3, 6-diazabicyclo[3.2.1]octane-7-carboxylic acid derivative and preparation method

A technology of diazabicyclo and carboxylic acid derivatives, which can be applied in the fields of drug combination, bulk chemical production, organic chemistry, etc., can solve the problems of poor water solubility of spatial structure extension compounds, and achieve the effect of changing physiological activity and improving water solubility.

CN104098566AInactive Publication Date: 2014-10-15上海药明康德新药开发有限公司
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Patent Information

Authority / Receiving Office
CN · China
Patent Type
Applications(China)
Current Assignee / Owner
Publication Date
2014-10-15
Estimated Expiration
Not applicable · inactive patent

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Abstract

The invention relates to a 3, 6-diazabicyclo[3.2.1]octane-7-carboxylic acid and its derivative, and a preparation method thereof, and mainly solves the current technical problems of limited extension of bridged ring compounds with a diazabicyclo[3.2.1]octane structure in a space structure and poor water solubility of the compounds. The 3, 6-diazabicyclo[3.2.1]octane-7-carboxylic acid and its derivative has a chemical structure general formula as the following, wherein R1 and R2 are substituted functional groups or protection groups of amino, and are one of H, alkyl of C1-C6, benzyl, 2, 4-dimethoxy benzyl, 4-methoxy benzyl, t-butyloxycarboryl, benzyloxycarbonyl, alkanoyl and aroyl; and R3 is a substituted functional group, like one of H, alkyl of C1-C6, benzyl, 2, 4-dimethoxy benzyl, tert-butyl or substituted benzene. The invention also provides the preparation method and application of the 3, 6-diazabicyclo[3.2.1]octane-7-carboxylic acid and its derivative.
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Description

technical field

[0001] The present invention relates to a 3,6-diazabicyclo[3.2.1]octane-7-carboxylic acid derivative and its preparation method, especially 3,6-diazabicyclo[3.2.1]octane-7 -Carboxylic acid and its derivatives and 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 c...

Examples

Embodiment 1

[0056] Example 1: (1R,5R,7S)-3-(4-methoxybenzyl)-6-((R)-1-phenylethyl)-3,6-diazabicyclo[3.2. 1] The preparation reaction formula of ethyl octane-7-carboxylate:

[0057] Steps:

[0058] The first step: (1R,3S,4S,5S,6R)-5,6-dihydroxy-2-((R)-1-phenylethyl)-2-azabicyclo[2.2.1]heptane Ethyl-3-carboxylate (3.1 g, 10 mmol) was dissolved in 40 mL of dichloroethane, and slowly added dropwise to 20 mL of sodium periodate (4.2 g, 20 mmol) aqueous solution at 0 °C. The reaction was stirred at 0 °C for 1 hour, and the layers were separated. The organic phase was washed with water and then concentrated to obtain 3 g of ethyl 3,5-dialdehydepyrrolidine-2-carboxylate. (Yield 99%)

[0059] HNMR (CDCl3): δ9.72 (s, 1H), 8.46 (d, J = 3.9Hz, 1H), 7.26 (s, 5H), 4.51 (s, 1H), 4.32-4.22 (m, 2H), 3.97 (q, J = 5.1Hz, 1H), 3.59-3.54 (m, 1H), 2.92 (d, J = 6.3Hz, 1H), 2.47-2.39 (m, 1H), 2.17 (dd, J1= 3.0Hz, J2 = 10.8Hz, 1H), 1.44 (d, J = 4.8Hz, 3H), 1.34 (t, J = 5.4Hz, 3H).

[0060] MS: 318.1 [M+1...

Embodiment 2

[0064] Example 2: Preparation of (1R,5R,7S)-3-(4-methoxybenzyl)--3,6-diazabicyclo[3.2.1]octane-7-carboxylic acid ethyl ester Mode:

[0065]

[0066] Operation steps: specifically refer to embodiment 1.

[0067] The first step: dichloromethane is used as the reaction solvent, and the yield is 95%.

[0068] MS: 300.1 (M+1).

[0069] The second step: sodium acetate borohydride was used as the reducing agent, and the yield was 75%.

[0070] HNMR (CDCl3): δ7.19-7.14 (m, 2H), 6.83-6.80 (m, 2H), 4.27-4.03 (m, 4H), 3.78 (s, 3H), 3.51-3.47 (m, 2H), 3.19-3.00 (m, 1H), 2.95-2.92 (m, 1H), 2.40-2.38 (m, 1H), 2.22 (d, J = 8.1Hz, 1H), 2.17-2.04 (m, 1H), 1.95 ( dd, J1= 3.0Hz, J2 = 8.1Hz, 1H), 1.47-1.39 (m, 10H), 1.25 (q, J = 5.4Hz, 3H).

[0071] MS: 405.3 [M+1].

[0072] The third step: the compound (1R,5R,7S)-3-(4-methoxybenzyl)-6-tert-butoxycarbonyl-3,6-diazabicyclo[3.2.1]octane-7 - Ethyl carboxylate (0.81g, 2mmol) was dissolved in 15mL of ether hydrochloride and stirred for 2 ho...

Embodiment 3

[0075] Example 3: Preparation of ethyl (1R,5R,7S)-6-tert-butoxycarbonyl-3,6-diazabicyclo[3.2.1]octane-7-carboxylate Reaction formula:

[0076]

[0077] Operation steps: (1R,5R,7S)-3-(4-methoxybenzyl)-6--tert-butoxycarbonyl-3,6-diazabicyclo[3.2.1]octane-7- Ethyl carboxylate (2.2 g, 5 mmol) was dissolved in 30 mL of methanol, Pd / C (0.2 g, 10% wt) was added, and the reaction was carried out under 15 psi hydrogen pressure for 4 hours. The reaction solution was filtered and concentrated to obtain 1.56 g (1R,5R,7S)-6-tert-butoxycarbonyl-3,6-diazabicyclo[3.2.1]octane-7-carboxylic acid ethyl ester, yield 100 %.

[0078] MS: 285.1 (M+1).