CA2256251C - A method of producing aminocyanoacetamide - Google Patents
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- CA2256251C CA2256251C CA2256251A CA2256251A CA2256251C CA 2256251 C CA2256251 C CA 2256251C CA 2256251 A CA2256251 A CA 2256251A CA 2256251 A CA2256251 A CA 2256251A CA 2256251 C CA2256251 C CA 2256251C
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- nitrosocyanoacetamide
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- C07C253/00—Preparation of carboxylic acid nitriles
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Abstract
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 to form nitrosocyanoacetamide at a pH of around 2 and on the subsequent catalytic hydrogenation of nitrosocyanoacetamide to form aminocyanoacetamide.
Description
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 nitroso-cyanoacetamide to form aminocyanoacetamide.
_3 _ Cyanoacetamide is a starting material which is cotnmcrcially available on a large scale.
Cyanoacetamide is nitrosylated with nitrites at a pE-I of around 2 to form nitrosocyanoacetamide. An alkali nitrite is preferably used f:or nitrosylation, and is preferably added to an acidic solution or suspension of cyanoacetainide. The pH is pr=eferably lield at arouttd 2 during nitrosylation. 'I'his procedure prevents the formation o(' very large arnounts of by-products, reduces the arnoun.t of nitrous gases which are formed and yields a product which can readily be centrifuged. `I'he customary nitrites for nitrosylation are alkali nitrites, preferably sodiutn nutrite The rritrite is used in an amount of 1-5 equivalents with respect to cyanoac.etarnide, preferably 1-2 equivalents with respect to cyanoacetaniide. 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. In particular, a pi-l of preferably around 2 within this reaction step results in a direct crystallization of nitrosocyanoacetarnide. At higher p:El values, namely above 2.6, which is the IrII o1' an aqueous solution of nitrosocyanoacetamide, the undesired semi-sodium salt precipitates. 'rhis undesired sewni-sodium salt is obtained in a very fine form and therefore on an industrial scale the product is hardly separable and washable. Such a product will always also contain higir arnounts of sodium chloride and by-products of the reactiorr. Another drawback of' the precipitation of the semi-sodium salt is that it is a highly exothermal reaction forcing the hydrolysis of cyarioacetamide.
Thus, the reaction is conclucted at a pIl lower than 2.6 under conditions wherein essentially no undesired semi-alkali metal (especially sodium) salt precipitates. 'The reaction takes place in a concentrated solution or preferably in a suspension, at temperatures between 0"C and 50"C, preferably between 0 (' and 5 C.
The nitrosocyanoacetamide which is thus obtained is reacted by catalytic hydrogenation to form aminocyanoacetamide. Hydrogenation is eff-ected with hydrogen in the present of' a catalyst. Suitable catalysts are preterably noble rnetal catalysts such as platinum, which is finely divided in arYrounts oi' 1 io to 20%' on the usual support materials such as carbon, alumina, silica, barium sulphate or calciunr carbonate, or platinum oxide.
Platinum in an amount of 20rO to 10% otl carbon is prel'erably used as the catalyst.
The catalyst is advantageously used in ainounts of 19/o to 30% with respect to the nitrosocyanoacetamide, most preferably 20ii) t<10`', "a with respect to the nitrosocyanoaeetamide.
Hydrogenation is conducted either in aqueous media such as water, or is preferably conducted in what are predominantly nonaqueous med'ra, 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 ltydrogenation solutions. Other additives can be, added to the hvdxogertation 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, tllc catalvst:s used can easilv be worked up again and used for the next reactions.
Hydrogenation is effected at a pressure of I bar to 100 bai-, preferably 1 bar to 10 bar, and at temperatures between 0 C: aird 80 C:, preferably between 20 C and 50 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. 'I his procedure prevents the formation of'very large amounts ofb~=-l.~roducts, Iri another aspect, the present invention provides a method of providing aminocyanoacetamide comprising reacting cyanoacetamide with an alkali metal nitrite, at a pH of less than 2.6 and under conditions wherein little or no semi-alkali metal salt precipitates, to form nitrosocyanoacetaniide and subjecting the latter to catalytic hydrogenation to form aminocyanoacetarnide, In another aspect, the present invention provides a method of preparing aminocyanoacetamide comprising catalytically hydrogenating nitrosocyanoacetamide.
