Synthesis of substituted pyrazolopyrimidines

Details Synthesis of substituted pyrazolopyrimidines Synthesis of substituted pyrazolopyrimidines

2000-08-09

2002-10-29

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C546S119000, C546S121000, C548S365700

Reexamination Certificate

active

06472528

ABSTRACT:

TECHNICAL FIELD
This invention is directed to the synthesis of substituted pyrazolopyrimidines, which compounds have utility over a wide range of indications including treatment of insomnia.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 4,521,422 to American Cyanamid Company is directed to certain aryl and heteroaryl[7-(aryl and heteroaryl)-pyrazolo[1,5-a]pyrimidin-3-yl]methanones which are active as anxiolytic, anticonvulsant, sedative-hypnotic and skeletal muscle relaxant agents. Such compounds may generally be classified as “substituted pyrazolopyrimidines” having the following structure (I):
wherein R
2
, R
3
, R
5
, R
6
, and R
7
are as defined in U.S. Pat. No. 4,521,422 (but under a different numbering scheme for the various R groups).
Compounds of structure (I) are made according to U.S. Pat. No. 4,521,422 by reacting an appropriately substituted pyrazole (a) with an appropriately substituted 3-dimethylamino-2-propen-1-one (b) as represented by the following Reaction Scheme A
U.S. Pat. No. 4,900,836, also to American Cyanamid Company, discloses novel pyrazoles (a) for use in Reaction Scheme A. More specifically, in this patent pyrazoles (a) are made, as represented below in Reaction Scheme B, by reacting appropriately substituted acetonitrile (c) with a dimethylamide dimethyl acetal (d) to yield the corresponding propanenitrile (e), which is then reacted with aminoguanidine nitrile (f) to give the correspondingly substituted pyrazole (a).
U.S. Pat. No. 4,521,422 also discloses the synthesis of substituted pyrazolopyrimidines of structure (I) using starting intermediates other than substituted 3-dimethylamino-2-propen-1-ones (b). For example, as represented by Reaction Scheme C, U.S. Pat. No. 4,521,422 teaches that the intermediate alkali metal salts of hydroxymethyleneketones (g) can be acylated by reacting with acid chlorides or anhydrides to give O-acyl derivatives (h), and that neutralization of (g) with certain acids affords hydroxymethylene ketones (i), all of which may be reacted with pyrazole (a) to give compounds of structure (I).
Further, U.S. Pat. No. 4,521,422 discloses that hydroxymethyleneketones (i) may be converted to other aldehyde equivalents, such as alkoxymethyleneketones (j), alkylthiomethyleneketones (k) and aminomethyleneketones (1)—as represented by Reaction Scheme D - and reacted with pyrazole (a) to give compounds of structure (I). Other hydroxymethieneketone and derivatives which are chemical equivalents of the same may also be used, such as 2-(dialkylamino)-1-aryl or (heteroaryl)-2-propen-1-ones.
In addition, other United States patents have issued directed to the synthesis of substituted pyrazolopyrimidines. For example, U.S. Pat. Nos. 4,654,347 and 4,626,538, both to American Cyanamide, disclose substituted pyrazolopyrimidines of structure (I) made by the techniques discussed above, but having different substituents than those of U.S. Pat. No. 4,521,422.
While U.S. Pat. Nos. 4,521,422 and 4,900,836, among others, teach techniques for the synthesis of compounds of structure (I), such procedures are relatively time consuming, involve numerous steps, and are not particularly economical or efficient for large-scale synthesis. Accordingly, there is a need in the art for improved synthetic techniques which overcome these shortcomings. The present invention fulfills these needs, and provides further related advantages.
SUMMARY OF THE INVENTION
In brief, the present invention is directed to the synthesis of substituted pyrazolopyrimidines having the following structure (I), which compounds have utility over a wide range of indications, including treatment of insomnia.
In structure (I) above, R
2
, R
3
, R
5
, R
6
and R
7
may be any of a number of substituents, and represent the remainder of the compound. Thus, in one embodiment, the present invention is directed generally to the synthesis of the pyrazolopyrimidine “core” or “template” itself, regardless of the nature of the various R substituents.
