Process for the manufacture of pharmaceutically active compounds
The present invention further relates to a process for the manufacture of compound (I), wherein X is —Br or —Cl.
1. A process for the manufacture of compound (I),
comprising the steps of:
aa) reacting the compound of formula (II),
with the compound of formula (III),
in the presence of a catalyst, copper(I)iodide and a base, to produce the compound of formula (IV),
bb) reacting said compound of formula (IV) in the presence of aqueous alkali metal hydroxide at 50-90° C. and under reduced pressure to produce the compound of formula (V),
and
cc) reacting said compound of formula (V) in the presence of aqueous alkali metal hydroxide or a strong base to produce the compound of formula (I);
wherein
R 1 and R 2 are each independently a C1-C4 alkyl, and
X is —Br or —Cl.
2. The process according to claim 1 , wherein X is —Br.
3. The process according to claim 1 , wherein R 1 and R 2 are both methyl.
4. The process according to claim 2 , wherein reaction step bb) is carried out under reduced pressure below 100 mbar.
5. The process according to claim 1 , wherein the catalyst in step aa) is PdCl 2 (PPh 3 ) 2 and the alkali metal hydroxide in step bb) is lithium- or sodium hydroxide.
6. The process according to claim 1 , wherein the compound of formula (IV) is dissolved in a mixture of water and N-methylpyrrolidone, and is reacted in the presence of aqueous sodium hydroxide at about 75 to about 85° C. and under reduced pressure for 15 to 20 hours to give directly the compound of formula (I) without the need to apply an aqueous work-up of the compound of formula (V).