Methods of Preparing 2-Imidazol-1-Yl-4-Methyl-6-Pyrrolidin-2-Yl-Pyrimidine and 4-(1-Alkylpyrrolidin-2-Yl)-2-(1H-Imidazol-1-Yl)-6-Methylpyrimidine Derivatives
First Claim
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1. A method for the preparation of a compound of structural formula (VI):
- or a salt, ester, or prodrug thereof, wherein;
R1 is selected from the group consisting of hydrogen, acyl, alkanoyl, alkenyl, alkenyloxycarbonyl, alkoxy, alkoxyalkyl, alkyl, alkylaminocarbonyl, alkylsulfonyl, alkynyl, amido, amidoalkyl, amino, aroyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, aryloxyarylalkyl, arylsulfonyl, arylalkylsulfonyl, arylalkenylsulfonyl, carbamoyl, carboalkoxy, carboarylalkoxy, carboaryloxy, carboarylalkenyloxy, carboalkoxyamino, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaroyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylsulfonyl, heteroarylarylalkylsulfonyl, heteroarylalkenylsulfonyl, heteroalkyl, heterocycloalkyl, hydroxyalkyl, perhaloalkyl, and trisubstituted silyl, any of which may be optionally substituted;
comprising;
a) treating the reaction product of structural formula (V),
with suitable reagents including, but not limited to, an excess of an inorganic salt of guanidine, and an inorganic base, in a suitable protic solvent, using an appropriate reaction time over a suitable temperature range; and
b) optionally isolating the reaction product of structural formula (VI).
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Abstract
The present invention is directed to a novel, high yield method for preparing 2-imidazol-1-yl-4-methyl-6-pyrrolidin-2-yl-pyrimidine, particularly to a method of preparing 4-(1-alkylpyrrolidin-2-yl)-2-(1H-imidazol-1-yl)-6-methylpyrimidine, more particularly, 2-(2-(2-(1H-imidazol-1-yl)-6-methylpyrimidin-4-yl)pyrrolidrn-1-yl)-N-(benzo[d][1,3]dioxol-5-yh-nethyl)-N-methylethanamine. These compounds and pharmaceutical compositions thereof are inhibitors of nitric oxide synthase, are selective for inducible nitric oxide synthase, and are useful in treating diseases and disorders including inflammation and pain.
5 Citations
50 Claims
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1. A method for the preparation of a compound of structural formula (VI):
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or a salt, ester, or prodrug thereof, wherein; R1 is selected from the group consisting of hydrogen, acyl, alkanoyl, alkenyl, alkenyloxycarbonyl, alkoxy, alkoxyalkyl, alkyl, alkylaminocarbonyl, alkylsulfonyl, alkynyl, amido, amidoalkyl, amino, aroyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, aryloxyarylalkyl, arylsulfonyl, arylalkylsulfonyl, arylalkenylsulfonyl, carbamoyl, carboalkoxy, carboarylalkoxy, carboaryloxy, carboarylalkenyloxy, carboalkoxyamino, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaroyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylsulfonyl, heteroarylarylalkylsulfonyl, heteroarylalkenylsulfonyl, heteroalkyl, heterocycloalkyl, hydroxyalkyl, perhaloalkyl, and trisubstituted silyl, any of which may be optionally substituted; comprising; a) treating the reaction product of structural formula (V),
with suitable reagents including, but not limited to, an excess of an inorganic salt of guanidine, and an inorganic base, in a suitable protic solvent, using an appropriate reaction time over a suitable temperature range; andb) optionally isolating the reaction product of structural formula (VI). - View Dependent Claims (2, 3, 4)
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5. A method for the preparation of a compound of structural formula (I):
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or a salt, ester, or prodrug thereof, wherein; R1 is selected from the group consisting of hydrogen, acyl, alkanoyl, alkenyl, alkenyloxycarbonyl, alkoxy, alkoxyalkyl, alkyl, alkylaminocarbonyl, alkylsulfonyl, alkynyl, amido, amidoalkyl, amino, aroyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, aryloxyarylalkyl, arylsulfonyl, arylalkylsulfonyl, arylalkenylsulfonyl, carbamoyl, carboalkoxy, carboarylalkoxy, carboaryloxy, carboarylalkenyloxy, carboalkoxyamino, cycloalkyl, cycloalkylalkyl, haloalkyl, heteroaroyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylsulfonyl, heteroarylalkylsulfonyl, heteroarylalkenylsulfonyl, heteroalkyl, heterocycloalkyl, hydroxyalkyl, perhaloalkyl, and trisubstituted silyl, any of which may be optionally substituted; comprising; a) treating the reaction product of structural formula (VI),
