U.S. patent number 3,624,142 [Application Number 04/395,553] was granted by the patent office on 1971-11-30 for substituted biphenyl acetic acid derivatives.
This patent grant is currently assigned to Merck & Co., Inc.. Invention is credited to Conrad P. Dorn, Jr., Tsung-Ying Shen, Bruce E. Witzel.
United States Patent |
3,624,142 |
Shen , et al. |
November 30, 1971 |
SUBSTITUTED BIPHENYL ACETIC ACID DERIVATIVES
Abstract
The invention relates to new substituted biphenyl acetic acids
and derivatives thereof. These novel compounds are useful as
antiinflammatory agents and for the control of arthritic
conditions.
Inventors: |
Shen; Tsung-Ying (Westfield,
NJ), Dorn, Jr.; Conrad P. (Plainfield, NJ), Witzel; Bruce
E. (Rahway, NJ) |
Assignee: |
Merck & Co., Inc. (Rahway,
NJ)
|
Family
ID: |
23563534 |
Appl.
No.: |
04/395,553 |
Filed: |
September 10, 1964 |
Current U.S.
Class: |
562/492; 546/226;
534/556; 544/165; 544/176; 548/379.4; 548/540; 548/558; 558/414;
560/12; 560/19; 560/48; 560/81; 562/418; 562/429; 562/435; 562/443;
562/459; 562/532; 564/139; 568/42; 568/306; 568/807; 250/396R;
544/159; 544/169; 544/403; 548/518; 548/557; 548/568; 560/9;
560/13; 560/21; 560/59; 560/101; 562/426; 562/430; 562/457;
562/469; 564/87; 568/31; 568/63; 568/331 |
Current CPC
Class: |
C07C
255/35 (20130101); C07C 309/58 (20130101); C07C
49/784 (20130101); C07C 323/62 (20130101); C07C
49/784 (20130101); C07C 49/813 (20130101); C07C
47/24 (20130101); C07C 311/16 (20130101); C07C
49/813 (20130101); C07C 255/57 (20130101); C07C
233/65 (20130101); C07C 233/54 (20130101); C07C
317/44 (20130101); C07C 323/62 (20130101); C07C
45/004 (20130101); C07C 57/62 (20130101); C07C
317/44 (20130101); C07C 319/02 (20130101); C07C
253/00 (20130101); C07C 253/00 (20130101); C07C
45/46 (20130101); C07C 303/38 (20130101); C07C
45/46 (20130101); C07C 205/56 (20130101); C07C
303/16 (20130101); C07C 315/02 (20130101); C07C
253/30 (20130101); C07C 45/004 (20130101); C07C
45/41 (20130101); C07C 45/46 (20130101); C07C
59/56 (20130101); C07C 205/45 (20130101); C07C
319/14 (20130101); C07C 45/41 (20130101); C07C
205/57 (20130101); C07C 231/02 (20130101); C07C
303/38 (20130101); C07C 319/02 (20130101); C07C
57/58 (20130101); C07D 231/06 (20130101); C07C
253/30 (20130101); C07C 303/16 (20130101); C07C
57/38 (20130101); C07C 231/02 (20130101); C07C
323/62 (20130101); C07C 231/02 (20130101); C07C
45/004 (20130101); C07C 315/02 (20130101); C07C
319/14 (20130101) |
Current International
Class: |
C07C
57/38 (20060101); C07C 59/00 (20060101); C07C
59/56 (20060101); C07C 57/00 (20060101); C07C
57/62 (20060101); C07C 57/58 (20060101); C07C
17/00 (20060101); C07D 231/00 (20060101); C07D
231/06 (20060101); C07C 205/00 (20060101); C07C
205/56 (20060101); C07C 205/57 (20060101); C07c
063/52 (); C07c 069/76 () |
Field of
Search: |
;260/515,469 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
1,152,761 |
|
Feb 1958 |
|
FR |
|
316,252 |
|
Jan 1961 |
|
IT |
|
Other References
Blicke, F. F. et al.: J.A.C.S., vol. 65, 1943, pp. 1725-1778 .
Cavallini (4), G. et al.: J.A.C.S., vol. 81, 1959, pp.
2564-2567.
|
Primary Examiner: Patten; James A.
Claims
We claim:
1. A compound of the formula ##SPC10##
where
X is COOH or COOR (where R is methyl or diethylaminoethyl);
R.sub.1 is hydrogen;
R.sub.2 is lower alkyl;
R.sub.3 and R.sub.4 are fluoro; and
n and m are 0 to 1; no more than one of n and m is to be zero at
any one time.
2. A compound according to claim 1 where
X is COOH;
R.sub.1 is hydrogen;
R.sub.2 is lower alkyl;
R.sub.4 is fluoro;
m is 0; and
n is 1.
3. .alpha.-Methyl-4'-fluoro-4-biphenylacetic acid.
Description
This invention relates to new biphenyl aliphatic acids, aldehydes,
alcohols, and derivatives thereof and to methods of preparation of
the same. More specifically, this invention relates to
substituted-biphenylacetic acids and the esters and amides thereof
as well as to the corresponding aldehydes, alcohols, acetals,
ethers, and the nontoxic salts thereof. More specifically, also,
the compounds embraced within the scope of the present invention
may be represented by the following structural formulas:
##SPC1##
Wherein:
R' is halogen, lower alkoxy (such as methoxy, ethoxy, propoxy, and
the like), or lower alkyl (such as methyl, ethyl, butyl, and the
like);
R" is hydrogen, or lower alkyl when R' is also lower alkyl;
R.sub.1 is hydrogen;
R.sub.2 is lower alkyl, lower alkenyl, lower alkynyl, halo lower
alkyl, and when R.sub.1 and R.sub.2 are taken together, are
methylene, ethylidene, or form with the .alpha.-carbon a
cyclopropyl group;
R.sub.3 and R.sub.4 may be hydrogen, lower alkyl (such as methyl,
ethyl, propyl, butyl, and the like), halogen, trihalomethyl, lower
alkylthio, mercapto, amino, di(lower alkyl)amino (such as
dimethylamino, dipropylamino, ethylmethylamino, ethylbutylamino,
and the like), cyano, nitro, carboxamido, di(lower alkyl) carbamyl,
lower alkanoylamino, lower alkylsulfonyl, di(lower alkyl)sulfamyl
(such as dimethylsulfamyl, dipropylsulfamyl, methylpropylsulfamyl,
ethylbutylsulfamyl, and the like), phenyl, trifluoracetyl, acetyl,
or trifluoromethylthio. In formulas I, II, and III, at least one of
R.sub.3 and R.sub.4 must be other than hydrogen at any one time,
whereas in formula IV, R.sub.3 and R.sub.4 may be hydrogen as well
as any of the other groups.
n and m are each a number from 0 to 2; no more than one of n and m
is to be zero at any one time, and in addition, when one of n or m
is 2, the other may be no more than 1.
X may be COOH; COOR, wherein R may be lower alkyl, lower alkenyl
(such as prop-2-en, but-3-en, and the like), lower alkynyl (such as
prop-2-yn, pent-3-yn), cyclo lower alkyl (such as cyclopropyl,
cyclobutyl, cyclopentyl, and the like), phenyl, lower
alkanoylaminophenyl, carboxyphenyl, carboxamidophenyl, lower alkoxy
lower alkyl (such as methoxymethyl, ethoxymethyl, methoxyethyl,
ethoxyethyl, and the like), poly lower alkoxy lower alkyl (such as
dimethoxypropyl, diethoxypropyl, and the like), poly hydroxy lower
alkyl (such as 1,4-dihydroxybutyl, 2,3-dihydroxypropyl, and the
like), di(lower alkyl)amino lower alkyl (such as
dimethylaminoethyl, diethylaminoethyl, diethylaminobutyl, and the
like);
lower alkyl, hydroxy lower alkyl (such as hydroxyethyl,
3-hydroxypropyl, 3-hydroxybutyl, and the like), poly hydroxy lower
alkyl (such as dihydroxypropyl, dihydroxypentyl, and the like),
phenyl lower alkyl (such as phenylethyl, phenylpropyl, phenylbutyl,
and the like), phenyl, lower alkoxyphenyl (such as methoxyphenyl,
ethoxyphenyl, propoxyphenyl, and the like), halogenophenyl (such as
chlorophenyl, fluorophenyl, and the like), trifluoromethylphenyl,
cyclohexyl, carboxymethyl, 1-carboxyl-3-carbamylpropyl, N-dilower
alkyl carboxamidomethyl (such as N,N-dimethylcarboxamidomethyl,
N,N-dipropylcarboxamidomethyl, N,N,-diethylbutylcarboxamidomethyl,
and the like), N,N-dilower alkylamino lower alkyl (such as
dimethylaminoethyl, ethylbutylaminoethyl, and the like), N-lower
alkyl pyrrolidyl (such as N-methyl-3-pyrrolidyl,
N-ethyl-3-pyrrolidyl, and the like), N-lower alkyl pyrrolidyl lower
alkyl (such as N-ethyl-2-pyrrolidylmethyl,
N-methyl-3-pyrrolidylmethyl, and the like), or Y may form a
heterocyclic group with the nitrogen when Y is the group --CH.sub.2
--CH.sub.2 --O--CH.sub.2 --CH.sub.2 --,
in which R.sub.5 is lower alkyl (such as methyl, ethyl, propyl,
butyl, and the like), --CH.sub.2 --CH.sub.2 --NH--CH.sub.2
--CH.sub.2 --,
--ch.sub.2 --ch.sub.2 --n--ch.sub.2 --ch.sub.2 --, and CH.sub.2
--CH.sub.2 OH --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2
--CH.sub.2 --; CH.sub.2 OH; CH.sub.2 OR.sub.6 where R.sub.6 is
alkyl (such as ethyl, propyl, butyl, pentyl, and the like); CHO;
CH(OR.sub.7).sub.2 where R.sub.7 is alkyl (such as ethyl, propyl,
butyl, pentyl, and the like); and the pharmaceutically nontoxic
salts of the acid. These salts may be the ammonium, alkali and
alkali earth, amine, magnesium, aluminum, iron salts and the
like.
In the preferred aspects of this invention, X is COOH or COOR
(where R is methyl, diethylaminoethyl, and the like), but
especially COOH; R.sub.2 is hydrogen or lower alkyl (methyl, ethyl,
pentyl, and the like); R.sub.1 is hydrogen; R.sub.3 and R.sub.4 are
hydrogen, halogen (chloro, fluoro, and bromo), lower alkyl (methyl,
ethyl, butyl), or trifluoromethyl, but especially a halogen (chloro
and fluoro); n and m are 0 to 1; R' is fluoro or R' and R"
together, lower alkyl, but especially fluoro.
Representative compounds encompassed within the scope of the
present invention include 2-chloro-4-biphenylacetic acid,
2-methyl-4-biphenylacetic acid, 4'-chloro-4-biphenylacetic acid,
4'-bromo-4-biphenylacetic acid, 4'-fluoro-4-biphenylacetic acid,
.alpha.-methyl-2-chloro-4-biphenylacetic acid,
.alpha.-methyl-4'-fluoro-4-biphenylacetic acid,
.alpha.-methyl-2'-chloro-4-biphenylacetic acid,
.alpha.-trifluoro-methyl-4-biphenylacetic acid,
.alpha.-trifluoromethyl-4'-fluoro-4-biphenylacetic acid, and
.alpha.-trifluoromethyl-2'-chloro-4-biphenylacetic acid.
We have found that the compounds described above have a high degree
of anti-inflammatory activity and are effective in the prevention
and inhibition of granuloma tissue formation. Certain of them
possess this activity in high degree and are of value in the
treatment of arthritic and dermatological disorders and in like
conditions which are responsive to treatment with antiinflammatory
agents. For these purposes, they are normally administered orally
in tablets or capsules, the optimum dosage depending, of course, on
the particular compound being used and the type and severity of the
condition being treated. Although the optimum quantities of these
compounds of this invention to be used in such manner will depend
on the compound employed and the particular type of disease
condition treated, oral dose levels of preferred compounds in the
range of 1-2000 mg. per day are useful in control of arthritic
conditions, depending on the activity of the specific compound and
the reaction sensitivity of the patient.
The .alpha.-substituted biphenylacetic acid compounds of the
invention possessing an asymmetric carbon atom are ordinarily
present in the form of a racemic mixture. The resolution of such
racemates can be carried out by a vast number of known methods.
Thus, some racemic mixtures can be precipitated as eutectics
instead of mixed crystals and can thus be quickly separated and in
such cases can sometimes be selectively precipitated. The more
common method of chemical resolution is, however, greatly
preferred. By this method diastereomers are formed from the racemic
mixture by reaction with an optically active resolving agent. Thus,
an optically active base can be reacted with the carboxyl group.
The difference in solubility between the diastereomers formed
permits the selective crystallization of one form and regeneration
of the optically active acid from the mixture. There is, however, a
third method of resolving which shows great promise. This is one or
the other forms of biochemical procedures using selective enzymatic
reaction. Thus, the racemic acid can be subjected to an asymmetric
oxidase or decarboxylase which will, by oxidation or
decarboxylation, destroy one form, leaving the other form
unchanged. Even more attractive is the use of a hydroylsase on a
derivative of the racemic mixture to form preferentially one form
of the acid. Thus, esters or amides of the acids can be subjected
to an esterase which will selectively saponify one enantiomorph and
leave the other unchanged.
When the free acid is resolved into (d) and (1) enantiomorphs, the
anti-inflammatory activity is found to reside virtually completely
in the (ti d) isomer. The desired (d) isomer of the free acid may
be prepared by any one of the preceding described resolving
methods, preferably working from the free acid as the starting
material. For example, amide or salt disastereomers of the free
acid may be formed with optically active amines, such as quinine,
brucine, cinchonidine, cinchonine, hydroxyhydrindamine,
methylamine, morphine, .alpha.-phenylethylamine,
phenyloxynaphthylmethylamine, quinidine, 1-fenchylamine,
strychnine, basic amino acids such as lysine, arginine, amino acid
esters, and the like. Similarly, ester diastereomers of the free
acid may be formed with optically active alcohols, such as borneol,
menthol, 2-octanol and the like. Especially preferred is the use of
cinchonidine to give the readily decomposable diastereomer salt
which may then be resolved by dissolving in a solvent. such as
acetone, and distilling the solvent at atmospheric pressure until
crystals begin to appear and further crystallization produced by
allowing the mixture to cool to room temperature, thereby
separating the two enantiomorphs. The (d) acid may then be
recovered from its salt by partitioning the salt between an organic
solvent, such as benzene or ether, and dilute hydrochloric
acid.
Derivatives of the resolved (d) form the free acid then may be
prepared in the usual way. These derivatives generally are more
active than racemates of the same compounds. Consequently, the (d)
form of these compounds, substantially free of the (1) form, is a
still further aspect of this invention.
For purposes of further clarity, the preparation of the compounds
of this invention will be discussed under four separate areas. Each
area will refer to the structural formulas I, II, III, or IV
previously described.
Structural Formula I
The compounds of structural formula I, wherein X is COOH, may be
prepared by two separate syntheses (designated as processes A and
B) from the known p-phenylacetophenone compounds of the structural
formula: ##SPC2## The nitro substituent on the ketone compound may
be converted to the desired R.sub.3 and R.sub.4 group by an
appropriate series of known reactions. This conversion is carried
out at various steps of the synthesis, depending upon the effect
upon the substituent during the reactions to the final acetic acid
compound. At whatever stage the conversion is carried out, the
procedure is similar. For example, using the nitro ketone, the
nitro group may be reduced such as, in the presence of palladium
under an atmosphere of hydrogen to form the amino group. The amino
group may be reacted with an organic halide, such as methyl iodide,
to form the mono- or disubstituted amino group, or it may be
acylated (using an alkanoic acid, halide or anhydride) to form an
alkanoylamino group. The amino group may also be diazotized and the
diazo replaced by a hydroxyl group, which, in turn, may be
alkylated to form an alkoxy group. The diazonium salt derived from
the amino group may also be treated with ethyl xanthate followed by
saponification of the xanthate under alkaline conditions to give
the mercapto group, which, if desired, may then be alkylated with a
dialkyl sulfate or alkyl halide to the alkyl mercapto group. The
alkyl mercapto group may be oxidized, for example, with potassium
permanganate in alkaline solution, to the alkylsulfonyl group. In
addition the mercapto group may be oxidized to a sulfonic acid
group which may be treated with thionyl chloride and an amine to
obtain the di(alkyl)sulfonamides. Also the diazonium compound may
be reacted with a cuprous halide in the cold under acid conditions
to form a halide group, or it may be reacted with cuprous cyanide
to form a cyano group, which may then be subjected to acid
hydrolysis to form a carboxamido group.
The trifluoromethyl group may be formed from a carboxyl group.
After the formation of the biphenylacetic acid, the acid side chain
is converted to the ester or tertiary amide. This compound is then
reacted to obtain a cyano group on the phenyl ring. The cyano is
converted to the carboxyl group via an imido ester which is treated
with sulfur tetrafluoride and converted to the trifluoromethyl
group. The protected side chain may then be converted to the acid
by hydrolysis. In addition, the carboxyl group may be converted to
the acid halide with thionyl halide, subsequently reduced to the
aldehyde group, further reduced to the hydroxymethyl group, which
is converted to the chloromethyl group, which group may then be
converted to a methyl substituent. If other lower alkyl
substituents are desired, the aldehydo group may be converted to a
lower alkene by means of a Wittig reaction using the appropriately
substituted triphenylphosphorane compound, and the lower alkene
then reduced to the desired lower alkyl substituent. This
preparation of the lower alkyl group is carried out on the acetic
acid ester compound and the ester subsequently hydrolyzed or
saponified to the final desired acid.
When more than one substituent is to be present and each is to be
the same group, the conversion from the nitro compound is carried
out with multiple nitro substituents. However, when different
substituents are desired, the ketone containing less than three
nitro groups may either be converted to the desired group or groups
followed by nitration of the compound obtained and subsequent
reaction of the nitro to obtain mixed substituents on the biphenyl
ring, or, the desired ketone may be prepared from an appropriately
substituted benzene and a substituted bromo aniline compound. In
this method, the amino group on the aniline is used to form the
biphenyl moiety and the bromo group on the aniline is used to form
the ketone moiety. For example, 2-chloro-4-bromoaniline and
fluorobenzene are refluxed with i-amyl nitrite to form a mixture of
the 4-bromo-2-chloro-4'-fluorobiphenyl and the 2'-fluorobiphenyl
compounds. Either biphenyl compound may be reacted with magnesium
in an inert solvent to obtain the Grignard reagent. This compound
is then treated with cadmium chloride to obtain the corresponding
diphenyl cadmium compound. This compound is then treated with a
lower alkyl acid chloride to give the corresponding ketone. This
procedure can also be used to prepare the starting ketone
containing a lower alkyl group, or a trihalomethyl group, by using
the appropriately substituted benzene and/or aniline compound as
starting material.
