Note: Descriptions are shown in the official language in which they were submitted.
~ossal4~
1 This inverltion rel<~tes to a class or novel ben~henones, and derivatives
thereof, to methods of preparing such derivatives, to phann3ceutical
formulations and to methods of Lreating allergic conditions in-~olving use of
o-hydroxybenzophenones.
There is a wealth of literature concerning the benzophenones, their
preparation and their uses.- However, it has nor heretofore been appreciated
that o-hydroxybenzophenones, and derivati~Tes thereof~ can be used in the
treatment of allergic conditions.
According to the present invention therefore, there is provided a
pharmaceutical formulation containing an active ingredient in association
. with a pharmaceutically acceptable carrier therefor, said active ingredient
being a compound of the formula :-
R2 ~ C Ar (I)
wherein R2 is hydrogen or ethyl~ Rl and R represent hydrogen~ methyl or
ethyl, at least one.of Rl, R2 and R3 not being hydrogen; Ar is a phenyl
group optionally substituted by from one to three groups selected from chlorine -
fluorine, methyl, carboxy, CoOR5 and trifluoromethyl; Z is hydrogen or CoR5;
and Y is 0~ NOH or NOCOR ~ R being Cl 4 alkyl or phenyl~ provided that
(l) when Ar is 4-chlorophenyl~ Y and Z are as defined above and Rl and
R2 are hydrogen, R is methyl;
(ii)when Ar is unsubstituted phenyl~ Z is as defined above~ Rl and R
are hydrogen and R3 is ethyl, Y is O;
(iii)~hen * is ethyl, * and R3 are hydrogen and Y and Z are as defined
above, Ar is not 2,4- or 3,4-dichlorophenyl, 2- or 3-chlorophenyl or
4-fluorophenyl;
(iv)when Ar is unsubstituted phenyl~ Y and Z are as defined above, and
L -2-
~05CiO41
1 and R are hydrogen~ R is ~thyl.
In a further aspect of the invention, there is provided a method of
treating a mammal suffering from an allergic condition, and particularly
a method of treating immediate hypersensitivity diseases such as asthma
in animals, including humans, which comprises administering to said mammal
an anti-allergically effective dose of a compound of formula (I) as defined
above.
In the formulation and method aspects of the present invention, a
preferred sub-genus of the compounds of formula (I) are those wherein
Rl, R2 and R3 are as defined above, Ar is a phenyl group optionally
substituted by from one to three groups selected from chlorine, fluorine
or methyl, Z is hydrogen or CoR5 and Y is 0, NOH or NoCoR5, R5 being as
defined above. Advantageously, the compound of formula (I) is one wherein
one of R , R and R3 is ethyl and the others are hydrogen; Ar is phenyl,
4-chlorophenyl~ 4-fluorophenyl or 4-methylphenyl; Z is hydrogen; and Y is
O and, within the latter group, a preferred sub-class are those compounds
of formula (I) wherein Z is hydrogen; Y is O and either
(i) Rl is ethyl~ R2 and R3 are hydrogen and Ar is 4-chlorophenyl;
(ii) R3 is ethyl~ Rl and R2 are hydrogen and Ar is 2,4-dichlorophenyl; or
(iii) R is ethyl~ Rl and R3 are hydrogen and Ar is 3- or 4-fluorophenyl.
As well as the above particularly preferred groups of compounds of the
present invention, it has been found that the compounds of formula (I)
likely to possess the most useful therapeutic index, i.e. combination of
efficacy and lack of toxicity, are those having one or more of the following
features :
(a) Z is hydrogen.
(b) Y is 0.
(c) one of Rl, R2 and R3 is ethyl, the other Rl, R2, R3 substituents
being hydrogen.
(d) Rl is ethyl when R2 and R are hydrogen.
.-
~ ., ~ ~
lOSSiO ~1
1 (e) Ar i a 4-chlorophenyl group,
(f) Ar is a 4-fluorophenyl group.
(g) Ar is unsubstituted phenyl.
A number of the most useful compounds of formula (I) are novel and
form a part of this invention. Such novel compounds are those of formula (I)
wherein R , R and R represent hydroger or ethyl, at least one being ethyl,
Ar is a phenyl group substituted by from one to three groups selected from
chlorine, fluorine, methyl, carboxy, CoOR5 and trifluoromethyl; Z is
hydrogen or co~5; and Y is O, NOH or NoCoR5, R5 being Cl 4 alkyl or phenyl~
provided thatJ
when Rl is ethyl, R2 and R3 are hydrogen and Y and Z are as defined
above, Ar is not 2,4- or 3,4-dichlorophenyl, 2- or 3-chlorophenyl
or 4-fluorophenyl.
