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Patent 2386981 Summary

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(12) Patent: (11) CA 2386981
(54) English Title: PREPARATION OF 4-(4-FLUOROPHENYL)-N-ALKYLNIPECOTINATE ESTERS, 4-(4-FLUOROPHENYL)-N-ARYLNIPECOTINATE ESTERS AND 4-(4-FLUOROPHENYL)-N-ARALKYLNIPECOTINATE ESTERS
(54) French Title: PREPARATION DE 4-(4-FLUOROPHENYL)-N-ALKYLNIPECOTINATES, DE 4-(4-FLUOROPHENYL)-N-ARYLNIPECOTINATES ET DE 4-(4-FLUOROPHENYL)-N-ARYLALKYLNIPECOTINATES
Status: Deemed expired
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07D 211/60 (2006.01)
  • C07D 405/12 (2006.01)
(72) Inventors :
  • REY, ALLAN W. (Canada)
  • MURTHY, K.S. KESHAVA (Canada)
  • RADATUS, BRUNO K. (Canada)
  • ZHAO, YAJUN (Canada)
  • NISH, TANIA E. (Canada)
(73) Owners :
  • APOTEX PHARMACHEM INC. (Canada)
(71) Applicants :
  • BRANTFORD CHEMICALS INC. (Canada)
(74) Agent: MCKINNON, GRAHAM J.K.
(74) Associate agent:
(45) Issued: 2007-05-08
(22) Filed Date: 2002-05-16
(41) Open to Public Inspection: 2003-11-16
Examination requested: 2002-05-16
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data: None

Abstracts

English Abstract




A process for the industrial scale manufacture of 4-(4-fluorophenyl)-N-
alkylnipecotinate esters by the addition of 4-fluorophenylmagnesium halide in
tetrahydrofuran to 3,4-unsaturated-3-piperidine esters.


Claims

Note: Claims are shown in the official language in which they were submitted.




17
CLAIMS
1. A process for the preparation of a compound of structure A or salts thereof
Image
in which R and R' are selected from alkyl, cycloalkyl, aryl, or aralkyl group,
which
comprises reacting a compound of structure B
Image
with an organometallic compound of structure C,
Image
where X is Cl or Br, the reaction occurring in a suitable organic reaction
solvent,
wherein the reaction solvent is dibutyl ether wherein said reaction is in the
complete




18

absence of diethyl ether throughout the process wherein the resultant compound
A is
substantially free of a 1,2-conjugate by-product.
2. A process for the preparation of a compound of structure A or salts thereof
Image
in which R and R' are selected from alkyl, cycloalkyl, aryl, or aralkyl group,
which
comprises reacting a compound of structure B
Image
with an organometallic compound of structure C,
Image




19
where X is Cl or Br, the reaction occurring in a suitable organic reaction
solvent wherein
the reaction solvent is dibutyl ether and wherein said reaction is in complete
absence of
diethyl ether throughout the process.
3. Process of claim 1 or 2 where R and R' are methyl.
4. Process of claim 1 or 2 where R is methyl and R' is (1R,2S,5R)-(-)-menthyl.
5. Process of claim 1 or 2 where X is Br.
6. Process of claim 1 or 2 where the salt form of A is HBr.
7. A process of claim 1 or 2 whereby the yield of A the 1,4-conjugated product
is
50% or greater.
8. A process for the preparation of 1 according to the procedure of claim 1
Image
9. The process according to claim 8 where 1 is further converted to paroxetine
hydrochloride.
10. A process for the preparation and isolation of 6 according to the
procedure of
claim 1 or 2



20
Image
11. The process according to claim 10 where 6 is further converted to (+)-
(3R,4S)-
trans-3-[(1,3-Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine
hydrochloride.
12. A method of preparing paroxetine, its salts, and esters thereof comprising
carrying out a process of any of claims 9 or 11.
13. A method of preparing paroxetine, its salts, and esters thereof comprising
carrying out a process of any of claims 1-8, or 10 and further converting the
product to
paroxetine.
14. The method of claim 12 wherein the paroxetine formed is substantially
crystalline.
15. The method of claim 13 wherein the paroxetine formed is substantially
crystalline.
16. The method of claim 12 wherein the paroxetine formed is substantially
amorphous.
17. The method of claim 13 wherein the paroxetine formed is substantially
amorphous.




21
18. The process of any of claims 1-9 or 11 wherein the yield of the compound
of
structure A or salts thereof is greater than about 10%.
19. The process of claim 1 or 2 wherein the yield of the compound of structure
A or
salts thereof is greater than about 10%.
20. The process of claim 18 wherein the yield is greater than about 30%.
21. The process of claim 19 wherein the yield is greater than about 30%.

