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1.
Org Process Res Dev ; 25(12): 2806-2815, 2021 Dec 17.
Article in English | MEDLINE | ID: mdl-35095257

ABSTRACT

Herein is described the development of a large-scale manufacturing process for molnupiravir, an orally dosed antiviral that was recently demonstrated to be efficacious for the treatment of patients with COVID-19. The yield, robustness, and efficiency of each of the five steps were improved, ultimately culminating in a 1.6-fold improvement in overall yield and a dramatic increase in the overall throughput compared to the baseline process.

2.
Acc Chem Res ; 52(7): 1990-2002, 2019 07 16.
Article in English | MEDLINE | ID: mdl-31198042

ABSTRACT

Manufacturing process development of new drug substances in the pharmaceutical industry combines numerous chemical challenges beyond the efficient synthesis of complex molecules. Optimization of a synthetic route involves the screening of multiple reaction variables with a desired outcome that not only depends on an increased product yield but is also highly influenced by the removal efficacy of residual chemicals and reaction byproducts during the subsequent synthetic route. Consequently, organic chemists must survey a wide array of synthetic variables to develop a highly productive, green, and cost-effective manufacturing process. The time constraints of developing robust quantitative methods prior to each processing step can easily lead to sample analysis becoming a bottleneck in synthetic route development. In this regard, conventional "on demand" analytical method development and optimization approaches, traditionally used for guiding synthetic chemistry efforts, become unsustainable. This Account introduces recent efforts to address the aforementioned challenges through the development and implementation of generic or more universal chromatographic methods that can cover a broad spectrum of targeted compound classes. Such generic methods require significant resolving power to enable baseline resolution of multicomponent mixtures in a single experimental run without additional method customization but must be simple enough to allow for routine use by chemists, chemical engineers and other researchers with little experience in chromatographic method development. These powerful analytical methodologies are often employed to minimize the time spent developing new analytical assays, while also facilitating method transfer to manufacturing facilities and application in regulatory settings. Diverse examples of universal and fit-for-purpose analytical procedures are presented herein, illustrating the power of modern readily available analytical technology for streamlining the development of new drug substances in organic chemistry laboratories across both academic and industrial sectors. With recent advances in analytical instrumentation and column technologies, universal chromatographic methods are quickly becoming a proactive and effective strategy to accelerate the discovery and implementation of new synthetic methodologies, especially but not limited to laboratories where the synthetic process route is undergoing rapid change and optimization. Targets of these generic methods include analysis of organic solvents, acid and basic additives, nucleotide species, palladium scavengers, impurity mapping, enantiopurity, synthetic intermediates, active pharmaceutical ingredients and their counterions, dehalogenation byproducts, and mixtures of organohalogenated pharmaceuticals, among other chemicals used or formed in process chemistry reactions.


Subject(s)
Chromatography, High Pressure Liquid/methods , Pharmaceutical Research/methods , Antineoplastic Agents/analysis , Drug Contamination/prevention & control , Research
3.
Org Lett ; 21(11): 4210-4214, 2019 06 07.
Article in English | MEDLINE | ID: mdl-31117712

ABSTRACT

Synthetic diazeniumdiolate (DAZD)-based nitric oxide is utilized to modulate the nitric oxide (NO) concentration in cellular environments and to control physiological processes, yet chemists are still struggling to find efficient and scalable methodologies that will enable them to access sufficient quantities of the high-energy diazeniumdiolate intermediates for biological studies. Now, a general, scalable, safer, and high-yielding new methodology adaptable to the large-scale synthesis of DAZDs has been developed.

4.
Chem Sci ; 9(34): 6922-6927, 2018 Sep 14.
Article in English | MEDLINE | ID: mdl-30210766

ABSTRACT

Quantitative structure-activity relationships have an extensive history for optimizing drug candidates, yet they have only recently been applied in reaction development. In this report, the predictive power of multivariate parameterization has been explored toward the optimization of a catalyst promoting an aza-Michael conjugate addition for the asymmetric synthesis of letermovir. A hybrid approach combining 2D QSAR and modern 3D physical organic parameters performed better than either approach in isolation. Using these predictive models, a series of new catalysts were identified, which catalyzed the reaction to provide the desired product in improved enantioselectivity relative to the parent catalyst.