In another aspect, the present invention provides a method of preparing nitrosocyanoacetomide comprising reacting an alkali metal nitrite with cyanoacetamide at a pH below 2.6 under conditions wlierein little or no semi-alkali rnetal salt precipitates.
^~ ..
Examples to illustrate the invention Example 1 Production of nitrosocyanoacetamidt 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 r~. hydrochloric acid. A solution of 28.7 kg, sodium nitrite in 45 I water was then added over 7 hours. ln the course of the addition, the pH of the reaction solution was held between 11.5 and 2.5 by adding a total of 36 kg of 37% hydrochloric acici. The te.rnp~:.rature of the reaction solution was maintained below 40 C. Nitrosocyanoacetarnide crystaliised from the clear yellowish-red solution which was formed durinc, the acldirion of tk-ie sodium nitrite solution , even before the addition was complete. The yellow suspension was stirred overnight at room temperature and was subsequently cooled to 5''C.
The thick, white cryst,allisation slurry which was tlius obtained was centrifuged off at 5 C, and was subsequently washed with water and dried at 50 C utider vacuum.
33.9 kg nitrosocyanoacet.amide 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 witla those of a reference substance showed that the values were identical.
Example 2 Production of nitrosocyanoacetamide 250 ml 37 % hydrochloric acid (3 moles) were placed in a reaction vessel at 0 C and were treated with 171.6 g cyanoacetamide (2 rnoles). 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 maintairied at 0"C to 3 C during the addition.
The resulting white crystalline product was filtered r,,ff under suction, and was subsequently washed with water and dried at 40 C under vacuurn. 142.6 g nitrosocyanoacetarnide was obtained, wit'h a cont(,nt of 97.4% as dererrnined by M,..,',..,...,. .
means of HPLC. The proportion of cyanoacetamide in the product thus obtained was 0.3%, as determined by mearis of 1-1Pi..,C.
Example 3 Production of nitrosocvanoacetamide 2.0 kg cyanoacetamide and 1..8 kg sodiurrt nitrite were placed iri 4.3 1 water. After heating to 20 C, 2.4 1 37% hydrochloric acid were added drop-wise over 6 hours.
The temperature was maintained at 40"C' to 56'(:; cluring the addition. After-the addition was complete, the resulting suspension was st.irred for a further 40-minutes at 35 C to 40 C and was thereafter cooled to 10 C.
The resulting white crystalline product. was filtered off under suction, and was subsequently washed with water and dried at 400 C under vacuum. 2.5 kg nitrosocyanoacetamide was obtained, with a content of 90, 7 50 .
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 C overnight.
The resulting white crysta9line product was filtered off under suction, and was subsequently washed with water and dried at 40t under vacuum. 2.0 kg nitrosocyanoacetamide was obtained, which ha(i a content of 10C).0% and a decomposition point of about 170 C:, 'I`he proportion of NaCI in the product thus obtained was less than 0.5 %.
Example 4 Production of nitrosocyanoacetarnidv 7.5 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, ovet- 3 hours. "t'hc, temperature was maintained at 5 C during this addition.
The resulting white crystalline product was filtered off under suction, and was subsequently washed with water and dried at 40"C. under vacuum. 5.47 kg nitrosocyanoacetamide were obtained, ~.Ohic.h had a content of 98.7% as determined by means of HPLC. The chloride content of theproduc.t thus obtained was 0.4%.
Example 5 Production of aminocyanoacetauiide 31 g nitrosocyanoacetamide (0.27 moies) were placed in 700 ml methanol in a steel autoclave and were treated with 20 g of a platinum catalyst (5 % on carbon with 50% water). After flushing with nitrogen and hydrogen the batch was hydrogenated at room temperature and 2 bar hydrogen pressure for 14 hours.
After depressurisatian, tlie autoclave contents were filtered under suctiort and the light yellow filtrate obtained was concentrated under vacuum until crystallisation occurred. The crystalline product was slurried in 250 mt isopropanol, filtered under suction and at dried at 40 C under vacuum. 23 g aminocyanoacetamide were obtained, which was slightly light beige in colour and had a content of 84.1 %
as deternlined by means of NPL(' and a decompositiora point of about 120``C:.
