A process is disclosed for preparing arylpropionic acids of formula Ar--CH(CH.sub.3)--COOH, by reacting an aryl Grignard reagent with a metal pyruvate or with a pyruvamide, to form a hydroxy acid of formula Ar--C(OH)(CH.sub.3)--COOH or its amide, and converting the acid or amide to the product.

This invention relates to therapeutic agents and in particular to a process 
for preparing therapeutic agents. 
It is well known that a large number of 2-arylpropionic acids, and 
derivatives thereof have valuable therapeutic properties, and many 
possess, for example, anti-inflammatory activity. The present invention 
relates to a method of preparing such acids and to methods for preparing 
intermediates to these acids. 
Various methods have been proposed for the preparation of 2-arylpropionic 
acids including processes which involve 2-aryl-2-hydroxypropionic acids or 
their derivatives, as intermediates. In such processes the 
2-aryl-2-hydroxypropionic acids are converted to the desired 
2-arylpropionic acid, in which the hydroxyl group is replaced by hydrogen, 
in various known ways. For example, 2-aryl-2-hydroxypropionic acids can be 
dehydrated to the corresponding 2-arylacrylic acids. These can then be 
hydrogenated to form the desired 2-arylpropionic acids. It is known that 
with some 2-arylpropionic acids, the majority or nearly all the 
therapeutic activity of one of the stereoisomers is greater than that of 
its enantiomer. If desired the 2-arylacrylic acid can be hydrogenated 
under conditions which will preferentially form one of the stereoisomers 
of the 2-arylpropionic acid in a greater proportion than its enantiomer. 
Thus, an effective route for the preparation of 2-aryl-2-hydroxypropionic 
acids is highly desirable. 
In our B. Pat. No. 971,700 we disclose a process in which ethyl pyruvate is 
reacted with a Grignard reagent to give a 2-aryl-2-hydroxypropionic acid 
ester which is hydrolysed to the 2-aryl-2-hydroxypropionic acid. It has 
also been disclosed (Chemistry and Industry 1970, 159) that an 
arylmagnesium bromide can be reacted with pyruvic acid to give a 
2-aryl-2-hydroxypropionic acid. However, the yields in these processes 
tend to be low. For instance, in two typical processes, the details of 
which are given below, the yields are 14.5 and 18%. 
We have now found that when an arylmagnesium bromide is reacted with 
certain salts or with certain amides of pyruvic acid, the resultant 
addition product is obtained in a higher yield than when the arylmagnesium 
bromide is reacted with pyruvic acid or an ester thereof. For example, 
yields of over 70% of high quality 2-(2-fluoro-4-biphenylyl) propionic 
acid have been obtained by reacting sodium pyruvate with 
2-fluoro-4-biphenylylmagnesium bromide. 
Thus, according to the present invention, there is provided a process for 
preparing a compound of formula I, 
##STR1## 
wherein Ar is an aryl group, which comprises reacting a Grignard compound 
obtained from Ar.sub.1 Br and magnesium, wherein Ar.sub.1 is Ar or a group 
convertible to Ar on acidification, with a compound of formula II, 
EQU CH.sub.3 --CO--COZ II 
wherein Z is OM or NR.sub.1 R.sub.2 wherein M is an alkali metal and 
R.sub.1 and R.sub.2 are the same or different alkyl, alkenyl, or aryl or 
together with the nitrogen atom to which they are attached form a 5 to 7 
membered ring, and acidifying the mixture to give a compound of formula 
III 
##STR2## 
where Q is OH or NR.sub.1 R.sub.2 and converting this, in known manner, to 
the compound of formula I. 
The invention also includes the process of preparing the compounds of 
formula III as described above. 
Generally Ar.sub.1 =Ar. The term "aryl" also includes heteroaryl e.g. 
thienyl, thiazolyl, pyrrolyl and triazinyl. 
