Title of Invention

A PROCESS FOR PREPARING (2-CYANO-N-ALKOXY) ACETINMIDOYL HALIDE

Abstract

The invention relates to a process for preparing (2-cyano-N-alkoxy) acetimidoyl halide of the general formula I by halogenation of a (2-cyano-N-alkoxy) acetamide of the general formula II in the presence of a halogenated solvent at a reaction temperature of from-20c to 150c. (57) Abstract: The invention relates to a process for preparing (2-cyano-N-alkoxy) acetimidoyl halide of the general formula I by halogenation of a (2-cyano-N-alkoxy) acetamide of the general formula II in the presence of a halogenated solvent at a reaction temperature of from -20°C to 150°C.

Full Text

The invention relates to a process for preparing (2-cyano-N-alkoxy)acetimidoyl halide. Malononitrile is a starting material and intermediate of central importance for the preparation of an exceptionally wide range of, for example, pharmaceutical or agrochemical active ingredients (Ullmann's Encyklopadie der technischen Chemie, 4th revised and enlarged edition, Verlag Chemie Weinheim, Volume 16, p. 419-423). Although a large number of processes are known for the preparation of malononitrile, the only one to achieve importance on an industrial scale is the high-temperature reaction of acetonitrile with cyanogen chloride at temperatures above 700°C. The object of the invention was to develop an alternative process with the potential for use on an industrial scale. The object was achieved by the novel process according to Patent Claim 1. According to the invention, a (2-cyano-N-alkoxy)acetimidoyl halide of the general formula I in which R1 and R2 are identical or different and are hydrogen or alkyl, R3 is alkyl, cycloalkyl, aryl, arylalkyl or a group in which R4 is an alkyl, aryl or arylalkyl group, and X is a halogen atom, is converted to malononitrile at a temperature of from 500°C to 1000°C. Alkyl group is expediently taken to mean a C1-6-alkyl group, namely methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl and its isomers or hexyl and its isomers. A preferred meaning of R1 is methyl, Cycloalkyl is expediently a C1-6-cycloalkyl group, namely cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Aryl is expediently optionally substituted phenyl or naphthyl, and arylalkyl is expediently a benzyl group. Both the alkyl and the aryl group can be provided with suitable substituents. Examples which may be mentioned are: C1-4-alkyl, C1-4-alkoxy, C1-4-alkanoyl, halogen, nitro, amino, alkylamino or dialkylamino. Halogen has the meaning of fluorine, chlorine, bromine or iodine, preferably bromine or chlorine. The (2-cyano-N-alkoxy)acetimidoyl halides, as starting compound for the high-temperature treatment, can be expediently prepared by halogenation of a (2-cyano-N-alkoxy) acetamide of the general formula n in which R^, R^ and R"^ are as defined above. The halogenation is preferably a chlorination and is carried out using suitable halogenating agents, such as, for example, phosphorus pentachloride, phosgene, phosphorus oxychloride or tetrachloromethane and triphenylphosphine. The reaction is expediently carried out in a suitable solvent, preferably a halogenated solvent, such as, for example, chloroform or methylene chloride. The reaction temperature for the halogenation is expediently from -20°C to 150°C. The corresponding (2-cyano-N-alkoxy)acetimidoyl halide can be obtained from the reaction mixture in an expert manner, e.g. by extraction, and, following removal of the solvent, be used for the further conversion. The high-temperature conversion according to the invention preferably proceeds at a temperature of from 700°C to 1000°C. The reaction is usually carried out in a tubular reactor. The conversion time is generally a few seconds. The reaction is advantageously carried out in the presence of a hydrogen donor, such as, for example, in the presence of alkyl-substituted aromatics, preferably toluene. Unreacted starting material can be recycled. The malononitrile can be obtained from the reaction product e.g. by extraction using a hydrocarbon and water, the aqueous phase being saturated with sodium chloride, and the malononitrile being re-extracted with an ether. The (2-cyano-N-alkoxy)acetimidoyl