U.S. patent number 3,671,580 [Application Number 04/887,416] was granted by the patent office on 1972-06-20 for substituted biphenyl acetic acids and ester derivatives thereof.
This patent grant is currently assigned to Merck & Co.. Invention is credited to Conrad P. Dorn, Jr., Tsung-Ying Shen.
United States Patent |
3,671,580 |
|
June 20, 1972 |
SUBSTITUTED BIPHENYL ACETIC ACIDS AND ESTER DERIVATIVES THEREOF
Abstract
New 4(and 5)-substituted phenylacetic acids useful as
anti-inflammatory, analgesic and anti-pyretic agents. 4 Claims, No
Drawings
Inventors: |
Tsung-Ying Shen (Westfield,
NJ), Conrad P. Dorn, Jr. (Plainfield, NJ) |
Assignee: |
Merck & Co. (Inc.,
Rahway)
|
Family
ID: |
25391088 |
Appl.
No.: |
04/887,416 |
Filed: |
December 22, 1969 |
Current U.S.
Class: |
562/469;
250/396R; 544/173; 546/190; 560/59; 562/435; 564/307; 568/746;
544/171; 544/174; 548/533; 560/141; 564/171; 568/642; 568/643;
568/928 |
Current CPC
Class: |
C07C
37/045 (20130101); C07C 59/56 (20130101); C07C
205/11 (20130101); C07C 65/105 (20130101); C07C
37/055 (20130101); C07C 37/055 (20130101); C07C
37/045 (20130101); C07C 245/14 (20130101); C07C
41/30 (20130101); C07C 41/30 (20130101); C07C
39/367 (20130101); C07C 39/367 (20130101); C07C
43/225 (20130101) |
Current International
Class: |
C07C
245/14 (20060101); C07C 37/00 (20060101); C07C
37/055 (20060101); C07C 37/05 (20060101); C07C
59/56 (20060101); C07C 59/00 (20060101); C07C
65/00 (20060101); C07C 65/105 (20060101); C07C
205/11 (20060101); C07C 205/00 (20060101); C07C
245/00 (20060101); C07c 065/14 () |
Field of
Search: |
;260/520,473R,473S,479R |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Roberts et al., "Basic Principles of Organic Chemistry," W. A.
Benjamin .
Inc., N.Y., N.Y. (1965) p. 556, 694.
|
Primary Examiner: Lorraine A. Weinberger
Assistant Examiner: John F. Terapane
Attorney, Agent or Firm: Michael C. Sudol, Jr. Harry E.
Westlake, Jr. I. Louis Wolk
Claims
1. A compound of the formula: ##SPC4## or a pharmaceutically
non-toxic acid addition salt thereof, wherein X is chloro or
fluoro; R is hydrogen, loweralkyl or lower alkoxy; R.sub.1 is
hydroxy or lower alkoxy; R.sub.2 is hydrogen or lower alkanoyl;
2. A compound of the formula: ##SPC5## or a pharmaceutically
non-toxic acid addition salt thereof, wherein: R is methyl or
methoxy; R.sub.2 is hydrogen or acetyl;
Description
This invention relates to new biphenyl compounds, to a method of
treating inflammation using these compounds and to processes for
producing the same. More specifically, this invention relates to
substituted 4(or 5)-(phenyl)-phenylacetic acids, esters, amides,
anhydrides and non-toxic pharmaceutically acceptable salts thereof.
Still more specifically, this invention relates to compounds having
the following formula: ##SPC1## Wherein: X.sub.( 1-5) is halogen
(chloro, bromo, fluoro and iodo); R is selected from the group
consisting of hydrogen, halogen (chloro, bromo, and fluoro), lower
alkyl (such as methyl, ethyl, butyl, pentyl, and the like), and
lower alkoxy (such as methoxy, ethoxy, butoxy, and the like);
R.sub.1 is selected from the group consisting of hydroxy, amino,
lower alkoxy (such as methoxy, ethoxy, butoxy, pentoxy, and the
like), lower alkylamino (methylamino, propylamino, pentylamino, and
the like), di(lower alkyl)amino (dimethylamino, dibutylamino,
propylpentylamino, and the like), diloweralkylaminoloweralkylamino,
dloweralkylaminoloweralkoxy, hydroxyloweralkoxy, (3-hydroxypropoxy,
2-hydroxypropoxy, 4-hydroxybutoxy and the like),
polyhydroxyloweralkoxy (2,3-dihydroxypropoxy,
2,3,4,5,6-pentahydroxyhexyloxy and the like),
loweralkoxyloweralkoxy (ethoxyethoxy), phenyl-loweralkoxy
(benzyloxy, phenethoxy and the like), phenoxy, substituted phenoxy
(such as loweralkoxy, diloweralkylamino, loweralkanoylamino,
benzyloxy-2-carboxy-4-(4'-fluorophenyl), loweralkanolyamino-
loweralkoxy, hydrazino, (hydroxylamino), N-morpholino,
N-(4-loweralkyl-piperidino)-N-[4-(hydroxyloweralkyl)-piperidino],
(hydroxyloweralkyl)amino and a naturally occurring amino acid
radical with attachment at the N, such as glycine, phenylalanine,
proline, methionine and taurine; R.sub.2 is selected from the group
consisting of hydrogen, lower alkyl (such as methyl, ethyl, butyl,
pentyl, and the like), lower alkanoyl (such as acetyl, propionyl,
butyryl, and the like), and lower alkenyl (such as allyl, butenyl,
and the like); and R.sub.3 is selected from the group consisting of
hydrogen, 3-lower alkenyl, 3- and 4-lower alkyl, lower alkoxy,
benzyl and halo; the pharmaceutically non-toxic salts of the acid
[such as the ammonium, alkali (Na,K) and alkali earth (Ca,Ba,Mg),
amine, aluminum, iron, choline, glucosamine, and S-methyl
methionine salts, piperazine, diloweralkylaminoloweralkanol,
chloroquine, hydroxychloroquine and the like]; the anhydride of
said acids and the mixed anhydrides of said acids and 2-acetoxy
phenyl acetic acid.
