A method for synthesizing olafluanid derivatives

Abstract

The invention discloses a method for synthesizing an olafluanid derivative, comprising taking R-X as a raw material, reacting with 1,3-propylenediamine, adding a Lewis acid and a solvent to the obtained product, reacting with a hydroxyalkylating agent, and reacting the obtained product with hydrofluoric acid to obtain the olafluanid derivative. The synthesis method of the invention has a simple process, reduces costs, and has a high yield and high purity of the obtained product. The olafluanid derivative can be used as a reference substance for quality research and quality control of the olafluanid, provides guidance for controlling the impurity content of the product, and further provides a guarantee for the safe use of the olafluanid.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing an olafluanid derivative. Background Art

[0002] Olafur (English name: Olafur, CAS No: 6818-37-7) is an important organic ammonium fluoride compound and is widely used in the field of oral care. Patent US6464962 discloses a currently commercialized method for synthesizing Olafur, and its synthesis route is as follows:

[0003]

[0004] The method starts with beef tallow, which is hydrolyzed to obtain stearic acid, which is then converted into the corresponding amide, which is catalytically reduced to a primary amine; then it is added with acrylonitrile and reduced to obtain N-alkyl-1,3-propylenediamine; the two nitrogen atoms react with ethylene oxide to form a tertiary amine; finally, hydrofluoric acid is added to obtain the final product. Since the starting material beef tallow used is a mixture, it is mixed with many other components, especially palmitic acid (16 carbon atoms) and oleic acid (monounsaturated fatty acid) with high content, which are also synthesized into olaflu derivatives (olaflu derivative A and olaflu derivative B) through this synthetic route. These derivatives not only affect the purity of the final product, but also affect the research and formulation of its quality standards.

[0005]

[0006]

[0007]

[0008] Patent CN118150729A reports a method for detecting oraflu in toothpaste using an oraflu mixture reference substance containing oraflu derivative A (C16-AMF) and derivative B (C18:1-AMF). However, using a mixture as a reference substance will affect the accuracy of the analytical method, so it is necessary to provide a qualitative and quantitative high-purity analytical reference substance for the quality study of oraflu. Summary of the invention

[0009] The present invention aims to provide a method for synthesizing an olafluanid derivative, which can obtain an olafluanid derivative with high purity, so that the olafluanid derivative can be used as a standard reagent or reference substance for quality control of the olafluanid.

[0010] The method for synthesizing an olafluanid derivative provided by the present invention comprises the following steps:

[0011] Step 1: RX is used as a raw material and reacted with 1,3-propylenediamine to obtain ;

[0012] Step 2, Add Lewis acid and solvent, react with hydroxyalkylating agent to obtain ;

[0013] Step 3, Reaction with hydrofluoric acid to obtain olaflurane derivatives ;

[0014] In the above steps,

[0015] The R group is or ;

[0016] The X group is halogen, hydroxyl or sulfonyloxy;

[0017] The hydroxyalkylating agent is one or more of ethylene oxide, 2-chloroethanol, 2-bromoethanol or 2-fluoroethanol;

[0018] Preferably, in step 1 of the synthesis method:

[0019] (1) When X represents a halogen, it is selected from any one of chlorine, bromine and iodine; when X represents a sulfonyloxy group, it is selected from any one of methanesulfonyloxy, benzenesulfonyloxy and p-toluenesulfonyloxy;

[0020] (2) Additional solvent may or may not be added during the reaction. If added, the solvent is selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, dichloromethane or chloroform;

[0021] (3) The molar ratio of RX to 1,3-propylenediamine is 1:(1-20), preferably 1:(8-12);

[0022] (4) The reaction is carried out at 60-80°C until the reaction is complete;

[0023] (5) After the reaction is completed, the intermediate product can be purified by two methods: adding water to the reaction system for crystallization, filtering, taking the solid, and drying to obtain the intermediate product; or removing 1,3-propylenediamine from the reaction solution, adding ethyl acetate and sodium carbonate aqueous solution for crystallization, filtering to retain the solid, and drying to obtain the intermediate product;

[0024] Preferably, in step 2 of the synthesis method:

[0025] (1) The Lewis acid is selected from any one or more of tetraalkyl titanate, zinc chloride, ferric chloride, calcium chloride, aluminum chloride, boron trifluoride or magnesium chloride;

[0026] (2) The molar ratio of the hydroxyalkylating agent is 1:(5-15), and the molar ratio of the Lewis acid is 1:(0.1-3), preferably 1:(8-12);

[0027] (3) The solvent is selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, dichloromethane or chloroform;

[0028] (4) The reaction is carried out at 20-30°C until the reaction is complete;

[0029] (5) After the reaction is completed, the reaction solution obtained by reacting N-octadecyl-1,3-dipropylamine with a hydroxyalkylating agent in the presence of a Lewis acid is washed with saturated brine and ammonia water in sequence, and concentrated to obtain an intermediate product;

