Preparation method of oxilafluorine

Abstract

The invention discloses a preparation method of oxilafluorine, which comprises the following step: carrying out alkylation, deprotection, hydroxyethylation and salt forming reaction on a compound (II) to prepare the oxilafluorine as shown in a formula (I). The method has the advantages of low raw material cost, simple process operation, environmental friendliness, high reaction yield, high product purity and wide industrial prospect.

Description

Technical Field

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

[0002] Studies have shown that fluoride can combine with minerals on the surface of teeth to form a hard protective film, which can prevent acidic substances from corroding the tooth surface, thereby reducing the occurrence of caries. In addition, fluoride can also inhibit the growth of bacteria in the mouth, thereby reducing the occurrence of caries. Olafluor is a new type of organic fluoride. The difference from traditional inorganic fluorides is that one end of it is a hydrophilic amino group and the other end is a hydrophobic fatty chain, which makes it have good surface activity. It can quickly wrap each tooth to form an anti-caries protective layer, disperse dental plaque, and can penetrate the bacterial cell membrane well, interfere with bacterial metabolism, and inhibit the production of organic acids.

[0003] Currently, there are four publicly disclosed methods for synthesizing olaflurane: Patent US6464962 uses beef tallow as a mixture, which has a long reaction route, high difficulty in separation and purification, high requirements on equipment, and low yield; Patent CN118496111A uses all materials mixed together for reaction, which has many reaction sites, high difficulty in reaction purification, and low yield; Patent CN118515573A uses a long reaction time, and the product separation and purification method is not suitable for industrial production; Patent CN118530128A uses highly toxic and unstable acrolein, and the product separation and purification method is not suitable for industrial production. Summary of the invention

[0004] In order to solve the problems existing in the prior art, the present invention provides a method for preparing olafluanid, which has simple process operation, is environmentally friendly, has high reaction yield, high product purity, and has broad industrialization prospects.

[0005] In order to achieve the above object, the present invention adopts the following technical solution, which includes the following steps:

[0006] S1: Compound (II) reacts with octadecylamine to form compound (III);

[0007] S2: Compound (III) is deprotected to generate compound (IV);

[0008] S3: Compound (IV) is hydroxyethylated to generate compound (V);

[0009] S4: Compound (V) is salified to form compound (I);

[0010] The structures of the compounds shown in compound (I), compound (II), compound (III) and compound (IV) are respectively:

[0011]

[0012] According to the above scheme, in step S1, octadecylamine is added to the alkaline solution of compound (II) at room temperature, and the temperature is raised to 70-80°C for reaction. After the reaction, hot filtration is performed, the mother liquor is cooled to 10-15°C for crystallization, filtered with suction, and the filter cake is slurried with a solvent to obtain a solid compound (III).

[0013] According to the above scheme, the temperature of hot filtration is 70-80°C.

[0014] According to the above scheme, in step S1, the molar ratio of compound (II), octadecylamine and base is 1:1-1.2:1-1.5.

[0015] According to the above scheme, in step S2, acid is added to compound (III), and the temperature is raised to 50-80°C for reaction. After the reaction, the reaction solution is slowly dripped into a sodium hydroxide solution at -10-0°C. After the addition, the pH of the reaction solution is 11-12, and the solution is filtered to obtain a solid compound (IV).

[0016] According to the above scheme, in step S2, the acid is one or a mixture of two or more of hydrochloric acid, hydrobromic acid, acetic acid or trifluoroacetic acid.

[0017] According to the above scheme, in step S2, the molar ratio of compound (III) to acid is 1:5-8.

[0018] According to the above scheme, in step S3, compound (IV), methanol, and hydroxyethyl reagent are added to the reactor at room temperature, and then the temperature is slowly raised to 30-60°C for reaction. After the reaction is completed, the temperature is lowered to room temperature, and the reaction solution is concentrated under reduced pressure to obtain compound (V).

[0019] According to the above scheme, in step S3, the hydroxyethyl reagent is one of EO, 2-fluoroethanol, 2-chloroethanol, 2-bromoethanol, and 2-iodoethanol.

[0020] According to the above scheme, in step S3, the molar ratio of compound (IV) to hydroxyethyl reagent is 1:3-5.

