2-methylbenzofuran derivative containing isoxazole heterocycle, and preparation method and application thereof

Abstract

The invention discloses a 2-methylbenzofuran derivative containing isoxazole heterocycle shown as formula (I), wherein, in formula (I), R1 represents a substituted phenyl; R2 and R4 individually represent benzoyl or substituted benzoyl; and R3 represents H, hydroxy, halogen, nitryl or C1-C3 alkyl. The invention has beneficial effects that (1) a new 2-methylbenzofuran derivative containing isoxazole heterocycle is provided; (2) the compound can substantially inhibit monoamine oxidase activity and provide researching foundations for screening of new antidepressant and Parkinson-resistant medicaments; (3) the preparation method is easy to realize automatic operation to accelerate synthesis process and increase efficiency, and recycle of raw materials can be realized; (4) a synthesis technology of the compound of the invention is convenient for operation, and is apt to be applied to new compound synthesis through a high-throughput compound screening.

Description

(1) Technical field

[0001] The invention relates to a 2-methylbenzofuran derivative containing an isoxazole heterocycle and its preparation and application. (2) Background technology

[0002] Combinatorial chemistry was born in the 1980s. In the 1990s, due to the rapid development of the world's pharmaceutical industry, the pressure on new drug development and high-throughput screening has increased. Synthesizing organic molecules for screening has become the key to the problem. It is against this background that combinatorial chemistry has achieved unprecedented rapid development. Solid phase organic synthesis (SPOS, solid phase organic synthesis) is the core technology for the synthesis of combinatorial compound libraries. Since American chemist Merrifield proposed solid-phase synthesis in 1963 (Merrifield, R.B.J.Am.Chem.Soc., 1963, 85(14), 2149-2154.), SPOS was quickly applied to drug synthesis.

[0003] Monoamine oxidase (monoamine oxidase) is an enzyme that catalyzes ...

Examples

Embodiment 1

[0044] Embodiment 1: the preparation of selenium resin load (IV-1)

[0045] The reaction formula is as follows:

[0046]

[0047] Under a nitrogen atmosphere, 0.8 grams of 1.25mmol / g (1.00mmol) polystyrene-loaded selenium bromide resin (II) in 30mL CHCl 3 Soak in the middle for 12 hours, then add 1.79g (5.0mmol) compound shown in formula (III-1), 0.580g (5.0mmol) tetramethylethylenediamine, stir and react at 60°C for 4.0 hours, filter the reaction solution, filter The cake was successively filled with 20mL of water, 20mL of tetrahydrofuran, 20mL of tetrahydrofuran and water mixture (volume ratio of 1:1), 20mL of tetrahydrofuran, 20mL of tetrahydrofuran and water mixture (volume ratio of 1:1), 20mL of tetrahydrofuran, 20mL of chloroform, 20mL Washed with dichloromethane, dried under vacuum at 45° C. for 6 hours to obtain 1.076 g of the selenium resin supported substance represented by formula (IV-1).

Embodiment 2

[0048] Embodiment 2: Preparation of selenium resin load (V-1)

[0049] The reaction formula is as follows:

[0050]

[0051] Under a nitrogen atmosphere, 1.076 g of the selenium resin load (IV-1) obtained in Example 1 (the amount of the material loaded with selenium is 1.0 mmol) was soaked in 30 mL of chloroform for 5 hours, and 0.75 mL (8.0 mmol) of alkyne was added thereto. Propyl bromide, 1.12g (8.0mmol) potassium carbonate, reacted at 60°C for 8.0 hours, filtered the reaction solution, and washed the filter cake with 30mL of water, 30mL of tetrahydrofuran, 30mL of tetrahydrofuran and water mixture (volume ratio: 1:1), Wash with 30mL tetrahydrofuran, 30mL tetrahydrofuran and water mixture (1:1 volume ratio), 30mL tetrahydrofuran, 30mL chloroform, and 30mL dichloromethane, and vacuum-dry at 40°C for 6 hours to obtain the selenium resin-loaded solution shown in formula (V-1). Material 1.110g.

Embodiment 3

[0052] Embodiment 3: The preparation reaction formula of 2-methylbenzofuran derivative (I-1) containing isoxazole heterocycle is as follows:

[0053]

[0054]

[0055] (1) Under a nitrogen atmosphere, 0.54g (4.0mmol) of 4-methylbenzaldehyde oxime (VI-1) was reacted in methylene chloride at 30°C for 4 hours, and then soaked in methylene chloride for 5 The selenium resin loading (V-1) 1.110g (the amount of the material of loading selenium is 1.0mmol) prepared by the embodiment 2 method of 1 hour mixes, stirs, then in the mixture, dropwise add 0.70mL (5.0mmol) triethylamine , reacted for 18 hours at 25°C, ended the reaction, filtered the reaction solution, and the filter cake was successively washed with 40mL of water, 40mL tetrahydrofuran, 40mL tetrahydrofuran and water mixed solution (volume ratio is 1: 1), 40mL tetrahydrofuran, 40mL tetrahydrofuran and water mixed solution ( The volume ratio is 1:1), 40mL tetrahydrofuran, 40mL chloroform, 40mL dichloromethane washing, 40...

