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).
![(4Z)-7-[(1R,2R,3S,5S)-5-([1,1'-BIPHENYL]-4-YLMETHOXY)-3-HYDROXY-2-(1-PIPERIDINYL)CYCLOPENTYL]-4-HEPTENOIC ACID HYDROCHLORIDE Structure](https://www.chemicalbook.com/CAS/GIF/85505-64-2.gif)