MXPA01001853A - Process for preparing regiospecific substituted pyrazine isomers - Google Patents

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 TO PREPARE ISRAELS OF PIRAZINA SUBSTITUIDA REGIOESPECÍFICA This application is a continuation in parts of at the request of E. U. serial number 09/1 36,983, filed on August 20, 1998, incorporated herein by reference.

BACKGROUND OF THE INVENTION The Patent of E. U. No. 4, 990,630 to Sato et al., Discloses a process for reacting a 2,3-diamino-3-phenylthioacyl-nitrile compound with a symmetrical 1,2-dicarbonyl compound to produce a symmetrical pyrazine compound. One limitation of this process is that it can not produce asymmetric pyrazine compounds with predictable regiospecificity. The present invention relates to a process for producing specific isomers of substituted pyrazine, substituted thieno [b] pyrazine compounds, substituted pteridines, compounds, and derivatives thereof. The regiospecific substituted compounds are useful in the preparation of pharmaceuticals, including compounds useful in the treatment of benign prosthetic hyperplasia.

DETAILED DESCRIPTION OF THE INVENTION For purposes of this description, the term "regiospecific" as used herein, is defined as the formation of an isomer of a compound in an amount greater than that of other isomers. The terms "lower alkyl" 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, isobutyl, 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 similar. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, 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 lower alkyl 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 so on. The cycloalkyl groups may be unsubstituted or substituted with two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, dialkylamino, halo, nitro, alkoxycarbonyl and carboxamide. The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group attached to a lower alkyl radical, including but not limited to cyclohexylmethyl. In one embodiment of the present invention shown in Scheme I, a 2,3-diamino compound (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 can be 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 pyrazole compound (3) in the presence of acid in excess and a solvent. R3 and R4 are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl,? R3 and R4 taken together can form a ring with the oxygen atoms to which they are attached.

Scheme I In a preferred embodiment of the present invention as shown in Scheme 2, 2, 3-diamino-3-phenylthioacrylonitrile (5) from lower alkyl, haloalkyl, alkoxy, thioalkoxy, dialkylamino, halo, nitro, alkoxycarbonyl and carboxamide. The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group attached to a lower alkyl radical, including but not limited to cyclohexylmethyl. In one embodiment of the present invention shown in Scheme I, a 2,3-diamino compound (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 can be 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 pyrazole compound (3) in the presence of acid in excess 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.

Scheme I In a preferred embodiment of the present invention as shown in Scheme 2, 2, 3-diamino-3-phenylthioacrolonitrile (5) wherein R 1 is phenyl, it is reacted with a ketone compound (2) in wherein R2 is selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl, to produce a regioselectively 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 takes place in the presence of excess acids in a solvent to produce a regioselective substituted pyrazine isomer (6) on the isomer (7).

Scheme 2 In a 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 regio-specific substituted pyrazine isomer (10) on the (1 1) isomer.

Scheme 3 Solvents suitable for the present invention include, but are not limited to, alkanol solvents. The alkanol solvents include, but are not limited to, methanol, ethanol, propanol, isopropanol, butanol, and sobutanol. 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. The substituted thieno [b] pyrazines can be prepared by reacting Compounds (12) and (1 3) with a thioglycolate ester in the presence of a base. Suitable bases for the reaction include, but are not limited to, tertiary amines such as triethylamine and diisopropylethylamine. The substituted thieno [b] pyrazines can 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, potassium carbonate and potassium bicarbonate. The sulfone can be prepared by reacting the compound (10) with a peracid carboxylic acid, which includes, but is not limited to, meta-chloroperbenzoic acid, peracetic acid and the like. The sulfone can also be prepared by reacting the 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 include, but are not limited to, acetic acid, chloroacetic acid, dichloroacetic acid, and the like.

Scheme 4 The resulting sulfone (1-3) can be reacted with a thioglycolate ester of the formula HS (CH2) nC (0) OR5 wherein n = 1-10 and R5 is selected from the group consisting of alkyl, cycloalkyl, and cycloalkylalkyl, in the presence of a tertiary amine base and a co-solvent. Co-solvents suitable for the invention include, but are not limited to, methanol, ethanol and isopropanol. Suitable bases for the invention include, but are not limited to, tertiary amines such as triethylamine and diisopropylethylamine, and the like or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium, potassium bicarbonate. or lithium. The substituted pyrrolo [b] pyrazines are prepared by reacting a sulfone with H2 NCH2CO2 R6 wherein R6 is alkyl in the presence of a base as described above. Substituted pteridines can be prepared by reacting a sulfone with imidines such as H2 NCR7N H wherein R7 is selected from the group consisting of alkyl, aryl or arylalkyl of hydrogen in the presence of a base. Suitable bases for the invention include, but are not limited to, alkylamines such as triethylamine, diisopropylethylamine, diisopropylamine, and the like, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium bicarbonate, of potassium, or lithium. The following examples are intended to be illustrative of the present invention and not limiting of its scope.

