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Synthesis method of 6,6-dialkyl piperidine-2-carboxylic acid compound

A synthetic method and compound technology, applied in organic chemistry and other fields

Active Publication Date: 2021-09-14
上海毕得医药科技股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no relevant prior art regarding the preparation of 6,6-dialkylpiperidine-2-carboxylic acid compounds, and some similar compounds such as 1,2,3,4-tetrahydro-1,1- Dimethyl-3-isoquinolinecarboxylic acid, ethyl 6,6-dimethyl-3-oxo-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate, 6 -Synthetic technology of methylpiperidine-2-carboxylic acid, etc., which is completely different from 6,6-dialkylpiperidine-2-carboxylic acid in terms of synthesis mechanism

Method used

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  • Synthesis method of 6,6-dialkyl piperidine-2-carboxylic acid compound
  • Synthesis method of 6,6-dialkyl piperidine-2-carboxylic acid compound
  • Synthesis method of 6,6-dialkyl piperidine-2-carboxylic acid compound

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Experimental program
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Effect test

Embodiment 1

[0030] The first step: the synthesis of the compound 1-acetyl-6,6-dimethylpiperidine-2-carboxylic acid ethyl ester

[0031] Add 2-(acetylamino)-6-methyl-5-heptanoic acid ethyl ester (10g, 44mmol, 1eq) into 100ml of trifluoroacetic acid, react at 50°C for 2 hours until detected by TLC Reach the end of the reaction, cool to room temperature, add to ice water, adjust the pH to 8-9 with sodium bicarbonate, extract twice with 600mL ethyl acetate, combine the organic phases and backwash with saturated brine, add anhydrous sodium sulfate to dry, Distilled under reduced pressure and eluted by column chromatography. The eluent used in column chromatography was a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 5:1 to obtain 8.1 g of compound 1-acetyl-6,6- Ethyl dimethylpiperidine-2-carboxylate, the yield is 81.00%, the purity is 98%, 1 HNMR (500MHz, CDCl 3 )δ4.66(t, J=8.0Hz, 1H, NCH), 4.14(q, J=6.0Hz, 2H, CH 2 CH 3 ), 2.22 (ddd, J=18.2Hz, 7.9Hz, 5.6Hz, 1H, ...

Embodiment 2

[0038]Step (1) in embodiment 2 to embodiment 3 adopts the acid solution different from embodiment 1 to carry out reaction, and embodiment 2 adopts glacial acetic acid to carry out reaction, with respect to embodiment 1, yield decreases to some extent, is 70.00%. In particular, in Example 3, hydrochloric acid is used for the reaction, not only the reaction rate is obviously slow, but also more by-products are generated during the heating process, which makes the reaction yield significantly lower than that of Example 1, only 23.01%.

Embodiment 4

[0039] Step (1) in embodiment 4 to embodiment 5 adopts the reaction temperature different from embodiment 1. With respect to embodiment 1, embodiment 4 reduces reaction temperature to 25 ℃, and reaction rate obviously reduces, and the reaction yield in the same reaction time reduces to some extent, only 9.30%; embodiment 5 raises reaction temperature to 70 ℃, has promoted The occurrence of side reactions reduces the reaction yield to 75.00% compared to Example 1.

[0040] Step (2) in embodiment 6 to embodiment 7 adopts the sodium hydroxide of different consumption with embodiment 1 to react, with respect to embodiment 1, embodiment 6 and embodiment 7 reduce sodium hydroxide with respect to embodiment 1 respectively to 3 equivalents of ethyl 1-acetyl-6,6-dimethylpiperidine-2-carboxylate and to increase the amount of sodium hydroxide to 1-acetyl-6,6-dimethylpiperidine- 5 equivalents of ethyl 2-carboxylate, the reaction yield is slightly lower than that of Example 1, being 72.70...

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Abstract

The embodiment of the invention provides a brand-new synthesis method of the 6,6-dialkyl piperidine-2-carboxylic acid compound; a compound I, trifluoroacetic acid, sodium hydroxide and the like are used as raw materials, and the target product 6,6-dialkyl piperidine-2-carboxylic acid is obtained through two-step reaction. The synthesis method provided by the embodiment of the invention has the advantages of simple operation, mild reaction conditions, high yield, environmental friendliness, low production cost and the like, and is suitable for industrial large-scale production.

Description

technical field [0001] The embodiment of the present invention belongs to the field of chemical industry, and particularly relates to a synthesis method of 6,6-dialkylpiperidine-2-carboxylic acid compound. Background technique [0002] Selective N-type voltage-activated calcium channel (VACC) blockers have shown efficacy in several models of stroke and pain, and in the search for small molecules as N-type calcium channel blockers, a series of N, N-dialkylpeptideamines have strong functional activity on N-type VACC, and 6,6-dialkylpiperidine-2-carboxylic acid compounds are important intermediates for the synthesis of N,N-dialkylpeptideamines body. However, there is no relevant prior art regarding the preparation of 6,6-dialkylpiperidine-2-carboxylic acid compounds, and some similar compounds such as 1,2,3,4-tetrahydro-1,1- Dimethyl-3-isoquinolinecarboxylic acid, ethyl 6,6-dimethyl-3-oxo-1-(2,2,2-trifluoroacetyl)piperidine-2-carboxylate, 6 Synthetic techniques for -methylpi...

Claims

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Application Information

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IPC IPC(8): C07D211/60
CPCC07D211/60
Inventor 王治国余国春郦荣浩罗春艳
Owner 上海毕得医药科技股份有限公司
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