Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~2932~;~
--2--
~ This is a divisional applicat~on of copending
applïcation 516,173, filed August 18, 1986.
BAC~G~OUND OF THE INVENTION
l-Cyclopropyl-6,7,8 trifluoro-1,4 oxo-3-auinoline
carboxylic acid is a key intermediate in the prepara-
tion of 7-aminosubstituted-1-cyclopropyl-6,8-difluoro-
1,4-dihydro-4-oxo-3-quinolinecarboxylic acids described
in German Offenlegun~schrift 3,318,145 and United
- States Pa~ent ~,665,a79.
These 7-aminosubstitu~ed-1-cyclopropyl-6 ,8-difluoro-
4-oxo~uinolines are useful as antibacterial agents.
1-Cyclopzopyl-6,7,8-trifluoro 1,4-dihydro~4-
oxo-3~quinolinecarboxylic acid may be, in turn,
prepared by a series of steps starting with ~,3,4,5-
tetrafluorobenzoic acid.
2,3,4,5-Tetrafluoroben20ic acid is not commer-
lS cially available ~ince it i~ di~ficult to ~ynthesize.G. C. Yakobson, et al., in Zhurnal Ob~hchei Rhimii,
36 ~1), pgs 139-42 (19661, de~cribe such synthesi3
by the decarboxylation o~ tetrafluorophthalic acid
at 145C. The pre~ent invention relate~ to a new
proces~ for ~,3,4,5-~etrafluo~obenzoic acid which
provide~ a 2S-30~ yield improvement over the previ-
ou~ly de~cribed methodO
SUMM~RY OF T~ INVENTION
Accordingly, the present invention in it~ first
aspec~ is a process for preparing 2,3,4,5-tetrafluoro-
benzoic acid comprising heating te~rafluorophthalic
: acid with a base cataly~t in a polar, aprotic solvent
at a temperature of 90 to 140C.
A qecond aspect of the present invention i~
an improved process ~or ~he preparation of 3,4,5,6-
tetrafluorophthalic acid which comprises: heating
p~rchlorophthalide and potassium fluoride at a
~k
3--
temperature of about 100-170C in a polar, aprotic
solvent, such as sulfolane;
extracting tetrafluorophthaloyl fluoride from
the reaction mixture,.for example from the KF KCl
sulfolane salt, with an ether solvent, such as
tetrahydrofuran;
hydrolyzing the extract with a~ueous acid,
e.g~ hydrochloric acid, distilling off the solvent
and isolating the desired product by extraction
with an ether solvent, such as n-butyl ether.
A t.bird aspect of the present invention is
a one-pot process for the preparation of 2,3,4,5-
tetrafluorobenzoic acid which comprises:
(a) heating perchlorophthalide and potassium
fluoride at about 100-170C in a polar, ap;otic
solvent, such as sulfolane:
(b) extracting tetrafluorophthaloyl fluoride r
from the reaction mixture, for example the RF-KC1
sulfolane ~alt, with an ether solvent, such a9
ZO tetrahydrofuran;
(c) hydrolyzing the te~rafluorophthaloyl fluoride
with aqueous ba~e, e.g. sodium bicarbonate, ~odium
hydroxide or calcium hydroxide, followed by removal
o~ the ether 401vent;
(d) heating the remaining reaction mixture
at about 90-140 & with a base catalyst, ~uch as
triet~ylamine in a polar, aprotic solvent and isolatin~
the product according to known means.
DETAILED DESCRIPTION OF PREFER~ED EMBODIMENTS
In the firRt aspect of the present invention,
the 25-30% yield improvement achieved by the present
process is due to the use of a base catalyst in
the decarboxyLation reaction. This not only affords
--4--
better yields but allows the use of lower temperatures
than previously reported. For example, the process
may be carried out at a range of 90 to 140C, but,
preferably in the range of 105-125C. The heating
S period ran~es from a half hour to 3 hours, preferably,
about one hour.
As base catalysts, organic amines are preferred.
More preferred are tertiary amines such as trialkylamines
in which each alkyl group is a straiqht or branched
hydrocarbon radical containing one to six carbon
atoms, p~ridines, alkylaminopyridines~ anilines,
dialkylanilines, alkylcycloalkyleneimines in which
alkyl is a straight or branched hydrocarbon radical
containing one to 5iX carbon atoms and the nitrogen
atom is part of a five to seven membered rin~, or
bicyclicimlnes containing five-, ~ix-, and ~even-
ring members, or diazabicycloalkanes, 3uch as heptanes,
octaneq, nonanes, or decanes. Particularly use~ul
amines ~rom the above are triethylamine, diisopropyl-
et~ylamine, pyridine, 4-dimethylaminopyridine, dimethyl-
aniline, N-methylpyrrolidine, N-methylpiperidine,
quinuclidine or diazabicyclo[2.2.2~octanel Particularly
valuable are triethylamine and diazabicyclo[2.2.2~octane.
