2,5-diazabicyclo heptane compound and application thereof
A technology of diazabicyclo and diazabis, which is applied in the field of chemical synthesis, can solve problems such as difficulty in obtaining, limited application, and long route, and achieve the effect of improving synthesis efficiency and fewer steps
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Embodiment 1
[0059] Example 1: The preparation of (1R,4R)-2-benzoyl-6-carbonyl-2,5-diazabicyclo[2.2.1]heptane is as follows:
[0060] (1) Preparation of (2S,4R)-1-benzoyl-4-hydroxyproline
[0061]
[0062]L-Hydroxyproline (0.50 g, 3.81 mmol) was added to water (2.0 ml), NaOH aqueous solution (25%, 0.61 g, 3.81 mmol) was added under ice-bath cooling, and then benzoyl chloride (0.96 g, 6.86 mmol), NaOH aqueous solution was added during the dropwise addition to control the pH to 9. After the reaction was complete, hydrochloric acid was added to adjust the pH to 2, extracted with chloroform, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 0.70 g of white solid powder with a yield of 78%. .
[0063] (2) Preparation of (2S,4S)-1-benzoyl-4-hydroxyproline methyl ester
[0064]
[0065] (2S,4R)-1-Benzoyl-4-hydroxyproline (2.50 g, 10.6 mmol) was dissolved in dichloromethane (25 ml), and pyridine (2.5 g, 31.6 mmol) was added under ice cooling, and slowly Metha...
Embodiment 2
[0077] Example 2: Preparation of (1R,4R)-2-(4-methoxy)benzoyl-6-carbonyl-2,5-diazabicyclo[2.2.1]heptane
[0078] (1) Preparation of (2S,4R)-1-(4-methoxy)benzoyl-4-aminoproline methyl ester
[0079]
[0080] The synthesis method is similar to the method described in Example 1 steps (1)-(4);
[0081] (2) Preparation of (1R,4R)-2-(4-methoxy)benzoyl-6-carbonyl-2,5-diazabicyclo[2.2.1]heptane
[0082]
[0083] Under nitrogen protection, (2S,4R)-1-(4-methoxy)benzoyl-4-aminoproline methyl ester (100 mg, 0.36 mmol) was dissolved in anhydrous tetrahydrofuran (2.0 ml), drop Add KHMDS solution (1.0 M, 0.36 ml), stir at room temperature for 0.5 h, add acetic acid (1.0 eq.) to quench the reaction, remove the solvent by rotary evaporation, add dichloromethane and water, separate the organic layer, and wash the aqueous layer with two Extracted once with methyl chloride, combined the organic phases, washed with brine and water successively, dried over anhydrous magnesium sulfate, fil...
Embodiment 3
[0085] Example 3: Preparation of (1R,4R)-2-acetyl-6-carbonyl-2,5-diazabicyclo[2.2.1]heptane
[0086] (1) Preparation of (2S,4R)-1-acetyl-4-aminoproline methyl ester
[0087]
[0088] The synthesis method is similar to the method described in Example 1 steps (1)-(4);
[0089] (2) Preparation of (1R,4R)-2-acetyl-6-carbonyl-2,5-diazabicyclo[2.2.1]heptane
[0090]
[0091] Under nitrogen protection, (2S,4R)-1-acetyl-4-aminoproline methyl ester (500 mg, 2.69 mmol) was dissolved in anhydrous tetrahydrofuran (15 ml), and KHMDS solution (1.0 M, 2.7 ml), stir at room temperature for 0.5 h, add acetic acid (1.0 eq.) to quench the reaction, remove the solvent by rotary evaporation, add dichloromethane and water, separate the organic layer, extract the aqueous layer with dichloromethane once more, and combine the organic phases , washed with brine and water successively, dried over anhydrous magnesium sulfate, concentrated by filtration, and the crude product was subjected to si...
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