Preparation method of oxilafluorine

Abstract

The invention relates to a preparation method of oxilafluorine, which comprises the following steps: by taking a fat alkane compound and a hydroxyethyl reagent as raw materials, carrying out tank closing reaction, then reacting under the action of an alkaline reagent, and finally salifying to obtain the target product oxilafluorine. According to the method, the tank closing reaction is directly carried out, other auxiliaries are not needed, the amino compound serves as a reaction raw material and also serves as an acid-binding agent, use of other organic reagents can be reduced, and the method is more environmentally friendly. Meanwhile, the synthesis method provided by the invention is novel, good in reaction selectivity, simple and convenient in route and high in yield.

Description

Technical Field

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

[0002] Dental caries, commonly known as "tooth decay" or "cavities", is a common oral disease. Together with cardiovascular disease and cancer, it constitutes the three major diseases that endanger human health. Therefore, it is of great significance to prevent dental caries for a healthy oral cavity. The internationally recognized dental caries preventive agent is fluoride. Olafluor 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 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. It is recommended by dentists from various countries for refluoridation of damaged tooth enamel to clean, prevent caries and prevent tooth sensitivity.

[0003] At present, the existing disclosed methods for synthesizing olafluanid mainly include:

[0004] (1) Patent US6464962 discloses a method for synthesizing olafluanid: the main component, stearic acid (C 17 H 35 COOH), through amidation reaction, catalytic reduction reaction, addition with acrylonitrile, reduction, ring opening, and finally, adding hydrofluoric acid to obtain the final product. Because beef tallow is a mixture, there are many by-products, the reaction steps are cumbersome, the purification is difficult, and the yield is low.

[0005] (2) Patent CN118530128A discloses a method for synthesizing olafluanid: starting from phthalimide, adding acrolein, then undergoing reductive amination, hydrolysis, and ring opening to obtain N-alkyl-1,3-propylenediamine, and finally salifying with hydrofluoric acid to obtain the target product. However, the raw material acrolein used in this method is a highly toxic and flammable compound with strong irritation.

[0006] (3) Patent CN118496111A discloses a method for synthesizing olaflu: 1,3-propylenediamine, 2-bromoethanol, bromooctadecane and a base are mixed in an organic solvent to obtain a reaction intermediate, and the reaction intermediate is reacted with hydrofluoric acid in an alcohol solvent to form a salt to synthesize an olaflu compound. This method has two bromides as raw materials and four reaction sites with ammonia, resulting in many side reactions, and the purification method is not convenient for industrial scale-up production.

[0007] (4) Patent CN118515573A discloses a method for synthesizing olafluanid: N-tert-butyloxycarbonyl-1,3-propylenediamine is reacted with 2-bromoethanol-D4, octadecane bromide, and ethylene oxide in sequence to obtain olafluanid-D8. This method requires anhydrous reagents and a large amount of reaction solvent, and the reaction conditions are not suitable for industrial scale-up production.

[0008] In view of the above reasons, the present invention overcomes various drawbacks of the above methods and develops a new method for synthesizing olafluanid with good reaction selectivity, simple route, high yield and easy industrialization. Summary of the invention

[0009] In order to solve the above technical problems, the present invention provides a method for preparing olafluanid which has good reaction selectivity, simple route, high yield and is easy to realize industrialization.

[0010] In order to achieve the above object, the technical solution adopted by the present invention is:

[0011] A method for preparing olafluanid, comprising the following steps:

[0012] S1: using aliphatic alkane compound (II) and hydroxyethyl reagent (III) as raw materials, reacting to obtain a compound of formula (IV);

[0013] S2: Compound (IV) reacts with compound (V) in the presence of an alkaline reagent to obtain a compound of formula (VI);

[0014] S3: The compound of formula (VI) is subjected to a salt-forming reaction to obtain the target product as shown in formula (I), and the process route is as follows:

[0015]

[0016] Wherein: R1 is amino or halogen, R2 is amino or halogen, and R1 and R2 are different; X is F, Cl, Br or I.

