Process for the production of piperidine derivatives

Details Process for the production of piperidine derivatives Process for the production of piperidine derivatives

2002-06-11

2004-06-01

Chang, Celia (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S081000, C562S489000

Reexamination Certificate

active

06743941

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to processes for preparing certain piperidine derivatives, including fexofenadine (F), the active ingredient in the non-sedating antihistamine sold in the U.S. under the designation “Allegra®”. This invention also relates to novel synthetic intermediates useful in the processes of the present invention.
SUMMARY OF THE INVENTION
The present invention relates to processes for the preparation of piperidine derivatives of the formulas I, II, VI and VII:
wherein
n is 0 or 1;
R1 is hydrogen or hydroxy;
R2 is hydrogen;
R1 and R2 taken together form a double bond between the carbon atoms bearing R1 and R2;
R3 is COOH, CO
2
alkyl, CH
2
OH, hydroxyl, protected hydroxyl, cyano, CONH
2
, CONHalkyl or CON(alkyl)
2
, wherein each of the alkyl groups contained in any of them contains from 1-6 carbon atoms
A, B, and D may be substituents of their respective rings in the meta, para or ortho position and which may be different or the same and are hydrogen, halogens, alkyl, hydroxy, or alkoxy,
and pharmaceutically acceptable salts thereof, with the proviso that where R1 and R2 are taken together to form a double bond between the carbon atoms bearing R1 and R2 or where R1 is hydroxy, n is 0.
The present invention also relates to novel synthetic intermediates for formulas III and IIIa, and VI which are useful in the preparation of the piperidine derivatives of formulas I, II, VI and VII:
wherein A, B, D, R1, R2, R3 and n are as previously defined and X
+
is a Lewis Acid.
Although a wide variety of piperidine derivatives can be prepared by the process of the present invention, it is particularly useful for preparing fexofenadine (F), the active ingredient in the non-sedating antihistamine sold in the U.S. under the designation “Allegra®”:
Thus, particularly preferred novel synthetic intermediates for use in the processes of the present invention which are useful in the preparation of the fexofenadine (F) are compounds of the formulas VIII, VIIIa, and IX:
wherein alkyl is 1-6 carbon atoms and X
+
is a Lewis acid.
The processes of the present invention for the preparation of piperidine derivatives of the formulas I, II, VI and VII comprise:
a) acylating a starting compound of the formula 19:
 with a compound of the formula 18:
 under conditions effective to produce a mixture of regioisomers of the formula XI:
b) recovering from the mixture of regioisomers the compound of the formula III:
c) converting the compound of step b) to the piperidine derivative compound of the formula VI:
 with a piperidine compound of the formula 17:
d) optionally reducing the piperidine derivative compound of step c) to give the compound of the formula I:
e) optionally reducing the piperidine derivative compound of step c) to give the piperidine derivative of the formula VII;
 and
f) optionally oxidizing the piperidine derivative of step d to give the piperidine derivative of formula II:
 wherein all substituents are as previously defined.
Included within this process is a process for preparation of fexofenadine (F), the active ingredient in the non-sedating antihistamine sold in the U.S. under the designation “Allegra®”, which comprises:
a) acylating a starting compound of the formula 21:
 with a compound of the formula 20:
 under conditions effective to produce a mixture of regioisomers of the formula 25:
b) recovering from the mixture regioisimers the compound of the formula VIII:
c) converting the compound of step b) to the piperidine derivative compound of the formula IX:
 with a piperidine compound of the formula 23:
d) reducing the piperidine derivative compound of step c) to provide a piperidine derivative of the formula 24;
 and
e) converting the CO
2
alkyl moiety of the piperidine derivative of formula 24 to CO
2
H moiety to produce fexofenadine (F)
 wherein alkyl is 1-6 carbon atoms.


REFERENCES:
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patent: WO95/00482 (1995-01-01), None
Smeyers et al. “Conformational analysis . . . ” CA 102:125100 (1985).*
Bounaim et al. “Ab initio structural study . . . ” CA 137:241669 (2002).*
Smeyers et al, Conformational analysis of some .alpha.-phenylpropionic acids with anti-inflammatory activity, Journal of Pharmaceutical Sciences (1985); 74(10); pp. 47-49.
Graul, A. et al., Fexofenadine Hydrochloride, Drugs of the Future, 1996, vol. 21, No. 10, pp. 1017-1021.
Hester, Jackson, B. et al., N-[(uomega-Amino-1-hydroxyalkyl)phenyl]methanesulfonamide Derivatives with Class III Antiarrhythmic Activity, J. Med. Chem., 1991, vol. 34, No. 1, pp. 308-315.

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