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Preparation method of piperidine spiro derivative

A technology of derivatives and spiro rings, applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as inappropriateness

Inactive Publication Date: 2020-04-21
CHEMVON BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, there is no public report on the effective synthesis of the methyl-substituted piperidine spirocyclic fragment BB-1 or 2. During the development of the previous route, the applicant found that: in the structures BB-1 and BB-2, the monomethyl or geminal The presence of dimethyl makes the preparation of Segment1 or 2 unsuitable

Method used

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  • Preparation method of piperidine spiro derivative
  • Preparation method of piperidine spiro derivative
  • Preparation method of piperidine spiro derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033]

[0034] Step 1: In a 10L three-necked flask equipped with mechanical stirring, add 189g of N-benzyl-4-piperidone 1a [1.0mol], 71.5g of activated zinc powder [1.1mol] and 2.0L of anhydrous tetrahydrofuran in sequence. Under protection, turn on mechanical stirring. Then the temperature was raised to 70-80°C, and 2.0g of ethyl bromide 1,1-dimethylcarboxylate 2 was added dropwise. After stirring and initiation (about 5 minutes), 210g [1.1mol] of bromide was added dropwise to the reaction system. A mixture of ethyl 1,1-dimethylcarboxylate 2 dissolved in 500 mL of anhydrous tetrahydrofuran. The rate of addition was such that the temperature of the system did not exceed 80°C. After the addition was complete, the reaction was continued for 2 hours while the temperature was maintained. TLC detected that the raw materials disappeared, and the reaction was stopped. After cooling to room temperature, the above reactants were separated into layers, the aqueous phase was extract...

Embodiment 2

[0039]

[0040] Step 1: In a 10L three-necked flask equipped with a mechanical stirrer, add 175g [1.0mol] N-benzyl-3-pyrrolone 1b, 71.5g activated zinc powder [1.1mol] and 2.0L anhydrous tetrahydrofuran, under nitrogen protection , turn on the mechanical stirring. Then the temperature was raised to 70-80°C, 2.0g of 2a was added dropwise, and after the reaction was initiated with stirring, a mixture of 210g of ethyl bromocarboxylate 2a [1.1mol] dissolved in 500mL of anhydrous tetrahydrofuran was continued to be added dropwise to the reaction system. It is advisable to control the temperature of the system not to exceed 80°C for the rate of addition, and continue stirring for 2 hours after addition. TLC detects that the starting material disappears, and the reaction is stopped. After the post-treatment in Example 1, 251 g of light yellow oily liquid 3b was obtained, M / z=292 [M+1], and the yield was 86.2%.

[0041]Step 2: In a 5.0L three-necked flask equipped with a mechanic...

Embodiment 3

[0045]

[0046] Step 1: In a 10.0L three-necked flask equipped with mechanical stirring, add 203g of N-benzyl-4-homopiperidone 1c [1.0mol], 71.5g of activated zinc powder [1.1mol] and 2.0L of anhydrous 2-formazol Based tetrahydrofuran, under the protection of nitrogen, start the mechanical stirring. Then the temperature was raised to 70-80°C, 2.0g of ethyl bromocarboxylate 2a was added dropwise, and after stirring (about 10 minutes), 200g of ethyl bromocarboxylate 2a [1.1mol] dissolved in 500mL of anhydrous 2-methyltetrahydrofuran mixed solution. During the dropwise addition process, the temperature of the system should not exceed 80°C. After the addition, the reaction was continued for 2 hours, and the reaction was stopped after TLC detected that the raw materials disappeared. After cooling to room temperature, the layers were separated, the aqueous phase was extracted with 3.0L ethyl acetate, and the organic phases were combined. Wash with saturated brine and concentrat...

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Abstract

The invention discloses a preparation method of a piperidine spiro derivative, and belongs to the field of synthesis of medical intermediates. The method comprises the following steps: 1, enabling N-benzyl substituted cyclic ketone 1 to react with bromo-carboxylic ester 2 in the presence of zinc powder to obtain an addition product 3, reducing with sodium bis(2-methoxyethoxy)aluminiumhydride to obtain a diol product 4, performing cyclization in the presence of a leaving reagent to obtain bicyclo-spirooxetane 5, and finally performing palladium-carbon catalytic hydrogenation debenzylation to obtain a BB piperidine spiro compound. The synthesis route is simple, the total synthesis yield is high, the method is suitable for various different rings, a series of compounds are obtained, and a newdiversified structural fragment is provided for new drug development.

Description

technical field [0001] The invention relates to the preparation of pharmaceutical chemical intermediates, in particular to a method for preparing piperidine spiro derivatives, and belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] Piperidine is one of the components normally present in the mammalian brain. It affects the mechanism of action of synapses in the central nervous system, as well as the mechanism of action of regulating emotional behavior and extrapyramidal system function neurons. In addition to the above-mentioned central activities of piperidine and its derivatives, there are also many natural products containing piperidine ring structures in nature, which themselves show various biological activities. [0003] Typical natural product structures are as follows: [0004] [0005] The piperidine ring is a ubiquitous structural unit in pharmaceutical intermediates, and its synthetic analogs also have a wide range o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107
CPCC07D491/107
Inventor 叶太金吴伟锋匡正霞黄焱伟王东王猛王方道
Owner CHEMVON BIOTECH CO LTD
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