DD215085B1 - PROCESS FOR PREPARING PHOSPHONO FORMATS - Google Patents

Description

Field of application of the invention

The invention relates to a process for the preparation of phosphonoformates of the general formula I.

о о _n ι

RO-C-P (

OR ¹

in which R is an alkyl radical of C ¹ -C ₈ , cycloalkyl or benzyl, R ^{1 is} trimethylsilyl.

The compounds are intermediates for the preparation of trisodium phosphonoformate and other derivatives of phosphonoformic acid which possess selective viricidal properties, for example against herpesviruses, hepatitis viruses and RNA tumor viruses.

Characteristic of the known state of the art

Phosphonoformates of the general formula I can be obtained by various processes, starting from trialkyl esters of phosphonoformic acid. The dealkylation of the phosphonic ester groups by means of trimethylbromosilane proves to be favorable, bis (trimethylsilyl) phosphonoformic acid alkyl esters being obtained which are readily hydrolyzable and can be quantitatively converted into the corresponding salts under mild conditions. Disadvantageous here is the additional expenditure for the synthesis of the trimethylbromosilane. (McKenna, C.E., and Schmidhauser, J .; J. Chem. Soc.Chem.Commun.1979, 739).

Another method is the reaction of tris (trimethylsilyl) phosphite with chloroformates to give bis (trimethylsilyl) phosphonoformiate in a quantitative reaction. The disadvantage of the method, however, is that tris (trimethylsilyl) phosphite can be prepared only with considerable effort in the necessary pure form, for example by reaction of mixtures of bis- and TrisCtrimethylsilyOphosphit with sodium. (Sekine, M., Okimoto, K. and Hata, T .; J. Org. Chem. 46,2097 [1981]).

Object of the invention

The aim of the invention is a simpler preparation of compounds of general formula I, which yields approximately quantitative yields in a few process steps.

Explanation of the essence of the invention

The object of the invention is a process for the preparation of phosphonoformates of the general formula I using readily available starting materials.

According to the invention bis (trimethylsilyl) phosphite in the presence of hexamethyldisilazane, or mixtures of bis- and tris (trimethylsilyl) phosphite of any composition in the presence of hexamethyldisilazane or a tertiary amine with chloroformate quantitatively converted to bis (trimethylsilyl) phosphonoformiaten. These can be converted into the salts of phosphonoformic acid in a known manner by alkaline solvolysis.

Surprisingly, only a small starting amount of tris (trimethylsilyl) phosphite is necessary for the course of the reaction. Advantageously, the resulting from the reaction of tris (trimethylsilyl) phosphite and chloroformate trimethylchlorosilane in the presence of hexamethyldisilazane or tertiary amine as the silylating agent for the continuous conversion of bis- used in tris (trimethylsilyl) phosphite Thus, the complex representation of pure tris (trimethylsilyl) phosphite avoided, d. H. the problem of difficult silylation of low levels of bis-trimethylsilyl phosphite in tris (trimethylsilyl) phosphite is easily solved by the continuous removal of tris (trimethylsilyl) phosphite from equilibrium.

The process is preferably carried out without solvent. However, it is necessary to wash out the ammonium salts obtained by the silylation reaction during filtration with a low-boiling aprotic solvent such as diethyl ether. In order to keep the amount of these ammonium salts as low as possible, as starting materials, the readily available by reaction of bis (trimethylsilyl) phosphite with hexamethyldisilazane in a molar ratio of 1: 0.5 to 1: 0.8 mixtures of bis / tris (trimethylsilyl) phosphite / Hexamethyldisilazane containing about 70-80% tris (trimethylsilyl) phosphite.

The molar ratio of the reaction components, bis (trimethylsilyl) phosphite (a), tris (trimethylsilyl) phosphite (b), chloroformate (c), hexamethyldisilazane (d) and tertiary amine (e), can be varied over a wider range but not freely selectable in every respect.

While a: b can be used practically arbitrarily, the ratio (a + b): c must be approximately 1: 1. Hexamethyldisilazane is used as a function of the present (a) in the ratio a: d of at least 1: 0.33 to 0.5, while the ratio of a tertiary amine a: e must be at least 1: 1 to 1: 1.5. However, it is possible to use hexamethyldisilazane or a tertiary amine in excess. An example 1: 3 molar mixture of bis- and tris (trimethylsilyl) phosphite reacts in the presence of 0.33 mol of hexamethyldisilazane according to equation 1 quantitatively with chloroformate.