When R.sub.4 is to be a phenyl group, still another procedure is
employed. For example, p-terphenyl or an appropriately substituted
terphenyl with at least one of the end rings unsubstituted, is
reacted with acetyl chloride under Friedel-Crafts conditions to
form a p-biphenyl-acetophenone.
The appropriately substituted p-phenylacetophenones, obtained as
described above, may then be converted to the desired acid of
formula I, by one of two processes: ##SPC3##
In this process, the p-phenylacetophenone may be reacted with
ammonium polysulfide in an inert solvent, such as dioxane or
pyridine, at elevated temperatures under pressure for at least
several hours to obtain the desired acid. Alternatively, it is
preferred to carry out this step in an organic amine with sulfur at
elevated temperatures and subsequent hydrolysis at any suitable
temperature of the thioamide formed with an alkali or alkali earth
base. The preferred amines which are used as solvents in this
reaction are generally dimethylamine, morpholine, methylamine,
piperidine, and anhydrous ammonia, especially morpholine. The
reaction may be carried out at any suitable elevated temperature,
preferably at or near the reflux temperature of the system. (With
low boiling amines, a bomb is used). The subsequent hydrolysis may
preferably be carried out with such bases as sodium hydroxide or
potassium hydroxide at elevated temperatures.
When groups which are easily reduced or oxidized are desired-- such
as the nitro, amino, and cyano groups--the biphenylacetic acid is
prepared first followed by appropriate reactions on the acid
compound. For example, the nitro, amino, or cyano
substituted-biphenylacetic acid compound may be prepared by
nitration of the unsubstituted biphenylacetic acid and subsequent
reaction to the desired amino or cyano group. The nitration may be
carried out in sulfuric acid with fuming nitric acid at low
temperatures, such as -5.degree. to +10.degree. C., preferably at
or around 0.degree. C.; or with fuming nitric acid alone or with
concentrated nitric acid at low temperatures (-15.degree. to
10.degree. C.), preferably -5.degree. to 0.degree. C.; or with
fuming nitric acid in acetic acid at low temperatures, or by any
other known conditions which will afford the appropriate nitration.
The nitro compound may then be catalytically reduced to the amino
group. Such catalysts as platinum and palladium and the like are
representative of this catalytic reduction. The amine may be
diazotized by well-known methods and the diazo compound reacted
with a cyanide salt, such as cuprous cyanide, to form the desired
cyano group.
Process B
The alternative preparation of these .alpha.-unsubstituted acids of
formula I may be illustrated as follows: ##SPC4##
In this process, the acetophenone compound (Step 1) is reacted with
an alkali hypohalite followed by treatment of the reaction mixture
with sulfur dioxide and acidification of the solution to
precipitate a p-phenylbenzoic acid compound. In Step 2, the acid is
converted to its acid halide by well-known means, e.g., reaction
with a thionyl halide in an inert solvent. The acid halide is
subsequently treated with a solution of ethereal diazomethane to
form the corresponding diazoketone (Step 3). This diazo compound is
then reacted with silver oxide in alcohol (Step 4) to form the
corresponding biphenylacetic ester. The ester is then converted by
any known means to the desired biphenylacetic acid compound (Step
5). Alternatively, the diazoketone may be reacted with silver oxide
in H.sub.2 O to form the free acid compound directly.
In this synthesis, only the acetophenone compounds containing the
halogen, trifluoromethyl nitro, di(lower alkyl)sulfonyl, or
di(lower alkyl)carboxamido may be used as the starting material and
maintained throughout the subsequent reactions. When it is desired
to obtain any other R.sub.3 or R.sub.4 group, the nitro
acetophenone compounds may be used as the starting material and the
nitro substituent converted to the desired group at the acetic acid
stage of the synthesis (Step 4 or 5) employing the appropriate
reactions, as previously described. However, such groups as cyano,
benzylthio, or lower alkylthio may also be placed on the ring by
appropriate conversion of the nitro group at any stage of the
synthesis from the benzoic acid compound to the final acetic acid
compound.
Reactions and Conditions of Process B
Step 1.
Reaction with an alkali or alkali earth hypohalite, such as sodium
hypobromite, potassium hypochlorite, and the like, especially
sodium hypobromite, with or without an inert solvent at any
suitable temperature (R.T. to reflux), preferably at or near the
reflux temperature of the solvent; consumption of the excess
hypohalite with any suitable reducing agent, preferably sulfur
dioxide, followed by acidification of the reaction mixture with any
suitable acid, such as a mineral acid (hydrohalic acid, sulfuric
acid, and the like), preferably dilute hydrochloric acid; the
reaction is preferably carried out in an inert solvent; suitable
solvents are dioxane, ethers (dimethoxyethane, tetrahydrofuran),
alcohols, and the like, preferably dioxane.
Step 2.
Reaction by any known means, such as reaction with an acid halide
of an inorganic acid, such as thionyl chloride, phosphorus
pentachloride, phosphorus oxychloride, phosphorus trichloride, and
the like, preferably thionyl chloride in an inert solvent [ethers,
chloroform, aromatic solvents (benzene, toluene) and the like],
preferably chloroform or ethers at any suitable temperature
(0.degree. -reflux), preferably at elevated temperatures, but
especially at or near the reflux temperature of the system.
Step 3.
Reaction with diazomethane in an inert solvent, such as ethers,
chloroform, aromatic solvents (benzene, toluene) and the like,
preferably ether, (THF) tetrahydrofuran or chloroform, but
especially ether at any suitable temperature (R.T. or below),
preferably 0.degree. to -5.degree. C.
Step 4.
Reaction with an alcohol and a catalyst, such as silver oxide,
copper, or platinum, preferably silver oxide, either in the alcohol
as solvent also or in an inert solvent, such as aromatic solvents,
ethers, and the like, preferably using the alcohol as solvent, at
any suitable temperature (R.T. to reflux), preferably at elevated
temperatures, but especially at elevated temperatures, but
especially at or near the reflux temperature of the system.
Step 5.
Saponification or hydrolysis by any known means, such as reaction
with a base and subsequent neutralization of the mixture with a
mineral acid.
Step 6.
Same as step (4) except an inert solvent, such as dioxane, is used
and water is used in place of the alcohol.
In reaction step (1), the excess hypohalite is consumed prior to
acidification of the reaction mixture; however, this is not
necessary, and acidification may be carried out directly. The
amount of hypohalite and/or acid used is not critical; only the
yield of the desired acid will be affected by changing amount of
either of them.
Reaction step (2) is a common reaction of converting an acid to an
acid halide, and although a method has been indicated, many other
methods well known in the art may also be employed.
Step (3) in the above illustration is carried out by reacting the
acid halide, preferably the acid chloride, in an inert solvent with
a solution of an excess of diazomethane in an inert solvent. The
inert solvent used is not critical; therefore, any solvent inert to
the reactants, such as aromatic solvents (benzene, toluene) or
various ethers, may be used. It is preferred, however, to use ether
or THF. In order to avoid side reactions and loss of yield, the
acid halide-inert solvent mixture is generally added to an excess
of diazomethane solution at reduced temperatures. However, any
molar ratio of diazomethane and the acid halide, low temperatures
to slightly elevated temperatures, are within the contemplation of
this invention. This reaction step is preferably carried out at
0.degree. to -5.degree. C., adding the acid chloride-ether solution
to at least 3 moles of a solution of diazomethane in ether.
In reaction step (4), it is highly preferred as a safety precaution
to first remove the excess diazomethane from the previous step.
Almost any alcohol may be used in this step, and generally the
alcohol which will yield the desired ester, as described in this
invention, is used. When the alcohol is also suitable as a solvent,
it is preferred over the use of an inert solvent; however, when
solubility or other factors dictate the use of an inert solvent,
the results are the same. The amount of alcohol is not critical and
will only determine the extent of ester formation.
In reaction step (5), any of the many well-known methods of
converting an ester to an acid may be used; the method indicated is
only one of such methods.
Preparation of Compounds of Structural Formula II
The compounds of structural formula II, wherein X is COOH and
R.sub.3 and R.sub.4 are as previously defined, may be prepared by
two separate syntheses (designated as process A and B) from a
ketone compound of the formula: ##SPC5##
The compounds of formula II require the starting ketone to be
methyl, when the .alpha.-methyl compound is desired and higher
alkyl groups when compounds other than .alpha.-methyl are desired,
such as .alpha.-ethyl and .alpha.-butyl. Therefore, the procedures
described in the literature for the preparation of the p-phenyl
acetophenone nitro compounds are used, varying the reactants, to
obtain the proper ketone compound. For example, when a nitro
biphenyl compound is used, and a lower alkyl is desired other than
.alpha.-methyl a lower alkanoic acid halide other than an acetyl
halide as described in the literature, is reacted with the biphenyl
under Friedel-Crafts conditions to obtain the desired ketone
compound, or, as described in the literature, known biphenyl
ketones may be nitrated in the appropriate positions to obtain
other nitro substituted biphenyl lower ketones.
In the first process (Process A), the appropriately substituted
ketone is converted to a cyanohydrin, which is treated with a
mineral acid to form a hydroxy amide. The The hydroxy amide is then
converted to the hydroxy acid compound. The hydroxy acid may then
either be converted directly to the desired .alpha.-lower alkyl
acetic acid compound or first to the .alpha.-alkylidene acetic
acids of this invention, which may then be converted to the
.alpha.-cyclopropyl or .alpha.-pyrrolizino acetic acids (using the
.alpha.-methylene compound when the latter two groups are desired)
or to the .alpha.-lower alkyl acetic acid. This process is used to
prepare the compounds of structural formula II excepting the
.alpha.-halo lower alkyl, .alpha.-alkene and .alpha.-alkyne,
process B is used for this purpose. This process may be illustrated
as follows: ##SPC6##
Equivalents
R.sub.3 and R.sub.4 are as previously indicated, excepting such
groups as later indicated.
Reactions and Conditions
Step 1.
Reaction with a cyano compound, such as sodium cyanide, potassium
cyanide, hydrogen cyanide, lower ketone cyanohydrin, and the like
[preferably hydrogen cyanide with an amine such as a primary,
secondary, or tertiary aliphatic amine (ethylamine, propylamine,
diethylamine, and trimethylamine, piperidine)] in a solvent such as
lower alkanols (methanol, ethanol, propanol, and the like), liquid
hydrogen cyanide ethers, dioxane, tetrahydrofuran, water, mixtures
of water and the above organic solvents, lower alkanoic acids
(acetic, propionic, and the like), and mixtures of the acids and
above solvents, preferably, however, using liquid hydrogen cyanide
as the reactant as well as the solvent, at any suitable
temperature, preferably -10.degree.-25.degree. C., but especially
0.degree.-5.degree. C., until the reaction is substantially
complete.
Step 2.
Reaction with a mineral acid (hydrogen chloride, hydrogen bromide,
sulfuric acid, phosphoric acid, and the like, preferably fortified
hydrochloric acid) in an inert solvent, such as lower alkanols
(methanol, ethanol, propanol), ether, dioxane, tetrahydrofuran, and
the like, preferably employing the acid as the solvent also,
between temperatures of 0.degree. and 50.degree. C., preferably at
or below room temperature until the reaction is substantially
complete.
Step 3.
Reaction with aqueous alkali or alkali earth hydroxides, such as
sodium, potassium, barium, lithium, and strontium hydroxides, or
nonaqueous alkali and alkali earth hydroxides with lower alkanols
(methanols, propanol, and the like), ethylene glycol, and the like,
aqueous ammonium hydroxide organic amines, (such as lower aliphatic
amines, and the like) preferably aqueous sodium or potassium
hydroxide, but especially concentrated aqueous sodium hydroxide
(6-12 or) using the above aqueous hydroxides as the solvents or
lower alkanols as the solvents, preferably using the aqueous
hydroxide reactants as solvents also, at any desirable temperature
(0.degree. C. to reflux,) preferably at or near reflux, until the
reaction is substantially complete.
Step 4.
Reaction with an acid such as lower aliphatic acids (acetic acid,
propionic acid and the like), aromatic acids, inorganic acids, such
as phosphoric acid, hydrochloric acid, and the like; and with
phosphorus and iodine or hydrogen iodide preferably phosphorus and
iodine, using the above acids as solvents also or in ether,
dioxane, tetrahydrofuran, and the like, preferably the above acids
as solvents at elevated temperature (75.degree.-150.degree. C.,
preferably 100.degree.-120.degree. C.) until the reaction is
substantially complete.
Step 5.
Reaction in an acid medium using strong acids such as p-toluene
sulfonic acid, p-nitrobenzenesulfonic acid, benzenesulfonic acid,
trichloroacetic acid, a mixture of acetic acid and sulfuric acid,
and the like (preferably toluenesulfonic acid) in an inert solvent
such as aromatic compounds (benzene, toluene, xylene, and the
like), dioxane, tetrahydrofuran, lower alkanoic acids (acetic acid,
propionic acid, and the like) preferably acetic acid or
tetrahydrofuran at elevated temperatures (75.degree.-150.degree.
C., preferably at or near the reflux temperature of the system)
until the reaction is substantially complete.
Step 6.
Reduction over a catalyst such a palladium, platinum, or Raney
nickel, preferably 5-10 percent platinum oxide under moderate
hydrogen pressure (5-60 pounds, preferably 40 pounds) in an inert
solvent such as lower alkanols (methanol, ethanol, butanol, and the
like), aromatic compounds (benzene, toluene, xylene, and the like),
tetrahydrofuran, dioxane, acetic acid, and the like at any suitable
temperature (0.degree. C. to the reflux temperature of the system,
preferably at room temperature) in ethanol until the reaction is
substantially complete.
Step 7.
Reaction with diazomethane in an inert solvent, such as aromatic
hydrocarbons (benzene, toluene, and the like) or various ethers; at
ambient temperatures until the reaction is complete.
Step 8.
Reaction at elevated temperatures until reaction is substantially
complete. Preferably, reaction on a steam bath.
In Step (1) when it is desired to employ the cyanide salt, it is
necessary to have the reaction mixture at a pH below 7. This is
necessary in order to have the cyanide salt react as the acid. When
the preferred procedure is used, namely, using hydrogen cyanide,
the use of an amine, such as piperidine or a tertiary amine, is
highly preferred, although not absolutely necessary.
In Step (2), an acid condition is necessary to obtain this
reaction, and those acids as previously indicated may be used. The
reaction may be run above a temperature of 50.degree. C. However,
when higher temperatures are used, a mixture of the desired
compound as well as the alkylenyl acid is obtained, and it is
possible that the reaction may be run at temperatures wherein only
the alkylenyl acid compound is obtained.
In Step (4), the reaction may be properly carried out only under
acid conditions. A dilute to concentrated acid reaction mixture may
be employed. However, it is preferred to use a concentrated
reaction mixture, preferably an aliphatic acid such as acetic acid.
The nitro ketones may be converted to the R.sub.3 and/or R.sub.4
substituents, as previously described prior to Step (1) above or
the nitro ketone may be first converted to the nitro
.alpha.-hydroxy acid compound (Step 3) and the nitro group
converted to the desired substituent at this point. It is to be
noted that when a nitro, trihalomethyl, cyano, carboxamido, or
alkanoylamino group is desired, the -4-biphenyl acetic acid
compound is prepared first after which the compound is nitrated to
form the desired nitro compound, and the nitro compound
subsequently converted to the other desired groups by the processes
previously indicated.
In Step (7), generally an excess of diazomethane in an inert
solvent, such as ether, is added to the .alpha.-methylene compound
at ambient temperatures. After addition, the excess diazomethane
may be evaporated. When the .alpha.-methylene acid is used, the
diazomethane also esterfies the free acid; therefore, the
.alpha.-pyrazolino compound is obtained as the ester. This ester
may be converted to the acid by hydrolysis or saponification and/or
converted to other compounds of this invention.
In Step (8), the .alpha.-cyclopropyl compound is formed as the
ester when obtained directly from Step (7). However, this step may
be carried out on the free acid also. When the t-butyl ester is
used, the free acid may be obtained from the ester by prolysis.
Process B for Preparation of Formula II
This process may be used when structural formula II is desired
wherein X is COOH, R.sub.1 is hydrogen, and R.sub.2 is a lower
alkyl, lower alkenyl, lower alkynyl, or halo lower alkyl. In this
process, the .alpha.-unsubstituted-4-biphenylacetic acid compound
of structural formula I, prepared as previously indicated, is
converted to an ester, which through a series of reactions is
alkylated to an .alpha.-substituted compound followed by conversion
back to the desired acid. The process may be represented as
follows: ##SPC7##
Equivalents
R is a lower alkyl, lower alkenyl, lower alkynyl, or halo lower
alkyl.
Reactions and Conditions of Process B
Step 1.
Reaction with a lower alkyl oxalate, such as dimethyl oxalate,
diethyl oxalate, dibenzyl oxalate, and the like, preferably
dimethyl oxalate and with a strong base, such as potassium
t-butoxide, sodium t-butoxide, sodium ethoxide, sodium hydride
methyl lithium, and the like, preferably an alkali t-butoxide and
especially potassium t-butoxide in an inert solvent, such as
aromatic solvents (benzene), ethers, and the like preferably
aromatic solvents and especially benzene, at any suitable
temperature (R.T.-reflux), preferably at elevated temperatures, but
especially at or near the reflux temperature of the system until
the reaction is substantially complete.
Step 2.
Reaction of the alkali enolate with a lower alkyl halide, (methyl
iodide, isopropyl bromide, ethyl bromide, and the like), lower
alkyl dihalide (.beta.-chloropropyl iodide, .gamma.-chlorobutyl
iodide, .beta.-bromopropyl iodide and the like) lower alkene halide
(prop-2-en chloride, but-3-en bromide and the like) or with a lower
alkyne halide (prop-2-yn bromide, but-3-yn chloride and the like)
preferably a lower alkyl iodide and especially methyl iodide in an
enolate salt-dissolving solvent, such as dimethylformamide,
tetrahydrofuran, dimethoxyethane, and dimethylsulfoxide at any
suitable temperature (R.T. to reflux), preferably at elevated
temperatures until the reaction is substantially complete.
Step 3.
Reaction with an alkali alkoxide, such as sodium methoxide in an
inert solvent, such as aromatic solvents, ethers, alcohols, and the
like, preferably lower alcohols and especially methanol at any
suitable temperature (R.T. to reflux), preferably elevated
temperatures and especially at or near the reflux temperature of
the system until the reaction is substantially complete, followed
by addition to an aqueous dilute mineral acid, such as hydrohalic
acids, sulfuric acid, and the like, preferably hydrochloric
acid.
Step 4.
Conversion to the corresponding acid by any well-known means, such
as saponification or hydrolysis, preferably saponification with an
inorganic base and neutralization of the acid salt with a dilute
mineral acid.
In reaction step (1), the type of ester used is not critical, since
the ester is used primarily as a protecting group. The amount of
alkoxide and/or oxalate used is only a factor in obtaining higher
yields of enolate, therefore, less than equimolar ratios may be
used. However, it is preferred to use an excess of both the
alkoxide and oxalate.