In the more preferred aspects of this invention, is hydrogen or
lower alkyl, particularly, methyl or lower alkoxy, particularly
methoxy; R.sub.1 is hydroxy or amino, particularly hydroxy; R.sub.2
is hydrogen or lower alkanoyl, particularly acetyl; R.sub.3 is
hydrogen or lower alkyl; X is chloro or fluoro, particularly fluoro
and is on the 4-position of the phenyl moiety.
Representative compounds of this invention are: 2-hydroxy-4(or
5)-(4'-fluorophenyl)-phenylacetamide; 2-hydroxy-4(or
5)-(4'-fluorophenyl)-3-methylphenylacetamide; 2-acetoxy-4(or
5)-(4'-fluorophenyl)-phenylacetamide; 2-acetoxy-4(or
5)-(4'-fluorophenyl)-phenylacetmorpholide; 2-hydroxy-4(or
5)-(4'-fluoro-2'-methoxyphenyl)-phenylacetic acid; 2-acetoxy-4(or
5)-(4'-fluoro-2'-methoxyphenyl)-phenylacetic acid; 2-hydroxy-4(or
5)-(4'-fluoro-2'-methylphenyl)-phenylacetic acid; 2-acetoxy-4(or
5)-(4'-fluoro-3'-methylphenyl)-phenylacetic acid;
2-hydroxy-3-allyl-4(or 5)-(4'-fluorophenyl)-phenylacetic acid; and
2-hydroxy-3-propyl-4(or 5)-(4'-fluorophenyl)-phenylacetic acid.
This invention also relates to a method of treating inflammation in
patients using a compound of formula I, particularly an especially
preferred compound as the active constituent.
The compounds of the instant invention can be used to reduce
inflammation and relieve pain in such diseases as rheumatoid
arthritis, osteoarthritis, gout, infectious arthritis and rheumatic
fever. Furthermore, the compounds of the instant invention have
better potency at the same dosage levels than similar type
compounds known in the prior art and exhibit a lower incidence of
side effects.
The compounds of formula I also have antipyretic and analgesic
activity and would be administered and used in the same manner and
in the same dosage ranges as if they were being used to treat
inflammation as discussed further on.
The treatment of inflammation in accordance with the method of the
present invention is accomplished by orally, parenterally,
topically or rectally administering to patients (animal or human) a
composition of a compound of formula I, particularly the especially
preferred compounds in a non-toxic pharmaceutically acceptable
carrier, preferably in tablet or capsule form.
The non-toxic pharmaceutical carrier may be, for example, either a
solid or a liquid. Exemplary of solid carriers are lactose, corn
starch, gelatin, talc, sterotix, stearic acid, magnesium stearate,
terra alba, sucrose, agar, pectin, cab-o-sil, and acacia. Exemplary
of liquid carriers are peanut oil, olive oil, sesame oil and water.
Similarly, the carrier or diluent may include a time delay material
such as glyceryl monostearate or glyceryl distearate alone or with
a wax.
Several pharmaceutical forms of the therapeutically useful
compositions can be used. For example, if a solid carrier is used,
the compositions may take the form of tablets, capsules, powders,
troches or lozenges, prepared by standard pharmaceutical
techniques. If a liquid carrier is used, the preparation may be in
the form of a soft gelatin capsule, a syrup or a liquid suspension.
Creams, gels, and salves may be prepared in conventional manners
for topical administration and suppositories may be prepared for
rectal administration.
The active compounds of formula I and of the compositions of this
invention are present in an amount sufficient to treat
inflammation, that is to reduce inflammation. Advantageously, the
composition will contain the active ingredient, namely, the
compounds of formula I in an amount of from about 1 to 140 mg. per
day), preferably from about 2 mg. to 70 mg./kg. body weight per day
(100 mg. to 5 g. per patient per day).
The method of treatment of this invention comprises internally
administering to a patient (animal or human), a compound of formula
I, particularly an especially preferred compound admixed with a
non-toxic pharmaceutical carrier such as exemplified above. The
compounds of formula I and particularly the especially preferred
compounds will be present in an amount of from 1 mg. to 140 mg./kg.
body weight per day, preferably from about 2 mg. to about 70 mg.
per kilogram body weight per day and especially from 4 mg. to 10
mg./kg. body weight per day. The most rapid and effective
anti-inflammatory effect is obtained from oral administration of a
daily dosage of from about 4 to 10 mg./kg./day. It should be
understood, however, that although preferred dosage ranges are
given, the dose level for any particular patient depends upon the
activity of the specific compound employed. Also many other factors
that modify the actions of drugs will be taken into account by
those skilled in the art in the therapeutic use of medicinal
agents, particularly those of formula I, for example, age, body
weight, sex, time of administration, route of administration, rate
of excretion, drug combination, reaction sensitivities and severity
of the particular disease.
The compounds of this invention may be prepared either from a
biphenyl phenol or from the following type starting material:
##SPC2## wherein: A is an alkali metal ion; and X, r.sub.3 and R
are as previously defined.
Some of these compounds are prepared from the individual phenyl
moieties of the above starting material by the well-known Gomberg
reaction. Others, where the biphenyl moiety is known, require the
appropriate reactions to obtain the functional group, if needed, as
well as the metal salts. However, all of the compounds may be
obtained by first preparing an aniline compound containing an X
and, if desired, an R group, followed by a Gomberg reaction with
nitrobenzene or anisole or an R.sub.3 substituted nitrobenzene or
anisole, subsequently reacting either the nitro group or the
methoxy group (from nitrobenzene or anisole) of the biphenyl
compound thus prepared so as to obtain the alkali salt starting
material. For example, 2-fluoro-5-nitroaniline may be diazotized to
the corresponding 2-fluoro-5-nitrophenol which in turn may be
alkylated to form the corresponding 3-alkoxy-4-fluoronitrobenzene,
and finally reducing the nitro group to obtain the appropriate
aniline compound needed for the Gomberg reaction. (When as in this
cited example, the benzene compound contains an alkoxy group, the
Gomberg reaction is carried out with nitrobenzene). The methoxy
substituted aniline compound is then reacted with nitrobenzene in
the presence of isoamyl nitrite. The nitrobiphenyl compound thus
obtained may be readily reduced to the amino compound and
subsequently diazotized to the corresponding hydroxy compound.
