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Preparing method of N-Boc-4-piperidine arboxyaldehyde

A technology of piperidine formaldehyde and n-boc-4-, which is applied in the field of preparation of N-Boc-4-piperidine formaldehyde, can solve the problems of easy safety accidents, low product purity, and easy generation of impurities, so as to avoid excessive Effects of oxidation or reduction, high yield and purity, and mild reaction conditions

Active Publication Date: 2018-02-02
SHANGHAI HOBOR CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Because aluminum hydride is used in this type of method, there are disadvantages such as prone to safety accidents, polluting the environment, easily producing impurities, and the purity of the product is low.

Method used

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  • Preparing method of N-Boc-4-piperidine arboxyaldehyde
  • Preparing method of N-Boc-4-piperidine arboxyaldehyde
  • Preparing method of N-Boc-4-piperidine arboxyaldehyde

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] 1. Add 18.62g of p-toluenesulfonylhydrazide (0.10mol, 1.0eq), 19.92g of N-Boc-4-piperidone (0.10mol, 1.0eq), 100mL of methanol to a 250mL single-necked bottle with magnetic stirring, and heat to reflux After 3 hours, it was cooled to room temperature, filtered, and dried to obtain 32.78 g of p-toluenesulfonyl ketone hydrazone as a white solid, with an HPLC content of 99.0% and a yield of 89.23%.

[0031] 2. Under the protection of nitrogen, the system was cooled to -70°C with a dry ice / ethanol external bath, and 178mL of n-butyl lithium in n-hexane solution (2.5mol / L, 0.445mol, 5eq ) and 95mL tetrahydrofuran were added dropwise to a solution of 32.78g p-toluenesulfonyl ketone hydrazone (0.089mol, 1eq) dissolved in 51.71g tetramethylethylenediamine (0.445mol, 5eq) in the dropping funnel. Keep warm for 3 hours. Continue to lower the temperature to below -70°C, add 13.01g DMF (0.178mol, 2.0eq) dropwise, after dropping, keep warm for 1 hour, naturally rise to room temperat...

Embodiment 2

[0035] 1. Add 18.62g of p-toluenesulfonylhydrazide (0.10mol, 1.0eq), 19.92g of N-Boc-4-piperidone (0.10mol, 1.0eq), 100mL of ethanol to a 250mL single-necked bottle with magnetic stirring, and heat to reflux After 3 hours, it was cooled to room temperature, filtered, and dried to obtain 33.42 g of p-toluenesulfonyl ketone hydrazone as a white solid, with an HPLC content of 98.5% and a yield of 90.96%.

[0036] 2. Under the protection of nitrogen, the system was cooled to -70°C with a dry ice / ethanol external bath, and 146mL of n-butyl lithium in n-hexane (2.5mol / L, 0.364mol, 4eq ) and 65mL of tetrahydrofuran were added dropwise to a solution of 33.42g p-toluenesulfonyl ketone hydrazone (0.091mol, 1eq) dissolved in 42.28g tetramethylethylenediamine (0.364mol, 4eq) in the dropping funnel. Keep warm for 3 hours. Continue to cool down to below -70°C, add 20.60g of N-formylpiperidine (0.182mol, 2.0eq) dropwise, after dropping, keep warm for 1 hour, naturally rise to room temperatu...

Embodiment 3

[0039] 1. Add 35.38g of p-toluenesulfonylhydrazide (0.19mol, 0.95eq), 39.85g of N-Boc-4-piperidone (0.20mol, 1.0eq), 100mL of isopropanol to a 500mL single-necked bottle with magnetic stirring, Heated to reflux for 3 hours, lowered to room temperature, filtered, and dried to obtain 65.78 g of p-toluenesulfonyl ketone hydrazone as a white solid, with an HPLC content of 98.3% and a yield of 89.52%.

[0040] 2. Under the protection of nitrogen, the system was cooled to -40°C with a dry ice / ethanol external bath, and 358mL of n-butyl lithium in n-hexane (2.5mol / L, 0.896mol, 5eq ) and 80mL tetrahydrofuran, add dropwise the solution of 65.78g p-toluenesulfonyl ketone hydrazone (0.179mol, 1eq) dissolved in 104.06g tetramethylethylenediamine (0.896mol, 5eq) in the dropping funnel, after dropping, naturally rise to room temperature Keep warm for 3 hours. Continue to cool down to below -40°C, add 19.62g DMF (0.268mol, 1.5eq) dropwise, after dropping, keep warm for 1 hour, naturally ris...

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Abstract

The invention discloses a preparing method of N-Boc-4-piperidine arboxyaldehyde, and belongs to the technical field of organic chemistry. Firstly, N-Boc-4-piperidine is reacted with p-Toluenesulfonylhydrazide to generate ketone hydrazone, then butyl lithium / tetramethylethylenediamine / formylation reagent is added to be subjected to a reaction to obtain 1-Boc-4-formyl group-3,6-dihydro-2H-pyridine, and then palladium on carbon is catalyzed and hydrogenated to obtain N-Boc-4-piperidine arboxyaldehyde. The preparing method has the advantages of being easy to operate and high in yield, utilized original raw materials are cheap and easy to obtain, and the preparing method is a proper method for preparing N-Boc-4-piperidine arboxyaldehyde.

Description

Technical field: [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of N-Boc-4-piperidine formaldehyde. Background technique: [0002] N-Boc-4-piperidinecarbaldehyde, English name: N-Boc-4-piperidine arboxyaldehyde, CAS: 137076-22-3, off-white solid, can be used to synthesize and treat JAK-related diseases, KDM1A / LSD1 reversible inhibitor and other potential drug molecules. Therefore, as an important pharmaceutical and chemical intermediate, the preparation method of N-Boc-4-piperidinecarbaldehyde has been extensively studied. At present, the most commonly used methods mainly contain two kinds: [0003] 1) The first oxidation synthesis method [0004] Using N-Boc-4-piperidinemethanol as a raw material, under the action of an organic base, undergoes Swern oxidation reaction with a mixed oxidant of dimethyl sulfoxide, oxalyl chloride or DCC to obtain N-Boc-4-piperidinecarbaldehyde. [0005] The synthetic route i...

Claims

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Application Information

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IPC IPC(8): C07D211/32
CPCC07D211/32
Inventor 帅小华洪伟
Owner SHANGHAI HOBOR CHEM CO LTD
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