Title of Invention

METHOD FOR PREPARING 3-CYCLOPENTYLOXY 4- METHOXYBENZALDEHYDE

Abstract Processes for coupling phenol and cycloalkyls including combining an optionally substituted phenol, a cycloalkyl substituted with a leaving group, carbonate salt, tetrahydrofuran, and an optional phase transfer agent are provided. Also provided are processes for preparing 3-cyclopentyloxy-4-methoxybenzaldehyde by combining 3-hydroxy-4-methoxybenzaldehyde, a cyclopentyl compound, a carbonate salt, a solvent, and an optional phase transfer agent.
Full Text METHOD FOR PREPARING 3-CYCLOPENTYLOXY-4-
METHOXYBENZALDEHYDE
BACKGROUND OF THE INVENTION
The present invention is drawn to processes for coupling phenols and
optionally substituted cycloalkyls.
3-Cyclopentyloxy-4-methoxybenzaldehyde (formula I) is a key intermediate
in the preparation of compounds that are useful in the treatment of asthma,
inflammatory disorders including psoriasis, proliferative skin disease, Crohns disease,
urticaria, rhinitis, arthritis and neurogenic inflammation, and depression.

One current preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde
includes alkylating 3-hydroxy-4-methoxybenzaldehyde (isovanillin) with cyclopentyl
bromide in a solvent such as N,N-dimethylformamide (DMF), acetone or acetonitrile
(MeCN) in the presence of anhydrous potassium or cesium carbonate. However,
product isolation from the reaction mixture is cumbersome, especially on a large
scale. Specifically, in order to isolate 3-cyclopenryloxy-4-methoxybeazaldehyde, an
aqueous work-up must be performed including the addition of water, extraction,
separation, and drying to give variable yields of 3-cyclopentyloxy-4-
methoxybenzaldehyde. The compound of formula I can then be utilized in further
reactions.
The solvents utilized during alkylation of isovanillin are also incompatible
with the reagents used in certain subsequent reactions. For example, DMF, acetone or
MeCN can react with organometallic reagents, ylides, glycidyl esters, and carbanions,
among reagents. These organometallic reagents, ylides, glycidyl esters, and
carbanions usually require anhydrous conditions and anhydrous solvents, such as
tetrahydrofuran (THF). It is therefore necessary tp isolate 3-cyclopentyloxy-4-

methoxybenzaldehyde from the DMF, acetone, or MeCN prior to performing
subsequent steps.
What is needed in the art are other methods for preparing compounds of
formula I.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides processes for coupling phenol
and cycloallcyl compounds.
In another aspect, the present invention provides processes for preparing 3-
cyclopentyloxy-4-methoxybenzaldehyde.
Other aspects and advantages of the present invention are described further in
the following detailed description of the preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a simple, environmentally-friendly, and a low-
cost process for the preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde.
Further, the present invention also provides for the preparation of 3-cyclopentyloxy-4-
methoxybenzaldehyde in a solvent that can be used in situ, i.e., taken directly to a
next step. By doing so, the lengthy and cumbersome workup, isolation and drying of
3-cyclopentyloxy-4-methoxybenzaldehyde can be avoided.
Thus, 3-cyclopentyloxy-4-methoxybenzaldehyde can efficiently be utilized in
further reactions, such as Wittig olefination reaction, reaction with organomerallic
species such as Grignard reagents, alkyllithim, or aryllithium reagents; reaction with
carbanions; oxidations; reductions; hydrocyanation; acetalization; bisulfite addition;
reductive animation; demethylation; aromatic electrophilic substitution; among
further reactions known to those of skill in the art.
I. Definitions
The term "alky!" is used herein as a group or part of a group to refer to both
straight- and branched-chain saturated aliphatic hydrocarbon groups having 1 to about
10 carbon atoms, or about 1 to about 8 carbon atoms. The term "alkenyl" is used
herein to refer to both straight- and branched-chain alkyl groups having one or more

