5-amino-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof

A technology of carboxylic acid derivatives and azabicycle, which is applied in the field of 5-amino-2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivatives and preparation, can solve the limitation of spatial structure extension, compound Problems such as poor water solubility, to achieve the effect of improving water solubility

Inactive Publication Date: 2009-06-24
上海药明康德新药开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It mainly solves the technical problems that the current bridged ring compound of 2-azabicyclo[2.2.1]heptane structure is limited in spatial structure extension and poor water solubility of the compound

Method used

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  • 5-amino-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof
  • 5-amino-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof
  • 5-amino-2-azabicyclo [2.2.1] heptane-3-carboxyl acid derivatives, and preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Preparation of (1R, 3S, 4R, 5R)-5-benzyloxycarbonylamino-2-azabicyclo[2.2.1]heptane-2-carboxylate-tert-butyl-3-carboxylate

[0065] The first step reaction: preparation of (1R, 3S, 4S)-5-hydroxyimine-2-azabicyclo[2.2.1]heptane-2-tert-butyl carboxylate-3-ethyl carboxylate

[0066] Reaction formula:

[0067] Steps:

[0068] The compound (1R, 3S, 4S)-5-carbonyl-2-azabicyclo[2.2.1]heptane-2-carboxylate tert-butyl-3-carboxylate ethyl ester (1.4g, 5mmol) and hydrochloric acid hydroxy Dissolve ammonia in ethanol, stir at room temperature, add sodium acetate aqueous solution (sodium acetate is dissolved in 17mL water), heat to reflux, react for 2 hours, TLC detects the reaction progress, after the reaction is completed, cool the reaction mixture to room temperature, and concentrate by rotary evaporation , then add 50 mL of water to dilute, then adjust the pH to 5 with 1mol / L hydrochloric acid, extract with ethyl acetate, wash the organic phase with saturated brine, dry with...

Embodiment 2

[0090] Preparation of (1R, 3S, 4R, 5S)-5-benzyloxycarbonylamino-2-azabicyclo[2.2.1]heptane-2-carboxylate-tert-butyl-3-carboxylate

[0091] Reaction formula:

[0092]

[0093] Steps:

[0094] The compound (1R, 3S, 4R)-5-benzyloxycarbonylamino-2-azabicyclo[2.2.1]heptane-2-carboxylate tert-butyl-3-carboxylate was subjected to chiral separation, The compound (1R,3S,4R,5S)-5-benzyloxycarbonylamino-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl-3-carboxylic acid ethyl ester was obtained.

[0095] HNMR (CDCl 3 )δ: 7.39(m, 5H); 5.15(s, 2H); 4.73(s, 1H); 4, 38(m, 1H); 4.22(m, 2H); , 1H); 2.30(m, 2H); 1.99(m, 1H); 1.46(m, 9H); 1.30(m, 3H)

[0096] Mass: 418.2

Embodiment 3

[0098] Preparation of (1R, 3S, 4R, 5R)-5-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate tert-butyl-3-carboxylate ethyl ester

[0099] Reaction formula:

[0100]

[0101] Steps:

[0102] Compound (1R, 3S, 4R, 5R)-5-benzyloxycarbonylamino-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl-3-carboxylic acid ethyl ester (0.42g , 1 mmol) was dissolved in 20 mL of absolute ethanol, 0.04 g of palladium / carbon was added, and 50 psi of hydrogen was pressurized to react overnight at room temperature.

[0103] HNMR (CDCl 3 )δ: 4.38(d, 1H); 4.20(m, 3H); 3.62(m, 1H); 2.76(m, 1H); 2.07(m, 3H); 1.43(m, 9H); )

[0104] Mass: 285.2

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PUM

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Abstract

The invention relates to a 5-amino-2-diazabicyclo (2.2.1) heptane-3-carboxylic acid derivative and a preparing method thereof, solving the technical problems of poor water solubility and low bioavailability of the existing diazabicyclo structure. The chemical structural formula of the 5-amino-2-diazabicyclo (2.2.1) heptane-3-carboxylic acid derivative is shown in the formula above. (1R, 3S, 4S)-2boc-5-carbonyl-2-diazabicyclo (2.2.1) heptane-3-carboxylic ester (II) is used as raw material for obtaining non-optically pure 5-amino-2-diazabicyclo (2.2.1) heptane-3- carboxylic ester (III) by reduction amination reaction. Carbobenzoxy is added for the protection to obtain 5-benzyloxycarbonylamino-2-diazabicyclo (2.2.1) heptane-3-carboxylic ester (IV) which is condensated into acid amide with amine after resolution of chiral column, removing of protecting groups, hydrolysis and alkylation or arylation reaction and the acid amide reacts with alcohol or halohydrocarbon to form ester series to obtain a final product.

Description

Technical field: [0001] The invention relates to a 5-amino-2-azabicyclo[2.2.1]heptane-3-carboxylic acid derivative and a preparation method. Background technique: [0002] The bridge ring structure connects or integrates the key pharmacophore units into its rigid structure to form molecules with special spatial configuration and conformation, which can match the spatial structure of different biomacromolecules in the organism and produce different biological activities or effects , many compounds have different biological activities, so they have broad application value, especially as template compounds in the process of drug research. Bridged ring compounds containing 2-azabicyclic structures have been proved by many experiments to have various biological activities. The following part is some examples that have been disclosed in some patents and literatures and are closely related to the technology of the present invention. [0003] Patent WO2005042533 reports the inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/52C07D403/12C07D401/04
CPCY02P20/55
Inventor 姜胜天曹茉莉胡斌杜峰吴颢董径超马汝建陈曙辉李革
Owner 上海药明康德新药开发有限公司
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