Note: Descriptions are shown in the official language in which they were submitted.
594Z
This invention relates to the preparation of optically
active 2-arylpropionic acids. Certain 2-arylpropionic acids
are known to have valuable biological properties and in
particular anti-inflammatory properties.
It is believed that,with some 2-arylpropionic acids,
biological activity of one of the optical isomers is
greater than that of its enantiomer and it is desirable that
a simple method of obtaining a preponderance of one
enantiomer be achieved.
Conventional resolution techniques involving separation
of a mlxture of diastereoisomeric salts of an acid are
usually very tedious since they often require several
recrystallisation stages and also racemisation of the unwanted
enantiomer to improve yields.
We have now found that a desired enantiomer of a 2-
arylpropionic acid can be obtained from a mixture of
diastereoisomeric salts in a simple manner in which generally
fewer stages are involved than in conventional resolution
techniques.
According to the invention, there is provided a process
for increasing the proportion of a desired enantiomer of a
2-arylpropionic acid which comprises heating at a temperature of
at least 80C a mixture comprising a salt of said
2-arylpropionic acid with an enantiomer of a chiral organic
25 nitrogenous base and an inert liquid organic diluent in which
the salt of the racemic acid has a solubility of 0.1 to 10% w/v
at the operating temperature, and is used in an amount such that
a portion of the salt is undissolved in the diluent, continuing
the heating until a portion of one optical isomer of the acid
~3J'
' '
..
: ~ ' ~-. ' `
, ~
--- " 1161 5942
~omponent of the salt is converted into its enantiomer, then
recovering the solid salt of whic~ the acid component now has an
increased and preponderant proportion of that enantiomer, and
separating the acid component therefrom.
The 2-arylpropionic acid is generally one ln which the
aryl group is of formula
(Q)n
~ ' ~
in which n is an integer of 1 to 4, preferably 1 or 2, and Q
is the same or different and is selected from/ alkyl, e.g. methvl;
aralkyl, e.g. benzyl; cycloalkyl, e.g. of three to seven carbon
atoms, and especially cyclohexyl; alkyl substituted cycloalkyl,
e.g. monomethyl and monoethyl substituted cyclohexyl; aryl,
e.g. phenyl and phenyl substituted with, for example 1 or 2
alkyl, preferably C1 4 alkyl, alkoxy, preferably C1 4 alkoxy,
alkylthio preferably C1 4 alkylthio, cyano or halogen; alkoxy,
preferably C1 4 alkoxy; cycloalkoxy, e.g. cyclohexyloxy; aryloxy, ¦
e.g. phenoxy and phenoxy substituted with, for example 1 or 2
halogen atoms especially chlorine or fluorine; alkylthio,
preferably C1 4 alkylthio; aralkylthio; cycloalkylthio;
arylthio, e.g. phenylthio; arylcarbonyl, e.g. benzoyl and
-thenoyl; cycloalkenyl e.g. cyclohexenyl; trifluoromethyl; halogen,
e.g. fluorine or chlorine; furyl; pyrrolidinyl; pyrrolyl;
pyrrolinyl; thienyl; or 1-oxo-2-isoindolinyl; or two Q groups
together form a carbocyclic or heterocyclic ring, which rings
may be aromatic and may be substituted. Examples of groups
formed by two Q groups together with the benzene to which they
are attached include naphthyl and substituted naphthyl,
especially alkoxynaphthyl, fluorenyl, benzoxazolyl, optionally
substituted e.g. by p-chlorophe3nyl, carbazoly~ optionally
1 5942
substituted by chloro, benzothiazolyl, optionally substituted
~ by phenyl, phenothiazinyl, optionally substituted by alkoxy
and alkyl, benzofuranyl optionally substituted by phenyl,
benzopyrano [2,3-b]-pyridinyl, and 9-oxoxanthenyl.
Instead of being a substituted phenyl the aryl group
may be a heteroaryl group e.g. benzothiazolyl, pyrrolyl,
or thienyl, which groups may be substituted by groups
designated for Q above.
Particularly preferred compounds are those in which
the aryl group is of the formula:
R3~(0)
R4 R5
in which m is O or 1, and R3, R4 and R5 may be the same or
different and are selected from hydrogen, chlorine, fluorine,
hydroxyand methoxy. Especially preferred are those compounds
in which m is 0.