carbon-carbon double bonds and containing about 2 to about 10 carbon atoms. In one
embodiment, the term alkenyl refers to an alkyl group having 1 or 2 carbon-carbon
double bonds and having 2 to about 6 carbon atoms. The term "alkynyl" group is
used herein to refer to both straight- and branched-chain alkyl groups having one or
more carbon-carbon triple bonds and having 2 to about 8 carbon atoms. In one
embodiment, the term alkynyl refers to an alkyl group having 1 or 2 carbon-carbon
triple bonds and having 2 to about 6 carbon atoms.
The terms "substituted alkyl" refers to an group having one or more
substituents including, without limitation, halogen, CN, OH, NO2, amino, aryl,
heterocyclic, alkoxy, aryloxy, alkylcafbonyl, alkylcarboxy, and arylthio which groups
can be optionally substituted. These substituents can be attached to any carbon of an
alkyl, alkenyl, or alkynyl group provided that the attachment constitutes a stable
chemical moiety.
The term "aryl" as used herein as a group or part of a group, e.g., aryloxy,
refers to an aromatic system, e.g., of 6 to 14 carbon atoms, which can include a single
ring or multiple aromatic rings fused or linked together where at least one part of the
fused or linked rings forms the conjugated aromatic system. The aryl groups can
include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl,
tetrahydronaphthyl, phenanthryl, indene, benzonaphthyl, fluorenyl, and carbazolyl.
The term "substituted aryl" refers to. an aryl group which is substituted with
one or more substituents including halogen, CN, OH, NO2, amino, alkyl, cycloalkyl,
alkenyl, alkynyl, alkoxy, aryloxy, alkyloxy, alkylcarbonyk alkylcarboxy, arnirioalkyl,
and aryltbio, which groups can be optionally substituted. In one embodiment, a
substituted aryl group is substituted with 1 to about 4 substituents.
The term "heterocyclic" as used herein refers to a stable 4- to 7-membered
monocyclic or multicyclic heterocyclic ring which is saturated, partially unsaturated,
or wholly unsaturated. The heterocyclic ring has carbon atoms and one or more
heteroatoms including nitrogen, oxygen, and sulfur atoms. In one embodiment, the
heterocyclic ring has 1 to about 4 heteroatoms in the backbone of the ring. When the
heterocyclic ring contains nitrogen or sulfur atoms in the backbone of the ring, the
nitrogen or sulfur atoms can be oxidized. The term "heterocycic" also refers to
multicyclic rings in which a heterocyclic ring is fused to an aryl ring. The

heterocyclic ring can be attached to the aryl ring through a heteroatom or carbon atom
provided the resultant heterocyclic ring structure is chemically stable.
A variety of heterocyclic groups are known in the art and include, without
limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing
rings, mixed heteroatom-containing rings, fused heteroatom-containing rings, and
combinations thereof. Oxygen-containing rings include, but are not limited to, furyl,
tetrahydrofuranyl, pyranyl, pyronyl, and dioxinyl rings. Nitrogen-containing rings
include, without limitation, pyrrolyl, pyrazolyl, imidazolyl, triaLZolyl, pyridyl,
piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyraziriyl, piperazinyl,
azepnryl, triazinyl, pyrrolidinyl, and azepinyl rings. Sulfur-containing rings include,
without limitation, thienyl and dithiolyl rings. Mixed heteroatom containing rings
include, but are not limited to, oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl,
oxatriazolyl, dioxazohyl, oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl, morpholinyl,
thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, and diazepinyl rings.
Fused heteroatom-containing rings include, but are not limited to, benzofuranyl,
thionapthene, indolyl, benazazolyl, purindinyl, pyranopyrrolyl., isoindazolyl,
indoxazinyl, benzoxazolyl, anthranilyl, benzopyranyl, quinolirxyl, isoquinolinyl,
benzodiazonyl, napthylridinyl, benzothienyl, pyridopyridinyl, foenzoxazuryl,
xanthenyl, acridinyl, and purinyl rings.
The term "substituted heterocyclic" as used herein refexs to a heterocyclic
group having one or more substituents including halogen, CN, OH, NO2, amino,
alkyl, cycloalkyl, alkenyl, alkynyl, altoxy, aryloxy, alkyloxy, alkylcarbonyl,
alkylcarboxy, aminoalkyl, and arylthio, which groups can be optionally substituted.
In one embodiment, a substituted heterocyclic group is substituted with 1 to about 4
substituents.
The term "aminoalkyl" as used herein refers to both secondary and tertiary
amines where the point of attachment is through the nitrogen-a.tom and the alkyl
groups are optionally substituted. The alkyl groups can be the same or different.
The term "halogen" as used herein refers to Cl, Br, F, or I groups.
The term "alkoxy" as used herein refers to the O(alkyl) group, where the point
of attachment is through the oxygen-atom and the alkyl group is optionally
substituted.

