Efficient Synthesis of Empagliflozin, an Inhibitor of SGLT-2, Utilizing an AlCl₃‑Promoted Silane Reduction of a β‑Glycopyranoside

An efficient production synthesis of the SGLT-2 inhibitor Empagliflozin (<b>5</b>) from acid <b>1</b> is described. The key tactical stage involves I/Mg exchange of aryl iodide <b>2</b> followed by addition to glucono lactone <b>3</b> in THF. Subsequent in situ treatment of the resulting lactol with HCl in MeOH produces β-anomeric methyl glycopyranoside <b>4</b> which is, without isolation, directly reduced with Et₃SiH mediated by AlCl₃ as a Lewis acid in CH₂Cl₂/MeCN to afford <b>5</b> in 50% overall yield. The process was implemented for production on a metric ton scale for commercial launch

Zinc Catalyzed and Mediated Asymmetric Propargylation of Trifluoromethyl Ketones with a Propargyl Boronate

The development of zinc-mediated and -catalyzed asymmetric propargylations of trifluoromethyl ketones with a propargyl borolane and the <i>N</i>-isopropyl-l-proline ligand is presented. The methodology provided moderate to high stereoselectivity and was successfully applied on a multikilogram scale for the synthesis of the Glucocorticoid agonist <b>BI 653048</b>. A mechanism for the boron–zinc exchange with a propargyl borolane is proposed and supported by modeling at the density functional level of theory. A water acceleration effect on the zinc-catalyzed propargylation was discovered, which enabled a catalytic process to be achieved. Reaction progress analysis supports a predominately rate limiting exchange for the zinc-catalyzed propargylation. A catalytic amount of water is proposed to generate an intermediate that catalyzes the exchange, thereby facilitating the reaction with trifluoromethyl ketones

Development of a Large Scale Asymmetric Synthesis of the Glucocorticoid Agonist BI 653048 BS H₃PO₄

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H₃PO₄ (<b>1·H</b>_<b>3</b><b>PO</b>_<b>4</b>) is presented. A key trifluoromethyl ketone intermediate <b>22</b> containing an <i>N</i>-(4-methoxyphenyl)­ethyl amide was prepared by an enolization/bromine–magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone <b>22</b> 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

Development of a Large Scale Asymmetric Synthesis of the Glucocorticoid Agonist BI 653048 BS H₃PO₄

The development of a large scale synthesis of the glucocorticoid agonist BI 653048 BS H₃PO₄ (<b>1·H</b>_<b>3</b><b>PO</b>_<b>4</b>) is presented. A key trifluoromethyl ketone intermediate <b>22</b> containing an <i>N</i>-(4-methoxyphenyl)­ethyl amide was prepared by an enolization/bromine–magnesium exchange/electrophile trapping reaction. A nonselective propargylation of trifluoromethyl ketone <b>22</b> 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

Development of a Scalable, Chromatography-Free Synthesis of <i>t</i>‑Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF₃‑Alcohol Derivative with High Enantioselectivity Using Rh-Catalyzed Asymmetric Hydrogenation

A chromatography-free, asymmetric synthesis of the C2-symmetric P-chiral diphosphine <i>t</i>-Bu-SMS-Phos was developed using a chiral auxiliary-based approach in five steps from the chiral auxiliary in 36% overall yield. Separtion and recovery of the auxiliary were achieved with good yield (97%) to enable recycling of the chiral auxiliary. An air-stable crystalline form of the final ligand was identified to enable isolation of the final ligand by crystallization to avoid chromatography. This synthetic route was applied to prepare up to 4 kg of the final ligand. The utility of this material was demonstrated in the asymmetric hydrogenation of trifluoromethyl vinyl acetate at 0.1 mol % Rh loading to access a surrogate for the pharmaceutically relavent chiral trifluoroisopropanol fragment in excellent yield and enantiomeric excess (98.6%)

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain

Process Development of the BACE Inhibitors BI 1147560 BS and BI 1181181 MZ

The development of large-scale syntheses of two beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitors is described. New methodologies were discovered to overcome safety and scalability problems with existing procedures. The sterically hindered quaternary, neopentyl stereocenter was formed in high diastereoselectivity by the addition of a carbamoyl anion to an N-sulfinyl ketimine. An aryl nitrile was installed by a palladium- and cyanide-free electrophilic cyanation affected by transnitrilation of an arylmagnesium derivative with dimethylmalononitrile. A safe route to an oxetanylmethylamine side chain was devised based on diethyl malonate and dibenzylamine starting materials. A mild enamine fluorination was developed for the synthesis of a fluoroisobutylamine side chain