A method for preparing high-purity olaflurane raw material

Abstract

The present invention provides a method for preparing a high-purity orafur raw material, belonging to the technical field of organic synthesis, and comprising the following steps: Step 1, n-C 18 H 37 X reacts with 1,3-propanediamine to obtain N-octadecyl-1,3-dipropylamine; Step 2, N-octadecyl-1,3-dipropylamine reacts with a hydroxyalkylation reagent in the presence of a Lewis acid to obtain bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine. The synthesis route of the present 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.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing a high-purity olaflurane raw material. Background Art

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

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

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

[0005]

[0006] On the one hand, this synthetic route is relatively lengthy and has a low reaction yield. On the other hand, it is not suitable for industrial production because of the need to use dangerous reagents such as lithium aluminum tetrahydride. Summary of the invention

[0007] The present invention is made to solve the above problems, and aims to provide a method for preparing a high-purity olafluanid raw material with a short route, high yield and strong safety.

[0008] The present invention provides a method for preparing a high-purity olafluran raw material, comprising the following steps:

[0009] Step 1, nC 18 H 37 X reacts with 1,3-propylenediamine to obtain N-octadecyl-1,3-dipropylamine;

[0010] Step 2, N-octadecyl-1,3-dipropylamine reacts with a hydroxyalkylating agent in the presence of a Lewis acid to obtain bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine.

[0011] Wherein, X is halogen, hydroxyl or sulfonyloxy;

[0012] The hydroxyalkylating agent is any one or more of ethylene oxide, 2-chloroethanol, 2-bromoethanol or 2-fluoroethanol.

[0013] The method for preparing a high-purity olafluran 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.

[0014] The method for preparing the high-purity olafluor raw material provided by the present invention may also have the following characteristics: 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.

[0015] The method for preparing a high-purity olafluran raw material provided by the present invention may also have the following characteristics: wherein step 1 is carried out in the presence of a solvent, and the solvent is selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, dichloroethane or chloroform.

[0016] The method for preparing a high-purity olafluanid raw material provided by the present invention may also have the following characteristics: wherein step 1 is carried out in the presence of a solvent, nC 18 H 37 The mass volume ratio of X to the solvent is 1 g: (3-10) mL.

[0017] The method for preparing the high-purity olafluran raw material provided by the present invention may also have the following characteristics: wherein, in step 1, nC 18 H 37 No additional solvent is added during the reaction of X with 1,3-propylenediamine.

[0018] The method for preparing the high-purity olafluran raw material provided by the present invention may also have the following characteristics: wherein, in step 1, nC 18 H 37 The molar ratio of X to 1,3-propylenediamine is 1:(1-20), preferably 1:(5-12).

[0019] The method for preparing a high-purity olafluanid raw material provided by the present invention may also have the following characteristics: wherein step 1 further includes a first purification step, and the first purification step includes:

[0020] To nC 18 H 37 Water is added to the reaction solution obtained by the reaction of X and 1,3-propylenediamine for crystallization, and the solid is taken out and dried to obtain N-octadecyl-1,3-dipropylamine.

[0021] or,

[0022] Remove nC 18 H 37 Ethyl acetate and sodium carbonate aqueous solution are added to the 1,3-propylenediamine in the reaction solution obtained by the reaction of X with 1,3-propylenediamine for crystallization, and the solid is collected by filtration and dried to obtain N-octadecyl-1,3-dipropylamine.

[0023] The method for preparing a high-purity olafluran raw material provided by the present invention may also have the following characteristics: wherein step 2 is carried out in the presence of a solvent, and the solvent is selected from any one of acetonitrile, water, ethyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, methanol, ethanol, tert-butanol, dichloroethane or chloroform.

[0024] The method for preparing a high-purity olafluran raw material provided by the present invention may also have the following characteristics: wherein, in step 2, the mass ratio of the solvent to the N-octadecyl-1,3-dipropylamine is (2-10):1.

[0025] In the preparation method of the high-purity olafluran raw material provided by the present invention, it can also have the following characteristics: wherein the molar ratio of the 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.

[0026] The method for preparing the high-purity olafluran raw material provided by the present invention may also have the following characteristics: wherein the molar ratio of the N-octadecyl-1,3-dipropylamine to the Lewis acid is 1:(0.05-5), preferably 0.1-2.

[0027] In the method for preparing the high-purity olaflu raw material provided by the present invention, the method may also have the following characteristics: wherein step 2 further includes a second purification step, and the second purification step includes:

[0028] 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 bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine.

[0029] The method for preparing the high-purity olafluran raw material provided by the present invention may also have the following characteristics: wherein, the method comprises the following steps:

[0030] Step 1: nC 18 H 37 X is mixed with 1,3-propylenediamine, reacted at 60-80°C until the reaction is complete, and purified to obtain N-octadecyl-1,3-dipropylamine;

[0031] Step 2, N-octadecyl-1,3-dipropylamine, Lewis acid and solvent are mixed to obtain a mixed solution, a hydroxyalkylating agent is added to the mixed solution, and the mixture is reacted at 20-30° C. until complete, and purified to obtain N-octadecyl-1,3-dipropylamine.

