CA1081240A - Preparation of 6,11-dihydro-11-oxodibenz (b-e)-oxepin-alkanoic acids - Google Patents
Preparation of 6,11-dihydro-11-oxodibenz (b-e)-oxepin-alkanoic acidsInfo
- Publication number
- CA1081240A CA1081240A CA243,400A CA243400A CA1081240A CA 1081240 A CA1081240 A CA 1081240A CA 243400 A CA243400 A CA 243400A CA 1081240 A CA1081240 A CA 1081240A
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- Canada
- Prior art keywords
- chloride
- temperature
- diacid
- halide
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
Abstract
PREPARATION OF 6,11-DIHYDRO-11-OXODIBENZ[b,e]OXEPIN-ALKANOIC ACIDS
Abstract of the Disclosure:
This invention relates to a novel method of preparing 6,11-dihydro-11-oxodibenz[b,e]oxepin-alkanoic acids. Said acids possessing antiinflammatory and analgesic activity.
Abstract of the Disclosure:
This invention relates to a novel method of preparing 6,11-dihydro-11-oxodibenz[b,e]oxepin-alkanoic acids. Said acids possessing antiinflammatory and analgesic activity.
Description
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~ -
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 - ~ .
~, , .. . . ~ .
- . . ~ ~ . ; . :, , ~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 - , . .. ..
: : -: . , : . : - , : . : .: , - , : - - .. . . . ~ : :
: . , , : - . : :.. ,~ , .: :.
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-fluoromethyl~ n is 0, 1 or 2, and the C-C02H group is on the , 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 ~ ;
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-
~, , .. . . ~ .
- . . ~ ~ . ; . :, , ~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 - , . .. ..
: : -: . , : . : - , : . : .: , - , : - - .. . . . ~ : :
: . , , : - . : :.. ,~ , .: :.
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-fluoromethyl~ n is 0, 1 or 2, and the C-C02H group is on the , 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 ~ ;
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-.:~ - , : . . .
'~ - - : ' .' .: : , :
.: . . . .
.
: ~ ., .: :.,, `' ~: .
`. ,- ' ' ; ' 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 .
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; :
.
'~
: ~ ,: ,. . . . . . . ... .. . .
, .. . , ~ , :., .. : :
: ,, ,, . : . . . . : :
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.
.. . , . ,. ~ : :
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-.:~ - , : . . .
'~ - - : ' .' .: : , :
.: . . . .
.
: ~ ., .: :.,, `' ~: .
`. ,- ' ' ; ' 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 .
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; :
.
'~
: ~ ,: ,. . . . . . . ... .. . .
, .. . , ~ , :., .. : :
: ,, ,, . : . . . . : :
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.
.. . , . ,. ~ : :
Claims (19)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-alkanoic acid in which (a) a diacid halide of the formula I
(I) wherein R1 and R2 are hydrogen or methyl; X is bromine, chlorine or fluorine; Y is alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms, halogen or tri-fluoromethyl; n is the integer 0, 1 or 2; and the group is attached to the 3 or 4 position of the phenyl ring is reacted with a Lewis acid suitable for use in Friedel-Crafts reaction at a temperature of from 0°C
to ambient in the presence of a solvent, and the resultant oxepinalkanoyl halide is hydrolized; or (b) a dicarboxylic acid of the formula II
(II) wherein R1, R2, X, Y and n are as defined above and the group is attached to the 3 or 4 position of the phenyl ring is reacted with a thionyl chloride-iron mix-ture which contains several parts per million of iron at a temperature of from ambient to the boiling point of the reaction mixture to produce a diacid chloride; the diacid chloride is heated at a temperature of from 100 to 150°C
and the resultant oxepinalkanoyl chloride is hydrolized;
or (c) a diacid halide of the formula I as defined above is heated in the presence of ferric chloride at a temperature of from 100 to 150°C and the resultant oxepinalkanoyl halide is hydrolized.
(I) wherein R1 and R2 are hydrogen or methyl; X is bromine, chlorine or fluorine; Y is alkyl of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms, halogen or tri-fluoromethyl; n is the integer 0, 1 or 2; and the group is attached to the 3 or 4 position of the phenyl ring is reacted with a Lewis acid suitable for use in Friedel-Crafts reaction at a temperature of from 0°C
to ambient in the presence of a solvent, and the resultant oxepinalkanoyl halide is hydrolized; or (b) a dicarboxylic acid of the formula II
(II) wherein R1, R2, X, Y and n are as defined above and the group is attached to the 3 or 4 position of the phenyl ring is reacted with a thionyl chloride-iron mix-ture which contains several parts per million of iron at a temperature of from ambient to the boiling point of the reaction mixture to produce a diacid chloride; the diacid chloride is heated at a temperature of from 100 to 150°C
and the resultant oxepinalkanoyl chloride is hydrolized;
or (c) a diacid halide of the formula I as defined above is heated in the presence of ferric chloride at a temperature of from 100 to 150°C and the resultant oxepinalkanoyl halide is hydrolized.