The term "aryloxy" as used herein refers to the O(aryl) group, where the point
of attachment is through the oxygen-atom and the aryl group is optionally substituted.
The term "arylthio" as used herein refers to the S(aryl) group, where the point
of attachment is through the sulfur-atom and the aryl group can be optionally
substituted.
The term "alkylcarbonyl" as used herein refers to the C(O)(alkyl) group,
where the point of attachment is through the carbon-atom of the carbonyl moiety and
the alkyl group is optionally substituted.
The term "alkylcarboxy" as used herein refers to the C(O)O(alkyl) group,
where the point of attachment is through the carbon-atom of the carboxy moiety and
the alkyl group is optionally substituted.
The term "leaving group" as used herein refers to a substituent that is present
on a chemical compound and can be displaced. The particular leaving group utilized
in the present invention is dependent upon the specific reaction being performed and
can readily be determined by one of skill in the art. Common leaving groups include,
without limitation, halides, triflates (OTf), boron moieties including "boronic acids and
trihaloborate salts such as trifluoroborate salts (BF3-), zinc halides, magnesium
moieties, diazonium salts (N2+), tosylates (OTs) and other sulfonic esters, mesylates
(OMs), and copper moieties. In one embodiment, the leaving group is ahalide such
as bromine, chlorine, or iodine; OTosylate; OMesylate; and OTrifiate. In another
embodiment, the leaving group is bromine.
The term "phase transfer agent" as used herein refers to a chemical compound
that increases the rate of the coupling reaction. Numerous phase transfer agents are
known in the art and are readily available. Examples of phase transfer agents include,
without limitation, ammonium salts. In one embodiment, the phase transfer agent
includes tetraalkylammonium salts. In another embodiment, the phase transfer agent
includes tetrabutylammonium salts. In yet another embodiment, the phase transfer
agent includes tetrabutylammonium halide salts. In still another embodiment, the
phase transfer agent includes tetrabutylammom'um bromide (Bu4NBr-).
The term "purified" or "pure" as used herein refers to a compound that
contains less than about 10% impurities. In one embodiment, the term "purified" or
"pure" refers to a compound that contains less than about 5% impurities, less than

about 2.5% impurities, less than about 2% impurities, less than about 1.5% impurities,
and less than about \% impurities. In another embodiment, the impurities are in the
range of 1.6 to 2.4%. The term "purified" or "pure" can also refer to a compound that
contains about 0% impurities.
II. Methods of the Present Invention
The present invention therefore provides processes for coupling an optionally
substituted phenol and cjrcloalkyl. See, Scheme 1.

The optionally substituted phenol can first be combined with a cycloalkyl
substituted with a leaving group, a carbonate salt, and a solvent.
The phenol utilized according to the present invention can be an unsubstituted
or phenol substituted with one or more substituents as defined above fox substituted
aryl that do not react with the reagents utilized during the coupling reaction. One of
skill in the art would readily be able to select the particular phenol for use in the
present invention. In one embodiment, the phenol is optionally substituted with a
methoxy group, among other substituents. In another embodiment, the phenol is
optionally substituted with methoxy and C(0)H groups. In a further erribodiment, the
phenol is 3-hydroxy-4-methoxybenzaldehyde, or a derivative thereof.
The cycloalkyl used in the present invention is a saturated hydro carbon group
that is cyclic in structure and has about 3 to about 10 carbon atoms, about 5 to about 8
carbon atoms, or about 5 carbon atoms. The cycloalkyl has a leaving group, as
, described above, attached to a carbon-atom of the cyclic structure. The cycloalkyl
group can also be optionally substituted with any substituent that does not interfere
with the coupling reaction and can be readily selected by one of skill in the art and

