Process for the preparation of stable acid addition salt of 2,3-disubstituted pyrazine compounds
View Patent ↗The present invention relates to a process for the preparation of compounds which are therapeutically active in the central nervous system. In one aspect, the invention relates to a process for the preparation of compounds of the general formula (I): wherein HA is a pharmaceutically acceptable acid and R 1 –R 4 are each independently selected from the group consisting of hydrogen, halogen, C 1 –C 6 -alkyl, C 1 –C 6 -alkoxy, and di-C 1 –C 6 -alkylamino-C 2 –C 6 -alkoxy. The invention also relates to the use of said compound to manufacture a medicament for the treatment of a serotonin-related disorder.
1. A process for the preparation of a pharmaceutically acceptable salt of a compound of the general formula (I):
comprising the steps of:
(i) O-alkylating a 3-pyridinol derivative of the general formula (II) or the corresponding hydrochloride:
to give another 3-pyridinol derivative of the general formula (III):
(ii) reacting the 3-pyridinol derivative of the general formula (III) with (2R)-1-(3-chloro-2-pyrazinyl)- 2-methylpiperazine of the formula (IV) in the presence of an alkali metal tert-butoxide or an alkali earth metal tert-butoxide,
to give a compound of the general formula (I):
(iii) converting the compound of the general formula (I) to a pharmaceutically acceptable salt thereof by treatment with a pharmaceutically acceptable organic or inorganic acid,
wherein each of R 1 , R 2 , R 3 , and R 4 , independently, is hydrogen, halogen, C 1 –C 6 -alkyl, C 1 –C 6 -alkoxy, and di-C 1 –C 6 -alkylamino-C 2 –C 6 -alkoxy.
2. The process according to claim 1 , wherein (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV) is prepared by:
(iv) acidification of racemic 2-methylpiperazine of the formula (VI):
with L-tartaric acid and fractional crystallization to give (R)-2-methylpiperazine, L-tartrate of the formula (VII):
(v) basification of (2R)-2-methylpiperazine, L-tartrate of the formula (VII) to give (R)-2-methylpiperazine of the formula (VIII):
(vi) tritylation of (R)-2-methylpiperazine of the formula (VIII) to give (R)-3-methyl-1-tritylpiperazine of the formula (IX):
(vii) condensation of (R)-3-methyl-1-tritylpiperazine of the formula (IX) with 2,3-dichloropyrazine to give (2R)-1-(3-chloro-2-pyrazinyl)-2-methyl-4-tritylpiperazine of the formula (X):
(viii) detritylation of (2R)-1-(3-chloro-2-pyrazinyl)-2-methyl-4-tritylpiperazine of the formula (X) to give (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV),
(ix) and conversion of (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV) to a suitable acid addition salt.
3. The process according to claim 1 , wherein the alkali metal tert-butoxide is potassium tert-butoxide.
4. The process according to any one of claims 1 to 3 , wherein step (ii) is performed in a solvent system comprising tetrahydrofuran.
5. The process according to claim 2 , wherein step (iv) is performed by using water and ethanol as solvents.
6. The process according to claim 2 , wherein step (v) is performed by using a hydroxide as a base.
7. The process according to claim 2 , wherein step (vi) is performed with trityl chloride in the presence of triethylamine.
8. The process according to claim 2 , wherein step (vii) is performed in the presence of an alkali metal carbonate or an alkali earth metal carbonate, with dimethyl formamide as a solvent.
9. The process according to claim 2 , wherein step (viii) is performed in 10% sulfuric acid in isopropanol.
10. The process of claim 2 , wherein the salt formed in step (ix) is a hydrochloride salt.
11. The process of claim 1 , wherein (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV) is in the form of an acid addition salt.