O O

"I!

(Me ₀ SiO) ₀ PH + 3 (Me-SiO) ₀ P + 4 RO-C-Cl + 0.33 (Me-Si) -NFI ^

О гі»J ό tj i

о о ⁽¹⁾

II!

4 RO-CP (OSiMe ₃ ) "+ 0.33 NH ₄ Cl + 3.66 Me ₀ SiC]

An analogous mixture can be reacted in the presence of a tertiary amine according to Equation 2.

O O

Il II (Me ₃ SiO) ₂ PH + 3 (Me ₃ SiO) ₃ P + 4 RO-C-Cl ¥ NR ₃ >

(2)

0 o

4 RO-CP (OSiMe ₀₎ "+ [NR ₃ H] Cl 3 + Ue ₀ SiCl

The reactions are carried out under protective gas in a temperature range of 60-100 ⁰ C, preferably at 75-8O ⁰ C. The order of addition of the reaction components is practically arbitrary. Conveniently, however, a mixture of bis- / tris (trimethylsilyl) phosphite / hexamethyldisilazane is treated with chloroformate, with greater preference being given to larger reaction batches of a continuous procedure.

embodiments

Example 1: Bis (trimethylsilyl) phosphono-formic acid ethyl ester

To a mixture of 226.2 g (1 mol) of bis (trimethylsilyl) phosphite and 108.5 g (1 mol) of ethyl chloroformate in a suitable reaction vessel equipped with reflux condenser, stirrer and thermometer, under nitrogen atmosphere at a temperature of 70-75 ⁰ C. 64.5 g (0.4 mol) of hexamethyldisilazane added dropwise. Subsequently, the reaction mixture is stirred for 2 hours at 75 ° C. After cooling, it is filtered, the separated ammonium chloride is washed with ether and the filtrate is distilled in vacuo after removal of volatile constituents.

Yield: 268 g, 90% of theory, (Me ₃ SiO) ₂ P (O) -C (O) -O-CH ₂ -CH ₃

Kp _o , o, 63 ° C; ³¹ P NMR -23 ppm

¹ H-NMRSiMe ₃ 0,29ppm, CH ₂ 3,88ppm (2qu, ³ J _H H7Hz, ⁴ Jp _H 1,2Hz)

CH ₃ 0.89 ppm (2 t, ³ J _HH 7 Hz, ⁵ J _PH 1.5 Hz)

Example 2: Bis (trimethylsilyl) phosphono-formic acid ethyl ester

To a mixture of 45.2 g (0.2 mol) of bis (trimethylsilyl) phosphite, 238.5 g (0.8 mol) of tris (trimethylsilyl) phosphite and 16.1 g (0.1 mol) of hexamethyldisilazane are added under protective gas 108, 5 g (1 mol) of ethyl chloroformate added dropwise.

The temperature set here 75-8O ⁰ C. After completion of the addition is stirred for a further 2 hours at 80 ⁰ C, then cooled, filtered and distilled.

Yield: 282 g, 94.5% of theory, (Me ₃ SiO) ₂ P (O) -C (O) -O-CH ₂ -CH ₃

Example 3: Bis (trimethylsilyl) phosphono-formic acid methyl ester

By reaction of 94.5 g (1 mol) of methyl chloroformate after distillation, 260 g, 91.5% of theory, (Me ₃ SiO) ₂ P (O) -C (O) -O-CH ₃ are obtained analogously to Example 2.

Κρο, οι 58 ⁰ C, ¹ H-NMR SiMe ₃ 0.25ppm benzene / TMS

0-CH ₃ 3.26 ppm (d, \ JpH 1 Hz)

Example 4: Ethyl bis (trimethylsilyl) phosphodnoformate

To a mixture of 40.7 g (0.18 mol) of bis (trimethylsilyl) phosphite and 246 g (0.82 mol) TrisitrimethylsilyOphosphit under protective gas 108.5 g of ethyl chloroformate are added dropwise at a temperature of 75-80 ° C. Thereafter, 25 g (0.25 mol) of triethylamine are slowly added dropwise and the reaction mixture stirred at 75-80 ° C for 3 hours. It is then cooled, filtered and distilled in a fine vacuum.