can include allcyl, halogen, CN, OH, NO2, amino, aryl, heterocyclic, alkoxy, aryloxy,
alkylcarbonyl, alkylcarboxy, and arylthio substituents, which groups can be optionally
substituted. The substituents can be attached to any carbon atom of the cycloalkyl
ring provided that the attachment constitutes a stable chemical moiety.
In one embodiment, the cycloalkyl is an optionally substituted cyclopropyl,
cyclobutyl, cyclopentyl, or cyclohexyl group, and in another embodiment is an
optionally substituted cyclopentyl group of the formula CpX, wherein X denotes a
leaving group as previously described. In yet another embodiment, the cycloalkyl is
cyclopentyl bromide. See, Scheme 2.

In one embodiment, an excess of the cycloalleyl is utilized in the coupling
reaction. In another embodiment, the ratio of cycloaliyl to phenol is at least about
1:1, in the range of 1:1 to 1.5:1, or about 1.5:1. However, equimolar amounts of
phenol and cycloalkyl can be utilized. In still anothex embodiment, a ratio of greater
than 1.5:1 can be utilized. However, in such embodiments, the excess reagent can
necessitate removal of the cycloalkyl following the next step.
A carbonate salt is also utilized in the coupling reaction. A variety of
carbonate salts are known in the art and can be used according to the present
invention. In one embodiment, the carbonate salt has a granularity of less than about
520 µm, less than about 250 µm, less than about 100 µm, less than about 75 µm, or
less than about 50 µm. In another embodiment, the carbonate salt has a granularity of
30 to 50 µm. Carbonate salts can include potassium carbonate (K2CO3) or
bicarbonate, sodium carbonate or bicarbonate, cesiuna carbonate or bicarbonate, and
lithium carbonate or bicarbonate, as well as anhydrous forms of the same. In one
embodiment, the carbonate salt is potassium carbonate, potassium carbonate

sesquihydrate, or potassium bicarbonate, and in another embodiment the anhydrous
forms of the same.
The coupling process can also be carried out in the presence of a phase
transfer agent, as described above.
In one embodiment, the solvent utilized to couple the phenol and cycloalkyl
does not react with the phenol, cycloalkyl, carbonate salt, or optional phase transfer
agent. In another embodiment, the solvent also does not react with the reagents
utilized in subsequent steps, in one embodiment, the solvent is an ether, and in
another embodiment is tetrahydrofuran. One of skill in the art would readily be able
to select a suitable solvent for use in the present invention. The solvent can also
contain small amounts of acetone, DMF, MeCN, water, alcohols including methanol,
among others, if any. In one embodiment, the solvent contains less than about 0.05
equivalents of acetone, DMF, MeCN, water, alcohol or combinations thereof. In
another embodiment, the solvent is anhydrous.
The coupling reaction is typically performed at temperatures ranging from
about room temperature to elevated temperatures. One of skill in the art would
readily be able to determine the temperature required to perform the coupling
reaction. In one embodiment, a temperature at or less than the boiling point of the
solvent is utilized. In another embodiment, the coupling reaction is performed in THF
at the boiling point of the same or at the reflux temperature of the reaction mixture.
The coupling reaction is also performed for a period of time that permits
coupling of the cycloalkyl and phenol. One of skill in the art would readily be able to
determine the amount of time required for the coupling to be completed using
techniques known to those of skill in the art. Typically, spectroscopic techniques
including chromatography, such as thin layer chromatography (TLC), gas
chromatography (GC), liquid chromatography (LC), or high performance liquid
chromatography (HPLC); nuclear magnetic resonance (NMCR); infrared spectroscopy
(IR); mass spectroscopy (MS); and combinations thereof, among others, can be
utilized to determine the status of the reaction and formation of the coupled product.
In one embodiment, the cycloalkyl and phenol are combined with the other
reagents in one vessel and the reaction performed in the selected solvent
Alternatively, the phenol, solvent, carbonate salt, and optional phase transfer agent are

