Synthetic method of isoindolone

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of isoindolone. N-methylbenzylamine derivative as shown in formula 1, N-methyl-N-(4-pyridylmethyl) amine as shown in formula 4, N-methyl-2-thiophenemethylamine as shown in formula 6, 2-methoxy methyl benzoate derivative as shown in formula 2 and 2-methoxy methyl nicotinate pyridine as shown in formula 9 in bis (trimethylsilyl) The method comprises the following steps of: mixing and reacting with an organic solvent methyl tert-butyl ether in the presence of a catalyst, lithium amide and a cesium fluoride additive to synthesize isoindolone as shown in a formula 3, isoindolone as shown in a formula 5, isoindolone as shown in a formula 7 and isoindolone as shown in a formula 10.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing isoindolone compounds. Background Technology

[0002] Isoindolones are the most common core structure among natural alkaloids and form the basic framework of many naturally active molecules. Many isoindolone derivatives can be used to synthesize drug molecules with natural activity. As a nitrogen-containing heterocyclic alkaloid, isoindolone can be used as a drug for treating mental illnesses and as an anesthetic. Further research has revealed that isoindolones and other derivatives possess anti-inflammatory, analgesic, antipyretic, antioxidant, and antitumor effects. Examples include pazinaclone, pagoclone, and zopiclone. Early synthesis of isoindolones generally involved condensation reactions, but this method typically required stringent conditions. Due to the increasing importance of isoindolone compounds, many new methods have been developed, primarily using more expensive transition metals such as palladium, nickel, and rhodium for catalytic reactions. These reactions suffer from problems such as expensive metal catalysts, toxic metal pollution, and demanding reaction conditions. Summary of the Invention

[0003] This invention provides a one-pot synthesis reaction of isoyindolones from N-methylbenzylamine and methyl 2-methoxybenzoate, which is expected to simplify the synthesis of isoyindolones, reduce the production cost of these valuable building blocks, and increase the sustainability of isoyindolone synthesis, thus complementing state-of-the-art technologies. The specific scheme is as follows:

[0004]

[0005] The isoindolone shown in Formula 3 was synthesized by reacting the N-methylbenzylamine derivative shown in Formula 1 and the methyl 2-methoxybenzoate derivative shown in Formula 2 with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride; the isoindolone shown in Formula 5 was synthesized by reacting the N-methyl-N-(4-pyridinemethyl)amine shown in Formula 4 and the methyl 2-methoxybenzoate derivative shown in Formula 2 with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride additive. Indodotones: Isoindotone as shown in Formula 7 was synthesized by reacting N-methyl-2-thiophene methylamine as shown in Formula 6 and methyl 2-methoxybenzoate derivative as shown in Formula 2 with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride; Isoindotone as shown in Formula 9 was synthesized by reacting N-methylbenzylamine derivative as shown in Formula 1 and methyl 2-methoxynicotinate pyridine as shown in Formula 8 with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride.

[0006] Where R1 Selected from any one of hydrogen, 3-methyl, 4-methyl, 4-methoxy, 3-methoxy, 2-methoxy, and chlorine; wherein R 2 Selected from hydrogen.

[0007] The method of this invention can achieve one-pot synthesis of isoyindolone compounds, reducing reaction steps and thus improving product yield; the raw materials used in the synthesis method are simple and economical; R in this invention 1 and R 2 It offers a variety of options and has wider applicability.

[0008] Preferred, R 1 It is selected from any one of hydrogen, 3-methyl, 4-methyl, 4-methoxy, and chlorine. Preferably, R 2 It is selected from any one of hydrogen, 6-methyl, 3-methoxy, fluorine, etc.

[0009] Preferably, the reaction is carried out under the protection of an inert gas, and preferably, the inert gas is nitrogen.

[0010] Preferably, the molar ratio of N-methylbenzylamine derivatives of Formula 1, methyl 2-methoxybenzoate of Formula 2, lithium di(trimethylsilyl)amino and cesium fluoride in the reaction is 1:1:2:2; and the reaction temperature is 110°C.

[0011] Preferably, using the method of the present invention, N-methyl-2-phenylindole with the following structure can be synthesized:

[0012]

[0013]

[0014] Isoindolone was synthesized by reacting N-methylbenzylamine derivative and methyl 2-methoxybenzoate in a mixture of a strong base (lithium di(trimethylsilyl)amino) and a cesium salt (cesium fluoride) with an organic solvent (methyl tert-butyl ether).

