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The development of a safe, robust, and efficient manufacturing route for the synthesis of diaminopyrimidine 1, a key intermediate to gefapixant citrate (MK-7264), is described. A full mechanistic u...

We report the practical synthesis of a key fragment of islatravir (MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) currently under investigation for treatment and...

The ability of maleate half-ester salts to serve as electrophilic partners in 1,4-conjugate addition reactions with control of regioselectivity has previously been explored in only a limited context with soft nucleophiles. We have demonstrated that benzylic anions of picolines, as well as enolates of ketones, esters, and nitriles, react with lithium 4-(tert-butoxy)-4-oxobutenoate in a completely regioselective manner. This new method was applied to an expedient two-step process for preparing a key azaindanone intermediate for the clinical-candidate drug MK-8666.

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl3/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides., An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield.

A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (1) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael-lactolization-dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps.

Relebactam, a potent β-lactamase inhibitor, in combination with Primaxin is an FDA-approved (Recarbrio) treatment for serious and antibiotic-resistant bacterial infections. An efficient synthesis of key chiral piperidine intermediate

An asymmetric synthesis of a silicon-containing proline surrogate, N-Boc-(R)-silaproline (1), is described. Starting from N-Boc-dehydroalanine ester, deprotonation, followed by N-alkylation with chloromethyldimethylsilane under flow conditions, afforded the N-alkylated product 8 in 91% yield. An unprecedented enantioselective (NBD)2RhBF4/Josiphos 404-1 catalyzed 5-endo-trig hydrosilylation afforded the silaproline ester in 85–90% yield and >95% ee. Subsequent saponification and salt formation upgraded 1 to >99% ee.

An asymmetric synthesis of orexin receptor antagonist MK-6096 piperidine core, ((3R,6R)-6-methylpiperidin-3-yl)methanol (3), is described. The target is synthesized in four steps and 40% overall yield from methyl vinyl ketone and diethyl malonate. The key operation is a practical crystallization-induced dynamic resolution for the conversion of a trans/cis mixture of lactam acid 17 into the desired trans-lactam acid salt in >95% de and 91% yield. The substrate lactam acid mixture was prepared via a solvent-free Michael reaction and a practical biocatalytic transamination process.

A general and efficient asymmetric synthesis of cyclic indoline aminals was developed with a high level of 1,3-stereoinduction through a dynamic crystallization-driven condensation. Dehydrogenation of the indoline aminals with potassium permanganate produced the corresponding cyclic indole aminals in high yields and excellent enantioselectivities. This general methodology was successfully applied to the synthesis of a wide variety of chiral cyclic indoline aminals and indole aminals with aromatic and aliphatic functional groups.

Development of a practical asymmetric synthesis of a glucagon receptor antagonist drug candidate for the treatment of type 2 diabetes is described. The antagonist consists of a 1,1,2,2-tetrasubstituted ethane core substituted with a propyl and three aryl groups including a fluoro-indole. The key steps to construct the ethane core and the two stereogenic centers involved a ketone arylation, an asymmetric hydrogenation via dynamic kinetic resolution, and an anti-selective Friedel–Crafts alkylation of a fluoro-indole with a chiral α-phenyl benzyl cation. We also developed two new efficient syntheses of the fluoro-indole, including an unusual Larock-type indole synthesis and a Sugasawa-heteroannulation route. The described convergent synthesis was used to prepare drug substance in 52% overall yield and 99% ee on multikilogram scales.

With the goal of improving the synthetic efficiency, the development of a convergent synthesis of a minocycline derivative PTK0796 via an intermolecular acyliminium Friedel–Crafts reaction (Tscherniac–Einhorn reaction) is described. The entire C9 neopentylaminomethyl side chain was installed in one step using an electronically optimized chloromethylacyliminium precursor in 83% yield. Deprotection and re-equilibration to the C4 α-epimer in the presence of CaCl 2 and ethanolamine or NaOH afforded the target aminomethylcycline antibiotic. The corresponding crystalline tosylate salt was found to exhibit improved solid state stability.

A screening approach for identifying adsorbents and conditions for selective removal of colored impurities from solutions of pharmaceutical intermediates is described. In this method, a variety of process adsorbents are evaluated using a combination of HPLC or LC−MS and 96-well microplate UV–vis spectroscopy. Several representative examples are shown that illustrate the use of the technique for the selective removal of colored impurities from pharmaceutical development candidates or related intermediates.

Efficient catalyst systems and reaction protocols were discovered for the regioselective Suzuki coupling of 1,6-naphthyridone dichloride through high-throughput experimentation. With Pd2(dba)3·CHCl...

