Process of preparing...

Details Process of preparing... Process of preparing...

2000-03-21

2001-07-03

Raymond, Richard L. (Department: 1624)

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

Organic compounds

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

Reexamination Certificate

active

06255487

ABSTRACT:

The present invention relates to novel compounds, substituted [2-(1-piperazinyl)ethoxy]methyl compounds of formula
in which
R
1
represents a —CONH
2
, —CN, —COOH, —COOM or —COOR
3
group, M being an alkali metal and R
3
being an alkyl radical having from 1 to 4 carbon atoms; and
R
2
represents a hydrogen atom or a group —COR
4
or —R
5
, where R
4
is chosen from the groups —OR
6
or —R
7
, in which
R
5
represents an allyl or alkylaryl radical,
R
6
represents a linear or branched alkyl radical having from 1 to 4 carbon atoms, a haloalkyl, alkylaryl, alkylnitroaryl or alkylhaloaryl radical, and
R
7
represents a haloalkyl radical,
to a process for the preparation of these compounds, and to their use for the preparation of compounds of formula
in which R
1
has the same meaning as in formula I and X
1
and X
2
independently represent a hydrogen, fluorine, chlorine or bromine atom. In the case where R
1
represetns a —COOH group and where X
1
represents a chlorine atom in position 4 and X
2
represents a hydrogen atom, the compound of formula II is 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid of formula
In the case where R
1
represents a —CONH
2
, —CN, —COOM or —COOR
3
group, M being an alkali metal and R
3
being an alkyl radical having from 1 to 4 carbon atoms and where X
1
represents a chlorine atom in position 4 and X
2
a hydrogen atom, the compounds of formula II are valuable intermediates for the preparation of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid of formula III, as well as pharmaceutically acceptable salts thereof. 2-[2-[4-[(4-Chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, a product which is also known under the common international name of cetrizine, is described in U.S. Pat. No. 4,525,358 and has been introduced as a medicament for the treatment of allergic syndromes, for instance chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria, etc. In its therapeutic application, this product proved to be remarkably free of side effects on the central nervous system, such as drowsiness, attenuated mental performance, etc. (cfr. D. P. TASHKIN et. al., Annals of Allergy, Part II, 59, (1987), 49-52, as well as F. M. GENGO et al., Annals of Allergy, Part II, 59, (1987), 53-57). In the case where R
1
represents a —COOH group and where X
1
and X
2
each represent a fluorine atom in position 4, the compound of formula II is 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid of formula
In the case where R
1
represents a —CONH
2
, —CN, —COOM or —COOR
3
group, M being an alkali metal and R
3
being an alkyl radical having from 1 to 4 carbon atoms and where X
1
and X
2
each represent a fluorine atom in position 4, the compounds of formula II are valuable intermediates for the preparation of 2-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid of formula IV as well as pharmaceutically acceptable salts. 2-[2-[4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride is also known under the common international name of efletrizine. The use of efletirizine for the treatment of rhinitis or rhino-conjunctivitis of allergic origin has been suggested in several recent communications (51
st
Annual Meeting or American Academy of Allergy and Immunology, reproduced in J. Allergy Clin. Immunol., 95/1 (1995), part 2, Abstract 229 and XV
th
Congress of Allergology and Clinical Immunology, reproduced in Allergy & Clin. Immunol. News, (1994) suppl. No. 2, abstracts 428, 1136, 1496 and 1864). These communications indicate that the intranasal administration of efletirizine might provide an effective therapeutic treatment of rhinitis or rhino-conjunctivitis of allergic origin. U.S. Pat. No. 4,525,358 in the name of the Applicant, describes the synthesis of 2-[2-[4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]acetic acid and its dihydrochloride. In this synthesis, the starting material is 1-[(4-chlorophenyl)phenylmethyl]piperazine, which may be reacted with methyl (2-chloroethoxy)acetate or 2-(2-chloroethoxy)acetamide to form respectively methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate (compound of formula II which R
1
=—COOH
3
, X
1
=—Cl (position 4) and X
2
=—H) or 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide (compound of formula II with R
1
=—CONH
2
, X
1
=—Cl (position 4) and X
2
=—H). This methyl ester as well as this acetamide may then be subjected to hydrolysis with an inorganic base (potassium or sodium hydroxide) to form the sodium or potassium salt, which is readily converted into cetirizine and its dihydrochloride.
British Patent application 2,225,320, also in the name of the Applicant, gives an alternative synthetic route for the preparation of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid and its dihydrochloride.
According to that patent, 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid and its dihydrochloride are prepared by a process which is characterized in that 2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethanol is reacted with an alkali metal haloacetate, in the presence of an alkali metal alkoxide, and in that the alkali metal salt thus obtained is converted into the corresponding acid and, where appropriate, into its dihydrochloride.
British Patent Application 2,225,321, also in the name of the Applicant provides another synthetic process which makes it possible to prepare 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid and its dihydrochloride.
According to that patent, 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid and its dihydrochloride are prepared by a process which is characterized in that 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetonitrile (compound of formula II with R
1
=—CN, X
1
=—Cl (position 4) and X
2
=—H) is hydrolysed in aqueous, alcoholic or aqueous-alcoholic medium and with a base or with an acid, and in that the acid thus obtained is converted, where appropriate, into its dihydrochloride.
The 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetonitrile used as starting material is obtained by reacting 1-[(4-chlorophenyl)phenylmethyl]piperazine with a 2-haloethoxyacetonitrile. This reaction is carried out in the presence of an acid acceptor, such as an alkali metal carbonate, and optionally in the presence of a small amount of alkali metal iodide to accelerate the reaction, in an inert organic solvent such as an alcohol (for example n-butanol, etc.), preferably at a temperature in the region of the reflux temperature.
Given the increasing therapeutic value of cetirizine and of compounds of similar structure, the Applicant set itself the objective and undertook research studies with the aim of developing a new synthetic route to 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid and pharmaceutically acceptable salts thereof which would make it possibe to obtain this compound from known and/or readily accessible reagents and which would moreover provide this compound in a sufficient purity and an economically acceptable yield. Moreover, for the puprose of simplifying the industrialization of the process, the Applicant set itself the further objective of developing a synthetic route which might have fewer steps than the known processes.
In addition, given the therapeutic value of other compou

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