Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-17
2002-11-26
Morris, Patricia L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S207000
Reexamination Certificate
active
06486325
ABSTRACT:
The present invention relates to a novel process for the preparation of a diastereomeric mixture of piperidinylaminomethyl trifluoromethyl cyclic ether compounds of formulae Ia and Ib:
and pharmaceutically acceptable salts thereof, wherein
R
1
is C
1
-C
6
alkyl;
R
2
is C
1
-C
6
alkyl, halo C
1
-C
6
alkyl or phenyl or substituted phenyl;
R
3
is hydrogen or halo;
m is zero, one or two.
Further, the present invention also relates to a process for the preparation of a diastereomeric mixture of compounds of formulae Ia and Ib, and pharmaceutically acceptable salts thereof, highly enriched in the compound of formula Ia. The process of the present invention permits via selective crystallization the isolation of diastereomeric mixtures of compounds of formula Ia and Ib wherein the ratio of compounds of formula Ia to Ib are in excess of 90:10.
In addition, the present invention relates to novel processes for the preparation of a compound of formula II:
an intermediate compound useful in the preparation of compounds of formulae Ia and Ib. In addition, the present invention is also directed to other novel intermediates useful in the process for preparing the mixture of compounds of formulae Ia and Ib. The present invention is also directed to a novel process for the purification of certain intermediates for use in the methods of the invention.
The compounds of formula Ia and Ib, particularly compounds of formula Ia, and pharmaceutically acceptable salts thereof, are useful as antagonists of substance P, a naturally-occurring undecapeptide belonging to the tachykinin family of peptides that is widely involved in the pathophysiology of numerous diseases, including central nervous system disorders such as depression, anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, in gastrointestinal disorders and diseases of the GI tract such as ulcerative colitis and Crohn's disease, and in the transmission of pain, including migraine.
The diastereomeric mixture of compounds of formulae Ia and Ib and a process of making that diastereomeric mixture are described in International Patent Publication No. WO 99/25714, published May 27, 1999. That reference refers to methods of preparing the diastereomeric mixture using methods other than those of the present invention, and is hereby incorporated by reference in its entirety. The present invention provides a more practical, more direct and higher yielding process for preparing a mixture of diastereomers of compounds of formulae Ia and Ib, highly enriched in the compound of formula Ia, via novel synthetic pathways.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of a mixture of compounds of formulae Ia and Ib:
highly enriched in the presence of the compound of formula Ia, and pharmaceutically acceptable salts thereof, wherein
R
1
is C
1
-C
6
alkyl;
R
2
is C
1
-C
6
alkyl, halo C
1
-C
6
alkyl or phenyl or substituted phenyl;
R
3
is hydrogen or halo;
m is zero, one or two;
comprising the steps of (a1) reacting a mixture of compounds of formulae Ia and Ib:
with an acid of formula HX, wherein HX is selected from the group consisting of (S)-(+)-mandelic acid, D-(−)-tartaric acid, di-p-toluoyl-D-tartaric acid, ((1R)-endo,anti)-(+)-3-bromocamphor-8-sulfonic acid, quinic acid, acetic acid and hydrobromic acid, to form a mixture of diastereomeric compounds of formulae Va and Vb, respectively, enriched in the presence of a compound of formula Va:
(b1) permitting the HX salt of the diastereomeric product mixture of step (a1) to crystallize out of a solution thereof in an appropriate solvent; and
(c1) treating the resulting mixture of compounds obtained from step (c1) with a base.
A most preferred embodiment of the invention is where the acid HX of step (a1) is (S)-(+)-mandelic acid. A more preferred embodiment of the invention is where the appropriate solvent of step (a1) is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, diisopropyl ether, toluene, acetonitrile, acetone, water and a mixture of any of the foregoing solvents. A most preferred embodiment is where the appropriate solvent of step (a1) is ethanol. A more preferred embodiment of the invention is where the base of step (c1) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
The present invention also relates to the preparation of the pharmaceutically acceptable salts of the mixture of compounds of formula Ia and Ib, highly enriched in the compound of formula Ia, which comprises treating the mixture of compounds Ia and Ib that is enriched in one of the diastereomeric compounds of formula Ia with a proton acid, H
+
Y
−
, wherein the anion, Y
−
, is selected from the group consisting of hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)), to form a mixture of compounds VIa and VIb, highly enriched in the diastereomeric compound acid addition salt of formula VIa:
wherein n is determined by the intrinsic characteristics of the form of the compounds Ia and Ib when complexed with the particular acid HY, and n is an integer from one to two. The process of the invention also relates to the preparation of the hydrates of the compounds of formula VIa and VIb, in which between zero and three molecules of water may be associated with each molecule of the compounds of formula VIa and VIb, said hydrates being formed in the step in which compounds of formula Ia and Ib are treated with a proton acid.
A more preferred embodiment of the invention is where the proton acid used is hydrochloric acid, and n is 2. A preferred embodiment of the invention is where the ratio of compound VIa and VIb obtained is 90:10 or greater. A more preferred embodiment of the invention is where the ratio of compound VIa and VIb obtained is 98:2 or greater.
The present invention also relates to a process for the preparation of compounds of formulae Ia and Ib, highly enriched in the presence of a compound of formula Ia, further comprising the step of reacting a compound of formula III:
with a compound of formula IV:
in the presence of a reducing agent to obtain a mixture of compounds of formula Ia and Ib.
A preferred embodiment of the invention is where the reducing agent is selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride. A more preferred embodiment of the invention is where the reducing agent is sodium triacetoxyborohydride.
The present invention also relates to the process for the preparation of compounds of formulae Ia and Ib, highly enriched in the presence of a compound of formula Ia, further comprising the step of formylating a compound of formula II:
wherein R
1
, R
2
and R
3
are as defined above; m is 0, 1 or 2 with hexamethylenetetramine, in the presence of an acid to form a compound of formula III. A preferred embodiment of the invention is where the acid in the formylation reaction is trifluoroacetic acid, glyceroboric acid, acetic acid or hydrochloric acid. The most preferred acid is trifluoroacetic acid.
The present invention also relates to the process for the preparation of compounds of formulae Ia and Ib, highly enriched in the presence of a compound of formula Ia, wherein the compound of formula II:
wherein R
1
, R
2
and R
3
are as defined above; m is 0, 1 or 2; is prepared by a process comprising the steps of
(a2) reacting a compound of formula VII:
with a compound of formula CF
3
SiR
4
3
, wherein R
4
is (C
1
-C
6
)alkyl or phenyl, in the presence of a fluoride source to form a compound of formula VII
Caron Stephane
Vasquez Enrique
Ginsburg Paul H.
Morris Patricia L.
Pfizer Inc
Richardson Peter C.
Waldron Roy F.
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