U.S. patent application number 10/065725 was filed with the patent office on 2003-12-25 for process for the preparation of piperidinylaminomethyl trifluoromethyl cyclic ether compounds.
Invention is credited to Caron, Stephanie, Vazquez, Enrique.
Application Number | 20030236268 10/065725 |
Document ID | / |
Family ID | 22576040 |
Filed Date | 2003-12-25 |
United States Patent
Application |
20030236268 |
Kind Code |
A1 |
Caron, Stephanie ; et
al. |
December 25, 2003 |
Process for the preparation of piperidinylaminomethyl
trifluoromethyl cyclic ether compounds
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: 1 and
pharmaceutically acceptable salts thereof, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl; R.sup.3 is
hydrogen or halo; m is zero, one or two, and wherein said mixture
is highly enriched in the compound of formula Ia, and to novel
processes for the preparation and purification of intermediate
compounds useful in the preparation of compounds of formulae Ia and
Ib.
Inventors: |
Caron, Stephanie;
(Stonington, CT) ; Vazquez, Enrique; (South
Plainfield, NJ) |
Correspondence
Address: |
PFIZER INC
150 EAST 42ND STREET
5TH FLOOR - STOP 49
NEW YORK
NY
10017-5612
US
|
Family ID: |
22576040 |
Appl. No.: |
10/065725 |
Filed: |
November 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10065725 |
Nov 13, 2002 |
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09690346 |
Oct 17, 2000 |
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6486325 |
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60160226 |
Oct 18, 1999 |
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Current U.S.
Class: |
514/255.01 ;
514/317; 544/382; 546/223 |
Current CPC
Class: |
C07C 69/96 20130101;
A61P 25/18 20180101; C07D 405/12 20130101; C07D 311/76 20130101;
A61P 25/00 20180101; A61P 25/24 20180101 |
Class at
Publication: |
514/255.01 ;
514/317; 544/382; 546/223 |
International
Class: |
A61K 031/495; C07D
211/92; A61K 031/445 |
Claims
1. A process for preparing a mixture of compounds of formulae Ia
and Ib: 46enriched in the compound of formula Ia, and
pharmaceutically acceptable salts thereof, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl; R.sup.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: 47with
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-sulfo- nic acid, quinic acid,
acetic acid and hydrobromic acid, to form a mixture of
diastereomeric compounds of formulae Va and Vb, respectively:
48(b1) permitting the HX salt of the diastereomeric product mixture
of step (a1) to crystallize out of a solution thereof in an
appropriate solvent; (c1) treating the resulting mixture of
compounds obtained from step (b1) with a base to obtain a mixture
of compounds Ia and Ib, that is enriched in the compound of formula
Ia; said process further comprising the step of reacting a compound
of formula III: 49wherein R.sup.1 is C.sub.1-C.sub.6 alkyl; R.sup.2
is C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl or phenyl or
substituted phenyl; m is zero, one or two; with a compound of
formula IV: 50wherein R.sup.3 is hydrogen or halo; in the presence
of a reducing agent to form a mixture of diastereomeric compounds
of formula Ia and Ib:
2. A process according to claim 1 wherein the reducing agent is
selected from the group consisting of sodium triacetoxyborohydride,
sodium cyanoborohydride and sodium borohydride.
3. A process according to claim 1 wherein the reducing agent is
sodium triacetoxyborohydride.
4. A mixture of compounds of formulae Ia and Ib: 51or
pharmaceutically acceptable salts thereof, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl; R.sup.3 is
hydrogen or halo; m is zero, one or two; and ratio of the compound
of formula Ia to Ib is 90:10 or greater.
5. A mixture according to claim 4 wherein the ratio is 98:2 or
greater.
6. A mixture of compounds of the formulae Va and Vb: 52highly
enriched in the compound of formula Va, wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl; R.sup.3 is
hydrogen or halo; m is zero, one or two; wherein HX is selected
from the group consisting of (S)-(+)-mandeli 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.
7. A mixture according to claim 6 wherein HX is (S)-(+)-mandelic
acid.
8. A process according to claim 1 further comprising the step of
formulating a compound of formula II: 53wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl or phenyl or
substituted phenyl; R.sup.3 is hydrogen or halo; m is zero, one or
two; via the reaction with hexamethylenetetramine in the presence
of an acid to form a compound of formula III: 54
9. A process according to claim 8 wherein the acid is selected from
the group consisting of trifluoroacetic acid, glyceroboric acid,
acetic acid and hydrochloric acid.
10. A process according to claim 8 wherein the acid is
trifluoroacetic acid.
11. A process according to claim 1 wherein the compound of formula
II: 55wherein R.sup.1 is C.sub.1-C.sub.6 alkyl; R.sup.2 is
C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl or phenyl or
substituted phenyl; R.sup.3 is hydrogen or halo; m is 0, 1 or 2; is
prepared by a process comprising the steps of: (a2) reacting a
compound of formula VII: 56with a compound of formula
CF.sub.3SiR.sup.4.sub.3, wherein R.sup.4 is (C.sub.1-C.sub.6)alkyl
or phenyl, in the presence of a fluoride source to form a compound
of formula VIII: 57(b2) removing the silyl protecting group from
the product of step (a2) via treatment with a base or a fluoride
source to form a compound of formula IX: 58(c2) hydrolysis of the
ester group of the product of step (b2) in the presence of a base
to fo a compound of formula X: 59and (d2) performing a ring
cyclization reaction on the product of step (c2) in the presence
base and an activating agent selected from the group consisting of
methanesulfonyl chlori methanesulfonic anhydride, p-toluenesulfonyl
chloride, p-toluenesulfonic anhydride and triflic anhydride.
12. A process according to claim 11 wherein the fluoride source in
step (a2) is selected from the group consisting of cesium fluoride,
potassium fluoride and an alkylammonium fluoride.
13. A process according to claim 11 wherein the alkylammonium
fluoride is tetrabutylammonium fluoride.
14. A process according to claim 11 wherein the fluoride source in
step (a2) is cesium fluoride.
15. A process according to claim 11 wherein the base in step (b2)
is sodium hydroxide or potassium hydroxide.
16. A process according to claim 11 wherein the preferred fluoride
source of step (b2) is tetrabutylammonium fluoride, cesium
fluoride, hydrofluoric acid-pyridine complex or hydrofluoric
acid.
17. A process according to claim 11 wherein the fluoride source in
step (b2) is tetrabutylammonium fluoride.
18. A process according to claim 11 wherein the base in step (c2)
is selected from the group consisting of sodium hydroxide,
potassium hydroxide, sodium carbonate, sodium bicarbonate,
potassium carbonate, and potassium bicarbonate.
19. A process according to claim 11 wherein the base in step (c2)
is sodium hydroxide.
20. A process according to claim 11 wherein the activating agent in
step (d2) is methanesulfonyl chloride.
21. A process according to claim 11 wherein the base for step (d2)
is selected from the group consisting of triethylamine,
diisopropylethylamine, 2,6-lutidine, pyridine, sodium hydroxide,
potassium hydroxide, cesium carbonate and potassium carbonate.
22. A process according to claim 11 wherein the base for step (d2)
is triethylamine.
23. A process according to claim 1 wherein the compound of formula
II: 60wherein R.sup.1 is C.sub.1-C.sub.6 alkyl; R.sup.2 is
C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl or phenyl or
substituted phenyl; R.sup.3 is hydrogen or halo; m is 0, 1 or 2; is
prepared by a method comprising the steps of: (a3) reacting a
compound of formula XI: 61with an alcohol of formula R.sup.1OH in
the presence of an acid, wherein R.sup.1 is as defined abo to form
a compound of formula XII: 62(b3) reacting the product of step (a3)
with compound of formula CF.sub.3SiR.sup.4.sub.3, wherein R.sup.4
(C.sub.1-C.sub.6)alkyl or phenyl, to form a compound of formula
XIII: 63(c3) reacting the product of step (b3) with a fluoride
source to obtain a lactone compound formula XIV: 64(d3) reacting
the lactone product of step (c3) with a reducing agent optionally
in the presen of a Lewis acid to obtain a compound of formula XV:
65and (e3) reacting the product of step (d3) with a reducing agent
in the presence of a Lewis acid.
24. A process according to claim 23 wherein the acid of step (a3)
is chosen from the group consisting of sulfuric acid, hydrochloric
acid, hydrobromic acid, trifluoroacetic acid and methanesulfonic
acid.
25. A process according to claim 23 wherein the acid of step (3) is
sulfuric acid.
26. A process according to claim 23 wherein the fluoride source of
step (b3) is selected from the group consisting of cesium fluoride,
potassium fluoride, and an alkylammonium fluoride.
27. A process according to claim 26 wherein the alkylammonium
fluoride is tetrabutylammonium fluoride.
28. A process according to claim 23 wherein the fluoride source of
step (b3) is cesium fluoride.
29. A process according to claim 23 wherein the fluoride source for
step (c3) is selected from the group consisting of
tetrabutylammonium fluoride, cesium fluoride, hydrofluoric
acid-pyridine complex, and hydrofluoric acid.
30. A process according to claim 23 wherein the fluoride source for
step (c3) is tetrabutylammonium fluoride.