[0021] According to the above scheme, in step S4, hydrogen fluoride is added to the methanol solution containing compound (V) at 5-10°C, the mixture is stirred at 5-10°C until the reaction is complete, and the mixture is filtered to obtain the compound represented by formula (I).

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] 1. The Boc protecting group selected in the present invention can complete the hydroxyethylation of three reaction sites at one time, shortening the reaction steps; at the same time, it ensures that the initial raw materials do not undergo two-by-two reactions or tail reactions during the first step of the reaction, inhibits the generation of impurities, and reduces the difficulty of product purification.

[0024] 2. The raw materials used in the present invention are cheap and easily available, and are all compounds with little irritation, little odor, and little toxicity; the four-step reaction has high selectivity, no side reaction, few impurities, simple separation and purification, and high product purity; the four-step reaction process is easy to operate, has low equipment requirements, high reaction yield, and is suitable for industrial production. DETAILED DESCRIPTION

[0025] Some specific examples are provided below to verify the performance of the implementation method of the present invention.

[0026] Example 1

[0027] This embodiment provides a method for preparing olafluanid (I), which specifically comprises the following steps:

[0028] The structures of the compounds shown in compound (I), compound (II), compound (III) and compound (IV) are respectively:

[0029]

[0030] (1) Synthesis of compound (III)

[0031] At room temperature, compound (II) (7.1 kg, 30.0 mol), potassium carbonate (4.1 kg, 30.0 mol), N,N-dimethylformamide (21 kg) were added to a 50 L reactor in sequence. After stirring evenly, octadecylamine (8.5 kg, 31.5 mol) was added, and then the temperature was raised to 70-80 ° C for reaction for 3 h. The reaction was monitored by TLC until completion, and the mixture was hot filtered at 70-80 ° C. The mother liquor was cooled to 10-15 ° C and filtered. The filter cake was slurried once with twice the amount of isopropanol at room temperature, filtered, and dried to obtain 11.4 kg of white solid (III) with a yield of 89.1%. 1 H-NMR (400MHz, CDCl3), δ (ppm): 6.29 (br s; 1H); 4.96 (br s; 1H); 3.30 (dt; J = 13.33, 6.13Hz; 2H); 3.22-3.10 (m; 2H); 2.20 (t; J = 7.93Hz; 2 H); 1.69-1.57 (m; 4H); 1.44 (s; 9H); 1.36-1.22 (m; 28H); 0.88 (t; J=6.80Hz; 3H).

[0032] (2) Synthesis of compound (IV)

[0033] At room temperature, compound (III) (10.7 kg, 25.0 mol) and 30 wt% hydrochloric acid (15.2 kg, 125.0 mol) were added to a 50 L reactor in sequence, and the temperature was raised to 70-80 ° C for 1 h. The reaction was monitored by TLC. Another 50 L reactor was added with 30 wt% liquid alkali (16.8 kg, 126.0 mol), cooled to -10-0 ° C, and then the reaction solution of compound (III) was added dropwise thereto. After the addition was completed, the pH was tested to be 11-12, filtered, and dried to obtain 8.1 kg of white solid (IV) with a yield of 99.3%. 1 H-NMR (400 MHz, DMSO-d 6 ), δ (ppm): 7.94 (t; J = 5.62Hz; 1H); 7.75 (br; 3H); 3.09 (q; J = 6.10Hz; 2H); 2.76 (br; 2H); 2.05 (t; J=7.4Hz; 2H); 1.65 (m; 2H); 1.53-1.42 (m; 2H); 1.31-1.15 (m; 28H); 0.85 (m; 3H).

[0034] (3) Synthesis of Compound (V)

[0035] At room temperature, compound (Ⅳ) (11.4 kg, 35.0 mol) and methanol (20.0 kg) were added to a 50 L high pressure reactor. After covering the reactor, the atmosphere was replaced with N2 three times. EO was introduced into the reactor until the internal pressure reached 2.0 MPa, and the reaction was continued at 55-60°C for 3 h. After the reaction was completed under TLC monitoring, the reaction solution was cooled and concentrated to obtain 15.4 kg of a transparent oily substance (V) with a yield of 95.6%. 1 H NMR (400MHz, CDCl3), δ (ppm): 4.23 (s, 3H), 3.58 (dt, J = 9.8, 4.9Hz, 6H), 2.64-2.43 (m, 10H), 2.43- 2.36(m,2H),1.61(p,J=6.1Hz,2H),1.40(q,J=12.5,10.3Hz,2H),1.21(s,30H),0.86–0.81(m,3H).

