DD286590A5 - METHOD FOR PRODUCING N-PHOSPHONOMETHYL-GLYCINE AND ITS DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of N-phosphonomethyl-glycine and its derivatives of the formula I by reacting N-chloromethyl-N-acyl-glycinalkylestern with (Me3SiO) 3P or (Me3SiO) 3P in the presence of hexamethyldisilazane (HMDZ) or with a reaction mixture of * (Me3SiO) 3P and (Me3Si) 2NH to N-bis (trimethylsilyl) phosphonomethyl-N-acyl-glycine alkyl esters, which are optionally derivatized by solvolysis to compounds of the formula I. In formula I, R represents an alkyl radical of C1-C6, hydrogen, an alkali metal; R 1, R 2 are identical or different radicals, such as trimethylsilyl, hydrogen, an alkali metal, ammonium or substituted ammonium radical; R3 is an acyl radical such as acetyl, methoxy or ethoxycarbonyl, or hydrogen. Formula I {N-phosphonomethyl-glycine; N-chloromethyl-N-acyl-glycinalkylester; Bis (trimethylsilyl) phosphite; Tris (trismethylsilyl) phosphite; hexamethyldisilazane; N-bis (trimethylsilyl) phosphonomethyl-N-acyl-glycinalkylester}

Description

Process for the preparation of N-phosphonomethyl-glycine and its derivatives

Field of application of the invention

The invention relates to a process for the preparation of N-phosphonomethyl-glycine and its derivatives of general formula I.

pl _n 0 R ³ κ υ Ii ι

"> P-CH ,, - N-CH ₉ -COOR I

in which R is an alkyl radical of C _{1 -C fi} , hydrogen, an alkali metal

12 ίο

metal; R and R are the same or different radicals such as Trirnethylsilyl, hydrogen, an alkali metal, ammonium or

3 subst. Amrnoniumrest; R is an aoyl radical such as acetyl, methoxy or

Ethoxycarbonyl, or hydrogen. Characteristic of the known state of the art

N-phosphonomethyl-glycine can be prepared by various methods whose problem solutions are mainly to avoid a double phosphonomethylation of glycine au. This is generally achieved by using N-protected glycine derivatives such as N-tert-butylglycine (US 3927080) or substituted N-benzyl-glycines (US 3956370) or diketopiperasines (DD 123192). The disadvantage of these methods consists mainly in the fact that the groups of animals concerned often have to be removed with considerable effort. This also applies to the reaction of N-chloroethyl-N-acyl-glycinalkylestern with trialkyl phosphites to N-dialkylphosphoriomethyl-N-acyl-glyeinalky! Esters and their subsequent hydrolysis by means of concentrated mineral acids. (EP 97522; 104775) Also disadvantageous are undesirable side reactions of the trialkyl phosphites with the alkyl halides formed in the Michaelis-Arbusow reaction. The reaction of N-chloroethyl-N-acyl-glyoinalkylestern with tris (trirnebhylsilyl) phosphite is not described.

Object of the invention

The aim of the invention is a simple preparation of compounds of the formula I which are obtained in high yields in a few process steps.

zn fjo -3-

Explanation of the essence of the invention

The object of the invention is a novel process for the preparation of these compounds using readily available Trirnethylsilylphosphite as starting materials. According to the invention, N-chloromethyl-N-acyl-glycine alkyl esters with (MeoSiO) oP or (Me ,, SiO) oP in the presence of hexamethyl

OO OO

Disilazane (HMDZ) or with a Reaktionsgernisch of <(Me ₃ SiO) ₂ P (O) H, (Me ₃ SiO) ₃ P and (Me ₃ Si) ₂ NH under inert gas at a temperature of 90-100 ⁰ C according to equation 1 or 2 in high yields to give bis (trimethylsilylJphosphonojiethyl-N-acylglycinalkylestern reacted, which are optionally converted by solvolysis under mild basic or acidic conditions in a compound of formula I.

