1- biguanide

Submitted by Samuel N. Holteb and W. Conabd Febnelius Checked by Devon Meek  

From biguanide sulfate (synthesis 14) the free base can be obtained by treating a solution of the sulfate with barium hydroxide or sodium hydroxide/ or by refluxing biguanide sulfate with alcoholic sodium ethoxide. The procedure using sodium hydroxide is simple and cheap and produces a satisfactory product. 

To a solution of 16 g. (0.4 mol) of sodium hydroxide in 350 ml. of dry methanol, 19.9 g. (0.1 mol) of anhydrous biguanide sulfate is added. The mixture is stirred for 2 hours at room temperature and then for 45 min. at the reflux temperature. The hot solution is filtered and the sodium sulfate cake is washed with 40 ml. of hot methanol. The filtrate and wash are concentrated under reduced pressure (solution temperature below 45°) until a heavy crop of crystals separates. Precipitation is completed by the addition of 150 ml. of dry ethyl ether. The product is filtered, washed with dry ether, and dried in a vacuum desiccator. Yield 9.0 g. (89%) m.p. 133 to 134° (decomp. 137 to 139°). The product is stored in a desiccator since it turns yellow on exposure to the atmosphere. 

Inorganic Syntheses, Volume VII Edited by Jacob KJeinberg Copyright 1963 by McGraw-Hill Book Company, Inc. 

Black phosphorus was prepared for the first time by Bridgman by heating white phosphorus to 200° under a pressure of 12,000 atmospheres. This modification of phosphorus can also be prepared without the application of pressure by heating an intimate mixture of white phosphorus and metallic mercury at temperatures between 200 and 400°. Above 400° red phosphorus is formed below 360° the rate of conversion is very slow. 

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Biguanide salts Biimidazole dimer Biisobutyryl [4388-87-8] Bilarcil Bile acids... 

An effective, but not very practical, flame retardant for cotton based on 2,4-diamino-6-(3,3,3-tribromopropyl)-l,3,5-tria2ine [62160-38-7] (DABT) was prepared from ethyl y-tribromobutyrate and biguanide [56-03-1] ... 

Three classes of oral therapeutic agent are available for treating patients with diabetes mellitiis (NIDDM) the arylsulfonylureas (known simply as sulfonylureas), biguanides, and a-glycosidase inhibitors. Since 1977, only the sulfonylureas have been approved for use in the United States, although the other classes are used elsewhere. 

Trivalent complexes of biguanide and periodate are also prepared commercially for water sanitation. The trivalent silver periodate, for example, is prepared by the action of potassium periodate and potassium hydroxide on Ag O ... 

Heating with aromatic amines in water in the presence of an equivalent amount of mineral acid gives high yields of aryl biguanide salts (45). 

Reaction with ammonium salts gives biguanide salts which react further with the ammonium salt forming guanidine salts. Guanidine nitrate [506-93 ] is manufactured by this route (46). 

Uses. Dicyandiamide is used as a raw material for the manufacture of several chemicals, such as guanamines, biguanide and guanidine salts, and various resias. Siace 1975, it has also been used ia the manufacture of potassium or sodium dicyanamide which are used as iasecticides and ia chemotherapy. Melamine has extensive appHcations ia the resia and plastic iadustry guanamines are used as copolymers (qv) ia many resia compositions. Guanidine phosphate [1763-07-1] is employed as a fire retardant ia appHcations where water solubiHty is not a drawback. 

Ghlorhexidine Gluconate. Chlorhexidine gluconate [18472-51 -0] (l,l -hexamethylene bis[5-(p-chlorophenyl) biguanide] di-D-gluconate) is used as an antimicrobial against both aerobic and anaerobic bacteria ia the oral cavity. It is used as a therapeutic supplement ia the treatment of gingivitis, periodontal disease, and dental caries. A mouth riase form is available as a 0.12 wt% aqueous solution (288). 

Yet another example of a so-called pharmacophoric group is the biguanide functionality, a grouping associated with oral antidiabetic activity (see the section on sulfonylureas for a fuller discussion of this activity). Condensation of 2-phenethylamine with dicyanamide affords directly the orally active hypoglycemic agent phenformin (88). ... 

The analog program on pyrimidines included some open-chain versions of this heterocycle as well. These last, the biguanides, were found to be quite active in their own right. (It was subsequently established that these compounds undergo oxidative cyclization to dihydropyrimidines in the body to give the actual antimalarial—see cycloguanyl). 

The activity of compounds incorporating the biguanide function as oral antidiabetic agents has been alluded to previously. 

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

Aryl-substituted biguanides (c.g. 1) can be condensed with 1-benzoylacetone to provide 1,3,5-triazocine derivatives,13 Two isomers of product 2 can be isolated upon recrystallization from ethanol. The isomers, probably tautomers 2A and 2B, exhibit the same melting point and rapidly interconvert in solution, thereby giving identical NMR spectra in deuteriochloroform at room temperature. 

To a solution of l-(4-methoxyphenyl)-biguanide (2.07 g, 10 mmol) and l-(4-methoxyphenyl)-biguanide hydrochloride (0.2 g, 1 mmol) in EtOH (50 mL) was added 1-benzoylacetone (1.62 g, 10 mmol) and the solution was heated under reflux for 10 h. After the solution was concentrated, the oily residue was poured into H20 and repeatedly washed with H20. The resulting solidified mass was collected by filtration and dissolved in EtOH by heating. After standing overnight at rt, a mixture of needles and prisms was isolated yield 1.5 g (45%). The mixture was dissolved in a suitable amount of EtOH by heating and, after 2 h at rt, the deposited, needles were collected by filtration mp 166 C. The needles were dissolved in a suitable amount of EtOH and the solution was left to stand at rt for a couple of days. The deposited prisms were collected by filtration mp 166°C. 

The longest established silver(III) complexes are the red to brown bi-guanides, like the ethylene bis(biguanide) shown in Figure 4.14 persulphate oxidation of Ag+ in the presence of this ligand gives a silver(III) complex with essentially square planar coordination. 

Figure 4.14 The coordination geometry of silver in the silver(III) ethylenebis(biguanide)...

Biguanide Metformin Improve insulin action Oral... 

Complex compounds of biguanides and guanylureas with metallic elements. P. Ray, Chem. Rev., 1961,61,313-359(188). 

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