Methods for the manufacture of cetirizine

Details Methods for the manufacture of cetirizine Methods for the manufacture of cetirizine

1999-01-20

2000-04-04

Ambrose, Michael G.

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C07D24104

Patent

active

060463325

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to a new process for the manufacture of [2-[4-[4-(chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid derivatives of formula I and in particular for the manufacture of cetirizine. ##STR1## where R.sup.1 and R.sup.2 represent independently a hydrogen atom, a halogen atom, a lower alkoxy radical or a trifluoromethyl radical. branched chain aliphatic alcohols having from 1 to 4 carbon atoms, such as methoxy, ethoxy, butoxy and the like.


BACKGROUND OF INVENTION

[2-[4-[4-(chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid also known by the generic name of cetirizine is a non-sedating type histamine H1-receptor antagonist and is used in the treatment of allergic syndromes. It's pharmacological and medicinal properties have been described in the literature, C. De. Vos et. Al., Ann. Allergy 59, 278, 1987; L. Juhlin et. Al, J. Allergy Clin. Immunol., 80, 80, 599 (1987).
Canadian Patent 1.199,918 describes the synthesis of cetirizine following two different routes as illustrated in Scheme 1: ##STR2##
All the starting materials require for these 2 routes are not commercially available and accordingly these two routes involve a multi step process resulting in low overall yields.
Canadian Patent 1,317,300 teaches a process for preparing cetirizine by reaction of 1-[(4-chlorophenyl)phenylmethyl-piperazine with an haloethoxyacetonitrile. Again as all the starting materials are not commercially available and it results in a multi step process which generally is costly.
Canadian Patent 1,320,732 relates to a process for preparing cetirizine by reacting [2-[4-[4-(chlorophenyl)phenylmethyl]-1-piperazinyl]-ethanol with an alkali metal haloacetate. Again the starting alcohol results from a multi step process adding to the cost of the whole process and decreasing the overall yield.
There is a need to find an economical process for the production of these [2-[4-[4-(chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid derivatives which will allow for higher yields than those obtained in the prior art.


SUMMARY OF THE INVENTION

According to the present invention a process is provided for manufacture compounds of formula I: ##STR3## wherein R.sup.1 and R.sup.2 represent independently a hydrogen atom, a halogen atom, a lower alkoxy radical or trifluoromethyl radical. ##STR4## wherein R.sup.1 and R.sup.2 are as defined above
In another embodiment of the invention there is provided a process to prepare a compound of formula I where R.sup.2 =H and R.sup.1 =-parachloro by reacting hydroxyzine, a compound of formula II where R.sup.2 =H and R.sup.1 =-parachloro with an oxidizing agent as illustrated in Scheme 2: ##STR5##


DETAILED DESCRIPTION OF THE INVENTION

The oxidation of the starting material of formula II takes place at room temperature in the presence of Jones reagent in acetone. Jones reagent is well known in the art and is prepared from chromium trioxide and sulphuric acid. As the oxidation of alcohols to carboxylic acids is well documented in the art, it would be obvious to any skilled reader that the oxidizing agent is not limited to Jones reagent but include many others, as for example platinum dioxide Pl/C with oxygen in the presence of an inert solvent.
Preferably the starting material of formula II used is hydroxyzine which is commercially available. Its synthesis was disclosed in Canadian Patent No. 568,380. The product of oxidation i.e. cetirizine is isolated by conventional means.
The present invention will be more fully understood by the following examples which illustrate the invention, but are not considered limiting the scope of the invention.


EXAMPLE 1
[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-ethoxy]acetic acid (cetirizine).
To a stirred suspension of hydroxyzine dihydrochloride (70.0 g, 0.156 mol) in acetone (560 ml), Jones reagent (130 ml, 0.351 mol), which was made by adding sulphuric acid (115 ml) to a solution of chromium trioxide (133.7 g) in water (250 ml) and adding water to the total volume of 500 ml, was adde

REFERENCES:
E. Dorosec; D. Poljsak; U. Urleb: "Synthesis of N-Acylamino-ethoxyacetic Acid Derivatives" Archiv Der Pharmazie, vol. 325, No. 4, 1992, pp. 251-252.
Ligang Qian et al.: "A convenient Synthesis of Macrocyclic Lactams" Tetrahedron Lett., vol. 31, No. 45, 1990, pp. 6469-6472.
Jerry March: "Advanced Organic Chemistry" 1985, Wiley-Interscience, p. 1084--p. 1057-59.

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