Stereoselective Catalytic Synthesis of Active Pharmaceutical Ingredients in Homemade 3D-Printed Mesoreactors.

3D-printed flow reactors were designed, fabricated from different materials (PLA, HIPS, nylon), and used for a catalytic stereoselective Henry reaction. The use of readily prepared and tunable 3D-printed reactors enabled the rapid screening of devices with different sizes, shapes, and channel dimensions, aimed at the identification of the best-performing reactor setup. The optimized process afforded the products in high yields, moderate diastereoselectivity, and up to 90 % ee. The method was applied to the continuous-flow synthesis of biologically active chiral 1,2-amino alcohols (norephedrine, metaraminol, and methoxamine) through a two-step sequence combining the nitroaldol reaction with a hydrogenation. To highlight potential industrial applications of this method, a multistep continuous synthesis of norephedrine has been realized. The product was isolated without any intermediate purifications or solvent switches.

Synthesis of BF3 catalyzed Mannich derivatives with excellent ee from phenylpropanolamine, study of their antimicrobial activity and molecular docking.

Antimicrobial agents 4a-g and 5a-g with very good potency were synthesized with 100% ee from phenylpropanolamine (norephedrine) by BF3 catalyzed three components one pot Mannich reaction in good yields. Obtained compounds were characterized using spectral techniques. Antimicrobial study of these compounds revealed a good to very high potential activity against tested microbes when compared to standard antimicrobial drugs streptomycin and ketoconazole. These synthesized compounds exhibited significant minimum inhibitory concentration (MIC) values against Gram positive and Gram negative bacteria. Amongst compound 4b, 4c, 4d, 4e, 5a, and 5e exhibited very high potent MIC values against tested twelve bacteria and three fungi when compared to control. When subjected to molecular docking, in silico studies revealed significant binding energies ranging from -7.06 to -8.90 kcal/mol for all obtained compounds towards target receptor DNA topoisomerase IV and amongst compounds 4b and 4d have shown maximum binding energies 8.70 and 8.90 kcal/mol, respectively.

Copper-catalysed selective hydroamination reactions of alkynes.

The development of selective reactions that utilize easily available and abundant precursors for the efficient synthesis of amines is a long-standing goal of chemical research. Despite the centrality of amines in a number of important research areas, including medicinal chemistry, total synthesis and materials science, a general, selective and step-efficient synthesis of amines is still needed. Here, we describe a set of mild catalytic conditions utilizing a single copper-based catalyst that enables the direct preparation of three distinct and important amine classes (enamines, α-chiral branched alkylamines and linear alkylamines) from readily available alkyne starting materials with high levels of chemo-, regio- and stereoselectivity. This methodology was applied to the asymmetric synthesis of rivastigmine and the formal synthesis of several other pharmaceutical agents, including duloxetine, atomoxetine, fluoxetine and tolterodine.

Coumarins from free ortho-hydroxy cinnamates by Heck-Matsuda arylations: a scalable total synthesis of (R)-tolterodine.

Free ortho-hydroxy cinnamate ester derivatives are evaluated in the synthesis of structurally diverse 4-aryl-coumarins via a tandem Heck-Matsuda cyclization reaction. Free phenolic groups were considered incompatible with such a reaction, which usually provide the corresponding diazo dyes. A concise and scalable route employing a ligand-free, Pd-catalyzed Heck-Matsuda arylation under aerobic conditions for the preparation of (R)-Tolterodine in high overall yield and ee is also presented.

Stereoselective synthesis of norephedrine and norpseudoephedrine by using asymmetric transfer hydrogenation accompanied by dynamic kinetic resolution.

Each of the enantiomers of both norephedrine and norpseudoephedrine were stereoselectively prepared from the common, prochiral cyclic sulfamidate imine of racemic 1-hydroxy-1-phenyl-propan-2-one by employing asymmetric transfer hydrogenation (ATH) catalyzed by the well-defined chiral Rh-complexes, (S,S)- or (R,R)-Cp*RhCl(TsDPEN), and HCO(2)H/Et(3)N as the hydrogen source. The ATH processes are carried out under mild conditions (rt, 15 min) and are accompanied by dynamic kinetic resolution.