A preferred group of novel compounds are those wherein Ar is a phenyl group
substituted by from one to three groups selected from chlorine, fluorine or
methyl. Particularly useful activity is found in those compounds wherein
one of Rl, R2 and R3 is ethyl and the others are hydrogen, Ar is 4-chloropheny
4-fluorophenyl or 4-methylphenyl, Z is hydrogen, and Y is O~ and especially
in these compounds wherein Z is hydrogen, Y is O and e~ther
(i) Rl is ethyl, R2 and R3 are hydrogen and Ar is 4-chlorophenyl;
(ii) R is ethyl~ Rl and R are hydrogen and Ar is 2,4-dichlorophenyl; or
(iii) R2 is ethyl, Rl and R3 are hydrogen and Ar is 3- or 4-fluorophenyl.
Compounds in which Y is not O can exist in both syn and anti forms and
it is to be understood that both of these isomers, and mixtures thereof, are
included within the scope of the invention.
The preferred compound of the inventio~ is 4'-chloro-5-ethyl-2-
iO'5504~
hydroxyben7~0r)1lenone .
¦ The present invention also provides a process for preparing the afore~
mentioned novel compounds of formula (I) characterised in that a carboxyli.c
acid of the formula A-COOH or a derivative thereof wherein A is selected
from the groups
R2~0~
or Ar- is reacted under Friedel-Crafts' acylating conditions with a
substituted benzene of formula B-H wherein B is selected from the same
groups as A but is different therefrom to produce a compound of formula (I)
in which Y is O and thereafter, where desired~ the resultant product is
reacted with hydroxylamine in the presence of a base to produce the
corresponding oxime in which Y is NOH~ a compound in which Z is CoR5
and/or Y is NoCOR5 being then obtained by acylation of the aforementioned
compounds in which Z is hydrogen and/or Y is NOH.
Illustrative of a Friedel-Crafts'acylation as described above is the
reaction between a compound of formula ArCOX and a compound of formula :
R3~oz ~
Z~ being hydrogen or a protecting group such as methyl.
The reaction may be represented by the following reaction scheme :
Rl R
~ R2 ~ + ArCOX ------------~R2 ~ 0 ~ O _ Ar
10550~i
1 ~herein X is a halo~en atom or hydroxyl.
h~en X is halogerl, the reaction may be carried out using a Lewis acid
such as an aluminium halide (e.g~ the chloride) as catalyst in a suitable
inert solvent such as 1,1,2,2-tetrachloroethane or carbon disulphide.
When X is hydroxyl~ boron trifluoride or (CF3CO~20 are preerred
catalysts, used with or without a suitable solvent.
If Z'is a protecting group, it may be removed in situ or subsequently5
should it be desired to form a compound of formula (I) in which Z~ hydrogen
Reduction of unwanted isomer(s) can be achieved by suitable choice of
reaction conditions, temperature control being especially important. Ideally
the reaction temperature is from 20C to the reflux temperature and
preferably from 80C. up to reflux temperature.
Similarly, the benzophenones can be prepared by the following reaction
2 R3~ COX + HAr --3 ~LC
similar reaction conditions be-ing applicable.
In the case of the reaction with a compound of the formula ArCOX,
an initial reaction product (A) below may be obtained and isolated. This
may be subjected to a Fries rearrangement using similar catalytic
conditions : ~
R~ R~?lCOAr
OCO Ar OH
~L055041
as those described above, for example using aluminium chloride.
A furtller example of the acylation lnvolving a der;vative of A-C00II
is the use of the compound Ar-CN as acylating agent. This modified process
is known as the ~ouben-Hoesch Reaction which proceeds as shown below :
Rl R
R2 ~ R2 "~
R3 ~ Lew s cid ~ COAr
Where a protected hydroxy group Z~ is used in the foregoin& reactions,
it may be converted to the desired hydroxy group by cleavage with, for
example, HBr, BF3~ AlC13 or HI.
