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A kind of method for preparing diaza spiro compound

A technology for diazaspiro compounds, applied in the field of preparing diazaspiro compounds, which can solve the problems of expensive reagents, high reaction costs, and low total yield

Inactive Publication Date: 2011-12-07
SHANGHAI AQ BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0035] The technical problem to be solved by the present invention is that the existing method for preparing diazaspiro compounds has the disadvantages of expensive reaction reagents, low temperature operation, etc., which lead to increased reaction costs, and at the same time, there are many intermediate steps that require column chromatography separation and purification. The problem of low yield, and a kind of method for preparing diaza spiro compound is provided for this problem

Method used

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  • A kind of method for preparing diaza spiro compound
  • A kind of method for preparing diaza spiro compound
  • A kind of method for preparing diaza spiro compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1 (preparation of formula 14 and formula 16)

[0069]

[0070] 1). N 2 For protection, add LDA 300ml (0.6mol, 2.0eq) dropwise to 200ml 4-Boc ethyl piperidinecarboxylate (Formula 11) (77g, 0.3mol) in dry THF (200mL) solution solvent at -15°C, and continue After stirring at low temperature for 1 hour, the reaction solution was added dropwise at -15°C to 100ml of 1-bromo-3-chloropropane (Formula 15) (95.0g, 2.0eq) in dry THF solution, then slowly warmed up to RT and stirred overnight; The next day, ammonium chloride aqueous solution was added for treatment, and after THF was spun off, the aqueous phase was extracted 3 times with ethyl acetate, dried and concentrated to obtain a concentrate;

[0071] 2). Dissolve the concentrate in step 1) in 250ml DMF, and add NaN in batches 3 (40.0g, 2.0eq), N 2 Protect and stir overnight at 50°C to 60°C, extract 3 times with pure petroleum ether the next day, combine organic phases, wash with water, dry and concentrate t...

Embodiment 2

[0079] Embodiment 2 (preparation of formula 24)

[0080]

[0081] 1). N 2 For protection, add LDA 300ml (0.6mol, 2.0eq) dropwise to 4-Boc ethyl piperidinecarboxylate (Formula 21) (77g, 0.3mol) in dry THF (200ml) at -15°C, and continue stirring at low temperature for 1 hour Finally, the reaction solution was added dropwise to 100ml of 1-bromo-2-chloroethane (Formula 25) (86.0g, 2.0eq) in dry THF solution at -15°C, and the temperature was slowly raised to RT and stirred overnight; the next day Ammonium chloride aqueous solution was added for treatment, and after THF was spinned off, the aqueous phase was extracted three times with ethyl acetate, dried and concentrated to obtain a concentrate;

[0082] 2). Dissolve the concentrate in step 1) in 250ml DMF, and add NaN in batches 3 (40.0g, 2.0eq), N 2 Stir overnight at 50°C to 60°C under protection, extract 3 times with pure petroleum ether the next day, combine organic phases, wash with water, dry and concentrate to obtain a...

Embodiment 3

[0086] Embodiment 3 (preparation of formula 34)

[0087]

[0088] 1).N 2 Protection, under the condition of -15°C, dropwise add LDA 300ml (0.6mol, 2.0eq) to the dry THF (200mL) solution of 3-Boc methyl piperidinecarboxylate (Formula 31) (77g, 0.3mol), and continue the low temperature After stirring for 1 hour, the reaction solution was added dropwise to 100ml of 1-bromo-3-chloropropane (Formula 35) (95.0g, 2.0eq) in dry THF solution below -15°C, and the temperature was slowly raised to RT and stirred overnight; The next day, ammonium chloride aqueous solution was added for treatment, and after THF was spinned off, the aqueous phase was extracted three times with ethyl acetate, dried and concentrated to obtain a concentrate;

[0089] 2). Dissolve the concentrate in step 1) in 250ml DMF, and add NaN in batches 3 (40.0g, 2.0eq), N 2 Stir overnight at 50°C to 60°C under protection, extract 3 times with pure petroleum ether the next day, combine organic phases, wash with wate...

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Abstract

The invention belongs to the technical field of drug synthesis. In order to solve the reactions involved in the preparation of diazaspiro compounds in the prior art, there are disadvantages such as requiring some relatively expensive reagents and requiring low temperature for operation. The invention provides a method for preparing diazaspirocyclic compounds. The method of the spiro compound, the diaza spiro compound has the structure of formula I or formula VI, the method uses the compound formula V as the initial raw material, comprising: a, removing the No. 1 position in the compound formula V with a proton-removing reagent and then carry out alkylation reaction with the saturated chain alkane formula III with halogenation at both ends to form the first intermediate product formula II; b, replace the carbon at the 2nd position in the first intermediate product formula II with an azide reagent On the halogen X2, form the second intermediate product formula IV; c, carry out reduction ring closure reaction on the second intermediate product formula IV, form the diaza spiro compound formula I; d, carry out the diaza spiro compound formula I Reduction gives the diaza spiro compound formula VI.

Description

technical field [0001] The present invention belongs to the technical field of drug synthesis, and relates to a method for preparing important intermediates for medicine and new drug research and development. The intermediates in the present invention are diazaspiro compounds, and all have the structure of formula I or formula VI , various restrictions on the structure (such as X, m, n, etc.) all comply with the relevant limitations of this specification, the preparation method provided by the invention optimizes the synthesis route for the preparation of formula I or VI, and simplifies the reaction steps while The yield of the diazaspiro compound formula I is increased. [0002] Background technique [0003] Diazaspirocyclic compounds are a class of important medicines and new drug research and development intermediates, and their importance in medicine research has been described in prior art documents (see patent CN101081851 or Syn.Comm., 2007, 3793) . [0004] It ha...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/10C07D487/10
Inventor 卢寿福于新民
Owner SHANGHAI AQ BIOPHARMA CO LTD
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