DD219198A1 - PROCESS FOR PREPARING PHOSPHONO FORMATS - Google Patents

Abstract

The invention relates to a novel simple process for the preparation of Phosphonoformiaten of formula I by reacting Bistrimethylsilylhypophosphit in the presence of hexamethyldisilazane with chloroformates to bis-trimethylsilyl phosphonigoformiaten by oxidation by means of oxygen or sulfur and subsequent partial or complete solvolysis in conjunction of the formula I. be transferred. In formula I, R is an alkyl radical of C1 to C6, cycloalkyl, benzyl, phenyl, substituted phenyl or an alkali metal R1 trimethylsilyl, hydrogen, an alkali metal, ammonium or substituted ammonium radical X is sulfur or oxygen. The compounds have viricidal properties, for example against herpesviruses.

Description

Process for the preparation of phosphonoformates

Field of application of the invention

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

RG-C-PCT ₁

OFTEN '

in the -

X in particular sulfur, but also oxygen R. Alkyl of C 1 to Cg, cycloalkyl, benzyl, phenyl,

substituted phenyl radical or an alkali metal R trimethylsilyl, hydrogen _# an alkali metal, ammonium

or substituted ammonium radical ·;

The compounds have viricidal properties, for example against herpesviruses.

Characteristic of the known technical solutions.

Phosphonoformates of the general formula 1 (X =O) can be obtained from trialkyl esters of phosphonoearic acid by alkaline hydrolysis in low yields (Nylen, P. Chem., 57, 1023 (1924) or by dealkylation by means of tri-methylbromosilane and subsequent alkaline solvolysis , (Mc Kenna, C. and Schmidhauser, D * D. Chem. Soc.Chera. Comtnun., 1979, (17), 739)

The disadvantage here is the additional expense for the synthesis of trimethylbromosilane.

Another method is the reaction of tris-trimethylsilylphosphit rait chloroformates, wherein bis-trimethylsilyl-phosphonoformiate be obtained 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

Reactions of mixtures consisting of bis-trimethylsilyl phosphite and tris-trimethylsilyl-phosphite, with sodium. (Sekine, M., Okiraoto, K. Yamada, K. and Hata, T.O.Org.Chem 46, 2097 (1981).

The process described in the patent application DD ₇ WP C07F / 249328/6 for the preparation of phosphonoformates is to be regarded as equivalent for compounds of the formula I (X =O). However, it is not suitable, like all abovementioned methods for preparing the hitherto unknown monothiophosphonoformates of the formula I (X =S).

Object of the invention

The aim of the invention is a simple 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 new process for the preparation of these compounds using readily available starting materials. It has been found that in the presence of hexamethyldisilazane BiSu-tri methylsilyl-hypophosphite can surprisingly be reacted quantitatively with chloroformates to form bis-trimethylsilylphosphonoformates which are converted into compounds of the formula I by oxidation by means of oxygen or sulfur and subsequent partial or complete solvolysis , The reactions proceed under mild conditions in a protective gas atmosphere according to Equations (1) and (2).

(Me ₃ SiO) ₂ PH +, Cl-C (O) OR + 0.33 (Me ₃ Si) NH * - (1)

R0-C (0) -P (0SiMe _{3) 2} +0.33 NH ₄ Cl + 0.66 Me ₃ SiCl

X.

R0-C (0) P (0SiMe _{3) 2} + X *> R0-C (0) -P (0SiMe _{3) 2} (2)

    x = o, s

wherein the silylated Phosphonigformiate prove to be stable intermediates.

The process is preferably carried out in the first reaction step without solvent. Bis-trimethylsilyl hypophosphite and chloroformate are used approximately in the molar ratio of 1: 1, while hexamethyldisilazane can also be used in excess, based on equation (1). The reactions are carried out in the temperature range of SO-IOO ⁰ C, preferably at 50-80 ⁰ C. The order of addition of the reaction components is not arbitrary. It is expedient to add a mixture of β-trimethylsilyl hypophosphite and hexamethyldisilazane with chloroformate. The mixtures of (Me ₃ SiO) ₂ PH and (Me ₃ Si) pNH used as starting components can also be prepared directly by reacting ammonium hypophosphite (Me ₃ Si) ₂ NH in a molar ratio of 1: 1, -33 to 1.5 and be used without further purification by distillation for the further reactions · The oxidation of bis-trimethylsilyl-hypophosphite, according to equation (2), is expediently with dry Air or with a suspension of elemental sulfur in an aprotic solvent to better control the highly exothermic reaction, ^r . ''' The equation (2) resulting groups in a conventional V / else by alkaline solvolysis to compounds of formula I bis-trimethylsilyl-phosphonoformiate can.

AusführungsbeispieIe

Example 1 .' ^[

Ethoxycarb.onylphosphonous-bis-t rimetnylsilylsster _

41.5 g (0.5 mol) of anhydrous ammonium hypophosphite is heated under inert gas with 120 g (0.75 mol) of hexamethyldisilazane until completion of the MH ₃ evolution to 100 ⁰ C. After cooling to 50-60 ⁰ C is added dropwise in the resulting mixture of bistrimethylsilyl hypophosphite and hexamethyldisilazane 54 g of ethyl chloroformate. The reaction temperature should not significantly exceed 60 ⁰ C. Subsequently, the resulting ammonium chloride is also separated under protective gas and in the

Distilled vacuum. ,

Yield: 126.5 g 90% of theory CH ₃ -CH ₂ OC (O) -P (OSiMe _{3) 2} MW 282.4

Bp ₈ 106-108 ⁰ C

³¹ P NMR 120 ppm; ¹ H, NMR CH ₃ 0.98 ppm (t * ^ _HCCH 7Hz)

CH ₂ 3.98 ppm (qu * 0 _HCCH 7 Hz)

(CH ^) - Si .0,24'ppm

ο o

Example 2 Ethoxycarbonyl-thiophosphonic acid bis-trimethylsilyl ester

28.2 g (0.1 mol) of ethoxycarbonyl-phosphonous-bis-trirethyl ethyl ester are added dropwise under inert gas to a suspension of 3.2 g (0.1 mol) of sulfur in 40 ml of absolute dioxane, so that the reaction temperature is 6O ⁰ C does not significantly exceed. The mixture is then heated to complete the reaction for an hour to 8O ⁰ C and distilled in vacuo.

