Synthesis of antidiabetic rosiglitazone derivatives
A process of preparing rosiglitazone, or a pharmaceutically acceptable salt thereof, which process employs an intermediate metabisulphite complex of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde, which metabisulphite complex is represented by following formula (III): where X represents an alkali metal. The present invention further provides rosiglitazone, or a pharmaceutically acceptable salt thereof, prepared by the above process.
1. A process of preparing rosiglitazone of formula (I), or a pharmaceutically acceptable salt thereof,
comprising reacting a thiazolidine 2,4 dione and an intermediate metabisulphite complex of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde, which metabisulphite complex is represented by following formula (III):
where X represents an alkali metal.
2. A process according to claim 1 , wherein X is sodium or potassium.
3. A process according to claim 2 , wherein X is sodium.
4. A process according to claim 1 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione in toluene in the presence of a catalytic amount of piperidine and acetic acid.
5. A process according to claim 1 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione in a C 1-4 alcohol or in a mixture of water and a C 1-4 alcohol.
6. A process according to claim 5 , wherein said C 1-4 alcohol is ethanol.
7. A process according to claim 5 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione at a temperature in the range of about 40° C. to about reflux temperature.
8. A process according to claim 7 , wherein said temperature is about 80° C.
9. A process according to claim 5 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione in the presence of an alkali or alkaline earth metal hydroxide, alkoxide or carboxylate.
10. A process according to claim 1 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione so as to yield a benzylidene intermediate of formula (II):
which is subsequently reduced to yield rosiglitazone free base of formula (I), and optionally reacting rosiglitazone free base with an acid to form a pharmaceutically acceptable salt of rosiglitazone.
11. A process according to claim 10 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione in toluene in the presence of a catalytic amount of piperidine and acetic acid.
12. A process according to claim 10 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione in a C 1-4 alcohol or in a mixture of water and a C 1-4 alcohol.
13. A process according to claim 12 , wherein said C 1-4 alcohol is ethanol.
14. A process according to claim 12 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione at a temperature in the range of about 40° C. to about reflux temperature.
15. A process according to claim 14 , wherein said temperature is about 80° C.
16. A process according to claim 12 , wherein said metabisulphite complex of formula (III) is reacted with the thiazolidine 2,4 dione in the presence of an alkali or alkaline earth metal hydroxide, alkoxide or carboxylate.