Cyclic indole aminals are efficiently prepared through a highly stereoselective, dynamic crystallization-driven cyclocondensation followed by dehydrogenation of the primary indoline aminals.

A practical synthesis of benzisoxazole 1 and its conversion to α-aryloxyisobutyric acid 2 using 1,1,1-trichloro-2-methyl-2-propanol (chloretone) was developed. Benzisoxazole 1 was formed in high yields by the action of either methanesulfonyl chloride/base upon intermediate oxime 8 or with thionyl chloride/base, which initially forms cyclic sulfite 10. A highly reactive, short-lived intermediate derived from chloretone was detected by ReacIR and its half-life determined to be ∼5 min. Reaction conditions for the Bargellini reaction were developed that resulted in a 95% yield of 2 from the reaction of highly hindered phenol 1 with chloretone hemihydrate and powdered NaOH in acetone. Thus highly hindered α-aryloxyisobutyric acids can be made in a single step in high yield.

A practical asymmetric synthesis of N-tert-butyl disubstituted pyrrolidines via a nitrile anion cyclization strategy is described. The five-step chromatography-free synthesis of (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid (2) from 2-chloro-1-(2,4-difluorophenyl)-ethanone achieved a 71% overall yield. The cyclization substrate was prepared via a catalytic CBS asymmetric reduction, t-butylamine displacement of the chlorohydrin, and a conjugate addition of the hindered secondary amine to acrylonitrile. The key nitrile anion 5-exo-tet cyclization concomitantly formed the pyrrolidine ring with clean inversion of the C-4 center to afford 1,3,4-trisubstituted chiral pyrrolidine in >95% yield and 94−99% ee. Diethyl chlorophosphate and lithium hexamethyldisilazide were shown to be the respective optimum activating group and base in this cyclization. The trans-cis mixture of the pyrrolidine nitrile undergoes a kinetically controlled epimerization/ saponification to afford the pure trans...

Two efficient routes to 1-tert-butyl-4-chloropiperidine are described. In the first route, the key thionyl chloride mediated chlorination reaction features the use of tetrabutylammonium chloride as an additive that effectively suppresses the formation of an elimination-derived side product. In the second route, a novel alternative synthesis of 1-tert-butyl-4-chloropiperidine was developed in which the tertiary butyl group on the nitrogen is efficiently generated through the addition of methylmagnesium chloride to a dimethyliminium salt in 71% overall yield.

An efficient, high yield process for the synthesis of a GnRH antagonist has been developed. We have demonstrated that under boron trifluoride mediation, nosyl aziridines will react with 2-arylindole derivatives to afford β-substituted tryptamines in an enantiospecific process with remarkably high regioselectivity. The scope of the reaction was explored with several 2-substituted nosyl aziridines. The key reaction was developed expressly for the GnRH antagonist program and has been demonstrated on 40 kilogram scale.

An improved preparative four-step synthesis to isoquinuclidine tosylate salt 4 has been demonstrated in 70% overall yield from p-aminobenzoic acid (PABA) 1. Hydrogenation of PABA 1 affords 4-aminocyclohexane carboxylic acid 2 as an 80 : 20 mixture of cis- and trans-isomers. Heating the mixture at 250°C effected epimerization and cyclization to provide the bicyclic lactam 3. Subsequent Red-Al reduction and treatment with tosic acid furnished the desired bicyclic amine, tosylate salt 4.

An asymmetric synthesis of dual orexin receptor antagonist MK-6096 (1) is described. Key steps for the trans-2,5-disubstituted piperidinyl ether fragment include a biocatalytic transamination, a trans-selective Mukaiyama aldol, and a regioselective pyridyl SNAr process. The pyrimidyl benzoic acid was synthesized via a Negishi coupling and a nitrile hydrolysis. Coupling of the two fragments via a catalytic T3P-mediated amidation completed the synthesis. Unusual behaviors in the hydrolysis of pyrimidyl benzonitrile and the amide coupling of the pyrimidyl benzoic acid are also described.

A microbial screen identified the yeast Candida sorbophila MY 1833 as a suitable biocatalyst for the asymmetric bioreduction of a ketone (2-(4-nitro-phenyl)-N-(2-oxo-2-pyridin-3-yl-ethyl)-acetamide) to its corresponding (R) alcohol [(R)-N-(2-hydroxy-2-pyridin-3-yl-ethyl)-2-(4-nitro-phenyl)-acetamide]. Studies yielded the formulation of a chemically defined cultivation medium that supported excellent growth and bioconversion activity. Process development showed that the optimization of the bioreduction environmental conditions (pH, temperature), the timing of ketone addition, and the implementation of a nutrient feeding strategy were key factors in achieving increased bioreduction rates. The optimized process achieved a 10-fold bioreduction rate improvement over the original process, while reaching final product concentrations of up to 60 g/l. When scaled up in Pilot Plant bioreactors (280 l), the bioreduction process supported the production of several kilograms of highly optically pure (R) alcohol (enantiomeric excess > 98%).