In reaction steps (2) and (3), the molar ratios of reactants are
not critical and, as in step (1), are only a factor in obtaining
higher yields.
Reaction step (4) is simply the conversion of the ester back to its
corresponding acid, which can be carried out by any known means,
one such means being indicated and preferred. If it is desired,
this step may be eliminated, and the esters of step (3) will
represent still other compounds of structural formula II.
The R.sub.3 and R.sub.4 substituents of the starting
.alpha.-unsubstituted-4-biphenylacetates in this process may be
lower alkyl, nitro, halo, trifluoromethyl di(lower alkyl)sulfamyl,
lower alkylthio, lower alkyl sulfonyl, and di(lower
alkyl)-carbamyl. When the other R.sub.3 and R.sub.4 groups are
desired, the .alpha.-substituted-nitro-substituted-4-biphenylacetic
acid or ester final compound may be converted to the desired group
by proper reaction of the nitro substituent according to the
description described previously.
Preparation of Compounds of Structural Formula III
The procedure used to prepare these compounds depends upon the
particular .alpha.-substituent desired.
A. To prepare the compounds of formula III, wherein X is COOH and
R' and R" are other than lower alkyl, an
.alpha.-unsubstituted-4-biphenylacetic acid of structural formula I
is reacted with sulfuryl chloride to form the
.alpha.-chloro-4-biphenylacetic acid or reacted with thionyl
chloride followed by sulfuryl chloride and an alcohol to form the
.alpha.-chloro-4-biphenylacetate. The .alpha.-lower alkoxy acid
compound may then be prepared from the .alpha.-chloro acid by
reaction with sodium and a lower alkanol. The .alpha.-hydroxy acid
or ester compound can be obtained by hydrolysis of the
corresponding .alpha.-chloro compound. The .alpha.-fluoro acid or
ester compound may be prepared by reacting the corresponding
.alpha.-chloro or .alpha.-tosyl (from .alpha.-hydroxy) compound
with potassium fluoride.
B. To prepare those compounds wherein X is COOH and R' and R" are
each lower alkyl, an .alpha.-unsubstituted-4-biphenylacetic acid of
structural formula I is converted to the corresponding amide, which
then is converted to the corresponding nitrile. The nitrile
compound is then di-alkylated at the .alpha.-position and
subsequently hydrolyzed to the desired free acid of formula
III.
The process for the preparation of the compounds of Group (A) may
be illustrated as follows: ##SPC8##
Equivalents
R is H or lower alkyl;
R.sub.1 is lower alkyl.
Reactions and Conditions of Process A
Step 1.
Reaction with a thionyl halide, sulfuryl chloride and a lower
alkanol using the sulfuryl halide as solvent also or with an inert
solvent, such as aromatic solvents (benzene, toluene, and the like)
or alcohols and the like at any suitable temperature (R.T. to
reflux), preferably at elevated temperatures and especially at or
near the reflux temperature of the system, until the reaction is
substantially complete to produce the compound wherein R is lower
alkyl; or when the compound wherein R is hydrogen is desired,
reaction with sulfuryl chloride without employing the thionyl
halide and the lower alkanol.
Step 2.
Hydrolysis by any well-known means, such as reaction in water with
a dilute inorganic base, such as dilute sodium hydroxide, potassium
carbonate, and the like, or in water itself at any suitable
temperature (R.T. to reflux), preferably at ambient temperatures,
until the reaction is substantially complete.
Step 3.
Reaction with an alkali fluoride, such as sodium fluoride and
potassium fluoride, in a high boiling alcohol, such as diethylene
glycol, at elevated temperatures (75.degree.-125.degree. C.),
preferably about 125.degree. C., until the reaction is
substantially complete.
Step 4.
Reaction with an alkali alkoxide and a lower alkanol in an inert
solvent, such as aromatic solvents (benzene, toluene), or using the
alcohol itself as the solvent at any suitable temperature
(0.degree. C., -reflux), preferably below room temperature until
the reaction is substantially complete, and when R is hydrogen,
followed by addition of a mineral acid, such as hydrohalic acid,
sulfuric acid, and the like, preferably dilute hydrochloric acid,
to make the reaction mixture acid.
In reaction step (1), it is not required that the ester be formed;
therefore, the sulfuryl chloride may be used alone to chlorinate
the .alpha.-position. It is preferred to use the sulfuryl compound
both as the chlorinating agent and as solvent to produce the
.alpha.-chloro acid. Although one may use the acid instead of the
ester to place the desired .alpha.-substituent upon the molecule
use of the ester is prepared.
Reaction step (2) can be easily carried out by placing the
.alpha.-chloro compound, preferably the acid, in water and an inert
solvent. The sole purpose of the solvent is to afford solubility of
the reactant and it is not required when the reactant is soluble in
water alone. The use of base increases the ability to hydrolyze the
compound and although preferred, is not needed here.
In reaction step (3), it is preferred to use a small amount of
potassium iodide to act as a catalyst. The reaction is generally
carried out at temperatures of 125.degree. C. and below.
In all of the above reactions, the R.sub.3 and R.sub.4 group may be
halo, trihalomethyl, di(lower alkyl)sulfonamido, cyano, di(lower
alkyl)carboxamido, nitro, or lower alkyl. When the other R.sub.3
and R.sub.4 groups are desired, the nitro substituent is used and
converted to the desired group as described previously, after the
final .alpha.-substituent is prepared.
In the process for preparing the compounds of group (B), the
.alpha.-unsubstituted acid is converted to the amide, as indicated
previously. The amide is reacted with a dehydrating agent-- such as
PCl.sub.5, P.sub.2 O.sub.5, POCl.sub.3, SOCl.sub.2, and the
like--preferably PCl.sub.5, in an inert solvent which will dissolve
both the dehydrating agent and the compound, preferably POCL.sub.3
or pyridine as solvent, at any suitable temperature (R.T. to
reflux), preferably at elevated temperatures, until the reaction is
substantially complete. The nitrile thus produced is dialkylated by
reaction with an alkali amide or hydride-- such as potassium
hydride or sodium amide--preferably the latter, and with a lower
alkyl halide--such as methyl iodide, propyl bromide, and the
like--preferably with methyl iodide, in an inert solvent (aromatic;
benzene, toluene), preferably benzene, at temperatures above
0.degree. C., preferably at elevated temperatures and especially at
75.degree.-85.degree. C., until the reaction is substantially
complete. The .alpha.-dilower alkyl nitrile compound is then
hydrolyzed by any one of many well-known means, such as dilute
aqueous mineral acid hydrolysis (hydrohalic acids, sulfuric acid),
preferably hydrochloric acid, in an inert solvent in which both the
water and nitrile are soluble, such as acetic acid, at any suitable
temperature (R.T. to reflux), preferably at elevated temperatures,
until the hydrolysis is substantially complete to afford the
.alpha.-dilower alkyl compounds of structural formula III.
In the reactions of group B, the substituents on the starting acid
may not be, amino, mercapto, di(lower alkyl) amino, cyano or lower
alkanoylamino. When these groups are desired the .alpha.-di(lower
alkyl) group is first made from the nitro .alpha.-unsubstituted
acid, followed by reaction of the nitro group to the desired
substituent, as described previously.
Preparation of Compounds of Structural Formula IV
The preparation of compounds of formula IV, wherein X is COOH, may
be carried out by the following process.
In this process the starting material is the known 4-biphenyl
trifluoromethyl ketone or a substituted 4-biphenyl trifluoromethyl
ketone, which is prepared by procedures similar to those previously
described, e.g., the Friedel-Crafts reaction of an appropriately
substituted biphenyl compound with trifluoroacetic anhydride. This
starting trifluoromethyl ketone is treated with a lower
carbalkoxymethylene triphenylphosphorane to form the
.beta.-trifluoromethyl-4-biphenyl-prop-2-enoate compound, which is
subsequently reduced to form an
.alpha.-trifluoromethyl-4-biphenylpropionate. This ester is then
reacted with a Grignard reagent to form a propan-1-ol compound.
This compound is then dehydrated to form a prop-1-ene compound,
which is then oxidized to form the desired
.alpha.-trifluoromethyl-4-biphenylacetic acid compound. The process
may be illustrated as follows: ##SPC9##
Equivalents
R.sub.3 and R.sub.4 are as previously described with the exceptions
hereinbelow indicated.
Reactions and Conditions
Step 1.
Reaction with a lower carbalkoxymethylene triphenylphosphorane in
an inert solvent, such as ethers and aromatic solvents (benzene,
toluene, xylene, and the like), preferably aromatic solvents and
especially toluene, at any suitable temperature (room temperature
to reflux), preferably at elevated temperatures and especially at
or near reflux, until the reaction is substantially complete.
Step 2.
Catalytic reduction in an inert solvent, such as alcohols, dioxane,
and lower alkanoic acids, preferably lower alkanols and especially
ethanol, in the presence of a catalyst, such as platinum oxide,
palladium oxide, and the like preferably platinum oxide, under an
atmosphere of hydrogen, preferably greater than 5 pounds of
hydrogen pressure, but especially 35-55 pounds of hydrogen
pressure, at any suitable temperature (0.degree. C. to reflux),
preferably at ambient temperatures until the reaction is
substantially complete.
Step 3.
Reaction with diphenylmagnesium bromide in an inert solvent, such
as ether or tetrahydrofuran, preferably ether, at any suitable
temperature (0.degree. C. to reflux), preferably at or near the
reflux temperature of the system, until the reaction is
substantially complete, followed by addition of an aqueous mineral
acid (sulfuric acid, hydrochloric acid, hydrobromic acid, and the
like) or with an aqueous ammonium halide solution, preferably with
a dilute mineral acid, especially aqueous sulfuric acid.
Step 4.
Dehydration by heating at any suitable temperature until all of the
water is substantially split out of the molecule.
Step 5.
Oxidation, such as by reaction with chromium trioxide in an inert
solvent (lower alkanoic acids, such as acetic acid, propionic acid,
and the like), preferably glacial acetic acid at any suitable
temperature (room temperature to reflux), preferably at or near the
reflux temperature of the system, until the reaction is
substantially complete followed by addition of a mineral acid
(hydrochloric acid, sulfuric acid, hydrobromic acid, and the like),
preferably aqueous sulfuric acid.
In reaction step (3), the mineral acid or ammonium halide employed
is used to hydrolyze the Grignard addition product. Under these
circumstances, any of the many well-known means to hydrolyze
Grignard addition products may be used.
In reaction step (4), it is preferred to first remove the solvents
of the product from reaction step (3) before dehydrating the
product. However, the dehydration step may be carried out directly
on the reaction mixture of step (3). In this case, the reaction
mixture of step (3) is continuously heated, whereupon the solvent
is removed followed by the splitting off of water from the product.
The temperature required in this dehydration step will vary
depending upon the product involved. Therefore, as a practical
matter, the crude mixture is heated to the minimum temperature
required to split out the water without substantially affecting the
product thus obtained.
In reaction step (5), any of the many well-known oxidation
procedures for unsaturated compounds may be employed. In addition
to the one procedure previously indicated, oxidation may also be
carried out with the use of potassium permanganate under alkaline
or acidic conditions. Another appropriate method is the ozonation
of the unsaturated compound. In this procedure the unsaturated
compound is placed in a solvent, such as methylene chloride, at low
temperatures (approximately -75.degree. C.), an excess of ozone
added, the solvent removed and replaced by another solvent, such as
glacial acetic acid, whereupon aqueous hydrogen peroxide is added
to complete the oxidation. In the procedure previously described,
the mineral acid is used to hydrolyze the chromate ester which is
formed after the oxidation. Under these circumstances, any variety
of procedures well known in the art may be used to hydrolyze this
chromate ester.
In carrying out this process the R.sub.3 and/or R.sub.4 group is
restricted to hydrogen, halogen, trihalomethyl, lower alkylthio,
lower alkyl, phenyl, and diloweralkyl-sulfamyl. When it is desired
to obtain the .alpha.-trifluoromethyl-4-biphenylacetic acid
compound containing other substituents, the final acid compound is
nitrated and then treated according to the procedures previously
described to obtain the desired R.sub.3 and/or R.sub.4
substituent.
The compounds of formulas I, II, III, and IV of this invention,
wherein X is other than COOH, may be prepared from the
corresponding acid compounds.
The process for the preparation of the esters may be carried out by
reaction of the corresponding acid with a strong acid, such as
hydrochloric acid, sulfuric acid, toluenesulfonic acid,
p-nitrotoluenesulfonic acid, benzenesulfonic acid, and the like
(preferably 1-3 percent concentrated sulfuric acid), and with the
appropriate alcohol. The alcohol may be used as a solvent also or
an inert solvent, such as tetrahydrofuran, ether, or dioxane, may
be used. The reaction may be carried out at any suitable
temperature; however, it is preferably carried out at or near the
reflux temperature of the system. Esterifications are well-known
reactions in the art, and although a particular esterification
reaction is indicated here, the acid may be esterified by any known
means. When the alcohol is not suitable for use as a solvent, inert
solvents are used along with the alcohol. When using phenol as the
alcohol for the esterification step, it is highly preferred to
azeotrope the water formed so as to allow ester formation. Another
highly suitable procedure for this esterification step is the
reaction of the acid with at least 1 mole of a diimide (such as
dicyclohexylcarbodiimide) and the appropriate alcohol in an inert
solvent, such as tetrahydrofuran.
The process for the preparation of the amide compounds of this
invention, may be carried out by reacting the corresponding acid
with thionyl chloride, thionyl bromide, phosphorus oxychloride,
phosphorus oxybromide, phosphorus pentachloride, or phosphorus
pentabromide in an inert solvent--such as ether, benzene, toluene,
xylene, tetrahydrofuran, dioxane, and the like-- followed by
reaction with an excess of the desired amine at any suitable
temperature (0.degree. C. to room temperature preferred) or
reaction with dicyclohexylcarbodiimide and an excess of the amine
at any suitable temperature until the reaction is substantially
complete. When primary amides are desired, ammonia maybe employed;
when secondary amides are required, primary aliphatic or aromatic
amines are employed--such as propylamine, benzylamine,
.beta.-phenethylamine, aniline, and the like. To obtain cyclic
amides, N-unsubstituted cyclic amines-- such as pyrrolidine,
piperidine, morpholine, and the like--are employed. It is generally
preferred to run this reaction with the amine acting as the solvent
also; however, when this cannot be conveniently done, an inert
solvent such as indicated above may be used. In addition, it is
preferred to remove the excess reagent and acidic byproduct formed
in this reaction prior to the addition of the amine. However, the
acid may be neutralized by using an excess of the amine. An
alternative procedure is to react the biphenyl acid compound with
dicyclohexylcarbodiimide and the desired amine. The three
components may be mixed at any suitable temperature (-10.degree. C.
to 50.degree. C.), but are preferably mixed at ambient temperatures
for several hours. The dicyclohexylcarbodiimide procedure is
exclusively used when the R.sub.3 and R.sub.4 groups are affected
by the acid halide procedure. Such groups are the amino, monoalkyl
and dialkylamino, and carboxamido.
The process for the preparation of the aldehyde compounds of this
invention may be carried out by reacting the corresponding biphenyl
acid compounds with a compound such as thionyl chloride, thionyl
bromide, phosphorus pentachloride, phosphorus pentabromide,
phosphorus oxychloride, phosphorus oxybromide, and the like, but
preferably thionyl chloride in an inert solvent to form the acid
halide and subsequent reduction of the acid chloride to the
aldehyde. The inert solvents used may be benzene, toluene, xylene,
ethers (diethyl ether, dioxane), tetrahydrofuran, or the like,
preferably benzene or toluene. Any suitable temperature may be
employed (room temperature to reflux); however, it is preferred to
use temperatures at or near the reflux temperature of the system
until the formation of the acid halide is substantially complete.
The acid halide is then reacted with a Rosenmund catalyst such as 5
percent Pd on BaSO.sub.4 with quinoline, or with a
tritertiarybutoxy alkali or alkali earth aluminum hydride, such as
potassium, sodium, or lithium aluminum hydride and the like. The
reduction is preferably carried out with a tritertiarybutoxy alkali
or alkali earth aluminum hydride, particularly with
tritertiarybutoxy lithium aluminum hydride in tetrahydrofuran or
ether. However, the inert solvent may also be benzene, toluene,
xylene, ethers (diethyl ether, dioxane), and the like. The reaction
may be carried out at any suitable temperature (-80.degree. C. to
room temperature), but preferably -35.degree. to -15.degree. C.
until the reaction is substantially complete.
It is preferred to remove the inorganic acid formed after the acid
halide preparation; otherwise, the inorganic acid would
preferentially consume the subsequent addition of the hydride.
However, if it is desired, the inorganic acid may remain if an
excess of the hydride is used to react with the inorganic acid as
well as with the acid halide. When the butoxide reagent is used, it
is preferred to use temperatures below 0.degree. C. If temperatures
above 0.degree. C. are used, the reduction will lead to the
corresponding alcohol instead of the aldehyde. As indicated,
although higher temperatures may be used, it is not economically
feasible, for a reaction temperature will be reached wherein the
corresponding alcohol will be almost exclusively produced. However,
if the alcohol is desired, this is still another way of going
directly from the acid to the alcohol.
In the preparation of these aldehydes, the acid starting materials
containing the primary amino, or secondary amino group and
carboxamido group may not be used unless these groups are protected
in some way. Protection may be accomplished by benzylating the
amino group prior to this reaction. During the reaction, the acid
group will be reduced to the aldehyde and the protected amino group
will be debenzylated to yield the desired amino group.
The process for the preparation of the acetal compounds of this
invention may be carried out by reacting the previously prepared
aldehyde compound with a lower alkanol in the presence of a strong
acid. Examples of strong acids contemplated for this reaction are
toluenesulfonic acid, p-nitrobenzenesulfonic acid, and mineral
acids (hydrochloric acid, sulfuric acid, and borontrifluoride). It
is preferred to use a catalytic amount of toluenesulfonic acid or
concentrated hydrochloric acid in a lower alkanol (methanol,
ethanol, butanol, and the like) at any suitable temperature.
However, the solvents used may be aromatic compounds or
combinations of the alcohol and ethers as well as the alcohol
itself. The reaction temperature is not critical, and, therefore,
temperatures from 0.degree. C. to reflux may easily be used,
although ambient temperatures are preferred. The quantity of acid
is not critical; all that is required is that the acid be of
sufficient strength to catalyze the reaction. Alternatively, the
reaction may be carried out by employing the aldehyde and the
appropriate lower alkyl orthoformate. When it is desired to isolate
the acetal and water is to be used in the isolation, the reaction
mixture must be neutralized with a base such as sodium carbonate so
as to prevent the hydrolysis of the acetal back to the
aldehyde.
The alcohols of this invention may be obtained by reaction of the
corresponding acid compound with an alkali or alkali earth aluminum
hydride. Almost any solvent may be used as long as it is inert to
the hydride and the reactants have some degree of solubility in it.