The Ar group is generally a substituted phenyl group of formula 
##STR3## 
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, preferably C.sub.1-8 alkyl, e.g. 
methyl, ethyl, propyl, butyl, (especially isobutyl), pentyl, branched 
hexyl and heptyl; 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 
C.sub.1-4 alkyl, alkoxy, preferably C.sub.1-4 alkoxy, alkylthio, 
preferably C.sub.1-4 alkylthio, especially methylthio, cyano or halogen, 
e.g. fluorine and chlorine; alkoxy preferably C.sub.1-4 alkoxy, e.g. 
methoxy and isopropoxy; 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 C.sub.1-4 
alkylthio, e.g. methylthio, ethylthio, propylthio and n-butylthio; 
aralkylthio; cycloalkylthio; arylthio, e.g. phenylthio; arylcarbonyl, e.g. 
benzoyl and thenoyl; N-alkyl-N-arylamino in which the aryl is e.g. phenyl 
or phenyl substituted with, for example, one or more halogen atoms, 
especially fluorine or chlorine; N-alkyl-arylsulphonamido; 
trifluoromethyl; halogen, e.g. fluorine or chlorine; dialkylamino; 
pyridyl; piperidyl; furyl; morpholino; thiamorpholino; pyrrolidinyl; 
pyrrolyl; thienyl; or two Q groups together form a carbocyclic or 
heterocyclic ring, which rings may be aromatic, e.g. naphthyl and 
substituted naphthyl. When Q is a heterocyclic group it may be substituted 
or unsubstituted. 
Examples of compounds are those in which the substituent or one of the 
substituents, Q, is in the 4-position, and is alkyl, e.g. isobutyl or 
cycloalkyl, e.g. cyclohexyl. Particularly preferred compounds are those in 
which Ar is 
##STR4## 
in which m is 0 or 1, and R.sub.3, R.sub.4 and R.sub.5 may be the same or 
different and are selected from hydrogen, chlorine, fluorine or methoxy, 
at least one being chlorine, fluorine or methoxy and preferably fluorine. 
Especially preferred are those compounds in which m is 0. 
Examples of such preferred Ar groups are the following; 
______________________________________ 
m R.sub.3 R.sub.4 R.sub.5 
0 H F H 
0 H H F 
0 H F F 
0 F F H 
0 F H F 
0 F F F 
0 F H H 
1 F H H 
1 F F H 
1 H F H 
1 F Cl H 
1 Cl H H 
0 H H OMe 
0 Cl F F 
0 F F Cl 
0 F Cl F 
0 Cl H H 
______________________________________ 
Other particularly suitable Ar 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. 
R.sub.1 and R.sub.2 are for example lower alkyl, e.g. of 1 to 4 carbon 
atoms, and especially both methyl or both ethyl. Examples of suitable 
rings of which R.sub.1 and R.sub.2 can form part, include 
##STR5## 
which rings may optionally carry one or more substitutents, e.g. C.sub.1-4 
alkyl. When R.sub.1 or R.sub.2 is aryl, this is generally phenyl but it 
may also be substituted phenyl, e.g. tolyl. It is generally preferred, 
however, that in compound II, Z is OM, and M is preferably sodium. When a 
metal salt is used the method of its preparation may affect the yield of 
the 2-aryl-2-hydroxypropionic acid. If the salt forms a hydrate then it is 
preferable that it is prepared in a non-aqueous medium, preferably a 
C.sub.1-4 alkanol, e.g. methanol. In the case of sodium pyruvate however, 
satisfactory results are obtained when the salt is prepared by reacting 
pyruvic acid with sodium carbonate in water, evaporating the solution and 
drying the residue in a vacuum. 
The reaction for producing the compound of formula III is generally carried 
out in a conventional manner for Grignard reactions, e.g. in an anhydrous 
aprotic medium, preferably an ether, for example tetrahydrofuran, diethyl 
ether, 1,2-dimethoxyethane or a mixture of one or more of these. The 
reaction is generally carried out at a temperature of -20.degree. to 
+150.degree. C., preferably -10.degree. to 70.degree. C. It may suitably 
be carried out under reflux. 
When the acid of formula III is one in which the aryl group contains a 
functional group which is itself reactive with the Grignard compound e.g. 
a carbonyl group, it is usually necessary that this functional group be 
protected before the Grignard compound is formed. The protecting group is 
then removed on acidification. An example of a suitable carbonyl 
protecting group is a ketal, for example gem-dimethoxy. 
As previously stated the compound of formula III can be converted to the 
compound of formula I in various known ways. The following scheme 
illustrates typical methods that can be applied. 
##STR6## 
In the above reactions it may be desirable to convert any of the acids to 
esters before proceeding to the next stage. The ester group is then 
eventually hydrolysed to give compound I. 
If compound V is replaced by the corresponding amide the amide group can be 
hydrolysed to carboxyl at any suitable stage to obtain I. 
