Note: Descriptions are shown in the official language in which they were submitted.
HOE 75/F 0~1
This ~nvention relates to a method of preparation of 6,11-
dihydro~ oxodibenz~b,e~oxepin-alkanoic acids, Said acids
possessing anti.inflammatory and analgesic activity.
To the best of our knowledge the method of preparing of
this invention has not heretofore been described. The -teach-
ings of the prior art resulted in side reactions, polymeri-
zation or in substantially lower yieldsO An article by
E. Stach and H. Spingler, Mh. Chem., Bd. ~, 1962 and the
German Patent, ~umber 1,279,682 of Stach and Spingler teach
cyclization o~ oC-phenoxy-o-toluic acids under drastic condi-
tions, ~or example by prolonged heating with thioriyl chloride
at an elevated temperature o~ about 160C, provides the 6,11
dihydro-11-oxodibenz~b,e~oxepines in su.bstantially lower yields.
The above prior art also teaches the cycliza~ion of mono acid
chlorides of the formula
~c~
wherein R is hydrogen9 methyl, methoxy~ chloro or bromo at
elevated temperatures, 130 -- 220C, to gi~e a corresponding
oxepine.
Also a di.carboxylio acid of the ~ormula
~0~
is known to be cyc3ized by treatment w~th a dehydrating or
condensing mediu~ such a~s polyphosphoric acid, ethanol--phos~ -
- 2 - ~ .
~, ,
.. . . ~ .
- . . ~ ~ . ; . :, ,
HOE 75/F 091
~3B~
phorous pentoxide, phosphoric anh~dride, anhydrous trifluoro~
acetic acid, or sulfuric acld with or without a solvent at a
temperature of from about 20 to 150C. This cycliza-tion is
disclosed in Canadian Application Serial Number 208,542,
filed September 5, 1974 of Helsley, Mc Fadden and Hoffman and in
Belgian Patent Number 818,055, published November 18, 1974 of
Ueno, et al.
However, the prior art does not teach the present in-
vention. ~he procedures of the prior art either produce low
yields and high production of side products or polymerization, ;
and it would not be anticipated by those skilled in the art that
our products could be produced in the yields obtained. The
exceptionally hiyh yields, approaching 100~, obtained under the
disclosed conditions are unexpected. The present invention
cyclizes a diacid halide and it is unusual and unexpected that
under the conditions of this lnvention apparently only intra-
molecular cyclization is observed. The anticipated and equally
possible intermolecular Friedel-Crafts reaction does not occur.
It is this absence of intermolecular reaction that permits
the excellent yields of pure products of this invention.
Irrespective of the absence of intermolecular reaction
it is surprising that exceptionally high yields are achieved by
utilizing very small amounts of a Lewis acid catalyst. One
skilled in the art ~70uld anticipate that completion of a
Friedel-Crafts reaction requires a mole ratio of acyl group
to catalyst to be about 1:1. Accordingly, it is rather sur-
prising that the high yields disclosed herein can be achieved
utilizing as little as l/lOth mole of catalyst per mole of
acyl group. _ 3
- , . .. ..
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: - - .. . . . ~ : :
: . , , : - . : :.. ,~ , .: :.
HOE 75/F_091
It is alsD surprising that high yields of the cyclic alka~
noic acids can be achieved under rather drastic conditions,
elevated temperatures of between 100 and 150C. It is recog-
nized that a common cause of poor yields in the Friedel-Crafts
cyc' za' i~L UP ao~d c~'o-ide~ i~ drastic react on corLditior.s
(Friedel-Crafts and Related Reactions, Edited by George A. Olah,
Interscienee Pub~ishers, New York ~1964), at page 912). This
is illustrated by the lower yields reported in the afore-cited
prior art.
