The Development of a New Manufacturing Route to the Novel Anticonvulsant, SB-406725A

We report herein an improved synthesis of 6-nitrovanillin, an important building block used in pharmaceuticals and agrochemicals. The key step in this sequence is the nitration of O-Bn vanillin, which was carried out using fuming HNO 3 . Sulfolane emerged as the solvent of choice for this transformation due to its high stability toward strongly acidic and oxidizing conditions. The specific hazards of this reaction were studied, and the nitration was efficiently and safely conducted leveraging flow conditions.

Section: Resultssupporting

confidence: 71%

Nitration Using Fuming HNO₃ in Sulfolane: Synthesis of 6-Nitrovanillin in Flow Mode

Lakshminarasimhan

Guturi

Kanagavel

et al. 2018

“…The nitration of 5,8-dichloroisoquinoline (45) is very difficult under standard conditions; either there is no conversion, or the reaction delivers a very low yield of the wanted product, in some cases with extremely long reaction times. 22 Walker et al found that nitronium salts as a neutral source of the nitronium ion gave an improved conversion of the 5,8-dichloroisoquinoline. The authors found sulfolane to be the solvent of choice; although dichloromethane could be used as a cosolvent, other solvents were either incompatible or led to no reaction.…”

Section: ■ Introductionmentioning

confidence: 99%

Sulfolane: A Versatile Dipolar Aprotic Solvent

Tilstam¹

2012

155

124

Sulfolane is a highly stable and attractive alternative to other more common dipolar aprotic solvents such as DMSO, DMF, DMAC, and NMP. Sulfolane is more toxic than the other solvents but has a very low skin penetration in comparison to that of the others. A high skin penetration is not beneficial for organic solvents as dissolved toxic compounds might be transferred through the skin. Sulfolane has a high dipole moment (μ = 4.7 debye), elevated relative permittivity (ευ = 43.4), and a high Hildebrand solubility parameter (δ = 27.2 [MPa]1/2). This means a high solvency power for reactions containing polarizable intermediates. Sulfolane is capable of strong solvation of cations by the oxygens in the sulfone group which increases the nucleophilicity of the corresponding less solvated anions. With its high stability against strong acids and bases as well as its thermal stability sulfolane is a solvent that can be operated within a wide range of reaction conditions. This makes it the solvent of choice for different acid-catalyzed reactions at elevated temperatures. Sulfolane has also found use in halo exchange reactions for the formation of various fluoroaromatic compounds. It has also been used as solvent for oxidations, nitrations, rearrangements, phosphonylations, and condensation reactions.

“…The treatment of carbon-14-labeled standard 18 with BBr 3 provided intermediate acid 19 (Scheme ). Without further purification, 19 was treated with NO 2 BF 4 /sulfolane in CH 3 CN to afford the desired radiotracer 20 in 59% yield . Pleasingly, ecotoxicology studies conducted using standards 9 and 20 showed low toxicity to nontarget species.…”

Section: Results and Discussionmentioning

confidence: 99%

Identification and Synthesis of a Nitrophenyl Metabolite of Rinskor Active from Terrestrial Aerobic Soil Studies

Canturk

Johnson

Taylor

et al. 2019

To support the registration of crop protection products, over 100 regulatory studies are conducted for an active ingredient. These studies allow regulatory agencies and the agroscience industry to ensure that new crop protection products meet the requirements for users, consumers, and the environment prior to their use in agriculture. Rinskor active is a Corteva Agriscience auxinic herbicide, which was launched in 2018 for the control of broadleaf weeds, grass weeds, and sedges in rice fields. To support the registration of Rinskor, four terrestrial aerobic soil studies were conducted to determine the soil degradation profile and rate of the active ingredient. These studies were conducted using carbon-14-labeled active ingredient test systems. From these studies, three major metabolites were generated, and the structures of these metabolites had to be identified via the preparation of an authentic standard of each metabolite. This Article discusses the identification and synthesis of one of the major metabolites, a nitrophenyl metabolite, formed from terrestrial aerobic soil studies.