Other preferred aryl groups include 2-(6-methoxy-2-
naphthyl) and those in which n is 1 and Q is in the 3-
position and is benzoyl or phenoxy or is in the 4-position
and is l-oxo-2-isoindolinyl.
The invention is particularly applicable to 2-(2-fluoro-
4-biphenylyl)propionic acid and especially in obtaining
a preponderance of the (+)-isomer.
-- 4 --
.
, .
,.
: ' ~ ,
59f~2
The invention can be carried out by using a racemic
2-arylpropionic acid, either enantiomer of a 2-arylpropionic
acid, or mixtures containing a preponderance of either
enantiomer. Depending on the particular salts involved
the process may result in an increase of either enantiomer
of the acid. The use of racemic acid results in
formation of a salt containing a preponderance of one
enantiomer of the acid. The process does not convert
material to give salt of one enantiomer of the acid
exclusively in all cases so it is often desirable to treat
the material obtained to a minimal number, generally not more
than two, conventional recrystallisation stages or other
means of purification.
The desired acid may be recovered from the salt by
conventional means, e.g. by acidification of the salt with
a dilute mineral acid followed by extraction from the
aqueous mixture with a suitable organic solvent.
Recrystallisation of the acid may increase the optical
purity still further.
It will be appreciated that the choice of base will .
depend on the 2-arylpropionic acid. The choice of diluent
will depend on the 2-arylpropionic acid and the base.
Generally the base is an a-monosubstituted alkylamine,
and preferably an a-monosubstituted ethylamine, especially
an a-phenylethylamine in which the phenyl ring may be
substituted by one or more groups such as alkyl e.g. Cl 4
alkyl, especially isopropyl, halogen, e.g. chlorine or
fluorine, alkoxy e.g. Cl 4 alkoxy, especially methoxy.
Particularly preferred bases are (-)-a-methylbenzylamine and
- 5 -
~5~42
(-)-a-(2-methoxyphenyl)ethylamine. Other suitable bases
include (-)-a-(4-isopropylphenyl)ethylamine, (-)-a-
(3-chlorophenyl)ethylamine, (-)-a-(4-fluorophenyl)ethylamine
(-)-a-(3-fluorophenyl)ethylamine, (-)-a-(2-fluorophenyl)
ethylamine, (-)-a-(2-chlorophenyl)ethylamine, (+)-a-
(2-methoxyphenyl)ethylamine, (-)-a-(2,6-dimethoxyphenyl)
ethylamine and also (+)-a-cyclohexylethylamine.
Preferably the mixture of diluent and salt is heated
at a temperature of 90-150C e.g. 95-130C. The heating
is usually carried out for at least 1 hour e.g. 8-96 hours.
It is preferred that the ratio of the salt to the
diluent is from 1:1 to 1:100 W/v, e.g. 1:5 to 1:15 W/v.
Preferably the solubility of the salt of the racemic
acid in the diluent at the operating temperature is from
0 5 to 2% W/v.
Preferably 50 to 98~ by weight of the salt e.g. 80-95%,
is undissolved in the diluent at the operating temperature.
The inert diluent is a liquid at the temperature at
which the mixture is heated and may comprise one or more
organic compounds. Usually the diluent is of low polarity
and for example may comprise one or more hydrocarbons. The
diluent is preferably a mixture of hydrocarbons which are
predominantly aliphatic and it preferably has a boiling
point in the range 110-135C. Polar compounds, in amounts
of e.g. up to 1% may be included in the diluent.
It is prefera~le that the diluent is such that the
reaction can be carried out under reflux conditions.
It may be desirable, to avoid by-product formation,
that heating is carried out under an inert atmosphere, e.g.
-- 6 --
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5942
nitrogen.
The invention is illustrated in the following Examples
in which flurbiprofen is (+)-2-(2-fluoro-4-biphenylyl)propionic
acid. Unless otherwise stated specific rotations were
measured in ethanol at a concentration of 1% W/v and
at ambient temperature.
Examples 1 to 31
Various mixtures comprising an amine salt of a 2-
arylpropionic acid and a diluent consisting of one or
more liquid organic compounds were stirred and heated.
On completion of the heating, the hot mixtures were
filtered through a steam heated Buchner funnel, the salts
were washed with the hot diluent, dried in vacuo, acidified
with dilute sulphuric or hydrochloric acid and the acid
mixtures extracted with ether . The ether extracts were
washed with water, dried and evaporated to give 2-
arylpropionic acids having a different optical activity
from the acid component of the salt from the start of the
experiment.
