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Codeine to codeinone
To a solution of dimethylsulfoxide (16.53 g, 0.21 mole) in CH 2Cl2 (80 ml) at -78C was
added dropwise a solution of oxalyl chloride (13.01 g, 0.10 mole) in CH 2Cl2 (50 ml) over
a period of 40 min. After stirring for 10 min., a solution of codeine (20.33 g, 0.068
mole) in CH2Cl2 (100 ml) was added over 50 min. while keeping the reaction mixture at
-78C. After stirring at -78C for 2 hr., Et3N (50 ml) was added, followed by CH2Cl2 (100
ml). The reaction mixture was allowed to warm-up to room temperature, washed with
water (6 x 150 ml), dried over anhydrous Na2SO4 and evaporated to dryness in vacuo
to give codeinone (25.57 g).
A mixture of codeinone (5.98 g, 0.02 mole), sodium acetate (1.77 g, 0.02 mole) and
acetic anhydride (35.76 g, 0.35 mole) in toluene (6 ml) was heated at 90C about
105C for 5 hr, cooled, diluted with CH2Cl2 (300 ml), and basified with NaHCO3 (66 g in
300 ml of ice-cold water). The organic portion was separated, washed with water (4 x
150 ml), dried over anhydrous Na2SO4, and evaporated to dryness in vacuo to give an
oil (9.4 g), which was chromatographed on silica gel with 5% CH 3OH in CH2Cl2 to give
codeinone dienol acetate as brown needles (5.62 g, 83% yield).
A solution of codeinone dienol acetate (0.50 g, 1.48 mmol), formic acid (0.7 ml),
hydrogen peroxide (0.43 g, 30%, 3.79 mmol), and water (1.4 ml) was heated at 43-
44C for 6 hr and cooled to rt. over night. To the solution was added 5% Pd/C (80 mg)
and hydrogenated at rt. under 28 psi of hydrogen gas for 18 hr. The reaction mixture
was filtered. The filtrate was basified with NH4OH and extracted with methylene
chloride. The extract was washed with water, dried over anhydrous sodium sulfate, and
evaporated in vacuo to dryness to give oxycodone (0.40 g, 85% yield). The R f value in
TLC and the IR spectrum of the product were comparable to those obtained from an
authentic sample.
ADDITIONAL INFORMATION:
A solution of codeinone dienol acetate (1.16 g, 3.4 mmol), oxalic acid (0.70 g, 7.4
mmol) and 3-chloroperoxybenzoic acid (57.about.86%, 0.83 g) in glacial acetic acid
(10.02 g) was allowed to stir at room temperature for 6 hr, basified with concentrated
NH4OH, and extracted with CH2Cl2 (50 ml). The extract was washed with water (10 ml),
dried over anhydrous Na2SO4, and evaporated to dryness in vacuo to give a crude
product (1.29 g), which was chromatographed on silica gel to give pure 14-
hydroxycodeinone (0.76 g, 72% yield).
A solution of codeinone (0.503 g, 1.7 mmol), formic acid (0.7 ml) and H 2O2 (1.0 ml) in
Water (1.4 ml) was allowed to stir at 50-55C for 7 hr. The mixture was cooled, basified
with NH4OH, and extracted with CHCl3 (3x15 ml). The extract was washed with water,
dried over anhydrous Na2SO4 and evaporated to dryness in vacuo to give a solid residue
(0.17 g), which is comparable to 14-hydroxycodeinone in its IR spectrum, NMR
spectrum, and the R.sub.f value in TLC with those of an authentic sample.
Codeine to codeinone
An aqueous solution of 13 wt. % Rochelle salt was then prepared by dissolving 19.5 g
of potassium sodium tartrate tetrahydrate in 130.5 g of de-ionized water at 205C.
The aqueous Rochelle salt solution (90 ml) was added into the reaction mixture in one
portion at ambient temperature, the batch stirred for about 10 minutes, and filtered.
Both layers were saved. The organic layer was washed with 60 ml of aqueous Rochelle
salt solution (both layers were saved). The organic layer was washed with a mixture of
30 ml brine solution and 30 ml 5% sodium bicarbonate solution (both layers were
saved). All aqueous layers were then combined and extracted with 43 g (50 ml) of
toluene. The aqueous layer was discarded. The organic layers were then combined and
concentrated in vacuo at temperature NMT 55C to near dryness. Twenty-two grams
(25 ml) of toluene was added and the resultant organic layer concentrated in vacuo
twice more to remove residual cyclohexanone. Subsequently, 11.8 g (15 ml) of 2-
propanol was added and the mix slurried at 0-5C for at least eight hours under a
nitrogen atmosphere. Solids were then filtered and the flask/wet cake rinsed with the
chilled (about 5C) recycled filtrate. The latter operation was repeated until no solids
were left in the flask. The chilled wet cake was then rinsed with chilled (5-10C) 2-
propanol (12 g, 15 ml), and filter dried. The wet cake was then rinsed with heptane (6.8
g, 10 ml) and filter-dried. The resulting solids were vacuum dried at temperature NMT
50C to a constant weight. A yield of 5.2 to 6.45 g (65.4 to 81.2%) of off-white solids,
with HPLC purity of about 96A%-99.3A% was obtained. The compound was stored in a
dark and cool place.
