Search

Simple and robust derivatization methods for monitoring the formation of (tributylstannyl)methanol from tributyltin hydride via unstable lithiated intermediates have been developed and validated. These analytes present both chromatographic and detection difficulties in their native states due to low volatility, poor aqueous solubility/stability, and lack of a chromophore. Derivatization of these analytes to trimethylsilyl analogues for gas chromatographic analysis or to benzenesulfonyl urethane analogues for reversed-phase liquid chromatographic analysis was evaluated. The derivatization/gas chromatographic methods developed were demonstrated to be more specific and sensitive for impurity monitoring during (tributylstannyl)methanol preparation.

Crystalline p -nitrobenzyl esters of 2-hydroxymethyl carbapenem derivatives were prepared in one pot from the corresponding diazo compounds and Bu 3 SnCH 2 OH. The TES protected 2-hydroxymethyl carbapenem was successfully converted to an anti-MRS carbapenem L-786,392.

Anti-MRSA carbapenem, L-742,728, has been prepared in large quantity using the Suzuki−Miyaura cross-coupling as the key reaction. Three approaches have been examined by varying the coupling reaction between carbapenem nucleus A and side chains B, BC, and BCD, wherein BCD represents the fully elaborated side chain. The coupling of A with BCD offers the advantage of convergence and requires fewer chemical steps after installation of the thermally unstable carbapenem skeleton. This key reaction highlights the versatility and efficiency of the Suzuki−Miyaura reaction. This approach offers a general method for the preparation of the 3-aryl carbapenems, which possess strong antibacterial activity against resistant strains.

An efficient, diastereoselective [2,3]-Wittig rearrangement of α-allyloxy-amide enolates has been developed using (1S,2R)-1-amino-indan-2-ol as a chiral auxiliary. After auxiliary removal, the resultant optically active α-hydroxy acids have been transformed to functionalized amino acid derivatives.

The goal of process chemistry is to identify cost-effective, robust and environmentally friendly manufacturing routes for drug candidates. This article outlines the importance of scientific ­innovation to overcome the many challenges along the journey ­towards a drug filing. ��

The reaction of an ester with N , O -dimethylhydroxylamine and a suitable organomagnesium reagent or lithium amide base provides a general method for the preparation of N -methoxy- N -methylamides. Application in the direct conversion of a highly hindered ester to a ketone, the azasteroid 5α-reductase inhibitor MK-0434, is described.

An efficient, new, and scalable semisynthesis of glucan synthase inhibitors 1 and 2 from the fermentation product enfumafungin 3 is described. The highlights of the synthesis include a high-yielding ether bond-forming reaction between a bulky sulfamidate 17 and alcohol 4 and a remarkably chemoselective, improved palladium(II)-mediated Corey-Yu allylic oxidation at the highly congested C-12 position of the enfumafungin core. Multi-hundred gram quantities of the target drug candidates 1 and 2 were prepared, in 12 linear steps with 25% isolated yield and 13 linear steps with 22% isolated yield, respectively.

Ortho acylation of anilines by nitriles in the presence of BCl 3 and a second Lewis acid appear to proceed through an intermediate “supercomplex” including all four components. Yield improvements were obtained based on recognition that chloride affinity of the second Lewis acid governs supercomplex formation. Aniline protonation was found to be the cause of incomplete reaction.

An extraordinarily mild procedure for the synthesis of 2-aryl- and 2-alkenyl-substituted carbapenems via palladium-catalyzed coupling of a vinyl triflate with aryl or vinyl boronic acids is described. A major advantage of this procedure is the use of nontoxic boronic acid intermediates in place of highly toxic organostannane compounds which are used in the corresponding Stille cross-coupling reactions.

[reaction: see text]. A highly regioselective Friedländer reaction is described. By introduction of a phosphonate group at one of the alpha-carbons of a ketone, regioselectivity can be perfectly controlled.

An extraordinarily mild procedure for the synthesis of 2-aryl- and 2-alkenyl-substituted carbapenems via palladium-catalyzed coupling of a vinyl triflate with aryl or vinyl boronic acids is described. A major advantage of this procedure is the use of nontoxic boronic acid intermediates in place of highly toxic organostannane compounds which are used in the corresponding Stille cross-coupling reactions.

An efficient, diastereoselective [2,3]-Wittig rearrangement of α-allyloxy-amide enolates has been developed using (1S,2R)-1-amino-indan-2-ol as a chiral auxiliary. After auxiliary removal, the resultant optically active α-hydroxy acids have been transformed to functionalized amino acid derivatives.

A key intermediate for 2-(functionalized-methyl)-1-β-methylcarbapenems, 3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(2R)-4-halo-3-oxo-2-butyl]azetidinone, was prepared efficiently from a commercially available carboxylic acid in 3 steps.

Crystalline 1β-methyl-2-formyl carbapenem pNB esters were prepared by osmium-mediated oxidative cleavage of the corresponding 2-vinyl derivatives. Reduction of the 2-formyl compounds gave the corresponding 2-hydroxymethyl derivatives, which are key intermediates for the anti-MRS carbapenem candidate (1).

[formula: see text] A short synthesis of carbapenem 1 is described. They key step involves the cross-coupling of an enol triflate with an amino-substituted sp3 carbon. This cross-couping, which allows the introduction of the complete side chain in one step, utilizes a stannatrane as the heteroalkyl transfer reagent.