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 Content catalyst content ature of hydrog-enation a tetrahydrofuran 5 g 5.0% RT 27 hrs 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 C 10 hrs 66.2% 94.2%
e 40% acetic acid 7.75 g 5.0% 24 C 8 hrs 69.4% 97.5%
f 40 % acetic acid 7.75 g 5.0% 25 C 7 hrs 72.6% 99.2%
g water 7.75 g 5.0% 24 C 6 hrs 66.5% 89.6%
h 0.25 % acetic acid 7.75 g 5.0% 24 C 5 hrs 75.7% 97.0%
i water 7.75 g 5.0% 24 C 6 hrs 68.1% 98.9%
j water 7.75 g 5.0% 10 C 9 hrs 73.8% 99.9%
k water 7.75 g 5.0% 12 C 9 hrs 69.0% 99.9%
1 water 7.75 g 5.0% 11 C 8 hrs 72.1% 99.5%
m water 7.75 g 5.0% 12 C 17 hrs 81.4% 96.0%
n water 7.75 g 5.0% 12 C 20 hrs 77.8% 88.8%
o water 7.75 g') 5.0% 23 C 9 hrs 74.4% 85.6%
p water 7.75 g') 5.0% 23 C 7 hrs 78.5% 99.5%
q water 7.75 g') 5.0% 23 C 7 hrs 80.1% 99.9%
r water 7.75 g') 5.0% 23 C 7 hrs 83.0% 99.9%
s water 7.75 gl) 5.0% 23 C 7 hrs 81.9 % 99.9%
t water 7.75 g 1) 5.0% 23 C 7 hrs 82.6% 99.9%
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 C.
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 (5 % on carbon).
After flushing with nitrogen and hydrogen, the batch was hydrogenated at 24 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 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 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 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 C under vacuum. 79.2 g of colourless amino-cyanoacetamide 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 C and rapidly cooled to 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 40 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.
Example 8 Production of aminocyanoacetamide 8.5 kg of platinum catalyst (5% on carbon with about 50% water) were placed in a 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 hydrogenated at 40-45 C and 2 bar hydrogen pressure for 11 hours.
After depressurisation, the hydrogenation solution was clarified by filtration and the filtrate was cooled to -18 C overnight.
The resulting crystalline product was centrifuged off, and was subsequently washed with cold ethanol and dried at 40 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 nitrosocyanoactamide of 3.5% as determined by means of HPLC.
By recrystallisation in an analogous manner to example 7, colourless aminocyanoacetamide was obtained, without a content of 100.0% as determined by means of HPLC and a content of nitrosocyanoacetamide of <0.1% as determined by means of HI'LC.
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 nitroso-cyanoacetamide to form aminocyanoacetamide.
_3 _ Cyanoacetamide is a starting material which is cotnmcrcially available on a large scale.
Cyanoacetamide is nitrosylated with nitrites at a pE-I of around 2 to form nitrosocyanoacetamide. An alkali nitrite is preferably used f:or nitrosylation, and is preferably added to an acidic solution or suspension of cyanoacetainide. The pH is pr=eferably lield at arouttd 2 during nitrosylation. 'I'his procedure prevents the formation o(' very large arnounts of by-products, reduces the arnoun.t of nitrous gases which are formed and yields a product which can readily be centrifuged. `I'he customary nitrites for nitrosylation are alkali nitrites, preferably sodiutn nutrite The rritrite is used in an amount of 1-5 equivalents with respect to cyanoac.etarnide, preferably 1-2 equivalents with respect to cyanoacetaniide. 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. In particular, a pi-l of preferably around 2 within this reaction step results in a direct crystallization of nitrosocyanoacetarnide. At higher p:El values, namely above 2.6, which is the IrII o1' an aqueous solution of nitrosocyanoacetamide, the undesired semi-sodium salt precipitates. 'rhis undesired sewni-sodium salt is obtained in a very fine form and therefore on an industrial scale the product is hardly separable and washable. Such a product will always also contain higir arnounts of sodium chloride and by-products of the reactiorr. Another drawback of' the precipitation of the semi-sodium salt is that it is a highly exothermal reaction forcing the hydrolysis of cyarioacetamide.
