An interesting sidetrack in the tofisopam synthesis: lithium variant of a stereospecific Oppenauer oxidation

Abstract

In the course of the elaboration of a new manufacturing process of anxiolytic drug tofisopam, a stereospecific lithium-catalyzed Oppenauer-type oxidation was observed. Bromine-lithium exchange on the ethylene ketal of 3-(2-bromo-4,5-dimethoxyphenyl)pentan-2-one followed by quenching with 1 equivalent of 3,4-dimethoxybenzaldahyde gave the corresponding alcohols as a mixture of two diastereomeric racemates. On the other hand, when 2.5 equivalents of the aldehyde were applied, only one of the two alcohol diastereomers could be isolated. The lithium alkoxide precursor of the other diastereomeric alcohol, due to the presence of the excess of benzaldehyde as the oxidant, underwent an Oppenauer-type oxidation to give the corresponding ketone.

Points of Interest in the Chemistry of the Levomepromazine Drug Substance: Recycling of Undesired Enantiomer, Identification of New Phenothiazine Dimers, Synthesis of a Pharmacopeial Impurity, and an Unexpected Rearrangement

“…Compound 15 was finally transformed to dimer 9 by Omethylation carried out with methyl p-tosylate. 37 As regards the surprising formation of dimer hydroxyphenyl)-sulfanylphenol (17). 38 In this case, the sulfur and oxygen atoms, which were originally in para position, got into ortho position.…”

“…In continuation of our efforts aiming at the technological − and analytical , development of drug substance manufacturing processes, we also tried to achieve economical improvements in the synthetic procedure leading to levomepromazine [( R )- 1 ]. In order to obtain recovered 2-methoxyphenothiazine ( 2 ) in a reasonable yield and required purity, we aimed to transform the one-pot procedure (see above, Scheme ) into an easily scalable process by isolating and purifying certain intermediates.…”

Computational Studies on the Diastereospecific Lithium Variant of Oppenauer Oxidation of a Tofisopam Intermediate

“…This is in line with the observation that isomer 14A, which reacted further in the Oppenauer-type oxidation reaction, shows a methyl signal at 0.67 and 0.76 ppm in DMSO-d 6 and CDCl 3 , respectively, while the nonreacting isomer (14B) has a signal at 0.15 ppm in DMSO-d 6 and at 0.25 ppm in CDCl 3 . 12…”

“…Both diastereomers were oxidized to keto-ketal 12 with pyridinium dichromate (PDC). 12 The absolute configuration of the diastereomers has not been determined, and compounds While working on the synthetic route via intermediates 14, we met a related reaction in the literature published by Capilla et al: 13 lithiation of bromo derivative 15 and subsequent reaction with 3,4,5-trimethoxybenzaldehyde (16), followed by the reaction of lithium salt 17 with an excess of aldehyde 16 gave benzophenone 18 in 71% yield (Scheme 3). Although the authors did not comment on the mechanism of the reaction, the second step is obviously lithium-catalyzed Oppenauer oxidation.…”

“…i n d i v i d u a l n o t d i r e c t l y a s s o c i a t e d w i t h s c i t e i s p r o h i b i t e d .only lithium salt 13A has been transformed to ketone 12 by Oppenauer oxidation,12 while alcohol 14B has been generated from lithium salt 13B in the course of the aqueous workup.…”