Note: Descriptions are shown in the official language in which they were submitted.
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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
s 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
to substituted pyrazine compounds, substituted thieno[b]pyrazine, substituted
pteridins,
compounds, and derivatives thereof. The regiospecific substituted compounds
are useful
in the preparation of pharmaceuticals, including compounds useful in treating
benign
prostatic hyperplasia.
~s Detailed Description of the Invention
For the purposes of this disclosure, the term 'regiospecific' 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
2o 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,
2s 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
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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
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.
to 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
is 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
2o with the oxygen atoms to which they are attached.
HZN A + O OR3 RZ N\ A + N\ A
R~ --
OR N B
H2N B 4 R2 N B
4
Scheme I
2s In a preferred embodiment of the present invention as shown in Scheme 2, 2,
3-
diamino-3-phenylthioacrylonitrile (5) wherein R1 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
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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
s to produce a regioselective substituted pyrazine isomer (6) over isomer (7).
H2N CN O CN
~OR3 R2 N~ + N' CN
R2 >
i
H2N SRS OR4 N SRS R2 N SRS
2 6
Scheme 2
~o 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 regiospecific
substituted pyrazine
isomer ( 10) over isomer ( 1 I ).
I-~N CN O ~ CN
+ OC~C~ ~ I N CN I N
N S OCh~CI-~ ~ N S
8 ~ \ \ I ~ N S/ \ ~ ~ ll / \
to ~/
~s
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,
2o 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
SUBSTITUTE SHEET (RULE 26)
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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 diisopropylethylamine. 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
t s 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
/ /
N CN I CN I CN
I ~ NaB03 ~ I Nw ~ I N\
N S
N SO N S02
12 / \ 13 ~ \
HS(CH2)"C(O)ORs
Base
/
I N NH2
~N~ /"CO2R5
S
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The resulting sulfone (13) may be reacted with a thioglycolate ester of the
formula
HS(CH2)nC(O)ORS wherein n=1-10 and RS 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,
s ethanol, and isopropanol. Bases suitable 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, or lithium biocarbonate.
Substituted pyrrolo[b]pyrazines are prepared by reacting a sulfone with
io H2NCH2C02R6 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, diisopropylethylamine,
diisopropylamine,
is 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.
2o Example 1
5-phenyl-2-phenylthiopyrazine-3-carbonitrile
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
zs 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 S-phenyl-2-
phenylthiopyrazine-3-carbonitrile. 1H NMR (CDCI3) 8 8.9 (s, IH), 8.0-7.9 (m,
2H), 7.7-
7.6 (m, 2H), 7.59-7.45 (m, 6H).
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Example 2
5-phenyl-2-phenvlsulfin~pyrazine-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 IO 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 S-phenyl-2-phenylsulfinylpyrazine-3-
carbonitrile (2.82
g, 88%). 1 H NMR (DMSO) b 9.67 (s, 1 H), 7.97 (m, 2H), 7.78-7.62 (m, 6H).
to Example 3
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 (Sg, l7mmol) in methylene
chloride
(100m1) at <6°C and this was stirred at room temperature for 18 h.
Methanol (100 mL)
~s 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. 1 HNMR
(CDCI3 )
8 (ppm) 9.19 (s,lH)8.21 (dd, 2H, J1 =BHz, J2=2.SHz), 8.08 (dd, 2H, J1=8 Hz,
J2=3Hz),
7.73 (dt, 2H, J1=8, J2 =2.SHz), 7.6, (m, SH). 13C NMR(DMSO-d6) 8(ppm).
IR(ICBr)
20 3125, 3070, 2250, 1555, 1325, 1160, 730. HRMS(FAB) Calculated m/z for M+H
C17H12N3O2S 322.0650, Observed m/z 322.0652.
Example 4
Alternative synthesis of 5-uhenvl-2-phenvlsulfonvluvrazine-3-carbonitrile
2s A slurry of 5-phenyl-2-phenylthiopyrazine-3-carbonitrile (SOg), 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 %).
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Example 5
Thienopyrazine formation
To a suspension of 85% S-phenyl-2-phenylsulfonyl-pyrazine-3-carbonitrile, 15%
5-phenyl-2-phenylsulfinylpyrazine-3-carbonitrile (3.2 g 10 mmol), and
diisopropylethyl
s 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 SS°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.
1 H NMR
(CDCI 3) b 9.09 (dd, 2H, JI=8, J2=2 Hz), 7.53 (m, 3H), 6.27 (br s, 2H), 3.393
(s, 3H).
to I3C NMR (CDCI3) 8 165.30, 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-ethoxvcarbonyl-5-phenylpvrrolo[blp ry azine
is 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 diisopropylethylamine (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
2o purified by flash chromatography (90% ethyl acetate/10% heptane) to give,
after removing
solvents, 0.54g (62%). 1H NMR (CDC13): 8 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 (rn, 3H), 7.91 (m, 2H), 8.7I (s, 1H).
Example 7
2s Preparation of 4-amino-6-phen~pteridin
To S-phenyl-2-phenylsulfonylpyrazine-3-carbonitrile (I.0 g, 3.1 mmol)), and
formamidine acetate (0.32 g, 3.1 mmol) in tetrahydrofuran ( 1 SmL) was added
diisopropylethylamine ( 1.62 mL, 9.3 mmol). The mixture was heated at relux
for 24 h
then anhydrous sodium carbonate (0.49 g, 4.65 nunol) was added. The mixture
was
3o refluxed for an additional 3 h before its solvent was removed in vacuo. The
residue was
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purified by flash chromatography (90% ethyl acetate/10% heptane) to give,
after removing
solvents, 0.52 g (78%). 1 H NMR (DMSO-d6): 87.68 (m, 3H), 8.59 (m, 2H), 8.72
(s, 1 H),
8.85 (s, 1 H), 8.95 (s, 1 H), 9.85 (s, 1 H).
s Example 8
Preparation of 4-amino-1-meth~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
~o 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%). 1H NMR (DMSO-d6): 8 2.60 (s, 3H), 7.64 (m, 3H), 8.31
(s, 1H),
8.42 (s, 1 H), 8.56 (m, 2H), 9.76 (s, 1 H).
