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Paul J Reider

Publications and source records attributed to Paul J Reider.

At least 19 recordsLinked to original sources
PubMed2006

New air-stable catalysts for general and efficient suzuki-miyaura cross-coupling reactions of heteroaryl chlorides.

[reaction: see text] New air-stable PdCl(2){P(t)Bu(2)(p-R-Ph)}(2) (R = H, NMe(2), CF(3),) complexes represent simple, general, and efficient catalysts for the Suzuki-Miyaura cross-coupling reactions of aryl halides including five-membered heteroaryl halides and heteroatom-substituted six-membered heteroaryl chlorides with a diverse range of arylboronic acids. High product yields (89-99% isolated yields) and turn-over-numbers (10,000 TON) are observed.

Journal Article↗
PubMed2004

An efficient synthesis of an alphavbeta3 antagonist.

A practical preparation of an alpha(v)beta(3) antagonist is reported. The antagonist consists of three key components, a tetrahydronaphthyridine moiety, a beta-alanine moiety, and a central imidazolidone moiety. The tetrahydronaphthyridine component was prepared using two different methods, both of which relied on variations of the Friedländer reaction to establish the desired regiochemistry. The beta-alanine component was prepared using Davies' asymmetric 1,4-addition methodology as the key stereo-defining step. The central imidazolidone portion was created from these two components using an effective three-step cyclization protocol. Thus, a highly convergent process for the drug candidate was defined.

Catalysis↗
PubMed2003

Asymmetric synthesis of cyclic hydroxy ketones derived from enol ethers via sharpless asymmetric dihydroxylation. A study in the correlation of the enol ether chain length and enantioselectivity.

The Sharpless asymmetric dihydroxylation reaction of enol ethers derived from their corresponding cyclic ketones, gave alpha-hydroxyketones with high enantioselectivity. The enantiomeric excess was found to be proportional to the length of the unbranched enol ether chain with a maximum ee for the pentyl enol ether. An efficient synthesis of alpha-hydroxy chromanone in >90% ee was demonstrated using this method.

Journal Article↗
PubMed2003

A practical synthesis for the core structure of a family of selective prostaglandin D2 receptor antagonists.

A convergent synthesis was developed for the production of the core structure of prostaglandin D(2) receptor antagonists for the treatment of allergic rhinitis. The key steps in this synthesis were a highly diastereoselective alkylation of (+)-nopinone, a chemo- and stereoselective reduction of an oxime to an amine, and a well-controlled reduction of an aminoalkyne to a (Z)-olefin.

Alkylation↗
PubMed2003

Efficient synthesis of NK(1) receptor antagonist aprepitant using a crystallization-induced diastereoselective transformation.

An efficient stereoselective synthesis of the orally active NK(1) receptor antagonist Aprepitant is described. A direct condensation of N-benzyl ethanolamine with glyoxylic acid yielded a 2-hydroxy-1,4-oxazin-3-one which was activated as the corresponding trifluoroacetate. A Lewis acid mediated coupling with enantiopure (R)-1-(3,5-bis(trifluoromethyl)phenyl)ethan-1-ol afforded a 1:1 mixture of acetal diastereomers which was converted into a single isomer via a novel crystallization-induced asymmetric transformation. The resulting 1,4-oxazin-3-one was converted via a unique and highly stereoselective one-pot process to the desired alpha-(fluorophenyl)morpholine derivative. Interesting and unexpected [1,2]-Wittig and [1,3]-sigmatropic rearrangements were identified during the optimization of these key steps. In the final step, a triazolinone side chain was appended to the morpholine core. The targeted clinical candidate was thus obtained in 55% overall yield over the longest linear sequence.

Aprepitant↗
PubMed2002

Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction.

A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.

Journal Article↗
PubMed2002

Asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes as key components of substance p antagonists.

An efficient asymmetric synthesis of 1,2,3-trisubstituted cyclopentanes and cyclohexanes is described. Three methods were developed for the preparation of the 2,3-disubstituted cyclopentenones and cyclohexenones, which are key achiral building blocks. These intermediates are reduced catalytically with (R)-2-methyloxazaborolidine in high yield (82-98%) and excellent ee (89-96%). Directed reduction of the chiral allylic alcohols using Red-Al gives exclusively the 1,2-anti stereochemistry (>99:1). Epimerization of the ester center followed by saponification/crystallization affords the desired hydroxyacids in good yield (65-70%) and in high enantiomeric excess (>99%).

