Enantiomers of 1[(4-chloro-phenyl)...

Details Enantiomers of 1[(4-chloro-phenyl)... Enantiomers of 1[(4-chloro-phenyl)...

1999-07-19

2002-08-20

Bernhardt, Emily (Department: 1611)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S396000

Reexamination Certificate

active

06436942

ABSTRACT:

The present invention relates to new compounds, the substantially optically pure levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of the formula
to a process for the preparation of these compounds and to their use for the preparation of substantially optically pure levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine. The latter compounds, are valuable intermediates for the preparation of substantially optically pure therapeutically active compounds, in the levorotatory and dextrorotatory forms.
These therapeutically active compounds may be used in the treatment of asthma, allergies, inflammation and anxiety, and as sedative or tranquilizing agents. A property frequently observed with these compounds is their high degree of peripheral and/or central antihistaminic activity, as the basis for their use as a drug.
It is well known that the biological properties of many compounds, such as for example drugs, hormones, herbicides, insecticides or sweetening agents, are influenced by stereochemical factors. The importance of the relationships between the optical activity and the biological properties, has been stressed since 1926 (A. R. CUSHNY, Biological.Relations of optically Isomeric Substances, Williams and Williams Co., Baltimore, 1926). Since that time, many examples abound which have confirmed the now generally accepted principle that a racemic compound and its levorotatory and dextrorotatory enantiomers should be considered as entirely distinct pharmacological entities. The optical activity, which is an image of the asymmetrical structure of an organic compound is one of the important factors which govern the pharmacological activity of this compound and its biological response. Indeed, according as to whether the levorotatory or dextrorotatory form of a drug is used, considerable differences in the properties, such as its transport, its distribution in the organism or its elimination can appear. These properties are decisive for the concentration of the drug in the organism or its exposure time at the site of activity. Furthermore, the pharmacological activity of the two isomers can differ considerably. For example, one enantiomer may be much more active than the other or, in a border-line case, this enantiomer could possess alone all the pharmacological activity, the other being totally inactive and serving only as a simple diluent. It can also occur that the pharmacological activities of the two isomers are different, which produces consequently two compounds having distinct therapeutic properties. Moreover, the metabolism and the toxicity can be very different from one isomer to another, so much so that one of the optically active isomers can be more toxic than the other. One of the most striking examples in this field is that of thalidomide, where the two enantiomers possess similar hypnotic effects but only the S enantiomer has teratogenic effects.
Finally, it has also to be added that the optical isomers are useful as probes which are of uttermost importance in the study of chemical interactions with physiological mechanisms (for example, the selectivity of binding to a receptor).
That is the reason why many pharmaceutical laboratories devote much time and efforts to isolate or synthesize the enantiomers of pharmacologically active compounds and to study the therapeutic properties thereof.
A process for the preparation of the enantiomers of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid dihydrochloride, known as a non-sedative antihistamine drug under the generic name of cetirizine, is described in British Patent No. 2,225,321. This process is based on the use of levorotatory or dextrorotatory 1-[(4-chlorophenyl)phenylmethyl]piperazine as starting material. In that patent, the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained by chemical resolution of the racemic form, using conventional methods, in particular, by salt formation with a suitably selected optical isomer of tartaric acid.
The major disadvantages of this process are, on the one hand, that the yield of the resolution step of the racemic 1-[(4-chlorophenyl)phenylmethyl]piperazine is extremely low (only 12.7%) and, on the other hand, that the optical purity of the dextrorotatory and levorotatory enantiomers so obtained is insufficient and does not allow the final product to be prepared with an optical purity greater than 95%.
Consequently, it appears to be very desirable to provide new routes for preparing the enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine with improved optical purity and in better yields and, thereby, to provide excellent starting materials to produce optically active isomers of useful drugs with a very high degree of optical purity.
But, to achieve this object, it is necessary to find precursors having already the correct stereochemical configuration and which, on the one hand, can be themselves prepared relatively simply and economically with satisfactory optical purity, and, on the other hand, which can be converted easily and with high yields into the substantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine.
We have now discovered a new compound, 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine, the levorotatory and dextrorotatory forms of which comply perfectly with this object.
Accordingly, the present invention provides as new compounds, the levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of the formula
According to the present invention, the enantiomers of the compound of formula I are advantageously in a substantially optically pure form.
In the present specification, by “substantially optically pure”, is meant an optical purity greater than 98% and this optical purity corresponds to the percent excess of the optically active isomer present in major amount with respect to the optically active isomer present in minor amount, and determined by high performance liquid phase chromatography (HPLC) on a chiral stationary phase.
This optical purity can be defined by the equation described on page 107 of the book of J. MARCH, “Advanced Organic Chemistry”, John Wiley & Sons, Inc., New York, 3
rd
Edition, 1985:
Optical purity (in %)
=
[
(
+
)
]
-
[
(
-
)
]
[
(
+
)
]
+
[
(
-
)
]
×
100
Where
[(+)]=concentration of the dextrorotatory enantiomer; and
[(−)]=concentration of the levorotatory enantiomer.
The present invention further relates to a process for preparing the levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of formula I, which comprises reacting an enantiomer of (4-chlorophenyl)phenylmethylamine of the formula
with a N,N-diethyl-4-methylbenzenesulfonamide of the formula
wherein X is a chlorine, bromine or iodine atom or the (4-methylphenyl)sulfonyloxy or methylsulfonyloxy group, in the presence of 2.2 to 4.4 equivalents of an organic or inorganic base per equivalent of the enantiomer of (4-chlorophenyl)phenylmethylamine and at the boiling point of the reaction mixture.
Bases suitable for use to prepare compounds of formula I include organic bases such as ethyldiisopropylamine, N-ethylmorpholine, 2,4,6-trimethylpyridine or triethylamine, preferably ethyldiisopropylamine, and inorganic bases such as sodium carbonate.
The levorotatory and dextrorotatory enantiomers of (4-chlorophenyl)phenylmethylamine of formula II, used as starting materials are known compounds; they can be prepared by chemical resolution of racemic (4-chlorophenyl)phenylmethylamine by known methods using tartaric acid. These enantiomers can be prepared with an optical purity of at least 98%.
The compounds of formula III used as starting materials

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