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Structure of 33494-81-4
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 33494-81-4 |
Formula : | C8H19O4P |
M.W : | 210.21 |
SMILES Code : | O=P(OC(C)(C)C)(OC(C)(C)C)O |
MDL No. : | MFCD08443810 |
InChI Key : | YEWZQCDRZRYAEB-UHFFFAOYSA-N |
Pubchem ID : | 429756 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H302-H314 |
Precautionary Statements: | P280-P301+P312-P303+P361+P353-P304+P340-P305+P351+P338-P310 |
Class: | 8 |
UN#: | 3261 |
Packing Group: | Ⅲ |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 52.64 |
TPSA ? Topological Polar Surface Area: Calculated from |
65.57 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.25 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.95 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.72 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.04 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.76 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.54 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.48 |
Solubility | 7.0 mg/ml ; 0.0333 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.91 |
Solubility | 2.56 mg/ml ; 0.0122 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.23 |
Solubility | 12.3 mg/ml ; 0.0587 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.91 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
3.84 |
* 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. |
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). |