WO2000010983A1 - Process for preparing regiospecific substituted pyrazine isomers - Google Patents
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- FFMFKPGYBOCOSW-UHFFFAOYSA-N N#Cc(nc(cn1)-c2ccccc2)c1S(c1ccccc1)(=O)=O Chemical compound N#Cc(nc(cn1)-c2ccccc2)c1S(c1ccccc1)(=O)=O FFMFKPGYBOCOSW-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present invention relates to a process of producing specific isomers of substituted pyrazine compounds, substituted thieno[b]pyrazine, substituted pteridins, compounds, and derivatives thereof.
- the regiospeciflc substituted compounds are useful in the preparation of pharmaceuticals, including compounds useful in treating benign prostatic hyperplasia.
- 'regiospeciflc' as used herein, is defined as the formation of one isomer of a compound in greater quantity than other isomers.
- loweralkyl or “alkyl” as used herein refer to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
- aryl refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, naphthyridinyl, indanyl, indenyl and the like.
- Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, dialkylamino, halo, nitro, alkoxycarbonyl and carboxamide.
- substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
- arylalkyl refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like.
- cycloalkyl refers to an aliphatic ring system having 3 to
- Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, dialkylamino, halo, nitro, alkoxycarbonyl and carboxamide.
- cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
- a 2, 3- diaminocompound (1) wherein A is nitrile and B is -SR wherein R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl.
- Compound 1 may be reacted with an ketone compound (2) wherein R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl to produce a regioselective substituted pyrazine compound (3) in the presence of excess acid and a solvent.
- R3 and R4 are independently selected from the group consisting of of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, or R3 and R4 taken together can form a ring with the oxygen atoms to which they are attached.
- R3 and R4 are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, or R3 and R4 taken together can form a ring with the oxygen atoms to which they are attached.
- the reaction proceeds in the presence of excess acids in a solvent to produce a regioselective substituted pyrazine isomer (6) over isomer (7).
- 3-diamino-3-phenylthioacrylonitrile (8) is reacted with 2, 2-diethoxyacetophenone (9) in the presence of excess acids in a solvent to produce a regiospeciflc substituted pyrazine isomer (10) over isomer (1 1).
- Solvents suitable for the present invention include, but are not intended to be limited to alkanol solvents.
- Alkanol solvents include, but are not intended to be limited to, methanol, ethanol, propanol, isopropanol, butanol, and isobutanol.
- Acids suitable for the present invention include, but are not intended to be limited to, carboxylic acids and halogenated carboxylic acids. Suitable halogenated carboxylic acids include, but are not intended to be limited to trifluoroacetic acid, tribromoacetic acid, trichloroacetic acid, and the like.
- Substituted thieno[b]pyrazines may be prepared by reacting Compounds (12) and (13) with a thioglycolate ester in the presence of a base.
- Bases suitable for the reaction include, but are not limited to, tertiary amines such as triethylamine and dusopropylethylamine.
- the substituted thieno[b]pyrazines may be prepared by first preparing the pyrazine sulfone (13) from the substituted pyrazine and reacting the pyrazine sulfone with a thioglycolate ester in the presence of a base such as, but not limited to, a tertiary amine as described above or in the presence of an inorganic base including, but not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
- a base such as, but not limited to, a tertiary amine as described above or in the presence of an inorganic base including, but not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
- the sulfone may be prepared by reacting compound (10) with a carboxylic peracid, including, but not limited to, metachloroperbenzoic acid, peracetic acid and the like.
- the sulfone may also be prepared by reacting compound (10) with a peracid generated in situ from sodium perborate and an acid selected from the group consisting of carboxylic acids and halogenated carboxylic acids. Examples of carboxylic acids and halogenated carboxylic acids including, but not limited to, acetic acid, chloroacetic acid, dichloroacetic acid, and the like.
- Co-solvents suitable for the invention include, but are not limited to methanol, ethanol, and isopropanol.
- Bases suitable for the invention include, but are not limited to tertiary amines such as triethylamine and dusopropylethylamine, and the like or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium biocarbonate.
- Substituted pyrrolo[b]pyrazines are prepared by reacting a sulfone with H2NCH2CO2R6 where R6 is alkyl in the presence of a base as described above.