Yield; 27.2 g 86.5% of theory C ₂ H ₅ OC (O) -P (S) (OSiMe ₃ J ₂ MW 314.493 Kp ₄ HO ⁰ C

³¹ P NMR -8.7 ppm; ¹ H NMR SiMe ₃ 0.31 ppm

CH ₃ 1.24 ppra (t, 0 _HCCH 7Hz) CH ₂ 4.02 ppm (q * 3 _HCCH 7Hz)

Example 3 Ethoxycarbonylphosphonic acid bis-trimethylsilyl ester

By 28.2 g (0.1 mol) of ethoxycarbonyl-phosphonous acid bis-trimethylsilylester, dissolved in 40 ml of absolute dioxane is passed through a molecular sieve 3 A dried air stream that the temperature does not exceed 75 ⁰ C. After completion of the reaction is separated from the dioxane and distilled in vacuo.

Yield: 28 g 93.8% of theory. C ₂ H ₅ OC (O) -P (O) (OSxMe ₃ J ₂ MW 298.43

86 ⁰ C

³¹ P NMR -23.13 ppm; ¹ H NMR SiMe ₃ 0.21 ppm

CH ₃ 1.0 ppm (t, ö _HCCH 7Hz) CH ₂ 3.98 ppm (q ^ _HCCH 7Hz)

Example 4 Ethoxycarbonyl-thiophosphonic acid disodium salt

31.4 g (0.1 mol) of ethoxycarbonyl-thiophosphonic acid bis-trimethylsilylester under inert gas and cooling to -5 C slowly mixed with 0.2 mol of sodium alcoholate, then the excess alcohol is removed in vacuo, the title compound remains quantitatively ,

Yield: 21.4 g 100% of theory. C ₂ H ₅ OC (O) -P (S) (ONa) ₂ MW 214.1

³¹ P NMR 33.0 ppm; ¹ H NMR CH ₃ 1.64 ppm (t | 3 _HCCH 7 Hz)

CH ₂ 4.54 ppra (q * 3 _HCCH 7 Hz)

Example 5.

Trinatriumthiophosphonoformiat

15.7 g (0.05 mol) of ethoxycarbonyl-thiophosphonic acid bis-tri-methylsily! Ester are added dropwise, while stirring and cooling to 50 g, into a solution of ⁶ g NaOH (0.15 mol) in 40 ml of H 2 SO 4. It is then concentrated to dryness on a rotary evaporator.

Yield: 10.4 g of 100% dTh NaO-C (O) -P (S) (ONa) ₂ MW 208.1 ³¹ P NMR 36.7 ppm

•. - 6 -

Example 6 Ethoxycarbonyl phosphonic acid disodium salt

14.9 g (0.05 mol) of ethoxycarbonylphosphonic acid bis-trimethylsilyl ester is slowly added at ⁰ ° C. under protective gas with 0.1 mol of a sodium alkoxide solution. Thereafter, freed of volatile constituents on a rotary evaporator.

Yield: 9.8 g 100% D.T. C ₂ H ₅ OC (O) -P (O) (ONa) ₂ KG 198.02 ³¹ P NMR -2.5 ppm ¹ H NMR CH ₃ 1.63 ppm - (t »3 _HCCH 7 Hz)

CH

₂ 4.53 ppm (q »3 _HCCH 7 Hz)

Example 7 Trisodium phosphonoforraiate

29.8 g (0.1 mol) of ethoxycarbonyl-phosphonic acid bis-trimethylsilyl are 'at 5 ⁰ C slowly. a solution of 12 g of NaOH (0.3 mol) in 60 ml of water. After warming to room temperature is concentrated on a rotary evaporator to dryness. ,

Yield; 19.2 g 100% of theory NaO-C (O) -P (O) (ONa) ₂ . 6 H ₃ O MW 191.95 ³¹ P NMR 0.5 ppm

Claims (2)

Invention claim, 1. Process for the preparation of Phosphonoformates of the general formula I. H 'H ^ - * ^0R R-O-C-P CT <I OR ¹ in the . , X especially sulfur, but also oxygen ' R is an alkyl radical of C. to Cg, cycloalkyl, benzyl, phenyl, substituted phenyl radical or an alkali metal R is a trimethylsilyl radical, hydrogen, e-ip alkali metal / ammonium or substituted ammonium radical, characterized in that bis-trimethylsilyl hypophosphite in the presence of hexamethyldisilazane reacted with chloroformates to form Bis-trimethylsilylphosphonigformiaten, which are converted by oxidation by means of oxygen or sulfur and subsequent partial or complete. Solvolysis in compounds of formula I. 2. The method according to item 1, characterized in that the reactions under protective gas and in a temperature range of 50-100 C, preferably at 50-80 ° C are performed.