CA2015578A1 - Substituted biphenylcarboxylic acids, a process for their preparation and novel intermediates - Google Patents
Substituted biphenylcarboxylic acids, a process for their preparation and novel intermediatesInfo
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- CA2015578A1 CA2015578A1 CA002015578A CA2015578A CA2015578A1 CA 2015578 A1 CA2015578 A1 CA 2015578A1 CA 002015578 A CA002015578 A CA 002015578A CA 2015578 A CA2015578 A CA 2015578A CA 2015578 A1 CA2015578 A1 CA 2015578A1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/04—Monocyclic monocarboxylic acids
- C07C63/06—Benzoic acid
- C07C63/10—Halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
- C07C63/72—Polycyclic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract of the disclosure Substituted biphenylcarboxylic acids, a process for their preparation and novel intermediates Novel biphenylcarboxylic acids of the formula I
I
in which R1 has the meansings indicated, and a process for their preparation are described.
I
in which R1 has the meansings indicated, and a process for their preparation are described.
Description
2~ 7~
HOECHST AKTIENGESELLSCH~FT HOE 89/F 138 Dr.D/fe Description Substituted biphenylcarboxylic acids, a process for their preparation and novel intermediates The invention relates to substituted biphenylcarboxylic acid6 of tho formula I
F ~ F
COOH
in which R1 is hydrogen or methoxy, and to a process for I their preparation.
The substituted biphenylcarboxylic acids of the formula I can be converted by cyclization into the corresponding 2,7-difluorofluorenones of the formula IX
IX
F O F
2,7-Difluorospiro~9H-fluorenyl-9,4~-imidazolidine]-2',5'-~ 15 dione (also called AL 1576, HOE 843 and imirestate), and ,~ 2,7-difluoro-4-methoxyspiro[9H-fluorenyl-9,4'-imidazoli-dine]-2~,5~-dione, which can used a~ pharmaceuticals for the treatment of the late effects of diabetes (cf. US
~atent 4,438,272), can be prepared from these in a single reaction step.
The 2,7-difluorofluorenone, which can easily be prepared from 4,4'-difluorobiphenyl-2-carboxylic acid, can be prepared from fluorene in accordance with the prior art in a 9-stage synthesis, in particular by nitration in the 2-position, reduction to the amine, diazotization and ~' Schiemann reaction to give 2-fluorofluorenone, then ~-nitration in the 7-position and repetition of the ~aid reaction sequence to give 2,7-difluorofluorene ~nd final ,,~
~ .. . .
~.~' '' ' '' , 2- 2~ 8 oxidation with sodium dichromate to give 2,7-difluoro-9-fluorenone IX (cf., for example, Chem. Ind. 1961, 179, J. Ned. Chem. ~, 491 (1965), Isr. J. Chem. 1,1 (1963) and Chem. Ber. 112, 3490 (1979)).
S Thi6 preparation process has many ~tages and the total yield is 10%, partly on account of isomer separations necessary in the nitro compound~ stage.
A process for the preparation of 2,7-difluoro-9-fluore-none described in ~S Patent 4,438,272 starts from 2,7-diaminofluorene, which is converted into the correspond-$ng salt of fluoroboric ac~d by treatment with fluoro-boric acid. The bis-diazonium salt i8 obtained by ~ubse-quent diazotization, from which 2,7-difluorofluorine is liberated by warming in xylene. Oxidation to 2,7-difluoro-9-fluorenone is carried out with RMnO~ in pyridine.
The 2,7-diaminofluorene used as a starting material in this synthesis, however, can only be prep~red with difficulty and in unsatisfactory yields by nitration of fluorene to 2,7-dinitrofluorene and subsequent reduction, sinceiSomer mixtures are formed in nitration which have to be separated ~nd sLnce the 2,7-diaminofluorene is very sensitive to light and oxidation. Even in this process, the total yield~ based on fluorene are only about 10%.
A partieul~rly increasingly aerious disadvantage of the known syntheses of the fluorenones of the formula IX lies in the fact that amino and nitrofluorene deriv~tives have carcinogenic properties (cf. J. Natl. Cancer In~t. 10, - 1201 ~1950), Cancer Res. ~, 1002 (1962), Brit. J. Cancer 4, 235 (1950), Brit. J. Exptl. Pnth. 25, 1 (1944) and Progressus Med. ~, 79 (1940)).
2,7-Difluoro-4-methoxy-9-fluorenone is prepared ~ia 4 or 5 further reaction steps from 2,7-difluoro-9-fluorenone.
I .:
HOECHST AKTIENGESELLSCH~FT HOE 89/F 138 Dr.D/fe Description Substituted biphenylcarboxylic acids, a process for their preparation and novel intermediates The invention relates to substituted biphenylcarboxylic acid6 of tho formula I
F ~ F
COOH
in which R1 is hydrogen or methoxy, and to a process for I their preparation.
The substituted biphenylcarboxylic acids of the formula I can be converted by cyclization into the corresponding 2,7-difluorofluorenones of the formula IX
IX
F O F
2,7-Difluorospiro~9H-fluorenyl-9,4~-imidazolidine]-2',5'-~ 15 dione (also called AL 1576, HOE 843 and imirestate), and ,~ 2,7-difluoro-4-methoxyspiro[9H-fluorenyl-9,4'-imidazoli-dine]-2~,5~-dione, which can used a~ pharmaceuticals for the treatment of the late effects of diabetes (cf. US
~atent 4,438,272), can be prepared from these in a single reaction step.
The 2,7-difluorofluorenone, which can easily be prepared from 4,4'-difluorobiphenyl-2-carboxylic acid, can be prepared from fluorene in accordance with the prior art in a 9-stage synthesis, in particular by nitration in the 2-position, reduction to the amine, diazotization and ~' Schiemann reaction to give 2-fluorofluorenone, then ~-nitration in the 7-position and repetition of the ~aid reaction sequence to give 2,7-difluorofluorene ~nd final ,,~
~ .. . .
~.~' '' ' '' , 2- 2~ 8 oxidation with sodium dichromate to give 2,7-difluoro-9-fluorenone IX (cf., for example, Chem. Ind. 1961, 179, J. Ned. Chem. ~, 491 (1965), Isr. J. Chem. 1,1 (1963) and Chem. Ber. 112, 3490 (1979)).
S Thi6 preparation process has many ~tages and the total yield is 10%, partly on account of isomer separations necessary in the nitro compound~ stage.
A process for the preparation of 2,7-difluoro-9-fluore-none described in ~S Patent 4,438,272 starts from 2,7-diaminofluorene, which is converted into the correspond-$ng salt of fluoroboric ac~d by treatment with fluoro-boric acid. The bis-diazonium salt i8 obtained by ~ubse-quent diazotization, from which 2,7-difluorofluorine is liberated by warming in xylene. Oxidation to 2,7-difluoro-9-fluorenone is carried out with RMnO~ in pyridine.
