, and the oil phase was decompressed at 50°C to recover 2kg of solvent, and then cooled to 10°C, allowed to stand for 0.5h, and the upper solvent was separated to obtain 2.52kg of crude oil compound (III). The crude compound (III) was added with 6.3kg of acetonitrile solvent, heated to 80°C and refluxed to dissolve, and then 50g of activated carbon was added, stirred for 0.5h, and the activated carbon was filtered while hot, and the filtrate was cooled to 40-55°C, allowed to stand for 0.5h to precipitate oil, and the separated oil was cooled to 5-15°C and allowed to stand for crystallization to obtain 0.8kg of pure compound (III).

[0080] S3: Compound ( Ⅰ ) Synthesis of Olaflu

[0081] Add 0.80 kg of pure compound (III) and 3.2 kg of methanol to a 25 L reactor equipped with a stirring device, a thermometer, and a condensing device, and slowly pass 0.5 kg of dry hydrofluoric acid gas. After passing, control the temperature at 25 ° C and react for 1 h. After the reaction is completed, cool the reaction solution to 5 ° C and filter to obtain 0.85 kg of pure olaflu ( Ⅰ )。 The total reaction yield is 35.6%, and the purity is 85.60%.

[0082] Example 2

[0083] This embodiment provides a method for preparing olafluanid, comprising the following steps:

[0084] S1: Synthesis of compound (II)

[0085] 1.56 kg 2-(octadecylamino)-ethanol (5 mol, 1.0 eq), 0.44 kg 3-chloropropylene (5.75 mol, 1.15 eq), 0.029 kg potassium fluoride (0.5 mol, 0.1 eq), 1.57 g tetra(acetonitrile)copper tetrafluoroborate (0.005 mol, 0.001 eq) and 7.5 kg tetrahydrofuran were added to a 25 L reactor equipped with a stirring device, a thermometer and a condensing device. After the addition of the materials, the reaction mixture was reacted at 40°C for 6 hours. After the reaction was completed, the reaction solution was directly used for the next step without separation and purification. ， The structural characterization data of compound (II) are the same as those in Example 1.

[0086] S2: Compound (III) Synthesis

[0087] Previous Compound The reaction liquid of (II) was cooled to -15°C, and then 0.63kg diethanolamine (6mol, 1.20eq) and 0.64kg N,N-diisopropylethylamine (5mol, 1.0eq) were added. After the addition, the temperature was kept at -15°C for 0.5h. Then, tin tetrachloride tetrahydrofuran solution (6.96g tin tetrachloride dissolved in 100g tetrahydrofuran) was slowly added dropwise. During the addition, the temperature was kept at -15°C to -10°C. After the addition was completed, the mixture was stirred for 15min, and then the mixture was heated to 20°C for 6h. The reaction was completed. The reaction liquid was cooled to 0°C, and 2kg ice water was slowly added dropwise to quench the reaction. After the addition was completed, the mixture was stirred for 0.5h. The copper catalyst was centrifuged and filtered to obtain the copper catalyst. The catalyst can be recycled after drying. The filtrate was allowed to stand for 15min, and the upper oil phase was separated. 2kg water was added to the oil phase, and the oil phase was washed twice, each time with stirring for 0.5h. After washing, the oil phase was allowed to stand to separate the oil phase. The oil phase was dried by adding 200g of anhydrous sodium sulfate, and the oil phase was reduced in pressure at 50°C to recover 2kg of solvent, and then cooled to 10°C, allowed to stand for 0.5h, and the upper layer of solvent was separated to obtain 2.52kg of crude oily compound (III). The crude compound (III) was added with 6.3kg of n-hexane solvent, heated to 80°C and refluxed to dissolve, and then 50g of activated carbon was added, stirred for 0.5h, and the activated carbon was filtered while hot, and the filtrate was cooled to 40-55°C, allowed to stand for 0.5h to precipitate oil, and the separated oil was cooled to 5-15°C and allowed to stand for crystallization to obtain 2.25kg of pure compound (III). ， The structural characterization data of compound (II) are the same as those in Example 1.