Codeinone (6.0 g) with toluene (104 g) was added to a reaction flask equipped with a
mechanical stirrer, thermocouple, Dean-Stark trap with condenser attached, and a
nitrogen-inlet adapter. The batch was heated to reflux and about 27.7 g (32 ml) of
distillate was collected in the Dean-Stark trap. The contents were then cooled to
205C under a nitrogen atmosphere. A solution of DBU (4.22 g) in toluene (3 g) was
added in one portion. Subsequently, a solution of t-BDMSiCl (4.22g) in toluene (5 g)
was likewise added in one portion. The batch was slowly warmed to 583C and stirred
at this temperature for about 2 hours. Completion of the reaction was adjudged by
withdrawing a small sample from the batch, extracting it with a mixture of ethyl acetate
and saturated sodium bicarbonate solution, spotting the organic layer on a TLC plate,
and then eluting it with a mobile phase of 9:1 mixture of dichloromethane and methanol
plus 3-4 drops of concentrated ammonium hydroxide. If the reaction was determined to
be incomplete, stirring was continued at 583C for an additional 2 hours and a TLC
check performed once more. Alternatively reaction completion was accomplished by
adding about 5-10% more of both DBU and tBDMSiCl to the reaction mixture at the
same temperature. The contents were then cooled to 205C, and a mixture of 5%
sodium bicarbonate solution (80 ml) and 60 ml of water was added in one portion.
Stirring continued for about 10 minutes. The aqueous layer was then separated and
discarded. The organic layer was washed with a mixture of 50 ml brine and 50 ml
saturated ammonium chloride solution (the aqueous layers were discarded). The
organic layer was concentrated to near dryness in vacuo at temperature NMT 50C, and
the residue diluted with 33.2 g of toluene to make up a 20 wt. % stock solution. Yield
was approximately quantitative. The stock solution was found to be stable at ambient
temperature under nitrogen atmosphere for at least 6 months.
Peracetic acid solution(for prep see below) (107.7 g of 9.0 wt. % peracetic acid) at
ambient temperature (225C) was added to a reaction flask (3-neck, 500 ml)
equipped with mechanical stirrer and thermocouple, nitrogen-inlet adapter and addition
funnel. A 20 wt. % stock solution of the dienolsilyl ether of codeinone (41.7 g) was
added through the addition funnel over a period of about 5 minutes and the
temperature of the contents maintained at NMT 28C The batch was stirred at 225C
for at least 3 hours. In order to test reaction completeness, a small sample was
withdrawn from the batch and quenched with saturated sodium bicarbonate solution,
and extracted with ethyl acetate. The EtOAc layer was spotted onto a TLC plate and
subsequently checked for the disappearance of starting dienolsilyl ether of codeinone.
The TLC mobile phase was a mixture of 95:5 of dichloromethane and methanol plus 3-5
drops of concentrated ammonium hydroxide. If the reaction was adjudged incomplete,
the mixture was stirred at the same temperature for an additional 2 hours then
analyzed by TLC again. Alternatively completion of the reaction was pushed by the
addition of 10 g of peracetic acid (9.0 wt. %) and stirring for an additional 1 h (analysis
was then once more preformed using TLC).
Acetic anhydride (80.0 g) and concentrated sulfuric acid (0.15 g, or about 6 drops) at
ambient temperature were added to a clean and dried round bottom flask (3-neck, 250
ml) equipped with mechanical stirrer, thermocouple, nitrogen-inlet adapter and addition
funnel. The mixture was cooled to about 103C under a nitrogen atmosphere. A 14.0
g of 30% aqeous hydrogen peroxide solution was slowly added through the addition
funnel. The addition of hydrogen peroxide was performed drop by drop maintaining
content temperature at NMT 27C. (formation of peracetic acid and the hydrolysis of
acetic anhydride are strongly exothermic, cooling is absolutely essential, but over-
chilling the batch is not recommended). After complete addition, the batch was stirred
for about 30 minutes in a 103C bath. Acetic acid (10.0 g) was then added through
the addition funnel, and the batch slowly warmed to 255C The batch was then stirred
for an additional hour (the batch should be kept in water bath all the time in order to
avoid any unexpected exotherm).
14-Hydroxycodeinone (4.98 g) and acetic acid (155 g) were added to a Parr shaker
equipped with hydrogen inlet and outlet connectors. The mixture was shaken for about
5 minutes to completely dissolve the 14-hydroxycodeinone at ambient temperature.
The system was then evacuated and the Parr shaker was filled with nitrogen. In one
portion, under the nitrogen atmosphere, 10% Pd/C (50% water wet, 4.0 g) was added.
The system was then evacuated, and was filled with hydrogen gas to a pressure of
about 38 psi. The hydrogen inlet from the supply tank was then closed and the mixture
was shaken at an initial pressure of 38 psi for about 3 hours (at ambient temperature).
