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Method #1: (Via Codeinone Dienol Acetate)1
Codeine to codeinone
To a solution of dimethylsulfoxide (16.53 g, 0.21 mole) in CH2Cl2 (80 ml) at -78°C was added dropwise a solution of oxalyl chloride (13.01 g, 0.10 mole) in CH2Cl2 (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 -78°C. After stirring at -78°C 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).
Codeinone to codeinone dienol acetate
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 90°C about 105°C 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% CH3OH in CH2Cl2 to give codeinone dienol acetate as brown needles (5.62 g, 83% yield).
Codeinone dienol acetate to Oxycodone
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 43-44°C 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 Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.
Additional information:
Codeinone dienol acetate to 14-hydroxycodeinone with H2O2
A solution of codeinone dienol acetate (1.12 g, 3.3 mmol), formic acid (90% aqueous solution, 0.80 g, 15.6 mmol), hydrogen peroxide (31% aqueous solution, 0.90 g, 8.2 mmol), and water (1.60 g) was allowed to stir at 40-42°C for 4.5 hr, cooled to room temperature, basified with concentrated NH4OH, and extracted with CH2Cl2 (50 ml). The extract was washed with water (20 ml), dried over anhydrous Na2SO4, and evaporated to dryness in vacuo to give 1,4-hydroxycodeinone (0.80 g, 78% yield). The Rf value in TLC, the IR spectrum and the NMR spectrum of the product were comparable to those obtained from an authentic sample.
Codeinone dienol acetate to 14-hydroxycodeinone with MCPBA
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).
Codeinone to 14-hydroxycodeinone with H2O2
A solution of codeinone (0.503 g, 1.7 mmol), formic acid (0.7 ml) and H2O2 (1.0 ml) in Water (1.4 ml) was allowed to stir at 50-55°C 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.
14-Hydroxycodeinone from Codeinone (PDF)
Method #2: (Via Codeinone Dienolsilyl Ether)2
Codeine to codeinone
Codeinone was prepared by oxidation of codeine sulfate trihydrate. A reaction mixture was prepared containing codeine sulfate trihydrate (10.4 g), de-ionized water (20 g) and isopropyl acetate (87.2 g) at ambient temperature. The reaction mixture was agitated and the resultant mixture cooled to about 20±5°C Concentrated ammonium hydroxide (18.0 g) was added in several portions and the mixture was maintained at a temperature of about 20±5°C with stirring. Stirring was continued for about 15 minutes, and then a small portion of the aqueous layer was withdrawn to check for pH value, which was to be advantageously maintained between 11.0 and 12.0. The aqueous layer was then separated and re-extracted with isopropyl acetate (35 g). The combined organic layers (isopropyl acetate) were concentrated in vacuo to near dryness at temperature NMT 45.degree. C. The residual isopropyl acetate solvent was chased by adding 18 g of toluene. The concentration process was then repeated in vacuo. Codeine free base dissolved in a mixture of toluene (177 g) and cyclohexanone (47.4 g) at temperature NMT 45°C was then transferred to the reaction flask which was equipped with magnetic stirrer, thermocouple, Dean-Stark trap with condenser attached, addition funnel with an extender (about 4 inches height), and a nitrogen-inlet adapter. The mixture was heated to boiling temperature (about 116-118°C) under a nitrogen atmosphere and 26 g (30 ml) of distillate were collected in the Dean-Stark trap. A solution of aluminum isopropoxide (3.5 g) in 35.5 g (41 ml) of toluene was then added to the addition funnel. The heating rate was adjusted and the aluminum isopropoxide/toluene solution was added into the reaction mixture at such a rate that the total volume was added over a 10-20 minute period (approximately the same volume (41 ml) of distillate was collected in the Dean-Stark trap). After completion of the addition, collection of the distillate was continued such that 57 g (66 ml) of distillate was collected in the Dean-Stark trap at a similar distillation rate. The heat source was removed and the mixture allowed to cool down to ambient temperature (under nitrogen atmosphere) over a period of about 30 minutes. Reaction completeness was determined by withdrawing a small sample from the batch, extracting it with a saturated sodium bicarbonate solution and ethyl acetate, concentrating the organic layer, re-dissolving it with the HPLC mobile phase, and analyzing the sample on HPLC. The reaction was considered complete if the area % of codeine was less than 3.5A%.