[0088] S3: Compound ( Ⅰ ) Synthesis of Olaflu

[0089] Add 2.25 kg of pure compound (III) and 9.0 kg of methanol to a 25 L reactor equipped with a stirring device, a thermometer, and a condensing device, and slowly pass 0.5 kg of dry hydrofluoric acid gas. After passing, control the temperature at 25 ° C and react for 1 h. After the reaction is completed, cool the reaction solution to 5 ° C and filter to obtain 2.30 kg of pure olaflu ( Ⅰ )。 The total reaction yield is 96.2%, and the purity is 99.28%.

[0090] Example 3

[0091] This embodiment provides a method for preparing olafluanid, comprising the following steps:

[0092] S1: Synthesis of compound (II)

[0093] 1.56 kg 2-(octadecylamino)-ethanol (5 mol, 1.0 eq), 0.60 kg 3-bromopropylene (5 mol, 1.0 eq), cesium carbonate (0.5 mol, 0.1 eq), 4.3 g Cu(Ⅰ) tri[3,4-bis(trifluoromethyl)phenyl]phosphine (0.005 mol, 0.001 eq) and 7.5 kg acetonitrile were added to a 25 L reactor equipped with a stirring device, a thermometer and a condensing device. After the addition of the materials, the reaction mixture was reacted at 40°C for 4 hours. The reaction was completed without separation and purification, and the reaction solution was directly used for the next step. ， The structural characterization data of compound (II) are the same as those in Example 1.

[0094] S2: Compound (III) Synthesis

[0095] Previous CompoundThe synthesis reaction liquid of (Ⅱ) was cooled to -15℃, and then 0.63kg diethanolamine (6mol, 1.20eq) and 0.64kg N,N-diisopropylethylamine (5mol, 1.0eq) were added. After the addition, the temperature was kept at -15℃ for 0.5h. Then, tetraisopropanol titanium tetrahydrofuran solution (3.55g tetraisopropanol titanium dissolved in 100g tetrahydrofuran) was slowly added dropwise. The temperature was kept at -15℃ to -10℃ during the addition. After the addition was completed, the mixture was stirred for 15min, and then the mixture was heated to 20℃ for 6h. The reaction was completed. The reaction liquid was cooled to 0℃, and 2kg ice water was slowly added dropwise to quench the reaction. After the addition was completed, the mixture was stirred for 0.5h. The copper catalyst was centrifuged and filtered to obtain the copper catalyst. The catalyst can be recycled after drying. The filtrate was allowed to stand for 15min, and the upper oil phase was separated. 2kg water was added to the oil phase, and the oil phase was washed twice, each time with stirring for 0.5h. After washing, the oil phase was allowed to stand and separated. The oil phase was dried by adding 200g of anhydrous sodium sulfate, and the oil phase was reduced in pressure at 50°C to recover 2kg of solvent, and then cooled to 10°C, allowed to stand for 0.5h, and the upper layer of solvent was separated to obtain 2.52kg of crude oily compound (III). The crude compound (III) was added with 6.3kg of n-heptane solvent, heated to 80°C and refluxed to dissolve, and then 50g of activated carbon was added, stirred for 0.5h, and the activated carbon was filtered while hot, and the filtrate was cooled to 40-55°C, allowed to stand for 0.5h to precipitate oil, and the separated oil was cooled to 5-15°C and allowed to stand for crystallization to obtain 2.25kg of pure compound (III). ， The structural characterization data of compound (II) are the same as those in Example 1.

[0096] S3: Compound ( Ⅰ ) Synthesis of Olaflu

[0097] Add 2.25 kg of pure compound (III) and 8.9 kg of methanol to a 25 L reactor equipped with a stirring device, a thermometer, and a condensing device, and slowly pass 0.5 kg of dry hydrofluoric acid gas. After passing, control the temperature at 25 ° C and react for 1 h. After the reaction is completed, cool the reaction solution to 5 ° C and filter to obtain 2.32 kg of pure olaflu ( Ⅰ )。 The total reaction yield is 97.3%, and the purity is 99.53%.

