(+)-2β4β-Dihydroxy-3α-iodo-5α-(methoxymetyl)cyclopentane-1β-acetic acid γ-
lactone 4-benzoate:
To a stirred solution at 20°C of 75 g of (+)-2β,4β-dihydroxy-3α-iodo-5α -
(methoxymetyl)cyclopentane-1β-acetic acid γ-lactone (M.P. 101-102°C, [α]D =
-50° (c 0.98, CHCl3) in 135 ml of dry pyridine was added 30.4 ml of benzoyl
chloride. After 30 min, 250 ml of toluene was added and the resulting solution
evaporated to dryness under reduced pressure. The residue was dissolved in
1000 ml of ethyl acetate. The organic solution was washed with 200 ml 20%
of aqueous sulfuric acid and 200 ml of brine. The aqueous solution was
washed with 200 ml of ethyl acetate. The ethyl acetate solution was dried and
evaporated under reduced pressure to give 95 g of oil which crystallized. The
crude product was recrystallized to give 90 g of the white solid, M.P. 84-86°C,
[α]D = +5° (c 1.03, CHCl3).
(-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1-α-acetic acid γ-
lactone 3-benzoate:
To a solution of 4.2 g of lithium aluminum hydride in 420 ml of ether under a
nitrogen atmosphere and cooled in a ice bath was added dropwise a solution
of 99 g of tributyltin chloride in 210 ml of ether. The cooling bath was
removed and stirring continued at ambient temperature for 1.5 hours. To the
cooled solution was added 260 ml of water. The organic layer was washed
with water and dried. This solution was added slowly at 15°C to a solution of
(+)-2β,4β-dihydroxy-3α-iodo-5α-(methoxymethyl)cyclopentane-1β-acetic acid
γ-lactone 4-benzoate in 240 ml of benzene. Then the solution was evaporated
and the product was stirred with water. Yield of (-)-3α,5α-dihydroxy-2β-
(hydroxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 93%.
(-)-3α,5α-Dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone
3-benzoate:
To a solution of 20 g of (-)-3α,5α-dihydroxy-2β-(hydroxymethyl)cyclopentane-
1α-acetic acid γ-lactone 3-benzoate in 320 ml of methylene chloride under
nitrogen atmosphere and cooled in an ice bath was added dropwise 24.8 ml of
boron trifluoride in 320 ml of methylene chloride. After 1 hour to the solution
was added 78 g of sodium carbonate in 200 ml of water and then 66 g of
solid sodium chloride. The aqueous phase was extracted with ethyl acetate.
Yield of (-)-3α,5α-dihydroxy-2β-(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate 95%, M.P. 116-118°C.
(-)-3α,5α-Dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid γ-
lactone 3-benzoate:
To a mixture of 1.75 g of sodium hydride and 2509 ml of tetrahydrofuran at
5°C was added 8.0 g of (2-oxoheptyl)phosphonate. After 2.5 hours a thick
white precipitate formed (ilide mixture). To a stirred mixture of 11 g of
anhydrous cromium trioxide and 150 ml of methylene chloride under
nitrogene atmosphere and cooled in an ice bath was added 17 g of anhydrous
pyridine. The mixture was stirred for 15 min at 0°C for 2 hours at room
temperature, then at 0°C again. A solution of 5.0 g of (-)-3α,5α-dihydroxy-2β-
(methoxymethyl)cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 150 ml
methylene chloride was added to at 0°C to a to the cold Collins oxidant
solution. The resulting black mixture was stirred 5 min. After addition of 100
ml of benzene, the mixture was filtered through Celite, washing with benzene.
The filtrate was concentrated to 50 ml under reduced pressure and then
diluted with 100 ml of benzene. This solution was added to the cold ilide
mixture. The resulting dark mixture was stirred for 1.5 hours at room
temperature. After dropwise addition of 3 ml of acetic acid the mixture was
concentrated to dryness. The residue was dissolved in 400 ml of ethyl acetate.
The solution was washed with water and then with brine. Organic phase was
dried and evaporated to give dark oil. This oil was purified on silica gel, yield
of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl)cyclopentane-1α-acetic acid
γ-lactone 3-benzoate 48%, M.P. 63-63.8°C, [α]D = -113° (c 1.18, CHCl3).