Yield: 265 g, 89% of theory, (Me ₃ SiO) ₂ P (O) -C (ObO-CH ₂ -CH ₃

Example 5: Trisodium phosphonoformate hexahydrate

A solution of 124 g (3.1 mol) of sodium hydroxide in 500 ml of water with vigorous stirring at 10-20 ⁰ C with 298g (1 mol) of bis (trimethylsilyl) phosphonoameisensÄureethylester. After completion of the addition is warmed to 5O ⁰ C on the water bath and stirred at this temperature for 30 minutes. It is cooled to 15-2O ⁰ C, separated from the deposited hexamethyldisiloxane, sucks the white crystalline trisodium phosphonoformate, washed with a little ice water and dried in vacuo over calcium chloride.

By cooling the filtrate to 0-5 ° C, a further fraction can be isolated.

Yield: 290 g, 97.5%, Na ₃ [PO ₃ CO ₂ ] x 6H ₂ O; ³¹ P NMR 0.5 ppm

Example 6: Disodium phosphonoformate

4.6 g (0.2 mol) of sodium are dissolved in 100-15OmL of absolute ethanol. 29.8 g (0.1 mol) of ethyl bis (trimethylsilyl) phosphonoformate are added dropwise to the resulting solution at room temperature, and the solution is largely concentrated in vacuo, filtered off with suction and dried in vacuo over calcium chloride.

Yield: 18 g Na ₂ PO ₃ C (O) -O-CH ₂ CH ₃ , 91.5% of theory

³¹ P NMR-2.59 ppm; ¹ H-NMR in D ₂ O / HMDS ext.

CH ₃ 1.63 ppm (2 t, ³ h 7 Hz, ⁵ J _PH 1.2 Hz)

CH ₂ 4.53 ppm (2 qu, ³ J _HH 7 Hz, ⁴ JpH 1.2 Hz)

Example 7: Methyl disodium phosphonoformate

Analogously to Example 6, in methanol by solvolysis of 28.4 g (0.1 mol)

Methyl (trimethylsilyl) phosphonoformate 16.5 g (Na ₂ PO ₃ COOCH ₃ , 89.5% of theory).

Example 8:

Bis / tris (trimethylsilyl) phosphite / hexamethyldisilazane mixtures

Under inert gas 452.4g (2 mol) of 8is (trimethylsilyl) phosphite with 245g (1.5 mol) of hexamethyldisilazane are added dropwise with stirring with stirring and then heated to 120-150 ° C. The mixture is heated under reflux for 8-10 hours, with the resulting ammonia is continuously removed by means of a protective gas stream. The temperature should not exceed 140-150 ° C. The remaining mixture can be used for the further reactions by 'H-NMR spectroscopic determination of its constituents.

¹ H-NMR in benzene / TMS

(Me ₃ SiO) ₃ P 0.23 ppm

(Me ₃ SiO) ₂ P (O) H 0.18 ppm

(Me ₃ Si) ₂ NH 0.09 ppm

Claims (3)

1. A process for the preparation of phosphonoformates of the general formula I. ⁰ ° npl
и и, -OE RO-C-Pi ₁
⁴ OR ¹ in which R is an alkyl radical of C ₁ -C ₈ , cycloalkyl or benzyl, R ^{1 is} trimethylsilyl, characterized in that bis (trimethylsilyl) phosphite in the presence of hexamethyldisilazane or mixtures of bis- and tris (trimethylsilyl) phosphite of any composition in the presence of hexamethyldisilazane or in the presence of a tertiary amine with chloroformates to give bis (trimethylsilyl) phosphonoformates of the formula I. 2. The method according to item 1, characterized in that the molar ratio of the reactants bis (trimethylsilyl) phosphite (a), tris (trimethylsilyl) phosphite (b), chloroformate (c), hexamethyldisilazane (d), or tertiary amine (e ) with respect to the ratio a: b, (a + b): c1: 1, a: d 1: 0.33 to 0.5 and a: e is 1: 1 to 1.5. 3. The method according to item 1, characterized in that the reaction under protective gas in a temperature range of 60-100 ⁰ C, preferably at 75-80 ⁰ C, is performed.