Preferred inert solvents are tetrahydrofuran and diethyl ether. The
temperature of this reaction is not critical; therefore, under
these conditions, temperatures from -15.degree. C. to reflux are
well within the contemplation of this invention. The complex metal
hydrides--such as lithium, aluminum hydride, and the like--used may
be less than the theoretical amount, however, it is preferred to
use 200-400 percent excess of the preferred lithium aluminum
hydride. After the reaction, the excess hydride is decomposed by
addition of ethyl acetate or an active hydrogen reactant such as
alcohols, water, or dilute aqueous mineral acids. The alcohol
compound obtained from this reaction is in the form of its salt,
and therefore an aqueous acid is used to convert the alcohol salt
to the free alcohol. Such acids may be hydrochloric, ammonium
chloride, sulfuric, and the like.
This portion of the reaction is preferably carried out at 0.degree.
to ambient temperatures by first adding water followed by dilute
sulfuric acid. The ester may also be reduced catalytically using
such catalysts as reuthenium. When the former procedure is used,
the R.sub.3 and R.sub.4 substituents may only be lower alkylthio,
halogen, trihalomethyl, lower alkyl, and dilower alkylamino. When
the later procedure is used the R.sub.3 AND R.sub.4 may be any
group other than cyano, nitro or sulfonyl.
The ether compounds of this invention are prepared from the
corresponding alcohols. The alcohol is reacted with a strongly
basic condensing agent such as sodium hydride, potassium hydroxide,
potassium tertiary butoxide, or sodamide and a lower alkyl halide,
(methyl iodide, alkyl chloride, .beta.-phenethyl bromide or ethyl
bromide and the like), preferably sodium hydride and 50 percent
excess of methyl iodide. Although dimethylformamide is generally
used as the solvent, any nonactive hydrogen solvent may be used,
such as aromatic solvents (benzene, toluene), ethers (diethyl
ether, dioxane, tetrahydrofuran), and the like. The reaction is
generally carried out at ambient temperatures; however,
temperatures from 0.degree.-50.degree. C. may be conveniently used
also. The quantity of reagents used will affect the yield of the
ether; therefore, it is generally preferred to use an excess of the
hydride and halide. Additionally, the excess hydride is used to
consume any active hydrogen materials which may be present in the
starting alcohol compound. Additionally, since this reaction
employs a strongly basic condensing agent, as in the first alcohol
synthesis, the same limitations as to substituents apply to this
reaction as did with that alcohol synthesis.
It is to be noted that whenever a nitro group is desired on the
biphenyl ring and the synthesis of the side chain will affect the
nitro group, the nitro group is placed on the biphenyl ring by
proper nitration after the side chain has been obtained.
The nontoxic salts of the acid compounds of this invention may be
conveniently prepared by procedures well known in the art. For
example, the biphenyl acetic acid maybe reacted with an inorganic
base in an inert solvent and the solution evaporated to yield the
desired salt.
The following examples are given by way of illustration:
EXAMPLE 1
3-Chloro-4-phenylacetophenone
To mixture of 1.85 grams of magnesium turnings in 8 ml. of ether is
added a solution consisting of 11.5 grams of
4-bromo-2-chlorobiphenyl and 5 grams of ethyl bromide in 50 ml. of
ether. The solution is brought to reflux and the remaining biphenyl
solution is added over a period of 25 minutes, maintaining gentle
reflux. The solution is then cooled and 7.0 grams of cadmium
chloride is added portionwise over approximately 7 minutes. The
solution is refluxed for 1 hour, after which it is recooled to room
temperature. A solution of 6 ml. of acetyl chloride in 20 ml. of
ether is added with stirring over a period of 5 minutes. The
solution is then refluxed for approximately 2 hours, recooled to
room temperature, and poured onto a mixture of 1 liter of ice in 56
ml. of 2.5N hydrochloric acid. The ether layer is separated and
washed with 25 ml. of water and dried over magnesium sulfate. The
ether solution is then chromatographed on a 500-gram silica gel
column. The column is eluted with ether-petroleum ether (v/v 20-80
percent ether) to yield 3-chloro-4-phenylacetophenone.
EXAMPLE 2
4-Biphenylacetophenone
To a mixture of 0.05 mole of terphenyl and 0.05 mole of acetyl
chloride in 80 ml. of carbon disulfide is added 0.06 mole of
aluminum chloride in small portions over 30 minutes. This reaction
mixture is then placed in a water bath at 68.degree. C. and the
bath allowed to come to room temperature. The reaction mixture is
then stirred for 48 hours. The reaction mixture is then poured into
a mixture of 10 ml. of concentrated hydrochloric acid and 200 grams
of ice and water added to bring the volume to 500 ml. The reaction
mixture is then stirred over a period of 1 hour. The reaction
mixture is then extracted with (3.times. 50 ml.) chloroform. The
combined chloroform extract is then washed with an excess of water
and dried over sodium sulfate. The chloroform extract is then
filtered and the filtrate concentrated in vacuo of yield
4-biphenylacetophenone, m.p. 235.5.degree.-236.degree. C.
EXAMPLE 3
2-Methyl-4-phenylacetophenone
To a mixture of 1.85 grams of magnesium turnings in 8 ml. of ether
is added with stirring 3 ml. of a solution of 10.6 grams of
4-bromo-3-methylbiphenyl and 5 grams of ethyl bromide and 50 ml. of
dry ether. The mixture is heated in a water bath and the remaining
portion of the bromobiphenyl solution is added dropwise over a
period of 25 minutes. After complete addition, the reaction mixture
is refluxed for approximately 2 hours. At this point, the mixture
is cooled and 7.0 grams of cadmium chloride is added portionwise
over a period of 3 minutes. The reaction mixture is refluxed for an
additional hour, cooled, and a solution of 6 ml. of acetyl chloride
and 20 ml. of ether is added. The mixture is refluxed again for an
additional hour and cooled to room temperature. The mixture is then
poured onto a solution of 1 liter of ice in 52 ml. of 2.5N
hydrochloric acid. The ether layer is then separated and dried over
magnesium sulfate. The ether solution is then concentrated in vacuo
to yield a crude residue. This residue is then dissolved in a
minimum amount of ether and chromatographed on a 430-gram silica
gel column to yield 2-methyl-4-phenylacetophenone, m.p.
53.degree.-55.degree. C.
When 4-bromo-2-methylbiphenyl and 4-bromo-2-chlorobiphenyl are used
in place of 4-bromo-3-methylbiphenyl in the above example, there
are obtained 3-methyl-4-phenylacetophenone and
3-chloro-4-phenylacetophenone.
EXAMPLE 4
2' -Chloro-4-biphenylmethyl ketone
To a cooled mixture of 14.2 grams of aluminum chloride in 100 ml.
of ethylene dichloride is added a solution of 20 grams of
2-chlorobiphenyl and 8.5 grams of acetyl chloride in 50 ml. of
ethylene dichloride. After complete addition, the mixture is
allowed to slowly come to room temperature. The reaction mixture is
then poured into 300 ml. of ice water and the resultant mixture is
separated and the aqueous layer extracted with 150 ml. of methylene
chloride. The combined organic layer is then concentrated in vacuo.
The residue thus obtained is dissolved in a minimum amount of
benzene and chromatographed on a 705-gram silica gel column using
petroleum ether and benzene as eluents to yield
2'-chloro-4-biphenylmethyl ketone, m.p. 52.degree.-53.degree.
C.
EXAMPLE 5
4-(p-Nitrophenyl)-benzoic acid
0.01 mole of 4-(p-nitrophenyl)-acetophenone in 30 ml. of dioxane is
added to an aqueous solution of 0.05 mole of sodium hypobromite and
the resulting mixture stirred at room temperature for 1 hour. The
mixture is then warmed to 60.degree. C. and stirred for an
additional 2 hours at that temperature. The reaction mixture is
then concentrated in vacuo. The alkaline solution is treated with
sulfur dioxide and then acidified with dilute hydrochloric acid.
The mixture is then filtered and the cake washed with (2.times. 10
ml.) dilute hydrochloric acid. The cake is then dried in vacuo to
yield 4-(p-nitrophenyl)-benzoic acid.
When 4-phenylacetophenone, 3-chloro-4-phenylacetophenone,
4-(p-dimethylsulfonylphenyl)-acetophenone,
4-(p-dimethylcarboxamidophenyl)-acetophenone,
3-nitro-4-(p-nitrophenyl)-acetophenone,
3-nitro-4-phenylacetophenone, 4-(o-nitrophenyl)-acetophenone,
4-biphenylacetophenone, and 4-(m-nitrophenyl)-acetophenone are used
in place of the 4-(p-nitrophenyl)-acetophenone in the above
example, there are obtained the corresponding benzoic acids.
EXAMPLE 6
4-(p-Nitrophenyl)-diazoacetophenone
A. 4-(p-Nitrophenyl)-benzoic acid chloride
0.01 mole of 4-(p-nitrophenyl)-benzoic acid and 0.02 mole of
thionyl chloride are added to 50 ml. of chloroform. After the
initial reaction, the mixture is refluxed on a steam bath for 2
hours. The reaction mixture is then concentrated in vacuo, 20 ml.
of benzene added, and again concentrated in vacuo.
B. 4-(p-Nitrophenyl)-diazoacetophenone
The residue obtained from Part A is added to 30 ml. of cold ether
and the ethereal solution added to an excess of diazomethane. The
reaction mixture is allowed to warm to room temperature and stirred
for 6 hours. The solvent is then removed in vacuo to yield crude
4-(p-nitrophenyl)-diazoacetophenone.
When the benzoic acid compounds obtained from example 5 are used in
place of 4-(p-nitrophenyl)-benzoic acid in the above example, there
are obtained the corresponding diazoacetophenones.
Similarly, when 4-(p-methylthiophenyl)-benzoic acid,
4-(p-cyanophenyl)-benzoic acid, 4-(p-benzylthiophenyl)-benzoic
acid, and 3-nitro-4-phenylbenzoic acid are used in place of
4-(p-nitrophenyl)-benzoic acid in the above example, there are
obtained the corresponding diazoacetophenones.
EXAMPLE 7
Ethyl 4'-nitro-4-biphenylacetate
To a solution of 0.01 mole of 4-(p-nitrophenyl)-diazoacetophenone
in 50 ml. of ethanol at 55.degree. C. is added portionwise a slurry
of 3 grams of freshly precipitated silver oxide in 30 ml. of
ethanol and the reaction mixture stirred. After evolution of the
nitrogen subsides, the reaction mixture is refluxed for
approximately 1 hour, subsequently treated with charcoal, filtered,
and the filtrate concentrated in vacuo. The crude ester residue is
purified by chromatography on an acid-washed alumina column using
ether-ethyl acetate as the eluent.
When the diazoacetophenones obtained from example 6 are used in
place of 4-(p-nitrophenyl)-diazoacetophenone in the above example,
there are obtained the corresponding ethyl esters.
EXAMPLE 8
4-Nitro-4-biphenylacetic acid
A solution of 15 grams of 4-(p-nitrophenyl)-diazoacetophenone in
100 ml. of dioxane is added dropwise with stirring to a mixture of
2 grams of silver oxide, 5 grams of anhydrous sodium carbonate, and
3 grams of sodium thiosulfate in 200 ml. of water at
50.degree.-60.degree. C. The reaction mixture is stirred for an
additional hour at a temperature of 90.degree.-100.degree. C. The
reaction mixture is then cooled, diluted with 200 ml. of water, and
acidified with dilute nitric acid. The reaction mixture is then
filtered and the cake washed with (3.times. 25 ml.) dilute nitric
acid. The cake is then dried in vacuo to yield
4'-nitro-4-biphenyl-acetic acid.
When the diazoacetophenones obtained from example 6 are used in
place of 4 -(p-nitrophenyl)-diazoacetophenone in the above example,
there are obtained the corresponding 4-biphenylacetic acids.
EXAMPLE 9
4'-Nitro-4-biphenylacetic acid
A solution of 0.01 mole of potassium hydroxide in 3 ml. of water is
added to a cool solution of 0.01 mole of ethyl
4'-nitro-4-biphenylacetate in 30 ml. of methanol. Additional water
or methanol is added until the faintest cloudiness persists, and
the mixture is stirred overnight at room temperature. To this
reaction mixture is added an excess of water and the methanol is
removed in vacuo. The aqueous mixture is then washed well with
ether, made acidic with 2.5N hydrochloric acid, and extracted with
(3 .times. 25 ml.) ether. The combined ether extracts are dried
over anhydrous magnesium sulfate, the mixture filtered, and the
ether removed in vacuo to yield 4'-nitro- 4-biphenylacetic
acid.
When the ethyl esters obtained from example 7 are used in place of
ethyl 4'-nitro-4-biphenylacetate in the above example, there are
obtained the corresponding 4-biphenylacetic acids.
EXAMPLE 10
4'-Amino-4-biphenylacetic acid
To a solution of 23 grams of 4'-nitro-4-biphenylacetic acid and 250
ml. of absolute ethanol is added 1/2 gram of platinum oxide. The
mixture is then hydrogenated at room temperature for 1 hour. The
product is then dissolved as much as possible by heating on a steam
bath and filtered. The moist cake is treated with 500 ml. of hot
ethanol and the catalyst removed by filtration. After removal of
the combined solvents in vacuo, the product thus obtained is
dissolved in ether, extracted with 2N hydrochloric acid, and
recovered by neutralization and extraction of the aqueous layer
with ether. The ether extract is then dried over sodium sulfate,
filtered, and the solvent removed to yield
4'-amino-4-biphenylacetic acid.
When the nitro biphenylacetic acids obtained from example 9, the
nitro ethyl esters obtained from example 7, and the nitro benzoic
acid compounds obtained from example 5 are used in place of
4'-nitro-4-biphenylacetic acid in the above example, there are
obtained the corresponding amino biphenylacetic acids, amino ethyl
esters, and amino benzoic acid compounds respectively.
Similarly, when 4-(p-nitrophenyl)-acetophenone,
3-nitro-4-(p-nitrophenyl)-acetophenone,
3-nitro-4-phenylacetophenone, 4-(o-nitrophenyl)-acetophenone,
4-(p-nitrophenyl)-propiophenone, 4-(p-nitrophenyl)-butyrophenone,
3-nitro-4-(p-nitrophenyl)-propiophenone,
3-nitro-4-(p-nitrophenyl)-butyrophenone,
3-nitro-4-phenylpropiophenone, 3-nitro-4-phenylbutyrophenone,
4-(o-nitrophenyl)-propiophenone, 4-(o-nitrophenyl)-butyrophenone,
4-(m-nitrophenyl)-propiophenone, 4-(m-nitrophenyl)-butyrophenone
(the propiophenones and butyrophenones are obtained by carrying out
the Friedel-Crafts reaction using the propionic or butanoic acid
chloride in place of acetyl chloride), and
4-(m-nitro-phenyl)-acetophenone are used in place of
4-nitro-4-biphenylacetic acid in the above example, there are
obtained the corresponding amino ketone compounds.
EXAMPLE 11
4'-Chloro-4-biphenylacetic acid
A suspension of 9 grams of 4'-amino-4-biphenylacetic acid and 18
ml. of concentrated hydrochloric acid in 16 ml. of water is heated
until the solid dissolves. The solution is then cooled to 0.degree.
C. (whereupon the hydrochloride precipitates) and 3.24 grams of
sodium nitrite and 6 ml. of water are added to the chilled, stirred
mixture. After the suspension has remained in the ice bath for 15
minutes, 13.2 grams of cuprous chloride dissolved in 240 ml. of
concentrated hydrochloric acid is added dropwise with vigorous
stirring to the chilled mixture. The mixture is then stirred
overnight at room temperature. At this point, the reaction mixture
is poured into 500 grams of ice, the product extracted with
(5.times. 200 ml.) ether, and the combined ether extracts washed
successively with water until neutral, dried over magnesium
sulfate, filtered, and concentrated in vacuo to yield a residue of
4'-chloro-4-biphenylacetic acid.
When the amino-4-biphenylacetic acids and esters of the amino
benzoic acid compounds obtained from example 10 are used in place
of the 4'-amino-4-biphenylacetic acid in the above example, there
are obtained the corresponding chloro-4-biphenylacetic acids,
esters, and chlorobenzoic acid compounds.
Similarly, when the amino ketone compounds obtained from example 10
are used in place of 4'-amino-4-biphenylacetic acid in the above
example, there are obtained the corresponding chloro ketone
compounds.
When cuprous bromide in concentrated hydrobromic acid is used in
place of cuprous chloride in concentrated hydrochloric acid in the
above example, there is obtained 4'-bromo-4-biphenylacetic acid,
m.p. 175.degree.-177.degree. C.
When an equivalent amount of fluoroboric acid is used in place of
the cuprous chloride in concentrated hydrochloric acid in the above
example, the reaction mixture stirred, decanted, and the residue
placed in toluene, heated carefully, poured into water, and the
organic layer separated, washed with water, dried over sodium
sulfate, and concentrated in vacuo, there is obtained
4'-fluoro-4-biphenylacetic acid.
EXAMPLE 12
4'-Mercapto-4-biphenylacetic acid
To 19 grams of 4'-amino-4-biphenylacetic acid in 17 ml. of
concentrated hydrochloric acid in 30 grams of ice is added 6.5
grams of sodium nitrite in a small volume of water. The reaction
mixture is then added portionwise with stirring over a 1/2-hour
period to 16.4 grams of potassium ethyl xanthate in 21 ml. of water
heated at 40.degree.-45.degree. C. After stirring an additional
hour, the reaction mixture is cooled and extracted with (3.times.
75 ml.) ether. The combined ether extracts are then washed
successively with water, dilute sodium hydroxide, and water to
neutrality. The extract is then dried and evaporated in vacuo. The
residue is then dissolved in 54 ml. of ethanol, and while refluxing
the reaction mixture, 20.5 grams of potassium hydroxide pellets are
added portionwise. After complete addition, the reaction mixture is
refluxed until a few drops of water give an almost clear solution.
The reaction mixture is then concentrated to dryness in vacuo. The
residue is then dissolved in water and extracted three times with
ether to remove the alkali insoluble material. The alkaline layer
is charcoaled, acidified with 6N sulfuric acid, and extracted with
ether. The ether solution is then dried over sodium sulfate and
concentrated in vacuo to yield 4'-mercapto-4-biphenylacetic
acid.
When the amino-4-biphenylacetic acids, esters, and amino benzoic
acid compounds obtained from example 10 are used in place of
4'-amino-4-biphenylacetic acid in the above example, there are
obtained the corresponding mercapto-4-biphenylacetic acids, esters,
and mercapto benzoic acid compounds.
Similarly, when the amino ketone compounds obtained from example 10
are used in place of 4'-amino-4-biphenylacetic acid in the above
example, there are obtained the corresponding mercapto ketone
compounds.