2. A process as claimed in claim 1 for the preparation of a 6,11-dihydro-11-oxodibenz[b,e]oxepin-alkanoic acid in which a diacid halide of the fromula I as defined in claim 1 is re-acted with a Lewis acid suitable for use in a Friedel-Crafts reaction at a temperature of from 0°C to ambient in the presence of a solvent and the resultant oxepinalkanoyl halide is hydro-lyzed.
3. A process as claimed in claim 2 in which the Lewis acid is aluminum chloride, stannic chloride or ferric chloride.
4. A process as claimed in claim 3 in which the solvent is 1,2-dichloroethane.
5. A process as claimed in claim 2, claim 3 or claim 4 in which the reaction is carried out at a temperature of from 5 to 15°C.
6. A process as claimed in claim 2, claim 3 or claim 4 in which about 0.1 to 1.0 mole of Lewis acid is used for each mole of the diacid halide.
7. A process as claimed in claim 2, claim 3 or claim 4 in which about 0.1 mole of Lewis acid is used for each mole of the diacid halide.
8. A process as claimed in claim 2, claim 3 or claim 4 in which about 0.1 to 1.0 mole of Lewis acid is used for each mole of the diacid halide and the reaction is carried out at a temperature of from 5 to 15°C.
9. A process as claimed in claim 2, claim 3 or claim 4 in which X is chlorine.
10. A process as claimed in claim 2, claim 3 or claim 4 in which Y is chlorine and n is the interger 0 or 1.
11. A process as claimed in claim 2, claim 3 or claim 4 in which n is the integer 0 and R1 and R2 are hydrogen.
12. A process as claimed in claim 2, claim 3 or claim 4 in which n is the integer 0, R1 and R2 are hydrogen and the reaction is carried out with aluminum chloride in 1,2-dichloro-ethane as a solvent at a temperature of from 5 to 15°C.
13. A process as claimed in claim 1 for the preparation of a 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-alkanoic acid in which a dicarboxylic acid of the formula II as defined in claim 1 is reacted with thionyl chloride-iron mixture which contains several parts per million of iron at a temperature of from ambient to the boiling point of the reaction mixture to pro-duce a diacid chloride; the diacid chloride is heated at a temperature of from 100 to 150°C and the resultant oxepinalkanoyl chloride is hydrolized.
14. A process as claimed in claim 13 in which the diacid chloride is heated at a temperature of from 100 to 120°C.
15. A process as claimed in claim 13 in which the thionyl chloride-iron mixture contains about 60 parts per million of iron.
16. A process as claimed in claim 13, claim 14 or claim 15 in which n is the integer 0 and R1 and R2 are hydrogen.
17. A process as claimed in claim 1 for the preparation of a 6,11-dihydro-11-oxodibenz[b,e]oxepin-alkanoic acid in which a diacid halide of the formula I as defined in claim 1 is heated in the presence of ferric chloride at a temperature of from 100 to 150°C and the resultant oxepinalkanoyl halide is hydro-lized.
18. A process as claimed in claim 17 in which the diacid halide is heated to a temperature of from 110 to 120°C.
19. A process as claimed in claim 17 or claim 18 in which n is the integer 0 and R1 and R2 are hydrogen.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US54096375A | 1975-01-14 | 1975-01-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1081240A true CA1081240A (en) | 1980-07-08 |
Family
ID=24157637
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA243,400A Expired CA1081240A (en) | 1975-01-14 | 1976-01-13 | Preparation of 6,11-dihydro-11-oxodibenz (b-e)-oxepin-alkanoic acids |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS5195085A (en) |
| AT (1) | AT362376B (en) |
| BE (1) | BE837561A (en) |
| CA (1) | CA1081240A (en) |
| CH (1) | CH627464A5 (en) |
| CS (2) | CS190509B2 (en) |
| DK (1) | DK12376A (en) |
| ES (1) | ES444144A1 (en) |
| FI (1) | FI760052A (en) |
| FR (1) | FR2297852A1 (en) |
| GB (1) | GB1538775A (en) |
| HU (1) | HU175610B (en) |
| IE (1) | IE41999B1 (en) |
| IT (1) | IT1054782B (en) |
| LU (1) | LU74174A1 (en) |
| MX (1) | MX3745E (en) |
