U.S. patent application number 10/974447 was filed with the patent office on 2005-04-21 for process for the preparation of (s,s)-cis-2-benzhydryl-3-benzylaminoquinucl- idine.
This patent application is currently assigned to PFIZER INC.. Invention is credited to Nugent, Thomas C., Seemayer, Robert.
Application Number | 20050085641 10/974447 |
Document ID | / |
Family ID | 32108014 |
Filed Date | 2005-04-21 |
United States Patent
Application |
20050085641 |
Kind Code |
A1 |
Seemayer, Robert ; et
al. |
April 21, 2005 |
Process for the preparation of
(S,S)-cis-2-benzhydryl-3-benzylaminoquinucl- idine
Abstract
A process for preparing
(S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine. The process
includes the steps of contacting a compound containing a mixture of
R- and S-isomers and having the formula 1 with an effective amount
of a chiral organic acid in the presence of an organic solvent and
an effective amount of an organic carboxylic acid for converting
the R-isomer into an acid salt of the S isomer, wherein the organic
solvent is capable of solubilizing the compound containing the
mixture of R- and S-isomers, while precipitating the acid salt and
the organic carboxylic acid is different from the chiral organic
acid; neutralizing the acid salt with a base to provide an
S-isomer-of a chiral ketone of the formula 2 reacting the chiral
ketone with an organic amine in the presence of a Lewis acid to
provide the corresponding imine and reducing the imine.
Inventors: |
Seemayer, Robert; (Palo
Alto, CA) ; Nugent, Thomas C.; (San Francisco,
CA) |
Correspondence
Address: |
Ladas & Parry
26 West 61st Street
New York
NY
10023
US
|
Assignee: |
PFIZER INC.
DSM PHARMACEUTICALS, INC.
|
Family ID: |
32108014 |
Appl. No.: |
10/974447 |
Filed: |
October 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10974447 |
Oct 27, 2004 |
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10679961 |
Oct 6, 2003 |
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6861526 |
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60419051 |
Oct 16, 2002 |
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Current U.S.
Class: |
546/134 |
Current CPC
Class: |
A61P 21/00 20180101;
C07D 453/02 20130101 |
Class at
Publication: |
546/134 |
International
Class: |
C07D 453/04 |
Claims
1-30. (canceled)
31. A salt of 2(S)-benzhydryl-3-quinuclidinone, said salt being
substantially enantiomerically pure.
32. The salt of claim 30, which is the tartrate salt.
33. A substantially enantiomerically pure
2(S)-benzhydryl-3-quinuclidinone- .
34. A substantially enantiomerically pure irnine of
2(S)-benzhydryl-3-quinuclidinone.
35. A process for preparing a substantially enantiomerically pure
heat of 2(S)benzhyryl-3-quinuclidinone comprising the steps of:
contacting a compound containing a mixture of R- and S-isomers and
having the formula 11with an effective amount of a chiral organic
acid in the presence of an organic solvent and an effective amount
of an organic carboxylic acid for converting said R-isomer into an
acid salt of said S isomer, said organic solvent being capable of
solubilizing said compound containing said mixture of R- and
S-isomers, while precipitating said acid salt and said organic
carboxylic acid being different from said chiral organic acid;
neutralzing said acid salt with a base to provide an S-isomer of a
chiral ketone of the formula 12
36. The process of claim 35, wherein the compound is present as a
racemic mixture.
37. The process of claim 35, wherein said acid salt is a tartrate
salt of (2S)-benzhydryl-3-quinuclidinone.
38. The process of claim 35, wherein said chiral organic acid is
L-tartaric acid.
39. The process of claim 35, wherein said effective amount of said
chiral organic acid employed is at least one equilivant or
more.
40. The process of claim 35, wherein said organic solvent is an
alcohol.
41. The process of claim 35, wherein said alcohol is ethanol.
42. The process of claim 40, wherein said alcohol is a denatured
alcohol.
43. The process of claim 35, wherein said organic carboxylic acid
is acetic acid, propionic acid or butyric acid.
44. The process of claim 43, wherein said organic carboxylic acid
is acetic acid.
45. The process of claim 35, wherein said effective amount of said
organic carboxylic acid employed is at least one equivalent,
relative to said compound.