Description

Note: Descriptions are shown in the official language in which they were submitted.



CA 02386981 2002-05-16
TITLE OF THE INVENTION
Preparation of 4-(4-fluorophenyl)-N-alkylnipecotinate esters, 4-(4-
fluorophenyl)-N-
arylnipecotinate esters and 4-(4-fluorophenyl)-N-aralkylnipecotinate esters.
BACKGROUND OF THE INVENTION
4-(4-Fluorophenyl)-N-alkylnipecotinate esters of general formula A represent
key
intermediates in the synthesis of 4-arylpiperidine-based compounds. It is
noteworthy
that 4-arylpiperidine is an important structural motif in many biologically
active
compounds (M. Engelstoft and J.B. Hansen, Acta Chemical Scandinavica, 50,1996,
pp.
164-169).
F
O
~OR'
N
R
A
An example is (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate
hydrobromide (1) which is a key intermediate in the synthesis of paroxetine.
Paroxetine
(Paxil~ is a highly effective chiral pharmaceutical that is useful for the
treatment of
depression and obsessive compulsive disorder.
F F
O O
a' a
N~. N
. H8r ~ . HCI
CH3 H
Paroxetine (Paxil~


CA 02386981 2002-05-16
2
The use of this compound for this purpose was disclosed in US patents
3,912,743 and
4,007,196 whereby 4-fluorophenylmagnesium bromide was added to arecoline. The
resulting adduct was epimerized and the methyl ester functionality hydrolyzed,
activated using thionyl chloride; esterified using (-)-menthol, and salt
formation using
hydrobromic acid to provide compound 1, as depicted in Scheme 1, which was
further
elaborated to paroxetine using standard procedures.
SCHEME 1
F F F F
w OMa
M~Br 1. Ms0'Na +
Me O~ 2. HCI ~ pN
Me Me.HO Me.HO
1. SOC12
2. ~(
(R'~
F F F F F
O ~---~--~-- HBr ~ +
R. t-- 1
OR' ~R~
H .H~ ~.H3r ~.hBr
Paroxetlne Me Me
1 6
The procedure disclosed in these patents for the key Grignard conjugate
addition step
was based on a procedure developed by Plati et al. (US Patent 2,546,652 and
Journal of
Organic Chemistry, 22,1957, pp. 261-265) for the reaction of phenylmagnesium
bromide
in diethyl ether with arecoline, also in diethyl ether. Thus, a major
deficiency of this
process, and likewise the processes disclosed in US patents 3,912,743 and
4,007,196, was
the diethyl ether in both the arylmagnesium bromide reagent and the reaction
media.
Diethyl ether is a highly flammable solvent which is undesirable to use
industrially.
According to patents by Ward [(US patent 6,172,233) and Ward et al. (WO
01/17966A1


CA 02386981 2002-05-16
3
and WO 01/29032A1)], the use of other ether solvents conventionally used in
Grignard
reactions, such as tetrahydrofuran (THF) or diisopropyl ether, furnished
little, if any, of
the desired 1,4-conjugate addition product, with the main by-product arising
from 1,2-
addition of the Grignard reagent on the ester grouping. From an industrial
perspective,
a multistep transformation in which one step resulted in, "little if any of
the desired
product" (for instance <10% yield) would be prohibitively expensive.
Compounding
this deficiency, if this process were to be used for the synthesis of
paroxetine, is the fact
that the low yielding step occurs at a rather late-stage in the paroxetine
process, thereby
necessitating the processing of large volumes of intermediary products in
order to reach
the Grignard reaction step. Also, disclosed in the Ward patent was the
observation that
when performing the reaction using the process described by Plati et al., the
reaction
mixture purportedly generated thick unstirrable gels.
These deficiencies were purportedly overcome by Ward by the use of a reaction
solvent
mixture which was non-wholly ether, as utilized by Plati et al. As well, the
Ward
patents purport that the use of organometallic compounds in place of the
Grignard
reagent also overcame these deficiencies. However, in all examples in the Ward
patents, the Grignard reagent used was always a 2M solution of 4-
fluorophenylmagnesium bromide in diethyl ether. Specifically, in examples 2,
3, 4 and
of US patent 6,172,233, the weight percentage of diethyl ether introduced by
the 4-
fluorophenylmagnesium bromide in diethyl ether reagent relative to the total
reaction
volume was about 23 to 31% range. Therefore the disadvantage of having a
process
which necessitated diethyl ether, with all of the disadvantages associated
with this
solvent, largely remained. In example 1 of the same patent, the diethyl ether
is removed
from the 2M 4-fluorophenylmagnesium bromide reagent prior to the addition to
arecoline by co-distillation with toluene. However, this requires an extra
process
operation and, again, does not avoid the use of diethyl ether on an industrial
scale.
Similar reactions have also been utilized for transformations of this type.
For instance,
Murthy and Rey in US patent 5,962,689 disclose the stereoselective addition of
4-