After 3 hours of shaking, the system was evacuated and filled with nitrogen. The
contents were filtered over a hyflo-supercel filtering pad (3 g, wetted with water). The
Parr bottle and wet cake were then rinsed with acetic acid (2 x 21 g). The filtrate was
concentrated in vacuo to dryness at temperature NMT 50C The residue was then
dissolved with de-ionized water (50 g), and the pH adjusted to about 11.0 to 12.0 using
20% aqueous KOH solution and concentrated ammonium hydroxide (4 g). The mixture
was then extracted with ethyl acetate (4 x 135 g), and the combined organic layers
concentrated in vacuo to dryness. A yield of 3.51 to 4.26 g of crude oxycodone with
HPLC purity of over 85A% (70.0 to 85.0% yield) was obtained.
14-Hydroxycodeinone (4.98 g) and acetic acid (137 g) were added to a reaction flask
(3-neck, 250 ml) equipped with mechanical stirrer, addition funnel, thermocouple and
nitrogen-inlet adapter. The system was evacuated and the flask filled with nitrogen.
Subsequently, 5% Pd/C (50% water wet, 3.0 g) in one portion was added under the
nitrogen atmosphere. While the mixture was stirred for about 5 minutes at ambient
temperature (225C), a solution of sodium hypophosphite (6.0 g) in de-ionized water
(25 g) was prepared. The aqueous sodium hypophosphite solution was transferred into
the addition funnel, and added to the reaction mixture over a period of about 30
minutes with maintenance of content temperature at about 225C The mixture was
then warmed to about 45C and stirred for about 1 hour.
To determine the completeness of the reaction, a small sample was withdrawn from the
batch and the sample was filtered by means of a syringe filter into a mixture of ethyl
acetate and saturated sodium bicarbonate solution. After extraction, the organic layer
was concentrated to dryness and the residue dissolved with HPLC mobile phase. The
disappearance of 14-hydroxycodeinone was determined. If the reaction was discerned
to be incomplete, the batch was stirred for an additional 2 h period at 45C, and the
HPLC check performed once more.
Upon determination that the reaction was complete, the batch was cooled to ambient
temperature (225C) under the nitrogen atmosphere, and the contents filtered over a
hyflo-supercel filtering pad (3.0 g, wetted with water). The flask and wet cake were
rinsed with acetic acid (20 g). The filtrate was concentrated in vacuo to near dryness at
temperature NMT 50C The residue was dissolved with de-ionized water (50 g) and the
pH adjusted to 11.0 to 12.0 with 20% aqueous KOH solution and concentrated
ammonium hydroxide (about 4 g). The mixture was then extracted with ethyl acetate (4
x 135 g) and the combined organic layers concentrated to dryness in vacuo. Crude
oxycodone with an HPLC purity of over 85% was obtained in a yield of 70.0 to 85.0%
(3.51 to 4.26 g).
IPA (14)
1 Codeine (0.5) 6N HCl (0.5) -MnO2 (1.6) 1.62 94% 95%
H2O (14)
IPA (22)
2 Codeine [PO4] (1) - -MnO2 (3.2) 4.5 NA 34%
H2O (22)
IPA (40)
4 Codeine (2) 6N HCl (2) -MnO2 (4) 1.44 NA 60.3%
H2O (40)
IPA (40)
5 Codeine (2) 6N HCl (3) -MnO2 (7) 1.3 86% 91.8%
H2O (40)
IPA (10)
6 Codeine (0.5) 6N HCl (2) -MnO2 (1.5) 0.73 75% 82%
H2O (10)
IPA (10)
7 Codeine (0.5) 6N HCl (1) -MnO2 (1.5) 1.16 92% 97%
H2O (10)
IPA (10)
10 Codeine (0.5) 6N HCl (4) -MnO2 (1.5) 0.1 50.4% 71%
H2O (10)
11 Codeine (0.5) Acetone (10) 6N HCl -MnO2 (1.5) 0.92 95.2% 94%
H2O (10) (0.75)
NMP (10)
14 Codeine (0.5) 6N HCl (1) -MnO2 1.45 NA 90%
H2O (10)
Acetone
15 Codeine (11.45) (200) 6N HCl (16) -MnO2 (36) 1.02 83.5% 95.5%
H2O (200)
Manganese (II) sulphate monohydrate (140 g) was dissolved in 2.66 liters of water and
heated to 60C. Potassium permanganate (97.3 g) in 1.85 liter of water was added over
a period of 15 minutes and stirred at 60C for 1 hour, until manganese dioxide
precipitated out. The reaction mixture was filtered and the residue was washed with
deionised water until no sulphate ion was present. The solid was dried under suction for
2 hours followed by drying at 70C under vacuum to a constant weight (about 8 days)
to give 115 g of a dark brown powder.
REFERENCES
1. US Pat. 5,869,669
2. US Pat. 6,177,567
3. US Pat. 6,235,906