46. The process of claim 35, wherein said base is sodium
bicarbonate, potassium bicarbonate, sodium carbonate, potassium
carbonate, sodium hydroxide or potassium hydroxide.
47. The process of claim 35, wherein said base is added with
cooling to maintain a temperature below 25.degree. C. until
reaching a pH of about 9.
48. The process of claim 35, wherein said neutralizing is performed
in the presence of a biphasic solvent mixture.
49. The process of claim 48, wherein said biphasic solvent mixture
comprises a second organic solvent and water.
50. The process of claim 49, wherein said second organic solvent is
toluene, ethyl acetate, or methyl t-butyl ether.
51. The process of claim 35, wherein said acid salt is produced in
a yield greater than 50%.
52. The process of claim 51, wherein said yield is from 85 to 90%.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to the method of the
preparation of the title compound,
(S,S)-cis-2-benzhydryl-3-benzylaminoquinuciidine (4).which is a
useful intermediate in the preparation of optically active
quinuclidine analogues which have utility as non-peptide
antagonists of Substance P. 3
BACKGROUND OF THE INVENTION
[0002] Substance P is a naturally occurring undecapeptide belonging
to the tachykinin family of peptides, members of which exert prompt
stimulatbry action on smooth muscle tissue. Substance P is a
pharmaceutical active neuropeptide that is produced in mammals and
possesses a characteristic amino acid sequence that is illustrated
in U.S. Pat. No. 4,680,283. A variety of substance P antagonists
could be prepared from the title compound; for example, U.S. Pat.
No. 5,162,339 describes Substance P antagonists of formula 2 where
R.sup.1 is methoxy and R.sup.2 is independently selected from the
group consisting of isopropyl, tert-butyl, methyl, ethyl, and
sec-butyl. 4
[0003] These substance P antagonists can be prepared by the
reductive amination of cis-2-benzhydryl-3-amino-quinuclidine 1
5
[0004] using the appropriate aldehyde of the formula R.sup.3CHO
where R.sup.3 is defined as a benzaldehyde derivative with the
phenyl ring substituted with R.sup.1 and R.sup.2 as described
above. This reductive amination may be achieved with a variety of
reagents such as hydrogen in the presence of a suitable metal
catalyst, sodium cyanoborohydride, sodium triacetoxyborohydride,
sodium borohydride, zinc and hydrochloric acid, borane
dimethylsulfide or formic acid as described, for example, in
WO92/21677, WO94/10170, WO94/11368, WO94/26740,
WO94/08997WO97/03984,; and U.S. Pat. Nos. 5,162,339, 5,721,255,
5,939,433, and 5,939,434. An alternative strategy is the conversion
of 1 to 2 by an alkylation with an appropriate electrophile as is
taught, for example, in U.S. Pat. Nos. 5,807,867 and 5,939,433 and
WO92/21677. A further alternative strategy for the conversions of 1
to 2 is the acylation of 1 with an activated carboxylic acid
derivative followed by reduction of the resultant amide with a
reagent such as. lithium aluminum hydride as described in
WO92/21677 and the Journal of Medicinal Chemistry, 35, 2591
(1992).
[0005] The cis-2-benzhydryl-3-amino-quinuclidine 1, which is an
intermediate in the formation of 2, is available from the
3-benzylamine-2-benzhydryl-quinuclidine 4 by debenzylation with
hydrogen gas and a catalyst. A process for preparing benzylamine 4
has been described by Warawa in the Journal of Medicinal Chemistry,
18, 587 (1975) and is illustrated in Scheme 1. The process starts
with 3-quinuclidinone 5, available by the method of Clemo et at in
the Journal of the Chemical Society (London) p1241 (1939), which is
condensed with. benzaldehyde to generate enone 6. In turn, this is
reacted with phenylmagnesium chloride to form
2-benzhydryl-3-quinuclidinbne 3. Reductive alkylation of ketone 3
with benzylamine provides 4. 6
[0006] The approach is amenable to adaptation to allow access to
aryl and quihuclidine analogs as described in WO92/20676 and U.S.
Pat. No. 5,162,339. The use of methoxybenzylamine has been used in
place of benzylamine as this allows for hydrolytic removal to
afford theamine 1 as well as hydrogenolysis, as described in U.S.