η ³ η R ³ / η

Y (HMDZ) ί! γ ^{1)

(Me ₃ SiO) ₃ P + Cl-CH ₂ -N-CH ₂ -COOR ► (Me ₃ SiO) ₂ P-CH ₂ -N-CH ₂ -COOR

0 R ³

X (Me ₃ SiO) ₃ P + y (Me ₃ Si0) ₂ p'H > ^ (Me ₃ Si) ₂ NH + x + y Cl-CHg-N-CHg-COOR

0 R ³ ►x + y (Me ₃ SiO) ₂ P-CH ₂ -N-CH ₂ -COOR + ^ NH ₄ Cl (2)

The reaction in the presence of HMDZ guarantees a quantitative implementation of the total phosphorus components, ie even small amounts of bis (trimethylsilyl) phosphite, which are always present in technically available tris (trimethylsilyl) phosphite, during the reaction by silylation, using HMDZ / Me ₃ SiCl the Ur Nsetzung with N-chloro-N-acylglycinalkylestern made accessible. In principle, a complex purification of tris (trirnethylsilyl) phosphite is unnecessary. The readily available reaction mixtures of (Me ₃ SiO) ₂ P (O) H, (Me ₃ SiO) ₃ P and HMDZ of approximate composition of 20:70:10 mol% are suitably used. The hydrolysis of N-bis (trirnethylsilyl) phosphonomethyl-N-acylglycinalkylester can be carried out in contrast to the known methods under mild conditions.

EMBODIMENTS

Example 1: N-bis (trimethylsilyl) phosphonomethyl-N-acetylglycine ethyl ester

To 29.8 g (0.1 mmol) of tris (trirnethylsilyl) phosphite in an inert gas atmosphere with stirring at a temperature of 95 ⁰ C 19.3 g (0.1 mol) of N-chloro-N-methyl-N-acetyl-g · ethyl ester added dropwise in the white, that the resulting Me ₃ SIvIl continuously distilled off. After the Au expected amount of Me ₃ SiCl (12.6 ml) is separated, the reaction mixture is stirred for 2 h at 95 ⁰ C. The ³¹ P NMR study of the reaction mixture indicates a quantitative reaction.

38.4 g; ³¹ P NMR 4.01 ppm;

P over. 8.07 % 7.92 %

Yield: 38.4 g; ³¹ P NMR 4.01 ppm; MW 383, ϊ ^; 3;

Example 2: N-bis (trimethylsilyl) phosphonomethyl-N-acetylglycine methyl ester

To 29.8 g (0.1 mol) of tris (trimethylsilyl) phosphite and 5 mrnol HMDZ can be in a Inertgasatrnosphäre with stirring at a temperature of 95 ⁰ C 17.9 g (0.1 mol) of N-Chlorrnethyl-N-acetylglycinmethylester dripped so that resulting trimethylchlorosilane continuously distilled off. After 12.6 ml of Meo were separated, the mixture is stirred for a further 2 h at 95 C. The P-NMR study of the reaction mixture indicates a quantitative reaction.

Yield: 36.9 g; ³¹ P NMR 3.89 ppm; MW 369.50; C ₁₂ H ₂₈ OgNSi ₂ PP calc. 8.38% gef. 8.18 %

Example 3: N-bis (trirnethylsilyl) phosphono-ethyl N-acetylglycine ethyl ester

A mixture of 0.02 mmol of bis (trirnethylsilyl) phosphite, 0.08 mol of tris (trimethylsilyl) phosphite and 0.02 mol of hexamethyldisilazane in an inert gas atmosphere with stirring at a temperature of 95 ⁰ C within 30 minutes with 19.3 g (0.1 mol) N-chloroethyl-N-acetyl-glycine ethyl ester and stirred for a further 2 h at this temperature. The course of the

31 Reaction is monitored by P-NMR spectroscopy. After 2 h, a complete reaction of the phosphorus components is observed. The volatile constituents, mainly Me ₃ SiCl and HMDZ, are removed in vacuo. The reaction product, which contains small amounts of NH.Cl (about 6 mmol), is not worked up before hydrolysis. ³¹ P NMR 4.31 ppm.

