AU9711798A - A method of producing aminocyanoacetamide - Google Patents

Abstract

Preparation of aminocyanoacetamide (I) comprises reacting cyanoacetamide with nitrites at pH 2 to give nitrosocyanoacetamide, followed by catalytic hydrogenation.

Description

Our Ref: 710942 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): Eprova AG Im Laternenacker CH-8200 Schaffhausen

SWITZERLAND

Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 A method of producing aminocyanoacetamide The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 -2- A method of producing aminocyanoacetamide This invention relates to a new method of producing aminocyanoacetamide which can be employed industrially. Aminocyanoacetamide is an intermediate which is of interest for the production of imidazoles, pyrazines, purines or pteridines for example.

Various methods of producing aminocyanoacetamide are -known. Those which should be mentioned in particular are that of Taylor et al., who in J. Am. Chem.

Soc., 76, 6080 (1954) describe a method of producing aminocyanoacetamide from hydroxyiminocyanoacetamide by hydrogenation with -aluminium amalgam, and various methods of producing aminocyanoacetamide from esters of cyanoacetic acid via esters of aminocyanoacetic acid such as that according to EP 0 342 616, which discloses the production of aminocyanoacetamide by the nitrosylation of an ester of cyanoacetic acid by means of an alkali nitrite, hydrogenation of the resulting ester of hydroxyiminocyanoacetic acid with platinum/hydrogen and the subsequent liberation of aminocyanoacetamide with aqueous ammonia. The method of Taylor et al. cannot be employed industrially due to the problems of using a mercury catalyst.

Methods of producing aminocyanoacetamide from esters of cyanoacetic acid via esters of aminocyanoacetic acid such as that described in EP 0 342 616 are methods which are costly on an industrial scale and which are based on the cumbersome reaction of cyanoacetic acid which is protected by an ester function to form an ester of aminocyanoacetic and the subsequent liberation of aminocyanoacetamide.

With the present method, a process which can be employed industrially can be used for the first time for the direct production of aminocyanoacetamide. The method is based on the reaction of cyanoacetamide with nitrites at a pH of around 2 to form nitrosocyanoacetamide and the subsequent catalytic hydrogenation of nitrosocyanoacetamide to form aminocyanoacetamide.

207/INT -3- Cyanoacetamide is a starting material which is commercially available on a large scale. Cyanoacetamide is nitrosylated with nitrites at a pH of around 2 to form nitrosocyanoacetamide. An alkali nitrite is preferably used for nitrosylation, and is preferably added to an acidic solution or suspension of cyanoacetamide. The pH is preferably held at around 2 during nitrosylation. This procedure prevents the formation of very large amounts of by-products, reduces the amount of nitrous gases which are formed and yields a product which can readily be centrifuged. The customary nitrites for nitrosylation are alkali nitrites, preferably sodium nitrite. The nitrite is used in an amount of 1-5 equivalents with respect to cyanoacetamide, preferably 1-2 equivalents with respect to cyanoacetamide. Nitrosylation is conducted in acidic media, preferably in strong, concentrated mineral acids, and in particular is conducted in hydrochloric acid at a pH of around 2. The reaction takes place in a concentrated solution or preferably in a suspension, at temperatures between 0°C and 50 0 C, preferably between o0C and 5 0

C.

The nitrosocyanoacetamide which is thus obtained is reacted by catalytic hydrogenation to form aminocyanoacetamide. Hydrogenation is effected with hydrogen in the presence of a catalyst. Suitable catalysts are preferably noble metal catalysts such as platinum, which is finely divided in amounts of 1% to 20% on the usual support materials such as carbon, alumina, silica, barium sulphate or calcium carbonate, or platinum oxide. Platinum in an amount of 2% to 10% on carbon is preferably used as the catalyst.

The catalyst is advantageously used in amounts of 1% to 30% with respect to the nitrosocyanoacetamide, most preferably 2% to 10% with respect to the nitrosocyanoacetamide.

Hydrogenation is conducted either in aqueous media such as water, or is preferably conducted in what are predominantly nonaqueous media, e.g. in low molecular weight, water-miscible alcohols such as methanol or ethanol, in low molecular weight, water-miscible carboxylic acids such as formic acid or acetic acid, or in tetrahydrofuran. A little sodium hydrogen phthalate can be added to buffer aqueous 207/INT hydrogenation solutions. Other additives can be added to the hydrogenation solution, such as iron sulphate to prevent the formation of gaseous hydrogen cyanide, Raney nickel to prevent poisoning of the catalyst, etc.