5.
Org Lett ; 19(21): 5880-5883, 2017 11 03.
Article in English | MEDLINE | ID: mdl-29052413

ABSTRACT

A practical and asymmetric synthesis of a functionalized trans-cyclopropoxy building block for the preparation of the HCV NS3/4a protease inhibitor grazoprevir is reported. Intramolecular SN2 displacement-ring closure, followed by a Baeyer-Villiger oxidation, yields the desired trans-cyclopropanol with full control of diastereoselectivity. A terminal alkyne is then effectively installed using LiNH(CH2)2NEt2. Starting from (S)-epichlorohydrin, the cyclopropoxy building block is prepared in 51% overall yield with >99.8% optical purity without isolation of any intermediates.

6.
J Am Chem Soc ; 139(31): 10637-10640, 2017 08 09.
Article in English | MEDLINE | ID: mdl-28737937

ABSTRACT

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,ß-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.


Subject(s)
Acetates/chemical synthesis , Antiviral Agents/chemical synthesis , Quantum Theory , Quinazolines/chemistry , Acetates/chemistry , Acetates/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Catalysis , Cyclization , Hydrogen Bonding , Molecular Structure , Quinazolines/chemical synthesis , Quinazolines/pharmacology
7.
J Org Chem ; 81(21): 10256-10265, 2016 11 04.
Article in English | MEDLINE | ID: mdl-27471910

ABSTRACT

The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.


Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , HIV Integrase/drug effects , Carbon-13 Magnetic Resonance Spectroscopy , Cyclization , HIV Integrase Inhibitors/chemistry , Naphthyridines/chemistry , Proton Magnetic Resonance Spectroscopy
8.
Org Lett ; 18(6): 1394-7, 2016 Mar 18.
Article in English | MEDLINE | ID: mdl-26950496

ABSTRACT

The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Drug Discovery , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Macrocyclic Compounds/chemistry , Molecular Structure , Spiro Compounds/chemistry , Structure-Activity Relationship
9.
Org Lett ; 17(6): 1353-6, 2015 Mar 20.
Article in English | MEDLINE | ID: mdl-25751537

ABSTRACT

The development of an efficient and robust process for the production of HIV NNRTI doravirine is described. The synthesis features a continuous aldol reaction as part of a de novo synthesis of the key pyridone fragment. Conditions for the continuous flow aldol reaction were derived using microbatch snapshots of the flow process.


Subject(s)
HIV Infections/drug therapy , HIV Reverse Transcriptase/antagonists & inhibitors , Pyridones/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Triazoles/chemical synthesis , Aldehydes/chemistry , Molecular Structure , Pyridones/chemistry , Pyridones/pharmacology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Triazoles/chemistry , Triazoles/pharmacology
11.
J Org Chem ; 76(19): 7804-15, 2011 Oct 07.
Article in English | MEDLINE | ID: mdl-21838271

ABSTRACT

Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.


Subject(s)
Chemistry Techniques, Synthetic/methods , Indoles/chemistry , Indoles/chemical synthesis , Lactams/chemistry , Macrocyclic Compounds/chemistry , Catalysis , Cyclization , Cyclopropanes , Hydrogenation , Isoindoles , Lactams, Macrocyclic , Leucine/analogs & derivatives , Palladium/chemistry , Proline/analogs & derivatives , Sulfonamides
12.
J Org Chem ; 75(22): 7829-41, 2010 Nov 19.
Article in English | MEDLINE | ID: mdl-20954694

