Note: Descriptions are shown in the official language in which they were submitted.
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-- 1 --
-This is~a divislon of copending application . - -
505,467, filed March 27, 1986~
This invention relates to 6-alkoxy-5-trifluoro-
methyl~l-naphthoic acids and more particularly to
processes for preparing them.
As disclosed in Sestanj et al., J. Med~ Chem.,
1984, Vol. 27, pp. 255-256 (Sestan; et al. I) and U. S.
Patents 4,408,077 (Sestanj et alO II) and 4,439,617
(Sestanj et al. III), it is known that 6-alkoxy-5-tri-
fluoromethyl l-naphthoic acids are useful as pharma-
ceutical intermediates and that they can be pxepared by a
variety of techniques. It is also known that the
syntheses of Sestanj et al. I and III can be modified by
conducting the trifluoromethylation step as in ~atsui e~
al., Chemistry Letters, 1981~ pp. 1719-1720, and that
particularly good results are obtained when N,N-dimethyl-
acetamide is employed as the solvent in this step.
The known techniques of synthesizing these pharma-
ceutical intermediates have their relative advantages and
disadvantages, but there is still a need for a 5ynthe~is
that would be more attractive as a commercial process.
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In one aspect the invention provides the intermediates
- 6-alkoxy-5-halo-1-cyanonaph~halenes and 6-alkoxy-5-tri-
fluoromethyl-l-cyanonaphthalenes for the process:
.. ..,' (1)
cyanating a 6-alkoxytetralone so as to form a 6-alkoxy-
l-cyano-3,4-dihydronaphthalene, (2) converting the
6-alkoxy-1-cyano-3,4-dihydronaphthalene to a naphthoic
acid precursor selected from a 6-alkoxy-1-cyano-
naphthalene and a hydrocarbyl 6-alkoxy-1-naphthoate, (3)
halogenating the naphthoic acid p~ecursor to ~he corre-
ponding 5-halo derivative, (4) ~rifluoromethylating the
5-halo derivative to replace the 5-halo ~ubstituent with a
S-trifluoromethyl group, and (5) hydrolyzing the resultant
product to a 6-alkoxy-5-trifluoromethyl-1-naphthoic acid~
Cyanat.ion
6-AlkoxytetralOnes that can be used in the prac-
tice of the invention embrace all 6-alkoxytetralones
capable of being converted to 6-alkoxy-5-tri~luoromethyl-
l-naphthoic acids by the present process, incLuding the
6-alkoxytetralones wherein the 6-substituent is an alkoxy
group containing 1-20 carbons or such an alkoxy group
bearin~ an inert substituent such as a phenyl, alkylphenyl,
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or alkoxyphenyl group, etc. Howevex, the preferred
6-alkoxytetralones are those wherein the alkoxy group is
a lower alkoxy group (i.e., an alkoxy group containing
1-6 carbons), most preferably a straight-chain alkoxy
group of 1-3 carbons or a branched-chain alkoxy group o~
3 or 4 carbons, such as methoxy, ethoxy, l-methylethoxy,
butoxy, hexoxy, etc. A particu]arly preferred 6-alkoxy-
tetralone is 6-methoxytetralone.
The 6-alkoxytetralones, when not commercially
0 available, can be prepared by known techniques, e.g~, the
techniques which can be learned directly or analogized
` from the teachings of Stork, Journal of the American
Chemical Society, Vol. 69, pp. 576-579 (1947); Thomas et
al , Journal of the American Chemical Society, Vol. 70,
.
pp. 331-334 (1948); and Papa, Journal of_the American
Chemical Society, Vol 71, pp. 3246-3247 (1949); as well
as the references cited therein.
As lndicated above, the 6-alkoxytetralone is
converted to a 6-alkoxy-1-cyano-3,4-dihydronaphthalene by
a cyanation reaction. This type o~ reaction, as is
known, involves the addition of a cyanide group to the
starting material and the subsequent dehydroxylation or
dehydration of the resultant intermediate to form the
desired product. In the practice of the invention, this
cyanation may be accomplished by the known techniques
that require more than one step, e.g., the techniques of
,
.