Alternatively, when the aniline compound used in the Gomberg
reaction does not have an alkoxy substituent on it, it may be
reacted with an alkoxy benzene rather than nitrobenzene. Using this
procedure, the alkoxy biphenyl compound obtained after the Gomberg
reaction may, by one step, be converted to the corresponding
hydroxy-biphenyl compound, for example, by reaction with hydriodic
acid.
Although the above reaction sequence can be used when R.sub.3 is
methyl, it is preferred to carry out the following reaction
sequence when R.sub.3 is lower alkyl: For example, the
methyl-2-hydroxy-5-(4'-fluorophenyl)- benzoate compound of this
invention is reduced to the corresponding alcohol. This alcohol
compound is then acylated, whereupon it is subsequently
hydrogenated to the corresponding 4-(4'-fluorophenyl)-2-
methylphenyl acetate. This compound is then saponified or
hydrolyzed to the corresponding phenol compound, which in turn is
carbonated to form the
5-(4'-fluorophenyl)-2-hydroxy-3-methyl-benzoic acid. Further, when
R.sub.3 is to be a lower alkenyl group, the following procedure is
preferred: For example, methyl 5-(4'-fluorophenyl)-2-hydroxy
benzoate is heated with potassium carbonate in acetone to form the
corresponding 2-allyloxy compound. This product is then heated at
high temperatures to cause a rearrangement to the corresponding
3-allyl-2-hydroxy compound. Further, an additional method for
preparing an R.sub.3 alkyl is by reduction, for example, of the
above-noted 3-allyl compound to the corresponding 3-propyl
compound. In addition, the 3-allyl compound above may be heated
with potassium hydroxide to obtain a double bond shift to form the
3-propenyl compound.
In the Gomberg reaction mentioned above, a mixture of isomers of
the biphenyl compound is obtained; therefore, in order to obtain
the desired 4(and 5)-(substituted phenyl)-benzene compounds in a
pure form a chromatographic separation is required.
The (substituted phenyl)-phenol compounds obtained as described
above may then be converted to the corresponding alkali salt by any
well-known means, for example, reaction with an appropriate alkali
metal in an inert solvent.
The benzoic acid compounds may be prepared from the previously
prepared alkali phenolate or phenol compound. The preparation of
these acid compounds are carried out by using the well-known
Kolbe-Schmidt carbonation procedure. In this carbonation step, the
phenolate is reacted with carbon dioxide or the phenol is reacted
with carbon dioxide in the presence of an alkali carbonate. Many of
the acids which are not claimed in this invention can be used as
starting materials for the novel esters and amides of this
invention. The process may be shown as follows: ##SPC3##
Equivalents: As previously indicated. Reactions and Conditions:
Step 1. Reaction with carbon dioxide at elevated temperatures
(above 75.degree. C. preferably above 100.degree. C.) with or
without a solvent preferably without a solvent (or if the solvent
is used, any high-boiling inert solvent may be used) until the
reaction is substantially complete; and subsequent acidification of
the mixture. Step 2. Reaction with carbon dioxide in the presence
of an alkali carbonate, such as potassium, sodium and the like,
especially potassium, at elevated temperatures (above 75.degree. C.
preferably above 100.degree. C.) with or without a solvent
preferably without a solvent (or if the solvent is used, any
high-boiling inert solvent may be used) until the reaction is
substantially complete; and subsequent acidification of the
reaction mixture.
Reaction steps 1 and 2 are the well-known Kolbe-Schmidt reaction.
Since the reaction conditions are not critical, this invention
contemplates not only the particular procedure shown but all other
variations of this carbonation step which are well known in the
art.
The phenylacetic acid compounds of this invention may be prepared
by reacting the corresponding hydroxy benzoic acid with a lower
alkanoic acid anhydride (preferably acetic anhydride) in the
presence of a catalyst, such as sulfuric acid, pyridine,
p-toluenesulfonic acid and the like (preferably pyridine), at any
suitable temperature from room temperature to elevated temperatures
(preferably at elevated temperatures) to form the desired R.sub.2
compound which then undergoes the Arndt-Erstert synthesis to form
the desired acetic acid compound. This synthesis involves three
steps:
1. formation of the acid chloride by reacting the benzoic acid with
any suitable chloride of the formula SOCl.sub.2, POCl.sub.3 or
R-COCl wherein R = alkyl, aryl or heteroaryl;
2. reaction of the acid chloride with diazomethane to form a
diazoketone; and
3. rearrangement of the diazoketone, with loss of nitrogen, in the
presence of a catalyst (silver, platinum, copper). An acid is
formed in the presence of water, an ester is produced in an
alcohol, and an amide results when ammonia is used.
The compounds of this invention, wherein R.sub.1 is a group such
that an ester is the final compound, (i.e. R.sub.1 = alkoxy), are
prepared by any esterification procedure, using an esterifying
agent containing the appropriate R.sub.1 group. For example, the
phenylacetic acid compounds of this invention may be reacted with
the appropriate lower alkanol (preferably methanol) at elevated
temperatures in the presence of a strong acid, such as hydrochloric
acid, sulfuric acid, p-toluenesulfonic acid, and the like, to form
the desired R.sub.1 compound.
The compounds of this invention, wherein R.sub.1 is a group such
that an amide is the final compound (i.e., R.sub.1 is amino), may
also be present by any suitable amidation reaction. For example,
the phenylacetic acid compound (preferably the methyl or ethyl
ester) may be reacted with ammonia, ammonium hydroxide, or an amine
compound, at any suitable temperature (room temperature to reflux).
