Convergent Asymmetric Synthesis of Two Complex TRPV1 Antagonists

Abstract

The convergent scale-up synthesis of two complex TRPV1 antagonists to support exploratory toxicology studies is described. Both compounds contain three chiral centers introduced by asymmetric synthesis with chiral control being critical for the success of the project. Preparation of the key cyclopropyl intermediate utilised an asymmetric cyclopropanation using thermally unstable ethyl diazoacetate. Ellman's auxiliary was used to synthesize the chiral R-methyl benzylamine fragments. This paper highlights some of the key synthetic challenges, processing issues, and safety aspects from the scale-up of this chemistry.

Gram‐Scale Synthesis of Chiral Cyclopropane‐Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity

“…[2k] Upon screening over 120 different catalytic conditions, the best results were obtained using Ru( i Pr-PyBox) as the catalyst to give 23 in 40% de and 65% ee . [14] Using whole cells expressing Mb(H64V,V68A), 0.83 g of 23 could be obtained in high yield (75%) with much greater diastereo- and stereoselectivity (99.9% de , 99.9% ee ) (Scheme 1c). The cyclopropanation product was further processed to afford 24 (see SI for details).…”

Gram‐Scale Synthesis of Chiral Cyclopropane‐Containing Drugs and Drug Precursors with Engineered Myoglobin Catalysts Featuring Complementary Stereoselectivity

“…[2d, 2e] The asymmetric cyclopropanation of olefin 18 to give 19 represents a key step in the synthesis of Tasimelteon as reported by chemists at BMS. [17] Under best performing conditions, this transformation was realized in 91% de and 85% ee using Nishiyama's The stereoselective cyclopropanation of 22 into 23 was denoted by Pfizer chemists as "the most challenging step" in the preparation of the advanced drug candidate 24, [14] due to the presence of a pyridine functionality and formation of a trisubstituted cyclopropane. [2k] Upon screening over 120 different catalytic conditions, the best results were obtained using Ru(iPr-PyBox) as the catalyst to give 23 in 40% de and 65% ee.…”

“…Notably,t he desired 1R,2R-configured cyclopropanation product 19 was obtained in 99.9 % de and 96 % ee and in 91 %isolated yield (0.96 g), thus furnishing ak ey intermediate en route to Tasimelteon (20). [17] Thes tereoselective cyclopropanation of 22 into 23 was denoted by Pfizer chemists as "the most challenging step" in the preparation of the advanced drug candidate 24, [14] owing to the presence of apyridine functional group and formation of at risubstituted cyclopropane. [2k] Upon screening over 120 different catalytic conditions,t he best results were obtained using Ru(iPr-PyBox) as the catalyst to give 23 in 40 % de and 65 % ee.…”

“…Furthermore, the substrate loading in these whole-cell reactions could be increased up to 0.5 M styrene and 0.5 M EDA in a 1:1 ratio, while maintaining high conversion ratio (62%) along with excellent selectivity (99.9% de, 99.9% ee, Table S5). Aryl-substituted trans-cyclopropanes are found in several marketed and investigational drugs (Scheme 1), [1] including the MAO inhibitor Tranylcypromine ((±)-16, former Parnate®), [12] the melatonin receptor agonist Tasimelteon (20), [13] the TRPV1 antagonist 24, [14] and the platelet aggregation inhibitor Ticagrelor (28, Brilinta®) [15] . Although tranylcypromine has been used in clinical settings in racemic form, the two enantiomers display different biological potency.…”

2,6-Bis[(4S)-4-isopropyloxazolin-2-yl]pyridine

“…39, 40 This demand has led to method development and computational analysis of the mechanism by which these reactions occur. 41 Improvement over past procedures 17, 18 has been achieved through the use of a ruthenium i-Pr-PyBox catalyst (eq 14).…”