[0017] According to the above scheme, in step S1, after nitrogen replacement, compound (II) and compound (III) are added to the sealed tank reactor, first reacted at low temperature, then reacted at high temperature and high pressure, and sampling and monitoring were performed until the reaction was completed. The temperature was lowered to 25-30°C, the reaction solution was slowly added to water, filtered, and the filter cake was slurried with a solvent to obtain a solid compound of formula (IV).

[0018] According to the above scheme, in step S2, under nitrogen protection, compound (IV), compound (V), alkaline reagent and organic solvent are added to the reaction container, the temperature is raised to 80-120°C, and the reaction is kept warm for 10-15 hours. The reaction solution is cooled and filtered, the filter cake is washed with the above reaction organic solvent, the filtrate is concentrated under reduced pressure, and recrystallized to obtain the compound of formula (VI).

[0019] According to the above scheme, in step S3, under nitrogen protection, compound (VI) and hydrogen fluoride are added to the alcohol solution at -10-20°C, the temperature is raised to 20-60°C, and the reaction is completed to obtain the target product shown in formula (I).

[0020] According to the above scheme, in step S1, the hydroxyethyl reagent is selected from one of 2-fluoroethanol, 2-chloroethanol, 2-bromoethanol, 2-iodoethanol, ethylene oxide, and ethanolamine.

[0021] According to the above scheme, in step S1, the molar ratio of the halogenated compound to the amino compound is 1:2-3.

[0022] According to the above scheme, in step S1, the low-temperature reaction temperature is 20-40°C, and the low-temperature reaction time is 1-3h; the high-temperature reaction temperature is 150-200°C, and the high-temperature reaction pressure is 0.1-1.5MPa, and the reaction time under this pressure is 3-6h.

[0023] According to the above scheme, in step S1, the pulping solvent is selected from one or a combination of two or more of methanol, ethanol, acetonitrile or toluene.

[0024] According to the above scheme, in step S2, the molar ratio of compound (IV) to compound (V) is 1:1-1.1.

[0025] According to the above scheme, in step S3, the hydrogen fluoride is one of hydrogen fluoride gas, hydrofluoric acid aqueous solution or hydrofluoric acid ethanol solution.

[0026] Compared with the prior art, the technical scheme provides a novel method for synthesizing olaflu with good reaction selectivity, simple route, and easy industrialization. The method directly reacts in a sealed tank without adding other additives. The amino compound is used as both a reaction raw material and an acid binding agent, which can reduce the use of other organic reagents and is more environmentally friendly. At the same time, the method provided by the present invention has a novel route, good reaction selectivity, simple route, and high yield. The yield of each step of the present invention can reach more than 85%, and the purity of the obtained olaflu is more than 99.0%. DETAILED DESCRIPTION

[0027] The present invention will be further described below in conjunction with examples, but the following examples should not be construed as limiting the present invention.

[0028] Example 1

[0029] This embodiment provides a method for preparing olafluanid, and the specific synthesis steps are as follows:

[0030] S1: Add octadecylamine (26.9 g, 0.1 mol) to a clean and dry tank reactor, replace with nitrogen three times, control the temperature at 20°C, slowly introduce ethylene oxide gas (4.6 g, 0.105 mol) under stirring, stir and react at this temperature for 1 hour, then raise the temperature to 200°C, and make the internal pressure 0.6 MPa, continue to react at this temperature and pressure for 5 hours, take samples and monitor by TLC (developing solvent chloroform: methanol = 1:3) until the reaction is completed. Cool to room temperature, add the reaction solution to ethanol (100 mL), stir for 10 minutes and filter, wash the filter cake with ethanol, and dry to obtain 28.3 g of white solid compound (IV), with a yield of 90.2% (calculated as octadecylamine), (R1 is amino group). 1H-NMR (400MHz, CDCl3) δ (ppm): 3.60~3.63(t,2H,-CH2-OH), 2.72~2.74(t,J=8.0Hz,2H,-CH2-), 2.60~2.56(t,J =8.0Hz,2H,-CH2-),2.40(s,1H,-OH),2.45(s,1H,-NH-),1.44~147(t,J=8.0Hz,2H,-CH2-),1.23~1.25(s,30H,-C 15 H 30 -),0.83~0.87(t,J=8.0Hz,2H,-CH3).