Even when working in nonaqueous media, the use of hydrous catalysts does not give rise to problems. After the reaction is complete, the catalysts used can easily be worked up again and used for the next reactions.

Hydrogenation is effected at a pressure of 1 bar to 100 bar, preferably 1 bar to 1W bar, and at temperatures between OOC and 80 0 C, preferably between 20 0 C and 50 0

C.

The time of hydrogenation can vary between 30 minutes and- 20 hours depending on the pressure, temperature, medium and amount of catalyst.

After the completion of hydrogenation in aqueous media the pH of the reaction solution can be lowered by the addition of an acid such as acetic acid. This procedure prevents the formation of very large amounts of by-products.

207/INT Examples to illustrate the invention Example 1 Production of nitrosocyanamide 33.5 kg cyanoacetamide were placed in 78 1 water in a reaction vessel and adjusted to pH 2.3 with 0.1 kg of 37% hydrochloric acid. A solution of 28.7 kg sodiuji nitrite in 45 1 water was then added over 7 hours. In the course of the addition, the pH of the reaction solution was held between 1.5 and 2.5 by adding a total of 36 kg of 37% hydrochloric acid. The temperature of the reaction solution was maintained below 40 0 C. Nitrosocyanoacetamide crystallised from the clear yellowish-red solution which was formed during the addition of the sodium nitrite solution even before the addition was complete. The yellow suspension was stirred overnight at room temperature and was subsequently cooled to The thick, white crystallisation slurry which was thus obtained was centrifuged off at 50C, and was subsequently washed with water and dried at 500C under vacuum.

33.9 kg nitrosocyanoacetamide were obtained, with a content of 99.1% as determined by titration. The substance was identified by means of IR and NMR measurements. Comparison of these spectra with those of a reference substance showed that the values were identical.

Example 2 Production of nitrosocyanamide 250 ml 37% hydrochloric acid (3 moles) were placed in a reaction vessel at 00C and were treated with 171.6 g cyanoacetamide (2 moles). A solution of 156.0 g sodium nitrite (2.26 moles) in 600 ml water was added drop-wise thereto, with stirring, over 5-7 hours. The temperature was maintained at 0°C to 30C during the addition.

The resulting white crystalline product was filtered off under suction, and was subsequently washed with water and dried at 400C under vacuum. 142.6 g nitrosocyanoacetamide was obtained, with a content of 97.4% as determined by 207/INT -6means of HPLC. The proportion of cyanoacetamide in the product thus obtained was as determined by means of HPLC.

Example 3 Production of nitrosocyanamide kg cyanoacetamide and 1.8 kg sodium nitrite were placed in 4.3 1 water. After heating to 20 0 C, 2.4 1 37% hydrochloric acid were added drop-wise over 6 hours.

The temperature was maintained at 40 0 C to 50 0 C during -the addition. After the addition was complete, the resulting suspension was stirred for a further 40-50 minutes at 35 0 C to 40 0 C and was thereafter cooled to 10 0

C.

The resulting white crystalline product was filtered off under suction, and was subsequently washed with water and dried at 40 0 C under vacuum. 2.5 kg nitrosocyanoacetamide was obtained, with a content of 90.7%.

The 2.5 kg nitrosocyanoacetamide which were thus obtained were heated to boiling in 7.1 1 isopropanol and were treated with 70 ml water. After 2 hours the suspension was filtered to clarify it.. The residue was washed with 800 ml of hot isopropanol. After concentrating the filtrates to about 4 1, the yellowish suspension was maintained at -20 0 C overnight.

The resulting white crystalline product was filtered off under suction, and was subsequently washed with water and dried at 40 0 C under vacuum. 2.0 kg nitrosocyanoacetamide was obtained, which had a content of 100.0% and a decomposition point of about 170 0 C. The proportion of NaCl in the product thus obtained was less than 0.5 207/INT

I

-7- Example 4 Production of nitrosocyanamide 1 of 37% hydrochloric acid were placed in a vessel and treated with 5.15 kg cyanoacetamide. A solution of 4.68 kg sodium nitrite in 1.8 1 water was added drop-wise thereto, with stirring, over 3 hours. The temperature was maintained at during this addition.

