Diamino derivatives

Replacement of carbon by nitrogen at position 8 of the pteridine ring in MTX and AMT has been accomplished by Srinivasan and Broom [36]. Starting from 6-bromomethylpyrido[3,2-rf]pyrimidine-2,4(lf/,3/f)-dione (III. 115), the xV-oxide was prepared by w-chloroperbenzoic acid oxidation and subjected to Polonovski rearrangement (AcjO-AcOH) to obtain the 6-acetoxymethyl derivative (III.116). Treatment of (III.116) with POCI3 afforded the 2,4-dichloro derivative (III.117), which on being heated at 160-170 °C in liquid ammonia in a pressure vessel was converted to the 

4- diamino-6-hydroxymethyl compound, (III. 118). The latter was treated with PBrj in dry THF to form the corresponding bromide (III. 119), which was coupled directly to diethyl A-(4-aminobenzoyl)-L-glutamate or diethyl A-[4-(A-methylamino)benzoyl]-L-glutamate in DMA to obtain the esters 

8-DeazaAMT (III. 122) was tested for in vivo antitumour activity against 

In a variant of the above approach, Temple et al. [37c] converted (III. 129) successively to the dichloride (III.134) (72%) and the 2-amino-4(377)-oxo derivative (III.135) (75%). Treatment of (III.135) with acetic anhydride and sulphuric acid followed directly by bromination at 95 °C in acetic acid in the presence of sodium acetate, condensation with 7V-(4-aminobenzoyl)-L-glutamic acid, and alkaline hydrolysis afforded a low yield of (III. 124), whose UV spectral properties (pH 1) 250 nm (e 15,100), 298 (19,400)  

In the preparation of the multisubstrate analogue (III.140) [39], diethyl 8-deazafolate (III.126) was reduced catalytically with Pt02 in ethanolic HCl to obtain a 60% yield of the tetrahydro derivative (III.141). Condensation of (III. 141) with 2 -0-acetyl-5 -[bis(2,2,2-triehloroethyl)phosphono]-5-bromo-methyl-2 -deoxyuridine in dry DMF in the presence of NaHCOj, followed by phosphate deprotection with Zn/Cu couple and acetylacetone, and finally ester hydrolysis, afforded a 41% overall yield (3 steps) of (III.140). 

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The triaryknethane dyes are broadly classified into the triphenyknethanes (Cl 42000—43875), diphenylnaphthyknethanes (Cl 44000—44100), and miscellaneous triphenylmethane derivatives (Cl 44500—44535). The triphenyknethanes are classified further on the basis of substitution in the aromatic nuclei, as follows (/) diamino derivatives of triphenylmethane, ie, dyes of the malachite green series (Cl 42000—42175) (2) triamino derivatives of triphenylmethane, ie, dyes of the fuchsine, rosaniline, or magenta series (Cl 42500—42800) (J) aminohydroxy derivatives of triphenylmethane (Cl 43500—43570) and (4) hydroxy derivatives of triphenylmethane, ie, dyes of the rosoHc acid series (Cl 43800—43875). Monoaminotriphenyknethanes are known but they are not included in the classification because they have Httie value as dyes. 

As in the pyridopyrimidines, the MacFadyen-Stevens degradation of tosylhydrazino derivatives has been used to prepare the parent [2,3-tf] compound (63JCS6073), and 1,4-bishydrazinopyrido[3,4-tf] pyridazines are reduced to the 1,4-diamino derivatives by Raney nickel (68AJC1291). 

The main reaction of this type has been the reductive cyclization of nitropyridine derivatives carrying an o-amino ester or o-aminocarbonyl substituent. These cyclize in situ via the o-diamino derivative to give pyridopyrazines of known constitution, either for establishment of structure of products obtained in the ambiguous Isay synthesis (see Section 2.15.15.6.1), or in the synthesis of aza analogues of biologically active molecules. 

This reactivity of A-unsubstituted amino-pyrazoles and -indazoles which can be regarded as 1,3-diamino derivatives has been used to build a great variety of fused six-membered heterocycles such as the 1,2,4-triazine derivatives (540) and (541), the 1,3,5-triazine derivatives (542) and (543), and benzothiadiazines (544). 

The preparation of 3,5-diamino derivatives from 3,5-dithioxotria-zines or from 6-methyl-3,5-dimethylmercapto-l,2,4-triazine was also described. ... 

For the preparation of triazolopyrimidines three main types of synthesis are in use. The first of these proceeds from a pyrimidine derivative (especially the 4,5-diamino derivatives) and closes the triazole ring. The second method proceeds, on the contrary, from derivatives of u-triazole to close the pyrimidine ring. The third method finally is one which yields the derivatives through substitution or replacement of substituents in compounds prepared by one of the first-named procedures. 

