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Levocetirizine preparation method and levocetirizine dihydrochloride preparation method

A technology of levocetirizine and levocetirizine, applied in the field of medicine and chemical industry, can solve the problems of environmental pollution, few reaction steps, expensive Pt/C catalyst, etc., and achieve the effect of high optical purity

Active Publication Date: 2013-10-16
HAISO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0039] The method has few reaction steps, the raw materials are easy to obtain, and the yield is about 60%. The disadvantage is that the Jones reagent (chromium trioxide and sulfuric acid) will cause environmental pollution, and the Pt / C catalyst is expensive.

Method used

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  • Levocetirizine preparation method and levocetirizine dihydrochloride preparation method
  • Levocetirizine preparation method and levocetirizine dihydrochloride preparation method
  • Levocetirizine preparation method and levocetirizine dihydrochloride preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Synthesis of Levo-Hydroxyzine Dihydrochloride

[0066]

[0067] Add 2.9g (0.01mol) (R)-4-chlorobenzhydrylpiperazine to 100mL three-necked flask and dissolve in 10ml ethyl acetate, then add 3.0g K 2 CO 3 And 0.05g tetrabutylammonium bromide, stir well. Dissolve 2.0g (0.016mol) of monochlorodiethylene glycol in 10mL of water and add dropwise to the above reaction system. After the dropwise addition, raise the temperature to 80°C and reflux for 5h, track with TLC to determine the end point of the reaction (developer: methanol / chloroform =1:5 (v / v)), after the reaction is completed, cool to room temperature, transfer the reaction solution into a separatory funnel, separate the water layer, add toluene for extraction (10mL×2), and initially separate the extracted organic layer from the reaction solution to obtain The organic layers were combined, ethyl acetate was distilled off, and then toluene was added until completely dissolved, then washed with water (6×2mL) and wa...

Embodiment 2

[0075] Add 0.01mol L-hydroxyzine to a 100ml reactor, add 50ml of a mixed solvent of 1.4-dioxane and distilled water (1:1, v / v) and stir to form a homogeneous phase, then add 2ml of 2mol / L NaOH solution to adjust the pH =12.5, finally add 0.75g catalyst to feed oxygen, heat to reflux, and in the reflux reaction process, the pH of the system is maintained at 12.5 by dripping 2mol / L of NaOH, TLC monitors the reaction until the left-handedness disappears completely, stops the reaction, and takes a sample to neutralize To pH~8, carry out HPLC analysis, the result is as follows:

[0076] Reaction ID catalyst Conversion rate 1 % selectivity% Chromatographic yield 2 % 1 5%Pd / C 95.1 95.3 91 2 1O%Pd / C 98.5 97.7 96.2 3 5%Pd / C-1%Pb / C 94.5 896 84.7 4 5%pd / C-3%Co / C 97.7 95.4 93.2 5 5%Pd / C-1%Bi / C 98.9 98.7 97.6

[0077] 1 Conversion %, based on consumption of raw material L-hydroxyzine

[0078] 2 Chromatographic yield %,...

Embodiment 3

[0080] In order to confirm the process stability, under the reaction conditions described in Example 2, the experiment was repeated three times with the catalyst numbered 5, and the chromatographic yields of the three times were respectively: 97.2%, 96.8%, and 97.6%.

[0081] The results show that the process has good stability and stable yield, and the average chromatographic yield is 97.2%.

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Abstract

The invention relates to a levocetirizine preparation method and a levocetirizine dihydrochloride preparation method. Levocetirizine is prepared through a synthesis route shown in the specification, and levocetirizine dihydrochloride is prepared through hydrochlorinating the prepared levocetirizine to form a salt, and recrystallizing the salt. The preparation method which adopts cheap and easily available Pd-M / C to realize the catalytic oxidation of L-hydroxyzine as a catalyst in order to prepare levocetirizine realizes the high conversion rate of the substrate L-hydroxyzine and the high selectivity and high optical purity of the target product levocetirizine, and is an environmentally-friendly technology.

Description

technical field [0001] The invention relates to a levocetirizine (common name levocetirizine, chemical name: (R)-(-)-[2-[4-(p-chlorophenylbenzyl)-1-piperazinyl]ethoxy ] Acetic acid) and the preparation method of dihydrochloride thereof belong to the technical field of medicine and chemical industry. Background technique [0002] Levocetirizine dihydrochloride, chemical name: (-)-[2-[4-(R)-4-chlorophenyl-benzyl-1-piperazinyl]ethoxy]acetic acid di-salt acid salt, CAS registration number: 130018-87-0; English common name levocetirizine dihydrochloride. Levocetirizine dihydrochloride has the following structural formula: [0003] [0004] Levocetirizine dihydrochloride is the third generation H 1 Receptor antagonist, first listed in Germany in February 2001, trade name Xyzal, cetirizine hydrochloride (levocetirizine dihydrochloride) is cetirizine hydrochloride (cetirizine dihydrochloride) )’s R-type optical isomer, which overcomes the mid-polar neurological side effects c...

Claims

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Application Information

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IPC IPC(8): C07D295/088
Inventor 喻宗沅李翔刘小成徐小军尤庆亮易小莉赵蒙蒙邓嘉伦余丹
Owner HAISO TECH
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