Robust and Scalable Reductive Amination Protocol for Electron-Poor Heterocyclic Amines Using Et3SiH/TFA as Reducing Agent

Abstract

A novel reductive amination procedure for electron-poor heterocyclic amines with aromatic and aliphatic aldehydes has been developed. The key to success was the use of triethylsilane (Et3SiH) as reducing agent, in combination with trifluoroacetic acid (TFA) in refluxing CH2Cl2. The reductive aminations are fast, clean and allow for the isolation of the alkylated amines in high yields and purity after crystallization or chromatographic purification. The robustness and scalability of the process has been demonstrated for one substrate combination on 750 g scale, leading to the isolation of the corresponding product in 93% yield.

Scalable Synthesis of C5aR1 Antagonist ACT-1014-6470 via N7-Selective Reductive Amination of an Unprotected Pyrazole Starting Material and Intramolecular Urea Formation with 1,1′-Carbonyl-di(1,2,4-triazol) (CDT)

“…In the case of 15, the formation of the intermediate imine was challenging and not surprisingly the use of common reagents such as NaBH(OAc) reported a facile reductive amination procedure for electronpoor heterocyclic amines with aromatic and aliphatic aldehydes. 12 The key to success was the use of triethylsilane (Et 3 SiH) as reducing agent, in combination with trifluoroacetic acid (TFA) in refluxing CH 2 Cl 2 . We applied this protocol to couple ethyl 3-amino-1H-pyrazole-4-carboxylate ( 15) with 2-(trifluoromethyl)benzaldehyde (16) in the presence of Et 3 SiH and TFA in CH 2 Cl 2 to give pyrazole 17 (Scheme 3).…”

“…In total, 1 was isolated in an overall yield of 12% over 10 steps, after half of which CC purification was required to obtain the intermediates in the desired purity. This synthetic sequence�while very suitable to generate structural diver-sity�was problematic in view of a future scale up: (1) nitropyrazole 3 is a highly energetic intermediate, which is not commercially available on kg-scale; 5 (2) the subsequent intermediates until the reduction step are also highly energetic compounds; (3) the SEM-protection of pyrazole methylester 5 was not regioselective and the regioisomers 6a/6b needed to be separated by CC; (4) the alkylation of precursor 11 with 1-(bromomethyl)-2-(trifluoromethyl)benzene (12) was performed with NaH in N,N-dimethylformamide (DMF)�a highly hazardous combination, 6 which also produced many impurities; (5) the last step before isolation of API 1 was low yielding and required high temperatures. The sum of all these challenges led us to the decision to develop a completely new route for 1 and to immediately start with the route scouting activities.…”

“…In the case of 15 , the formation of the intermediate imine was challenging and not surprisingly the use of common reagents such as NaBH­(OAc) 3 , NaBH 3 CN, or H 2 -gas in the presence of a Pd-catalyst led to poor conversions and low IPC purity of 17 . To overcome this limitation, we recently reported a facile reductive amination procedure for electron-poor heterocyclic amines with aromatic and aliphatic aldehydes . The key to success was the use of triethylsilane (Et 3 SiH) as reducing agent, in combination with trifluoroacetic acid (TFA) in refluxing CH 2 Cl 2 .…”