Process for preparing optically active alpha-haloalkyl-aryl-ketones

A process is described for preparing alpha-haloalkyl-aryl-ketones, comprising reacting a substantially anhydrous strong acid with a ketal of formula ##STR1## in which Ar, R, R.sub.1, R.sub.2 and X have the meanings given in the description.

This invention relates to a process for preparing optically active 
alpha-haloalkyl-aryl-ketones. 
Alpha-haloalkyl-aryl-ketones are useful intermediates in the synthesis of 
organic compounds, for example compounds of pharmaceutical activity or 
compounds useful in agriculture. 
In certain cases the availability of optically active 
alpha-haloalkyl-aryl-ketones is very useful. A typical example of this 
requirement is the synthesis of optically active alpha-aryl-alkanoic acids 
which are used in pharmaceutics. 
These acids can be prepared from optically active 
alpha-haloalkyl-aryl-ketones by forming ketals with glycols or alcohols 
and rearranging them. The main known rearrangement methods are reported in 
Angew. Chem. Int. Ed. 23, 413 (1984) and in the description of European 
patent application No. 81993 (Syntex). 
This latter publication describes a process for preparing optically active 
alpha-haloethyl-aryl-ketones by a coupling or Friedel-Crafts reaction 
between an aromatic compound and the optically active 
alpha-bromo-propionyl-bromide. This latter, which is prepared from lactic 
acid and alanine, racemises at temperatures exceeding -10.degree. C. [J. 
Am. Chem. Soc. 76, 6054 (1954)], making implementation of the process of 
an industrial scale difficult. 
Italian patent application Nos. 7204 A/84, 7206 A/84 and 7207 A/84 in the 
name of the present applicant describe ketals obtained from 
alkyl-aryl-ketones and L(+) or D(-)-tartaric acid or derivatives, their 
diastereoselective halogenation and their use in the preparation of 
optically active alpha-arylalkanoic acids. The ketal intermediates 
described in the said italian patent applications have the following 
formula 
##STR2## 
in which Ar represents an aryl, possibly substituted; 
R represents a C.sub.1 -C.sub.4 alkyl; 
R.sub.1 and R.sub.2, which can be the same or different, represent a 
hydroxyl, an alkoxy, an amino group possibly mono- or di-substituted, or a 
O.sup.- M.sup.+ group where M.sup.+ represents the cation of an alkaline 
metal; 
X represents, inter alia, a chlorine, bromine or iodine atom; the carbon 
atoms marked with an asterisk both having R or S configuration. 
According to the description of said Italian patent applications, 
halogenating the compounds of formula I in which X=H leads to compounds of 
formula I in which X=halogen, in which there strongly prevails one of the 
two diastereoisomers with reference to the new centre of asymmetry which 
is generated (carbon atom to which the substituent X is bonded); 
rearranging the compounds of formula I in which X=halogen then leads to 
the corresponding optically active alpha-arylalkanoic acids. 
If however compounds of formula I in which X=halogen are used for preparing 
optically active alpha-haloalkyl-aryl-ketones, ie compounds of formula 
##STR3## 
(in which Ar and R have the meanings given for formula I and X represents 
a chlorine, bromine or iodine atom), the ketal hydrolysis must be carried 
out under non-racemising conditions and in a reaction environment such 
that the product obtained (compound II) does not racemise. The normal 
ketal hydrolysis conditions (water and acid pH) have proved unsuitable 
because the hydrolysis requires drastic conditions and gives rise to the 
formation of undesirable by-products and racemisation of any ketone 
formed. 
According to the present invention, we have now found that optically active 
compounds of formula II can be obtained by treating optically active 
ketals of formula I with a strong acid in a substantially anhydrous 
environment, possibly in the presence of an inert solvent. 
In the compounds of formula II obtained in this manner, the enantiomeric 
excess reflects the diastereoisomeric excess of the starting compounds of 
formula I. The reaction is preferably conducted between 0.degree. C. and 
50.degree. C., and in particular around 10.degree.-15.degree. C. 
Suitable strong acids are methanesulphonic, sulphuric, p-toluenesulphonic, 
fluorosulphonic and trifluoromethanesulphonic acid, and generally those 
strong acids available in substantially anhydrous form. 
To obtain acceptable reaction rates, an acid excess is used of around 3-10 
times the compound of formula I by weight. 
Depending on the nature of the substrate, it can be useful to use an 
organic solvent for optimising the results. 
In all cases the organic solvent is used in small quantity, around 10-30% 
of the acid by weight. 
Suitable solvents are lower alcohols, chlorinated hydrocarbons such as 
1,2-dichloroethane and methylene chloride or their mixtures.