Synthetic method of oxilafluorine

Abstract

The synthetic method comprises the following steps: S1, reacting octadecylamine with acrylonitrile to obtain an intermediate (II), and carrying out catalytic hydrogenation on the intermediate (II) to generate a compound (III); s2, performing hydroxyethylation on the compound (III) to obtain a compound (IV); and S3, salifying the compound (IV) to obtain the compound as shown in the formula (I). The synthetic method of the oxilafluorine disclosed by the invention is high in reaction selectivity, simple to operate, convenient in post-treatment, high in yield and suitable for industrial production, and has a wide application prospect.

Description

Technical Field

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

[0002] Fluoride has been used to prevent dental caries for more than 70 years and has achieved great success. The main ingredients of fluoride toothpaste on the market are sodium fluoride, sodium monofluorophosphate and stannous fluoride. On the one hand, fluoride can improve tooth structure, reduce tooth solubility in acid, prevent demineralization, and enhance tooth resistance; on the other hand, fluoride ions can promote tooth recalcification and play a role in repairing early defects. Fluoride can also affect bacterial metabolism and play an antibacterial role.

[0003] In-depth research on the caries prevention properties of fluoride has discovered aminofluoride. Studies have shown that olafluor is more likely to adhere to the tooth surface than inorganic fluoride and has a stronger cleaning effect. On the other hand, in vitro experiments have shown that olafluor can better inhibit bacterial adhesion to the enamel membrane and reduce the formation of dental plaque than other fluorides.

[0004] The synthesis method of olafluanid has been reported, and its synthesis routes mainly include the following: Patent US 6464962 uses beef tallow as raw material and obtains the target product through multi-step reactions. Beef tallow is a mixture with many impurities, a long reaction route, and a low yield. Patent CN 118496111A mixes multiple raw materials to obtain the target product. In this route, the reaction raw materials have multiple reaction sites, many side reactions, and a long reaction time. Patent CN 118515573A requires the use of anhydrous reagents, harsh reaction conditions, and a low yield. Patent CN 118530128A uses highly toxic acrolein and a relatively expensive phase transfer catalyst, and the column chromatography separation method is not suitable for industrial production. Summary of the invention

[0005] In order to solve the above technical problems, the object of the present invention is to provide a method for synthesizing olafluanid which is economical, has high reaction selectivity, is easy to operate, has high yield and is suitable for industrialization.

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

[0007] S1, octadecylamine reacts with acrylonitrile to obtain an intermediate (II), and the intermediate (II) is catalytically hydrogenated to generate a compound (III);

[0008] S2, compound (III) is hydroxyethylated to obtain compound (IV);

[0009] S3, compound (IV) is salted to obtain the compound olafluanid represented by formula (I);

[0010] The structures of compound (II), compound (III), compound (IV) and the compound represented by formula (I) are:

[0011]

[0012] Specifically, in step S1, octadecylamine, acrylonitrile and a reaction solvent are added to a reactor at 10 to 50° C., and the reaction is completed at this temperature to obtain an intermediate (II). A catalyst and hydrogen are directly added, and the reaction is carried out at 10 to 80° C. for 1 to 4 hours. The reaction liquid is filtered, and the filtrate is concentrated under reduced pressure to obtain a solid compound (III).

[0013] Specifically, in step S1, the molar ratio of octadecylamine to acrylonitrile is 1:1-2, preferably 1:1.1.

[0014] Specifically, in step S1, the solvent is one of ethanol, isopropanol, n-butanol, tetrahydrofuran, and acetone, preferably ethanol.

[0015] Specifically, in step S1, the catalyst is one of nickel, Raney nickel, palladium carbon, rhodium carbon or aluminum nickel, preferably palladium carbon.

[0016] Specifically, in step S1, the initial pressure of the reaction system after the introduction of hydrogen is 0.5-4 MPa, preferably 2 MPa.

[0017] Specifically, in step S2, compound (III) and reaction solvent tetrahydrofuran are added to a sealed tank reactor at room temperature. After sufficient N2 replacement, ethylene oxide is introduced into the reactor to make the reactor pressure 0.1-2 MPa, and then the temperature is increased to 30-60°C. When the pressure drops to a constant value, the reaction is stopped, and the reaction solution is concentrated under reduced pressure to obtain compound (IV).

[0018] Specifically, in step S3, hydrogen fluoride is added to a solvent containing compound (IV) at 5-10° C., stirred at room temperature for 2-4 hours, preferably 3 hours, filtered, and dried to obtain a compound represented by formula (I).