As outlined above! preparation of ketonic derivatives such as the
oxime can be effected by combining a solution of the ketone, for example,
an aqueous or alcoholic solution, with a derivative, preferably the
hydrochloride, of hydroxylamine in the presence of a base, for instance
sodium or potassium hydroxide.
Also~ as stated above, preparation of the acyl derivatives of the
o-hydroxy or oxime groups can be carried out by a variety of methods, for
example, by treating the o-hydroxybenzophenone or oxime in a basic solution
(e.g. pyridine or an aqueous solution of a group IA hydroxide such as
sodium or potassium hydroxide) with an acid anhydride or halide (preferably
the chloride) or with a solution of the acylating acid in the presence of
the acid anhydride with a trace of catalyst (e.g. perchloric acid - 70%),
or by refluxing the o-hydroxybenzophenone or oxime with the acylating acid.
The o-hydroxybenzophenones and derivatives thereof of the present
invention have been shown to possess activity in one or more of the four
tests regularly used to detect anti-allergy activity. Two of said tests
~re in vitro tests - the guinea pig and human chopped lung tests - and involve
the direct measurement of the tnediators, histamine and slow reacting
~ , ~
:10550~1
1 substance in anaphyla~i~ (SRS-A), shown to be released by asthmatic human
lullg. 1~or compolmds of the type comprising the present invention, a corl~poundis considered to be active if at least 30% inhibition of SRA-A release
in the guinea pig chopped lung test is achieved at a dose of 10 ~g/ml or
less. Depending on absorption, distribution and metabolism of the drug
under test, activity in the chopped lung test at this level indicates'
in vivo dosage ranging from 0.5 to about 100 mg/Kg orally.
The other two tests are in vivo tests - the Herxheimer and rat
peritoneal anaphylaxis - and reflect oral activity in two different species.
In the Herxheimer test, sensitised guinea pigs are protected against the
bronchospasm induced by an aerosol of antigen whilst, in the rat peritoneal
anaphylaxis test, the SRS-A released on challenge is measured directly.
~here an active compound is tested in these in vivo tests~ activity at
doses of 300 mg/Kg orless is normally achieved.
The compounds of the present invention display activity in one or
more of the foregoing tests (the broadest spectrum compounds being those whic~
display anti-allergy activity in all four tests) and are therefore useful
in the prophylactic and therapeutic treatment of immediate hypersensitivity
diseases including asthma and in the alleviation of status asthmaticus.
In certain cases the compounds have been found to be useful in diseases in
which excessive amounts of prostaglandins are released and as a respiratory
stimulant. The compounds have low toxicity.
The compounds or compositions of the present invention may be
administered by various routes and for this purpose may be formulated in
a variety of forms. Thus the compounds or compositions may be administered
by the oral and rectal routes, topically, parenterally, e.g. by injection
and by continuous or discontinuous intra-arterial ir.fusion, in the form of~
for example, tablets, lozenges, sub-lingual tablets, sachets, cachets,
elixirs, suspensions, aerosols, ointments, for example, containing from
1 to 10% by weight of the active compound in a suitable base~ soft and
~OSS041
1 hflrd gelatin capsules~ slppositories~ injec~ion solutions and suspensions
in physioLogicall~ acceptable media, and sterile packaged powders adsorbed
onto a support material for making injection solutions. Advantageously for
this purpose, compositions may be provided in dosage unit form, preferably
each dosage unit containing from 5 to 500 mg. (from 5.0 to 50 mg. in the case
of parenteral administration, from 5.0 to 50 mg. in the case of inhalation
and from 25 to 500 rng~ in the case of oral or rectal administration) of a
compound of formula (I).
As indicated by the tests referred to above, dosages of from 0.5 to
300 mg/kg per day~ preferably 0.5 to 20 mg/kg, of active ingredient may
be administeredO It will however readily be understood that the amount
of the compound or compounds of formula (I) actually to be administered will
be determined by a physician, in the light of all the relevant circumstances
including the condition to be treated, the choice of compound to be
administered and the choice of route of administration and therefore the
above preferred dosage range is not intended to limit the scope of the
present invention in any way.
In this specification, the expression "dosage unit form" is used as
meaning a physically discrete unit containing an individual quantity of the
active ingredient, generally in admixture with a pharmaceutical diluent
therefor, or otherwise in association with a pharmaceutical carrier, the
quantity of the active ingredient being such that one or more units are
normally required for a single therapeutic administration or that, in the case
of severable units such as scored tablets, at least one fraction such as a
half or a quarter of a severable unit is required for a single therapeutic
administration.
