Preparation method for high-purity olaflur raw material

Abstract

The present invention belongs to the technical field of organic synthesis. Provided is a preparation method for a high-purity olaflur raw material. The preparation method comprises the following steps: step 1, reacting n-C18H37X with 1,3-propane diamine, so as to obtain N-octadecyl-1,3-dipropylamine; and step 2, reacting N-octadecyl-1,3-dipropylamine with a hydroxyalkylating reagent in the presence of an Lewis acid, so as to obtain bis(ethoxyl)-aminopropyl-N-ethoxyl octadecylamine. The synthetic route of the present invention is not only shorter and more efficient, and has a higher overall yield, but also avoids the use of dangerous reagents such as lithium aluminum hydride, such that the industrial production is safer.

Description

A method for preparing high-purity olaflurane raw material Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing high-purity olaflurane raw material. Background Technology

[0002] Olaflu is bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine dihydrofluoride. Patents such as CN 102099003A and CN116546956A disclose that adding an appropriate amount of olaflu to oral cleaning agents such as toothpaste or mouthwash has a therapeutic or preventive effect on tooth demineralization caused by food acids.

[0003] Bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine is an important raw material for the preparation of oraflu.

[0004] In the prior art, the article "Synthesis and CMC Determination of a Series of A / iphatic Diamines" (Journal of Pharmaceutical Sciences, 1975, 64(5): 883-885) discloses a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, and its synthetic route is as follows:

[0005] This synthetic route is rather lengthy and has a low reaction yield. Furthermore, the use of hazardous reagents such as lithium aluminum hydride makes it unsuitable for industrial production. Summary of the Invention

[0006] This invention was made to solve the above-mentioned problems, and its purpose is to provide a method for preparing high-purity olafur raw materials with short route, high yield and strong safety.

[0007] This invention provides a method for preparing high-purity olafon raw material, comprising the following steps:

[0008] Step 1, nC 18 H 37 X reacts with 1,3-propanediamine to give N-octadecyl-1,3-dipropylamine;

[0009] Step 2: N-octadecyl-1,3-dipropylamine reacts with a hydroxyalkylating agent in the presence of a Lewis acid to give bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine.

[0010] Wherein, X is a halogen, hydroxyl group or sulfonyl group;

[0011] The hydroxyalkylating agent is any one or more of ethylene oxide, 2-chloroethanol, 2-bromoethanol, or 2-fluoroethanol.

[0012] The method for preparing high-purity olaflue raw material provided by the present invention may also have the following characteristics: wherein the halogen is selected from any one of chlorine, bromine, and iodine, and the sulfonyloxy group is selected from any one of methanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy.

[0013] The method for preparing high-purity olaflue raw material provided by the present invention may also have the following feature: wherein 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.

[0014] The method for preparing high-purity olaflue raw material provided by the present invention may also have the following feature: step 1 is carried out in the presence of a solvent, wherein the solvent is selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, alkyl dichloride or chloroform.

[0015] The method for preparing high-purity olafon raw material provided by this invention may also have the following feature: step 1 is carried out in the presence of a solvent, nC 18 H 37 The mass-to-volume ratio of X to the solvent is 1 g:(3-10) mL.

[0016] The method for preparing high-purity olafon raw material provided by this invention may also have the following feature: wherein, in step 1, nC 18 H 37 No additional solvent is added during the reaction of X with 1,3-propanediamine.

[0017] The method for preparing high-purity olafon raw material provided by this invention may also have the following feature: wherein, in step 1, nC 18 H 37 The molar ratio of X to 1,3-propanediamine is 1:(1-20), preferably 1:(5-12).

[0018] The method for preparing high-purity olaflurane raw material provided by the present invention may also have the following feature: step 1 further includes a first purification step, which includes:

[0019] To nC 18 H 37 The reaction solution obtained by reacting X with 1,3-propanediamine was subjected to crystallization by adding water, filtered, and the solid was collected and dried to obtain N-octadecyl-1,3-dipropylamine.

[0020] or,

[0021] Remove nC 18 H 37 The 1,3-propanediamine in the reaction solution obtained by reacting X with 1,3-propanediamine was crystallized by adding ethyl acetate and sodium carbonate aqueous solution, filtered, and the solid was dried to obtain N-octadecyl-1,3-dipropane.

[0022] The method for preparing high-purity olaflue raw material provided by the present invention may also have the following feature: step 2 is carried out in the presence of a solvent, wherein the solvent is selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, alkyl dichloride or chloroform.

