A preparation method of indomethacin ester derivatives

Abstract

The present invention discloses a method for preparing an indomethacin ester derivative. The indomethacin ester derivative is shown in formula (I). The preparation method of the derivative is to use a 2-(trimethylsilyl)phenyl trifluoromethanesulfonate compound as a benzylene precursor and cesium fluoride as a base to achieve a reaction with indomethacin under conditions without the addition of an external condensing agent or metal catalyst. The method is simple to operate and has concise steps, providing a safe, efficient, and practical synthesis method for the preparation of valuable indomethacin ester derivatives. The indomethacin ester derivatives prepared by the present invention are expected to be used in the preparation of COX-2 inhibitors or non-steroidal anti-inflammatory drugs.

Description

Technical Field

[0001] The present invention relates to a method for preparing indomethacin derivatives, in particular to a method for preparing indomethacin ester derivatives. Background Art

[0002] Indomethacin is a common nonsteroidal anti-inflammatory drug used clinically. Most of these drugs are nonspecific cyclooxygenase (COX) inhibitors, meaning they can simultaneously inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Further studies have shown that greater COX-2 inhibition is associated with more pronounced anti-inflammatory and analgesic effects, while stronger COX-1 inhibition is associated with greater adverse reactions (Drugs, 1997, 53, 563-582).

[0003] Existing studies have found that indomethacin ester derivatives, obtained by esterifying the carboxylic acid group on indomethacin, have a highly effective and specific inhibitory effect on COX-2 (Proc. Natl. Acad. Sci. USA 2000, 97, 925-930). Consequently, methods for preparing indomethacin ester derivatives have been reported, primarily in the following two ways:

[0004]

[0005] Method (a) requires the addition of 1,3-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) to promote the condensation of indomethacin with alcohol compounds. However, the major drawback of this reaction is that the byproduct dicyclohexylurea is difficult to completely remove using conventional purification methods, affecting the purity of the product. Method (b) requires the use of hexamethylphosphoramide (HMPA), a potential carcinogen that can cause inflammation in contact with the skin within 24 hours, posing a significant safety hazard. Therefore, the development of simple, safe, and efficient methods for the preparation of indomethacin ester derivatives is crucial. Summary of the Invention

[0006] Purpose of the invention: The purpose of the present invention is to provide a method for preparing indomethacin ester derivatives to solve the problems of difficult removal of by-products and high toxicity of reaction reagents in existing preparation methods.

[0007] Technical solution: The method for preparing an indomethacin ester derivative of the present invention comprises the following steps:

[0008]

[0009] Wherein, R1 is selected from H, halogen, C 1-3 Alkyl, C 1-3Alkoxy, cycloalkane or aromatic hydrocarbon group; R2 is selected from H or halogen, TMS is a trimethylsilyl group, and OTf is a trifluoromethanesulfonate group.

[0010] The structural formula of compound III is as follows:

[0011]

[0012] R1 and R2 can be located at any substitutable position on the benzene ring.

[0013] Preferably, the base is cesium fluoride, and the solvent is at least one of acetonitrile, chloroform, ethyl acetate, and tetrahydrofuran.

[0014] Preferably, the molar ratio of compound II to compound III is 1:1-2.

[0015] Preferably, the molar ratio of the compound II to the base is 1:1-3.

[0016] Preferably, the reaction conditions of compound II and compound III are 20-30° C. and 4-10 hours.

[0017] Preferably, after the reaction, the following steps are further included: washing the crude product with water, extracting with ethyl acetate, drying under reduced pressure, and then performing column chromatography separation and purification using ethyl acetate: petroleum ether in a volume ratio of 1:10-20 as eluent.

[0018] Preferably, the concentration of the compound II in the solvent is 0.1-0.25 mol / L.

[0019] Preferably, the compound III is at least one of the following compounds:

[0020]

[0021] The compound I obtained from the above compound III is any one of the following:

[0022]

[0023] The preparation reaction mechanism of the present invention is as follows:

[0024]

[0025] 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate compounds can generate in situ benzyne intermediates by leaving the trimethylsilyl (-TMS) group and trifluoromethanesulfonate (-OTf) group under the action of fluoride ions in cesium fluoride. The benzyne intermediates are then captured by the carboxyl oxygen atom on indomethacin in the form of nucleophilic attack, ultimately obtaining indomethacin ester derivatives.