The preferred method of converting III or V to I is by dehydration to IV 
followed by hydrogenation. 
The dehydration reaction may be carried out merely by heating the compound 
of formula III or V. However, it is preferred to use a dehydrating agent 
e.g. polyphosphoric acid. Other dehydrating agents which may be used 
include formic acid; phosphorus pentoxide alone or mixed with 
methanesulphonic acid or a tertiary amine; iodine, mesyl chloride mixed 
with sulphur dioxide; toluene p-sulphonic acid; naphthalene 
.beta.-sulphonic acid; phthalic anhydride mixed with propionic acid; 
potassium hydrogen sulphate; phosphoryl chloride in pyridine or dimethyl 
formamide; concentrated hydrochloric acid mixed with glacial acetic acid; 
propionic acid mixed with o-sulphobenzoic anhydride; and dimethyl 
sulphoxide. The dehydration may be carried out at a temperature for 
example of 0.degree. C. to 300.degree. C., preferably 0.degree. C. to 
200.degree. C. and especially 80.degree. C. to 150.degree. C. 
The hydrogenation of the compound of formula IV is generally carried out 
using a catalyst, e.g. palladium, usually on charcoal, platinum, 
ruthenium, Raney nickel or rhodium. The reaction is usually carried out in 
an inert solvent, e.g. a lower alkanol, benzene, toluene, xylene, 
tetrahydrofuran, dioxan, acetic acid or mixtures of two or more of these. 
The temperature of the hydrogenation may be, for example from 0.degree. C. 
to 200.degree. C. 
If desired, the hydrogenation may be carried out using a catalyst which may 
form one of the stereoisomers in a greater proportion than its enantiomer. 
Such catalysts are usually complexes of transition metals with an organic 
compound having one or more asymmetric carbon atoms, for example, the 
reaction product of a Group VIII transition metal salt or a complex 
thereof and an optically active bidentate compound of formula: 
EQU (R).sub.2 P--R'--P(R).sub.2 
in which R' is a bivalent hydrocarbon group containing one or more 
asymmetric carbon atoms and optionally bearing one or more substituents, 
the asymmetric carbon atom(s) optionally forming part of a ring and each R 
is a substituted or unsubstituted aliphatic, cycloaliphatic or aromatic 
hydrocarbon radical. Examples of these catalysts are described in B. Pat. 
No. 1,341,857. 
Generally this hydrogenation is carried out in the presence of a base 
usually an organic amine e.g. morpholine, aniline, isopropylamine, 
di-n-propylamine and tri-n-butylamine. A particularly suitable base is 
.alpha.-methylbenzylamine. 
If a hydrogenolysis reaction is used this may be carried out using 
conditions similar to that of the hydrogenation including using catalysts 
to obtain a stereospecific reaction. However, it is not always necessary 
to use hydrogen and hydrogenolysis may sometimes be carried out, for 
example by heating the compound to be hydrogenolysed with a mixture of 
phosphorus and hydriodic acid. 
If desired when the 2-aryl-2-hydroxypropionic acid is converted to the 
2-arylpropionic acid, by means other than via the acrylic acid, then it 
may be possible to resolve this compound or, when going through an 
intermediate resolve the intermediate, by conventional means. The resolved 
products may then be hydrogenolysed to give the 2-arylpropionic acid in 
which one stereoisomer is present in a greater amount than its enantiomer. 
As stated previously, compounds of formula I generally possess 
anti-inflammatory activity. Similarly, many compounds of formula III and 
IV also possess anti-inflammatory activity. Some of the compounds of 
formula III and IV are novel. Thus, the invention also provides compounds 
of formula 
##STR7## 
in which R.sub.6 and R.sub.7 are hydrogen or fluorine at least one being 
fluorine and especially 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid 
as well as enantiomers of these compounds. The invention also provides 
compounds of formula 
##STR8## 
in which R.sub.6 and R.sub.7 are as defined above, and especially 
2-(2-fluoro-4-biphenylyl)acrylic acid.

The invention is illustrated in the following Examples, in which "parts" 
and "percentages" are by weight, unless otherwise stated. 
In the Examples "DIOP" is: 
(-)-2,3-O-Isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)butane 
(J. Am. Chem. Soc. 1972,94,6429), DTDR is 
.mu.-dichlorotetracyclooctenedirhodium and DODDR is 
.mu.-dichlorodicycloocta-1,5-dionedirhodium. Optical rotations were 
determined in ethanol at a concentration of 1%. 
