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Synthesis method for levorotatory citirizine dihydrochloride

A levocetirizine and synthetic method technology, applied in the direction of organic chemistry, etc., can solve the problems of harsh reaction conditions, expensive reagents, poor stereoselectivity, etc., and achieve the effect of simple synthesis process, good optical purity, and easy availability of raw materials

Inactive Publication Date: 2010-01-27
HEBEI NORMAL UNIV
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

In 1994, UCB applied for a synthesis process (European Patent EP0617028) and mentioned the synthesis of chiral mono-p-chlorobenzhydrylamine intermediates, but there was no chiral mono-p-chlorobenzhydrylamine preparation method, and the process used Many raw materials are difficult to obtain, and industrial production is difficult
D.A.Pflum, et.al. reported a kind of asymmetric synthetic method of levocetirizine in Tetrhedron Lett.43 (6), 923-926, 2002, but the stereoselectivity of this method is poor, and reaction condition is harsh , the reagents used are very expensive and not suitable for industrial production
U.S. Patent No. 5,698,558 discloses a patent application about levocetirizine preparations, but the synthesis method of levocetirizine is not mentioned in the article

Method used

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  • Synthesis method for levorotatory citirizine dihydrochloride
  • Synthesis method for levorotatory citirizine dihydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0022] The synthesis of embodiment 1 mixed-rotating mono-p-chlorobenzhydrylamine

[0023] In a 3-liter reaction bottle, add 2 liters of formamide and 500 grams of mono-p-chlorobenzophenone, heat to 170-180°C, and react for 17-24 hours. After the reaction of mono-p-chlorobenzophenone is completed, After cooling, add it to 5 liters of water to form a yellow-white solid. After cooling for 4 to 5 hours, filter, wash with water, and directly hydrolyze without drying. Add the above solid to 900 ml of concentrated hydrochloric acid, add 440 ml of water, heat and reflux for 2 hours, place in the refrigerator to cool for 7 to 10 hours, filter and wash with water, decolorize the solid wet material with 5 liters of water, 30 to 50 grams of activated carbon, and recrystallize . After cooling for 7 to 10 hours, filter and dry 450 grams of diphenylmethylamine hydrochloride.

Embodiment 2

[0024] Embodiment 2 Preparation of L-mono-p-chlorobenzhydrylamine

[0025] Mix 340 grams of mono-p-chlorobenzhydrylamine hydrochloride into a mixed solvent of 2000 milliliters of methanol and 1000 milliliters of water, add 54 grams of NaOH, then add 250 grams of L-o-chloromandelic acid, and heat to dissolve

[0026] After stirring and crystallizing at room temperature, 250 grams of o-chloromandelate solid of L-mono-p-chlorobenzhydrylamine was obtained. The pH was adjusted to alkaline with NaOH solution, and then extracted three times with 2000 ml of ethyl acetate. The ethyl acetate was evaporated to dryness to obtain 120 g of L-mono-p-chlorobenzhydrylamine.

Embodiment 3

[0027] Example 3 Synthesis of L-1-N-mono-p-chlorobenzhydryl-4-N-p-toluenesulfonylpiperazine

[0028] 120 grams of L-mono-p-chlorobenzhydrylamine, dissolved in 1200 milliliters of xylene, added 152 grams of N, N-dimethylsulfonate ethyl p-benzenesulfonamide, Na 2 CO 3 117.2 g, stirred and refluxed for 24 hours, separated the xylene organic phase, evaporated to dryness, added 200 ml of methanol, cooled and crystallized for 4 to 5 hours, filtered to obtain L-1-N-mono-p-chlorobenzhydryl-4 -N-p-toluenesulfonylpiperazine 90 g.

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Abstract

Synthesis of levo-citilitrin chloride is carried out by taking mono-p-chlorophenacyl ketone as raw material, synthesizing mixed active mono-p-chlorobenzhydrylamine, resoluting to obtain levo-mono-p-chlorobenzhydrylamine by levo-o-chloromandelic acid, synthesizing levo-1-N-mono-p-chlorodiphenyl-methyl-4-N-toluene-p-sulfonyl-piperazine, removing protection to obtain levo-N-mono-p-chlorodiphenyl-methyl-piperazine, reacting with ethylene chlohydrin to synthesize levo-1-N-mono-p-diphenyl-methyl-4-N-piperaethanol, reacting with sodium acetate chloride, and adding into hydrochloride to obtain final product. It costs low and is simple and can be used for industrial production.

Description

technical field [0001] The invention relates to a method for synthesizing levocetirizine hydrochloride, which belongs to the technical field of synthesis of chemical raw materials and organic synthesis. Background technique [0002] Levocetirizine is selective H 1 Receptor antagonists are third-generation antihistamines and the single optical isomer of the second-generation antihistamine cetirizine. Jointly developed by Sepracor Company of the United States and UCB Company of Belgium, it is a new chiral drug for the treatment of seasonal allergic rhinitis, perennial rhinitis, adult and juvenile chronic and idiopathic urticaria. It was launched in Europe in 2001 and in the United States in 2002. The dosage of its preparation is half of that of cetirizine hydrochloride, its side effects are smaller than that of cetirizine, and its efficacy is higher. It is especially suitable for children and pregnant women. other allergy medicines. In 1994, UCB applied for a synthesis pro...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/084
Inventor 刘庆彬张福军张占辉
Owner HEBEI NORMAL UNIV
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