DE3544373A1 - Process for the preparation of phosphinothricin-carboxamides - Google Patents

Abstract

Process for the preparation of phosphinothricin-carboxamides by reacting phosphinothricin (which is protected on the NH2 group) with amines in the presence of a suitable condensing agent, such as dicycloacetic anhydride, followed by elimination of the protective groups.

Description

The present invention relates to a process for the preparation of carboxamides of the general formula wherein
R ¹ and R ² independently of one another are hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₈ ) alkenyl, (C ₃ -C ₈ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl, aryl , Heteroaryl with 1 or 2 N, O or S atoms, aryl (C ₁ -C ₂ ) alkyl, arylamino, where the groups mentioned in turn are formed by one or more halogen atoms, NH ₂ , NH- (C ₁ - C ₄ ) alkyl, OH, SH, NO ₂ , CF ₃ , (C ₁ -C ₄ ) alkoxy, aryloxy, (C ₁ -C ₄ ) alkylthio, (C ₁ -C ₄ ) alkoxycarbonyl, COOH, CONH ₂ , CN, ((C ₁ -C ₄ ) alkylamino), di (C ₁ -C ₄ ) alkylamino or sulfamoyl may be substituted, or
R ¹ and R ² together form an optionally substituted (C ₂ -C ₇ ) alkylene chain which can be interrupted by one or more heteroatoms,
mean, and of their salts, which is characterized in that phosphinothricine derivatives of the formula wherein
A represents a common amino protecting group, with a condensing agent from the series of carbodiimides or carboxylic anhydrides and an amine of the formula implemented and the protective groups then split off.

The compounds of formula I are partly from DE-OS 27 17 440 known as total herbicides. In the same place is a method for the preparation of phosphinothricin carbanilide given, but only a very unsatisfactory one provides low yield. The present procedure is broadly applicable and is characterized by clear higher yields.

"Aryl" generally means phenyl or naphthyl radicals. The following are considered as "heteroaryl":
Pyrrolyl, pyrrolidinyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, isothiazolyl, 1.3.4-thiadiazolyl, 1.3.5- and 1.2.4-triazinyl, benzothiazolyl, benzoxazolyl, benzimidazolidyl, pyrid , Quinolyl, isoquinolyl, quinoxalyl or quinazolyl.

R ¹ and R ² together with the N atom z. B. form an aziridine, pyrrolidine, piperidine, N-methyl or ethylpiperazine, morpholine, 3,5-dimethylmorpholine, hexamethyleneimine or heptamethyleneimine ring.

The compounds II can be prepared from phosphinothricin (Helv. Chim. Acta 55, 224-239 (1972)) by methods known from the literature (Houben-Weyl 15/2, p. 149 ff). For masking the amino group, z. B. the benzyloxycarbonyl (Cbo, Z) -, tert-butyloxycarbonyl (BOC) -, phthaloyl (PHT) - or the trifluoroacetyl (TFA) group. It is not necessary to mask the phosphinic acid group, although this would in itself be capable of reactions with the amine component or the condensing agent. Surprisingly, II forms a cyclic anhydride of the formula under the action of carbodiimide or carboxylic acid anhydride which protects the phosphinic acid group from further attack by the amine or the condensing agent and is of critical importance for the smooth course of the reaction and the high yields. Condensing agents that cause the formation of this cyclic anhydride are carbodiimides (such as dicyclohexyl carbodiimide) and anhydrides of lower aliphatic carboxylic acids such as acetic anhydride.

By reaction of an amine component of formula III with the Anhydride IV takes place with the formation of a ring N-protected phosphinothricinamids. The reaction sequence can be carried out without or with isolation of the intermediate IV will.

(a) When using a carbodiimide, the condensation of components II and III (with the intermediate formation of IV) is advantageously carried out in a one-pot reaction. It is convenient to work in an inert solvent such as CH ₂ Cl ₂ , dioxane, tetrahydrofuran, ethyl acetate, dimethoxyethane, acetonitrile or dimethylformamide at temperatures between -20 ° C and 60 ° C, preferably between -10 ° C and 50 ° C. In addition to dicyclohexylcarbodiimide, other dialkylcarbodiimides are also suitable as condensing agents.