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 20±5°C. 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 55°C 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 0-5°C for at least eight hours under a nitrogen atmosphere. Solids were then filtered and the flask/wet cake rinsed with the chilled (about 5°C) recycled filtrate. The latter operation was repeated until no solids were left in the flask. The chilled wet cake was then rinsed with chilled (5-10°C) 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 50°C 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 to Dienolsilyl Ether of Codeinone
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 20±5°C 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 58±3°C 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 58±3°C 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 20±5°C, 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 50°C, 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.
Dienolsilyl Ether of Codeinone to 14-hydroxycodeinone
Peracetic acid solution(for prep see below) (107.7 g of 9.0 wt. % peracetic acid) at ambient temperature (22±5°C) 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 28°C The batch was stirred at 22±5°C 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).
Upon determination of the completion of the reaction 20.0 g of 10 wt. % of aqueous sodium hydrogen sulfite solution was added in one portion, and the resultant admixture stirred for 10 minutes at ambient temperature. The batch was then concentrated in vacuo at temperature NMT 45°C to dryness. Subsequently water (180 g), toluene (69 g), ethyl acetate (36 g) were added and vigorous stirring for about 10 minutes undertaken. The resulting layers were separated and the aqueous layer saved in a flask. The organic layer was washed thrice with a solution of 26 ml of 2.5% HCl. The combined aqueous layers were then filtered through a pad of wet (with water) hyflo-supercel filter aid. Subsequently, EtOAc (85 g) was added to the filtrate and concentrated ammonium hydroxide added in a quantity to adjust the pH of the aqueous layer to about 11. The mixture was stirred for 10 minutes at about 60°C and the layers were separated and saved. The aqueous layer was washed with EtOAc (50g) and then discarded. The combined organic layers were concentrated in vacuo to dryness at temperature NMT 50°C To the residue was added 2-propanol (13 g), and the resultant mixture stirred at 5-10C for at least 5 hours. The solids were filtered, the flask and solids rinsed with the chilled (5°C) filtrate followed by chilled (5-10°C) 2-propanol (10 g) and heptane (8 g). The solid was then vacuum dried at temperature NMT 50°C to a constant weight. A yield of between 3.50-4.96g (55-78%) of 14-hydroxycodeinone free base with a purity of over 96A % was obtained.
Making Peracetic Acid
14-Hydroxycodeinone was synthesized from the dienolsilyl ether of codeinone by oxidative hydroxylation using a peracetic acid solution preparation. The peracetic acid solution was prepared as follows:
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 10±3°C 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 27°C. (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 10±3°C bath. Acetic acid (10.0 g) was then added through the addition funnel, and the batch slowly warmed to 25±5°C 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).
Oxycodone from 14-Hydroxycodeinone By Catalytic Hydrogenation
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 50°C 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.
Oxycodone from 14-Hydroxycodeinone By Catalytic Transfer Hydrogenation Method
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 (22±5°C), 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 22±5°C The mixture was then warmed to about 45°C 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 45°C, and the HPLC check performed once more.
Upon determination that the reaction was complete, the batch was cooled to ambient temperature (22±5°C) 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 50°C 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).
gamma-MnO2 Oxidation of Codeine to Codeinone3
Codeinone was prepared by oxidation of codeine phosphate or codeine. A solution of codeine or codeine phosphate was dissolved in the appropriate solvent system and a specified volume of hydrochloric acid of varying concentration was added. Manganese dioxide (freshly prepared gamma-manganese dioxide) was added and the reaction mixture was stirred at ambient temperature for 1.5 to 4 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was filtered through a celite pad, washed with additional solvent or water, and neutralized with ammonium hydroxide. The product was extracted with methylene chloride (3 x 150 ml) and the combined extracts washed with water and dried over anhydrous sodium sulphate. The organic layer was then evaporated to yield codeinone. The results can be seen in the following table.
Exp.
