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Synthetic method of 6,6-dialkylpiperidine-2-carboxylic acid compound

A synthetic method and compound technology, applied in the direction of organic chemistry, etc., to achieve the effect of avoiding by-products, less reaction by-products, and high economic benefits

Active Publication Date: 2022-06-24
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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  • Synthetic method of 6,6-dialkylpiperidine-2-carboxylic acid compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0031] 2-(Acetylamino)-6-methyl-5-heptanoic acid ethyl ester (10g, 44mmol, 1eq) was added to 100ml of trifluoroacetic acid, and the reaction was carried out at 50°C for 2 hours until TLC detection Reached the reaction end point, cooled to room temperature, added to ice water, adjusted the pH to 8-9 with sodium bicarbonate, extracted twice with 600 mL of ethyl acetate, combined the organic phases and backwashed with saturated brine, added anhydrous sodium sulfate to dry, It was distilled under reduced pressure and eluted by column chromatography. The eluent used in the 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- Dimethylpiperidine-2-carboxylate, 81.00% yield, 98% purity, 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...

Embodiment 2

[0038]Step (1) in Example 2 to Example 3 was carried out with an acid solution different from that in Example 1. In Example 2, glacial acetic acid was used for the reaction. Compared with Example 1, the yield decreased and was 70.00%. Especially, using hydrochloric acid to carry out the reaction in Example 3, not only the reaction rate is obviously slow, and more by-products are generated during the heating process, so that the reaction yield is significantly lower than that of Example 1, only 23.01%.

Embodiment 4

[0039] Step (1) in Example 4 to Example 5 adopts a reaction temperature different from that in Example 1. Compared with Example 1, Example 4 lowers the reaction temperature to 25°C, the reaction rate is significantly reduced, and the reaction yield within the same reaction time is reduced to only 9.30%; Example 5 raises the reaction temperature to 70°C, which promotes The occurrence of side reactions reduces the reaction yield to 75.00% compared to Example 1.

[0040] Step (2) in Example 6 to Example 7 adopts the sodium hydroxide of different dosage from Example 1 to react, and relative to Example 1, Example 6 and Example 7 reduce sodium hydroxide relative to Example 1 respectively. amount to 3 equivalents of ethyl 1-acetyl-6,6-dimethylpiperidine-2-carboxylate and 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, which are 72.70% and 80.00%, respectivel...

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Abstract

The embodiment of the present invention provides a new synthesis method of 6,6-dialkylpiperidine-2-carboxylic acid compound, using compound I, trifluoroacetic acid, sodium hydroxide, etc. as raw materials, and obtaining the target product through two-step reaction 6,6-dialkylpiperidine-2-carboxylic acid, the synthesis method of the embodiment of the present invention has the advantages of simple operation, mild reaction conditions, high yield, environmental friendliness, low production cost, etc., and is suitable for industrial scale production.

Description

technical field [0001] The embodiments of the invention belong to the field of chemical industry, and particularly relate to a method for synthesizing a 6,6-dialkylpiperidine-2-carboxylic acid compound. Background technique [0002] Selective N-type voltage-activated calcium channel (VACC) blockers have shown efficacy in several stroke and pain models, and in the search for small molecules as N-type calcium channel blockers, a series of N, N-dialkylpeptide amines 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-dialkylpeptide amines body. However, there is no relevant prior art about the preparation method of 6,6-dialkylpiperidine-2-carboxylic acid compounds, 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 -The synthesis technology of methylpipe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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