Solid-State Stereochemistry and Activity of 3-Methylnefopam Diastereomers: Manipulation of Eight-Membered Ring Conformations in Analogues of the Non-narcotic Analgesic Drug

Eight-Membered-Ring Solid-State Conformational Interconversion via the Atom-Flip Mechanism, a CPMAS13C NMR and Crystallographic Stereochemical Study

“…However, placement of nonprotonated atoms at ring-positions 2 and 11 [O(2) and quaternary C(11)] enables these interactions to be either completely or partially removed in 9 . BB- 9 is more spatially “compact” compared to TCC- 10 and has been crystallographically found before for nefopam and N- desmethylnefopam salts. ,,, …”

The stereochemistry of a nine-membered ring analogue of nefopam, a nonnarcotic analgesic drug

“…The previously used boat-flattened chair (BfC) descriptor for crystalline le was recently replaced by the more accurate boat-boat (seen when le is viewed from a different orientation) [16]. Dissolution (CD2C12 or acidic aqueous medium) of crystalline BB-le affords ~H and J3C NMR chemical shift parameters for two N-methyl diastereomeric species at the slow exchange limit for epimerization via a prototropic shift-nitrogen inversion at the chirotopic and labile stereogenic nitrogen (e.g., BB-le ~ BB-la) [4,6,[14][15][16]. Weighted time-averaged ~H NMR vicinal coupling constants 3JHH were constituent with BB conformational interchange with a twist-chair-flattened chair (TCfC) (e.g., BB-le ~ TCfC-la) either at the fast exchange limit or the fast magnetic site-exchange broadening kinetic regime [6,[9][10][11][13][14][15].…”

“…The single-crystal X-ray crystallographic determination of solid-state conformations for epimeric C(3)-methyl cis-and trans-tophenyl analogues of nefopam were recently reported [14]. Crystalline (1R, 3S, 5R)/(1S, 3R, 5S)-3-methylnefopam hydrochloride (2) and (1R, 3R, 5R)/(1S, 3S, 5S)-3-methylnefopam hydrochloride (3) were found in the respective TCfC-2e and BB-3e conformations, as expected [14]. The two epimers are pharmacologically different in terms of their antinociceptive activity in mice (antinociception in animals parallels analgesia in humans) [14].…”

“…Dissolution (CD2C12 or acidic aqueous medium) of crystalline BB-le affords ~H and J3C NMR chemical shift parameters for two N-methyl diastereomeric species at the slow exchange limit for epimerization via a prototropic shift-nitrogen inversion at the chirotopic and labile stereogenic nitrogen (e.g., BB-le ~ BB-la) [4,6,[14][15][16]. Weighted time-averaged ~H NMR vicinal coupling constants 3JHH were constituent with BB conformational interchange with a twist-chair-flattened chair (TCfC) (e.g., BB-le ~ TCfC-la) either at the fast exchange limit or the fast magnetic site-exchange broadening kinetic regime [6,[9][10][11][13][14][15]. Confor-mational interchange occurs via partial ring inversion involving torque about the adjacent N--CH2--CH20 bonds and thereby removes the C--Heneo" " " D0,~o interaction seen in BB-1 [6,9,10,[13][14][15][16].…”

“…Weighted time-averaged ~H NMR vicinal coupling constants 3JHH were constituent with BB conformational interchange with a twist-chair-flattened chair (TCfC) (e.g., BB-le ~ TCfC-la) either at the fast exchange limit or the fast magnetic site-exchange broadening kinetic regime [6,[9][10][11][13][14][15]. Confor-mational interchange occurs via partial ring inversion involving torque about the adjacent N--CH2--CH20 bonds and thereby removes the C--Heneo" " " D0,~o interaction seen in BB-1 [6,9,10,[13][14][15][16]. Direct observation of the TCfC conformation for the nefopam 2,5-benzoxazocine ring was forthcoming from the X-ray crystallography determined structure of crystalline nefopam methiodide quaternary ammonium salt [10].…”