When the amino group is desired, it is preferred to carry out the
reaction with ammonia in a bomb at temperatures above 100.degree.
C. to form the desired R.sub.1 (amino) compound. Preferably, when
an amide is desired which is derived from an amino acid, the
following reaction sequence is followed: The phenylacetic acid
final compound is reacted with isobutyl chlorocarbonate to form the
mixed anhydride. This compound is in turn reacted when the desired
amino acid ester and subsequently hydrolyzed to form the desired
amide.
The final compound, wherein R.sub.2 is lower alkanoyl (preferably
acetyl), may be prepared by any suitable alkanoylation reaction.
For example, the corresponding hydroxy phenylacetic acid, ester or
amide (preferably the ester), may be reacted with a lower alkanoic
acid anhydride (preferably acetic anhydride) in the presence of a
catalyst, such as sulfuric acid, pyridine, p-toluenesulfonic acid,
and the like (preferably pyridine), at any suitable temperature
(room temperature to elevated temperatures) preferably at elevated
temperatures to form the desired R.sub.2 compound.
The final compound, wherein R.sub.2 is lower alkyl (preferably
methyl), may be prepared by any appropriate alkylation reaction.
For example, the corresponding hydroxy phenylacetic acid, ester, or
amide (preferably the ester), may be reacted with a di(lower
alkyl)sulfate (preferably dimethyl sulfate) in the presence of a
base (such as an alkali carbonate) at any suitable temperature
(room temperature to reflux but preferably at or near reflux) with
subsequent acidification of the reaction mixture, such as with
hydrochloric acid, sulfuric acid, and the like, to form the desired
R.sub.2 compound.
The final compound, wherein R.sub.2 is a lower alkenyl (preferably
allyl), may also be prepared by any appropriate alkylation
reaction. For example, the hydroxy phenylacetic acid, ester, or
amide (preferably the ester), may be reacted with an alkenyl halide
in the presence of a base containing an inorganic cation, such as
sodium methoxide, potassium ethoxide, sodium carbonate, and the
like, in an inert solvent which affords at least some
solubilization [such as dioxane, tetrafuran, lower alkanol,
dimethoxy ethane, acetone, and the like (preferably a lower
alkanol, such as methanol)] at any suitable temperature (room
temperature to elevated temperatures, preferably at elevated
temperatures) to form the desired R.sub.2 compound.
The salts of the final acid compounds of this invention may be
prepared by any of the well-known metathesis procedures. For
example, the phenylacetic acid compound may be reacted with an
inorganic base, such as sodium hydroxide, potassium hydroxide,
ammonium hydroxide, barium hydroxide, and the like. The anhydrides
of this invention may be prepared by any of the well-known
procedures in the art.
The preparation of these compounds containing the R.sub.1 and
R.sub.2 groups other than hydrogen may be prepared in any order.
The R.sub.1 group could be placed on the molecule followed by
addition of the R.sub.2 substituent or by first obtaining the
R.sub.2 compound followed by addition of the R.sub.1 group. The
order of these reactions is not critical; they can be run in any
desired fashion.
The following examples are used by way of illustration:
EXAMPLE 1 4-(4'-fluorophenyl)aniline
A solution of 3 g. 4'-fluoro-4-nitrobiphenyl in 125 ml. methanol is
reduced by hydrogen at room temperature and 40 p.s.i. pressure
using 100 mg. platinum oxide catalyst. After the required uptake of
hydrogen, the mixture is filtered, 50 ml. 2.5 N hydrochloric acid
added and the resulting solution is evaporated in vacuo. After
washing the residue with ether, it is dissolved in methanol,
filtered and diluted with excess ether. The precipitate which is
4-(4'-fluorophenyl)aniline hydrochloride is filtered, washed with
ether and dried in vacuo at room temperature.
EXAMPLE 2 2',3',4',5.dbd.,6'-pentafluoro-4-nitrobiphenyl and
2',3',4',5',6'- Pentafluoro-3-nitrobiphenyl
A mixture of 7.5 g. of pentafluoroaniline, 200 ml. of nitrobenzene,
and 9.0 g. of iso-amyl nitrite, is warmed on the steam bath until a
vigorous reaction with evolution of gas sets in. This evolution is
allowed to proceed without heating until it has subsided, and the
mixture is then heated on the steam bath for an additional 3 hours.
The excess of nitrobenzene is removed in vacuo. The residue is
purified for the desired isomer by elution from a silica gel column
using petroleum-benzene to yield
2',3',4',5',6'-pentafluoro-4-nitrobiphenyl and 2',3',4',5'
,6'-pentafluoro-3-nitrobiphenyl.
When 2-fluoroaniline is used in place of pentafluoroaniline in the
above example, there is obtained 2'-fluoro-4-nitrobiphenyl and
2'-fluoro-3-nitrobiphenyl.
When 2-nitrotoluene, 2-ethyl-nitrobenzene, 2-methoxy-nitrobenzene,
2-ethoxy-nitrobenzene, 2-chloro-nitrobenzene, 2-bromo-nitrobenzene,
3-nitrotoluene, 3-ethylnitrobenzene, 3-methoxy-nitrobenzene,
3-ethoxy-nitrobenzene, 3-chloro-nitrobenzene, or
3-bromo-nitrobenzene are used in place of nitrobenzene in the above
example, there is obtained the corresponding 2- and 3-alkyl, halo
or alkoxy biphenyls.
When 4-fluoroaniline and 2-methyl-nitrobenzene are used in the
above example in place of 4-fluoro-2-methoxyaniline and
nitrobenzene there is obtained 4'-fluoro-3-methyl-4-nitrobiphenyl
and 4'-fluoro-4-methyl-3- nitrobiphenyl.
EXAMPLE 3 4-(pentafluorophenyl)-aniline
A mixture of 5 g. of 2',3',4',5',6'-pentafluoro-4-nitrobiphenyl in
250 ml. of ethanol is reduced by hydrogen at atmospheric pressure
and at room temperature using 5 percent palladium-on-charcoal (0.5
g.) catalyst. After the required uptake of hydrogen, the mixture is
filtered and the catalyst washed with fresh ethanol. The ethanol
solution is then concentrated in vacuo, and the residue
recrystallized from aqueous ethanol to yield
4-(pentafluorophenyl)aniline.