[0026] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the synthesis method of the present invention is simple, does not require the addition of an external condensing agent or metal catalyst, and provides a new approach for the development of indomethacin ester derivatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The synthetic route of indomethacin ester derivatives is shown in the figure below:

[0028] Figure 2 Schematic diagram of the reaction mechanism of the present invention;

[0029] Figure 3 This is the H NMR spectrum of the indomethacin ester derivative 3a prepared in Example 1;

[0030] Figure 4 The C NMR spectrum of the indomethacin ester derivative 3a prepared in Example 1;

[0031] Figure 5 This is the H NMR spectrum of the indomethacin ester derivative 3b prepared in Example 2;

[0032] Figure 6 This is the C NMR spectrum of the indomethacin ester derivative 3b prepared in Example 2;

[0033] Figure 7 This is the H NMR spectrum of the indomethacin ester derivative 3c prepared in Example 3;

[0034] Figure 8 This is the C NMR spectrum of the indomethacin ester derivative 3c prepared in Example 3;

[0035] Figure 9 This is the H NMR spectrum of the indomethacin ester derivative 3d prepared in Example 4;

[0036] Figure 10 This is the carbon NMR spectrum of the indomethacin ester derivative 3d prepared in Example 4. DETAILED DESCRIPTION

[0037] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0038] Example 1: A method for preparing an indomethacin ester derivative 3a is as follows:

[0039]

[0040] Raw materials preparation:

[0041] Indomethacin, purity >99%, Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0042] 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate, purity >95%, Shanghai Adamas Reagent Co., Ltd.;

[0043] Specific synthesis process:

[0044] At room temperature, 1 mmol of indomethacin, 1.2 mmol of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, and 2 mmol of cesium fluoride were reacted in 6 mL of anhydrous acetonitrile solvent for 5 hours to obtain a crude indomethacin ester derivative. The crude indomethacin ester derivative was washed with water, extracted with ethyl acetate, and dried under reduced pressure. The product was then separated by column chromatography using a volume ratio of ethyl acetate:petroleum ether = 1:10 to obtain a white solid product, i.e., indomethacin ester derivative 3a, in a column chromatography yield of approximately 83%.

[0045] The product structure is 1 H NMR, 13 C NMR was used to determine the results, as follows:

[0046] 1 H NMR (400MHz, CDCl3) δ7.68(d,J=6.4Hz,2H),7.48(d,J=6.8Hz,2H),7.36(t,J=6.0Hz,2H),7.22(t,J=5.6Hz ,1H),7.07-7.05(m,3H),6.90(d,J=7.2Hz,1H),6.71-6.69(m,1H),3.91(s,2H),3.84(s,3H),2.46(s,3H);

[0047] 13 C NMR (100MHz, CDCl3) δ169.5,168.5,156.2,150.8,139.5,136.4,133.9,131.4,130. 9,130.6,129.6,129.3,126.1,121.5,115.2,112.2,112.0,101.3,55.9,30.7,13.6.

[0048] Example 2: A method for preparing an indomethacin ester derivative 3b is as follows:

[0049]

[0050] Raw materials preparation:

[0051] Indomethacin, purity >99%, Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0052] 3-Methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, purity >97%, Shanghai Adamas Reagent Co., Ltd.;

[0053] Specific synthesis process:

[0054] At room temperature, 1 mmol of indomethacin, 1.2 mmol of 3-methoxy-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, and 2 mmol of cesium fluoride were reacted in 6 mL of anhydrous acetonitrile solvent for 5 hours to obtain a crude indomethacin ester derivative. The crude indomethacin ester derivative was washed with water, extracted with ethyl acetate, and dried under reduced pressure. The product was then separated by column chromatography using a volume ratio of ethyl acetate:petroleum ether of 1:10 to obtain a white solid product, i.e., indomethacin ester derivative 3b, in a column chromatography yield of approximately 72%.

[0055] The product structure is 1 H NMR, 13 C NMR was used to determine the results, as follows:

[0056] 1 H NMR (400MHz, CDCl3) δ7.67(d,J=8.4Hz,2H),7.47(d,J=8.4Hz,2H),7.25(t,J=8.0Hz,1H),7.06-7.05(m,1H),6.91-6.89(m,1H), 6.78-6.75(m,1H),6.71-6.68(m,1H),6.67-6.64(m,1H),6.62-6.61(m,1H),3.90(s,2H),3.84(s,3H),3.77(s,3H),2.45(s,3H);

[0057] 13 C NMR (100MHz, CDCl3) δ169.5,168.5,161.0,160.7,157.1,156.2,151.7,139.5,136.4,133.9,131.3,131.0,130.6,130 .2,130.0,129.3,115.2,113.7,112.1,112.0,111.8,107.9,107.6,106.3,101.6,101.3,55.9,55.6,55.3,30.7,13.6.

