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CAS No. : | 33494-80-3 | MDL No. : | MFCD03840344 |
Formula : | C8H18KO4P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZSWXMOQFFWMZQH-UHFFFAOYSA-M |
M.W : | 248.30 | Pubchem ID : | 23674467 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 51.11 |
TPSA : | 68.4 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.14 cm/s |
Log Po/w (iLOGP) : | -2.64 |
Log Po/w (XLOGP3) : | 0.95 |
Log Po/w (WLOGP) : | 3.16 |
Log Po/w (MLOGP) : | 1.04 |
Log Po/w (SILICOS-IT) : | 0.76 |
Consensus Log Po/w : | 0.65 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.71 |
Solubility : | 4.8 mg/ml ; 0.0193 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.97 |
Solubility : | 2.64 mg/ml ; 0.0106 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.23 |
Solubility : | 14.6 mg/ml ; 0.0587 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.99 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride In water at 0℃; | Concentrated HC1 (2.89 mL, 34.6 mmol) was added slowly to a solution ofpotassium di-tert-butyl phosphate (8.6 g, 34.6 mmol) in water (10 mL) at 0°C. Theprecipitated solid was collected by filtration, washed with a small amount of ice-water (5 mL), and dried in vacuo to provide Intermediate 7A (7.1 g, 33.8 mmol, 98 percent yield) as awhite solid. |
4 g | With hydrogenchloride In water | [095] In one embodiment, the present invention pmvides a method of preparing a reagent for use in preparing a prodrug of 6-cyclohexyl-1-hydroxy-4-methylpyridin-2(1H)-one, which method can include reaction Scheme 2 as shown in Figure 2. The reaction Scheme 2 provides a reagent for preparation of a reagent of the POM prodrug moiety, which is ditert-butyl(choloromethyl)phosphate. Briefly, potassium di-tert phosphate (5 g, 20 mmol)is dissolved in a minimum amount of cold water and 6 N HC1 is added drop-wise in order to form a precipitate, and then the precipitate is washed with cold water, which is then filtered and dried under vacuum in order to form di-tert phosphate. The di-tert-phosphate (4 g, 19 mmol) is then dissolved in about 100 mL acetone with tetramethylammonium hydmxide added drop-wise until reaching about pH 7, and then the solvent is removed anddried under vacuum to pmduce tetra-methyl ammonium di-tert-butyl phosphate. Tetramethyl ammonium di-tert-butyl phosphate (5.11 g, 18 mmol) is then reacted with iodocholoro methane (CH2CII) (25 g, 142 mmol, 7.88 equivalent) in about 150 ML DME and refluxed for about 2 hours before being filtered to remove the precipitate, removal of the solvent, and then dissolved in EA/H, and then filtered through a silica bed, and thesolvent is removed and the product is dried to obtain di-tertbutyl(choloromethyl)phosphate. A TLC is shown to confirm product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 g | Stage #1: With potassium permanganate; potassium hydrogencarbonate In water at 20℃; for 1.5 h; Cooling with ice Stage #2: With pyrographite In water at 60℃; for 0.25 h; |
Di-tert-butyl phosphohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time. The reaction as then allowed to continue at room temperature for an additional half hour. Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C. a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the crude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16percent in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60percent yield): 1HNMR (CD3OD, 300 MHz) δ 1.51 (s, 12H), 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) δ −11.3 (s, 1P) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium permanganate; potassium hydrogencarbonate; In water; at 5 - 20℃; for 19h; | Intermediate 59: Bis(1,1 -dimethylethyl) hydrogen phosphate potassium salt; A solution of bis(1 ,1-dimethylethyl) hydrogen phosphite (100 g, 515 mmol, Alfa Aesar) and potassium bicarbonate (30.9 g, 309 mmol) in water (800 ml) was cooled to 5 0C in an ice bath. To this mixture, potassium permanganate (57.0 g, 360 mmol) was added portionwise over 1 h maintaining the temperature below 20 0C. The reaction mixture was stirred at ambient temperature for 18 h. The reaction was heated to 60 0C and then filtered slowly through a pad of celite. The filtrate was evaporated in vacuo to give the title compound as a white solid (109.7 g); 1H NMR (d6-DMSO) delta 1.26 (18 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium permanganate; potassium hydrogencarbonate; In water; at 0 - 20℃; for 1.5h; | The conversion of di-tert-butyl phosphite into the corresponding phosphate is performed by a slight modification of the method published by Zwierzak and Kluba (Zwierzak, A and Kluba, M., 1971). Di-tert-butyl phosphite (40.36 mmole) is combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution is stirred in an ice bath and potassium permanganate (28.25 mmole) is added in three equal portions over one hour's time. The reaction is then allowed to continue at room temperature for an additional half hour. Decolorizing carbon (600 mg) is then incorporated as the reaction is heated to 60°C for 15 minutes. The reaction is then vacuum filtered to remove solid magnesium dioxide. The solid is washed several times with water. The filtrate is then combined with one gram of decolorizing carbon and heated at 60°C for an additional twenty minutes. The solution is again filtered to yield a colorless solution, to which a slight excess of concentrated HCl is slowly added wich efficient stirring in an ice bath. The addition of acid causes the precipitation of the di-tert-butyl phosphate free acid. The free acid is then filtered and washed with ice cold water. The compound is then converted to the salt form by dissolving the free acid in acetone and adding an equal molar amount of tetramethylammonium hydroxide while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give 7.16 grams of crude product. This product is then recrystallized by refluxing in dimethoxyethane and slow cooling at room temperature to give 6.52 g of pure product (57percent yield). 12.75 mmole of the tetramethylammonium di-tert-butyl-phosphate is then mixed with 70 ml of dimethoxyethane and brought to reflux. Twenty-five grams of chloroiodomethane is then added and stirred for one and a half hours. The reaction is then filtered and the filtrate is placed under reduced pressure to remove excess chloroiodomethane and solvent. The two products are then separated via flash column chromatography. The stationary phase is normal phase silica (30 g). The mobile phase consists of ethyl acetate and hexane in a 3 to 7 (v/v) ratio respectively. The chloromethyl di-tert-butyl phosphate is isolated as a pale gold oil (63percent yield): 1H NMR (CDCl3, 300 MHz) delta 1.51 (s, 12H), 5.63 (d, 2H, J = 14.8). Mass spectrum (FAB +, GLY) 259 (M+1). | |
5 g | Di-tert-butyl phosphohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time. The reaction as then allowed to continue at room temperature for an additional half hour. Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C. a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the crude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16percent in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60percent yield): 1HNMR (CD3OD, 300 MHz) delta 1.51 (s, 12H), 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) delta ?11.3 (s, 1P) | |
With potassium permanganate; potassium hydrogencarbonate; In water; at 20℃; for 1.5h; | Di-tert-butyl phosphohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time. The reaction as then allowed to continue at room temperature for an additional half hour. (0203) Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C. a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the crude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16percent in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60percent yield): 1HNMR (CD3OD, 300 MHz) delta 1.51 (s, 12H), 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) delta ?11.3 (s, 1P). |