~63~71~
Nagata et al.,~ Organic Syntheses, 1972, Vol. 52, pp. -
96-99, and those of Jacobs et al., Journal of Organic
Chemistr~,.1983, Vol. 48, pp. 5134-5135. However,
in order for the advantages of the invention to be fully
realized, it is preferably accomplished by a one-step
technique.
This preferred method of preparing a 6-alkoxy-
l-cyano-3,4-dihydronaphthalene is unconventional but can
be realized fairly simply by reacting the 6-alkoxytetra-
lone with cyanide ion and a Lewis acid, such as hydrogenfluoride, a trialkylaluminum, or, more preferably, a
metal halide, such as boron or aluminum trifluoride,
triiodide, trichloride, or tribromide, tin tetrachloride,
zinc dichloxide, gallium trichloride, titanium tetra-
chloride, diethylaluminum chloride, ethylaluminumdichloride, ethoxyaluminum dichloride, diethoxyaluminum
chloride, hydroxyaluminum dichloride, dihydroxyaluminum
chloride, and other such compounds wherein at least one
halogen is attached to a metal atom, any remaining
valences of which are usually satisfied by hydroxy, hydro-
carbyl, or hydrocarbyloxy groups, generally hydroxy or
alkyl or alkoxy groups containing 1-10 carbons. The
preferred Lewis acids are boron trifluoride and aluminum
chloride, especially aluminum chloride. This ingredient
of the reaction mixture is ordinarily employed in the
amount of 0.5-1.5, preferably 1-1.1, mols per mol of the
' . ' ' , :
- 6-alkoxytetralone~ althoug~ smaller or larger amoun~s can
be employed if desired.
In this preferred cyanation reaction, the cyanide
ion may be provided by any known source of cyanide ion
that is free of radicals which would stabilize the cyano-
hydrin that is believed to be initially formed in the
reaction. However, it is most commonly provided by
hydrogen cyanide, a tri- or tetraalkylammonium cyanide
(generally such a compound containing up to about 50 car-
bons) such as trimethylammonium cyanide, tributylmethyl-
ammonium cyanide, tetrabutylammonium cyanide, etc., or a
metal cyanide, such as cuprous cyanide or an alkali or
alkaline earth metal cyanide such as lithium, sodium,
potassium, rubidium, cesium, beryllium, magnesium,
calcium, strontium, or barium cyanide. The sodium,
potassium, and hydrogen cyanides are generally the
preferred sources of cyanide ion. The amount o~ cyanide
ion employed is not critical, but it is usually desirable
to employ 1-5, preferably 1-2, mols of cyanide io~ per
mol of 6-alXoxytetralone to produce good yields of
product.
Other ingredients that are suitably included in
the reaction mixture in the preferred cyanation process
are a solvent and a phase transfer catalyst. Solvents
that may be employed include all solvents in which the
reactants are soluble, such as aliphatic and aromatic
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hydrocarbons ~e.g., toluene, xylenes, heptanes, arld thelike), chlorobenzene, nitrobenzene, etc.; but the pre-
ferred solvent is generally nitrobenzene. Particularly
useful phase transfer catalysts are tetralkylammonium
halides (generally such halides containing up to a~out 50
carbons), preferably bromides and chlorides, such as
tetrabutylammonium bromide, tributylmethylammonium
chloride, etc. When employed, the catalyst is used in a
catalytic amount, e.g., 2-6~ by weight of the 6-alkoxy-
tetralone; and its use sometimes seems to permit theattainment of higher yields than can be obtained in its
absence.
In the practice of the preferred cyanation
reaction, the ingredients of the reaction mixture may be
15 combined in any suitable manner, preferably with the
solids in finely-divided form, and heated at a suitable
temperature, e~g., 60-120C., preferably about 90C., to
produce the desired product. Lower temperatures can be
used but are less desirable because of their leading to
20 slower reactions; higher temperatures are apt to be
undesirable because of the tendency for by-products to be
formed at the higher temperatures. The time required to
obtain good yields varies with the temperature but is
frequently in the range of 4-10 hours.