EXAM PLO 1 5-phenyl-2-phenylthiopyrazine-3-carbonitrile To a suspension of 2,3-diamino-3-phenylthioacyl-nitrile toluenesulfonic acid (8 grams (g), 22 mmol (mmol)), and trifluoroacetic acid (14.8) g, 1 30 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 room temperature before adding 80 μL of water. The slurry was stirred for 1 hour and the solid filtered and rinsed with 50 mL of 50% aqueous isopropanol to deliver, after drying, 4.25g (73%) of 5-phenyl-2-phenylthiopyrazine-3-carbonitrile. 1 H NMR (CDCl 3) d 8.9 (s, 1 H), 8.0-7.9 (m, 2 H), 7.7-7.6 (m, 2 H), 7.59-7.45 (m, 6H).

EXAM PLO 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) at 45-50 ° was heated. 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 room temperature, and water (50 mL) was added. The slurry was filtered, rinsed with water (100 mL) and dried to deliver 5-phenyl-2-phenylsulfinylpyrazine-3-carbonitrile. (2.82 g, 88%). 1 H N MR (DMSO) d 9.67 (s, 1 H), 7.97 (m, 2H), 7.78-7.62 (m, 6H).

EXAMPLE 3 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile 3-chloroperoxy benzoic acid (mCP BA) (8.9g, 52 mmol) was added in a solution of 5-phenyl-2-phenylthiopyrazine-3-carbonitrile, (5g, 17mmol) in methylene chloride (100 ml) at < 6 ° C and it is 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 rinsed with methanol (20 mL) to deliver 4.5 g (80% product) of 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile, mp 222-224 ° C. 1H NMR (CDCl 3) d (ppm) 9.19 (s, 1H) 8.21, (dd, 2H, J1 = 8Hz, J2 = 2.5 Hz), 8.08 (dd, 2H, J1 = 8 Hz, J2 = 3Hz), 7.73 ( dt, 2H, J1 = 8, J2 = 2.5Hz), 7.6, (m, 5H). 13 C NMR (DMSO-d 6) d (ppm). IR (KBr) 3125, 3070, 2250, 1555, 1325, 1160, 730. HRMS (FAB) m / z calculated for M + H C17H12N302S 322.0650, m / z observed 322.0652 EXAMPLE 4 Alternative Synthesis of 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile A slurry of 5-phenyl-2-phenylthiopyrazine-3-carbonitrile (50 g) and chloroacetic acid (176 g) in acetic acid (530 g) was heated. ) at 45-55 ° C for approximately 24 hours. The mixture was cooled to room temperature, and 500 mL of water was added. The slurry was filtered, rinsed with 300 mL of water and dried to yield 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, 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (32 g, 10 mmol) and Diisopropylethyl amine (2.58 g, 20 mmol) in 47 mL of ethanol was added methylthioglycolate (1.06 g, 10 mmol). This was stirred at 20 ° C for 1 h and then at 55 ° C for 7 h. Then methylthioglycolate (0.18 g, 0.17 mmol) and heated at 55 ° C for 4 h. Then it was cooled to 5 ° C. The solid was filtered, rinsed with methanol (10 mL) and dried to yield 2.4 g (84% product) 4. 1 H NMR (CDCl 3) d 9.09 (dd, 2 H, J 1 = 8, J 2 = 2 Hz) , 7.53 (m, 3H), 6.27 (br s, 2H), 3.393 (s, 3H). 13 C NMR (CDCl 3) d 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 + 1).

EXAMPLE 6 Preparation of 3-amino-2-ethoxycarbonyl-5-phenylpyrrolofblpyrazine 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 tetrahydrofuran (15 mL) was added diisopropylethylamine (1.62 mL, 9.3 mmol). The mixture was heated at reflux for 24 h and then anhydrous sodium carbonate (0.49 g, 4.65 mmol) was added. The mixture was refluxed for an additional 10 h before the solvent was removed in vacuo. The residue was purified by flash chromatography (90% ethyl acetate / 10% heptane) to deliver, after extracting the solvents, 0.54g (62%). 1 H NMR (CDCl 3): d 1.34 (d, J = 6.8 Hz, 3 H), 4.31 (q, J = 6.8 Hz, 2 H), 4.33 (s, 2 H), 5.85 (s, 1 H), 7.49 (m, 3 H) ), 7.91 (m, 2H), 8.71 (s, 1H).

EXAMPLE 7 Preparation of 4-amino-6-phenylpteridine A 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (1.0 g, 3.1 mmol), and formamidine acetate (0.32 g, 3.1 mmol) in tetrahydrofuran (15 g. mL) was added diisopropylethylamine (1.62 mL, 9.3 mmol). The mixture was heated at reflux for 24 h and then the 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 deliver, after removal of the solvents, 0.52 g (78%). 1 H NMR (DMSO-d 6): d 7.68 (m, 3 H), 8.59 (m, 2 H), 8.72 (s, 1 H), 8.85 (s, 1 H), 8.95 (s, 1 H), 9.85 (s, 1 H) .