Thus, the reaction is conclucted at a pIl lower than 2.6 under conditions wherein essentially no undesired semi-alkali metal (especially sodium) salt precipitates. 'The reaction takes place in a concentrated solution or preferably in a suspension, at temperatures between 0"C and 50"C, preferably between 0 (' and 5 C.
The nitrosocyanoacetamide which is thus obtained is reacted by catalytic hydrogenation to form aminocyanoacetamide. Hydrogenation is eff-ected with hydrogen in the present of' a catalyst. Suitable catalysts are preterably noble rnetal catalysts such as platinum, which is finely divided in arYrounts oi' 1 io to 20%' on the usual support materials such as carbon, alumina, silica, barium sulphate or calciunr carbonate, or platinum oxide.
Platinum in an amount of 20rO to 10% otl carbon is prel'erably used as the catalyst.
The catalyst is advantageously used in ainounts of 19/o to 30% with respect to the nitrosocyanoacetamide, most preferably 20ii) t<10`', "a with respect to the nitrosocyanoaeetamide.
Hydrogenation is conducted either in aqueous media such as water, or is preferably conducted in what are predominantly nonaqueous med'ra, 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 ltydrogenation solutions. Other additives can be, added to the hvdxogertation 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, tllc catalvst:s used can easilv be worked up again and used for the next reactions.
Hydrogenation is effected at a pressure of I bar to 100 bai-, preferably 1 bar to 10 bar, and at temperatures between 0 C: aird 80 C:, preferably between 20 C and 50 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. 'I his procedure prevents the formation of'very large amounts ofb~=-l.~roducts, Iri another aspect, the present invention provides a method of providing aminocyanoacetamide comprising reacting cyanoacetamide with an alkali metal nitrite, at a pH of less than 2.6 and under conditions wherein little or no semi-alkali metal salt precipitates, to form nitrosocyanoacetaniide and subjecting the latter to catalytic hydrogenation to form aminocyanoacetarnide, In another aspect, the present invention provides a method of preparing aminocyanoacetamide comprising catalytically hydrogenating nitrosocyanoacetamide.
In another aspect, the present invention provides a method of preparing nitrosocyanoacetomide comprising reacting an alkali metal nitrite with cyanoacetamide at a pH below 2.6 under conditions wlierein little or no semi-alkali rnetal salt precipitates.
^~ ..
Examples to illustrate the invention Example 1 Production of nitrosocyanoacetamidt 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 r~. hydrochloric acid. A solution of 28.7 kg, sodium nitrite in 45 I water was then added over 7 hours. ln the course of the addition, the pH of the reaction solution was held between 11.5 and 2.5 by adding a total of 36 kg of 37% hydrochloric acici. The te.rnp~:.rature of the reaction solution was maintained below 40 C. Nitrosocyanoacetarnide crystaliised from the clear yellowish-red solution which was formed durinc, the acldirion of tk-ie sodium nitrite solution , even before the addition was complete. The yellow suspension was stirred overnight at room temperature and was subsequently cooled to 5''C.
The thick, white cryst,allisation slurry which was tlius obtained was centrifuged off at 5 C, and was subsequently washed with water and dried at 50 C utider vacuum.
33.9 kg nitrosocyanoacet.amide 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 witla those of a reference substance showed that the values were identical.
Example 2 Production of nitrosocyanoacetamide 250 ml 37 % hydrochloric acid (3 moles) were placed in a reaction vessel at 0 C and were treated with 171.6 g cyanoacetamide (2 rnoles). 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 maintairied at 0"C to 3 C during the addition.
The resulting white crystalline product was filtered r,,ff under suction, and was subsequently washed with water and dried at 40 C under vacuurn. 142.6 g nitrosocyanoacetarnide was obtained, wit'h a cont(,nt of 97.4% as dererrnined by M,..,',..,...,. .
means of HPLC. The proportion of cyanoacetamide in the product thus obtained was 0.3%, as determined by mearis of 1-1Pi..,C.
Example 3 Production of nitrosocvanoacetamide 2.0 kg cyanoacetamide and 1..8 kg sodiurrt nitrite were placed iri 4.3 1 water. After heating to 20 C, 2.4 1 37% hydrochloric acid were added drop-wise over 6 hours.