It is sometimes preferred to combine the ingre-
dients by prestirring the cyanide ion source, the Lewis
acid, and a solvent beore combining these ingredients
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wit~ the 6-al~oxytetralone, and it appears to be
desirable ~o maintain the temperature of these ingre-
dients below 60C., e.g., at 10-50C., conveniently at
20-30C., until the addition of the 6-alkoxytetralone has
been completed.
It is also sometimes preferred to conduct the
cyanation in the presence of a small amount of water
and/or concentrated HCl -- additives which appear to
effect an activation of one or more of the reactants and
increase yields. The particular amount of water and/or
HCl employed is an activating amount, i.e., an amount
insufficient to hydrolyze the Lewis acid completely, and
may be provided simply by the water naturally present in
one or more of the aforementioned ingredients of the
reaction mixture. When it is desired to employ addi-
tional water and/or HCl, the added amount is generally in
the range of 0.1-1.0 mol per mol of the 6-alkoxy-
tetralone.
Conversion of 6-Alkoxy-l-Cyano-3,4-Dih~dronaehthalene
As mentioned above, the cyanation of the 6-alkoxy-
tetraLone results in the formation of a 6-alkoxy-1-cyano-
3,4-dihydronaphthalene, which is then converted to a
naphthoic acid precursor selected from a 6-alkoxy-1-cyano-
naphthalene and a hydrocarbyl 6-alkoxy-1-naphthoate. The
6-alkoxy-L-cyano-3,4-dihydronaphthalene formed in the
cyanatlon step may be recovered by conventional means
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prior to being subjected to this conversion, but such a
recovery is unnecessary, inconvenient, and therefore not
preerred.
When the naphthoic acid precurgor desired is a
6-alkoxy-1-cyanonaphthalene, the conversion i5 simply an
aromatization which may be accomplished by techniques
already known to the art, e.g., heating the reaction
mixture containing the 6-alkoxy-1-cyano-3,4-dihydro-
naphthalene, preferably at reflux temperaturPs, in the
presence of a palladium-on-carbon, platinum, nickel, or
other dehydrogenation catalyst; aromatizing the compound
with sulfur, etc. It i5 ordinarily preferred to
aromatize the compound by dehydrogenation in the presence
of a palladium-on-carbon catalyst.
When the naphthoic acid precursor desired is a
hydrocarbyl 6-alkoxy-l-naphthoate, the 6-alkoxy-1-cyano-
3,4-dihydronaphthalene is first converted to a 6-alkoxy-1-
cyanonaphthalene as described above, then hydrolyzed to
the corresponding 6-alkoxy-1-naphthoic acid, and then
esterified by known techniques, such as the hydrolyzation
and esterification techniques taught in March, Advanced
Organic Chemistry, Second Edition, McGraw-Hill (New
York), pp. 809-810 and 363-365. In a preferred qmbodi-
ment of the invention, the 6-alkoxy~l-cyanonaphthalene is
hydrolyzed in the presence of a base such as sodium
hydroxide and then esterified with an appropriate alcohol,
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generally an alcohol corresponding to the formula ROH
wherein R is a satura~ed hydrocarbyl group (i.e., a
hydrocarbyl group that is free of aliphatic unsaturation)
such as an alkyl, cycloalkyl, aryl, alkaryl, or aralkyl
S group containing l-10 carbons, in the presence of an acid
such as HCl, sulfuric acid, etc. Ordinarily the alcohol
employed in the esterifica~ion reaction is methanol.