The resulting white crystalline product was filtered off under suction, and was subsequently washed with water and dried at 40 0 C under vacuum. 5.47 kg nitrosocyanoacetamide were obtained, which had a content of 98.7% as determined by means of HPLC. The chloride content of the product thus obtained was 0.4%.

Example Production of aminocyanoacetamide 31 g nitrosocyanoacetamide (0.27 moles) were placed in 700 ml methanol in a steel autoclave and were treated with 20 g of a platinum catalyst (5 on carbon with water). After flushing with nitrogen and hydrogen the batch was hydrogenated at room temperature and 2 bar hydrogen pressure for 14 hours.

After depressurisation, the autoclave contents were filtered under suction and the light yellow filtrate obtained was concentrated under vacuum until crystallisation occurred. The crystalline product was slurried in 250 ml isopropanol, filtered under suction and at dried at 40 0 C under vacuum. 23 g aminocyanoacetamide were obtained, which was slightly light beige in colour and had a content of 84.1% as determined by means of HPLC and a decomposition point of about 120 0

C.

207/INT -8- Example 6 Production of aminocyanoacetamide Hydrogenations were performed, analogously to example 5, in the following media and with the catalysts listed.

Solvent Amount of Pt Tempe- Duration Yield 'Coxint catalyst content ature of hydrogenation a tetrahydrofuran 5 g 5.0% RT 27iirs 52.7% 88.0% b ethanol 5 g 5.0% RT 50 hrs 79.2% 79.1% c methanol 20 g 2.5% RT 17 hrs 87.1% 80.8% d 40% acetic acid 7.75 g 5.0% 25 0 C 10 his 66.2% 94.2% e 40% acetic acid 7.75 g 5.0% 24PC 8 his 69.4% 97.5% f 40% acetic acid 7.75 g 5.0% 25 0 C 7 his 72.6% 99.2% g water 7.75 g 5.0% 24PC 6 hrs 66.5% 89.6% h 0.25% acetic acid 7.75 g 5.0% 24PC 5 his 75.7% 97.0% Swater 7.75 g 5.0% 24PC 6 hrs 68.1% 98.9% j water 7.75 g 5.0% 10 0 C 9 hrs 73.8% 99.9% k water 7.75 g 5.0% 12 0 C 9 his 69.0% 99.9% 1 water 7.75 g 5.0% 11ft 8 hrs 72.1% 99.5% m water 7.75 g 5.0% 12 0 C 17 his 81.4% 96.0% water 7.75 g 5.0% 12C 20 hrs 77.8% 88.8% water 7.75 gi) 5.0% 23 0 C 9 his 74.4% 85.6% p water 7.75 g 1 5.0% 23 0 C 7 his 78.5% 99.5% q water 7.75 g 1 5.0% 23 0 C 7 his 80.1% 99.9% r water 7.75 gI1) 5.0% 23 0 C 7 his 83.0% 99.9% s water 7.75 gi) 5.0% 23 0 C 7 his 81.9% 99.9% t water 7.75 g 5.0% 23 0 C 7 hrs 82.6% 99.9% 1) The catalyst used in the preceding batch in each case was used in examples o to t. The catalyst was worked up each time by washing with water/dilute hydrochloric acid and subsequent drying at 130 0

C.

207/INT -9- Example 7 Production of aminocyanoacetamide 200 g nitrosocyanoacetamide (1.77 moles) were placed in 2 1 water in a steel autoclave and treated with 49.45 g of a platinum catalyst on carbon). After flushing with nitrogen and hydrogen, the batch was hydrogenated at 24 0 C and 2 bar hydrogen pressure for 8 hours.

After depressurisation, 117 ml acetic acid was added to the hydrogenation solution.

The clarified, filtered yellowish hydrogenation solution was concentrated under vacuum at 50 0 C until crystallisation occurred. The crystalline product was treated with 450 ml isopropanol and maintained at 0°C overnight.