halides of the general formula in which R1, R2 and R3 are as defined above, are hitherto not known in the literature and are thus also provided hv the invention. Preferred (2-cyano-N-alkoxy)acetimidoyl halides are (2-cyano-N-methoxy)acetimidoyl chloride and (2-cyano-N-ethoxy)acetimidoyl chloride. Accordingly, the present invention provides a process for preparing (2-cyano-N-alkoxy) acetimidoyl halide of the general formula I I in which R and R are identical or different and hydrogen or alkyl, R is C1-6-alkyl, C3-6-cycloalkyl, optionally substituted phenyl or naphthyl, benzyl or a group in which R4 is C1-6-alkyl, optionally substituted phenyl or naphthyl or benzyl group and X is a halogen atom, by halogenation of a (2-cyano-N-alkoxy) acetamide of the general formula II n in which R1, R2 and R3 are as defined above, in the presence of a halogenated solvent such as herein described at a reaction temperature of from -20°C to 150°C. Example la: Preparation of (2-cyano-N-methoxy) acetimidoyl chloride 13.8 g (119.7 mmol) of (2-cyano-N-methoxy)-acetamide were introduced at room temperature into 200 ml of chloroform. The solution was cooled to 3°C, then 29.6 g (139 mmol) of PCI5 in 70 ml of chloroform were carefully added. After the evolution of gas had subsided, 90 ml of water were carefully added at 5°C. The aqueous phase was separated off and extracted two more times with 50 ml of methylene chloride. The combined organic phases were washed with NaHCOa until neutral, dried and concentrated by evaporation. The brown residue (11.34 g) was subjected for further purification to distillation at 85°C/10 mbar. This gave 8.5 g (53%) of a colourless liquid which, according to 1H-NMR, was pure. 1H-NMR (400 MHz, CDCl3)5: 3.60 (s, 3H, CH2) ; 4.01 (s, 3H, OCH3) . "C-NMR (400 MHz, CDCl3)6: 128.3 (s) ; 113 (s); 63.4 (q); 26.3 (t). Example lb: Preparation of (2-cyano-N-ethoxy)acetamide 13.69 g (135.3 mmol) of triethylamine were slowly added dropwise at room temperature to a solution of 12.0 g (123.0 mmol) of 0-ethylhydroxylamine hydrochloride and 11.61 g (117.2 mmol) of methyl cyanoacetate in 100 ml of methanol, and the resulting mixture was stirred at room temperature for 60 hours. Although the conversion was not yet complete, the reaction mixture was evaporated to dryness. Flash column chromatography (silica gel, firstly 1:1 ethyl acetate/hexane, then ethyl acetate) of the residue produced 8.20 g (55%) of the title product as a white solid. ^H-NMR (400 MHz, DMSO-dg) : 11.2 (s, broad, NH) ; 3.80 (q, 2H); 3.55 (s, 2H); 1.15 (t, 3H). 13C-NMR (400 MHz, DMSO-dg) : 159.37 (C=0) ; 115.53 (C=N); 70.88 (OCH2); 22.8 9 (CH2) ; 13.27 (CH3) . Exeunple Ic: Preparation of (2-cyano-N-ethoxy)acetimidoyl chloride A suspension of 7.60 g (0.037 mmol) of phosphorus pentachloride in 30 ml of chloroform was slowly added dropwise at 3°C to a solution of 3.90 g (0.030 mol) of (2-cyano-A7-ethoxy) acetamide in 70 ml of chloroform. The slightly cloudy reaction mixture was stirred at room temperature for one hour. 40 ml of H2O were added dropwise with ice cooling. The phases were separated and the aqueous phase was extracted with chloroform (2 x 50 ml). The combined organic phases were washed with a Na2C03 solution (pH w 11; 2 x 20 ml), dried using Na2S04, and the solvent was distilled off on a rotary evaporator. Kugelrohr distillation (2-4 mbar, 150°C oven temperature) of the residue produced 3.21 g (72%) of the title product as a clear, colourless oil. 1H-NMR (400 MHz, CDCI3) : 4.25 (q, 2H) ; 3.60 (s, 2H); 1.32 (t, 3H) . 13C-NMR (400 MHz, CDCI3) : . 127.78 (C1-C=N) ; 113.46 (C=N); 71.62 (OCH2) ; 2 6.41 (CH2); 14.36 (CH3) . Example 2a: Preparation of malononitrile 129 mg of (2-cyano-N-methoxy)acetimidoyl chloride were dissolved in 10 ml of toluene. This solution was injected in portions, divided into 100 µl portions, over the course of 45 minutes into a spherical vaporization flask, which was connected to a quartz pyrolysis tube (length 30 cm, internal diameter 2.5 cm and heated to 870°C) such that the pressure, reduced by means of the vacuum pump, was maintained at 0.2 mbar. The reaction products were collected in a cold trap cooled to -196°C. Analysis of the reaction mixture using ■^H-NMR and GC-MS