33494-80-3

Basic information

• Product Name: Potassium di-tert-butylphosphate
• Synonyms: DI-TERT-BUTYLPHOSPHATE, POTASSIUM SALT;DI-TERTIARYBUTYL PHOSPHATE (POTASSIUM SALT);POTASSIUM DI-TERT-BUTYLPHOSPHATE;Di-t-butyl phosphate, potassium salt;Nsc264063;Potassium di-t-butylphosphate, min. 91% (contains ;Di-tert-butyl phosphate;PotassiuM di-t-butyl phosphate
• CAS NO: 33494-80-3
• Molecular Formula: C₈H₁₈O₄P*K
• Molecular Weight: 248.3
• Mol File: 33494-80-3.mol
• Article Data: 6

Chemical Properties

• Melting Point: 247-252°C
• Boiling Point: 252.3°C at 760 mmHg
• Flash Point: 106.4°C
• Appearance: white/Powder
• Vapor Pressure: 0.00611mmHg at 25°C
• Storage Temp.: 2-8°C
• CAS DataBase Reference: Potassium di-tert-butylphosphate(CAS DataBase Reference)
• NIST Chemistry Reference: Potassium di-tert-butylphosphate(33494-80-3)
• EPA Substance Registry System: Potassium di-tert-butylphosphate(33494-80-3)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26
• WGK Germany: 3
• TSCA: No
• Hazardous Substances Data: 33494-80-3(Hazardous Substances Data)

Usage

Uses

Di-tert-butylphosphate Potassium Salt is a catalyst used in organic synthesis. Also used in the preparation of HIV attachment inhibitor BMS-663068.

Application

Utilized as an intermediate to prepare N-phosphonooxymethyl prodrugs, which increase bioavailability, and to prepare Nasicon-type phosphates (i.e., KTi2(PO4)3) used in fast ion conductors with low thermal expansion ceramics.appl

Preparation

Potassium di-tert-butyl phosphate synthesis: Di-tert-butyl phosphite (40.36 mmol) was combined with potassium bicarbonate (24.22 mmol) 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 a period of one hour. The reaction was then allowed to continue for another half hour at room temperature. Decolorizing carbon (600 mg) was then incorporated as the reaction was heated to 60 °C for 15 min. 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 another twenty minutes. The solution was filtered again to give a colorless solution, which was then evaporated in vacuo to give the crude potassium di-tert-butyl phosphate salt.

Flammability and Explosibility

Nonflammable

InChI:InChI=1/C8H19O4P/c1-7(2,3)11-13(9,10)12-8(4,5)6/h1-6H3,(H,9,10)/p-1

Synthetic route

di-tert-butyl phosphite (13086-84-5) → potassium di-tert-butylphosphate (33494-80-3)

Conditions	Yield
With pyridine; potassium dihydrogenphosphate; dihydrogen peroxide; potassium iodide In water; toluene; acetonitrile at 20℃; Inert atmosphere;	81%
With potassium permanganate; potassium hydrogencarbonate
With potassium permanganate; potassium hydrogencarbonate In water at 5 - 20℃; for 19h;

di-tert-butyl phosphite (13086-84-5) → potassium di-tert-butylphosphate (33494-80-3)

Conditions	Yield
With potassium permanganate; potassium hydrogencarbonate In water at 0 - 20℃; for 1.5h;
Stage #1: di-tert-butyl phosphite With potassium permanganate; potassium hydrogencarbonate In water at 20℃; for 1.5h; Cooling with ice; Stage #2: With pyrographite In water at 60℃; for 0.25h;	5 g
With potassium permanganate; potassium hydrogencarbonate In water at 20℃; for 1.5h;
With potassium permanganate; potassium hydrogencarbonate In water at 60℃; for 1.5h;

potassium di-tert-butylphosphate (33494-80-3) → phosphoric acid di-tert-butyl ester (33494-81-4)

Conditions	Yield
With hydrogenchloride In water at 0℃;	98%
With hydrogenchloride In water at 0℃;
With hydrogenchloride In water Cooling with ice;

potassium di-tert-butylphosphate (33494-80-3) + Dimethyl-(3-methyl-2-butenyl)-sulfonium tetrafluoroborate → dimethylsulfide (75-18-3) + Di-t-butyl prenyl phosphate (82753-91-1)

Conditions	Yield
With potassium carbonate In dichloromethane for 48h; Heating;	A n/a B 97%

chlorosulfuric acid chloromethyl ester (49715-04-0) + potassium di-tert-butylphosphate (33494-80-3) → di-tert-butyl chloromethyl phosphate (229625-50-7)

