Solid-state Structure of Orphenadrine Hydrochloride and Conformational Comparisons with Diphenhydramine Hydrochloride and Nefopam Hydrochloride ROBERTGLASER*',DAVIDDONNELL*, AND KNUT MAARTMANN-MOE5 Received June 21, 1991, from the 'Department of Chemistry, Ben-Gurion University of the Negev, Eeersheva 84105, Israel, *3M Health Care Ltd., Loughborough, Leicestershire LE11 IEP, U.K., and the §Departmentof Chemistry, University of Eergen, N-5007 Bergen, Noway. Accepted for publication October 10, 1991. Abstract 0 The solid-state structure of (2)-orphenadrinehydrochloride [(CH3)2NCH,CH,0CH(~CH3C,H,)(Ph) . HCI], a skeletal muscle relaxant drug, was determined by single-crystal X-ray diffraction analysis.

Orphenadrine hydrochloride gave crystals belonging to the monoclinic f2,ln space group, and at low temperature (92 K), the following parameters were found: a = 6.923 (4), b = 7.508 (5),c = 33.22(3) A, V = 1720 (3) A3, Z = 4, R(F) = 0.109, and RJF) = 0.131. Data were collected from poor crystalline material because of the low volume of the needle-shaped crystals (0.025 x 0.025 x 0.15 mm3). A molecular mechanics model was calculated by using an input structure based on atomic coordinates of the crystallographically determined molecular structure. The resulting molecular mechanics model and the structure determined by X-ray crystallography have the same molecular conformation. Whereas both solid-state (?)-orphenadrinehydrochloride and diphenhydramine hydrochloride [(CH3),NCH2CH,0CH(Ph), HCI] have synclinal N-C-GO and antiperiplanar NC-C4-CAr2torsion angles, the former has a helical arrangement for Ar,CH, as expected, and the phenyl rings in the latter are disposed in a nonhelical, "open-book'' arrangement.

chair) conformation (3e),with an equatorial N-methyl group and an exo-oriented phenyl ring.SJ0 Dissolution of either crystalline (+)-3e or (+)-3e results in a prototropic shift and a nitrogen inversion diastereomerization process forming an equilibrium mixture of equatorial (3e) and axial (3a) N-methyl isomers of 3 [3e:3a ratio, -1 :1 (acidic D,O, pD -1) and -2:3 (CD2C12)].9J1The (lS,5S)-3e and (lS,5S)-3a diastereomeric pair from the dissolution of crystalline (+)(1S,5S)-3e is illustrated below. Results of proton nuclear magnetic resonance ('H NMR; CD2C12)studies show a third species present as a hidden partner in equilibrium with 3e.9-11.12Results of molecular mechanics modeling suggest that the twist chair-(flattened chair) conformer 4 is the additional species.10 This hypothesis was later found to be consistent with the X-ray crystallographic observation of both conformations in the crystal of the quaternary ammonium salt.14 We have recently described the solid-state structure of 1.I5 The solid-state structure of 2 is reported in this paper as part of a program to correlate stereochemical structure with pharmacological activity in this family of molecules.