ABSTRACT

A highly efficient, asymmetric synthesis of telcagepant (1), a CGRP receptor antagonist for the treatment of migraine, is described. This synthesis features the first application of iminium organocatalysis on an industrial scale. The key to the success of this organocatalytic transformation was the identification of a dual acid cocatalyst system, which allowed striking a balance of the reaction efficiency and product stability effectively. As such, via an iminium species, the necessnary C-6 stereogenicity was practically established in one operation in >95% ee. Furthermore, we enlisted an unprecedented Doebner-Knoevenagel coupling, which was also via an iminium species, to efficiently construct the C3-C4 bond with desired functionality. In order to prepare telcagepant (1) in high quality, a practical new protocol was discovered to suppress the formation of desfluoro impurities formed under hydrogenation conditions to <0.2%. An efficient lactamization facilitated by t-BuCOCl followed by a dynamic epimerization-crystallization resulted in the isolation of caprolactam acetamide with the desired C3 (R) and C6 (S) configuration cleanly. Isolating only three intermediates, the overall yield of this cost-effective synthesis was up to 27%. This environmentally responsible synthesis contains all of the elements required for a manufacturing process and prepares telcagepant (1) with the high quality required for pharmaceutical use.


Subject(s)
Azepines/chemical synthesis , Azepines/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Migraine Disorders/drug therapy , Azepines/chemistry , Catalysis , Imidazoles/chemistry , Molecular Structure
13.
J Org Chem ; 75(5): 1343-53, 2010 Mar 05.
Article in English | MEDLINE | ID: mdl-20128619

ABSTRACT

A practical asymmetric synthesis of a novel aminopiperidine-fused imidazopyridine dipeptidyl peptidase IV (DPP-4) inhibitor 1 has been developed. Application of a unique three-component cascade coupling with chiral nitro diester 7, which is easily accessed via a highly enantioselective Michael addition of dimethyl malonate to a nitrostyrene, allows for the assembly of the functionalized piperidinone skeleton in one pot. Through a base-catalyzed, dynamic crystallization-driven process, the cis-piperidionone 16a is epimerized to the desired trans isomer 16b, which is directly crystallized from the crude reaction stream in high yield and purity. Isomerization of the allylamide 16b in the presence of RhCl(3) is achieved without any epimerization of the acid/base labile stereogenic center adjacent to the nitro group on the piperidinone ring, while the undesired enamine intermediate is consumed to <0.5% by utilizing a trace amount of HCl generated from RhCl(3). The amino lactam 4, obtained through hydrogenation and hydrolysis, is isolated as its crystalline pTSA salt from the reaction solution directly, as such intramolecular transamidation has been dramatically suppressed via kinetic control. Finally, a Cu(I) catalyzed coupling-cyclization allows for the formation of the tricyclic structure of the potent DPP-4 inhibitor 1. The synthesis, which is suitable for large scale preparation, is accomplished in 23% overall yield.


Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Piperidones/chemical synthesis , Catalysis , Chromatography, Gel , Crystallography, X-Ray , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Heterocyclic Compounds, 3-Ring/chemistry , Isomerism , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure , Piperidones/chemistry
14.
J Am Chem Soc ; 128(51): 17063-73, 2006 Dec 27.
Article in English | MEDLINE | ID: mdl-17177459

ABSTRACT

Ruthenium complexes employing axially chiral ligands were found to be effective asymmetric hydrogenation catalysts for the reduction of alpha,beta-unsaturated ene acid 1-E to give 2, a prostaglandin D2 (PGD2) receptor antagonist. With [(S-BINAP)Ru(p-cymene)Cl2]2 (3, S-BINAP = (S)-(+)-2,2'-bis(diphenylphospino)-1,1'-binapthyl), it was discovered that low hydrogen pressures (<30 psi) were essential to achieve high enantioselectivities (92% ee). A detailed mechanistic study was undertaken to elucidate this pressure dependence. It was determined that compound 1-E is in a ruthenium-catalyzed equilibrium with endocylic isomer 1-Endo and in photochemical equilibrium with Z isomer 1-Z. Each isomer could be hydrogenated to give 2, albeit with different rates and enantioselectivities. Hydrogenation of 1-Endo with 3 was found to give 2 in high enantiomeric excess, regardless of pressure and at a rate substantially faster than that of hydrogenation of 1-E and 1-Z. In contrast, isomers 1-E and 1-Z exhibited pressure-dependent enantioselectivities, with higher enantiomeric excesses obtained at lower pressures. A rationale for this pressure dependence is described. Deuterium labeling studies with 1-Endo and tiglic acid were used to elucidate the mechanism of hydride insertion and product release from ruthenium. Under neutral conditions, protonolysis was the major pathway for metal-carbon cleavage, while under basic conditions, hydrogenolysis of the metal-carbon bond was predominant.