Additionally, prior art methods of preparing 6,11-dihydro-
11~oxodibenz~,e~-oxepin-3-alkanoic acids have the disadvan-
tage that both the 3-alkanoic and the 1-alkanoic acid isomers
are formed. This can be seen in Example 6 of the afore-cited
Belgian Patent. Whereas the method described therein is not
regio specific, the method described herein has been surprising-
ly found to be regio specific and thus enables the attainment
of 3-alkanoic acid without the simultaneous production of the
1-alkanoic acid. This ls totally unobvious over the prior
art.
tre have now discovered that treatment of a dicarboxylic
acid with a sufficient amount of an agent, such as thionyl
halide or phosphorus pentahalide, to ~orm the diacid halide~
followed by cyclization under specific Friedel-Crafts condi-
tions, provides in exceptionally hig~h yields the valuable 6,11--
dihydro~ oxodibenz~b,e~oxepin-alka~oic acids according to
the following equation:
.
~ 4 ~ ~
"' ', ;. ', .~
', ' ' , . : ";
. H ~
~Cl12-o
Y ~ -C-Co.,H
wherein R1 and R2 are hydrogen or methyl, Y is alkyl of 1 to 4
carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen or tri-
- R1
fluoromethyl~ n is 0, 1 or 2, and the C-C02H group is on the
R2
,
2 or 3 positio~ o~ the phenyl ring. In our procedure we are
cyclizing a diacid halide as opposed to a mono acid chloride
described by Stach and Spingler to produce considerably higher
yields than in known procedures.
Mbre particularly, a diacid halide intermediate, o~ the
~or~ula
V~ ~kcox
wherein Y, R1, R2 and n are as described earlier and X is
chlorine, bromine or fluorine 1s prepared by the treatment oE
a dicarboxylic acid of the ~ormula
-
: ~ YD ~O/~R
~ with a suEficient amount o:E an agent such as thlo.rlyl halide o.r
F
.. . , . .. , .. . . , . . . , . ~,~,
1~8~24~ ~IOE 75/F 091
a phosphorous pentahalide .in the presence or absence of a sol-
vent, at a temperature of from ambient to the boiling point o~
the reac-tion mixture Eor from 15 minutes to four hours. The
diacid halide can be cyclized by one of two methods, A or B.
Method A
The diacid halide can be reacted under specific
Friedel-Crafts conditions and then hydrolyzed by a method known
to the art to provide a 6,11-dihydro-11-oxodibenzEb,e] oxepin-2-
or-3-alkanoic acid of the formula
YD ~ C CO~H
O R
In this new procedure the specific Friedel-Crafts conditions
require the presence of a Lewis acid catalyst such as aluminium
chloride, stannic chloride, ferric chloride or other Lewis
acids known to be suitable in Friedel-Crafts reactions and
the reaction is carried out at low temperatures of about OC
to ambient temperature in the presence of a suitable solvent,
preferably l,2-dic~loroethane. Additionally, each mole of
diacid chloride cyclized in the reaction requires as little as
0.1 mole of the Lewis acid. A preferred Lewis acid catalyst
is aluminum chloride and optimum yields are achieved at a tem-
perature between 5 and 15C.
Method B
The diacid halide is heated ~or from 10 minutes to 24
hours in the presence of ferric chloride at a temperature of
from 100 to 150C, and hydrolized to provide a 6,11-dihydro-11-
oxodibenz5b,e]oxepin-2- or -3-alkanoic acid. It has been found
that this embodiment of the invention can also be achieved ~ ;
-- 6 --
HOE 75/E 091
by preparin~ t~e diacid halide by -treating -the dicarboxy-
lic acid wi-th -thionyl chloride that contains small quantities
of iron, several parts per million tPPM), which acts as the
Lewis acid ca~alyst in -the Friedel-Crafts cyclization. A pre-
ferred embodiment of Method B involves reacting the dicarbox-
- ylic acid with a thionyl chloride-iron mixture wherein the
iron content represents about 60 PPM of said mixture.
It will be readily appreciated by those skilled in the
art tha~ yields are dependent upon time of reaction and tem-
perature and particular derivative involved.
