Process for the preparation of (±) 1-3-dioxolanes and the optical resolution thereof
(±) 3-(4-Phenyl-1-piperazinyl)-1,2-propanediol cyclic acetals, a process for the optical resolution thereof and their use as intermediates for the preparation of (−) 3-(4-phenyl-1-piperazinyl)-1,2-propanediol (levodropropizine) and salts thereof are described herein.
1. A compound of formula (1)
wherein:
each of Ra and Rb, which can be the same or different, is hydrogen, C 1 -C 6 -alkyl, phenyl, or Ra and Rb taken together with the C atom they are linked to, form a 4- to 7-membered carbocyclic ring, or a salt thereof.
2. The compound as claimed in claim 1 , wherein Ra and Rb are the same.
3. The compound as claimed in claim 1 , wherein each of Ra and Rb is methyl or ethyl.
4. A compound selected from the group consisting of:
(±) 1,2-cyclopentylidene-3-(4-phenyl-piperazin-1yl)-propane-1,2-diol;
(±) 1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;
(±) 1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;
(±) 1,2-(3-pentylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;
S(−)-1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol L-tartrate; and
S(−)-1,2-cyclopentylidene-3-(4-phenyl-piperazirin-1-yl)-propane-1,2-diol L-tartrate.
5. A process for the preparation of a compound of formula (1):
wherein each of Ra and Rb, which can be the same or different, is hydrogen, C 1 -C 6 -alkyl, phenyl, or Ra and Rb taken together with the C atom they are linked to, form a 4- to 7-membered carbocyclic ring, and salts thereof, said method comprising the steps of
reacting phenylpiperazine with a (±) 1,2-glyceryl-dioxolane of formula (2):
wherein X is selected from the group consisting of Cl, Br, I and a suitable sulfonic ester (R—SO 3 —), R is selected from the group consisting of C 1 -C 3 -alkyl, trifluoromethyl, phenyl, p-tolyl and p-methoxy phenyl, and Ra and Rb have the same meanings as defined above; and
recovering the compound of formula (1).
6. The process as claimed in claim 5 , wherein the reaction is carried out in the presence of a base, using toluene or xylene as solvents.
7. The process according to claim 5 , wherein R of the suitable ester of X in formula (2) is methyl.
8. The process for the optical resolution of the compounds of any one of claims 1 - 4 by salification with L-tartaric acid.
9. A process for the synthesis of corresponding (S) enantiomers of the compounds of any one of claims 1 - 4 comprising the step of salificating said compounds with a chiral acid.
10. A process for the synthesis of (−) 3-(4-phenyl-1-piperazinyl)-1,2-propanediol wherein the tartaric-acid salts of a compound of formula (1)
wherein:
each of Ra and Rb, which can be the same or different, is hydrogen, C 1 -C 6 -alkyl, phenyl, or
Ra and Rb taken together with the C atom they are linked to, form a 4- to 7-membered carbocyclic ring, and salts thereof, are optically resolved to recover the S (−)-enantiomers which are then subjected to hot hydrolysis catalyzed by a molar excess of a diluted aqueous solution of a mineral acid.
11. The process according to claim 10 , wherein the mineral acid is hydrochloric acid, acetic acid, malonic acid or citric acid.
12. A method for preparing (−) 3-(4-phenyl-1-piperazinyl)-1,2-propanediol comprising the steps of catalyzing the compounds of any one of claims 1 - 4 with a molar excess of a diluted aqueous solution of a mineral acid, and hot hydrolyzing said aqueous solution.