EXAMPLE 13
4'-Methylmercapto-4-biphenylacetic acid
6 grams of 4'-mercapto-4-biphenylacetic acid is mixed with 16 ml.
of water containing 1 gram of sodium hydroxide. To this reaction
mixture is added dropwise 3.1 ml. of dimethylsulfate while
stirring. The reaction mixture is stirred for an additional 2
hours. The reaction mixture is then extracted with ether and the
ether extract washed with water, dried over sodium sulfate, and
concentrated in vacuo. The residue is then dissolved in benzene and
chromatographed on 168 grams of silica gel. The column is eluted
with benzene to yield 4'-methylmercapto-4-biphenylacetic acid.
When dipropylsulfate is used in place of dimethylsulfate in the
above example, there is obtained 4'-propylmercapto-4-biphenylacetic
acid.
Similarly, when the mercapto-4-biphenylacetic acids, esters, and
mercapto benzoic acid compounds obtained from example 12 are used
in place of 4'-mercapto-4-biphenylacetic acid in the above example,
there are obtained the corresponding
methylmercapto-4-biphenylacetic acids, esters, and methylmercapto
benzoic acid compounds.
Similarly, when the mercapto ketone compounds obtained from example
12 are used in place of 4'-mercapto-4-biphenylacetic acid in the
above example, there are obtained the corresponding methylmercapto
ketone compounds.
EXAMPLE 14
4'-Methylsulfonyl-4-biphenylacetic acid
A mixture of 0.01 mole of 4'-methylmercapto-4-biphenylacetic acid,
excess potassium permanganate, and 50 ml. of 2N sodium hydroxide is
stirred at room temperature for 2 hours. To the mixture is then
added sufficient ethanol to consume the excess potassium
permanganate. The reaction mixture is then filtered and the
filtrate treated with an excess of dilute aqueous hydrochloric
acid. This reaction mixture is then filtered and the cake washed
with (2.times. 15 ml.) water to obtain
4'-methylsulfonyl-4-biphenylacetic acid.
When 4'-propylmercapto-4-biphenylacetic acid and the
methylmercapto-4-biphenylacetic acids, esters, and methylmercapto
benzoic acid compounds obtained from example 13 are used in place
of 4'-methylmercapto-4-biphenylacetic acid in the above example,
there are obtained the corresponding
4'-propylsulfonyl-4-biphenyl-acetic acid,
methylsulfonyl-4-biphenylacetic acids, esters, and methylsulfonyl
benzoic acid compounds respectively.
Similarly, when the methylmercapto ketone compounds obtained from
example 13 are used in place of 4'-methylmercapto-4-biphenylacetic
acid in the above example, there are obtained the corresponding
methylsulfonyl ketone compounds.
EXAMPLE 15
4'-(N,N-dimethylsulfonamido)-4-biphenylacetic acid
A. Ethyl 4'-(N,N-dimethylsulfonamido)-4-biphenylacetate
A solution of 0.1 mole of ethyl 4'-mercapto-4-biphenylacetate in
100 ml. of 1N sodium hydroxide solution is treated with a slight
excess of potassium permanganate. When the oxidation is complete,
the manganese dioxide is removed by filtration, the filtrate
concentrated to a small volume, and the
4'-carboethoxymethyl-4-biphenylsulfonic acid is isolated by
acidification with hydrochloric acid. The sulfonic acid compound is
then thoroughly dried and heated at reflux with an excess of
thionyl chloride. The excess thionyl chloride is then removed by
distillation, leaving a residue of
4'-carboethoxymethyl-4-biphenylsulfonyl chloride. To this residue
is added a solution of 100 ml. of chloroform with an excess of
dimethylamine and the mixture stirred for an hour. The mixture is
then washed with water, dried over sodium sulfate and concentrated
in vacuo, to yield ethyl
4'-(N,N-dimethylsulfonamido)-4-biphenylacetate.
B. 4'-(N,N-dimethylsulfonamido)-4-biphenylacetic acid
A solution of the ethyl ester thus obtained in 90 percent aqueous
ethanol containing 2 equivalents of sodium hydroxide is allowed to
stand at room temperature for 18 hours. The mixture is then
concentrated in vacuo and acidified with dilute hydrochloric acid
to yield 4'-(N,N-dimethylsulfonamido)-4-biphenylacetic acid.
When the mercapto-4-biphenylacetates obtained from example 12 are
used in place of ethyl 4'-mercapto-4-biphenylacetate in the above
example, there are obtained the corresponding
(N,N-dimethylsulfonamido)-4-biphenylacetic acids.
Similarly, when the mercapto ketone compounds obtained from example
12 are used in place of ethyl 4'-mercapto-4-biphenylacetate in the
above example, there are obtained the corresponding
N,N-dimethylsulfonamido ketone compounds.
EXAMPLE 16
4'-Fluoro-4-biphenylacetic acid
A solution of 0.01 mole of 4'-amino-4-biphenylacetic acid in 50 ml.
of 5N hydrochloric acid is cooled to 5.degree. C. and diazotized
with 0.02 mole of sodium nitrite in 4 ml. of water. After the
addition of 10 ml. of 50 percent fluoboric acid, the supernatant is
decanted from the remaining reaction mixture. This remaining
portion of the reaction mixture is warmed with 30 ml. of toluene on
a steam bath until evolution of nitrogen ceases. The cooled mixture
is extracted with dilute sodium hydroxide. The alkaline solution is
treated with charcoal, filtered, acidified, and extracted with
(3.times. 25 ml.) ether. The ethereal solution is then washed,
dried, and concentrated to yield 4'-fluoro-4-biphenylacetic
acid.
When the amino-4-biphenylacetic acids and esters obtained from
example 10 are used in place of 4'5N -amino-4 -biphenylacetic acid
in the above example, there are obtained the corresponding
fluoro-4-biphenylacetic acids and esters.
Similarly, when the amino ketone compounds obtained from example 10
are used in place of 4'-amino-4-biphenyl-acetic acid in the above
example, there are obtained the corresponding fluoro ketone
compounds.
EXAMPLE 17
4'-Dimethylamino-4-biphenylacetic acid
To a solution of 0.005 mole of a hydrochloride of
4'-amino-4-biphenylacetic acid in 50 ml. of methanol is added 1/2
gram of anhydrous sodium acetate, 4 ml. of 37 percent formaldehyde,
and 11/2 grams of 10 percent palladium on charcoal. The mixture is
then hydrogenated at room temperature and 40 p.s.i. The reaction
mixture is filtered and the solids washed with fresh methanol. The
combined methanol filtrate is then evaporated in vacuo and the
residue is extracted with boiling benzene. The benzene extract is
the evaporated in vacuo to yield 4'-dimethyl-amino-4-biphenylacetic
acid.
When the amino-4-biphenylacetic acids obtained from example 10 are
used in place of the 4'-amino-4-biphenylacetic acid in the above
example, there are obtained the corresponding
dimethylamino-4-biphenylacetic acids.
Similarly, when the amino ketone compounds obtained from example 10
are used in place of 4'-amino-4-biphenylacetic acid in the above
example, there are obtained the corresponding dimethylamino ketone
compounds.
EXAMPLE 18
Ethyl 4'-cyano-4-biphenylacetate
A mixture of 10 millimoles of ethyl 4'-amino-4-biphenylacetate, 3
ml. of concentrated hydrochloric acid, and 15 grams of ice is
diazotized with ice-cooling by adding a concentrated aqueous
solution of sodium nitrite until a slight excess of nitrous acid is
present. The solution is then carefully neutralized by adding solid
sodium carbonate. This reaction mixture is then slowly added to a
solution of 15 millimoles of cuprous cyanide and 30 millimoles of
potassium cyanide in 10 ml. of water maintained at 5.degree. C. The
temperature of the solution is slowly increased to
50.degree.-60.degree. C. until the diazonium salt has decomposed.
The reaction mixture is then cooled and rendered acidic and is
extracted with (3.times. 25 ml.) benzene. The benzene solution is
then dried and chromatographed on a silica gel column to yield
ethyl 4'-cyano-4-biphenylacetate.
When the ethyl amino-4-biphenylacetates obtained from example 10
are used in place of the ethyl 4'-amino-4-biphenylacetate in the
above example, there are obtained the corresponding ethyl
cyano-4-biphenylacetates.
Similarly, when the amino ketone compounds obtained from example 10
are used in place of ethyl 4'-amino-4-biphenylacetate in the above
example, there are obtained the corresponding cyano ketone
compounds.
When the amino-4-biphenylacetic acids obtained from example 10 are
used in place of ethyl 4'-amino-4-biphenylacetate in the above
example, there are obtained the corresponding
cyano-4-biphenylacetic acids.
EXAMPLE 19
Ethyl 4'-carbobenzyloxy-4-biphenylacetate
A mixture of 0.01 mole of ethyl 4'-cyano-4-biphenylacetate, 0.01
mole of anhydrous benzyl alcohol, and 25 ml. of anhydrous benzene
is cooled to 0.degree. C., saturated with anhydrous hydrogen
chloride, and the resulting mixture allowed to stand at room
temperature for several days. The solvent is then removed in vacuo,
the residue triturated well with ether, and the ether decanted from
the residue. 250 ml. of water and 10 ml. of 2.5N hydrochloric acid
is then added to the residue and the mixture refluxed for 21/2
hours. The cooled reaction mixture is then extracted with (3.times.
50 ml.) ether, the ether extract dried over anhydrous magnesium
sulfate, charcoaled, and filtered. The ether filtrate is then
concentrated in vacuo to yield ethyl
4'-carbo-benzyloxy-4-biphenylacetate.
When the ethyl cyano-4-biphenylacetates obtained from example 18
are used in place of ethyl 4'-cyano-4-biphenylacetate in the above
example, there are obtained the corresponding ethyl
carbobenzyloxy-4-biplenyl-acetates.
Similarly, when the cyano ketone compounds obtained from example 18
are used in place of ethyl 4'-cyano-4-biphenylacetate in the above
example, there are obtained the corresponding carbobenzyloxy ketone
compounds.
EXAMPLE 20
Ethyl 4'-carboxy-4-biphenylacetate
A solution of 0.01 mole of ethyl
4'-carbo-benzyloxy-4-biphenylacetate in 200 ml. of methanol is
treated with hydrogen at room temperature and an initial pressure
of 40 p.s.i. in the presence of 21/2 grams of 5 percent palladium
on carbon. When the theoretical yield of hydrogen is absorbed, the
reaction mixture is filtered and the filtrate concentrated in
vacuo. This residue is then partitioned between ether and dilute
potassium hydrogen carbonate solution, the layers separated, the
ether solution extracted with fresh bicarbonate solution, and the
bicarbonate layers combined. The bicarbonate reaction mixture is
then washed with ether, acidified with hydrochloric acid with
cooling, and extracted with ether. The ether extract is then dried
over anhydrous magnesium sulfate, charcoaled, filtered, and
concentrated to yield ethyl 4'-carboxy-4-biphenylacetate.
When the ethyl carbobenzyloxy-4-biphenylacetates obtained from
example 19 are used in place of ethyl 4'
-carbobenzyloxy-4-biphenylacetate in the above example, there are
obtained the corresponding ethyl carboxy-4-biphenylacetates.
Similarly, when the carbobenzyloxy ketone compounds obtained from
example 19 are used in place of ethyl
4'-carbobenzyloxy-4-biphenylacetate in the above example, there are
obtained the corresponding carboxy ketone compounds.
EXAMPLE 21
Ethyl 4'-trifluoromethyl-4-biphenylacetate
A mixture of 0.1 mole of ethyl 4'-carboxy-4 -biphenylacetate and
0.3 mole of sulfur tetrafluoride is heated at 150.degree. C. for 12
hours in a sealed stainless steel bomb. After cooling, the bomb is
vented to release all gaseous material, the residue taken up in
ether, washed with dilute potassium bicarbonate solution, water,
and dried over anhydrous magnesium sulfate. The ether solution is
then charcoaled, filtered, and the filtrate concentrated to a
residue. The residue is then chromatographed on a 1-kilogram silica
gel column using an ether-petroleum ether system (v/v 0-60 percent
ether) as eluent to yield ethyl
4'-trifluoromethyl-4-biphenylacetate.
When the ethyl carboxy-4-biphenylacetates obtained from example 20
are used in place of ethyl 4'-carboxy-4-biphenylacetate in the
above example, there are obtained the corresponding ethyl
trifluoromethyl-4-biphenylacetates.
EXAMPLE 22
Ethyl 4'-carboxamido-4-biphenylacetate
0.1 mole of ethyl 4'-carboxy-4-biphenylacetate is slowly added to a
cooled portion of 60 ml. of thionyl chloride and the resulting
mixture refluxed for 2 hours. The excess thionyl chloride is then
removed in vacuo. The residual acid halide is then taken up in 70
ml. of dry ether and the resulting ether solution slowly added to a
stirred solution of 28 percent ammonium hydroxide over a period of
30 minutes. The reaction mixture is then allowed to stir for an
additional hour at room temperature. The reaction mixture is then
filtered and the cake air-dried to yield ethyl
4'-carboxamido-4-biphenylacetate.
When the equivalent amount of dimethylamine, dipropylamine, or
methylethylamine in water is used in place of the ammonium
hydroxide in the above example, there is obtained the corresponding
4'-dimethylcarboxamido, 4'-dipropylcarboxamido, or
4'-methylethylcarboxamido esters respectively.
Similarly, when the ethyl carboxy-4-biphenylacetates obtained from
example 20 are used in place of ethyl 4'-carboxy-4-biphenylacetate
in the above example, there are obtained the corresponding ethyl
carboxamido-4-biphenylacetates.
Similarly, when the carboxy ketone compounds obtained from example
20 are used in place of ethyl 4'-carboxy-4-biphenylacetate in the
above example, there are obtained the corresponding carboxamido
ketone compounds, and when the equivalent amount of dimethylamine,
dipropylamine, or methylethylamine in water is used in place of the
ammonium hydroxide in the above example and the carboxy ketone
compounds are used in place of ethyl 4'-carboxy-4-biphenylacetate
in the above example, there are obtained the corresponding
substituted carboxamido ketone compounds.
EXAMPLE 23
4'-Trifluoromethyl-4-biphenylacetic acid
A solution of 0.01 mole of potassium hydroxide in 3 ml. of water is
added to a cooled solution of 0.01 mole of ethyl
4'-trifluoromethyl-4-biphenylacetate in 30 ml. of methanol,
additional water or methanol added until the faintest cloudiness
persists, and the resulting mixture stirred overnight at room
temperature. Excess water is then added to the reaction mixture,
the methanol removed in vacuo, and the aqueous mixture washed well
with either. The aqueous mixture is then made acidic with 2.5N
hydrochloric acid, extracted with (3.times. 25 ml.) ether, and the
combined ether extracts dried over anhydrous magnesium sulfate. The
ether extract is then filtered and the filtrate concentrated in
vacuo to yield 4'-trifluoromethyl-4-biphenylacetic acid.
When the ethyl trifluoromethyl-4-biphenylacetates obtained from
example 21 are used in place of ethyl
4'-trifluoromethyl-4-biphenylacetate in the above example, there
are obtained the corresponding trifluoromethyl-4-biphenylacetic
acids.
Similarly, when the ethyl carboxamido-4-biphenylacetates obtained
from example 22 are used in place of ethyl
4'-trifluoromethyl-4-biphenylacetate in the above example and
1,2-dimethoxyethane is used in place of methanol in the above
example, there are obtained the corresponding
carboxamido-4-biphenylacetic acids.
EXAMPLE 24
Methyl 2-methyl-4-biphenylacetate
A. Methyl 2-carboxychloro-4-biphenylacetate
The procedure of example 6, Part A, is used, using methyl
2-carboxy-4-biphenylacetate in place of 4 -(p-nitrophenyl)-benzoic
acid to obtain methyl 2-carboxychloro-4-biphenylacetate.
B. Methyl 2-aldehydo-4-biphenylacetate
The residue obtained from A above is reacted with 0.01 mole of
lithium aluminum tritertiarybutoxy hydride in 50 ml. of
tetrahydrofuran over a period of 3 hours at -10.degree. C. The
reaction mixture is then concentrated in vacuo to a residue to
obtain crude methyl 2-aldehydo-4-biphenylacetate.
C. Methyl 2-hydroxymethyl-4-biphenylacetate
The residue obtained from B above is reacted with 0.01 mole of
sodium borohydride in 25 ml. of methanol at 0.degree. C. for 2
hours. The reaction mixture is then concentrated in vacuo to obtain
methyl 2-hydroxymethyl-4-biphenylacetate.
D. Methyl 2-chloromethyl-4-biphenylacetate
The residue obtained from C above is treated with 25 ml. of thionyl
chloride at room temperature overnight. The reaction mixture is
then concentrated in vacuo to obtain a crude residue of methyl
2-chloromethyl-4-biphenylacetate.
E. Methyl 2-methyl-4-biphenylacetate
The residue obtained from D above is reacted with 1.0 gram of 10
percent palladium on charcoal in 15 ml. of methyl acetate at
50.degree. C. over a period of 4 hours.
When the ethyl carboxy-4-biphenylacetates obtained from example 20
are used in place of the methyl 2-carboxy-4-biphenylacetate in the
above example, there are obtained the corresponding ethyl
methyl-4-biphenylacetates.
EXAMPLE 25
Methyl 2-ethyl-4-biphenylacetate
A. Methyl 2-ethylidene-4-biphenylacetate
To a solution of 0.01 mole of methyl 2-aldehydo-4-biphenylacetate
in 50 ml. of benzene is added 0.01 mole of methylene
triphenylphosphorane and the reaction mixture stirred at room
temperature for 2 hours followed by heating the reaction at
80.degree. C. for an additional 6 hours. The reaction mixture is
then concentrated in vacuo to yield a crude residue of methyl
2-ethylidene-4-biphenylacetate.
B. Methyl 2-ethyl-4-biphenylacetate
The residue obtained from A above in 25 ml. of methanol is reacted
with 0.2 gram of palladium on carbon under 40 p.s.i. of hydrogen
pressure at room temperature until the theoretical amount of
hydrogen is taken up. The reaction mixture is then filtered and the
filtrate concentrated in vacuo to yield a crude residue of methyl
2-ethyl-4-biphenylacetate.
When ethylidene triphenylphosphorane is used in place of methylene
triphenylphosphorane in part A of the above example and the product
thereof is reacted as in part B above, there is obtained methyl
2-propyl-4-biphenylacetate.
Similarly, when the ethyl aldehydo-4-biphenyl-acetates obtained
from example 24, part B, are used in place of the methyl
2-aldehydo-4-biphenylacetate in the above example, there are
obtained the corresponding ethyl ethyl 4-biphenylacetates.
EXAMPLE 26
When the lower alkyl 4-biphenylacetates obtained from examples 24
and 25 are used in place of ethyl
4'-trifluoromethyl-4-biphenylacetate in example 23, there are
obtained the corresponding lower alkyl 4-biphenylacetic acids.