The resulting crystalline product was filtered under suction, and was subsequently washed with cold isopropanol and dried at 40 0 C under vacuum. 136.7 g of very slightly light yellowish aminocyanoacetamide were obtained, with a content of 99.7% as determined by means of titration and a content of aminomalonic acid diamide of 0.26% as determined by means of HPLC.

100 g of the crude aminocyanoacetamide which was thus obtained were dissolved in 240 ml water at 85 0 C and rapidly cooled to 0°C. The crystalline product which was thus obtained was filtered under suction, and was subsequently washed with cold isopropanol and dried at 40 0 C under vacuum. 79.2 g of colourless aminocyanoacetamide was obtained, which had a content of 100.0% as determined by means of HPLC.

Similarly, 20 g of the crude aminocyanoacetamide obtained were dissolved in a mixture of 200 ml water and 600 ml isopropanol at 20 0 C and rapidly cooled to 0 0

C.

The crystalline product thus obtained was filtered off under suction, and was subsequently washed with a cold mixture of water and isopropanol and was dried at 0 C under vacuum. 11.6 g of colourless aminocyanoacetamide was obtained, with a content of 100.0% as determined by means of HPLC.

At room temperature, the product which was thus obtained exhibited a solubility in methanol of 1.65 g/100 ml and a solubility in ethanol of 0.85 g/100 ml.

207/INT 10 Example 8 Productionx of aminocyauoacetamide kg of a platinum catalyst (S5% on carbon with about S0% water) were placed ina hydrogenation reactor which had been rendered inert and were treated with 119 kg.

methanol. 14.7 kg nitrosocyanoacetamide (130 moles) were added to this suspension. After flushing with nitrogen and hydrogen, the batch was hydrogenate4~ at 40-45 0 C and 2 bar hydrogen pressure for I I hours.

After depressurisation, the hydrogenation solution was clarified by fltcration and the filtate was cooled to -18 0 C overnight.

The resulting crystalline product was centrifuged off, and was subsequently washed with cold ethanol and dried at 40 0 C under vacuum. 8.3 kg of slightly yellowish aminocyanoacetamide was obtained, with a content of 99.2 as determined by means of HPLC and a content of nitrosocyanoacetainide of 3.5 as determined by means of HPLC.

By recrystallisation in an analogous manner to example 7, colourless aminocyanoaceramide was obtained, with a content of 100. 0% as determined by means of HPLC and a content of nitrosocyanoacetamide of 0. 1% as determined by means of HPLC 207/INT

Claims (2)

12- 8 A method according to claim 1, characterised in that nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in aqueous media. 9 A method according to claim 1, characterised in that nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in nonaqueous media, preferably in low molecular weight, water-miscible alcohols such as methanol or ethanol, in low molecular weight, water- miscible carboxylic acids such as formic acid or acetic acid, or in tetrahydrofuran. A method according to claim 9, characterised in that nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in methanol. 11 A method according to claims 1, 8, 9 or 10, characterised in that noble metal catalysts such as platinum, which is finely divided in amounts of 1% to 20% on customary support materials such as carbon, alumina, silica, barium sulphate or calcium carbonate, or platinum oxide, are used as a catalyst for the catalytic hydrogenation of nitrosocyanoacetamide to form aminocyanoacetamide. 12 A method according to claims 1, 8, 9, 10 or 11, characterised in that platinum in an amount of 2% to 10% on carbon is used as a catalyst for the catalytic hydrogenation of nitrosocyanoacetamide to form amino- cyanoacetamide. 13 A method according to claims 1, 8, 9, 10, 11 or 12, characterised in that the catalyst for the catalytic hydrogenation of nitrosocyanoacetamide to form aminocyanoacetamide is used in amounts of 1% to 30% with respect to 207/INT

13- nitrosocyanoacetamide, preferably 2% to 10% with respect to nitroso- cyanoacetamide. 14 A method according to claims 1, 8, 9, 10, 11, 12 or 13, characterised in that nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation with hydrogen at 1 bar to 100 bar, preferably at 1 bar to bar and at temperatures between 0°C and 80°C, preferably between 20 0 C and4 500C. A method for the production of aminocyanoacetamide, and aminocyanoacetamide so produced, substantially as hereinbefore described with reference to the Examples. DATED this 14th day of December 1998 EPROVA AG By its Patent Attorneys DAVIES COLLISON CAVE 207/INT