The preferred method is A, preferred diacid halides are
chlorides and preferred eompounds prepared by the teaching of
the present invention are 6,11-dihydro-11-oxodibenz [b,e]`-
oxepin-2-acetic acid and 6,11-dihydro-ll-oxodibenz[~7e~oxepin-
3-acetic acid. Other very good com~ounds are 6,11-dihy(dro-
-methyl-ll-oxodibenz [bje~'oxepin-2-acetic acid, 6,11-dihydro-
-methyl-ll-oxodibenz [b,e]oxepin-3-acetie acid and 8-ehloro-
6,11-oxodibenz [b,e]oxepin-2-acetic acid.
The method of this invention is further illustrated in
greater detail in the examples below.
E X A M P L E 1:
To 16 ml of thionyl chloride is added 28.6 g of 4-(2-
earboxy-benzyloxy)phenylaeetie aeid and the mixture is slowly
heated to reflux and allowed to reflux for one hour. The ex-
eess thionyl chloride is removed under reduced pressure at
90C to provide a diaeid chloride as an oil. The oil is dis-
solved in 160 ml o~ 1,2-diehloroethane and cooled to a tem-
perature of 5 to 10C. To the reaetion mixture is added
14.1 g of anhydrous aluminum chloride and the mixture is stir-
7 --
.:~ - , : . . .
'~ - - : ' .' .: : , :
.: . . . .
.
: ~ ., .: :.,, `' ~: .
`. ,- ' ' ; '
HOE 75/F 091
red for 9o minutes at 5 to 10C. The mixtur~ is poured onto
ice and stirred fox one hour, extracted with chloroform and
the chloroform removed to provide an oil. The oil is taken up
in a 15% sodium hydroxide solution and heated for 30 minu-
tes. The solution is acidified and extracted with chloroformto provide 2S.6 g of 6,11~dihydro~ oxodibenz [b,e] oxepin-2-ace-
tic acid ~95.5%), which is identical with an authentic sample
by thin layer chromatography, nuclear magnetic resonance, and
mixed melting point determination.
E X A M P L E 2:
A diacid chloride is prepared according to the manipula
tive procedure of Example 1 from 34~ ml of thionyl chloride
which contains 60 PPM of iron and 400 g of 4-(2-carboxybenzyl-
oxy)phenylacetic acid. The diacid chloride is heated at a
temperature of from 110 to 120C, for 2 hours under nitrogen.
The reaction mixture is cooled and 1500 ml of water is added
and heated to 65C to effect hydrolysis. After hydrolysis is
completed, the oily product is dissolved in a 20% solution of
sodium hydroxide at 50 - 55C, and the solution is brought to
a pH of 1 with 6N hydrochloride acid. The acidified solution
is cooled to 10C, the resultant precipitate filtered, washed
with water, collected and dried to provide 362 g (96.5%)
of 6,11-dihydro~ oxodibenz~b,eloxepin-2-acetic acid, which
is identical with an authentic sample by thin layer chromato-
graphy, nuclear magnetic resonance and mixed melting point.E X A; M P L ;E ; 3:
To 20 ml of thionyl chloride is added 20 g of ~-~2-carb-
oxybenzyloxy)phenylacetic acid and the mixture is slowly heat-
ed to reflux and allowed to reflux for 2 hours. The excess
- 8 -
.
L24al
thionyl chloride is removed under reduced pressure at gOC toprovide a diacid chl'oride as an oil. The oil is dissolved in
75 ml of 1.2-dichloroethane, cooled to ambient temperature and
to the cooled solution is added 1.82 g of stannic chloride. The
reaction mixture is stirred for 4 hours at ambient temperature
and then poured onto 35 g of ice. The resulting mixture is
stirred for 1 hour and the biphasic mixture separates. The
organic phase is collected and then concentrated under pres-
sure to provide an oily solid which is poured into 200 ml of
water and the aqueous mixture is heated to 60C, which hydro-
lyzes the mono acid chloride to the free acid. The acid is neu-,
tralized with caustic, treated with 0.4 g of charcoal and 0.4 g
of CELITE* and filtered. The clear filtrate solidifies upon
the addition of 12N hydrochloric acid and the solid precipi-
tate collected by filtration, washed with water and dried un-
der reduced pressure to provide 17.2 g of 6,11-dihydro ll-oxo-
dibenz~b,e]~xepin-2-acetic acid (91.4~.
