Pyrrolidine derivatives as oxytocin/vasopressin via receptors antagonists
The present invention relates to a compound of formula (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-meth19243yloxime, and/or an active metabolite thereof having antagonist action at the oxytocin receptor and/or vasopressin V1a receptor, to processes for their preparation, pharmaceutical compositions containing them and their use.
1. A method of preparing a compound, (3Z,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (I)
in substantially pure form, the method comprising:
(i) loading a mixture comprising the compound and one or more impurities onto a silica gel chromatography column; and subsequently
(ii) contacting the column with an eluant comprising toluene and methanol, wherein the eluant has a ratio of toluene:methanol of from about 96:4 (v/v) to about 99:1 (v/v),
wherein the compound is eluted from the silica gel chromatography column in substantially pure form.
2. The method of claim 1 , wherein the one or more impurities comprise a diastereomer, (3E,5S)-5-(hydroxymethyl)-1-[(2′-methyl-1,1′-biphenyl-4-yl)carbonyl]pyrrolidin-3-one O-methyloxime, represented by formula (II)
3. The method of claim 1 , wherein the column is contacted with the eluant in two or more steps.
4. The method of claim 3 , wherein the contacting of the column with the eluant comprises:
(a) applying a solution of 1% methanol in toluene (v/v) to the column; and subsequently
(b) applying a solution of 4% methanol in toluene (v/v) to the column.
5. The method of claim 3 , wherein the contacting of the column with the eluant comprises:
(a) applying a solution of 1% methanol in toluene (v/v) to the column; and subsequently
(b) applying a solution of 2% methanol in toluene (v/v) to the column.
6. The method of claim 1 , wherein the compound is eluted from the silica gel chromatography column with a purity that is at least in the range of from 85% to 99.9%.
7. The method of claim 1 , wherein the compound is eluted from the silica gel chromatography column with a purity of at least 90%.
8. The method of claim 7 , wherein the compound is eluted from the silica gel chromatography column with a purity of at least 95%.
9. The method of claim 1 , wherein the compound is eluted from the silica gel chromatography column with a purity of from about 90% to about 99.9%.
10. The method of claim 9 , wherein the compound is eluted from the silica gel chromatography column with a purity of from about 95% to about 99.9%.