EXAMPLE 1 
A solution of 4-bromo-2-fluorobiphenyl (5 g., 0.02 mole) in dry 
tetrahydrofuran (20 ml.) was added dropwise, with stirring, to magnesium 
turnings (0.49 g.) in dry tetrahydrofuran (13 ml.). When the addition was 
complete, the mixture was stirred and boiled under reflux for one hour. A 
suspension of sodium pyruvate (2.2 g., 0.02 mole) in dry tetrahydrofuran 
(20 ml.) was added rapidly to the refluxing solution. Frothing occurred 
and when this had subsided the mixture was boiled under reflux with 
stirring for a further hour. The mixture was then cooled in an ice-bath 
and dilute hydrochloric acid (5 N; 50 ml.) was added. The mixture was 
stirred and extracted with ether. The extract was then extracted with 
aqueous potassium carbonate (1 N) and this extract acidified with dilute 
hydrochloric acid. The precipitate which separated, was collected and 
dried to give 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid, m.p. 
166.degree.-9.degree. C. in 71% yield. 
EXAMPLE 2 
The product of Example 1 (2 g.) was mixed with polyphosphoric acid (10 g.) 
and heated at 100.degree. C. for 30 minutes. Water was added and the 
mixture stirred and extracted with ether. The extract was dried, filtered 
and evaporated to give crude 2-(2-fluoro-4-biphenylyl)acrylic acid in a 
yield of 91%, m.p. 169.degree.-172.degree. C. This was recrystallised from 
a mixture of ether and light petroleum (b.p. 40.degree.-60.degree. C.) to 
give pure material, m.p. 176.degree.-177.degree. C. 
EXAMPLE 3 
The product of Example 2 (0.5 g.) was hydrogenated in ethanol (10 ml.) at 
room temperature and atmospheric pressure using a platinum catalyst (5 
mg.). After 41/2 hours the mixture was filtered and the filtrate 
concentrated. The product was recrystallised from a mixture of ether and 
light petroleum (b.p. 40.degree.-60.degree. C.) to give 
2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 112.degree.-113.degree. C. 
EXAMPLE 4 
DIOP (64.8 mg.) was added to a solution of DTDR (46 mg.) in benzene (9 ml.) 
under nitrogen and the mixture allowed to stand for 15 minutes. This 
complex was then added to a mixture, prepared by adding ethanol (16 ml.) 
followed by (-)-.alpha.-methylbenzylamine (24 mg.) in ethanol (2 ml.) to 
the product of Example 2 (0.5 g.), under hydrogen. The reaction mixture 
was stirred under hydrogen for 51/2 hours at room temperature and then 
kept under hydrogen overnight. The solution was concentrated under reduced 
pressure and the residue treated with ether and aqueous 10% potassium 
carbonate. The ether extract was treated with the potassium carbonate 
extract, which was then acidified. The oil which separated, solidified and 
was extracted with ether and the extract dried, filtered, evaporated and 
the product recrystallised from light petroleum (b.p. 
60.degree.-80.degree. C.) to give 2-(2-fluoro-4-biphenylyl)propionic acid, 
m.p. 101.degree.-103.degree. C., having an optical rotation 
[.alpha.].sub.D.sup.20 +35.5.degree. C. representing 89% of the (+) isomer 
in the product. 
EXAMPLES 5-12 
In a similar manner to that described in Example 1 the following compounds 
were obtained from the appropriate bromo compound. The compounds were 
purified by recrystallisation from the solvent given in Table I. 
__________________________________________________________________________ 
Recrystallisation 
M.P. 
Ex. No. 
Compound Obtained Solvent (.degree.C.). 
__________________________________________________________________________ 
5 2-Hydroxy-2-(6-methoxy-2-naphthyl)propionic acid 
Methanol/water 167-168 
6 2-Hydroxy-2-(3-phenoxyphenyl)propionic acid 
" 99-101 
7 2-Hydroxy-2-(4-isobutylphenyl)propionic acid 
Petroleum (b.p. 40-60.degree. C.) 
104.5-105.5 
8 2-(4-Cyclohexylphenyl)-2-hydroxypropionic acid 
Ether/petroleum (b.p. 40-60.degree. 