The 2,7-diaminofluorene used as a starting material in this synthesis, however, can only be prep~red with difficulty and in unsatisfactory yields by nitration of fluorene to 2,7-dinitrofluorene and subsequent reduction, sinceiSomer mixtures are formed in nitration which have to be separated ~nd sLnce the 2,7-diaminofluorene is very sensitive to light and oxidation. Even in this process, the total yield~ based on fluorene are only about 10%.
A partieul~rly increasingly aerious disadvantage of the known syntheses of the fluorenones of the formula IX lies in the fact that amino and nitrofluorene deriv~tives have carcinogenic properties (cf. J. Natl. Cancer In~t. 10, - 1201 ~1950), Cancer Res. ~, 1002 (1962), Brit. J. Cancer 4, 235 (1950), Brit. J. Exptl. Pnth. 25, 1 (1944) and Progressus Med. ~, 79 (1940)).
2,7-Difluoro-4-methoxy-9-fluorenone is prepared ~ia 4 or 5 further reaction steps from 2,7-difluoro-9-fluorenone.
I .:
- 3 ~
The ob~ect of the present invention is to make available a process for the preparation of 2,7-difluoro-9-fluore-nones of the formula IX which i8 economical and can be carried out on a large ~cale, nnd in which the disad-vantages which occur in the preparation according to theprior art are avoided. This means that the total yield is high, the product i8 obtained in high purity and that no reputedly carcinogenic intermediates occur.
Thi6 ob~ect is achieved according to the invention in that novel biphenylcarboxylic acids of the formula I are made available, which are converted by cyclization into the corresponding fluorenone~ in a simple manner, the latter being obtained in high yields. The disadvantages described do not occur in the preparation of the bi-phenylcarboxylic acids of the formula I according to theinvention and in their further processing to give the fluorenones IX.
The invention therefore relates to the biphenylcarboxylic acids of the formula I and to a process for their pre-paration.
The process for the preparation of substituted biphenyl-carboxylic acids of the formula I comprises a) reacting a 2-methoxybenzoic acid of the formula II
~ CO2H II
or a reactive derivative of this acid with an ethanolamine of the formula III
~:J'' ' ~ . :
~; . . ' , H ~ ~ OH III
~2 R3 in which RZ and R3 are hydrogen or ( Cl-~3 )-alkyl~
preferably methyl~ but where R2 and ~3 are not simultaneously alkyl, to give an amide of the genersl formula IV
--C- NH - C - C - OH
~ o 12 13 IV
.. . .
in which R2 and R3 have the meanings indicated for formula III, then cyclizing the amide of the formula -IV to a dihydrooxazole of the formula V
lD ~ N ~R3 RFj23 in which R2 and R3 have the meanings indicated for formula III, then reacting the dihydrooxazole of the formula V with an organometallic reagent of the formula VI :
Rl ~
F ~ ~
in which Rl has the meaning indicated for formula I
and ~ i8 lithium or Zn-Hal or, preferably, Mg-Hal and Hal i~ chlorine, brsmine or iodine, to give a biphenyl derivative of the general formula VII
~ 7 Rl F ~ F
~ VII
N O
R2 ~ R3 in which R1 h~s the meaning indicated for formul~ I
and R2 and R3 have the meaning~ indicated for formuls - III, and hydrolyzing the biphenyl derivative of the formula VII obt~ined, optionally after converQion into the corre~ponding alkylated compound of the formula VIII
F ~ F
¦ VIII
~ R3 _ in which Rl ha~ the meaning indicated for formula I
and R2 and R3 have the meanings indic~ted for formula III, R4 is (Cl-C3)-alkyl, preferably methyl, and X~ ~8 chloride, bromide, iodide, methylsulfate or othyl-~ulfate, to the carboxylic acid of the formula I
F ~ F
COOH
in which R1 ha~ the meaning indicated for formula I.
The biphenylcarboxylic acids of the formula I can then be cyclized directly, or via the corre~ponding acid chloride or the amide to give the ~ubstituted fluorenone of the %~ i7~3 formula IX in a manner known per ~e.
The process according to the invention ~as the advantage that it starts from appropriately 6ubstituted starting materials and leads in a specific manner to pure bi-phenylcarboxylic acids of the formula I, in which thepositions of the substituents are unequivocally fixed by means of the synthesi~ omer separations which ~re complicated and high in los~es are not nece6sary and the total yield (about 65%) i~ clearly higher than in the known processes (about 10%). Only two isolated inter-mediates (compounds V and VII) have to be passed through, for example, for the ynthe~is of 4,4'-difluorobiphenyl-2-carboxylic acid starting from 5-fluoro-2-methoxybenzoic acid by the process accordin~ to the invention.
The 4,4'-difluorobiphenylcarboxylic acids of the formula I are obtained in very pure form by the process according to the invention. This also applies to the fluorenones which can be prepared therefrom.
It is particularly important that the known carcinogenic nitro- and aminofluorine derivatives are not passed through.
In detail, the preparation of the benzamide IV from the benzoic acid II using the amino alcohol III i~ carried out in a manner known per ~e by the process according to the invent$on, for example, the reaction of a (C1-C~)-alkyl ester of II with the amino alcohol III can be carried out by heating the components in the presence or absence of a ~olvent. Acids of the formula II can also be converted by reaction of the acid II with an acid chloride, such as ethyl chlorofo~mate or toluenesulfonyl chloride, in the pre~ence of a base such as, for example, triethylamine, into a mixed anhydride which then reacts with an amine of the formula III to give the smides IV.
In a preferred embodiment of the process according to the invention, the acid II is converted, for example with PC15 ~ :J.'` . . ' : ` .- . . ,, , . :
"' : .
- 7 - 2~.55~
or, preferably, thionyl chloride, into the corresponding acid chloride, which yields the corre~ponding ~mlde IV in nearly quan~itative yield with an amine III.
The cyclization of amides of the formula IV to the dihydrooxazoles V can be carried out in a manner known per se using dehydrating agents, such as concentrated ~ulfuric acid, polyphosphoric acid or phosphorus pen-toxide. Cyclization with thionyl chloride in an inert solvent such as, for example, diethyl ether, methylene chloride or toluene is preferred. It can be carried out at temperatures between -10 and 50~C, preferably at 0 to - 30C. The free dihydrooxazole derivative V i~ prepared from the initially resulting hydrochloride using base~
such as, for example, sodium hydroxide solution.
In a particularly preferred embodiment of the process according to the invention, the dihydrooxazoles V are prepared from the benzoic acid II without isolating the amides of the formula IV. In detail, the benzoic acid II
is in this case heated with a small excess of thionyl chloride in the absence or presence of an inert solvent such as me~hylene chloride or toluene and the solution of the resulting acid chloride iB added dropwi~e to the amino alcohol III. As the amino alcohol alio function6 as ian wid scavenger (accep~or), it is emploved in twice the m~lar amount. An alternative to this i8 the use of one mole each of amino alcohol III and of an inert base such a8 triethylamine. Ring closure to give the dihydrooxazole V
takes place as a result of ~ubsequent addition of the molar amount of thionyl chloride to the reaction mixture.