[0031] S2: Take a clean and dry reaction container, pass nitrogen protection, add compound (IV) (31.3g, 0.1mol), compound (V) (24.9g, 0.11mol), potassium carbonate (13.8g, 0.1mol) to benzyl alcohol (200mL) in turn, stir until clear, heat to 80℃, and keep warm for 10h. After the reaction is completed, cool the reaction solution to 30℃, filter, wash the filter cake with benzyl alcohol (20mL), collect the filtrate and concentrate under reduced pressure to obtain a crude solid, and recrystallize the crude product with 5 times the weight of isopropanol to obtain 24.9g of compound (VI). 1H-NMR (400MHz, CDCl3) δ (ppm): 3.25(s,3H,-CH2-CH2-OH), 3.61~3.56(m,10H,-CH2-), 2.56~2.47(m,10H,-CH2- ),2.41~2.37(t,J=8.0Hz,2H,-CH2-),1.65~1.58(m,2H,-CH2-),1.45~1.37(m,2H,-CH2-),1.27~1.21(m,30H,-C 15 H 30 -),0.85~0.83(t,J=8.0Hz,2H,-CH3).

[0032] S3: In a reactor, add compound (VI) (22.9 g, 0.05 mol) to ethanol (200 mL), stir to dissolve, introduce nitrogen protection, control the temperature at -10°C, slowly introduce hydrogen fluoride gas into the reaction solution, raise the temperature to 50°C after addition, stir for 1-2 h, react until completion, cool, filter, and obtain 22.1 g of light yellow solid compound (I) with a purity of 99.85% and a yield of 92.5% (calculated based on compound (VI)).

[0033] 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.

[0034]

[0035] Where: X-olafluor purity, %;

[0036] V- is the volume of the standard hydrochloric acid solution to be titrated, mL;

[0037] C-concentration of hydrochloric acid standard solution, mol / L;

[0038] m-sample weight, g;

[0039] M-Molar mass of free hydroxylamine of olaflurane, g / mo1.

[0040] Example 2

[0041] This example is substantially the same as Example 1, except that the steps for synthesizing compound (IV) are different, as follows:

[0042] S1: Add 2-bromoethanol (12.5 g, 0.1 mol) and octadecylamine (67.4 g, 0.25 mol) to a clean and dry tank reactor, replace with nitrogen three times, control the temperature at 20°C, stir and react at this temperature for 1 hour, then raise the temperature to 150°C, and make the internal pressure 0.5 MPa. Continue to react at this temperature and pressure for 5-6 hours, and take samples to monitor the reaction by TLC until the reaction is completed. Cool down to room temperature, slowly add the reaction solution to water (150 mL), stir for 10 minutes and filter, the filter cake is slurried at 50°C for 1 hour with a mixed solution of acetonitrile and toluene (150 mL, the volume ratio of acetonitrile to toluene is 1:2), filter, and rinse the filter cake with a mixed solution of acetonitrile and toluene (20 mL). All filtrates are collected and recycled, and the filter cake is dried to obtain 27.8 g of white solid compound (IV), with a yield of 88.5% (calculated as 2-bromoethanol), (R1 is amino, R2 is halogen).

[0043] The obtained compound (IV) was synthesized in the same manner as steps S2 and S3 of Example 1 to obtain 21.5 g of olaflurane with a purity of 99.68% and a yield of 89.9%.