E X A M P L E 4:
To 80 ml of thionyl chloride is added 80 g of 4-(2-carb-
oxybenzyloxy)phenylacetic acid and the mixture is slowly heat-
ed to reflux over a 2 hour span and allowed to remain at re-
flux for 2 hours. The excess thionyl chloride is removed un-
der reduced pressure at 90aC to provide the diacid chloride.
The diacid chloride is dissolved in 250 ml of 1,2~dichloro-
ethane, cooled to 10C,,and to the cooled solution is added3.73 g o~ aluminum chloride. The reaction mixture is stirred
* denotes trade mark for diatomaceous earth prod~cts.
.
:, : . . .
, . : . , , , ~ ,
Z~
at 10C ~or 4 hours and then poured onto 250 g of ice. Th~ re-
sultin~ mixture is stirred for 1 hour and the biphasic mixture
separates. The organic phase is collected and then concentrat-
ed under reduced pressure to provide an oily solid which is
poured into 500 ~1 of water and the aqueous mixture is heated
to 60C which hydrolyzes the mono acid chloride to the free
acid. The acld is neutralized by addition of caustic and
this solution is treated with 2.4 g of charcoal and 2.4 g of
celite and filtered. The clear filtrate solidifies upon
addition of 12N hydrochloric acid and the resulting solid pre-
cipitate is washed with water and dried under reduced pres-
sure to provide 72.5 g of 6,11-dihydro-11-oxodibenzEb,e]oxe-
pin-2-acetic acid (96~).
E X A M P L E 5:
To 10 ml of thionyl chloride is added 5.1 g of 3-(2-carb-
ox~benzyloxy)phenyl acetic acid and the mixture is slowly
heated to reflux and allowed to remain at reflux for 2 hours.
The excess thionyl chloride is removed under reduced pressure
at 90C to provide diacid chloride. The diacid chloride is
dissolved in 25 ml of 1,2-dichloroethanet cooled to between
10 and 15C and to the cooled solution is added 0.2 g of alu-
minum chloride. The reaction mixture is stirred at between
10 and 15C for ~ hours and then poured onto 25 g of ice. The
resulting mixture is stirred causing the biphasic mixture to
separate. The organic phase is collected and concentrated
under reduced pressure, to provide the mono acid chloride.
,~ - 10 - ~
`j; :
.
'~
: ~ ,: ,. . . . . . . ... .. . .
, .. . , ~ , :., .. : :
: ,, ,, . : . . . . : :
0
The acid chloride is poured into water and heated to 60~C
which hydrolyzes the acid chloride to the free acid. The
acid is neutralized wi-th caustic and the solution clarified
by treatment with 0.15 g of charcoal and 0.15 g of CE~ITE*.
Reacidification of the clear solution with 12N hydrochloric
acid causes a solid to form which is collected by filtration,
wash-
* denotes trade mark for diatomaceous earth produts.
- lOa -
.
HOE~ F 09,
ed with water and dried under reduced pressure to proride
an off-white crystalline product. Nuclear magnetic resonance
spectra and thin layer chromatography confirms the presence
of the desired 6,11-dihydro~ oxodibenzLb, ~ oxepin-3-acetic
&cid and the ab~c.Lco o the le~ de~irable 6,11~ihyd~v~
oxodibenzLb,e70xepin-1-acetic acid.
By following the procedures of Examples 1 through 5 the
following compounds are produced in good yieldsc
6,11-dihydro-oC-methyl-11-oxodibenz/b 3 e~oxepin-2-acetic acid;
6,11-dihydro-~-methyl-11-oxodibenz~, ~ oxepin-3-acetic acid;
8-chloro-6,11-dihydro-11-oxodibenæ ~,e~oxepin -2-acetic acid;
6 9 11 -dihydro-~ dimethyl-11-oxodibenz~b,e~oxepi~-2-acetic
acid, and
6,11-dihydro-9-trifluoromethyl-11-oxod1benzLb,e~oxepin-2
acetic acid.
.. . , . ,. ~ : :