The temperature was maintained at 40"C' to 56'(:; cluring the addition. After-the addition was complete, the resulting suspension was st.irred for a further 40-minutes at 35 C to 40 C and was thereafter cooled to 10 C.
The resulting white crystalline product. was filtered off under suction, and was subsequently washed with water and dried at 400 C under vacuum. 2.5 kg nitrosocyanoacetamide was obtained, with a content of 90, 7 50 .
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 C overnight.
The resulting white crysta9line product was filtered off under suction, and was subsequently washed with water and dried at 40t under vacuum. 2.0 kg nitrosocyanoacetamide was obtained, which ha(i a content of 10C).0% and a decomposition point of about 170 C:, 'I`he proportion of NaCI in the product thus obtained was less than 0.5 %.
Example 4 Production of nitrosocyanoacetarnidv 7.5 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, ovet- 3 hours. "t'hc, temperature was maintained at 5 C during this addition.
The resulting white crystalline product was filtered off under suction, and was subsequently washed with water and dried at 40"C. under vacuum. 5.47 kg nitrosocyanoacetamide were obtained, ~.Ohic.h had a content of 98.7% as determined by means of HPLC. The chloride content of theproduc.t thus obtained was 0.4%.
Example 5 Production of aminocyanoacetauiide 31 g nitrosocyanoacetamide (0.27 moies) were placed in 700 ml methanol in a steel autoclave and were treated with 20 g of a platinum catalyst (5 % on carbon with 50% water). After flushing with nitrogen and hydrogen the batch was hydrogenated at room temperature and 2 bar hydrogen pressure for 14 hours.
After depressurisatian, tlie autoclave contents were filtered under suctiort and the light yellow filtrate obtained was concentrated under vacuum until crystallisation occurred. The crystalline product was slurried in 250 mt isopropanol, filtered under suction and at dried at 40 C under vacuum. 23 g aminocyanoacetamide were obtained, which was slightly light beige in colour and had a content of 84.1 %
as deternlined by means of NPL(' and a decompositiora point of about 120``C:.
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 Content catalyst content ature of hydrog-enation a tetrahydrofuran 5 g 5.0% RT 27 hrs 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 C 10 hrs 66.2% 94.2%
e 40% acetic acid 7.75 g 5.0% 24 C 8 hrs 69.4% 97.5%
f 40 % acetic acid 7.75 g 5.0% 25 C 7 hrs 72.6% 99.2%
g water 7.75 g 5.0% 24 C 6 hrs 66.5% 89.6%
h 0.25 % acetic acid 7.75 g 5.0% 24 C 5 hrs 75.7% 97.0%
i water 7.75 g 5.0% 24 C 6 hrs 68.1% 98.9%
j water 7.75 g 5.0% 10 C 9 hrs 73.8% 99.9%
k water 7.75 g 5.0% 12 C 9 hrs 69.0% 99.9%
1 water 7.75 g 5.0% 11 C 8 hrs 72.1% 99.5%
m water 7.75 g 5.0% 12 C 17 hrs 81.4% 96.0%
n water 7.75 g 5.0% 12 C 20 hrs 77.8% 88.8%
o water 7.75 g') 5.0% 23 C 9 hrs 74.4% 85.6%
p water 7.75 g') 5.0% 23 C 7 hrs 78.5% 99.5%
q water 7.75 g') 5.0% 23 C 7 hrs 80.1% 99.9%
r water 7.75 g') 5.0% 23 C 7 hrs 83.0% 99.9%
s water 7.75 gl) 5.0% 23 C 7 hrs 81.9 % 99.9%
t water 7.75 g 1) 5.0% 23 C 7 hrs 82.6% 99.9%
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 C.
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 (5 % on carbon).
After flushing with nitrogen and hydrogen, the batch was hydrogenated at 24 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 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 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 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 C under vacuum. 79.2 g of colourless amino-cyanoacetamide 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 C and rapidly cooled to 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 40 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.
Example 8 Production of aminocyanoacetamide 8.5 kg of platinum catalyst (5% on carbon with about 50% water) were placed in a 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 hydrogenated at 40-45 C and 2 bar hydrogen pressure for 11 hours.