(1) Technical field

[0001] The invention relates to a 2-methylbenzofuran derivative containing an isoxazole heterocycle and its preparation and application. (2) Background technology

[0002] Combinatorial chemistry was born in the 1980s. In the 1990s, due to the rapid development of the world's pharmaceutical industry, the pressure on new drug development and high-throughput screening has increased. Synthesizing organic molecules for screening has become the key to the problem. It is against this background that combinatorial chemistry has achieved unprecedented rapid development. Solid phase organic synthesis (SPOS, solid phase organic synthesis) is the core technology for the synthesis of combinatorial compound libraries. Since American chemist Merrifield proposed solid-phase synthesis in 1963 (Merrifield, R.B.J.Am.Chem.Soc., 1963, 85(14), 2149-2154.), SPOS was quickly applied to drug synthesis.

[0003] Monoamine oxidase (monoamine oxidase) is an enzyme that catalyzes ...

Examples

Embodiment 1

[0044] Embodiment 1: the preparation of selenium resin load (IV-1)

[0045] The reaction formula is as follows:

[0046]

[0047] Under a nitrogen atmosphere, 0.8 grams of 1.25mmol / g (1.00mmol) polystyrene-loaded selenium bromide resin (II) in 30mL CHCl 3 Soak in the middle for 12 hours, then add 1.79g (5.0mmol) compound shown in formula (III-1), 0.580g (5.0mmol) tetramethylethylenediamine, stir and react at 60°C for 4.0 hours, filter the reaction solution, filter The cake was successively filled with 20mL of water, 20mL of tetrahydrofuran, 20mL of tetrahydrofuran and water mixture (volume ratio of 1:1), 20mL of tetrahydrofuran, 20mL of tetrahydrofuran and water mixture (volume ratio of 1:1), 20mL of tetrahydrofuran, 20mL of chloroform, 20mL Washed with dichloromethane, dried under vacuum at 45° C. for 6 hours to obtain 1.076 g of the selenium resin supported substance represented by formula (IV-1).

Embodiment 2

[0048] Embodiment 2: Preparation of selenium resin load (V-1)

[0049] The reaction formula is as follows:

[0050]

[0051] Under a nitrogen atmosphere, 1.076 g of the selenium resin load (IV-1) obtained in Example 1 (the amount of the material loaded with selenium is 1.0 mmol) was soaked in 30 mL of chloroform for 5 hours, and 0.75 mL (8.0 mmol) of alkyne was added thereto. Propyl bromide, 1.12g (8.0mmol) potassium carbonate, reacted at 60°C for 8.0 hours, filtered the reaction solution, and washed the filter cake with 30mL of water, 30mL of tetrahydrofuran, 30mL of tetrahydrofuran and water mixture (volume ratio: 1:1), Wash with 30mL tetrahydrofuran, 30mL tetrahydrofuran and water mixture (1:1 volume ratio), 30mL tetrahydrofuran, 30mL chloroform, and 30mL dichloromethane, and vacuum-dry at 40°C for 6 hours to obtain the selenium resin-loaded solution shown in formula (V-1). Material 1.110g.

Embodiment 3

[0052] Embodiment 3: The preparation reaction formula of 2-methylbenzofuran derivative (I-1) containing isoxazole heterocycle is as follows:

[0053]

[0054]

[0055] (1) Under a nitrogen atmosphere, 0.54g (4.0mmol) of 4-methylbenzaldehyde oxime (VI-1) was reacted in methylene chloride at 30°C for 4 hours, and then soaked in methylene chloride for 5 The selenium resin loading (V-1) 1.110g (the amount of the material of loading selenium is 1.0mmol) prepared by the embodiment 2 method of 1 hour mixes, stirs, then in the mixture, dropwise add 0.70mL (5.0mmol) triethylamine , reacted for 18 hours at 25°C, ended the reaction, filtered the reaction solution, and the filter cake was successively washed with 40mL of water, 40mL tetrahydrofuran, 40mL tetrahydrofuran and water mixed solution (volume ratio is 1: 1), 40mL tetrahydrofuran, 40mL tetrahydrofuran and water mixed solution ( The volume ratio is 1:1), 40mL tetrahydrofuran, 40mL chloroform, 40mL dichloromethane washing, 40...

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