Development of a Pilot-Plant Process for a Nevirapine Analogue HIV NNRT Inhibitor

Busacca, Carl A.; Cerreta, Mike; Dong, Yong Qiang; Eriksson, Magnus; Farina, Vittorio; Feng, XuWu; Kim, Jiyoung; Lorenz, Jon C.; Sarvestani, Max; Simpson, Robert E.; Varsolona, Rich; Vitous, Jana; Campbell, Scot; Davis, Mark S.; Jones, Paul‐James; Norwood, Daniel L.; Qiu, Fenghe; Beaulieu, Pierre L.; Duceppe, Jean‐Simon; Haché, Bruno; Brong, Jim; Chiu, Fang-Ting; Curtis, Tom; Kelley, Jason; Lo, Young S.; Powner, Tory H.

doi:10.1021/op8000756

Cited by 29 publications

(13 citation statements)

References 34 publications

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“…With the availability of 3-amino-2-chloropyridine, [2,6-14 C]-, we followed the route developed by Boehringer's chemists to prepare (1) on a large scale to introduce the C14 atoms in the tricyclic moiety. 16,17 Thus, 5-bromo-2-chloronicotinoyl chloride (5) was reacted with 3-amino-2-chloropyridine, [2,6,-14 C]-, in acetonitrile and a saturated solution of sodium bicarbonate to give the amide (6) in 41% yield. Treatment with a THF solution of ethylamine gave the amine (7) in 87% yield.…”

Section: Resultsmentioning

confidence: 99%

“…This reaction was followed by hydrolysis and decarboxylation to the carboxylic acid in one pot. 17 This one pot transformation of the bromide (8) to carboxylic acid (13), Scheme 3, was shown to proceed via ester hydrolysis first and then there is loss of carbon dioxide before the cyano group gets hydrolyzed to the acid. Therefore, when carbon-13 labeled at the cyano carbon of isopropyl cyanoacetate was used in this procedure, it gave the carboxylic acid with more than 95% of the carbon-13 retained in the product.…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, when carbon-13 labeled at the cyano carbon of isopropyl cyanoacetate was used in this procedure, it gave the carboxylic acid with more than 95% of the carbon-13 retained in the product. 17 The arylacetonitrile intermediate was isolated and characterized. Arylcyanoacetates have been reported to undergo hydrolysis to arylacetonitriles using diluted hydrochloric acid.…”

Section: Resultsmentioning

confidence: 99%

“…Reduction of acid (13) to alcohol (14) was accomplished using BH 3 /THF in 91% yield. 17 Mitsunobu's etherification with 4-hydroxyquinoline derivative gave (15) To prepare [ 13 C 6 ]-(1), Scheme 4, the commercially available [ 13 C 6 ]-aniline was condensed with diethyl ethoxymethylene malonate first at 1101C neat and then in phenyl ether at 2601C. Saponification, followed by decarboxylation, gave [ 13 C 6 ]4-hydroxyquinoline in 44% overall yield.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

Latli

Hrapchak

Busacca

et al. 2008

Labelled Comp Radiopharmac

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5,11-Dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2 0 ,3 0 -e][1,4]diazepin-6-one, (1), labeled with carbon-14 in the quinoline-benzene ring, in one of the pyridine rings of the dipyridodiazepinone tricyclic moiety, and in the side chain, was prepared in three different syntheses with specific activities ranging from 44 to 47 mCi/mmol (1.63-1.75 GBq/mmol). In the first synthesis, 5,11 ,4]diazepin-6-one (2) was coupled to 4-hydroxyquinoline, [benzene-14 C(U)]-, using Mitsunobu's reaction conditions, followed by the oxidation of the quinoline nitrogen with 3-chloroperoxybenzoic acid to give ([ 14 C]-(1a)) in 43% radiochemical yield. Second, 3-amino-2-chloropyridine, [2,6-14 C]-, was used to prepare 8-bromo-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2 0 ,3 0 -e][1,4]diazepin-6-one (8), and then Stille coupled to allyl(tributyl)tin followed by ozonolysis of the terminal double bond and in situ reduction of the resulting aldehyde to alcohol (10). Mitsunobu etherification and oxidation as seen before gave ([ 14 C]-(1b)) in eight steps and in 11% radiochemical yield. Finally, carbon-14 potassium cyanide was used to prepare isopropyl cyanoacetate (12), which was used to transform bromide (8) to labeled aryl acetic acid (13) under palladium catalysis. Trihydroborane reduction of the acid gave alcohol (14) labeled in the side chain, which was used as described above to prepare ([ 14 C]-(1c)) in 4.3% radiochemical yield. The radiochemical purities of these compounds were determined by radio-HPLC and radio-TLC to be more than 98%. To prepare [ 13 C 6 ]-(1), [ 13 C 6 ]-4-hydroxyquinoline was prepared from [ 13 C 6 ]-aniline and then coupled to (2) and oxidized as seen before.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

