Solid-state stereochemistry of anhydrous (–)-scopolamine hydrobromide

Abstract

The solid-state structure of anhydrous (Nr,C,-S) -( -)-scopolamine hydrobromide [ ( -)-hyoscine], an acetylcholine antagonist, has been determined by single crystal X-ray diffraction analysis. ( -) -Scopolamine hydrobromide [an hydrous form] gives crystals belonging to the orthorhombic P2,2,2, space group, and at 298 K: a = 7.348(1), b = 10.482(1), c = 22.867(1) 8, V = 1 761.26(1) A3, Z = 4, R ( F ) = 0.053, and R,(F) = 0.049. The (S)-absolute configuration was determined from the effects of anomalous dispersion of the bromide atom. The N-methyl group exists in an axial configuration similar to that previously described for the hemihydrate. However, in the anhydrous form the tropate residue exhibits a different conformation from that noted for the hemihydrate. The tropate ester moiety in (Nr,C,-S)-( -) -scopolamine hydrobromide [anhydrous form] and (Ns,C,-S) -Nbutylhyoscinium bromide both exhibit very similar crystalline-state conformations, while that in

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

“…In conclusion, using the (lR,3S)/(1S13R)-cis-1,3-diequatorial spatial disposition of the exo-oriented phenyl ring relative to the 3-methyl group of (21-8 as a model, the structurally analogous (+)-(lR,3S)l(lS,3R)-3-methylnefopam hydrochloride (9) was prepared and a similar TCfiC conformation solid-state geometry was indeed observed. In contrast, the (1RI3R)/( 1S,3S)-epimer (10) afforded the same BfiC conformation noted in parent nefopam hydrochloride (1) and derivatives. Whereas epimers 9 and 10 were differentiated in one test for antinociception, much further work is needed to adequately correlate benzoxazucine ring conformation and N-methyl configuration with analgesic activity.…”

Scopolamine and atropineN-methyl diastereomer stability.Ab initio calculations onO-formylscopine andO-formyltropine model compounds

“…As opposed to the case of 17 above, the transannular oxiranyl function appears to partially overcome the extra "pinching"-derived cis-l,3-diaxial interactions involving the axial N-methyl group in diastereomer 19. The N--H(8eq) bond of 19 is closer to C(6) and C(7) relative to 11, 13, and 17 as seen by the 4.6 ~ The ab initio-calculated model 19 also represents an accurate representation of reality since a similar N--C(9ax) bond tilting away from C(2ax) and C(4ax), and a concomitant N--H(8eq) bond tilting toward C (6) and C(7), was also found in the crystallographically determined structure of scopolamine hydrobromide anhydrate (2) , while the H(8eq) 9 9 9 0(3) transannular distance is 2.066 ,~ versus 1.982 A in 19 [5].…”

“…The structures of la [5] and the sesquihydrate pseudopolymorph lb [6] have recently been reported by Glaser and co-workers. Drawings la and lb, as well as all others to follow, depict actual twodimensional iconic projections [7] of the respective three-dimensional X-ray crystallographically deter- '0-4 II lb mined (or ab initio-calculated) structures [5,6].…”

“…The structures of la [5] and the sesquihydrate pseudopolymorph lb [6] have recently been reported by Glaser and co-workers. Drawings la and lb, as well as all others to follow, depict actual twodimensional iconic projections [7] of the respective three-dimensional X-ray crystallographically deter- '0-4 II lb mined (or ab initio-calculated) structures [5,6]. The issue of polymorphism for scopolamine hydrobromide has not been adequately resolved in the United States Pharmacopoeia XXII [8], since only a maximum permissible 13% weight loss after drying at 105~ for 3 hr is specified, while no lower limit is stated [6].…”

“…7: 1 and 18 : 1 ratios of 4 : 5 in D20 and CD2C12, respectively) [12]. These solution-state diastereomerization reactions at the labile chirotopic and stereogenic nitrogen interconvert the two protonated N-methyl species via a prototropic shift/nitrogen inversion mechanism [12].The orientation of the N-methyl group is axial in both crystalline anhydrous (-)-Nr, C~-S)-scopolamine hydrobromide (la) [5] and in the (-)-(Nr, C~-S)-scopolamine hydrobromide sesquihydrate (lb) [6] The two N-methyl diastereomers of both scopolamine and atropine free bases were at the NMR fast exchange limit (FEL) for epimerization at nitrogen in ambient-temperature solutions of CDC13 solvent. 13C NMR spectroscopy unequivocally showed that the appropriate equatorial N-methyl diastereomers were the predominant contributors to the time-averaged spectral parameters for solutions of both alkaloid free bases [12].…”