Process for the preparation of alkyl phosphinates

The invention relates to a new process for the production of alkyl dialkoxyalkylphosphinates. A hypophosphite salt is used in the process.

FIELD OF THE INVENTION

The present invention is directed to a new process for the production of alkyl dialkoxyalkylphosphinates.

BACKGROUND OF THE INVENTION

EP 307362 A2 describes the production of aliphatylphosphinic acid derivatives from aqueous phosphinic acid.

A process for esterification of hypophosphite salts has been published in Deprèle, S. Montchamp, J.-L.J. Organomet. Chem.2002, 643-644. 154-165 and is outlined below:

One object of the present invention was to develop a process for the production of alkyl dialkoxyalkylphosphinates that is more suitable for large-scale production.

Outline of the Invention

The present invention is directed to a new process for the production of alkyl dialkoxyalkylphosphinates of formula (I):

whereinR1, R2and R3each and independently represents methyl or ethyl; andR4represents hydrogen or methyl;whereby a hypophosphite salt is reacted with a compound of formula (II):

whereinR1, R2, R3and R4are as defined above;in the presence of a solvent and an acid.

The process according to the present invention may be used for the synthesis of inter alia ethyl (diethoxymethyl) phosphinate. By using this method the hazardous handling of neat phosphinic acid can be avoided. Further, the amount of by-products may be controlled.

Methods of Preparation

In one embodiment of the invention, the compound of formula (II) is charged to a stirred slurry of hypophosphite salt and a suitable solvent such as toluene-ethanol (20:1). The mixture is carefully inerted and acid is charged at a controlled speed. The slurry is stirred at from 0° C. to 20° C. during 1 to 20 hours or until most of the intermediate alkyl ester is consumed. The mixture is quenched by the addition of aqueous sodium hydrogen carbonate and the organic layer is concentrated.

In one embodiment of the present invention, the hypophosphite salt is selected from ammonium hypophosphite, sodium hypophosphite and potassium hypophosphite.

In one embodiment of the present invention, the compound of formula (II) is selected from trimethylorthoformate, triethylorthoformate, trimethylorthoacetate and triethylorthoacetate.

In one embodiment of the present invention, the acid used in the reaction is selected from methane sulphonic acid, sulphuric acid, boron trifluoride etherate and trifluoromethane sulphonic acid. In a further embodiment of the invention, the acid is essentially water-free. In one embodiment, the acid contains up to 10% water, up to 5% water or up to 2% water.

In one embodiment, the solvent used in the process according to the present invention is toluene, acetonitrile, tetrahydrofuran (THF), methylene chloride, benzene or a mixture of toluene and ethanol.

EXAMPLES

Synthesis of ethyl(diethoxymethyl)phosphinate using methane sulphonic acid

Synthesis of ethyl(diethoxymethyl)phosphinate using methane sulphonic acid in 2-L-scale

Synthesis of ethyl(diethoxymethyl)phosphinate using methane sulphonic acid in 500-L-Scale

Triethylorthoformate (133.6 kg, 901.4 mol, 2.1 eq) was charged to a cold (0° C.), vigorously stirred mixture of ammonium hypophosphite (35.6 kg, 429.2 mol, 1.0 eq), toluene (107 L) and ethanol (11 L) under a nitrogen atmosphere. The slurry was carefully inerted while cooled to ˜0° C. The slurry was then continuously purged with nitrogen in order to reduce the amount of oxidized by-products. Methane sulphonic acid (43.3 kg, 450.7 mol, 1.05 eq) was then charged (exothermic) during 30 minutes (Tiwas kept below 10° C.). The slurry was stirred at 0° C. and after 2.5 hours the reaction mixture was quenched by a controlled charge (Ti≦10° C.) of a mixture with sodium hydrogen carbonate (14.4 kg, 171.7 mol, 0.4 eq) and water (128 L). The charging vessel was rinsed with water (14 L) and the reaction mixture was stirred vigorously during 10 minutes After phase separation the organic layer was concentrated under reduced pressure at 40° C. to ˜⅓ of the volume. (82 L, 0.991 kg/L, 81.3 kg, GC-purity 89.6%, assay 61%). (Amount of ethyl (diethoxymethyl) phosphinate: 49.6 kg, 252.7 mol, yield 58.9%).

