Imidazopyridine derivatives and process for making them

Details Imidazopyridine derivatives and process for making them Imidazopyridine derivatives and process for making them

2000-02-25

2001-08-28

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06281360

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a synthetic route for producing various imidazopyridine derivatives, to certain intermediates useful therein, and to highly pure compounds produced thereby.
Imidazopyridines of the formula (1) are described in U.S. Pat. No. 4,382,938 as useful pharmaceutical agents.
Y is hydrogen, halogen, or C
1
-C
4
alkyl and X
1
and X
2
are independently a hydrogen, halogen, C
1
-C
4
alkoxy, C
1
-C
6
alkyl, CF
3
, CH
2
S, CH
3
SO
2
or NO
2
. R
1
and R
2
are independently hydrogen, C
1
-C
5
alkyl, which may be substituted with, inter alia, halogen, hydroxy, etc., or together they form a heterocyclic ring. The compounds of formula (I) include the commercial product zolpidem which is sold in the hemitartrate form under the brand names Stilnox, Stilnoct, and Ambien. Zolpidem has the following formula.
The method disclosed in the above-cited patent for making the compounds of formula (I) can be outlined as follows:
The nitrile compound is converted to the primary amide compound by conventional methods and then the amide is saponified to form the acid compound. The acid compound can be converted to the final tertiary amide by known techniques including a reaction with an amine of the formula HNR
1
R
2
in the presence of carbonyldiimidazole or by forming the chloride of the acid and then reacting with amine of the formula HNR
1
R
2
.
This process suffers from several drawbacks, especially from the commercial point of view. For example, the starting nitrile must be formed from the corresponding imidazopyridine compound (unsubstituted in the 3 position) which adds additional synthetic steps. Moreover, the use of toxic reactants such as potassium cyanide are required. A shorter reaction scheme that avoids the use of highly toxic reagents would be advantageous.
An improved synthesis scheme, as shown below, is disclosed in U.S. Pat. No. 4,794,185.
The above process is believed to correspond to the commercial process presently used for the production of zolpidem. The process is described in the patent as providing high yield with “excellent purity, after work up.” While the number of steps has been reduced over the earlier process and the use of potassium cyanide can be avoided, the process uses special reactants, specifically the compounds of formula (III). Moreover, the replacement of the hydroxyl group with a chloride to form the compound of formula (V) and its subsequent removal means that chloride is a potentially troubling impurity in the final product. In addition, chlorination agents such as thionylchloride are highly hazardous compounds; making this synthetic scheme potentially dangerous to the operators and the environment. It would be desirable to have a process that could use inexpensive and safe reactants and that could form the free base of the final compound with very high purity.
Additional methods for making various imidazopyridines are disclosed by Schmitt et al., Aust. J. Chem., 1997, 50, 719-725. Among them is the reaction of certain 2-phenylimidazo[1,2-a]pyridines with freshly distilled ethyl glyoxylate to form ethyl 2-hydroxy-2-(2′-phenylimidazo[1,2-a]pyridin-3′-yl) acetate. This compound is reduced by adding phosphorous tetraiodide in dichloromethane to form ethyl 2-(2′-phenylimidazo[1,2-a]pyridin-3′-yl) acetate. Regarding such a procedure, Schmitt et al. states “The foregoing method of preparing the 2-hydroxyacetate and its conversion into the acetate may provide a convenient synthesis of the relevant intermediates for the preparation of alpidem and zolpidem.”
Exactly what the alpidem or zolpidem intermediates would be and how they would be used (the intended synthesis scheme) is not explained. Indeed, it is not possible to directly convert the ester compounds of Schmitt et al. to the desired amide using conventional amidation techniques. Moreover, the use of ethyl glyoxylate is not convenient for a commercial scale production. Such a product is commercially sold, apparently exclusively, as a 50% toluene solution. In such a solution, a portion of the ethyl glyoxylate exists in a partly polymerized, and thus unreactive, form. De-polymerization can be carried out by heating. This appears to explain the need to use freshly distilled ethyl glyoxylate as taught in Schmitt et al. Besides the impracticability of using ethyl glyoxylate, the only disclosed reducing agent, phosphorous tetraiodide, is expensive, not readily available, and produces iodine- and phosphorous-containing wastes. Furthermore, Schmitt et al. teaches the isolation of the intermediates by column chromatography. These reactants and procedures are not convenient for scale up to a commercial size production.
Accordingly, it would be desirable to have a process that can use inexpensive and/or readily available reactants. It would also be desirable to have a process that can be readily scaled up, that does not require special purification techniques and that can produce a highly pure product.
SUMMARY OF THE INVENTION
The present invention relates to a process, which comprises reacting a compound of formula (2):
wherein Y and Z each independently represent a lower alkyl group; with glyoxylic acid or a compound of formula (6):
wherein R
3
and R
4
each independently represent hydrogen or a lower alkyl;
to form a compound of formula (5).
Further, the present invention relates to removing the alpha hydroxyl group of the compound of formula (5) with a hydrogenolysis agent in the presence of a hydrogenolysis catalyst to thereby form a compound of formula (3).
The compounds of formula (3) can be converted into compounds of formula (1) by the use of an amidation agent;
wherein R
1
and R
2
each independently represent hydrogen or a lower alkyl group.
The process of the present invention can produce compounds of formula (1) in very high purity, even higher than 99.5%, through the use of common reactants and is susceptible of being scaled. The compounds of formula (5) as well as the highly pure compounds of formula (1) are additional aspects of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The starting compounds of formula (2) are commercially available and/or readily attained by methods known in the art. Y and Z each independently represent a lower alkyl group. As used throughout this specification, the term “lower alkyl group” means a straight chain, branched chain, or cycloalkyl group having 1 to 6 carbon atoms for a straight chain and 3 to 6 carbon atoms for a branched chain or cycloalkyl group. Typically Y and Z represent methyl, ethyl, propyl (n-or iso-propyl), or butyl (n-, iso-, or t-butyl), and preferably are both methyl.
Glyoxylic acid (CHO—COOH) and the compounds of formula (6) are also commercially available or readily attainable by known techniques. The compounds of formula (6) are derivatives of glyoxylic acid. Glyoxylic acid itself is an unstable compound so that it easily forms in a water solution a geminal diol compound (2,2-dihydroxyacetic acid also known as glyoxylic acid monohydrate-formula (6) where R
3
═R
4
═H). This monohydrate form is stable as both a solid crystal and as a water solution. Similarly, glyoxylic acid readily reacts with an alkanol to yield the corresponding acetal (formula (6) where at least one of R
3
and R
4
is not H). R
3
and R
4
each independently represent hydrogen or a lower alkyl group. Typically, R
3
and R
4
are both hydrogen, methyl or ethyl, although they are not limited thereto.
In the “reaction,” the compounds of formula (6) are believed to convert to glyoxylic acid as an intermediate which then reacts with the compound of formula (2). In a certain sense, the reaction is thus always between glyoxylic acid and a compound of formula (2). The compounds of formula (6) serve as a convenient precursor compound for providing the active but unstable glyoxylic acid for reaction. It is, however, possible to add glyoxylic acid itself as the reactant to form the compounds of formula (5). The phrase “reacting a compound of formula (2) wi

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