Halogenation
Regardless of whether the desired naphthoic acid
precursor formed in the conversion step is a 6-alkoxy-1-
cyanonaphthalene or a hydrocarbyl 6-alkoxy-l-naphthoate,
it is then halogenated to a corresponding 5-halo deriva-
tive, i.e., a 6-alkoxy-S-halo-l-cyanonaphthalene or a
hydrocarbyl 6-alkoxy-5-halo-1-naphthoate, generally after
having been isolated from its synthesis mixture by
conventional techniques. This halogenation may be a
fluorination, chlorination, bromination, or iodination
and may be accomplished by known techniques, such as the
techniques disclosed in March, pp. 482-484, and the
references cited therein. However, since the 5-halo
compounds are prepared as precursors to 5-tri~luoro-
methyl compounds, and at least the preferred trifluoro-
methylation techniques are most satisfactorily performed
on iodo and bromo compounds, the preferred halogenation
techniques are those for the iodination or bromination of
aromatic corpounds.
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-- 10 --
When a 5-iodo compound is desired, it is ordi-
narily preferred to prepare the product by reacting the
6-alkoxy-1-cyanonaphthalene or hydrocarbyl 6-alkoxy-1-
naphthoate with iodine/iodic acid as in March, Sestanj ét
al. I, and Sestanj et al. III (especially Example lf).
However, other oxidizing agents, such as hydrogen
peroxide, etc., can be used instead of iodic acid, or the
iodic acid may be generated in situ instead of being
incorporated per se.
When a 5-bromo compound is desired, it is prepared
so easily that it is not even necessary to employ a
catalyst, though the conventional bromination catalysts
could be employed without adversely affecting the
reaction. Thus, it i5 ordinarily preferred to prepare
the compound simply by reacting the 6-alkoxy-1-cyano-
naphthalene or hydrocaxbyl 6-alkoxy-1-naphthoate with
bromine in a suitable solvent, e.g., a halogenated alkane
such as methylene chloride, ethylene bromide, carbon
tetrachloride, etc., at any suitable temperature, e.g.,
-5C. to 20C. Lower reaction temperatures can be used
but do not appear to offer any particular advantage, and
higher temperatures are also utilizable but are conducive
to the loss of bromine.
The us~e of a 6-alkoxy-1-cyanonaphthalene in the
halogenation reaction is particularly advantageous , and
it leads to the formation of a novel compound, i.e., a
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6-alkoxy-5-halo-1-cyanonaphthalene wherein the alkoxy
substituent is the alkoxy group corresponding 'co the
alkoxy substituent in the initial 6-alkoxytetralone,
generally, as indicated above, an alkoxy group containing
1-20, preferably 1-6, carbons, and most preferably
methoxy; and the halo substituent is fluoro, chloro,
bromo, or iodo, preferably bromo or iodo. These novel
compounds are advantageous in that they have higher
melting points and lower degrees of solubility than the
corresponding esters.
Trifluoromethylation
The 5-halo derivative prepared in the halogenation
step, generally after being recovered by conventional
techniques, may be converted to the corresponding
5-trifluoromethyl compound by known trifluoromethylation
techniques, e.g., the techniques taught in Sestanj et al.
I, Sestanj et al. II, Sestanj et al. III ~especially
Example lh), Matsui et al., and the refe~ences cited
therein. In a preferrPd embodiment of the invention, the
5-ha~o derivative is trifluoromethylated, as in Matsui et
al., by reacting it with a trifluoroacetate salt, prefera-
bly sodium trifluoroacetate, at a suitable temperature,
conveniently at reflux temperatures, in the presence of
cuprous iodide and a dipolar aprotic solvent, such as
~-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethyl-
acetamide, hexamethylphosphoric triamide, etc., most de-
sirably N,W-dimethylacetamide.
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~ - As in the halogenation reaction, the use of the
nitrile reactants is preferred to the use of the ester
reactants, and this use leads to the formation of novel
compounds which have the advantages of higher melting
points and lower degrees of solubility than the corre-
sponding esters. In this case, the novel compounds are
the 6-alkoxy-5-trifluoromethyl-1-cyanonaphthalenes
corresponding to the 6-alkoxy-5-halo-1-cyanonaphthalenes
described in the previous section.
