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Cinchona alkaloid quaternary ammonium salt derivatives as well as preparation method and application thereof

A technology of cinchona alkaloids and quaternary ammonium salts, applied in the direction of cyanide reaction preparation, organic compound preparation, chemical instruments and methods, etc., can solve the problem of narrow substrate range, low catalytic activity of catalyst, and little effect of asymmetric induction Ideal and other problems, to achieve a wide range of substrates, high catalytic efficiency, and good asymmetric induction effect

Inactive Publication Date: 2009-09-16
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0004] In 2006, the inventor first reported the asymmetric phase-transfer alkylation reaction catalyzed by the methylbenzimidazolium salt of cinchona alkaloids in "Organic Chemistry" (2006, 7, 1008-1011). The amino acid precursor of optical purity can be obtained, but the catalyst has low catalytic activity (the catalytic reaction yield is only 70-85%), and the substrate range is narrow (such as for the alkylating reagent t-BuO 2 CCH 2 The effect of Br asymmetric induction is not ideal, only reaching 60% ee) and other deficiencies

Method used

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  • Cinchona alkaloid quaternary ammonium salt derivatives as well as preparation method and application thereof
  • Cinchona alkaloid quaternary ammonium salt derivatives as well as preparation method and application thereof
  • Cinchona alkaloid quaternary ammonium salt derivatives as well as preparation method and application thereof

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Effect test

Embodiment 1

[0027] Embodiment 1 The synthesis of chiral cinchona alkaloid quaternary ammonium salt catalyst L1 (R 1 = H, R 2 =PhCH 2 , X=Cl, n=1)

[0028] Under nitrogen protection, cinchonidine (10mmoL) was added to benzyl bromide (18mmol) and potassium hydroxide (18.8mmol) with a concentration of 50% by mass. Stir vigorously at room temperature for 4h, during which all solids dissolve. Add 30 mL of water for dilution, separate the layers, extract the aqueous layer with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, recover the solvent under reduced pressure, and recrystallize the residue with methanol-ether to obtain a light red solid.

[0029] Suspend the above substance in 40mL of toluene, add 1-chloromethylbenzotriazole (10.5mmoL), slowly heat, and reflux for 2h (CH 2 Cl 2 / MeOH as the eluent, TLC to detect the end point of the reaction), cooled to room temperature, precipitated solid, placed overnight in the refrigerator, filtered, the o...

Embodiment 2

[0030] Embodiment 2 The synthesis of chiral cinchona alkaloid quaternary ammonium salt catalyst L2 (R 1 =OCH 3 , R 2 =CH 2 =CHCH 2 , X=Cl, n=1)

[0031] Under nitrogen, quinine (10 mmol) was added to allyl bromide (18 mmol) and 50% potassium hydroxide (18.8 mmol). Stir vigorously at room temperature for 4h, during which all solids dissolve. Add 30 mL of water for dilution, separate the layers, extract the aqueous layer with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, recover the solvent under reduced pressure, and recrystallize the residue with methanol-ether to obtain a light red solid.

[0032] Suspend the above substance in 40mL of toluene, add 1-chloromethylbenzotriazole (10.5mmoL), slowly heat, and reflux for 2h (CH 2 Cl 2 / MeOH as the eluent, TLC to detect the end point of the reaction), cooled to room temperature, precipitated solid, placed overnight in the refrigerator, filtered, the obtained crude product was washed w...

Embodiment 3

[0033] Embodiment 3 The synthesis of chiral cinchona alkaloid quaternary ammonium salt catalyst L3 (R 1 =OH, R 2 =C 6 h 9 CH 2 , X=Br, n=2)

[0034] Under nitrogen, hydroxyquinidine (10 mmol) was added to chloromethylcyclohexene (18 mmol) and 50% potassium hydroxide (18.8 mmol). Stir vigorously at room temperature for 4h, during which all solids dissolve. Add 30 mL of water for dilution, separate the layers, extract the aqueous layer with dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, recover the solvent under reduced pressure, and recrystallize the residue with methanol-ether to obtain a light red solid.

[0035] Suspend the above substance in 40mL toluene, add chloroethyl benzotriazole (10.5mmoL), slowly heat, and reflux for 2h (CH 2 Cl 2 / MeOH as the eluent, TLC to detect the end point of the reaction), cooled to room temperature, precipitated solid, placed overnight in the refrigerator, filtered, the obtained crude product wa...

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Abstract

The invention relates to cinchona alkaloid quaternary ammonium salt derivatives and a synthesis method thereof as well as application of the derivatives in synthetizing high optical purity natural amino acid and non-natural amino acid. A structural general formula (I) represents a chiral cinchona alkaloid quaternary ammonium salt, wherein R1 is methoxyl, hydroxyl, hydrosulfuryl or hydrogen; R2 is alkyl with 3 to 20 carbon atoms; X is halogen; and n is a positive integer from 1 to 4. The cinchona alkaloid quaternary ammonium salt catalyst has high activity in an alkylation reaction, good stereoselectivity, high catalysis efficiency, a wide substrate range and good asymmetric induction.

Description

technical field [0001] The invention relates to cinchona alkaloid quaternary ammonium salt derivatives, a synthesis method thereof and an application in synthesizing natural amino acids and unnatural amino acids with high optical purity. Background technique [0002] Amino acids are important raw materials or intermediates for the synthesis of peptides, drugs, pesticides and food additives. Among the top 500 medicines listed in terms of sales volume, 60% of them are synthesized from amino acids as raw materials and intermediates. Natural amino acids are all L-type, and some amino acids can be obtained by hydrolyzing natural proteins, but their variety and quantity are far from meeting people's needs. There are few D-amino acids with important uses in natural products, but they have very important applications in drug synthesis. For example, the esters of D-phenylglycine and D-hydroxyphenylglycine are the main intermediates in the semi-synthesis of penicillins and cephalosp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/04B01J31/02C07C227/32C07C229/36
Inventor 张生勇何炜刘鹏王全军石鑫韦玉
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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