Amidines 2- ethyl

Reaction of pyridinium-A -(2-pyridyl)amidine (402) and alkyl haloace-tates in the presence of K2CO3 afforded a mixture of 4-oxo-4/f-pyrido[l, 2-u]pyrimidine-2-carboxylates 407 and 2-aminopyridine derivatives 406 through intermediers 403- 05, as depicted in Scheme 15 (00TL5837). Compound 406 could be cyclized on the action of heat or silica gel into 407. The best yield was achieved in the case of ethyl bromoacetate. 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

Reaction of 2,4-xylidine with methylamine and ethyl orthoformate leads to the amidine 119 condensation of that product with a second mole each of orthoformate and 2,4-xylidine gives the scabicide amitraz (120) [29]. 

Ammonium acetate, reaction with tn-ethyl orthoformate to give form-amidine acetate, 46, 39 Ammonium p chlorophenyldithiocarba mate, 46, 21... 

Complete reduction of the azepine ring to hexahydroazepine has been effected with hydrogen and palladium,40 or platinum,135 239 catalysts. For example, ethyl 1 f/-azepine-l-carboxylate is reduced quantitatively at room temperature to ethyl hexahydroazepine-l-carboxylate (92% bp 118 —120 3C).134 136 TV-Phenyl-S/Z-azepin -amine (1), however, with platinum(IV) oxide and hydrogen in methanol yields the hexahydroazepine 2 in which the amidine unit is preserved in the final product.34 The same result is obtained using 5% palladium/barium carbonate, or 2 % palladium/Raney nickel, as catalyst. 

The synthesis of pyrido[2,3-d]pyrimidin-7(8H)-ones has also been achieved by a microwave-assisted MCR [87-89] that is based on the Victory reaction of 6-oxotetrahydropyridine-3-carbonitrile 57, obtained by reaction of an Q ,/3-unsaturated ester 56 and malonitrile 47 (Z = CN). The one-pot cyclo condensation of 56, amidines 58 and methylene active nitriles 47, either malonitrile or ethyl cyanoacetate, at 100 °C for benzamidine or 140 °C for reactions with guanidine, in methanol in the presence of a catalytic amount of sodium methoxide gave 4-oxo-60 or 4-aminopyridopyrimidines 59, respectively, in only 10 min in a single-mode microwave reactor [87,88]... 

Because free or esterified imidazole(4,5)-acetates 745 are currently accessible only via a rather tedious multistep synthesis via (4,5)hydroxymethylimidazole [224— 226], it seemed obvious to react amidines such as isobutyraminidine-HCl 742 with commercially available methyl or ethyl 4-chloroacetoacetates 743a, b to obtain 745 directly in one step. Because of the low reactivity of the 4-chlorine in 743, however, reaction of 743, e.g. with isobutyramidine-HCl 742 in the presence of sodium methylate in methanol, affords exclusively 2-isopropyl-6-chloromethyl-pyri-midin-4-one 744 [227], whereas treatment of 743b with NaOEt in EtOH gives, in the absence of amidines, 2,5-bis(ethoxycarbonyl)cyclohexane-l,4-dione in nearly quantitative yield [228, 229]. 

As already discussed in Section 5.5.2, amidine hydrochlorides 743 react with O-silylated methyl (or ethyl) 4-chloroacetoacetate 746, in which the 4-chlorine atom... 

Fluoroethyl fluoroacetate is a compound of considerable toxicity. Its l.c. 50 for rabbits (inhalation) is 0-05 mg./l., i.e. about half as great as for M.F.A. It is therefore placed in class A. Other factors apart from hydrolysis to fluoroethanol and fluoroacetic acid appear to be operative, and it seems that the molecule is toxic per se. The related fluoroacetylimino-2-fluoro-ethyl ether hydrochloride, [CH2F C( NH2) O CH2 CH2F]+CT, is also placed in class A. This is understandable as it is readily hydrolysed by water to 2-fluoroethyl fluoroacetate. Other fluoroacetylimino ether hydrochlorides containing, however, only one fluorine atom fall into class B, as does also fluoroacet-amidine hydrochloride itself. 

Wolfbeis investigated the reactions of amines and orthoesters with different CH-acid molecules (81CB3471). When the reactions of aniline, ethyl orthoformate, and dialkyl malonates (2 mol) were carried out at 130-140°C for 4 hr, phenylaminomethylenemalonamates (245) were obtained (81CB3471). Similar reactions with aliphatic amines were unsuccessful. Phenylaminomethylenemalonic acid could not be prepared in the reactions of aniline, methyl orthoformate or orthoacetate, and malonic acid. When these reactions were carried out in 2-propanol, only amidines (246) were obtained. 