CA 02386981 2002-05-16
4
fluorophenylmagnesium bromide to various 3,4-unsaturated-3-piperidine esters,
amides and N-enoylsultams in toluene. Xu and Trudell (j. Heterocyclic Chem.,
33,1996,
pp. 2037-2039) also described the addition of various arylmagnesium bromide
reagents,
including 4-fluorophenylmagnesium bromide, to R-(-)-anhydroecgonine methyl
ester
substrates in dichloromethane. The disadvantage in both of these publications
is that a
solution of the aryl Grignard reagent in diethyl ether was employed.
It is therefore an object of the invention to provide a process which utilizes
solvents
other than diethyl ether to arrive at yields greater than "little if any" of
the desired
product.
It is therefore also another object of the invention to provide a process that
is easy to
perform and incorporates solvents that are less flammable and/or less toxic
relative to
solvents used as reaction media in the prior art.
It is also an object of the invention to provide a process which results in
substantially no
gels being formed, even on scale up to industrial quantities.
Further and other objects of the invention will become apparent to a person
reading the
following.
SUMMARY OF THE INVENTION
To overcome these difficulties, we sought an alternative method whereby the
aryl
Grignard reagent in a solvent which was not diethyl ether could be used for
the
conjugate addition to an arecoline based substrate 2 (Scheme 2). Surprisingly,
we
discovered that using the 4-fluorophenylmagnesium bromide reagent in THF,
contrary
to the teachings of the Ward patent, resulted in clean 1,4-conjugate addition
when
dibutyl ether was used as the reaction media producing about in one instance a
50-90%
(which is at least greater than about 10% of a more than "little if any")
molar yield of the
desired adduct 3. Surprisingly, none of the 1,2-byproduct was noted but rather
the 4,5-
isomer 4 (7-15%). Only a trace amount of product arising from 1,2-addition was
noted,


CA 02386981 2002-05-16
namely the 1,2:1,4-compound 5. The Ward patents teach away from the use of a
solvent
other than diethyl ether since Ward reported "little if any" desired product.
Furthermore, it appears that Ward did not carry out the processes, since in
carrying out
the process using solvents other than diethyl ether we arrive at results in
yield
substantially more than "little if any" of the desired product.
SCHEME 2
F F F
O ~ in THF ~ ~ O
MgBr v O O O
---s
Bu20 or N ~O~
Me toluene ~ Me N~ ~F
Me Me
50-90°h
4
For this type of reaction, there are several beneficial features of using 4-
fluorophenylmagnesium bromide in a suitable reagent, such as a THF reagent and
in a
suitable reaction media, such as dibutyl ether as the reaction media. The
beneficial
features include, but are not limited to, substantially no gels are formed,
even on scale-
up to industrial quantities. Also in terms of industrial applicability, the
suitable
reaction media, such as dibutyl ether is less flammable and/or toxic relative
to diethyl
ether, toluene and dichloromethane which were used as the reaction media in
the prior
art. This is due to the reduced volatility of dibutyl ether (bp =142-
143°C) relative to the
other solvents. Another industrial advantage is that it is substantially
facile to perform
the reaction under substantially if not completely anhydrous conditions by
azeotropically removing water by distilling a small amount of the dibutyl
ether solvent
from the reaction mixture. This avoids the necessity of pre-drying the solvent
using
drying reagents such as metallic sodium or calcium oxide. Finally, the high
boiling
point of dibutyl ether facilitates solvent recovery which represents an
industrially
important advantage since it minimizes costs by solvent recycling and waste
reduction.


