Amidines hydroxy

This route has many ramifications depending on the nature of R and R" in Scheme 2 thus R may be alkyl, aryl, amino (thioamide), alkylthio, or thiol and R" may be alkyl, aryl, amino (amidine), hydroxy (amide), or alkoxy (imino ether), although as yet not all of the possible combinations of these groups has been fully examined. In practice, the utility of the route depends on the availability of the requisite intermediates, and the situation is further complicated by the numerous routes which have been devised to these precursors. 

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

In the 1880s, Pinner found that the amidine derivative 2 reacted with acetoacetic ester (4) to furnish 2-substituted-6-hydroxy-4-methylpyrimidine 5. The condensation of amidine derivative 2 with other (l-keto esters, malonic esters, and (l-diketones proceeded similarly (see the following pages for examples). ... 

The condensation of diethyl formylsuccinate with amidines is an established p3mmidine synthesis (16, 714). Extended to 1-substituted biguanides, the reaction yields 2-guanidino-4-hydroxy-5-carbethoxy-methylpyrimidines as follows (684) ... 

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]. 

Diese Synthese ist verwandt mit der Herstellung von Imidazolen aus a-Hydroxy- bzw. oc-Ha-logen-ketonen und Amidinen (s.S. 26), da aus den Carbonsiiure-ester-imiden mit Ammoniak die entsprechenden Amidine gebildet werden. Die Umsetzung wird in fltissigem Ammoniak unter Druck bei Temperaturen von 20 bis 70° durchgefiihrt. 

Auch die Umsetzung von Amidin-Hydroacetaten oder -Hydrochloriden mit a-Halogen- oder oc-Hydroxy-ketonen in fliissigem Ammoniak unter Druck bei 40-70° liefert in zum Teil guten Ausbeuten 5-Acetyl-imidazole93" 9S. 

Werden anstelle von a-Halogen- oder a-Hydroxy-ketonen a-Halogen-carbonsaure-nitrile ein-gesetzt und ist die Amidin-Komponente N,N -Diary -substituiert, so erhalt man in guten Aus-beuten 4-Amino-l,3-diaryl-imidazolium-Salze113 z.B. ... 

Aus a-Dicarbonyl-Verbindungen und Amidinen bilden sich zunachst 4,5-Dihydroxy-4,5-dihydro-imidazole, die isoliert werden konnen127 128. Setzt man eine disubstituierte a-Dicarbonyl-Verbindung und statt des Amidins ein Guanidin-Derivat ein, so erhalt man unter Abspaltung eines Aquivalents Wasser 4,5-disubstituierte 2-Amino-4-hydroxy-4H-imidazole, die in vielen Fallen ebenfalls isoliert werden konnen129,130 ... 

There has been considerable variation in the choice of base used. In most cases, hot, concentrated potassium hydroxide gives good results, but sometimes potassium hydroxide in aqueous DMSO, potassium f-butoxide in DMSO or NaH in DMSO is more satisfactory (80TL585). The tercyclic oxetane (50), however, was not formed from the hydroxy-cyclic sulfate precursor under any of these conditions, but use of the amidine base (49) at room temperature produced it in 46% yield (81JOC3144). 

Guanidines with a-halo ketones form 2-aminoimidazoles. a-Hydroxy ketones also react with amidines to form imidazoles, and a variety of substituents can be introduced into the imidazole nucleus (CHEC 4.08). 

Patel and coworkers87"89 and others90 have been carrying out detailed investigations on the analytical applications of a number of amidines, e.g. JV-hydroxy-JV-phenyl-iV -benzylbenzamicline,91 JV.AT -diaryl substituted A-hydroxy-p-toluamidines87 and hydroxydiarylbenzamidines.88"90... 

Pinacolone, o-(diphenylphosphino)benzoyl-coordination chemistry, 401 Piperidine, IV-hydroxy-metal complexes, 797 pA a values azole ligands, 77 Plant roots amino acids, 962 carboxylic acids, 962 Plastocyanin copper binding site, 557 copper(II) complexes, 772 copper(II) site in, 770 Platinum, dichlorobis(benzonitrile)-IR spectrum, 264 Platinum, cis-dichlorodianunine-antitumor activity, 34, 979 Platinum, ethylenebis(triphenylphosphine)-reactions with 5,6-dimethyl-2,l,3-benzothiadiazole, 194 Platinum blue formation, 265 Platinum complexes acetylacetone reactions, 380 amides, 491 amidines... 

A solution of benzalacetone 2 (2.9 g, 0.02 mol) in dry acetone (50 ml) was added drop wise (30 min) at 0-10°C to a solution of amidine 1 (2.4 g, 0,02 mol) in dry acetone (50 ml) with constant magnetic stirring in a dry inert atmosphere (Scheme A.20). Following the addition, the mixture was stirred for another 30 min, after which the cooling bath was removed and the mixture was stirred at room temperature. The reaction was monitored by TLC. A white solid started to precipitate after the first hour. When the starting materials had disappeared almost completely (TLC), the white copious precipitate was filtered and washed with dry diethyl ether. The mother liquor was evaporated to dryness, the crude residue was triturated with a small amount of dry diethyl ether, and an additional portion of undissolved tetrahydropyrimidine was filtered off. The white solids were combined, dried and recrystallized. The yield of 6-hydroxy-6-methyl-2,4-diphenyl-1,4,5,6-tetrahydropyrimidine 3 was 82%. Melting point 80-81°C. 

From a.-Amino Acid Amides and Amidines a-Amino acid amides, which fall into the amine-imine class according to the general model (beginning of Section II,B), are converted to 3-alkyl-4-hydroxy-l,2,5-thiadiazoles by reaction with sulfur mono-chloride, thionyl chloride, or thionyl aniline. A large number of -amino acid amides were employed in the synthesis (see Table I)... 

Pyrimidin 4-Hydroxy-2-methyl-4-(nonafluor-butyl)-l(3),4,5,6-tetrahydro- E14a/2, 459 (En-on + Amidin)... 

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