WO1999019314A1 - Process for preparing substituted pyrazine compounds - Google Patents

Process for preparing substituted pyrazine compounds Download PDF

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Publication number
WO1999019314A1
WO1999019314A1 PCT/US1998/021245 US9821245W WO9919314A1 WO 1999019314 A1 WO1999019314 A1 WO 1999019314A1 US 9821245 W US9821245 W US 9821245W WO 9919314 A1 WO9919314 A1 WO 9919314A1
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Prior art keywords
added
amino
phenyl
stirred
azadiene
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PCT/US1998/021245
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French (fr)
Inventor
Weijiang Zhang
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Abbott Laboratories
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Priority to CA002305770A priority Critical patent/CA2305770A1/en
Priority to EP98951005A priority patent/EP1023278A1/en
Priority to JP2000515887A priority patent/JP2001519423A/en
Publication of WO1999019314A1 publication Critical patent/WO1999019314A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings

Definitions

  • Pyrazine compounds are widely used in the pharmaceutical, chemical, and agricultural fields. Condensation reactions involving reacting malononitrile oximinotosylate with an enamine followed by quenching with ammonia to form 2-amino-3-cyano-6-substituted pyrazines has been reported. Fleury et al., Tetrahedron Letters. 1974, 3967. However, the enamines used in such reactions were prepared from ketones in the presence of ammonia. This preparation lead to synthesis of 6-substituted 2-aminopyrazine compounds. There still is a need for a process of forming 6-unsubstituted 2-substituted pyrazine heterocycles.
  • the present invention relates to a process of producing 6-unsubstituted 2-substituted pyrazine heterocycles involving the reaction of an oxime with an enamine.
  • the present invention also relates to producing novel intermediates which are useful in producing pyrazine compounds as well as novel substituted pyrazine compounds.
  • 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 quenching with ammonia provides a 2-aminopyrazine.
  • the pyrazine may 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 2-thioalkyl substituted pyrazines and 2-thioaryl substituted pyrazines.
  • pyrrolidine (2) is added to phenylacetaldehyde (1) to form the a novel enamine (3).
  • Malononitrile oximinotosylate (4) is added to the enamine (3) to form a 2-azadiene intermediate (5).
  • the 2-azadiene intermediate (5) is then subsequently quenched with ammonia to provide a 2-amino-3-cyano- hydridopyrazine (8).
  • pyrrolidine (2) is added to phenylacetaldehyde (1) to form the a novel enamine (3).
  • Malononitrile oximinotosylate (4) is added to the enamine (3) to form a 2-azadiene intermediate (5).
  • the 2-azadiene intermediate (5) is then reacted with a thioaryl such as thiophenol (6) to form a novel 3-cyano-5- phenyl-2-phenyIthiopyrazine (7).