- Substituted pteridins may be prepared by reacting a sulfone with imidines such as H2NCR7NH where R7 is selected from the group consisting of hydrogen alkyl, aryl, or arylalkyl in the presence of a base.
- Bases suitable for the invention include, but are not limited to alkylamines such as triethylamine, dusopropylethylamine, diisopropylamine, and the like, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium bicarbonate.
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Abstract
The present invention relates to a process of producing specific isomers of substituted pyrazine compounds, substituted thieno[b]pyrazine, substituted pteridins, compounds, and derivatives thereof. The regiospecific substituted pyrazine compounds are useful in the preparation of pharmaceuticals, including compounds useful in treating benign prostatic hyperplasia.
Description
PROCESS FOR PREPARING REGIOSPECIFIC SUBSTITUTED PYRAZINE ISOMERS
This application is a continuation-in-part of US application serial number 09/136,983, filed August 20,1998, incorporated herein by reference.
Background of the Invention US 4,990,630 to Sato et al discloses a process for reacting a 2,3-diamino-3- phenylthioacrylonitrile compound with a symmetric 1 ,2-dicarbonyl compound to produce a symmetric pyrazine compound. A limitation of this process is that it cannot produce unsymmetrical pyrazine compounds with predictable regiospecificity.
The present invention relates to a process of producing specific isomers of substituted pyrazine compounds, substituted thieno[b]pyrazine, substituted pteridins, compounds, and derivatives thereof. The regiospeciflc substituted compounds are useful in the preparation of pharmaceuticals, including compounds useful in treating benign prostatic hyperplasia.
Detailed Description of the Invention
For the purposes of this disclosure, the term 'regiospeciflc' as used herein, is defined as the formation of one isomer of a compound in greater quantity than other isomers.
The terms "loweralkyl" or "alkyl" as used herein refer to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like.
The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, naphthyridinyl, indanyl, indenyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, dialkylamino, halo, nitro, alkoxycarbonyl
and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term "arylalkyl" as used herein refers to an aryl group as previously defined, appended to a loweralkyl radical, for example, benzyl and the like. The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to
10 carbon atoms and 1 to 3 rings including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, dialkylamino, halo, nitro, alkoxycarbonyl and carboxamide. The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
In one embodiment of the present invention shown in Scheme I, a 2, 3- diaminocompound (1) wherein A is nitrile and B is -SR wherein R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl. Compound 1 may be reacted with an ketone compound (2) wherein R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl to produce a regioselective substituted pyrazine compound (3) in the presence of excess acid and a solvent. R3 and R4 are independently selected from the group consisting of of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, or R3 and R4 taken together can form a ring with the oxygen atoms to which they are attached.
1 2 3 4
Scheme I
In a preferred embodiment of the present invention as shown in Scheme 2, 2, 3- diamino-3-phenylthioacrylonitrile (5) wherein Rl is phenyl, is reacted with a ketone compound (2) wherein R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, to produce a regioselective substituted pyrazine
compound (6) in the presence of excess acid and a solvent. R3 and R4 are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, or R3 and R4 taken together can form a ring with the oxygen atoms to which they are attached. The reaction proceeds in the presence of excess acids in a solvent to produce a regioselective substituted pyrazine isomer (6) over isomer (7).
Scheme 2
In a more preferred embodiment of the present invention as shown in Scheme 3, 2,
3-diamino-3-phenylthioacrylonitrile (8) is reacted with 2, 2-diethoxyacetophenone (9) in the presence of excess acids in a solvent to produce a regiospeciflc substituted pyrazine isomer (10) over isomer (1 1).
Scheme 3
Solvents suitable for the present invention include, but are not intended to be limited to alkanol solvents. Alkanol solvents include, but are not intended to be limited to, methanol, ethanol, propanol, isopropanol, butanol, and isobutanol. Acids suitable for the present invention include, but are not intended to be limited to, carboxylic acids and halogenated carboxylic acids. Suitable halogenated carboxylic acids include, but are not
intended to be limited to trifluoroacetic acid, tribromoacetic acid, trichloroacetic acid, and the like.