31. A process according to claim 23 wherein the reducing agent for
step (d3) is selected from the group consisting of sodium
borohydride, borane tetrahydrofuran complex, borane dimethylsulfide
complex, diborane, lithium borohydride, calcium borohydride,
lithium aluminum hydride, diisobutylaluminum hydride, L-selectride
and K-selectride.
32. A process according to claim 23 wherein the Lewis acid for step
(d3) is boron trifluoride diethyl ether complex.
33. A process according to claim 23 wherein the reducing agent for
step (e3) is triethylsilane or triphenylsilane.
34. A process according to claim 23 wherein the Lewis acid for step
(e3) is boron trifluoride etherate or trifluoroacetic acid.
35. A process according to claim 23 wherein the reducing agent for
step (e3) is selected from the group consisting of platinum,
platinum oxide, and palladium hydroxide in the presence of hydrogen
gas.
36. A process according to claim 1 further comprising the step of
purifying a compound of formula III: 66wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl; and m is
zero, one or two, comprising the steps of (a4) forming a hydrazone
via the reaction of a compound of formula III with a hydrazone of
formula XVI: 67wherein R.sup.1 is as defined above, in the presence
of an acid to afford a compound of formu XVII: 68and (b4)
hydrolyzing the product of step (a4) via treatment with a reagent
selected from th group consisting of copper(II)chloride,
copper(II)iodide, copper(II)acetate, copper sulfate, sulfuric acid,
acetic acid and hydrochloric acid.
37. A process according to claim 36 wherein the acid in step (a4)
is selected from the group consisting of acetic acid, sulfuric
acid, hydrochloric acid, methanesulfonic acid and p-toluenesulfonic
acid.
38. A process according to claim 36 wherein the acid in step (a4)
is acetic acid.
39. A process according to claim 36 wherein the reagent for step
(b4) is copper(II)chloride.
40. A compound of formula VIII: 69wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl; R.sup.4 is
(C.sub.1-C.sub.6)alkyl or phenyl; and m is zero, one or two.
41. A compound of formula IX: 70wherein R.sup.1 is C.sub.1-C.sub.6
alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl
or phenyl or substituted phenyl; and m is zero, one or two.
42. A compound of formula XIII: 71wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl; R.sup.4 is
(C.sub.1-C.sub.6)alkyl or phenyl; and m is zero, one or two.
43. A compound of formula XIV: 72wherein R.sup.1 is C.sub.1-C.sub.6
alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl
or phenyl or substituted phenyl; and m is zero, one or two.
44. A compound of formula XV: 73wherein R.sup.1 is C.sub.1-C.sub.6
alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl
or phenyl or substituted phenyl; and m is zero, one or two.
45. A compound of formula XVII: 74wherein R.sup.1 is
C.sub.1-C.sub.6 alkyl; R.sup.2 is C.sub.1-C.sub.6 alkyl, halo
C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl; and m is
zero, one or two.
Description
BACKGROUND OF INVENTION
[0001] 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: 2
[0002] and pharmaceutically acceptable salts thereof, wherein
R.sup.1 is C.sub.1-C.sub.6 alkyl;R.sup.2 is C.sub.1-C.sub.6 alkyl,
halo C.sub.1-C.sub.6 alkyl or phenyl or substituted phenyl;R.sup.3
is hydrogen or halo; m is zero, one or two.
[0003] 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.
[0004] In addition, the present invention relates to novel
processes for the preparation of a compound of formula II: 3
[0005] 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.
[0006] 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.
[0007] 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 INVENTION
[0008] The present invention relates to a process for the
preparation of a mixture of compounds of formulae Ia and Ib: 4
[0009] highly enriched in the presence of the compound of formula
Ia, and pharmaceutically acceptable salts thereof, wherein
[0010] R.sup.1 is C.sub.1-C.sub.6 alkyl;
[0011] R.sup.2 is C.sub.1-C.sub.6 alkyl, halo C.sub.1-C.sub.6 alkyl
or phenyl or substituted phenyl;
[0012] R.sup.3 is hydrogen or halo;
[0013] m is zero, one or two;
[0014] comprising the steps of (a1) reacting a mixture of compounds
of formulae Ia and Ib: 5
[0015] 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-sulfo- nic 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: 6
[0016] (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
[0017] (c1) treating the resulting mixture of compounds obtained
from step (c1) with a base.
[0018] 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.
[0019] 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.sup.+Y.sup.-, wherein the anion, Y.sup.-, 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, pand pamoate (i.e., 1,1'to form
a mixture of compounds VIa and VIb, highly enriched in the
diastereomeric compound acid addition salt of formula VIa: 7
[0020] wherein n is determined by the intrinsic characteristics of
the form of the compounds Ia and Ib when completed 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.
[0021] 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.
[0022] 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: 8
[0023] with a compound of formula IV: 9
[0024] in the presence of a reducing agent to obtain a mixture of
compounds of formula Ia and Ib.
[0025] 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.
[0026] 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: 10
[0027] wherein R.sup.1, R.sup.2 and R.sup.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 formulation 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: 11
[0028] wherein R.sup.1, R.sup.2 and R.sup.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: 12
[0029] with a compound of formula CF.sub.3SiR.sup.4.sub.3, wherein
R.sup.4 is (C.sub.1-C.sub.6)alkyl or phenyl, in the presence of a
fluoride source to form a compound of formula VIII: 13
[0030] (b2) removing the silyl protecting group from the product of
step (a2) via treatment with a base or a fluoride source to form a
compound of formula IX: 14
[0031] (c2) hydrolyzing the ester group of the product of step (b2)
in the presence of a base to form a compound of formula X: 15
[0032] and (d2) performing a ring cyclization reaction on the
product of step (c2) in the presence of a base and an activating
agent selected from the group consisting of methanesulfonyl
chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p
anhydride and triflic anhydride.
[0033] A more preferred embodiment of the present invention is
where the fluoride source in step (a2) is selected from the group
consisting of cesium fluoride, potassium fluoride and an
alkylammonium fluoride. The most preferred alkylammonium fluoride
is tetrabutylammonium fluoride. A most preferred embodiment of the
invention is where the fluoride source in step (a2) is cesium
fluoride. Preferred solvents for step (a2) are dimethylformamide,
dimethylacetamide, toluene, dichloromethane, dichloroethane and
tetrahydrofuran. The most preferred solvent for step (a2) is
dimethylformamide.
[0034] In step (b2), the preferred bases are sodium hydroxide or
potassium hydroxide, and the preferred fluoride sources are
tetrabutylammonium fluoride, cesium fluoride, hydrofluoric
acid-pyridine complex and hydrofluoric acid. The most preferred
fluoride source is tetrabutylammonium fluoride. Preferred solvents
for step (b2) are tetrahydrofuran, diisopropyl ether, acetonitrile,
methyl-tert-butyl ether, dichloromethane and toluene. The most
preferred solvent for step (b2) is tetrahydrofuran.
[0035] The preferred bases in step (c2) are sodium hydroxide,
potassium hydroxide, sodium carbonate, sodium bicarbonate,
potassium carbonate and potassium bicarbonate. The preferred base
in step (c2) is sodium hydroxide. Preferred solvents for step (c2)
are water, tetrahydrofuran, methanol, ethanol, isopropanol,
1,4-dioxane and a combination of any of these solvents. The most
preferred solvent for step (c2) is a mixture of water and
tetrahydrofuran.
[0036] In step (d2), the most preferred activating agent is
methanesulfonyl chloride. Preferred bases for step (d2) are
triethylamine, diisopropylethylamine, 2,6-lutidine, pyridine,
sodium hydroxide, potassium hydroxide, cesium carbonate and
potassium carbonate. The most preferred base for step (d2) is
triethylamine. Preferred solvents for step (d2) are
dichloromethane, tetrahydrofuran, toluene, diisopropyl ether and
methyl-tert-butyl ether. The most preferred solvent for step (d2)
is dichloromethane.
[0037] 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: 16
[0038] wherein R.sup.1, R.sup.2 and R.sup.3 are as defined above; m
is 0, 1 or 2; comprising the steps of (a3) reacting a compound of
formula XI: 17
[0039] with an alcohol of formula R.sup.1OH in the presence of an
acid, wherein R.sup.1 is as defined above, to form a compound of
formula XII: 18
[0040] (b3) reacting the product of step (a3) with compound of
formula CF.sub.3SiR.sup.4.sub.3, wherein R.sup.4 is
(C.sub.1-C.sub.6)alkyl or phenyl, to form a compound of formula
XII: 19
[0041] (c3) reacting the product of step (b3) with a fluoride
source to obtain a lactone compound of formula XIV: 20
[0042] (d3) reacting the lactone product of step (c3) with a
reducing agent optionally in the presence of a Lewis acid to obtain
a compound of formula XV: 21
[0043] and (e3) reacting the product of step (d3) with a reducing
agent optionally in the presence of a Lewis acid to obtain a
compound of formula II.
[0044] Another preferred embodiment of the invention is where the
acid of step (a3) is chosen from the group consisting of sulfuric
acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and
methanesulfonic acid. The most preferred acid for step (a3) is
sulfuric acid.