CA 02386981 2002-05-16
6
Methods for the preparation of the (1R,2S,5R)-(-)-menthyl arecoline substrate
2 and
other substrates of this type are described in US patent 5,962,689 by Murthy
and Rey.
In general, the conjugate addition reaction may be performed using 4-
fluorophenylmagnesium bromide Grignard reagent preferably in THF preferably at
a
stoichiometry of 1.0 to 2.0 equivalents relative to the arecoline-based
substrate, more
preferably at 1.1 to 1.5 equivalents and most preferably at 1.2 to 1.4
equivalents. The
reaction may be performed in an organic solvent such as a hydrocarbon
(aliphatic and
aromatic), halogenated hydrocarbon, or ether. Preferably suitable solvents
include
toluene, heptanes, dibutyl ether, methyl tent-butyl ether, isopropyl ether,
tetrahydrofuran or mixtures thereof. More preferable solvents include dibutyl
ether,
tetrahydrofuran or toluene. The most preferred solvent is dibutyl ether. The
reaction is
preferably carried out under an inert atmosphere, for example under argon or
nitrogen.
The reaction may be conducted at a temperature of preferably -10°C to
50°C, more
preferably at -10° to 30°C, and most preferably at -10°
to 20°C. Under these conditions,
the reaction is complete in less than about 8 hours. If desired, a copper
species may be
added to the reaction mixture such as cuprous chloride, cuprous bromide,
cuprous
iodide, or cuprous bromide-dimethyl sulfide complex. The use of 4-
fluorophenylmagnesium chloride in diethyl ether may also be used as the
Grignard
source.
The conjugate addition product 3 (Scheme 2) was further elaborated to 1 by
epimerization to the thermodynamically more stable traps-geometry at the C-3
and C-4
position of the piperidine ring using potassium tert-butoxide followed by salt
formation
using 48% hydrobromic acid. The stereoisomer requisite for further elaboration
to
paroxetine, (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-methylnipecotinate
hydrobromide (1), precipitated from the reaction mixture and was isolated by
filtration.
The menthyl (3R,4S)-traps-4-(4-fluorophenyl)-N-methylnipecotinate hydrobromide
(6)
stereoisomer remained in the filtrate. These transformations are described in
the
examples 1 to 8.


CA 02386981 2002-05-16
7
In another aspect of the invention, we were surprisingly able to isolate in
high purity
and yield and as a crystalline solid the stereoisomer menthyl (3R,4S)-traps-4-
(4-
fluorophenyl)-N-methylnipecotinate hydrobromide (6) by concentration of the
filtrate
after the precipitation of 1. This compound may be of use for either
conversion to (-)-
menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-methylnipecotinate hydrobromide by
epimerization of the stereocentres at C-3 and C-4 of the piperidine ring or
for producing
the (3R,4S)-enantiomer of paroxetine.
F
O
..
~N
. HBr
CH3
6
In another aspect of the invention, a cost effective, safe and scalable method
for the
synthesis exemplified by (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) has been discovered using 4-
fluorophenylmagnesium bromide in THF and, most preferably, where the reaction
is
performed in a wholly ether reaction media. This method avoids the
deficiencies of the
prior art where diethyl ether was used either as part of the Grignard reagent
or as
reaction media. The compound 1 represents a key intermediate in the synthesis
of the
medicinally valuable antidepressant paroxetine. Also, this route permits the
isolation of
6 which can be further elaborated to (+)-(3R,4S)-traps-3-[(1,3-Benzodioxol-5-
yloxy)methyl]-4-(4-fluorophenyl)piperidine hydrochloride, or else recycled to
1.
Thus, according to one aspect of the invention, there is provided a process
for the
industrial scale preparation of a compound of structure A or salts thereof


CA 02386981 2003-11-26
g
F
Oo
~OR'
N
R
A
in which R and R' are selected from an alkyl, cycloalkyl (such as (1R,2S,5R)-(-
)-
menthyl), aryl, or aralkyl group, which comprises reacting a compound of
structure B
0
'OR'
N
R
B
with an organometallic compound of structure C, in a suitable organic solvent
with the
proviso that it is not diethyl ether
F
O
where X is Cl or Br. Preferably the suitable organic solvent is selected from
the group
consisting of dibutyl ether, tetrahydrofuran, or toluene.
In one embodiment, R is methyl and R' is (1R,2S,5R)-(-)-menthyl. Preferably,
the salt
form of A is HBr.


CA 02386981 2002-05-16
9
In another embodiment, the yield of A is greater than "little if any" product,
preferably
greater than 10°!°, preferably yet 50°!° or
greater.
In yet another embodiment, as part of the invention, there is provided a
process for the
preparation of 1 according to the procedure described herein.
F
O
...."'O . . , ,
NJ
. Hsr
CH3
In another embodiment,1 is further converted to paroxetine hydrochloride.
In yet another embodiment, there is provided a process for the preparation and
isolation of 6 according to the procedures described herein.
F
0
_ ,,
~a~'
N
. HBr
CH3
6
Preferably, 6 is further converted to (+)-(3R,4S)-traps-3-[(1,3-Benzodioxol-5-
yloxy)methyl]-4-(4-fluorophenyl)piperidine hydrochloride.
In another aspect of the invention, there is provided menthyl (3R,4S)-traps-4-
(4-
fluorophenyl)-N-methylnipecotinate hydrobromide in crystalline form.


