A series of acyclic symmetrical and asymmetrical quaternary ammonium chlorides of the general formula R 1 R (O)O) was synthesized by the alkylation of tertiary amines in a two phase system containing water. A convenient method for the synthesis of the initial symmetrical and asymmetrical tertiary amines of the general formula MeNR 1 R 2 (R 1 = Me, Bu; R 2 = n С 12 Н 25 , PhCH 2 , C n H 2n+1 (OCH 2 CH 2 ) m , n = 9 and 12, m = 1 and 2) in an organic phase-aqueous phase heterogeneous system, which allows the use of aqueous solutions of alkali and amines, was developed. The improved method for the prepara tion of intermediate ethylene glycol and diethylene glycol monoethers is monoalkylation of glycols in dioxane using solid KOH in a two phase system.The discovery of bactericidal properties of quaternary ammonium compounds 1 (QACs) against a series of patho genic microorganisms at the beginning of the last century resulted in their wide use in the production of disinfec tants. 2 Recently, QACs have been applied for the local prevention of infection processes by their combination with diverse materials in medical devices and with materials that permanently contact with the human organism. This intense use of biocides led to the enhancement of safety requirements imposed on these materials. Meanwhile, the absence of systematic studies of a relationship between the structure of quaternary ammonium derivatives and their biological activity restrains the purposeful synthesis of new highly efficient compounds with both bactericidal properties and low toxicity for warm blooded organisms. Therefore, to study the influence of the character of the functional substituent at the nitrogen atom and the dispo sition of the N atom and the long chain alkyl and benzyl substituents in a QAC molecule on the bactericidal activi ty, a series of QACs containing ethylene glycol and di ethylene glycol moieties and hydroxycarbonylmethyl group were synthesized from dimethyl and 2 butyl N methylamines. It should be mentioned that these com pounds have very low toxicity against warm blooded or ganisms. 3 Results and DiscussionCompounds 1-5 were synthesized by traditional trans formation of secondary amines into tertiary amines 6 fol lowed by their reaction with functionally substituted alkyl chlorides (Scheme 1).The most efficient order for introducing substituents to the nitrogen atom is the NH alkylation of secondary amines by less reactive alkylating agents: dodecyl bromide (7a), 2 nonyloxy (7с) and 2 dodecyloxyethyl chlorides (7d), and 2 (2 dodecyloxyethoxy)ethyl chloride (7e) fol lowed by N alkylation of tertiary amines 6a-h with active benzyl chloride (7b), ethylene chlorohydrin, 2 benzyloxy ethyl (7f) and 2 (2 benzyloxyethoxy)ethyl chlorides (7g), dodecyl and benzyl monochloroacetates (7h,i), and sodi um monochloroacetate.The starting reagents for the synthesis of QACs of sym metrical and asymmetrical structures were dimethylamine as a 38% aqueous solution and N butyl N methylamine obtained from methylamine using the earlier developed * ...
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A facile method for the synthesis of nonsymmetrical dialkylamines (C n H 2n+1 ) 2 NH (n = 1-12) using the Ph 2 P(O) protecting group was developed. The method includes successive transfor mation of monoalkylamines to primary diphenylphosphinic N alkylamides Ph 2 P(O)NHR( R´ = C n H 2n+1 , n = 1-12) by the Todd-Atherton reaction, phase transfer N alkylation of these compounds, and hydrolysis of the secondary amides Ph 2 P(O)NR´R ″ thus formed. When the (EtO) 2 P(O) and Bu 2 P(O) protecting groups are used, N alkylation of primary amides is accompanied by the formation of Et-O and P-N bond cleavage products, respectively. A study of the stability of the N alkylamides R 2 P(O)NHR´ (R = Ph, p MeC 6 H 4 , p ClC 6 H 4 , Bu) under strong alkaline conditions used in the phase transfer N alkylation showed that an increase in the electron donating ability of substituents at both the nitrogen atom and the phosphorus atom results in a decrease in the degree of P-N bond cleavage. The primary and secondary diphenylphosphinic amides containing a β hydroxyethyl group at the nitrogen atom are extremely unstable under the alkaline conditions and are converted quantitatively to the diphenylphosphinic acid salt.Quaternary ammonium compounds exhibit rather broad range of bactericidal activity. 1 Compounds con taining at least one higher radical in the molecule are the most active. 2 Besides, it was found that the activity of compounds with nonsymmetrical structure is much higher than that of symmetric salts. 3 In order to obtain a number of nonsymmetrical ammonium salts and study the struc ture-bactericidal activity relationship, we first prepared the starting nonsymmetrical dialkylamines. Among numerous methods for the synthesis of these compounds, which are surveyed rather comprehensively in a review, 4 the main methods are direct N alkylation and reductive alkylation of primary amines. However, these reactions lead very often (especially in the case of sterically non hindered amines) to mixtures of secondary and tertiary amines and in some cases, quaternary ammonium salts, 5,6 whose separation creates difficulties and reduces the yield of the target product. These drawbacks can be eliminated by using protecting groups. We chose diethoxy , 7 diphe nyl , and dibutylphosphoryl groups. This route 7 comprises successive transformation of primary amines to the cor responding primary diethylphosphoric, diphenyl and dibutylphosphinic amides, their subsequent N alkyla tion, and cleavage of the resulting secondary amides with HCl in THF (Scheme 1). Scheme 1R´, R ″ = C n H 2n+1 , n = 1-12; R = EtO, Ph, Bu It is noteworthy that the acidifying effect* of substi tuted P=O groups and the known stability of both primary and secondary amides of P V acids in alkaline medium 10 provide for easy introduction of various alkyl substituent to nitrogen 7,11 in stage 2, while the high lability of the P-N bonds of these compounds in acidic medium, which * The replacement of the hydrogen atom in the NH 2 group of aniline by (EtO) 2 P(O) increases the NH aci...
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