Method for enriching piperidine-2-formanilide optically active compound

A formanilide and piperidine enrichment technology, applied in the direction of organic chemistry, can solve the problems of increased production of by-products, non-compliance with energy saving and consumption reduction, time-consuming crystallization process, etc., to achieve increased yield, reduced cost, reduced by-product effects

Active Publication Date: 2011-06-15
YICHANG HUMANWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Such as the patent CN1168134A, the disadvantage of this method is that the energy consumption is high, and the temperature is generally required to be above 130°C, which does not meet the national energy saving and consumption reduction initiative, and the reaction time is long, and the same high temperature and long time reaction, the amide in formula 1 The bond faces the possibility of hydrolysis, which increases the production of by-products
[0009] Patent CN1189822A discloses an intermediate pipecoloxylidide crystallized with a chiral resolving agent to form a stable aqueous crystal system for resolution. This method is cumbersome to operate and the crystallization process is time-consuming

Method used

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  • Method for enriching piperidine-2-formanilide optically active compound
  • Method for enriching piperidine-2-formanilide optically active compound
  • Method for enriching piperidine-2-formanilide optically active compound

Examples

Experimental program
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Effect test

Embodiment 1

[0062] The racemization and resolution of embodiment 1 intermediate

[0063] In 150ml toluene, add 17gR type intermediate (ee%=100, figure 1 ), 5ml of ethyl mercaptoacetate, and 5g of azobisisobutyronitrile were added to the racemization reaction system three times every 2 hours, and refluxed at 70°C for reaction.

[0064] After reacting for 8 hours, add purified water to the reaction solution, adjust the pH value of the water layer to 4 with hydrochloric acid, extract with toluene, and separate the organic phase. The pH of the aqueous phase was adjusted to 10-11 with potassium hydroxide, extracted with toluene, the organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain 15 g of racemic product (R=50.2%, S=49.8%, figure 2 ).

[0065] 15g of racemic intermediate pipecoloxylidide, and 11g of L-(-)-dibenzoyltartaric acid (DBTA) resolving agent were dissolved in 100ml of ethanol and stirred, then 35ml of acetone was added, and the separated white solid...

Embodiment 2

[0069] Embodiment 2 Racemization and resolution of ropivacaine

[0070] In 200ml toluene, add 10g ropivacaine (ee%=100, Figure 5 ), 3.1ml ethyl mercaptoacetate and 3.1g azobisisobutyronitrile were added to the racemization reaction system three times every 2 hours, and reflux reaction at 75-85°C.

[0071] After reacting for 2 hours, add purified water to the reaction solution, adjust the pH value of the aqueous layer to 3-5 with hydrochloric acid, extract with p-xylene, and discard the organic phase. The aqueous phase was adjusted to a pH value of 9-11 with sodium hydroxide, extracted with p-xylene, and the organic layer was dried with anhydrous sodium sulfate and concentrated to obtain 8.7 g of a racemic product (ee%=0, Image 6 ).

[0072] 8.7g of racemic ropivacaine was dissolved in 45ml of n-butanol with 6.5g of L-(-)-dibenzoyltartaric acid (DBTA) resolving agent and stirred to form a salt. 19 ml of acetone was added, and the precipitated white solid was suction-filter...

Embodiment 3

[0076] Example 3 Racemization of Levobupivacaine

[0077] In 300ml toluene, add 15g levobupivacaine (ee%=100, Figure 9 ), 4.6ml of ethyl mercaptoacetate and 4.6g of azobisisobutyronitrile were added to the reaction system three times every 2h, and the reaction was refluxed at 85-95°C.

[0078] After reacting for 10 hours, add purified water to the reaction solution, adjust the pH of the aqueous layer to 4-5 with hydrochloric acid, extract with o-xylene, and discard the organic phase. The aqueous phase was adjusted to a pH of 10 to 11 with sodium hydroxide, extracted with ortho-xylene, the organic layer was dried with anhydrous sodium sulfate, and concentrated to obtain 12.3 g of racemic product (ee%=0, Figure 10 )

[0079] 12.3 g of racemic levobupivacaine, and 9.18 g of L-(-)-dibenzoyltartaric acid (DBTA) resolving agent were dissolved in 35 ml of methanol and stirred to form a salt. 15ml of acetone was added, and the precipitated white solid was suction-filtered to obta...

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Abstract

The invention relates to a method for enriching a piperidine-2-formanilide optically active compound. The method comprises the following steps of: mixing R type ropivacaine and bupivacaine or an intermediate thereof with an inert solvent, an initiating agent and mercaptan and carrying out a racemization reaction to obtain a reaction solution containing RS configuration ropivacaine, bupivacaine orthe intermediate thereof; adding acid to the reaction solution to carrying out salifying reaction, bleaching and extracting through an organic solvent, drying and dewatering an organic phase, and carrying out spinning evaporating to obtain racemized ropivacaine, bupivacaine or the intermediate solid thereof; adding the obtained solid salt to acetone to separate out DBTA (Dibenzoyl Tartaric Acid) salt which is an S type enantiomer, wherein at the moment, a large quantity of white precipitates are generated in the solution, and bleaching to obtain white solid; and dissolving the solid into alkali, and then bleaching to obtain an enriched piperidine-2-formanilide optically active compound. The method provided by the invention shortens the time and reduces the temperature of the racemization reaction, reduces pollution to environment, caused by wastes and improves the production efficiency.

Description

technical field [0001] The invention relates to a method for enriching piperidine-2-carboxanilide optically active compounds. Background technique [0002] Compound of structural formula 1 [0003] [0004] where R 2 is 2,6-dimethylphenyl, and R 1 Methyl (mepivacaine), n-propyl (ropivacaine), n-butyl (levobupivacaine) are widely used in clinical local anesthesia. When R 1 When it is H, the corresponding compounds are important intermediates for the synthesis of these local anesthetics. [0005] Biological studies have shown that the (S)-enantiomer of this type of N-alkyl-piperidine-2-carboxanilide has lower cardiotoxicity than its corresponding racemate at the same anesthetic potency, so Their (S)-enantiomers have greater potential for clinical application. There is thus a need for efficient methods of preparing single enantiomers of compounds of formula 1 . However, the yield of the single enantiomer is only 50% at most in theory when the corresponding racemate is...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/60
Inventor 严波张毅徐华斌李仕群胡雯袁瑛
Owner YICHANG HUMANWELL PHARMA
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