[0030] Preferably, in step 3 of the synthesis method:

[0031] (1) The molar ratio with hydrofluoric acid is 1:(2~3);

[0032] (2) The reaction process is carried out in the presence of a solvent, wherein the solvent is selected from any one or more of water and ethanol;

[0033] (3) The reaction is carried out at 10-20°C until the reaction is complete;

[0034] The beneficial effects of the present invention are as follows: the present invention provides a method for synthesizing an olafluanid derivative, using a new synthetic route. The synthetic method has a simple process, reduces costs, and obtains a product with high yield and high purity. The product can be used as a reference for olafluanid quality research and quality control, provides guidance for controlling the impurity content of the product, and further provides a guarantee for the safe use of olafluanid. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the following briefly introduces the drawings required for describing the embodiment, wherein:

[0036] Figure 1 This is the NMR spectrum of olaflurane derivative A;

[0037] Figure 2 This is the liquid phase spectrum of the olaflurane derivative A;

[0038] Figure 3 This is the NMR spectrum of olaflurane derivative B;

[0039] Figure 4 This is the liquid phase spectrum of olaflurane derivative B. DETAILED DESCRIPTION

[0040] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with specific embodiments.

[0041] Embodiment 1:

[0042] Synthesis of Olaflurane Derivative A:

[0043]

[0044] Reaction step 1:

[0045]

[0046] When X is Br, 1-bromohexadecane (3053.14 mg, 10.00 mmol) and 1,3-propylenediamine (7410.7 mg, 100.00 mmol) were added to the reaction vessel, heated to 75°C and stirred for 15 hours, cooled to room temperature, added with water (30 mL), stirred at room temperature for 1 hour, filtered to collect the solid, washed with water and dried to obtain the intermediate product N 1 -Hexadecylpropane-1,3-diamine (2825.06 mg, yield 94.6%).

[0047] Table 1 Results of condition screening of derivative A step 1

[0048]

[0049] Reaction step 2:

[0050]

[0051] N 1 -Hexadecylpropane-1,3-diamine (1493.16 mg, 5.00 mmol), anhydrous zinc chloride (1363.15 mg, 10.00 mmol, 2eq), and tetrahydrofuran (20 mL) were added to the reaction vessel, 2-bromoethanol (6251.26 mg, 50.00 mmol) was added dropwise at 20°C and stirred for 24 hours, saturated brine was added for washing, the solvent was removed under reduced pressure, dichloromethane and saturated sodium carbonate aqueous solution were added, extraction was performed, the organic phase was retained, and it was concentrated under reduced pressure to obtain the intermediate product 2,2'-((3-(hexadecyl(2-hydroxyethyl)amino)propyl)imino)bis(ethane-1-ol) (2073.82 mg, yield 96.3%).

[0052] Table 2 Results of condition screening of derivative A step 2

[0053]

[0054] Reaction step 3:

[0055]

[0056] Dissolve 2,2'-((3-(hexadecyl(2-hydroxyethyl)amino)propyl)imino)bis(ethane-1-ol) (1100 mg, 2.55 mmol) in water (30 mL), control the temperature at 10-20°C, prepare hydrofluoric acid (255.52 mg, 5.11 mmol, 2eq) into a 40% aqueous solution and add it dropwise to the above reaction solution, detect the pH value, and make the pH value of the reaction system between 4 and 5. After the addition is completed, stir at 10-20°C for 2 hours, and concentrate under reduced pressure to a solid to obtain the product 2,2'-((3-(hexadecyl(2-hydroxyethyl)amino)propyl)imino)bis(ethane-1-ol) hydrofluoride (1166.89 mg, yield 97.3%). See the attached NMR spectrum of olaflurane derivative A. Figure 1 , liquid phase spectrum see attached Figure 2 .

[0057] Table 3 Results of condition screening in step 3 of derivative A

[0058]

[0059] Embodiment 2:

[0060] Synthesis of olaflurane derivative B:

[0061]

[0062] Reaction step 1:

[0063]

[0064] When X is Br, the reaction process is similar to step 1 of the olaflurane derivative A. The starting material 1-bromohexadecane is replaced with (Z)-1-bromo-9-octadecene (3000.51 mg, 9.05 mmol) and 1,3-propylenediamine (6706.06 mg, 90.50 mmol) are added to the reaction vessel, the temperature is raised to 75°C and stirred for 15 hours, the temperature is lowered to room temperature, water (30 mL) is added, the mixture is stirred at room temperature for 1 hour, the solid is collected by filtration, washed with water and dried to obtain the product (Z)-N 1 -(Octadeca-9-en-1-yl)propane-1,3-diamine (2656.80 mg, yield 90.4%).