[0015] The technical solution of the present invention can achieve at least one of the following beneficial effects:

[0016] The raw materials used in the synthesis method of this invention are all inexpensive and readily available;

[0017] The synthesis method of this invention does not use transition metal catalysts, making it green and environmentally friendly;

[0018] This invention employs a one-pot synthesis method, which reduces the loss of raw materials and increases the yield of the product due to fewer reaction steps.

[0019] The operation steps required by this invention are relatively simple, requiring no extreme heating or cooling, and the reaction can be carried out under normal pressure, making it safe and convenient.

[0020] R in this invention 1 and R 2 Since there are multiple options, the method of the present invention has a wider range of applications and can synthesize a variety of isoindolone compounds. Attached Figure Description

[0021] The attached figures show the proton and carbon NMR spectra of the products from each embodiment. The figure numbers correspond to the embodiment numbers. Figure A is the proton NMR spectrum, and Figure B is the carbon NMR spectrum. Figure 1A The above is the proton NMR spectrum of the product obtained in Example 1. Figure 1B The carbon NMR spectrum of the product obtained in Example 1; Figure 2A The above is the proton NMR spectrum of the product obtained in Example 2. Figure 2B The carbon NMR spectrum of the product obtained in Example 2; Figure 3A The image shows the proton NMR spectrum of the product obtained in Example 3. Figure 3B The carbon NMR spectrum of the product obtained in Example 3; Figure 4A The above is the proton NMR spectrum of the product obtained in Example 4. Figure 4B The carbon NMR spectrum of the product obtained in Example 4; Figure 5A The above is the proton NMR spectrum of the product obtained in Example 5. Figure 5B The carbon NMR spectrum of the product obtained in Example 5; Figure 6A The above is the proton NMR spectrum of the product obtained in Example 6. Figure 6B The carbon NMR spectrum of the product obtained in Example 6; Figure 7A The above is the proton NMR spectrum of the product obtained in Example 7. Figure 7B The carbon NMR spectrum of the product obtained in Example 7; Figure 8A The above is the proton NMR spectrum of the product obtained in Example 8. Figure 8B The carbon NMR spectrum of the product obtained in Example 8; Figure 9A The image shows the proton NMR spectrum of the product obtained in Example 9. Figure 9B The image shows the carbon NMR spectrum of the product obtained in Example 9. Figure 10A The above is the proton NMR spectrum of the product obtained in Example 10. Figure 10B The image shows the carbon NMR spectrum of the product obtained in Example 10. Figure 11A The above is the proton NMR spectrum of the product obtained in Example 11. Figure 11B The image shows the carbon NMR spectrum of the product obtained in Example 11. Specific Implementation

[0022] To facilitate understanding by those skilled in the art, the concept of the present invention will be further explained below with reference to embodiments. The specific descriptions of the following embodiments are not intended to limit the present invention, but are merely for the convenience of those skilled in the art to understand the technical solution. All raw materials mentioned in the specification were purchased from the market or synthesized through simple methods. Other pharmaceuticals were purchased from Amex, Bide, Sigma-Aldrich, Acros, Alfa Aesar, Adamas-beta, or J&K. The nuclear magnetic resonance spectrometer was a Bruker 400M and a JEOL 400M.

[0023] Example 1

[0024] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine (14 μL, 0.1 mmol), methyl 2-methoxybenzoate (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic inlet. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (85% yield). 1 H NMR (400MHz, CDCl3) δ7.89-7.83 (m, 1H), 7.44-7.41 (m, 2H), 7.36-7.31 (m, 3H), 7.16-7.11 (m, 3H), 5.32 (s, 1H), 2.95 (s, 3H)ppm. 13 C NMR (101MHz, CDCl3) δ168.8, 146.1, 137.03, 131.8, 131.7, 129.3, 128.8, 128.4, 127.5, 123.5, 123.1, 66.7, 27.6ppm.

[0025] By changing the raw materials in Example 1, the following 11 sets of experimental examples were designed, where the first set of experiments is Example 1, and the corresponding NMR spectrum of the product is shown in Figure 1. The NMR spectra of the products in the remaining sets 2-11 correspond to the sequence numbers of the respective examples.

[0026] The table lists the structural formulas of the products in each of the 1-11 embodiments. The last column lists the yield of the products in each embodiment and indicates the specific implementation conditions of each embodiment. The specific meaning of the implementation conditions of each embodiment is shown below the table.