[0045] In step (b3), preferred fluoride sources are cesium
fluoride, potassium fluoride and an alkylammonium fluoride, such as
tetrabutylammonium fluoride. The most preferred fluoride source is
cesium fluoride. Preferred solvents for step (b3) are
dimethylformamide, dimethylacetamide, dichloromethane and
tetrahydrofuran. The most preferred solvent for step (b3) is
dimethylformamide.
[0046] Preferred fluoride sources for step (c3) are
tetrabutylammonium fluoride, cesium fluoride, hydrofluoric
acid-pyridine complex and hydrofluoric acid. The most preferred
fluoride source for step (c3) is tetrabutylammonium fluoride.
Preferred solvents for step (c3) are tetrahydrofuran, diisopropyl
ether, acetonitrile, methyl-tert-butyl ether, dichloromethane and
toluene. The most preferred solvent for step (c3) is
tetrahydrofuran.
[0047] Preferred reducing agents for step (d3) are sodium
borohydride, borane tetrahydrofuran complex, borane dimethylsulfide
complex, diborane, lithium borohydride, calcium borohydride,
lithium aluminum hydride, diisobutylaluminum hydride, L-selectride
and K-selectride. The most preferred reducing agent is sodium
borohydride. The preferred Lewis acid for step (d3) is boron
trifluoride diethyl ether complex. Preferred solvents for step (d3)
are tetrahydrofuran, diisopropyl ether, methyl-tert-butyl ether and
dimethoxyethane. The most preferred solvent for step (d3) is
tetrahydrofuran.
[0048] The preferred reducing agents for step (e3) are
triethylsilane or triphenylsilane, in the presence of a Lewis acid
such as boron trifluoride etherate or trifluoroacetic acid,
preferably trifluoroacetic acid. Preferred solvents for step (e3)
are dichloromethane, dichloroethane and chloroform. The most
preferred solvent for step (e3) is dichloromethane.
[0049] Another preferred embodiment is where in step (e3) a
compound of formula XIV is treated with a catalyst such as
platinum, platinum oxide, or palladium hydroxide, preferably
platinum, in a solvent such as methanol, ethanol, or isopropanol,
preferably ethanol, under an atmosphere of hydrogen, optionally
under pressure greater than atmospheric pressure.
[0050] 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 III: 22
[0051] is purified by a method comprising the steps of (a4) forming
a hydrazone via the reaction of a compound of formula III with a
hydrazone of formula XVI: 23
[0052] in the presence of an acid to afford a compound of formula
XVII: 24
[0053] and (b4) hydrolyzing the product of step (a4) via treatment
with a reagent selected from the group consisting of
copper(II)chloride, copper(II)iodide, copper(II)acetate, copper
sulfate, sulfuric acid, acetic acid and hydrochloric acid.
[0054] Preferred acids for step (a4) include acetic acid, sulfuric
acid, hydrochloric acid, methanesulfonic acid and p-toluenesulfonic
acid. The most preferred acid for step (a4) is acetic acid.
Preferred solvents for step (a4) are methanol, ethanol,
isopropanol, tetrahydrofuran, water and a mixture of any of the
foregoing solvents. The most preferred solvent for step (a4) is a
mixture of methanol and water.
[0055] The more preferred reagent for step (b4) is
copper(II)chloride. Preferred solvents for step (b4) are tert-butyl
alcohol, methanol, ethanol, isopropanol, tetrahydrofuran, water and
a mixture of any of the forgoing solvents. The most preferred
solvent for step (b4) is a mixture of tert-butyl alcohol and
water.
[0056] In addition, methods for the preparation of pharmaceutical
compositions of mixtures of the compounds of formula Ia or Ib or
pharmaceutically acceptable salts thereof are encompassed by the
present invention. A method for the preparation of such a
pharmaceutical composition comprises the addition of a mixture of
compounds of formula Ia and Ib or pharmaceutically acceptable salts
thereof to a pharmaceutically acceptable carrier or diluent.
[0057] The present invention is also directed to the novel
intermediates used in the methods of the invention, including but
not limited to those compounds of formula VII, IX, XII, XIV, XV and
XVII and salts thereof.
[0058] The term alkyl, as used herein, unless otherwise indicated,
includes saturated monovalent hydrocarbon radicals having straight,
branched or cyclic moieties or combinations thereof.
[0059] The term substituted phenyl, as used herein, unless
otherwise indicated, means phenyl substituted by one or more,
preferably one or two substituent(s) such as halogen, hydroxy,
(C.sub.1-C)alkyl or (C.sub.1-C)alkoxy.
[0060] The term halo or halogen, as used herein, unless otherwise
indicated, means fluorine, chlorine, bromine or iodine.
[0061] The term suitable solvent or appropriate solvent, as used
herein, unless otherwise indicated, means a medium which serves to
dissolve particular indicated substance(s), compound(s) or
reagent(s) to form a uniformly dispersed mixture of that substance
or compound at the molecular or ionic level.
[0062] The term proton acid used to prepare acid addition salts of
the compounds of the process of this invention are those which form
nonacid addition salts, i.e., salts containing pharmacologically
acceptable anions, such as the hydrochloride, hydrobromide,
sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,
citrate, acid citrate, tartrate, bitartrate, succinate, maleate,
fumarate, gluconate, saccharate, benzoate, methanesulfonate,
ethanesulfonate, benzenesulfonate, pand pamoate (i.e.,
1,1'salts.
[0063] The term enriched, as used herein, unless otherwise
indicated, means to predominate in a ratio of greater than 1:1 of
one particular compound or isomer over another or other components
in a mixture. The term highly enriched, as used herein, unless
otherwise indicated, means to predominate in a ratio of at least
90:10 of one particular compound or isomer over another or other
component in a mixture. Unless otherwise indicated, this invention
relates to all optical isomers, tautomers and stereoisomers of the
any of compounds described herein.
[0064] The term pharmaceutically acceptable salt, as used herein,
unless otherwise indicated, refers to an acid addition salt of a
proton acid, as defined herein, or a hydrate of an acid addition
salt.
DETAILED DESCRIPTION
[0065] A diastereomeric mixture of piperidinylaminomethyl
trifluoromethyl cyclic ether compounds of formulae Ia and Ib,
highly enriched in a compound of formula Ia, may be prepared in
accordance with the novel method shown in reaction scheme 1
below.
[0066] Novel methods for the preparation of a critical intermediate
in the preparation of piperidinylaminomethyl trifluoromethyl cyclic
ether compounds, a compound of formula II, may be carried out in
accordance with schemes 2 and 3, below. A novel means for purifying
a key intermediate in the process of scheme 1 is shown in scheme 4.
Unless otherwise indicated, the variables R.sup.1, R.sup.2,
R.sup.3, R.sup.4, m and n are as described above.
[0067] Step 1 of scheme 1 is a formulation. A compound of formula
II is treated with hexamethylenetetramine, in the presence of an
acid such as trifluoroacetic acid, glyceroboric acid, acetic acid
or hydrochloric acid, preferably trifluoroacetic acid, optionally
in a solvent such as dichloromethane, dichloroethane, heptane, or
nitromethane, preferably without a solvent at a temperature between
0 and 100.degree. C., preferably at 70.degree. C., for a period of
time between 10 minutes and 24 hours, preferably 3 hours, followed
by addition of water, to afford a compound of formula III. At this
point, the compound of formula III may be purified according to the
method of the invention as set forth below at scheme 4 prior to
proceeding with step 2.
[0068] Step 2 of scheme 1 is a reductive coupling. An aldehyde of
formula III is treated with an amine of formula IV, or a salt
thereof, in the presence of a reducing agent, such as sodium
triacetoxyborohydride, sodium cyanoborohydride, or sodium
borohydride, preferably sodium triacetoxyborohydride, in a solvent,
such as dichloromethane, dichloroethane, tetrahydrofuran, toluene,
acetic acid, diisopropyl ether, or methyl-tert-butyl ether,
preferably dichloromethane, at a temperature between -20 and
60.degree. C., preferably 0.degree. C., for a period of time
between 30 minutes and 24 hours, preferably 3 hours, to afford a
mixture of compounds of formulae Ia and Ib. 2526
[0069] Step 3 of scheme 1 is a salt formation. The mixture of
compounds Ia and Ib is treated with an acid of formula HX, such as
(S)-(+)-mandelic acid, D-(-)-tartaric acid, Di-p-toluoyl-D-tartaric
acid, ((1R)-endo,anti)-(+)-3-bromocamphor-8-sulfonic acid, quinic
acid, acetic acid, hydrobromic acid, preferably (S)-(+)-mandelic
acid, in a solvent, such as methanol, ethanol, isopropanol,
tetrahydrofuran, ethyl acetate, isopropyl acetate,
methyl-tert-butyl ether, diisopropyl ether, toluene, acetonitrile,
acetone, water, or a mixture of the foregoing solvents, preferably
ethanol, at a temperature between -20 and 70.degree. C., preferably
room temperature, for a period of time between 30 minutes and 48
hours, preferably 18 hours, to afford a mixture of compounds of
formula Va and Vb which is enriched in compound of formula Vb. Step
3 permits the isolation of mixtures of compounds of formula Va and
Vb wherein the ratio of compounds of formula Va to Vb is greater
than 70:30, and generally 80:20 or greater.