Another embodiment of the present invention, as shown in Scheme 4, includes the formation of substituted thieno[b]pyrazines. Substituted thieno[b]pyrazines may be prepared by reacting Compounds (12) and (13) with a thioglycolate ester in the presence of a base. Bases suitable for the reaction include, but are not limited to, tertiary amines such as triethylamine and dusopropylethylamine. The substituted thieno[b]pyrazines may be prepared by first preparing the pyrazine sulfone (13) from the substituted pyrazine and reacting the pyrazine sulfone with a thioglycolate ester in the presence of a base such as, but not limited to, a tertiary amine as described above or in the presence of an inorganic base including, but not limited to, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
The sulfone may be prepared by reacting compound (10) with a carboxylic peracid, including, but not limited to, metachloroperbenzoic acid, peracetic acid and the like. The sulfone may also be prepared by reacting compound (10) with a peracid generated in situ from sodium perborate and an acid selected from the group consisting of carboxylic acids and halogenated carboxylic acids. Examples of carboxylic acids and halogenated carboxylic acids including, but not limited to, acetic acid, chloroacetic acid, dichloroacetic acid, and the like.
Scheme 4
Substituted pyrrolo[b]pyrazines are prepared by reacting a sulfone with H2NCH2CO2R6 where R6 is alkyl in the presence of a base as described above.
Substituted pteridins may be prepared by reacting a sulfone with imidines such as H2NCR7NH where R7 is selected from the group consisting of hydrogen alkyl, aryl, or arylalkyl in the presence of a base. Bases suitable for the invention include, but are not limited to alkylamines such as triethylamine, dusopropylethylamine, diisopropylamine, and the like, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium bicarbonate.
The following examples are intended to be illustrative of the present invention and not limiting in scope.
Example 1
5-phenyl-2-phenylthiopyrazine-3-carbonitriIe
To a suspension of 2,3-diamino-3-phenylthioacrylonitrile toluenesulfonic acid (8 grams (g), 22 millilmoles (mmol)), and triflouroacetic acid (14.8 g, 130 mmol) in isopropanol (100 milliliters (mL)) was added 2,2-diethoxy-acetophenone (4.2 g, 20 mmol). The mixture was stirred for 24 hours (h) at ambient temperature before adding
80mL water. The slurry was stirred for 1 h and the solid filtered and washed with 50 mL of 50% aqueous isopropanol to yield after drying, 4.25g (73%) of 5-phenyl-2- phenylthiopyrazine-3-carbonitrile. IH NMR (CDCI3) δ 8.9 (s, IH), 8.0-7.9 (m, 2H), 7.7- 7.6 (m, 2H), 7.59-7.45 (m, 6H).
Example 2 5-phenyl-2-phenylsulfinylpyrazine-3-carbonitrile
A slurry of 5-phenyl-2-phenyl-thiopyrazine-3-carbonitrile, (2.89 g) in acetic acid (40 mL) was heated to 45-50 °C and sodium perborate monohydrate (2.5 g) was added in two portions over 10 minutes. The slurry was stirred at 45-50°C for 2.5 h, cooled to ambient temperature, and water (50 mL) was added. The slurry was filtered, washed with water (100 mL) and dried to give 5-phenyl-2-phenylsulfinylpyrazine-3-carbonitrile (2.82 g, 88%). IH NMR (DMSO) δ 9.67 (s, IH), 7.97 (m, 2H), 7.78-7.62 (m, 6H).
Example 3
5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile
3-Chloroperoxy benzoic acid (mCPBA) (8.9 g, 52 mmol) was added into a solution of 5-phenyl-2-phenylthiopyrazine-3-carbonitrile (5g, 17mmol) in methylene chloride (100ml) at <6°C and this was stirred at room temperature for 18 h. Methanol (100 mL) was added and this was concentrated to 100 ml and repeated once more. The solid that formed was filtered and washed with methanol (20 ml) to give 4.5 g (yield 80%) of 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile, mp 222-224°C. 1HNMR (CDCI3 ) δ (ppm) 9.19 (s,lH)8.21 (dd, 2H, Jl =8Hz, J2=2.5Hz), 8.08 (dd, 2H, Jl=8 Hz, J2=3Hz), 7.73 (dt, 2H, Jl=8, J2 =2.5Hz), 7.6, (m, 5H). 13C NMR(DMSO-d6) δ(ppm). IR(KBr) 3125, 3070, 2250, 1555, 1325, 1 160, 730. HRMS(FAB) Calculated m/z for M+H
C17H12N3O2S 322.0650, Observed m/z 322.0652.