154-155 
9 2-Hydroxy-2-(2-methoxy-4-biphenyl)propionic acid 
Toluene 157.5-158 
10 2-Hydroxy-2-(2,2',4'-trifluoro-4-biphenyl) 
N.C. 132-134 
propionic acid 
11 2-(2,2'-Difluoro-4-biphenyl)-2-hydroxy- 
Toluene 154-155 
propionic acid 
12 2-[4-(2-Fluorophenoxy)phenyl]-2-hydroxypropionic 
Toluene 123-125 
acid 
__________________________________________________________________________ 
N.C. = Product not recrystallised. 
EXAMPLE 13 
In a similar manner to that described in Example 1, the Grignard compound 
was formed from 3-bromobenzophenone dimethyl ketal and reacted with sodium 
pyruvate. Crude 2-(3-benzoylphenyl)-2-hydroxy propionic acid was obtained 
as an oil. 
EXAMPLES 14 AND 15 
Example 1 was repeated in which the sodium pyruvate was replaced in turn by 
equivalent amounts of lithium pyruvate and potassium pyruvate. 
2-(2-Fluoro-4-biphenylyl)-2-hydroxypropionic acid was obtained in a yield 
of 32.4% having an m.p. of 163.degree.-166.degree. C. and in a yield of 
28% having an m.p. of 161.degree.-163.degree. C. respectively. 
EXAMPLES 16-19 
In a similar manner to that described in Example 2 the products of Examples 
7, 8, 10 and 11 were treated to give the following acrylic acids. The 
products were recrystallised from the solvent given in the Table II. 
TABLE II 
__________________________________________________________________________ 
Product form 
Ex. No. which is 
Acrylic acid Recrystallisation M.P. 
Ex. No. 
dehydrated 
obtained Solvent .degree.C. 
__________________________________________________________________________ 
16 7 2-(4-isobutylphenyl)acrylic acid 
Light petroleum (b.p. 40-60.degree. 
92-94 
17 8 2-(4-cyclohexylphenyl)acrylic acid 
Ether/light petroleum (b.p. 40-60.degree. 
C.) 148-149 
18 10 2-(2,2',4'-trifluoro-4-biphenylyl) 
acrylic acid Toluene 193-194 
19 11 2-(2,2'-difluoro-4-biphenylyl)acrylic 
Toluene 182-183 
acid 
__________________________________________________________________________ 
EXAMPLES 20 AND 21 
The product of Exampl 9 (2.6 g.) was mixed with p-toluenesulphonic acid 
(2.63 g.) and benzene (110 ml.) and the mixture heated under reflux for 2 
hours. Water, which formed, was removed by means of a Dean and Stark 
apparatus. The benzene was evaporated and the residue extracted with 
ether. The extracts were washed with water and extracted with aqueous 
potassium carbonate (10%). This extract was washed with ether and 
acidified to give crude 2-(2-methoxy-4-biphenylyl)acrylic acid. 
In a similar manner the product of Example 12 gave crude 
2-[4-(2-fluorophenoxy)phenyl]acrylic acid. 
EXAMPLES 22-27 
Example 3 was repeated in which the platinum catalyst was replaced by 10% 
palladium/charcoal. After recrystallising the product from light petroleum 
(b.p. 80.degree.-100.degree. C.) 2-(2-fluoro-4-biphenylyl)propionic acid, 
m.p. 113.degree.-114.degree. C. was obtained. 
In a similar manner, the following compounds were obtained by hydrogenating 
the acrylic acids from Examples 16 and 18-21. The products were 
recrystallised from the solvent given in the Table III. 
TABLE III 
__________________________________________________________________________ 
Product from 
Ex. No. which is Recrystallisation 
M.P. 
Ex. No. 
hydrogenated 
Propionic acid obtained 
Solvent .degree.C. 
__________________________________________________________________________ 
23 16 2-(4-isobutylphenyl)propionic acid 
Light 72-76 
Petroleum (b.p. 60-80.degree. C.) 
24 18 2-(2,2',4'-trifluoro-4-biphenylyl) 
Light 
propionic acid Petroleum (b.p. 60-80.degree. C.) 
106-107 
25 19 2-(2,2'-difluoro-4-biphenylyl)propionic 
acid None 117 
26 20 2-(2-methoxy-4-biphenyl)propionic 
acid None 119-120 
27 21 2-[4-(2-fluorophenoxy)phenyl]propionic 
Light 
acid Petroleum (b.p. 100-120.degree. C.) 