[0070] Step 4 of scheme 1 is the formation of an acid addition
salt. The mixture of compounds of formula Va and Vb highly enriched
in compound Va is treated with a base such as sodium hydroxide,
potassium hydroxide, sodium carbonate, sodium bicarbonate,
potassium carbonate or potassium bicarbonate, in water in the
presence of a cosolvent such as toluene, diisopropyl ether,
methyl-tert-butyl ether, ethyl acetate, or dichloromethane,
preferably diisopropyl ether, at a temperature between 0 and
40.degree. C., preferably room temperature, for a period of time
between 10 minutes and 48 hours, preferably 18 hours, to afford a
mixture of compounds of formula Ia and Ib which is enriched in
compound of formula Ia. The ratio of compound Ia to Ib, obtained
from this part of step 4 is 70:30 or greater, but in general 80:20
or greater. This mixture is treated with a proton acid, HY, as
defined above, preferably hydrochloric acid, in a solvent, such as
methanol, ethanol, isopropanol, tetrahydrofuran, diisopropyl ether,
water or a mixture of the foregoing solvents, preferably a mixture
of methanol and water, at a temperature between 0 and 60.degree.
C., preferably room temperature, for a period of time between 1
hour and 48 hours, preferably 18 hours, to afford a mixture of
compounds of formula VIa and VIb which is highly enriched in
compound of formula VIa, and wherein n is as defined above. Step 4
permits the isolation of mixtures of compounds of formula VIa and
VIb wherein the ratio of compounds of formula VIa to VIb are
greater than 90:10, and may approach 98:2 or better. Step 4 may be
repeated to obtain higher ratios if needed. 27
[0071] Step 1 of scheme 2 is an acylation of an arene which
proceeds with protection of an alcohol in a way similar to a known
procedure (Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem.
1984, 49, 1574-1583). An arene of formula XVIII is treated with an
acylating agent of formula R.sup.2(C.dbd.O)--X", wherein R.sup.2 is
as defined above and X" is halo, R.sup.2(C.dbd.O)--O--, or other
suitable group in an acylating agent recognized by those of skill
in the art, in the presence of an acid such as aluminum tribromide,
aluminum trichloride, tin tetrachloride, titanium tetrachloride, or
polyphosphoric acid, preferably aluminum tribromide, in a solvent
such as dichloromethane, dichloroethane, nitromethane,
nitrobenzene, carbon disulfide, or chlorobenzene, preferably
dichloromethane, at a temperature between -20.degree. C. and
125.degree. C., preferably between 0 and 20.degree. C., for a
period between 10 minutes to 10 hours, preferably about 1 hour, to
afford a compound of formula VII.
[0072] Step 2 of scheme 2 is the addition of a trifluoromethyl
group to a ketone using a modification of a known method (Prakash,
G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989,
111, 393-395). Ketone of formula VII is treated with a compound of
formula CF.sub.3SiR.sup.4.sub.3, wherein R.sup.4 is defined above,
in the presence of a fluoride source such as cesium fluoride,
potassium fluoride, or an alkylammonium fluoride such as
tetrabutylammonium fluoride, preferably cesium fluoride, in the
presence of a solvent such as dimethylformamide, dimethylacetamide,
toluene, dichloromethane, dichloroethane, or tetrahydrofuran,
preferably dimethylformamide, at a temperature between -78.degree.
C. and 50.degree. C. preferably at room temperature, for a period
of time between 10 minutes and 18 hours, preferably 45 minutes, to
afford a compound of formula VIII.
[0073] Step 3 of scheme 2 is the deprotection of an alcohol. A
compound of formula VIII is treated with a reagent such as sodium
hydroxide, potassium hydroxide, or a fluoride source such at
tetrabutylammonium fluoride, cesium fluoride, hydrofluoric
acid-pyridine complex, or hydrofluoric acid, preferably
tetrabutylammonium fluoride, in a solvent such as tetrahydrofuran,
diisopropyl ether, acetonitrile, methyl-tert-butyl ether,
dichloromethane, or toluene, preferably tetrahydrofuran, at a
temperature between -40 and 60.degree. C., preferably room
temperature, for a period of time between 5 minutes and 5 hours,
preferably one hour, to afford a compound of formula IX.
[0074] Step 4 of scheme 2 is the hydrolysis of an ester. A compound
of formula IX is treated with a reagent such as sodium hydroxide,
potassium hydroxide, sodium carbonate, sodium bicarbonate,
potassium carbonate, potassium bicarbonate, preferably sodium
hydroxide, in a solvent such as water, tetrahydrofuran, methanol,
ethanol, isopropanol, 1,4-dioxane, or a combination of the above
solvents, preferably a mixture of water and tetrahydrofuran, at a
temperature between 0 and 75.degree. C., preferably room
temperature, for a period of time between 1 and 48 hours,
preferably 12 hours, to afford a compound a formula X.
[0075] Step 5 of scheme 2 is a cyclization. A compound of formula X
is treated with an activating agent such as methanesulfonyl
chloride, methanesulfonic anhydride, p toluenesulfonyl chloride,
p-toluenesulfonic anhydride, or triflic anhydride, preferably
methanesulfonyl chloride, and a base such as triethylamine,
diisopropylethylamine, 2,6-lutidine, pyridine, sodium hydroxide,
potassium hydroxide, cesium carbonate, or potassium carbonate,
preferably triethylamine, in a solvent such as dichloromethane,
tetrahydrofuran, toluene, diisopropyl ether, or methyl-tert-butyl
ether, preferably dichloromethane, at a temperature between -40 and
75.degree. C., preferably between 0.degree. C. and room
temperature, for a period of time between one and 48 hours,
preferably 12 hours, to afford a compound of formula II.
[0076] Step 1 of scheme 3 an acylation of an arene. An arene of
formula XIX is treated with an acylating agent of formula
R.sup.2(C.dbd.O)--X", wherein R.sup.2 is as defined above and X" is
halo, R.sup.2(C.dbd.O)--O-- or other suitable group in an acylating
agent recognized by those of skill in the art, in the presence of
an acid, such as aluminum tribromide, aluminum trichloride, tin
tetrachloride, titanium tetrachloride, or polyphosphoric acid,
preferably aluminum tribromide, in a solvent such as
dichloromethane, dichloroethane, nitromethane, nitrobenzene, carbon
disulfide or chlorobenzene, preferably dichloromethane, at a
temperature between -20.degree. C. and 125.degree. C., preferably
between 0 and 20.degree. C., for a period between 10 minutes to 10
hours, preferably about 1 hour, to afford a compound of formula
XI.
[0077] Step 2 of scheme 3 is an esterification. A carboxylic acid
of formula XI is treated with an alcohol of formula R.sup.1OH,
wherein R.sup.1 is defined above, in the presence of an acid such
as sulfuric acid, hydrochloric acid, hydrobromic acid,
trifluoroacetic acid or methanesulfonic acid, preferably sulfuric
acid, at a temperature between 0 and 100.degree. C., preferably at
room temperature, for a period between 10 minutes to 48 hours,
preferably 16 hours, to afford a compound of formula XII. 28
[0078] Step 3 of scheme 3 is the addition of a trifluoromethyl
group to a ketone using a modification of a known method (Prakash,
G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989,
111, 393-395). Ketone of formula XII is treated with a compound of
formula CF.sub.3SiR.sup.4.sub.3, wherein R.sup.4 is defined above,
in the presence of a fluoride source such as cesium fluoride,
potassium fluoride or an alkylammonium fluoride, such as
tetrabutylammonium fluoride; preferably cesium fluoride, in the
presence of a solvent such as dimethylformamide, dimethylacetamide,
dichloromethane or tetrahydrofuran, preferably dimethylformamide,
at a temperature between -78.degree. C. and 50.degree. C.
preferably at 0.degree. C., for a period of time between 10 minutes
and 18 hours, preferably 7 hours, to afford a compound of formula
XII.
[0079] Step 4 of scheme 3 is a lactonization. A compound of formula
XIII is treated with a fluoride source such at tetrabutylammonium
fluoride, cesium fluoride, hydrofluoric acid-pyridine complex or
hydrofluoric acid, preferably tetrabutylammonium fluoride, in a
solvent such as tetrahydrofuran, diisopropyl ether, acetonitrile,
methyl-tert-butyl ether, dichloromethane or toluene, preferably
tetrahydrofuran, at a temperature between -40 and 60.degree. C.,
preferably room temperature, for a period of time between 5 minutes
and 5 hours, preferably one hour, to afford a compound of formula
XIV.
[0080] Step 5 of scheme 3 is the reduction of a lactone. A compound
of formula XIV is treated with a reducing agent such as sodium
borohydride, borane tetrahydrofuran complex, borane dimethylsulfide
complex, diborane, lithium borohydride, calcium borohydride,
lithium aluminum hydride, diisobutylaluminum hydride, L-selectride
or K-selectride, optionally in the presence of a Lewis acid, such
as boron trifluoride diethyl ether complex; preferably sodium
borohydride in the presence of boron trifluoride diethyl ether
complex, in a solvent, such as tetrahydrofuran, diisopropyl ether,
methyl-tert-butyl ether or dimethoxyethane, preferably
tetrahydrofuran, at a temperature between -78 and 60.degree. C.,
preferably between 0.degree. C. and room temperature, for a period
of time between 30 minutes and 48 hours, preferably 16 hours, to
afford a compound of formula XV.