Diphenhydramine hydrochloride [2-(diphenylmethoxy)Experimental Section NJV-dimethylethylamine hydrochloride,l 11, orphenadrine Compound 2 was obtained as a gift from 3M Health Care Ltd., hydrochloride [(~)-N,N-dimethyl-2-(o-methyl-cr-phenylbenLoughborough, U.K. Dissolution in absolute ethanol, followed by zy1oxy)ethylamine hydrochloride,2 21, and nefopam hydrovapor diffusion of acetone, yielded clear, colorless, crystalline needles chloride [(~)-3,4,5,6-tetrahydro-5-methyl-l-phenyl-l~-2,5-belonging to the monoclinic system P2,ln. The melting point [160.5benzoxazocine hydrochloride,3 31 have structural similarities. 162.5 "C (uncorr.); lit.' 156-157 "C] was determined on a Wild Compound 1 is a well-known antihistamine,l 2 is a skeletal Heerbrugg stereomicroscope equipped with a Mettler model FP-52 muscle relaxant,2 and 3 is a nonnarcotic analgesic drug.3 hot stage. Klohs et al.4 compared some of the pharmacological activities Intensity data were collected from poor crystalline material a t low of the three drugs: the relative antihistaminic potencies of 1-3 temperature (92 K)on an Enraf-Nonius CAD4 automatic diffractometer. Table I provides crystallographic and data collection details are 1, 1/15, and 1/90, respectively, and the relative muscle (crystallographic structure factors for 2 are available upon request relaxant potencies of 1-3 are 1,2-3, and 10-30, respectively. from the authors). The unit cell dimensions were obtained by a Compound 2 and histamine H, receptor blockers such as 1 least-squares fit of 17 centered reflections in the range 6" 5 0 5 10". produce antinociception in mice"' and exhibit analgesic Reflections were measured at a scan speed of T h i n . During data activity in clinical trials8 but are considerably less potent collection, the intensities of two standard reflections were monitored than 3.8 Substitution of the skeleton of 1 at the ortho position after every 120 min. No decay was observed in the crystal. lowers the antihistaminic potency and strongly increases the The structure was solved by direct methods (SPD-MULTAN) and anticholinergic activity of this drug.2.3 refined by full-matrix least squares by use of the Enraf-Nonius Stereochemical investigationss12 of 3 and modeling studSDP-87 programs. l6 The final refinement included isotropic thermal parameters for the nonhydrogen atoms (geometrically placed hydroies13 of a hypothetical model for the reuptake site of 5-hygen atoms were included but not refined) and unit weights. At droxytryptamine have been reported by Glaser et al. Comconvergence, the final discrepancy index on F was R(F)= 0.109, and pound 3 exists in the crystalline state in a boat4flattened the weighted value was R , (F)= 0.131 for the 499 reflections with I

3e

858 I Journal of Pharmaceutical Sciences Vol. 81, No. 9, September 1992

38

4

OO~-3549/92/0900-0858$02.50/0 0 7992, American Pharmaceutical Association

Table CCrystallagraphic Detalls for 2

Parameter Formula Formula weight, a m u Space group a, A b, A c, A Pt deg

v, A3

Z Pcalcd* 9



Linear absorption coefficient, cm-’ Temperature, K Crystal size, rnm3 Radiation

Collection range 20 limits

Value or DescriDtion C1H ,N ,O

*

HCI

305.85

CI

i??,ln 6.923 (4) 7.508 (5) 33.22 (3) 95.01 (6) 1720 (3) 4 1.18 2.19 92 0.025 x 0.025 x 0.15

Graphite-monochromated MoK,-(A = 0.71073 A) h, k, 21

oo 5 20 s 500

tvpe Scan width, deg Scan speed, deg * min-‘ Background time/scan time Unique data Unique data with I s 341) Number of variables

RF) Rwm Weighting factor, w

0

Table ICAtomlc Parameters x, y, t for Nonhydrogen Atoms of 2 and Isotropic Thermal Parameters (B,,)’

-

1.20 + 0.35 tan0 5 0.33 3278 499 85 0.109 0.131 1

C(1) C(2) C(3) C(4) C(5) C(6) C(7) C(8) C(9) C(10) C(11) C(12) C(13) CU4) C(15) C(16) CV7) C(W

Results and Discussion X-ray Diffraction Studies-Compound 2 gave crystals (needles) belonging to the monoclinic P2,ln space group, and at low temperature (92 K),the crystal data shown in Table I were found. The atomic parameters are listed in Table I1 (see labeled diagram of 5 for numbering). Intramolecular distances and angles are given in Tables IIIA and IIIB, respectively, and torsion angles are presented in Table IV. Data were collected from poor crystalline material because of the low volume of the needle-shaped crystals (0.025 x 0.025 x 0.15 mm3). Larger crystals have a propensity to twin, resulting in broad double reflections. Although the crystal size was far from optimum in terms of the X-ray crystallographic investigation, direct methods located all the nonhydrogen atoms. Although better crystal data might be found eventually, we can assume that the present molecular geometry [see (R)-61is not expected to change radically into that of another conformation (although the new bonding parameters therein would be expected to be more accurate). To test this assump-