Starting Material
(g)
Solvent
Mix (ml)
Acid (ml)
Oxidant (g)
pH
Yield
Purity
1
Codeine (0.5)
IPA (14)
H2O (14)
6N HCl (0.5)
γ-MnO2 (1.6)
1.62
94%
95%
2
Codeine (1)
IPA (22)
H2O (22)
-
γ-MnO2 (3.2)
4.5
NA
34%
3
Codeine (0.5)
IPA (14)
H2O (14)
6N HCl (0.5)
γ-MnO2 (1.6)
1.6
80%
91.8%
4
Codeine (2)
IPA (40)
H2O (40)
6N HCl (2)
γ-MnO2 (4)
1.44
NA
60.3%
5
Codeine (2)
IPA (40)
H2O (40)
6N HCl (3)
γ-MnO2 (7)
1.3
86%
91.8%
6
Codeine (0.5)
IPA (10)
H2O (10)
6N HCl (2)
γ-MnO2 (1.5)
0.73
75%
82%
7
Codeine (0.5)
IPA (10)
H2O (10)
6N HCl (1)
γ-MnO2 (1.5)
1.16
92%
97%
8
Codeine (0.5)
IPA (10)
H2O (10)
6N HCl (0.75)
γ-MnO2 (1.5)
1.41
95%
95%
9
Codeine (0.5)
CH3CN (10)
H2O (10)
6N HCl (0.75)
γ-MnO2 (1.5)
0.9
89.7%
93%
10
Codeine (0.5)
IPA (10)
H2O (10)
6N HCl (4)
γ-MnO2 (1.5)
0.1
50.4%
71%
11
Codeine (0.5)
Acetone (10)
H2O (10)
6N HCl (0.75)
γ-MnO2 (1.5)
0.92
95.2%
94%
12
Codeine (0.5)
THF (10)
H2O (10)
6N HCl (0.75)
γ-MnO2 (1.5)
1.21
89%
93%
13
Codeine (0.5)
NMP (20)
-
γ-MnO2
-
NA
21.6%
14
Codeine (0.5)
NMP (10)
H2O (10)
6N HCl (1)
γ-MnO2
1.45
NA
90%
15
Codeine (11.45)
Acetone (200)
H2O (200)
6N HCl (16)
γ-MnO2 (36)
1.02
83.5%
95.5%
Preparation of gamma-Manganese Dioxide
Manganese (II) sulphate monohydrate (140 g) was dissolved in 2.66 liters of water and heated to 60°C. Potassium permanganate (97.3 g) in 1.85 liter of water was added over a period of 15 minutes and stirred at 60°C 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 70°C under vacuum to a constant weight (about 8 days) to give 115 g of a dark brown powder.
References
US Pat. 5,869,669
US Pat. 6,177,567
US Pat. 6,235,906
Codeine to codeinone
To a solution of dimethylsulfoxide (16.53 g, 0.21 mole) in CH2Cl2 (80 ml) at -78°C was added dropwise a solution of oxalyl chloride (13.01 g, 0.10 mole) in CH2Cl2 (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 -78°C. After stirring at -78°C 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).
Codeinone to codeinone dienol acetate
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 90°C about 105°C 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% CH3OH in CH2Cl2 to give codeinone dienol acetate as brown needles (5.62 g, 83% yield).
Codeinone dienol acetate to Oxycodone
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 43-44°C 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 Rf value in TLC and the IR spectrum of the product were comparable to those obtained from an authentic sample.
Additional information:
Codeinone dienol acetate to 14-hydroxycodeinone with H2O2
A solution of codeinone dienol acetate (1.12 g, 3.3 mmol), formic acid (90% aqueous solution, 0.80 g, 15.6 mmol), hydrogen peroxide (31% aqueous solution, 0.90 g, 8.2 mmol), and water (1.60 g) was allowed to stir at 40-42°C for 4.5 hr, cooled to room temperature, basified with concentrated NH4OH, and extracted with CH2Cl2 (50 ml). The extract was washed with water (20 ml), dried over anhydrous Na2SO4, and evaporated to dryness in vacuo to give 1,4-hydroxycodeinone (0.80 g, 78% yield). The Rf value in TLC, the IR spectrum and the NMR spectrum of the product were comparable to those obtained from an authentic sample.
Codeinone dienol acetate to 14-hydroxycodeinone with MCPBA
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).
Codeinone to 14-hydroxycodeinone with H2O2
A solution of codeinone (0.503 g, 1.7 mmol), formic acid (0.7 ml) and H2O2 (1.0 ml) in Water (1.4 ml) was allowed to stir at 50-55°C 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.