With potassium permanganate; potassium hydrogencarbonate; In water; at 60℃; for 1.5h; | Di-tert-butyl phosphite (40.36 mmole)Was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water.The solution was stirred in an ice bath and potassium permanganate (28.25 mmole)Was added in three equal portions over 1 hour.Thereafter, the reaction was continued at room temperature for an additional 0.5 hour.Thereafter, decolorizing carbon (600 mg)The reaction was taken up when heated to 60 ° C. for 15 minutes.Thereafter, the reaction product was subjected to vacuum filtration to remove manganese dioxide as a solid component.The solid was washed several times with water. The filtrate was then combined with 1 gram of decolorizing carbon and heated at 60 ° C. for a further 20 minutes. The solution was again filtered to give a colorless solution which was then evaporated under vacuum to provide the crude di-tert-butyl phosphate potassium salt.Dissolve di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) in methanol (15 g) and add a slight excess of concentrated HCl to this solution at 0 ° C. while slowing the efficiency Stirring was carried out. The addition of acid causes the precipitation of potassium chloride. The solids are then filtered and washed with methanol. Thereafter, the compound in the mother liquor was treated with ammonium (3.65 g, 20.14 mmole) by adding an equimolar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while efficiently stirring the reaction and cooling with a salt / ice bath Morphology. The resulting clear solution is placed under reduced pressure to provide a crude product.To tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane, 4.3 grams of chloroiodomethane (24.16 mmole) is then added and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure and the solution is concentrated in DME. 12 to 16percent of chloromethyl di-tert-butyl phosphate in DME4- (5- (2- (3,5-bis (trifluoromethyl) phenyl)-N, 2-dimethylpropanamido-4- (o-tolyl) pyridin-2-yl)-1-methyl-1 - ((phosphonooxy) methyl) piperazin-1-ium used without further purification (60percent yield): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With hydrogenchloride; In water; at 0℃; | Concentrated HC1 (2.89 mL, 34.6 mmol) was added slowly to a solution ofpotassium di-tert-butyl phosphate (8.6 g, 34.6 mmol) in water (10 mL) at 0°C. Theprecipitated solid was collected by filtration, washed with a small amount of ice-water (5 mL), and dried in vacuo to provide Intermediate 7A (7.1 g, 33.8 mmol, 98 percent yield) as awhite solid. |
With hydrogenchloride; In water; at 0℃; | The conversion of di-tert-butyl phosphite into the corresponding phosphate is performed by a slight modification of the method published by Zwierzak and Kluba (Zwierzak, A and Kluba, M., 1971). Di-tert-butyl phosphite (40.36 mmole) is combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution is stirred in an ice bath and potassium permanganate (28.25 mmole) is added in three equal portions over one hour's time. The reaction is then allowed to continue at room temperature for an additional half hour. Decolorizing carbon (600 mg) is then incorporated as the reaction is heated to 60°C for 15 minutes. The reaction is then vacuum filtered to remove solid magnesium dioxide. The solid is washed several times with water. The filtrate is then combined with one gram of decolorizing carbon and heated at 60°C for an additional twenty minutes. The solution is again filtered to yield a colorless solution, to which a slight excess of concentrated HCl is slowly added wich efficient stirring in an ice bath. The addition of acid causes the precipitation of the di-tert-butyl phosphate free acid. The free acid is then filtered and washed with ice cold water. The compound is then converted to the salt form by dissolving the free acid in acetone and adding an equal molar amount of tetramethylammonium hydroxide while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give 7.16 grams of crude product. This product is then recrystallized by refluxing in dimethoxyethane and slow cooling at room temperature to give 6.52 g of pure product (57percent yield). 12.75 mmole of the tetramethylammonium di-tert-butyl-phosphate is then mixed with 70 ml of dimethoxyethane and brought to reflux. Twenty-five grams of chloroiodomethane is then added and stirred for one and a half hours. The reaction is then filtered and the filtrate is placed under reduced pressure to remove excess chloroiodomethane and solvent. The two products are then separated via flash column chromatography. The stationary phase is normal phase silica (30 g). The mobile phase consists of ethyl acetate and hexane in a 3 to 7 (v/v) ratio respectively. The chloromethyl di-tert-butyl phosphate is isolated as a pale gold oil (63percent yield): 1H NMR (CDCl3, 300 MHz) delta 1.51 (s, 12H), 5.63 (d, 2H, J = 14.8). Mass spectrum (FAB +, GLY) 259 (M+1). | |
With hydrogenchloride; In water;Cooling with ice; | Potassium di-tert-butyl phosphate (18.94 g, 76.28 mmol) was dissolved in water (140 ml) and cooled in an ice bath. The solution was swirled by hand and treated dropwise with concentrated HCl (28 ml), which resulted in a white precipitate. The precipitate was collected on a Buechner funnel, washed with water (70 ml), and air-dried for several minutes. In a 2 L beaker, the resulting damp powder (15.09 g) was dissolved in a mixture of barium hydroxide octahydrate (24.12 g, 76.45 mmol) in water (400 ml). Carbon dioxide (g) was bubbled through the solution resulting in copious formation of white precipitate. The mixture was filtered through Buchner funnel, and the cloudy filtrate was evaporated to give a white solid (21 g). Most of the material was dissolved in MeOH (250 ml). A white, powdery suspension was removed by filtration through Celite.(R). and the clear filtrate was evaporated to give damp white solid (20 g). The material was dissolved in MeOH (25-30 ml), and precipitated by the addition of acetone (900 ml). The white precipitate was collected on a Buchner funnel and washed with acetone to give barium di-tert-butyl phosphate as a white solid (14.60 g, 26.27 mmol). The barium di-tert-butyl phosphate was dissolved in water (100 ml), and added to a solution of silver sulfate (8.19 g, 26.27 mmol) in water (1100 ml), which resulted in formation of a white precipitate. The mixture was filtered through Celite.(R). and the clear filtrate was evaporated to give a white solid. Most of the material was dissolved in MeOH (600 ml) and a white powdery suspension was removed by filtration through Celite.(R).. The filtrate was concentrated, treated with toluene (200 ml) and evaporated to dryness to give the title compound (15.1 g, yield: 62percent).LCMS: (ESI) m/z 209 [M-Ag]. |
With hydrogenchloride; In methanol; at 0℃; | Di-tert-butyl phosphohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time. The reaction as then allowed to continue at room temperature for an additional half hour. Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C. a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the crude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16percent in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60percent yield): 1HNMR (CD3OD, 300 MHz) delta 1.51 (s, 12H), 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) delta ?11.3 (s, 1P) | |
With hydrogenchloride; In water;pH Ca. 3; | Potassium di-tert-butyl phosphate (45 g) was dissolved in water (160 mL). Hydrochloric acid (1M, aq) was added until the pH was ?3. The resultant precipitate was collected by filtration, washed with water, and dried under vacuum overnight to give di-tert-butyl phosphonic acid as a white solid. | |
With hydrogenchloride; In water; | The reaction Scheme 2 provides a reagent for preparation of a reagent of the POM prodrug moiety, which is di-tert-butyl(choloromethyl)phosphate. Briefly, potassium di-tert phosphate (5 g, 20 mmol) is dissolved in a minimum amount of cold water and 6 N HCl is added drop-wise in order to form a precipitate, and then the precipitate is washed with cold water, which is then filtered and dried under vacuum in order to form di-tert phosphate. | |
4 g | With hydrogenchloride; In water; | [095] In one embodiment, the present invention pmvides a method of preparing a reagent for use in preparing a prodrug of 6-cyclohexyl-1-hydroxy-4-methylpyridin-2(1H)-one, which method can include reaction Scheme 2 as shown in Figure 2. The reaction Scheme 2 provides a reagent for preparation of a reagent of the POM prodrug moiety, which is ditert-butyl(choloromethyl)phosphate. Briefly, potassium di-tert phosphate (5 g, 20 mmol)is dissolved in a minimum amount of cold water and 6 N HC1 is added drop-wise in order to form a precipitate, and then the precipitate is washed with cold water, which is then filtered and dried under vacuum in order to form di-tert phosphate. The di-tert-phosphate (4 g, 19 mmol) is then dissolved in about 100 mL acetone with tetramethylammonium hydmxide added drop-wise until reaching about pH 7, and then the solvent is removed anddried under vacuum to pmduce tetra-methyl ammonium di-tert-butyl phosphate. Tetramethyl ammonium di-tert-butyl phosphate (5.11 g, 18 mmol) is then reacted with iodocholoro methane (CH2CII) (25 g, 142 mmol, 7.88 equivalent) in about 150 ML DME and refluxed for about 2 hours before being filtered to remove the precipitate, removal of the solvent, and then dissolved in EA/H, and then filtered through a silica bed, and thesolvent is removed and the product is dried to obtain di-tertbutyl(choloromethyl)phosphate. A TLC is shown to confirm product. |