After depressurisation, the hydrogenation solution was clarified by filtration and the filtrate was cooled to -18 C overnight.
The resulting crystalline product was centrifuged off, and was subsequently washed with cold ethanol and dried at 40 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 nitrosocyanoactamide of 3.5% as determined by means of HPLC.
By recrystallisation in an analogous manner to example 7, colourless aminocyanoacetamide was obtained, without a content of 100.0% as determined by means of HPLC and a content of nitrosocyanoacetamide of <0.1% as determined by means of HI'LC.
Claims (46)
1. A method of producing aminocyanoacetamide, characterised in that cyanoacetamide is reacted with nitrites at a pH of about 2 to form nitrosocyanoacetamide, and the nitrosocyanoacetamide is reacted by catalytic hydrogenation to form aminocyanoacetamide.
2. The method according to claim 1, characterised in that in order to produce nitrosocyanoacetamide, cyanoacetamide is placed in an acidic medium and the nitrite is added thereto.
3. The method according to claim 1 or 2, characterised in that the pH is held constant during the nitrosylation of cyanoacetamide to form nitroso-cyanoacetamide.
4. The method according to any one of claims 1 to 3, characterised in that an alkali nitrite, is used as the nitrite.
5. The method according to any one of claims 1 to 4, characterised in that the nitrite is used in an amount of 1 to 5 equivalents with respect to cyanoacetamide.
6. The method according to any one of claims 1 to 5, characterised in that cyanoacetamide is reacted with nitrites to form nitrosocyanoacetamide in a concentrated solution.
7. The method according to any one of claims 1 to 6, characterised in that cyanoacetamide is reacted with nitrites to form nitrosocyanoacetamide at temperatures between 0°C and 50°C.
8. The method according to claim 1, characterised in that nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in aqueous media.
9. The method according to claim 1, characterised in that nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in nonaqueous media.
10. The method according to claim 9, characterised in that nitro so cyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in methanol.
11. The method according to any one of claims 1, 8, 9 and 10, characterised in that noble metal catalysts finely divided on support materials, said noble metal catalysts being in amounts of 1% to 20% by weight with respect to the support materials, are used as a catalyst for the catalytic hydrogenation of nitrosocyanoacetamide to form aminocyanoacetamide.
12. The method according to any one of claims 1, 8, 9, 10 and 11, characterised in that platinum on a carbon support, said platinum being in an amount of 2% to 10% by weight with respect to the carbon support, is used as a catalyst for the catalytic hydrogenation of nitrosocyanoacetamide to form aminocyanoacetamide.
13. The method according to any one of claims 1, 8, 9, 10, 11 and 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 nitrosocyanoacetamide.
14. The method according to any one of claims 1, 8, 9, 10, 11, 12 and 13, characterised in that nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation with hydrogen at 1 bar to 100 bar, and at temperatures between 0°C and 80°C.
15. A method of producing aminocyanoacetamide, comprising reacting cyanoacetamide with an alkali metal nitrite, at a pH between 1.5 and 2.5 and under conditions wherein little or no semi-alkali metal salt precipitates, to form nitrosocyanoacetamide and subjecting the latter to catalytic hydrogenation to form aminocyanoacetamide, wherein the nitrite is a sodium nitrite.
16. The method according to claim 15, wherein the cyanoacetamide is placed in a hydrochloric acid medium and the nitrite is added thereto in order to form the nitrosocyanoacetamide.
17. The method according to claim 15, wherein the pH is held constant at about during the nitrosylation of cyanoacetamide to form nitrosocyanoacetamide.
18. The method according to claim 15, wherein the nitrite is used in an amount of 1 to equivalents with respect to the cyanoacetamide.
19. The method according to claim 15, wherein the cyanoacetamide is reacted with a nitrite to form nitrosocyanoacetamide in a suspension.
20. The method according to claim 15, wherein cyanoacetamide is reacted with a nitrite to form nitrosocyanoacetamide at temperatures between 0°C and 50°C.
21. The method according to claim 15, wherein the nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in an aqueous media.
22. The method to claim 15, wherein the nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in a nonaqueous media selected from the group consisting of, a water-miscible alcohol, a water-miscible carboxylic acid and tetrahydrofuran.