14-Hydroxycodeinone from Codeinone (PDF)
Method #2: (Via Codeinone Dienolsilyl Ether)2
Codeine to codeinone
Codeinone was prepared by oxidation of codeine sulfate trihydrate. A reaction mixture was prepared containing codeine sulfate trihydrate (10.4 g), de-ionized water (20 g) and isopropyl acetate (87.2 g) at ambient temperature. The reaction mixture was agitated and the resultant mixture cooled to about 20±5°C Concentrated ammonium hydroxide (18.0 g) was added in several portions and the mixture was maintained at a temperature of about 20±5°C with stirring. Stirring was continued for about 15 minutes, and then a small portion of the aqueous layer was withdrawn to check for pH value, which was to be advantageously maintained between 11.0 and 12.0. The aqueous layer was then separated and re-extracted with isopropyl acetate (35 g). The combined organic layers (isopropyl acetate) were concentrated in vacuo to near dryness at temperature NMT 45.degree. C. The residual isopropyl acetate solvent was chased by adding 18 g of toluene. The concentration process was then repeated in vacuo. Codeine free base dissolved in a mixture of toluene (177 g) and cyclohexanone (47.4 g) at temperature NMT 45°C was then transferred to the reaction flask which was equipped with magnetic stirrer, thermocouple, Dean-Stark trap with condenser attached, addition funnel with an extender (about 4 inches height), and a nitrogen-inlet adapter. The mixture was heated to boiling temperature (about 116-118°C) under a nitrogen atmosphere and 26 g (30 ml) of distillate were collected in the Dean-Stark trap. A solution of aluminum isopropoxide (3.5 g) in 35.5 g (41 ml) of toluene was then added to the addition funnel. The heating rate was adjusted and the aluminum isopropoxide/toluene solution was added into the reaction mixture at such a rate that the total volume was added over a 10-20 minute period (approximately the same volume (41 ml) of distillate was collected in the Dean-Stark trap). After completion of the addition, collection of the distillate was continued such that 57 g (66 ml) of distillate was collected in the Dean-Stark trap at a similar distillation rate. The heat source was removed and the mixture allowed to cool down to ambient temperature (under nitrogen atmosphere) over a period of about 30 minutes. Reaction completeness was determined by withdrawing a small sample from the batch, extracting it with a saturated sodium bicarbonate solution and ethyl acetate, concentrating the organic layer, re-dissolving it with the HPLC mobile phase, and analyzing the sample on HPLC. The reaction was considered complete if the area % of codeine was less than 3.5A%.
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 20±5°C. 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 55°C 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 0-5°C for at least eight hours under a nitrogen atmosphere. Solids were then filtered and the flask/wet cake rinsed with the chilled (about 5°C) recycled filtrate. The latter operation was repeated until no solids were left in the flask. The chilled wet cake was then rinsed with chilled (5-10°C) 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 50°C 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 to Dienolsilyl Ether of Codeinone
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 20±5°C 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 58±3°C 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 58±3°C 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 20±5°C, 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 50°C, 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.
Dienolsilyl Ether of Codeinone to 14-hydroxycodeinone
Peracetic acid solution(for prep see below) (107.7 g of 9.0 wt. % peracetic acid) at ambient temperature (22±5°C) 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 28°C The batch was stirred at 22±5°C 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).
Upon determination of the completion of the reaction 20.0 g of 10 wt. % of aqueous sodium hydrogen sulfite solution was added in one portion, and the resultant admixture stirred for 10 minutes at ambient temperature. The batch was then concentrated in vacuo at temperature NMT 45°C to dryness. Subsequently water (180 g), toluene (69 g), ethyl acetate (36 g) were added and vigorous stirring for about 10 minutes undertaken. The resulting layers were separated and the aqueous layer saved in a flask. The organic layer was washed thrice with a solution of 26 ml of 2.5% HCl. The combined aqueous layers were then filtered through a pad of wet (with water) hyflo-supercel filter aid. Subsequently, EtOAc (85 g) was added to the filtrate and concentrated ammonium hydroxide added in a quantity to adjust the pH of the aqueous layer to about 11. The mixture was stirred for 10 minutes at about 60°C and the layers were separated and saved. The aqueous layer was washed with EtOAc (50g) and then discarded. The combined organic layers were concentrated in vacuo to dryness at temperature NMT 50°C To the residue was added 2-propanol (13 g), and the resultant mixture stirred at 5-10C for at least 5 hours. The solids were filtered, the flask and solids rinsed with the chilled (5°C) filtrate followed by chilled (5-10°C) 2-propanol (10 g) and heptane (8 g). The solid was then vacuum dried at temperature NMT 50°C to a constant weight. A yield of between 3.50-4.96g (55-78%) of 14-hydroxycodeinone free base with a purity of over 96A % was obtained.