[0036] (4) Synthesis of compound (I)

[0037] At room temperature, compound (V) (11.5 kg, 25.0 mol) and methanol (23.0 kg) were added to a 50 L reactor, and the temperature was lowered to 5-10 ° C. Hydrogen fluoride was introduced into the reactor until saturated. The reaction was stirred at 5-10 ° C for 1 h, and filtered to obtain 12.4 kg of a yellow transparent colloidal solid (I) with a purity of 99.8%, a yield of 99.8%, and a total yield of 84.4%.

[0038] 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.

[0039]

[0040] Where: X-olafluor purity, %;

[0041] V- is the volume of the standard hydrochloric acid solution to be titrated, mL;

[0042] C-concentration of hydrochloric acid standard solution, mol / L;

[0043] m-sample weight, g;

[0044] M-Molar mass of free hydroxylamine of olaflurane, g / mo1.

[0045] Comparative Example 1

[0046] This comparative example is substantially the same as Example 1, except that in the synthesis step of compound (III), Br in compound (II) is replaced by F (5.3 kg, 30.0 mol), and 1.5 kg of white solid is obtained with a yield of 13.3%.

[0047] Comparative Example 2

[0048] This comparative example is substantially the same as Example 1, except that in the synthesis step of compound (III), Br in compound (II) is replaced by Cl (5.8 kg, 30.0 mol), and 7.3 kg of white solid is obtained with a yield of 63.8%.

[0049] Comparative Example 3

[0050] This comparative example is substantially the same as Example 1, except that in the synthesis step of compound (III), Br in compound (II) is replaced by I (8.5 kg, 30.0 mol), and 5.2 kg of white solid is obtained with a yield of 36.7%.

[0051] Comparative Example 4

[0052] (1) Synthesis of compound (III)

[0053] This step is substantially the same as that of Example 1, except that in the step of synthesizing compound (III), the tert-butyloxycarbonyl Boc in compound (II) is replaced with benzyloxycarbonyl Cbz (8.2 kg, 30.0 mol), to obtain 8.8 kg of white solid with a yield of 63.7%.

[0054] (2) Synthesis of compound (IV)

[0055] At room temperature, the compound (III) (11.5 kg, 25.0 mol) prepared in (1) and 48 wt% hydrobromic acid (12.6 kg, 75.0 mol) were added to a 50 L reactor in sequence, and the temperature was raised to 40-50°C for reaction for 1 h. The reaction was monitored by TLC. Another 50 L reactor was added with 30% liquid alkali (16.8 kg, 126.0 mol), cooled to -10-0°C, and then the reaction solution of compound (III) was added dropwise thereto. After the addition was completed, the pH was tested to be 11-12, filtered, and dried to obtain 7.2 kg of white solid with a yield of 88.7%.

[0056] Comparative Example 5

[0057] This step is substantially the same as that of Example 1, except that in the step of synthesizing compound (III), the tert-butyloxycarbonyl Boc in compound (II) is replaced with p-toluenesulfonyl Tos (8.8 kg, 30.0 mol), to obtain 7.8 kg of white solid with a yield of 54.2%.

[0058] Comparative Example 6

[0059] (1) Synthesis of compound (III)

[0060] This step is substantially the same as that of Example 1, except that in the step of synthesizing compound (III), the tert-butyloxycarbonyl Boc in compound (II) is replaced with benzyl Bn (6.8 kg, 30.0 mol), to obtain 8.9 kg of white solid with a yield of 70.8%.

[0061] (2) Synthesis of compound (IV)

[0062] At room temperature, the compound (III) (10.4 kg, 25.0 mol) prepared in (1), methanol (20.8 kg), 10% Pd / C (2.1 kg) were added to a 50 L autoclave in sequence, and hydrogen gas (3.0 MPa) was introduced. The mixture was stirred at 25-35°C for 12 h, and the reaction was monitored by TLC. The reaction was filtered and the mother liquor was dried to obtain 4.7 kg of a white solid with a yield of 57.9%.