Conditions	Yield
Stage #1: potassium di-tert-butylphosphate With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate In dichloromethane; water at 0℃; for 0.166667h; Stage #2: chlorosulfuric acid chloromethyl ester In dichloromethane; water at 20℃; for 20h;	95.3%
With potassium hydrogenphosphate trihydrate; tert-butyl methyl ether; tetra(n-butyl)ammonium hydrogensulfate In water at 0 - 20℃; for 2.41667h;	94%
With potassium hydrogenphosphate trihydrate; tetra(n-butyl)ammonium hydrogensulfate In tert-butyl methyl ether; water at 0 - 30℃; for 2.41667h;	94%

N-(1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide + potassium di-tert-butylphosphate (33494-80-3) → di-tert-butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl) phosphate

Conditions	Yield
With tetra-(n-butyl)ammonium iodide In ethyl acetate at 41 - 71℃; for 4.16667h; Temperature; Solvent; Reagent/catalyst; Inert atmosphere; Large scale;	88%
With tetra-(n-butyl)ammonium iodide In ethyl acetate at 71℃; for 4.83333h; Solvent; Reagent/catalyst; Temperature; Inert atmosphere;	88%

potassium di-tert-butylphosphate (33494-80-3) + n-Butyldiphenylsulfoniumtetrafluoroborat → diphenyl sulfide (139-66-2) + phosphoric acid butyl ester di-tert-butyl ester (58389-60-9)

Conditions	Yield
With potassium carbonate In dichloromethane at 20℃; for 5h;	A n/a B 85%

potassium di-tert-butylphosphate (33494-80-3) + tetrafluoroborate de dimethylgeranylsulfonium → dimethylsulfide (75-18-3) + Phosphoric acid di-tert-butyl ester (E)-3,7-dimethyl-octa-2,6-dienyl ester (82771-12-8)

Conditions	Yield
With potassium carbonate In dichloromethane for 30h; Heating;	A n/a B 78%

diphenylethylsulphonium tetrafluoroborate + potassium di-tert-butylphosphate (33494-80-3) → phosphoric acid di-tert-butyl ester ethyl ester (14540-31-9) + diphenyl sulfide (139-66-2)

Conditions	Yield
With potassium carbonate In dichloromethane at 20℃; for 48h;	A 76% B n/a

2-(4-fluoro-2-methylphenoxy)-N-(1-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide + potassium di-tert-butylphosphate (33494-80-3) → tert-butyl ((4-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl) hydrogen phosphate

Conditions	Yield
Stage #1: 2-(4-fluoro-2-methylphenoxy)-N-(1-(hydroxymethyl)-2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide With methanesulfonyl chloride; N-ethyl-N,N-diisopropylamine In ethyl acetate at 5 - 15℃; for 4.33333h; Stage #2: potassium di-tert-butylphosphate With sodium iodide In ethyl acetate at 65 - 75℃; for 5h;	75%

diphenylisopropylsulfonium tetrafluoroborate + potassium di-tert-butylphosphate (33494-80-3) → diphenyl sulfide (139-66-2) + phosphoric acid di-tert-butyl ester isopropyl ester (68695-42-1)

Conditions	Yield
With potassium carbonate In dichloromethane for 42h; Heating;	A n/a B 72%

C22H22BrCl2N5O2 + potassium di-tert-butylphosphate (33494-80-3) → (3-((5-bromo-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-4,6-dimethyl-2-oxopyridin-1(2H)-yl)methyl di-tert-butyl phosphate

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; triethylamine In N,N-dimethyl-formamide at 20℃; for 72h; Cooling with ice;	64%

N-[1-(chloromethyl)-2-oxo-1,2-dihydropyridin-4-yl]-2-[4-fluoro-2-(methyl-d3)phenoxy]-4-(trifluoromethyl)benzamide + potassium di-tert-butylphosphate (33494-80-3) → di-tert-butyl ((4-(2-(4-fluoro-2-(methyl-d3)phenoxy)-4-(trifluoromethyl)benzamido)-2-oxopyridin-1(2H)-yl)methyl) phosphate

Conditions	Yield
With tetra-(n-butyl)ammonium iodide In ethyl acetate at 70℃; for 3h;	60%

benzyl 6-[8-[chloromethoxycarbonyl(methyl)amino]-5-cyano-6-fluoro-4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylate + potassium di-tert-butylphosphate (33494-80-3) → benzyl 6-[5-cyano-8-[di-tert-butoxyphosphoryloxymethoxycarbonyl(methyl)amino]-6-fluoro-4-[(3aS,6aS)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[2,3-c]pyrrol-1-yl]-9H-pyrido[2,3-b]indol-3-yl]-1-methyl-4-oxo-1,8-naphthyridine-3-carboxylate

