Process for the preparation of biguanidines and triazines
AssigneeAdama Agan Ltd.
InventorsMarwan E. SIMAAN, Leonid ERCHOV
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Abstract
A process for the preparation of biguanidine compounds of formula (I) and triazine compounds of formula (IV); wherein R1, R2 and R3 are each independently hydrogen or an optionally substituted C1-C4 alkyl group, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, halo aliphatic, alicyclic, alkoxy, thioalkyl, cyano or nitro groups; A is —CH2-, —O— or a direct bond; and n is 0, 1, 2 or 3.
Claims15
A process for the preparation of a biguanidine compound of formula (I) or an acid addition salt thereof:
- wherein R1 and R2 are each independently hydrogen or an optionally substituted C1-C4 alkyl group, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, halo aliphatic, alicyclic, alkoxy, thioalkyl, cyano or nitro groups;
- A is —CH2—, —O— or a direct bond;
- and n is 0, 1, 2 or 3;
- which comprises the reaction of 1-cyanoguanidine with an amine of formula (II) or an acid addition salt thereof
- wherein R1, R2, A and n are as defined in formula (I), in a mixture which comprises a trimethylsilyl-containing compound, and an optionally alkyl substituted N-alkyl γ-, δ-, ε-lactam or an optionally alkyl substituted γ-, δ-, ε-lactone.
The process according to any of previous claims, wherein the compound of formula (I) is (1R,2S)-1-(bisguanidino)-2,6-dimethylindane or (1R,2S)-1-(bisguanidino)-2,6-dimethylindane monohydrochloride and the compound of formula (II) is (1R,2S)-1-amino-2,6-dimethylindane or (1R,2S)-1-amino-2,6-dimethylindane monohydrochloride.
The process according to any of previous claims, wherein the temperature of the reaction ranges from 60° C. to 100° C.
The process according to any of previous claims, wherein the mole ratio between the trimethylsilyl-containing compound, and the optionally alkyl substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl substituted γ-, δ-, ε-lactone ranges from 1:1 to 1:20.
The process according to any of previous claims, wherein the trimethylsilyl-containing compound is selected from the group consisting of trimethylsilyl halide, trimethylsilyl haloalkylsulfonate, trimetylsilyl halosulfonate, trimethylsilyl azide, trimethylsilyl cyanide, hexamethyldisilane, optionally halogen substituted alkyl trimethylsilane, trimethylsilylalkyne, tris(trimethylsilyl)silane, tris(trimethylsilyl)methane, tetrakis(trimethylsilyl)silane, optionally halogen substituted (trimethylsilyl)alkylamide, or secondary or tertiary (trimethylsilyl)amines.
The process according to any of previous claims, wherein the optionally alkyl substituted N-alkyl γ-, δ-, ε-lactam or the optionally alkyl substituted γ-, δ-, ε-lactone is selected from the group consisting of optionally alkyl substituted N—(C1-C18) alkyl pyrrolidones, optionally alkyl substituted N—(C1-C4) alkyl 2-piperidones, optionally alkyl substituted N—(C1-C4) alkyl caprolactams, optionally alkyl substituted γ-butyrolactones, optionally alkyl substituted δ-valerolactones, optionally alkyl substituted ε-caprolactones.
The process according to any of previous claims, wherein it further contains an aprotic solvent.
A process for the preparation of a triazine compound of formula (IV):
- wherein R1, R2 and R3 are each independently hydrogen or an optionally substituted C1-C4 alkyl group, wherein the optional substituents are selected from the group consisting of halogen, aliphatic, halo aliphatic, alicyclic, alkoxy, thioalkyl, cyano or nitro groups;
- A is —CH2—, —O— or a direct bond;
- and n is 0, 1, 2 or 3;
- which comprises
- a) a first step of preparation of a biguanidine compound of formula (I) or an acid addition salt thereof according to any of previous claims;
- b) a base and a carboxylic acid derivative of formula (III) are added to the biguanidine compound of formula (I) or an acid addition salt thereof, obtained in step a)
- wherein R3 is as defined in formula (IV), and Z—R3 is selected from the group consisting of carboxylic acid esters, carboxylic orthoesters, carboxylic acid chlorides, carboxamides, nitriles, or carboxylic anhydrides.
Dependencies are inferred from the claim text.