[0065] Table 4 Results of condition screening of derivative B step 1

[0066]

[0067] Reaction step 2:

[0068]

[0069] The reaction process refers to step 2 of olafluanid derivative A, and the starting material N 1 -hexadecylpropane-1,3-diamine was replaced by (Z)-N 1 -(Octadeca-9-en-1-yl)propane-1,3-diamine (1500.05 mg, 4.62 mmol), anhydrous zinc chloride (1256.03 mg, 9.24 mmol, 2.0 eq) and tetrahydrofuran (20 mL) were added to a reaction vessel, 2-bromoethanol (5777.48 mg, 46.21 mmol) was added dropwise at 20°C and stirred for 24 hours, saturated brine was added for washing, the solvent was removed under reduced pressure, dichloromethane and saturated sodium carbonate aqueous solution were added, extraction was performed, the organic phase was retained, and it was concentrated under reduced pressure to obtain the product (Z)-2,2'-((3-((2-hydroxyethyl)(octadeca-9-en-1-yl)amino)propyl)imino)bis(ethane-1-ol) (1884.89 mg, yield 94.7%).

[0070] Table 5 Results of condition screening of step 2 of derivative B

[0071]

[0072] Reaction step 3:

[0073]

[0074] The reaction process refers to step 3 of the olafluran derivative A, and the starting material 2,2'-((3-(hexadecyl(2-hydroxyethyl)amino)propyl)imino)bis(ethane-1-ol) is replaced with (Z)-2,2'-((3-((2-hydroxyethyl)(octadec-9-en-1-yl)amino)propyl)imino)bis(ethane-1-ol) (1000.11 mg, 2.19 mmol), which is dissolved in water (30 mL), and the temperature is controlled at 10-20°C. Hydrofluoric acid (219.11 mg, 4.38 mmol) is prepared into a 40% aqueous solution and added dropwise to the above reaction solution. The pH value is detected to make the pH value of the reaction system between 4 and 5. After the addition was completed, the mixture was stirred at 10-20°C for 2 hours and concentrated under reduced pressure to a solid to obtain the product (Z)-2,2'-((3-((2-hydroxyethyl)(octadec-9-en-1-yl)amino)propyl)imino)bis(ethane-1-ol) hydrofluoride (1039.83 mg, yield 95.6%). The NMR spectrum of olafluran derivative B is attached. Figure 3 , liquid phase spectrum see attached Figure 4 .

[0075] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A method for synthesizing an olafluanid derivative, characterized in that: include, Step 1: Take RX as raw material and react with 1,3-propylenediamine to obtain Step 2: Add Lewis acid and solvent to the product obtained in step 1, and react with a hydroxyalkylating agent to obtain Step 3: The product obtained in step 2 is reacted with hydrofluoric acid to obtain an olaflurane derivative Among them, the R group is The X group is a halogen, a hydroxyl group or a sulfonyloxy group; wherein X is a sulfonyloxy group and is selected from any one of a methanesulfonyloxy group, a benzenesulfonyloxy group and a p-toluenesulfonyloxy group; In step 2, the Lewis acid is selected from any one or more of zinc chloride, aluminum chloride, boron trifluoride or magnesium chloride; The hydroxyalkylating agent is any one or more of ethylene oxide, 2-chloroethanol, 2-bromoethanol or 2-fluoroethanol.

2. The method for synthesizing the olafluanid derivative according to claim 1, characterized in that: In step 1, when X is a halogen, it is selected from any one of chlorine, bromine and iodine.

3. The method for synthesizing an olafluanid derivative according to claim 1 or 2, characterized in that: In step 1, the molar ratio of RX to 1,3-propylenediamine is 1:(1-20); a solvent may or may not be added during the reaction of step 1. When a solvent is added, the solvent is selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, dichloromethane or chloroform; and the reaction temperature in step 1 is 60-80°C.

4. The method for synthesizing an olafluanid derivative according to claim 1 or 2, characterized in that: In step 2, the molar ratio of the product obtained in step 1 to the hydroxyalkylating agent is 1:(5-15), and the molar ratio of the product obtained in step 1 to the Lewis acid is 1:(0.1-3).

5. The method for synthesizing an olafluanid derivative according to claim 1 or 2, characterized in that: In step 2, the solvent is selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, dichloromethane or chloroform.

6. The method for synthesizing an olafluanid derivative according to claim 1 or 2, characterized in that: In step 2, the reaction temperature is 20-30°C.

7. The method for synthesizing an olafluanid derivative according to claim 1 or 2, characterized in that: In step 3, the molar ratio of the product obtained in step 2 to hydrofluoric acid is 1:(2-3).

8. The method for synthesizing an olafluanid derivative according to claim 1 or 2, characterized in that: In step 3, the reaction temperature is 10-20°C.

9. The method for synthesizing an olafluanid derivative according to claim 1 or 2, characterized in that: In step 3, the reaction process is carried out in the presence of a solvent, and the solvent is selected from any one or more of water and ethanol.

Images