Development of Scalable Processes for the Preparation of N-Methyl-3-Bromo-5-Methyl Pyrazole

Abstract

The development and optimization of two scalable routes to N-methyl-3-bromo-5-methyl pyrazole is described. The initial Sandmeyer route entailed a three-step sequence from crotonitrile and methyl hydrazine, proceeding through the 3amino pyrazole intermediate. Due to the GTI liability of the 3-amino pyrazole intermediate, a tedious steam-distillation, and <30% overall yield, we developed a second-generation Sandmeyer-free approach from methyl crotonate and methyl hydrazine which leveraged a condensation, bromination, and oxidation sequence. Process development led to the improved preparation of N-methyl-3-bromo-5-methyl pyrazole with increased efficiency and overall yield. The isolation, handling, and storage of the final product was greatly improved through the generation of the triflic acid salt, and salt form studies are also discussed.

Strategy To Prepare 3-Bromo- and 3-Chloropyrazoles

“…As previously disclosed (Scheme b), the oxidation of 8a using NaOCl/KBr and K 3 PO 4 under biphasic DCM/water conditions led to a 2.1:1 crude ratio of 9a:10a . Following workup and purification, 9a was isolated in 58% yield as a single compound.…”

“…In the few examples in which R 1 was alkyl, R 2 remained electron-withdrawing, and when R 2 was not electron-withdrawing, R 1 remained aromatic . Our report describing the preparation of >150 kg of 3 was the first example to sequentially halogenate/oxidize a pyrazolidin-3-one to prepare a 3-bromopyrazole with alkyl substitution at both R 1 and R 2 (Scheme b). , Interestingly, during our initial studies we observed competitive endo- versus exocyclic proton elimination during oxidation (i.e., H a versus H b in 5 , Scheme ), leading to 3 and des-methyl pyrazole 4 , respectively. This regioselectivity challenge supported why previous reports to prepare 3-halopyrazoles utilizing this methodology were focused on substrates that either lacked H b protons (e.g., R = aromatic) or contained electron-withdrawing groups at C(5) (e.g., R 2 ) to favor H a elimination.…”

Development of a Scalable Route for a Key Thiadiazole Building Block via Sequential Sandmeyer Bromination and Room-Temperature Suzuki–Miyaura Coupling

“…After establishing the stability of the fluorinated boronic acid at room temperature, we started with the development of the Sandmeyer bromination of 5 . After initial screenings with different bromide and nitrite sources, the dosing of tert -butyl nitrite to a mixture of CuBr 2 and the starting material in MeCN at room temperature was found to be optimal with regard to reaction conversion and impurity profile.…”

Development of a Scalable Process for the Insecticidal Candidate Tyclopyrazoflor. Part 1. Evaluation of [3 + 2] Cyclization Strategies to 3-(3-Chloro-1H-pyrazol-1-yl)pyridine

“…Condensation of a hydrazine with an acrylate to give a dihydropyrazole is well-documented in the literature. , Compound 2 was obtained in 49% yield over two steps by treatment of 3 with methyl 2-acetamidoacrylate ( 30 ) in the presence of 4.0 equiv of NaOEt followed by treatment of 31 with 7.0 equiv of POCl 3 (Scheme ). Although oxidation of the dihydropyrazole was avoided, this route was not pursued further because of the relatively high cost of 30 .…”