Inorganic bases ~uch as sodium bicarbonate, potassium
carbonate and sodium hydroxide may also be used.
The amount of ba~e catalyst employed in the
reaction may vary. Normally, 0.05 to 0.75 mole
per mole, or preferably 0.2 to 0.5 mole per mole
of tetrafluorophthalic acid is used.
rhe reaction may be carried out in any polar,
aprotic solvent~ Examples of ~uch solvent3 are
sulfolane (tetramethylenesulfone), dimethyl sulfoxide,
dimethylsulfone, diphenylsulfone, dimethylormamide,
dimethylacetamide, N methylpyrrolidone, benzonitrile,
~z~
nitrobenzene, diglyme, tetraglyme or hexamethylphos-
phoric triamide.
Isolation and purificatlon of the tetrafluoro-
benzoic acid obtained in the above manner may be
facilitated by the extraction of the product with
an ether solvent, such as, di-n-butyl ether, tert-
butyl methyl ether or ~iisopropyl ether, or ethyl
acetate, toluene, methylene chloride, or combinations
of the above. Preferred is di-n-butyl ether. The
product is then recrystallized from isooctane, heptanes
or hexanes~ Preferred is isooctane.
2,3,4,5-Tetrafluorobenzoic acid prepared by
tbe proces~ of the present invention is used to
prepare l-~yclopropyl-6,7,8-trifluoro-1,4-d ihyar
4-oxo-3-~uinolinecarboxylic acid, which, in turn,
i~ converted to antibacterial agents as described
in DE 3318145 and United States paten~ 4,665,079~
. The qodium salt o 2,3,4,5-tetra-
fluorobenzoic acid is reacted with oxalyl ~hloride
and the product condensed with diethyL ~alonate
in the pre~ence of magnesium turnings to afford
after hydxolysi~ 2,3,4,5-tetrafluorobenzoylacetic
acid, ethyl ester. The compound i~ treated with
triethylortho~ormate and acetic anhydride, followed
by cyclopropylamine to afford 2-(2,3,4,5-tetrafluoro-
benzoyl)-2-cyclopropylaminoacrylic acid, ethyl ester,
which is ring closed and hydrolyzed with sodium
hydroxide to give the desired l-oyclopropyl-6,7,8-
trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid.
The tarting material in the present process,
; tetrafluorophthalic acid, may be prepared by known
methods. For example, tetrachlorophthalonitrile,
which i~ commercially available, is treated with
po~assium fluoride a~ eleva~ed temperatures in a
~L~3~
--6
polar, aprotic solvent such as dimethylsulfoxide
to give the tetrafluorophthalonitrile which is
converted to the corresponding phthalic acid by
acid hydrolysis.
s An alternate method to prepare tetrafluoro-
phthalic acid is to treat tetrachlorophthali
anhydride, also commercially available, with
phosphorus pentachloride and phosphorus oxychloride
to yield 3,3,4,5,6,7-hexachloro-1-r3H]-isobenzofuranone,
otherwise known as perchlorophthalide. This compound
is heated with dry potassium fluoride in an autoclave
to give tetrafluorophthaloyl fluoride which is conve~ted
to the methyl ester. Acid hydrolysis of the diester
provides the de~ired tetrafluorophthalic acid.
A new and improved method for preparing 3,4,5,6-
tetrafluorophthalic acid forms the second aspect
of the present invention which comprises heatin~
perchloroph~halide wlth potal~sium Eluoride at a
temperature of about 100-17CIC, preferably at about
1~0~170C and more preerably at about 155-16~C,
for 2 to 12 hours, preferably abou~ 4 hours, in
a polar aprotic solvent defined previously, preferably
sulfolane. PotaRsium fluoride is used in excesst
for example, from about 9 to about la e~uivalentg
per equivalent of perchlorophthalide~ Preferably
14-16 equivalent~ are used to minimize the amount
of chlorinated impurities.
~he above reaction may be carried out in the
presence o~ a catalyst such as a crown ether, e.g.
tetra~lyme, 18-crown-6 or Carbowax~ MPEG 2000, (a
monopropylene ethylene glycol polymer of approximate
molecular weight of 2000~ or a phase transfer catalyst
such as tetrabutylammonium bromide or sulfate or
a metal catalyst ~uch as cesium fluoride.