0.267 (1) 0.447 (2) 0.259 (4) 0.199 (4) 0.114 (4) 0.432 (4) 0.519 (4) 0.581 (4) 0.716 (4) 0.685(4) 0.817 (4) 0.984 (5) 1.016 (5) 0.886 (4) 0.468 (4) 0.486 (4) 0.400 (4) 0.292 (5) 0.253 (7) 0.363 (5) 0.338 (7)

0.5350(2) 0.6171 (5) 0.5325 (6) 0.4908 (9) 0.5610 (8) 0.5437 (9) 0.5808(8) 0.6497 (9) 0.6420 (7) 0.6202 (8) 0.616 (1) 0.630 (1) 0.651 (1) 0.6584 (9) 0.6870 (8) 0.7108 (9) 0.7478 (9) 0.759 (1) 0.7370 (9) 0.701 (1) 0.679 (1)

2.2 (1) 1.4 (4) 2.0 (4) 3.3 (8) 1.6 (6) 2.6 (7) 1.4 (6) 3.4 (8) 1.8 (6) 2.2 (6) 3.4 (8) 4.3 (9) 3.6 (8) 2.1 (6) 2.2 (6) 3.2 (7) 2.5 (7) 4.6 (9) 5.1 (9) 4.1 (8) 9 (1)

* Nonhydrogen atoms were refined isotropically; numbers in parentheses are esd values of last digit printed.

1 1 1

2 3dI) and 85 variables. [The final discrepancy index R(F) is defined

as RQ = (Zi 1 1 Fob I - 1 Fd 1 I )/(Pi 1 F b, I J; the weighted value R , is defined as R,(F) = [(Zi(wi(I Fob, f - I F,, I I 1 1 2 ~ (Zilwi( I Fo6. I i)~*)]l’z; the particular weighting factor used (wi) is given in Table I.] The residual positive and negative electron densities in the final map were +0.69 and -0.48 electrondh, respectively, and the maximum shift per estimated standard deviation (esd) was 0.01. The minimized-energy geometries of the model compounds, calculated by molecular mechanics, were determined by the MMX89 program17 on a Micro VAX-I1 computer under Micro VMS V4.5 (MMX8917 is an enhanced version of Allinger’sMM2 program,’*with MMPl w-subroutineslgincorporatedfor localized Ir-electronsystem). Structures 5-11 were drawn with the BALL AND STICK 2.2 program.” Solid-state 13C NMR (75.34 MHz) spectra were recorded on a Chemagnetics CMX solid-state Fourier transform spectrometer operating in the CP-MAS (cross polarization-magic-angle spinning) mode. The adamantane methine carbon peak (29.5 ppm) was used as an external secondary reference. An evolutiondelay of 40 jta was used in the dipolar dephasing experiment.21

0.326 (1) 0.861 (2) 0.759 (3) 0.803 (4) 0.828 (4) 0.836 (4) 0.767 (4) 0.869 (5) 1.024 (4) 1.179 (4) 1.319 (5) 1.274 (5) 1.121 (5) 0.986 (4) 0.907 (4) 1.084 (4) 1.116 (4) 0.977 (5) 0.798 (5) 0.778 (8) 0.591 (7)

0 N

,

15

1

9

zd* 5

Bond C(1)-N C(2W N-c(3) C(3)-C(4) C(4W

0-w

C(5)-C(6) C(5)-C(12) C(6)-C(7) C(6)-C(11) C(7)-c@)

Distance, An

Bond

Distance, A”

1.51 (1) 1.49 (1) 1.44 (2) 1.51 (2) 1.43 (1) 1.48 (1) 1.51 (2) 1.51 (2) 1.37 (2) 1.42 (2) 1.40 (2)