The amino component III can be introduced into the reaction in free form or as the ammonium salt of an inorganic acid, for example as the hydrochloride. In the latter case, it must be added by adding an equivalent amount of a tertiary organic base such. B. triethylamine, N-ethylmorpholine, pyridine can be converted into the free form. If the amine component contains other reactive groups (such as OH, SH, COOH, NH ₂ or NH-alkyl), these must also be inactivated beforehand by protective groups. Such protecting groups are well known to those skilled in the art. The following are only examples:

For the OH function: tetrahydropyranyl (THP) or methoxyethoxymethyl (MEM) (Lit .: TW Greene, Protective Groups in Organic Chemistry, Verlag John Wiley & Sons, New York 1981, p. 10).
For the SH function: Benzyl (Lit .: ibid. P. 193
For the COOH function: lower alkyl esters (Lit .: ibid. P. 152)
For the NH ₂ and NHR function: cf. above (Lit .: ibid. p. 218)

About 1-1.2 moles are required to form intermediate IV Carbodiimide required per mole of II. You use that Amine III expedient in a stoichiometric amount or in Excess or leads the reaction in the presence of a tertiary organic base such as triethylamine, N-ethylmorpholine or pyridine.

(b) When using an anhydride (e.g. acetic anhydride) it is convenient to isolate intermediate IV and it then react with an amine of formula III. To Formation of IV uses about 2-20 molar equivalents Acetic anhydride (which is also a solvent serves) and works at temperatures from 0 ° C to 80 ° C, preferably 20 ° C-60 ° C. The subsequent implementation with the amine takes place under the same conditions (Temperature, solvent, etc.) as in (a).

The protective group A is split off in itself known manner z. B. by hydrogenolysis (in the Cbo Group), acid hydrolysis (BOC and TFA) or hydrazinolysis (PHT). Salts of I with acids can also be found in converted into the free amino compounds in a known manner be, e.g. B. by treatment of the hydrohalides with propylene oxide.

The following examples serve to illustrate the invention:  

example 1 2-amino-4-methylphosphonyl-butyric acid-N-methylanilide

22.1 g (0.07 mol) of II (A = benzyloxycarbonyl) and 7.5 g (0.07 mol) of N-methylaniline are dissolved in 120 ml of tetrahydrofuran and cooled to 0 ° C. At this temperature, 17.5 g (0.085 mol) of dicyclohexylcarbodiimide dissolved in 40 ml of THF are added and the mixture is stirred for a further 20 h. Excess DCC is decomposed with 2 ml of glacial acetic acid, the dicyclohexylurea is filtered off and the solvent is removed in vacuo. It is taken up in methylene chloride and the org. Phase out with NaHCO ₃ solution. The aqueous phase is acidified to pH 1 with hydrochloric acid and extracted 3 × with methylene chloride. It is dried over sodium sulfate, the solvent is removed in vacuo and 22.2 g of crude 2- (N-benzyloxycarbonylamino) -4-methyl-phosphonyl-butyric acid-N-methylphenylamide are obtained, which is dissolved in 120 ml of ethanol to split off the Cbo group . 0.5 ml of glacial acetic acid and 3 g of palladium on activated carbon (5%) are added and hydrogen is passed in at room temperature until the evolution of CO _{2 has} ended. Filtering off the catalyst and evaporation gives 13.8 g (yield over both stages 73%) of 2-amino-4-methylphosphonyl-butyric acid-N-methylphenylamide, mp. 135-136 ° C. (dec.).

Example 2 2-amino-4-methylphosphonyl-butyric acid-4-amino sulfonylphenylamide hydrochloride

22.1 g (0.07 mol) of II (A = benzyloxycarbonyl) and 12.0 g (0.07 mol) of sulfanilamide are dissolved in 200 ml of tetrahydrofuran. 17.5 g (0.085 mol) of dicyclohexylcarbodiimide in 40 ml of THF are added at 0 ° C. and the mixture is stirred for a further 20 h. Excess DCC is decomposed with 2 ml of glacial acetic acid, filtered off from the dicyclohexylurea and the solvent is removed in vacuo. It is taken up in methylene chloride and the org. Phase with NaHCO ₃ solution. The aqueous phase is acidified to pH 1 with hydrochloric acid and extracted 3 × with methylene chloride. It is dried over sodium sulfate, the solvent is removed in vacuo and 29.9 g of crude 2- (N-benzyloxycarbonylamino) -4-methylphosphonyl-butyric acid-4-aminosulfonylphenylamide are obtained, which is dissolved in 600 ml of methanol to split off the Cbo group. 20 ml of conc. HCl and 3 g of palladium on activated carbon (5%) and introduces hydrogen at room temperature until the CO ₂ evolution has ended. Filtration of the catalyst and evaporation gives 16.8 g (yield over both stages 67%) of 2-amino-4-methylphosphonyl-butyric acid-4-aminosulfonylphenylamide hydrochloride, mp. 243-245 ° C. (dec.).