23. The method according to claim 22, wherein the nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation in methanol.
24. The method according to claim 15, wherein the catalyst for hydrogenation is platinum oxide or a finely divided noble metal catalyst on a support, said platinum oxide or finely divided noble metal catalyst being in amounts of 1% to 20% by weight with respect to the support, said support being selected from the group consisting of carbon, alumina, silica, barium sulphate and calcium carbonate.
25. The method according to claim 15, wherein the catalyst for hydrogenation is platinum on a carbon support, said platinum being in an amount of 2% to 10% by weight with respect to said carbon support.
26. The method according to claim 24, wherein in the catalytic hydrogenation of nitrosocyanoacetamide to form aminocyanoacetamide, the catalyst is used in amounts of 1% to 30% with respect to nitrosocyanoacetamide.
27. The method according to claim 15, wherein nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation with hydrogen at 1 bar to bar, and at temperatures between 0°C and 80°C.
28. The method according to claim 18, wherein the amount of nitrite used is 1 to 2 equivalents with respect to cyanoacetamide.
29. The method according to claim 20, wherein the temperature is between 0°C and 5°C.
30. The method according to claim 27, wherein the pressure is 1 bar to 10 bar and the temperature is between 20°C and 50°C.
31. A method of preparing aminocyanoacetamide comprising: (i) reacting an alkali metal nitrite with cyanoacetamide at a pH between 1.5 and 2.5 under conditions wherein little or no semi-alkali metal salt precipitates to form nitrosocyanoacetamide; and (ii) catalytic hydrogenation of said nitrosocyanoacetamide to form aminocyanoacetamide.
32. The method according to claim 31, wherein the pH is about 2.
33. The method according to claim 32, wherein the nitrite is sodium nitrite and the cyanoacetamide is placed in an aqueous solution of hydrochloric acid.
34. The method of any one of claims 1 to 14, wherein the pH is between 1.5 and 2.5.
35. The method of claim 4, wherein said alkali nitrite is sodium nitrite.
36. The method of claim 5, wherein the nitrite is used in an amount of 1 to 2 equivalents with respect to cyanoacetamide.
37. The method of any one of claims 1 to 5, wherein cyanoacetamide is reacted with nitrites to form aminocyanoacetamide in a suspension.
38. The method of claim 7, wherein said temperatures are between 0°C
and 5°C.
and 5°C.
39. The method of claim 9, wherein said nonaqueous media is selected from the group consisting of: (i) low molecular weight, water miscible alcohols; (ii) low molecular weight, water miscible carboxylic acids; and (iii) tetrahydrofuran.
40. The method of claim 39, wherein said water miscible alcohols are selected from the group consisting of methanol and ethanol.
41. The method of claim 39, wherein said water miscible carboxylic acids are selected from the group consisting of formic acid and acetic acid.
42. The method of claim 11, wherein said noble metal catalysts are platinum.
43. The method of claim 11 or 42, wherein said support materials are selected from the group consisting of carbon, alumina, silica, barium sulphate, calcium carbonate and platinum oxide.
44. The method of claim 13, wherein said catalyst is used in amounts of 2% to 10%
with respect to nitrosocyanoacetamide.
with respect to nitrosocyanoacetamide.
45. The method of claim 14, wherein nitrosocyanoacetamide is reacted to form aminocyanoacetamide by catalytic hydrogenation with hydrogen at 1 bar to 10 bar.