ZfCSSO

Example 4: H-bis (trimethylsilyl) phosphonomethyl-N-acetylglycine methyl ester

Analogously to Example 3, a mixture of (Me ₃ SiO) ₂ P (O) H, (Me ₃ SiO) ₃ P and (Me ₃ Si) ₂ NH, which contains a total of 0.1 mol silyl phosphites, with 17.9 g ( 0.1 mol) of N-chloromethyl

O 1

N-acetyl-glycine methyl ester implemented. The P-NMR spectroscopic study also indicates complete conversion of the phosphorus components.

Example 5:

N-BisitrimethylsilyDphosphonomethyl-N-methoxycarbonyl-glycine ethyl ester

Analogously to Example 1, 0.1 mmol of tris (trimethylsilyl) phosphite are reacted with 20.9 g (0.1 mol) of N-chloromethyl-N-rnethoxycarbonyl-glycine ethyl ester and, after removal of volatile constituents, examined by NMR spectroscopy.

Yield: 39.8 g; ³¹ P NMR 2.99 ppm; MW 399.53; C ₁₃ H ₃₀ O ₇ NSi ₂ P;

P over. 7.75 %; gef. 7.53 %

Example 6: N-phosphonomethyl-glycine: 38.3 g (0.1 mol) of the N-bis (trimethylsilyl) phosphonomethyl-M-acetyl-glycine ethyl ester obtained according to Example 1 are stirred at room temperature with vigorous stirring with 250 ml of 20% hydrochloric acid mixed and refluxed for 5 h. Subsequently, the reaction mixture is concentrated in a rotary evaporator in vacuo, redissolved in hot water and concentrated again. This procedure is repeated several times to free the phosphonomethylglycine from adhering hydrogen chloride. The reaction product is subsequently converted from water into a glass.

Yield: 15 g (88.7%); MW 169.07; C ₃ H ₉ O ₅ NP; ³¹ P-NMR 8.78 ppm (t, ² J _CH 12.7 Hz; ¹ H-NMR P-CH ₂ 3.27 ppm (d, ² J _cn 12.76 Hz); N-CH ₉ 4.05 ppm (s);

¹³ C-NMR P-CH ₂ 44.32 ppm (d, J _pc 138.64 Hz); CH ₂ -C (O) 49.11 ppm (d, J _pcN 4.1 Ha); COOH 169.29 ppm (s)

Example 7: N-phosphonomethylglycine

30.9 g (0.1 mmol) of the product obtained according to Example 5

N-bis (trimethylsilyl) phosphonoromethyl-N-methoxycarbonyl-glycine ethyl ester are stirred at room temperature with vigorous stirring

mixed with 250 ml of 1 molar hydrochloric acid and refluxed for 5 h

heated. Subsequently, the Reaktionsansats is concentrated in a rotary evaporator in vacuo, redissolved in hot water and concentrated again. This procedure is repeated several times. The reaction product is then recrystallized from water.

Yield: 14.2 g (83.9 %); NMR spectroscopic data

correspond to example 6

Claims (3)

no ~ ^x ~ claim 1. Method Eur production of N-phosphono-ethyl-glycine and its derivatives of general formula I. pin 0 R ³ ₉ / P-CH ₉ -N-CH ₉ -COOR I R ^ O ^{Δ Δ} in the R is an alkyl radical of C ₁ -C _e , hydrogen, an alkali metal; 12 'id R, R are the same or different radicals, such as trimethylsilyl, hydrogen, an alkali metal, ammonium or substituted ammonium radical; 3
R 'is an acyl radical such as acetyl, methoxy or ethoxycarbonyl, or hydrogen, characterized in that N-chloromethyl-N-acyl-glycinalkylester with tris (trimethylsilyl) phosphite or with tris (trimethylsilyl) phosphite in the presence of hexamethyldisilaan or with a mixture of bis (trimethylsilyl) phosphite tris (trimethylsilyl) phosphite and hexamethyldisiasiasan are reacted at elevated temperature to N-bis (trimethylsilyl) phosphonomethyl-N-acyl-glycinalkylester which optionally by solvolysis under mildly basic or acidic conditions in a compound of formula I. Be transferred. 2. The method according to item 1, characterized in that the reactions are carried out at elevated temperature in a range of 90-100 ⁰ C under Schutagas. 3. The method according to item 1, gekennseichnet characterized in that the solvolysis is carried out with equivalent amounts of dilute bases or by means of dilute acids.