(4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-BIPHENYL]-4-YLMETHOXY)-3-HYDROXY-2-(1-PIPERIDINYL)CYCLOPENTYL]-4-HEPTENOIC ACID HYDROCHLORIDE

Originator

Vapiprost,GlaxoSmithKline

The Uses of (4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-BIPHENYL]-4-YLMETHOXY)-3-HYDROXY-2-(1-PIPERIDINYL)CYCLOPENTYL]-4-HEPTENOIC ACID HYDROCHLORIDE

Antagonist (thromboxane A2).

The Uses of (4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-BIPHENYL]-4-YLMETHOXY)-3-HYDROXY-2-(1-PIPERIDINYL)CYCLOPENTYL]-4-HEPTENOIC ACID HYDROCHLORIDE

Vapiprost is a potent and specific thromboxane A2 receptor blocking drug on platelets, vascular and airways smooth muscle.

Manufacturing Process

[1R-[1α(Z),2β,3β,5α]]-7-[5-([1,1'-Biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1- piperidinyl)cyclopentyl]-4-heptenoic acid may be prepared in 9 steps: 1). [1R-(endo,anti)]-(+)-5-[[4'-Methoxy-(1,1'-biphenyl)-4-yl]methoxy]-7-(1- piperidinyl)bicyclo[2.2.1]heptan-2-one: A mixture of 1-[1R-(endo,anti)]-(+)-5-Hydroxy-7-(1- piperidinyl)bicyclo[2.2.1]heptan-2-one (30.51 g), benzyltriethylammonium chloride (6.65 g) and 4-(bromomethyl)-4'-methoxy(1,1'-biphenyl) (52.6 g) in CH2Cl2 (365 ml) and 17 N NaOH (325 ml) was vigorously stirred at ambient temperature for 18 h. The mixture was diluted with water (1 L) and extracted with CH2Cl2 (3x150 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using ether-petroleum ether (boiling point 60°C) 1:1 followed by 7:3 as eluent to give the title compound (40.2 g). A portion was recrystallized from ether-petroleum ether (boiling point 60°C). MP: 109.5-110.5°C [α]D23 =+22.7° (CHCl3)
2). [1R-(endo,anti)]-(-)-6-[[4'-Methoxy(1,1'-biphenyl)-4-yl]methoxy]-8-(1- piperidinyl)-2-oxabicyclo[3.2.1]octan-3-one: A solution of peracetic acid in acetic acid (5.6 M, 124 ml) was added slowly to a stirred mixture of [1R(endo,anti)]-(+)-5-[[4'-Methoxy(1,1'-biphenyl)-4-yl]methoxy]-7-(1- piperidinyl)bicyclo[2.2.1]heptan-2-one (42 g) in CH2Cl2 (235 ml), 2 N H2SO4 (29 ml) and water (159 ml) and the mixture stirred at ambient temperature for 24 h. The mixture was adjusted to ca. pH 7 using 5 N NaOH and pH 6.5 phosphate buffer then extracted with CH2Cl2 (3x200 ml). The combined organic extracts were added to an excess of sodium metabisulphite solution and stirred for 24 h. The mixture was extracted with ethyl acetate (1x500, 2x250 ml) and the combined organic extracts were dried and evaporated and the residue was purified by chromatography using 1:1 ethyl acetate-petroleum ether as eluent to give the title compound (24.4 g). A portion was recrystallized from ethyl acetatepetroleum ether MP: 116.5-117.5°C [α] D23 =-24.5° (CHCl3).
3). [1R-(1α,2β,3α,5α)]-(3-Hydroxy-5-[[4'-methoxy(1,1'-biphenyl)-4- yl]methoxy]-2-(1-piperidinyl)cyclopentane acetaldehyde: Diisobutylaluminum hydride in hexane (1 M, 114 ml) was added slowly to a cold (-70°C) stirred solution of the above made compound from item 3 (24 g) in CH2Cl2 (240 ml). After 0.5 h methanol (240 ml) was added, slowly at first, and the mixture was stirred at ambient temperature for 16 h. The precipitate was filtered off and the filtrate evaporated to give the title compound as a foam (24.1 g).
4). [1R-(1α,2β,3α,5α)]-(+)-4-[[4'-Methoxy(1,1'-biphenyl)-4-yl]methoxy]-3-(3- methoxy-2-propenyl)-2-(1-piperidinyl)cyclopentanol, hydrochloride: A solution of [1R-(1α,2β,3α,5α)]-(3-Hyoroxy-5-[[4'-methoxy(1,1'-biphenyl)-4- yl]methoxy]-2-(1-piperidinyl)cyclopentane acetaldehyde (24.1 g) in THF (75 ml) was added to a cooled (-5° to 0°C), stirred solution of the ylid derived from methoxymethyltriphenylphosphonium chloride (78 g) and potassium tertbutoxide (25.5 g) in THF (800 ml). After 1.5 h methanol (100 ml) was added and the solvents removed in vacuo. The residue in pH 6.5 phosphate buffer (600 ml) was extracted with CH2Cl2 (3x150 ml) and the combined extracts were dried and evaporated. The residue was purified by chromatography using 4:1 ethyl acetate-methanol as eluent to give the title compound, base as an oil (24.8 g). A portion was converted into the hydrochloride salt; m.p. 150- 151°C (dec.), [α]D23 = +38.1 (CHCl3).