~3~
,
Extraction of the tetrafluorophthaloyl fluoride
prior to hydrolysis may be carried out with an ether
solvent such as tetrahydrofuran or dioxane, or methylene
chloride. The preferred solvent is tetrah~drofuran.
~ydrolysis of the tetrafluorophthaloyl fluoride
is carried out with aqueous acid, e.g. hydrochloric
acid. However when thls reaction is carried out
as a one-pot preparation of tetra~luorobenzoic acid,
the hydrolysis is preferably carried out with base,
for example, sodium hydroxide, sodium bicarbonate,
potassium carbonate, sodium carbonate, potassium
hydroxide, calcium hydroxide, ferrous hydroxide
or triethylamine. Preferred are sodium hydro~ide
or calcium hydroxide.
The tetrafluorophthalic acid is isolated by
extraction with an ether -~olvent, such as, di-n-
butyl ether, tert-butyl methyl ether or diisopropyl
ether, or an ester solvent, such as, ethyl acetate.
The preferred olvent is di-n-butyl ether.
The third aspect of the present invention is
the combination of the above inventions into a one-
pot preparation of 2,3,4,5-tetrafluorobenzoic acid
as above d~cribed which results in an overall yield
o~ 72~ from perchlorophthalide as compared to a
32~ overall yield for the literature preparation
of tetrafluorobenzoic acid from perchlorophthalide
~nvolving i~olation of dimethyl tetrafluorophthalate
and tetra~luorophthalic acid intermediates.
Th~ ~ollowing examples are illustrative to
show the present process, the preparation of starting
materials9 and the use of the product obtained by
the pre3ent process to prepare the key intermediate
in the synthesis of quinolone antibacterial agents.
~29326i2
--8
EXAMPLE 1
?.c 3l4~5-Tetrafluorobenzoic Acid
3,4,5,6-Tetrafluorophthalic acid (58 g) was
added to a two liter flask. Dimethyl sulfoxide
(230 ml) followed by triethylamine (11.5 ml) were
then added and the mix~ure heated over a 20 minute
period to 115-120C. The solution was heated with
stirring at 115-120C for another 35-40 minutes
and then cooled with an ice bath. Demineralized
water (580 ml) followed by n~butyl e~her (250 ml)
and toluene (350 ml) were addedO Sulfuric acid
(99%~ 3.5 ml) was then cautiously added with stirring
and cooling. The layers were separated and the
aqueous layer extracted with two portions of toluene
~580 ml and 290 ml). The combined organic layers
were extracted with 2~ a~ueous sulfuric acid (3 x
150 ml). The or~anic layer was dried over anhydrous
sodium sulfate (60 g) and Darco S-51 (11.5 g) was
added. After filtering the mixture was concentrated
under reduced pressure and the re-~ulting solid dried
under vacuum at 50 60C for ~even hours to give
2,3,4,5-tetrafluorobenzoic acid (44.3 g, 94~); mp
77-80C.
EXAMPLE 2
?, 3,4,5-Tetrafluorobenzoic Acid
A 22 liter flask was charged with 2O085 kg
: tetrafluorophthalic acid followed by 8.4 liter
dimet~ylsulfoxide and 30~3 g triethylamine. The
: reaction mix~ure was warmed with stirring over a
50 minute period to 118C. The resulting solution
was stirred at 115-118C for another 45 minutes
before ice bath cooling wa~ applied. When the
.
~Z93~:~2
temperature had reached 25C the solution was added
with stirring to a mixture of lO kg ice, 8 liter
demineralized water, 8.4 liter n-butyl ether and
lO liter toluene in a 50 liter flask. Sulfuric
acid (9g%) was added dropwise to the mixture to
bring the pH to 2. After stirring the orqanic
layer was separated frcm the aqueous layer which
was extracted two more times first with toluene
(15 liters) and then with a mixture of toluene (7
liters) and n-butyl ether (l liter~. The combined
organic extracts were back extracted three times
with six liter portions of an aqueous suLfuric acid
~olution prepared from 360 ml 99~ ~ulfuric acid
and 18 liters demineralized water. The organic
extract was treated with anhydrous sodium sulfate
~2 kg) and Darco S-51 (300 g) filtered and the
filtrate concentrated under reduced pressure on
the rotary evaporator to a solid which was finally
dried under vacuum at 35-40C for 21 hours to give
1.62 kg (95~) 2,3,4,5-tetrafluorobenzoic acid: mp 82-84C.