C(8)-c(9) C(9)-C(1 0) C(lO)-C(11) C(12)-C( 13) C(12)-C(17) C(13)-C(14) C(14)-C(15) C(15)-C(16) C(16)-C(17) C( 17)-C(18) CI N

1.39 (2) 1.33 (2) 1.39 (2) 1.41 (2) 1.31 (2) 1.39 (2) 1.33 (2) 1.40 (2) 1.45 (2) 1.44 (2) 3.01 (1)

-*a-

tion, a molecular mechanics model (7) was calculated by the MMX89 program with atomic coordinates of the crystallographically determined molecular structure 6 as an input structure. Structure 6 relaxed to that of model 7, which has the same molecular conformation as 6 [compare torsion angles in Table IV and the two stereoviews (aromatic and methyl protons were omitted from drawings for clarity)]. Detailed Comparison of Structures Determined by X-ray and Molecular Mechanics-In both (R)-6and (R)-7, the ammonium and benzhydrylic protons each have a cis-1,3Journal of Pharmaceutical Sciences 1 859 Vol. 81, No. 9, September 1992

Table IIIB-Nonhydrogen Bond Angles for 2

Bond C(1 C(1k-KC(3) w9-N-c(3) N-c(3)-c(4) C(3)4(4)-0 C(4)-04(5) O-C(5)-C(6) O-C(5)-C(12) C(6)4(5)-C(12) G(5)4(6)4(7) c(5)4(6)4(11) C(7)4(6)4(11) c(6)4(7)4(8) C(7)4(8)4(9)

Bond

Angle, 107 (1) 114 (1) 114 (1) 118 (1) 112 (1) 110 (1) 109 (1) 102 (1) 116 (1) 125 (1) 112 (11 123 (1) 121 (11 115 (1)

C~~)-c(9)4(10) C(9)4(10)4(11) C(6)4(11)4(10) C(5)4(12)4(13) C(5)4(12)-C(17) C(13)4(12)4(17) C(12)4(13)4(14) C(l3)4(14)4(15) C(14)4(15)4(16) C(15)-C( 16)-C(17) C(12)4(17)4(16) C(l2)4(17)4(18) C(16)-C(17)4(18)

Angle, 123 (2) 123 (2) 114 (1) 119 (1) 124 (1) 117 (1) 121 (1) 117 (1) 128 (2) 109 (2) 128 (2) 121 (2) 111 (2)

diaxial-type relationship with the pro-R diastereotopic proton on C(4).The synclinal (gauche) N-C(3)-C(4)-0 angle found in both 6 and 7 can be assigned a P or M descriptor according to its sign. In both structures, the C-methyl group in the tolyl ring is oriented up toward the proton ligated to the apex [C(5)1 of a pyramid whose base is denoted by the two ipso carbons [C(6,12)] and 0. There is also a helical arrangement in the diarylmethane moiety, as expeded.22.23 The ring-tilt angle24 is defined as the dihedral angle between the average plane of the aromatic ring and a line that passes through C(5) normal to the reference plane denoted by C(6)-C(12)-0. The tilt angle is calculated as the average dihedral angle C(5bm-Ci,,.Cod,,. and C(5)-m-Cip,,-Co,,., where m is the intersection point of the perpendicular from C(5) to the reference plane.24 The phenyl ring-tilt angles are similar for both 6 and 7 (34 and 36", respectively), but those for the tolyl ring are different in the two structures (52 and 32", respectively). In both (R)-6and (R)-7,the aryl rings afforded left-handed propeller helicities (M) relative to the reference plane, and the N-C(3W(4)-0 angles exhibited (P)-gauche chirality. The 152" C(3kC(4)0 4 5 ) angle in 6 was relaxed by the MMX89 program to a more ideal 178" antiperiplanar value in 7. Thus, despite the poor crystalline material available to ascertain the spatial features in 6 , these features were quite similar to those for model 7, which represents a bona fide energy minimum on the hypersurface for N-protonated 2. NMR Studies-The solution- and solid-state 13C NMR spectral parameters of the hydrochloride salts 1 and 3 have been presented by Glaser et aI.,gJOJ4 and similar data have been presented for orphenadrine citrate.16 The solid-state CP-MAS "C NMR spectral parameters of 2 are listed in Table V. Assignments were made by analogy with the corresponding solution-state spectrum of the citrate salt16 in which the DEPT (distortionlees enhancement by polarization transfer) pulse sequence (135"and 90" angles) was used to ascertain the multiplicities of protonated carbon resonances.26 The NCH, and quaternary carbon resonances were confirmed by a dipolar dephasing experiment21 based on less efficient solidstate relaxation for these nuclei (vis-&,is methylene and methine carbons). After a suitable delay period was introduced prior to fid (free induction decay) acquisition, NCH, and Cquaamarymagnetization was still noted in the spectrum. This technique has been used previously to assign N-methyl resonances in crystalline atropine sulfate (equatorial NCH,) and scopolamine hydrobromide (axial NCH,).26 The internally diastereotopic NCH, carbons in 2 were readily found in the spectrum, but specific C(1) and C(2) resonances cannot be unequivocally assigned. Chemical shifts for corresponding nuclei in solution- and solid-state spectra of 2 and orphenadrine citrate were reasonably similar. 860 / Journal of Pharmaceutical Sciences Vol. 81, No. 9, September 1992