Making Peracetic Acid
14-Hydroxycodeinone was synthesized from the dienolsilyl ether of codeinone by oxidative hydroxylation using a peracetic acid solution preparation. The peracetic acid solution was prepared as follows:
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 10±3°C 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 27°C. (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 10±3°C bath. Acetic acid (10.0 g) was then added through the addition funnel, and the batch slowly warmed to 25±5°C 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).
Oxycodone from 14-Hydroxycodeinone By Catalytic Hydrogenation
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 50°C 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.
Oxycodone from 14-Hydroxycodeinone By Catalytic Transfer Hydrogenation Method
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 (22±5°C), 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 22±5°C The mixture was then warmed to about 45°C 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 45°C, and the HPLC check performed once more.
Upon determination that the reaction was complete, the batch was cooled to ambient temperature (22±5°C) 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 50°C 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).
gamma-MnO2 Oxidation of Codeine to Codeinone3
Codeinone was prepared by oxidation of codeine phosphate or codeine. A solution of codeine or codeine phosphate was dissolved in the appropriate solvent system and a specified volume of hydrochloric acid of varying concentration was added. Manganese dioxide (freshly prepared gamma-manganese dioxide) was added and the reaction mixture was stirred at ambient temperature for 1.5 to 4 hours. The progress of the reaction was monitored by HPLC. The reaction mixture was filtered through a celite pad, washed with additional solvent or water, and neutralized with ammonium hydroxide. The product was extracted with methylene chloride (3 x 150 ml) and the combined extracts washed with water and dried over anhydrous sodium sulphate. The organic layer was then evaporated to yield codeinone. The results can be seen in the following table.
Exp.
Starting Material
(g)
Solvent
Mix (ml)
Acid (ml)
Oxidant (g)
pH
Yield
Purity
1
Codeine (0.5)
IPA (14)
H2O (14)
6N HCl (0.5)
γ-MnO2 (1.6)
1.62
94%
95%
2
Codeine (1)
IPA (22)
H2O (22)
-
γ-MnO2 (3.2)
4.5
NA
34%
3
Codeine (0.5)
IPA (14)
H2O (14)
6N HCl (0.5)
γ-MnO2 (1.6)
1.6
80%
91.8%
4
Codeine (2)
IPA (40)
H2O (40)
6N HCl (2)
γ-MnO2 (4)
1.44
NA
60.3%
5
Codeine (2)
IPA (40)
H2O (40)
6N HCl (3)
γ-MnO2 (7)
1.3
86%
91.8%
6
Codeine (0.5)
IPA (10)
H2O (10)
6N HCl (2)
γ-MnO2 (1.5)
0.73
75%
82%
7
Codeine (0.5)
IPA (10)
H2O (10)
6N HCl (1)
γ-MnO2 (1.5)
1.16
92%
97%
8
Codeine (0.5)
IPA (10)
H2O (10)
6N HCl (0.75)
γ-MnO2 (1.5)
1.41
95%
95%
9
Codeine (0.5)
CH3CN (10)
H2O (10)
6N HCl (0.75)
γ-MnO2 (1.5)
0.9
89.7%
93%
10
Codeine (0.5)
IPA (10)
H2O (10)
6N HCl (4)
γ-MnO2 (1.5)
0.1
50.4%
71%
11
Codeine (0.5)
Acetone (10)
H2O (10)
6N HCl (0.75)
γ-MnO2 (1.5)
0.92
95.2%
94%
12
Codeine (0.5)
THF (10)
H2O (10)
6N HCl (0.75)
γ-MnO2 (1.5)
1.21
89%
93%
13
Codeine (0.5)
NMP (20)
-
γ-MnO2
-
NA
21.6%
14
Codeine (0.5)
NMP (10)
H2O (10)
6N HCl (1)
γ-MnO2
1.45
NA
90%
15
Codeine (11.45)
Acetone (200)
H2O (200)
6N HCl (16)
γ-MnO2 (36)
1.02
83.5%
95.5%
Preparation of gamma-Manganese Dioxide
Manganese (II) sulphate monohydrate (140 g) was dissolved in 2.66 liters of water and heated to 60°C. Potassium permanganate (97.3 g) in 1.85 liter of water was added over a period of 15 minutes and stirred at 60°C 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 70°C under vacuum to a constant weight (about 8 days) to give 115 g of a dark brown powder.