EXAMPLE 3
l-Cvclopropyl-6,7,8-trifluoro-1,4-dihYdro-4-oxo-
3-quinolinecarboxylic Acid~ -
2 ~ 3 ~ 4 r 5 -Tetrafluoro-~-o~ob _
Ethyl_Ester
To 30.0 g (155 mmol) of 2,3,4,5-tetrafluoro-
benzoic acid in 75 ml of diGhloromethane was added
14.8 ml (1.1 equivalents) of oxalyl chloride. The
mixture W25 then treated with three drops of dry
N,N-dimethylformamide and the vigorous reaction
was stirred at room temperature overnight. The
mixture was then concentrated to an oil, taken up
~93;~
in toluene, and reconcentrated to afford 2,3,4,5-
tetrafluorobenzoyl chloride which was used in the
next ste20
To 40.92 g (310 mmol) of malonic acid half
ethyl ester in 700 ml of dry tetrahydrofuran at
-35C was added a stream of n-butyllithium until
one equivalent was del-vered. The mixture was
maintained at -15 to -30 during the addition, then
warmed to ~5C treated with 10 mg of bipyrid~l. -
The remainder of the n-butyllithium was added at
this temperature until the indicator turned pink.
A total of 282 ml of 2.2 N n-butyllithium was added.
The mixture was recooled to -78C and a solution
of 2,3,4,5-tetrafluorobenzoyl chloride in 100 ml
of dry tetrahydrofuran was added keepiny the
temperature constant. The reaction mixture was
~tirred for 45 minutes after the acid chloride
addition. It was warmed to -35C and poured into
155 ml of 2 N hydrochloric acid. To thi~ mixture
wa~ added one liter o~ water and 1.5 liters of
dichloromethane~ The aqueou3 phase was sepa~ated
and extracted with an additional 1.5 liters of
dichloromethane. The combined organic phases were
washed with sodium bicarbonate and then 1 N
hydrochloric acid. The dichloromethane was dried
(magnesium sulfate) an~ concentrated to a ~olid
which was triturated with coId pentane to give 37.8
of 2~3t4~5-tetrafluoro-B-oxobenzenepropanoic acid,
ethyl ester; mp 63-65~C.
1-Cyclopro~yl-6,7,8-trifluoro-1,4-dihydro-4
3-q~ino inecarboxylic Acid
To 17.6 g (66.6 mmol) of ethyl 2,3,4,5-tetra-
luoro-B-oxobenzenepropanoate was added 14.6 g (~ 1.5
equivalents) of triethylorthoformate and 16.19 g
. .
(2.38 equivalents) of acetic anhydride. The mixture
was refluxed for two hours at 1~0C tand was then
cooled to 80C and concentrated in vacuo). The
mixture was diluted with t-butanol, cooled to 10C,
and 3.8 g rl.os equivalents) of cyclopropylamine
in 120 ml of t-butanol was added. The mixture was
stirred at 20C for 30 minutes and then warmed to
50C overnight. At this temperature 7.5 g of
potassium t-butoxide was added in 50 ml of t-butanol
and the mixture was stirred for four hours. It
wa-~ filtered and the solids dissolved in 250 ml
o hot acetic acid and 200 ml of 3 N hydrochloric
acid was added in portions over four hours at 100C.
The mixture was cooled and the solids collected
lS to ~ive 15.44 g (82%) o~ the 1-cyclopropyl-6,7,8-
triflùoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid; mp 226-228C~
EXAMPLÆ 4
7-~3-Amino-l-pvrrolidinyll-l-cyclo~ropyl-6,8-difluoro-
1,4-dihyd ~ carboxylic Acid
.~ .
7-L3-t-Butoxycarbonylamino-l-pyrrolidin
propyl-6,8-diflui~c~ hYdro-4 oxo-3-auinoline-
carbo~ylic Acid
A ~uspen~ion of 4g.5 g (0.175 mole) of l-cyclo-
25 propyl-1/4-dihydro-4-oxo-6~7~8-trifluoroquinoline-
3-carboxylic ac~d, 37.3 g (0~ mole) of l,l-dimethyl-
e~hyl (3-pyrrolidinyl)carbamate, 4~.4 g (0.4 mole)
of triethylamine in 1.5 liters o~ acetonitrile was
refluxed for three hours. The precipitate was removed
by filtration, washed with acetonitrile, then ethyl
ether, and dried in vacuo to give 75.0 g of the
title compound; mp 239-240C.