[0019] The synthesis method of olafluanid provided by the present invention has the following technical effects:

[0020] 1. The synthesis method of olafluanid provided by the present invention has the advantages of high reaction selectivity and high yield.

[0021] 2. The synthesis method of olafluanid provided by the present invention is simple to operate, convenient for post-treatment, has low requirements on equipment, and is suitable for industrial production. DETAILED DESCRIPTION

[0022] 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.

[0023] Example 1

[0024] This embodiment provides a method for synthesizing olafluanid, and the specific synthesis steps are as follows:

[0025] S1: At 30°C, octadecylamine (2.69kg, 10mol), acrylonitrile (0.58kg, 11mol), and ethanol (13.45kg) were added to a 50L reactor, and the reaction was completed at this temperature to obtain intermediate (II). The intermediate did not need to be purified, and palladium carbon (0.16kg, calculated as 5% of the theoretical mass of the intermediate) was directly added to the reactor. After H2 was fully replaced, H2 was introduced into the reactor to make the pressure of the reaction system 2MPa, and then the temperature was raised to 50°C and the reaction was continued for 2h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound (III), 3.18kg, with a yield of 97.2%. 1 H NMR(400MHz, CDCl3)δ2.57(dd,J=12.7,5.5Hz,3H),2.46–2.21(m,5H),1.61(dt ,J=13.9,6.9Hz,2H),1.51–1.34(m,5H),1.34–1.12(m,59H),0.90–0.82(m,6H).

[0026] S2: Add compound (III) (2.61 kg, 8 mol) and ethanol (15.66 kg) into a 50 L reactor. After sufficient N2 replacement, introduce ethylene oxide into the reactor to make the pressure of the reaction system 0.5 MPa, and then start to heat up to 40°C. When the pressure drops to a constant level, stop the reaction, and concentrate the reaction solution under reduced pressure to obtain compound (IV), 3.35 kg, with a yield of 91.2%. 1 H NMR(400MHz, CDCl3)δ4.23(s,3H),3.58(dt,J=9.8,4.9Hz,6H),2.64–2.43(m,10H),2.43–2.36(m,2H ),1.66–1.57(m,2H),1.40(dd,J=19.4,12.5Hz,2H),1.32–1.09(m,30H),0.83(dd,J=6.9,6.1Hz,3H).

[0027] S3: Under N2 protection, compound (IV) (3.21 kg, 7 mol) and ethanol (22.47 kg) were added into a 50 L reactor. Hydrogen fluoride gas was introduced into the reactor at 10°C. After the addition, the mixture was stirred at room temperature for 3 h, filtered, and dried to obtain the compound represented by formula (I), 3.40 kg, with a yield of 97.4%.

[0028] Example 2

[0029] This example is substantially the same as Example 1, except that in the step of synthesizing intermediate (II), the molar ratio of octadecylamine to acrylonitrile is 1:1, and compound (III) is obtained, 3.06 kg, with a yield of 93.6%.

[0030] Example 3

[0031] This example is substantially the same as Example 1, except that in the step of synthesizing intermediate (II), the molar ratio of octadecylamine to acrylonitrile is 1:1.5, and compound (III) is obtained, 3.17 kg, with a yield of 96.9%.

[0032] Example 4

[0033] This example is substantially the same as Example 1, except that in the step of synthesizing intermediate (II), the reaction solvent is tetrahydrofuran, and compound (III) is obtained, 2.87 kg, with a yield of 87.7%.

[0034] Example 5

[0035] This example is substantially the same as Example 1, except that in the step of synthesizing intermediate (II), the reaction solvent is acetone, and compound (III) is obtained, 2.74 kg, with a yield of 83.8%.

[0036] Example 6

[0037] This example is substantially the same as Example 1, except that in the step of synthesizing compound (III), the catalyst for the hydrogenation reaction is Raney nickel, and compound (III) is obtained, 2.95 kg, with a yield of 90.2%.

[0038] Example 7

[0039] This example is substantially the same as Example 1, except that in the step of synthesizing compound (III), the catalyst for the hydrogenation reaction is rhodium-carbon, and compound (III) is obtained, 2.88 kg, with a yield of 88.1%.

[0040] Example 8

[0041] This example is similar to Example 1, except that in the step of synthesizing compound (III), the pressure of the reaction system after the introduction of hydrogen is 0.5 MPa, and compound (III) is obtained, 2.92 kg, with a yield of 89.3%.