When 2'-fluoro-4-nitrobiphenyl is used in place of 2',3',4',5',6'-
pentafluoro-4-nitrobiphenyl in the above examples, there is
obtained 4-(2'-fluorophenyl)-aniline.
When 2'-fluoro-3-nitrobiphenyl is used in place of 2'-fluoro-4-
nitrobiphenyl according to the above procedure, there is obtained
3'-(2'-fluorophenyl)-aniline.
Similarly, when 4'-fluoro-2-methyl-3-nitrobiphenyl obtained from
Example 2 is used in place of
2',3',4',5',6'-pentafluoro-4-nitrobiphenyl in the above example,
there is obtained 2-methyl-3-(4'-fluorophenyl)-aniline.
When the 2- and 3-alkyl, halo or alkoxy biphenyls obtained from
Example 2 are used in place of 4'-fluoro-2-methoxy-4-nitrobiphenyl
in the above example, there are obtained the corresponding 2- or
3-alkyl, halo or alkoxy aniline compounds.
EXAMPLE 4 3-(3'-chloro-4'-fluorophenyl)-anisole and
4-(3'-chloro-4'-fluorophenyl)- anisole
A mixture of 8.0 g. of 3-chloro-4-fluoroaniline, 200 ml. of
anisole, and 9.0 grams of iso-amylnitrite, is warmed on a steam
bath until a vigorous reaction with evolution of gas sets in. This
evolution is allowed to proceed without heating until it has
subsided, and the mixture is then heated until it has subsided, and
the mixture is then heated on the steam bath for an additional 3
hours. The excess anisole is removed in vacuo, and the residue is
chromatographed on a silica gel column using petroleum-benzene as
eluent to yield 3-(3'-chloro-4'-fluorophenyl)- anisole and
4-(3'-chloro-4-fluorophenyl)-anisole.
When 2-chloro-4-fluoroaniline, 2,4-difluoroaniline and
3-fluoroaniline are used in place of 3-chloro-4-fluoroaniline in
the above example, there are obtained the corresponding 3(and
4)-(2'-chloro-4'-fluorophenyl)- anisole, 3(and
4)-(2',4'-difluorophenyl)-anisole and 3(and
4)-(3'-fluorophenyl)-anisole.
When 2-methylanisole, 2-ethylanisole, 2-benzylanisole,
3-methylanisole, 3-ethylanisole, 3-benzylanisole, 2-chloroanisole,
2-bromoanisole, 3-chloroanisole or 3-bromoanisole is used in place
of anisole in the above example, there is obtained the
corresponding 2- or 3- alkyl, benzyl or halo substituted biphenyl
compound.
EXAMPLE 5 4'-(3'-chloro-4'-fluorophenyl)-phenol
To a solution of 2.1 g. of 4-(3'-chloro-4'-fluorophenyl)-anisole in
50 ml. of boiling acetic acid is added 5 ml. of hydriodic acid and
the boiling continued for 3 hours. Water is added and the reaction
mixture cooled and the 4-(3'-chloro-4'-fluorophenyl)-phenol
crystallizes. Further purification is then achieved by
recrystallization of the solid from aqueous ethanol to yield
4-(3'-chloro-4'-fluorophenyl)-phenol.
When 4-(2'-chloro-4'-fluorophenyl)-anisole,
3-(2',4'-difluorophenyl)- anisole and 4-(3'-fluorophenyl)-anisole
obtained from Example 4 are used in place of
4-(3'-chloro-4'-fluorophenyl)-anisole in the above example, there
are obtained the corresponding 4-(2'-chloro-4'-fluorophenyl)-
phenol, 3-(2',4'-difluorophenyl)-phenol and
4-(3'-fluorophenyl)-phenol.
When the 2- or 3-alkyl, benzyl or halo substituted biphenyl
compounds obtained from Example 4 above are used in place of
4-(3'-chloro-4'- fluorophenyl)-anisole in the above example, there
is obtained the corresponding 4-(substituted phenyl)-2- or 3-alkyl,
benzyl or halo phenol compound.
EXAMPLE 6 4-(4'-fluorophenyl)-phenol
A solution of 32.66 g. of 4-(4'-fluorophenyl)-aniline in 120 ml. of
glacial acetic acid is cooled to 10.degree.-12.degree. C. To this
solution is added slowly a solution of 12.25 grams of sodium
nitrite in 120 ml. of water with stirring and continued cooling.
Five minutes after this addition, the suspension of the diazonium
acetate is added slowly to a boiling solution of 100 ml. of
concentrated sulfuric acid and 200 ml. of water. After the final
addition of the diazonium salt, the suspension is boiled for an
additional 5 minutes and then allowed to cool to room temperature.
The reaction mixture is then filtered and the cake dried in vacuo
to yield 4-(4'-fluorophenyl)-phenol, (m.p. 152.degree.-161.degree.
C., 24.07 g.).
When 4-(2'-fluorophenyl)-aniline, 3'-(pentafluorophenyl)-aniline,
and 3-(4'-fluoro-3'-methoxyphenyl)-aniline, obtained from Example 3
are used in place of 4-(4'-fluoro-2'-methoxyphenyl)-aniline in the
above example, there are obtained the corresponding
4-(2'-fluorophenyl)-phenol, 3-(pentfluorophenyl)-phenol, and
3-(4'-fluoro-3'-methoxyphenyl)-phenol.
When the alkyl, halo or alkoxy aniline compounds obtained from
Example 3 are used in place of 4-(4'-fluorophenyl)-aniline in the
above example, there is obtained the corresponding 2- or 3-alkyl,
halo or alkoxy phenol compound.
Similarly, when 2-methyl-4-(4'-fluorophenyl)-aniline obtained from
Example 3 is used in place of -(4'-fluorophenyl)-aniline in the
above example, there is obtained
2-methyl-4-(4'-fluorophenyl)-phenol.