With hydrogenchloride; In methanol; water; at 0℃; | Di-tert-butyl phosphohite (40.36 mmole) was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution was stirred in an ice bath and potassium permanganate (28.25 mmole) was added in three equal portions over one hour's time. The reaction as then allowed to continue at room temperature for an additional half hour. (0203) Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60° C. for 15 minutes. The reaction was then vacuum filtered to remove solid magnesium dioxide. The solid was washed several times with water. The filtrate was then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution was again filtered to yield a colorless solution, which was then evaporated under vacuum to afford crude Di-tert-butyl phosphate potassium salt. Di-tert-butyl phosphate potassium salt (5 g, 20.14 mmole) was dissolved in methanol (15 g): to this solution at 0° C. a slight excess of concentrated HCl is slowly added with efficient stirring at 0° C. The addition of acid causes the precipitation of potassium chloride. The solid is then filtered and washed with methanol. The compound in the mother liquor is then converted to the ammonium form by adding an equal molar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give the crude product. To the tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane is then added 4.3 grams of chloroiodomethane (24.16 mmole) and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure to concentrate the solution in DME. The chloromethyl di-tert-butyl phosphate 12-16percent in DME is used in the synthesis of 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium without further purifications (60percent yield): 1HNMR (CD3OD, 300 MHz) delta 1.51 (s, 12H), 5.63 (d, 2H, J=14.8). 31P-NMR (CD3OD, 300 MHz) delta ?11.3 (s, 1P). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.3% | General procedure: 2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)acetic acid (1 g, 4.1 mmol) was dissolved in DCM (25 mL) and H2O(25mL), And sodium hydrogencarbonate (1.38 g, 16.4 mmol) was added thereto.with tetrabutylammonium hydrogen sulfate (0.14g,0.41 mmol).After the mixture was stirred at 0 C for 10 minutes,System Inside add chloromethyl chlorosulfonate (499 muL, 5.5 mmol)A solution of dichloromethane (5 mL).The reaction solution was stirred at room temperature for 20 hours, the reaction was completed, and the mixture was washed with brine (25 mL).Dry over anhydrous Na2SO 4 and concentrate under reduced pressure.The residue was purified by silica gel column chromatography (EtOAc /EtOAcGet titledThe compound was a colorless oil (826 mg, 69.1%). | |
94% | With potassium hydrogenphosphate trihydrate; tert-butyl methyl ether; tetra(n-butyl)ammonium hydrogensulfate; In water; at 0 - 20℃; for 2.41667h; | The compound sery433 was prepared according to published protocol (7). To a mixture of di- tert-butyl potassium phosphate (35 g, 141 mmol), KT 1P04* H;0 (127 g, 557 mmol), n- BU4NHSO4 (4 g, 1 1 mmol), H2O (125 ml) and tBuOMe (170 ml) a solution of chloromethyl chloro sulfate (35 g, 212 mmol) in tBuOVIe (35 ml) was added dropwise with continuous vigorous stirring in 25 minutes at 0 C. After the addition was completed stirring was continued for 2 hours at room temperature (the reaction mixture was cooled if internal temperature exceeded 30 C). The reaction mixture was quenched with H20 (350 ml) and tBuOMe (200 ml), the organic phase was separated, washed with aqueous 1 M K2HPO4 solution (200 ml), water (200 ml), brine (50 ml) and dried over a2S04. After sodium sulfate was filtered, n-Bu3N (3 ml) was added to the solution and the solution was concentrated under a reduced pressure to provide the product as oil (34.4 g, 94%). An additional portion of n- Bu3N (3 iTiL) was added to the product in order to increase the stability during the storage in the freezer (-21 C). |
94% | With potassium hydrogenphosphate trihydrate; tetra(n-butyl)ammonium hydrogensulfate; In tert-butyl methyl ether; water; at 0 - 30℃; for 2.41667h; | The compound sery433 was prepared according to published protocol (C. E. Muller, ?Prodrug approaches for enhancing the bioavailability of drugs with low solubility? Chem. Biodiversity 6,2071-2083 (2009); EP2133355A1 2009). To a mixture of di-tert-butylpotassium phosphate (35 g, 141 mmol), K2HPO4?3H20 (127 g, 557 mmol), n-Bu4NHSO4 (4 g,11 mmol), H20 (125 ml) and tBuOMe (170 ml) a solution of chloromethyl chlorosulfate (35 g,212 mmol) in tBuOMe (35 ml) was added dropwise with continuous vigorous stirring in 25minutes at 0 C. After the addition was completed, stirring was continued for 2 hours at roomtemperature (the reaction mixture was cooled if internal temperature exceeded 30 C). Thereaction mixture was quenched with H20 (350 ml) and tBuOMe (200 ml), the organic phasewas separated, washed with aqueous 1M K2HPO4 solution (200 ml), water (200 ml), brine(50 ml) and dried over Na2SO4. After sodium sulfate was filtered, n-Bu3N (3 ml) was added tothe solution and the solution was concentrated under a reduced pressure to provide theproduct as oil (34.4 g, 94%). An additional portion of n-Bu3N (3 mL) was added to the product in order to increase the stability during the storage in the freezer (-21C). |
90% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate; In Isopropyl acetate; water; at 35℃; for 4.75h;Large scale; | Example 2 Preparation of ditert-butyl Chloromethyl Phosphate To a mixture of potassium ditert-butyl phosphate (261 kg, 1.00 mol eq), tetra-n-butylammonium hydrogensulphate (18.5 kg, 0.05 mol eq) and sodium hydrogencarbonate (400 kg, 4.50 mol eq) in water (1150 kg) is added isopropyl acetate (1275 kg). The mixture is warmed to about 35 C. and then to this is added chloromethylchlorosulphate (313 kg, 1.80 mol eq) over about 4 hours. The mixture is further stirred for about 45 minutes, cooled to about 25 C. and then the layers separated. The organic phase is cooled to about 10 C. and washed twice with 2% w/v aqueous potassium hydrogencarbonate solution (2*800 kg) and then with a mixed 2% w/v potassium hydrogencarbonate and 20% w/v potassium hydrogencarbonate aqueous solution (640 kg). The resulting organic solution is then distilled at <100 mbar to half volume, maintaining the temperature below 45 C. The resulting mixture is filtered, washing the filter with isopropyl acetate (115 kg), to give the title compound as a solution, with typical solution strength of about 25% w/v and yield of about 90%. |
89% | With dipotassium hydrogenphosphate; tetra(n-butyl)ammonium hydrogensulfate; In tert-butyl methyl ether; water; at 23 - 28℃; for 4h;Product distribution / selectivity; | A 2L four-neck round bottom flask was equipped with a mechanical stirrer and a thermometer, potassium di-tert-butyl phosphate (100g), dipotassium hydrogenphosphate (561.2g), tetrabutylammonium hydrogen sulfate(13.7g), tert-butyl methyl ether (400mL) and water (700mL) were added and stirred under cooling with a water bath. At the internal temperature of 23 C, chloromethyl chlorosulfonate (99.7g) was added dropwise over two hours, with an internal temperature of 28 C or lower. After termination of the dropwise addition, the solution was stirred for two hours, water (300mL) was added thereto, the lower layer was separated, and the organic layer was washed with an aqueous solution of 5N sodium hydroxide (600mL) and an aqueous solution of 2M dipotassium hydrogen phosphate (600mL). The organic layer was added with N,N-diisopropyl ethylamine (10.4g) and washed with water (200mL). In addition, after adding N,N-diisopropyl ethylamine (10.4g) and washing with water (200mL), tri-n-butylamine (1.49g) was added, and the organic layer was dried over anhydrous sodium sulfate (20g). After sodium sulfate was filtered, the bath temperature was set to 35 C, the solution was concentrated under a reduced pressure, then, tri-n-butylamine (0.75g) was added thereto and mixed to obtain 92.6g of the title compound (yield: 89%). Note that according to analysis by gas chromatography, the obtained title compound contained N,N-diisopropyl ethylamine (3.1%) and tri-n-butylamine (2.0%), respectively 5.5mol% and 2.5mol% based on the raw material potassium di-tert-butyl phosphate, which was a total of 8.0mol% as tertiary amine. Furthermore, they were respectively 6.6mol% and 3.0mol% based on the obtained di-tert-butyl chloromethyl phosphate, which was a total of 9.6mol% as tertiary amine. In addition, the content (purity) immediately after the title compound was obtained was 94%, and the content (purity) after sealed storage for three weeks was at room temperature 92%. The content (purity) was calculated by 1H-NMR measurements with 4-thiomethyl acetophenone as the internal standard substance. |