[0023] The method for preparing high-purity olaflue raw material provided by the present invention may also have the following feature: wherein, in step 2, the mass ratio of the solvent to the N-octadecyl-1,3-dipropylamine is (2-10):1.

[0024] The method for preparing high-purity olaflue raw material provided by the present invention may also have the following feature: wherein the molar ratio of N-octadecyl-1,3-dipropylamine to the hydroxyalkylating agent is 1:(5-15); for example, it can be 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, etc.

[0025] The method for preparing high-purity olaflue raw material provided by the present invention may also have the following feature: wherein the molar ratio of N-octadecyl-1,3-dipropylamine to the Lewis acid is 1:(0.05-5), preferably 0.1-2.

[0026] The method for preparing high-purity olaflurane raw material provided by the present invention may also have the following feature: step 2 further includes a second purification step, which includes:

[0027] The reaction solution obtained by reacting N-octadecyl-1,3-dipropylamine with a hydroxyalkylating agent in the presence of a Lewis acid was washed successively with saturated brine and ammonia water, and then concentrated to obtain bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine.

[0028] The method for preparing high-purity olaflurane raw material provided by the present invention may also have the following characteristics: it includes the following steps:

[0029] Step 1, nC 18 H 37 X was mixed with 1,3-propanediamine and reacted at 60-80℃ until the reaction was complete. After purification, N-octadecyl-1,3-dipropane was obtained.

[0030] Step 2: Mix N-octadecyl-1,3-dipropylamine, Lewis acid and solvent to obtain a mixture. Add hydroxyalkylating agent to the mixture and react at 20-30°C until complete. Purify to obtain N-octadecyl-1,3-dipropylamine.

[0031] The beneficial effects of this invention are as follows: This invention provides a method for preparing high-purity olafluric acid raw material, which adopts a new synthetic route. The synthetic route of this invention is not only shorter and more efficient, with a higher overall yield, but also avoids the use of dangerous reagents such as lithium aluminum hydride, making industrial production safer. Attached Figure Description

[0032] Figure 1 shows the proton NMR spectrum of N-octadecyl-1,3-dipropylamine prepared by the method described in item 3 of Table 1 in Example 1. 1 HNMR);

[0033] Figure 2 shows the proton NMR spectrum of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine prepared in Example 3. 1 HNMR). Detailed Implementation

[0034] To make the above-mentioned objectives, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to specific examples.

[0035] In the following embodiments, unless otherwise stated, all raw materials are commercially available products.

[0036] In the following embodiments, nuclear magnetic resonance (NMR) 1 The HNMR detection parameters are shown in the table below:

[0037] In the following embodiments, the yield is calculated as follows: Yield = (mass of collected product / molar mass of product) / (mass of raw materials used / molar mass of raw materials) × 100%.

[0038] Example 1:

[0039] Synthesis of N-octadecyl-1,3-dipropylamine:

[0040] This embodiment provides a method for preparing N-octadecyl-1,3-dipropylamine, and the reaction formula is as follows:

[0041] Includes the following steps:

[0042] 6g of compounds 1 and 1,3-propanediamine (compound 2, purity 99.0%) and solvent were added to a reaction vessel. The mixture was heated to 75℃ and stirred for 16h. After cooling to room temperature, 300mL of water was added, and the mixture was stirred at room temperature for 1h. A solid precipitated out. The solid was filtered, washed with water, and dried to obtain the product (compound 3). The product was weighed and a sample was sent for NMR analysis to determine its purity. The NMR spectrum of N-octadecyl-1,3-dipropane prepared by method 3 in Table 1 is shown below. 1 The HNMR (H2NMR) is shown in Figure 1.

[0043] The reaction results under different reaction conditions are shown in Table 1.

[0044] Table 1 Screening of preparation methods and conditions for N-octadecyl-1,3-dipropylamine

[0045] As shown in Table 1, ideal reaction results can be obtained when X is OTs or Br, especially when 2-methyltetrahydrofuran or tert-butanol is used as solvent, the yield is relatively higher. Furthermore, this invention unexpectedly discovered that the reaction can achieve similar technical results as when using a solvent, even without omitting the solvent.

[0046] Example 2:

[0047] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine:

[0048] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, comprising the following steps:

[0049] 20 g of N-octadecyl-1,3-dipropylamine (61.2 mmol, 1.0 eq, purity 97.5%), hydroxyalkylating agent (612 mmol, 10.0 eq), additives and solvent were added to a reaction vessel, and the reaction was carried out at a certain reaction temperature with stirring for 24 h. Samples were taken and sent for HPLC analysis.