Compound 2 is an inherently asymmetric molecule because of the presence of a stereogenic27 and chirotopic27 bemhydrylic carbon atom. Compound 2 occupies a position of general symmetry in the unit cell, and the diastereotopic N-methyl carbon nuclei therein reside in different magnetic environments, giving rise to an anisochronicity (A61 of 3.51 ppm (5.16 ppm16 for solid orphenadrine citrate) in contrast to the situation for solid-state 1.16 In as much as 1does not occupy a site of special mirror symmetry in the unit cell, its molecular conformation cannot be achiral in the crystal. However, its molecular conformation shows almost mirror symmetry (through N, CH,N, benzhydryl-C, and between the phenyls), because the C-face appears to act as a plane of pseudo-mirror symmetry (see below).16 Therefore, in this case, internally diastereotopic pairs of nuclei [(CH,),N, the two ips0 carbons, etc.] appear to be pseudo enantiotopic because of negligible differences in chemical shifts from pairs of what should be anisochronous carbons.16 Comparison of 2 and 1-The structure of 1determined by the X-ray crystallography also shows a synclinal (gauche) N-C(3)-C(4)-0 angle that is quite shallow (38") because of the presence of a bihrcated hydrogen bond involving N'H C1- and internal N'-H 0 . 1 6 Therefore, the ammonium proton in (P)-1 is approximately orthogonal to the pr0-R proton on C(4) [as opposed to the cis-1,3-diaxial-type arrangement in (R)-6].A single hydrogen bond between N'-H .*.C1was found in crystalline 2 (6). Both 1and 2 show antiperiplanar C(5)-O-C(4)-C(3) angles. The benzhydrylic proton in both structures has a pseudo-cis-1,3-diaxial-type relationship involving a different C(4) methylene proton in each case [i.e., pro-S H(4) in (PI-1mdpro-R H(4) in (R)-61.The most striking difference between he two solid-state structures is the pseudo-mirror relationship between the two phenyl rings of 1, which result in their adoption of a nonhelical open-book conformation. This relationship is evidenced by the 4" C(7b C(6) C(12)-C(13) and the 6" C(llbC(6) C(12X(17) synperiplanar torsion angles in (PI-1 and the corresponding values of 66 and 80", respectively, in (R)-6. Diarylmethane moieties (and Ar2ZX'X2 systems in general) usually show helical dispositions giving the appearance of either a right- or left-handed two-bladed propeller subunit (see structures 5 and 6).22,23 The two aryl rings are differentiated by stereochemical labeling in 2, and there is also differentiation of the two edges of the 0-tolyl ring. It was of interest to compare o-methyl substitution of the pro-R or pro-S phenyl ring in 1 while keeping the directionality of the N-C(3bC(4)-0 torsion angle invariant. In addition, on both pro-R or pro-S phenyl rings, the methyl group may be ligated to ortho carbons that are disposed either syn or anti to C(5)relative to the reference plane. Molecular mechanics models were calculated by using the structure of 1determined by X-ray crystallography for the initial coordinates. Four diastereomeric conformations for N-protonated 2 exhibiting a (PI-gauche N-C(3)-C(4)-0 angle were calculated: model 8, R, P , syn; model 9, S,P, syn; model 10, R, P, anti; and model 11, S, P , anti. All of these models contain an internal N'-H 0 hydrogen bond, and all are calculated to have less energy than that for model 7, corresponding to the crystalline-state conformation. Model 8 had the lowest energy in the series [energy for models 9, 10, 11, and 7 (similar to X-ray structure) were, respectively, 0.20, 0.48, 1.39, and 3.76 kcaYmol higher than that for 81. Models with the methyl group pointing up (syn) toward the less congested C(5) apex of the pyramid whose base is the reference plane were lower in energy than those pointing down (anti). Similar to the situation with the MMX model for 1 (with the coordinates determined by X-ray as input),16 the nonhelical, open-book Ar,CH conformation of all the input structures changed to helical arrangements for the diarylmethane moiety. The C(7)-C(6) ..*C(12)-C(13) and C(11)-