85.2% | Add S.M.11 (2.50 g, 10 mmol, 1.00 eq) to a 100 mL 3-neck reaction flask.Sodium bicarbonate (3.78 g, 45 mmol, 4.50 eq), tetrabutylammonium hydrogen sulfate (169 mg, 0.5 mmol, 0.05 eq).Water (12 ml) and isopropyl acetate (14 ml) were stirred for 30 minutes, then S.M.A (2.97 g, 18 mmol, 1.80 eq) was added dropwise and the reaction was stirred for about 13 h.The reaction was stopped, the liquid was separated, and the organic phase was concentrated under reduced pressure to give 2.20 g of a colorless liquid. The recovery was 85.2%. | |
59% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate; In dichloromethane; water; at 0 - 20℃;Inert atmosphere; | To a solution of <strong>[33494-80-3]potassium di-tert-butylphosphate</strong> (2.45 g, 9.51 mmol), sodium bicarbonate (3.19 g, 38.0 mmol) and tetrabutylammonium hydrogen sulfate (340.2 mg, 0.972 mmol) in water (80 mL), was added methylene chloride (50 mL). The mixture was cooled to 0 C. and stirred vigorously under argon for 10 min. Chloromethyl chlorosulfate (1.92 g, 1.2 mL, 11.6 mmol) in methylene chloride (30 mL) was added slowly and the reaction was stirred at room temperature overnight. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate and concentrated to give di-tert-butyl chloromethyl phosphate as a colorless oil (1.46 g, 59% yield). |
With sodium carbonate;tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; at 18℃; for 4.5h; | The following ingredients were combined in a vented glass reactor (C4H9)4NHSO4 (0.05 eq) (catalyst) Na2CO3 (4.00 eq) (base) KOP(O)(OtC4H9)2 (1.00 eq) (reactant B) Water was added to bring the aqueous volume to 7.5 mL per gram activity of input. CH2Cl2 was added as a solvent (7.5 mL per gram activity of input). To the resulting reaction mixture maintained at about 18 C. was added chloromethyl chlorosulfate (2.00 eq) and the reaction mixture was agitated vigorously for 4.5 hours at 18 C. The reaction was worked up as follows. Water was added to the reaction mixture (12 mL per gram activity of input) and the solution was stirred to dissolve the solids. The resulting organic and aqueous phases were separated and the spent aqueous phase was then backwashed with CH2Cl2 (about 2 mL per gram activity input). The phases were separated and the organic splits were combined and the aqueous volume recorded. The aqueous phase was sampled to quantify the unreacted starting material via 31P NMR. The rich organic phase was washed with water (7.5 mL per gram activity input) and the phases were separated so that the rich organic phase was free of water. The rich organic phase was distilled (moderate vacuum, 20 C. jacket) to remove CH2Cl2 and obtain the product rich oil. The weight of product oil was recorded and potency was obtained by sampling for 31P NMR. The productivity was reported as M % activity yield. The product oil was stored in the freezer (?5 C.). An 11.0 g (activity) input reaction yielded 11.3 g of product oil with a potency of 91.9% (via 31P NMR int. std.). This gives an M % activity yield to product of 90.9%. The unreacted starting material in the reaction aqueous phase was 3.3M % (via 31P NMR int. std.). 1H NMR revealed about 5 mol % residual (C4H9)4NHSO4 present in the product oil. | |
With sodium hydrogencarbonate;tetra(n-butyl)ammonium hydrogensulfate; In dichloromethane; water; at 0 - 20℃; | STEP A: Synthesis of phosphoric acid di-tert-butyl ester chloromethyl ester; 1. EPO <DP n="11"/>According to a literature procedure (Tetrahedron Letters; 2002, 43, 3793), compound 1 was prepared as follows: Potassium di-tert-butyl phosphate (6.35 g), tetra-n-butylammonium hydrogen sulphate (917 mg) and sodium bicarbonate (8.96 g) were dissolved in water (230 ml_). Dichloromethane was added (130 ml.) and the resulting mixture was cooled down to 0 0C. A solution of chloromethylchlorosulphate (917 mg) in dichloromethane (100 ml.) was slowly added under vigorous stirring. The reaction mixture was allowed to reach room temperature and further stirred overnight at this temperature. The organic layer was then separated, washed with brine (50 ml_), dried over Na2SO4 and concentrated under vacuum. The desired product 1 was obtained as a colourless oil (2.4 g).Phosphoric acid di-tert-butyl ester chloromethyl ester 1. Colourless oil, 1H-NMR (CDCI3) delta 5.65 (d, J = 15.0 Hz, 2H), 1.52 (s, 18H); 13C-NMR (CDCI3) delta 84.2 (d, J = 7.6 Hz), 73.3 (d, J = 6.9 Hz), 29.8 (d, J = 4.3 Hz); 31 P-NMR (CDCI3) delta -11.8. | |
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate; In dichloromethane; water; at 5 - 20℃; for 18.8333h; | Intermediate 60: Chloromethyl bis(1,1-dimethylethyl) phosphate; To a solution of bis(1 ,1-dimethylethyl) hydrogen phosphate potassium salt (for a preparation see Intermediate 59)(109.7 g, 442 mmol) in water (500 ml) was added sodium bicarbonate (148 g, 1767 mmol) and tetrabutylammonium hydrogen sulfate (15.00 g, 22.09 mmol). To this mixture was added dichloromethane (500 ml) and the reaction mixture was cooled to 5 0C. A solution of chloromethyl chloridosulfate (91 g, 552 mmol, Apollo Scientific) in dichloromethane (500 ml) was then added dropwise over 50 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The two phases were separated and the aqueous phase was extracted using DCM (250 ml). The combined organics were washed with brine (4 x 200 ml) and dried over sodium sulphate. The solvent was removed in vacuo to give a liquid. This was redissolved in DCM (250 ml) and washed with water (2 x 150 ml). The organic phase was dried over sodium sulphate and evaporated in vacuo to give the title compound as a liquid (68.2 g); 1H NMR (CDCI3) delta 5.64 (2 H, d, J=15 Hz), 1.52 (18 H, s). | |
Example 1A. Preparation of di-tert-butyl Chloromethyl PhosphateProcedure IPreparation of Stabilized di-tert-butyl Chloromethyl PhosphatePreparation of di-tert-butyl chloromethyl phosphate, has been described in the literature, such as in Mantyla, et al. Tetrahedron Letters, 43 (2002), 3793-3794 and Chadwick, et al. US 2006/0047135. We have found improvements to these processes whereby the yield is increased, with high purity, and the di-tert-butyl chloromethyl phosphate is stabilized via exposure to an amide. The specific example below illustrates this aspect of the invention.Surprisingly, it was found that di-tert-butyl chloromethyl phosphate could be synthesized in excellent yield (>90%) and purity (>99%) by dosing 2.5 eq. CMCS to a two phase mixture of PDP and phase transfer catalyst TBAHS in DCM/water and adjusting pH value to 8 at the same time by addition of 20% aqueous NaOH. Additionally it was found, that the stability of di-tert-butyl chloromethyl phosphate was tremendously enhanced and no auto catalytic decomposition behaviour was observed by preparation of a 30 w % solution in dimethylacetamide (DMAc).Description of the Process:Di-tert-butyl chloromethyl phosphate was synthesized using a TBAHS phase transfer catalysed reaction of PDP in DCM/H2O with 2.5 eq. CMCS at 18 C. The pH was monitored and adjusted to 8 by addition of 20% aqueous NaOH. The DCM was removed at 20 C. and a pH>7 at reduced pressure (recycling of DCM). To the crude di-tert-butyl chloromethyl phosphate was added MtBE, and the TBASHS was removed by washing the MtBE layer with 2% aqueous bicarbonate solution. To stabilize the di-tert-butyl chloromethyl phosphate, DMAc was added, and then the MtBE was distilled off. The yield was >90% based on PDP starting material. The purity of di-tert-butyl chloromethyl phosphate in DMAc according to 1H-NMR>99% | ||