The compounds 87a and 87b are aminated at position 4, yielding the 4-amino compound (88a, 40%) and the 2,4-diamino compound (88b, 11%) respectively the 2-ethoxy compound (87c), however, undergoes amination at position 4 as well at position 5, giving a mixture of the 4-amino compound (88c, 20%) and the 5-amino compound (89a, 14%).Tlie 2-chloro compound (87d) yields a highly complex reaction mixture from which the 5-amino compound (89b), the 2,4-diamino derivative (88b), and 2,5-diamino-l,8-naphthyridine (89c) could be isolated. l-Ethyl-3-nitro-l,8-naphthyridin-2(lH)-one (90a) and 3,6-dinitro-l-ethyl-l,8-naphthyridin-2(lH)-one (90b) were aminated exclusively in the 4-position to give compounds 91a (62%) and 91b (45%), respectively (93LA471). 

Ethoxy, aminochloro, aminoethoxy, and diamino derivatives of the 3-nitronaphthyridines show a more differentiated mass fragmentation. Besides the loss of NO2, HCN, and NO, expulsion of OH, CO, C2H4, and O was observed as well. 

Cyclic ureas can be obtained by reaction of simple urea with 1,2-diamino derivatives in DMF in the presence of ZnO and under microwave irradiation (Scheme 53). In this unusual condensation, two molecules of ammonia are eliminated. The reaction is very sensitive to the presence of ZnO. Without this catalyst, a yield of 20% is reported together with the formation of several by-products. The reaction was also carried out under reduced pressure... 

Direct amination of benzo[l,2-aqueous base with hydroxylamine-0-sulfonic acid gives a mixture of three diamino derivatives and two monoamino derivatives (Equation (15)). The combined yields of diamino and monoamino products are 45% and 48%, respectively. The three diamino derivatives can be separated by fractional crystallization from ethanol <86JOC979>. A-Amination of triazoles can also be achieved by treatment with NaH in DMF followed by O-amino-2,4-dinitrophenol <85TL335> or 0-(mesitylsulfonyl)hydroxyamine (9lJCS(Pl)2045>. 

Arylbenzotriazoles (797) are prepared via 2-nitro- and 2-amino-diphenylamines (Scheme 161). The 2-nitrodiphenylamines (796) are prepared from the appropriate aniline by reaction with 2-fluoronitrobenzene in the presence of KF <808215,85JCS(Pl)2725>. Azo-coupling of 2-amino-1-cyano-azulene (798) with p-tolyldiazonium chloride gives (799) (Scheme 162). Catalytic reduction of (799) quantitatively yields the diamino derivative (800), which on diazotization affords 9-cyano-azuleno[l,2-J]triazole (801) in 77% yield <85TL335>. 

Polyamides derived from o-glucose and o-glucosamine by interfacial and solution polycondensations of the sugar diamino derivatives with aromatic and aliphatic acyl chlorides have also been described [83]. 

Reaction of 4-chloro-6-fluoropyrido[3,4- pyrimidine 59 with [3-methyl-4-(pyridin-3-yloxy)phenyl]amine 60, followed by coupling the formed amine 61 with (3-azabicyclo[3.1.0]hex-6-yl)carbamic acid fi r7-butyl ester, afforded the substituted derivative 62 <2002EPP1249451>. Compound 59 was also reacted with 3-bromoaniline to give the 4-anilino derivative 63 that upon treatment with either methyl- or dimethylamine gave the corresponding 4,6-diamino derivatives 64 (Scheme 2) <1997W09726259, 1995W09519774>. 

It has been reported that some aldehydes react with secondary amines to give first a diamino derivative (aminal) which then decomposes on distillation to give the enamine and the starting secondary amine. Some aromatic aldehydes have been reported to give isolatable carbinolamines first [47]. 

Scheme 2.2 Synthesis of di(trinitrophenyl)ethylenediamine and its diamino derivative.

The 4,7-Diamino deriv, red crysts (from hot w), mp 193-94° sol in methanol, acet, chlf toluene giving a red colored soln results from the catalytic reduction of 4,7-benzofura-2anquinone dioxime in MeOH. Several other derivs and salts were also prepd, some of which are probably mild expls (Ref 2)... 

Access to this type of compound is illustrated in Scheme 30 by the preparation of retro-sulfonamide tripeptide Boc-Pro-Leuijt[NH—S02]Gly-NH2(78). The two false termini used are the prochiral gem-diamino analogue of Leu and sulfoacetic acid. Amide to amine conversion according to Hofmann, carried out on the dipeptide Boc-Pro-Leu-NH2 (76) with iodobenzene l,l-bis(trifluoroacetate) gave the gem-diamino derivative 77. Coupling of the resulting gem-diamino derivative with methyl (chlorosulfonyl)acetate, followed by amida-tion of the intermediate methyl ester, afforded the desired pseudopeptide 78J1341 Full experimental details have not yet been reported. 

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