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3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and preparation method thereof

A technology of tert-butoxycarbonyl and trifluoromethyl, applied in the field of 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and its preparation, can solve Low total yield, many synthetic steps, poor water solubility, etc., to achieve the effect of improving drug-like properties

Inactive Publication Date: 2011-08-31
上海药明康德新药开发有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems of 2,5-biheterobicyclo[2.2.1]heptane compounds with methyl derivatives introduced at the 3-position, many synthetic steps, poor water solubility and low total yield

Method used

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  • 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and preparation method thereof
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  • 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and preparation method thereof

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specific Embodiment approach ： Embodiment ， Embodiment 。 Embodiment 1

[0044] Specific embodiments: Examples are given to describe the present invention in detail, but the present invention is not limited to these examples. Example 1: Preparation of (2S, 4S)-N-tert-butoxycarbonyl-2-methoxycarbonyl-4-dibenzylaminotetrahydropyrrolidine 2

[0045]

[0046] Steps:

[0047] Under nitrogen protection, compound (2S, 4S)-N-tert-butoxycarbonyl-4-aminotetrahydropyrrolidine-2-carboxylic acid methyl ester 1 (20 g, 81.96 mmol) and Acetonitrile (100ml), triethylamine (33.1g, 327.84mmol), and benzyl bromide (41.80g, 246mol) were added slowly under ice-cooling. The reaction solution was stirred at 0°C for 1 hour, slowly raised to room temperature (20-30°C) and stirred overnight (12-16 hours), quenched with saturated ammonium chloride aqueous solution, adjusted to pH 7 with 1N sodium hydroxide aqueous solution, and filtered , concentrated the filtrate, added water, extracted with ethyl acetate, dried and concentrated the organic phase to obtain 30.5 g of pro...

Embodiment 2

[0049] Example 2: Preparation of (S2,4S)-N-tert-butoxycarbonyl-2-methoxycarbonyl-4-dibenzylaminotetrahydropyrrolidine 2

[0050]

[0051] Steps:

[0052] Under nitrogen protection, compound (2S, 4S)-N-tert-butoxycarbonyl-4-aminotetrahydropyrrolidine-2-carboxylic acid methyl ester 1 (10 g, 40.98 mmol) and Dichloromethane (100ml), anhydrous potassium carbonate (16.6g, 122.94mmol), and benzyl chloride (15.5g, 122.94mol) were added slowly under ice-cooling. The reaction solution was stirred at 0°C for 1 hour, slowly raised to room temperature and stirred overnight, quenched with saturated ammonium chloride aqueous solution, adjusted to pH 7 with 1N aqueous sodium hydroxide solution, filtered, concentrated filtrate, added water, extracted with ethyl acetate , the organic phase was dried and concentrated to obtain 14.2 g of the product (2S, 4S)-N-tert-butoxycarbonyl-2-methoxycarbonyl-4-dibenzylaminotetrahydropyrrolidine 2 through column chromatography, with a yield of 82%.

[0...

Embodiment 3

[0054] Example 3: Preparation of (2S, 4S)-N-tert-butoxycarbonyl-2-carboxy-4-dibenzylaminotetrahydropyrrolidine 3

[0055]

[0056] Steps:

[0057](2S,4S)-N-tert-butoxycarbonyl-2-methoxycarbonyl-4-dibenzylaminotetrahydropyrrolidine 2 (20 g, 47.16 mmol), dissolved in lithium hydroxide (2 g, 72 mmol) In a mixed solvent consisting of 100 milliliters of methanol and 50 milliliters of water, the reaction solution was stirred at room temperature for 2-3 hours, followed by TLC. After the reaction was completed, the solution was adjusted to be acidic with 1N hydrochloric acid, and then methanol and water were removed under reduced pressure. Phase was extracted 3 times with ethyl acetate, and the combined organic phases were washed with 10% sodium bicarbonate and water to neutrality, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 18 grams of compound (2R , 4R)-N-tert-butoxycarbonyl-2-carboxy-4-dibenzylaminot...

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Abstract

The invention discloses 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and a preparation method thereof. The invention mainly solves the technical problems that when a methyl derivative is introduced to the 3-site of the 2,5-diheterobicyclo[2.2.1]heptane compound, the synthesis steps are complicated, the water solubility is poor and the total yield is low. The structural formula of the compounds is shown as below, wherein R is NH or O; when R is NH, the compound is 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diazabicyclo[2.2.1]heptane; and when R is O, the compound is 3-trifluoromethyl-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane. The obtained compounds are mainly used to effectively connect the pharmacophore unit.

Description

technical field [0001] The present invention relates to a kind of 3-trifluoromethyl-5-tert-butoxycarbonyl-2,5-diheterobicyclo[2.2.1]heptane and its preparation method, especially 3-trifluoromethyl-5-tert-butyl Oxycarbonyl-2,5-diazabicyclo[2.2.1]heptane and 3-trifluoromethyl-5-tert-butoxycarbonyl-2-oxa-5-azabicyclo[2.2.1]heptane and preparation method. Background technique: [0002] 2,5-Diheterobicyclo[2.2.1]heptane compounds are a class of molecules with special structures, which can effectively link key pharmacophore units into their rigid structures to form special spatial configurations / conformations Molecules, so as to match the spatial structure of different biological macromolecules in the organism, produce different biological activities or effects, such as connecting 2,5-biheterobicyclo[2.2.1]heptane to analgesic quinolones, Has good analgesic activity (J. Med. Chem.; 31; 1988; 1598-1611). At present, the synthesis of 2,5-diheterobicyclo[2.2.1]heptane reported in ...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07D491/048
Inventor 张永明彭宣嘉胡利红汪秀董径超吴颢马汝建陈曙辉
Owner 上海药明康德新药开发有限公司
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