The formulations of the present invention normally will consist of at
¦ least one compound of formula (I) associated with a ~harmaceutically acceptab4e
¦ carrier therefor~ i.e. mixed with a carrier~ or diluted by a carrier~ or
enclosed or encapsulated by an ingestible carrier in the form of a capsule,
1055041
1 sachet, cachet, paper or other container or by a disposable container sllcl- as
an ampoule. A carrier or diluent may be a solid, semi-solid or liquid materi 1
which serves as a vehicle, excipien~ or medium for the active therapeutic
substance.
S . Some examples of the diluents or carriers which may be employed in tne
pharmaceutical compositions of the present invention are lactose, dextrose,
sucrose, sorbital, mannitol, propylene glycol, liquid paraffin, white soft
paraffin, kaolin, fumed silicon dioxideS microcrystalline cellulose, calcium
silicate, silica, polyvinylpyrrolidine, cetostearyl alcohol, starch, modified
starches~ gum acacia, calcium phosphate~ cocoa butter~ ethoxylated esters, oil
. of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup B.P~, methylcellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and
propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl
alcohol and propellants.such as trichloromonofluoromethane, dichlorodifluoro.
methane and dichlorotetrafluoroethane. In the case of tablets, a lubricant
may be incorporated to prevent sticking and binding of the powdered ingredientlsin the dies and on the punch of the tabletting machineO For such purpose
there may be employed for instance aluminium, magnesium or calcium stearates~
talc or mineral oil.
1055041
1 The foilowing ~xa~lples f~lrther illus~rate tlle irlvention :
EXAMPLE 1
2-Hydroxy-5-Methyl-4'-Chlorobenzophenone Oxime (syn and anti).
(a) 2-Hydroxy-5-methyl-4'chlorobenzophenone (13.5 g, 0.055 moles)
was stirred with a solution of potassium hydroxide (44 g.) in water (150 ml.)
and then hydroxylamine hydrochloride (17.4 g, 0.25 mole) was added with ice
cooling. After stirring overnight at room temperature 100 ml. of water was
added and the mixture was acidified with 5N-hydrochloric acid to give an
off-white precipitate which was filtered, washed and dried (14.7 g).
Recrystallisation of the product from benzene gave 2-hydroxy-5-
methyl-4'-chlorobenzophenone oxime (7 g.) m.p. 163C. (This was the stereo-
isomer in which the oxime -OH group and the 4'-chlorophenyl group were in the
syn positi~n relative to each other).
(b) The above procedure was repeated this time using 192 g (0.78 mole)
of the benzophenone used in (a). The benzene solution deposited a second and
third crop of crystals. The second crop (31.5 g) was a mixture of the two
forms of the oxime whereas the third crop (1.9 g) was the stereoisomer in
which the oxime hydroxyl group and the 4'-chlorophenyl group were in the
anti-position rela~ive to each other. (m.p. of product was 145-7C).
The C~H~N~Cl microanalysis for each isomer was satisfactory.
(c) 4'-Chloro-2-hydroxy-5-methyl-benzophenone-oxime diacetate.
The oxime produced in (a) above (26.2 g) was dissolved in warm
acetic anhydride (50 ml.), and on cooling a solid separated. This was
filtered off and the filtrate evaporated to dryness, leaving a residue which
was crystallised from ethanol to give the diacetate as the second crop.
(m.p. 136C.)
10550~1
1 EX~MPLE 2
4~-Cl?loro-5-etllyl-2-1lydrox~
Aluminium chloride (267 g) was added in portions over 30 minutes
to a stirred solution of 4-ethylphenol (122.1 g.) and 4-chlorobenzoyl
chloride (140 ml.) in dry 1~1,2,2-tetrachloroethane (800 ml.). The mixture
was heated at 105C. for 22 hours with stirring, and on cooling a mixture
of ice (600 g) and concentrated hydrochloric acid was added slowly. A
vigorous reaction occurred and some material was lost. The remaining
material was separated, the agueous fraction extracted twice with
chloroform (200 mlc)~ and the combined organic layers evaporated to a dark
oil which was distilled in vacuo giving two main fractions: B (17.4 g)
150-160C @ 0.3 mmHg; C (110.8 g) 160-168 C. @ 0.3 mmHg.