Pat. Nos. 5,807,867and 5,939,433.
[0007] The use of 9-BBN to effect the imine reduction formed from
the reaction of benzylamine with the ketone 3 has been advocated as
this maximizes formation of the desired cis-isomer of 4. This
procedure is described in the Journal of Medicinal Chemistry, 35,
2591 (1992).
[0008] In all of these examples, the materials were racemic. The
separation of enantiomers has been done on compound 1, 2, or 4 by
classical resolution techniques. This is illustrated by the
methodology described, for example, in U.S. Pat. No. 5,138,060,
where the methoxyphenyl derivative 7 is separated to provide the
desired (-)-isomer by crystallization of racemic 7 with
(-)-mandelic acid from ethyl acetate, purification of the salt by
subsequent recrystallization from ethyl acetate,. and release of,
the free amine product by treatment with base. In a related
procedure, N-[[2-methoxy-5-(1-methylethyl)phenyl]methy-
lj-2-(diphenylmethyl)-1-azabicyclo[2.2.2]octan-3-amine is resolved
by use of (1R)-(-)-10-camphorsulfonic acid, as described in WO
97/03984. 7
[0009] Use of D-tartaric acid has been disclosed in Japanese Patent
No. 07025874 by Murakami, et al. for the resolution of
cis-3-amino-2-benzhydrylquinuclidine (1) in methanol. Separation of
the diastereoisomers of an intermediate carbamate have also been
used to obtain 1 as a single enantiomer as described in the Journal
of Medicinal Chemistry, 35, 2591 (1992).
SUMMARY OF THE INVENTION
[0010] The present invention relates to a process for the
preparation of (S,S)-cis-2-benzhydryl-3-benzylamino quinuclidine;
The inventive process includes contacting a compound containing a
mixture of R- and S-isomers and having the formula 8
[0011] with an effective amount of a chiral organic acidin the
presence of an organic solvent and an effective amount of an
organic carboxylic acid for converting the R-isomer into an acid
salt of the S isomer. In accordance with the inventive method, the
organic solvent employed is capable of solubilizing the compound
containing the mixture of R- and S-isomers, while precipitating the
acid salt. Moreover, the organic carboxylic acid employed in the
inventive process is different from the chiral organic acid
employed.
[0012] The contacting step mentioned above is performed such that a
dynamic kinetic resolution is occurring. That is, the inventive
contacting step is carried out using reactants and conditions which
drive the reaction to the formation of the S isomer. In accordance
with the present invention, this dynamic kinetic resolution is
obtainable when an effective amount of the organic carboxylic acid
is employed to soldbilize the quinuclidinone and provide an acidic
environment to racemize the R isomer to the S isomer. It is
preferred that the organic carboxylic acid is not chiral.
Preferably, at least one equivalent, of organic carboxylic acid is
used, and more preferably greater than one equivalent is used
relative to the quinuclidinone. Likewise, the dynamic kinetic
resolution is obtainable when an effective amount of at least one
equivalent, preferably greater than 1 equivalent, of the chiral
organic acid is employed.
[0013] After the contacting step, the resultant acid salt is
neutralized with an organic base to provide an S-isomer of a chiral
ketone of the formula 9
[0014] Next, the chiral ketone is reacted with an organic amine in
the presence of a Lewis acid to provide the corresponding imine and
then the imine is reduced. In accordance with the present
invention, an effective amount of the Lewis acid, preferably at
least one equivalent and, more preferably, greater than
one.equivalent is employed for optimal converision. The inventive
reaction scheme is depicted in Scheme 2 below.
[0015] In a preferred embodiment, the starting material is racemic
2-benzhydryl-3-quinuclidinone (3). In a preferred embodiment, the
process starts with racemic 2-benzhydryl-3-quinuclidinone (3)
prepared as described by the method of Warawa in the Journal of
Medicinal Chemistry, 18, 587 (1975). When treated with L-tartaric
acid, a preferred chiral organic acid, the (S)-isomer of 3
crystallized as its tartrate salt in 85-90% yield. As a resolution
can only deliver a 50% yield of one isomer, the remainder being the
undesired antipode, a dynamic kinetic resolution is occurring.