References
US Pat. 5,869,669
US Pat. 6,177,567
US Pat. 6,235,906
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clanzy
clanzy
jiggago
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which method do you prefer in yr everyday life?? you'll NEVER make the front page with such glaring gaps
Meursault
Meursault
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Waiter, I ordered my drink with No ice
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GoldenLionTamarin
GoldenLionTamarin
Goldgelbes Löwenäffchen
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if you want to psot about codeine. make a codeine megathread
GoldenLionTamarin
GoldenLionTamarin
Goldgelbes Löwenäffchen
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this is our safe space
Meursault
Meursault
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[account deactivated]
animedad
animedad
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A solution of codeinone dienol acetate (1.12 g, 3.3 mmol),
uh no. try again fucktard. dont bring that mehthead science into my house
KilledInADuel
KilledInADuel
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Now I'm out of prison, I got me a friend at last
He don't drink or steal or cheat or lie
Well his name's codeine, he's the nicest thing I've seen
And together we're gonna wait around to die
Well together we're gonna wait around to die
He don't drink or steal or cheat or lie
Well his name's codeine, he's the nicest thing I've seen
And together we're gonna wait around to die
Well together we're gonna wait around to die
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dipshit420
dipshit420
political car tune
Post rating:
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Shuck and methstroy
littlegreenpills
littlegreenpills
Poronto
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Ich warf einen Wunsch in den Brunnen,
Frag mich nicht danach, ich werde ihn niemals verraten,
Ich sah dich an, als er fiel
und jetzt bist du mir im Weg
Ich tausche meine Seele gegen einen Wunsch,
Pfennige und Groschen für einen Kuss
Ich suchte nicht danach,
aber jetzt bist du mir im Weg
Dein Blick hielt meinem stand, zerrissene Jeans, Haut war zu sehen
Heiße Nacht, der Wind wehte
Was glaubst du, wohin du gehen wirst, Baby?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Es ist schwer, dir geradewegs
in die Augen zu schauen, Baby
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Und all die anderen Jungs,
versuchen, mir nachzulaufen,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Du hast dir Zeit gelassen mit dem Anruf,
Ich konnte mich gar nicht früh genug hingeben
Du gabst mir gar nichts,
und doch bist du mir noch immer im Weg
Ich würde alles darum geben, dich zu bekommen
stelle es dir vor und es wird wahr
Ich wusste nicht, wie es sich anfühlt
aber es ist mir im Weg
Dein Blick hielt meinem stand, zerrissene Jeans, Haut war zu sehen
Heiße Nacht, der Wind wehte
Was glaubst du, wohin du gehen wirst, Baby?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Es ist schwer, dir geradewegs
in die Augen zu schauen, Baby
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Und all die anderen Jungs,
versuchen, mir nachzulaufen,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Bevor du in mein Leben kamst
vermisste ich dich so sehr
vermisste ich dich so sehr
vermisste ich dich so, so sehr!
Bevor du in mein Leben kamst
vermisste ich dich so sehr
und das solltest du wissen,
Ich vermisste dich so, so sehr!
Es ist schwer, dir geradewegs
in die Augen zu schauen, Baby
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Und all die anderen Jungs,
versuchen, mir nachzulaufen,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Bevor du in mein Leben kamst
vermisste ich dich so sehr
vermisste ich dich so sehr
vermisste ich dich so, so sehr!
Bevor du in mein Leben kamst
vermisste ich dich so sehr
und das solltest du wissen
Also ruf mich vielleicht mal an?