Hydrolysis
Hydrolysis of the 6-alkoxy-5-trifluoromethyl-1-
cyanonaphthalene or hydrocarbyl 6-alkoxy-5-trifluoro-
methyl-l-naphthoate to the corresponding acid is
accomplished by conventional techniques, such as those
described above in connection with the hydrolysis of
6-alXoxy-l-cyanonaphthalenes, generally by reaction with
water in the presence of a base such as sodium or
potassium hydroxide.
After completion of the hydrolysis step, the
resultant 6-alkoxy-5-trifluoromethyl-1-naphthoic acid may
be recovered by conventional means and/or converted to a
desired derivativei such as the pharmaceutical materials
taught in the Sestanj ~t al. references.
The invention is particularly advantageous as a
commercially-attractive process for preparin~ 6~alkoxy-
5-trifluoromethyl-l~naphthoic acids, especially
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5-methoxy-5-trifluoromethy~ naphthoic acid, which c~n
then be converted to other products, such as tolrestat
and similar pharmaceuticals. The aspect of the invention
wherein the nitrile formed in the cyanation step is not
converted to an acid until the trifluoromethyl group has
been attached to the ring is preferred because of the
greater reactivities of the nitrile intermediates in the
halogenation and trifluoromethylation steps and because
of the greater ease with which the intermediates can be
recovered. However, both aspects have economic
advantages over known techniques of preparing 6-alkoxy-5-
trifluorome~hyl-l-naphthoic acids.
The following examples are given to illustrate the
invention and are not intended as a limitation thereof.
A. CYANATION REACTIONS
_
EXAMPLE I
A mixture of 1.3 g of dry AlC13, 0.64 9 of dry
NaCN, and 87 mg of tetrabutylammonium bromide (TBAB) in
8.7 ml of dry nitrobenzene (NB) was stirred for two hours
under a nitrogen atmosphere. Then 1.53 g of 6-methoxy-
tetralone (6-MT) were added to provide a reaction mixture
containing the 6-MT, NaCN, and AlC13 in a mol ratio of
1/1.5/1.1 and containing 5.6% of TBAB, based on the
weight of 6-MT. The reaction mixture was stirred at 9O~C.
for 10~hours to form 6-methoxy-l~cyano-3,4-dihydro-
naphthalene (6-MCDN). After workup the VPC ratio of
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- 14
~ 6-MT/6-MCDN was determined to be 8/92. The process
resulted in an 85~ isolated yield of 6-MCDN.
EXAMPLE II
Example I was essential.ly repeated except that the
AlC13/MaCN/TBAB/NB mixture was not subjected to the two
hour stirring period prior to the addition of the 6-MT.
After workup the VPC ratio of 6-MT/6-MCDN was determined
to be 41/59~
EXAMPLE III
A mixture of 1.56 g of boron trifluoride etherate,
0.98 g o NaC~, and 100 mg of TBAB in 10 ml of ~B was
stirred for two hours. Then 1.76 g of 6-MT were added to
provide a reaction mixture containing the 6-MT, NaCN, and
15 BF3 in a mol ratio of 1/2/ 1.1. The mixture was heated
at ~0C. for two hours and then at 120C. for six hours
to form 6-MCDN. Analysis showed the 6-MT/6-MCDN ratio to
be 5/4.
EXAMPLE IV
-
An 8.47 g portion of AlC13 was added under
nitrogen in a dry box to a suitable reaction vessel,
followed by the addltion of a 50 ml portion of dry NB.
The resulting mixture was stirred for 15 minutes, after
which 5.57 9 of powde~ed NaCN and 0.50 g of dry TBAB were
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successively added. The resulting yellow slurry was~
stirred for two hours. Then 10 g of distilled 6-MT were
added to provide a green slurry containing the 6-MT,
NaCN, AlC13, and TBAB in a mol ratio of l/2/1.1/0.03,
and the reaction mixture was heated to 90C. and main-
tained at that temperature for six hours. Analysis of the
slurry after completion of the reaction showed it to
contain 78.8~ 6-MT and 19.5% 6-MCDN by GC area ~.