5). [1 R-(1α,2β,3α,5α)-(+)-3-Hydroxy-5-[[4'-methoxy(1,1'-biphenyl)-4- yl]methoxy]-2-(1-piperidinyl)cyclopentanepropanol, hydrochloride: A solution of the end product from item4 (24.3 g) in 2 N HCl (55 ml) and acetone (250 ml) was stirred at ambient temperature for 1 h. Most of the acetone was removed in vacuo and the residue in water was extracted with CH2Cl2 (3x150 ml). The combined extracts were dried and evaporated to give a solid (23.6 g). A portion was triturated with ether to give the title compound as a powder; m.p.182-185°C (dec.) [α]D23 =+51.5° (CHCl2).
6). [1R-[1α(Z),2β,3α,5α]]-(+)-Methyl-7-[3-hydroxy-5-[[4'-methoxy(1,1'- biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclopentyl]-4-heptenoate, hydrochloride: A suspension of [1 R-(1α,2β,3α,5α)-(+)-3-hydroxy-5-[[4'- methoxy(1,1'-biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclopentanepropanal, hydrochloride (23.6 g) in THF (300 ml) was added to the derived from 3- (carboxypropyl)triphenylphosphonium bromide (69.5 g) and potassium tertbutoxide (36.3g) in THF (1000 ml). After 2 h water (200 ml) was added and the THF was removed in vacuo. The residue was diluted with water (250 ml)and extracted with ether (3 x 200 ml; discarded). The aqueous layer was made neutral using 5 N HCl and extracted with CH2Cl2 (3 x 200 ml). The combined extracts were dried and evaporated and the residue was left to stand in methanol (250 ml) containing concentrated sulfuric acid (5 ml) for 19 h. Most of the methanol was removed in vacuo and the residue made neutral using 2 N NaOH and pH 6.5 phosphate buffer (150 ml). The mixture was extracted with ethyl acetate (3 x 150 ml) and the combined extracts were dried and evaporated. The residue was purified by chromatography using initially 9:1 ether-methanol followed by 4:1 ether-methanol as eluent to give the title compound, base as an oil (15.9 g). A portion was converted into the hydrochloride salt. MP: 122-125°C (dec.). [α]D22 = +55.9° (CHCl3). 7). [1 R-[1α(Z),2β,5α]]-(-)-Methyl-7-[5-[[4'-methoxy(1,1'-biphenyl)-4- yl]methoxy]-3-oxo-2-(1-piperidinyl)cyclopentyl]-4-heptenoate: A solution of pyridine-sulfur trioxide complex (10.33 g) in dry DMSO (17 ml) was added to a cold (0°C) solution of above compound (item 6), base (8.47 g) in Et3N (13.5 ml), CH2Cl2 (30 ml) and DMSO (20 ml). After 1 h at 0°C, the mixture was diluted with pH 6.5 phosphate buffer (140 ml) and extracted with ethyl acetate (3x50 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using ethyl acetate-petroleum ether (1:3) as eluent to give the title compound as a solid (5.69 g). A portion was recrystallized from ether-petroleum ether. MP: 61.5-62.5°C. [α]D22 =-19.8° (CHCl3).
8). [1R-[1α(Z),2β,3β,5α]]-(+)-Methyl-7-[3-Hydroxy-5-[[4'-methoxy(1,1'- biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclopentyl]-4-heptenoate: A solution of dibal in hexane (1 M, 93 ml) was added dropwise to a cold (-5°C) stirred solution of 2,6-di-tert-butyl-4-methylphenol (30.75 g) in dry toluene (350 ml). After 1 h at -5°C the mixture was cooled to -70°C and a solution of above compound from the item 7 (9.67 g) in toluene (50 ml) was added dropwise. After 1 h at -70°C and 1 h at -10°C the mixture was washed with 2 N HCl (7x60 ml) and the toluene was discarded. The acidic extracts were neutralised with 5 N NaOH solution (200 ml) and extracted with CH2Cl2 (4x80 ml). The combined extracts were dried and evaporated and the residue was purified by chromatography using 17:3 ether-methanol as eluent to give the title compound (7.02 g) as an oil. [α]D21 =+63.2° (CHCl3).
9). [1R-[1α(Z),2β,3β,5α]]-(+)-Methyl-7-[3-hydroxy-5-[[4'-methoxy(1,1'- biphenyl)-4-yl]methoxy]-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid, hydrochloride: A mixture of heptenoate from the item 8 (5.89 g) 5 N NaOH solution (6.77 ml) and methanol (40 ml) was vigorously stirred at ambient temperature for 18 h. Most of the methanol was removed in vacuo and the residue in pH 6.5 phosphate buffer (150 ml) was extracted with CH2Cl2 (3x40 ml). The combined extracts were dried and evaporated to give the title compound, base as a foam (5.79 g). A portion (0.67 g) in ether-CH2Cl2 was treated with an excess of ethereal HCl to give the title compound (0.61 g). MP: 122-124°C [α]D22=+61.2° (CHCl3).

Therapeutic Function

Thomboxane A2-antagonist

Biological Activity

Potent thromboxane A 2 (TP) receptor antagonist. Inhibits platelet aggregation (pA 2 ~ 8.3) and relaxes vascular and airway smooth muscle (pA 2 = 7.9-10.3).