Example 4
Alternative synthesis of 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile A slurry of 5-phenyl-2-phenylthiopyrazine-3-carbonitrile (50g), and chloroacetic acid (176 g) in acetic acid (530g) was heated to 45-55°C for approximately 24 hours. The mixture was cooled to ambient temperature, and 500 mL of water was added. The slurry was filtered, washed with 300 mL of water and dried to give 5-phenyl-2- phenylsulfonylpyrazine-3-carbonitrile (48.3 g, 91%).
Example 5 Thienopyrazine formation
To a suspension of 85% 5-phenyl-2-phenylsulfonyl-pyrazine-3-carbonitrile, 15% 5-phenyl-2-phenylsulfinylpyrazine-3-carbonitrile (3.2 g 10 mmol), and diisopropylethyl amine (2.58 g, 20 mmol) in 47 mL ethanol was added methylthioglycolate (1.06 g, 10 mmol). This was stirred at 20°C for 1 h and then 55°C for 7 h. Then methylthioglycolate (0.18 g, 0.17 mmol) and heated to 55°C for 4 h. After cooling to 5°C. The solid was filtered, washed with methanol (10 mL) and dried to give 2.4 g (84% yield) 4. IH NMR (CDCI 3) δ 9.09 (dd, 2H, Jl=8, J2=2 Hz), 7.53 (m, 3H), 6.27 (br s, 2H), 3.393 (s, 3H). 13C NMR (CDCI3) δ 165.30, 153.78, 149.19, 145.47, 142.34, 140.30, 136.06, 129.25,
129.11, 127.02, 51.87. MS(CI) 286 (M+l).
Example 6
Preparation of 3-amino-2-ethoxycarbonyl-5-phenylpyrroloFbl pyrazine To 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (1.0 g, 3.1 mmol)), and glycine ethyl ester hydrochloride (0.43 g, 3.1 mmol) in tetrahydrofunan (15 mL) was added dusopropylethylamine (1.62 mL, 9.3 mmol). The mixture was heated at reflux for 24 h then anhydrous sodium carbonate (0.49 g, 4.65 mmol) was added. The mixture was refluxed for an additional 10 h before its solvent was removed in vacuo. The residue was purified by flash chromatography (90% ethyl acetate/ 10% heptane) to give, after removing solvents, 0.54g (62%). IH NMR (CDC13): δ 1.34 (d, J= 6.8 Hz, 3H), 4.31 (q, J= 6.8 Hz, 2H), 4.33 (s, 2H), 5.85 (s,lH), 7.49 (m, 3H), 7.91 (m, 2H), 8.71 (s, IH).
Example 7 Preparation of 4-amino-6-phenylpteridin
To 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (1.0 g, 3.1 mmol)), and formamidine acetate (0.32 g, 3.1 mmol) in tetrahydrofuran (15mL) was added dusopropylethylamine (1.62 mL, 9.3 mmol). The mixture was heated at relux for 24 h then anhydrous sodium carbonate (0.49 g, 4.65 mmol) was added. The mixture was refluxed for an additional 3 h before its solvent was removed in vacuo. The residue was
purified by flash chromatography (90% ethyl acetate/10%) heptane) to give, after removing solvents, 0.52 g (78%). IH NMR (DMSO-d6): δ7.68 (m, 3H), 8.59 (m, 2H), 8.72 (s, IH), 8.85 (s, IH), 8.95 (s, IH), 9.85 (s, IH).
Example 8
Preparation of 4-amino-l-methyl-6-phenylpteridin
To 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (1.0 g, 3.1 mmol)), and acetamidine hydrochloride (0.29 g, 3.1 mmol) in tetrahydrofuran (15 mL) was added diisopropylethyl-amine (1.62 mL, 9.3 mmol). The mixture was heated at reflux for 3 h then anhydrous sodium carbonate (0.49 g, 4.65 mmol) was added. The mixture was refluxed for an additional 7 h before its solvent was removed in vacuo. The residue was purified by flash chromatography (50%> ethyl acetate/50%) heptane) to give, after removing solvents, 0.63 g (89%). IH NMR (DMSO-d6): δ 2.60 (s, 3H), 7.64 (m, 3H), 8.31 (s, IH), 8.42 (s, IH), 8.56 (m, 2H), 9.76 (s, IH).
