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New method for synthesis of substituted furo-piperidine derivatives

A technology of substituents and compounds, applied in the field of preparation of substituted furopiperidine derivatives, can solve the problems of 3-furfural expensive, high production cost, cumbersome operation, etc.

Active Publication Date: 2013-10-30
JIANGSU SIMCERE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The raw material 3-furfural used in Scheme-1 is expensive, and the production cost is high, and in the preparation process, multi-step column purification is required, and the operation is cumbersome

Method used

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  • New method for synthesis of substituted furo-piperidine derivatives
  • New method for synthesis of substituted furo-piperidine derivatives
  • New method for synthesis of substituted furo-piperidine derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Step 1: 2-Nitrovinylfuran

[0035]

[0036] Method one: under the condition of -20°C, add furfural (230g), nitromethane (232g) and methanol (800mL) to the reaction flask, mechanically stir, add dropwise methanol (900mL) solution of sodium hydroxide (100g), keep The internal temperature of the reaction system was not higher than -5°C. After the dropwise addition was completed, the reaction was continued at -5°C for 30 minutes. Stop the reaction, add concentrated sulfuric acid (150mL) in methanol (300mL) solution and water (3.6L) to the above system successively, the product is precipitated as a yellow solid, suction filtered and dried to obtain a yellow powdery solid (165g, 49.5%)

[0037] Method two: under the condition of -20°C, add furfural (230g), nitromethane (232g) and methanol (800mL) to the reaction flask, mechanically stir, add dropwise a solution of sodium hydroxide (100g) in water (900mL), keep The internal temperature of the reaction system was not higher...

Embodiment 2

[0061] Example 2 Preparation of 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinoanilino)- 6-Methyl)pyrimidinyl-furo[3,2-c]piperidine

[0062] The first step 1-benzyl-4-tributyltin-furo[3,2-c]piperidine

[0063] Under nitrogen protection, 1-benzyl-furo[3,2-c]piperidine (11.2 mg, 1 eq) and dry tetrahydrofuran (150 μL) were added to the reaction flask, and n-butyllithium (16.05 μL, 1eq), continue to add tributyltin chloride (20.8mg, 1.6eq) dropwise, after the addition is complete, continue to react for 2.5 hours. The reaction was stopped, quenched with water, extracted with ethyl acetate (10mL*5), combined the organic phases, dried over anhydrous sodium sulfate, filtered with suction, concentrated, and the crude product was chromatographed on silica gel to obtain 1-benzyl-4-tributyltin-furano [3,2-c]piperidine (19.25mg).

[0064] The second step 1-benzyl-4-(3-chloro-6-methyl)pyrimidinyl-furo[3,2-c]piperidine

[0065] Add 1-benzyl-4-tributyltin-furo[3,2-c]piperidine (3.2 mg, 1 eq),...

Embodiment 3

[0073] Example 3 Compound 1-cyanoacyl-4-(3-(3,5-difluoro-4-morpholinoanilino)-6-methyl)pyrimidinyl-furo[3,2-c]piper In vitro biochemical level inhibition of JAK kinase (PK) activity experiment

[0074] In the biochemical level enzyme activity test, HTRF technology is used to detect the activity of tyrosine kinase. HTRF is a time-resolved fluorescence resonance capacity transfer technology. HTRF (Homogeneous Time-Resolved Fluorescence) is the most commonly used method for detecting analytes in homogeneous systems. This technique combines fluorescence resonance energy transfer (FRET) and time-resolved technology (TR), and has been widely used. Applied to different stages of drug development based on cell experiments and biochemical experiments. According to the measurement principle of HTRF method, after incubating the pure enzyme JAK2 with biotinylated substrate and ATP, add avidin-labeled XL-665 and Eu-labeled antibody that recognizes phosphorylation of the substrate. After ...

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Abstract

The invention discloses a new method for synthesis of substituted furo-piperidine derivatives. The substituted furo-piperidine derivatives are synthesized based on furfural compound raw material which is cheap and easy to get and after a series of simple and practicable unit operations of condensation, reduction, Pictet-spengler reaction and the like.

Description

Technical field: [0001] The invention relates to the field of organic synthesis of medicine, pesticide and dye, and mainly relates to a new method for preparing substituted furopiperidine derivatives from cheap and easy-to-obtain furfural raw materials. Background technique: [0002] The current method for preparing substituted furopiperidine derivatives is usually as follows: [0003] [0004] Process-1 [0005] The raw material 3-furfural used in Scheme-1 is expensive, and the production cost is high, and in the preparation process, multi-step column purification is required, and the operation is cumbersome. [0006] Therefore, it is necessary to choose a new cheap and easy method to purify the product. Invention content: [0007] The invention uses cheap and easy-to-obtain furfural as a starting material, and synthesizes substituted furopiperidine derivatives through a series of simple and feasible unit operations such as condensation, reduction, Pictet-spengler re...

Claims

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Application Information

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IPC IPC(8): C07D491/048
Inventor 骆宏鹏刘飞陈盼赵鑫鑫朱新荣桂力王亚洲
Owner JIANGSU SIMCERE PHARMA
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