DD242811A1 - METHOD FOR PRODUCING N-SUBSTITUTED N-PHOSPHONOFORMYLAMINOSAURES AND THEIR DERIVATIVES - Google Patents

Abstract

The invention relates to a process for preparing N-Phosphonoformylaminosaeuren and their derivatives of the formula I, by reacting bis-trimethylsilyl phosphite with Isocyanatocarbonsaeureestern, at elevated temperature to N- (bis (trimethylsilyl) phosphonoformyl) amino acid esters, which by means of alkaline solvolysis in Compounds of formula I can be converted, wherein R1 is trimethylsilyl, hydrogen, an alkali metal, ammonium, substituted ammonium radical; R2 is alkyl of C1 to C4, hydrogen or an alkali metal; A is branched or unbranched, substituted or unsubstituted alkylene of C1 to C9, cycloalkylene or heterocyclic radical. N-phosphonoformylamino acids have antiviral properties. Formula I

Description

In the formulas III and IV mean

R ^{3 is} alkyl of C 1 to C ₄ and A is the same radicals as in formula I. The reactions according to equation 1 can be carried out in polar or nonpolar aprotic solvents, such as benzene, toluene or 1,4-dioxane, but preferably without them. The reactions are exothermic, the compounds of the general formula IV being obtained quantitatively in high purity. The selective solvolysis of the phosphonic ester groups succeeds in each case by means of equivalent amounts of alcohol, alkali metal alcoholate, water, aqueous alkali metal hydroxide solution or by means of aqueous or alkaline solutions of ammonia or amines.

Complete hydrolysis of the carboxylic and phosphonic ester groups is achieved by reaction with stoichiometric amounts of aqueous alkali metal hydroxides.

The solvolysis products or their salts can be isolated in pure form after removal of the solvent.

embodiments example 1

N-ibis itrimethylsilyD-phosphonoformyll-glycine ethyl ester 22.6 g of bis (trimethylsilyl) are added dropwise with stirring in an argon atmosphere slowly added to 12.9 g Isocyanatoessigsäureester in such a way that the reaction mixture is not heated above 45 ⁰ C phosphite. The mixture is then stirred for a further 2 hours at room temperature. The title compound is obtained analytically pure in approximately quantitative yield

(Me ₃ SiO) ₂ P (O) -C (O) -NH-CH ₂ -COOEt CnH ₂₆ O ₆ Si ₂ NP Mg 355.86 31 _P -18.6ppm Analysis: P, Calc., 8.71, m.p. , 8.63

Example 2

N- [bis (trimethylsilyl) -phosphonoformyl] -beta-alanine ethyl ester

To 14.3 g of 2-isocyanato-propionic acid, dissolved in 30 ml of diethyl ether 22.6 g of bis (trimethylsilyl) phosphite are added dropwise in an argon atmosphere with stirring in such a way that the diethyl ester gently boils at reflux. The mixture is then stirred for an hour and concentrated in a water jet vacuum with an intermediate cold trap. The reaction product is obtained in pure form and quantitative yield by NMR spectroscopy. (Me ₃ SiO) ₂ P (O) -C (O) -NH-CH ₂ -CH ₂ -COOEt C ₁₂ H ₂₈ O ₆ Si ₂ NP MW 369.51 ³ l P-18.3 ppm, analysis: P% calc 8.38, gef. 8.24 ·

Examples 3 to 9

Analogously to Example 1 or 2 are obtained from 0.1 mol of bis (trimethylsilyl) phosphite and 0.1 mol of the corresponding Isocyanocarbonsäureesters following N- [bis (trimethylsilyl) phosphonoformyl] amino acid ethyl ester in 96-99% yield.

Ex. A Mol. ³¹ P-NMR ppm 3 -CH-CH ₂ -CH ₂ -CH ₃ 397.57 -19.2 4 -CH-CH ₃ 369.51 -19.4 CJL -CH-CH ₂ -CH ₂ -COOEt 455.60 -19.4 6 -CH-CH ₂ -Ph 445.61 -18.8 7 - (CH ₂ ) S- 399.58 -17.8 8th -CH-CH ₂ -COOEt 441.58 -18.6 9 -CH-CH ₂ -CH ₂ -S-Me 429.63 - 8,6

Table 1: N- [bis (trimethylsilyl) phosphonoformyl] amino acid ethyl ester

Example 10:

N-IPhosphonoformyl-glycine-disodium salt hexahydrate 22.6 g (0.1 mol) of bis-trimethylsilyl-phosphite are added dropwise without solvent to 12.1 g (0.1 mol) of isocyanatoacetic acid ethyl ester in a protective atmosphere in such a way that the Internal temperature does not significantly exceed 50 ° C. After completion of the reaction is stirred for 2 hours at room temperature. The resulting crude N- [bis (trimethylsilyl) phosphonoformyl] -glycine ethyl ester is added dropwise without further purification in a solution of 12 g (0.3 mol) of sodium hydroxide in 50 ml water at 0 ⁰ C to 5 ° C. The title compound is obtained after concentration of the solution as hexahydrate in approximately quantitative yield.

