MXPA00003506A - Process for preparing substituted pyrazine compounds - Google Patents

Abstract

The present invention relates to novel intermediate, processes, and novel pyrazine compounds which are ultimately useful in the preparation of chemicals and pharmaceuticals.

Description

PROCESSES FOR PREPARING SUBSTITUTE PIRAZINE COMPOUNDS Background of the Invention Pyrazine compounds are widely used in the pharmaceutical, chemical and agricultural fields. Condensation reactions have been reported which involve reacting malonitrile oximinotosylate with an enamine followed by cooling with ammonia to form 2-amino-3-cyano-6-substituted pyrazines. Fleury et al., Tetrahedron Letters. 1974. 3967. However, the enamines used in said reactions were prepared from ketones in the presence of ammonia. This preparation leads to the synthesis of 6-substituted 2-aminopyrazine compounds. There is still a need for a process of forming unsubstituted 6 and 2-substituted pyrazine heterocycles. Detailed Description of the Invention The present invention relates to a process for producing unsubstituted 6 and 2-substituted pyrazine heterocycles that involve the reaction of an oxime with an enamine. The present invention also relates to the production of novel intermediates that are useful in the production of pyrazine compounds as well as novel substituted pyrazine compounds. In one embodiment, a pyrazine heterocycle is formed by reacting a secondary amine with an aldehyde to form an enamine. The enamine compound is then reacted with an oxime to produce a novel 2-azadiene compound. Subsequent cooling with ammonia provides a 2-aminopyrazine. Alternatively, pyrazine can be formed by reacting the 2-azadiene compound with a thiol-bearing compound, such as, but not intended to be limited to, thioalkyls, thioalkenyls, thioalkynyls and thioaryls to produce pyrazines substituted with 2-thioalkyl. and pyrazines substituted with 2-thioaryl. In a preferred embodiment of the present invention as shown in Scheme 1, pyrrolidine (2) is added to phenylacetaldehyde (1) to form the novel enamine (3). Malonitrile oximinotosylate (4) is added to the enamine (3) to form an intermediate of 2-azadiene (5). The 2-azadiene intermediate (5) is then subsequently cooled with ammonia to provide a 2-amino-3-cyano-hydridoprazine (8). In a preferred embodiment of the present invention as shown in Scheme 1, pyrrolidine (2) is added to phenylacetaldehyde (1) to form the novel enamine (3). Malonitrile oximinotosylate (4) is added to the enamine (3) to form an intermediate of 2-azadiene (5). The 2-azadiene intermediate is then reacted with a thioaryl such as thiophenol (6) to form a novel 3-cyano-5-phenyl-2-phenylthiopyrazine (7).

SCHEME 1 EXAMPLE 1 Malonitrile Oximinotosilate Malonitrile sodium oximin (12.9 grams (g), 0.11 moles) and 150 milliliters (ml) of acetonitrile were added together and cooled to 0-5 ° C. Toluenesulfonyl chloride (19.1 g, 0.11 mol) was slowly added to maintain the temperature below 10 ° C. The solution was stirred for 10 minutes at 10 ° C and then 500 ml of water was added and the mixture was stirred for 20 minutes. The solids in the mixture were filtered and the solid was washed with 50 ml of water, followed by 50 ml of heptane and dried in vacuo to give a white solid (20 g, 78% yield), 1 HNNN (300 MHz, CDCl 3) d 7.80 (d, J = 7Hz), 7.35 (d, J = 7 Hz), 2.41 (s, 3H). EXAMPLE 2 Trans-N- (2-phenyl) ethylene pyrrolidine Pyrrolidine (10g, 0.14 mole) and 5 g of sodium sulfate were added to a flask and cooled to < 0 ° C. Phenacetaldehyde (2.4 g, 0.02 mole) was slowly added to the flask at the temperature maintained at < 2 C. The mixture was stirred at 0 ° C for one hour. The mixture was filtered and the filtered solid was washed with 10 ml of heptane and the combined filtrates were then distilled (< 40 ° C) in an oil. Heptane (30 ml) was added and distilled in an oil. EXAMPLE 3 3-aza-2-cyano-4-phenyl-5-N-pent-2,4-dienitrile Pyrrolidine (7.1 g, 0.10 mol) and sodium sulfate (5 g) were added to a flask and cooled to a < 0 ° C. Phenylacetaldehyde (2.4 g, 0.02 mole) was slowly added to the flask at a temperature maintained at < 2 C). The mixture was stirred at 0 ° C for 1 hour.