Study of the effect induced by the substituents on the ring-chain tautomerism of Schiff bases derived from norephedrine.

The solution behavior and the spectroscopic properties of the novel Schiff bases (1S,2R)-R(1)CH=NCH(Me)CH(OH)Ph [with R(1) = ferrocenyl-[Fc (2b)], 5- or 3-methylthienyl [hereafter referred to as 5-MeTf and 3-MeTf (2c and 2d), respectively]] are reported. NMR studies show the existence of a tautomeric equilibrium between these imine forms (2b-d) and 2-substituted 4-methyl-5-phenyloxazolidines. The comparison of the results reveals that the molar ratios imine/oxazolidines (K): (a) are solvent and temperature dependent, (b) are higher than that obtained for (1S,2R)-PhCH=NCH(Me)CH(OH)Ph (2e), (c) are strongly affected by the nature of the R(1) group, and (d) increase according to the sequence Ph < Fc < 5-MeTf < 3-MeTf. Density functional theory (DFT) calculations on the open forms (imines 2b-e) and on the diastereomers of the closed forms (2-substituted 4-methyl-5-phenyl oxazolidines) have also been carried out in order to rationalize the differences detected in the solution behavior of 2b-d and their analogue with R(1) = Ph (2e).

Asymmetric conjugate reductions of coumarins. A new route to tolterodine and related coumarin derivatives.

The combination of catalytic amounts of [(R)-DTBM-SEGPHOS]CuH in the presence of stoichiometric DEMS (diethoxymethylsilane) in toluene at room temperature leads to asymmetric reductions of 4-substituted coumarins. Several targets or their known precursors can be prepared in high yields and ee's, including the muscarine receptor antagonist (R)-tolterodine.

Enantioselective synthesis of (R)-tolterodine via CuH-catalyzed asymmetric conjugate reduction.

An efficient and highly enantioselective method for the preparation of (R)-tolterodine is described. The synthesis was performed by CuH-catalyzed asymmetric conjugate reduction of a beta,beta-diaryl-substituted unsaturated nitrile as a key step, which is prepared by a stereoselective hydroarylation of alkynenitrile with aryl boronic acid. The synthesis was accomplished without employing the protection-deprotection sequence.

Enantioselective synthesis of (s)- and (R)-tolterodine by asymmetric hydrogenation of a coumarin derivative obtained by a Heck reaction.

An efficient and short enantioselective synthesis of (S)- and (R)-tolterodine was performed by asymmetric hydrogenation of a coumarin intermediate, easily obtained by a Heck reaction from inexpensive and commercially available starting materials.

Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins: asymmetric synthesis of (R)-tolterodine.

[reaction: see text]. Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins proceeded with high enantioselectivity in the presence of a rhodium catalyst (3 mol %) generated from Rh(acac)(C2H4)2 and (R)-Segphos to give the corresponding (R)-4-arylchroman-2-ones in over 99% ee. This asymmetric reaction was applied to the synthesis of (R)-tolterodine.

Design, synthesis and activity of novel derivatives of oxybutynin and tolterodine.

Novel derivatives of Tolterodine (1) and Oxybutynin (2) have been designed using conformationally restricted azabicyclics as replacement for open-chain amines. The synthesis and structure-activity relationships are presented.

Enantioselective [4 + 2] cycloadditions of o-quinone methides: total synthesis of (+)-mimosifoliol and formal synthesis of (+)-tolterodine.

The first example of an enantioselective cycloaddition of an o-quinone methide (o-QM) with a chiral enol ether is described along with the total synthesis of (+)-mimosifoliol and the formal synthesis of (+)-tolterodine. These syntheses exemplify a three-component, one-pot benzopyran approach for the construction of chiral benzylic junctions. Cycloadditions of various enol ethers and o-QMs are examined, and diastereoselectivities >95% are obtained with trans-2-phenyl-1-cyclohexanol and 2,2-diphenylcyclopentanol vinyl ethers.

Design of scytalone dehydratase inhibitors as rice blast fungicides: derivatives of norephedrine.

