Triazole heterocycle-containing 2-methyl benzofuran compound, and preparation and application thereof

Abstract

The invention discloses a triazole heterocycle-containing 2-methyl benzofuran compound shown as a formula (I), and a preparation method and application thereof. In the formula (I), R1 is substituted phenyl; R2 and R4 are benzoyl or substituted benzoyl independently; and R3 is H, hydroxyl, halogen, nitryl or C1-C3 alkyl. The invention has the advantages that: (1) the invention provides a new inhibitor medicament capable of obviously inhibiting activity of monoamine oxidase and provides research basis for screening new medicaments for resisting depression, parkinsonism and the like; (2) automatic operation is easy to implement, the synthetic process is accelerated, efficiency is improved, and raw materials can be recycled; and (3) the synthetic process is convenient to operate and is easily applied to synthesizing new compounds for screening high-flux compounds.

Description

(1) Technical field

[0001] The invention relates to a 2-methylbenzofuran compound containing a triazole 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 (high-throughput screening) was increased. Synthesizing organic molecules for screening has become the crux of the problem, and it is against this background that combinatorial chemistry has developed unprecedentedly rapidly. 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 ...

Examples

Embodiment 1

[0042] Embodiment 1: the preparation of selenium resin load (IV-1)

[0043] The reaction formula is as follows:

[0044]

[0045] 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

[0046] Embodiment 2: Preparation of selenium resin load (V-1)

[0047] The reaction formula is as follows:

[0048]

[0049] 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

[0050] Embodiment 3: The preparation reaction formula of the 2-methylbenzofuran compound (I-1) containing triazole heterocycle is as follows:

[0051]

[0052]

[0053] (1) Under a nitrogen atmosphere, 0.4g (3.0mmol) 2-methylphenyl azide (VI-1) was added to the selenium resin load prepared by the method of Example 2 soaked in 30mL dimethyl sulfoxide for 5 hours in advance (V-1) 1.110g (the amount of selenium-loaded substance is 1.0mmol), then add 5mL water, finally add 0.2g (0.8mmol) copper sulfate pentahydrate and 0.8g vitamin C, stir, and react at 35°C for 10 hours , to end the reaction, the reaction solution was filtered, 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 (volume ratio is 1: 1) ), 40mL tetrahydrofuran, 40mL chloroform, 40mL dichloromethane, and vacuum-dried at 40° C. for 6 hours to...

(1) Technical field

[0001] The invention relates to a 2-methylbenzofuran compound containing a triazole 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 (high-throughput screening) was increased. Synthesizing organic molecules for screening has become the crux of the problem, and it is against this background that combinatorial chemistry has developed unprecedentedly rapidly. 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 ...

Examples

Embodiment 1

[0042] Embodiment 1: the preparation of selenium resin load (IV-1)

[0043] The reaction formula is as follows:

[0044]

[0045] 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

[0046] Embodiment 2: Preparation of selenium resin load (V-1)

[0047] The reaction formula is as follows:

[0048]

[0049] 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

[0050] Embodiment 3: The preparation reaction formula of the 2-methylbenzofuran compound (I-1) containing triazole heterocycle is as follows:

[0051]

[0052]

[0053] (1) Under a nitrogen atmosphere, 0.4g (3.0mmol) 2-methylphenyl azide (VI-1) was added to the selenium resin load prepared by the method of Example 2 soaked in 30mL dimethyl sulfoxide for 5 hours in advance (V-1) 1.110g (the amount of selenium-loaded substance is 1.0mmol), then add 5mL water, finally add 0.2g (0.8mmol) copper sulfate pentahydrate and 0.8g vitamin C, stir, and react at 35°C for 10 hours , to end the reaction, the reaction solution was filtered, 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 (volume ratio is 1: 1) ), 40mL tetrahydrofuran, 40mL chloroform, 40mL dichloromethane, and vacuum-dried at 40° C. for 6 hours to...

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