EXAMPLE 7 2-hydroxy-5-(4'-fluorophenyl)-benzoic acid
A mixture of 10 g. of 4-(4'-fluorophenyl)-phenol and 27.2 g. of
potassium carbonate is exposed to carbon dioxide at 1,300 p.s.i.
and 175.degree. C. The dark mass obtained from this carbonation is
dissolved in 300 ml. of water and 200 ml. of methylene chloride and
the two layers separated. The water layer is extracted with 100 ml.
of methylene chloride and then acidified with 2.5 normal
hydrochloric acid. This mixture is filtered and the cake dried in
vacuo to yield 5.32 g. of the crude product. The crude product is
recrystallized from benzene-methanol to yield 2.7 grams of material
(m.p. 200.degree.-204.degree. C.). An additional crystallization of
this semi-pure material from benzene-methanol yields analytically
pure 2-hydroxy-5-(4'-fluorophenyl)- benzoic acid (m.p.
199.degree.-203.degree. C.).
When 4-(3'-chloro-4'-fluorophenyl)-phenol,
4-(2'-chloro-4'-fluorophenyl)- phenol,
4-(2',4'-difluorophenyl)-phenol and 4-(3'-fluorophenyl)-phenol
obtained from Example 5 and 4'-(2'-fluorophenyl)-phenol and
4-(pentafluorophenyl)-phenol obtained from Example 6 are used in
place of 4(4'-fluorophenyl)-phenol in the above example, there are
obtained the corresponding
2-hydroxy-5-(3'-chloro-4'-fluorophenyl)-benzoic acid,
2-hydroxy-5-(2' -chloro-4'-fluorophenyl)-benzoic acid,
2-hydroxy-5-(2',4'-difluorophenyl)-benzoic acid (m.p.
210.degree.-211.degree. C.), 2-hydroxy-5-(3'-fluorophenyl)-benzoic
acid (m.p. 196.degree.-197.degree. C.),
2-hydroxy-5-(2'-fluorophenyl)-benzoic acid (m.p.
201.degree.-203.degree. C.) and 2-hydroxy-5-
(pentafluorophenyl)-benzoic acid (m.p. 241.degree.-243.degree.
C.).
When the 3(or 4)-(substituted-phenyl) 2- or 3-alkyl, benzyl or halo
phenol compounds of Example 5 or the 2- or 3-alkyl, halo or alkoxy
phenol compounds of Example 6 are used in place of
4-(4'-fluoro-2'-methoxy- phenyl)-phenol in the above, there are
obtained 2-hydroxy-3-methyl-4(and
5)-(4'-fluoro-2'-methoxyphenyl)-benzoic acid,
2-hydroxy-3-ethyl-4(and 5)-(4'-fluoro-2'methoxyphenyl)-benzoic
acid, 2-hydroxy-3-methoxy-4(and
5)-(4'-fluoro-2'-methoxyphenyl)-benzoic acid,
2-hydroxy-3-3-ethoxy-4(and 5)-(4'-fluoro-2'-methoxyphenyl)-benzoic
acid, 2-hydroxy-3-chloro-4(and
5)-(4'-fluoro-2'-methoxyphenyl)-benzoic acid,
2-hydroxy-3-bromo-4(and 5)-(4'-fluoro-2'-methoxyphenyl)-benzoic
acid, 2-hydroxy-4-methyl-5-(4'- fluoro-2'-methoxyphenyl)-benzoic
acid, 2-hydroxy-4-ethyl-5-(4'-fluoro-2'- methoxyphenyl)-benzoic
acid, 2-hydroxy-4-methoxy-5-(4'-fluoro-2'- methoxyphenyl)-benzoic
acid, 2-hydroxy-4-ethoxy-5-(4'-fluoro-2'- methoxyphenyl)-benzoic
acid, 2-hydroxy-4-chloro-5-(4'-fluoro-2'- methoxyphenyl)-benzoic
acid, 2-hydroxy-4- bromo-5-(4'-fluoro-2'- methoxyphenyl)-benzoic
acid, 2-hydroxy-3-methyl-4(and
5)-(3'-chloro-4'-fluorophenyl)-benzoic acid,
2-hydroxy-3-ethyl-4(and 5)-(3'-chloro-4'-fluorophenyl)-benzoic
acid, 2-hydroxy-3-benzyl-4(and
5)-(3'-chloro-4'-fluorophenyl)-benzoic acid,
2-hydroxy-3-chloro-4(and 5)-(3'-chloro-4'-fluorophenyl)-benzoic
acid, 2-hydroxy-3-bromo-4(and
5)-(3'-chloro-4'-fluorophenyl)-benzoic acid,
2-hydroxy-3-chloro-4(and 5)-(3'-chloro-4'-fluorophenyl)-benzoic
acid, 2-hydroxy-3-bromo-4(and
5)-(3'-chloro-4'-fluoro-phenyl-benzoic acid,
2-hydroxy-4-methyl-5-(2'- chloro-4'-fluorophenyl)-benzoic acid,
2-hydroxy-4-ethyl-5-(2'-chloro-4'- fluorophenyl)-benzoic acid,
2-hydroxy-4-benzyl-5-(2'-chloro-4'- fluorophenyl)-benzoic acid,
2-hydroxy-4-chloro-5-(2'-chloro-4'- fluorophenyl)-benzoic acid, and
2-hydroxy-4-bromo-5-(2'-chloro4'- fluorophenyl)-benzoic acid,
respectively.
Similarly, when 2-methyl-4-(4'-fluorophenyl)-phenol obtained from
Example 6 is used in place of 4-(4'-fluorophenyl)-phenol in the
above example, there is obtained
2-hydroxy-5-(4'-fluorophenyl)-3-methyl-benzoic acid.