EXAMPLE 27
Ethyl 4'-acetamido-4-biphenylacetate
To a solution of 0.01 mole of ethyl 4'-amino-4-biphenylacetate in
100 ml. of benzene is added 0.01 mole of acetic anhydride and the
reaction mixture is then refluxed for 3 hours. The reaction mixture
is then cooled to room temperature, washed with (3.times. 50 ml.)
water, the benzene solution dried over sodium sulfate and
concentrated in vacuo to yield ethyl
4'-acetamido-4-biphenylacetate.
When the amino ethyl esters obtained from example 10 are used in
place of ethyl 4'-amino-4-biphenylacetate in the above example,
there are obtained the corresponding acetamido esters.
EXAMPLE 28
3-Methyl-4-biphenylacetic acid
A mixture of 3.5 grams of 2'-methyl-4'-phenylacetophenone, 1.03
grams of sulfur, and 8 ml. of morpholine is refluxed overnight
under nitrogen. To the solution is then added 105 ml. of 15 percent
potassium hydroxide and the reaction mixture refluxed for an
additional 16 hours. The reaction mixture is then filtered while
hot and the filtrate acidified with concentrated hydrochloric acid.
The mixture is then filtered and the cake washed with (2.times. 10
ml.) water. The cake is then placed in approximately 500 ml. of
ethanol, the mixture boiled for several minutes, and filtered. The
filtrate is taken to a small volume in vacuo. The solution is then
heated and water added until it becomes turbid. The mixture is then
cooled and filtered. The cake thus obtained is dissolved in
chloroform and the solution evaporated to a small volume. The
solution is then diluted with an excess of petroleum ether, cooled
overnight, filtered, and the solid washed with petroleum ether and
air-dried to yield 3-methyl-4-biphenylacetic acid, m.p. 138.degree.
- 140.degree. C.
When 3'-methyl-4'-phenylacetophenone,
2'-chloro-4'-phenylacetophenone, 4'-(p-bromophenyl)-acetophenone,
and 4'-(p-methylphenyl)-acetophenone are used in place of
2'-methyl-4'-phenylacetophenone in the above example, there are
obtained 2-methyl-4-biphenylacetic acid (m.p., 110.5.degree. -
111.5.degree. C.), 2-chloro-4-biphenylacetic acid (m.p.,
102.5.degree. - 104.degree. C.), 4'-bromo-4-biphenylacetic acid
(m.p., 175.degree. - 177.degree. C.), 4'-methyl-4-biphenylacetic
acid (m.p., 178.degree. - 180.degree. C.), and
4'-chloro-4-biphenylacetic acid (m.p., 158.degree. - 160.degree.
C.).
Similarly, when the chloro-4'-phenylacetophenones,
mercapto-4'-phenylacetophenones,
methylmercapto-4'-phenylacetophenones,
methylsulfonyl-4-phenylacetophenones,
(N,N-dimethylsulfonamido)-4'-phenylacetophenones,
fluoro-4'-phenylacetophenones, and
dimethylamino-4'-phenylacetophenones obtained from examples 11, 12,
13, 14, 15, 16, and 17 are used in place of
2'-methyl-4'-phenylacetophenone in the above example, there are
obtained the corresponding substituted 4-biphenylacetic acids.
EXAMPLE 29
2'-Chloro-4-biphenylacetic acid
A mixture of 3.8 grams of 2'-chloro-4-biphenylmethyl ketone, 1.03
grams of sulfur, and 8 ml. of morpholine is refluxed under nitrogen
for 16 hours. To the reaction mixture is added 105 ml. of 15
percent potassium hydroxide and the reaction mixture refluxed for
an additional 16 hours. The reaction mixture is then filtered while
hot and the filtrate acidified with concentrated hydrochloric acid
and cooled. The reaction mixture is then filtered, the cake washed
with water and dissolved in a minimum amount of chloroform. The
chloroform solution is then taken to a small volume and an excess
of petroleum ether added. After crystallization begins, the mixture
is cooled in an ice bath, subsequently filtered, and the solid thus
obtained washed with petroleum ether and air-dried to yield
2'-chloro-4-biphenylacetic acid, m.p., 121.degree. - 123.degree.
C.
EXAMPLE 30
.alpha.-Hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetic acid
A.
.alpha.-Hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetonitrile
To a solution of 4 ml. of hydrogen cyanide containing 0.02 ml. of
piperidine in an ice water bath is added 3.5 grams of
3'-chloro-4'-phenylacetophenone over a period of 8 minutes. The
solution is stirred in the cold over a period of 80 minutes, during
which time 2.times. 0.02 ml. portions of piperidine are added.
B. .alpha.-Hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetamide
To the solution of part A is added 2 ml. of ether and the solution
then poured into 15 ml. of concentrated hydrochloric acid with
stirring in an ice-salt bath. At this point, sufficient gaseous
hydrochloric acid is bubbled into the solution so as to saturate
the solution. The solution is then allowed to warm to room
temperature and is stirred overnight. 50 ml. of water is then added
and the solution extracted with (3.times. 50 ml.) ether. The ether
solution is then washed with (3.times. 15 ml.) water and dried over
magnesium sulfate. The ether solution is then concentrated in vacuo
to a solid.
C. .alpha.-Hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetic
acid
To 500 mg. of the solid thus obtained in part B in 13 ml. of
ethanol is added a solution of 250 mg. of potassium hydroxide in 3
ml. of water and the mixture refluxed gently under nitrogen for 15
hours. To the solution is then added 25 ml. of water and the
solution extracted with (3.times. 25 ml.) ether. The aqueous
solution is then made acid with dilute aqueous hydrochloric acid
and filtered. The cake is then washed with (2.times. 25 ml.) water
and subsequently dried to yield
.alpha.-hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetic acid,
m.p., 142.5.degree. - 145.degree. C.
When the amino ketones, halo ketones, mercapto ketones,
methylmercapto ketones, methylsulfonyl ketones,
(N,N-dimethylsulfonamido) ketones, fluoro ketones, dimethylamino
ketones, 4-biphenylacetophenone, and 4-phenylacetophenone obtained
from examples 10, 11, 12, 13, 14, 15, 16, 17, and 2 respectively
are used in place of 3'-chloro-4'-phenylacetophenone in the above
example, there are obtained the corresponding
.alpha.-hydroxy-.alpha.-methyl-substituted-4-biphenylacetic acids,
.alpha.-hydroxy-.alpha.-ethyl-substituted-4-biphenylacetic acids,
.alpha.-hydroxy-.alpha.-propyl-substituted-4-biphenylacetic acids,
and .alpha.-hydroxy-.alpha.-methyl-4-biphenylacetic acids.
EXAMPLE 31
Ethyl 2'-chloro-4-biphenylglyoxalate
To a solution of 100 ml. of carbon tetrachloride and 15.7 grams of
ethyl oxalyl chloride at -5.degree. C. is added with stirring 17
grams of aluminum chloride followed by a solution of 21.7 grams of
2-chlorobiphenyl in 50 ml. of chloroform. After complete addition
of the chloroform solution (approximately 11/2 hours), 150 ml. of
ethylene dichloride is added and the reaction mixture allowed to
come to room temperature. The reaction mixture is then poured into
300 grams of ice and 10 ml. hydrochloric acid. The organic layer is
separated, dried, and concentrated in vacuo. The residue is then
dissolved in a minimum amount of benzene-petroleum ether and
chromatographed on 1059 grams of silica gel and eluted with benzene
to yield ethyl 2'-chloro-4-biphenylglyoxalate.
When 4-fluorobiphenyl is used in place of 2-chlorobiphenyl and
ethylene dichloride is used in place of carbon tetrachloride in the
above example, there is obtained ethyl
4'-fluoro-4-biphenylglyoxalate, m.p. 52.degree. - 53.degree. C.
EXAMPLE 32
.alpha.-Hhydroxy-.alpha.-methyl-2'-chloro-4-biphenylacetic acid
To a mixture of 1.54 grams of magnesium turnings in 40 ml. of ether
is added with stirring 9.3 grams of methyl iodide. After complete
addition, more methyl iodide is added to consume any unreacted
magnesium. This Grignard solution is then added dropwise to a cold,
stirred solution of 12.9 grams of ethyl
2'-chloro-4-biphenylglyoxalate in 75 ml. of ether. After complete
addition, the reaction mixture is allowed to stir in the cold for
an additional hour. The reaction mixture is then refluxed for 3
hours, cooled, and poured into 200 ml. of ice-dilute sulfuric acid
solution. The ether layer is then separated, washed with water,
dried, and concentrated in vacuo to a crude syrup. The syrup is
then placed in 150 ml. of 10 percent potassium hydroxide-methanol
and refluxed for approximately 2 hours. The reaction mixture is
then poured into approximately 500 ml. of water, acidified with
2.5N hydrochloric acid, extracted with (2.times. 50 ml.) ether, and
the ether solution dried and concentrated in vacuo to a residue.
The residue is then dissolved in a minimum amount of methanol,
charcoaled, filtered, and the filtrate concentrated in vacuo. The
residue is then dissolved in a small volume of boiling benzene.
Sufficient petroleum ether is then added to make the solution
turbid, and after crystallization starts, a large excess of
petroleum ether is added and the mixture allowed to remain at room
temperature overnight. The mixture is then filtered and the cake
washed with petroleum ether and air-dried to yield
.alpha.-hydroxy-.alpha.-methyl-2'-chloro-4-biphenylacetic acid,
m.p. 135.degree. - 137.degree. C.
When ethyl 4'-fluoro-4-biphenylglyoxalate is used in the above
example in place of ethyl 2'-chloro-4-biphenylglyoxalate, there is
obtained .alpha.-hydroxy-.alpha.-methyl-4'-fluoro-4-biphenylacetic
acid, m.p. 163.degree. - 164.degree. C.
EXAMPLE 33
.alpha.-Methylene-2-chloro-4-biphenylacetic acid
A mixture of 1.5 grams of
.alpha.-hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetic acid, 260
mg. of p-toluenesulfonic acid and 30 ml. of toluene is refluxed for
5 hours and the water produced removed by means of a Dean Stark
trap. The solution is then cooled to room temperature and filtered.
The cake is washed with (2.times. 25 ml.) benzene. The cake is then
mixed with 25 ml. of ether and the ether solution washed with
(2.times. 10 ml.) water and dried over magnesium sulfate. The ether
solution is then concentrated in vacuo to yield crude
.alpha.-methylene-2-chloro-4-biphenylacetic acid, m.p. 131.degree.
- 144.degree. C.
When .alpha.-hydroxy-.alpha.-methyl-2'-chloro-4-biphenylacetic acid
and .alpha.-hydroxy-.alpha.-methyl-4'-fluoro-4-biphenylacetic acid
are used in place of
.alpha.-hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetic acid in
the above example, there are obtained
.alpha.-methylene-2'-chloro-4-biphenylacetic acid and
.alpha.-methylene-4'-fluoro-4-biphenylacetic acid (m.p. 172.degree.
- 174.degree. C.).
Similarly, when the
.alpha.-hydroxy-.alpha.-methyl-substituted-4-biphenylacetic acids,
.alpha.-hydroxy-.alpha.-ethyl-substituted-4-biphenylacetic acids,
.alpha.-hydroxy-.alpha.-propyl-substituted-4-biphenylacetic acids,
and the .alpha.-hydroxy-.alpha.-methyl-4-biphenylacetic acids
obtained from example 30 and the 2'-chloro and 4'-fluoro compounds
obtained from example 32 are used in place of
.alpha.-hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetic acid in
the above example, there are obtained the corresponding
.alpha.-methylene-substituted-4-biphenylacetic acids,
.alpha.-ethylidene-substituted-4-biphenylacetic acids,
.alpha.-propylidene-substituted 4-biphenylacetic acids,
.alpha.-methylene-4-biphenylacetic acids, and .alpha.-methylene,
2'-chloro, and 4'-fluoro 4-biphenylacetic acids.
EXAMPLE 34
.alpha.-Methyl-2-chloro-4-biphenylacetic acid
A mixture of 0.8 gram of .alpha.-methylene-
2-chloro-4-biphenylacetic acid and 0.03 mg. of platinum oxide in 10
ml. of ethanol is hydrogenated at room temperature under 40 p.s.i.
The solution is then filtered and the filtrate concentrated in
vacuo. The crude material is then taken up in 25 ml. of ether and
the ether solution washed with (1.times. 15 ml.) water and dried
over magnesium sulfate. The ether solution is then extracted with
(3.times. 25 ml.) aqueous sodium carbonate. The sodium carbonate
solution is then made acid by the addition of sufficient dilute
hydrochloric acid, and then extracted with (3.times. 25 ml.) ether
and the ether extract dried over magnesium sulfate. The ether
solution is then concentrated in vacuo to a crude solid of
.alpha.-methyl-2-chloro-4-biphenylacetic acid, m.p. 122.degree. -
128.degree. C.
When .alpha.-methylene-2'-chloro-4-biphenylacetic acid and
.alpha.-methylene-4'fluoro-4 -biphenylacetic acid are used in place
of .alpha.-methylene-2-chloro-4-biphenylacetic acid in the above
example, there are obtained
.alpha.-methyl-2'-chloro-4-biphenylacetic acid and
.alpha.-methyl-4'-fluoro-4-biphenylacetic acid, m.p. 150.degree. -
152.degree. C.
Similarly, when the .alpha.-alkylidene biphenylacetic acids
obtained from example 33 are used in place of
.alpha.-methylene-2-chloro-4 -biphenylacetic acid in the above
example, there are obtained the corresponding .alpha.-lower alkyl
biphenylacetic acids.
EXAMPLE 35
.alpha.-Methyl-2-chloro-4-biphenylacetic acid
To a solution of 1.8 grams of
.alpha.-hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetic acid in 40
ml. of glacial acetic acid is added 0.79 gram of phosphorus and
0.32 gram of iodine. The mixture is then refluxed for 16 hours,
filtered while hot, and the filtrate poured into 150 ml. of ice
water. The mixture is then filtered and the cake thus obtained
dissolved in chloroform, washed with water, dried over magnesium
sulfate, charcoaled, and the solvent removed in vacuo to yield
.alpha.-methyl-2-chloro-4-biphenylacetic acid.
When the .alpha.-hydroxy-.alpha.-lower alkyl-4-biphenylacetic acids
obtained from example 30 are used in place of
.alpha.-hydroxy-.alpha.-methyl-2-chloro-4-biphenylacetic acid in
the above example, there are obtained the corresponding
.alpha.-lower alkyl-4-biphenylacetic acids.
EXAMPLE 36
4'-Nitro-4-biphenylacetic acid
2'-Nitro-4-biphenylacetic acid
2-Nitro-4-biphenylacetic acid
A mixture of 100 ml. of glacial acetic acid and 150 ml. of nitric
acid (d= 1.42) is gradually added to 0.18 mole of ethyl
4-biphenylacetate in 100 ml. of glacial acetic acid. The reaction
mixture is stirred at room temperature for 24 hours, at which time
the reaction mixture is concentrated in vacuo to a residue. The
residue is then chromatographed on a silica gel column using
ether-petroleum ether as the eluent (0- 100 percent) to yield the
various fractions of ethyl 4'-nitro-4-biphenylacetate, ethyl
2'-nitro-4-biphenylacetate, and ethyl 2-nitro-4-biphenylacetate.
The ether-petroleum ether fractions are then concentrated in
dryness, and each residue is separately saponified using the method
described in example 23 to yield the corresponding nitro
4-biphenylacetic acids.
When ethyl .alpha.-methyl-4-biphenylacetate, ethyl
.alpha.-propyl-4-biphenylacetate, ethyl
.alpha.-diethyl-4-biphenylacetate, ethyl
.alpha.-fluoro-4-biphenylacetate, ethyl
.alpha.-methoxy-4-biphenylacetate, and ethyl
.alpha.-trifluoromethyl-4-biphenylacetate obtained from example 57
are used in place of ethyl 4-biphenylacetate in the above example,
there are obtained the corresponding 4'-nitro, 2'-nitro, and
2-nitro 4-biphenylacetic acids.
EXAMPLE 37
When the nitro compounds obtained from example 36 are used in place
of the 4'-nitro-4-biphenylacetic acid in example 10, there are
obtained the corresponding amino 4-biphenylacetic acids. When these
amino 4-biphenylacetic acids are successively treated according to
examples 11 through 14 and 16 through 27, there are obtained the
corresponding appropriately substituted 4-biphenylacetic acids and
esters.
When the mercapto compounds obtained from the above example are
used in place of the 4'-fluoro-4-biphenylacetic acid of example 57
and the esters thus obtained treated in accordance with example 15,
there are obtained the corresponding
N,N-dimethylsulfonamido-4-biphenylacetic acids.
EXAMPLE 38
Methyl .alpha.-pyrazolino-2-chloro-4-biphenylacetate
To a solution of 0.0241 mole of
.alpha.-methylene-2-chloro-4-biphenylacetic acid in 200 ml. of
ether-ethyl acetate (1:1) is added an excess of a solution of
diazomethane in ether. The reaction mixture is stirred at room
temperature for 16 hours. At this point, the excess diazomethane is
removed by the dropwise addition of acetic acid. The reaction
mixture is concentrated in vacuo to a residue and the residue
chromatographed on 500 grams of silica gel using 10 percent
ether-petroleum ether as eluent to yield methyl
.alpha.-pyrazolino-2-chloro-4-biphenylacetate.
When the .alpha.-methylene-substituted-4-biphenylacetic acids,
.alpha.-methylene-2'-chloro-4-biphenylacetic acid, and
.alpha.-methylene-4'-fluoro-4-biphenylacetic acid obtained from
example 33 are used in place of
.alpha.-methylene-2-chloro-4-biphenylacetic acid in the above
example, there are obtained the corresponding methyl
.alpha.-pyrazolino-4-biphenylacetates.
EXAMPLE 39
Methyl .alpha.-cyclopropyl-2-chloro-4-biphenylacetate
300 mg. of methyl .alpha.-pyrazolino-2-chloro-4-biphenylacetate is
heated on a steam bath for 15 minutes. To the reaction mixture is
then added 20 ml. of benzene and 300 mg. of osmium oxide and the
reaction mixture stirred for 16 hours. The reaction mixture is then
poured into 25 ml. of 2.5N hydrochloric acid. The organic layer is
then separated, washed with water, dried, and chromatographed on a
silica gel column using benzene as eluent to yield methyl
.alpha.-cyclopropyl-2-chloro-4-biphenylacetate.
When the methyl .alpha.-pyrazolino-substituted-4-biphenylacetates,
methyl .alpha.-pyrazolino-2'-chloro-4-biphenylacetate, and methyl
.alpha.-pyrazolino-4'-fluoro-4-biphenylacetate obtained from
example 37 are used in place of methyl
.alpha.-pyrazolino-2-chloro-4-biphenylacetate in the above example,
there are obtained the corresponding methyl
.alpha.-cyclopropyl-substituted-4-biphenylacetates, methyl
.alpha.-cyclopropyl-2'-chloro-4-biphenylacetate, and methyl
.alpha.-cyclopropyl-4'-fluoro-4-biphenylacetate respectively.