combined and the cycloalkyl added thereafter. In one embodiment, the cycloalkyl is
added in one aliquot, or in two or more aliquots. In another embodiment, the
cycloalkyl is added in two aliquots. The intervals between the separate additions of
cycloalkyl to the phenol can he about 1 minute to about 8 hours, about 4 to about 6
hours. In one embodiment, the interval is about 6 hours. However, shorter or longer
intervals can be utilized as determined by one of skill in the art
Subsequent to the coupling reaction, the coupled product can be isolated as a
solid or isolated in the solvent and utilized in in further reactions. If isolated as a
solid, basic techniques known to those of skill in. the art to isolate solids dissolved
therein solvents can be followed and include, without limitation, extraction,
precipitation, recrystallization, evaporation, drying.
The present invention includes using the coupled product in the solvent
without isolating the same as a solid and is pure enough in solution to use in
subsequent reactions without isolation as a solid and/or without further purification,
The solvent containing the coupled product can be filtered to remove any extraneous
solid materials.
The present invention provides for processes where the coupled product is
produced in an about 100% yield, i.e., a quantitative yield. However, yields of about
80% to about 100% of the coupled product are expected depending upon the reaction
conditions and purity of the phenol, cycloalkyl, solvent, and optional phase transfer
agent.
In one embodiment, the present invention, provides a process for coupling a
phenol and cycloalkyl including combining an optionally substituted phenol, a
cycloalkyl substituted with a leaving group, carbonate salt, and tetrahydrofuran; and
isolating the coupled product.
In a further embodiment, the present invention provides a process for
preparing a substituted benzaldehyde including combining a substituted phenol, a
cycloalkyl substituted with a leaving group, carbonate salt, and THF; and isolating the
substituted benzaldehyde.
In another embodiment, the present invention provides a process for preparing
3-cyclopentyloxy-4-methoxybenzaldehyde including combining 3-hydroxy-4-

rnethoxybenzaldehyde, a cyclopentyl compound, a carbonate salt, and
tetrahydrofuran; and isolating 3-cyclopentyloxy-4-methoxybenzaldehyde.
In a further embodiment, the present invention provides a process for
preparing 3-cyclopentyloxy-4-methoxybenza ldeh.yde including combining 3-hydroxy-
methoxybenzaldehyde, cyclopentyl bromide, potassium carbonate, and THF; and
nitering the THF solution.
In yet another embodiment, the present invention provides a process for
preparing -4-raethoxybenza lde.hyde including combining 3-hydroxy-
4-methoxybenzaldehyde, cyclopentyl bromide, potassium carbonate, a phase transfer
agent, and tetrahydrofuran; and filtering the coupled product.
In still a further embodiment, the present invention provides a product
prepared according to the processes of the present invention.
III. Methods of Using the Compounds Prepared
A compound prepared according to the present invention is a key intermediate
in the formation of a number of compounds, and notably, a number of biologically
active compounds.
For example, a 3-cyclopentyloxy-4-m.ethoxybenzaldehyde produced by the
method of the invention is a useful intermediate for production of compounds that are
selective inhibitors of PDE4. Such compounds are useful in the treatment of
inflammatory diseases and other diseases involving elevated levels of cytokines, as
well as central nervous system (CNS) disorders, also is disclosed. See, e.g., US
Patent 6,716,871 [use in production of pyrrolidone compounds that are cyclic AMP-
specific phosphodie sterase inhibitors]. See, US 6,518,306 [use in production of 1,4-
substituted 4,4-diaryl cyclohexanes]. Further; the 3-cyclopentyloxy-4-
methoxybenzaldehyde produced by the method of the invention is a useful
intermediate in production of oxime carbamates and oxime carbonates useful as
bronchodilators and antiinflammatories. See, e.g., US Patent No. 5,459,151 and US
Patent No. 5,124,455.
Thus, the processes of the invention provide a method of forming a key
intermediate used in the production of a number of biologically active small
molecules. The processes in the 3-cyelopentyloxy-4-methoxybenzaldehyde by

