Process for preparing triazolopyrimidine derivatives

Details Process for preparing triazolopyrimidine derivatives Process for preparing triazolopyrimidine derivatives

2002-04-30

2003-05-27

Ford, John M. (Department: 1624)

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

Organic compounds

Pteroyl per se or having -c-, wherein x is chalcogen, bonded...

Reexamination Certificate

active

06570014

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a novel process for preparing triazolopyrimidine derivatives of the formula (I):
wherein R
1
represents a hydrogen or an alkyl radical of one to ten carbon atoms, or a cycloalkyl radical of three to six carbon atoms, or an alkenyl radical of up to four carbon atoms; R
2
represents a hydrogen, a halogen atoms, a hydroxyalkyl or alkyl radical of one to ten carbon atoms; R
3
represents a hydrogen, a hydroxyalkyl or alkyl radical of one to four carbon atoms.
BACKGROUND OF THE INVENTION
The compounds of the formula (I) are known and described in U.S. Pat. No. 3,689,488. They are capable of preventing bronchospasm and therefore useful in the treatment of diseases that involve spasm or constriction of the bronchial muscle, for example asthma or bronchitis. A process for the preparation of the formula (I) described in U.S. Pat. No. 3,689,488 are summarized as follows:
(a) Preparation of diamino-1,2,4-triazole (shown in Scheme 1)
(b) Preparation of triazolopyrimidines (shown in Scheme 2)
There are several disadvantages for manufacturing in the aforementioned processes. First of all, the process for preparing diamino-1,2,4-triazole (Scheme 1) taking several days is inefficient. Second, the condensation of diamino-1,2,4-triazole and &agr;, &bgr;-unsaturated acid derivatives of the formula (II) that obtained mixture isomers is unselective and need further purification (Scheme 2). Third, The hydrogenolysis of benzyl group (deprotection of amino group) to get triazolopyrimidines of the formula (I) taking 10 days is time-consuming (Scheme 2). From the commercial point of view, the processes shown in scheme 1 and 2 are inefficient and costly.
SUMMARY OF THE INVENTION
Therefore, it is an object of the present invention to provide a more efficient, cheaper and selective process for preparing triazolopyrimidines derivatives of formula (I) that is capable of overcoming the aforesaid drawbacks.
According to the present invention, there is provided a process for preparing triazolopyrimidines derivatives of the formula (I). This process comprises preparing rapidly diamino-1,2,4-triazole of the formula (III) from dialkyl cyanodithioimino carbonate of the formula (V); and efficient protection and deprotection of amino group; and selective condensation of &agr;, &bgr;-unsaturated acid derivatives of the formula (II) and imine of the formula (VI).
DETAILED DESCRIPTION OF THE INVENTION
A process for preparing triazolopyrimidines derivatives of the formula (I) according to the present invention comprises four steps. The first step is the efficient preparation of diamino-1,2,4-triazole of the formula (III), wherein 1 to 2 equivalent of alkyl amine of the formula (IV) is added slowly into the mixture of the dialkyl cyanodithioimino carbonate of the formula (V) (1 equivalent) and appropriate solvent at room temperature, and then 1 to 4 equivalent of the hydrazine is added dropwisely after heating to reflux.
Schematic illustration of preparing diamino-1,2,4-triazole of the formula (III) is shown in scheme 3, wherein R
1
has the meaning indicated above; and R represents an alkyl radical of one to four carbon atoms; and solvent can use water, acetonitrile or alcoholic solvent, such as methanol, ethanol, propanol, or butanol, etc.
The second step is the formation of imine of the formula (VI), wherein 1 to 5 equivalent of aldehyde of the formula (VII) is reacted with 1 equivalent of the diamino-1,2,4-triazole of the formula (III) in an organic solvent under acid catalysis (0 to 1 equivalent) at 50~150° C.
Schematic illustration of preparing imine of the formula (VI) is shown in scheme 4, wherein R
1
has the meaning indicated above; and R
8
represents an alkyl radical of one to ten carbon atoms, or a phenyl, or a substituted phenyl; and solvent can use acetonitrile, toluene; xylene, chlorobenzene, chloroform, dichloromethane, ethylene dichloride or alcoholic solvent, such as methanol, ethanol, propanol, or butanol, etc.; and catalyst can be not necessary to add, or catalyst can be organic or inorganic acid such as acetic acid, toluene sulfonic acid, sulfuric acid, or hydrogen chloride.
The third step is the condensation of &agr;, &bgr;-unsaturated acid derivatives of the formula (II) and imine of the formula (VI), wherein 1 to 2 equivalent of &agr;, &bgr;-unsaturated acid derivatives of the formula (II) is reacted with 1 equivalent of the imine of the formula (VI) in the present of a base (0.1 to 2 equivalent) and a polymer inhibitor (0.005 to 0.2 equivalent) in an organic solvent at reflux temperature (40~150° C.)
Schematic illustration of the condensation of &agr;, &bgr;-unsaturated acid derivatives of the formula (II) and imine of the formula (VI) is shown in scheme 5, wherein R
1
, R
2
, R
3
and R
8
have the meaning indicated above, and R
5
represents a halogen atom or OR
9
, wherein R
9
represents an alkyl radical of one to six carbon atoms; and R
6
represents an alkyl radical of one to six carbon atoms; and the solvent can be acetonitrile, toluene, xylene, chlorobenzene, chloroform, dichloromethane or ethylene dichloride; and the base can be metal carbonate or metal hydrogencarbonate, wherein metal can be Li, Na, K, Rb, Cs, Be, Mg, Ca, Sr, or Ba etc.; and polymer inhibitor can use hydroquinone or monomethyl ether hydroquinone.
The last step is the formation of triazolopyrimidines derivatives of the formula (I), wherein imine of the formula (VIII) is hydrolyzed in the present of an acid (0.1 to 10 equivalent), water and solvent at room temperature to refluxing temperature.
Schematic illustration of the formation of triazolopyrimidines derivatives of the formula (I) is shown in scheme 6, wherein R
1
, R
2
, R
3
and R
8
have the meaning indicated above; and the acid can be inorganic or organic acid such as hydrochloride, sulfuric acid, acetic acid, or oxalic acid, etc.; and solvent can use water, methanol, ethanol, acetonitrile, toluene, xylene, chlorobenzene, chloroform, dichloromethane, or ethylene dichloride, etc.


REFERENCES:
patent: 3689488 (1972-09-01), Dukes

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