[0058] Example 3: A method for preparing an indomethacin ester derivative 3c is as follows:

[0059]

[0060] Raw materials preparation:

[0061] Indomethacin, purity >99%, Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0062] 6-Methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, purity >94%, Shanghai Adamas Reagent Co., Ltd.;

[0063] Specific synthesis process:

[0064] At room temperature, 1 mmol of indomethacin, 1.2 mmol of 6-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, and 2 mmol of cesium fluoride were reacted in 6 mL of anhydrous acetonitrile solvent for 5 hours to obtain a crude indomethacin ester derivative. The crude indomethacin ester derivative was washed with water, extracted with ethyl acetate, and dried under reduced pressure. The product was then separated by column chromatography using a volume ratio of ethyl acetate:petroleum ether = 1:20 to obtain a white solid product, i.e., indomethacin ester derivative 3c, in a column chromatography yield of approximately 78%.

[0065] The product structure is 1 H NMR, 13 C NMR was used to determine the results, as follows:

[0066] 1 H NMR (500MHz, CDCl3) δ7.68-7.65(m,4H),7.48-7.46(m,4H),7.19-7.11(m,5H),7.07-6.97(m,4H),6.91-6.84(m,3H ),6.70-6.68(m,2H),3.93-3.89(m,4H),3.84-3.83(m,6H),2.46-2.45(m,6H),2.33-2.04(m,6H); Representative peak of minor isomer, 1 HNMR(500MHz, CDCl3) of minor isomerδ2.33(s,1H),2.04(s,5H);

[0067] 13 C NMR (125MHz, CDCl3) δ169.6,169.2,168.4,156.3,150.8,149.4,139.8,139.5,136.3,134.0,131.3,131.2,131.0,130.6,130.0,12 9.3,127.1,126.9,126.3,122.1,121.9,118.5,115.2,112.3,112.2,112.0,111.9,101.3,55.8,30.7,30.5,21.4,16.1,13.6,13.5.

[0068] Example 4: A method for preparing an indomethacin ester derivative 3c is as follows:

[0069]

[0070] Raw materials preparation:

[0071] Indomethacin, purity >99%, Shanghai Aladdin Biochemical Technology Co., Ltd.;

[0072] 4,5-Difluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, purity >97%, Shanghai Bid Pharmaceutical Technology Co., Ltd.;

[0073] Specific synthesis process:

[0074] At room temperature, 1 mmol of indomethacin, 1.2 mmol of 4,5-difluoro-2-(trimethylsilyl)phenyl trifluoromethanesulfonate, and 2 mmol of cesium fluoride were reacted in 6 mL of anhydrous acetonitrile solvent for 5 hours to obtain a crude indomethacin ester derivative. The crude indomethacin ester derivative was washed with water, extracted with ethyl acetate, and dried under reduced pressure. The product was then separated by column chromatography using a volume ratio of ethyl acetate:petroleum ether = 1:10 to obtain a white solid product, i.e., indomethacin ester derivative 3d, in a column chromatography yield of approximately 88%.

[0075] The product structure is 1 H NMR, 13 C NMR was used to determine the results, as follows:

[0076] 1 H NMR (400MHz, CDCl3) δ7.67(d,J=8.4Hz,2H),7.47(d,J=8.0Hz,2H),7.16-7.10(m,1H),7.02-7.01(m,1H),6.98 -6.93(m,1H),6.89-6.87(m,1H),6.82-6.80(m,1H),6.71-6.68(m,1H),3.89(s,2H),3.83(s,3H),2.45(s,3H);

[0077] 13 C NMR (100MHz, CDCl3) δ169.0,168.4,156.3,151.4(d,J C-F =14.0Hz),149.6(d,J C-F =13.0Hz),148.9(d,J C-F =14.0Hz),147.2(d,J C-F =12.0Hz),146.3(dd,J C-F=8.0,3.0Hz),139.6,136.5,133.8,131.3,131.0,130.5,129.3,117.6,117.5,117.4,117.3,115.2,111.9,111.7,111.6,111.5,101.3,55.9,30.5,13.5。

Claims

1. A method for preparing indomethacin ester derivatives, characterized in that: The steps include: Among them, TMS is a trimethylsilyl group and OTf is a trifluoromethanesulfonate group; The base is cesium fluoride, and the solvent is at least one of acetonitrile, chloroform, ethyl acetate, and tetrahydrofuran; The compound III is at least one of the following compounds: ； The reaction conditions of compound II and compound III are 20-30° C. and 4-10 hours.

2. The method for preparing indomethacin ester derivatives according to claim 1, wherein: The molar ratio of compound II to compound III is 1:1-2.

3. The method for preparing indomethacin ester derivatives according to claim 1, wherein: The molar ratio of the compound II to the base is 1:1-3.

4. The method for preparing indomethacin ester derivatives according to claim 1, wherein: After the reaction, the method further comprises the following steps: washing the crude product with water, extracting with ethyl acetate, drying with reduced pressure, and performing column chromatography separation and purification using ethyl acetate and petroleum ether in a volume ratio of 1:10-20 as eluent.

5. The method for preparing indomethacin ester derivatives according to claim 1, characterized in that: The concentration of the compound II in the solvent is 0.1-0.25 mol / L.

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