.-12-
7-[3-Amino-l-pyrrolidinyl~ cyclo~ro~yl-6,8-difluoro-
1~4-dlhydro-4-oxo-3-quinolinecarboxylic Acid
A solution of 1.4 g (3.1 mmole) of 7-[3-t-butoxy-
carbonylamino-l~pyrrolidinyl~ cyclopropyl-6,8-
: S difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic
acid in 25 ml of trifluoroacetic acid was stirred
at room temperature un'il gas evolution ceased.
The solvent was removed in vacuo and the residue
dissolved in 1 N sodium hydroxide. The solution
was diluted to 100 ml wit~ water and acidlfied to
pH 5.5 with 6 N hydrochloric acid. The precipitate
was removed by filtration, washed with water, ethanol,
and ethyl ether. The residue was dried in vacuo
to give 1.05 g (97%) of the title com~ound; mp 290-292C.
7-~3-~a no-1-~Yrrolidinvll-l-cyclopropvl-~,8-difluoro-
~4-dihvdro-4-oxo-3-guinolinecarhoxylic Acid ~ydro-
chloride
A su~pension of 72.4 g ~0.16 mole) of 7-[3-
t-butoxycarbonylamino-l-pyrrolidinyl~ cyclopropyl-
6,8-difluoro-1,4-dihydro-4-oxo-3-auinolinecarboxylic
acid, 375 ml of 6 N hydrochloric acid, and 750 ml
of glacial acetic acid was heated at 60C for four
hours and the re~ulting 3Glution wa~ stirred at
room temperature for 18 hour~. The reaction was
filtered through a fibergla s pad to clarify and
the filtrate was evaporated in vacuo. The residue
was triturated with 600 ml of e~hanol:ether (1:1),
the solid removed by filtration, washed with
ethanol:ether (1:1), ether and dried in vacuo to
give 63.8 g (98%3 of the title compound; mp 313-315C.
The title compound displays potent antibacterial
activity when tested by the microtitration dilution
method as described in Heifetz, et al, Antimicrobial
Agents and Chemotherapy, 6, 1~4 (1974). By use
.
.. . . . .
3~
-13-
of the referenced method~ minimum inhibitory concen-
tration values (MICs in ~g/ml) of les~ than o.l
were obtained for the following organisms:
Enterobacter cloacae MA 2646, Escherichia coli Vogel,
S Klebsiella pneumoniae MGH-2, Proteus rettgeri M1771,
Pseudomones aeruginosa ~I-18, Staphyloccus aureus
H282, Staphyloccus aureus UC-76, Str~ptococcus faecalis
MG~-2, Streptococcus pneumoniae SV-l, and Streptococcus
pyogenes C-203.
EXAMPLE 5
3,4,5,6-TetrafluoroPhthalic Acid
Perchlorophthalide (24 g) was added to a 250 ml
flask followed by anhydrous potassium fluoride (62 g)
and ~ulfolane (55 ml). The mixture was heated to
165-175C where it was maintained for one hour.
Additional sulfolane (15 ml) was added and ~tirring
continued another hour at 165-175C. Finally 15 ml
additional ~ulfolane was added and heating and stirring
continued another three hour~ at 1~5-175C. The
mixture wa~ cooled to room temperature and tetrahydro-
furan ~100 ml) was added. A~ter stirring for 10
minutes, the mixture was filtered and the salt washed
with tetrahydrofuran (2 x 50 ml). 36~ hydrochloric
acid ~0 ml) was then added to the combined ~iltrates
and the solution was allowed to stand at room tempera-
ture overnight. The next day the solution was concen-
trated under reduced pr2ssure at 40C to remo~e
te~rahydrofuran. 36% hydrochloric acid (125 ml)
wa~ added and the re~ulting solution was extracted
with n-butyl ether (4 x 50 ml)~ The combined
n-butYl ether extracts were bac~-extra~ted with 36%
hydrochloric acid (2 x 10 ml) and then concentrated
under reduced pressure to a solid material which
3L2~3~6~:
-14-
was dried under vacuum to give 3,4,5r6-tetrafluoroph-
thalic acid (13.6 g, 81%), mp 151-153C.
ExAMæLE 6
2.3 ! 4,5-Tetrafluorobenzoic Acid (Hydrolysis with
Na~CO3~
Perchlorophthalide (24 g) was added to a 250 ml
flask followed by anhydrous potassium fluoride (62 g)
and sulfolane ~85 ml). The mixture was heated witb
stirring to 155-165C where it was maintained for
a period of four hours. The mixture was then cooled
~o 15C and tetrahydrofuran ~175 ml) was added.