In a more specific embodiment, R
2
, R
3
, R
5
, R
6
and R
7
of structure (I) are as defined in U.S. Pat. No. 4,521,422, but under a different numbering scheme for the respective R groups. In particularly, R
2
, R
3
, R
5
, R
6
and R
7
of structure (I) correspond to R
2
, R
1
, R
5
, R
4
and R
3
, respectively, of U.S. Pat. No. 4,521,422.
In another more specific embodiment, R
2
, R
3
, R
5
, R
6
and R
7
of structure (I) are as defined in U.S. Pat. No. 4,654,347, wherein R
5
and R
6
of structure (I) are both hydrogen and R
2
, R
3
and R
7
of structure (I) correspond to R
2
, R
1
and R
3
, respectively, of U.S. Pat. No. 4,654,347.
In yet another more specific embodiment, R
2
, R
3
, R
5
, R
6
and R
7
of structure (I) are as defined in U.S. Pat. No. 4,626,538, wherein R
5
and R
6
of structure (I) are both hydrogen and R
2
, R
3
and R
7
of structure (I) correspond to R
2
, R
4
(when R
1
is —C(═O)R
4
) and R
3
, respectively, of U.S. Pat. No. 4,626,538.
For purpose of convenience, the more specific embodiments disclosed above are also referred to herein as “the R groups of U.S. Pat. Nos. 4,521,422, 4,654,347 and 4,626,538.” Thus, in one embodiment, the present invention is directed to the synthesis of substituted pyrazolopyrimidines having structure (I) above, which compounds have utility over a wide range of indications, including treatment of insomnia, wherein structure (I) is substituted with the R groups of U.S. Pat. Nos. 4,521,422, 4,654,347 and 4,626,538.
The synthetic techniques of this invention represent significant improvements over the prior techniques, including those disclosed in U.S. Pat. Nos. 4,521,422 and 4,900,836, particularly with regard to enhanced efficiency for large scale manufacture, reduced cost, better yield and/or simplified reaction conditions. In addition, improved techniques are also disclosed which do not require isolation of the pyrazole intermediate, as well as improved techniques for making intermediates for synthesis of compounds of structure (I).
These and other aspects of this invention will be apparent upon reference to the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
As mentioned above, the present invention is directed to improved synthetic routes for the synthesis of substituted pyrazolopyrimidines which are active as anxiolytic, anticonvulsant, sedative-hypnotic and skeletal muscle relaxant agents. Such compounds are represented by structure (I) above, and have previously been disclosed in U.S. Pat. Nos. 4,521,422, 4,900,836, 4,654,347 and 4,626,538 (which patents are each incorporated herein by reference in their entirety).
More specifically, in one embodiment of this invention, the pyrazolopyrimidine of structure (I) is N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-&agr;]-pyrimidin-7-yl}phenyl)acetamide, which compound has the following structure (hereinafter referred to as “Compound 1” or “1”):
As noted above, U.S. Pat. Nos. 4,521,422 and 4,900,836 disclose the synthesis of compounds of structure (I) via pyrazole intermediate (a). In one embodiment of this invention, synthesis does not proceed by way of this intermediate, which offers significant advantages over prior techniques, including enhanced efficiency, particularly in the context of large scale manufacture.
In one aspect of this embodiment, a compound of structure (I) generally, or Compound 1 specifically, is prepared by the following Reaction Scheme 1.
wherein compound 8 (see step b above) is an enaminone having the structure:
In Reaction Scheme 1, bromination of the aminopyrazole affords the bromopyrazole 9. This is then cyclized with enaminone 8 (which may be made according to the techniques disclosed in U.S. Pat. No. 4,521,422) in acetic acid affording the bromopyrazolopyrimidine 10. This bromopyrazolopyrimidine 10 is then reacted with 2-thiophenecarboxylic acid chloride in the presence of zinc or magnesium affording the desired product, Compound 1. Alternatively, this product may be prepared from the bromopyrazolopyrimidine 10 using a Suzuki

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