[0098] Example 4

[0099] The other steps are the same as those in Example 2, except that the catalyst is applied three more times. The results of applying the tetra(acetonitrile)copper tetrafluoroborate catalyst three times are as follows:

[0100] From the comparison of the data in the examples, it can be seen that the catalyst was reused three times, the reaction yield was maintained above 94%, the main content of the product was above 99%, and the repeated use of the catalyst did not affect the reaction effect.

[0101] Example 5

[0102] The other steps are the same as those in Example 3, except that the catalyst is applied three times. The results of applying the Cu(Ⅰ) tris[3,4-bis(trifluoromethyl)phenyl]phosphine catalyst three times are as follows:

[0103]

[0104]

[0105] From the comparison of the data in the examples, it can be seen that the catalyst was reused three times, the reaction yield was maintained above 95%, the main content of the product was above 99%, and the repeated use of the catalyst did not affect the reaction effect.

[0106] The above described embodiments are selected from some of the embodiments of the present invention, but not all of them. Other embodiments obtained by those skilled in the art based on the present invention all belong to the protection scope of the present invention.

Claims

1. A method for preparing olafluanid, characterized in that: The steps include: S1, 2-(octadecylamino)-ethanol reacts with halogenated propylene to obtain Compound (Ⅱ); S2, Directly add diethanolamine, base, and catalytic amount of Lewis acid solution to the reaction solution of step S1, After the reaction is completed, compound (III) is obtained by post-treatment; S3, compound (III) is salified to obtain the compound olaflur represented by formula (I); The synthetic route is as follows:

2. The method for preparing olaflurane according to claim 1, characterized in that: In step S1, 25～60 At ℃, a base and a copper catalyst are added to 2-(octadecylamino)-ethanol and halogenated propylene to carry out a catalytic coupling reaction, and the reaction time is 2 to 10 hours.

3. The method for preparing olafluran according to claim 2, characterized in that: In the step S1, the molar ratio of halogenated propylene, base, copper catalyst and 2-(octadecylamino)-ethanol is 1.0-1.15:0.05-0.1:0.001-0.005:

1.

4. The method for preparing olafluran according to claim 2, characterized in that: In step S1, the base is one of cesium carbonate, potassium fluoride, imidazole, 2-aminopyridine or tetrabutylammonium fluoride.

5. The method for preparing olafluran according to claim 2, characterized in that: In the step S1, the copper catalyst is one of copper acetate, tetrakis(acetonitrile)copper tetrafluoroborate, copper acetylacetonate, Cu(II) / bisoxazoline or Cu(I) tris[3,4-bis(trifluoromethyl)phenyl]phosphine.

6. The method for preparing olafluran according to claim 1, characterized in that: In step S2, diethanolamine, a base, and a catalytic amount of Lewis acid are added directly to the reaction solution of step 1) at a reaction temperature of -15 to 60°C. Solution , react for 4 to 10 hours, and post-treat to obtain compound (III).

7. The method for preparing olaflurane according to claim 2, characterized in that: In the step S2, the molar ratio of diethanolamine, base, Lewis acid and compound (II) is 1.2-2.4:1.0-1.6:0.001-0.005:

1.

8. The method for preparing olafluran according to claim 1, characterized in that: In step S2, the Lewis acid is one of boron trifluoride etherate solution, tin tetrachloride, stannous chloride, titanium tetrachloride or titanium tetraisopropoxide.

9. The method for preparing olaflurane according to claim 1, characterized in that: In the step 2), the specific process of post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to 0°C, ice water is slowly added to quench the reaction, and centrifugation is performed; the filtrate is separated into an oil phase, the oil phase is washed with water, and dried, the oil phase is decompressed to recover part of the solvent, the temperature is lowered and allowed to stand to obtain a crude oily compound (III), which is then purified by solvent hot extraction to obtain a pure compound (III).

10. The method for preparing olafluran according to claim 9, characterized in that: In the step 2), the specific process of hot extraction and purification is as follows: the crude compound (III) is added with a solvent, heated under reflux to dissolve, then cooled to 40-55°C, allowed to stand to precipitate an oily substance, the oily substance is separated and then cooled to 5-15°C and allowed to stand to crystallize, thereby obtaining the pure compound (III).

Images