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Novel chiral amino acid derivative and its synthetic method and use

A technology of chiral amino acid and synthesis method, which is applied in the field of chiral amino acid derivatives, can solve the problems of high price and unsuitability for large-scale splitting, and achieve the effect of simple and effective method

Inactive Publication Date: 2005-05-18
WENZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the above method has a good resolution effect, N-benzyl cinchonidine is an expensive derivative of the alkaloid cinchonidine, which is not suitable for large-scale resolution

Method used

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  • Novel chiral amino acid derivative and its synthetic method and use
  • Novel chiral amino acid derivative and its synthetic method and use
  • Novel chiral amino acid derivative and its synthetic method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-2

[0031] Embodiment 1-2; Synthesis of L-phenylalaninol by L-phenylalanine ethyl ester

[0032] Method (1): 1000mL three-neck alkaloid is equipped with magnetic stirring, reflux condenser, constant pressure dropping funnel, and 166mmol NaBH is added to the flask 4 , 55mmol L-phenylalanine and 220ml anhydrous THF, the reaction flask was cooled to 0°C in an ice bath, and 60mmol TiCl was added within 30min 4 Slowly drop into the reaction mixture through the dropping funnel, hydrogen gas is generated, react overnight at room temperature, then reflux the reaction mixture for 3 hours until no gas is released, cool to room temperature, add 200ml of diethyl ether to dilute, and then add an appropriate amount of Stop the reaction with water, add NaOH (20%) 150mL and stir for 30min, filter, separate the organic layer, wash the filter cake with diethyl ether (3×20mL), combine the organic layers, anhydrous NaOH 2 SO 4 After drying, the solvent was evaporated under reduced pressure, and the...

Embodiment 1-4

[0035] Embodiment 1-4; By N, N-dimethyl-L-phenylalaninol synthetic trimethyl (1-hydroxyl-3-phenylpropan-2-yl) ammonium bromide

[0036] Add 10mmol of N,N-dimethyl-L-phenylalaninol, 15mmol of methyl bromide and 100mL of acetonitrile into a 250mL three-neck flask equipped with a stirring and reflux device, and stir for 6h in an ice-water bath. Atmospheric distillation recovers acetonitrile and excess methyl bromide. Remove the remaining small amount of acetonitrile and methyl bromide under reduced pressure at 100°C to obtain a light yellow solid, then add 50 mL of absolute ethanol to reflux for 0.5 h, and cool to crystallize. Filter and remove the remaining anhydrous ethanol from the product under reduced pressure at 50°C to obtain the product. The product is white crystal, and the yield is 95%. m.p.196~198℃; [α] D 20 =+4.40(c0.5, CH 3 OH); 1 H NMR (300MHz, D 2 O)δ: 2.86(dd, J=8.5, 13.4Hz, 1H, 3-H), 3.02(dd, J=5.3, 13.4Hz, 1H, 3-H), 3.20(s, 9H, N(CH 3 ) 3 ), 3.25~3.33(m...

Embodiment 2

[0037] Embodiment 2; Synthetic trimethyl (1-hydroxy propan-2-base) ammonium bromide by L-alanine synthesis

[0038] Trimethyl(1-hydroxypropan-2-yl)ammonium bromide can be prepared from L-alanine in the same manner as above. Yield 72%. m.p.127~129℃; [α] D 20 =-4.6(c0.5, CH 3 OH); 1 H NMR (300MHz, D 2 O)δ: 1.36~1.44(m, 3H, 3-H), 3.07(s, 9H, N(CH 3 ) 3 ), 3.82(dd, J=7.4, -10.4Hz, 1H, 1-H), 4.00(dd, J=4.0, -10.4Hz, 1H, 1-H), 4.02~4.14(m, 1H, 2- H),; IR (KBr) υ: 3292, 2966, 2920, 2893, 1668, 1596, 1458, 1378, 1311, 1263, 1218, 1147, 1066, 989, 984, 834, 798, 624, 619cm -1 . Anal.calcd for C 6 h 16 ONBr: C 36.38, H 8.14, N 7.07; found C 36.35, H 8.12, N 7.10.

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Abstract

The present invention relates to one chiral amino acid derivative. L-amino acid as initial material is processed through four steps of esterification, carboxyl reduction, amino methylation and forming salt with bromomethane to synthesize the R-configuration chiral amino acid derivative. The derivative is used as novel chiral inclusion resolving agent and may be used in the resolving inclusion of ketoprofen as one non-steroid antiphlogistic medicine.

Description

technical field [0001] The invention relates to a chiral amino acid derivative, which is synthesized from L- or D-amino acid as the initial raw material through four steps of esterification, carboxyl reduction, amino methylation, and methyl bromide salt formation. The derivative The substance is a new type of chiral inclusion resolving agent, which can be used for the inclusion and resolution of non-steroidal anti-inflammatory drugs such as ketoprofen. Background technique [0002] Ketoprofen is an alpha-aryl propionate NSAID with the chemical name 3-benzoyl-alpha-methylphenylacetic acid. What is sold on the market now is its racemate (wherein S-(+) ketoprofen and R-(-) ketoprofen each account for 50%). Clinically, it is mainly used for the treatment of chronic rheumatoid arthritis, trauma and postoperative pain. Racemic ketoprofen is potentially toxic to the gastrointestinal tract, liver, and kidney, and causes leukopenia. The drug structure-activity relationship shows t...

Claims

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Application Information

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IPC IPC(8): C07C51/00C07C59/84C07C213/00C07C213/06C07C215/08
Inventor 陈帆
Owner WENZHOU UNIVERSITY
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