100-101 
__________________________________________________________________________ 
EXAMPLES 28-30 
Example 1 was repeated in which the sodium pyruvate was replaced by an 
equivalent amount of the following amides. After the reaction with the 
Grignard reagent by heating under reflux for 60 minutes the product was 
isolated by addition of water (200 ml.) followed by extraction with ether. 
The ether extract was washed with water, dried and concentrated under 
reduced pressure. Light petroleum (b.p. 62.degree.-8.degree. C.) was added 
and the solution concentrated by evaporation under reduced pressure when 
the product crystallised and was collected. 
The details of the products are given in the Table IV. 
TABLE IV 
__________________________________________________________________________ 
Starting Yield 
M.P. 
Ex. No. 
Amide Product (%) (.degree.C.) 
__________________________________________________________________________ 
28 CH.sub.3 COCONMe.sub.2 
2-(2-fluoro-4-biphenylyl)-2- 
37 135-137 
hydroxy-N,N-dimethylpropionamide 
29 CH.sub.3 COCONEt.sub.2 
N,N-diethyl-2-(2-fluoro-4- 
64 111-112 
biphenylyl)-2-hydroxy- 
propionamide 
30 
##STR9## 2-(2-fluoro-4-biphenylyl)-2- hydroxy-N,N-3-oxapentamethyl- 
nepropionamide 42 155-156 
__________________________________________________________________________ 
The N,N-3-oxapentamethylene pyruvic acid amide was prepared by heating 
hydroxymaleic anhydride-pyridine complex with morpholine in toluene to 
100.degree. C. until evolution of carbon dioxide ceased. The product was 
recovered by distillation, b.p. 126.degree.-8.degree. C./8 mm. 
EXAMPLES 31-33 
The products from Examples 28-30 were treated in a similar manner to that 
described in Example 2. The product of Example 28 gave 
2-(2-fluoro-4-biphenylyl)-N,N-dimethyl acrylamide, obtained as an oil; the 
product of Example 29 gave 
N,N-diethyl-2-(2-fluoro-4-biphenylyl)acrylamide, obtained as an oil, and 
the product of Example 30 gave 
2-(2-fluoro-4-biphenylyl)-N,N-3-oxapentamethyleneacrylamide, obtained as a 
white solid, m.p. 102.degree. C., after recrystallising from light 
petroleum (b.p. 62.degree.-68.degree. C.). 
EXAMPLES 34-36 
The products of Examples 31-33 were hydrogenated in a similar manner to 
that described in Example 22. The product of Example 31 gave 
2-(2-fluoro-4-biphenylyl)-N,N-dimethyl propionamide, obtained as a white 
solid, m.p. 67.degree.-69.degree. C. after recrystallising from light 
petroleum (b.p. 62.degree.-68.degree. C.); the product of Example 32 gave 
N,N-diethyl-2-(2-fluoro-4-biphenylyl)propionamide, obtained as an oil, and 
the product of Example 33 gave 
2-(2-fluoro-4-biphenylyl-N,N-3-oxapentamethylenepropionamide, obtained as 
a white solid m.p. 96.degree.-98.degree. C. after recrystallising from 
light petroleum (b.p. 62.degree.-68.degree. C.) 
EXAMPLE 37 
The products from Example 34 were heated under reflux for two days with a 
mixture of glacial acetic acid, concentrated sulphuric acid and water 
(volume ratio 10:1:1.5). The reaction mixture was added to water, 
extracted with ether and then aqueous potassium carbonate (10%) and this 
extract acidified and the precipitate collected to give 
2-(2-fluoro-4-biphenylyl)propionic acid. The products of Examples 35 and 
36 also gave the same product when treated in a similar manner. 
EXAMPLE 38 
Example 4 was repeated in which the DTDR was replaced by an equivalent 
amount of DODDR and the DIOP was replaced by an equivalent amount of 
(-)-2,3-bis(diphenylphosphinomethyl)-1,4-dioxaspiro[4,4]nonane, prepared 
by: (a) reacting L-(+)-diethyl tartrate with cyclopentanone in benzene in 
the presence of p-toluenesulphonic acid to give diethyl 
1,4-dioxaspiro[4,4]nonan-2,3-dicarboxylate, b.p. 154.degree.-158.degree. 