Process design and development of drug candidates using cross-coupling reactions as key steps are discussed. In the anti-MRS carbapenem project, all drug candidates were prepared effectively in a few steps from the commercially available diazo intermediate by either Suzuki–Miyaura cross-coupling or Stille–Migita cross-coupling, demonstrating the versatility, effectiveness, functional group tolerability, and mild reaction conditions of cross-coupling methods.

A general and efficient synthetic method for the synthesis of biologically important series of 3,6-disubstituted-1H-pyrazolo[3,4-b]pyridines was discovered. 2,6-Difluoropyridine was deprotonated using 1.1 equiv of n-BuLi in THF at

An effective strategy has been developed for the preparation of 3-alkoxymethyl-pyrazolo[3,4-b]pyridines, compounds that are currently not readily accessible by existing synthetic methods. Further manipulation of these compounds allows for access to 3-alkoxymethyl-pyrazolo[3,4-b]pyridines with a variety of substitution patterns as well as 3-aminomethyl-pyrazolo[3,4-b]pyridines.

In a three-step sequence starting from readily available starting materials, 2,3-carbon disubstituted furo[2,3-b]pyridines can be accessed in good yields and purity. Furo[2,3-b]pyridines bearing ester, amide and ketone groups at the 2-position can be prepared with a variety of aryl and alkyl groups at the 3-position.

An effective strategy has been developed for the preparation of 3-alkoxymethyl-pyrazolo[3,4-b]pyridines, compounds that are currently not readily accessible by existing synthetic methods. Further manipulation of these compounds allows for access to 3-alkoxymethyl-pyrazolo[3,4-b]pyridines with a variety of substitution patterns as well as 3-aminomethyl-pyrazolo[3,4-b]pyridines.

An efficient and practical method for the preparation of benzyloxyacetic acids is described. The procedure involves the reaction of readily available chloroacetic acid with benzyl alcohol in the presence of powdered KOH providing a safer alternative to the known literature procedures, which completely eliminates the use of pyrophoric bases such as sodium hydride and sodium metal.

Copper-mediated coupling reactions of cyclopropylboronic acid with indoles and cyclic amides are described. The process utilizes catalytic or stoichiometric amounts of copper(II) acetate, DMAP, and NaHMDS at 95 °C under an atmosphere containing oxygen. A variety of functional groups remain intact throughout the reaction.

Copper-mediated coupling reactions of cyclopropylboronic acid with indoles and cyclic amides are described. The process utilizes catalytic or stoichiometric amounts of copper(II) acetate, DMAP, and NaHMDS at 95 degrees C under an atmosphere containing oxygen. A variety of functional groups remain intact throughout the reaction.

Two new 3-cyano-3-cephem derivatives, potassium 3-cyano-3-cephem-4-carboxylate (2) and potassium 7α-phenylacetamido-3-cyano-3-cephem-4-carboxylate (3), were prepared from 7β-aminocephalosporanic acid. Compounds 2 and 3 showed only weak β-lactamase inhibitory activity in contrast to sodium 7α-[(1R)-1-hydroxyethyl]-3-cyano-3-cephem-4-carboxylate (1), indicating the important role of the 7α-(1-hydroxyethyl) substituent for β-lactamase inhibitory activity.

The synthesis and biological properties of some 3-vinylthio- and 3-vinylthiomethylcephem derivatives are described. Both series possess potent antibacterial activity. Among them, 3-[(Z)-2-cyanovinylthiomethyl]cephem derivative was found to have an expanded antibacterial spectrum.

A practical and efficient protocol for the three-step synthesis of (S)-N-ethoxycarbonyl-alpha-methylvaline 3 is described which utilizes readily available commercial starting materials. The key transformations involve resolution-crystallization of tartrate salt 6 followed by a one-pot procedure for the preparation of 3 which is isolated as the dicyclohexylamine salt in 45% overall yield and in 91-95% ee.

A highly efficient copper-catalyzed coupling reaction of aryl iodides and thiobenzoic acid, using 10 mol % of copper iodide, 20 mol % of 1,10-phenanthroline, and iPr2NEt in toluene, was developed. This methodology is applicable to a variety of aryl iodides.

Here, we report a short and efficient synthesis of isoindolin-1-ones. Base-induced cyclization of o-hydroxymethyl-benzamides, which was easily prepared from the corresponding phthalides and amines, led predominantly to N-alkylation in good yield. The reaction proceeded under mild conditions and bromine and nitrile substituents were tolerated. The selectivity is explained by HASB theory.

The organomagnesium complex n Bu 2 i PrMgLi, readily prepared from n BuLi and i PrMgCl (2:1), is quite efficient for the bromine–magnesium exchange of 5-bromo-2-picoline under noncryogenic conditions (at −10 °C). The resulting picolylmagnesium complex reacts with various electrophiles to afford functionalized picolines.

Here, we report a highly effective and chemoselective method of preparing substituted indoles from (E)-2-nitropyrrolidinostyrenes via hydrogenation in the presence of a rhodium catalyst doped by additives such as Ni(NO3)2·6H2O, Fe(OAc)2 or Co(acac)3. These hydrogenation conditions may also be applied to other substrates. Aromatic nitro compounds and olefins can be selectively reduced in the presence of aromatic benzyl ethers, aromatic halides and aromatic aldehydes.

A few different approaches for the preparation of highly substituted bicyclo[3.1.0]hexane mGluR2/3 agonists are reviewed. Addition and elimination, carbene insertion, S N 2 type cyclization, and application of Trost's asymmetric allylic alkylation (AAA) are methods of choice for the construction of the ring system. Functionalization of the bicyclo[3.1.0]hexane core structure and synthesis of one of the most potent and selective mGluR2/3 agonists, MGS0028, are also reviewed.