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1-substituted-3,8-diazabicyclo[3.2.1]octane derivative and preparation method

A technology of diazabicyclo and azabicyclo, applied in 1-substitution-3, can solve problems such as limitation of spatial structure extension and poor water solubility of compounds

Active Publication Date: 2015-11-25
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 bridged ring compounds with azabicyclo[3.2.1]octane structure are limited in spatial structure extension and the compounds have poor water solubility

Method used

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  • 1-substituted-3,8-diazabicyclo[3.2.1]octane derivative and preparation method
  • 1-substituted-3,8-diazabicyclo[3.2.1]octane derivative and preparation method
  • 1-substituted-3,8-diazabicyclo[3.2.1]octane derivative and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1 : 1-methoxycarbonyl-3-benzyl-8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane

[0071]

[0072] Steps:

[0073] Add tetrahydrofuran (10 ml) and 1-methoxycarbonyl-3-carbonyl-7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptane (1 g, 3.7 mg Moore). A tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1 mol / L, 4.6 ml, 4.6 mmol) was added dropwise at -78°C under nitrogen protection. The reaction system was stirred for half an hour at 0°C under a nitrogen atmosphere, and N, N - Bis(trifluoromethanesulfonyl)aniline (1.98 g, 5.5 mmol), stirred at room temperature for 12 hours, quenched with water (10 mL). The reaction solution was extracted with ethyl acetate. The organic phase was dried, concentrated, and the crude product was chromatographed to give 1 g of 1-methoxycarbonyl-3-trifluoromethanesulfonate-7-tert-butoxycarbonyl-7-azabicyclo[2.2.1] as a colorless oil -2-heptene, yield 67%. HNMR (CDCl 3 ) δ: 4.78 (s, 1H), 3.83 (s, 3H), 2.35-2.39 (m,...

Embodiment 2

[0078] Example 2 : 1-methoxycarbonyl-3-benzyl-3,8-diazabicyclo[3.2.1]octane

[0079]

[0080] Add 1-methoxycarbonyl-3-benzyl-8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane to a one-necked flask 6 (0.15 g, 0.42 mmol) and methanol (2 ml), hydrogen chloride methanol solution (1 ml) was added dropwise at 0°C, and stirred at room temperature for 2 hours under an atmospheric pressure of nitrogen. The reaction solution was concentrated to obtain 98 mg of 1-methoxycarbonyl-3-benzyl-3,8-diazabicyclo[3.2.1]octane I-a , the yield is 90%.

[0081] HNMR (MeOD) δ: 7.69-7.73 (m, 2H), 7.40-7.50 (m, 3H), 4.50-4.58 (m, 1H), 4.42-4.49 (m, 2H), 3.93-3.99 (m, 1H) , 3.88 (s, 3H), 3.80-3.85 (m, 1H), 3.50-3.60 (m, 2H), 2.80-2.82 (m, 1H), 2.25-2.50 (m, 3H).

Embodiment 3

[0082] Example 3 : 1-methoxycarbonyl-3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane

[0083]

[0084] Steps:

[0085] Add 1-methoxycarbonyl-3-benzyl-3,8-diazabicyclo[3.2.1]octane to a one-necked flask I-a (40 mg, 0.15 mmol) and N,N-dimethylformamide (2 ml), adding sodium hydrogen (6 mg, 0.15 mmol, 60%) at 0 ° C and stirring for 0.5 hours, dropwise adding iodomethane (21 mg, 0.15 mmol), stirred at room temperature for 2 hours in an atmosphere of nitrogen at an atmospheric pressure. The reaction solution was concentrated, and the crude product was separated on a silica gel plate to obtain 25 mg of 1-methoxycarbonyl-3-benzyl-8-methyl-3,8-diazabicyclo[3.2.1]octane I-b , yield 59%.

[0086] HNMR (MeOD) δ: 7.44-7.53 (m, 5H), 4.50-4.58 (m, 1H), 4.42-4.49 (m, 2H), 3.93-3.99 (m, 1H), 3.88 (s, 3H), 3.80 -3.85 (m, 1H), 3.50-3.60 (m, 2H),

[0087] 2.88 (s, 3H), 2.80-2.82 (m, 1H), 2.25-2.50 (m, 3H).

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Abstract

The invention relates to a 1-substituted-3,8-diazabicyclo[3.2.1] octane derivative and a preparation method thereof. The technical problems of limit to the extension of a space structure of the conventional endocyclic compound with a 3,8-diazabicyclo[3.2.1] octane structure and low water solubility of the compound are mainly solved. The 1-substituted-3,8-diazabicyclo[3.2.1] octane derivative has a chemical structural formula shown in the specification, wherein X and Y are protective groups of substituted functional groups or amino, and may be one of H, direct chain having 1 to 10 carbon atoms or alkyl, benzyl, tert-butoxycarbonyl, alkanoyl, sulfonyl, urea and sulfourea which contains substituent side chains, and Z is one of alkylene or carbonyl; and when Z is the carbonyl, G is one of hydroxyl, amino or alkoxy, and when Z is the alkylene, G is one of the hydroxyl or halogens.

Description

technical field [0001] The present invention relates to 1-substituted-3,8-diazabicyclo[3.2.1]octane derivatives and a preparation method thereof, especially 1-acyl substituted-3,8-diazabicyclo[3.2.1]octane Alkane derivatives and 1-alkyl substituted-3,8-diazabicyclo[3.2.1]octane derivatives and processes for their preparation. Background technique [0002] Bridged ring compounds are a class of molecules with a special structure, which can effectively link and integrate key pharmacophore units into their rigid structures to form molecules with special spatial configurations and conformations, which can match the biological macromolecules in the body. Spatial structure produces different biological activities or effects. Many bridged ring compounds have different biological activities, so they have broad application value, especially as template compounds in the process of drug research. The bridged ring compounds containing 3,8-diazabicyclic structure have been proved by many...

Claims

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Application Information

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IPC IPC(8): C07D487/08A61K31/4995A61P35/00
CPCY02P20/55
Inventor 张鹏彭宣嘉胡利红房顺大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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