Catalysis↗
PubMed2002

Development of a new and practical route to chiral 3,4-disubstituted cyclopentanones: asymmetric alkylation and intramolecular cyclopropanation as key C-C bond-forming steps.

An efficient and practical asymmetric synthesis of (+)-trans-3-hydroxymethyl-4-(3-fluorophenyl)cyclopentanone (1) is described. An asymmetric Mo-catalyzed alkylation reaction was used to establish the first stereocenter and a Cu-catalyzed intramolecular diastereoselective cyclopropanation reaction was used to set the second stereocenter. The last step involved a one-pot ring-opening/deprotection/hydrolysis/decarboxylation sequence that furnished the desired product in good yield.

Cyclopentanes↗
PubMed2002

Efficient one-pot synthesis of the 2-aminocarbonylpyrrolidin-4-ylthio-containing side chain of the new broad-spectrum carbapenem antibiotic ertapenem.

An efficient synthesis of the 2-aminocarbonylpyrrolidin-4-ylthio containing side chain of ertapenem (MK-0826) is described. Starting material N-(O,O-diisopropyl phosphoryl)-trans-4-hydroxy-L-proline is converted in a one-pot process to (2S)-cis-3-[[(4-mercapto-2-pyrrolidinyl)carbonyl]amino]benzoic acid monohydrochloride in 70-75% overall yield via a series of six reactions. The development of each of these reactions and the isolation of the product is discussed in detail.

Anti-Bacterial Agents↗
PubMed2002

Solvent-dependent dynamic kinetic asymmetric transformation/kinetic resolution in molybdenum-catalyzed asymmetric allylic alkylations.

Catalytic asymmetric alkylation reactions of branched racemic carbonates 1a and 1b with sodium dimethyl malonate, promoted by molybdenum and ligand 5, proceed by a kinetic resolution in toluene, THF, tetrahydropyran, i-PrOAc, 1,2-dichloroethane, and MeCN with k(rel) of 7-16. In THF, MeCN, tetrahydropyran, and i-PrOAc using the (S,S)-5 ligand, the fast reacting (S)-carbonate enantiomer provides the branched product with high ee (97-99.5%) and branched/linear selectivity, but the ee erodes as the reaction of the slow-reacting (R)-enantiomer takes place. This implies that the rate of equilibration of the oxidative addition complexes in these solvents is competitive with the subsequent malonate displacement step. In toluene and dichloroethane, the ee and branched/linear ratios diminish during the reaction of the slow-reacting (R)-isomer, but not nearly as much as in the other solvents. This is most likely due to either an increase in the rate of equilibration of the oxidative addition complexes relative to the malonate displacement step, or vice versa. Because of the minimal stereochemical memory effect in toluene and 1,2-dichloroethane, the reactions in these solvents can be carried to completion (dynamic kinetic asymmetric transformation) and still provide product with excellent ee (>95%). The anion of dimethyl methylmalonate also reacts via a kinetic resolution, although the ee's, rates, and k(rel) values differ from those of the reactions with dimethyl malonate.

Journal Article↗
PubMed2002

Ullmann diaryl ether synthesis: rate acceleration by 2,2,6,6-tetramethylheptane-3,5-dione.

[reaction: see text]. In the copper salt catalyzed ether formation from aryl bromides or iodides and phenols, 2,2,6,6-tetramethylheptane-3,5-dione (TMHD) was found to greatly accelerate the ordinarily difficult reaction, making it occur under more moderate temperatures and reaction times. A series of aryl halides and phenols were shown to form ethers in NMP as the solvent, cesium carbonate as the base, and CuCl and TMHD as the catalysts. The reaction was shown to tolerate electron-rich aryl bromides and electron-neutral phenols.

Catalysis↗
PubMed2002

Stereoselective synthesis from a process research perspective.

The process chemists' primary responsibility is to develop efficient and reproducible syntheses of pharmaceutically active compounds. This task is complicated when dealing with chiral molecules that often must be made as single isomers according to regulatory guidelines. The presence of any isomeric impurity in the final product, even in small amounts, is usually not acceptable. This requirement necessitates an exquisite understanding of the methods employed in the construction of chiral drugs. However, the chemistry available for this purpose is sometimes limited and often requires a significant amount of effort and creativity to be made both functional and consistent.

Animals↗