After rendering the reaction mixture alkaline with sodium hydroxide solution and evaporating the organic phase, the dihydrooxazole V is obtained in nearly quantitative yield. The product can be purified by di~till~tion.
Surprisingly, the reaction of the dihydrooxazole V with an organometallic reagent VI proceeds in a si~ple manner with the substitution of the methoxy group, biphenyl . ~ .
~ , ~ . ' .' .~
!..-.
- 8 - ZQ~S~8 derivatives of the formula VII being obtained. Signifi-cant side rea~tions as a re~ult of nucleophilic exchange, for example of a fluorene atom in the compounds V or VII, do not occur. Solvents which ~an be usedfor thi~ reaction are ethers, ~uch as diethyl ether, methyl t-butyl ether or dibutyl ether; tetrahydrofuran iB preferred. With organomagne6ium or organozinc compounds, the reaction takes place at temperatures between 0C and the boiling point of the solvent, with 4-fluorophenyllithium the reaction mixture i8 allowed to react at between -60-C and room temperature. The organometallic reagents VI are preferably employed in excess to attain a satisfactory yield, in particular 1.2 to 3.0 moles, preferably 2-3 moles, per mole of dihydrooxazole V. The reaction can be carried out in the presence or absence of 8 catalytic amount of palladium compounds such as, for example, Pd(PPh3)4-The formation of the biphenyl derivatives VII from the dihydrooxazoles V and the Grignard reagent ~I (M ~ MgBr) is preferred. In thi~ case, the Grignard reagent can be added to the dihydrooxazole or the dihydrooxazole V to the Grignard reagent.
In a particularly preferred embodiment of the process according to the invention, for example in the pre-paration of 4,4'-difluorobiphenyl-2-carboxylic acid, the magnesium i~ initially introduced with the total amount of THF, and Vitride (NaAlHz (OCH2CH20CH3)2, 70% strength in toluene) is added until the evolution of hydrogen iB
complete. The 4-bromofluorobenzene i8 then allowed to run into the boiling T~, the Grignard reaction starting immediately. After completion of the formation of the d~
Grignard reagent, the dihydrooxazole V is added with, or preferably without, solvent. The reaction is complete after a short time (about 10 minute~). The mixture i~
hydrolyzed with water or saturated ammonium chloride solution and ad~usted to pH 4-7 with hydrochloric acid in order to achieve a good phase ~eparation. The product can ~-.. ~. . , . .: , . . . . .... .. ..
2~
be purified by crystallization and/or distillation.
The hydroly~is of the dihydro-1,3-oxazole VII to the biphenylcarboxylic acid I i6 carried out by hydroly~is with aqueous acids, for example ~y heating with hydro-chloric acid, ~ulfuric acid or methanesulfonic acid.
In a preferred variant of the process according to the invention, compounds of the general formula VII are reacted with alkylating agents such as, for example, (Ca-C3)-alkyl halides, ( C~-C3 )alkyl methanesulfonates, (Cl-C3)-alkyl toluenesulfonates or di(Cl-C3)alkyl sulfates to give compounds of the general formula VIII. Dimethyl sulfate, methyl iodide, methyl bromide and methyl chloride in solvents such a~ toluene, acetone, 2-butanone or low molecular weight alcohols are particularly prefer-red as alkylating agents. The alkylation reaction can becarried out in the presence or, preferably, in the absence of a base such as ~odium hydroxide solution, potas~ium carbonate or triethylamine, if appropriate ~lso in the presence of phase transfer catalysts such as tetrabutylammonium sulfate. The resulting dihydro-1,3-oxazolium salt VIII is then hydrolyzed to the biphenyl-carboxylic acid I. This can be carried out by heating with aqueous alkali metal hydroxide solutions, such as sodium hydroxide solution or potassium hydroxide solution, preferably in the sen~e of a one-pot reaction, without isolating the salt VIII.
The ring closure of the carboxylic acid I to the fluore-none IX is carried out in a manner known per ~e, for example with dehydrating agent such as, for ex~mple, polyphosphoric acid, at temperatures between about 80 nnd The compounds of the formulae V, VII and VIII are novel and repre~ent useful intermediates, for example for the preparation of biphenylcarboxylic acids of the formula I.
The invention therefore also relates to these !: .
; ; . , ..
_ 10 -intermediatec and to processes for their preparation.
Example I
The ob~ect of the present invention is to make available a process for the preparation of 2,7-difluoro-9-fluore-nones of the formula IX which i8 economical and can be carried out on a large ~cale, nnd in which the disad-vantages which occur in the preparation according to theprior art are avoided. This means that the total yield is high, the product i8 obtained in high purity and that no reputedly carcinogenic intermediates occur.
Thi6 ob~ect is achieved according to the invention in that novel biphenylcarboxylic acids of the formula I are made available, which are converted by cyclization into the corresponding fluorenone~ in a simple manner, the latter being obtained in high yields. The disadvantages described do not occur in the preparation of the bi-phenylcarboxylic acids of the formula I according to theinvention and in their further processing to give the fluorenones IX.
The invention therefore relates to the biphenylcarboxylic acids of the formula I and to a process for their pre-paration.
The process for the preparation of substituted biphenyl-carboxylic acids of the formula I comprises a) reacting a 2-methoxybenzoic acid of the formula II
~ CO2H II
or a reactive derivative of this acid with an ethanolamine of the formula III
~:J'' ' ~ . :
~; . . ' , H ~ ~ OH III
~2 R3 in which RZ and R3 are hydrogen or ( Cl-~3 )-alkyl~
preferably methyl~ but where R2 and ~3 are not simultaneously alkyl, to give an amide of the genersl formula IV
--C- NH - C - C - OH
~ o 12 13 IV
.. . .
in which R2 and R3 have the meanings indicated for formula III, then cyclizing the amide of the formula -IV to a dihydrooxazole of the formula V
lD ~ N ~R3 RFj23 in which R2 and R3 have the meanings indicated for formula III, then reacting the dihydrooxazole of the formula V with an organometallic reagent of the formula VI :
Rl ~
F ~ ~
in which Rl has the meaning indicated for formula I
and ~ i8 lithium or Zn-Hal or, preferably, Mg-Hal and Hal i~ chlorine, brsmine or iodine, to give a biphenyl derivative of the general formula VII
~ 7 Rl F ~ F
~ VII
N O
R2 ~ R3 in which R1 h~s the meaning indicated for formul~ I
and R2 and R3 have the meaning~ indicated for formuls - III, and hydrolyzing the biphenyl derivative of the formula VII obt~ined, optionally after converQion into the corre~ponding alkylated compound of the formula VIII
F ~ F
¦ VIII
~ R3 _ in which Rl ha~ the meaning indicated for formula I
and R2 and R3 have the meanings indic~ted for formula III, R4 is (Cl-C3)-alkyl, preferably methyl, and X~ ~8 chloride, bromide, iodide, methylsulfate or othyl-~ulfate, to the carboxylic acid of the formula I
F ~ F
COOH
in which R1 ha~ the meaning indicated for formula I.