[0081] Step 6 of scheme 3 is a reduction. A compound of formula XV
is treated with a reducing agent such as triethylsilane or
triphenylsilane, in the presence of a Lewis acid such as boron
trifluoride etherate or trifluoroacetic acid preferably
trifluoroacetic acid, in a solvent such as dichloromethane,
dichloroethane, or chloroform, preferably dichloromethane at a
temperature between -78 and 60.degree. C., preferably room
temperature, for a period of time between 5 minutes and S hours,
preferably 2 hours, to afford a compound of formula II.
Alternatively, a compound of formula XV is treated with a reducing
agent that is a catalyst, such as platinum, platinum oxide, or
palladium hydroxide, preferably platinum, in a solvent such as
methanol, ethanol, or isopropanol, preferably ethanol, under an
atmosphere of hydrogen, optionally under pressure, at a temperature
between room temperature and 100.degree. C., preferably room
temperature, for a period of time between 1 and 48 hours,
preferably 5 hours, to afford a compound of formula II. 29
[0082] Alternatively, compound III can be purified by
derivatization. Step 1 of scheme 4 is the formation of a hydrazone.
A compound of formula III is treated with a hydrazone of formula
XVI with an acid such as acetic acid, sulfuric acid, hydrochloric
acid, methanesulfonic acid or p-toluenesulfonic acid, preferably
acetic acid, in a solvent such as methanol, ethanol, isopropanol,
tetrahydrofuran, water or a mixture of any of the foregoing
solvents, preferably a mixture of methanol and water, at a
temperature between 0 and 110.degree. C., preferably at reflux, for
a period of time between 30 minutes and 10 hours, preferably 90
minutes, to afford a compound of formula XVII.
[0083] Step 2 of scheme 4 is the hydrolysis of a hydrazone. A
compound of formula XVII is treated a reagent such as
copper(II)chloride, copper(II)iodide, copper(II)acetate, copper
sulfate, sulfuric acid, acetic acid or hydrochloric acid,
preferably copper(II)chloride, in a solvent such as tert-butyl
alcohol, methanol, ethanol, isopropanol, tetrahydrofuran, water or
a mixture of any of the foregoing solvents, preferably a mixture of
tert-butyl alcohol and water, at a temperature between 0 and
110.degree. C., preferably at 70.degree. C., for a period of time
between 30 minutes and 10 hours, preferably 2.5 hours, to afford a
compound of formula III.
[0084] The preparation of other compounds of the present invention
not specifically described in the foregoing experimental section
can be accomplished using combinations of the reactions described
above that will be apparent to those skilled in the art.
[0085] In each of the reactions discussed or illustrated in Schemes
1-4 above, pressure is not critical, unless otherwise indicated.
Pressures from about 0.9 atmospheres to about 2 atmospheres are
generally acceptable and ambient pressure, i.e., about 1
atmosphere, is preferred as a matter of convenience.
[0086] Intermediate compounds of invention referred to above may
contain chiral centers, and therefore may exist in different
enantiomeric and diastereomeric forms; this invention is directed
to all such optical and stereoisomers of said intermediate
compounds, as well as mixtures thereof.
[0087] This invention is also directed to isotopically-labeled
compounds identical to those recited in formulae Ia or Ib, or
pharmaceutically acceptable salts thereof, but for the fact that
one or more atoms are replaced therein by an atom having an atomic
mass or mass number different from the atomic mass or mass number
usually found in nature. Examples of isotopes that can be
incorporated into compounds of this invention include isotopes of
hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and
chlorine, such as .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F and
.sup.36Cl, respectively.
[0088] Compounds of the present invention, prodrugs thereof, and
pharmaceutically acceptable salts of said compounds, or of said
prodrugs, which contain the aforementioned isotopes and/or other
isotopes of other atoms are within the scope of this invention.
Certain isotopically-labeled compounds of the present invention,
for example those into which radioactive isotopes such as .sup.3H
and .sup.14C are incorporated, are useful, for example, in drug
and/or substrate tissue distribution assays. Tritiated, i.e.,
.sup.3H, and carbon-14, i.e., .sup.14C, isotopes are particularly
preferred for their ease of preparation and detectability.
Furthermore, substitution with heavier isotopes such as deuterium,
i.e., .sup.2H, can afford certain therapeutic advantages resulting
from greater metabolic stability, for example increased in vivo
half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances.
[0089] Isotopically labeled compounds of formulae Ia and Ib of this
invention and prodrugs thereof can generally be prepared by
carrying out the procedures set forth herein, by substituting a
readily available isotopically labeled reagent for a
non-isotopically labeled reagent.
[0090] The activity, methods for testing activities, dosages,
dosage forms, methods of administration and background information
concerning the compounds of formula Ia and Ib are set forth in
International Patent Publication No. WO 99/25714, published May 27,
1999. The piperidinylaminomethyl trifluoromethyl cyclic ether
compounds prepared by the methods of the present invention exhibit
significant substance P receptor-binding activity and are of value
in the treatment of a wide variety of clinical conditions which are
characterized by the presence of an excess of said substance P
activity. Such conditions include cardiovascular diseases, allergic
disorders, angiogenesis, gastrointestinal disorders, central
nervous system disorders, inflammatory diseases, emesis, urinary
incontinence, pain, migraine, sunburn, and diseases, disorders and
conditions caused by Helicobacter pylori, in a mammal, especially
humans. For treatment of emesis, these compounds may preferably be
used in combination with a 5-HT.sub.3 antagonist.
[0091] The active piperidinylaminomethyl trifluoromethyl cyclic
ether compounds of formulae Ia and Ib may be administered via
either oral, parenteral (e.g., intravenously, intramuscularly or
subcutaneously) or topical routes to mammals. These compounds may
be administered alone or in combination with pharmaceutically
acceptable carriers or diluents by any of the routes indicated
above, and may be carried out in single or multiple doses. The
compounds prepared by the methods of the invention may be
administered in a wide variety of different dosage forms, e.g.,
combined with various pharmaceutically acceptable inert carriers in
the form of tablets, capsules, lozenges, trochees, hard candies,
powders, sprays, creams, salves, suppositories, jellies, gels,
pastes, lotions, ointments, aqueous suspensions, injectable
solutions, elixirs, syrups and the like.
EXAMPLES
[0092] The present invention is illustrated by the following
examples. It will be understood, however, that the invention is not
limited to the specific details of these examples.
Example 1
[0093] 30
[0094] Acetic acid 2-(2-acetyl-5-methoxy-phenyl)-ethyl esterThis
compound was prepared by modification of a known procedure.
Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem. 7984, 49,
1574-1583. To a solution of aluminum tribromide (43.8 g, 164 mmol)
in dichloromethane (70 mL) at 0.degree. C. was slowly added acetyl
bromide (14.6 mL, 197 mmol). The reaction mixture was warmed to
15.degree. C. and 2-(3-methoxy-phenyl)-eth- anol (10.0 g, 65.7
mmol) in dichloromethane (20.0 mL) was added over 45 minutes. The
reaction mixture was stirred for one hour and then poured over ice
(100 mL). To the mixture was added 1 N aqueous hydrochloric acid
(100 mL). The organic layer was separated and the aqueous layer was
extracted with dichloromethane (100 mL). The combined organic
extracts were washed with 1N aqueous sodium hydroxide (100 mL),
dried over magnesium sulfate, filtered through Celite and
concentrated to afford acetic acid
2-(2-acetyl-5-methoxy-phenyl)-ethyl ester as an oil (14.8 g,
95%)..sup.1H NMR (300 MHz, CDCl.sub.3) .delta.2.05(s, 3), 2.59 (s,
3), 3.29 (t, 2,J=6.9), 3.89 (s, 3), 4.33 (t, 2, J=6.9), 6.81 (d, 1,
J=2.5), 8.85 (dd, 1, J=8.6, 2.6), 7.82 (d, 1, J=8.6).
[0095] .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.22.28, 30.37,
35.36, 56.63, 66.11, 101.21, 112.63, 119.17, 131.00, 134.23,
142.90, 163.24, 172.32. IR 1737, 1674, 1604, 1567, 1358, 1239, 1037
cm.sup.-1. Analysis calculated for C.sub.13H.sub.16O.sub.4: C,
66.09; H, 6.83. Found: C, 65.71; H, 7.21.
Example 2
[0096] 31
[0097] Acetic acid
2-[5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsil-
anyloxy-ethyl)-phenyl]-ethyl esterTo a solution of acetic acid
2-(2-acetyl-5-methoxy-phenyl)-ethyl ester (12.5 g, 52.9 mmol)and
cesium fluoride (0.964 g, 6.35 mmol) in dimethylformamide (75 mL)
at 0.degree. C. was slowly added trifluoromethyltrimethylsilane
(10.2 mL, 69.0 mmol). The reaction mixture was stirred 45 minutes
after which GS/MS and HPLC analysis showed no starting material.