Frag mich nicht danach, ich werde ihn niemals verraten,
Ich sah dich an, als er fiel
und jetzt bist du mir im Weg
Ich tausche meine Seele gegen einen Wunsch,
Pfennige und Groschen für einen Kuss
Ich suchte nicht danach,
aber jetzt bist du mir im Weg
Dein Blick hielt meinem stand, zerrissene Jeans, Haut war zu sehen
Heiße Nacht, der Wind wehte
Was glaubst du, wohin du gehen wirst, Baby?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Es ist schwer, dir geradewegs
in die Augen zu schauen, Baby
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Und all die anderen Jungs,
versuchen, mir nachzulaufen,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Du hast dir Zeit gelassen mit dem Anruf,
Ich konnte mich gar nicht früh genug hingeben
Du gabst mir gar nichts,
und doch bist du mir noch immer im Weg
Ich würde alles darum geben, dich zu bekommen
stelle es dir vor und es wird wahr
Ich wusste nicht, wie es sich anfühlt
aber es ist mir im Weg
Dein Blick hielt meinem stand, zerrissene Jeans, Haut war zu sehen
Heiße Nacht, der Wind wehte
Was glaubst du, wohin du gehen wirst, Baby?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Es ist schwer, dir geradewegs
in die Augen zu schauen, Baby
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Und all die anderen Jungs,
versuchen, mir nachzulaufen,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Bevor du in mein Leben kamst
vermisste ich dich so sehr
vermisste ich dich so sehr
vermisste ich dich so, so sehr!
Bevor du in mein Leben kamst
vermisste ich dich so sehr
und das solltest du wissen,
Ich vermisste dich so, so sehr!
Es ist schwer, dir geradewegs
in die Augen zu schauen, Baby
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Hey, ich hab dich gerade erst getroffen,
und das ist verrückt,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Und all die anderen Jungs,
versuchen, mir nachzulaufen,
aber hier ist meine Nummer,
Also ruf mich vielleicht mal an?
Bevor du in mein Leben kamst
vermisste ich dich so sehr
vermisste ich dich so sehr
vermisste ich dich so, so sehr!
Bevor du in mein Leben kamst
vermisste ich dich so sehr
und das solltest du wissen
Also ruf mich vielleicht mal an?
Impper
Impper
Post rating:
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mm oxycodone gibs me dat
Transient_Grace
Transient_Grace
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Transient_Grace
Transient_Grace
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#13 A yellowish-green gelantious unknown - annoying: This has been something that's been going on for about 2 years by now and it's extremely annoying. While I'm sleeping, there's about a 10% chance each sleep-wake cycle of mine that this will happen. When it does happen, I'm otherwise forced to wake up and take care of the mess. What's the problem? I wake up to a sticky, yellowish green (hue 100°, saturation 70%, value 80%), gelatinous substance in my underwear. I've been thinking I'm piddling in my underwear, much like 1-year-olds often do (only in diapers). I have no idea why this is happening. How to stop it? That I don't know either. At least it's rare, but I would like it to stop. I don't know what's different that I'm doing that's causing this to happen.
Transient_Grace
Transient_Grace
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Despite being able to listen to the same song and speed for days or even weeks on end, for thousands upon thousands of loops, surprisingly, I'm unable to identify instruments or the genre of music. Despite this major weakness, at least I'm able to create music, through software programs that generate it. I use FL Studio. Though only 1/3 done for what I would like, this video gives a good example as to what music in Platform Masters will actually be like, or, at least, what I intend it to be like - catchy, rhythmic, and also peaceful. This song has the intro and 2 parts so far. The first part is measures 2 through 17 (16 total). The second part is measures 18 through 25 (8 total). A third part is intended and perhaps a fourth, both likely 8 measures.
When it comes to music, I have a big problem to solve. The problem isn't creating the music, rather, it's programming-related. In order to play music, it has to be loaded into RAM in a decompressed state. Trouble is, I only know RLE compression. Decompressing OGG Vorbis or MP3 is just too advanced for me. Thus, I'm stuck with WAV. There's a big problem with WAV though - download size and horrible compression. All the graphics compress very well, outside the ground. It's quite common I see things like 30% compression, or even 90%+ when I do tests in Winzip (using legacy compression, for maximum compatibility, rather than it's own). WAV files compress not 90%, not 30%, not even 10%, but more around 3% from what I often get. Only songs with a lot of silence get over 10%. I would like to go with 48,000 Hz, 16-bit, mono for the audio quality and a 90-second target duration per loop. Until this issue is resolved, the duration will be cut to about 60 seconds and the quality will be reduced considerably to 16,000 Hz, 8-bit, mono.
