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The pH-rate profile of the pseudo-first-order rate constants for the rearrangement and hydrolysis of Ezetimibe giving (2R,3R,6S)-N,6-bis(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxamide (2) as the main product at pH of less than 12.5 and the mixture of 2 and 5-(4-fluorophenyl)-5-hydroxy-2-[(4-fluorophenylamino)-(4-hydroxyphenyl)methyl]-pentanoic acid (3) at pH of more than 12.5 in aqueous tertiary amine buffers and in sodium hydroxide solutions at ionic strength I = 0.1 mol L−1 (KCl) and at 39°C is reported. No buffer catalysis was observed and only specific base catalysis is involved. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple β-lactams and it contains several breaks. Up to pH 9, the log kobs linearly increases with pH, but between pH 9 and 11 a distinct break downwards occurs and the values of log kobs slightly decrease with increasing pH of the medium. At pH of approximately 13, another break upwards occurs that corresponds to the formation of compound 3 that is slowly converted to (2R,3R,6S)-6-(4-fluorophenyl)-2-(4-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-3-carboxylic acid (4). The kinetics of base-catalyzed hydrolysis of structurally similar azetidinone is also discussed. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2240–2247, 2014

The paper deals with a simple and sufficient synthesis of key precursor of Lasofoxifene. The 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-3,4-dihydronaphthalene was prepared by a sequence of five reactions steps: first 1-(4-benzyloxyphenyl)-6-methoxy-3,4-dihydronaphthalene was prepared (70%), and this was quantitatively epoxidized to 7b-[4-(benzyloxy)phenyl]-5-methoxy-1a,2,3,7b-tetrahydronaphtho[1,2-b]oxirene. Catalytic (ZnI2) isomerization of the epoxide gave 1-(4-benzyloxyphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalen-2-one (75%). Its subsequent reaction with phenylmagnesium bromide gave 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydro-2-naphthol (87%). Acid-catalysed dehydration of this alcohol by polyphosphoric acid (25°C) provides 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-1,4-dihydronaphthalene (80%). Dehydration in the system of acetic anhydride/polyphosphoric acid gives 1-(4-benzyloxyphenyl)-6-methoxy-2-phenyl-3,4-dihydronaphthalene (66%).

The kinetics and mechanism of transformation reaction of S-[1-(4- methoxyphenyl)pyrrolidin-2-one-3-yl]-N-methyl-isothiuronium bromide into 2-methylimino-5-[2-(4-methoxyphenylamino) ethyl)]thiazolidin-4-one have been studied in aqueous solutions of amine buffers (pH 8.1-11.5) and sodium hydroxide solutions (0.005-0.5 mol l-1) at 25 degrees C and at I = 1 mol l-1 at pseudo-first-order reaction conditions. The kinetics observed shows that the transformation reaction is subject to general base, general acid, and hydroxide-ion catalyses. The rate-limiting step of transformation is the splitting-off a proton from the tetrahedral intermediate In. The value of pKa for S-[1-(4-methoxyphenyl)- pyrrolidin-2-one-3-yl]-N-methylisothiuronium bromide has been determined from the kinetic data (pKa = 8.75 +/- 0.10) and by potentiometric titration (pKa = 8.90 +/- 0.05). With increasing pKa value of the acid buffer component, the value of Brønsted coefficient beta gradually decreases from about 0.7 to almost zero. The value of pKa approximately 10 for the intermediate to base-catalysed transformation has been found from this dependence. In the N-methylpyrrolidine and triethylamine buffers, the rate-limiting step of transformation is changed into ring opening of In-, and the general-base-catalysed reaction changes into a specific-base-catalysed one.

A study of chemical behaviour of substituted 4-chloro-N-phenylbutanamides in aqueous solutions of sodium hydroxide showed that the substrate first undergoes ring closure to give substituted 1-phenylpyrrolidin-2-ones, which are subsequently hydrolysed to substitution derivatives of sodium 4-amino-N-phenylbutanoates. Kinetic measurements provided the values of dissociation constants pK a and cyclization rate constants k c in water at 25 °C for 2-bromo-4-chloro-N-(4-nitrophenyl)butanamide [pK a = 11.64 ′ 0.01; k c = (1.94 ′ 0.03) x 10 - 2 s - 1 ], 4-chloro-N-(4-nitrophenyl)butanamide [pK a = 13.35 ′ 0.02; k c = (1.60 ′ 0.02) x 10 - 2 s - 1 ] and 4-chloro-2-methyl-N-(4-nitrophenyl)butanamide [pK a = 13.55 ′ 0.03; k c = (7.61 ′ 0.11) × 10 - 2 s - 1 ]. The pK a and k c values of individual derivatives differ depending on the substitution at the α-position of the butanamide skeleton. In methanolic sodium methoxide solutions, the course of ring closure of 2-bromo-4-chloro-N-(4-nitrophenyl)butanamide is of similar nature but slower [K = 60.10 ′ 0.08 and k c = (6.52 ′ 0.05) × 10 - 3 s - 1 ]. The subsequent hydrolyses of substituted 1-phenylpyrrolidin-2-ones to substituted 4-aminobutanoic acids also have different courses with different derivatives and depend on the substituents in the aromatic and/or heterocyclic moiety. The rate-limiting step of hydrolysis of 1-(4-nitrophenyl)pyrrolidin-2-one consists of the non-catalysed decomposition of the tetrahedral intermediate. In the case of 3-bromo-1-(4-nitrophenyl)pyrrolidin-2-one at sodium hydroxide concentrations below 0.1 mol l - 1 , the rate-limiting step is the second reaction pathway, i.e. the hydroxide ion-catalysed decomposition of the tetrahedral intermediate. At sodium hydroxide concentrations above 0.1 mol l - 1 , the rate-limiting step shifts to formation of the tetrahedral intermediate. This formation of the intermediate is 140 times slower than its hydroxide ion-catalysed decomposition [k 3 /k - 1 =(1.40 ′ 0.04) × 10 2 1 mol - 1 ]. Introduction of a 3-bromo substituent into 1-(4-nitrophenyl)pyrrolidin-2-one results in acceleration of all the reaction steps of hydrolysis and increases the acidity of the intermediate.