-..

1

-..

...

U

Table V-CP-MAS

I3C NMR Spectral Parametera for Ctyatalilne 2

44.51 58.13 66.30 83.04

C(4) C(5)

Other Cwmu,

8

9

10

11

139.48 140.26 138.3 20.57 129.17and 126.79

Chemical shifts (ppm) downfield from tetramethylsilane, with 29.5ppm peak of solid adamantane as secondary reference. Assignments

may be reversed.

--

C(6) C(12)-C(17)torsion angles for models 8,9, 10, and 11 were, respectively, 28 and 27", 33 and 31", 52 and 50°, and 25 and 23". It is quite reasonable that 1 may exist in solution in all the conformations exhibited by 2. However, it is very unlikely that the converse can be true, because under the proper circuIT18t8nces,l may adopt a nonhelical, open-book disposition for the Ar,CH moiety. It waa indeed fortunate that crystal packing forces enabled the observation of this nonhelical arrangement for 1 Whereas this arrangement may not

.

represent the optimum energy structure, it cannot be too unreasonable because it is found in the solid-state structure.16 The Ar-H,,h, -.Horrh0-Ar' nonbonding distances are -2.91 and 2.78 A in the open-book conformation of 1.16 Substitution of a methyl group for one of the ortho protons would result in very close Ar-o-CH, .* Hortho-Ar'contacts, thus making any Journal of Phamaceuticel Sdences 1 881 Vol. 81, No. 9, September 1992

nonhelical arrangement for 2 highly improbable. The arrangement of the -CH,N+H(CH,)CH,CH,Ofragment in solid-state 39.10 is very similar to that noted in crystalline 1 (61, with the important exception that ring closure results in a gauche NC-C-O-C(Ar,) torsion angle. Molecular mechanics modeling shows severe close contacts between Ar-H and NCH, in 1 and 2 that are bent into conformations like that of 3.16

