A method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt

Abstract

The invention provides a method for inhibiting racemization in a preparation process of ifluprofen axetil by using a buffer salt. S-flurbiprofen and 1-bromoethyl acetate are used as reaction raw materials, and a buffer salt is added in the process of preparing ifluprofen axetil, so that racemization and decomposition of a product can be effectively inhibited, and the content of a single isomer impurity can be controlled to be below 0.1%, and the yield of the product can be improved, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for inhibiting racemization in the preparation process of ifluprofen axetil by utilizing buffer salt. Background Art

[0002] Ifluprofen axetil, chemically named 1-acetoxyethyl (2S)-2-(2-fluoro-4-biphenyl)-2-hydroxypropionate, is a new type of non-steroidal anti-inflammatory analgesic with small dosage, good selectivity and long-lasting effect. Its structure is as follows:

[0003]

[0004] However, due to its chirality, racemization is very easy to occur during the synthesis and preparation process, generating isomeric impurities, so controlling its racemization is the key to the preparation of ifluprofen axetil. At present, there are few reports on chirality control. Patent CN105777544A discloses a preparation of S-(+)-flurbiprofen axetil with high optical purity, using S-(+)-flurbiprofen as a raw material, reacting with 1-substituted ethyl acetate in the presence of a base and a solvent, and the preparation method is simple. Common racemization and product decomposition phenomena are not found in the preparation process, but the total isomer impurity is large, a single isomer is greater than 0.1%, the raw material is more residual, the yield of the product is low, and the isomer is difficult to stably control. Summary of the invention

[0005] The purpose of the present invention is to provide a method for inhibiting the racemization in the preparation process of ifluprofen axetil by using a buffer salt on the basis of the prior art. The method uses S-fluprofen and 1-bromoethyl acetate as reaction raw materials, and adds a buffer salt in the process of preparing ifluprofen axetil, which can effectively inhibit the racemization and decomposition of the product, control the content of a single isomer impurity to less than 0.1%, and improve the yield of the product, which is suitable for industrial large-scale production.

[0006] The technical solution of the present invention is as follows:

[0007] A method for inhibiting racemization in the preparation process of ifluprofen axetil by using buffer salt comprises the following steps:

[0008] S-flurbiprofen, 1-bromoethyl acetate and solvent are mixed evenly, and buffer salt is added to the obtained mixed solution for stirring reaction at 15-20°C, and the obtained reaction solution is quenched with water, washed and dried to obtain iflurbiprofen axetil. The specific synthetic route is as follows:

[0009]

[0010] For the present invention, the buffer salt includes buffer salt A and buffer salt B, wherein buffer salt A is N,N-diisopropylethylamine, 2,4,6-trimethylpyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene, preferably N,N-diisopropylethylamine, and buffer salt B is trifluoroacetic acid.

[0011] In the present invention, the molar ratio of buffer salt A to buffer salt B is 1.5-3.5:1, and may be but not limited to 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1 or 3.5:1, preferably 2.0-2.5:1, and more preferably 2.0:1.

[0012] In the present invention, the molar ratio of S-flurbiprofen to buffer salt A is 1:0.8-2.0, and may be but not limited to 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.5, 1:1.8 or 1:2.0, preferably 1:1.0-1.5, and more preferably 1:1.0.

[0013] In the present invention, the molar ratio of S-flurbiprofen to 1-bromoethyl acetate is 1:0.8-2.5, and may be but not limited to 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.5, 1:1.8, 1:2 or 1:2.5, preferably 1:1.0-1.5, and more preferably 1:1.0.

[0014] In the present invention, the solvent is dichloromethane, tetrahydrofuran, acetone or acetonitrile, preferably dichloromethane.

[0015] The technical solution of the present invention has the following advantages:

[0016] The invention provides a method for inhibiting racemization in the preparation process of ifluprofen axetil by using a buffer salt. S-flurbiprofen and 1-bromoethyl acetate are used as reaction raw materials. The buffer salt is added in the process of preparing ifluprofen axetil, which can effectively inhibit the racemization and decomposition of the product, control the content of a single isomer impurity to less than 0.1%, and improve the yield of the product, which is suitable for industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is a liquid chromatogram of the product prepared in Example 1;

[0018] Figure 2 is a liquid chromatogram of the product prepared in Comparative Example 1;

[0019] Figure 3 The liquid chromatogram of the product prepared in Comparative Example 2. DETAILED DESCRIPTION

[0020] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0021] Example 1

[0022] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 6.70, 0.04 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The obtained mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) and trifluoroacetic acid (2.28 g, 0.02 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The obtained reaction solution was quenched by adding water. The obtained organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurbiprofen axetil. The content of isomer 1 was 0.053%, the content of isomer 2 was 0.053%, and the yield was 96.8%.

[0023] like Figure 1 The RTs of isomer 1 and isomer 2 are 9.25min and 13.85min respectively; the RTs of ifenprofen axetil are 11.37min and 12.18min respectively.

[0024] The specific synthetic route is as follows:

[0025]

[0026] The structural formulas of isomer 1 and isomer 2 are shown below:

[0027]

[0028] Embodiment 2:

[0029] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 6.70, 0.04 mol) and 75 ml of acetone were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) and trifluoroacetic acid (2.28 g, 0.02 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then spin-dried to obtain iflurfen axetil, the content of isomer 1 was 0.083%, the content of isomer 2 was 0.076%, and the yield was 91.2%.

[0030] Embodiment 3:

[0031] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 5.01, 0.03 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) and trifluoroacetic acid (2.28 g, 0.02 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurfen axetil. The content of isomer 1 was 0.066%, the content of isomer 2 was 0.065%, and the yield was 94.2%.