The resulting mixture was stirred at 10-lSC for
15 minutes and then filtered to remove insoluble
salts. ~he salts were washed with tetrahydrofuran
lS ~2 x S0 ml) and the combined filtrates were treated
with demineralized water (S ml). The resultina
solution was allowed to stand at room temperature
overnight. The next day NaHC03 ~11.0 g) was added
and the mixture concentrated under reduced pressure
at 30-35C until essentially all the tetrahydrofuran
had been removed. ~he re~ulting mixture was filtered
and the insoluble residue wa~hed with sulfolane
(10 ml). The combined ~ulfolane filtrates were
treated with triethylamine (3.8 g) and the solution
heated to 120-130C where it was maintained for
45 minute~ The solution was cooled to room
temperature and treated with 10% ~Cl ~100 ml) followed
by n-butyl ether (75 ml). After stirring, the layers
were qeparated and the aqueou~ layer extracted with
n-butyl ether t4 x 50 ml). The com~ined n-butyl
ether ex~racts were back extracted with 2% ~Cl
(2 x ~0 ~1) and then concentrated under reduced
pre~ure to give 14.g g of crude tetrafluorobenzoic
. .
~93~G~2
-15-
acid which was recrystallized from isooctane (10 ml!.
The crystals were collected and washed with isooctane
(10 ml) and dried under vacuum to give 2,3,4,5-tetra-
fluorobenzoic acid (8.0 ~, 59%); mp 84-86C. A
second crop of material was isolated from the mother
liauors (1.5 g, 11%); mp 79-83C.
EXAMPLE 7
2,3,4,5-Tetra.fluorobenzoic Acid (~YdrolYsis with
NaOEI?
Perchlorophthalide (24.0 g), anhydrous potassium
fluoride (62~0 9) and sulfolane ~85 ml) were combined
and the mixture heated at lSS-16QC with stirxing
for four hours. The reaction wa¢ cooled to 15-20C,
Tetrahydrofuran (175 ml) was added and the mixture
~tirred 30 minutes at 15-20C. The salt was removed
by filtration and washed with T~F ~2 x 50 ml).
Water ~2.0 ml) was added to the combined filtrates
and the resulting solution stirred overnight at
ambient temperature. Sodium hydroxide (5.5 q) in
water (6.0 ml) was added dropwise with stirring
and cooling. After ~tirring an additional hour
the mixture was filtered and the solid washed with
tetrahydrofuran (2 x 50 ml). The combined filtrates
were then concentrated under reduced pressure at
40C to remove tetrahydrofuran. Water (2 ml) was
added to the sulfolane-product mixture followed
by triethylamine (3.5 g). The ~olution was heated
to 120C where it was maintained for one hour before
cooling to 10-15C. 36% ~Cl ~100 mll was added
3Q and the resulting solution extracted with n-bu~yl
ether (4 x 60 ml). The combined butyl ether extracts
were back extracted with 5~ 3 x 30 ml) and
then concentrated under reduced pressure to a solid.
3Z~i2.
-16-
,
This was treated with 20 ml isooctane and the mixture
heated until all of the solid dissolved. After
cooling the crystals were collected and washed with
isooctane (2 x 10 ml) and finally dried under vacuum
5 to give 2,3,4,5-tetrafluorobenzoic acid (9.85 9,
72~); mp 83-85C.
PREPAXATION OF STARTING MATERIALS
EXAMPLE A
-3,4,5,6-Tetrafluorophthalonitrile
Anhydrous potassium fluoride (11.0 kg) is added
to a 50 gallon stainless steel reactor. The salt
is dried under 28 inches vacuum at 115-138C for
48 hours. The salt is cooled to 100C and tetra-
methylenesulfone (l9 liters) added followed by
tetrachlorophthalonitrile (4.74 kg). The mixture
is heated with stirring to 156C over a 30 minute
period. ~eating with vigorous agitation is continued
~or another 2.5 hours at 135-162C. The mixture
was cooled to 31C (15 minutes) and ice (69 kg)
and demineralized water (119 liters) were added.
The resulting mixture was stirred l S hours before
centrifuging to collect crude product which was
washed with demineralized water (120 liters). The
crude product was trans~erred back into the 50 gallon
stainless steel still and deminera:Lized water (100
liters~ added. The mixture was steam distilled
until 80 liters of distillate were collected. The
distillate was cooled to 0-5C and the product
collected on a centrifuge. The crystals were washed
with demineralized water (2 x 90 liters) to give
2.82 kg wet product: LOD 6.4~; calculated yield:
74~.