combining 3-hydroxy-4-methoxybenzaldehyde prepared according to the invention
can be used is not a limitation of the invention.
Compounds produced using the 3-cyclopentyloxy-4-methoxybenzaldehyde by
combining 3-hydroxy-4-methoxybenzaldehyde prepared according to the present
invention are useful in the treatment of asthma, inflammatory disorders including
psoriasis, proliferative skin disease, Crohns disease, urticaria, rhinitis, arthritis and
neurogenic inflammation, and depression. Such compounds produced using the key
intermediate of the invention are also useful in inhibiting phosphodiesterase (PDE) TV
(PDEIV or PDE4) and treating bronchodilation, inflammation, acute or chronic
bronchial asthma.
The following examples are provided to illustrate the invention and do not
limit the scope thereof. One skilled in the art will appreciate that although specific
reagents and conditions are outlined in the following examples, modifications can be
made which are meant to be encompassed by the spirit and scope of the invention.
EXAMPLES
EXAMPLE 1 - PREPARATION OF 3-CYCLOPENTYLOXY-5-
METHOXYBENZALDEHYDE
A1-L flask equipped with a mechanical stirrer, nitrogen inlet, thermometer,
and condenser, were charged with isovanillin. (91.2 g, 0.60 mol, 1.0 equivalent) and
THF (250 mL), followed by addition of Bu4NBr (19.3 g, 0.06 mol, 10 mol%, 0.10
eq.) and anhydrous K2CO3 (124 g, 0.90 mol, 1.5 eq.). The reaction mixture was
stirred vigorously and heated to reflux (about 65 to about 75 °C). Cyclopentyl
bromide (89.4 g, 0.60 mol, 1.0 eq.) was added, dropwise and the mixture was stirred at
refluxed for 6 hours. A second portion of cyclopentyl bromide (44.7 g, 0.30 mol, 0.5
eq.) was added dropwise and stirring and heating was continued for 6 hours. The
reaction solution was monitored by TLC for completion, thereby cooled to room
temperature, and any remaining solids removed by filtration. The filter pad was
washed with THF (2 x 90 mL) to remove remaining 3-cyclopenryloxy-5-

methoxybenzaldehyde on the filter pad. 3-Cyclopentyloxy-5-rnethoxybenzaldebyde
was thereby isolated in TBDF and its purity verified using HPLC.
EXAMPLE 2 - PREPARATION OF 1-(3-CYCLOPENTYLOXY-4-
METHOXYPHENYL) ETHANOL
To the 3-cyclopentyloxy-4-methoxybenzaldehyde in THF solution from
Example 1,3 M methyl magnesium chloride in THF (240 mL) was added dropwise at
-10 to -4°C over 5 hours. After stirring an additional 1 hour at 0°C, HPLC showed
0.07% aldehyde remaining. The reaction mixture was slowly treated with 20%
ammonium chloride (340 g) and then acidified with 10% hydrochloric acid (270 g) to
a pH of S. The layers were separated, the aqueous layer extracted with THF, and the
combined extracts washed with brine. The organic solution was concentrated to give
l-(3-cyclopentyloxy-4-methoxyphenyl) ethanol as an oil (115.05 g, 81% yield, purity
94.4% by HPLC area). 1H-NMR: 6.93 (d, J = 1.8 Hz, 1H), 6.88 (dd, J = 8.2 Hz, J =
1.8 Hz, 1H), 6.83 (d, J= 8.2,1H), 4.80 (m, 2H), 3.S4 (s, 3H), 1.99-1.80 (m, 6H), 1.61
(m,2H),andl.48(d,J = 6.4Hz,3H). 13C-NMR: 149.2,147.6,138.5,117.5, 112.3,
111.7, 80.3,70.0, 56.0, 32.7, 25.0, and 24.0.
EXAMPLE 3 - PREPARATION OF (3-CYCLOPENTYLOXY-4-
METHOXYPHENYL)METHANOL
1M lithium aluminum hydride in THF (1.5 mL) was added into a stirred
solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (l.lg; 5 mmol) in THF
solution in an ice bam. After the reaction was completed (as evidenced by TLC), the
mixture was acidified with 2M HC1 and extracted with ether. The organic phase was
washed with water and dried over MgS04. Filtration, followed by evaporation gave
(3-cyclopenryloxy-4-methoxyphenyl)methanol as an oil (0.9 g; 81% yield; purity
98.1% by HPLC area).1H-NMR: 6.92 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.84 (d, J =
8.1 Hz, 1H), 4.80 (m, 1H), 4.61 (s, 2H), 3.84 (s, 3H), 2.13-1.78 (m, 6H), and 1.61 (s,
2H). 13C-NMR: 149.4,147.6,133.6, 119.3,114.0, 111.7, S0.3, 60.5, 56.0, 32.7, and
24.0.