[0032] Example 4

[0033] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 6.70, 0.04 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 7.76 g, 0.06 mol) and trifluoroacetic acid (3.42 g, 0.03 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurprofen axetil. The content of isomer 1 was 0.091%, the content of isomer 2 was 0.088%, and the yield was 94.1%.

[0034] Example 5

[0035] S-flurbiprofen (compound 1, 9.80g, 0.04mol), 1-bromoethyl acetate (compound 2, 6.70, 0.04mol) and 75ml of dichloromethane were added to a 250ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20°C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 6.50, 0.05mol) and trifluoroacetic acid (2.28g, 0.02mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20°C for 10-12 hours. The resulting reaction solution was quenched with water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurfen axetil. The content of isomer 1 was 0.079%, the content of isomer 2 was 0.078%, and the yield was 96.1%. Comparative Example 1

[0036] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 6.70, 0.04 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) was added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then spin-dried to obtain iflurfen axetil, the content of isomer 1 was 1.189%, the content of isomer 2 was 1.875%, and the yield was 83.2%.

[0037] like Figure 2 The RTs of isomer 1 and isomer 2 are 8.93min and 12.96min respectively; the RTs of ifenprofen axetil are 11.16min and 11.58min respectively.

[0038] Comparative Example 2

[0039] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 6.70, 0.04 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) and trifluoroacetic acid (1.14 g, 0.01 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurfen axetil. The content of isomer 1 was 0.233%, the content of isomer 2 was 0.221%, and the yield was 84.1%.

[0040] like Figure 3 The RTs of isomer 1 and isomer 2 are 8.82min and 12.39min respectively; the RTs of ifenprofen axetil are 10.51min and 11.10min respectively.

[0041] Comparative Example 3

[0042] S-flurbiprofen (compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (compound 2, 6.70, 0.04 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) and acetic acid (1.2 g, 0.02 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurfen axetil. The content of isomer 1 was 0.211%, the content of isomer 2 was 0.276%, and the yield was 82.1%.

[0043] Comparative Example 4

[0044] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 6.70, 0.04 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 2.65 g, 0.02 mol) and trifluoroacetic acid (2.28 g, 0.02 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurfen axetil. The content of isomer 1 was 0.473%, the content of isomer 2 was 0.501%, and the yield was 68.6%.

[0045] Comparative Example 5

[0046] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 6.70, 0.04 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) and trifluoroacetic acid (4.56 g, 0.04 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurfen axetil. The content of isomer 1 was 0.118%, the content of isomer 2 was 0.121%, and the yield was 83.4%.

[0047] Comparative Example 6

[0048] S-flurbiprofen (Compound 1, 9.80 g, 0.04 mol), 1-bromoethyl acetate (Compound 2, 6.70, 0.04 mol) and 75 ml of dichloromethane were added to a 250 ml reaction bottle, and stirred evenly. The resulting mixed solution was cooled to 15-20 ° C under nitrogen protection, and N, N-diisopropylethylamine (DIPEA, 5.20 g, 0.04 mol) and pyridine hydrobromide (3.2 g, 0.02 mol) were added dropwise. After the addition was completed, the reaction was continued to be stirred at 15-20 ° C for 10-12 hours. The resulting reaction solution was quenched by adding water, and the resulting organic phase was washed 4 times with 5% sodium carbonate aqueous solution, washed with water, dried over anhydrous magnesium sulfate, and then dried to obtain iflurfen axetil. The content of isomer 1 was 0.378%, the content of isomer 2 was 0.421%, and the yield was 85.0%.

[0049] The analytical comparison data of the embodiments and comparative examples are as follows:

[0050]

[0051] 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 aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for inhibiting the racemization of ifluprofen axetil in the preparation process using a buffer salt, characterized in that: The steps include: S-flurbiprofen, 1-bromoethyl acetate and a solvent are uniformly mixed, and a buffer salt is added to the obtained mixed solution for stirring reaction at 15-20° C. The obtained reaction solution is quenched with water, washed and dried to obtain iflurbiprofen axetil; wherein the buffer salt includes a buffer salt A and a buffer salt B, wherein the buffer salt A is N,N-diisopropylethylamine, 2,4,6-trimethylpyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene; and the buffer salt B is trifluoroacetic acid.

2. The method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt according to claim 1, characterized in that: The buffer salt A is N,N-diisopropylethylamine.

3. The method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt according to claim 2, characterized in that: The molar ratio of the buffer salt A to the buffer salt B is 1.5 to 3.5:

1.

4. The method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt according to claim 3, characterized in that: The molar ratio of the buffer salt A to the buffer salt B is 2.0-2.5:

1.

5. The method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt according to claim 4, characterized in that: The molar ratio of the buffer salt A to the buffer salt B is 2.0:

1.

6. The method for inhibiting racemization in the preparation process of ifluprofen axetil using a buffer salt according to any one of claims 3 to 5, characterized in that: The molar ratio of S-flurbiprofen to buffer salt A is 1:0.8-2.

0.

7. The method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt according to claim 6, characterized in that: The molar ratio of S-flurbiprofen to buffer salt A is 1:1.0-1.

5.

8. The method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt according to claim 7, characterized in that: The molar ratio of S-flurbiprofen to buffer salt A is 1:1.

0.

9. The method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt according to claim 1, characterized in that: The molar ratio of S-flurbiprofen to 1-bromoethyl acetate is 1:0.8-2.5, preferably 1:1.0-1.5, and more preferably 1:1.

0.

10. The method for inhibiting racemization in the preparation process of ifluprofen axetil using buffer salt according to claim 1, characterized in that: The solvent is dichloromethane, tetrahydrofuran, acetone or acetonitrile, preferably dichloromethane.

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