AM3-Chlorophenyl)aminomethylenemalonate (250) was obtained in pure form in 94% yield when /V,A, -bis(3-chlorophenyl)formamidine (248) (1 mol), diethyl malonate (I mol), and ethyl orthoformate (1.2 mol) were reacted for 20 hr at 126°C, the ethanol evolved being continuously distilled off. More diethyl malonate (1 mol) was then added to the half-converted reaction mixture, and the reaction mixture was stirred at 126°C for 48 hr (65MIP1 66JOC4003). Under these conditions, the formation of N- 3-chlorophenyl)aminomethylenemalonamate (252, R = 3-C1) could be excluded because the 3-chloroaniline formed in the reaction of amidine and malonate was simultaneously converted to amidine by ethyl orthoformate. 

V-(3-Ethoxy-4-decyloxyphenyl)aminomethylenemalonate (309) was prepared in the reaction of the amidine (308), diethyl malonate, and ethyl orthoformate in the presence of ammonium chloride at 125-130°C for 1 hr (68FRP1531495). The crude ester (309) was applied without purification in the cyclization step. 

Starting from the appropriate amidines (254, R = 3-C1, R1 = H, and R = R1 = 3,4-diisobutyl), diethyl malonate and ethyl orthoformate, N-(3-chlorophenyl)- and N-( 3,4-diisobutylphenyl)aminomethylenemalonates (250 and 257, R = diisobutyl) were prepared in 92% yields, respectively (69M1P1). 

The ring closure of the amidine derivative (1328) in refluxing ethanol in the presence of sodium ethylate afforded pyrimidin-4(3//)-one (1329) (59BCJ188). 

Ethyl 2-ethylthio-4-chloro-5-pyrimidinecarboxylate (XXIIa), as well as the corresponding4-hydroxy-(XXIIb) and 4-amino-(XXIIIa) derivatives, possess-anti-cytogenic activity on Neurospora crassa [223, 224]. Compounds (XXIIIa, b and c) were found to inhibit the conversion of orotic acid to the uridine nucleotides [202]. Ethyl 2-methylthio-4-(halo-substituted anilino)-5-pyrimidinecarboxylates (XXIV), particularly the o-bromo- and the o-chloro- derivatives, substantially inhibit the growth of five experimental mouse tumours (Krebs-2 ascites carcinoma, Ehrlich carcinoma clone 2, leukaemia L-1210, carcinoma 755 and lymphocytic neoplasm P-288) [225]. Compounds of this type are usually prepared by the base catalysed condensation of ethoxymethylenemalonic esters or related derivatives with urea, thiourea, guanidine, or substituted amidine-type analogues [212, 225-237]. 

In the reactions of cis- and rrans-2-aminomethyl-l-cyclohexanol or -1-cycloheptanol or cis- and trans-2-hydroxymethyl-l-cyclohexylamine or -1-cycloheptylamine with ethyl 4-chlorobenzimidate, the stereo- and regio-isomeric derivatives and homologs 164 and 165 were prepared (79T799). The amidine intermediate 166 of the benzimidate ring closure was also... 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Condensation of this with ethyl orthoacetate gives the anxiolytic agent brotizolam (167) [31]. 

Heteropolyacids Hi4[NaPsW29MoOno] and H3PMO12O4 have been shown to be efficient catalysts for consecutive condensation of aldehydes with 5-aminopyrazole -carboxamide and cyclization into pyrazolo[3,4-t4pyrimidines <2007MI1467>. The reaction of ethyl 5-acylaminopyrazoles with hexachloroethane and triphenylphosphine in the presence of a base has been recently reported to afford an imidoyl chloride that reacted in situ with ethylamine yielding an amidine in 71% yield that cyclized readily in DMF in the presence of potassium carbonate to yield pyrazolopyrimidines in 65% yield <2007TL3983>. 

Diese Methode entspricht der zweiten Stufe der auf S. 49 beschriebenen Umsetzungen von a-Amino-carbonyl-Verbindungen mit Carbonsaure-ester-imiden. Normalerweise werden die aus 2-Amino-O,O-acetalen mit Carbonsaure-ester-imiden hergestellten N-(2,2-Dialkoxy-ethyl)-carbonsaure-amidine mit Halogenwasserstoff in Alkoholen339,34°, Wasser341 oder DMF342 un-ter RiickfluB erhitzt (Arbeitsvorschriften hierzu s. S. 50). 

Das 2-(2-Aryl-2-oxo-ethyl)-l-methyl-benzimidazol VI kann in zwei tautomeren Formen vorliegen. Es entsteht durch Kondensation von 2-(2-Methylamino)-anilin mit 3-Aryl-l,l-bis-[methylthio]-3-oxo-propen. Mit Elektronen-ziehenden Substituenten am Aryl-Rest liegt die Keten-N,N-Acetal-Form V vor, mit Elektronen-reichen Aryl-Resten die Amidin-Form... 

The dimethylaminooxazolidone derivative thozalinone (40-3) is described as an antidepressant. The synthesis of this agent again uses a cyanamide, provided in this case as a preformed reagent. Thus, reaction of alkoxide from ethyl mandelate (40-1) with A,A-dimethylcyanamide leads to the amidine (40-2) by addition to the nitrile. Internal displacement of the ester ethoxide group closes the ring to an oxazo-lidinone, forming the product (40-3) [42]. 

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