CA 02386981 2005-05-18
In another aspect of the invention, there is provided (+)-(3R,4S)-traps-3-
[(1,3-
Benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine hydrochloride.
The following examples are illustrative of the invention and are not to be
construed as
limiting the scope of the invention in any manner.
Example 1: Preparation of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) in dibutyl ether (DBE)
A round bottom flask was charged with 4-fluorophenylmagnesium bromide (1M in
THF, 140 mL, 0.140 mol) and the flask was cooled to -10 to -8°C and
kept under a
nitrogen atmosphere. To this mixture was added (1R,2S,5R)-(-)-menthyl
arecoline (28.0
g, 0.100 mol) in DBE (total volume of solution =160 mL) over a period of about
1 hour.
The solution was warmed to 12 to 16°C and the reaction was kept at this
temperature a
further 4 hours. It was then cooled to -5 to -10°C and saturated
aqueous ammonium
chloride (158 mL) was added while maintaining the temperature below
10°C. The
mixture was filtered through a Celite~ pad and the filter cake washed with DBE
(2 X 31
mL) and the filtrate was transferred to a separatory funnel. The aqueous layer
was
removed and back-extracted with DBE (31 mL). The combined organic layers were
concentrated to 160 mL. A HPLC assay at this point indicated 33.5 g of
(cis/trans)-
menthyl-4-(4-fluorophenyl)-N-methylnipecotinate (89% yield from (IR,2S,5R)-(-)-

menthyl arecoline). The solution was cooled to -5°C whereupon potassium
tert-
butoxide (5.6 g, 0.050 mol, 0.5 eq) was added in portions over a 0.5 to 1 hour
period.
The reaction mixture was then stirred at 0°C until reaction completion.
The pH was
adjusted to 8-9 using 0.7 M HCl and the reaction mixture transferred to a
separatory
funnel and the layers were separated. The aqueous layer was back-extracted
with DBE
(62 mL) and the organic layers were combined and concentrated to 160 mL. This
solution was cooled to -5°C and 48% aqueous hydrobromic acid was added
(11.3 mL,
0.10 mol) over about 0.5 hours. The reaction mixture was charged with ethyl
acetate
(188 mL) and stirred at 0°C for a further 1.5 hours. The precipitated
product was


CA 02386981 2005-05-18
11
collected by filtration and the filter cake was rinsed with a portion of ethyl
acetate and
the solid dried a 40 to 45°C in vacuo. This provided 15.08 g (33% yield
from (1R,2S,5R)-
(-)-menthyl arecoline) of the (-)-menthyl (3S,4R)-trans-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide as a white solid.1H NMR (DMSO) b: 9.71 (1H,
br. s),
7.14-7.24 (4H, m), 4.37 (1H, atd, J=4.2, 10.8 Hz), 3.70 (1H, ad, J=10.4 Hz),
3.52 (1H, ad,
J=11.8 Hz), 3.13-3.19 (3H, m), 2.94-3.05 (1H, m), 2.86 (3H, s), 1.90-2.15 (m,
2H),1.69 (1H,
ad J=11.5 Hz),1.52-1.62 (1H, m),1.43-1.51 (1H, m), 1.25-1.42 (1H, br. m), 1.02-
1.13 (1H,
m), 0.80-0.92 (1H, m), 0.75-0.90 (1H, m), 0.64-0.87 (2H, m), 0.83 (3H, d,
J=6.5 Hz), 0.60
(3H, d, J=6.7 Hz), 0.29 (3H, d, J=6.6 Hz); Elemental analysis calculated for
C~H~sNOzFBr:
C, 60.52, H, 7.73, N, 3.07; found: C, 60.64, H, 7.87, N, 3.15; [a]D~ _ -
62.9° (c=1.0,
methanol).
Example 2: Preparation of (-)-menthyl (3S,4R)-trans-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) in DBE and copper chloride
A round bottom flask was charged with 4-fluorophenylmagnesium bromide (1M in
THF, 56 mL, 0.0560 mol) and the flask was cooled to -3 to 1°C and kept
under a nitrogen
atmosphere. To this mixture was added cuprous chloride (0.40 mg, 4.0 mmol)
followed
by (1R,2S,5R)-(-)-menthyl arecoline (11.2 g, 40.1 mmol) in DBE (total volume
of solution
= 68 mL) over a 35 minute period. The cooling bath was removed and the
solution was
warmed to room temperature (23°C) and the reaction was kept at this
temperature a
further 3 hours. It was then cooled to 10°C and saturated aqueous
ammonium chloride
(55 mL) was added while maintaining the temperature below 17°C. The
mixture was
filtered through a Celite~ pad and the filter cake washed with DBE (1 X 10 mL)
and the
filtrate was transferred to a separatory funnel. The aqueous layer was removed
and
back-extracted with DBE (2 X 15 mL). The combined organic layers were
concentrated
to a weight of 51 g and cooled to -6°C whereupon potassium tert-
butoxide (1.95 g, 17.4
mmol) was added in portions over a 0.5 hour period. The reaction mixture was
then
stirred at 0°C for about 3 hours and the pH was adjusted to 8.3 using
2.8% HCl at 0°C
and the reaction mixture transferred to a separatory funnel and the layers
were


