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Intermediate compound for preparing dextro cadotril and its preparation process and use

A kind of compound, halogenation reaction technology, applied in the field of synthetic drug dexcadotril

Active Publication Date: 2009-09-09
SHANGHAI SHYNDEC PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to solve the various problems of synthesizing D-cadotril in the prior art, the present invention was born

Method used

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  • Intermediate compound for preparing dextro cadotril and its preparation process and use
  • Intermediate compound for preparing dextro cadotril and its preparation process and use
  • Intermediate compound for preparing dextro cadotril and its preparation process and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Preparation of (S)-2-chloromethylphenylpropionyl chloride

[0042] I Halogenated with thionyl halides

[0043] Add 1.4ml (19.2mmol) thionyl chloride and 3 drops of DMF to a 25ml three-necked reaction flask, stir for 5 minutes, cool in an ice bath, add 1.0g (5.6mmol) (S)-2-benzyl-3-hydroxy Propionic acid was reacted at this temperature for 30 minutes, then raised to 60° C. for 1 hour, TLC judged that the reaction was complete, and the solution was evaporated to dryness under reduced pressure to obtain 1.0 g of a colorless oil. MS (EI): 217 (M + )

[0044] II Halogenated with phosphorus halide

[0045] Add 2.0g (11.2mmol) (S)-2-benzyl-3-hydroxypropionic acid into a 50ml three-necked reaction flask equipped with a drying tube, then add 20ml of dichloroethane and stir to dissolve, and cool in an ice bath to -10 After adding 3.5gPCl 5 , maintained the temperature for 30 minutes, then raised the temperature to 60°C for 20 minutes, TLC judged that the reaction was complet...

Embodiment 2

[0049] Preparation of (S)-2-bromomethylphenylpropionyl bromide

[0050] 1. Add 2.0g (11.2mmol) (S)-2-benzyl-3-hydroxypropionic acid into a 25ml three-necked reaction flask, add 10ml of dichloromethane and 1% pyridine, and stir to dissolve. Cool in an ice bath to -5°C, add 5.84 g (28 mmol) of thionyl bromide dropwise, maintain the temperature for 50 minutes, and evaporate the solution to dryness under reduced pressure to obtain 1.8 g of a colorless oil. MS(EI): 306(M + )

[0051] II Add 2.0g (4.5mmol) (S)-2-benzyl-3-hydroxypropionic acid to a 25ml three-necked reaction flask, add 10ml dichloroethane, and stir to dissolve. After cooling to -10°C in an ice bath, 4.5 g of boron tribromide was added, and the reaction was maintained at this temperature for 30 minutes, and the temperature was raised to 60°C for 20 minutes. TLC judged that the reaction was complete, and the solution was evaporated to dryness under reduced pressure to obtain 2.2 g of a colorless oil.

[0052] III Ad...

Embodiment 3

[0054] Preparation of N-[(2R)-2-chloromethyl-1-oxo-3-phenylpropyl]glycine benzyl ester

[0055] Add 1.9g (5.6mmol) p-toluenesulfonate of glycine benzyl ester and 60ml dichloromethane into a 100ml three-necked flask, cool in an ice bath to 0°C, add 4ml triethylamine, stir for 10 minutes, add dropwise 30ml dissolved in 1.1 g (5.1 mmol) of (S)-2-chloromethylphenylpropionyl chloride in dichloromethane. Reacted for 2 hours, TLC judged that the reaction was complete, washed twice with water, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, stirred and crystallized with 30ml of petroleum ether to obtain 1.5g of solid (yield 86.1%). mp88℃

[0056] 1 HNMR (CDCl 3 ): 7.16-7.39 (10H, m), 5.91 (1H, br), 5.17 (2H, m), 3.94-4.12 (2H, m), 3.56-3.78 (2H, m), 2.88-3.02 (2H, m ), 2.74-2.81 (1H, m)

[0057] MS (EI): 345 (M + )

[0058] [α] D 23 (c1.05, methanol) = -12.0°

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PUM

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Abstract

The invention discloses a novel intermediate compound for preparing dexcadotril with the general formula (1), wherein X represents Cl, Br, I and the like. The invention also discloses the preparation method of the intermediate compound and the application of the intermediate compound in the preparation of dexcadotril.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to an intermediate compound for preparing dexcadotril, a preparation method thereof and a method for synthesizing drug dexecadotril (dexecadotril4) with the intermediate compound. Background technique [0002] Dexecadotril (dexecadotril 4), the chemical name is N-[(2R)-2-acetylthiomethyl-1-oxo-3-phenylpropyl]glycine benzyl ester, the drug is before registration, Mainly used for the treatment of gastrointestinal disorders. [0003] [0004] Literature (synth.commun., 2001, 31 (2), 211-218) reported that dimethyl benzylmalonate was reduced by tetrahydrolithium aluminum, and then hydrolyzed by lipase to obtain a single isomer, and then chromium was used to obtain a single isomer. Reagent oxidation, thioacetic acid substitution, amidation to obtain dexcadotril: [0005] [0006] Because the reaction system has a greater impact on the activity of biological enzymes, the enzyme ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C233/47C07C231/10C07C327/52
Inventor 侯建赵惠清王国平何康永陈旭东
Owner SHANGHAI SHYNDEC PHARMA CO LTD
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