(-)-3α,5α-Dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]
cyclopentane-1α-acetic acid γ-lactone 3-benzoate:
To a solution of 0.20 g of (-)-3α,5α-dihydroxy-2β-(3-oxo-trans-1-octenyl)
cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of tetrahydrofuran
at -78°C under nitrogen was added dropwise 3 ml etheral solution 3 M
methylmagnesium bromide. The solution became heterogeneous after 2
hours, to the mixture was added 10 ml of saturated aqueous ammonium
chloride and then ether and water. Organic extract was washed with brine,
dried over sodium sulfate, and evaporated to give 0.21 g of (-)-3α,5α-
dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1α-acetic
acid γ-lactone 3-benzoate as a colorless oil; [α]D = -80° (c 1.0, CHCl3).
(-)-3α,5α-Dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl]
cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate:
To a solution of 0.50 g of (-)-3α,5α-dihydroxy-2β-[(3RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1α-acetic acid γ-lactone 3-benzoate in 15 ml of
tetrahydrofuran at -78°C under nitrogen was added 10 ml of 10%
diisobutylaluminum hydride in toluene. After a gas evolution was ceased, the
reaction was quenched by addition of 10 ml of saturated aqueous ammonium
chloride. The resulting mixture was stirred at room temperature, filtered
through Celite, and extracted with ethyl acetate. Extract was evaporated to
give 0.48 g of (-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl]cyclopentane-1-α-acetaldehyde γ-lactol 3-benzoate as an oil.
(15R)- and (15S)-15-methyl-PGF2α methyl esthers:
A mixture of 0.23 g sodium hydride (50% dispersion in mineral oil) and 10 ml
of dimethyl sulfoxide stirred under nitrogene at 70-75°C. After 1 hours, gas
evolution had ceased. After 0.5 hour, the mixture was cooled to room
temperature. To the mixture was added 1.06 g 4-
carboxybutyltriphenylphosphonium bromide and the resulting dark red
solution stirred 0.5 hour. To this solution was added a solution of 0.48 g of
(-)-3α,5α-dihydroxy-2β-[3-(RS)-3-hydroxy-3-methyl-trans-octenyl]
cyclopentane-1α-acetaldehyde γ-lactol 3-benzoate in 15 ml of dimethyl
sulfoxide. The resulting dark orange mixture was stirred at room temperature
for 12 hours. Another 1.2 mmol of freshly prepared ilide in 3.6 ml of solution
(prepared as above) was added. After 24 hours, the reaction was quenched by
addition to 15 ml of 2 M sodium bisulfate (diluted with ice water) and 25 ml of
ether. The organic extract was washed with 5 ml of 1 N sodium hydroxide,
and twice with water. The aqueous washings were combined (pH ￡ 11) and
acidified with sodium bisulfate to pH about 1 in the presence of ether. The
aqueous phase was extracted with ether. The extract was evaporated to give
0.45 g of dark oily solid. The crude product was dissolved in a mixture of
methylene chloride, ether and methanol and treated with excess etheral
diazomethane. Evaporation gave 0.40 g of dark oil. The crude product was
chromatographed on 10 g of silica gel. Fraction 9-12 contained a mixture of
epimers (15R)- and (15S)-15-methyl-PGF2α-methyl esthers, yield 160 mg
(35%) as an oil. The structure of product was confirmed by 1H-NMR spectrum.
(15S)-15-methyl-PGF2α methyl esthers:
1 g of the mixture of epimers was chromatographed on 100 g (eluent
acetone-methylene chloride). It was obtained 150 mg of pure (15S)-15-
methyl-PGF2α methyl esthers; M.P. 55-56°C, [α]D = +24° (c 0.81, ethanol).
Carboprost tromethamine:
The drug was prepared by mixing of (15S)-15-methyl-PGF2α methyl esthers
with 2-amino-2-(hydroxymethyl)-1,3-propanediol (1:1).
Carboprost tromethamine,15-(S)-methyl-PGF2α (Hemabate), is a prostaglandin derivativethat has been modified to prevent metabolic oxidation ofthe 15-position alcohol function. This derivative may be administeredin a hospital setting only in a dose of 250 μg bydeep intramuscular injection to induce abortion or to amelioratesevere postpartum hemorrhage.