CA 02386981 2002-05-16
12
separated. The aqueous layer was back-extracted with DBE (3 X 10 mL) and the
organic
layers were combined and concentrated to 58 g. This solution was cooled to -
5°C and
48% aqueous hydrobromic acid was added (6.69, 0.040 mol) over about 0.5 hours.
The
reaction mixture was charged with ethyl acetate (73 mL) and stirred at
0°C for a further
1.5 hours. The precipitated product was collected by filtration and the filter
cake was
rinsed with a portion of ethyl acetate and the solid dried a 40 to 45°C
in vacuo. This
provided 5.36 g (29.3% yield from(1R,2S,5R)-(-)-menthyl arecoline) of the (-)-
menthyl
(3S,4R)-traps-4-(4-fluorophenyl)-N-methylnipecotinate hydrobromide as a white
solid
and the material had the same'H NMR as the product from example 1.
Example 3: Preparation of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) in DBE, copper chloride and 30°C
Reaction
Temperature for the Grignard Addition
The same procedure as the one described in example 2 was followed except that
the
round bottom flask containing 4-fluorophenylmagnesium bromide (1M in THF, 56
mL,
0.0560 mol) and cuprous chloride (0.40 mg, 4.0 mmol) was maintained at 27-
32°C during
the addition of the (1R,2S,5R)-(-)-menthyl arecoline substrate (30 minutes)
and
subsequent maintain time of 2 hours. The yield of (-)-menthyl (3S,4R)-traps-4-
(4-
fluorophenyl)-N-methylnipecotinate hydrobromide was 5.03 g (27.5% yield from
(1R,2S,5R)-(-)-menthyl arecoline) and the material had the same 1H NMR as the
product
from example 1.
Example 4: Preparation of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) in Tetrahydrofuran (THF)
A round bottom flask is charged with 4-fluorophenylmagnesium bromide (1M in
THF,
56 mL, 0.0560 mol) and the flask was cooled to -10 to -5°C and kept
under a nitrogen
atmosphere. To this mixture was added a solution of (1R,2S,5R)-(-)-menthyl
arecoline
(11.2 g, 40.1 mmol) in THF (60 mL) over a 1.5 hour period. The cooling bath
was
removed and the solution was warmed to 15°C and the reaction was kept
at this


CA 02386981 2005-05-18
13
temperature a further 8 hours. It was then quenched using saturated aqueous
ammonium chloride (75 mL) while maintaining the temperature below 17°C.
T'he
mixture was filtered through a Celite~ pad and the filter cake washed with
toluene (1 X
mL) and the filtrate was transferred to a separatory funnel. The aqueous layer
was
removed and back-extracted with toluene (2 X 50 mL). The combined organic
layers
were concentrated to a weight of 55 g and cooled to -5°C whereupon
potassium tert-
butoxide (2.2 g, 19.6 mmol) was added in portions over a 0.5 hour period. The
reaction
mixture was then stirred at -3°C for 3.7 hours and the pH was adjusted
to 8 using 1.7%
HCl at -5 to 0°C and the reaction mixture transferred to a separatory
funnel and the
layers were separated. The aqueous layer was back-extracted with toluene (2 X
12 mL)
and the organic layers were combined and concentrated to 24.9 g. This solution
was
cooled to to 0°C and 48% aqueous hydrobromic acid was added (6.7, 0.040
mol) over
about 0.5 hours. The reaction mixture was charged with ethyl acetate (36 mL)
and
stirred at 0°C for a further 1.5 hours. This procedure was repeated
another time with 48
mL of ethyl acetate and the reaction mixture stirred a further 3 hours. The
precipitated
product was collected by filtration and the filter cake was rinsed with a 12
mL portion
of ethyl acetate and the solid dried a 50°C in vacuo for 2 hours. This
provided 5.2 g
(28.5% yield from (1R,25,5R)-(-)-menthyl arecoline) of (-)-menthyl (3S,4R)-
traps-4-(4-
fluorophenyl)-N-methylnipecotinate hydrobromide as a white solid and having
the
same 1H NMR as the product from example 1.
Example 5: Preparation of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) in Heptanes/DBE and Addition of the
Grignard
reagent to the (1R,2S,5R)-(-)-menthyl arecoline substrate
The same procedure as the one described in example 2 was followed except that
cuprous chloride was not used and that the 4-fluorophenylmagnesium bromide (1M
in
THF, 56 mL, 0.0560 mol) reagent was added to a solution of (1R,2S,5R)-(-)-
menthyl
arecoline substrate (11.2 g, 0.040 mol) in DBE (total volume of solution = 68
mL) and
heptanes (42 mL) while maintaining the solution at -7 to -5°C. The
yield of (-)-menthyl