[0027] Table 1 Yields of isoydinone compounds

[0028]

[0029] Example 2

[0030] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methyl-4-methoxybenzylamine (15 μL, 0.1 mmol), methyl 2-methoxybenzoate (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic flux. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (63% yield). 1 H NMR (400MHz, CDCl3) δ7.87-7.84 (m, 1H), 7.45-7.41 (m, 2H), 7.25-7.13 (m, 1H), 7 .07-7.01(m,2H), 6.89-6.83(m,2H), 5.27(s,1H), 3.78(s,3H), 2.93(s,3H)ppm. 13 C NMR (101MHz, CDCl3) δ168.7, 159.9, 146.4, 131.7, 128.8, 128.8, 128.3, 123.5, 123.0, 114.6, 66.2, 55.4, 27.5ppm.

[0031] Example 3

[0032] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N,3-dimethylbenzylamine (15 μL, 0.1 mmol), methyl 2-methoxybenzoate (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic inlet. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (78% yield). 1HNMR (400MHz, CDCl3) δ7.96-7.91 (m, 1H), 7.54-7.47 (m, 2H), 7.33-7.17 (m, 4H), 7.04-6.95 (m, 2H), 5.35 (s, 1H), 3.02 (s, 3H), 2.37 (s, 3H) ppm.13C NMR (101MHz, NONE) δ169.0, 146.3, 139.2, 1367.0, 131.8, 131.7, 129.6, 129.2, 128.4, 128.0, 124.8, 123.6, 123.1, 66.8, 27.7, 21.6ppm.

[0033] Example 4

[0034] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methyl-N-(4-methylbenzyl)amine (15 μL, 0.1 mmol), methyl 2-methoxybenzoate (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic flux. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (67% yield). 1H NMR (400MHz, CDCl3) δ7.90-7.86 (m, 1H), 7.46-7.41 (m, 2H), 7.26 (s, 0H), 7.19-7 .15(m, 3H), 7.02(d, J=8.0Hz, 2H), 5.30(s, 1H), 2.96(s, 3H), 2.35(s, 3H)ppm.13C NMR (101MHz, CDCl3) δ169.2, 146.7, 139.0, 134.4, 132.2, 130.3, 128.7, 127.87, 123.9, 123.4, 66.9, 278.0, 21.7ppm.

[0035] Example 5

[0036] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methyl-4-chlorobenzylamine (14 μL, 0.1 mmol), methyl 2-methoxybenzoate (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic flux. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (652% yield). 1HNMR (400MHz, CDCl3) δ7.91-7.86(m, 1H), 7.49-7.45(m, 2H), 7.36-7.33(m, 3H), 7.18-7.14(m, 1H), 7.11-7.07(m, 2H), 5.32(s, 1H), 2.97(s, 3H)ppm.13C NMR (101MHz, CDCl3) δ169.6, 146.5, 136.45, 135.5, 132.7, 132.4, 130.3, 130.2, 129.7, 129.4, 124.5, 123.8, 66.8, 28.4ppm.

[0037] Example 6

[0038] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methyl-2-thiophene methylamine (12 μL, 0.1 mmol), methyl 2-methoxybenzoate (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic flux. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (37% yield). 1HNMR (400MHz, CDCl3) δ7.89-7.86 (m, 1H), 7.49 (ddt, J=7.4, 5.0, 1.4Hz, 2H), 7.31-7.28 (m, 3H), 7.13 (dd, J=3.5, 1.5Hz, 1H), 7.03-7.00 (m, 1H), 5.66 (s, 1H), 3.02 (s, 3H)ppm.13C NMR (101MHz, CDCl3) δ169.8, 147.1, 142.0, 133.6, 1332, 130.5 129.1, 128.7, 128.3, 125.2, 124.8, 63.5, 29.2ppm.

[0039] Example 7

[0040] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methyl-4-pyridinemethylamine (12 μL, 0.1 mmol), methyl 2-methoxybenzoate derivative (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave tube equipped with a magnetic flux. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (80% yield). 1H NMR (400MHz, CDCl3) δ8.65-8.59 (m, 1H), 7.91 (ddd, J=5.7, 3.0, 0.8Hz, 0H), 7. 49(dd, J=5.6, 3.1Hz, 1H), 7.20-7.11(m, 1H), 5.34(s, 0H), 3.01(s, 1H)ppm.13C NMR (101MHz, CDCl3) δ169.7, 151.4, 147.1, 145.1, 132.8, 132.4, 129.6, 124.6, 123.5, 122.9, 66.2, 28.4ppm.