For characterization purposes, the reaction mixture was poured into
water and extracted with methyl tert-butyl ether (100 mL). The
organic layer was washed with water (2.times.75 mL) and brine (50
mL), dried over magnesium sulfate, filtered and concentrated to
provide acetic acid 2-[5-methoxy-2-(2,2,2-trifluoro-1-
-methyl-1-trimethylsilanyloxy-ethyl)-phenyl]-ethyl ester as a crude
oil. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.0.19 (s, 9), 1.93 (s,
3), 2.10 (s, 3), 3.23-3.33 (m, 1), 3.42-3.52 (m, 1), 3.83 (s, 3),
4.26-4.32 (m, 2), 6.77 (dd, 1, J=8.9, 2.8), 6.86 (d, 1, J=2.9),
7.32 (d, 1, J8.9). .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.2.03,
21.03, 24.64, 32.86, 55.11, 65.54, 78.90 (q, J=30.3), 111.26,
117.44, 125.70 (q, J=287), 129.56, 129.79, 139.77, 159.17, 171.09.
IR 2961, 1741, 1610, 1383, 1286, 1255, 1165, 1140, 1039, 864, 846
cm.sup.-1. Analysis calculated for C.sub.17H.sub.25F.sub.3O.sub.4
Si: C, 53.95; H, 6.66. Found: C, 53.72; H, 6.53.
Example 3
[0098] 32
[0099] Acetic acid
2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethy-
l)-phenyl]-ethyl esterTo the crude reaction mixture described in
example 2 containing a solution of acetic acid
2-[5-methoxy-2-(2,2,2-trifluoro-1-me-
thyl-1-trimethylsilanyloxy-ethyl)-phenyl]-ethyl ester was added
tetrabutylammonium fluoride (52.9 mL of a 1.0 M solution in
tetrahydrofuran, 52.9 mmol). The reaction mixture was stirred one
hour after which GC/MS and HPLC analysis showed no starting
material. For characterization purposes, the reaction mixture was
poured into water and extracted with methyl tert-butyl ether (75
mL). The organic layer was washed with water (75 mL) and brine (50
mL), dried over magnesium sulfate, filtered and concentrated to
provide a crude oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.1.82
(s, 3), 2.01 (s, 3), 2.98-3.06 (m, 2), 3.55 (dt, 1, J=13.7, 6.8),
3.79 (s, 3), 4.27-4.34 (m, 2), 6.73-6.77 (m, 2), 7.28 (d, 1,
J=8.5). .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.20.92, 25.50,
34.16, 55.10, 66.49, 76.67 (q, J=30.3),111.55, 118.25, 126.02 (q,
J=286),128.67, 129.56, 139.70, 159.20, 171.32. IR 3453, 1720, 1610,
1249, 1161, 1134, 1038 cm.sup.-1. Analysis calculated for
C.sub.14H.sub.17F.sub.3O.sub.4: C, 54.90; H, 5.59. Found: C, 55.03;
H, 5.85.
Example 4
[0100] 33
[0101]
1,1,1-Trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-o-
lTo the crude reaction mixture described in example 3 containing
acetic acid
2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-et-
hyl ester was added 1N aqueous sodium hydroxide (75.0 mL, 75 mmol).
The reaction mixture was allowed to warm to room temperature and
was stirred 12 hours. The reaction mixture was poured into water
(75 mL) and extracted with methyl tert-butyl ether (150 mL). The
organic layer was washed with water (75 mL) and brine (75 mL),
dried over magnesium sulfate, and concentrated to an oil. To the
crude oil was added hexanes (20 mL) and methyl tert-butyl ether (4
mL) and a solid precipitated. The mixture was stirred for 30
minutes and filtered to provide
1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol
(7.3 g, 52% overall yield from acetic acid
2-(2-acetyl-5-methoxy-phenyl)-ethyl ester). M.p. 110-111.degree. C.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.83 (s, 3), 2.91 (dt, 1,
J=13.7, 3.9), 3.76 (ddd, 1, J=13.7, 9.3, 4.4), 3.85 (s, 3),
3.85-3.93 (m, 1), 4.08 (dt, 1 ,J=9.3, 3.7), 6.80-6.83 (m, 2), 7.38
(d, 1, J=8.4).
[0102] .sup.13C NMR (100 MHz, CDCl.sub.3) .delta.26.01, 36.12,
55.19, 64.13, 76.52 (q, j=28.9), 111.47, 117.43, 125.99 (q, J=287),
129.69, 129.94, 140.86, 159.55. IR 3395, 3162, 1610, 1513,1467,
1248, 1157, 1087, 1046 cm.sup.-1. Analysis calculated for
C.sub.12H.sub.15F.sub.3O.sub.3: C, 54.54; H, 5.72. Found: C, 54.65;
H, 5.70.
Example 5
[0103] 34
[0104] 6-Methoxy-1-methyl-1-trifluoromethyl-isochromanTo a solution
of
1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol
(5.00 g, 18.9 mmol) in dichloromethane (30 mL) was added
triethylamine (9.20 mL, 66.3 mmol). The solution was cooled to
0.degree. C. and methanesulfonyl chloride (1.61 mL, 20.8 mmol) was
added dropwise. The reaction mixture was allowed to warm to room
temperature and was stirred 12 hours. The formation of
methanesulfonic acid 2-[5-methoxy-2-(2,2,2-tri-
fluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl ester is rapid and
its disappearance was monitored by HPLC (retention time=4.5
minutes, Zorbax Rx-C6 column 4.6.times.150 mm, 40.degree. C., 50%
CH.sub.3CN/50% (0.2% Et.sub.3N, 0.1% H.sub.3PO.sub.4 aqueous pH=3.2
buffer), 1 mL/min). At the end of the reaction, the mixture was
poured into 1N aqueous hydrochloric acid (30 mL) and was extracted
with dichloromethane (20 mL). The organic extracts were dried over
magnesium sulfate, filtered, and concentrated to afford
6-methoxy-1-methyl-1-trifluoromethyl-isochroman as an oil (3.40 g,
73%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.69 (s, 3),
2.85-2.90 (m, 2), 3.85 (s, 3), 3.90-3.98 (m, 1), 4.14-4.21 (m, 1),
6.72 (d, 1,J=2.6), 6.85 (dd, 1, J=8.7, 2.6), 7.31 (d, 1, J=8.7).
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta.23.25, 29.42, 55.19,
61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85, 125.96 eq,
J=289), 127.86, 136.49, 158.98. IR 2946, 2839, 1738, 1611, 1505,
1162, 1137, 1101 cm.sup.-1. Analysis calculated for
C.sub.12H.sub.13F.sub.3O.sub.2: C, 58.54; H, 5.32. Found: C, 58.27;
H, 5.35.
Example 6
[0105] 35
[0106] (2-Acetyl-5-methoxy-phenyl)-acetic acidTo a solution of
aluminum tribromide (57.6 g, 216 mmol) in dichloromethane (90 mL)
at 0.degree. C. was slowly added acetyl chloride (11.5 mL, 162
mmol). To the reaction mixture was added (3-methoxy-phenyl)-acetic
acid (17.9 g, 108 mmol) in dichloromethane (20.0 mL). The reaction
mixture was stirred for one hour and then poured over ice (100 mL).
The organic layer was separated and 1N aqueous sodium hydroxide was
added (100 mL). The biphasic mixture was stirred vigorously for 90
minutes and the layers were separated. The organic layer was
discarded and concentrated hydrochloric acid was added to the
aqueous layer until the pH reached 1. A solid precipitated and was
filtered and air-dried to afford (2-acetyl-5-methoxy-phenyl)-acetic
acid (16.8 g, 75%). M.p. 153-155.degree. C. .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta.2.68 (s, 3), 3.91 (s, 3), 3.92 (s, 2), 6.92-6.95
(m, 2), 7.88 (d, 1, J=9.5). .sup.13C NMR (100 MHz, CDCl.sub.3)
.delta.28.33, 41.43, 55.46, 112.54, 118.26, 129.17, 133.08, 136.94,
162.65, 174.80, 200.96. IR 3435, 1704, 1663, 1609, 1568, 1258
cm.sup.-1. Analysis calculated for C.sub.11H.sub.12O.sub.4: C,
63.45; H, 5.81. Found: C, 63.35; H, 5.46.
Example 7
[0107] 36
[0108] (2-Acetyl-5-methoxy-phenyl)-acetic acid methyl esterTo a
solution of (2-acetyl-5-methoxy-phenyl)-acetic acid (5.00 g, 24.0
mmol) in methanol (50 mL) was added concentrated sulfuric acid (1.0
mL). The reaction mixture was stirred at room temperature for 16
hours after which it was concentrated to a low volume.
Dichloromethane (50 mL) was added and the solution was washed with
1N sodium hydroxide (50 mL). The layers were separated and the
organic layer was dried over magnesium sulfate, filtered, and
concentrated to an oil which solidified on standing to afford
(2-acetyl-5-methoxy-phenyl)-acetic acid methyl ester (4.70 g, 88%).