Claims
Claims:
We claim:
1. A process for producing a regiospeciflc substituted pyrazine isomer compound of the formula
comprising reacting a 2,3,-diaminocompound of the formula
wherein A is nitrile and B is -SR wherein R is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl with a ketone compound of the formula
wherein R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, R3 and R4 are independently selected from the group consisting of of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, or R3 and R4 taken together can form a ring with the oxygen atoms to which they are attached, in the presence of excess acid and a solvent..
2. A process of claim 1 wherein said acid is selected from the group consisting of carboxylic acids and halogenated carboxylic acids.
3. A process of claim 1 wherein said solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and butanol and isobutanol.
4. A process of claim 2 wherein said acid is a halogenated carboxy acid.
5. A process of claim 4 wherein said halogenated carboxy acid is selected from the group consisting of trifluoroacetic acid, tribromoacetic acid, and trichloroacetic acid.
6. A process of claim 3 wherein said solvent is isopropanol.
7. A process of claim 1 wherein said 2,3-diamino compound is 2, 3-diamino-3- phenylthioacrylonitrile and said ketone compound is 2, 2-diethoxyacetophenone to produce regiospeciflc 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile.
8. A process for producing a substituted thieno[b]pyrazines of the formula
by reacting a sulfoxide compound of the formula
with a thioglycolate ester in the presence of a base.
9. A process of claim 8 wherein said base is selected from the group consisting of tertiary amines and inorganic bases.
10. A process of claim 9 wherein said tertiary amine is selected from the group consisting of triethylamine and dusopropylethylamine.
11. A process of claim 9 wherein said inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
12. A process of claim 8 wherein a co-solvent is added.
13. A process of claim 12 wherein said co-solvent is selected from the group consisting of methanol, ethanol, and isopropanol.
14. A process of claim 8 wherein said sulfone compound may be prepared by reacting a compound of the formula
with a carboxylic peracid, selected from the group consisting of, metachloroperbenzoic acid and peracetic acid.
15. A process of claim 8 wherein said sulfone compound is prepared by reacting a compound of the formula
with a peracid generated in situ from sodium perborate and a acid selected from the group consisting of carboxylic acids and halogenated carboxylic acids.
16. A process of claim 15 wherein said carboxylic acid is acetic acid.
15. A process of claim 15 wherein said halogenated carboxylic acid is selected from the group consisting of chloroacetic acid and dichloroacetic acid.
17. A process of claim 14 wherein a co-solvent is added.
19. A process of claim 18 wherein said co-solvent is selected from the group consisting of methanol, ethanol and isopropanol.
20. A process of claim 15 wherein a co-solvent is added.
21. A process of claim 20 wherein said co-solvent is selected from the group consisting of methanol, ethanol and isopropanol.
22. A process of claim 8 wherein said sulfone or sulfoxide compound is reacted with a thioglycolate ester of the formula HS(CH2)nC(O)OR5 wherein n=l-10 and R5 is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl, in the presence of a base.
23. A process of claim 21 wherein said base is selected from the group consisting of tertiary amines and inorganic bases.
24. A process of claim 22 wherein said tertiary amine is selected from the group consisting of triethylamine and dusopropylethylamine.
25. A process of claim 21 wherein said inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
26. A process for preparing a substituted pyrrolo[b]pyrazines are prepared by reacting a sulfone with H2NCH2CO2R6 where R6 is alkyl in the presence of a base as described above.
27. A process of claim 25 wherein said base is selected from tertiary amines such as triethylamine and dusopropylethylamine, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium bicarbonate.
28. A process for preparing a substituted pteridins may be prepared by reacting a sulfone with imidines such as H2NCR7NH where R7 is selected from the group consisting of hydrogen alkyl, aryl, or arylalkyl in the presence of a base.