[0063] Example 2

[0064] The hydrochloric acid used in the synthesis of compound (IV) in Example 1 was replaced with acetic acid (6.3 kg, 75.0 mol), and the other conditions were the same as in Example 1 to obtain 8.1 kg of white solid compound (IV) with a yield of 99.1%.

[0065] Example 3

[0066] The hydrochloric acid used in the synthesis of compound (IV) in Example 1 was replaced by a mixture of hydrochloric acid and acetic acid (7.6 kg of 30% hydrochloric acid and 3.8 kg of acetic acid). Other conditions were the same as in Example 1. 8.1 kg of white solid compound (IV) was obtained with a yield of 99.5%.

[0067] Example 4

[0068] The EO used in the synthesis of compound (V) in Example 1 was replaced with bromoethanol, and the rest was the same as in Example 1. The synthesis example of compound (V) is as follows:

[0069] At room temperature, compound (IV) (11.4 kg, 35.0 mol), methanol (20.0 kg), potassium carbonate (5.8 kg, 42 mol) were added to a 50 L reactor, and the temperature was raised to 55-60 ° C. Then, bromoethanol (13.6 kg, 108.5 mol) was added dropwise. After the addition was completed, the reaction was kept at 55-60 ° C for 4 h. After the reaction was completed under the control of TLC, the reaction solution was cooled, filtered, and the mother liquor was concentrated to obtain 15.0 kg of a transparent oil with a yield of 93.6%.

[0070] The above contents are only basic descriptions of the concept of the present invention, and any changes made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for preparing olafluanid (I), characterized in that: The steps include: S1: Compound (II) reacts with octadecylamine to form compound (III); S2: Compound (III) is deprotected to generate compound (IV); S3: Compound (IV) is hydroxyethylated to generate compound (V); S4: Compound (V) is salified to form compound (I); The structures of the compounds shown in compound (I), compound (II), compound (III) and compound (IV) are respectively:

2. The preparation method according to claim 1, characterized in that: In the step S1, octadecylamine is added to the alkaline solution of compound (II) at room temperature, the temperature is raised to 70-80°C, the reaction is completed, hot filtration is performed, the mother liquor is cooled to 10-15°C for crystallization, suction filtration is performed, and the filter cake is slurried with a solvent to obtain a solid compound (III).

3. The preparation method according to claim 2, characterized in that: The temperature of hot filtration is 70-80°C.

4. The preparation method according to claim 1, characterized in that: In the step S2, an acid is added to the compound (III), and the temperature is raised to 50-80°C. After the reaction is completed, the reaction solution is slowly dripped into a sodium hydroxide solution at -10-0°C. After the addition, the pH of the reaction solution is 11-12, and the solution is filtered to obtain a solid compound (IV).

5. The preparation method according to claim 1, characterized in that: In the step S3, compound (IV), methanol, and hydroxyethyl reagent are added to the reactor at room temperature, and then the temperature is raised to 30-60° C. After the reaction is completed, the temperature is lowered to room temperature, and the reaction solution is concentrated under reduced pressure to obtain compound (V).

6. The preparation method according to claim 5, characterized in that: The molar ratio of compound (IV) to the hydroxyethyl reagent is 1:3-5.

7. The preparation method according to claim 1, characterized in that: In the step S4, hydrogen fluoride is added to the solution containing compound (V) at 5-10°C, the solution is stirred at 5-10°C until the reaction is complete, and the solution is filtered to obtain the compound represented by formula (I).

8. The preparation method according to claim 2, characterized in that: The molar ratio of compound (II), octadecylamine and base is 1:1-1.2:1-1.

5.

9. The preparation method according to claim 4, characterized in that: The acid is one of hydrochloric acid, hydrobromic acid, acetic acid or trifluoroacetic acid, or a mixture of two or more thereof.

10. The preparation method according to claim 4, characterized in that: The molar ratio of compound (III) to acid is 1:5-8.

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