The details and results of various Examples are
given in Table I.
3o
- - -
O ~ O ~D 1~ ~ t\l ~ ~ ~ ~ O ~ 15~ D O Lr~
'-- h + + + + + + + + + + + + + + + + + +
~^ O O O ~ ~ o o ~ Lr ~ Lr o ~ o o U~ O O
a) u~ ~
.~ ~ 0 ~1 0 ~1 ~1 ~1 o~ D ~ ~1 1~ 0 U~ J
.
~ ~ h V ~ ~J ~I vJ ~1 ~ ~ r~ r I ~1 ~0 ~ ~1 ~J t\l ~ ~ ~1 ~
C~ o ~
Ln ~E~
.'
~ '~ ~
~tH ~ O h
O ~ IS~ ~
0 ~1 ~ h O O O 1~ 0 0 0 ~ 1 ~ ~ ~ ~ ~ O
u~ ~5 h 1~ ~ ~1 ~1 ~ ~1 ~1 ~1 1~ .-J ~1 ~1 ~1 o q~ + I ~ ~ a
V~ 0`~ +'
H¦ ~1
~1 ~~
. ~ O O O O O O O O O O O O O O O O O O
bO ~ ~ ~ ~ ~ ~ ~1
. ~ ~
~ . o ~ ~ ~ X ~ X
.~
~:
,~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ r-~ ~ ~ ~ ~ ~ ~
cl ~ m
o
æ ~ ~ o
- 8 -
~o~
o ~ O ~ r~
~1 0 _~ . . . . . . . . . . ..
r~ ~ Lr~ ~ ~ ~ L~
~ 0 a) ~ ~ ~ ~ ~ ~ r~
~ 5~ + + + + + + l + + + + +
a~ u,~ o U~ o ~ o o U~ ~ ~o o
O ~O C~ ~ O ~ ct
~ qo~ ~ 0 ~
- -
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0 E~ ~ C- ~ ~ ~ ~ ~ ~ t` ~ ~ C-
a,
O
--~ u~
h C~ ~1 ~1 ~1 ~1 ~1 ~1 ~1 ~1 ~1 ~1 ~1 ~1
0 ~
~'
. ,
~o ~ -u~
r~ 0
~1~1 0 ~ ~J) h~ ~ O ~) Lr~ ~ ~D O O ~ 00 0
~ i h ~ ~ ~1~ ..
oq~ +1~:+~ a~
U~ o ~ ,1
+, tn
. ~ O ~ J
~0 ~ O O ~ O I
h
P~
+'
:~ 1~ N
~ ~ O ~ ~ ~
~ .~ ~ ~ ~ ~ ~ ~ ~ ~ ~
+~ O '~ ~ ~ ~1 ~ ~ '~ 'C 'C 'C ~1 ¢,
~0 'C
~)
H O
~1 ~z; o ~I c\l ~\ ~ L~ '.D ~ t~ 0~ 0 ~1
E~ l~j
_ 9 ~
~ 5942 ~
o
~3 1 ~ N ~D ~ o
~1 0 ~ O
~ ~D _
~ + o ta ~D ~ + V ~ V V
h ~ td U~ ~ 'H I
O ~IV Ll~ u~
O + ~ ~ ~1 0 N ~1
O N
O t~
~1 h t~ h . ~n
+ ~ O h a) ~d h td t~
t~ h ~ +'
,~: a) ~ I o o ~
h ~ O + ~1 ,1 ,~:t ~1 rJ
u~ ~1 ^ h --' ~) - O ~: ~ O O O
+~ ~+~
^ O h h O ~1 ~1 O C)
O + rl ~O tlJ O o t~
~ O --' +~ +~ +~
O; ~ o~ ~ h
1~ i 0 h O ~1 0
h <) tll O ~1 O tl ~ O o ~ o
1) O +~ S ~ h I t) P: ~ h h
vl ~1 - ~ ~1 Dq +~ --~ h ~ ~ ~ +~ +S +~ ~
O +~ ~ O +~ ~ ) O
~ ~ ~ 0 ~ ~ ~ E~
O o -
~ ~ ~ +~ O t~ ~ h
rl ~ ~ ~ oP' ~ .,~ ~ ~) ~ ~3
~d ^ ^ ^ - h O ~ ~D
C) ~, ~ O O ~
~t[l 0 t~ O ~ rl O O h
O ~ h rl ~
O ~ ~ ~ ha) P~ ~I h ~ .q
h O O O 1~ O ~. P~
I--I 0 0 0 ~ P ^
h h h ~1 1 ~1 ~ ~ D~ ~ ~ ~, ~, ~ ,~ ~ ,~
a~ o +~ 1 +~
,1 N o ~ ~~1 ~1 +' o ~ ~ o a) Q) a
~ P1 ~ ~ I h I h I O~ ~ a~
u: I I ~1 H rl O ~) ~ O ~ H N ~:4 ~1 ~, ;~ ;>~ Q. ,~
I o .n n ,n h I X ~ X +~ ~ O h O X X O O O O
., h I I I O - O ~1 0 1~ ~ h X h O O h h ,h h
~ ~ ~ ~ ~ ~ CH h +' ,O ~ ~) o ~ ~ o o o o
t~ ~ I I I ~1 ~` +' I ~ O ~1 0 .~ ~1 +'
~1 O O O ~H - a~ N ~ h ~ CQ o ,s: ~ a~ ~ I ~ ~ ~
C~ CH h h h I N ~ ~ ~ -1 H O E; 13 CH CH t> ~H
H ,~ I O O O - ^ I I I O +) I O
_. N ~ ~ ~ N N ~D ~ N ,1 a~ ~ ~ ~ N N ~ N N r-~