Acylation of 2-aminothiobenzamide or 2-methylaminothiobenzamide with substituted benzoyl chlorides has been used to synthesise the corresponding 2-benzoyl-aminothiobenzamides whose subsequent sodium methoxide-catalysed ring closure gives the corresponding quinazoline-4-thiones. These compounds were characterised by means of their 1H- and 13C-NMR spectra. The preferred tautomeric form of selected compounds has been discussed on the basis of their 13C-NMR, IR and Raman spectra. It has been found that in the given medium 1-methyl-quinazoline-4-thiones undergo a replacement of the sulphur substituent by oxygen giving 1-methyl-quinazoline-4-ones. In strong acid media, 2-benzoylaminothiobenzamide is cyclised through its sulphur atom to give 2-phenylbenzo[d-1,3]thiazin-4-one.

Dedicated to Professor Jaromir Kavalek on the occasion of his 65th birthday Substituted S-(1-phenylpyrrolidin-2-on-3-yl)isothiuronium salts in weakly basic media undergo intramolecular recyclisation reaction in which the γ-lactam cycle is split and a thiazolidine cycle is formed. A series of six substituted 2-imino-5-[2-(phenylamino)ethyl]-thiazolidin-4-ones have been prepared by this reaction.

Ring transformations ofheterocyclic rings by temporary opening and subsequent closure to a new molecule are of particular interest both synthetically and theoretically. Only rearrangement offive-membered heterocycles are discussed and reviewed. These transformations are classified into four groups: (a) "classical ring transformations ", where the starting and resulting ring system is of the same size, but the heteroatoms and/or their positions have been changed; (b) "degenerate ring transformations" where during the course of the transformation the starting compound and product have the same ring system, but the reaction proceeds by a ring opening and subsequent ring closure process; (c) "ring contractions " and "ring expansions " where the sizes of the product rings are smaller or larger, respectively, than those of the starting compound, and (d) " pseudo ring transformations " or "ring-chain transfer ", where the process is formally a ring transformation, but is realised by a ring closure of a side chain of the starting heterocycle and opening of the original ring. Reaction mechanism of the most interesting ring transformations are also discussed.

Twelve new substituted S-(1-phenylpyrrolidin-2-on-3-yl)isothiuronium bromides and twelve corresponding 2-imino-5-(2-phenylaminoethyl)thiazolidin-4-ones have been prepared and characterised. Kinetics and mechanism of transformation reaction of S-[1-(4-methoxyphenyl)pyrrolidin-2-on-3-yl]isothiuronium bromide and its N,N-dimethyl derivative 5a into corresponding substituted thiazolidin-4-ones 2a and 6a have been studied in aqueous solutions of amine buffers (pH 8.1-11.5) and sodium hydroxide solutions (0.005-0.5 mol l(-1)) at 25 degrees C and at I= 1 mol l(-1) under pseudo-first-order reaction conditions. The kinetics observed show that the transformation reaction is subject to general acid-base, and hydroxide ion catalyses. Acid catalysis does not operate in the transformation of 1a; the rate-limiting step of the base-catalysed transformation is the decomposition of bicyclic tetrahedral intermediate In(+/-) and the Brønsted dependence is non-linear (pK(a) approximately 9.8). In the case of derivative 5a both base and acid catalyses make themselves felt. In the base catalysis, the rate-limiting step consists of the decomposition of bicyclic intermediate In, and the Brønsted dependence is linear (beta = 0.9; pK(a)11.5). The acid-catalysed transformation of 5a also proceeds via the intermediate In, and the reaction is controlled by diffusion (alpha approximately equal to 0). With compound 5a in triethylamine and butylamine buffers, the general base catalysis changes into specific base catalysis. The effect of substitution in aromatic moiety of compounds 1a-h and 3a-h on the course of the transformation reaction has been studied in solutions of sodium hydroxide (0.005-0.5 mol l(-1)) at 25 degrees C by the stopped-flow method. The electron-acceptor substituents 4-NO(2) and 4-CN do not obey the Hammett correlation, which is due to a suppression of cross-conjugation in the ring-closure step of the transformation reaction.

Kinetics of hydrochloric acid-catalyzed solvolysis of substituted phenyl and methyl N-phenylbenzimidoesters have been studied in methanol, 50 vol. % aqueous methanol, and 50 vol. % aqueous tetrahydrofurane, and the composition of the reaction products has been determined. The rate-limiting step consists in addition of water or methanol to the protonated substrate. The reaction of methyl N-phenylbenzimidoester with both water and methanol and that of substituted phenyl N-phenylbenzimidoesters with methanol produce aniline, the ester (or orthoester) and the corresponding phenol. The reaction of substituted phenyl N-phenylbenzimidoesters with water gives both the neutral tetrahedral intermediate (which is decomposed into phenol and anilide) and the protonated intermediate (which produces aniline and the ester). At the same proton concentration the phenol content increases with increasing value of the σ constant of the substituent.