Process for the preparation of a nitric oxide donating prostaglandin analogue
AssigneeNicox S.A.
InventorNicoletta Almirante
Life of this patent
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Abstract
The present invention relates to a process for preparing the 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). In accordance with the present invention, the compound (I) can be efficiently prepared with high purity by coupling bimatoprost in a boronate protected form with 6-(nitrooxy)hexanoyl chloride having an high chemical purity and removing the boronate protecting group. The high chemical pure 6-(nitrooxy)hexanoyl chloride is prepared from 6-(nitrooxy)hexanoic acid having a high chemical purity. The invention also relates to a process for the preparation and purification of 6-(nitrooxy) hexanoic acid.
Claims16
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):
- said process comprising the following steps:
- 1) reacting a compound of formula (II):
- with a 6-(nitrooxy)hexanoyl chloride of formula (IVa)
- in the presence of 4-dimethylaminopyridine in free form, to obtain a compound of formula (III) having a boronate protective group
- 2) removing the boronate protective group of the compound of formula (III) to obtain a compound of formula (I);
- and
- 3) purifying the compound of formula (I);
- wherein the 6-(nitrooxy)hexanoyl chloride (IVa) of step 1) is prepared by a process comprising:
- 4) reacting a 2-caprolactone of formula (V)
- with an inorganic base selected from KOH, NaOH and LiOH to obtain a 6-hydroxyhexanoic acid salt of formula (VI)
- wherein M is K, Na or Li;
- 5) nitrating a compound of formula (VI) with a mixture of HNO3 and H2SO4 to obtain a 6-(nitrooxy)hexanoic acid of formula (VIIa);
- 6) purifying the 6-(nitrooxy)hexanoic acid of formula (VIIa) to provide a pure 6-(nitrooxy)hexanoic acid of formula (VIIa) by reverse phase chromatography using formic acid in water (H2O+HCOOH) and acetonitrile as eluent to obtain a plurality of chromatographic fractions, wherein the pure 6-(nitrooxy)hexanoic acid of formula (VIIa) has a content of 6-{[6-(nitrooxy)hexanoyl]oxy}hexanoic acid (a compound of formula (VIIb))
- below an HPLC detection limit of 0.05%;
- and
- 7) reacting the pure 6-(nitrooxy)hexanoic acid of formula (VIIa) with a chlorinating agent to obtain the 6-(nitrooxy)hexanoyl chloride (IVa).
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:
- reacting a 2-caprolactone of formula (V)
- with an inorganic base selected from KOH, NaOH and LiOH to obtain a 6-hydroxyhexanoic acid salt of formula (VI)
- wherein M is K, Na or Li;
- nitrating the 6-hydroxyhexanoic acid salt of formula (VI) with a mixture of HNO3 and H2SO4 to obtain a 6-(nitrooxy) hexanoic acid of formula (VIIa)
- purifying the 6-(nitrooxy) hexanoic acid of formula (VIIa) to provide a pure 6-(nitrooxy) hexanoic acid of formula (VIIa) by reverse phase chromatography using formic acid in water (H2O+HCOOH) and acetonitrile as eluent to obtain a plurality of chromatographic fractions, wherein the pure 6-(nitrooxy) hexanoic acid of formula (VIIa) has a content of 6-{[6-(nitrooxy) hexanoyl]oxy}hexanoic acid (a compound of formula (VIIb))
- below an HPLC detection limit of 0.05%;
- reacting the pure 6-(nitrooxy) hexanoic acid of formula (VIIa) with a chlorinating agent to obtain a 6-(nitrooxy) hexanoyl chloride of formula (IVa)
- without purification of the 6-(nitrooxy) hexanoyl chloride of formula (IVa), reacting the 6-(nitrooxy) hexanoyl chloride of formula (IVa) with a compound of formula (II);
- in the presence of 4-dimethylaminopyridine in free form, to obtain a compound of formula (III) having a boronate protective group
- and
- removing the boronate protective group of the compound of formula (III) to obtain a compound of formula (I);
- and
- purifying the compound of formula (I).
A process for the preparation of 6-(nitrooxy) hexanoic acid (compound (VIIa)) having a purity of 99% and a content of {[6-(nitrooxy) hexanoyl]oxy}hexanoic acid (compound (VIIb)) less than 0.05%, wherein said process comprises the following steps:
- 4) Reacting 2-caprolactone (V)
- with KOH in methanol to obtain 6-hydroxyhexanoic acid salt of formula (VI)
- wherein M is K;
- 5) Nitrating the compound of formula (VI) with a mixture of HNO3 and H2SO4 in dichloromethane at a temperature from about 5° C. to 10° C.;
- 6) Purifying the mixture by reverse phase chromatography using a solution of 0.1% formic acid in water and acetonitrile as eluents, followed by extraction of fractions with dichloromethane to obtain the 6-(nitrooxy) hexanoic acid (VIIa)
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) having a chemical purity above 98% and containing an amount of 15-(6-chlorohexanoyl) ester of bimatoprost (compound (X)) of about 0.12%
- and an amount of 6-{[6-(nitrooxy) hexanoyl]oxy}hexanoic acid ester of bimatoprost (compound (XII)) below 0.05%
A pharmaceutical formulation containing 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) and at least a pharmaceutically acceptable excipient, wherein 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 has a chemical purity above 98%, and contains an amount of 15-(6-chlorohexanoyl) ester of bimatoprost (compound (X)) about 0.12% and an amount of the dimeric impurity 6-{[6-(nitrooxy) hexanoyl]oxy}hexanoic acid ester of bimatoprost (compound (XII)) below 0.05%.
Dependencies are inferred from the claim text.