Process for the preparation of a nitric oxide donating prostaglandin analogue

A process for the preparation of hexanoic acid, 6-(nitrooxy)-, (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 formula (I):

• comprising the following steps:
• Step A) preparation of the 6-(nitrooxy)hexanoyl chloride (VIIIb) by:
• 1a) reacting the ε-caprolactone
• with an inorganic base selected from KOH, NaOH and LiOH in a solvent selected from methanol, ethanol or isopropanol, at a temperature between 20° C. and the reflux temperature of the solvent to obtain 6-hydroxyhexanoic acid salt of formula (X)
• wherein M is K, Na or Li;
• 2a) purifying the 6-hydroxyhexanoic acid salt of formula (X) obtained in step 1a) which comprises:
• i. adding methyl tert-butyl ether to the reaction mixture of step 1a) in a ratio methyl tert-butyl ether/volume of the reaction mixture 2:1;
• ii. filtering the solid;
• iii. slurring the solid with a mixture of methyl tert-butyl ether, methanol in a ratio of 3:1 to 5:1 and water in an amount of 0.3-1 mole of water for mole of ε-caprolactone;
• iv. isolating the 6-hydroxyhexanoic acid salt of formula (X) as a solid;
• 3a) reacting the 6-hydroxyhexanoic acid salt with a mixture of fuming HNO3 and concentrated H2SO4 in dichloromethane, at a temperature ranging from 0° C. to 10° C.;
• 4a) adding water to the nitration mixture of step 3a) while keeping the temperature between 0° C. and 5° C.;
• 5a) separating the organic phase, drying on sodium sulfate said organic phase and distilling off the solvent to obtain crude 6-(nitrooxy)hexanoic acid (VIIIa)
• 6a) reacting the crude 6-(nitrooxy)hexanoic acid (VIIIa) with a chlorinating agent in dichloromethane to obtain the crude 6-(nitrooxy)hexanoyl chloride (VIIIb);
• Step B) preparation of hexanoic acid, 6-(nitrooxy)-, (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 (I) comprising the following steps:
• 1b) reacting bimatoprost with butyl boronic acid in methyl tert-butyl ether at temperature about 40° C., to obtain compound (II):
• 2b) reacting compound (II) with the crude 6-(nitrooxy)hexanoyl chloride (VIIIb) of step 6a) in the presence of 4-dimethylaminopyridine in free form in an aprotic organic solvent, to obtain the compound (XI)
• 3b) removing the boronate protective group to obtain the crude compound of formula (I);
• 4b) purifying the crude compound (I) by column chromatography.