[0050] The reaction results under different reaction conditions are shown in Table 2.

[0051] Table 2 Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine

[0052] Note: a. The reaction is carried out in a high-pressure autoclave with a pressure of 0.2 MPa.

[0053] In Table 2, except for experiment number 1, all other experimental groups were conducted under normal pressure.

[0054] As shown in the table above, without the use of Lewis acids, the hydroxyalkylation reaction can only be carried out under high pressure, and is difficult to carry out at room temperature and pressure. This invention also unexpectedly discovered that when a series of Lewis acids, represented by zinc chloride, are used, the reaction can not only be carried out at room temperature and pressure, but also achieve a relatively ideal conversion rate.

[0055] Example 3:

[0056] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine:

[0057] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, the reaction formula of which is as follows:

[0058] Includes the following steps:

[0059] 100 g of N-octadecyl-1,3-dipropylamine (0.306 mol, 1.0 eq, purity 97.5%), 83.4 g of anhydrous zinc chloride (0.612 mol, 2.0 eq), 800 mL of tetrahydrofuran, and 382.4 g of 2-bromoethanol (3.06 mol, 10.0 eq) were added to a reaction vessel and stirred at 20 °C for 24 h. The mixture was washed once with 200 mL of saturated brine, and the solvent was removed under reduced pressure. 1 L of dichloromethane and 100 mL of 10 wt% ammonia were added, followed by extraction. The organic phase was collected and concentrated under reduced pressure to give 114.7 g of the compound bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine. The yield was 92.4% ± 1.0%, and the purity was 98.2% ± 0.5%.

[0060] The proton NMR spectrum of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine prepared in this embodiment ( 1 The HNMR (H2NMR) is shown in Figure 2.

[0061] Example 4:

[0062] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine:

[0063] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, the reaction formula of which is as follows:

[0064] Includes the following steps:

[0065] 1 g of N-octadecyl-1,3-dipropylamine (3.06 mmol, 1.0 eq, purity 97.5%), 0.834 g of anhydrous zinc chloride (6.12 mmol, 2.0 eq), 8 mL of tetrahydrofuran, and 382.4 g of 2-bromoethanol (30.6 mmol, 10.0 eq) were added to a reaction vessel and stirred at 20 °C for 24 h. The mixture was washed once with 2 mL of saturated brine, and the solvent was removed under reduced pressure. The mixture was then subjected to column chromatography (chromatographic solvent: dichloromethane / methanol, volume ratio 20:1), and concentrated under reduced pressure to give 1.34 g of compound bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, with a yield of 95.1% and a purity of 99.0%.

[0066] Example 5:

[0067] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine:

[0068] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, the reaction formula of which is as follows:

[0069] Includes the following steps:

[0070] 100 g of N-octadecyl-1,3-dipropylamine (0.306 mol, 1.0 eq, purity 97.5%), 83.4 g of anhydrous zinc chloride (0.612 mol, 2.0 eq), 800 mL of tetrahydrofuran, and 382.4 g of 2-bromoethanol (3.06 mol, 10.0 eq) were added to a reaction vessel and stirred at 20 °C for 24 h. The mixture was washed once with 200 mL of saturated brine, and the solvent was removed under reduced pressure. 1 L of dichloromethane and 100 mL of 10 wt% sodium hydroxide aqueous solution were added, and the mixture was extracted. The organic phase was collected and concentrated under reduced pressure to give 92.5 g of the compound bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, with a yield of 65.9% and a purity of 95.3%.

[0071] Example 6:

[0072] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine:

[0073] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, the reaction formula of which is as follows:

[0074] Includes the following steps:

[0075] 100 g of N-octadecyl-1,3-dipropylamine (0.306 mol, 1.0 eq, purity 97.5%), 83.4 g of anhydrous zinc chloride (0.612 mol, 2.0 eq), 800 mL of tetrahydrofuran, and 382.4 g of 2-bromoethanol (3.06 mol, 10.0 eq) were added to a reaction vessel and stirred at 20 °C for 24 h. The mixture was washed once with 200 mL of saturated brine, and the solvent was removed under reduced pressure. 1 L of dichloromethane and 100 mL of 10 wt% sodium carbonate aqueous solution were added, and the mixture was extracted. The organic phase was collected and concentrated under reduced pressure to give 114.2 g of compound bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, with a yield of 81.3% and a purity of 86.9%.

