Process for preparing {6-[(diethylamino) methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl] carbamate having high purity
A process for obtaining {{6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate and/or pharmaceutically acceptable salts thereof having high purity is described. This process allows to obtain a product having an amount of any single unknown impurity equal to or less than 0.10%, as well as a product having a purity greater than 99.5%, preferably equal to or greater than 99.6%. An HPLC method for determining the purity of the product and possible impurities thereof is also described.
1 . {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate, having an amount of any single unidentified impurity equal to or lower than 0.10 area % as determined by HPLC, wherein the unidentified impurity is selected from the group consisting of an unidentified impurity at a Relative Retention Time (RRT) of 0.93±0.02, an unidentified impurity at an RRT of 1.21±0.02, an unidentified impurity at an RRT of 1.51±0.02, and an unidentified impurity at an RRT of 1.75±0.02, wherein the RRT is determined using an HPLC method under the following operating conditions:
Stationary phase: support based on silica particles containing C18 alkyl chains and having a carbon load lower than 9% by weight;
Mobile phase A: Water buffered at pH 3.7-3.8
Mobile phase B: Methanol buffered at pH 3.7-3.8
using the following gradient elution method:
Eluent A
Eluent B
Time
%
%
(min)
(v/v)
(v/v)
0
75
25
5
75
25
35
10
90
40
10
90
40.1
75
25
50 (end run)
75
25
and subsequent detection of the {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate by means of a detector;
or having an amount of any single impurity other than intermediate (I) or amide (la) equal to or lower than 0.15%.
2 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 1 , having an amount of a single impurity other than intermediate (I) or amide (la) equal to or lower than 0.10%.
3 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 1 , having a purity equal to or greater than 99.6%.
4 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 1 , wherein the detector employed in the HPLC method is a detector of UV, MS or RID type.
5 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 4 , wherein the detector employed in the HPLC method is a 263 nm UV detector.
6 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 1 , wherein the buffer employed in the HPLC method is formate-formic acid buffer at pH 3.7-3.8.
7 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 1 , wherein the temperature employed in the HPLC method is 25±1° C.
8 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 1 , wherein the injection volume employed in the HPLC method is 5 μL.
9 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 1 , wherein the flow rate employed in the HPLC method is 0.25 mL/min.
10 . The {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate hydrochloride monohydrate according to claim 1 , wherein DMSO is employed as a diluent for {6-[(diethylamino)methyl]naphthalen-2-yl}methyl [4-(hydroxycarbamoyl)phenyl]carbamate or a pharmaceutically acceptable salt in the HPLC method.