M.p. 74-76.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.2.58
(s, 3), 3.74 (s, 3), 3.89 (s, 3), 3.95 (s, 2), 6.78 (d, 1, J=2.6),
6.89 (dd, 1, J=8.7, 2.6), 7.89 (d, 1, J=8.6). .sup.13C NMR (75 MHz,
CDCl.sub.3) .delta.29.65, 42.35, 53.11, 56.69, 113.17, 120.00,
130.52, 134.39, 138.90, 163.54, 173.23, 200.35. IR 1739, 1665,
1605, 1568, 1321, 1247, 1165 cm.sup.-1.
[0109] Analysis calculated for C.sub.12H.sub.14O.sub.4: C, 65.85;
H, 6.35. Found: C, 64.87; H, 6.44.
Example 8
[0110] 37
[0111]
[5-Methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-
-phenyl]-acetic acid methyl esterTo a solution of
(2-acetyl-5-methoxy-phen- yl)-acetic acid methyl ester (2.00 g,
9.00 mmol) and cesium fluoride (96.0 mg, 0.632 mmol) in
dimethylformamide (12 mL) at 0.degree. C. was slowly added
trifluoromethyltrimethylsilane (1.73 mL, 11.7 mmol). The reaction
mixture was stirred at 0.degree. C. for 7 hours. For
characterization purposes, the reaction mixture was poured into
water and extracted with methyl tert-butyl ether (50 mL). The
organic layer was washed with water (2.times.75 mL) and brine (50
mL), dried over magnesium sulfate, filtered and concentrated to
provide [5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trim-
ethylsilanyloxy-ethyl)-phenyl]-acetic acid methyl ester as an oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.0.11 (s, 9), 1.89 (s, 2),
3.68 (s, 3), 3.77 (s, 3), 3.98 (d, 1, J=17.2), 4.28 (d, 1, J=17.0),
6.74-6.77 (m, 2), 7.29 (d, 1, J=9.1). .sup.13C NMR (100 MHz,
CDCl.sub.3) .delta.1.87, 24.25, 39.32, 51.75, 55.12, 78.67 (q,
J=30.3), 111.97, 118.30, 125.70 (q, J=286), 129.50, 129.57, 136.10,
159.17, 172.81. IR 2956, 1745, 1611, 1577, 1467, 1436, 1290, 1256,
1166, 1092, 989, 863, 847 cm.sup.-1. Analysis calculated for
C.sub.16H.sub.23F.sub.3O.sub.4Si: C, 52.73; H, 6.36. Found: C,
52.84; H, 6.36.
Example 9
[0112] 38
[0113] 6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-3-oneTo the
crude reaction mixture described in example 8 containing a solution
of
[5-methoxy-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilanyloxy-ethyl)-pheny-
l]-acetic acid methyl ester was added tetrabutylammonium fluoride
(9.00 mL of a 1.0 M solution in tetrahydrofuran, 9.00 mmol). The
reaction mixture was stirred for 1 hour after which it was poured
into water (50 mL) and extracted with methyl tert-butyl ether (50
mL). The organic layer was washed with water (50 mL) and brine (30
mL), dried over magnesium sulfate, filtered, and concentrated to
afford 6-methoxy-1-methyl-1-triflu- oromethyl-isochroman-3-one as
an oil (1.26 g, 54%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.1.89
(s, 3), 3.71 (d, 1, J=20.6), 3.79 (s, 3), 3.89 (d, 20.8), 6.65 (d,
1, J=1.5), 6.85-6.89 (m, 1), 7.29 (d, 1, J=8.7). .sup.13C NMR (100
MHz, CDCl.sub.3) .delta.21.45, 34.32, 55.33, 83.01 (q, J=30.3),
112.21, 113.88, 120.57, 124.68 (q, J=285.7), 127.73, 132.18,
160.75, 167.45. IR 1765, 1614, 1509, 1322, 1301, 1274, 1259, 1183,
1101, 997, 813 cm.sup.-1.
[0114] Analysis calculated for C.sub.12H.sub.11F.sub.3O.sub.3: C,
55.39; H, 4.26. Found: C, 55.03; H, 4.54.
Example 10
[0115] 39
[0116] 6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-3-olTo a
solution 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-one
(1.50 g, 5.76 mmol) in tetrahydrofuran (30 mL) at 0.degree. C. was
added sodium borohydride (0.240 g, 6.34 mmol) followed by boron
trifluoride diethyl ether complex (0.992 g, 8.07 mmol). The
reaction mixture was warmed to room temperature and was stirred
overnight. The reaction mixture was added to water (75 mL) and
extracted with methyl-tert-butyl ether (75 mL). The layers were
separated and the organic layer was washed with 1N aqueous
hydrochloric acid (50 mL), dried over magnesium sulfate, filtered,
and concentrated to afford
6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-ol as an oil and
a mixture of a and b anomers (1.19 g, 79%). Data reported for the
major diastereoisomer. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.1.74 (s, 3), 2.85 (dd, 1, J=15.7, 4.3), 2.88-2.99 (m, 1),
3.11 (dd, 1, J=15.7, 3.2), 3.80 (s, 3), 5.63 (t, 1, J=3.7), 6.69
(d, 1, J=2.7), 6.82 (dd, 1, J=8.7, 2.7), 7.22-7.27 (m, 1). .sup.13C
NMR (100 MHz, CDCl.sub.3, data reported for identifiable signals of
the major diastereoisomer) .delta.24.52, 35.46, 55.16, 90.71,
113.11, 113.98, 125.22, 127.57, 132.98, 159.59. IR 3439, 2949,
1735, 1613, 1506, 1166, 1141, 1070 cm.sup.-1
Example 11
[0117] 40
[0118] 6-Methoxy-1-methyl-1-trifluoromethyl-isochromanTo a solution
of 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-3-ol (8.36 g,
31.9 mmol) in dichloromethane (84 mL) was added triethylsilane
(15.3 mL, 95.8 mmol) followed by trifluoroacetic acid (14.7 mL, 191
mmol). The reaction was stirred at room temperature for 2 hours and
was poured into 1N aqueous sodium hydroxide (250 mL). The organic
layer was separated and washed with 1N aqueous sodium hydroxide
(100 mL). The organic layer was dried over magnesium sulfate,
filtered, and concentrated to afford
6-methoxy-1-methyl-1-trifluoromethyl-isochromanas an oil (6.88 g,
88%). .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.1.69 (s, 3),
2.85-2.90 (m, 2), 3.85 (s, 3), 3.90-3.98 (m, 1), 4.14-4.21 (m, 1),
6.72 (d, 1, J=2.6), 6.85 (dd, 1, J=8.7, 2.6), 7.31 (d, 1, J=8.7).
.sup.13C NMR (100 MHz, CDCl.sub.3 ) .delta.23.25, 29.42, 55.19,
61.37, 76.10 (q, J=27.4), 112.84, 113.43, 124.85, 125.96 (q,
J=289), 127.86,136.49, 158.98. IR 2946, 2839, 1738, 1611, 1505,
1162, 1137, 1101 cm.sup.-1. Analysis calculated for
C.sub.12H.sub.13F.sub.3O.sub.2: C, 58.54; H, 5.32. Found: C, 58.27;
H, 5.35.
Example 12
[0119] 41
[0120]
6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehydeTo
hexamethylenetetramine (31.3 g, 223 mmol) was added trifluoroacetic
acid (400 mL) and the mixture was heated to 70.degree. C. for 90
minutes. A solution of
6-methoxy-1-methyl-1-trifluoromethyl-isochroman (50.0 g, 203 mmol)
in trifluoroacetic acid (100 mL) was then added to the reaction
mixture over 40 minutes. The solution was stirred for 3 hours and
water was added (450 mL). The reaction mixture was stirred 16
hours, cooled to room temperature, and poured into methyl
tert-butyl ether (500 mL). The organic layer was separated and
washed with water (3.times.300 mL). The organic layer was poured
into a round bottom flask and cooled to 0.degree. C. 6N Sodium
hydroxide was added in portions until the pH raised to 10
(.about.500 mL). The organic layer was separated, washed with water
(200 mL), dried over magnesium sulfate, filtered, and concentrated
to afford 6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7--
carbaldehyde as an oil (54.2 g of a 12:1 mixture of regioisomers,
97%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.1.71 (s, 3), 2.95
(dt, 2, J=2.6, 5.3), 3.90-3.97 (m, 1), 3.97 (s, 3), 4.19 (dt, 1,
J=11.2, 5.6), 6.81 (d, 1, J=1.2), 10.4 (s, 1). .sup.13C NMR (75
MHz, CDCl.sub.3) .delta.23.07, 29.98, 55.73, 60.83, 76.03 (q,
J=27.4), 111.81, 112.50, 123.65, 125.32, 125.64 (q, J=287), 127.06,
160.89, 188.92. IR 1683, 1616, 1498, 1296, 1271, 1163, 1149, 1120,
1096, 874 cm.sup.-1. Analysis calculated for
C.sub.13H.sub.13F.sub.3O.sub.3: C, 57.13; H, 5.05. Found: C, 56.94;
H, 4.78.
