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Quaternary nitrogen varied volution derivate with 5 position as nitrogen and preparation method and use thereof

A technology for azaspiro rings and derivatives, which is applied in the field of quaternary azaspiro ring derivatives and their preparation, and can solve the problem of difficult control of reaction steps, high difficulty, and high tension of small rings in the lactam reduction of four-membered spiro rings And other issues

Active Publication Date: 2012-06-27
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] The quaternary azaspiro ring is widely used, but due to the high tension of the small ring, it is also difficult to synthesize
[0004] WO2006023630 discloses The preparation method is to first make a quaternary lactam, and then reduce the lactam to an imine, but the reduction of the quaternary spiro-lactam has always been a reaction step that is difficult to control
[0005] In summary, there is no report on the use of different amino protecting groups to protect two nitrogen quaternary azaspirocycles, and there is no report on the synthesis of quaternary azaspirocycles substituted by amino protecting groups, followed by deprotection to prepare Methods

Method used

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  • Quaternary nitrogen varied volution derivate with 5 position as nitrogen and preparation method and use thereof
  • Quaternary nitrogen varied volution derivate with 5 position as nitrogen and preparation method and use thereof
  • Quaternary nitrogen varied volution derivate with 5 position as nitrogen and preparation method and use thereof

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Experimental program
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Effect test

Embodiment 1

[0180]

[0181] To a solution of compound 1 (500g, 2.89mol) and diisopropylethylamine (649g, 5.00mol) in tetrahydrofuran (1200ml) was added p-toluenesulfonyl chloride (570g, 3.00mol) at room temperature. Stir overnight. The reaction solution was spin-dried in THF, diluted with dichloromethane (1,000ml), and washed with water (1,000ml). The organic layer was saturated NaHCO 3 (2×500ml) was washed twice, then washed with saturated brine (500ml), dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo. The product 2 was obtained as a yellow solid (945 g, 2.89 mol, 100% yield).

Embodiment 2

[0183]

[0184] Add 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (1,400ml) and NaCN (87g, 1.78mol) to the reaction flask at room temperature, Compound 2 (366g, 1.12mol) Was added to the mixture in portions. The reaction solution was stirred under reflux for 4 hours. The reaction solution was poured into ice water (2000ml). Extract 5 x 300ml with tert-butyl methyl ether. The MTBE layer was washed with saturated brine 3×200ml. It was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a black oily crude product, which was passed through a silica gel column to obtain a white solid product 3 (138 g, 0.758 mol yield 67.7%).

Embodiment 3

[0186]

[0187] Under nitrogen protection, n-BuLi (500 ml, 1.25 mol) was added in THF (1900 ml) at a temperature below -18°C. After compound 3 (155 g, 0.85 mol) was dissolved in THF (800 ml), the reaction mixture was added below -18°C. 1-Bromo-3-chloro-propane (200 g, 1.27 mol) was added to the reaction solution at an internal temperature below -18°C. The reaction was stirred for one hour below -18°C. Add saturated NH when the internal temperature is below -18°C 4 Cl solution (800ml), the reaction solution was extracted with ethyl acetate 3×800ml. The combined ethyl acetate solutions were washed with 1N HCl (100ml), saturated NaHCO 3 (100ml), washed with saturated brine (200ml). It was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and passed through a column to obtain white solid compound 4 (148 g, 0.571 mol, yield: 67.2%).

[0188] 1 H NMR (C2459-025CDCl 3 300MHz): δ4.28(d, J=8.7, 2H), 3.87(d, J=8.7, 2H), 3.6(m, 2H), 2.0(m, 4H)...

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Abstract

The invention belongs to the technical field of organic chemistry, in particular to a quaternary nitrogen varied volution derivate with 5 positions as nitrogen and a preparation method and use thereof. The novel quaternary nitrogen varied volution derivate with 5 positions as nitrogen is provided with a structure as the formula I. The quaternary nitrogen varied volution derivate with 5 positions as nitrogen can serve as a midbody for preparing quaternary nitrogen varied volution derivate, and the preparation method of the quaternary nitrogen varied volution derivate is more convenient.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and particularly relates to a quaternary azaspiro derivative whose 5-position is nitrogen, a preparation method and application thereof. Background technique [0002] Quaternary azaspiro rings are widely used, but due to the high tension of the small rings, it is difficult to synthesize them. The synthesis of aza four-membered spiro rings with nitrogen at the 2-position is mostly related to the synthesis of spiro rings from four-membered rings. This includes Sayago, Francisco J et al. (Tetrahedron, 2006, vol.62, #5p.915-921) using 1,3-aminoalcohols with methanesulfonyl chloride to generate 1-methanesulfonamide-3-mesylatepropane Class compounds, and then NaH ring closure to generate a methanesulfonamido azetidine spiro ring with nitrogen at the 2-position. Froehlich, Johannes (Heterocycles, 1994, vol.37, #3p.1879-1892) reacted with LDA and formaldehyde with 1-cyanocyclohexane to genera...

Claims

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Application Information

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IPC IPC(8): C07D205/04C07D487/10
Inventor 魏庚辉黄湘川李仟郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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