EXAMPLE 4 - COMPARISON OF REAGENTS IN THE PREPARATION OF
3-CYCLOPENTYLOXY-4-METHOXYBENZALDEHYDE
Cyclopentylbromide, a carbonate having the granularity set forth in Table 1,
and any additional reagents as set forth in Table 1 were added to a stirred solution of
3-hydroxy-4-methoxybenzaldehyde (isovanillin; See column (2) below). Each
reaction was monitored by TLC at 12 hours to determine the percentage conversion to
the 3-cyclopentyloxy-4-methoxybenzaldehyde (I) product (See column (1) below).
These data illustrate that samples containing tetrabutylammonium bromide
provide a faster conversion to product (I). These data also illustrate that the presence
of potassium carbonate having a granularity of less than about 536 µm provides a
faster conversion of isovanillin to the product (I) than samples containing potassium
carbonate having a coarser granularity. These data also illustrate that samples further
containing methanol and tetrabutylammonium bromide provide a nearly quantitative
conversion to (I).

All publications cited in this specification are incorporated herein by reference
herein. While the invention has been described with reference to a particularly

preferred embodiment, it will be appreciated that modifications can be made without
departing from the spirit of the invention. Such modifications are intended to fall
within the scope of the appended claims.

We Claim:
1. A process for preparing a phenoxycycloalkyl compound comprising:
(i) coupling 3-hydroxy-4-methoxybenzaldehyde and a cycloalkyl compound
substituted with a leaving group, in the presence of carbonate salt and an ether; and
(ii) isolating the product of step (i).
2. The process as claimed in claim 1, wherein said ether in step (i) is
tetrahydrofuran.
3. The process as claimed in claim 1 or 2, wherein the product is isolated in
tetrahydrofuran in step (ii).
4. The process as claimed in any one of claims 1 to 3, wherein said
phenoxycycloalkyl compound is a substituted benzaldehyde.
5. The process as claimed in any one of claims 1 to 4, wherein said cycloalkyl
compound is of the formula CpX, wherein X is Br, Cl, I, OTosylate, OMesylate, and OTriflate
and Cp is cyclopentyl.
6. The process as claimed in any one of claims 1 to 4, wherein said cycloalkyl
compound substituted with a leaving group is cyclopentyl bromide.
7. The process as claimed in any one of claims 1 to 3, wherein the product is 3-
cyclopentyloxy-4-methoxybenzaldehyde.
8. The process as claimed in claim 7, wherein said 3-cyclopentyloxy-4-
methoxybenzaldehyde is greater than 99 % pure.
9. The process as claimed in claim 7 or 8, wherein said 3-cyclopentyloxy-4-
methoxybenzaldehyde is dissolved in said ether.

10. The process as claimed in any one of claims 7 to 9, further comprising forming a
phannaceutically acceptable salt of said 3-cyclopentyloxy-4-methoxybenzaldehyde.
11. The process as claimed in any one of claims 1 to 10 wherein said carbonate salt is
a potassium carbonate.
12. The process as claimed in claim 11, wherein said potassium carbonate is
potassium carbonate sesquihydrate or potassium bicarbonate.
13. The process as claimed in any one of claims 1 to 12, wherein the granularity of
said carbonate salt is 30 to 50 µm.
14. The process as claimed in any one of claims 1 to 13, wherein said ether is
anhydrous.
15. The process as claimed in any one of claims 1 to 14, further comprising a phase
transfer agent.
16. The process as claimed in claim 15, wherein said phase transfer agent is
tetrabutylammonium bromide.
17. The process as claimed in any one of claims 1 to 16, wherein said process step (i)
is carried out in the absence of acetone, dimethylformamide, or acetonitrile.
18. The process as claimed in any one of claims 1 to 17, wherein process is performed
at the boiling point of said solvent.
19. The process as claimed in any one of claims 1 to 18, wherein step (ii) comprises
filtration.

