Process Chemistry Related to the Experimental Rice Herbicide 2,2-Dimethyl-1-(4-methylthio-5-pyrimidinyl)indane

Abstract

Two concise syntheses of the experimental rice herbicide 2,2dimethyl-1-(4-methylthio-5-pyrimidinyl)indane are reported. The initial synthesis relies on a low-temperature addition of 5-lithio-4-methylthiopyrimidine to 2,2-dimethyl-1-indanone to construct the pyrimidinylindane system. Process improvements to this route are described and resulted in the preparation of 90 kg of the title compound on pilot plant scale. Economics dictated the need to identify a new synthetic route which utilized inexpensive raw materials. Detailed herein is the initial discovery of a new route which features a novel combination of dissolving metal reduction/formylation/cyclization to construct the requisite pyrimidine ring. Process improvements to this chemistry have allowed us to deliver an appropriately substituted pyrimidinylindane in a minimal number of synthetic operations.

Pyridines and Pyrimidines Mediating Activity against an Efflux-Negative Strain of Candida albicans through Putative Inhibition of Lanosterol Demethylase

“…To each well, 50 l of reaction buffer (0. 4 (7), and plates were incubated at 30°C (model 5025 incubator; VWR Scientific). Color development was monitored hourly by mixing well contents, followed by measurement of the A 570 .…”

Computer-generated “synthetic contingency” plans at times of logistics and supply problems: scenarios for hydroxychloroquine and remdesivir

“…Regarding n -butyllithium – used in pathways 10 and 13 – the use of this reagent requires safety precautions, but there are examples of its usage in the pharmaceutical industry. 28 For instance, n -BuLi has been used in kilogram-scale syntheses of 2,2-dimethyl-1-(4-methylthio-5-pyrimidinyl)indane 29 and 1-[4-(2-chloroethoxy)phenyl]-1-(4-iodophenyl)-2-phenyl-1-butanol 30 as well as in the synthesis of AZD6906 performed in a flow-reactor. 31 In Chematica's synthetic plans, both reactions employing n -butyllithium are alkylations of esters and the reagent is used to generate LDA in situ ; this approach is also used in industry owing to its cost efficiency.…”

“… 31 In Chematica's synthetic plans, both reactions employing n -butyllithium are alkylations of esters and the reagent is used to generate LDA in situ ; this approach is also used in industry owing to its cost efficiency. 29 …”

“…31 In Chematica's synthetic plans, both reactions employing n-butyllithium are alkylations of esters and the reagent is used to generate LDA in situ; this approach is also used in industry owing to its cost efficiency. 29 Regarding LAHused in pathways 2, 9 and 16and according to the review by Magano and Dunetz on large-scale reductions, 32 it is the most common reagent for the reduction of acyclic esters. This assertion is supported by numerous kilogram-scale syntheses using this reducing agent (e.g., Glaxo's synthesis of Sodelglitazar, 33 Eli Lilly's route to DPP IV Inhibitor LY2497282, 34 or Sanochemia's nine-step synthesis leading to (À)-galanthamine 35 ).…”