Synthesis of ethyl(diethoxymethyl)phosphinate using sulphuric acid

Concentrated sulphuric acid (1.65 mL, 29.7 mmol, 0.5 eq) was charged to a mixture of ammonium hypophosphite (5 g, 60.2 mmol, 1 eq), toluene (45 mL) and ethanol (5 mL) at ambient temperature. After 2 hours triethylorthoformate (26.0 mL, 156.3 mmol, 2.6 eq) was added and the slurry was stirred over night. GC-analysis showed almost complete conversion of the intermediate ethylester to the desired product. The reaction mixture was then quenched with a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and brine (50 mL). The phases were separated and the organic layer was washed twice, first with the 1:1 mixture of saturated aqueous sodium hydrogen carbonate and brine (50 mL) and then with only brine (25 mL). The organic layer was then dried (Na2SO4) and concentrated under reduced pressure. Ethyl (diethoxymethyl) phosphinate was isolated as a colourless oil. (5.7 g, GC-purity ˜93%, yield ˜44%).

Synthesis of ethyl(diethoxymethyl)phosphinate using boron trifluoride-etherat

Synthesis of ethyl(diethoxymethyl)phosphinate using trifluoro methanesulphonic acid

Synthesis of ethyl(diethoxyethyl)phosphinate using methane-sulphonic acid

Triethylorthoacetate (4.6 mL, 25.1 mmol, 2.1 eq) was added to a cold (0° C.) mixture of ammonium hypophosphite (1.0 g, 12.0 mmol, 1.0 eq) and toluene (5 mL). The slurry was cooled to ˜0° C. and inerted. Methane sulphonic acid (0.84 mL, 12.7 mmol, 1.05 eq) was charged (exothermic) during 4 minutes (Tiwas kept below 10° C.). The reaction was stirred at 0° C. and after 1 hour GC-analysis showed ˜40% conversion to the desired product. After 3 hours the reaction mixture was quenched by the addition of saturated aqueous sodium hydrogen carbonate (3.6 mL). After phase separation the organic layer was concentrated to a colourless oil (1.1 g, GC-purity ˜81%, yield ˜35%).

Synthesis of methyl(dimethoxyethyl)phosphinate using methane-sulphonic acid

Trimethylorthoacetate (3.2 mL, 25.1 mmol, 2.1 eq) was added to a cold (0° C.) mixture of ammonium hypophosphite (1.0 g, 12.0 mmol, 1.0 eq) and toluene (5 mL). The slurry was cooled to ˜0° C. and inerted. Methane sulphonic acid (0.84 mL, 12.7 mmol, 1.05 eq) was charged (exothermic) during 4 minutes (Tiwas kept below 10° C.). The reaction was stirred at 0° C. and after 1 hour GC-analysis showed ˜50% conversion to the desired product. After 3 hours the reaction mixture was quenched by the addition of saturated aqueous sodium hydrogen carbonate (3.6 mL). After phase separation the organic layer was concentrated to a colourless oil (0.21 g, GC-purity ˜92%, yield ˜10%).

Synthesis of methyl(dimethoxymethyl)phosphinate using methane-sulphonic acid

Trimethylorthoformate (2.8 mL, 25.6 mmol, 2.1 eq) was added to a cold (0° C.) mixture of ammonium hypophosphite (1.0 g, 12.0 mmol, 1.0 eq) and toluene (5 mL). The slurry was cooled to ˜0° C. and inerted. Methane sulphonic acid (0.84 mL, 12.7 mmol, 1.05 eq) was charged (exothermic) during 4 minutes (Tiwas kept below 10° C.). The reaction was stirred at 0° C. and after 1 hour GC-analysis showed ˜84% conversion to the desired product. After 3 hours the reaction mixture was quenched by the addition of saturated aqueous sodium hydrogen carbonate (3.6 mL). After phase separation the organic layer was concentrated to a colourless oil (0.12 g, GC-purity ˜78%, yield ˜7%).