CA 02386981 2002-05-16
14
(3S,4R)-traps-4-(4-fluorophenyl)-N-methylnipecotinate hydrobromide was 5.94 g
(32.5%
yield from (1R,2S,5R)-(-)-menthyl arecoline) and the material had the same'H
NMR as
the product from example 1.
Example 6: Preparation of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) in Toluene
The same procedure as the one described in example 4 was followed except that
the 4-
fluorophenylmagnesium bromide (1M in THF, 56 mL, 0.0560 mol) reagent was added
to
a solution of (1R,2S,5R)-(-)-menthyl arecoline substrate (11.2 g, 0.040 mol)
in toluene (60
mL) instead of THF. The yield of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-
N-
methylnipecotinate hydrobromide was 5.35 g (29.3% yield from (1R,2S,5R)-(-)-
menthyl
arecoline) and the material had the same'H NMR as the product from example 1.
Example 7: Preparation of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) in dibutyl ether (DBE) and isolation of
(3R,4S)-
traps-4-(4-fluorophenyl)-N-methylnipecotinate hydrobromide (6)
The same procedure as the one described in example 1 was followed except that
scale of
the reaction was reduced by a factor of 2.5 [i.e., (1R,2S,5R)-(-)-menthyl
arecoline = 11.2 g
versus 28.0 g). The yield of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide was 6.0 g (33% yield from (1R,2S,5R)-(-)-
menthyl
arecoline) and the material had the same 1H NMR as the product from example.
Elemental analysis calculated for C~H35NOZFBr: C, 60.52, H, 7.73, N, 3.07;
found: C,
60.64, H, 7.79, N, 3.25; [a]D~ _ -64.8° (c=1.0, methanol).
The filtrate after isolation of 1 (77.83 g) was evaporated to 13.75 g and
ethyl acetate (30
mL) was added and the resulting mixture stirred at ambient temperature. The
precipitate was isolated by filtration to provide 3.1 g of 6 as a white solid.
'H NMR
(DMSO) 6: 9.88 (1H, br. s), 7.14-7.25 (4H, m), 4.38 (1H, atd, J=4.1,10.8 Hz),
3.71 (1H, ad,
J=9.0 Hz), 3.53 (1H, ad, J=12.0 Hz), 3.14-3.25 (3H, m), 2.94-3.03 (1H, m),
2.86 (3H, ad,


CA 02386981 2005-05-18
J=3.5 Hz), 1.91-2.09 (m, 2H), 1.51-1.55 (2H, m), 1.20-1.38 (1H, m), 1.04-1.20
(2H, m), 0.63-
0.92 (2H, m), 0.77 (3H, d, J=7.0 Hz), 0.74 (3H, d, J=6.5 Hz), 0.55 (3H, d,
J=6.8 Hz), 0.34
(1H, q, J=11.8 Hz); Elemental analysis calculated for Cz3H3sNOzFBr: C, 60.52,
H, 7.73, N,
3.07; found: C, 60.79, H, 7.77, N, 3.03; [a]DZ5 = -4.8° (c=1.0,
methanol).
Example 8: Preparation of (-)-menthyl (3S,4R)-traps-4-(4-fluorophenyl)-N-
methylnipecotinate hydrobromide (1) in dibutyl ether (DBE) and Cuprous
Chloride (0.2
equivalents)
A round bottom flask was charged with a solution of (1R,2S,5R)-(-)-menthyl
arecoline
(44.2 g, 0.158 mol), DBE (300 mL) and cuprous chloride (3.13 g, 0.0317 mol,
0.2 eq) and
the solution was cooled to 5°C with stirring and under a nitrogen
atmosphere. To this
solution was added 4-fluorophenylmagnesium bromide (1M in THF, 205.7 mL,
0.2057
mol, 1.3 eq) over a 1 hour period while maintaining the reaction temperature
below
11°C. The reaction was allowed to warm to room temperature and
maintained a further
3 hours. The flask is cooled to 0 to 5°C and saturated aqueous ammonium
chloride (250
mL) was added while maintaining the temperature below 5°C. The mixture
was filtered
through a Celite~ pad and the filter cake washed with DBE (2 X 25 mL) and the
filtrate
was transferred to a separatory funnel. The aqueous layer was removed and back-

