Preparation and unequivocal identification of the regioisomers of nitrocatechol monobenzyl ether

<p>The four positional isomers of nitrocatechol monobenzyl ether were prepared as intermediates to nitrobenzodioxanes directly from 2-benzyloxyphenol or, through two-four steps, from catechol. These preparations addressed the issue of the certain identification of the nitration products prescinding from chemical correlation to the synthetic precursors because the positional isomers are very similar for some properties and analytical data available from the literature are largely incomplete and not conclusive. The here provided NMR, DSC, and acidity data unequivocally distinguish each nitrocatechol monobenzyl ether from its regioisomers.</p

Simple route to synthesize (<i>E</i>)-3-propyl-4-oxo-2-butenoic acid esters through the <i>Z</i> isomer

<p>Esters of 3-alkyl-4-oxo-2-butenoic acid, which are very important synthons, are not equally accessible in both <i>E</i> and <i>Z</i> configurations. The (<i>Z</i>)-isomers can be easily obtained from 3-alkyl-4-hydroxybutenolides, in turn prepared by aminoalkylation of aliphatic aldehydes with glyoxylic acid. The (<i>E</i>)-isomers, on the contrary, result from laborious procedures: the condensation of aldehydes with glyoxylic acid, followed by separation from γ-hydroxybutenolide by-product and esterification, or of aldehyde enamines with glyoxylic esters, followed by <i>Z</i> ester by-product conversion into γ-aminobutenolide and purification. Here, we describe a straightforward route to the title compounds, applied to methyl (<i>E</i>)-3-propyl-4-oxo-2-butenoate, avoiding any problematic by-product or isomer chromatographic separation: pentanal and glyoxylic acid are condensed to 3-propyl-4-hydroxybutenolide, which is converted to methyl (<i>Z</i>)-3-propyl-4-oxo-2-butenoate and then isomerized to <i>E</i> ester under acidic conditions.</p

Green Oxidation of Heterocyclic Ketones with Oxone in Water

The recently reported efficient conversion of cyclic ketones to lactones by Oxone in neutral buffered water is extended to heterocyclic ketones, namely, cyclic N-Boc azaketones and oxoethers with the aim of obtaining N-protected azalactones and their analogues with oxygen in place of nitrogen. N-Boc-4-piperidinone and all the cyclic oxoethers were successfully oxidized to lactones, while the azacyclic ketones with nitrogen α-positioned to carbonyl were univocally transformed into N-Boc-ω-amino acids and N-Boc-N-formyl-ω-amino acids operating in alkaline water and DMF, respectively

One-Pot Racemization Process of 1‑Phenyl-1,2,3,4-tetrahydroisoquinoline: A Key Intermediate for the Antimuscarinic Agent Solifenacin

(<i>S</i>)-(+)-1-Phenyl-1,2,3,4-tetrahydroisoquinoline, which is the key intermediate in preparing the urinary antispasmodic drug solifenacin, was racemized in quantitative yield by a simple one-pot procedure through N-chlorination with trichloroisocyanuric acid, conversion of the <i>N</i>-chloroamine into the imine hydrochloride, and reduction of the imine double bond. The racemized amine was successfully resolved by d-(−)-tartaric acid obtaining (<i>S</i>)-1-phenyl-1,2,3,4-tetrahydroisoquinoline in 81% yield and with 96.7% ee and, from the crystallization mother liquors, the <i>R</i> enriched form. This was racemized by the same one-pot process and resolved by d-(−)-tartaric acid with the same efficiency. Such an approach to the racemization of 1-phenyl-1,2,3,4-tetrahydroisoquinoline can be industrially useful to recycle the waste <i>R</i> enantiomer resulting from the classical resolution used to obtain the <i>S</i> enantiomer on a large scale

Enantiomerically Pure Dibenzyl Esters of l‑Aspartic and l‑Glutamic Acid

(<i>S</i>)-Dibenzyl aspartate <i>p</i>-toluenesulfonate [(<i>S</i>)-<b>1·</b>TsOH] and (<i>S</i>)-dibenzyl glutamate <i>p</i>-toluenesulfonate [(<i>S</i>)-<b>2·</b>TsOH] were efficiently prepared from the respective l-amino acids and benzyl alcohol with very high yields by using cyclohexane as a water azeotroping solvent instead of benzene, carbon tetrachloride, toluene, or benzyl alcohol itself, as reported in literature methods. Preventively, chiral HPLC methods were developed to determine the enantiomeric excess of the two diesters and DSC analyses were performed on the respective <i>p</i>-toluenesulfonates. With the aid of such investigation tools, we demonstrated that (<i>S</i>)-<b>1</b>·TsOH and (<i>S</i>)-<b>2</b>·TsOH were formed enatiomerically pure in cyclohexane, whereas more or less pronounced racemization occurred both in toluene and in benzyl alcohol. The two one-pot procedures, which did not require crystallization of the product or any other purification step, were accomplished on multigram scale

Simple Process for the Preparation of Cetyltrimethylammonium Naproxenate (Naprocet)

Specifications for cetyltrimethylammonium (CTA) naproxenate (naprocet), the active ingredient of pharmaceutical liquid preparations used as antiseptic–antinflammatory detergents, fix severe limits to the presence of residual inorganic counteranion deriving from the starting CTA salt. A new simple procedure, which avoids ionic exchange chromatography and utilizes CTAHSO₄ in place of CTABr and CTACl, exploits the quantitative precipitation of K₂SO₄ from methanol to yield naprocet in line with such specification requirements

6‑Methoxy-7-benzofuranoxy and 6‑Methoxy-7-indolyloxy Analogues of 2‑[2-(2,6-Dimethoxyphenoxy)ethyl]aminomethyl-1,4-benzodioxane (WB4101): Discovery of a Potent and Selective α_1D-Adrenoceptor Antagonist

Previous results have shown that replacement of one of the two <i>o</i>-methoxy groups at the phenoxy residue of the potent, but not subtype-selective, α₁-AR antagonist (<i>S</i>)-WB4101 [(<i>S</i>)-<b>1</b>] by phenyl, or by ortho,meta-fused cyclohexane, or especially by ortho,meta-fused benzene preferentially elicits α_1D-AR antagonist affinity. Such observations inspired the design of four new analogues of <b>1</b> bearing, in lieu of the 2,6-dimethoxyphenoxy residue, a 6-methoxy-substituted 7-benzofuranoxy or 7-indolyloxy group or, alternatively, their corresponding 2,3-dihydro form. Of these new compounds, which maintain, rigidified, the characteristic ortho heterodisubstituted phenoxy substructure of <b>1</b>, the <i>S</i> enantiomer of the dihydrobenzofuranoxy derivative exhibited the highest α_1D-AR antagonist affinity (p<i>A</i>₂ 9.58) with significant α_1D/α_1A and α_1D/α_1B selectivity. In addition, compared both to α_1D-AR antagonists structurally related to <b>1</b> and to the well-known α_1D-AR antagonist BMY7378, this derivative had modest 5-HT_1A affinity and neutral α₁-AR antagonist behavior