with a combination of suitable reagents, comprising a formaldehyde equivalent, a glyoxal equivalent, a ammonia equivalent, and an appropriate amount of a protic acid in a suitable protic solvent, using an appropriate reaction time over a suitable temperature range;b) isolating the novel reaction product of structural formula (I in high yield and purity; c) optionally removing the R1 group to afford a compound of structural formula (I), wherein R1 is hydrogen; and d) optionally alkylating the compound of structural formula (I), wherein R1 is hydrogen, with an appropriate alkylating agent in a suitable solvent, using an appropriate reaction time over a suitable temperature range. - View Dependent Claims (6, 7, 8, 9, 10, 11, 12)
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13. A method for the preparation of a compound of structural formula (VII):
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or a salt, ester, or prodrug thereof, wherein; R2 is optionally substituted alkyl; comprising; a) treating the reaction product of structural formula (IIIa),
with an excess of the salt of a monoanion of alkylacetoacetate, in a suitable solvent, using an appropriate reaction time over a suitable temperature range reagents; andb) isolating the novel reaction product of structural formula (VII). - View Dependent Claims (14, 15, 16)
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17. A method for the preparation of a compound of structural formula (VIII):
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or a salt, ester, or prodrug thereof, comprising; a) treating the reaction product of structural formula (VII),
with a protic acid, in a suitable solvent, using an appropriate reaction time over a suitable temperature range; and
in a suitable solvent; anda) isolating the novel reaction product of structural formula (VIII). - View Dependent Claims (18, 20, 21)
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19. The method as recited in claim 19, wherein p-toluenesulfonic acid is present in catalytic amounts.
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22. A method for the preparation of a compound of structural formula (IX):
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or a salt, ester, or prodrug thereof, comprising; a) treating the reaction product of structural formula (VIII),
with suitable reagents including, but not limited to, an excess of an inorganic salt of guanidine, and an inorganic base, in a suitable protic solvent, using an appropriate reaction time over a suitable temperature range; andb) optionally isolating the reaction product of structural formula (IX). - View Dependent Claims (23, 24, 25, 26)
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27. A method for the preparation of a compound of structural formula (X):
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or a salt, ester, or prodrug thereof, comprising; a) treating the reaction product of structural formula (IX),
with a combination of suitable reagents, comprising a formaldehyde equivalent, a glyoxal equivalent, a ammonia equivalent, and an appropriate amount of a protic acid in a suitable solvent, using an appropriate reaction time over a suitable temperature range; andb) isolating the novel reaction product of structural formula (X) in high yield and purity. - View Dependent Claims (28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38)
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39. A method for the preparation of a compound of structural formula (XI):
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or a salt, ester, or prodrug thereof, comprising; a) treating the reaction product of structural formula (X),
with a hydrogen source in the presence of a catalyst in a suitable protic solvent, under an appropriate reaction pressure, using an appropriate reaction time over a suitable temperature range; andb) isolating the novel reaction product of structural formula (XI) in high yield and purity. - View Dependent Claims (40, 41, 42, 43, 44)
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45. A method for the preparation of a compound of structural formula (XII):
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or a salt, ester, or prodrug thereof, comprising; a) treating the reaction product of structural formula (XI),
with the alkylating agent benzo[1,3]dioxol-5-ylmethyl-(2-chloro-ethyl)-methyl-amine hydrochloride salt, in the presence of a tertiary amine base and a halide salt in a suitable dipolar aprotic solvent using an appropriate reaction time over a suitable temperature range; andb) isolating the novel reaction product of structural formula (XII) in high yield and purity.
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- 46. The method as recited in claim 46, wherein said tertiary amine base is N,N-diisopropylethylamine.
Specification