[0042] Example 9

[0043] This example is similar to Example 1, except that in the step of synthesizing compound (III), the pressure of the reaction system after the introduction of hydrogen is 1 MPa, and compound (III) is obtained, 3.03 kg, with a yield of 92.7%.

[0044] Example 10

[0045] This example is similar to Example 1, except that in the step of synthesizing compound (III), the pressure of the reaction system after the introduction of hydrogen is 4 MPa, and compound (III) is obtained, 3.18 kg, with a yield of 97.2%.

[0046] Comparative Example 1

[0047] Comparative Example 1 is substantially the same as Example 1, except that in the step of synthesizing intermediate (II), the molar ratio of octadecylamine to acrylonitrile is 1.5:1, and the yield is 5.5%. The electronegativity difference between carbon and N atoms in the cyano group is small, and it is difficult for hydrogen ions to add to carbon, resulting in a low yield of the hydrogenation reaction.

[0048] Comparative Example 2

[0049] Comparative Example 2 is similar to Example 1, except that in the step of synthesizing intermediate (II), the reaction solvent is water, and compound (III) is obtained, 0.32 kg, with a yield of 9.8%. Octadecanamine has poor solubility in water, and its reaction with acrylonitrile is a heterogeneous reaction, resulting in a low yield.

[0050] Comparative Example 3

[0051] Comparative Example 3 is substantially the same as Example 1, except that in the step of synthesizing compound (III), the catalyst for the hydrogenation reaction is sodium borohydride, and compound (III) is obtained, 0.18 kg, with a yield of 5.5%. The electronegativity difference between carbon and N atoms in the cyano group is small, and it is difficult for hydrogen ions to add to carbon, resulting in a low yield of the hydrogenation reaction.

[0052] Comparative Example 4

[0053] Comparative Example 4 is substantially the same as Example 1, except that in the step of synthesizing compound (III), hydrogen was introduced to make the pressure of the reaction system 0.3 MPa, and compound (III) was obtained, 1.37 kg, with a yield of 46.9%. When the hydrogen pressure is low, the hydrogen adsorbed by the catalyst is reduced, the efficiency of catalytic hydrogenation is low, and the yield is low.

[0054] 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 synthesizing olafluanid, characterized in that: The steps include: S1, octadecylamine reacts with acrylonitrile to obtain an intermediate (II), and the intermediate (II) is catalytically hydrogenated to generate a compound (III); S2, compound (III) is hydroxyethylated to obtain compound (IV); S3, compound (IV) is salted to obtain the compound olafluanid represented by formula (I); The structures of compound (II), compound (III), compound (IV) and the compound represented by formula (I) are respectively: .

2. The method for synthesizing olafluanid according to claim 1, characterized in that: In the step S1, octadecylamine, acrylonitrile and a reaction solvent are added to a reactor at 10 to 50° C., and the reaction is completed at this temperature to obtain an intermediate (II). A catalyst and hydrogen are directly added, and the reaction is carried out at 10 to 80° C. for 1 to 4 hours. The reaction liquid is filtered, and the filtrate is concentrated under reduced pressure to obtain a solid compound (III).

3. The method for synthesizing olafluanid according to claim 1, characterized in that: In the step S1, the molar ratio of octadecylamine to acrylonitrile is 1:1-2.

4. The method for synthesizing olafluran according to claim 2, characterized in that: In the step S1, the solvent is one of ethanol, isopropanol, n-butanol, tetrahydrofuran or acetone.

5. The method for synthesizing olafluanid according to claim 2, characterized in that: In step S1, the catalyst is one of nickel, Raney nickel, palladium carbon, rhodium carbon or aluminum nickel.

6. The method for synthesizing olafluran according to claim 2, characterized in that: In the step S1, the initial pressure of the reaction system after the hydrogen is introduced is 0.5-4 MPa.

7. The method for synthesizing olafluanid according to claim 1, characterized in that: In the step S2, compound (III) is added to a sealed tank reactor at room temperature. After sufficient N2 substitution, ethylene oxide is introduced into the reactor to make the reactor pressure 0.1-2 MPa, and then the temperature is raised to 30-60°C. When the pressure drops to a constant value, the reaction is stopped, and the reaction solution is concentrated under reduced pressure to obtain compound (IV).

8. The method for synthesizing olafluanid according to claim 1, characterized in that: In the step S4, hydrogen fluoride is added to a solvent containing compound (IV) at 5-10° C., stirred at room temperature, filtered, and dried to obtain a compound represented by formula (I).

Images