The biphenylcarboxylic acids of the formula I can then be cyclized directly, or via the corre~ponding acid chloride or the amide to give the ~ubstituted fluorenone of the %~ i7~3 formula IX in a manner known per ~e.
The process according to the invention ~as the advantage that it starts from appropriately 6ubstituted starting materials and leads in a specific manner to pure bi-phenylcarboxylic acids of the formula I, in which thepositions of the substituents are unequivocally fixed by means of the synthesi~ omer separations which ~re complicated and high in los~es are not nece6sary and the total yield (about 65%) i~ clearly higher than in the known processes (about 10%). Only two isolated inter-mediates (compounds V and VII) have to be passed through, for example, for the ynthe~is of 4,4'-difluorobiphenyl-2-carboxylic acid starting from 5-fluoro-2-methoxybenzoic acid by the process accordin~ to the invention.
The 4,4'-difluorobiphenylcarboxylic acids of the formula I are obtained in very pure form by the process according to the invention. This also applies to the fluorenones which can be prepared therefrom.
It is particularly important that the known carcinogenic nitro- and aminofluorine derivatives are not passed through.
In detail, the preparation of the benzamide IV from the benzoic acid II using the amino alcohol III i~ carried out in a manner known per ~e by the process according to the invent$on, for example, the reaction of a (C1-C~)-alkyl ester of II with the amino alcohol III can be carried out by heating the components in the presence or absence of a ~olvent. Acids of the formula II can also be converted by reaction of the acid II with an acid chloride, such as ethyl chlorofo~mate or toluenesulfonyl chloride, in the pre~ence of a base such as, for example, triethylamine, into a mixed anhydride which then reacts with an amine of the formula III to give the smides IV.
In a preferred embodiment of the process according to the invention, the acid II is converted, for example with PC15 ~ :J.'` . . ' : ` .- . . ,, , . :
"' : .
- 7 - 2~.55~
or, preferably, thionyl chloride, into the corresponding acid chloride, which yields the corre~ponding ~mlde IV in nearly quan~itative yield with an amine III.
The cyclization of amides of the formula IV to the dihydrooxazoles V can be carried out in a manner known per se using dehydrating agents, such as concentrated ~ulfuric acid, polyphosphoric acid or phosphorus pen-toxide. Cyclization with thionyl chloride in an inert solvent such as, for example, diethyl ether, methylene chloride or toluene is preferred. It can be carried out at temperatures between -10 and 50~C, preferably at 0 to - 30C. The free dihydrooxazole derivative V i~ prepared from the initially resulting hydrochloride using base~
such as, for example, sodium hydroxide solution.
In a particularly preferred embodiment of the process according to the invention, the dihydrooxazoles V are prepared from the benzoic acid II without isolating the amides of the formula IV. In detail, the benzoic acid II
is in this case heated with a small excess of thionyl chloride in the absence or presence of an inert solvent such as me~hylene chloride or toluene and the solution of the resulting acid chloride iB added dropwi~e to the amino alcohol III. As the amino alcohol alio function6 as ian wid scavenger (accep~or), it is emploved in twice the m~lar amount. An alternative to this i8 the use of one mole each of amino alcohol III and of an inert base such a8 triethylamine. Ring closure to give the dihydrooxazole V
takes place as a result of ~ubsequent addition of the molar amount of thionyl chloride to the reaction mixture.
After rendering the reaction mixture alkaline with sodium hydroxide solution and evaporating the organic phase, the dihydrooxazole V is obtained in nearly quantitative yield. The product can be purified by di~till~tion.
Surprisingly, the reaction of the dihydrooxazole V with an organometallic reagent VI proceeds in a si~ple manner with the substitution of the methoxy group, biphenyl . ~ .
~ , ~ . ' .' .~
!..-.
- 8 - ZQ~S~8 derivatives of the formula VII being obtained. Signifi-cant side rea~tions as a re~ult of nucleophilic exchange, for example of a fluorene atom in the compounds V or VII, do not occur. Solvents which ~an be usedfor thi~ reaction are ethers, ~uch as diethyl ether, methyl t-butyl ether or dibutyl ether; tetrahydrofuran iB preferred. With organomagne6ium or organozinc compounds, the reaction takes place at temperatures between 0C and the boiling point of the solvent, with 4-fluorophenyllithium the reaction mixture i8 allowed to react at between -60-C and room temperature. The organometallic reagents VI are preferably employed in excess to attain a satisfactory yield, in particular 1.2 to 3.0 moles, preferably 2-3 moles, per mole of dihydrooxazole V. The reaction can be carried out in the presence or absence of 8 catalytic amount of palladium compounds such as, for example, Pd(PPh3)4-The formation of the biphenyl derivatives VII from the dihydrooxazoles V and the Grignard reagent ~I (M ~ MgBr) is preferred. In thi~ case, the Grignard reagent can be added to the dihydrooxazole or the dihydrooxazole V to the Grignard reagent.
In a particularly preferred embodiment of the process according to the invention, for example in the pre-paration of 4,4'-difluorobiphenyl-2-carboxylic acid, the magnesium i~ initially introduced with the total amount of THF, and Vitride (NaAlHz (OCH2CH20CH3)2, 70% strength in toluene) is added until the evolution of hydrogen iB
complete. The 4-bromofluorobenzene i8 then allowed to run into the boiling T~, the Grignard reaction starting immediately. After completion of the formation of the d~
Grignard reagent, the dihydrooxazole V is added with, or preferably without, solvent. The reaction is complete after a short time (about 10 minute~). The mixture i~
hydrolyzed with water or saturated ammonium chloride solution and ad~usted to pH 4-7 with hydrochloric acid in order to achieve a good phase ~eparation. The product can ~-.. ~. . , . .: , . . . . .... .. ..
2~
be purified by crystallization and/or distillation.
The hydroly~is of the dihydro-1,3-oxazole VII to the biphenylcarboxylic acid I i6 carried out by hydroly~is with aqueous acids, for example ~y heating with hydro-chloric acid, ~ulfuric acid or methanesulfonic acid.