| NL (1) | NL7600204A (en) |
| NO (2) | NO149387C (en) |
| PT (1) | PT64691B (en) |
| SE (1) | SE422796B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56156273A (en) * | 1980-03-31 | 1981-12-02 | Dainippon Pharmaceut Co Ltd | Acetic derivative |
| US4515946A (en) * | 1981-12-23 | 1985-05-07 | Hoechst-Roussel Pharmaceuticals Inc. | 6,11-Dihydro-11-oxo-dibenz-[b,e]oxepin derivatives |
| US4576960A (en) * | 1981-12-23 | 1986-03-18 | Hoechst Roussel Pharmaceuticals Incorporated | 6,11-Dihydro-11-oxo-dibenz[b,e]oxepin derivatives |
| US4526891A (en) * | 1983-03-10 | 1985-07-02 | Hoechst Roussel Pharmaceuticals Inc. | Substituted alkyl amine derivatives of 6,11-dihydro-11-oxodibenz[b,e]oxepins |
| EP1487776A4 (en) * | 2002-03-27 | 2005-05-25 | Smithkline Beecham Corp | Acid and ester compounds and methods of using the same |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1279682B (en) * | 1961-08-12 | 1968-10-10 | Boehringer & Soehne Gmbh | Process for the preparation of 6, 11-dihydro-dibenzo- [b, e] -oxepin- or -thiepin-11-one |
| DE1294970B (en) * | 1961-09-28 | 1969-05-14 | Boehringer & Soehne Gmbh | Process for the preparation of substituted 6, 11-dihydrodibenzo [b, e] -oxepin- or -thiepin-11-ones |
| FR1449569A (en) * | 1961-10-07 | 1966-05-06 | Boehringer & Soehne Gmbh | Process for the preparation of basic derivatives of dibenzo-oxepin and dibenzo-thiepin, their salts and their quaternary ammonium compounds |
| YU204274A (en) * | 1973-07-24 | 1982-06-30 | Hoechst Ag | Process for preparing new dibenzoxepin derivatives |
-
1976
- 1976-01-08 ES ES444144A patent/ES444144A1/en not_active Expired
- 1976-01-09 NL NL7600204A patent/NL7600204A/en not_active Application Discontinuation
- 1976-01-12 FI FI760052A patent/FI760052A/fi not_active Application Discontinuation
- 1976-01-12 IT IT19179/76A patent/IT1054782B/en active
- 1976-01-13 IE IE54/76A patent/IE41999B1/en unknown
- 1976-01-13 HU HU76HO1871A patent/HU175610B/en unknown
- 1976-01-13 CS CS76222A patent/CS190509B2/en unknown
- 1976-01-13 NO NO760101A patent/NO149387C/en unknown
- 1976-01-13 LU LU74174A patent/LU74174A1/xx unknown
- 1976-01-13 GB GB1181/76A patent/GB1538775A/en not_active Expired
- 1976-01-13 PT PT64691A patent/PT64691B/en unknown
- 1976-01-13 CH CH33876A patent/CH627464A5/en not_active IP Right Cessation
- 1976-01-13 AT AT17476A patent/AT362376B/en not_active IP Right Cessation
- 1976-01-13 DK DK12376*#A patent/DK12376A/en not_active Application Discontinuation
- 1976-01-13 CS CS777409A patent/CS190550B2/en unknown
- 1976-01-13 CA CA243,400A patent/CA1081240A/en not_active Expired
- 1976-01-14 BE BE163509A patent/BE837561A/en not_active IP Right Cessation
- 1976-01-14 SE SE7600321A patent/SE422796B/en unknown
- 1976-01-14 JP JP51003719A patent/JPS5195085A/en active Pending
- 1976-01-14 FR FR7600784A patent/FR2297852A1/en active Granted
- 1976-01-14 MX MX762392U patent/MX3745E/en unknown
-
1981
- 1981-04-24 NO NO811390A patent/NO150157C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BE837561A (en) | 1976-07-14 |
| DK12376A (en) | 1976-07-15 |
| SE7600321L (en) | 1976-07-15 |
| NL7600204A (en) | 1976-07-16 |
| PT64691B (en) | 1977-08-09 |
| NO760101L (en) | 1976-07-15 |
| LU74174A1 (en) | 1976-12-31 |
| NO811390L (en) | 1976-07-15 |
| JPS5195085A (en) | 1976-08-20 |
| HU175610B (en) | 1980-09-28 |
| FI760052A (en) | 1976-07-15 |
| MX3745E (en) | 1981-06-11 |
| NO149387C (en) | 1984-04-11 |
| AT362376B (en) | 1981-05-11 |
| CS190550B2 (en) | 1979-05-31 |
| IE41999L (en) | 1976-07-14 |
| IE41999B1 (en) | 1980-05-07 |
| CH627464A5 (en) | 1982-01-15 |
| IT1054782B (en) | 1981-11-30 |
| NO149387B (en) | 1984-01-02 |
| CS190509B2 (en) | 1979-05-31 |
| FR2297852A1 (en) | 1976-08-13 |
| GB1538775A (en) | 1979-01-24 |
| NO150157B (en) | 1984-05-21 |
| PT64691A (en) | 1976-05-01 |
| SE422796B (en) | 1982-03-29 |
| NO150157C (en) | 1984-08-29 |
| ES444144A1 (en) | 1977-08-16 |
| FR2297852B1 (en) | 1979-08-31 |
| ATA17476A (en) | 1980-10-15 |
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