[0076] According to the preparation method of the olaflue raw material involved in the above embodiments, because a new synthetic route is adopted, the synthetic route provided by the above embodiments is not only shorter and more efficient, with a higher overall yield, but also avoids the use of dangerous reagents such as lithium aluminum hydride, making industrial production safer.

[0077] Furthermore, in the preparation method of N-octadecyl-1,3-dipropylamine, the use of water crystallization purification method not only allows for efficient separation of the target compound from the reaction system, but also ensures a purity of over 93%.

[0078] Furthermore, in the preparation method of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, because Lewis acids, represented by zinc chloride, are used as additives for the reaction, the applicant unexpectedly discovered that the Lewis acid-catalyzed hydroxyalkylation reaction can not only be carried out under mild conditions such as room temperature and pressure, but also achieve a relatively ideal yield.

[0079] Furthermore, in the preparation method of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, because dichloromethane / ammonia extraction is used in the post-processing, impurities are effectively separated while retaining the product, thus providing a simple, efficient method suitable for industrial production applications.

[0080] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for preparing high-purity olaflurane raw material, characterized in that: Includes the following steps: Step 1, nC 18 H 37 X reacts with 1,3-propanediamine to give N-octadecyl-1,3-dipropylamine; Step 2: Under ambient temperature and pressure, N-octadecyl-1,3-dipropylamine reacts with a hydroxyalkylating agent in the presence of a Lewis acid to give bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine. Wherein, X is a halogen, a hydroxyl group, or a sulfonyloxy group; the sulfonyloxy group is selected from any one of methanesulfonyloxy, benzenesulfonyloxy, and p-toluenesulfonyloxy. The hydroxyalkylating agent is selected from any one or more of ethylene oxide, 2-chloroethanol, or 2-bromoethanol; The Lewis acid is selected from any one or more of zinc chloride, aluminum chloride, boron trifluoride ether, or magnesium chloride.

2. The method for preparing high-purity olafon raw material according to claim 1, characterized in that: In step 1, nC 18 H 37 The molar ratio of X to 1,3-propanediamine is 1:(1-20).

3. The method for preparing high-purity olafon raw material according to claim 1, characterized in that: Step 1 also includes a first purification step, which includes: To nC 18 H 37 The reaction solution of X with 1,3-propanediamine was subjected to crystallization by adding water, followed by filtration, and the solid was collected and dried to obtain N-octadecyl-1,3-dipropylamine. or, Remove nC 18 H 37 The 1,3-propanediamine in the reaction solution obtained by reacting X with 1,3-propanediamine was crystallized by adding ethyl acetate and sodium carbonate aqueous solution, filtered, and the solid was dried to obtain N-octadecyl-1,3-dipropane.

4. The method for preparing high-purity olafon raw material according to claim 1, characterized in that: Step 2 is carried out in the presence of a solvent selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, alkyl dichloride, or chloroform.

5. The method for preparing high-purity olafon raw material according to claim 4, characterized in that, The mass ratio of the solvent to the N-octadecyl-1,3-dipropylamine is (2-10):

1.

6. The method for preparing high-purity olafluroline raw material according to claim 1, characterized in that, The molar ratio of N-octadecyl-1,3-dipropylamine to the hydroxyalkylating agent is 1:(5-15).

7. The method for preparing high-purity olafon raw material according to claim 1, characterized in that, The molar ratio of the N-octadecyl-1,3-dipropylamine to the Lewis acid is 1:(0.05-5).

8. The method for preparing high-purity olafon raw material according to claim 1, characterized in that, Step 2 also includes a second purification step, which includes: The reaction solution obtained by reacting N-octadecyl-1,3-dipropylamine with a hydroxyalkylating agent in the presence of a Lewis acid was washed successively with saturated brine and ammonia, and then concentrated to obtain bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine.

9. The method for preparing high-purity olafon raw material according to claim 1, characterized in that, Includes the following steps: Step 1, nC 18 H 37 X was mixed with 1,3-propanediamine and reacted at 60-80℃ until the reaction was complete. After purification, N-octadecyl-1,3-dipropane was obtained. Step 2: Mix N-octadecyl-1,3-dipropylamine, Lewis acid and solvent to obtain a mixture. Add hydroxyalkylating agent to the mixture and react at 20-30°C until complete. Purify to obtain N-octadecyl-1,3-dipropylamine.

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