- Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir
-
Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.
- Roy, Sarabindu,Yadaw, Ajay,Roy, Subho,Sirasani, Gopal,Gangu, Aravind,Brown, Jack D.,Armstrong, Joseph D.,Stringham, Rodger W.,Gupton, B. Frank,Senanayake, Chris H.,Snead, David R.
-
-
- Klein's Remdesivir-nucleobase synthesis revisited: Chemoselective cyanation of pyrrol-2-carboxaldehyde
-
4-Aminopyrrolo[2,1-f][1,2,4]triazine is a fundamental raw material in the synthesis of remdesivir, which demand has increased due to the tests and potential repositioning of this drug against Coronavirus disease 2019 (COVID-19). Here, three chemical steps route for the preparation of remdesivir's nucleobase is described. Particularly, a highly chemoselective cyanation of Klein's route and successful application of monochloramine prepared from commercial bleach as an N-amination reagent are presented.
- Amarante, Giovanni W.,Pereira, Vinicius R. D.,da Silva, Adilson D.,dos Santos, Juliana A.
-
p. 1391 - 1395
(2021/06/14)
-
- Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron-Complexing Agents prepared through the Castagnoli–Cushman Reaction of Unprotected Oximes
-
The first application of multicomponent chemistry (the Castagnoli–Cushman reaction) toward the convenient one-step preparation of cyclic hydroxamic acids is described. Cyclic hydroxamic acids are close analogues of bacterial siderophores (iron-binding com
- Bakulina, Olga,Bannykh, Anton,Dar'in, Dmitry,Krasavin, Mikhail
-
p. 17667 - 17673
(2017/12/26)
-
- 4-Pyridylnitrene and 2-pyrazinylcarbene
-
Both flash vacuum thermolysis (FVT) and matrix photolysis generate 2-diazomethylpyrazine (22) from 1,2,3-triazolo[1,5- a]pyrazine (24). FVT of 4-azidopyridine (18) as well as of 24 or 2-(5-tetrazolyl)pyrazine (23) affords the products expected from the nitrene, i.e., 4,4'-azopyridine and 2- and 3-cyanopyrroles. Matrix photolyses of both 18 and 24 result in ring expansion of 4-pyridylnitrene/2-pyrazinylcarbene to 1,5-diazacyclohepta-1,2,4,6-tetraene (20). Further photolysis causes ring opening to the ketenimine 27.
- Wentrup, Curt,Reisinger, Ales,Kvaskoff, David
-
p. 754 - 760
(2013/06/27)
-
- 2-pyridylnitrene and 3-pyridazylcarbene and their relationship via ring-expansion, ring-opening, ring-contraction, and fragmentation
-
(Figure Presented) Photolysis of triazolo[1,5-b]pyridazine 8 isolated in Ar matrix generates diazomethylpyridazines 9Z and 9E and diazopentenynes 11Z and 11E as detected by IR spectroscopy. ESR spectroscopy detected the 3-pydidazylcarbene 10 as well as pent-2-en-3-yn-l-ylidene 12 formed by loss of one and two molecules of N2, respectively. Further photolysis caused rearrangement of the carbenes to 1,2-pentadien-4-yne 13 and 3- ethynylcyclopropene 14. Flash vacuum thermolysis (FVT) of 8 at 400-500 °C with Ar matrix isolation of the products yielded 13, 14, and 1,4-pentadiyne 15. At higher temperatures, glutacononitriles 27Z and 27E were formed as well together with minor amounts of 2- and 3-cyanopyrroles 28 and 29. Tetrazolo[1,5-a]pyridine/2-azidopyridine 22T/22A yields 2-pyridylnitrene 19 as well as the novel open-chain cyanodienylnitrene 23 and the ring-expanded 1,3-diazacyclohepta-l,2,4,6-tetraene 21 on short wavelength photolysis. Nitrenes 19 and 23 were detected by ESR spectroscopy, and cumulene 21 by IR and UV spectroscopy. FVT of 22T/22A also affords 2-pyridylnitrene 19 and diazacycloheptatetraene 21, as well as glutacononitriles 27Z,E and 2- and 3-cyanopyrroles 28 and 29. Photolysis of 21 above 300 nm yields the novel spiroazirene 25, identified by its matrix 1R spectrum. The reaction pathways connecting the four carbenes (10Z,E and 12Z,E) and three nitrenes (19, 23EZ, and 23ZZ) in their open-shell singlet and triplet states are elucidated with the aid of theoretical calculations at DFT, CASSCF, and CASPT2 levels. Three possible mechanisms of ring-contraction in arylnitrenes are identified: (i) via ring-opening to dienylnitrenes, (ii) concerted ring-contraction, and (iii) via spiroazirenes 25, whereby (i) is the energetically most favorable.