Subject(s)
Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , Alkenes/chemistry , Carboxylic Acids/chemistry , Deuterium/chemistry , Hydrogen/chemistry , Hydrogenation , Kinetics , Molecular Structure , Pressure , Stereoisomerism , Temperature
16.
J Org Chem ; 71(11): 4336-8, 2006 May 26.
Article in English | MEDLINE | ID: mdl-16709084

ABSTRACT

An efficient, practical, and high yielding synthesis of (R)-2-methylpyrrolidine is described. The sequence allows for the scalable preparation of the target compound in just four synthetic steps and proceeds in 83% overall yield and >99% optical purity from readily available starting materials.


Subject(s)
Pyrrolidines/chemical synthesis , Molecular Biology
17.
J Org Chem ; 71(5): 2192-5, 2006 Mar 03.
Article in English | MEDLINE | ID: mdl-16497018

ABSTRACT

A highly efficient strategy has been developed for the rapid asymmetric synthesis of gem-dimethyl and spirocyclopropyl norbornyl carboxylic acids. The key transformation involved the unprecedented asymmetric Diels-Alder reaction of highly reactive beta,beta-cyclopropyl-alpha,beta-unstaturated N-acyloxazolidinones with cyclopentadiene affording the adducts in high yield and de.


Subject(s)
Carboxylic Acids/chemical synthesis , Norbornanes/chemical synthesis , Spiro Compounds/chemical synthesis , Cyclopropanes/chemistry , Imides/chemistry , Stereoisomerism
18.
Org Lett ; 8(4): 565-8, 2006 Feb 16.
Article in English | MEDLINE | ID: mdl-16468712

ABSTRACT

[reaction: see text] The reaction of a variety of indoles with N-thioalkyl- and N-thioarylphthalimides to produce 3-thioindoles is reported. Catalytic quantities of halide-containing salts are crucial to the success of this reaction. This highly efficient reaction provides sulfenylated indoles from bench-stable, readily available starting materials in good to excellent yields.


Subject(s)
Combinatorial Chemistry Techniques , Hydrocarbons, Halogenated/chemistry , Indoles/chemistry , Indoles/chemical synthesis , Sulfenic Acids/chemistry , Catalysis , Indicators and Reagents , Molecular Structure , Sulfenic Acids/chemical synthesis
19.
Org Lett ; 8(3): 395-8, 2006 Feb 02.
Article in English | MEDLINE | ID: mdl-16435843

ABSTRACT

[reaction: see text]. A highly regioselective amination of 6-aryl-2,4-dichloropyrimidine with aliphatic secondary amines and aromatic amines has been developed which strongly favors the formation of the C4-substituted product. The reactions with aliphatic amines are carried out using LiHMDS as the base and are catalyzed by Pd, while the aromatic amines require no catalyst.

20.
Org Lett ; 6(18): 3147-50, 2004 Sep 02.
Article in English | MEDLINE | ID: mdl-15330609

ABSTRACT

[reaction: see text] A facile preparation of chiral alpha-aryloxy carboxylic acids via asymmetric hydrogenation of the corresponding unsaturated acids has been discovered. A number of catalysts have been identified that give high product enantioselectivity, and the scope of the reaction has been examined with respect to substitution on the aromatic ring and olefin.

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