EXAMPLE 40
When the .alpha.-pyrazolino-4-biphenylacetates obtained from
example 38 and the .alpha.-cyclopropyl-4-biphenylacetates obtained
from example 39 are used in place of ethyl
4'-trifluoromethyl-4-biphenylacetate in example 23, there are
obtained the corresponding .alpha.-pyrazolino-4-biphenylacetic
acids and .alpha.-cyclopropyl-4-biphenylacetic acids.
EXAMPLE 41
When the .alpha.-pyrazolino-4-biphenylacetic acids obtained from
example 40 are used in place of methyl
.alpha.-pyrazolino-2-chloro-4-biphenylacetate in example 39 and the
compound heated above its melting point, there is obtained the
corresponding .alpha.-cyclopropyl-4-biphenylacetic acids.
EXAMPLE 42
4'-fluoro-4-biphenylacetamide
To 0.141 mole of 4'-fluoro-4-biphenylacetic acid is added dropwise
over a period of 5 minutes 100 grams of thionyl chloride. The
reaction mixture is heated on a steam bath for 31/2 hours. The
reaction mixture is then concentrated in vacuo and to the residue
is added 100 ml. of ether. This ether reaction mixture is then
added dropwise to 500 ml. of concentrated ammonium hydroxide. The
reaction mixture is then stirred for an additional hour, filtered,
and the cake washed with water until the washing is neutral. The
cake is then dried in vacuo to yield
4'-fluoro-4-biphenylacetamide.
When the 4-biphenylacetic acids, halo-4-biphenylacetic acids,
methylmercapto-4-biphenylacetic acids,
methylsulfonyl-4-biphenylacetic acids, (N,
N-dimethylsulfonamido)-4-biphenylacetic acids,
fluoro-4-biphenylacetic acids, and trifluoromethyl-4-biphenylacetic
acids obtained from examples 9, 11, 13, 14, 15, 16, and 23
respectively are used in place of 4'-fluoro-4-biphenylacetic acid
in the above example, there are obtained the corresponding
4-biphenylacetamides.
EXAMPLE 43
4'-Flouro-4-biphenylacetonitrile
To 0.03 mole of 4'-fluoro-4-biphenylacetamide is added 0.031 mole
of phosphorous pentachloride. After mixing for approximately 5
minutes, 30 ml. of phosphorous oxychloride is added to the reaction
mixture, which is then heated on a steam bath for 1 hour. The
phosphorous oxychloride is then removed in vacuo and the resulting
reaction mixture is poured into 200 ml. of an ice water mixture.
The reaction mixture is stirred for 40 minutes and then extracted
with (3.times. 50 ml.) ether. The combined ether extract is then
concentrated in vacuo to yield a crude residue of
4'-fluoro-4-biphenylacetonitrile.
When the 4-biphenylacetamides obtained from example 42 are used in
place of 4'-fluoro-4-biphenylacetamide in the above example, there
are obtained the corresponding 4-biphenylacetonitriles.
EXAMPLE 44
.alpha., .alpha.-Dimethyl-4'-fluoro-4-biphenylacetonitrile
To a cooled, stirred mixture of 0.05 mole of
4'-fluoro-4-biphenylacetonitrile, 0.16 mole of sodium amide, and 70
ml. of anhydrous benzene is added 0.19 mole of methyl iodide. The
reaction mixture is then allowed to warm to room temperature and
then heated slowly to 58.degree. C. for 1 hour. The reaction
mixture is then refluxed for an additional 8 hours. To the cooled
reaction mixture is then added dropwise 25 ml. of water, 50 ml. of
2.5N hydrochloric acid, and, finally, 50 ml. each of benzene and
water. After stirring for several minutes, the layers are allowed
to separate. The aqueous layer is extracted with (4.times. 25 ml.)
benzene and the combined benzene solution is dried over sodium
sulfate. The benzene solution is then filtered and the filtrate
concentrated to a residue to yield .alpha.,
.alpha.-dimethyl-4'-fluoro-4-biphenylacetonitrile.
When ethyl iodide or propyl iodide are used in place of methyl
iodide in the above example, there is obtained .alpha.,
.alpha.-diethyl-4'-fluoro-4-biphenylacetronitrile or .alpha.,
.alpha.-dipropyl-4'-fluoro-4-biphenylacetonitrile.
Similarly, when the 4-biphenylacetonitriles obtained from example
43 are used in place of 4'-fluoro-4-biphenylacetonitrile in the
above example, there are obtained the corresponding .alpha.,
.alpha.-dimethyl-4-biphenylacetonitrile compounds.
EXAMPLE 45
.alpha., .alpha.-Dimethyl-4'-fluoro-4-biphenylacetic acid
To a mixture of 0.0052 mole of .alpha.,
.alpha.-dimethyl-4'-fluoro-4-biphenylacetonitrile in 100 ml. of
acetic acid is added 15 ml. of 20 percent hydrochloric acid and the
reaction mixture refluxed for 19 hours. The cooled reaction mixture
is then poured into a mixture of 500 ml. of ice water, extracted
with ether, and the ether extract dried and concentrated to yield
.alpha., .alpha.-dimethyl-4'-fluoro-4-biphenylacetic acid.
When the 4-biphenylacetonitriles obtained from example 44 are used
in place of .alpha.,
.alpha.-dimethyl-4'-fluoro-4-biphenylacetonitrile in the above
example, there are obtained the corresponding 4-biphenylacetic acid
compounds.
EXAMPLE 46
Methyl .alpha.-methyl-4'-fluoro-4-biphenylacetate
A mixture of 0.2 mole of methyl 4'-fluoro-4-biphenylacetate, 40
grams of dimethyloxalate, and 40 grams of potassium
tertiarybutoxide in 500 ml. of benzene is refluxed under nitrogen
for 4 hours with stirring. The cooled reaction mixture is then
filtered and the cake washed with (4.times. 50 ml.) benzene
followed by (4.times. 50 ml.) ether and the cake dried in vacuo. A
mixture of 0.05 mole of this cake and 0.06 mole of methyl iodide in
300 ml. of dimethylformamide is stirred at room temperature for 4
hours, then heated on a steam bath until the reaction mixture is
neutral. To the cooled reaction mixture is then added 0.05 mole of
sodium methoxide in 30 ml. of methanol and the reaction mixture
heated for an additional 2 hours on a steam bath. The cooled
reaction mixture is then added to 1 liter of iced-water containing
0.06 mole of hydrochloric acid. The reaction mixture is then
extracted with (3.times. 200 ml.) either and the combined ether
extract washed with water, sodium carbonate, and water. The ether
solution is then dried over sodium sulfate and concentrated in
vacuo to yield methyl
.alpha.-methyl-4'-fluoro-4-biphenylacetate.
When ethyl iodide or propyl iodide is used in place of methyl
iodide in the above example, there is obtained methyl
.alpha.-ethyl-4'-fluoro-4-biphenylacetate or methyl
.alpha.-propyl-4'-fluoro-4-biphenylacetate.
Similarly, when the ethyl 4-biphenylacetates obtained from example
7, the ethyl halo-4-biphenylacetates, ethyl dilower
alkylsulfonamido-4-biphenylacetates, ethyl lower
alkylmercapto-4-biphenylacetates, ethyl dilower
alkylsulfonyl-4-biphenylacetates, ethyl dilower
alkylcarboxamido-4-biphenylacetates, and ethyl dilower
alkylamino-4-biphenylacetates are used in place of methyl
4'-fluoro-4-biphenylacetate in the above example, there are
obtained the corresponding
.alpha.-ethyl-substituted-4-biphenylacetate compounds.
Similarly, when prop-2-en iodide, but-3-yn iodide, and
2-chloropropyl iodide are used in place of methyl iodide in the
above example, there are obtained the corresponding
.alpha.-prop-2-enyl, .alpha.-but-3-ynyl, and .alpha.-2-chloropropyl
biphenyl compounds.
EXAMPLE 47
Methyl 2, .alpha.-dichloro-4-biphenylacetate
A mixture of 1.0 mole of 2-chloro-4-biphenylacetic acid and 300 ml.
of thionyl chloride is refluxed for 2 hours. 450 ml. of sulfuryl
chloride is then added over a period of 2- 3 hours, maintaining a
gentle reflux during the addition. The mixture is then allowed to
stand overnight at room temperature, after which the excess thionyl
and sulfuryl chlorides are removed in vacuo. The residue is then
carefully poured into 200 ml. of stirred, cooled methanol and
allowed to stand at room temperature for 2- 3 hours. The excess
methanol is then removed in vacuo to yield crude methyl 2,.alpha.
-dichloro-4-biphenylacetate.
When the 4-biphenylacetic acids obtained from examples 9, 11, 12,
13, 14, 15, 16, 17, 23, and 27 and the 4-biphenylacetates obtained
from examples 18, 21, 24, and 25 are used in place of
2-chloro-4-biphenylacetic acid in the above example, there are
obtained the corresponding .alpha.-chloro-4-biphenylacetates.
EXAMPLE 48
2,.alpha. -Dichloro-4-biphenylacetic acid
A mixture of 1.0 mole of 2-chloro-4-biphenylacetic acid in 450 ml.
of sulfuryl chloride is refluxed over a period of 2- 3 hours. The
mixture is then allowed to stand for 1 hour at room temperature and
the excess sulfuryl chloride removed in vacuo to yield crude
2,.alpha. -dichloro-4-biphenylacetic acid.
When the 4-biphenylacetic acids obtained from examples 9, 11, 12,
13, 14, 15, 16, 17, 23, and 27 are used in place of
2-chloro-4-biphenylacetic acid in the above example, there are
obtained the corresponding .alpha.-chloro-4-biphenylacetic
acids.
EXAMPLE 49
Methyl .alpha.-fluoro-2-chloro-4-biphenylacetate
To a mixture of 20 ml. of diethylene glycol, 0.02 mole of fused
potassium fluoride, and 0.03 gram of potassium iodide maintained at
125.degree. C. is added 0.0073 mole of methyl 2,.alpha.
-dichloro-4-biphenylacetate. The reaction mixture is then stirred
at 119.degree. - 121.degree. C. for 19 hours. The reaction mixture
is then allowed to cool to room temperature and poured into a
stirred mixture of ice and water. The ice-water mixture is then
extracted with 60 ml. of chloroform and the chloroform extract is
washed with water and dried over sodium sulfate. The chloroform
solution is then concentrated in vacuo and the residue taken up in
benzene. The benzene reaction mixture is then concentrated in vacuo
to yield crude methyl
.alpha.-fluoro-2-chloro-4-biphenylacetate.
When the 4-biphenylacetates obtained from example 47 are used in
place of 2,.alpha. -dichloro-4-biphenylacetate in the above
example, there are obtained the corresponding
.alpha.-fluoro-4-biphenylacetates.
EXAMPLE 50
When the .alpha.-chloro compounds obtained from examples 47 and 48
are placed in a mixture of water, methanol, and dilute sodium
hydroxide and the reaction mixture is stirred for approximately 1
hour, there are obtained the corresponding hydroxy compounds.
EXAMPLE 51
.alpha.-Methoxy-2-chloro-4-biphenylacetic acid
A mixture of 0.004 mole of 2,.alpha. -dichloro-4-biphenylacetic
acid in 35 ml. of anhydrous methanol is added to an ice-cooled
solution of 0.21 grams of sodium in 40 ml. of anhydrous methanol.
The reaction mixture is stirred in the ice bath until the reaction
mixture is at room temperature. The reaction mixture is then
stirred at room temperature for an additional 16 hours, whereupon
the mixture is refluxed for 1 hour and allowed to come to room
temperature again. Dilute hydrochloric acid is then added to the
reaction mixture until the reaction mixture becomes acidic. The
reaction mixture is then concentrated in vacuo and the residue
partitioned between ether and water. The ether layer is removed,
washed with water, and extracted with aqueous potassium bicarbonate
solution. The bicarbonate solution is then made acid with dilute
hydrochloric acid and the reaction mixture extracted with
chloroform. The chloroform extract is then dried over sodium
sulfate and concentrated in vacuo. The residue is then
recrystallized from benzene to yield
.alpha.-methoxy-2-chloro-4-biphenylacetic acid, m.p. 129.degree.-
131.5.degree. C.
When the .alpha.-chloro-4-biphenylacetates obtained from example 47
and the .alpha.-chloro-4-biphenylacetic acids obtained from example
48 are used in place of 2,.alpha. -dichloro-4-biphenylacetic acid
in the above example, there are obtained the corresponding
.alpha.-methoxy-4-biphenylacetates and
.alpha.-methoxy-4-biphenylacetic acids.
EXAMPLE 52
.alpha.-Fluoro-2-chloro-4-biphenylacetic acid
To a mixture of 0.0057 mole of methyl
.alpha.-fluoro-2-chloro-4-biphenylacetate in 20 ml. of ethanol is
added a mixture of 0.0057 mole of potassium hydroxide in 2 ml. of
water. The reaction mixture is then allowed to stir for 2 hours at
room temperature. At this point, an excess of hydrochloric acid is
added to the reaction mixture and it is thereafter concentrated in
vacuo to yield crude .alpha.-fluoro-2-chloro-4-biphenylacetic
acid.
When the fluoro-4-biphenylacetates obtained from example 49 are
used in place of methyl .alpha.-fluoro-2-chloro-4-biphenylacetate
in the above example, there are obtained the corresponding
.alpha.-fluoro-4-biphenylacetic acids.
Similarly, when the .alpha.-hydroxy -4-biphenylacetates obtained
from example 50 are used in place of methyl
.alpha.-fluoro-2-chloro-4-biphenylacetate in the above example,
there are obtained the corresponding
.alpha.-hydroxy-4-biphenylacetic acids.
EXAMPLE 53
Ethyl .beta.-trifluoromethyl-4-biphenyl-prop-2-enoate
0.01 mole of 4-biphenyl trifluoromethyl ketone and 0.01 mole of
carbethoxymethylene triphenylphosphorane are refluxed overnight in
75 ml. of dry toluene. The reaction mixture is then filtered and
concentrated in vacuo, the residue is chromatographed on 300 grams
of silica gel and eluted with 25 percent benzene-petroleum ether to
give the desired product. Ethyl
.beta.-trifluromethyl-4-biphenyl-prop-2-enoate is recrystallized
from petroleum ether, m.p. 55.degree.- 57.degree. C.
When 4-(4'-fluorobiphenyl)-trifluoromethyl ketone,
4-(2'-chlorobiphenyl)-trifluoromethyl ketone,
4-(4'-trifluoromethylbiphenyl)-trifluoromethyl ketone,
4-(2-ethylthiobiphenyl)-trifluoromethyl ketone,
4-(2'-carboxamidobiphenyl)-trifluoromethyl ketone,
4-(3'-ethylbiphenyl)-trifluoromethyl ketone,
4-(2'-acetylaminobiphenyl)-trifluoromethyl ketone,
4-(2-dimethylsulfonylbiphenyl)-trifluoromethyl ketone, and
4-(2'-dimethylsulfamylbiphenyl)-trifluoromethyl ketone are used in
place of 4-biphenyl trifluoromethyl ketone in the above example,
there are obtained the corresponding ethyl
.beta.-trifluoromethyl-4-biphenyl-prop-2-enoate compounds.
EXAMPLE 54
Ethyl .beta.-trifluoromethyl-4-biphenylpropanoate
0.0078 mole (2.50 grams) of ethyl
.beta.-trifluoromethyl-4-biphenyl-prop-2-enoate in 25 ml. of
ethanol containing 0.1 gram of PtO.sub.2 is reduced with hydrogen
at 40 pounds of pressure and at room temperature. When an
equivalent amount (0.0078 mole) of hydrogen is taken up, the
reaction mixture is filtered and concentrated to yield crude ethyl
.beta.-trifluoromethyl-4-biphenylpropanoate.
When the prop-2-enoate compounds obtained from example 53 are used
in place of ethyl .beta.-trifluoromethyl-4-biphenyl-prop-2-enoate
in the above example, there are obtained the corresponding
propanoates.
EXAMPLE 55
3-(p-Biphenyl)-1,1diphenyl-3-trifluoromethyl-prop-1-ene
A. 3-(p-Biphenyl)-1,1-diphenyl-3-trifluoromethyl-propan-1-ol
To 0.108 gram (0.023 mole) of magnesium, activated with iodine, in
25 cc. of dry ether containing 1 drop of methyl iodide is added
dropwise 0.022 mole of bromobenzene in 15 cc. of Et.sub.2 O. The
mixture is heated at reflux 2 hours after the addition is complete.
To the cooled mixture is added 0.01 mole of ethyl
.beta.-trifluoromethyl-4-biphenyl-propanoate in 50 ml. of dry
Et.sub.2 O and the reaction mixture allowed to reflux for 3 hours,
then allowed to stir at room temperature overnight. The mixture is
then poured onto a saturated ammonium chloride solution and
extracted well with ether. The ether is washed with water, dried,
and the ether solution concentrated in vacuo. The residue is
chromatographed on 200 grams of silica gel (eluted with 40 percent
ether in petroleum ether) to yield
3-(p-biphenyl)-1,1-diphenyl-3-trifluoromethyl-propan-1-ol.
B. 3-(p-Biphenyl)-1,1-diphenyl-3-trifluoromethyl-prop-1-ene
The crude alcohol obtained from part A is dehydrated by refluxing
with p-toluenesulfonic acid in toluene for 3 hours. The reaction
mixture is then cooled, washed with water, and concentrated. The
residue is chromatographed on 200 grams silica gel and eluted with
10 percent benzene-petroleum ether to give
3-(p-bipheynl)-1,1-diphenyl-3-trifluoromethyl-prop-1-ene.
When the .beta.-trifluoromethyl-4-substituted-biphenylpropanoate
compounds obtained from example 54, excluding the compounds
containing the 2'-carboxamido, 2'-acetylamino, 2-dimethylsulfonyl,
and 2'-dimethylsulfamyl groups, are used in place of
.beta.-trifluoromethyl-4-biphenylpropanoate in part A of the above
example and the product therefrom carried through part B of the
above example, there are obtained the corresponding prop-1-ene
compounds.
EXAMPLE 56
.alpha.-Trifluoromethyl-4-biphenylacetic acid
To a well-stirred solution of 0.01 mole of
3-(p-biphenyl)-1,1-diphenyl-3-trifluoromethyl-prop-1-ene in 10 ml.
of chloroform and 50 ml. of glacial HOAc is added 0.01 mole of
chromium trioxide in 5 ml. of water. After 1 hour, the acetic acid
is removed in vacuum; 100 ml. of 10 percent sulfuric acid is added.
The mixture is then extracted well with ether, the ether extracts
washed with bisulfite solution, water, then dried and concentrated.
The residue is recrystallized from hexane to yield .beta.
-trifluoromethyl-4-biphenylacetic acid.
When the prop-1-ene compounds obtained from example 55 are used in
place of 3-(p-biphenyl)-1,1-diphenyl-3-trifluoromethyl-prop-1-ene
in the above example, there are obtained the corresponding
substituted-biphenylacetic acids.