29. A process of claim 27 wherein said base is selected from tertiary amines such as triethylamine and dusopropylethylamine, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium, or lithium bicarbonate.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002340250A CA2340250A1 (en) | 1998-08-20 | 1999-08-20 | Process for preparing regiospecific substituted pyrazine isomers |
| EP99942378A EP1115710A1 (en) | 1998-08-20 | 1999-08-20 | Process for preparing regiospecific substituted pyrazine isomers |
| JP2000566257A JP2002523405A (en) | 1998-08-20 | 1999-08-20 | Process for producing regioselective substituted pyrazine isomers |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13698398A | 1998-08-20 | 1998-08-20 | |
| US09/136,983 | 1998-08-20 |
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| WO2000010983A1 true WO2000010983A1 (en) | 2000-03-02 |
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| PCT/US1999/019044 WO2000010983A1 (en) | 1998-08-20 | 1999-08-20 | Process for preparing regiospecific substituted pyrazine isomers |
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| EP (1) | EP1115710A1 (en) |
| JP (1) | JP2002523405A (en) |
| CA (1) | CA2340250A1 (en) |
| WO (1) | WO2000010983A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9376399B2 (en) | 2004-12-23 | 2016-06-28 | Medibeacon Llc | Fluorescent pyrazine derivatives and methods of using the same in assessing renal function |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8664392B2 (en) | 2004-12-23 | 2014-03-04 | Medibeacon, LLC | Pyrazine derivatives for bioconjugation |
| EP2038261A2 (en) | 2006-06-22 | 2009-03-25 | Mallinckrodt Inc. | Pyrazine derivatives with extended conjugation and uses thereof |
| CA2628661A1 (en) | 2006-06-22 | 2007-12-27 | Mallinckrodt Inc. | Pyrazine derivatives and uses thereof in renal monitoring |
| WO2023248964A1 (en) * | 2022-06-21 | 2023-12-28 | クミアイ化学工業株式会社 | Method for producing sulfone derivative using haloacetic acid |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4990630A (en) * | 1986-08-13 | 1991-02-05 | Nippon Soda Co., Ltd. | 2,3-diaminoacrylonitrile derivatives and process for making the same |
| CH681226A5 (en) * | 1990-05-02 | 1993-02-15 | Firmenich & Cie | Prepn. of unsymmetrical alkyl-pyrazine(s) - by thermal cyclisation of new oximino-aza:diene(s) |
| WO1996022992A1 (en) * | 1995-01-27 | 1996-08-01 | Abbott Laboratories | Tricyclic substituted hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists |
-
1999
- 1999-08-20 JP JP2000566257A patent/JP2002523405A/en not_active Withdrawn
- 1999-08-20 WO PCT/US1999/019044 patent/WO2000010983A1/en not_active Application Discontinuation
- 1999-08-20 EP EP99942378A patent/EP1115710A1/en not_active Withdrawn
- 1999-08-20 CA CA002340250A patent/CA2340250A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4990630A (en) * | 1986-08-13 | 1991-02-05 | Nippon Soda Co., Ltd. | 2,3-diaminoacrylonitrile derivatives and process for making the same |
| CH681226A5 (en) * | 1990-05-02 | 1993-02-15 | Firmenich & Cie | Prepn. of unsymmetrical alkyl-pyrazine(s) - by thermal cyclisation of new oximino-aza:diene(s) |
| WO1996022992A1 (en) * | 1995-01-27 | 1996-08-01 | Abbott Laboratories | Tricyclic substituted hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists |
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| Title |
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| T.L.GILCHRIST: "Heterocyclic Chemistry second edition", 1992, LONGMANN SCIENTIFIC & TECHNICAL, UK, XP002122586 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9376399B2 (en) | 2004-12-23 | 2016-06-28 | Medibeacon Llc | Fluorescent pyrazine derivatives and methods of using the same in assessing renal function |
| US10617687B2 (en) | 2004-12-23 | 2020-04-14 | Medibeacon Inc. | Fluorescent pyrazine derivatives and methods of using the same in assessing renal function |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002523405A (en) | 2002-07-30 |
| CA2340250A1 (en) | 2000-03-02 |
| EP1115710A1 (en) | 2001-07-18 |
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