C./6.0 mm., (b) reducing this with lithium aluminium hydride to give 
(-)-2,3-O-cyclopentylidene-L-threitol, b.p. 124.degree.-130.degree. C./0.2 
mm., (c) converting this to 
(-)-1,4-ditosyl-2,3-O-cyclopentylidene-L-threitol m.p. 
109.degree.-115.5.degree. C. by reaction with p-toluenesulphonyl chloride 
in pyridine and (d) treating with potassium and diphenylphosphine in 
tetrahydrofuran to give the desired compound m.p. 93.degree.-95.degree. C. 
The 2-(2-fluoro-4-biphenylyl)propionic acid obtained had an m.p. 
102.degree.-105.degree. C. and [.alpha.].sub.D.sup.20 +36.0.degree., 
representing 90% of the (+) isomer in the product. 
EXAMPLES 39-40 
Example 4 was repeated in which the .alpha.-methylbenzylamine was replaced 
with in turn di-n-propylamine and isopropylamine. The resulting 
2-(2-fluoro-4-biphenylyl)propionic acid had respectively m.p. 
101.degree.-104.5.degree. C. and [.alpha.].sub.D.sup.24 +37.0.degree., 
representing 91% of the (+) isomer in the product and m.p. 
102.degree.-104.degree. C. and [.alpha.].sub.D.sup.29 +36.0, representing 
90% of the (+) isomer in the product. 
EXAMPLE 41 
Nitrogen was bubbled through a mixture of DODDR (14 mg.), DIOP (30 mg.) and 
isopropanol (5 ml.) which had previously been degassed with nitrogen for 
1/2 hour and the flask was evacuated and then flushed with hydrogen 6 
times. The mixture was stirred under hydrogen for 20 minutes and then 
2-(2-fluoro-4-biphenylyl)acrylic acid (0.5 g.) from Example 2 and 
(-)-.alpha.-methylbenzylamine (22 mg.) in isopropanol (20 ml.), which had 
been degassed with nitrogen, was added with a syringe through a rubber cap 
covering the flask. The mixture was stirred for a further 20 hours until 
the requisite amount of hydrogen had been taken up. The solution was 
concentrated under reduced pressure and the residue isolated in ether and 
the ether solution extracted with aqueous potassium carbonate. The extract 
was washed with ether and acidified. The precipitate was extracted with 
ether and the extract washed with water, dried and evaporated to dryness. 
The residue was dissolved in hot light petroleum (b.p. 
60.degree.-80.degree. C.). This solution was treated with charcoal, 
filtered and rapidly cooled to room temperature by placing the flask 
containing it under cold running water. At the same time it was seeded 
with almost pure (+) product and the flask was scratched with a glass rod. 
The resultant, rapidly crystallised product, after separation and drying 
had an [.alpha.].sub.D.sup.20 +43.2.degree., representing 98% of the (+) 
isomer in the product, and m.p. 105.degree.-107.degree. C. 
EXAMPLE 42 
The product of Example 1 (5.2 g.; 0.02 mole) in warm industrial methylated 
spirits (50 ml.) was treated with (-)-.alpha.-methylbenzylamine (2.4 g.; 
0.02 mole) in industrial methylated spirits (2.0 ml.). The solution was 
allowed to stand at 25.degree. C. for two hours and the colourless 
crystals which separated were collected. This solid was recrystallised 
twice more from industrial methylated spirits. The product was collected, 
acidified with dilute sulphuric acid and the free acid extracted into 
ether. The extract was washed with water, dried and evaporated to dryness 
to give (+)-2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid having 
[.alpha.].sub.D.sup.20 +40.0.degree. and m.p. 150.degree.-152.degree. C. 
The mother liquors from the above recrystallisations were evaporated to 
dryness and the residue was acidified with dilute sulphuric acid. The acid 
was extracted with ether, the extract washed with water, dried, evaporated 
to dryness and the residue treated with an equivalent amount of 
(+)-.alpha.-methylbenzylamine in industrial methylated spirits. The 
product was allowed to crystallise and recrystallised from industrial 
methylated spirits. The product was acidified and the free acid extracted 
and purified as described above to give 
(-)-2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid, having 
[.alpha.].sub.D.sup.20 -39.5.degree. and m.p. 149.degree.-151.degree. C. 
