An industrial process for the preparation of (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester of 6-(nitrooxy)hexanoic acid and a high purity product

Claims

1. A method for obtaining (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester of 6-(nitrooxy)hexanoic acid of formula (I) , including the following stages: 1) reaction of bimatoprost with phenylboronic acid in toluene at reflux temperature and removal of water by azeotropic distillation to obtain bimatoprost phenylboronate of formula (V) , 2) cooling the solution to 25°C and adding N,N'-diisopropylcarbodiimide, a catalytic amount of dimethylaminopyridine and 6-(nitrooxy)hexanoic acid to obtain (1E,3S)-1-{(1S,5R,6R,7R)-7-[(2Z)-7-(ethylamino)-7-oxohept-2-en-1-yl]-3-phenyl-2,4-dioxa-3-borabicyclo[3.2.1]octan-6-yl}-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate of formula (VI) , 3) removal of the phenylboronate protecting group under basic conditions; 4) separation of the organic phase and evaporation of the solvent; 5) stirring the crude product in dichloromethane, filtering the mixture and evaporating the solvent to obtain the crude compound of formula (I); 6) purification of the crude compound of formula (I) by applying normal-phase gravity column chromatography on silica gel using an eluent mixture containing diisopropyl ether, acetone and water in a volume ratio of 40:15:0.5; 7) collecting fractions of acceptable purity and evaporating the solvent to obtain a pure compound of formula (I); 8) dissolving the pure compound of formula (I) from step (7) in distilled methylene chloride and methanol, purifying the solution by gravity chromatography using an eluent mixture containing distilled methylene chloride and methanol in a volume ratio of 30:1, and collecting fractions of acceptable purity and evaporating the solvent to obtain the pure compound of formula (I); 9) dissolving the pure compound of formula (I) from step (8) in ethanol, treating the solution with activated carbon, then removing the activated carbon by filtration and removing the solvent by evaporation under vacuum to obtain pure (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester of 6-(nitrooxy)hexanoic acid; wherein said method is characterized in that the obtained (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester of 6-(nitrooxy)hexanoic acid does not contain 15-(6-chlorohexanoyl) ester of bimatoprost of formula (II) and contains no more than (≤) 0.20% (% of HPLC area) of the total amount of impurities.

2. The method according to claim 1, wherein in step (1) of the reaction the molar ratio of bimatoprost: phenylboronic acid is 1:1.

1.

3. The method according to claim 1 or 2, wherein at step (2) of the reaction N,N'-diisopropylcarbodiimide 2.0 equiv., dimethylaminopyridine 0.2 equiv. and 6-(nitrooxy)hexanoic acid from 1.8 to 2.2 equiv. are added.

4. A method according to any one of the preceding claims, wherein in step (3) of the reaction the phenylboronate protecting group is removed using a NaOH solution.

5. The method according to claim 4, wherein the phenylboronate protecting group is removed by quenching the reaction mixture obtained in step (2) with methanol, followed by adding a mixture of methylene chloride and 6.3 equiv. NaOH as a 0.5 M NaOH solution.

6. A process according to any one of the preceding claims, wherein in step (4) of the reaction the organic phase is first washed with an aqueous solution of sodium hydrogen sulfate and then twice with a 15 w / w% aqueous solution of NaCl.

7. The compound (1S,2E)-3-[(1R,2R,3S,5R)-2-[(2Z)-7-(ethylamino)-7-oxo-2-hepten-1-yl]-3,5-dihydroxycyclopentyl]-1-(2-phenylethyl)-2-propen-1-yl ester of 6-(nitrooxy)hexanoic acid of formula (I) as a medicinal substance, containing a total amount of impurities of no more than (<) 0.20% (% of HPLC area) and not containing an impurity of 15-(6-chlorohexanoyl) ester of bimatoprost of formula (II) .

8. A compound of formula (I) according to claim 7, wherein the total amount of impurities is no more than (≤) 0.15% (HPLC area %).

9. A compound of formula (I) according to claim 8, wherein the total amount of impurities is no more than (≤) 0.10% (HPLC area %).

10. A compound of formula (I) according to any one of claims 7 to 9, wherein said compound of formula (I) contains no more than (≤) 0.05 w / w% of 6-{[6-(nitrooxy)hexanoyl]oxy}hexanoic acid bimatoprost ester impurity of formula (III), determined by HPLC, , and no more than (≤) 0.05 wt. / wt.% of the impurity (1E,3S)-1-((1R,2R,3S,5R)-2-((2E)-7-(ethylamino)-7-oxohept-2-en-1-yl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate of formula (VII), determined by HPLC, , and no more than (≤) 0.05% of the impurity (1E,3R)-1-((1R,2R,3S,5R)-2-((2Z)-7-(ethylamino)-7-oxohept-2-en-1-yl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate of formula (VIII), determined by HPLC, 11. A compound of formula (I) according to any one of claims 7 to 10, wherein said compound of formula (I) contains less than (<) 0.05 w / w% of 6-{[6-(nitrooxy)hexanoyl]oxy}hexanoic acid bimatoprost ester of formula (III), determined by HPLC, , and not more than (≤) 0.05 wt. / wt.% (1E,3S)-1-((1R,2R,3S,5R)-2-((2E)-7-(ethylamino)-7-oxohept-2-en-1-yl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate of formula (VII), determined by HPLC, , and less than (<) 0.05% (1E,3R)-1-((1R,2R,3S,5R)-2-(2Z)-7-(ethylamino)-7-oxohept-2-en-1-yl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate of formula (VIII), determined by HPLC, .

12. An ophthalmic pharmaceutical composition comprising a compound of formula (I) according to any one of claims 7 to 11 and at least a pharmaceutically acceptable excipient.