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate; In dichloromethane; water; at 0 - 20℃; | The following compound was synthesized: (0206) . (0207) A slurry of NONOate salt I (200 mg, 1.29 mmol) and sodium carbonate (205 mg, 1.93 mmol) were suspended in 3 mL of tetrahydrofuran and cooled to 0 C. Di-tert-butyl chloromethyl phosphate (500 mg, 1.93 mmol) was added, followed by the addition of 2.5 mL N,N-dimethylformamide and sodium iodide (290 mg, 1.93 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was concentrated on a rotary evaporator, treated with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated. The resulting mixture was dissolved in a minimum amount of dichloromethane and purified using column chromatography (biotage, SiO2, ethyl acetate/hexane gradient) (0208) The structure of the compound was confirmed using 1HNMR. (0209) Yield: 32.44 mg (7%) (0210) (0211) Potassium ditertiarybutyl phosphate (2 g, 8 mmol), tetra-n-butylammonium hydrogen sulfate (0.28 g, 0.8 mmol) and sodium bicarbonate (2.6 g, 30.90 mmol) were dissolved in water (100 mL). Dichloromethane was added (100 mL) and the resulting mixture was cooled down to 0 C. A solution of chloromethylchlorosulfate (1.6 g, 9.70 mmol) in dichloromethane (100 mL) was slowly added under vigorous stirring. The reaction mixture was allowed to reach room temperature and further stirred overnight at this temperature. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuuo to give the product. (0212) The structure of the compound was confirmed using LC/MS. (0213) Product was used directly without purification. (0214) Yield: 1.2 g (57.6%) | |
With n-butylammonium sulfate; sodium hydrogencarbonate; In dichloromethane; water; at 20℃; for 2h; | A 100 mL round bottomed flask was charged with potassium ditert-butyl phosphate (1.0 g, 4.03 mmol), sodium bicarbonate (677.4 mg, 8.06 mmol), n-butylammonium sulfate (68.2 mg, 0.403 mmol), water (10 ml) and methylene chloride (5 ml). To the mixture was added a solution of chloromethylchlorosulfonate (797.9 mg, 4.84 mmol) in methylene chloride (5 ml), and the mixture stirred at room temperature for 2 hours. To the reaction product was added water (30 ml), and the whole was extracted with methylene chloride (30 ml*3). The combined organic layers were washed with brine (30 ml), dried with Na2SO4, and solvent removed under reduced pressure. The residue was purified by column-chromatography (silica gel=80 g, hexane/ethyl acetate=1:1) to give di-t-butyl chloromethyl phosphate, as a colorless oil. | |
With sodium hydrogencarbonate; tetra-n-butylammonium hydrogen sulfate; In dichloromethane; water; at 20℃; for 2h; | Step 1 - Preparation of di-f-butyl chloromethyl phosphate[0243] A 100 mL round bottomed flask was charged with potassium ditert-butyl phosphate (1.0 g, 4.03 mmol), sodium bicarbonate (677.4 mg, 8.06 mmol), n- butylammonium sulfate (68.2 mg, 0.403 mmol), water (10 ml) and methylene chloride (5 ml). To the mixture was added a solution of chloromethylchlorosulfonate (797.9 mg, 4.84 mmol) in methylene chloride (5 ml), and the mixture stirred at room temperature for 2 hours. To the reaction product was added water (30 ml), and the whole was extracted with methylene chloride (30 ml x 3). The combined organic layers were washed with brine (30 ml), dried with Na2SO4, and solvent removed under reduced pressure. The residue was purified by column-chromatography (silica gel = 80 g, hexane/ethyl acetate = 1: 1) to give di-?-butyl chloromethyl phosphate, as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 14Compound 14: To a stirring solution of compound 10 (0.10 gram, 0.20 mmol) and triphenylphosphine (PL-TPP (Polymer Laboratories): 0.18 gram, 0.70 mmol) in THF (5 mL) was slowly added NBS (0.12 gram, 0.70 mmol). Reaction was stirred at room temperature for 1.5 hours then NaI (0.006g, 0.04 mmol) was added followed by di- tertbutyl phosphate, potassium salt (Digital Specialty, 0.20Og, 0.79 mmol). Reaction was heated to 55 °C and a slurry resulted. An additional amount of THF (2 mL) was added and the reaction was heated for 3.5 hours. Filtered the reaction mixture and washed resin with CH2CI2 and concentrated to a yellow oil. The oil was partitioned between CH2CL and aqueous sodium bicarbonate then dried over MgSO.. Triturated solid with hexane/MTBE and filtered light orange colored solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 0.85 (d, J=6.2 Hz, 3 H), 1.09 (d, J=6.1 Hz, 3 H), 1.24 (d, J=4.9 Hz, 18 H), 1.39 (s, 18 H), 3.05 (m, 2 H), 3.47 (d, J=14.8 Hz, 1 H), 3.59 (dd, J=8.3, 6.2 Hz, 1 H), 3.74.(m, 1 H), 3.94 (d, J=8.4 Hz, 1 H), 4.06 (dd, J=13.2, 1.5 Hz, 1 H), 5.30 (m, 1 H), 5.40 (m, 1 H), 5.55 (m, 2 H), 7.32 (d, J=7.0 Hz, 1 H), 8.49 (d, J=2.5 Hz, 1 H), 8.63 (m, 1 H), 8.90 (s, 1 H); MS(APCI+) m/z 888 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydrogencarbonate; In dichloromethane; water; | A 100 mL round bottomed flask was charged with potassium ditert-butyl phosphate (1.0 g, 4.03 mmol), sodium bicarbonate (677.4 mg, 8.06 mmol), n-butylammonium sulfate (68.2 mg, 0.403 mmol), water (10 ml) and methylene chloride (5 ml). To the mixture was added a solution of chloromethylchlorosulfonate (797.9 mg, 4.84 mmol) in methylene chloride (5 ml), and the mixture stirred at room temperature for 2 hours. To the reaction product was added water (30 ml), and the whole was extracted with methylene chloride (30 ml*3). The combined organic layers were washed with brine (30 ml), dried with Na2SO4, and solvent removed under reduced pressure. The residue was purified by column-chromatography (silica gel=80 g, hexane/ethyl acetate=1:1) to give di-t-butyl chloromethyl phosphate, as a colorless oil. Step 2-Preparation of di-tert-butyl (4-(7-((2-(3-fluoro-5-(trifluoromethyl)phenyl)oxazol-4-yl)methoxy)-4-oxo-4H-chromen-3-yl)phenoxy)methyl Phosphate |
Yield | Reaction Conditions | Operation in experiment |
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To the inerted reactor, di-tert-butyl potassium phosphate (1.69 kg), 4.0 eq. of sodium carbonate and 0.05 eq of tetrabutyl ammonium hydrogen sulfate were added through the manway. Methylene chloride(7.7 L/kg) was then pumped through the sprayball to wash down the reactor walls. With the jacket temperature below 10° C., the exothermic water charge was added over the course of ten minutes (7.6 L/kg). The associated exotherm was minor with a batch temperature rising from 11.1 to 16.2° C. over the course of the addition. With the jacket and batch temperature near 7 and 15° C., respectively, 2.0 eq. of chloromethylsulfonylchloride (CMCS) was charged via addition funnel. The charge continued for 2 hours while the jacket temperature was slowly raised to 20° C. during the charge. The maximum batch temperature during the CMCS charge was 25.3° C. The jacket temperature was slowly raised during the charge to ensure that the exotherm started as preliminary laboratory data indicated that the exotherm may be slowed at lower batch temperatures. The reaction mixture was agitated and after 3.5 hours, an NMR sample indicated that the reaction had progressed 72percent. The reaction was allowed to proceed overnight with a batch temperature between 19.7 and 23.6° C. (Delta V historian). An NMR sample taken after 16 hours indicated a reaction conversion of 76percent. Laboratory batches ranged in conversion from 60 to 80percent. Work-Up After the reaction was deemed complete, additional water at 9.3 L/kg was added to the batch to affect a phase split. The product rich lower phase was transferred to a carboy and the upper aqueous phase was sent to waste. A small rag layer was kept with the product rich organic. The organic phase was returned to R-1A and additional water at 5.1 L/kg was added as a wash. The phases were split with the product rich organic, approximately 18.5 kg, being sent to a carboy while the upper aqueous phase was sent to waste. No rag layer or solids were observed in the second split. However, it is recommended to polish filter the product rich organic to remove precipitated salts. Methylene Chloride Distillation The product rich organic was transferred to the rotovap bowl of EVAPO-1A. Distillation of the methylene chloride was initiated with a jacket temperature of approximately 22° C. The distillation rate slowed after 4.5 hours and a batch sample was taken to analyze the methylene chloride content. NMR analysis indicated a 4:1 ratio of di-tert-butyl chloromethyl phosphate to methylene chloride. Typical laboratory results of this stream would indicate a 10:1 ratio so the distillation was continued with an increase in the rotovap jacket temperature. After an additional 2.5 hours, the distillation rate stopped. An NMR sample of the batch indicated that the ratio had increased to 5:1 di-tert-butyl chloromethyl phosphate to methylene chloride. The maximum rotovap jacket temperature was 28.4° C. Purity of the di-tert-butyl chloromethyl phosphate oil NMR analysis of the di-tert-butyl chloromethyl phosphate oil indicated the potency to be greater than 100percent. Development work typically produced material with a potency of 100+/-10percent. Karl-Fischer analysis measured water content at 0.02 wt percent and GC analysis measured methylene chloride at 10.69 wt percent. Thus, the reported potency is 89.29 wt percent accounting for the methylene chloride and water contribution in the oil. Storage of di-tert-butyl chloromethyl phosphate The di-tert-butyl chloromethyl phosphate oil was placed in cold room and the temperature was monitored with a stripchart recorder. Laboratory batches were typically held between 0 to 5° C. An NMR of the product after the 104 hour hold in the cold room indicated that the material had not lost potency. (Safety testing conducted during the campaign indicates that upon holding the oil self-heats with a subsequent pressure build-up). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; at 70℃; for 2h; | Step 1 : Synthesis of methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate[00109] To a stirred solution of methyl-3-(bromomethyl)benzoate (0.5 g, 2 mmol) in THF (10 mL) was added potassium ditertiary butyl phosphate (0.5 g, 2 mmol). The reaction flask was heated to 70 °C for 2 h. After the flask was cooled to rt, EtOAc (50 mL) was added to the mixture. The organics were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to yield methyl 3-((di-tert- butoxyphosphoryloxy)methyl)benzoate (0.35 g, 0.9 mmol). 3/4 NMR (400MHz, CHC13- d): delta 1.47 (s, 18H), 3.91 (s, 3H), 5.03 (d, 2H, J=7.6 Hz), 7.44 (t, J= 7.6 1H), 7.60 (dd, J = 1.2 and 7.2), 7.98 (ddd, J= 1.2, 2.8 and 7.6, 1H), 8.05 (t, J= 0.4, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h; | 2,6-Dichloro-N-[4-(1-chloromethyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-benzamide from the previous step was dissolved in 50 mL DMF. Potassium carbonate (1 g) was added followed by potassium di(t-butyl)phosphate (2 g) and tetrabutylammonium iodide (50 mg). The mixture was stirred at 70 C. for four hours after which it was poured into 300 mL ethyl acetate. The organic phase was washed with water and brine, dried with magnesium sulfate and evaporated under vacuum. The crude product was further purified by silica gel chromatography (eluent: ethyl acetate), giving phosphoric acid di-tert-butyl ester 4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-1-ylmethyl ester as a colorless oil which slowly crystallized. | |
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h; | 2,6-Dichloro-N-[4-(l-chloromethyl-2-oxo-l,2-dihydro-pyridin-4-yl)-benzyl] -benzamide from the previous step was dissolved in 50 mL DMF. Potassium carbonate (lg) was added followed by potassium di(t-butyl)phosphate (2g) and tetrabutylammonium iodide (50mg). The mixture was stirred at 70 C for four hours after which it was poured into 300 mL ethyl acetate. The organic phase was washed with water and brine, dried with magnesium sulfate and evaporated under vacuum. The crude product was further purified by silica gel chromatography (eluent: ethyl acetate), giving phosphoric acid di-tert-butyl ester 4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-l- ylmethyl ester as a colorless oil which slowly crystallized. |
Yield | Reaction Conditions | Operation in experiment |
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54% | In N,N-dimethyl-formamide; at 60℃; for 6h; | To a solution of chiral 2-iodoethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 11, 20 mg, 0.026 mmol) in dimethyl formamide (2 mL) was added <strong>[33494-80-3]potassium di-tert-butylphosphate</strong> (Accela ChemBio, 21.8 mg, 0.088 mmol). The reaction mixture was heated at 60° C. for 6 h. The mixture was diluted with ethyl acetate, washed with water and then brine, dried over anhydrous sodium sulfate and concentrated. The crude material was purified by flash chromatography to give chiral 2-(di-tert-butoxyphosphoryloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (12 mg, 54percent yield). MS (ES+) m/z calcd. for C41H50Cl2F2N3O8PNa: [(M+Na)+]: 874. found: 874 |
Yield | Reaction Conditions | Operation in experiment |
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40% | Step 2) Di-tert-butyl 1-chloroethyl phosphate To a solution of <strong>[33494-80-3]potassium di-tert-butylphosphate</strong> (33 g, 133 mmol) in CH2Cl2/H2O (600 mL/600 mL) were added NaHCO3 (44.6 g, 531 mmol) and TBAHSO4 (4.52 g, 13.3 mmol), and then the mixture was stirred at 0° C. for 10 min. Then a solution of 1-chloroethyl sulfochloridate (26 g, 146 mmol) in CH2Cl2 (100 mL) was added dropwise over 30 min to the reaction mixture. The mixture was stirred further at room temperature for 20 h. The organic layer was separated, and then washed with water (300 mL*3) and brine (300 mL). Then it was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give light yellow oil (14.3 g, 40percent). The title compound was characterized by 1H NMR as shown below: 1H NMR (400 MHz, CDCl3): delta 1.52 (s, 18H), 1.81 (d, J=5.6 Hz, 3H), 6.17-6.24 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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30% | With sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere; | Methyl4-(bromomethyl)benzoate (1200 mg, 5.24 mmol), potassium di-tertbutylphosphate (1431 mg, 5.76 mmol) and sodium iodide (785 mg, 5.24 mmol) werecombined in DMF (3.00 mL) under nitrogen. The reaction mixture was stirred at roomtemperature for 24 h. The reaction mixture was diluted with ether, washed with 10percentLiCl solution and brine, then dried (MgS04), filtered and concentrated in vacuo. The10 residue was purified by silica gel chromatography (hexane/EtOAc) to provide Preparation55A (571 mg, 1.593 mmol, 30percent): 1H NMR (400MHz, CDCb) 8 8.03 (d, J=8.4 Hz, 2H),7.53-7.37 (m, 2H), 5.05 (d, J=7.5 Hz, 2H), 3.92 (s, 3H), 1.48 (d, J=0.4 Hz, 18H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 45℃; | A mixture of benzyl 4-((chloromethoxy)carbonyloxy)-4-(2- methylallyl)piperidine-l -carboxylate 62C (382 mg, 1.0 mmol) and potassium di-tert- butyl phosphate (496 mg, 2 mmol) in DMF (15 raL) was stirred at 45°C overnight. The solvent was removed under reduced pressure and the residue was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over Na2S04 and concentrated, then purified by standard methods to afford 62D. LC- MS: m/z 556.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80 mg | In N,N-dimethyl-formamide; at 75℃; for 1.25h;Microwave irradiation; | To a stirred solution of chloromethyl (6-chloro[1,2,4]triazolo[1,5-u]pyridin- 2-yl)[2-methoxy-4-(methylsulfonyl)phenyl]carbamate (200 mg) in DMF (6.0mL) was added potassium di-tert-butyl phosphate (278 mg) and the mixture was heated to 75°C for 75 minutes in a microwave oven. Water was added, the mixture was extracted with ethyl. acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silicagel chromatography gave 80 mg of the titlecompound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.7% | A solution of 2-(4-fluorophenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide (18a) (98 mg, 0.2498 mmol) and chloromethyl chloroformate (38.66 mg, 26.39 muL, 0.2998 mmol) in CH2Cl2 (1 mL) and DMF (100 muL) was stirred at room temperature for 4 hours (gas evolved). The reaction mixture was diluted with EtOAc and the organic phase washed with sat. aq. NaHCO3, brine, dried with Na2SO4 and evaporated to dryness. The residue was taken up in DMF (1 mL), <strong>[33494-80-3]di-tert-butoxyphosphoryloxypotassium</strong> (124.0 mg, 0.4996 mmol) and tetrabutylammonium iodide (9.227 mg, 0.02498 mmol) were added and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic layers were combined, washed with water then brine, dried with Na2SO4 and evaporated to dryness. Purification by column chromatography (4 g silica; 0-100percent EtOAc in Hx) gave di-tert-butyl [4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (22) (67 mg, 0.1090 mmol, 43.7percent) as a clear oil. ESI-MS m/z calc. 614.1805, found 615.5 (M+1)+; Retention time: 0.73 minutes |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.6% | To a solution of 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-5-(trifluoromethyl)benzamide (10a) (102 mg, 0.2510 mmol) and chloromethyl chloroformate (77.67 mg, 52.30 muL, 0.6024 mmol) in CH2Cl2 (2 mL) was added DMF (200 muL) and the reaction mixture was stirred at room temperature for 1 hour. At this time, more chloromethyl chloroformate (77.67 mg, 52.30 muL, 0.6024 mmol) was added and the reaction mixture was heated to 70° C. for 25 min. The reaction mixture was diluted with EtOAc, the organic phase washed with sat. aq. NaHCO3, brine, dried with Na2SO4 and evaporated to dryness. The residue was taken up in DMF (3 mL), <strong>[33494-80-3]di-tert-butoxyphosphoryloxypotassium</strong> (249.3 mg, 1.004 mmol) and tetrabutylammonium iodide (9.271 mg, 0.02510 mmol) were added and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic layers were combined, washed with water then brine, dried with Na2SO4 and evaporated to dryness. Purification by column chromatography (12 g silica; 0-100percent EtOAc in Hx) gave di-tert-butyl [4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (24) (23 mg, 0.03659 mmol, 14.6percent) as a clear glass. ESI-MS m/z calc. 628.19617, found 629.5 (M+1)+; Retention time: 0.78 minutes |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | To a solution of 4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide (1a) (101 mg, 0.2386 mmol) and chloromethyl chloroformate (36.92 mg, 24.86 muL, 0.2863 mmol) in CH2Cl2 (2 mL) was added DMF (200 muL) and the reaction mixture was stirred at room temperature for 1 hour. At this time, THF (1 mL) was added followed by more chloromethyl chloroformate (36.92 mg, 24.86 muL, 0.2863 mmol) and the reaction mixture stirred at room temperature for 1 h. More DMF (1 mL) and chloromethyl chloroformate (36.92 mg, 24.86 muL, 0.2863 mmol) was added and the reaction mixture was heated to 70° C. for 15 min. The reaction mixture was diluted with EtOAc and the organic phase washed with sat. aq. NaHCO3, brine, dried with Na2SO4 and evaporated to dryness. The residue was taken up in DMF (1.010 mL), <strong>[33494-80-3]di-tert-butoxyphosphoryloxypotassium</strong> (118.5 mg, 0.4772 mmol) and tetrabutylammonium iodide (8.813 mg, 0.02386 mmol) was added and the reaction mixture stirred at 70° C. for 4 h. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic layers were combined, washed with water then brine, dried with Na2SO4 and evaporated to dryness. Purification by column chromatography (12 g silica; 0-100percent EtOAc in Hx) gave di-tert-butyl [4-[[4,5-dichloro-2-(4-fluoro-2-methoxy-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (25) (40 mg, 0.06197 mmol, 26.0percent) as a clear glass. ESI-MS m/z calc. 644.12573, found 647.3 (M+1)+; Retention time: 0.81 minutes |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.8% | Example 15G Preparation of N-[1-(chloromethyl)-2-oxo-4-pyridyl]-2-(4-fluoro-2-methyl-phenoxy)-4-(trifluoromethyl)benzamide (21) A solution of 2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (2a) (99.9 mg, 0.2115 mmol) and chloromethyl chloroformate (32.73 mg, 22.04 muL, 0.2538 mmol) in DCM (900 muL) and DMF (100 muL) was stirred at room temperature for 4 hours (gas evolved). The reaction mixture was diluted with EtOAc, the organic phase washed with sat. aq. NaHCO3, brine, dried with Na2SO4 and evaporated to dryness. The residue was taken up in DMF (999 muL), <strong>[33494-80-3]di-tert-butoxyphosphoryloxypotassium</strong> (105.0 mg, 0.4230 mmol) and tetrabutylammonium iodide (7.81 mg, 0.021 mmol) were added and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3*). The organics were combined, washed with water then brine, dried with Na2SO4 and evaporated to dryness. Purification by column chromatography (4 g silica; 0-100percent EtOAc in hexanes) gave di-tert-butyl[4-[[2-(4-fluoro-2-methoxy-phenoxy)-4-(1,1,2,2,2-pentafluoroethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (21) (35 mg, 0.05039 mmol, 23.8percent) as a clear oil. ESI-MS m/z calc. 694.18787, found 695.4 (M+1)+; Retention time: 0.78. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.2% | A solution of 4-chloro-2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)benzamide (13a) (99 mg, 0.2656 mmol) and chloromethyl chloroformate (82.19 mg, 55.35 muL, 0.6374 mmol) in THF (2 mL) was added DMF (0.2 mL) and CH2Cl2 (0.5 mL) and was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and the organic phase washed with sat. aq. NaHCO3, brine, dried with Na2SO4 and evaporated to dryness. The residue was taken up in DMF (1 mL), <strong>[33494-80-3]di-tert-butoxyphosphoryloxypotassium</strong> (263.7 mg, 1.062 mmol) and tetrabutylammonium iodide (9.810 mg, 0.02656 mmol) were added and the reaction mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled, diluted with water and extracted with EtOAc (3×). The organic phases were combined, washed with water then brine, dried with Na2SO4 and evaporated to dryness. Purification by column chromatography (12 g silica; 0-100percent EtOAc in Hx) gave di-tert-butyl [4-[[4-chloro-2-(4-fluoro-2-methyl-phenoxy)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate (23) (35 mg, 0.05882 mmol, 22.2percent) as a clear foam. ESI-MS m/z calc. 594.1698, found 595.5 (M+1)+; Retention time: 0.77 minutes |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With tetra-(n-butyl)ammonium iodide; In ethyl acetate; at 41 - 71℃; for 4.16667h;Inert atmosphere; Large scale; | To a 50 liter jacketed glass reactor fitted with an N2 inlet and a mechanical stirrer, and with a jacket temperature set at 41° C., was added N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (1199.5 g, 2.64 moles, 1.0 eq) under nitrogen. Ethyl acetate (12 liters) was added with stirring to produce a suspension. To the mixture was added <strong>[33494-80-3]potassium di-tert-butylphosphate</strong> (792.7 g95percent purity, 3.03 moles, 1.15 eq), then TBAI (9.7 g, 0.026 moles, 0.01 eq), and the jacket temperature was ramped to 71° C. over 20 minutes. The resulting gelatinous suspension was stirred for 4.5 hours at which point HPLC analysis indicated that the reaction was complete. The jacket temperature was ramped to 30° C. over 15 minutes, and then water (6 liters) was added with stirring. The aqueous layer was drained off, and then the organic layer was washed twice with water (1×3.6 liters, then 1×2.4 liters). The organic layer was concentrated down to 3.0-3.5 volumes at 40° C. using a rotovap. Heptane (1.8 liters) was added as an antisolvent, and then the bath heater of the rotovap was turned off, and the mixture was allowed to cool to room temp and was stirred at 40 rpm overnight. The solids were collected by filtration, rinsed with heptanes (1.2 liters), and then dried in vacuo at 45° C. to give 1417.7 g (88percent) of di-tert-butyl((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl) phosphate (20) as a crystalline, light amber solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.3% | In N,N-dimethyl-formamide; at 80℃; | (a) di-tert-butyl (2-hydroxyethyl) phosphate To a solution of di-tert-butyl hydrogen phosphate, potassium salt (15 g, 60.2 mmol, Aldrich) in DMF (100 ml_), 2-bromoethanol (7.52 g, 60.2 mmol, Aldrich) was added. The resulting mixture was heated at 80 °C overnight. The reaction was poured into water (250 ml.) and extracted with EtOAc (3 x 250 ml_). The organic layer was dried over Na2S04, filtered, concentrated under reduced pressure and the residue was purified by flash column chromatography (0-5percent MeOH/DCM) to afford desired di-tert-butyl (2-hydroxyethyl) phosphate as a colorless oil (8g, 52.3percent). *H NMR (400 MHz, DMSO-d6) delta: 4.83 - 4.77 (1H, m), 3.86 - 3.80 (2H, m), 3.58 - 3.51 (2H, m), 1.42 (18H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra-(n-butyl)ammonium iodide; at 60℃; for 12h; | The resulting chloride (34 mg, 0.057 mmol) was combined with ditert-butyl phosphate, potassium salt (28 mg, 0.11 mmol) and tetrabutylammonium iodide (2.0 mg, 0.006 mmol) and stirred at 60 °C for 12 h. The reaction contents were then diluted with EtOAc, washed with water, brine and dried over magnesium sulfate. The crude product was purified via silica gel chromatography (eluent: EtOAc / hexanes) to yieldthe desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of anlel 38b (1 g, 2.9 mmol) and pyridine (0.276 g, 3.5 mmol) in DCM (10 ml) a solution of cliloromethyl chioro formate (0.452 g, 3.5 mmol) in DCM (5 ml) was added in 10 minutes with continuous vigorous stirring at room temperature. After stirring at room temperature for 2 h reaction mixture was diluted with DCM (20 ml), the organic phase was washed with water (2x30 ml), brine and concentrated under a reduced pressure. The resulting residue was recrystallized from acetonitrile to provide sery463 (0.85 g, 67percent) as a white solid. Sery463 is the mixture of isomers in ratio 2:3 (1H NMR). A mixture of sery463 (0.8 g, 1 .84 mmol), Nal (0.413 g, 2.76 mmol) in acetone (15 ml) was stirred for 3 days at 40°C and then concentrated under a reduced pressure. The residue was dissolved in DCM (30 ml), the organic phase was washed with water (20 ml), aqueous 1M 'Na2S20.i solution (20 ml), brine and dried over Na2S04. After sodium sulfate was filtered the solution was concentrated under a reduced pressure and the resulting mixture was purified by column chromatography on silica gel (EtOAc:hexane, 1 :3 v/v) to provide sery470 (0.73 g, 75percent) as a solid. Sery470 is the mixture of isomers in ratio 1 : 1 .2 ( NMR). TLC (EtOAc:hexane, 1 :3 v/v): RF = 0.55. A mixture of sery470 (53 mg. 0.1 mmol), <strong>[33494-80-3]di-tert-butylphosphate potassium salt</strong> (42 nig. 0.2 mmol) and Ag20 (24 mg, 0.1 mmol) in acctonitrilc (3 ml) was stirred for 2 hours at room temperature. Then insoluble material was filtered off and the solid was washed on the filter with acctonitrilc (2 ml). The combined organic solution was concentrated under reduced pressure and a resulting oil was purified by column chromatography on silica gel (EtOAcrhexane, 1 :2 v/v) to provide sery473 (45 mg, 74percent) as an oil. Sery473 is the mixture of isomers in ratio 1 : 1 .2 ( NMR). TLC (EtOAc:hexane, 1 :2 v/v): RF = 024. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a mixture of anlel 38b (1 g, 2.9 mmol) and pyridine (0.276 g, 3.5 mmol) in DCM (10 ml) a solution of cliloromethyl chioro formate (0.452 g, 3.5 mmol) in DCM (5 ml) was added in 10 minutes with continuous vigorous stirring at room temperature. After stirring at room temperature for 2 h reaction mixture was diluted with DCM (20 ml), the organic phase was washed with water (2x30 ml), brine and concentrated under a reduced pressure. The resulting residue was recrystallized from acetonitrile to provide sery463 (0.85 g, 67percent) as a white solid. Sery463 is the mixture of isomers in ratio 2:3 (1H NMR). A mixture of sery463 (0.8 g, 1 .84 mmol), Nal (0.413 g, 2.76 mmol) in acetone (15 ml) was stirred for 3 days at 40°C and then concentrated under a reduced pressure. The residue was dissolved in DCM (30 ml), the organic phase was washed with water (20 ml), aqueous 1M 'Na2S20.i solution (20 ml), brine and dried over Na2S04. After sodium sulfate was filtered the solution was concentrated under a reduced pressure and the resulting mixture was purified by column chromatography on silica gel (EtOAc:hexane, 1 :3 v/v) to provide sery470 (0.73 g, 75percent) as a solid. Sery470 is the mixture of isomers in ratio 1 : 1 .2 ( NMR). TLC (EtOAc:hexane, 1 :3 v/v): RF = 0.55. A mixture of sery470 (53 mg. 0.1 mmol), <strong>[33494-80-3]di-tert-butylphosphate potassium salt</strong> (42 nig. 0.2 mmol) and Ag20 (24 mg, 0.1 mmol) in acctonitrilc (3 ml) was stirred for 2 hours at room temperature. Then insoluble material was filtered off and the solid was washed on the filter with acctonitrilc (2 ml). The combined organic solution was concentrated under reduced pressure and a resulting oil was purified by column chromatography on silica gel (EtOAcrhexane, 1 :2 v/v) to provide sery473 (45 mg, 74percent) as an oil. Sery473 is the mixture of isomers in ratio 1 : 1 .2 ( NMR). TLC (EtOAc:hexane, 1 :2 v/v): RF = 024. A mixture of sery473 (10 mg), TFA (20 trig) in deuteraled chloroform (0.7 ml) was placed in the NMR tube and the reaction progression was monitored by NMR. After 6 h incubation at room temperature the spectrum demonstrated the reaction completion, the aqueous workout under neutral conditions resulted in decomposition of sery474 leading to formation of anle 138b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Di-tert-butyl phosphite (40.36 mmole)Was combined with potassium bicarbonate (24.22 mmole) in 35 ml of water.The solution was stirred in an ice bath and potassium permanganate (28.25 mmole)Was added in three equal portions over 1 hour.Thereafter, the reaction was continued at room temperature for an additional 0.5 hour.Thereafter, decolorizing carbon (600 mg)The reaction was taken up when heated to 60 ° C. for 15 minutes.Thereafter, the reaction product was subjected to vacuum filtration to remove manganese dioxide as a solid component.The solid was washed several times with water. The filtrate was then combined with 1 gram of decolorizing carbon and heated at 60 ° C. for a further 20 minutes. The solution was again filtered to give a colorless solution which was then evaporated under vacuum to provide the crude <strong>[33494-80-3]di-tert-butyl phosphate potassium salt</strong>.Dissolve <strong>[33494-80-3]di-tert-butyl phosphate potassium salt</strong> (5 g, 20.14 mmole) in methanol (15 g) and add a slight excess of concentrated HCl to this solution at 0 ° C. while slowing the efficiency Stirring was carried out. The addition of acid causes the precipitation of potassium chloride. The solids are then filtered and washed with methanol. Thereafter, the compound in the mother liquor was treated with ammonium (3.65 g, 20.14 mmole) by adding an equimolar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmole) while efficiently stirring the reaction and cooling with a salt / ice bath Morphology. The resulting clear solution is placed under reduced pressure to provide a crude product.To tetramethylammonium di-tert-butyl-phosphate dissolved in refluxing dimethoxyethane, 4.3 grams of chloroiodomethane (24.16 mmole) is then added and stirred for 1-2 hours. The reaction is then filtered and the filtrate is placed under reduced pressure and the solution is concentrated in DME. 12 to 16percent of chloromethyl di-tert-butyl phosphate in DME4- (5- (2- (3,5-bis (trifluoromethyl) phenyl)-N, 2-dimethylpropanamido-4- (o-tolyl) pyridin-2-yl)-1-methyl-1 - ((phosphonooxy) methyl) piperazin-1-ium used without further purification (60percent yield): |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tetra-(n-butyl)ammonium iodide; In ethyl acetate; at 70℃; for 3h; | To a suspension of N-[1- (chloromethyl)-2-oxo- 1 ,2-dihydropyridin-4-ylj -2-[4-fluoro-2-(methyl-d3)phenoxyj -4- (trifluoromethyl)benzamide (11) (2.1 g, 4.587 mmol) in EtOAc (25 mL) was added tetrabutylammomum iodide (30 mg, 0.08122 mmol) followed by <strong>[33494-80-3]di-tert-butoxyphosphoryloxypotassium</strong>(1.3 g, 5.236 mmol) and the mixture heated to 70°C for 3 hr. The reaction was quenched by pouring over ice water (50 mL) and diluting with EtOAc (100 mL). The organic phase was separated and washed with brine. The aqueous phases were extracted with EtOAc (100 mL) and the combined organic phases were dried over MgSO4, filtered and concentrated. The crude product was purified using reverse phase chromatography (50-100percent water/ACN) affording di-tert-butyl ((4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)- 2-oxopyridin-1(2H)-yl)methyl) phosphate (12) (1.75 g, 60percent). ESI-MS m/z caic. 63 1.21497, found 632.2 (M+1) LC/MS retention time (Method B): 2.25 minutes (3 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.22% | In N,N-dimethyl-formamide; at 50℃; for 72h;Inert atmosphere; | To a stirred solution of 2-(chloromethyl)-3-methyl-5-[2-methyl-4-[6- (trifluoromethyl)quinazolin-2-yl]phenyl]-4H,5H,6H,7H-pyrazolo[l,5-a]pyrazin-4- one (220.00 mg, 0.453 mmol, 1.00 equiv) in DMF (8.00 mL) in a 20 mL vial, di-tert- butyl potassium phosphate (1124.22 mg, 4.528 mmol, 10.00 equiv) at room temperature.The resulting mixture was stirred for 3 days at 50 degrees C under nitrogenatmosphere. The resulting mixture was diluted with water (30mL).The aqueous layer was extracted with EtOAc (4x30 mL).The resulting mixture was concentrated under vacuum. The residue was purified by Prep- TLC (CH2Cl2:MeOH=120: l) to afford di-tert-butyl (3-methyl-5-[2-methyl-4-[6- (trifluoromethyl)quinazolin-2-yl]phenyl]-4-oxo-4H,5H,6H,7H-pyrazolo[l,5-a]pyrazin-2- yl)methyl phosphate (150 mg, 50.22%) as a white solid. |
Tags: 33494-80-3 synthesis path| 33494-80-3 SDS| 33494-80-3 COA| 33494-80-3 purity| 33494-80-3 application| 33494-80-3 NMR| 33494-80-3 COA| 33494-80-3 structure
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P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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