EXAMPLE V
Example IV was essentially repeated except that
0.25 9 of concentrated HCl was added to the reaction
mixture after the addition of the TBAB had been com-
pleted, and the reaction mixture was maintained at 90C.
for only four hours. Analysis of the final reaction
mixture showed it to contain 7 area ~ 6-MT and 89.4 area
% 6-MCDN.
EXAMPLE VI
Example IV was essentially repeated except that
three drops of water were added to the reaction ~ixture
after the addition of the TBAB had been completed.
Analysis of the~final reaction mixture showed it to con-
tain 4.4 area ~ 6-MT and 90.5 area % 6-MCDN.
EXAMPLE VII
A solution of 22.7 g of anhydrous AlC13 in 100
ml of NB was cooled to 10C. in an ice bath, after which
' ' . ` ~ , ' `: '
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- 16 -
6-.9 g of liquid HCN were added~ The mixture was stirred
vigorously and 30 g of 6-MT were added to provide a
reaction mixture containing the 6-MT, HCN, and ALC13 in
a mol ratio of 1/1.5/1. When the 6-MT had completely
dissolved, the mixture was transferred to an autoclave
and heated at 70C. for ten hours. After cooling, the
contents of the autoclave were removed and treated with
100 ml of dilute HC1 and 100 ml of methylene chloride.
The mixture was shaken in a separatory funnel and allowed
to stand for phase separation. The lower organic layer
was removed and concentrated on a rotary evaporator to
remove methylene chloride. GC investigation (internal
standard method) of the nitrobenzene solution showed an
88% yleld of 6-MCDN.
15 B. CONVERSIONS OF 6-ALKOXY-1-CYAN0-3,4-DIHYDRONAPHTHALENES
. .
EXAMPLE VIII
A crude 6-MCDN in NB prepared essentially as in
Example I was treated w1th 5~ (based on the weight of the
original 6-MT) of 5% Pd/C at 150-220C. for 10 hours. The
process resulted in the conversion of 97% of the 6-MCDN to
6-methoxy-1-cyanonaphthalene (6-MCN).
EXAMPLE IX
Part A
A mlxture of 5 g of 6~MCN, 10 g of 50% NaOH, and 50
mg of TBAB was stirred for 2-3 hours at 120-130C. (HPLC
showed that the reaction was completed in two hours.)
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After workup HPLC analysis showed that the process had
resulted in a 96% yield of 6-methoxynaphthoic acid.
Part B
A mixture of 9.1 g of 6-methoxynaphthoic acid and
5 7 . 2 g of anhydrous potassium carbonate in 45 ml of acetone
was heated to 50-55C. for 15 minutes, and 4.5 ml of
dimethyl sulfate were then slowly dripped in over a period
of 15 minutes. The mixture was then heated at reflux for
one hour and cooled to room temperature, after which all
the acetone was stripped under vacuum. ~fter workup, it
was determined that the process resulted in the formation
of 8.85 g of methyl 6-methoxynaphthoate having an HPLC
purity of 83.3~.
C. HALOGENATIONS
lS EXAMPLE X
Methyl 6-methoxy-1-naphthoate can be iodinated to
methyl 5-iodo-6-methoxy-1-naphthoate by treatment with
iodine and iodic acid in the presence of acetic and
sulfuric acids as in Example lf of Sestanj et al~ III.
EXAMPLE XI
A solution of 5 g of 6-MCN in methylene chloride
was bromlnated with 1.1 molar equivalents of bromine at
-5C. to provide an 89~ yield of crude 5-bromo-6-methoxy-1-
cyanonaphthalene.
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- 18 -
EXAMPLE XII
A solution of 5 g of 6-MCN in methylene chloride
was brominated with 1.1 molar equivalents of bro~ine at
20C. to provide a 95% yield of crude 5-bromo-6-methoxy-1-
S cyanonaphthalene.
EXAMPLE XIII
Concentrated sulfuric acid (2.6 g) was slowly
dripped into a stirred mixture of 18.7 g of crude 6-MCN,
10.3 g of iodine, 4.06 g of iodic acid and 172 ml of
aqueous acetic acid over a period of 10 minutes. The
mixture was then slowly warmed to 70-75C. over a period
of one hour and maintained at that temperature for another
hour. After cooling the mixture was worked up to provide
a 93% isolated yield of 5-iodo-6-methoxy-1-cyano-
naphthalene.