EXAMPLE 8 Preparation of 4-amino-1-methyl-6-phenylpteridine A 5-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (1.0 g, 3.1 mmol), and acetamidine hydrochloride (0.29 g, 3.1 mmol) in tetrahydrofuran (15 g. mL) was added diisopropylethylamine (1.62 mL, 9.3 mmol). The mixture was heated at reflux for 3 h and then the 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 deliver, after removal of the solvents, 0.63 g (89%). 1 H NMR (DMSO-d 6): d 2.60 (s, 3 H), 7.64 (m, 3 H), 8.31 (s, 1 H), 8.42 (s, 1 H), 8.56 (m, 2 H), 9.76 (s, 1 H) .

Claims (9)

1. CLAIMS 1 . A process for producing a regiospecific substituted pyrazine isomer compound of the formula which comprises reacting a 2,3-diamino compound 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 alkyl, aryl, aplaxyl, 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 an excess acid and a solvent.
2. 2. A process according to claim 1, characterized in that said acid is selected from the group consisting of carboxylic acids and halogenated carboxylic acids. 3. A process according to claim 1, characterized in that said solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, and butanol and isobutanol. 4. A process according to claim 2, characterized in that said acid is halogenated carboxy acid. 5. A process according to claim 4, characterized in that said halogenated carboxy acid is selected from the group consisting of trifluoroacetic acid, tribromoacetic acid and trichloroacetic acid. 6. A process according to claim 3, characterized in that said solvent is isopropanol. 7. A process according to claim 1, characterized in that said 2,3-diamino compound is 2,3-diamino-3-phenylthioacrylonitrile and said ketone compound is 2,2-diethoxyacetophenone to produce 5-phenyl-2-phenylsulfonylpyrazine. -3-regiospecific carbonitrile. 8. A process to produce a thieno [b] pyrazine its formula substituted by reacting a sulfoxide compound of the formula with a thioglycolate ester in the presence of ester. 9. A process according to claim 8, characterized in that said base is selected from the group consisting of tertiary amines and inorganic bases. 1. A process according to claim 9, characterized in that said tertiary amine is selected from the group consisting of triethylamine and diisopropylethylamine. 1 - A process according to claim 9, characterized in that said inorganic base is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. 12. A process according to claim 8, characterized in that a co-solvent is added.
3. 3. A process according to claim 12, characterized in that said co-solvent is selected from the group consisting of methanol, ethanol and isopropanol. 14. A process according to claim 8, characterized in that said sulfone compound can be prepared by reacting a compound of the formula with a carboxylic peracid, selected from the group consisting of metachloroperbenzoic acid and peracetic acid. 5. A process according to claim 8, characterized in that said sulfone compound is prepared by reacting a compound of the formula with a peracid generated in situ from sodium perborate and an acid selected from the group consisting of carboxylic acids and halogenated carboxylic acids. 16. A process according to claim 1, characterized in that said carboxylic acid is acetic acid. 17. A process according to claim 1, characterized in that said halogenated carboxylic acid is selected from the group consisting of chloroacetic acid and dichloroacetic acid. 1 8. A process according to claim 14, characterized in that a co-solvent is added. 9. A process according to claim 18, characterized in that said co-solvent is selected from the group consisting of methanol., ethanol and isopropanol. 20. A process according to claim 1, characterized in that a co-solvent is added. twenty-one . A process according to claim 20, characterized in that said co-solvent is selected from the group consisting of methanol, ethanol and isopropanol. 22. A process according to claim 8, characterized in that said sulphone or sulfoxide compound is reacted with a thioglycolate ester of the formula HS (CH2) nC (0) COR5 wherein n = 1-10 and R5 is selected from starting from the group consisting of alkyl, cycloalkyl, and cycloalkyl, in the presence of a base. 23. A process according to claim 21, characterized in that said base is selected from the group consisting of tertiary amines and inorganic bases. 24. A process according to claim 22, characterized in that said tertiary amine is selected from the group consisting of triethylamine and diisopropylethylamine. 25. A process according to claim 21, characterized in that 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] pyrazine by reacting a sulfone with H2NCH2C02R6 wherein R6 is alkyl in the presence of a base as described above. 27. A process according to claim 25, characterized in that said base is selected from tertiary amines such as triethylamine and diisopropylethylamine, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium bicarbonate, of potassium or lithium. 28. A process for preparing a substituted pteridine can be prepared by reacting a sulfone with imidines such as H2 NC R7N H wherein R7 is selected from the group consisting of alkyl, aryl, or arylalkyl of hydrogen in the presence of a base. 29. A process according to claim 27, characterized in that said base is selected from tertiary amines such as tetylamine and diisopropylethylamine, or carbonates such as sodium, potassium, or lithium carbonate, or bicarbonates such as sodium bicarbonate, of potassium or lithium. SUMMARY The present invention relates to a process for producing specific isomers of substituted pyrazine, substituted thieno [b] pyrazine compounds, substituted pteridines, compounds and derivatives thereof. The regiospecific substituted pyrazine compounds are useful in the preparation of pharmaceuticals, including compounds useful in the treatment of benign prostatic hyperplasia