extracted with DBE (50 mL). The combined organic layers were concentrated to
250
mL, dried over sodium sulfate and filtered. The filter cake was rinsed with
dibutyl
ether (2 X 25 mL) and the filtrate was cooled to 0 to 5°C whereupon
potassium tert-
butoxide (14.21 g, 0.1266 mol, 0.8 eq) was added and the reaction mixture was
stirred a
further 1.5 hours until reaction completion. The reaction was then charged
with water
(200 mL) and the pH was adjusted to 8-9 using 32% HCl (10.8 g) and the
reaction
mixture transferred to a separatory funnel and the layers were separated. The
aqueous
layer was back-extracted with DBE (50 mL) and the organic layers were combined
and
concentrated to 150 mL. This solution was cooled to 0 to 5°C and 48%
aqueous
hydrobromic acid was added (12.81 g, 0.1583 mol) over about 0.25 hours. The
reaction
mixture was charged with ethyl acetate (416 mL) and stirred at 0°C for
a further 3 hours.


CA 02386981 2002-05-16
16
The precipitated product was collected by filtration and the filter cake was
rinsed with
two portion of ethyl acetate (50 mL) and the solid dried a 45°C in
vacuo. This provided
15.78 g (21.8% yield from (1R,2S,5R)-(-)-menthyl arecoline) of the (-)-menthyl
(3S,4R)-
trans-4-(4-fluorophenyl)-N-methylnipecotinate hydrobromide as a white solid.
HPLC
purity = 97.38% (by area); [a]D~ _ -65.52° (c=1.0, methanol).

Representative Drawing
A single figure which represents the drawing illustrating the invention.
Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date 2007-05-08
(22) Filed 2002-05-16
Examination Requested 2002-05-16
(41) Open to Public Inspection 2003-11-16
(45) Issued 2007-05-08
Deemed Expired 2012-05-16

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Request for Examination $400.00 2002-05-16
Registration of a document - section 124 $100.00 2002-05-16
Application Fee $300.00 2002-05-16
Maintenance Fee - Application - New Act 2 2004-05-17 $100.00 2004-04-28
Registration of a document - section 124 $100.00 2004-05-05
Maintenance Fee - Application - New Act 3 2005-05-16 $100.00 2005-04-27
Maintenance Fee - Application - New Act 4 2006-05-16 $100.00 2006-04-13
Final Fee $300.00 2007-02-23
Maintenance Fee - Application - New Act 5 2007-05-16 $200.00 2007-04-10
Maintenance Fee - Patent - New Act 6 2008-05-16 $200.00 2008-05-08
Maintenance Fee - Patent - New Act 7 2009-05-18 $200.00 2009-04-28
Maintenance Fee - Patent - New Act 8 2010-05-17 $200.00 2010-04-30
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
APOTEX PHARMACHEM INC.
Past Owners on Record
BRANTFORD CHEMICALS INC.
MURTHY, K.S. KESHAVA
NISH, TANIA E.
RADATUS, BRUNO K.
REY, ALLAN W.
ZHAO, YAJUN
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Description 
Date
(yyyy-mm-dd) 
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Claims 2002-05-16 3 67
Representative Drawing 2002-08-22 1 2
Cover Page 2003-10-21 1 27
Description 2003-11-26 16 744
Claims 2003-11-26 4 62
Abstract 2002-05-16 1 8
Description 2002-05-16 16 745
Description 2005-05-18 16 717
Claims 2005-05-18 4 62
Claims 2006-02-09 5 67
Claims 2006-10-06 5 81
Representative Drawing 2007-04-24 1 3
Cover Page 2007-04-24 1 28
Fees 2005-04-27 1 50
Assignment 2002-05-16 7 242
Prosecution-Amendment 2002-09-25 2 55
Correspondence 2002-09-25 5 205
Assignment 2002-05-15 9 316
Prosecution-Amendment 2003-11-26 7 135
Assignment 2004-05-05 8 302
Fees 2004-04-28 1 54
Prosecution-Amendment 2004-11-18 4 207
Prosecution-Amendment 2005-05-18 16 679
Prosecution-Amendment 2005-08-09 7 421
Prosecution-Amendment 2006-02-09 13 446
Prosecution-Amendment 2006-02-16 2 46
Prosecution-Amendment 2006-04-07 2 51
Fees 2006-04-13 1 52
Prosecution-Amendment 2006-10-06 7 153
Correspondence 2007-02-23 2 137
Fees 2007-04-10 2 101
Fees 2008-05-08 4 143
Correspondence 2008-08-13 14 449
Correspondence 2008-10-16 1 18
Correspondence 2008-10-16 1 21
Fees 2009-04-28 2 81
Fees 2010-04-30 2 80
Change of Agent 2015-08-06 1 35