D. TRIFLUOROMETHYLATIONS
EXAMPLE XIV
Methyl S-iodo-6 methoxy-l-naphthoate can be
trifluoromethylated with trifluoromethyliodide in the
presence of copper powder and pyridine as in Example lh of
Sestanj et al. III to prepare methyl 5-trifluoromethyl-
6-methoxy-1-naphthoate.
EXAMPLE XV
A 6.15~g portion of cuprous iodide and 5.5 g of
sodium trifluoroacetate were added to a stirred solution
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-- 19 --
of 4.2 g of 98% pur~ 5-bromo-6-methoxy-1-cyanonaphthalene
in 25 ml of toluene. The resulting slurry was heated to
reflux, and 10 ml of toluene were slowly distilled off.
Then 100 ml of dimethylacetamide (DMAC) were added, and
the resulting ~lurry was heat~d at reflux with distilla-
tion until ~he pot temperature rose to 154C. The mixture
was refluxed for six hours, at which point HPLC analysis
indicated complete conversion of starting material. After
workup the 6-methoxy-5-trifluoromethyl-1-cyanonaphthalene
product (98.5% pure by HPLC) was isolated in 82% yield.
EXAMPLE XVI
A mixture of 5 g of 5-iodo-6-methoxy-1-cyano-
naphthalene, 9.65 g of sodium tri~luoroacetate, and 6.15 g
of cuprous iodide was stirred into 40 ml of toluene, after
which about 30 ml of toluene was distilled over at atmos-
pheric pressure. Then 100 ml of dry N-methylpyrrolidone
(NMP) was added, and the mixture was heated at 150-155C.
for four hours. At the end of the reaction, most of the
NMP was distilled under vacuum at 80-100C. After workup
the 6-methoxy-5-trifluoromethyl-1-cyanonaphthalene product
was isoIated in 73~ yield.
EXAMPLE XVII
_
A mixture of 10 g of 5-iodo-6-methoxy-1-cyano-
naphthalene, 11 g of sodium trifluoroacetate, and 12.33 g
of cuprous iodide was stirred into 50 ml of toluene, after
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which about 20 ml of toluene was distilled over at 120C.,
760 mm of pressure. Then 200 ml of dry D~C were added,
and the mixture was heated while distilling over another
10-15 ml until the temperature reached 152C. The slurry
was gen~ly refluxed at 150-155C. for four hours and then
cooled to 120C. Another 1.1 g of sodium trifluoroacetate
were added, and the reaction mixtuxe was heated back up to
152C. and stirred for two hours at 150-155C. At the end
of the reaction, most of the DMAC was stripped under
vacuum at a temperature below 80C. After workup the
6-methoxy-5-trifluorome!thyl-1-cyanonaphthalene was
isolated in 90~ yield.
E~ HYDROLYSES
EXAMPLE XVIII
Methyl 5-trifluoromethyl-6-methoxy-1-naphthoate can
be converted to 5-trifluoromethyl-6-methoxy-1-naphthoic
acid by hydrolyzation with aqueous sodium hydroxide in the
presence of methanol as in Example lh of Sestanj et al.
III.
EXAMPLE XIX
A solution of 0.5 g of 6-methoxy-5-trifluoromethyl-
l-cyanonaphthalene and 0.6 g of potassium hydroxide in 25
ml of a 20/5 mixture o~ methanol and water was charged
into an autoolave, heated to 130C. and stirred for 5-6
25 hours at an~lnternal pressure of 90-100 psi. The reaction
: .
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- 21 -
mixture was then cooled and worked up to provide a 98~ -
recovered yield of lOO~ pure 6-methoxy-5-triEluoromethyl~
l-naphthoic acid.
It is obvious that many variations can be made in
the products and processes set forth above without
departing Erom the spirit and scope of this invention.
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