Five X-ray crystal structures of scytalone dehydratase complexed with different inhibitors have delineated conformationally flexible regions of the binding pocket. This information was used for the design and synthesis of a norephedrine-derived cyanoacetamide class of inhibitors leading to potent fungicides.

Phenylthioalkylamines in experimental tumor treatment in mice.

Two phenylthioalkylamines, phenylthioethylamine (PTEA) and phenylthiopropylamine (PTPA), were prepared and tested for cytotoxicity in vitro and as antitumor agents in (C57BL X DBA/2)F1 (BDF1) mice. Low concentrations of PTEA (median effective concentrations of 8.0, 12.0, and 1.3 micrograms PTEA/ml) inhibited the growth of P388 murine lymphoma, L1210 leukemia, and B16 melanoma cells in culture. PTPA was more effective; concentrations of 0.80, 0.56, and 0.35 micrograms PTPA/ml inhibited the growth of P388, L1210, and B16 in vitro by 50%. PTEA and PTPA treatment increased survival times in BDF1 mice bearing the P388 lymphoma, L1210 leukemia, B16 melanoma, and Lewis lung tumors. Multiple daily administrations of the test compounds were more effective than single daily injections in increasing the life-span in mice bearing the P388 lymphoma and B16 melanoma. Both PTEA and PTPA inhibited the enzyme copper-zinc superoxide dismutase.

[Syntheses of 14C-1-erythro-norephedrine and its N-substitution products 14C-oxyfedrine and 14C-D 13,625]. / Synthesen von 14C-1-erythro-Norephedrin sowie seiner N-Substitutionsprodukte 14C-Oxyfedrin und 14C-D 13 625.

Starting from 14C-benzene (--)-erythro-norephedrine (14C-1-norephedrine) was obtained in a 6-step synthesis. 14C-1-Norephedrine functioned as an intermediate for the synthesis of the carbon labelled partial beta-agonist oxyfedrine hydrochloride (ildamen) and the new positive inotropic agent D 13 625 (alifedrine hydrochloride).

[Synthesis, absolute configuration and mass spectroscopic fragmentation of the circulation analeptic cafedrine (author's transl)]. / Synthese, absolute Konfiguration und massenspektroskopische Fragmentierung des kreislaufanaleptisch wirksamen Cafedrin.

The synthesis of [R-(R*,S*)]-7-[2-[(2-hydroxy-1-methyl-2-phenylethyl)amino]-ethyl]-3,7-dihydro-1 ,2-dimethyl-1H-purine-2,6-dione (Cafedrine) and its stereoisomers is reported. By means of 1H- and 13C-nmr spectroscopy the relative configuration of the two asymmetric centres is ascertained and the absolute configuration is discussed. The EI-mass spectrometric fragmentation of cafedrine has been elucidated.

Adrenergic agents. 8.1 Synthesis and beta-adrenergic agonist activity of some 3-tert-butylamino-2-(substituted phenyl)-1-propanols.

Replacement of the benzylic hydroxyl group of N-tert-butylnorepinephrine with a hydroxymethyl substituent affords a propanolamine homologue which retains a high degree of beta-adrenergic agonist activity. As modification of the meta substituent of catecholic ethanolamines, such as N-tert-butylnorepinephrine, often provides compounds that exert a more pronounced effect in relaxing tracheobronchial smooth muscle (beta2-adrenergic agonist) than in stimulating cardiac muscle (beta1-adrenergic response), a series of 3-tert-butylamino-2-(3-substituted 4-hydroxyphenyl)-1-propanols was prepared. The 3-meta substituents included HOCH2 (1b), H2NCONH (1c), MeSO2NH (1d), H (le), and NH2 (1f). These phenylpropanolamine derivatives were compared with their phenylethanolamine counterparts in in vitro tests that measure the ability of these compounds to relax spontaneously contracted guinea pig tracheal smooth muscle (a measure of potential bronchodilating activity) and to increase the rate of contraction of a spontaneously beating guinea pig right atrial preparation (an indicator of potential cardiac stimulating activity). In these tests all of the propanolamine derivatives included in the study were less potent than their ethanolamine relatives. In both series replacement of the catecholic m-hydroxyl group with the indicated substituents usually resulted in compounds with increased selectivity for tracheobronchial vs. cardiac muscle.