m n N I I I N N N N N t>
c O I N N N I I I I I
c~ c ~ ~_ ~_ ~ ~ ~ ,_ ~ ~ ~,
.. ~+l I I I +l +l +l +l +l U~ I I + I + I I +
O ~1~-- N N N ~ * cn ~
E~ ~ 11 11 11 11 11 11 11 11 11 ~ 11 11 11 11 11 11 11 11 11 11
NN ~ ~ m v ~ ~ ~ ~ ~ x 1~ ~ ~ ~ ~:
- ln _
~i5942
Example 32
Flurbiprofen (4.75 kg.) was mixed with a petroleum
fraction b.p. 125C(48 litres)and the mixture stirred
under nitrogen and heated to form a solution. (- )-a-
Methylbenzylamine (2.35 kg.) in the same petrol (23 litres)was added with stirring and the mixture then heated under
reflux under nitrogen for 72 hours. The internal temperature
was 125C. The mixture was then filtered, and the salt
was washed with the hot petrol and dried to give the (-)-a-
methylbenzylamine salt of 2-(2-fluoro-4-biphenylyl)propionic
acid (5.4k.g.) in 76% yield. A small portion of this was
acidified to give 2-(2-fluoro-4-biphenylyl)propionic acid
having [ a ]D + 33 The remainder was recrystallised from
isopropanol and a portion acidified to give 2-(2-fluoro-4-
biphenylyl)propionic acid having [a]D + 41.
The remainder of the recrystallised salt (4.3 kg.) wasmixed with light petroleum (b.p. 102-120~C; 35 litres) and
water (37 litres), and the mixture stirred under nitrogen.
Concentrated hydrochloric acid (1 kg.) was added and the
mixture refluxed for 1 hour. The hot organic layer was
separated, washed with water, filtered, cooled and the
product collected by filtration, washed with hexane and dried
to give 2-(2-fluoro-4-biphenylyl)propionic acid, having
[a]D + 43 7 representing 98% optical purity.
The filtrate after the initial 72 hour heating of the
salt together with solid recovered from mother liquors from
the isopropanol recrystallisation of salt and the petrol
crystallisation of the acid were all recycled for treatment
with a further quantity of flurbiprofen.
3o
-- 11 --
~1~594;~
The amine salt of the racemic acid has a solubility
in the petroleum fraction of 124 ml/g. at 125C.
Example 33
The (-)-a-methylbenzylammonium salt (1 part by weight)
of flurbiprofen was mixed with light petroleum (b.p. 40-
60C; 10 parts by ~olume) and heated at 116C in a sealed
was
autoclave for 72 hours. The mixture/then cooled and
filtered and the salt was washed with light petroleum and dried
in vacuo to give a 93.5% yield of salt which gave 2~-fluoro-4-
biphenylyl)propionic acid having [a]D + 21.9.
.
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