Method for preparing latanoprostene bunod, and intermediate therefor

Abstract

The present invention relates to a process for preparing latanoprostene bunod and an intermediate therefor. In accordance with the preparation process of the present invention, latanoprostene bunod can be efficiently and cost-effectively prepared while reducing side reactions.

Claims

1. A process for preparing latanoprostene bunod of the following formula (1), which comprises the steps of: (i) subjecting a compound of the following formula (3) to esterification with a compound of the following formula (4) to obtain a compound of the following formula (5); and (ii) subjecting the bromide of the compound of the following formula (5) to nitration: ##STR00008##

2. The process according to claim 1, wherein the esterification of step (i) is carried out in the presence of a base.

3. The process according to claim 2, wherein the base is potassium carbonate.

4. The process according to claim 1, wherein the nitration of step (ii) is carried out using silver nitrate (AgNO.sub.3).

5. The process according to claim 1, wherein the compound of formula (3) is prepared by hydrolyzing an isopropyl ester group of a compound of the following formula (2): ##STR00009##

6. The process according to claim 5, wherein the hydrolysis is carried out using lithium hydroxide monohydrate.

7. A compound of the following formula (5): ##STR00010##

8. A process for preparing a compound of the following formula (5), which comprises a step of: (i) subjecting a compound of the following formula (3) to esterification with a compound of the following formula (4): ##STR00011##

Description

BEST MODE

(1) The present invention will be described in more detail by following examples. It will be obvious to those skilled in the art that these examples are merely described for illustration of the present invention and the scope of the present invention is not limited thereto.

Preparation Example 1: Preparation of Compound of Formula (3)

(2) Latanoprost (2) (30 g) was dissolved in methanol (600 mL), and water (120 mL) and lithium hydroxide monohydrate (14.55 g) were added thereto, followed by stirring at room temperature for about 15 hours. The process of the reaction was observed by thin layer chromatography (ethyl acetate:methanol=15:1). After the completion of the reaction, the reaction solvent was concentrated, and 1M ammonium chloride (300 mL), 2M sodium hydrogen sulfate (300 mL) and ethyl acetate (300 mL) were added thereto, followed by stirring for about 15 to 20 minutes. The organic layer was separated, and dried over anhydrous sodium sulfate, followed by filtration, and concentration under reduced pressure. The resulting residue was purified by chromatography using a silica gel (ethyl acetate:methanol=5:1) to give pure latanoprost acid ((Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-3-enoic acid) (3) (23.9 g, 88%).

(3) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.30-7.25 (2H, m), 7.20-7.14 (3H, m), 5.53-5.30 (2H, m), 4.16-4.08 (5H, m), 3.95-3.94 (1H, m), 3.74-3.66 (1H, m), 2.84-2.60 (2H, m), 2.36-2.31 (2H, t, J=6.7 Hz), 2.27-2.23 (2H, t, J=7.2 Hz), 2.18-2.10 (2H, q, J=7.3 Hz), 1.88-1.86 (2H, m), 1.84-1.47 (8H, m), 1.40-1.32 (2H, m);

(4) .sup.13C NMR (300 MHz, CDCl.sub.3): =177.5, 142.2, 129.6, 129.5, 128.6, 126.0, 78.7, 74.6, 71.7, 52.6, 51.9, 42.6, 38.9, 35.3, 33.2, 32.2, 29.2, 26.8, 26.5, 24.8, 14.3.

Example 1: Preparation of Compound of Formula (5)

(5) The compound of formula (3) (22.8 g) was dissolved in dimethylformimide (342 mL), and potassium carbonate (24.2 g) and 1,4-dibromobutane (4) (37.8 g) were added thereto, followed by heating and stirring at about 40 to 50 C. for about 2 hours. The process of the reaction was observed by thin layer chromatography (ethyl acetate 100%). After the completion of the reaction, saturated sodium chloride aqueous solution (684 mL) and ethyl acetate (684 mL) were added thereto, followed by stirring for about 15 to 20 minutes. The organic layer was separated and washed with saturated sodium chloride aqueous solution (456 mL). The organic layer was separated and dried over anhydrous sodium sulfate, followed by filtration, and concentration under reduced pressure. The resulting residue was purified by chromatography using a silica gel (ethyl acetate 100%) to give pure 4-bromobutyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-3-enoate (5) (25.5 g, 83%).

(6) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.31-7.16 (5H, m), 5.51-5.35 (2H, m), 4.17 (1H, s), 4.12-4.08 (2H, t, J=6.3 Hz), 3.95 (1H, s), 3.69-3.65 (1H, m), 3.45-3.41 (2H, t, J=6.5 Hz), 2.85-2.63 (2H, m), 2.60 (1H, s), 2.38-2.30 (3H, m), 2.28-2.07 (3H, m), 1.98-1.59 (14H, m), 1.56-1.47 (1H, m), 1.44-1.25 (2H, m);

(7) .sup.13C NMR (300 MHz, CDCl.sub.3): =174.0, 142.2, 129.6, 129.5, 128.6, 128.5, 126.0, 79.0, 74.9, 71.4, 69.6, 53.1, 52.0, 42.7, 39.2, 35.9, 33.8, 33.2, 32.3, 29.8, 29.4, 27.4, 27.1, 26.8, 25.0.

Example 2: Preparation of Compound of Formula (1)

(8) The compound of formula (5) (25.5 g) was dissolved in acetonitrile (382 mL), and silver nitrate (16.5 g) was added thereto, followed by heating and stirring at about 30 to 40 C. for about 40 to 50 hours. The process of the reaction was observed by thin layer chromatography (hexane:ethanol=5:1). After the completion of the reaction, the reaction product was cooled to room temperature, and the insoluble solid was removed by a celite filtration. The filtrate was concentrated under reduced pressure, and ethyl acetate (382 mL) and water (382 mL) were added thereto, followed by stirring for about 15 to 20 minutes. The organic layer was separated, and saturated sodium chloride aqueous solution (382 mL) was added thereto, followed by stirring for about 10 to 15 minutes. The organic layer was separated and dried over anhydrous sodium sulfate, followed by filtration, and concentration under reduced pressure. The resulting residue was purified by chromatography using a silica gel (hexane:ethanol=5:1) to give pure 4-(nitrooxy)butyl (Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-3-enoate (1) (14.0 g, 56.8%).

(9) .sup.1H NMR (300 MHz, CDCl.sub.3): 7.31-7.26 (2H, m), 7.21-7.15 (3H, m), 5.51-5.34 (2H, m), 4.49-4.45 (2H, t, J=6.2 Hz), 4.16-4.15 (1H, m), 4.12-4.08 (2H, t, J=6.0 Hz), 3.95-3.94 (1H, m), 3.67 (1H, m), 2.85-2.75 (1H, m), 2.72-2.62 (2H, m), 2.40-2.38 (1H, d, J=5.8 Hz), 2.35-2.30 (2H, t, J=7.3 Hz), 2.28-2.21 (1H, m), 2.17-2.09 (2H, m), 1.87-1.86 (2H, m), 1.84-1.58 (12H, m), 1.56-1.47 (1H, m), 1.43-1.27 (2H, m);

(10) .sup.13C NMR (300 MHz, CDCl.sub.3): =173.9, 142.2, 129.6, 129.5, 128.5, 128.5, 125.9, 78.9, 74.9, 72.7, 71.4, 63.6, 53.0, 52.0, 42.6, 39.2, 35.9, 33.9, 32.2, 29.7, 27.1, 26.7, 25.1, 24.9, 23.8.