Latli

Hrapchak

Busacca

et al. 2008

Labelled Comp Radiopharmac

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“…1, was found to be a good non-nucleoside HIV-1 reverse transcriptase inhibitor. Hence this compound became attractive as a drug development candidate with potential to be dispensed as a solid [1,2].…”

Section: Introductionmentioning

confidence: 99%

Study and characterization of crystalline hydrate/polymorph forms of 5,11-dihydro-11-ethyl-5-methyl-8-(2-(1-oxido-4-quinolinyl)ethyl-6H-dipyrido(3,2-B:2′,3′-E)(1,4)diazepin-6-one by solid-state NMR and solution NMR

Gonnella

Smoliga

Campbell

et al. 2010

Journal of Pharmaceutical and Biomedical Analysis

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The Krapcho Dealkoxycarbonylation Reaction of Esters with α‐Electron‐Withdrawing Substituents

Krapcho

Ciganek

2013

Organic Reactions

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The Krapcho reaction involves esters with α‐electron‐withdrawing substituents such as malonates, β‐keto esters, and α‐cyano esters, which undergo dealkoxycarbonylation on being heated in polar aprotic solvents (such as DMSO, DMF, or HMPT) in the presence of water, or in polar aprotic solvents with water in the presence of added salts (such as NaCN, NaCl, LiCl, LiI, or MgCl 2 ). This procedure avoids the use of strongly aqueous acidic and alkaline conditions and tolerates many functional and protecting groups. The chapter presents the mechanistic aspects of this procedure, which include reaction parameters such as solvents, salts, other additives, and the use of microwave irradiation. The diastereoselectivity of protonation of the enolate intermediate leading to the dealkoxycarbonylated products is discussed. Trapping of the intermediate enolate by electrophiles other than a proton is illustrated. Potential side reactions and same‐pot subsequent reactions of substrates are discussed along with functional‐group compatibility for halogens and nitrogen, oxygen, sulfur, selenium, and carbon functional groups. Several examples of applications of this methodology for the synthesis of natural products along with experimental conditions and procedures are presented. Closely related methods are discussed in the Comparison with Other Methods section. The tables, which consist of 371 pages, are grouped according to substrate structure. Selective entries for other methods (excluding classical aqueous acidic or basic methods) are included in the tabular survey for comparative purposes.

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Development of a Pilot-Plant Process for a Nevirapine Analogue HIV NNRT Inhibitor

Cited by 29 publications

References 34 publications

Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

Study and characterization of crystalline hydrate/polymorph forms of 5,11-dihydro-11-ethyl-5-methyl-8-(2-(1-oxido-4-quinolinyl)ethyl-6H-dipyrido(3,2-B:2′,3′-E)(1,4)diazepin-6-one by solid-state NMR and solution NMR

The Krapcho Dealkoxycarbonylation Reaction of Esters with α‐Electron‐Withdrawing Substituents

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Development of a Pilot-Plant Process for a Nevirapine Analogue HIV NNRT Inhibitor

Cited by 29 publications

References 34 publications

Synthesis of [14C]‐ and [13C6]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

Synthesis of [14C]‐ and [13C6]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

Study and characterization of crystalline hydrate/polymorph forms of 5,11-dihydro-11-ethyl-5-methyl-8-(2-(1-oxido-4-quinolinyl)ethyl-6H-dipyrido(3,2-B:2′,3′-E)(1,4)diazepin-6-one by solid-state NMR and solution NMR

The Krapcho Dealkoxycarbonylation Reaction of Esters with α‐Electron‐Withdrawing Substituents

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Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor

Synthesis of [¹⁴C]‐ and [¹³C₆]‐labeled potent HIV non‐nucleoside reverse transcriptase inhibitor