ABSTRACT
An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin (5) from acid 1 is described. The key tactical stage involves I/Mg exchange of aryl iodide 2 followed by addition to glucono lactone 3 in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces ß-anomeric methyl glycopyranoside 4 which is, without isolation, directly reduced with Et3SiH mediated by AlCl3 as a Lewis acid in CH2Cl2/MeCN to afford 5 in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch.
Subject(s)
Aluminum Compounds/chemistry , Benzhydryl Compounds/chemical synthesis , Benzhydryl Compounds/pharmacology , Chlorides/chemistry , Glucosides/chemical synthesis , Glucosides/pharmacology , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Silanes/chemistry , Sodium-Glucose Transporter 2 Inhibitors , Aluminum Chloride , Benzhydryl Compounds/chemistry , Glucosides/chemistry , Hypoglycemic Agents/chemistry , Molecular Structure , Oxidation-ReductionABSTRACT
A scalable de novo synthesis of difluoromethyl pyridines from inexpensive materials is reported. The pyridyl subunit is built around the difluoromethyl group rather than a late stage introduction of this moiety. This user-friendly approach allows access to a diverse range of substitution patterns on all positions on the ring system and on the difluoromethyl group.
Subject(s)
Hydrocarbons, Fluorinated/chemical synthesis , Pyridines/chemical synthesis , Combinatorial Chemistry Techniques , Hydrocarbons, Fluorinated/chemistry , Hydrocarbons, Fluorinated/economics , Molecular Structure , Pyridines/chemistry , Pyridines/economics , StereoisomerismABSTRACT
The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H3PO4 (1·H3PO4) is presented. A key trifluoromethyl ketone intermediate 22 containing an N-(4-methoxyphenyl)ethyl amide was prepared by an enolization/bromine-magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone 22 gave the desired diastereomer in 32% yield and with dr = 98:2 from a 1:1 diastereomeric mixture after crystallization. Subsequently, an asymmetric propargylation was developed which provided the desired diastereomer in 4:1 diastereoselectivity and 75% yield with dr = 99:1 after crystallization. The azaindole moiety was efficiently installed by a one-pot cross coupling/indolization reaction. An efficient deprotection of the 4-methoxyphenethyl group was developed using H3PO4/anisole to produce the anisole solvate of the API in high yield and purity. The final form, a phosphoric acid cocrystal, was produced in high yield and purity and with consistent control of particle size.