The title compound was crystallised by cooling to -20C. and recrystallised
from n-hexane at 0 C. to give a yellow crystalline solid m.p. 35-8 C.
Microanalysis: C15H13C102 requires 69.1~/oC, 5.0%H~ 13.6%Cl;
found 69.0%C, 5.~/~, 13~9%Cl~
EXAMPLE 3
4~-Chloro-5-ethyl-2-hydroxybenzophenone-oxime
4~-Chloro-5-ethyl-2-hydroxybenzophenone (65.2 g) and potassium
hydroxide (170 g) in water (700 ml) and ethanol (150 ml.) were treated with
hydroxylamine hydrochloride (70.0 g), with cooling, and the resulting
mixture was stirred for 18 hours at ambient temperature. Dissolution occurre~
during this time. The solution was acidified with 5N-hydrochloric acid and
then extracted with ether (3 x 200 ml.). The combined ether solutions
were washed with 10% aqueous sodium carbonate solution (2 x 200 ml.) and
¦ evaporated to dryness to give an off-~hite solid. This solid ~as
¦ recrystallised from 40% benzene / 60-80C petrol ether to give a white
crystalline solid (29.9 g), second crop (14.5 g) m.p. 117C.
1055041
1Microa~alysis: ~1511l4C]N0? req~ s 65~3%C~ 5~]%H~ 5~1%N~ 12.9%Cl;
found 65~3%C~ 4.9%H~ 5.1C/oN, 12.9%Cl.
(Stereoisomer ~s in Example l(a)).
EXAMPLE 4
_ .
2-Hydroxy~ hyl-4 t -chlorobenzophenone
Chlo~obenzene (78~79 g~ 71~6 ml; ~7 mole) and AlC13 (14 g~ 0~105 mole
were mixed, stirred and treated with a solution of 2-hydroxy-3-methylbenzoic
acid chloride (12 g, 0.07 mole) in chlorobenzene (20 ml). The mixture w~s
stirred and heated at 100C. overnight, ~le cooled mixture was added to conc
HCl (10 ml) and ice, extracted with ether, and ether washed with saturated
sodium bicarbonate solution~ dried (Na2S04), filtered and the filtrate
distilled, to give (after removal of the ether ), a main fraction 2-hydroxy-
3-methyl 4'-chlorobenzophenone, b.p. 148-152C/0.5 mm(8.18 g), which
solidified to yellow microplates, m.p. 55-58 C~
found: C.68.23; H.4.71; Cl.14.61;
14 11 2 requires: C.68.16; H.4.49; Cl.14.37%
EXAMPLE 5
4-Ethyl-4i-fluoro-2-hydroxybenzophenone
3-Ethylphenol (24.4 g) and 4-fluorobenzoyl chloride (34,9 g) were
reacted together as in Example 2 giving three main fractions: B (11.4 g)
126-129 C, @ 0.07 mmHg; C (7.9 g)~ 129-132 C @ 0.06 mmHg; D (5.9 g)~ 132-15~ 1C.
@ 0.06 mmHg, all containing ~ 8~/o of the required isomer. B (4.0 g) was
separated by preparative thin layer chromatography to give the title compound
(2.6 g)~ m.p. 44-48C. The same compound was obtained using the method of
Example 4.
; -13-
~05504~
1 EX~MPl.r 6
4-Ethyi-L'-rlllo~-o-2-hydro~y-be-nzophenolle oxime.
4-Ethyl 4'-fluoro-2-1ydroxybenzophenone (2L~0 g~ 80% pure) was
treated with hydroxylamine hydrochloride (24~0 g) in a manner similar
to that in Example 3, to give, after recrystallisation from benzene, the
title compound as a white crystalline solid ~10.7 g), m.p. 130~2C.
Microanalysis: C15H14FN02 requires 69.5%C~ 5~4~/oH~ 5~4/~N~ 7~3~/~;
found 69~2%C~ 5.5%H, 5.2~/~, 7.2/~.