indicated, as well as unreacted starting material and bibenzyl, a yield of malononitrile of 27%, based on starting material used. Example 2b: Preparation of malononitrile 146 mg of (2-cyano-N-ethoxy)acetimidoyl chloride were dissolved in 10 ml of toluene. This solution was injected in portions, divided into 100 µl portions, over the course of 45 minutes into a spherical vaporization flask, which was connected to a quartz pyrolysis tube (length 30 cm, internal diameter 2.5 cm and heated to 870°C) such that the pressure, reduced by means of the vacuum pump, was maintained at 0.2 mbar. The reaction products were collected in a cold trap cooled to -196°C. Analysis of the reaction mixture using 1H-NMR and GC-MS indicated, as well as unreacted starting material and bibenzyl, a yield of malononitrile of 25%, based on starting material used. Example 3: Preparation and purification of malononitrile 510 mg of (2-cyano-N-methoxy)acetimidoyl chloride were dissolved in 50 ml of toluene. This solution was injected in portions, divided into 100 µ1 portions, over the course of 130 minutes into a spherical vaporization flask, which was connected to a quartz pyrolysis tube (length 30 cm, internal diameter 2.5 cm and heated to 870°C) such that the pressure, reduced by means of the vacuum pump, was maintained at 0.3 mbar. The reaction products were collected in a cold trap cooled to -196°C. The contents of the cold trap were transferred to a separating funnel, and the cold trap was rinsed with 50 ml of hexane and twice with 40 ml of water. The combined solutions were extracted with water (a total of 150 ml) and the phases separated. 52 g of sodium chloride were added to the aqueous phase, which was then extracted by shaking three times with diethyl ether (a total of 700 ml). The etheric phase was dried using MgS04, and the solvent was removed under reduced pressure. According to 1H-NMR, the residue consisted of 95% of malononitrile and 5% of the starting material. The yield was 26%, based on starting material used. The following experiments were carried out as in Example 2 but with different quartz tube temperatures. This application has been divided out of Indian patent application no.249/MAS/99 which relates to "A process for the preparation of malononitrile". Claim 1 of the above patent application reads as: "A process for the preparation of malononitrile, characterized in that a (2-cyano-N-alkoxy) acetimidoyl halide of the general formula I in which R1 and R2 are identical or different and are hydrogen or C1-6-alkyl, R is C1-6-alkyl, C3.6-cycloalkyl, optionally substituted phenyl or naphthyl, benzyl or a group in which R4 is a C1-6-alkyl, optionally substituted phenyl or naphthyl or benzyl group, and X is a halogen atom, is converted at a temperature of from 500°C to 1000°C to obtain malononitrile. WE CLAIM; 1. A process for preparing (2-cyano-N-alkoxy) acetimidoyl halide of the general formula I in which R1 and R2 are identical or different and hydrogen or alkyl, R3 is C1-6-alkyl, C3-6-cycloalkyl, optionally substituted phenyl or naphthyl, benzyl or a group in which R4 is C1-6-alkyl, optionally substituted phenyl or naphthyl or benzyl group and X is a halogen atom, by halogenation of a (2-cyano-N-alkoxy) acetamide of the general formula II n in which R1, R2 and R3 are as defined above, in the presence of a halogenated solvent such as herein described at a reaction temperature of from -20°C to 150°C. 2. The process according to claim 1 wherein the halogenation is a chlorination and is carried out using phosphorus pentachloride, phosphene, phosphorus oxychloride or tetrachloromethane and triphenylphosphine. 3. A process for preparing (2-cyano-N-alkoxy) acetimidoyl halide, substantially as herein described and exemplified.

Documents:

0591-mas-2001 others.pdf

0591-mas-2001 abstract duplicate.pdf

0591-mas-2001 abstract.pdf

0591-mas-2001 claims duplicate.pdf

0591-mas-2001 claims.pdf

0591-mas-2001 correspondence others.pdf

0591-mas-2001 correspondence po.pdf

0591-mas-2001 description (complete) duplicate.pdf

0591-mas-2001 description (complete).pdf

0591-mas-2001 form-1.pdf

0591-mas-2001 form-26.pdf

0591-mas-2001 form-3.pdf

0591-mas-2001 form-4.pdf

0591-mas-2001 form-5.pdf