5 research outputs found
Development of a Scalable, Chromatography-Free Synthesis of <i>t</i>‑Bu-SMS-Phos and Application to the Synthesis of an Important Chiral CF<sub>3</sub>‑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