Chiral Resolution and Serendipitous Fluorination Reaction for the Selective Dopamine D3 Receptor Antagonist BAK2-66

Abstract

The improved chiral synthesis of the selective dopamine D3 receptor (D3R) antagonist (R)-N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-3-hydroxybutyl)1H-indole-2-carboxamide (( R )-PG648) is described. The same chiral secondary alcohol intermediate was used to prepare the enantiomers of a 3-F-benzofuranyl analogue, BAK 2-66. The absolute configurations of the 3-F enantiomers were assigned from their X-ray crystal structures that confirmed retention of configuration during fluorination with N,N-diethylaminosulfur trifluoride (DAST). ( R )-BAK2-66 showed higher D3R affinity and selectivity than its (S)-enantiomer; however, it had lower D3R affinity and enantioselectivity than ( R )-PG648. Further, importance of the 4-atom linker length between the aryl amide and 4-phenylpiperazine was demonstrated with the 4-fluorobutyl-product (8).

Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D3 Receptor (D3R)

“…trans -cyclohexyl or trans -olefin) can be attached to an extended aryl ring system, generally through an amide group, to create a secondary pharmacophore (SP) which, when suitably designed, results in D 3 R selectivity. 13,16–18 …”

An approach to (4-fluoroalkyl-1-alkyl-1H-pyrazol-3-yl)methylamines

“…Reaction of aldehydes 5, as well as the corresponding carboxylic acids or alcohols with sulfur-containing fluorinating reagents could be a method of choice to achieve this. It should be noted that such fluorinations in the presence of phtalimide moiety was described in the literature, however, it did not involve pyrazole derivatives [14][15][16][17][18][19][20][21]. It was found that fluorination of 5a with diethylaminosulfur trifluoride (DAST) proceeded smoothly and led to formation of the corresponding difluoromethyl derivative 14a in 82% yield (Scheme 3).…”

Identifying Medication Targets for Psychostimulant Addiction: Unraveling the Dopamine D3 Receptor Hypothesis

“… 5 From a structural point of view, this was significant and gave insight on differential binding interactions at the receptor protein level that were further explored. 5 , 27 To determine if behavioral effects were also enantioselective, we improved the enantioselective synthesis, 76 evaluated the microsomal metabolism and pharmacokinetics of the racemate, and then tested the racemate and the R - and S -enantiomers in behavioral models of cocaine and METH abuse.…”