[0044] Example 3

[0045] This example is substantially the same as Example 1, except that the steps for synthesizing compound (IV) are different, as follows:

[0046] S1: Add bromooctadecane (33.3 g, 0.1 mol) and ethanolamine (15.3 g, 0.25 mol) to a clean and dry tank reactor, replace with nitrogen three times, control the temperature at 20°C, stir and react at this temperature for 1 hour, raise the temperature to 200°C, and make the internal pressure 0.6 MPa at the same time. Continue to react at this temperature and pressure for 5-6 hours, take samples and monitor by TLC until the reaction is completed. Cool to room temperature, slowly add the reaction solution to water (150 mL), stir for 10 minutes and filter, the filter cake is slurried at 50°C for 1 hour with a mixed solution of acetonitrile and toluene (150 mL, the volume ratio of acetonitrile to toluene is 1:2), filter, rinse the filter cake with a mixed solution of acetonitrile and toluene (20 mL), collect all filtrates for recycling, and dry the filter cake to obtain 27.5 g of white solid compound (IV), with a yield of 87.6% (calculated as bromooctadecane), (R1 is halogen, R2 is amino).

[0047] The obtained compound (IV) was synthesized in the same manner as steps S2 and S3 of Example 1 to obtain 21.9 g of olaflurane with a purity of 99.71% and a yield of 91.3%.

[0048] Example 4

[0049] This example is substantially the same as Example 1, except that the steps for synthesizing compound (I) are different, as follows:

[0050] S3: In a reactor, add compound (VI) (22.9 g, 0.05 mol) to ethanol (200 mL), stir to dissolve, introduce nitrogen protection, control the temperature at -10°C, slowly drop 2.5 g of 40 wt% hydrofluoric acid aqueous solution into the reaction solution, raise the temperature to 50°C after addition, stir for 2-3 h, react until completion, cool, and concentrate to obtain 20.4 g of light yellow transparent colloidal solid compound (I) with a purity of 99.35% and a yield of 85.2% (calculated based on compound (VI)).

[0051] Comparative Example 1

[0052] The other steps are the same as those in Example 1, except that step S1 is a normal pressure and high temperature reaction. Octadecylamine (26.9 g, 0.1 mol) is added to a clean and dry tank reactor, and ethylene oxide gas (4.6 g, 0.105 mol) is slowly introduced under nitrogen protection. After the addition, the temperature is raised to 200°C, and the reaction is carried out for 24 hours. Samples are taken for monitoring by TLC. If the reaction is not complete and there are many impurities, the next step of reaction is not carried out.

[0053] Comparative Example 2

[0054] The other steps are the same as those in Example 2, except that step S1 is a normal pressure and high temperature reaction. 2-bromoethanol (12.5 g, 0.1 mol) and octadecylamine (67.4 g, 0.25 mol) are added to a clean and dry tank reactor, replaced with nitrogen three times, and the temperature is raised to 150°C. The reaction is carried out for 24 hours, and the sample is taken for monitoring by TLC. There are many impurities, and the next step of reaction is not carried out (R1 is amino, and R2 is halogen).

[0055] Comparative Example 3

[0056] The other steps are the same as those in Example 2, except that the post-treatment in step S1 is a single solvent. 2-bromoethanol (12.5 g, 0.1 mol) and octadecylamine (67.4 g, 0.25 mol) were added to a clean and dry tank reactor, replaced with nitrogen 3 times, and the temperature was controlled at 20 ° C. After stirring the reaction at this temperature for 1 h, the temperature was raised to 150 ° C., and the internal pressure was made 0.6 MPa at the same time. The reaction was continued for 5-6 h at this temperature and pressure, and the sample was monitored by TLC until the reaction was completed. Cooling to room temperature, the reaction solution was slowly added to 150 mL of water, stirred for 10 min, and then filtered. The filter cake was pulped with 150 mL of tetrahydrofuran solution at 30 ° C for 1 h, filtered, and the filter cake was rinsed with tetrahydrofuran (20 mL). All filtrates were collected and recycled, and the filter cake was dried to obtain 25.8 g of white solid compound (IV) with a yield of 82.4% (calculated as 2-bromoethanol).

[0057] The obtained compound (IV) was synthesized in the same manner as steps S2 and S3 of Example 1 to obtain 21.1 g of olaflurane with a purity of 98.12% and a yield of 82.2%.