EXAMPLE 8 2-acetoxy-5-(4'-fluorophenyl)-benzoic acid
A solution of 3.0 g. of 2-hydroxy-5-(4'-fluorophenyl)-benzoic acid
in 12 ml. of pyridine and 8 ml. of acetic anhydride is heated on a
steam bath for 20 minutes. The mixture is then poured onto ice and
the product extracted with methylene chloride. The methylene
chloride solution is dried and then evaporated. The residue is
recrystallized from benzene to yield
2-acetoxy-5-(4'-fluorophenyl)-benzoic acid (m.p.
134.degree.-137.degree. C.).
When the 2-hydroxy-benzoic acid compounds obtained from Example 7
are used in place of 2-hydroxy-5-(4'-fluorophenyl)-benzoic acid in
the above example, there are obtained the corresponding
2-acetoxy-benzoic acid compounds.
Similarly, when propionic acid anhydride is used in place of acetic
anhydride, the corresponding 2-propionoxy compound is obtained.
EXAMPLE 9 2-acetoxy-5-(p-fluorophenyl)-benzoyl chloride
A mixture of 4.3 g. of 2-acetoxy-5-(p-fluorophenyl)-benzoic acid
and 40 ml. of thionyl chloride is refluxed for 30 minutes on the
steam bath. The reaction mixture is concentrated in vacuo, 50 ml.
benzene added and this solution reconcentrated in vacuo. The
resulting oil is dried under vacuum to give 4.4 gm. of
2-acetoxy-5-(p-fluorophenyl-benzoyl chloride.
When the 2-acetoxy-4(or 5)-(phenyl)-benzoic acids of Example 8 are
used in the above procedure the corresponding benzoyl chloride is
obtained.
EXAMPLE 10 4-acetoxy-3-diazomethylcarbonyl-4'-fluorobiphenyl
A solution of 4.4 g. of 2-acetoxy-5-(p-fluorophenyl)-benzoyl
chloride in 40 ml. of dry ether is added slowly to the diazomethane
prepared from 7.0 g. of N-nitrosomethylurea and contained in 350
ml. ether. The reaction mixture gradually becomes cloudy and is
allowed to stir overnight at room temperature. The mixture is then
concentrated to half volume, cooled and the precipitate collected
to give 2.4 g. of 4-acetoxy-3-
diazomethylcarbonyl-4'-fluorobiphenyl in two crops.
When any of the benzoyl chlorides of Example 9 are utilized in the
above procedure the corresponding diazoketone is obtained.
EXAMPLE 11 5-(p-Fluorophenyl)-2-hydroxyphenylacetic acid
A solution of 2.4 g. of 4-acetoxy-3-diazomethylcarbonyl-4'-
fluorobiphenyl in 25 ml. of warm dioxane is added slowly to a
mixture of 100 ml. water, 0.8 g. of silver oxide, 1.6. g. potassium
carbonate and 0.8 g. of sodium thiosulfate which has been heated to
65.degree.-70.degree.. The mixture is kept at 65.degree.-70.degree.
for 30 minutes after the addition is complete and then refluxed for
1-2 minutes. The reaction mixture is filtered while hot, cooled and
acidified with concentrated nitric acid. The precipitate is
filtered and air dried to give 829 mg. of crude product.
Recrystallization from toluene gives 0.54 g. of pure
5-(p-fluorophenyl)-2-hydroxyphenyl acetic acid.
When any of the diazoketones produced by the procedure of example
10 are utilized by the above procedure, there is obtained the
corresponding 4(or 5)-phenyl-2-hydroxyphenyl acetic acid.
EXAMPLE 12 Sodium-2-hydroxy-5-(4'-fluorophenyl)-phenylacetate
A mixture of 0.1 mole of 2-hydroxy-5-(4'-fluorophenyl)-phenylacetic
acid and 0.1 mole of sodium hydroxide in 100 ml. of water is
stirred at room temperature for one-half hour. The reaction mixture
is then concentrated in vacuo to yield
sodium-2-hydroxy-5-(4'-fluorophenyl)-phenylacetate.
When the phenylacetic acid compounds obtained from Example 11 are
used in place of the 2-hydroxy-5-(4'-fluorophenyl)-phenylacetic
acid in the above example, there are obtained the corresponding
sodium salts.
Similarly, when choline, glucosamine, S-methyl-methionine,
potassium hydroxide, ammonium hydroxide, barium hydroxide, calcium
hydroxide, piperazine, chloroquine, hydroxychloroquine,
dimethylaminoethanol, and magnesium hydroxide, are used in place of
sodium hydroxide in the above example, there are obtained the
corresponding choline, glucoasmine, S-methyl-methionine, potassium,
ammonium, barium, calcium, piperazine, chloroquine,
hydroxychloroquine, dimethylaminoethanol and magnesium salts,
respectively.
EXAMPLE 13 A.
methyl-2-hydroxy-5-(4'-fluorophenyl)-phenylacetate
A solution of 0.01 mole of
2-hydroxy-5-(4'-fluorophenyl)-phenylacetic acid in 20 ml. of
methanol and 2 ml. of concentrated sulfuric acid is heated at
reflux for 5 hours. The mixture is then cooled and partitioned
between (75:150 ml.) water and ethyl acetate and the organic layer
washed with dilute sodium bicarbonate solution. The organic layer
is then dried over magnesium sulfate and concentrated in vacuo to
yield methyl-2-hydroxy-5-(4'-fluorophenyl)-phenylacetate.
When the phenylacetic acid compounds obtained from Example 11 are
used in place of 2-hydroxy-5-(4'-fluorophenyl)-phenylacetic acid in
the above example, there are obtained the corresponding methyl
esters.
Similarly, when ethanol and n-butanol are used in place of methanol
in the above example, there are obtained the corresponding ethyl
and n-butyl esters. B. phenyl
2-hydroxy-5-(4'-fluorophenyl)-phenylacetate
A mixture of 0.01 mole of
2-hydroxy-5-(4'-fluorophenyl)-phenylacetic acid, 2.8 g. of phenol
and 1.7 g. of phosphorus oxychloride is heated at 114.degree. C.
until no more hydrogen chloride is evolved. The reaction mixture is
cooled to room temperature and filtered. The resulting solid
material is digested in dilute sodium carbonate solution, filtered,
washed with water, dried and recrystallized from isopropyl alcohol
to yield phenyl 2-hydroxy-5-(4'-fluorophenyl)-phenylacetate.