20. The process as claimed in any one of claims 1 to 4 wherein the cycloalkyl is
cyclopentyl bromide, the carbonate salt is potassium carbonate, and the product is isolated by
filtration.
21. The process as claimed in claim 20, optionally comprising a phase transfer agent
in step (i).


Processes for coupling phenol and cycloalkyls including combining an optionally substituted phenol, a cycloalkyl
substituted with a leaving group, carbonate salt, tetrahydrofuran, and an optional phase transfer agent are provided. Also provided are
processes for preparing 3-cyclopentyloxy-4-methoxybenzaldehyde by combining 3-hydroxy-4-methoxybenzaldehyde, a cyclopentyl
compound, a carbonate salt, a solvent, and an optional phase transfer agent.

Documents:

02859-kolnp-2006 abstract.pdf

02859-kolnp-2006 assignment.pdf

02859-kolnp-2006 claims.pdf

02859-kolnp-2006 correspondence others.pdf

02859-kolnp-2006 description (complete).pdf

02859-kolnp-2006 form-1.pdf

02859-kolnp-2006 form-3.pdf

02859-kolnp-2006 form-5.pdf

02859-kolnp-2006 international publication.pdf

02859-kolnp-2006 international search report.pdf

02859-kolnp-2006 pct others.pdf

02859-kolnp-2006 priority document.pdf

02859-kolnp-2006-correspondence others-1.1.pdf

02859-kolnp-2006-correspondence-1.2.pdf

02859-kolnp-2006-form-3-1.1.pdf

02859-kolnp-2006-gpa.pdf

2859-KOLNP-2006-(12-10-2011)-CORRESPONDENCE.pdf

2859-KOLNP-2006-(12-10-2011)-FORM 3.pdf

2859-KOLNP-2006-ABSTRACT 1.1.pdf

2859-KOLNP-2006-AMANDED CLAIMS.pdf

2859-KOLNP-2006-AMANDED PAGES OF SPECIFICATION.pdf

2859-kolnp-2006-assignment.pdf

2859-kolnp-2006-correspondence.pdf

2859-KOLNP-2006-DESCRIPTION (COMPLETE) 1.1.pdf

2859-KOLNP-2006-EXAMINATION REPORT REPLY RECIEVED.pdf

2859-kolnp-2006-examination report.pdf

2859-KOLNP-2006-FORM 1 1.1.pdf

2859-kolnp-2006-form 18.1.pdf

2859-kolnp-2006-form 18.pdf

2859-KOLNP-2006-FORM 2.pdf

2859-KOLNP-2006-FORM 3 1.1.pdf

2859-kolnp-2006-form 3.pdf

2859-kolnp-2006-form 5.pdf

2859-KOLNP-2006-FORM-27.pdf

2859-kolnp-2006-gpa.pdf

2859-kolnp-2006-granted-abstract.pdf

2859-kolnp-2006-granted-claims.pdf

2859-kolnp-2006-granted-description (complete).pdf

2859-kolnp-2006-granted-form 1.pdf

2859-kolnp-2006-granted-form 2.pdf

2859-kolnp-2006-granted-specification.pdf

2859-KOLNP-2006-OTHERS 1.1.pdf

2859-kolnp-2006-others.pdf

2859-KOLNP-2006-PETITION UNDER RULE 137.pdf

2859-kolnp-2006-reply to examination report.pdf


Patent Number 249009
Indian Patent Application Number 2859/KOLNP/2006
PG Journal Number 38/2011
Publication Date 23-Sep-2011
Grant Date 21-Sep-2011
Date of Filing 04-Oct-2006
Name of Patentee WYETH
Applicant Address FIVE GIRALDA FARMS MADISON, NJ
Inventors:
# Inventor's Name Inventor's Address
1 WILK, BOGDAN, KAZIMIERZ 6 CONRAD LANE, NEW CITY, NY 10956
2 HELOM, JEAN, LOUISE 316, LIBERTY AVENUE HILLSDALE, NJ 07642
3 MWISIYA, NALUKUI 30, ODYSSEY DRIVE CHESTER, NY 01918
PCT International Classification Number C07C 41/01
PCT International Application Number PCT/US2005/014022
PCT International Filing date 2005-04-07
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/560,575 2004-04-08 U.S.A.