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Chemical Structure| 33494-81-4 Chemical Structure| 33494-81-4

Structure of 33494-81-4

Chemical Structure| 33494-81-4

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Product Details of [ 33494-81-4 ]

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

Safety of [ 33494-81-4 ]

GHS Pictogram:
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:

Computational Chemistry of [ 33494-81-4 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

65.57 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.25
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.95
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.72
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.04
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

0.76
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.54

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.48
Solubility 7.0 mg/ml ; 0.0333 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-1.91
Solubility 2.56 mg/ml ; 0.0122 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.23
Solubility 12.3 mg/ml ; 0.0587 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.91 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.56

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.84

Application In Synthesis of [ 33494-81-4 ]

* 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.

  • Downstream synthetic route of [ 33494-81-4 ]

[ 33494-81-4 ] Synthesis Path-Downstream   1~1

  • 1
  • [ 33494-80-3 ]
  • [ 33494-81-4 ]
YieldReaction ConditionsOperation 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).

 

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