Category:
People & Blogs
License:
Standard YouTube License
Transient_Grace
Transient_Grace
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"#12 Bathroom troubles - parents + mirror: Years ago, the main bathroom was rebuilt. It was in great need of it - the floor was weak and you could almost fall through it, especially in the areas near the toilet. As kids, me and my sister occasionally and deliberately flooded the bathroom. Then, around 6 years ago or so, my parents rebuilt the bathroom, including the floor. They rearranged everything. They got this one big mirror and placed it so that it was directly in front of the toilet. I warned them not to put it there, but they refused. I knew that later on down the road, arguments about it would occur and I'd keep saying "unblock it first" when they tell me to use it instead of the master bedroom's bathroom. This continued on for years, but usually only two to four incidents per year and nothing major. Then, along came July for 2008.
I got into a heated argument over it, the worst of all that I can recall. These actually continued for 2 or 3 days, longer than ever before. I began using my tricks to sort of "sneak it in" and this went for only 2 days. As I frequently had in my mind drifts (not my mind game), I often stated of the parents having three options. The first was to simply get rid of the mirror. It'd be the easiest and most trouble-free. The second would be to move it, as a recommended. The third would be to do nothing but let me use the then-current bathroom I was using. After getting into trouble over this, I, literally, avoided going to the bathroom. I drank a lot less than usual and I ate a lot less. At one point during the argument, I had thoughts of actually busting the mirror and I've busted many before that have blocked access to important areas (including the phone). The parents put curtains over it as an attempt, but that's nowhere near good enough."
I got into a heated argument over it, the worst of all that I can recall. These actually continued for 2 or 3 days, longer than ever before. I began using my tricks to sort of "sneak it in" and this went for only 2 days. As I frequently had in my mind drifts (not my mind game), I often stated of the parents having three options. The first was to simply get rid of the mirror. It'd be the easiest and most trouble-free. The second would be to move it, as a recommended. The third would be to do nothing but let me use the then-current bathroom I was using. After getting into trouble over this, I, literally, avoided going to the bathroom. I drank a lot less than usual and I ate a lot less. At one point during the argument, I had thoughts of actually busting the mirror and I've busted many before that have blocked access to important areas (including the phone). The parents put curtains over it as an attempt, but that's nowhere near good enough."
Transient_Grace
Transient_Grace
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One of my dogs, for the past 3 days or so, has been acting extremely weird. Here's a list of what he's doing:
1. He gets on the back of another dog and sort of rides on the back of the other dog sort of jumping.
2. If I get this dog separated from the others, he wines so much, it gets very annoying, so annoying that I lock him up behind another door far away, sometimes even out in the cold if it gets too overwhelming. If close, this doesn't happen as intensely.
3. If I let him out, he wants back in again. If I let the other dog out, he'll always want out.
4. Fairly recently, there was a bond made that was so strong, even with a 25-pound dog below and the 15-pound dog on top with the lower dog hanging and movement up and down to simulate about 2 G's of force, the bond wouldn't break. That's like 50 pounds of force for a bond no more than 2 cubic centimeters. That is such an intense force required. After repeated whacking (sometimes even hard whacks), the bond still remain as if not giving up. The bond finally broke and a lot of liquid came out (and it wasn't yellow suggesting urine). After this episode, I locked him up again and he was breathing in and out like 4 times a second, so fast, it doesn't seem right.
What is this all about? My dad is telling me to keep the two separate so I was. The whacks are to tell him that what he was doing was not allowed, and despite being whacked a lot for 3 days, this continued to happen.
1. He gets on the back of another dog and sort of rides on the back of the other dog sort of jumping.
2. If I get this dog separated from the others, he wines so much, it gets very annoying, so annoying that I lock him up behind another door far away, sometimes even out in the cold if it gets too overwhelming. If close, this doesn't happen as intensely.
3. If I let him out, he wants back in again. If I let the other dog out, he'll always want out.
4. Fairly recently, there was a bond made that was so strong, even with a 25-pound dog below and the 15-pound dog on top with the lower dog hanging and movement up and down to simulate about 2 G's of force, the bond wouldn't break. That's like 50 pounds of force for a bond no more than 2 cubic centimeters. That is such an intense force required. After repeated whacking (sometimes even hard whacks), the bond still remain as if not giving up. The bond finally broke and a lot of liquid came out (and it wasn't yellow suggesting urine). After this episode, I locked him up again and he was breathing in and out like 4 times a second, so fast, it doesn't seem right.
What is this all about? My dad is telling me to keep the two separate so I was. The whacks are to tell him that what he was doing was not allowed, and despite being whacked a lot for 3 days, this continued to happen.