EXAMPLE 7
2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime
The ketone of Example 4 (7.5 g, 0.03 mole) in ethanol (18 ml.) was added
with stirring to a solution of (85~/o) potassium hydroxide (20.74 g, 0~3 mole)
in water (85 ml) at 10C, this colloidal solution was treated with solid
hydroxylamine hydrochloride (8~54 g, 0.12 mole) and stirred overnight. The
solution was acidified with SN HCl to give a solid~ which was filtered~
washed with water and stirred for 45 minutes, then treated with 5% Na2C03
l solution (30~5 ml)~ to remove unwanted oxime stereoisomer~ filtered~ washed
with 5% Na2C03solution (100 ml) and then with water until free of alkali.
The dried solid had m.p. 175-177C. Recrystallisation from 54% benzene-
light petroleum (b.p 60-80C) mixture gave the oxime, m.p. 178C ("bonded
isomer") 5.45 g.
found: C~64~25; H.4.79; Cl.13.41; N~5~3%
C14H12Cl C2 requires : C~64~25; H~4~6; Cl.13.55; N~5~35%
~ EXAMPLE 8
2-Hydrox~r-3-methyl-4~-chlorobenzophenone oxime acetate.
Acetic anhydride (12 ml) was warmed to 60C. and treated with the oxime
lOS~041
1 of Example 7 (5.25 g, 0.02 mole). The stirred mixture was wanned to
80C. to dissolve the oxir,le and the so]u~ion was thell immediately cooled
in an ice bath. The precipitated solid was fi]tered off, washed with light
petroleum (b.p. 40-60~C) to give the acetate, 4.8 g, m.p. 154-156C.
S found: C.63.18; H.4.86; Cl.11.5; N.~.77
C16H14ClN3 requires: C.63~26; H.4.64; Cl.11.67;N.4.6%
EXAMPLE 9
2-Hydroxy-3-ethylbenzophenone
This compound (44.67 g) was prepared from benzene (172 g, 2.2 mole)
and 2-hydroxy-3-ethyl benzoic acid chloride (63.15 g, 0.34 mole), using the
same conditions as in Example 4. The b.p. of the compound was 123-126 C. J
0.14 mm~ ~ 2 1.6081~ ~ max. (film) 1630 cm 1. The same compound was
obtained using the method of Example 2.
EXAMPLE 10
2~l4~Dichloro-3-ethyl-2-hydroxybenzophenone
Aluminium chloride (26.7 g) was added in portions to a stirred
mixture of 2-ethylphenol (12.2 g) and 2,4-dichlorobenzoyl chloride (23.1 g)
in 1~1,2,2-tetrachloroethane (100 ml)~ and then the mixture was heated under
reflux ror 21 hours. On cooling, the solution was poured onto concentrated
hydrochloric acid (100 ml) cooled with ice (200 g). The organic fraction
~was separated and combined with two further chloroform washings of the
aqueous fraction, and then this was twice washed with 10% aqueous sodium
carbonate solution, dried over magnesium sulphate monohydrate and evaporated
to a dark viscous oil (30.0 g). This oil was distilled in vacuo, the first
fraction (156-172C at 0.06 mmHg) containing 85% of the required product.
(With ferric chloride solution a purple colour was obtained indicating the
I iQ55041
1 presence o an o-hydroxyketone). The ke~one product ~s purified by
chromatography on ~ silica column ~D 1.6163. The same product was
obtained using the method of Example 4.
XAMPLE ll
4-Ethyl-3~-fluoro-2-hydroxybenzophenone
This compound was prepared from 3-ethylphenol (12.2 g), 3-fluorobenzoyl
chloride (17.5 g) and aluminium chloride (26.7 g) in 1,1,2,2-tetrachloro-
ethane (75 ml) using the same conditions as in Example 2, but heating under
reflux, not at 105C. The product was purified by chromatography on a
silica column m.p. between 0 and 20C r~o2 1.5962L The same product was
obtained using the method of Example 4.
EXAMPLE 12
4-Chlorobenzoylchloride (1.35 g~ 0.0077 mole) was added dropwise to a
solution of 4-ethylphenol (0.86 g~ 0.0070 mole~ in 2.5 N aqueous sodium
hydroxide (5.6 ml). The mixture was shaken vigorously for 15 minutes when
a light brown solid separated out. The mixture was diluted with water
(10 ml) and the solid was filtered off, washed with water (3 x 20 ml), and
dried. The solid was recrystallised twice from n-hexane to yield pale
brown crystals of 4-ethylphenyl-4-chlorobenzoate, m.p. 66.5-67C.