References and Notes 1. TheMerckZnh,llthed.; Budavari, S., Ed.; Merck: Rahway, NJ, 1989; pp 523, 1018, 1087, and references therein. 2. Harms, A. F., Ph.D. Dissertation; Vrije Universiteit, Amsterdam, The Netherlands, 1956. 3. Harms, A. F.; Hespe, W.; Nauta, W. T.; Rekker, R. F.; Timmerman, H.; de Vries, J. In Drug Design; Ariens, E. J., Ed.; Academic: New York, 1975; Vol. 6, pp 1-60. 4. Klohs, M. W.; Draper, M. D.; Petracek, F. J.; Ginzel, K. H.; R4, 0. N. Anneim.-Forsch. 1972,22, 132. 5. Rumore, M. M.; Schlicting, D. A. Life Sci. 1985, 36, 403 and references therein. 6. Sun,C.-L.;Hui, F. W.; Hanig, J. P. Neuropharmology 1985,24, 1. 7. Hunekaar, S.; Berge, 0.-G.; Hole, K.Eur. J. Phurmacol. 1985, 111,221. 8. Rumore, M. M.; Schlicting, D. A. Pain 1986,25,7 and references therein. 9. Glaser, R.; Cohen, S.; Donnell, D.; Agranat, I. J . Phurm. Sci. 1986. 75. 772. 10. Gl&r, k.; Frenking, G.; Loew, G. H.; Donnell, D.; Cohen, S.; Anranat. I. J . Chem. SOC.Perkin Tmns. 2 1989, 113. 11. Giaser, R.; Frenking, G.; Loew, G. H.; Donnell,. D.; Agranat, I. New J . Chem. 1988,12,953.

662 I Journal of Pharmaceutical Sciences Vol. 87, No. 9, Seprember 1992

Glaaer, R. Mugn. Reson. Chem. 1989,27, 1142. Glaser, R.; Donnell, D. J. Phurm. Sci. 1989, 78, 87. Glaser, R.; Michel, A.; Drouin, M. Can. J . Chem. 1990,68,1128. Glaser, R.; Maartman-Moe, K. J . Chem. SOC., Perkin Tmns. 2 1990,1205. 16. MULTAN-83 In Structure Determination Package; Enraf-Noniue: Delft, The Netherlands, 1987. 17. hfMX89; Serena Software Inc.: Bloomington, IN, 1989. 18. Allinger, N. L. J. Am. Chem. Soc. 1977,99, 8127. 19. Allinger, N. L.; Sprague, J. T.J . Am. Chem. Soc. 1973,95,3893. 20. Miiller, N.; Falk, A. B A U AND STICK 2 2 Molecular Gmphics Progmm for Apple Macintosh Computers; Johannes Kepler University: Linz, Austria; 1989. lla, S. J.; Fre G. J.A m . Chem. SOC.1979,101,5854;(b) 21* S. J.; Frey, Cross,B. P. J . A m . Chem. SOC. 1979,101, SE6. 22. Mislow, K. Chemtmts-Org. Chem. 1989,2, 151 and references therein. 23. Glaser, R. In Acyclic Orgumnitro en Stereodynamics; Lambert, J. B.; Takeuchi, Y., Eds.; VCH: deinheim, 1992, pp 123-148. 24. Glaaer, R.; Blount, J. F.; Mislow, K. J.Am. Chem. SOC.1980,102, 2177. 25. Doddrell, D. M.; Pegg, D. T.; Dendall, M. R. J . Magn. Reson. 1982.48. 323. 26. Gl&r, R.; Peng, Q.J.;Perlin, A. S. J . Org. Chem. 1988,53,2172. 27. Mislow, K.; Siegel, J. J. A m . Chem. Soc. 1984,106, 3319. 12. 13. 14. 15.

d"' %

2:

Acknowledgments Gratitude is expressed to Prof. well Hole and Prof. Gunnar Aksnes (Univereitj of the Bergen) for hospitality extended to R. G. The CP-MAS C NMR spectrum was recorded by Dr. Fred Morin (McGill University). Appreciation is extended to Prof. Arthur S. Perlin (McGill University) for enabling us to obtain the solid-state spectrum.

Solid-state structure of orphenadrine hydrochloride and conformational comparisons with diphenhydramine hydrochloride and nefopam hydrochloride.

The solid-state structure of (+-)-orphenadrine hydrochloride [(CH3)2NCH2CH2OCH(o-CH3C6H4)(Ph).HCl], a skeletal muscle relaxant drug, was determined by...
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