Example 3 2-amino-4-methylphosphonyl-butyric acid hexylamide hydrochloride

22.1 g (0.07 mol) of II (A = benzyloxycarbonyl) and 7.1 g (0.07 mol) of hexylamine are dissolved in 120 ml of tetrahydrofuran. 17.5 g (0.085 mol) of dicyclohexylcarbodiimide in 40 ml of THF are added at 0 ° C. and the mixture is stirred for a further 20 h. Excess DCC is decomposed with 2 ml of glacial acetic acid, the dicyclohexylurea is filtered off and the solvent is removed in vacuo. It is taken up in NaHCO ₃ solution and washed with methylene chloride. The aqueous phase is acidified to pH 1 with hydrochloric acid and extracted 3 × with methylene chloride. It is dried over sodium sulfate, the solvent is removed in vacuo and 27.0 g of crude 2- (N-benzyloxycarbonylamino) -4-methylphosphonyl-butyric acid hexylamide are obtained, which is dissolved in 100 ml of ethanol to split off the Cbo group. 0.5 ml of glacial acetic acid and 3 g of palladium on activated carbon (5%) are added and hydrogen is passed in at room temperature until the evolution of CO _{2 has} ended. The product is filtered off together with the catalyst. It is taken up in 1N HCl, the catalyst is filtered off and the mixture is concentrated in vacuo. It leaves 14.0 g (yield over both stages 67%) of 2-amino-4-methylphosphonyl-butyric acid hexylamide hydrochloride, mp. 104-106 ° C.

Example 4 2-amino-4-methylphosphonyl-butyric acid phenylamide hydrochloride

5.1 g (0.016 mol) of II (A = benzyloxycarbonyl) are suspended in 25 ml of acetic anhydride. After stirring for three hours at 40 ° C., a clear solution is obtained. It is evaporated, volatile constituents are removed under high vacuum and the residue - the cyclic anhydride of the formula IV - is dissolved in 100 ml of methylene chloride. 3.0 g (0.032 mol) of aniline in 30 ml of methylene chloride are added dropwise at 0 ° C. and the mixture is stirred at room temperature for 1 h. The solution is then washed successively with 100 ml of 1N HCl and 100 ml of water, dried over sodium sulfate and evaporated in vacuo. 5.0 g of crude 2- (N-benzyloxycarbonyl-4-methyl-phosphonyl-butyric acid-phenylamide remain, which is dissolved in 100 ml of ethanol to split off the Cbo group. 1 g of palladium on activated carbon (5%) is added and introduces hydrogen until the evolution of CO ₂ is complete. The product is filtered off together with the catalyst. It is taken up in 1N HCl, the catalyst is filtered off and concentrated in vacuo. 3.6 g (yield over all Steps 77%) 2-amino-4-methylphosphonylbutyric acidphenylamide hydrochloride of mp. 140-143 ° C (dec.).

The following compounds listed in Table 1 of the general formula I can be obtained in an analogous manner will.

Table 1

Claims (2)

1. Process for the preparation of carboxamides of the general formula wherein
R ¹ and R ² independently of one another are hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₈ ) alkenyl, (C ₃ -C ₈ ) alkynyl, (C ₃ -C ₈ ) cycloalkyl, aryl , Heteroaryl with 1 or 2 N, O or S atoms, aryl (C ₁ -C ₂ ) alkyl, arylamino, where the groups mentioned in turn are formed by one or more halogen atoms, NH ₂ , NH- (C ₁ - C ₄ ) alkyl, OH, SH, NO ₂ , CF ₃ , (C ₁ -C ₄ ) alkoxy, aryloxy, (C ₁ -C ₄ ) alkylthio, (C ₁ -C ₄ ) alkoxycarbonyl, COOH, CONH ₂ , CN, ((C ₁ -C ₄ ) alkylamino), di (C ₁ -C ₄ ) alkylamino or sulfamoyl may be substituted, or
R ¹ and R ² together form an optionally substituted (C ₂ -C ₇ ) alkylene chain which can be interrupted by one or more heteroatoms,
mean, and of their salts, which is characterized in that phosphinothricine derivatives of the formula wherein
A represents a common amino protecting group, with a condensing agent from the series of carbodiimides or carboxylic anhydrides and an amine of the formula implemented and the protective groups then split off. 2. The method according to claim 1, characterized in that one as the condensing agent di-cyclohexylcarbodiimide or acetic anhydride is used.