In a preferred variant of the process according to the invention, compounds of the general formula VII are reacted with alkylating agents such as, for example, (Ca-C3)-alkyl halides, ( C~-C3 )alkyl methanesulfonates, (Cl-C3)-alkyl toluenesulfonates or di(Cl-C3)alkyl sulfates to give compounds of the general formula VIII. Dimethyl sulfate, methyl iodide, methyl bromide and methyl chloride in solvents such a~ toluene, acetone, 2-butanone or low molecular weight alcohols are particularly prefer-red as alkylating agents. The alkylation reaction can becarried out in the presence or, preferably, in the absence of a base such as ~odium hydroxide solution, potas~ium carbonate or triethylamine, if appropriate ~lso in the presence of phase transfer catalysts such as tetrabutylammonium sulfate. The resulting dihydro-1,3-oxazolium salt VIII is then hydrolyzed to the biphenyl-carboxylic acid I. This can be carried out by heating with aqueous alkali metal hydroxide solutions, such as sodium hydroxide solution or potassium hydroxide solution, preferably in the sen~e of a one-pot reaction, without isolating the salt VIII.
The ring closure of the carboxylic acid I to the fluore-none IX is carried out in a manner known per ~e, for example with dehydrating agent such as, for ex~mple, polyphosphoric acid, at temperatures between about 80 nnd The compounds of the formulae V, VII and VIII are novel and repre~ent useful intermediates, for example for the preparation of biphenylcarboxylic acids of the formula I.
The invention therefore also relates to these !: .
; ; . , ..
_ 10 -intermediatec and to processes for their preparation.
Example I
4,4'-Difluorobiphenyl~2-carbo~ylic acid 1) 5-Fluoro-2-metho~ybenzoic ~cid-2-(1-hydrosy-2-methyl)propyl~ide (IV) 23.0 g (0.135 mol) of 5-fluoro-2-~ethoxybenzoic acid are dissolved in 50 ml of methylene chloride. 17.6 ml (O.2 mol) of thionyl chloride and 2 drops of DNF are added at room temperature and the mixture i8 BlOWly - 10 heated to boiling. After reaction is complete (th~n layer checking by addition of methanol to a sample of the reaction mixture), the mixture is evaporated in vacuo and the excess of thionyl chloride is removed in vacuo after adding further methylene chloride twice. The residue (28.7 g) is di~solved in 100 ml of methylene chloride and the solution obtained iB added dropwise at 0-5-C to ~ -solution of 24.06 g (0.27 mol) of 2-amino-2-methyl-1-propanol in 50 ml of me~hylene chloride. The mixture is subsequently stirred for 1 hour without ice-coolinq ~nd washed twice with 100 ml of portion~ of water, then with 50 ml of dil. HCl, dried over anhydrous sodium ~ulfate and concentrated in vacuo. The crystalline residue (30.5 g, 93.5% of theory) is sufficiently pure for the further reactions.
m.p. 97 - 98C (from isopropanol) 'H-NMR: ~ = 4.8 ppm (t, lH), 3.95 ppm ( 8, 3H), 3.65 ppm (d,2H), 1.4 ppm ( 8, 6H) 2) 2-(5-Fluoro-2-~etho~yphenyl)-4,4-dimethyl-4,5-dihydro-1,3-o~azole (V) a) 20 g (0.083 mol) of N-2-(1-hydroxy-2-methyl)propyl 5-fluoro-2-methoxybenzamide are added in portions at 20-25C to 14.4 ml (0.17 mol) of thionyl chloride, the reaction mixture having to be cooled periodically with :-.. ! , , ~ , . , , :
t . '' ~. ':' , . . . .
m.p. 97 - 98C (from isopropanol) 'H-NMR: ~ = 4.8 ppm (t, lH), 3.95 ppm ( 8, 3H), 3.65 ppm (d,2H), 1.4 ppm ( 8, 6H) 2) 2-(5-Fluoro-2-~etho~yphenyl)-4,4-dimethyl-4,5-dihydro-1,3-o~azole (V) a) 20 g (0.083 mol) of N-2-(1-hydroxy-2-methyl)propyl 5-fluoro-2-methoxybenzamide are added in portions at 20-25C to 14.4 ml (0.17 mol) of thionyl chloride, the reaction mixture having to be cooled periodically with :-.. ! , , ~ , . , , :
t . '' ~. ':' , . . . .
5~3 ice water. The mixture i8 sub~equently stirred for onehour at room temperature, then 100 ml portion~ of ether are added twice, stirred and in each case the ether pha~e is then decanted off. The ~emi-crystalline residue i~
taken up in 100 ml of methylene chloride. The ~olution i~
added dropwise with ice cooling at about 15-C to 150 ml of half-concentrated sodium hydroxide solution. At the end of the dropwise addition, the pH of the agueous phhse must be above 10. The aqueous phase is ~eparated off and again extracted with methylene chloride. The combined organic phaces are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evapor-ated in vacuo. 18.7 g of an oil which gradually crystal-lizes are obtained. After distillation, the product melts lS at 35 - 36C. b.p. 0.5 98C
Yield: Crude product 93 - 100~, after distillation 85 - 95%.
H-NMR: ~ = 6.6 - 7.6 ppm, (m, 3H), 4.05 ppm t~, 2H) 3.8 ppm (s, 3H), 1.35 ppm (8, 6H) b) (One-pot reaction) `
230 g of 5-fluoro-2-methoxybenzoic acid are dissolved in 100 ml of methylene chloride and 1 ml of DMF. lOB ml of thionyl chloride are added to this. The mixture iB heated under reflux until the formation of acid chloride is complete (about 1 hour). A solution of 293.5 ml of 2-amino-2-methyl-1-propanol in 200 ml of methylene chloride is then allowed to run into the clear reaction solution at 10C. After ~ddition is complete, the mixture is sub-seguently stirred at room temperature for 30 minutes, and then 98 ml of thionyl chloride are added dropwise at 20C. The mixture is subseguently stirred for 15 minutes and about 250 ml of conc. sodium hydroxide solution are added dropwise until a pH of ~10 is achieved. The organic phase iB washed once with dilute ~odium hydroxide solu-tion, dried over sodium ~ulfate and distilled in vacuo.
Yield 276 g (92.9~).
.. . . .
.
, ~ . , .
:, - . , ~ . : .
- 12 - ~ 7~
3) 2-(4,4'-Difluorobiphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-l,3-osazole YII
1.18 kg of magnesium c~ips are initially introduced in 25 1 of THF and the mixture i8 heated to 50-60C. Vitride solution in toluene (70% strength) is added until the evolution of hydrogen iB complete (about 150 ml). The mixture is heated under reflux and 500 g of 4-bromo-fluorobenzene are added with ~igorous stirring. The exothermic reaction ~tarts almo~t in6tantansously. A
further 7.99 kg of 4-bromofluorobenzene are allowed to run in in such a way that the mixture always boils under reflux. After completion of the addition, the mixture i~
heated for a further 1 hour. 3.6 k~ of 2-(5-fluoro-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole in 5 1 of dry THF are then metered in at reflux temperature and the mixture i8 heated for a further 15 minutes. The mixture is c~oled to 10C. 20 1 of saturated nmmonium chloride solution are metered in at 10-20C with good cooling and the pH is ad~usted to 6 using about 3.5 1 of conc. hydrochloric acid. The precipitated salts are dissolved with water and the phases are separated. The organic phase is washed with 9 1 of saturated sodium chloride solution, ~tirred with 200 g of active carbon, dried with sodium sulfate and filtered off with ~uction.