The above ester (2.6 g) was heated with aluminium chloride (1.33 g!
in tetrachloroethane for 6 hours at 125C. A sample taken at the end of
this time was added to dilute hydrochloric acid and the organic material
was extracted into chloroform. Vapour phase chromatographic analysis of this
solution detected no remaining ester, and comparison with an authentic
l sample showed the product to be 4~-chloro-5-ethyl-2-hydroxybenzophenone.
l I
-16-
l 10550~1
1 Similarly prepared were:
5 Ethyl-2-hyaroxy-4r-m2thyljellzoyhetlo}le~ m.p. 49-51C. and
4'-Chloro-3,5-diethyl-2-hydroxybenæophenone b.p. 18~Co at 1~4 mmtHg.
EXAMPLE 13
2-Benzoyloxy-5-ethyl-4~-chlorobenzophenone
2-Hydroxy-5-ethyl-4C-chlorobenzophenone (5 g, 0.019 mole) was stirred
vigorously in a solution of NaO]I (7.5 g~ 0.187 mole) in water (75 ml) and
benzoyl chloride was added dropwise over 5 minutes. The temperature rose
,o around 50C. The mixture was stirred for 1.5 hours at room temperature
and was then extracted with ether, the ether washed with saturated NaCl
solution, dried (Na2S04)~ filtered and evaporated to leave the productS
which was recrystallised from n-hexane to give white crystals of the
desired product~ m.p. 79-81 C.
EXAMPLE 14
2-Acetoxy-4i-chloro-5-ethylbenzophenone
2-Hydroxy-5-ethyl-4~-chlorobenzophenone (3 g), in acetic anhydride
(10 ml) and acetic acid (1 ml) were refluxed for 3.5 hours~ and allowed
to cool. The mixture was poured into dilute NaOH solution and extracted
with chloroform. The chloroform was washed with 10% NaHC03 solution
(50 ml), dried (MgS04) and evaporated to leave an oil which was distilled~
b.p. 160-165C. at 3.5 mm/Hg (2.3 g) to give the desired product.
~` -17-
.' ~ ~
iOS5041
1 }~XAMrLE 15
5~Etllyl-2-hyd ~ _ ~ ~
Aluminium chloride (0.6 g, 0.004 mole) was stirred in dichloromethane
(2 ml) and treated with 4-trifluoromethylbenzoyl chloridc (1 g, O.OG48 mole)
(ice-bath cooling) ar.d then with 4-ethylanisole (0.6 g, 000044 mole) in
dichloromethane (1 ml), The mixture was stirred at room temperature
overnight and then poured into ice and concentrated hydrochloric acid
and extracted with chloroform. The chloroform solution was washed with
10% NaHC03 solution (100 ml)9 dried (MgS04)~ filtered and evaporated to
leave 5-ethyl-2-methoxy-4~-trifluoromethylbenzophenone (1.2 g) as a
yellow oil. The latter was heated in 55% agueous hydrogen bromide (27.5 ml)
at 110-120C. for 5 hours. The mixture was evaporated to dryness to leave
the required product.
EXAMPLE 16
5-Ethyl-2-hydroxy-3~-carboxv- and 3i carbomethoxybenzophenone
Aluminium chloride (39.9 g, 0.3 mole) was stirred in dichloro-
methane (133 ml) and treated with 3-carbomethoxybenzoyl chloride (59.5 g,
0.3 mole) (ice-bath cooling), over 0.5 hours.4-Ethylanisole ~40.8 g,
0.3 mole) in dichloromethane (70 ml) was added to the stirred~ cooled
mixture, which was then stirred at room temperature overnight. The
reaction mixture was processed as in Example 15 to leave 5-ethyl-2-
methoxy-3~-carbomethoxybenzophenone. The Latter was heated in 55% aqueous
hydrogen bromide (500 ml) at 110-120C for 5 hours. The mixture was
evaporated to dryness to leave 5-ethyl-2-hydroxy-3~-carboxybenzophenone,
which was characterised by having the correct C, H and N microanalysis.
The 1atter carboxylic acid was then refluxed overnight in methanol (500 ml)
containing concentrated s~lphuric acid (5 ml), poured into water (1 L
and extracted with ether. The combined ethereal extracts were washed
with saturated NaHC03 solution, dried (MgS04), filtered and evaporated
to leave the desired ester, which gave a satisfactory microanalysis.
-18-