[0058] Comparative Example 4

[0059] Other steps are the same as in Example 3, except that step S1 is a high-pressure and low-temperature reaction. In step S1, bromooctadecane (33.3g, 0.1mol) and ethanolamine (15.3g, 0.25mol) are added to a clean and dry stuffy tank reactor, replaced with nitrogen 3 times, temperature controlled at 20°C, and the internal pressure is 0.6MPa at the same time. The reaction is continued for 24h at this temperature and pressure, and sampling is monitored by TLC. The raw material bromooctadecane is reacted. Cooling to room temperature, the reaction solution is slowly added to water (150mL), stirred for 10min and then filtered, the filter cake is slurried at 50°C for 1h with a mixed solution of acetonitrile and toluene (150mL, a volume ratio of acetonitrile to toluene of 1:2), filtered, and rinsed with a mixed solution of acetonitrile and toluene (20mL). The filter cake is plated, and there are many impurities. The column is purified to obtain a white solid compound (IV) 9.6g, with a yield of 30.6% (calculated as bromooctadecane).

[0060] The present invention is described in detail through specific examples in the specification, but those skilled in the art can make various modifications and changes to the present invention within the scope and technical concept of the present invention, and these modifications 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 preparation method comprises the following steps: S1: using compound (II) and hydroxyethyl reagent (III) as raw materials, reacting to obtain a compound of formula (IV); S2: Compound (IV) reacts with compound (V) in the presence of an alkaline reagent to obtain a compound of formula (VI); S3: The compound of formula (VI) is subjected to a salt-forming reaction to obtain the target product as shown in formula (I), and the process route is as follows: Wherein: R1 is amino or halogen, R2 is amino or halogen, and R1 and R2 are different; X is F, Cl, Br or I.

2. The preparation method according to claim 1, characterized in that: In the step S1, after nitrogen replacement, compound (II) and compound (III) are added to the sealed tank reactor, first reacted at low temperature, then reacted at high temperature and high pressure, and sampling and monitoring were performed until the reaction was completed. The temperature was lowered to 25-30° C., the reaction solution was slowly added to water, filtered, and the filter cake was slurried with a solvent to obtain a solid compound of formula (IV).

3. The preparation method according to claim 1, characterized in that: In step S2, under nitrogen protection, compound (IV), compound (V), alkaline reagent and organic solvent are added to a reaction container, the temperature is raised to 80-120° C., and the reaction is kept warm for 10-15 hours. The reaction solution is cooled and filtered, the filter cake is washed with the above-mentioned reaction organic solvent, the filtrate is concentrated under reduced pressure, and recrystallized to obtain a compound of formula (VI).

4. The preparation method according to claim 1, characterized in that: In step S3, under nitrogen protection, compound (VI) and hydrogen fluoride are added to the alcohol solution at -10-20°C, the temperature is raised to 20-60°C, and the reaction is completed to obtain the target product shown in formula (I).

5. The preparation method according to claim 1, characterized in that: In the step S1, the hydroxyethyl reagent is selected from one of 2-fluoroethanol, 2-chloroethanol, 2-bromoethanol, 2-iodoethanol, ethylene oxide, and ethanolamine.

6. The preparation method according to claim 1, characterized in that: In the step S1, the molar ratio of the halogenated compound to the amino compound is 1:2-3.

7. The preparation method according to claim 2, characterized in that: In step S1, the low-temperature reaction temperature is 20-40°C, and the low-temperature reaction time is 1-3 hours; the high-temperature reaction temperature is 150-200°C, and the high-temperature reaction pressure is 0.1-1.5MPa, and the reaction time under this pressure is 3-6 hours.

8. The method according to claim 2, characterized in that: In step S1, the pulping solvent is selected from one or a combination of two or more of methanol, ethanol, acetonitrile or toluene.

9. The method according to claim 1 or 3, characterized in that: In step S2, the molar ratio of compound (IV) to compound (V) is 1:1-1.

1.

10. The preparation method according to claim 4, characterized in that: In the step S3, the hydrogen fluoride is one of hydrogen fluoride gas, hydrofluoric acid aqueous solution or hydrofluoric acid ethanol solution.

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