Following the above procedure but using an equivalent amount of
2-acetoxy-5-(4'-fluorophenyl)-phenylacetic acid in place of
2-hydroxy-5(4'-fluorophenyl)-phenylacetic acid, there is obtained
phenyl 2-acetoxy-5-(4'-fluorophenyl)-phenylacetate. C.
.beta.-diethylaminoethyl
2-hydroxy-5-(4'-fluorophenyl)-phenylacetate hydrochloride
A mixture of (0.0175 mole) of
2-hydroxy-5-(4'-fluorophenyl)-phenylacetic acid, 2.4 g. of
potassium carbonate in 50 ml. of isopropanol is refluxed for
one-half hour 3.0 g. (0.0175 m.) of
.beta.-diethylaminoethylchloride. HCl is added and the mixture
refluxed with stirring for 15 hours. The reaction mixture is then
distributed between water and ethyl ether. The ether layer is then
washed with water, dried and evaporated to a small volume. Dry
hydrogen chloride gas is then passed into the ether solution and
the resulting precipitate is filtered and recrystallized from
acetone/ethyl ether to yield .beta.-diethylaminoethyl
2-hydroxy-5-(4'-fluorophenyl)-phenylacetate hydrochloride.
EXAMPLE 14
N,n-dimethyl-2-hydroxy-5-(4'-fluorophenyl)-phenylacetamide
A mixture of 0.01 mole of methyl-2-hydroxy-5-(4'-fluorophenyl)-
phenylacetate and 20 ml. of dimethylamine is reacted in a bomb at
100.degree. C. for 4 hours. After cooling, the bomb is opened and
the excess dimethylamine removed. The residue is then
recrystallized from benzene to yield
N,N-dimethyl-2-hydroxy-5-(4'-fluorophenyl)- phenylacetamide.
When the phenylacetic acid methyl esters obtained from Example 13
are used in place of methyl-2-hydroxy-5-(4'-fluorophenyl)-benzoate
in the above example, there are obtained the corresponding
N,N-dimethyl- benzamide compounds.
EXAMPLE 15 Anhydride of 2-acetoxy-4-(4'-fluorophenyl)-phenylacetic
acid
A solution of 0.01 mole of
2-acetoxy-4-(4'-fluorophenyl)-phenylacetic acid and 0.01 mole of
thionyl chloride in 30 ml. of dry benzene is warmed until the
formation of the substituted benzoyl chloride is complete. The
resulting solution is concentrated to one-half volume in vacuo and
is added to a solution of 0.01 mole of
2-acetoxy-4-(4'-fluorophenyl)- phenylacetic acid and 0.01 mole of
pyridine in 30 ml. of benzene. The mixture is stirred at room
temperature overnight, filtered, and the filtrate washed with cold
dilute sodium bicarbonate solution. After drying and removal of
benzene, the product is recrystallized from benzene-hexane.
Alternatively, the anhydride may be formed by reacting for 5 hours
at room temperature 0.02 mole of
2-acetoxy-4-(4'-fluorophenyl)-phenylacetic acid and 0.01 mole of
dicyclohexylcarbodiimide in 20 parts of tetrahydrofuran, followed
by filtration and concentration of the filtrate to yield the
anhydride.
When a solution of 2-acetoxy phenylacetic acid in pyridine is used
in place of the 2-acetoxy-4-(4'-fluorophenyl)-phenylacetic acid
pyridine solution in the above example, there is obtained the
mixture anhydride of 2-acetoxy-4-(4'-fluorophenyl)-phenylacetic
acid and 2-acetoxy phenylacetic acid.
EXAMPLE 16
A dry filled capsule is prepared from the following components:
2-acetoxy- 5-(4'-fluorophenyl)phenylacetic acid 300 mg. corn starch
150 mg. Cab-o-sil 5 mg. Sterotix 15 mg.
A dry filled capsule can be prepared by using the following
compounds as active ingredients instead of
2-acetoxy-5-(4'-fluorophenyl)-phenylacetic acid: 2-hydroxy-4(or
5)-(4'-fluorophenyl)-phenylacetic acid; 2-acetoxy-4(or
5)-(2',4'-difluorophenyl)-phenylacetic acid;
2-hydroxy-3-methyl-4(or 5)-(4'-fluorophenyl)-phenylacetic acid;
phenyl 4(or 5)-(4'-fluorophenyl)-2-hydroxy phenylacetate;
2-hydroxy-4(or 5)-(3'-fluorophenyl)-phenylacetic acid; or any other
preferred compounds as shown in the specification.
If capsules of lower potency are to be made, the capsule size could
be reduced or the quantity of corn starch could be increased.
EXAMPLE 17
Compressed tablets are prepared with the following components:
2-acetoxy- 5-(4'-fluorophenyl)-phenylacetic acid 300 mg. cornstarch
30 mg. polyvinylpyrrolidone 10 mg. magnesium stearate 3 mg.
Tablets as above can be prepared by using the following compounds
as active ingredients instead of
2-acetoxy-5-(4'-fluorophenyl)-phenylacetic acid: 2-hydroxy-4(or
5)-(4'-fluorophenyl)-phenylacetic acid; 2-acetoxy-4(or
5)-(2',4'-difluorophenyl)-phenylacetic acid;
2-hydroxy-3-methyl-4(or 5)-(4'-fluorophenyl)-phenylacetic acid;
phenyl 4(or 5)-(4'-fluorophenyl)-2-hydroxy phenylacetate; -hydroxy
2-hydroxy-4(or 5)-(3'-fluorophenyl)-phenylacetic acid; or any other
especially preferred compound as shown in the specification.
Tablets of other potentials would be made by altering the tablet
size as necessary.
* * * * *