(Na ₂ O) ₂ P (O) -C (O) -NH-CH ₂ -COONa 6H ₂ OC ₃ H ₃ O ₆ Na ₃ NP x 6H ₂ O Mg 359.09 ³¹ P-NMR -1.1 ppm

Analyzes C N-N P

% Calc. 10.09 4.23 3.92 8.67

gef. 10.16 3.97 3.79 8.57

Examples 11 to 18

Analogously to Example 10, the following compounds are obtained in 95-99% yield from in each case 0.1 mol of bis (trimethylsilyl) phosphite and 0.1 mol of isocyanato-carboxylate after hydrolysis with aqueous sodium hydroxide solution.

Ex.

Formula Mol. Wt.

³¹ P-NMR ppm

11 12 13 14 15 16 17 18

-C H-C H 2 ~ "C H 2 ~ C H 3

-CH ₂ -CH ₂ -

-CH-CH ₃

-CH-CH ₂ -CH ₂ COONa

-CH-CH ₂ -Ph

- (CH ₂ is-

-CH-CH ₂ -COONa

-CH-CH2 ~ ~ S-CH3 Cn2

C ₆ H ₉ O ₆ Na ₃ NP x 6 H ₂ O +0.57

399.17

C ₄ H ₆ O ₆ Na ₃ NP χ 6 H ₂ O -1.14

371.11

C ₄ H ₆ O ₆ Na ₃ NP χ 6 H ₂ O + 0.86

371.11

C ₆ H ₆ O ₈ Na ₄ NP χ 8 H ₂ O +0.5

487.16

C ₁₀ H ₉ O ₆ Na ₃ NP χ 6 H ₂ O -1.1

447.22

C ₇ H ₁₁ O ₆ Na ₃ NPXeH ₂ O

413.19

C ₅ H ₄ O ₈ Na ₄ NP x 8 H ₂ O -0.5

476.11

C ₆ H ₉ O ₆ SNa ₃ NPx 6H ₂ O + 0.6

431.23

Claims (1)

Claim of invention: ... Process for the preparation of N-phosphonoformylamino acids and their derivatives of general formula I O 0
(R ¹ O) ₂ PC-NH-A-COOR ² _χ in the R ^{1 is} trimethylsilyl, hydrogen, an alkali metal, ammonium, a substituted ammonium radical R ^{2 is} alkyl of C ¹ to C ₄ , hydrogen or an alkali metal A is branched or unbranched, substituted or unsubstituted alkylene of C 1 to C ₉ , cycloalkylene or heterocyclic radical, characterized in that bis (trimethylsilyl) phosphite with isocyanato-carboxylic acid esters, at elevated temperature to N- [bis (trimethylsilyl) phosphonoformyl] - amino acid esters are reacted, which are optionally converted by means of alkaline solvolysis in compound of formula I. Field of application of the invention The invention relates to a process for the preparation of N-substituted N-phosphonoformylamino acids of general formula I. (R ¹ Q) PC-NH-A-COQR ^ I in the R ^{1 is} trimethylsilyl, hydrogen, an alkali metal, ammonium, a substituted ammonium radical R ² alkyl, VOnC ₁ to C ₄ , hydrogen or an alkali metal A branched or unbranched, substituted or unsubstituted alkylene of C ₁ to C ₉ , cycloalkylene or heterocyclic Mean rest.
N-Phosphonoformylaminqsäuren have antiviral properties. Characteristic of the known technical solutions ' N-Phosphonoformylaminosäuren the general formula I are not yet known. The same are not described reactions of bis-tri-methylsilyl-phosphite with isocyanates. Object of the invention The aim of the invention is an advantageous preparation of compounds of the general formula I, which yields almost quantitative yields in a few simple process steps. Explanation of the essence of the invention The object of the invention is a process for the preparation of N-phosphonoformylamino acids of the formula I using readily available stable starting materials. It has been found that by reacting bis-trimethylsilyl-phosphite of the formula II with isocyanato-carboxylic acid esters of the general formula III (equation 1), at elevated temperature, with the exclusion of water u. a. proton-active substances result in very good yields compounds of formula IV, which can be converted by alkaline solvolysis in conjunction according to formula I. O OO (Me ,, SiO) PH + O = C = NA-COOR ³ * (Me ^ S10) J> -C-NH-A-COOR ^J / -> II III IV