1358581-37-9Relevant articles and documents
Telescoped lithiation, C-arylation and methoxylation in flow-batch hybrid toward the synthesis of canagliflozin
Hone, Christopher A.,Oliver Kappe, C.,Polterauer, Dominik,Williams, Jason D.
supporting information, (2021/09/22)
We report a highly efficient three-step flow-batch hybrid procedure for the synthesis of a key canagliflozin intermediate. The telescoped process provides exquisite control over an exothermic and mixing sensitive lithiation and subsequent C-arylation within a microstructured flow reactor. Methoxylation reagents are then added in flow, before reaching completion in a batch vessel. The flow process afforded the target intermediate in 76% yield, with a throughput of 26.8 g/h.
Method for preparing intermediates of gliflozin hypoglycemic drugs
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Paragraph 0043; 0046-0047; 0050, (2020/05/02)
The invention belongs to the technical field of medicine synthesis, and relates to a novel method for preparing key intermediates of gliflozin hypoglycemic drugs, in particular to a preparation methodof key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin. The method comprises the following steps: 1) in the presence of a cosolvent, carrying out halogen metal exchange on a raw material, namely aryl bromide 2 and an organic lithium reagent to obtain an aryl lithium reagent 3, and carrying out a nucleophilic addition reaction on the aryl lithium reagent 3 and TMS-protected glucolactone 4 to obtain a transition product 5; and 2) removing a TMS protecting group from the transition product 5, and converting hemiketal into ketal to obtain the key intermediate 1with a single configuration. According to the method, the key intermediates (C-1, D-1 and E-1) of canagliflozin, dapagliflozin and empagliflozin can be stereoselectively synthesized, reaction yield isrelatively high (more than 75%), and product purity is high (wherein HPLC purity is about 95%); so reduction preparation of a final product in the next step is facilitated.
Preparation method of canagliflozin
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, (2019/02/27)
The invention relates to a synthesis method of canagliflozin. According to the synthesis method, 4-fluorophenylboronic acid is taken as an initial raw material to be coupled with 5-bromo-thiophene-2-formaldehyde to synthesize 5-(4-fluorophenyl)thiophene-2-formaldehyde, the 5-(4-fluorophenyl)thiophene-2-formaldehyde undergoes reduction and chlorination and then undergoes Friedel-Crafts alkylation reaction with 4-bromotoluene to synthesize 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene, and the 2-(2-methyl-5-bromobenzyl)-5-(4-fluorophenyl)thiophene undergoes condensation, etherificationand methoxyl removal with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone to obtain the hypoglycemic drug canagliflozin. The preparation method has the following advantages: compared with the conventional preparation methods, the synthesis process takes the 4-fluorobenzeneboronic acid as an initial raw material, so that the raw material is cheap and easy to get, the process is easy to realize industrialization, the synthesis route is short and the operation is easy; in the synthesis process, bromine is not used or butyl lithium does not need to be used twice, so that the risk of the process can be reduced; in addition, the preparation method is capable of improving the yield of canagliflozin products to 70% or more.