- Kvaskoff, David,Bednarek, Pawel,Wentrup, Curt
-
scheme or table
p. 1600 - 1611
(2010/05/01)
-
- Synthesis of 1-vinylpyrrole-2-carbonitriles
-
A new highly synthetically potent series of bifunctional pyrroles, 1-vinylpyrrole-2-carbonitriles, were synthesized from readily available 1-vinylpyrrole-2-carbaldehyde oximes by two methods: (1) reaction with acetylene (KOH/DMSO, 70 °C, 10 min, yields 58
- Trofimov, Boris A.,Vasil'tsov, Alexander M.,Mikhaleva, Al'bina I.,Ivanov, Andrey V.,Skital'tseva, Elena V.,Schmidt, Elena Yu.,Senotrusova, Elena Yu.,Ushakov, Igor A.,Petrushenko, Konstantin B.
-
body text
p. 97 - 100
(2009/04/14)
-
- Pyrolysis of 1-substituted pyrazoles and chloroform at 550°C: Formation of α-carboline from 1-benzylpyrazoles
-
Pyrolysis of 13CH3 labelled 1-methylpyrazole 8 with chloroform at 550°C in a continuous flow reactor yields unlabelled 2-chloropyrimidine 9 and 2-cyanopyrrole 10 labelled at the cyano group. However, pyrolysis of 1-benzylpyrazole 14 with chloroform under similar conditions gives 9,2-phenylpyrimidine 13 and, as the major product, α-carboline 15. Pyrolysis of several substituted 1-(arylmethyl)pyrazoles and the use of 13C and 15N labelled compounds provides direct evidence by which the positions of 7 atoms of 1-benzylpyrazole can be located in the α-carboline. These data support the mechanisms suggested for the formation of 9, 10, and 15.
- Bhatti, Inayat A.,Busby, Reginald E.,Bin Mohamed, Murtedza,Parrick, John,Shaw, C. J. Granville
-
p. 3581 - 3585
(2007/10/03)
-
- Synthesis of pyrrolo[2,1-f][1,2,4]triazine congeners of nucleic acid purines via the N-amination of 2-substituted pyrroles
-
The synthesis of several new 4-mono- and 2,4-disubstituted pyrrolo[2,1-f][1,2,4]triazines is described. Key 1-aminopyrrole-2-carbonitrile intermediates 3 and 15 were obtained by N-amination of the corresponding pyrrole-2-carboxaldehyde followed by CHO → CN conversion with either hydroxylamine-O-sulfonic acid for 3 or O-mesitylenesulfonylhydroxylamine for 15. Cyclization of 3 or 15 with a variety of amidine reagents or, after conversion of 3 to its corresponding amide, base-catalyzed annulation completed the synthesis of the title products.
- Patil,Otter,Klein
-
p. 781 - 786
(2007/10/02)
-
- Reactions of Halogenomethanes in the Vapour Phase. Part 5. The Reactions of Imidazolines, Anils, and 1-Methylimidazole with Chloroform at 550 deg C, and a Comparison with their Liquid-Phase Reactions with Trichloroacetate Ion or Hexachloroacetone and Base
-
The vapor-phase reactions of imidazolines and anils with chloroform at 550 deg C are compared with their liquid-phase reactions in the presence of hexachloroacetone and base or upon thermolysis with trichloroacetate ion.In the vapour-phase reactions imidazolines, unlike imidazoles, gave non-chlorinated pyrimidines, and 1-methyl-imidazole gave 2-cyanopyrrole and the four 3-chlorocyanopyridines.
- Busby, Reginald E.,Khan, Mohammad A.,Khan, Mohammad R.,Parrick, John,Shaw, C. J. Granville
-
p. 1431 - 1435
(2007/10/02)
-