EXAMPLE 43 
The product from Example 1 (5 g.) was added to acetic anhydride (50 ml.) 
and the mixture heated on a steam bath for 2 hours after the acid had all 
dissolved. The mixture was then cooled and poured into water (200 ml.). 
The aqueous mixture was allowed to stand for 2 hours and the product 
collected recrystallised from a mixture of ether and light petroleum (b.p. 
62.degree.-68.degree. C.) gave 
2-acetoxy-2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 
141.degree.-142.degree. C. 
EXAMPLES 44-45 
(+)-2-(2-Fluoro-4-biphenylyl)-2-hydroxypropionic acid (1 g.) from Example 
42 was added to acetic anhydride (10 g.) and the mixture stirred overnight 
at room temperature. The mixture was added to water (40 ml.) and allowed 
to stand for two hours. The product was collected and recrystallised from 
a mixture of ether and light petroleum (b.p. 62.degree.-68.degree. C.) to 
give (-)-2-acetoxy-2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 
125.degree.-127.degree. C. and [.alpha.].sub.D.sup.20 -33.0.degree.. 
In a similar manner, starting from 
(-)-2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid, there was obtained 
(30 )-2-acetoxy-2-(2-fluoro-4-biphenylyl)propionic acid, m.p. 
125.degree.-127.degree. C. and [.alpha.].sub.D.sup.20 +32.0.degree.. 
EXAMPLE 46 
The product from Example 44 was hydrogenated at 25.degree. C. in glacial 
acetic acid using a 10% palladium/charcoal catalyst, for 17 hours. The 
filtrate from catalyst was evaporated and applied to preparative thin 
layer chromatography plates and eluted with an ether/petroleum (b.p. 
62.degree.-68.degree. C.) mixture (5%: 95%) whereby 
2-(2-fluoro-4-biphenylyl)propionic acid, [.alpha.].sub.D.sup.20 
-29.5.degree., was recovered. This represents 82% of the (-)-isomer in the 
product. 
The products from Examples 43 and 45 were similarly hydrogenated, at 
60.degree. C. and 50.degree. C. respectively, but were not subjected to 
thin layer chromatography. In both cases 
2-(2-fluoro-4-biphenylyl)propionic was shown to have been produced in 
major amount by G.L.C. The reaction mixture obtained by hydrogenating the 
(-)-2-acetoxy-2-(2-fluoro-4-biphenylyl)propionic acid from Example 45 had 
[.alpha.].sub.D.sup.20 +34.0.degree.. 
EXAMPLE 47 
The product of Example I (5 g.) was heated under reflux with methanol (50 
ml.) and concentrated sulphuric acid (1 ml.) for 4 hours. The product was 
poured into water, extracted with ether, the ether extracts dried and 
evaporated to give methyl 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionate, 
m.p. 59.degree.-61.degree. C. This ester (1 g.) was dissolved in thionyl 
chloride (5 ml.) and heated on a water bath at 50.degree. C. for two 
hours. Thionyl chloride was removed and the product was applied to 
preparative thin layer chromatography plates, eluted with an 
ether/petroleum (b.p. 62.degree.-68.degree. C.) mixture (5% 95%) and 
methyl 2-chloro-2-(2-fluoro-4-biphenylyl)propionate recovered. This was 
dissolved in ethyl acetate (5 ml.) and hydrogenated at room temperature 
using a 10% palladium/charcoal catalyst (73 mg.) for 16 hours. The 
solution was filtered and evaporated to give methyl 
2-(2-fluoro-4-biphenylyl)propionate, whose structure was confirmed by 
n.m.r. This was hydrolysed by heating under reflux with aqueous ethanolic 
potassium hydroxide. The solution was acidified, extracted with ether and 
then aqueous potassium carbonate (10%) and this extract acidified and the 
precipitate collected to give 2-(2-fluoro-4-biphenylyl)propionic acid (m.p 
t. 105.degree.-106.degree. C.). 
COMATIVE EXAMPLES 
Example 1 was repeated in which the sodium pyruvate was replaced by an 
equivalent amount of pyruvic acid. The yield of 
2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid was only 18% and had a 
melting point of 163.degree.-165.degree. C. 
In a similar manner Example 1 was repeated in which the sodium pyruvate was 
replaced by an equivalent amount of ethyl pyruvate. An oil was obtained 
containing 21% of ethyl 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionate 
representing a yield of only 14.5% of this ester.