46. The method of claim 14 or 45, wherein said temperatures are between 20°C and 50°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH02907/97A CH692506A5 (en) | 1997-12-18 | 1997-12-18 | A process for producing aminocyanoacetamide. |
| CH2907/97 | 1997-12-18 |
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| Publication Number | Publication Date |
|---|---|
| CA2256251A1 CA2256251A1 (en) | 1999-06-18 |
| CA2256251C true CA2256251C (en) | 2010-05-18 |
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| CA2256251A Expired - Fee Related CA2256251C (en) | 1997-12-18 | 1998-12-17 | A method of producing aminocyanoacetamide |
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| EP (1) | EP0924195B1 (en) |
| JP (1) | JP3452818B2 (en) |
| CN (1) | CN1140504C (en) |
| AT (1) | ATE248808T1 (en) |
| AU (1) | AU750745B2 (en) |
| CA (1) | CA2256251C (en) |
| CH (1) | CH692506A5 (en) |
| DE (1) | DE59809481D1 (en) |
| DK (1) | DK0924195T3 (en) |
| ES (1) | ES2206813T3 (en) |
| HU (1) | HU225196B1 (en) |
| NO (1) | NO317039B1 (en) |
| PT (1) | PT924195E (en) |
| RU (1) | RU2213728C2 (en) |
| TW (1) | TW426657B (en) |
| ZA (1) | ZA9811569B (en) |
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| US6849735B1 (en) | 2000-06-23 | 2005-02-01 | Merck Eprova Ag | Methods of synthesis for 9-substituted hypoxanthine derivatives |
| EP3275537A1 (en) * | 2016-07-25 | 2018-01-31 | Omya International AG | Surface-modified calcium carbonate as carrier for transition metal-based catalysts |
| CN106552283B (en) * | 2016-10-31 | 2019-06-07 | 广东省第二人民医院 | It is a kind of can the sustained release growth factor Bone Defect Repari adhesive and preparation method thereof |
| DE102019109443B4 (en) * | 2019-04-10 | 2026-07-30 | Alzchem Trostberg Gmbh | Cyanidiazohydroxides and processes for their production |
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| US2367455A (en) * | 1941-04-09 | 1945-01-16 | Rohm & Haas | Aminocyanoacetamide resins |
| FI89906C (en) * | 1988-05-17 | 1993-12-10 | Lonza Ag | Process for Preparation of Aminocyanacetamide |
-
1997
- 1997-12-18 CH CH02907/97A patent/CH692506A5/en not_active IP Right Cessation
-
1998
- 1998-12-07 ES ES98123267T patent/ES2206813T3/en not_active Expired - Lifetime
- 1998-12-07 AT AT98123267T patent/ATE248808T1/en active
- 1998-12-07 DE DE59809481T patent/DE59809481D1/en not_active Expired - Lifetime
- 1998-12-07 PT PT98123267T patent/PT924195E/en unknown
- 1998-12-07 EP EP98123267A patent/EP0924195B1/en not_active Expired - Lifetime
- 1998-12-07 DK DK98123267T patent/DK0924195T3/en active
- 1998-12-10 NO NO19985775A patent/NO317039B1/en not_active IP Right Cessation
- 1998-12-14 TW TW087120751A patent/TW426657B/en not_active IP Right Cessation
- 1998-12-15 AU AU97117/98A patent/AU750745B2/en not_active Ceased
- 1998-12-16 JP JP35806098A patent/JP3452818B2/en not_active Expired - Fee Related
- 1998-12-17 ZA ZA9811569A patent/ZA9811569B/en unknown
- 1998-12-17 CN CNB981269907A patent/CN1140504C/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| EP0924195B1 (en) | 2003-09-03 |
| NO985775D0 (en) | 1998-12-10 |
| RU2213728C2 (en) | 2003-10-10 |
| CN1140504C (en) | 2004-03-03 |
| JPH11310563A (en) | 1999-11-09 |
| CA2256251A1 (en) | 1999-06-18 |
| ES2206813T3 (en) | 2004-05-16 |
| EP0924195A1 (en) | 1999-06-23 |
| HUP9802955A3 (en) | 2000-02-28 |
| TW426657B (en) | 2001-03-21 |
| PT924195E (en) | 2004-02-27 |
| ATE248808T1 (en) | 2003-09-15 |
| ZA9811569B (en) | 1999-06-18 |
| HU225196B1 (en) | 2006-08-28 |
| HUP9802955A2 (en) | 1999-07-28 |
| CN1224713A (en) | 1999-08-04 |
| NO985775L (en) | 1999-06-21 |
| NO317039B1 (en) | 2004-07-26 |
| AU9711798A (en) | 1999-07-08 |
| HU9802955D0 (en) | 1999-02-01 |
| DE59809481D1 (en) | 2003-10-09 |
| AU750745B2 (en) | 2002-07-25 |
| DK0924195T3 (en) | 2004-01-19 |
| CH692506A5 (en) | 2002-07-15 |
| JP3452818B2 (en) | 2003-10-06 |
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