A chemoenzymatic synthesis of β 3 agonist 1 suitable for large scale preparation is described. The key chiral 3-pyridylethanolamine intermediate ( R )- 7 was prepared via an improved Neber rearrangement and a yeast-mediated asymmetric reduction. The tetrazolone fragment of the molecule was constructed via a dipolar cycloaddition between 1-(cyclopentyl)-3-propylazide and p -chlorosulfonyl phenylisocyanate. Sulfonamide coupling of these two intermediates under Shotten-Baumann conditions, followed by a borane reduction of the amide afforded 1 in 20–32% overall yield from 3-acetylpyridine.

Crystalline 1beta-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).

A highly practical chromatography-free six-step synthesis of L-734,217 suitable for large scale preparation is described. The key chiral pyridine acid intermediate (R)-1 was prepared in four steps based on a novel chemoselective silyl-mediated conjugate addition of ethyl (2-oxopiperidin-1-yl)acetate to 4-vinylpyridine and a highly productive, recyclable, kinetic resolution with quinine. Subsequent salt breaking/peptide coupling with benzyl 3-(R)-aminobutyrate (2) in a biphasic system, followed by concomitant hydrogenation of the pyridine ring and debenzylation afforded L-734,217 in 20% overall yield (30% with one recyle) from 2-piperidone. The mechanism of this key conjugate addition to 4-vinylpyridine was studied by 13C NMR.

Efficient trapping of dimethylamine was the key to success in the transamination of 1,1-dimethyl-4-oxopiperidinium iodide with tert-butylamine to afford 1-tert-butylpiperidin-4-one in high yield. The use of sodium acrylate was found to provide an elegant way to both trap dimethylamine and provide a convenient method to allow purification in the subsequent extraction.

The enantioselectivity in the asymmetric hydrogenation of 3-alkylidene-2-piperidones catalyzed by BINAP-Ru(II) complex was found to be significantly effected by the internal substituents on the lactam nitrogen, affording the corresponding 3-alkyl-2-piperidones in 52–92% ee.

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.

A practical 4-step synthesis of fibrinogen receptor antagonist MK-383, N-(n-butanesulfonyl)-O-(4-(4-piperidinyl)-butyl)-(S)-tyrosine, is accomplished in 48% overall yield from (S)-tyrosine. Highlights include: (1) the dual use of 4-picoline as a masked form of piperidine, and as a nucleophile precursor for a 3-carbon homologation with 3-bromo-1-chloropropane; (2) the use of trimethylsilyl groups for temporary protection of phenolic and carboxylate oxygens of (S)-tyrosine that enable selective N-sulfonylation to be carried out in high yield; (3) the selective phenolic O-alkylation of the tyrosine derivative in high yield with no racemization using aqueous KOH/DMSO; and (4) the selective hydrogenation of the pyridine ring in the presence of the tyrosine ring using Pd/C in acetic acid.

Application of the Corey-Fuchs reaction on Boc-prolinal, Boc-4-hydroxyprolinal, Bocpiperidinal and Boc-serinal derivatives to give chiral 2-pyrrolidinyl-, 2-piperidinyl- and 4-oxazolidinyl-acetylene derivatives provided rapid access to a number of differentially constrained oxotremorine analogues as muscarinic agents.

The enantioselectivity in the asymmetric hydrogenation of 3-alkylidene-2-piperidones catalyzed by BINAP-Ru(II) complex was found to be significantly effected by the internal substituents on the lactam nitrogen, affording the corresponding 3-alkyl-2-piperidones in 52–92% ee.

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).

Sequential reactions of nitromethane via conjugate addition−elimination to β-trifloxy acrylates followed by Pd-catalyzed substitution of the resulting allyl nitro compounds with nucleophiles afforded homologation products at the β-position. 2-Naphthosultammethyl carbapenem, an anti-MRS carbapenem intermediate, was prepared in one pot from the corresponding 2-trifloxy compound. The scope and limitation of the one-pot method were investigated using several cyclic unsaturated esters and nucleophiles.

[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.