After evaporating the solvent and drying in vacuo, 4.5 kg of yellow crystalline product are obtained, which is sufficiently pure for the further reaction~ (97% pure after GC analysis, yield 94.2%). It can be purified by crystallization from isopropanol or diisopropyl ether and distillation of the mother liquor in a thin film evapora-tor.
b.p. 126-130C (0.1 mm) m.p. 83 - 84C
lH-NMRs ~ ~ 6.4 - 7.5 ppm (m~ 7H), 3.85 ppm (8, 2H), 1.28 ppm (8, 6H) s~ ` . . .
~, ;, . :
r : .
.. . . . .
- 13 - '~ 578 4. a) 2-(4,4'-Difluorobiphenyl-2-yl)~3,4,4-trim~thyl-4,5-dihydro-1,3-o~azoliu~ iodide (VII, Rl ~ ~, R2, R~ = C~3, R3 - H, ~
8.6 g of 2-(4,4'-difluorobiphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole are stirred under reflux for 2 days in 60 ml of acetone and 30 ml of methyl iodide. The mixture is concentrated in vacuo snd the oily re~idue is crystallized by adding a little ~cetone. After filtering off with suction and washing with a little ~cetone, 5.8 g of cry~tals of m.p. 179C are obtained.
-NMR: 6 = 8.3 - 8.6 ~m, lH), 7.1 - 7.6 (m, 6H), 5.25 (B, 2H), 2.85 (~, 3H), 1.6 (s, 6H).
b) 2-(4,4'-Difluorobiphenyl-2-yl)-3,4,4-trimethyl-4,5-dihydro-1,3-osazolium methylsulfate (VIII, R1 = ~, R2, R~ = CH3, R3 = H, X = So42) 4.3 g of the dihydrooxazole (from 3) are stirred under reflux for two hours in 30 ml of toluene and 1.7 ml of dimethyl sulfate. The salt cry6tallizes out overnight. It is filtered off with suction and washed with a little acetone, and 5.65 g (92.6%) of product are obtained. Thi6 i8 sufficiently pure for the further reactions. After recrystallization from isopropanol, it melts at 167-16g C.
lH-NMR: 6 ~ 8.05 - 8.35 (m, 1~), 7.0 - 7.6 (m, 6H), 5.05 (8, 2H), 3.7 (8, 3H), 2.75 (8~ 3H), 1.5 (8, 6H).
5. 4,4'-Difluorobiphenyl-2-carbo ylic acid (I) a) 7.18 g of 2-(4,4'-difluorobiphenyl-2-yl)-4,4'-dimethyl-4,5-dihydro-1,3-oxazole (compound VII) are hydrolyzed for 3 days under reflux in 75 ml of dioxane and 80 ml of half-concentrated hydrochloric acid. The solvent is removed in vacuo, the re~idue is taken up in a little half-concentrated sodium hydroxide solution, and the solution i~ wa~hed twice with S0 ml portions of ether, clarified with active carbon and acidified with dilute hydrochloric acid.
57~3 The precipitate i6 filtered off with suction and washed with water. Colorless crystal6 of m.p.
117-119C are obtained. After recrystallization from isopropanol/water, the product melt6 at 124C. Yield 61%
b) 4.0 g of 2-(4,4'-difluorobiphenyl-2-yl)-3,4,4-trimethyl-4,5-dihydro-1,3-oxazolium methylsulfate (compound VIII) and 30 ml of methanol are added to a 601ution of 1.6 g of NaOH in 30 ml of water. After 2 hours at 65C, the reaction solution i~ acidified with 2 N HCl and evaporated in vacuo. ~he residue i8 recrystallized in isopropanol/H20 1:4 and dried.
Yield: 2.25 g (99%) of m.p. 124C
c) The carboxylic acid I i8 obtained from the cor~
responding iodide VIII (from 4.a)) in a yield of 92.8% after recrystallization in an analogous manner. -~
d) One-pot reaction:
100 g (0.348 mol) of 2-(4,4'-difluorobiphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (compound VII) are heated under reflux for 1.5 hours with 40 ml (0.417 mol) of dimethyl 6ulfate in 100 ml of acetone. During the reaction, a colorles6 precipi-tate deposit~. 342 ml (1.54 mol) of 184 strength ~odium hydroxide solution are then added dropwi~e to the su6pension and the acetone i~ ~imultaneously removed by distillation. The mixture i8 then he~ted under reflux nt an internal temperature of about 90~C until the hydrolysi6 i6 complete (about 1 hour). The mixture i~ cooled to 20C, the reaction mixture separating into two pha~es. The lower pha~e i8 re~ected, and the upper i~ washed twice with 100 ml portions of toluene an~ then clarified with active carbon. It iB then acidified with concen-trated hydrochloric acid with cooling, the crystal-line, colorles6 4,4'-difluorobiphenyl-2-carboxylic ;. ~ - : . . .. - :
i8 acid precipitating. ~his i8 filtered off with suction, washed with water and dried in vacuo at 30C.
Yield 70.1 g (86.0%) The carboxylic acid obtained according to ~x~mple I c~n be cyclized to 2,7-difluoro-9-fluorenone (IX) ~8 follows:
2.34 g of 4,4~-difluorobiphenyl-2-carboxylic acid are added at 40-50C to 35 g of polyphosphoric acid. The mixture i~ heated to 100C with stirring for 1 hour. The yellow suspension is then poured into lS0 ml of ice water. ~he yellow precipitate is filtered off with suction and washed thoroughly with water.
Yield: 2.11 g (98%3 of compound IX
m.p. 208 - 210C
taken up in 100 ml of methylene chloride. The ~olution i~
added dropwise with ice cooling at about 15-C to 150 ml of half-concentrated sodium hydroxide solution. At the end of the dropwise addition, the pH of the agueous phhse must be above 10. The aqueous phase is ~eparated off and again extracted with methylene chloride. The combined organic phaces are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evapor-ated in vacuo. 18.7 g of an oil which gradually crystal-lizes are obtained. After distillation, the product melts lS at 35 - 36C. b.p. 0.5 98C
Yield: Crude product 93 - 100~, after distillation 85 - 95%.