It was then filtered and the solid was washed with 10 ml of heptane and the combined filtrate was distilled (<40 ° C) under vacuum in an oil. Heptane (30 ml) was added and then distilled in oil. The final oil was mixed with dimethylformamide (DMF) (7 ml) and triethylamine (3.03 g, 0.03 mol). The mixture was then slowly added to a flask containing malonitrile oximinotosylate (4.98 g, 0.02 mol) in DMF (20 mL) at 0 ° C + 5 ° C. This reaction mixture was stirred at 0 ° C for 5 minutes and then 100 ml of water was added at 10 ° C and this was stirred for 15 minutes at room temperature. The filtered solid was washed with 30 ml of water and then stirred with 60 ml of methanol for 15 minutes. The solid was filtered and washed with 10 ml of methanol and dried to give an orange solid (3.3 g, 66% yield). 1H NMR (300 MHz, CDCl 3) d, 7.71 (s, 1H), 7.5-7.47 (m, 6H), 7.22-7.15 (m, 4H), 6.96 (s, 1H), 4.09 (m, 1H), 3.80- 3.68 (m, 4H), 2.70 (t, J = 7H2, 3H), 2.2-2.05 (m, 2H), 2.07-1.93 (m, 2H), 1.93-1.8 (m, 4H). EXAMPLE 4 2-Amino 3-Cyano-5-phenyl-p -razine Pyrrolidine (10 g, 0.14 mol) and sodium sulfate (5 g) were added to a flask and cooled to < 0 ° C. Phenylacetaldehyde (2.4 g, 0.02 mol) was added slowly in the flask at a temperature maintained at < 2 C. The mixture was stirred at 0 ° C for 1 hour. It was then filtered and the solid was washed with 10 ml of heptane and the combined filtrate was distilled (<40 ° C) under vacuum in an oil. Heptane (30 ml) was added and then distilled in oil. The final oil was mixed with dimethylformamide (DMF) (6ml) and triethylamine (2.02g, 0.02 moles). The mixture was added slowly in a flask containing malonitrile oximonotosylate (4.98 g, 0.02 mol) in DMF (20 ml) at 0 ° C + 3 ° C. This reaction mixture was stirred at 0 ° C for 15 minutes and then aqueous ammonia hydroxide (11 ml, 28-33% w / w) in methanol (10 ml) was added. The mixture was stirred for 20 minutes at 15 ° C. 100 ml of 3% HCl was added at 10 ° C and it was stirred for 15 minutes at room temperature. The solid was filtered and mixed with 40 ml of methanol and stirred for 20 minutes at 10 ° C and filtered. The solid was washed with 10 mL of cold methanol and dried to give a yellow solid. 1H NMR (300 MHz) d 8.93 (s, 1H, 7.97-7.7.95 (m, 2H), 7.52-7.38 (m, 5H) EXAMPLE 5 3-Cyano-5-phenyl-2-phenylthiopyrazine Pyrrolidine was added (10 g, 0.14 mol) and sodium sulfate (5 g) were added to a flask and cooled to <0 ° C. Phenylacetaldehyde (2.4 g, 0.02 mol) was added slowly in the flask at a temperature maintained at <2 ° C. C. The mixture was stirred at 0 ° C for 1 hour, then filtered and the solid was washed with 10 ml of heptane and the combined filtrate was distilled (<40 ° C) under vacuum in oil. mi) and then distilled in an oil.The final oil was mixed with dimethylformamide (DMF) (6ml) and triethylamine (6.06g, 0.06 moles) .The mixture was then added slowly in a flask containing malonitrile oximinotosylate (4.98 g). 0.02 mole) in DMF (20 mL) at 0 ° C + 3 ° C. This reaction mixture was stirred at 0 ° C for 30 minutes and then thiophenol (2.4 g, 0.022 mole) was added. 3 hours at room temperature. 100 ml of water was added at 10 ° C and it was stirred for 20 minutes at room temperature. The solid was filtered and mixed with 50 ml of methanol and stirred for 20 minutes and filtered. The solid was washed with 10 ml of methanol and dried to give a grayish solid (2.98 g, 51%). 1 H NMR (300 MHz) d 8.9 (s, 1 H), 8.0-7.9 (m, 2 H), 7.7-7.6 (m, 2 H), 7.6-7.45 (m, 6 H).

Claims (13)

1. CLAIMS 1. A process for producing trans-N- (2-phenyl) ethylene-pyrrolidine by adding pyrrolidine to phenylacetaldehyde.
2. 2. A process according to claim 1, wherein the reaction is carried out in the presence of a drying agent.
3. 3. A process according to claim 2, wherein the drying agent is sodium sulfate.
4. 4. A compound of the formula
5. 5. A process for producing 1, 1-dicyano-4-hydro-4-amino-2-azadiene by the condensation of unsubstituted enamines in 1, with malonitrile oximinotosylate.
6. 6. A process according to claim 6, wherein the unsubstituted enamine in 1 is trans-N- (2-phenyl) ethylene-pyrrolidine.
7. 7. A compound of the formula
8. 8. A process for producing 2-amino-3-cyano-pyrazine by condensing 1, 1-dicyano-4-hydro-4-amino-2-azadiene with ammonia.
9. 9. A process for producing 2-amino-3-cyano-5-phenyl-pyrazine by condensing 1, 1-dicyano-4-hydrido-4-amino-2-azadiene with ammonia hydroxide.
10. 10. A process for the formation of 3-cyano-4-phenyl-2-phenylthiopyrazine by the condensation of azadienes prepared from enamines and malonitrile oximinotosylate with thiol compounds.
11. 11. A process of claim 9, wherein the thiol compounds are thioaryls.
12. 12. A process of claim 9, wherein the thiol compounds are selected from the group consisting of: thioaloalkyls, thioalkenyls and thioalkynyls.
13. 13. A compound of the formula