Thus, the undesired (R)-isomer is being converted to the (S)-isomer
under the reaction conditions. The solvent for the crystallization
is an alcohol in which the ketone 3 is soluble, of which ethanol is
preferred, in the presence of an organic carboxylic acid, of which
acetic acid is preferred.
[0016] The dynamic kinetic resolution allows for losses to be
minimized compared to the classical resolution approaches taught in
the literature as the undesired antipode does not have to be
discarded.
[0017] The optically active ketone can be recovered from this salt
and utilized in a reductive alkylation with benzylamine in a
process wherein the S-stereochemistry is maintained at C-2 and the
S-cis-stereochemistry is largely controlled at the new carbon
nitrogen bond at C-3.
[0018] The process for the asymmetric reductive alkylation with
benzylamine involves 1) formation of the intermediate imine by
treatment of S-3 with benzylamine in an organic solvent in the
presence of an excess of a mild Lewis acid such as aluminum
tri-isopropoxide or titanium tetra-isopropoxide followed by
reduction of the imine in-situ with hydrogen gas over a noble metal
catalyst. Without limitation, an appropriate solvent for the
reaction is tetrahydrofuran and the preferred catalyst for the
hydrogenation is Pt on carbon. 10
DETAILED DESCRIPTION
[0019] For those skilled in the art, the use of the reagents and
methods used in the racemic series to prepare the amine 1, and
analogs thereof, is an obvious extension. The invention comprises a
dynamic resolution of the ketone 3 by formation of a salt with a
chiral organic acid. As used herein a chiral organic acid is an
organic carboxylic acid which has an asymmetric center and has
stereoisomers, some of which are mirror images of each other
(enantiomers). The chiral organic acid is also soluble in the
organic solvent.
[0020] An effective amount of. chiral organic acid is utilized.
Preferably, at least about an equimolar amount of chiral organic
acid to quinuclidinone is utilized, although an excess amount of
chiral organic acid can be used; however, it is preferred that
about an equimolar amount of chiral organic acid is utilized.
Tartaric acid is the preferred example. An organic solvent in which
the racemic ketone is soluble but in which the resultant salt
precipitates is employed. Sufficient solvent is present to
solubilize the quinuclidinone and the various reagents. This
organic solvent is preferably an alcohol, where ethanol is the
preferred alcohol, and denatured alcphol is the preferred form of
ethanol.
[0021] A weak organic carboxylic acid is added to aid the salt
formation. The organic carboxylic acid may be a mono carboxylic
acid or a poly carboxylic acid, however, it is preferred that it is
a mono carboxylic acid or dicarboxylic acid. It is especially
preferred that it is a mono carboxylic acid. The carboxylic acid
includes, but is not limited to: acetic acid, propionic acid, and
butyric acid. The preferred acid is acetic acid.
[0022] As described hereinabove, the organic carboxylic acid
utilized is present in amounts sufficient to effect salt formation
and promote precipitation of the salt. Preferably, at least one
equivalent of organic carboxylic acid is utilized relative to the
quinuclidinone.
[0023] As used herein, the term "equivalent" as it relates to an
acid, refers to that amount, especially in weight or moles that
contains one atomic weight or mole, respectively, of acidic
hydrogen, i.e., hydrogen that reacts with base during
neutralization. For example, if the acid is a monocarboxylic acid,
such as acetic acid, one mole acetic acid produces one mole
(equivalent) of acid. However, if the carboxylic acid is a
dicarboxylic acid, said as oxalic acid, succinic acid, and the
like, one mole of the dicarboxylic acid produces 2 equivalents of
acid.
[0024] Thus, if the organic acid is a, monocarboxylic acid, it is
preferred that at least about an equimolar amount of monocarboxylic
acid relative to the quinuclidinone is utilized, while if the
carboxylic acid is a dicarboxylic acid, it is preferred that on a
molar basis, at least about twice as much quinuclidinone relative
to dicarboxylic acid is utilized. However, it is preferred that
excess amounts of organic carboxylic acid is utilized.
[0025] It is preferred that the quinuclidinone, the chiral organic
acid and the organic carboxylic. acid are mixed together at about
ambient temperatures, although they may be mixed at temperatures as
low as 0C up to the reflux temperature of the solvent. The reaction
is allowed to proceed until precipitation of the (S)-salt isomer
ceases, i.e., no more precipitation is observed.