,
-17- ~3~Z
A small sample was dried under vacuum for two
days at room temperature: mp 81-83C.
E%AMPLE B
3,4,5!6-Tetrafluorophthalic Acid
The above tetrafluorophthalonitrile (2.525 kg
wet weight corresponding to 2.36 kg dr~ weight)
was charged to a 22 liter flask. ~ premixed solution
o demineralized water (6.9 liters) and sulfuric
acid (99%, 7.1 liters) was added and a nitrogen
blanket introduced over the reaction mixture. The
mixture was heated with stirring over a two to three
hour period to 85-90C. Heating and stirring were
continued at 85-90C overnight (14 hours). The
temperature was increa ed to 160C (CAUTION! Mild
exotherm) and then lowered to 130C. Heptanes
(100 ml) were added dropwise. ~he mixture was then
heated at 135-140C ~or 18 hours. The solution
was cooled over a 4.5 hour period to ~0C. The
crystals were collected using a Buchner funnel and
washed with two liter~ 24~ hydrochloric acid. The
crude product was recrystallized in five liters
24% hydrochloric acid and ~inally washed with 1.5
liters 24% hydrochloric acid. Ater drying under
vacuum at 7SC there was obtained 2.11 kg f75~)
tetra1uorophthalic acid; mp 159-161C.
The combined aaueous mother liquors were extracted
with n-butyl ether ~4 x 10 1). The combined extracts
we~e dried over anhydrous -~odium sulfate (1.5 kg)
and concentrated under reduced pressure to give
a solid which was dried under vacuum: 510 g. This
material was recrystallized from 800 ~1 24% hydro-
chloric acid. The cry~tals were dried under vacuum
.
. . .
~2~ Z
-18
at 75C to give 443 g (15%) tetrafluoro~hthalic
acid; mp 157-159C.
ALTERNATE METHOD
EXAMPLE C
5 3, 3 . 4, 5, 6 ! ?-Hexachloro~ 3Hl-isobenzofuranone (Perch-
~!E~ .
Tetrachlorophthalic anhydride (3.365 kg, 11.77
moles~ followed by phosphorous pentachloride (2.97 kg,
14.27 moles) and phosphorous oxychloride (60~ ml~
were added to a 12 liter f}ask. The mixture was
heated to 130C without stirring. After two to
three hours at 130C the mixture became fluid and
mechanical stirrin~ was initiated. The mixture
was stirred at reflux overnigh~ while the pot
temperature was maintained at 130-133C. The next
morning additional phosphorou~ pentachloride ~270 g,
1.3 moles) was added and heating and stirring con-
tlnued until all the solid di~solved. Phosphorous
oxychloride was removed by distillation and ~he
pot temperature gradually increased to 143C. The
distillation was then stopped and refluxing continued
overnight. The next morning ~he residual phosphorous
oxychloride and phosphorous pentachloride were removed
at 145-lS0C pot temperature lnitially at atmospheric
pressure and then under vacuum until all PC15 and
POC13 appeared to be removed.
Toluene (two liters) was added lowly to the
~rude oil at 120C. The solution was transferred
to a 22 li~er flask and prehea~ed heptanes (18 liters
at 80C~ added slowly with stirring~ The resultin~
solution was aIlowed to stand at ambient temperature
overnight. The next day the~crystals were collected,
:
. - ~;~3~
--19--
.
washed with heptanes (four liters), and dried under
vacuum at ambient temperature to give the desired
product, 3,3,4,5,6,7-hexachloro-1-~3H]-isobenzo-
furanone 2.66 kg (66%); mp 134-138C.
EXAMPL~ D
Dimethyl Tetrafluorophthalate
Anhydrous, milled potassium fiuoride (9.5 kg,
I64 mole ) was added to a ~ive gallon stainless
steel autoclave. A full vacuum was introduced into
the autoclave and the salt heated at 1~5C for 48
hours before cooling to 40C. In a separate
container 3,3,4,5,6,7 hexachloro-1-[3H]-isobenzo-
furanone ~2.0 kg, 5.87 moles) was dissolved in
anhydrous toluene (ten liters, dried over 4A
molecula~ ~ieves). This solution was added over
a five to ten minute period to the -~alt at 40C
in the autoclave. The toluene wa~ then care~ully
distilled of~ without stirring under reduced pressure
while the temperature wa~ gradually increased to
100C ov~r a nine hour period. The remaining solids
were heated under ~ull vacuum at 95 to 1~0C Eor
another twelve hour
The autoclave was sealed at -30 inches vacuum
and the remaining solids baked without a~itation
over a 28 hour period while the temperature increased
to 229-288C as measured by a wall temperature probe.