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

PROCESS FOR PREPARING SUBSTITUTED PYRAZINE COMPOUNDS
Background of the Invention
Pyrazine compounds are widely used in the pharmaceutical, chemical, and agricultural fields. Condensation reactions involving reacting malononitrile oximinotosylate with an enamine followed by quenching with ammonia to form 2-amino-3-cyano-6-substituted pyrazines has been reported. Fleury et al., Tetrahedron Letters. 1974, 3967. However, the enamines used in such reactions were prepared from ketones in the presence of ammonia. This preparation lead to synthesis of 6-substituted 2-aminopyrazine compounds. There still is a need for a process of forming 6-unsubstituted 2-substituted pyrazine heterocycles.
Detailed Description of the Invention
The present invention relates to a process of producing 6-unsubstituted 2-substituted pyrazine heterocycles involving the reaction of an oxime with an enamine. The present invention also relates to producing novel intermediates which are useful in producing 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 quenching with ammonia provides a 2-aminopyrazine. Altenatively, the pyrazine may 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 2-thioalkyl substituted pyrazines and 2-thioaryl substituted pyrazines.
In a preferred embodiment of the present invention as shown in Scheme 1 , pyrrolidine (2) is added to phenylacetaldehyde (1) to form the a novel enamine (3). Malononitrile oximinotosylate (4) is added to the enamine (3) to form a 2-azadiene intermediate (5). The 2-azadiene intermediate (5) is then subsequently quenched with ammonia to provide a 2-amino-3-cyano- hydridopyrazine (8).
In a preferred embodiment of the present invention as shown in Scheme 1 , pyrrolidine (2) is added to phenylacetaldehyde (1) to form the a novel enamine (3). Malononitrile oximinotosylate (4) is added to the enamine (3) to form a 2-azadiene intermediate (5). The 2-azadiene intermediate (5) is then reacted with a thioaryl such as thiophenol (6) to form a novel 3-cyano-5- phenyl-2-phenyIthiopyrazine (7).
SCHEME 1
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
Figure imgf000005_0001
EXAMPLE 1 Malononitrile Oximinotosylate Sodium oximine malononitrile (12.9grams (g), 0.11 moles) and 150 milliliters (mL) of acetonitrile were added together and cooled to 0-5°C. Toluenesulfonyl chloride (19. lg, O. l lmoles) was added slowly to keep the temperature below 10°C. The solution was stirred for 10 minutes at 10° C and then 500mL 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 50mL water, followed by 50mL of heptane and dried under vacuum to give a white solid (20g, 78% yield). ! HNMR (300Mhz, CDCI3) d 7.80 (d,J=7 Hz), 7.35 (d, J=7 Hz), 2.41 (s,3H).
EXAMPLE 2 trans- N-(2-phenyPethylene pyrrol idine
Pyrrolidine (lOg, 0.14moles) and 5g of sodium sulfate were added to a flask and cooled to <0° C. Phenacetaaldehyde (2.4g., 0.02 moles) was added slowly to the flask to keep the temperature <2° C. The mixture was stirred at 0° C for one hour. The mixture was filtered and the filtered solid was washed with lOmL of heptane and the combined filtrates were then distilled (<40° C) to an oil.
Heptane (30 mL) was added and distilled to an oil.
EXAMPLE 3 3-aza-2-cyano-4-phenyl -5 -N-pent-2.4-dienitrile
Pyrrolidine (7.1g, O.lOmole) and sodium sulfate (5g) was added to a flask and cooled to <0°C. Phenylacetaldehyde (2.4g, 0.02mole) was added slowly to the flask to keep temperature <2°C. The mixture was stirred at 0°C for 1 hour. Then it was filtered and the solid was washed with lOmL heptane and the combined filtrate was distilled (<40°C) under vacuum to an oil. Heptane (30ml) was added and then distilled to oil. The final oil was mixed with dimethyformamide (DMF) (7ml) and triethylamine (3.03g, 0.03moles). The mixture was then slowly added into a flask containing malononitrile oximinotosylate (4.98g, 0.02moles) in DMF (20mL) at 0°C+5°C. This reaction mixture was stirred at 0°C for 5 minutes and then 100 ml of water was added 10°C and this was stirred for 15 minutes at room temperature. The solid was filtered washed with 30ml of water and then stirred with 60 ml methanol for 15 minutes. The solid was the filtered and washed with 10ml methanol and dried to give orange solid (3.3g, 66% yield). 1HNMR (300 Mhz, CDC13) d 7.71 (s, IH), 7.5-7.47 (m, 6H), 7.22-7.15 (m, 4H), 6.96 (s, IH), 4.09 (m, IH), 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-AmiPQ 3-Cyano-5-Phenyl-pyrazine
Pyrrolidine (lOg, 0.14mole) and sodium sulfate (5g) were added to a flask and cooled to <0°C. Phenylacetaldehyde (2.4g, 0.02mole) was added slowly to the flask to keep temperature <2°C. The mixture was stirred at 0°C for 1 hour. Then it was filtered and the solid was washed with 10ml heptane and the combined filtrate was distilled (<40°C) under vacuum to an oil. Heptane (30ml) was added then distilled to oil. The final oil was mixed with dimethyformamide (DMF) (6ml) and triethylamine (2.02g, 0.02moles). The mixture was then slowly added into a flask containing malononitrile oximinotosylate (4.98g, 0.02moles) in DMF (20ml) at 0°C+3°C. This reaction mixture was stirred at 0°C for 15 minutes and then aqueous ammonium hydroxide (11ml, 28-33%w/w) in methanol (10ml) was added. This mixture was stirred for 20 minutes at 15°C. 100 ml of 3% HCI was added at 10°C and this was stirred for 15 minutes at room temperature. The solid was filtered and mixed with 40ml methanol and stirred for 20 minutes at 10°C and filtered. The solid was washed with 10ml of cold methanol and dried to give a yellow solid (2.5g, 64%). 1HNMR (300 Mhz) d 8.93 (s, IH, 7.97-7.7.95 (m, 2H), 7.52-7.38 (m, 5H).
EXAMPLE 5 3 -C vano-5-phen vl -2 -phen vl th i o vrazine
Pyrrolidine (lOg, 0.14mole) and sodium sulfate (5g) was added to a flask and cooled to <0°C. Phenylacetaldehyde (2.4g, 0.02mole) was added slowly to the flask to keep temperature <2°C. The mixture was stirred at 0°C for 1 hour. Then it was filtered and the solid was washed with 10ml heptane and combined filtrate was distilled (<40°C) under vacuum to an oil. Heptane (30ml) was added and then distilled to oil. The final oil was mixed with dimethyformamide (DMF) (6ml) and triethylamine (6.06g, O.Oόmoles). The mixture was then slowly added into a flask containing malononitrile oximinotosylate (4.98g, 0.02moles) in DMF (20ml) at 0°C+3°C. This reaction mixture was stirred at 0°C for 30 minutes and then thiophenol (2.4g, 0.022moles) was added. This mixture was stirred 3 hours at ambient temperature. 100 ml of water was added at 10°C and this was stirred for 20 minutes at room temperature. The solid was filtered and mixed with 50ml methanol and stirred for 20 minutes and filtered. The solid was washed with 10ml of methanol and dried to give grayish solid (2.98g, 51%). IHNMR (300 Mhz, CDC 13) d 8.9 (s, IH), 8.0-7.9 (m, 2H), 7.7-7.6 (m, 2H), 7.6-7.45 (m, 6H)