Conditions	Yield
In toluene at 90℃; for 2h;	57.9%

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 + potassium di-tert-butylphosphate (33494-80-3) → 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

Conditions	Yield
In N,N-dimethyl-formamide at 60℃; for 6h;	54%

potassium di-tert-butylphosphate (33494-80-3) + 2-bromoethanol (540-51-2) → di-tert-butyl (2-hydroxyethyl) phosphate (54857-40-8)

Conditions	Yield
In N,N-dimethyl-formamide at 80℃;	52.3%

2-(chloromethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one + potassium di-tert-butylphosphate (33494-80-3) → di-tert-butyl (3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl phosphate

Conditions	Yield
In N,N-dimethyl-formamide at 50℃; for 72h; Inert atmosphere;	50.22%

Cp*TiCl3 (12129-06-5) + potassium di-tert-butylphosphate (33494-80-3) → C46H81O14P3Ti3

Conditions	Yield
In tetrahydrofuran at 25℃; for 24h;	46%

2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide (1620846-08-3) + potassium di-tert-butylphosphate (33494-80-3) + carbonochloridic acid, chloromethyl ester (22128-62-7) → di-tert-butyl [4-[[2-(4-fluorophenoxy)-5-(trifluoromethyl)benzoyl]amino]-2-oxo-1-pyridyl]methyl phosphate

Conditions	Yield
Stage #1: 2-(4-fluorophenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-(trifluoromethyl)benzamide; carbonochloridic acid, chloromethyl ester In dichloromethane; N,N-dimethyl-formamide at 20℃; for 4h; Stage #2: potassium di-tert-butylphosphate With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide at 70℃; for 4h;	43.7%

Upstream product

• 13086-84-5 di-tert-butyl phosphite 
• 13086-84-5 di-tert-butyl phosphite 

Downstream Products

• 14540-31-9 phosphoric acid di-tert-butyl ester ethyl ester 
• 139-66-2 diphenyl sulfide 
• 68695-42-1 phosphoric acid di-tert-butyl ester isopropyl ester 
• 75-18-3 dimethylsulfide 
• 82753-91-1 Di-t-butyl prenyl phosphate 
• 82771-12-8 Phosphoric acid di-tert-butyl ester (E)-3,7-dimethyl-octa-2,6-dienyl ester 
• 58389-60-9 phosphoric acid butyl ester di-tert-butyl ester 
• 33494-81-4 phosphoric acid di-tert-butyl ester 
• 229625-50-7 di-tert-butyl chloromethyl phosphate 
• 1456545-38-2 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid di-tert-butoxy-phosphoryloxymethyl ester 
• 1198393-90-6 4-(((di-tert-butoxyphosphoryl)oxy)methyl)benzoic acid 
• 1273191-44-8 di-tert-butyl iodomethyl phosphate 
• 1596347-54-4 di-tert-butyl (p-toluenesulfonylmethyl) phosphate 
• 427899-56-7 bis-di-tert-butyl methyl phosphate 

Relevant articles and documents

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 as a neurokinin receptor modulator

Compounds and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK1) receptor, based on 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)3yridine-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium and pharmaceutically acceptable salts thereof.

Development of efficient processes for the preparation of Di-tert-butyl potassium phosphate and Di-tert-butyl (Chloromethyl) phosphate

A new and efficient process to prepare di-tert-butyl (chloromethyl) phosphate, a key compound in the formation of many phosphon-oxymethyl pro-drugs, from chloromethyl chlorosulfate (CMCS) and di-tert-butyl potassium phosphate (DTBPP) is described. To develop a process to this important compound with overall efficiency, an improved synthesis of DTBPP was required. The two-step process to DTBPP starts from PCl3 and leverages a H2O 2/catalytic KI mediated oxidation of di-tert-butyl phosphite to provide DTBPP in 81% yield and high purity. In the development of the new process to di-tert-butyl (chloromethyl) phosphate, a comparison to the corresponding tosylate derivative was made. A rational selection of base, phase-transfer catalyst (PTC), and stabilizing additive minimized CMCS decomposition and led to an optimized yield (90% solution yield), improved product purity, and identification of a technique to enable the long-term storage of di-tert-butyl (chloromethyl) phosphate.

N-PYRAZOLYL CARBOXAMIDES AS CRAC CHANNEL INHIBITORS

The present invention relates to amide compounds, processes for their preparation, pharmaceutical compositions containing these compounds and to their use in the treatment of disorders, conditions or disorders such as allergic disorders, inflammatory disorders and disorders of the immune system.