H-NMR: ~ = 6.6 - 7.6 ppm, (m, 3H), 4.05 ppm t~, 2H) 3.8 ppm (s, 3H), 1.35 ppm (8, 6H) b) (One-pot reaction) `
230 g of 5-fluoro-2-methoxybenzoic acid are dissolved in 100 ml of methylene chloride and 1 ml of DMF. lOB ml of thionyl chloride are added to this. The mixture iB heated under reflux until the formation of acid chloride is complete (about 1 hour). A solution of 293.5 ml of 2-amino-2-methyl-1-propanol in 200 ml of methylene chloride is then allowed to run into the clear reaction solution at 10C. After ~ddition is complete, the mixture is sub-seguently stirred at room temperature for 30 minutes, and then 98 ml of thionyl chloride are added dropwise at 20C. The mixture is subseguently stirred for 15 minutes and about 250 ml of conc. sodium hydroxide solution are added dropwise until a pH of ~10 is achieved. The organic phase iB washed once with dilute ~odium hydroxide solu-tion, dried over sodium ~ulfate and distilled in vacuo.
Yield 276 g (92.9~).
.. . . .
.
, ~ . , .
:, - . , ~ . : .
- 12 - ~ 7~
3) 2-(4,4'-Difluorobiphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-l,3-osazole YII
1.18 kg of magnesium c~ips are initially introduced in 25 1 of THF and the mixture i8 heated to 50-60C. Vitride solution in toluene (70% strength) is added until the evolution of hydrogen iB complete (about 150 ml). The mixture is heated under reflux and 500 g of 4-bromo-fluorobenzene are added with ~igorous stirring. The exothermic reaction ~tarts almo~t in6tantansously. A
further 7.99 kg of 4-bromofluorobenzene are allowed to run in in such a way that the mixture always boils under reflux. After completion of the addition, the mixture i~
heated for a further 1 hour. 3.6 k~ of 2-(5-fluoro-2-methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole in 5 1 of dry THF are then metered in at reflux temperature and the mixture i8 heated for a further 15 minutes. The mixture is c~oled to 10C. 20 1 of saturated nmmonium chloride solution are metered in at 10-20C with good cooling and the pH is ad~usted to 6 using about 3.5 1 of conc. hydrochloric acid. The precipitated salts are dissolved with water and the phases are separated. The organic phase is washed with 9 1 of saturated sodium chloride solution, ~tirred with 200 g of active carbon, dried with sodium sulfate and filtered off with ~uction.
After evaporating the solvent and drying in vacuo, 4.5 kg of yellow crystalline product are obtained, which is sufficiently pure for the further reaction~ (97% pure after GC analysis, yield 94.2%). It can be purified by crystallization from isopropanol or diisopropyl ether and distillation of the mother liquor in a thin film evapora-tor.
b.p. 126-130C (0.1 mm) m.p. 83 - 84C
lH-NMRs ~ ~ 6.4 - 7.5 ppm (m~ 7H), 3.85 ppm (8, 2H), 1.28 ppm (8, 6H) s~ ` . . .
~, ;, . :
r : .
.. . . . .
- 13 - '~ 578 4. a) 2-(4,4'-Difluorobiphenyl-2-yl)~3,4,4-trim~thyl-4,5-dihydro-1,3-o~azoliu~ iodide (VII, Rl ~ ~, R2, R~ = C~3, R3 - H, ~
8.6 g of 2-(4,4'-difluorobiphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole are stirred under reflux for 2 days in 60 ml of acetone and 30 ml of methyl iodide. The mixture is concentrated in vacuo snd the oily re~idue is crystallized by adding a little ~cetone. After filtering off with suction and washing with a little ~cetone, 5.8 g of cry~tals of m.p. 179C are obtained.
-NMR: 6 = 8.3 - 8.6 ~m, lH), 7.1 - 7.6 (m, 6H), 5.25 (B, 2H), 2.85 (~, 3H), 1.6 (s, 6H).
b) 2-(4,4'-Difluorobiphenyl-2-yl)-3,4,4-trimethyl-4,5-dihydro-1,3-osazolium methylsulfate (VIII, R1 = ~, R2, R~ = CH3, R3 = H, X = So42) 4.3 g of the dihydrooxazole (from 3) are stirred under reflux for two hours in 30 ml of toluene and 1.7 ml of dimethyl sulfate. The salt cry6tallizes out overnight. It is filtered off with suction and washed with a little acetone, and 5.65 g (92.6%) of product are obtained. Thi6 i8 sufficiently pure for the further reactions. After recrystallization from isopropanol, it melts at 167-16g C.
lH-NMR: 6 ~ 8.05 - 8.35 (m, 1~), 7.0 - 7.6 (m, 6H), 5.05 (8, 2H), 3.7 (8, 3H), 2.75 (8~ 3H), 1.5 (8, 6H).
5. 4,4'-Difluorobiphenyl-2-carbo ylic acid (I) a) 7.18 g of 2-(4,4'-difluorobiphenyl-2-yl)-4,4'-dimethyl-4,5-dihydro-1,3-oxazole (compound VII) are hydrolyzed for 3 days under reflux in 75 ml of dioxane and 80 ml of half-concentrated hydrochloric acid. The solvent is removed in vacuo, the re~idue is taken up in a little half-concentrated sodium hydroxide solution, and the solution i~ wa~hed twice with S0 ml portions of ether, clarified with active carbon and acidified with dilute hydrochloric acid.
57~3 The precipitate i6 filtered off with suction and washed with water. Colorless crystal6 of m.p.
117-119C are obtained. After recrystallization from isopropanol/water, the product melt6 at 124C. Yield 61%
b) 4.0 g of 2-(4,4'-difluorobiphenyl-2-yl)-3,4,4-trimethyl-4,5-dihydro-1,3-oxazolium methylsulfate (compound VIII) and 30 ml of methanol are added to a 601ution of 1.6 g of NaOH in 30 ml of water. After 2 hours at 65C, the reaction solution i~ acidified with 2 N HCl and evaporated in vacuo. ~he residue i8 recrystallized in isopropanol/H20 1:4 and dried.
Yield: 2.25 g (99%) of m.p. 124C
c) The carboxylic acid I i8 obtained from the cor~
responding iodide VIII (from 4.a)) in a yield of 92.8% after recrystallization in an analogous manner. -~
d) One-pot reaction:
100 g (0.348 mol) of 2-(4,4'-difluorobiphenyl-2-yl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (compound VII) are heated under reflux for 1.5 hours with 40 ml (0.417 mol) of dimethyl 6ulfate in 100 ml of acetone. During the reaction, a colorles6 precipi-tate deposit~. 342 ml (1.54 mol) of 184 strength ~odium hydroxide solution are then added dropwi~e to the su6pension and the acetone i~ ~imultaneously removed by distillation. The mixture i8 then he~ted under reflux nt an internal temperature of about 90~C until the hydrolysi6 i6 complete (about 1 hour). The mixture i~ cooled to 20C, the reaction mixture separating into two pha~es. The lower pha~e i8 re~ected, and the upper i~ washed twice with 100 ml portions of toluene an~ then clarified with active carbon. It iB then acidified with concen-trated hydrochloric acid with cooling, the crystal-line, colorles6 4,4'-difluorobiphenyl-2-carboxylic ;. ~ - : . . .. - :
i8 acid precipitating. ~his i8 filtered off with suction, washed with water and dried in vacuo at 30C.