[0026] Without wishing to be bound it is believed that the
combination of the chiral organic acid with the quinuclidinone and
the organic carboxylic acid promotes the dynamic kinetic
resolution. More specifically, under the reaction conditions, not
only is the salt of the S-isomer precipitating but the undesired R
isomer is being converted to the S-isomer salt. Thus, since it is
being converted to the S isomer, little, if any, of R isomer is
discarded under the reaction conditions of the present
invention.
[0027] In the second step of the invention, the chiral ketone S-3
is obtained from the tartrate salt by neutralization of the S
isomer, e.g., S-tartaric acid salt. It is preferred that this
second step is conducted in a biphasic mixture of an organic
solvent and water. Suitable organic solvents include, but are not
limited to: toluene, ethyl acetate, and methyl t-butyl ether. The
preferred organic solvent is toluene. Appropriate bases for the
neutralization reaction include, but are not limited to: sodium
bicarbonate, potassium bicarbonate, sodium carbonate, potassium
carbonate, sodium hydroxide and potassium hydroxide. In a preferred
embodiment, the salt is suspended in the biphasic solvent mixture
and an aqueous solution of the base is added with cooling to
maintain a temperature below 25.degree. C. until reaching a pH of
about 9. The free base of optically active S-3 is recovered from
the organic layer as a solid.
[0028] Without limitation one application is described herein to
illustrate that the chiral ketone S-3 can be used to prepare
substance P antagonists and that racemization does not occur. For
those skilled in the art, other aldehydes, reducing agents for the
imine and deprotection methods can be envisioned from the
literature on the racemic compounds. Step three of this scheme
involves the formation of the imine with a nitrogenous organic
amine, such as alkyl amine, aryl amine or arylalkyl amine. It is
preferred that alkyl contains 1-6 carbon atoms, which may be
branched or straight chained. Examples include methyl, ethyl,
isopropyl, propyl, butyl, sec-butyl, t-butyl, isobutyl, pentyl and
hexyl. The term "aryl" when used alone or in combination, is an
aromatic compound containing 6, 10, 14 or 18 ring carbon atoms and
up to a total of 25 carbon atoms.. Examples include phenyl,
napthyl, and the like. The preferred amine is benzylamine. The
organic amine is reacted in the presence of a mild Lewis acid
in-situ to form the imine, which is then reduced to the
corresponding amine by techniques known to one of ordinary skill in
the art, such by reduction over a noble metal catalyst and
hydrogen. This approach avoids possible racemization during the
conversion of S-3 to S-4. Imine formation in the presence of a Br.o
slashed.nsted acid resulted in some racemization at C-2.
Epimerization is not observed if a Lewis acid is used to catalyze
formation of the imine and then the. reduction is directly
performed on the resultant mixture.
[0029] Solvents suitable for the imine formation reaction are any
homogenate hydrocarbons such as methylene chloride,
dichlorobenzene, chlorobenzene, dichloroethane, or other inert
solvents such as ethereal solvents including, buti not limited to:
THF and hydrocarbons including, but not limited to: toluene.
Appropriate Lewis acids include aluminum tri-isopropoxide and
titanium tetra-isopropoxide. The preferred Lewis acid is aluminum
tri-isoproxide. The Lewis acid is present in amounts effective to
form the imine. It is preferred that the nitrogenous orgahic amine
is present in at least about equimolar amounts to that of Ketone
S-3, but an,excess of amine may be present. Moreover, it is
preferred that the Lewis acid is present in at least catalytic
effective amounts to helpconvert the ketone S-3 to the imine.
Preferably, Lewis acid is present in at least equimolar amounts to
that of the ketone S-3, especially if the latter is the limiting
reagent. The resulting imine is reduced by standard techniques,
such as by using a noble metal catalyst and hydrogen. The noble
metal catalysts include platinum and palladium metals on various
supports. The preferred catalyst is platinum on carbon. For
example, one embodied step of the inventive process is carried out
by mixing S-3 and benzylamine in tetrahydrofuran as a. solvent and
aluminum tri-isopropoxide as the Lewis acid. The imine formation is
preferably carried out at room temperature for three hours. A
slurry of 5% PUC in tetrahydrofuran was added and the reaction is
stirred under a hydrogen atmosphere at 75 psi of hydrogen pressure
for 15 hours. Optically active S,S-4 was isolated from the
reaction.