[0032] Beneficial effects of the present invention: The present invention provides a method for preparing a high-purity olafluran raw material, which adopts a new synthesis route. The synthesis route of the present 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The hydrogen nuclear magnetic spectrum of N-octadecyl-1,3-dipropylamine prepared by the method described in No. 3 in Table 1 of Example 1 ( 1 HNMR);

[0034] Figure 2 The hydrogen nuclear magnetic spectrum of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine prepared in Example 3 ( 1 HNMR). DETAILED DESCRIPTION

[0035] 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.

[0036] In the following examples, unless otherwise specified, all raw materials are commercially available products.

[0037] In the following examples, NMR ( 1 HNMR) detection parameters are shown in the following table:

[0038]

[0039] In the following examples, the yield is calculated as follows: yield = (mass of collected product / molar mass of product) / (mass of raw material used / molar mass of raw material) × 100%.

[0040] Embodiment 1:

[0041] Synthesis of N-octadecyl-1,3-dipropylamine:

[0042] This embodiment provides a method for preparing N-octadecyl-1,3-dipropylamine, and the reaction formula is as follows:

[0043]

[0044] The steps include:

[0045] Take 6g of compound 1, 1,3-propylenediamine (compound 2, purity 99.0%) and solvent and add them to the reaction container, heat to 75℃ and stir for 16h, cool to room temperature, add 300mL of water, stir at room temperature for 1h, solid precipitates, filter, take the solid, wash with water, dry to get the product (compound 3). Weigh and take samples for NMR purity detection. Among them, the hydrogen NMR spectrum of N-octadecyl-1,3-dipropylamine prepared by method No. 3 in Table 1 ( 1 HNMR) Figure 1 shown.

[0046] The reaction results under different reaction conditions are shown in Table 1.

[0047] Table 1 Screening of preparation conditions of N-octadecyl-1,3-dipropylamine

[0048]

[0049] As shown in Table 1, when X is OTs or Br, an ideal reaction effect can be achieved, especially when 2-methyltetrahydrofuran or tert-butyl alcohol is used as a solvent, the yield is relatively higher. In addition, the present invention also unexpectedly found that when the solvent is omitted, the reaction can also achieve a similar technical effect as when a solvent is used.

[0050] Embodiment 2:

[0051] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine:

[0052] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, comprising the following steps:

[0053] 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 the reaction vessel, the reaction temperature was controlled at a certain level, the reaction was stirred for 24 h, and samples were taken and sent to HPLC for detection.

[0054] The reaction results under different reaction conditions are shown in Table 2.

[0055] Table 2 Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine

[0056]

[0057] Note: a. The reaction was carried out in an autoclave with a reaction pressure of 0.2 MPa.

[0058] In Table 2, except for experiment No. 1, the other experimental groups were carried out under normal pressure.

[0059] As can be seen from the above table, without using Lewis acid, the hydroxyalkylation reaction can only be carried out under high pressure conditions, and is difficult to carry out at room temperature and pressure. The present invention also unexpectedly found 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 a relatively ideal conversion rate can be obtained.

[0060] Embodiment 3:

[0061] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine:

[0062] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, and the reaction formula is as follows:

[0063]

[0064] The steps include:

[0065] 100 g N-octadecyl-1,3-dipropylamine (0.306 mol, 1.0 eq, purity 97.5%), 83.4 g anhydrous zinc chloride (0.612 mol, 2.0 eq), 800 mL tetrahydrofuran and 382.4 g 2-bromoethanol (3.06 mol, 10.0 eq) were added to a reaction vessel, the temperature was controlled at 20°C and stirred for 24 h, 200 mL saturated brine was added for washing once, the solvent was removed under reduced pressure, 1 L dichloromethane and 100 mL 10 wt% ammonia water were added, extraction was performed, the organic phase was taken, and it was concentrated under reduced pressure to obtain 114.7 g of the compound bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine. The yield was 92.4%±1.0%, and the purity was 98.2%±0.5%.

[0066] The hydrogen nuclear magnetic spectrum of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine prepared in this example ( 1 HNMR) Figure 2 shown.

[0067] Embodiment 4:

[0068] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine:

[0069] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, and the reaction formula is as follows:

[0070]

[0071] The steps include:

[0072] 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, the temperature was controlled at 20°C and stirred for reaction for 24 h, 2 mL of saturated brine was added for washing once, the solvent was removed under reduced pressure, column chromatography (chromatographic liquid: dichloromethane / methanol volume ratio 20:1), and concentrated under reduced pressure to obtain 1.34 g of the compound bis(hydroxyethyl)-aminopropyl-N-hydroxyethyloctadecylamine, with a yield of 95.1% and a purity of 99.0%.