Yield 70.1 g (86.0%) The carboxylic acid obtained according to ~x~mple I c~n be cyclized to 2,7-difluoro-9-fluorenone (IX) ~8 follows:
2.34 g of 4,4~-difluorobiphenyl-2-carboxylic acid are added at 40-50C to 35 g of polyphosphoric acid. The mixture i~ heated to 100C with stirring for 1 hour. The yellow suspension is then poured into lS0 ml of ice water. ~he yellow precipitate is filtered off with suction and washed thoroughly with water.
Yield: 2.11 g (98%3 of compound IX
m.p. 208 - 210C
Claims (5)
1. A biphenylcarboxylic acid of the formula I
I
in which R1 is hydrogen or methoxy.
I
in which R1 is hydrogen or methoxy.
2. A process for the preparation of biphenylcarboxylic acids of the formula I, which comprises a) reacting a 2-methoxybenzoic acid of the formula II
II
or a reactive derivative of this acid with an ethanolamine of the formula III
III
in which R2 and R3 are hydrogen or (C1-C3)-alkyl, but R2 and R3 are not simultaneously alkyl, to give an amide of the general formula IV
IV
in which R2 and R3 have the meanings indicated for formula III, then cyclizing the amide of the formula IV to a dihydrooxazole of the formula V
V
in which R2 and R3 have the meanings indicated for formula III, then reacting the dihydrooxazole of the formula V with an organometallic reagent of the formula VI
VI
in which R1 has the meaning indicated for formula I
and M is lithium, Zn-Hal or Mg-Hal and Hal is chlorine, bromine or iodine, to give a biphenyl derivative of the general formula VII
VII
in which R1 has the meaning indicated for formula I
and R2 and R3 have the meanings indicated for formula III, and hydrolyzing the biphenyl derivative of the formula VII obtained, optionally after conversion into the corresponding alkylated compound of the formula VIII
VIII
in which R1 has the meaning indicated for formula I
and R2 and R3 have the meanings indicated for formula III, R4 is (C1-C3)-alkyl, and X- is chloride, bromide, iodide, methylsulfate or ethylsulfate, to the carboxylic acid of the formula I
I
in which R1 has the meaning indicated for formula I.
II
or a reactive derivative of this acid with an ethanolamine of the formula III
III
in which R2 and R3 are hydrogen or (C1-C3)-alkyl, but R2 and R3 are not simultaneously alkyl, to give an amide of the general formula IV
IV
in which R2 and R3 have the meanings indicated for formula III, then cyclizing the amide of the formula IV to a dihydrooxazole of the formula V
V
in which R2 and R3 have the meanings indicated for formula III, then reacting the dihydrooxazole of the formula V with an organometallic reagent of the formula VI
VI
in which R1 has the meaning indicated for formula I
and M is lithium, Zn-Hal or Mg-Hal and Hal is chlorine, bromine or iodine, to give a biphenyl derivative of the general formula VII
VII
in which R1 has the meaning indicated for formula I
and R2 and R3 have the meanings indicated for formula III, and hydrolyzing the biphenyl derivative of the formula VII obtained, optionally after conversion into the corresponding alkylated compound of the formula VIII
VIII
in which R1 has the meaning indicated for formula I
and R2 and R3 have the meanings indicated for formula III, R4 is (C1-C3)-alkyl, and X- is chloride, bromide, iodide, methylsulfate or ethylsulfate, to the carboxylic acid of the formula I
I
in which R1 has the meaning indicated for formula I.
3. A compound of the formula V.
4. A compound of the formula VII or VIII.
5. The biphenylcarboxylic acid as claimed in claim 1 and substantially as described herein.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3914227A DE3914227A1 (en) | 1989-04-29 | 1989-04-29 | METHOD FOR PRODUCING 2,7-DIFLUOR-9-FLUORENONE AND NEW INTERMEDIATE PRODUCTS |
| DEP3914227.2 | 1989-04-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2015578A1 true CA2015578A1 (en) | 1990-10-29 |
Family
ID=6379764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002015578A Abandoned CA2015578A1 (en) | 1989-04-29 | 1990-04-27 | Substituted biphenylcarboxylic acids, a process for their preparation and novel intermediates |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0396014A2 (en) |
| JP (1) | JPH02295946A (en) |
| KR (1) | KR900016085A (en) |
| AU (1) | AU5390590A (en) |
| CA (1) | CA2015578A1 (en) |
| DE (1) | DE3914227A1 (en) |
| FI (1) | FI902111A0 (en) |
| HU (1) | HUT53584A (en) |
| NO (1) | NO901894L (en) |
| PT (1) | PT93914A (en) |
| ZA (1) | ZA903224B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5210206A (en) * | 1990-09-10 | 1993-05-11 | Abbott Laboratories | 1,3-oxazolyl substituted biphenyl |
| US5391817A (en) * | 1993-12-21 | 1995-02-21 | Bristol-Myers Squibb | Biaryl phospholipase A2 inhibitors |
| EP2536682A1 (en) * | 2010-02-19 | 2012-12-26 | Centre National De La Recherche Scientifique | Method for preparing chemical compounds of interest by nucleophilic aromatic substitution of aromatic carboxylic acid derivatives supporting at least one electro-attractive group |
-
1989
- 1989-04-29 DE DE3914227A patent/DE3914227A1/en not_active Withdrawn
-
1990
- 1990-04-26 EP EP90107910A patent/EP0396014A2/en not_active Withdrawn
- 1990-04-26 FI FI902111A patent/FI902111A0/en not_active Application Discontinuation
- 1990-04-26 HU HU902579A patent/HUT53584A/en unknown
- 1990-04-27 PT PT93914A patent/PT93914A/en not_active Application Discontinuation
- 1990-04-27 JP JP2110713A patent/JPH02295946A/en active Pending
- 1990-04-27 NO NO90901894A patent/NO901894L/en unknown
- 1990-04-27 ZA ZA903224A patent/ZA903224B/en unknown
- 1990-04-27 KR KR1019900005960A patent/KR900016085A/en not_active Application Discontinuation
- 1990-04-27 CA CA002015578A patent/CA2015578A1/en not_active Abandoned
- 1990-04-27 AU AU53905/90A patent/AU5390590A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| EP0396014A2 (en) | 1990-11-07 |
| KR900016085A (en) | 1990-11-12 |
| PT93914A (en) | 1990-11-20 |
| NO901894D0 (en) | 1990-04-27 |
| JPH02295946A (en) | 1990-12-06 |
| DE3914227A1 (en) | 1991-01-10 |
| FI902111A0 (en) | 1990-04-26 |
| AU5390590A (en) | 1990-11-01 |
| ZA903224B (en) | 1991-01-30 |
| NO901894L (en) | 1990-10-30 |
| HU902579D0 (en) | 1990-08-28 |
| HUT53584A (en) | 1990-11-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |