Biguanides amines

The method is normally limited to the production of s unmetrically substituted biguanides by the stepwise addition of unlike amines, biguanides bearing different 1- and 5-substituents (e.g. isoCsHisNH ... 

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

C20H22CINO2 118108-64-8) see Propiverine 7-chloro-5-phenyl-3ff-l -benzodiazepin-2-amine (C15H12CIN3 7564-07-0) see Estazolam l-(4-chl rophenyl)biguanide hydrochloride (CjHjjCliNs 4022-81-5) see Chlorazanil... 

In the context of preparing potential inhibitors of dihydrofolate reductase (DHFR), the group of Organ has developed a rapid microwave-assisted method for the preparation of biguanide libraries (Scheme 6.174) [330]. Initial optimization work was centered around the acid-catalyzed addition of amines to dicyandiamide. It was discovered that 150 °C was the optimum temperature for reaction rate and product recovery, as heating beyond this point led to decomposition. While the use of hydrochloric acid as catalyst led to varying yields of product, evaluation of trimethylsilyl chloride in acetonitrile as solvent led to improved results. As compared to the protic... 

Following the discovery of the antimalarial activity [148) of biguanides and quinoline derivatives, a variety of substituted quinolyl-b anides were synthesised [9, 42, 101, 188, 298, 303, 306, 428, 558, 583, 585) by these procedures. The production of a series of m.m-hexamethylenebi-guanides [724) illustrates the use of secondary amines in this synthesis. 

The use of diamines in this synthesis affords the expected dibiguanides 549, 562), or a bis-cyanoguanidine may be condensed with two moles of amine 345,358, 549). The use of both bis-cyanoguanidine and a diamine, however, may give rise to pol5nneric biguanides that are difficult to fractionate 549). 

In the above reactions, aromatic amine salts give better results than the free bases 14, 15), which are indeed reported to fail to react with cyanoguanidine (777). Aliphatic amines react more smoothly in the presence of some free amine 14,15). As aromatic amine salts dissociate to a much larger extent than do aliphatic amine salts, it is believed 14,15), that a considerable amount of free aromatic amine is present in the reaction mixture. Since Curd and Rose 148) have also shown that use of (100%) free aliphatic amine lowered the yields of biguanides, a mixture of free amine and amine salt would appear to be most favourable for biguanide formation. 

The formation of a biguanide as a by-product in a condensation of a cyanamide and amine (225) (which would normally be expected to yield a guanidine) and as main product in the reaction of glucosamine and cyanamide (437) has been noted. In the former example, the small amount of biguanide probably arose by further reaction of the primary guanidine (which formed the main product) with C5 namide. In the second example the biguanide may be the result of the interaction of the amine and intermediate cyanoguanidine. 

Another variation of the synthesis of biguanides utilising the condensation of cyano-compoimds and amines is the reaction of dicyanimide and two moles of amine (457, 465, 581, 582). In practice (457) a dicyanimide metal salt is fused, or heated in water or in an organic solvent with an amine salt, preferably between 90 and 130°. Condensation may also be effected using free dicyanimide in aqueous acid media (581). 

M. Miscellaneous Syntheses 1. From Biguanide and Aromatic Amines... 

The reaction between biguanides and carbodiimides in dimethyl-formamide provides a general route to substituted melamines (375). Thus, biguanide or its 1-mono- or 1.2-disubstituted homologues afford, respectively, satisfactory yields of mono- or 2.4-disubstituted melamines (CXLVIII) or 1.2.6-trisubstituted isomelamines (CXLIX). In each case, the reaction probably involves primary addition of the reactants, followed by the cydisation of the resulting intermediate labile triguanide, with loss of amine (375) ... 

The interaction of biguanide (CL) and isothiocyanate esters in dimethyl-formamide under mild conditions (376) gives excellent 3delds of 1-sub-stituted hexahydro-4,6-di-imino-s-triazine-2-thiones (CLII), together with small quantities of thioammeline (CLIII) and monosubstituted melamines (CLIV). Under more severe conditions, the latter (CLIV) become the main products. The production of these triazines is explained by a mechanism involving the primary formation of addition products (CLI), followed by their cydisation with loss of either ammonia, hydrogen sulphide, or primary amine (376). 

The preparation of alkylguanidines by fusing amine salts with dicyandiamide at 180° for three hours has been advocated [104], however it has been shown that, depending on the conditions, a guanidine or a biguanide can result [105, 106]. 

So as to get the strongest possible basicity, these biguanides were prepared with the highest possible degree of N-alkylation. However, no satisfactory precedure was described in the literature. So original synthetic methods were devised for this purpose. These rely essentially on the addition of guanidines to carbodiimides or of amines to cationic dimeric carbodiimides.18... 

The synthesis of the polystyrene-supported biguanides was performed in the same way as for the soluble ones. The starting polymers were gel-type polystyrenes with chloromethyl or 6-bromohexyl groups prepared according to Merrifield or Tundo respectively.19. These new catalysts were obtained either by sequential syntheses on aminated polystyrene or by covalent grafting of ready made biguanides. 

From cyanoguanidines Aminated polystyrenes were reacted to cyanoguanidines (from secondary amines and dicyanamides) to give type 4 N-trisubstituted biguanides 10 (Figure 14). 

Figure 14 Polystyrene-supported biguanides by amination reaction.

Reaction of the diazetidines 188 with amines afford pentasubstituted biguanides. ... 

Epoxy resins may be cured in the manner of polyadditions, i. e., homogeneously catalyzed by multifunctional amines and isocyanates, or cyclic anhydride, dicyan-diamide, or biguanide derivatives. On the other hand epoxy resins are also subject to homopolymerization. The catalysts represent Lewis bases, preferably tertiary amines, imidazoles, or ureas (the latter exclusively for the dicyandiamide curing)... 

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