An improved preparative four-step synthesis to isoquinuclidine tosylate salt 4 has been demonstrated in 70% overall yield from p-aminobenzoic acid (PABA) 1. Hydrogenation of PABA 1 affords 4-aminocyclohexane carboxylic acid 2 as an 80 : 20 mixture of cis- and trans-isomers. Heating the mixture at 250°C effected epimerization and cyclization to provide the bicyclic lactam 3. Subsequent Red-Al reduction and treatment with tosic acid furnished the desired bicyclic amine, tosylate salt 4.

A mild, high-yielding procedure for the preparation of β-ketophosphonates is described. The condensation is general with respect to the ester and phosphonate, and the products are obtained in high yields within minutes at 0 °C. The reaction procedure is operationally simple and amenable to large-scale preparations.

The intramolecular Friedel-Crafts acylation of 2-(3-indolythio)propionic acid 1 has been found to undergo an unprecedented rearrangement to provide a novel tricyclic indole having the sulfur substituted on C-4 rather than on the expected C-3. A mechanism for its formation is proposed. This rearrangement also proceeded with good optical retention when a chiral substrate was used.

The thermal lactamization of 4-(carboethoxy)-methyl-tryptophan ethyl ester (5), prepared from 4-(carboethoxy)methyl-indole 3 via Gilchrist′s method, in refluxing xylene followed by saponification provided the 8-membered cyclic tryptophan derivative 1. Selective reduction of lactam 6 via the iminium ion 9 furnished the cyclic tryptophan derivative 2

A mild, high-yielding procedure for the preparation of beta-ketophosphonates is described. The condensation is general with respect to the ester and phosphonate, and the products are obtained in high yields within minutes at 0 degrees C. The reaction procedure is operationally simple and amenable to large-scale preparations.

With the goal of improving the synthetic efficiency, the development of a convergent synthesis of a minocycline derivative PTK0796 via an intermolecular acyliminium Friedel–Crafts reaction (Tscherniac–Einhorn reaction) is described. The entire C9 neopentylaminomethyl side chain was installed in one step using an electronically optimized chloromethylacyliminium precursor in 83% yield. Deprotection and re-equilibration to the C4 α-epimer in the presence of CaCl 2 and ethanolamine or NaOH afforded the target aminomethylcycline antibiotic. The corresponding crystalline tosylate salt was found to exhibit improved solid state stability.

Sequential reactions of nitromethane via conjugate addition−elimination to β-trifloxy acrylates followed by Pd-catalyzed substitution of the resulting allyl nitro compounds with nucleophiles afforded homologation products at the β-position. 2-Naphthosultammethyl carbapenem, an anti-MRS carbapenem intermediate, was prepared in one pot from the corresponding 2-trifloxy compound. The scope and limitation of the one-pot method were investigated using several cyclic unsaturated esters and nucleophiles.

The reactions of chiral benzyl carbocations bearing α-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bach’s α-alkyl-bearing benzyl cations. The reactions are promoted by either a Bronsted acid (TFA) or Lewis acid (BF3·OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.

The reactions of chiral benzyl carbocations bearing alpha-phenyl substituents with N-sulfonylated indoles afford 1,1,2-triarylalkanes with anti-selectivities. This outcome is a reversal of facial diastereoselectivity relative to Bach's alpha-alkyl-bearing benzyl cations. The reactions are promoted by either a Brønsted acid (TFA) or Lewis acid (BF3.OEt2), offering differential diastereoselectivities and reactivities. The electronic properties of both reacting partners strongly influence the reaction rates and the product diastereoselectivities and appear to operate under kinetic control. This chemistry provides an efficient access to sterically congested tetrasubstituted ethanes.

Application of the Corey-Fuchs reaction on Boc-prolinal, Boc-4-hydroxyprolinal, Bocpiperidinal and Boc-serinal derivatives to give chiral 2-pyrrolidinyl-, 2-piperidinyl- and 4-oxazolidinyl-acetylene derivatives provided rapid access to a number of differentially constrained oxotremorine analogues as muscarinic agents.

La modification apportee dans la synthese de prolines substituees en 3 consiste en l'utilisation de triethyl silane et d'acide trifluoro acetique pour la reduction des pyrrolidine dicarboxylates-2,2 initiaux, et en la protection du N des prolines par le t-butoxycarbonyl; les racemiques obtenus sont ensuite dedoubles

Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity via chelation in directing the Grignard addition to the alpha position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated.

The Heck coupling of acrylanilides with 4-bromo-2-chloro-3-iodo-pyridine using palladium acetate can produce bis-Heck products or undergo an unusual tandem Heck-lactamization ring formation to generate 5-chloro-1-aryl-1,6-naphthyridin-2(1H)-ones.