[0041] Example 8

[0042] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine (14 μL, 0.1 mmol), methyl 2,4-dimethoxybenzoate (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic flux. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (78% yield). 1HNMR (400MHz, CDCl3) δ7.79 (d, J=8.5Hz, 1H), 7.38-7.35 (m, 2H), 7.16-7.14 (m, 1H), 6.96 ( dd, J=8.4, 2.2Hz, 1H), 6.64 (d, J=2.3Hz, 1H), 5.27 (s, 1H), 3.77 (s, 3H), 2.94 (s, 3H)ppm.13C NMR (101MHz, CDCl3) δ170.3, 164.5, 149.9, 138.8, 130.8, 130.3, 129.1, 128.9, 126.4, 116.5, 109.5, 68.0, 57.2, 29.1ppm.

[0043] Example 9

[0044] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine (14 μL, 0.1 mmol), methyl 2-methoxy-6-methylbenzoate (17 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic flux. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (76% yield). 1HNMR (400MHz, CDCl3) δ7.16-7.06 (m, 1H), 6.98-6.93 (m, 1H), 6.76 (dd, J=7.6, 1.1Hz, 0H), 5.07 (s, 0H), 2.74 (s, 1H), 2.58 (s, 1H)ppm.13C NMR (101MHz, CDCl3) δ169.5, 146.5, 137.4, 137.2, 131.1, 130.1, 129.0, 128.5, 128.4, 127.3, 65.9, 27.2, 17.2ppm.

[0045] Example 10

[0046] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine (14 μL, 0.1 mmol), methyl 2,5-dimethoxybenzoate (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic inlet. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (66% yield). 1HNMR (400MHz, CDCl3) δ7.38-7.35 (m, 1H), 7.35-7.32 (m, 1H), 7.14-7.11 (m, 1H), 7.07-6.99 (m, 1H), 5.28 (s, 1H), 3.86 (s, 2H), 2.96 (s, 2H) ppm.13C NMR (101MHz, CDCl3) δ162.0, 153.4, 131.7, 130.4, 126.2, 122.4, 121.8, 120.6, 117.1, 113.2, 99.4, 59.5, 48.9, 20.9ppm.

[0047] Example 11

[0048] In a nitrogen-filled glove box, LiN(SiMe3)2 (50.2 mg, 0.2 mmol), CsF (45.6 mg, 0.2 mmol), N-methylbenzylamine derivative (14 μL, 0.1 mmol), methyl 2-methoxynicotinic acid (14 μL, 0.1 mmol), and methyl tert-butyl ether (0.6 mL) were added sequentially to a dry microwave-safe tube equipped with a magnetic flux. The reaction was carried out at 110 °C for 15 h, then cooled to room temperature, and the reaction was quenched with a small amount of water. The crude product was purified by rapid silica gel column chromatography to obtain the final product (71% yield). 2 .91 (s, 3H) ppm. 13CNMR (101MHz, CDCl3) δ 170.8, 158.5, 153.4, 131.2, 131.2, 130.9, 130.7, 129.5, 129.3, 127.8, 68.5, 29.1ppm.

Claims

1. A method for synthesizing isoindolone, characterized in that: In an inert gas environment, isoindolone of formula 3 was synthesized by reacting the N-methylbenzylamine derivative of formula 1 and the methyl 2-methoxybenzoate derivative of formula 2 with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride; wherein R 1 Selected from any one of hydrogen, 3-methyl, 4-methyl, 4-methoxy, and chlorine; R 2 It is selected from any one of hydrogen, 4-methyl, 3-methoxy, and fluorine.

2. A method for synthesizing isoindolone, characterized in that: In an inert gas environment, isoindolone of Formula 6 was synthesized by reacting N-methyl-N-(4-pyridinemethyl)amine (Formula 4) and methyl 2-methoxybenzoate derivative (Formula 5) with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride.

3. A method for synthesizing isoindolone, characterized in that: In an inert gas environment, isoindolone of Formula 8 was synthesized by reacting N-methyl-2-thiophene methylamine (Formula 7) and methyl 2-methoxybenzoate derivative (Formula 5) with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride.

4. A method for synthesizing isoindolone, characterized in that: In an inert gas environment, isoindolone of Formula 11 was synthesized by reacting N-methylbenzylamine derivative of Formula 9 and 2-methoxynicotinic acid methyl pyridine of Formula 10 with the organic solvent methyl tert-butyl ether in the presence of lithium di(trimethylsilyl)amino and cesium fluoride.

5. The synthesis method according to claims 1, 2, 3 and 4, characterized in that, The inert gas mentioned is nitrogen.

6. The synthesis method according to claims 1, 2, 3 and 4, characterized in that, The N-methylbenzylamine derivative, the methyl 2-methoxybenzoate derivative shown in Formula 2, and the benzylphosphine compound are listed in one of the following tables:

Images