Example 13
[0121] 42
[0122]
N'-1-[(E)-1-(6-Methoxy-1,1-dimethyl-3,4-dihydro-1H-isochromen-7-yl)-
methylidene]-4-methyl-1-benzenesulfonohydrazideTo a solution of the
crude
6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehyde
(54.2 g, 198 mmol) obtained from example 12 in methanol (542 mL)
was added p-toluenesulfonhydrazide (36.9 g, 198 mmol) followed by
2% aqueous acetic acid (81.3 mL). The reaction mixture was heated
to reflux for 90 minutes and cooled to room temperature. A solid
precipitated and was filtered to provide
N'-1-[(E)-1-(6-methoxy-1,1-dimethyl-3,4-dihydro-1H-isochromen-7-y-
l)methylidene]-4-methyl-1-benzenesulfonohydrazide (45.46 g, 52%).
M.p.=181-183.degree. C. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.1.71 (d, 3, J=0.7), 2.44 (s, 3), 2.85-2.89 (m, 2), 3.84 (s,
3), 3.93 (dt, 1, J=11.2, 5.6), 4.16 (dt, 1, J=11.2, 5.6), 6.65 (s,
1), 7.33 (d, 2, J=8.1), 7.79 (d, 1, J=1.2), 7.89 (d, 2, J=8.4),
8.13 (s, 1). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.21.48, 23.07,
29.50, 55.47, 60.99, 76.02 (q, J=27.4), 110.91, 120.45, 124.74,
125.04, 125.72 (q, J=287), 127.95, 129.45, 134.97, 138.97, 143.34,
144.22, 157.04. IR 3223, 1623, 1505, 1417, 1325, 1289, 1275, 1172,
1157, 1123, 1098, 918, 658 cm.sup.-1. Analysis calculated for
C.sub.20H.sub.21F.sub.3N.sub.2O.sub.4S: C, 54.29; H, 4.78; N, 6.33.
Found. C, 54.34; H, 4.73; N, 6.37.
Example 14
[0123] 43
[0124]
6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-carbaldehydeA
mixture of copper(II)chloride (52.7 g, 309 mmol) and
N'.sup..about.1.sup..about.[(E)-1-(6-methoxy-1,1-dimethyl-3,4-dihydro-1H--
isochromen-7-yl)methylidene]-4-methyl-1-benzenesulfonohydrazide
(45.5 g, 103 mmol) in tert -butyl alcohol (910 mL) and water (228
mL) was heated to 70.degree. C. for 2.5 hours. The reaction mixture
was cooled to room temperature, concentrated to about 300 mL and
poured into methyl tert-butyl ether (500 mL) and water (500 mL).
The mixture was stirred 15 minutes and filtered. The filtrate was
poured into methyl tert-butyl ether (200 mL) and the layers were
separated. The organic layer was washed with water (4.times.250
mL), dried over magnesium sulfate, filtered, and concentrated to
provide 6-methoxy-1-methyl-1-trifluoromethy-
l-isochroman-7-carbaldehyde as an oil which solidified on standing
(26.8 g, 95%). M.p.=82-93.degree. C. .sup.1H NMR (400 MHz,
CDCl.sub.8) 1.71 (s, 3), 2.95 (dt, 2, J=2.6, 5.3), 3.90-3.97 (m,
1), 3.97 (s, 3), 4.19 (dt, 1, J=11.2, 5.6), 6.81 (d, 1, J=1.2),
10.4 (s, 1). .sup.13C NMR (75 MHz, CDCl.sub.3) .delta.23.07, 29.98,
55.73, 60.83, 76.03 (q, J=27.4), 111.81, 112.50, 123.65, 125.32,
125.64 (q, J=287), 127.06, 160.89, 188.92. IR 1683, 1616, 1498,
1296, 1271, 1163, 1149, 1120, 1096, 874 cm.sup.-1.
[0125] Analysis calculated for C.sub.13H.sub.13F.sub.3O.sub.3: C,
57.13; H, 5.05. Found: C, 56.94; H, 4.78.
Example 15
[0126] 44
[0127]
(2S,3S)-[(1R)-6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylm-
ethyl]-(2-phenyl-piperidin-3-yl)-amine (S)-(+)-mandelateSodium
triacetoxyborohydride (11.61 g, 54.8 mmol) was added in one portion
to water bath chilled slurry of
6-methoxy-1-methyl-1-trifluoromethyl-isochro- man-7-carbaldehyde
(7.51 g, 27.4 mmol) and (2S-3S)-2-phenyl-piperidin-3-yl- amine
dimandelate (13.8 g, 28.7 mmol) in dichloromethane (150 mL). Within
15 minutes most starting material was dissolved and slow
precipitation of product began shortly after. The reaction mixture
was stirred 2.5 hour at room temperature, cooled to 0.degree. C.,
and 1N aqueous sodium hydroxide (150 mL) was added slowly. The
layers were separated, the aqueous layer (pH 9) was extracted with
dichloromethane (50 mL). The combined organic extracts were stirred
one hour with 1N aqueous sodium hydroxide (100 mL), the layers were
separated and the organic layer was washed with water (50 mL),
brine (50 mL), dried over Na.sub.2SO.sub.4, and filtered. The
solvent was evaporated and the resulting off-white foam vacuum
dried to give 11.08 g ( 93% ) of the crude product. S-(+)Mandelic
acid (7.55 g, 49.6 mmol ) dissolved in ethanol (100 mL) was added
to a solution of the mixture of diastereomers of
(6-methoxy-1-methyl-1-trifluoromethyl-isochro-
man-7-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine (10.78 g, 24.8
mmol) in ethanol (300 mL) at room temperature. The mixture was
stirred and crystallization began to proceed. After stirring
overnight, the mixture was filtered to yield 4.66 g (32% ) of
(6-methoxy-1-methyl-1-trifluoromet-
hyl-isochroman-7-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine
(S)-(+)-mandelate as a mixture of diastereomers (81:19 ratio by
HPLC analysis). .sup.1H NMR (400 MHz, CDCl.sub.3 data reported for
major diastereoisomer) .delta.1.42-1.64 (m, 2), 1.53 (s, 3),
1.72-1.79 (m, 1), 1.94-1.98 (m, 1), 2.46-2.89 (m, 4), 3.15-3.28 (m,
3), 3.45 (s, 3), 3.47-3.78 (m, 1), 3.92-3.97 (m, 2), 4.27 (bs, 1),
4.52 (s, 1), 6.66 (s, 1), 7.04-7.19 (m, 4), 7.27-7.36 (m, 7).
.sup.13C NMR (100 MHz, CDCl.sub.3) .delta.16.99, 22.53, 25.96,
28.58, 45.05, 45.46, 53.52, 53.95, 55.08, 60.61, 61.86, 73.25,
75.54 (q, J=28.2), 110.36, 126.02, 126.27, 126.32, 126.42, 126.55,
127.01, 127.43, 127.57, 128.27, 135.04, 137.83, 143.16, 156.51,
174.59. IR 3441, 1576, 1358, 1160, 1136, 1098, 1038, 775, 756, 698
cm.sup.-1. Analysis calculated for
C.sub.32H.sub.37F.sub.3N.sub.2O.sub.5: C, 65.52; H, 6.36; N, 4.78.
Found: C, 65.55; H, 6.03; N, 4.84.
Example 16
[0128] 45
[0129]
(2S,3S)[(1R)-6-Methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylme-
thyl]-(2-phenyl-piperidin-3-yl)-amine
dihydrochloride(6-Methoxy-1-methyl-1-
-trifluoromethyl-isochroman-7-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine
(S)-(+)-mandelate (2.25 g of a 81:19 mixture of diastereoisomer,
3.84 mmol) was stirred overnight in diisopropyl ether (23 mL) and
1N aqueous sodium hydroxide (23 mL). The layers were separated and
the organic layer washed with water (20 mL) and brine (20 mL). The
organic layer was concentrated to a crude waxy solid and methanol
(15 mL) was added. The solution was stirred at room temperature and
a solution of 1.5N aqueous hydrochloric acid (5.0 mL) was added
dropwise. The dihydrochloride salt precipitated immediately and the
white slurry was stirred overnight at room temperature, filtered
and dried under vacuum to afford
(6-methoxy-1-methyl-1-trifluoromethyl-isochroman-7-ylmethyl)-(2-phenyl-pi-
peridin-3-yl)-amine dihydrochloride (1.282 g, 66%) as a 96:4
mixture of diastereoisomers. The diastereomeric ratio could be
further increase by crystallization from methanol/water (75/25).
.sup.1H NMR (400 MHz, D.sub.2O, data reported for major
diastereoisomer) .delta.1.52 (s, 3), 1.80-1.92 (m, 2), 1.95-2.50
(m, 1), 2.21-2.26 (m, 1), 2.63-2.71 (m, 2), 3.04-3.11 (m, 1), 3.36
(s, 3), 3.45-3.49 (m, 1), 3.65-3.81 (m, 3), 3.90-3.96 (m, 1), 4.09
(d, 1, J=13.5), 6.46 (s, 1), 6.98-7.07 (m, 3), 7.23-7.25 (m, 2),
7.30 (t, 1, J=7.5). IR 2958, 1457, 1377, 1143, 749, 692 cm.sup.-1.
Analysis calculated for C.sub.24H.sub.31Cl.sub.2F.sub.3N.sub.2-
O.sub.2: C, 56.81; H, 6.16; Cl, 13.97; N, 5.52. Found: C, 56.69; H,
6.31; Cl, 14.13; N, 5.55.
* * * * *