Baking wa continued at a wall ~empera~ure of 277-291C
for another 34 hour period. At the end of the heating
~ period, the pressure had risen to 38.~5 psi. ~ea~ing
was topped. After cooling for 12 hours, the wall
temperature was 62~C and the pressure -24 inches
of mercury. The vacuum was released with nitrogen
and anhydrous methyl alcohol (12 liters, dried over
- ~3~
-20-
4A molecular sieves) was added. Some agitation
was achieved during the extraction by bubbling nitrogen
gas throu~h the mixture. After 45-50 minutes the
methyl alcohol extract was taken off the top through
a tube and the residue extracted a second time with
12 liters anhydrous methanol.
The first methanol extract was concentrated
to dryness using a rotary evaporator and the residue
treated with three liters me~hylene chloride and
three liters demineralized water. After dissolving
the solids, ~he layers were separated and the aqueous
layer extracted with methylene chloride (two liters).
The combined methylene chloride extracts were treated
with anhydrous sodium sulfate (750 g) and Darco
S-51 (50 g), filtered, and the ~iltrate ooncentrated
to a solid whLch was cryst~llized from methylene
chloride and heptanes. The crystals were washed
with heptanes and dried overni~ht under vacuum at
25C to give dimethyl tetrafluorophthalate, 211
(13.5~); mp 70-72C.
The sec~nd methanol extract was worked up in
a similar manner to give additional dimethyl tetra-
fluorophthalate: 133 g (8.5%); mp 68-70~C.
EX~MPLE E
3L4~5f6-Tetrafluor~ a~
Sulfuric acid (99~, 45 ml) was added cautiously
to water (45 ml) and the resultin~ solution mixed
wlth glacial acetic acid ~450 ml)~ To this solution
was added dimethyl ~,4,5,6-te~rafluorophthalate
(90.0 g) and the resulting mixture heated at reflux
for six hours. The solution was concentrated under
reduced pressure to remove acetic acid and water.
Fresh acetic acid (450 ml) and water (75 ml) were
- ` 3L2~3Z62
-21-
added to the residue and refluxing continued overnight
(16 hours). The solution was concentrated again
under reduced pressure to a semisolid. Hydrochloric
acid (37%, 150 ml) was added and the mixture warmed
until all the solids dissolved. The solution was
concentrated under reduced pressure to 125 ml.
Cooling gave crystals ~ihich were collected and washed
with 37~ hydrochloric acid. Recrystallization from
130 ml 24% hydrochloric acid followed by drying
under vacuum at room temperature gave tetrafluoro-
phthalic acid (59 g, 73~); mp 159~161C.
EX~MPLE F
A. Perchlorophthalide
Tetrachlorophthalic anhydride (1.35 Rg),
phosphorous pentachloride (1.30 Kg) and phosphoryl
chloride (240 mL) were combined and the mixture
h~ated to 133C at which point phosphoryl chloride
began re~luxing. ~he mixture was allowed to reflux
with ~tirring ~or 38 hours. More phosphorous
pentachloride ~100 9) was added and refluxing continued
another 27 hours. The solution was distilled initially
at atmo~pheric pre~sure. After most of the phosphoryl
chloride had been removed, distillation was continued
at 10 torr while the pot temperature was increased
to 143C. When no additional distillate wa~ produced,
the liauid was cooled to 115C and xylenes (500 ml)
were added followed by isooctane (5.2 L) ln portions
over a 3Q minute period. The sol~tion was cooled
with stirring overnight. The crystals were collected
30 and wa~hed with heptanes ~1 L) and dried under vacuum
to give perchlorophthalide ~1~17 Rq, 72~; mp 136-138C.
- -22- ~Z9326Z
B. Perchlorophthalide Usina Zinc Chloride as Catalyst
Tetrachlorophthalic anhydride (57.2 g), phosphorous
pentachloride (50.5 g) and zinc chloride (1.0 g)
were combined and the mixture heated with stirring
S for 18 hours at 135-140C. The POC13 was then removed
by vacuum distillation and xylenes ~50 ml) were
added to the residue fGllowed by isooctane (150 ml).
The mixture was cooled with stirring to 10-15C.
The product was collected and washed with isooctane
(50 ml) and finally dried under vacuum at 38C to
give per~hlorophthalide ~37 g, 54~); mp 135-137C.
'
.