[0073] Embodiment 5:

[0074] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine:

[0075] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, and the reaction formula is as follows:

[0076]

[0077] The steps include:

[0078] 100 g N-octadecyl-1,3-dipropylamine (0.306 mol, 1.0 eq, purity 97.5%), 83.4 g anhydrous zinc chloride (0.612 mol, 2.0 eq), 800 mL tetrahydrofuran and 382.4 g 2-bromoethanol (3.06 mol, 10.0 eq) were added to a reaction vessel, the temperature was controlled at 20°C and stirred for reaction for 24 h, 200 mL saturated brine was added for washing once, the solvent was removed under reduced pressure, 1 L dichloromethane and 100 mL 10 wt% sodium hydroxide aqueous solution were added, extraction was performed, the organic phase was taken, and it was concentrated under reduced pressure to obtain 92.5 g of the compound bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, with a yield of 65.9% and a purity of 95.3%.

[0079] Embodiment 6:

[0080] Synthesis of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine:

[0081] This embodiment provides a method for preparing bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, and the reaction formula is as follows:

[0082]

[0083] The steps include:

[0084] 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, the temperature was controlled and stirred at 20°C for 24 h, 200 mL of saturated brine was added for washing once, the solvent was removed under reduced pressure, 1 L of dichloromethane and 100 mL of 10 wt% sodium carbonate aqueous solution were added, extraction was performed, the organic phase was taken, and it was concentrated under reduced pressure to obtain 114.2 g of the compound bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, with a yield of 81.3% and a purity of 86.9%.

[0085] According to the preparation method of the olafluran raw material involved in the above embodiment, since a new synthesis route is adopted, the synthesis route provided by the above embodiment 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.

[0086] Furthermore, in the preparation method of N-octadecyl-1,3-dipropylamine, because a purification method of adding water for crystallization is adopted, not only can the target compound be separated from the reaction system efficiently, but also a purity of more than 93% can be guaranteed.

[0087] Furthermore, in the preparation method of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, because a Lewis acid represented by zinc chloride is used as a reaction additive, the applicant unexpectedly discovered that the Lewis acid-catalyzed hydroxyalkylation reaction can not only react under mild conditions such as normal temperature and pressure, but also obtain a relatively ideal yield.

[0088] Furthermore, in the preparation method of bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine, because the dichloromethane / ammonia water extraction method is adopted in the post-treatment process, the impurities are effectively separated while retaining the product, thereby providing a simple, efficient and suitable method for industrial production applications.

[0089] 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 preparing a high-purity olafluran raw material, characterized in that: The steps include: Step 1, nC 18 H 37 X reacts with 1,3-propylenediamine to obtain N-octadecyl-1,3-dipropylamine; Step 2, at room temperature and pressure, N-octadecyl-1,3-dipropylamine reacts with a hydroxyalkylating agent in the presence of a Lewis acid to obtain bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine. Wherein, X is halogen, hydroxyl or sulfonyloxy; the sulfonyloxy 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, 2-bromoethanol or 2-fluoroethanol; The Lewis acid is selected from any one or more of zinc chloride, aluminum chloride, boron trifluoride etherate or magnesium chloride.

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

3. The method for preparing high-purity olafluor raw material according to claim 1, characterized in that: Step 1 also includes a first purification step, which includes: To nC 18 H 37 Water is added to the reaction solution obtained by the reaction of X and 1,3-propylenediamine for crystallization, and the solid is taken out by filtration and dried to obtain N-octadecyl-1,3-dipropylamine. or, Remove nC 18 H 37 Ethyl acetate and sodium carbonate aqueous solution were added to the 1,3-propylenediamine in the reaction solution obtained by the reaction of X with 1,3-propylenediamine for crystallization, and the solid was collected by filtration and dried to obtain N-octadecyl-1,3-dipropylamine.

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

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

7. The method for preparing high-purity olafluor 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 olafluor 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 with saturated saline and aqueous ammonia in sequence and concentrated to obtain bis(hydroxyethyl)-aminopropyl-N-hydroxyethyl octadecylamine.

9. The method for preparing a high-purity olafluor raw material according to claim 1, characterized in that: The steps include: Step 1: nC 18 H 37 X is mixed with 1,3-propylenediamine, reacted at 60-80°C until the reaction is complete, and purified to obtain N-octadecyl-1,3-dipropylamine; Step 2, N-octadecyl-1,3-dipropylamine, Lewis acid and solvent are mixed to obtain a mixed solution, a hydroxyalkylating agent is added to the mixed solution, and the mixture is reacted at 20-30° C. until complete, and purified to obtain N-octadecyl-1,3-dipropylamine.

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