EXAMPLE 57
Ethyl 4'-fluoro-4-biphenylacetate
A mixture of 0.05 mole of 4'-fluoro-4-biphenylacetic acid, 6 ml. of
concentrated sulfuric acid, and 200 ml. of anhydrous ethanol
(approximately 3 percent sulfuric acid) is stirred at room
temperature overnight. The solution is then concentrated in vacuo
to approximately 1/3 the volume. 200 ml. of water are added and the
mixture extracted with (3.times. 75 ml.) ether. The combined ether
extracts are then washed with saturated potassium bicarbonate
solution and water. The ether solution is then dried over magnesium
sulfate, filtered, and concentrated to a residue. The residue is
then chromatographed on a silica gel column (wt./wt. 50:1 gram
crude) using an ether-petroleum ether system (v/v 20- 60 percent)
as eluent to yield ethyl 4'-fluoro-4-biphenylacetate.
When a solution of gaseous hydrochloric acid in ethanol is used in
place of the sulfuric acid-ethanol solution in the above example,
there is obtained ethyl 4'-fluoro-4-biphenylacetate.
When methanol, n-propanol, i-butanol, prop-2-enol, but-3-ynol,
cyclopropanol, phenol, p-acetylaminophenol, p-carboxyphenol,
m-carboxamidophenol (in an inert solvent and azeotrope the water),
methoxymethanol, methoxycyclopropanol, dimethoxycyclobutanol,
glycerol, dimethylaminoethyl chloride, and aminocyclopropylmethyl
chloride (when reacting the chloride compounds, reflux the acid and
chloride compound in dry isopropanol for 12 hours) are used in
place of ethanol in the above example, there are obtained the
corresponding methyl 4'-fluoro-4-biphenylacetic acid esters.
Similarly, when the 4-biphenylacetic acids obtained from examples
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 23, 26, 27, 33, 34, 36, 37,
40, 45, 51, 52 (.alpha.-fluoro compounds), and 56 are used in place
of 4'-fluoro-4-biphenylacetic acid in the above example, there are
obtained the corresponding ethyl esters.
EXAMPLE 58
t-Butyl 4'-fluoro-4-biphenylacetate
0.05 mole of 4'-fluoro-4-biphenylacetic acid is treated with 0.2
mole of thionyl chloride and the resultant mixture gently heated on
a steam bath for 2 hours. The excess thionyl chloride is then
removed in vacuo. 50 ml. of benzene is added and the solvent again
removed in vacuo. 50 ml. of fresh, dry 1,2-dimethoxyethane is then
added and the resultant solution slowly added to a mixture of 0.06
mole of potassium tertiarybutoxide in 100 ml. of dimethoxyethane
with ice-cooling. The resultant mixture is then stirred at room
temperature for 4 hours and then concentrated to a residue in
vacuo. The residue is then dissolved in ether, washed with sodium
bicarbonate, dried, evaporated, and chromatographed on a silica gel
column (wt./wt. 50:1 gram crude) using an ether-petroleum ether
(v/v 20-60 percent) system as eluent to yield t-butyl
4'-fluoro-4-biphenylacetate.
When sodium ethoxide, sodium propoxide, sodium butoxide, sodium
benzylate, sodium phenoxide, and sodium phenylethoxide are used in
place of potassium t-butoxide in the above example, there are
obtained the corresponding ethyl, n-propyl, i-butyl, benzyl,
phenyl, and phenylethyl esters of 4'-fluoro-4-biphenylacetic acid
respectively.
Similarly, when the 4-biphenylacetic acids obtained from examples
9, 11, 12, 13, 14, 15, 16, 17, 18, 23, 26, 33, 34, 36, 37, 40, 45,
51, 52 (.alpha.-fluoro compounds), and 56 (excluding those
compounds containing an active hydrogen group) are used in place of
4'-fluoro-4-biphenylacetic acid in the above example, there are
obtained the corresponding ethyl esters.
EXAMPLE 59
Methyl 4'-fluoro-4-biphenylacetate
To a solution of 0.01 mole of 4'-fluoro-4-biphenylacetic acid in 30
ml. of anhydrous tetrahydrofuran is added 0.011 mole of methanol
followed by 0.011 mole of N,N'-dicyclohexylcarbodiimide (which has
been dissolved in a minimum amount of tetrahydrofuran). The mixture
is then shaken thoroughly for a minute and allowed to sit overnight
stoppered. The mixture is then filtered, the precipitated
N,N'-dicyclohexylurea obtained is washed with a small portion of
fresh tetrahydrofuran, and the wash combined with the filtrate. The
combined filtrates are concentrated to dryness. The residue is then
taken up in 100 ml. of ether, washed with bicarbonate solution,
water, dried over magnesium sulfate, filtered, and concentrated to
a residue. This residue is then chromatographed on a silica gel
column (wt./wt. 50:1 gram crude) using an ether-petroleum ether
(v/v 20-60 percent) system as eluent to yield methyl
4'-fluoro-4-biphenylacetate.
When ethanol, n-propanol, i-butanol, benzyl alcohol, phenylethanol,
N,N-diethylethanolamine, and N,N-dimethylethanolamine are used in
place of methanol in the above example, there are obtained the
ethyl, n-propyl, i-butyl, benzyl, phenylethyl,
N,N-diethylaminoethyl, and N,N-dimethylaminoethyl esters of
4'-fluoro-4-biphenylacetic acid respectively. The esters from the
N-substituted ethanolamines are extracted from the ether solution
indicated in the above example using dilute hydrochloric acid, the
acid solution washed well with ether, made slightly alkaline with
ammonium hydroxide, extracted with ether, the combined ether
extracts washed with water, dried over potassium carbonate and
charcoal, filtered, and the resulting ether solution concentrated
to a residue. The volatile ethanolamines are then removed in
vacuo.
Similarly, when the 4-biphenylacetic acids obtained from examples
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 23, 26, 33, 34, 36, 37, 40,
45, 51, 52 (.alpha.-fluoro compounds), and 56 are used in place of
4'-fluoro-4-biphenylacetic acid in the above example, there are
obtained the corresponding ethyl esters.
EXAMPLE 60
Sodium 4'-fluoro-4-biphenylacetate
A solution of 0.01 mole of sodium hydroxide in 15 ml. of water is
added with stirring to a solution of 0.01 mole of
4'-fluoro-4-biphenylacetic acid in 25 ml. of methanol. At this
point, additional methanol is added as needed to obtain complete
solution and the solution stirred for 1 hour. The solution is then
evaporated in vacuo to obtain a residue of sodium
4'-fluoro-4-biphenyl-acetate.
When potassium hydroxide is used in place of sodium hydroxide in
the above example, there is obtained the corresponding potassium
salt.
When ethylamine, N,N-dimethylaminoethanol, N,N-diethylethanolamine,
triethylamine, piperazine, morpholine, and choline are used in
place of sodium hydroxide in the above example and are dissolved in
methanol in place of water, there are obtained the corresponding
ethylamine, N,N-dimethylaminoethanol, N,N-diethylethanolamine,
triethylamine, piperazine, morpholine, and choline
4'-fluoro-4-biphenylacetic acid salts respectively.
Similarly, when the 4-biphenylacetic acids obtained from examples
9, 11, 12, 13, 14, 15, 16, 17, 18, 23, 26, 33, 34, 36, 37, 40, 45,
51, 52 (.alpha.-fluoro compounds), and 56 (excluding those
compounds containing an active hydrogen) are used in place of
4'-fluoro-4-biphenylacetic acid in the above example, there are
obtained the corresponding sodium salts.
EXAMPLE 61
2(4'-Fluoro-4-biphenyl)-ethanol
To a well-stirred suspension of 0.005 mole of lithium aluminum
hydride in 250 ml. of anhydrous ether is added dropwise a solution
of 0.01 mole of 4'-fluoro-4 -biphenylacetic acid with ice-cooling.
The reaction mixture is stirred at room temperature for 1 hour,
after which time 10 ml. of water is added dropwise with
ice-cooling. The reaction mixture is then poured into dilute
sulfuric acid and the aqueous layer is extracted with (2.times. 25
ml.) ether. The combined ether extracts are washed with water,
dilute bicarbonate, and water, then dried over sodium sulfate and
concentrated in vacuo. The residue is then chromatographed on a
silica gel column and eluted with ether-petroleum ether (10- 100
percent) to yield 2-(4'-fluoro-4-biphenyl)-ethanol.
When the 4-biphenylacetic acids obtained from examples 11, 13, 16,
17, 26, 40, 45, 51, 52 (.alpha.-fluoro compounds), and 56
(excepting those containing an active hydrogen, the
trifluoromethyl-4-biphenylacetic acids of example 23, the halo,
lower alkylthio, phenyl, dilower alkylamino, and fluoro
4-biphenylacetic acids of examples 33 and 34, and the lower alkyl
trifluoromethyl 4-biphenylacetic acids of example 37 are used in
place of 4'-fluoro-4-biphenylacetic acid in the above example,
there are obtained the corresponding alcohols. The compounds of
examples 10, 20, 22, 27, and 56 are used in place of
4'-fluoro-4-biphenylacetic acid in the above example, after
benzylating the active hydrogen group, to obtain the corresponding
alcohols.
EXAMPLE 62
Methyl 2-(4'-fluoro-4-biphenyl)-ethyl ether
To a well-stirred suspension of 0.01 mole of sodium hydride in 25
ml. of dry dimethylformamide, which has been cooled to 0.degree.
C., is added dropwise a solution of 0.01 mole of
2-(4'-fluoro-4-biphenyl)-ethanol in 10 ml. of dimethylformamide.
The reaction mixture is stirred for 15 minutes and 0.015 mole of
methyl iodide is then added dropwise. The mixture is allowed to
stir overnight at room temperature. 200 ml. of water is added and
the resultant mixture extracted well with ether. The combined ether
extracts are washed with water, dried over sodium sulfate, and
concentrated. The residue is chromatographed on 250 grams of silica
gel and eluted with ether-petroleum ether (10- 80 percent) to yield
methyl 2-(4'-fluoro-4-biphenyl)-ethyl ether.
When ethyl iodide, allyl bromide, benzyl chloride, and ethoxyethyl
chloride are used in place of methyl iodide in the above example,
there are obtained the corresponding ethyl, allyl, benzyl, and
ethoxyethyl ethyl ethers respectively.
Similarly, when the alcohols obtained from example 61 are used in
place of 2-(4'-fluoro-4-biphenyl)-ethanol in the above example,
there are obtained the corresponding methyl ethers.
EXAMPLE 63
4'-Fluoro-4-biphenylacetaldehyde
A. 4'-Fluoro-4-biphenylacetyl chloride
To a solution of 0.01 mole of 4'-fluoro-4-biphenylacetic acid in 50
ml. of benzene is added 0.011 mole of thionyl chloride. The
solution is then heated on a steam bath for 1 hour, subsequently
concentrated in vacuo to remove the solvent and any excess thionyl
chloride. 25 ml. of benzene is then added and removed in vacuo to
yield a residue of 4'-fluoro-4-biphenylacetyl chloride.
B. 4'-Fluoro-4-biphenylacetaldehyde
To a suspension of 0.01 mole of tritertiarybutoxy lithium aluminum
hydride in 50 ml. of dry tetrahdyrofuran is added dropwise with
stirring a solution of 0.01 mole of 4'-fluoro- 4-biphenylacetyl
chloride in 25 ml. of dry tetrahydrofuran. The reaction mixture is
stirred at -10.degree. C. for 3 hours followed by the addition of
200 ml. of 5 percent sulfuric acid added cautiously and the
resultant mixture extracted with (3.times. 75 ml.) ether. The
combined ether extracts are washed with water, dried over sodium
sulfate, and concentrated. The residue is chromatographed on 250
grams of silica gel and eluted with (10- 90 percent)
ether-petroleum ether to yield 4'-fluoro-4-biphenyacetaldehyde.
When the 4-biphenylacetic acids obtained from examples 9, 11, 13,
14, 15, 16, 17, 18, 23, 26, 36, 40, 45, 51, 52 (.alpha.-fluoro
compounds), and 56 (excepting those containing an acitve hydrogen),
and the 4-biphenylacetic acids of examples 33 and 34 (excepting
those with an active hydrogen), and the lower alkyl,
trifluoromethyl, cyano, and lower alkanoylamino 4-biphenylacetic
acids obtained from example 37 are used in place of
4'-fluoro-4-biphenylacetic acid in the above example, there are
obtained the corresponding aldehydes. when the compounds of
examples 10, 20, 22, 27, 33, 34, and 56 containing active hydrogens
are benzylated and subsequently treated according to the above
procedure, there are obtained the corresponding aldehydes.
EXAMPLE 64
4'-Fluoro-4-biphenylacetaldehyde dimethyl acetal
To a solution of 0.01 mole of 4'-fluoro-4-biphenylacetaldehyde in
100 ml. of anhydrous methanol is added 0.001 mole of
p-toluenesulfonic acid. The reaction mixture is stirred at room
temperature for 5 days. A solution of sodium methoxide in methanol
is then added until the solution is just alkaline to moistened
litmus paper. The methanol is removed in vacuo and the residue
taken up in ether and washed well with water. The ether solution is
dried over sodium sulfate and concentrated. The residue is then
chromatographed on neutral alumina. Elution with ether-petroleum
ether (10- 90 percent) gives the dimethyl acetal of
4'-fluoro-4-biphenylacetaldehyde.
When ethanol, n-propanol, and n-butanol are used in place of
methanol in the above example, there are obtained the corresponding
diethyl, dipropyl, and dibutyl acetals.
Similarly, when the aldehydes obtained from example 63 (excluding
those containing an active hydrogen) are used in place of
4'-fluoro-4-biphenylacetaldehyde in the above example, there are
obtained the corresponding dimethyl acetals.
Similarly, when the aldehydes of example 56 containing an active
hydrogen are benzylated, then treated according to the above
procedure, and then reduced according to example 11, there are
obtained the corresponding acetals.
EXAMPLE 65
4'-Fluoro-4-biphenylacetamide
0.05 mole of 4'-fluoro-4-biphenylacetic acid is slowly treated with
0.2 mole of thionyl chloride. The resultant mixture is heated
gently on a steam bath for 2 hours and the excess thionyl chloride
removed in vacuo. To this concentrated material is added 40 ml. of
1,2-dimethoxyethane and the solution then added dropwise to 100 ml.
of stirred ammonium hydroxide (approximately 30 percent) with
ice-cooling. The 4'-fluoro-4-biphenylacetamide is collected, washed
with water, and dried in vacuo.
When methylamine, ethanolamine, propylamine,
2,3-dihydroxybutylamine, benzylamine, aniline, o-methoxy aniline,
p-ethoxy aniline, p-chloro aniline, m-trifluoro-methyl aniline,
cyclohexylamine, carbobenzyloxymethylamine, carboxymethylamine,
glutamine, aminomethyl pyrrolidine, N-methyl pyrrolidine,
2-ethyl-N-methyl pyrrolidine, 3-aminomethyl-1-ethyl pyrrolidine,
dimethylcarboxamidomethylamine 1-diethylaminopropylamine,
morpholine, piperazine, N-ethyl piperazine, N-phenyl piperazine,
N-hydroxyethyl piperazine, piperidine, and pyrrolidine are used in
the above example in place of ammonium hydroxide, there are
obtained the corresponding 4'-fluoro-4-biphenyl-substituted
amides.
Similarly, when the 4-biphenylacetic acids obtained from examples
9, 11, 12, 13, 14, 15, 16, 17, 18, 23, 26, 36, 40, 45, 51, 52
(.alpha.-fluoro compounds), and 56 (excluding those compounds
containing an active hydrogen), the 4-biphenylacetic acids of
examples 33 and 34 (excepting those with an active hydrogen), and
the lower alkyl, trifluoromethyl, cyano, lower alkyanoylamino, and
carboxamide 4-biphenylacetic acids obtained from example 37 are
used in place of 4'-fluoro-4-biphenylacetic acid in the above
example, there are obtained the corresponding amides.
Similarly, when the compounds obtained from examples 10, 20, 22,
27, 33, 34, and 56 containing an active hydrogen are benzylated,
subsequently treated in accordance with the above example, and then
reacted according to example 11, there are obtained the
corresponding amides.
EXAMPLE 66
4'-Fluoro-4-biphenylacetamide
To a solution of 0.01 mole of 4'-fluoro-4-biphenylacetic acid in 40
ml. of 1,2-dimethoxyethane is added 0.01 mole of triethylamine. The
resulting mixture is ice-cooled, stirred, and 0.01 mole of i-butyl
chloroformate is added. Stirring is then continued in the cold for
an additional 30 minutes. The triethylamine hydrochloride is them
removed by filtration and the filtrate cooled again. Dry
dimethoxyethane saturated with dry ammonia gas is then added and
the ammonia gas bubbled through the resultant mixture for
approximately 1 minute. The mixture is then stirred at 5.degree. C.
for 16 hours. The solvent is removed in vacuo to yield
4'-fluoro-4-biphenylacetamide.
When methylamine, ethanolamine, propylamine,
2,3-dihydroxybutylamine, benzylamine, aniline, o-methoxy aniline,
p-ethoxy aniline, m-trifluoromethyl aniline, cyclohexylamine,
carbobenzyloxyamine, carboxymethylamine, glutamine, aminomethyl
pyrrolidine, 3-aminomethyl-1-ethyl pyrrolidine, morpholine,
piperazine, piperidine, and pyrrolidine are used in the above
example in place of ammonia gas, there are obtained the
corresponding 4'-fluoro-4-biphenyl-substituted amides.
Similarly, when the 4-biphenylacetic acids obtained from examples
9, 11, 12, 13, 14, 15, 16, 17, 18, 23, 26, 36, 40, 45, 51, 52
(.alpha.-fluoro compounds), and 56 (excluding those compounds
containing an active hydrogen), the 4-biphenylacetic acids of
examples 33 and 34 (excepting those with an active hydrogen), and
the lower alkyl, trifluoromethyl, cyano, lower alkanoylamino, and
carboxamido 4-biphenylacetic acids obtained from example 37 are
used in place of 4'-fluoro-4-biphenylacetic acid in the above
example, there are obtained the corresponding amides.
Similarly, when the compounds obtained from examples 10, 20, 22,
27, 33, 34, and 56 containing an active hydrogen group are
benzylated, then treated in accordance with the above example, and
subsequently reduced in accordance with the procedure of example
11, there are obtained the corresponding amides.
EXAMPLE 67
.alpha.-Methyl d-4'-fluoro-4-biphenylacetic acid
0.05 mole of cinchonidine is dissolved in boiling chloroform. To
this boiling solution is added 0.05 mole of
dl-4'-fluoro-4-biphenylacetic acid and the reaction mixture stirred
for 1/2 hour. The reaction mixture is then concentrated in vacuo
and the residue recrystallized from acetone. The recrystallization
is repeated until the acid obtained from the hydrolysis of a small
aliquot of the salt has a constant optical rotation.
* * * * *