[0030] The above-described process of the present invention
achieves a significant advantage over the conventional, classical
resolution approaches. The yield of the resolution step, i.e., the
first contacting step, is greater than 50%, which is the maximum
that can be achieved with by a typical resolution. The undesired
isomer is converted to the desired one, which is isolated from the
mixture, under the reaction conditions. This results in increased
throughput and cost savings. The use of the quinuclidinone as a
single enantiomer allows for asymmetric synthesis of the Substance
P antagonists in an optically pure form by a variety of routes and
alleviates the problems associated with late stage resolutions. The
problems associated with racemization during reductive amination
are eliminated by the use of a Lewis acid to catalyze imine
formation and in situ catalytic hydrogenation.
[0031] The process described herein is useful for preparing the
S,S-cis-2-benzhydryl-3-benzyl-amindquinuclidinone from a mixture of
R and S isomers of quinuclidinone. The R isomer may be present in
greater amounts or vice versa. The above process is also applicable
to the formation of the title compound from racemic
2-benzhydryl-3-quinuclidinon- e, which typically is the usual
starting material.
[0032] The product formed by the above-identified process is
substantially enantiomerically pure, that is, substantially free
from any other stereoisomers, i.e., the RR, RS or SR products.
Preferably, it contains less than. 10% impurity from the other
stereoisomers, and more preferably, less than about 5% impurity
from the other stereoisomers and even more preferably, less than
about 1% of the other stereoisomers.
[0033] The product thus formed is also preferably substantially
pure, i.e., contains less than 10% impurity and more preferably
contains less than 5% impurity. However, if desired, the
(S,S)-cis-2-benzyhydryl-3-benz- ylaminoquinuclidine thus formed can
be further purified by techniques known in the art, e.g.,
chromatography, including HPLC preparative chromatography, and
other column chromotagraphy, recrystallization and the like.
[0034] The examples that follow are intended as an illustration of
certain preferred embodiments of the invention, and no limitation
of the invention is implied.
EXMAPLE 1
(2S)-Brenzhydryl-3-quinuclidinone L-tartaric Acid Salt
[0035] Racemic 2-benzhydryl-3-quinuclidinone (52.45 g, 180 mmol)
was dissolved in denatured ethanol (525 ml) with acetic acid (10.4
ml, 180 mmol) and L-tartaric acid (27 g, 180 mmol) was added. The
mixture was heated to reflux for 12 hours and then allowed to cool
to room temperature and held for one hour. The solids were
collected and dried under vacuum at 40.degree. C. for 12 hours. The
yield of the desired salt was 69.9 g, 88% of theory.
EXAMPLE 2
(2S)-Benzhydryl-3-quinuclidinone (S-3)
[0036] The L-tartaric acid salt from the previous example (69.9 g,
158 mmol) was suspended in toluene (700 ml) and cooled with an ice
water bath while a saturated solution of sodium bicarbonate (500
ml) was added dropwise while maintaining a maximum temperature of
25.degree. C. The clear, biphasic mixture was stirred for 20
minutes at 25.degree. C. and the layers were separated. The organic
layer was washed with water (100 ml), the layers were separated and
the organics dried over sodium sulfate. The organics were filtered
and evaporated in vacuo to provide the desired, optically active
ketone as a colorless solid, 45.66 g; 99% yield. Mp 145-146.degree.
C. .sup.1HMR (300 MHz, CDCl.sub.3) .delta. 1.86-2.00 (m, 4),
2.41-2.43 (m, 1), 2.54-2.59 (m, 2), 3.08 (t, 2), 3.98 (d, 1), 4.55
(d, 1), 7.17 (m, 8), 7.38-7.41 (m, 2).
EXAMPLE 3
[0037] (S,S)-2-Benzylhydryl-3-benzylamino-quinuclidine (S,S-4)
[0038] With aluminum tri-isoproxide:
[0039] Under nitrogen, (2S)-benzhydryl-3-quinuclidinone:(0.50 g,
1.0 equiv, 1.72 mmol) was dissolved in anhydrous THF (2 mL).