Claims

CLAIMSWhat is claimed:
1. A process for producing trans-N-(2-phenyl)ethylene-pyrrolidine by adding pyrrolidine to phenylacetaldehyde.
2. A process according to Claim 1 wherein said reaction is carried out in the presence of a drying agent.
3. A process according to claim 2 wherein said drying agent is soldium sulfate.
4. A compound of the formula
Figure imgf000008_0001
5. A process for producing l,l-dicyano-4-hydrido-4-amino-2-azadiene by condensing 1-unsubstituted enamines with malonitrile oximinotosylate.
6. A process according to Claim 5 wherein said 1-unsubstituted enamine is trans-N-(2-phenyl)ethylene-pyrrolidine.
7. A compound of the formula
Figure imgf000009_0001
8. A process for producing 2-amino-3-cyano-pyrazine by condensing 1,1- dicyano-4-hydrido-4-amino-2-azadiene with ammonia.
9. A process for producing 2-amino-3-cyano5-phenyl-pyrazine by condensing l ,l -dicyano-4-hydrido-4-amino-2-azadiene with ammonia hydroxide.
10. A process for the formation of 3-Cyano-5-phenyl-2-phenylthiopyrazine by condensing azadienes prepared from enamines and malonitrile oximinotosylate with thiol compounds.
1 1. A process of claim 9 wherein said thiol compounds are thioaryls.
12. A process of claim 9 wherein said thiol compounds are selected from the group consisting of: thioalkyls, thioalkenyls, and thioalkynyls.
13. A compound of the formula
Figure imgf000010_0001
PCT/US1998/021245 1997-10-10 1998-10-08 Process for preparing substituted pyrazine compounds WO1999019314A1 (en)

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CA002305770A CA2305770A1 (en) 1997-10-10 1998-10-08 Process for preparing substituted pyrazine compounds
EP98951005A EP1023278A1 (en) 1997-10-10 1998-10-08 Process for preparing substituted pyrazine compounds
JP2000515887A JP2001519423A (en) 1997-10-10 1998-10-08 Method for preparing substituted pyrazine compounds

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US94905197A 1997-10-10 1997-10-10
US08/949,051 1997-10-10

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0249775A (en) * 1988-05-19 1990-02-20 Nippon Soda Co Ltd Heterocyclic compound having 6-membered or 7-membered ring and production thereof
WO1998024791A1 (en) * 1996-12-06 1998-06-11 Abbott Laboratories Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic compounds

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0249775A (en) * 1988-05-19 1990-02-20 Nippon Soda Co Ltd Heterocyclic compound having 6-membered or 7-membered ring and production thereof
WO1998024791A1 (en) * 1996-12-06 1998-06-11 Abbott Laboratories Benzopyranopyrrole and benzopyranopyridine alpha-1 adrenergic compounds

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
EDWARD C. TAYLOR: "Pteridines. XXIX. An Unequivocal Route to 2,4-Diamino-6-substituted Pteridines", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY., vol. 95, no. 19, 19 September 1973 (1973-09-19), DC US, pages 6413 - 64118, XP002089656 *
JOHN E. CRAGG ET AL.: "Phenanthroindozilidine and Related Alkaloids: Synthesis of Tylophorine, Septicine, and Deoxytylophorinine", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1., 1982, LETCHWORTH GB, pages 2477 - 2485, XP002089655 *
PATENT ABSTRACTS OF JAPAN vol. 014, no. 215 (C - 0716) 8 May 1990 (1990-05-08) *

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CA2305770A1 (en) 1999-04-22
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