Benzylamine (0.21 mL, 1.1 equiv, 1.89 mmol) was then added followed
by a solution of aluminum isopropoxide (0.42 g, 1.2 equiv, 2.06
mmol) in 2 mL of anhydrous THF. The solution was stirred for 3
hours. To this colorless solution was then added a slurry of 5%
Pt/C (0.063 g, Degussa F101 RA/W, .about.60% wet) in 1 mL anhydrous
THF. The reaction was placed in a Parr reactor, pressurized to 75
psi H.sub.2 and allowed to react at room temperature for 15 hours.
The reaction mixture was poured into 15 mL of 2M HCl, followed by
filtration, basification with 1 M NaOH and extraction with 50 mL
methyl tertiary butyl ether (MTBE). The MTBE layer was dried with
MgSO.sub.4, followed by removal of solvent in vacuo leaving a white
crystalline solid. This was analyzed as all cis isomer (<2%
trans -isomer), >99% ee (none of other enantiomer observed)
[0040] With titanium tetra-isoproxide:
[0041] (2S)-Benzhydryl-3-quinuclidinone (9.00 g, 30.9 mmol) was
dissolved in 75 mL of anhydrous THF. The solution is transferred
through a port to a 300 mL autoclave with the hydrogenation head
secured while maintaining a positive flow of nitrogen. Through the
same port on the hydrogenator head and under 300 rpm stirring
benzylamine (3.7 mL, 33.9 mmol) was added followed by titanium (IV)
isopropoxide (10.9 mL, 36.9 mmol). The port is closed and the
autoclave is pressure tested (150 psi nitrogen) while the reaction
mixture is stirred at 300 rpm. After 3.0 hours at 25.degree. C. the
pressure is released and under positive nitrogen flow a slurry of
5% Pt/C (1.13 g; 59.4% wet) in 3 mL THF is added via syringe
(14-gauge needle) through the port. Additional THF (2 mL) is used
to slurry remaining catalyst and added to the reaction. The port is
closed and the autoclave pressurized to 75 psi with hydrogen and
then slowly vented. This is repeated three times. The final
hydrogen pressure is adjusted to 75 psi and the reaction mixture is
hydrogenated overnight (12 hours) with the stirring maintained at
600 rpm. The vessel is then vented and subsequently pressurized
with nitrogen (100 psi) and vented. The reactor is pressurized with
nitrogen and vented three more times.
[0042] Under positive nitrogen flow 42 mL of ice-cold 12.4%
hydrochloric acid (28 mL water+14 mL 37% HCl) is added slowly and
the reaction mixture is stirred under nitrogen for 1 hour at
25.degree. C. and 900 rpm and. subsequently pressure transferred
into a 250 mL Erlenmeyer flask. The hydrogenator is charged with
toluene (50 mL) and 30 mL of 10% hydrochloric acid. The mixture is
agitated for 30 minutes at 900 rpm and subsequently pressure
transferred into an Erlenmeyer flask. The combined biphasic
heterogeneous solution is filtered through a 1 cm Celite pad under
vacuum to remove the Pt/C catalyst. The filter cake is further
rinsed with aqueous 10% HCl (100 mL). The clear filtrate phase
separates immediately and the organic layer is removed and
discarded. Under stirring and cooling, 50 mL of toluene is added
and the pH is adjusted to approximately 13 by slow addition of 50%
NaOH (30 mL). The biphasic slurry is filtered through a 1 cm Celite
pad to-remove titanium salts. The filter cake is washed with
toluene (2.times.50 mL), the layers are then separated and the
toluene layer is concentrated at 80.degree. C. until the volume of
toluene is reduced to 20 mL. Then, 40 mL of n-heptane. is added and
the mixture is slowly cooled to 10.degree. C. over 2-3 hours
(.about.0.5 g of seeds (.about.5%) is added at 55.degree. C.). The
precipitate is filtered, washed with 40 mL toluene/ n-heptane 1/6
(v/v) and dried in vacuum at 40.degree. C. The yield of colorless
solids is 7.3 g, 61% of theory.
* * * * *