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Nizatidine, N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl]thio]ethyl]-N′-methyl-2-nitro-1,1-ethenediamine
Journal of ELSEVIER
MOLECULAR STRUCTURE
Journal of Molecular Structure 380 (1996) 93-100
Nizatidine, N-[ 2-[[[ 2-[ (dime th ylamin o )m e th yl]-4- thiazo l yl]me th yl ]thi o ]e th yl]N'-methyl-2-nitro- 1,1-ethenediamine Gregory A. Stephenson *'a, Timothy J. Wozniak a, Joseph G. Stowell b, Stephen R. Byrn b aLilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA bDepartmenrof Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, IN 47907-1333, USA
Received 3 October 1995; accepted in final form 1 December 1995
Abstract
CI2H21NsS202, Mr=331.46, triclinic, P1, a=7.3645(5), b=8.8785(9), c=25.678(4) A, a = 8 9 . 3 5 ( 1 ) °, 13 = 82.49(I) °, ? = 87.46(1) °, V = .1662.9(5) ,~3, Z = 4, D x = 1.324 g cm -3, A(Cu Ka) = 1.54184 ,A, # = 29.57 cm -t, F(000) = 704.0, T = 293 K, final R = 0.057 for 4830 observed reflections. Nizatidine, Axid ®, is a selective H2-receptor antagonist used in the treatment of duodenal ulcers. The pharmaceutical nizatidine crystallizes with two independent molecules in the asymmetric unit. The two molecules have similar conformations, with the exception of the dimethylamino group. The bisalkylamino-2-nitroethene moiety differs from the structurally related hydrogen oxalate salt form of ranitidine in that the nitro group of nizatidine is the cis geometrical isomer with respect to the ethylamino group. Keywords: Axid®; Nizatidine; Solid-state; Structure; Tautomer
I. Introduction
Nizatidine is a specific H2-receptor antagonist [1,2]. Unlike cimetidine, which contains an imidazole ring, or ranitidine, which contains the furan ring, nizatidine has a thiazolyl ring structure. T h e molecule is m o r e p o t e n t than cimetidine at inhibiting the secretion o f gastric acid and lacks m a n y of cimetidine's anti-androgenic and hepatic m i c r o s o m a l enzyme inhibiting effects [3,4]. Nizatidine has been effective in the t r e a t m e n t of duodenal ulceration, and joins cimetidine and ranitidine in this very i m p o r t a n t class of p h a r m a ceuticals. Nizatidine and ranitidine each contain
the N-ethyl-N'-methylnitroethenediamine moiety. This functionality has been shown to undergo rapid tautomerization in solution. The barrier to rotation, as given by the difference in Gibbs free
* Corresponding author. 0022-2860/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0022-2860(96)09216-2
(CH3)2NCH2 N~S,,,~
IL
Nizatidine
NCH2SCH2CH2I~r'I~CH3 CHNO 2 II
(CH3)2NCH2
Scheme 1.
94
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
energy, has been estimated to be approximately 15.7 kcal mol -l [5]. The following article reports the crystal structure of nizatidine and many of its spectroscopic properties.
2. Experimental 2.1. Single crystal X-ray diffraction Nizatidine, a highly active H2-receptor antagonist, was provided by Eli Lilly and Company. A colorless plate (dimensions 0.25 x 0.19 x 0.06 mm) was obtained from a methanol solution. The solution was cooled from 50°C to 10°C at a rate of I°C h -l. The data were collected on an EnrafNonius CAD4 diffractometer, using SDP [6], with graphite monochromated Cu Ka radiation at 20 ° + 1° using the w-20 scan technique (w 2-16 ° min -1) to a 20 maximum of 120.0 °. A total number of 4830 unique reflections was measured within the range - 8 < h < 7 , -9 3.0cr were used for all calculations. Three standard reflections were measured every 97 reflections, and no crystal decay was detected. Cell constants were refined from 25 reflections in the range 27 < 20 < 42 °. Lorentz and polarization corrections were applied to the data; an empirical absorption correction based on the method of Walker and Stuart was applied [7]. The structure was solved by direct methods using SIRS8 [8] and the remaining atoms were located in succeeding difference Fourier syntheses. Except where noted in the table of positional parameters, hydrogen atoms were located and added to the structure factor calculations but not refined. The structure was refined with full-matrix least squares using SHELX76 [9], where the function minimized was Ew([ [Fo [ - [Fc [[)2 and the weight w is defined according to the Killean and Lawrence method [10] with terms of 0.020 and 1.0. Atomic scattering factors and the values for A f ' and A f t, were taken from International Tables for X-ray Crystallography [11]. Anomalous dispersion effects were included in Fc [12]. The final cycle of refinement included 395 variable parameters and converged with an unweighted agreement factor R (E[[Fo[-[Fc[[/EFo) of 0.057, a weighted
agreement factor wR of 0.07, and (A/if)max of 0.13. The standard deviation of an observation of unit weight was 1.63. There was one correlation coefficient greater than 0.50 which was between parameters 92 and 383. The final difference Fourier map showed no significant residual electron density and the highest peak had a maximum p of 0.37 e ,~-3 with an estimated error based on a A F of 0.06 [131. Plots of r~w(I I Fo [ - l Fc II) 2 versus [ F o 1, reflection order in data collection, sin0/A, and various classes of indices showed no unusual trends.
2.2. 13C CP/MAS solid-state N M R CP/MAS laC solid-state N M R spectra were recorded at 50.19 MHz on a Chemagnetics M200 F T N M R spectrometer. Approximately 250-300 mg of powdered sample were placed in a Kel-F rotor and spun at approximately 3.3 kHz. Free induction decays were defined typically by 8 K over a 3 kHz sweep width and were accumulated over 3000 transients with a recycle delay of 5 s for an acceptable signal-to-noise ratio. A proton decoupling field of 199.58 M H z and a contact time of 2.00 ms were used. Chemical shifts were measured relative to a hexamethylbenzene external standard with a methyl resonance at 17.36 ppm relative to tetramethylsilane.
2.3. FT-Raman spectroscopy Fourier-transform Raman spectroscopy was carried out using a Nicolet Raman 950 spectrometer equipped with a liquid nitrogen-cooled germanium detector. Nizatidine was placed in a 5 mL quartz N M R tube and its spectrum was acquired. Each spectrum was the result of 100 coadded double sided interferograms obtained at 4 cm -l resolution. The interferograms were apodized with a H a p p - G e n z e l function prior to transformation.
2.4. FT-infrare'd spectroscopy A Nicolet 5 SXC F T I R spectrometer with a D T G S detector was used to record the IR spectra. Solid nizatidine samples were gently ground with
95
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
Table 1 Fractional coordinatesof non-H atoms and equivalentisotropic temperature factors x
y
z
B (~2)
KB/" and pressed into 13 mm pellets. All spectra were from 128 coatided double sided interferograms obtained at 2.0 cm -1 resolution and apodized with a H a p p - G e n z e l function prior to transformation.
Molecule A
S(II) S(17) O(I 16) O(117) N(13) N(110) N(112) N(II5) N(13') C(12) C(14) C(l 5) C(16) C(18) C(19) C(lll) C(113) C(114) C(12') C(14') C(15')
0.1600(2) -0.3532(3) -0.7183(5) -0.8441(5) -0.1200(7) -0.3617(6) -0.2210(5) -0.7019(6) 0.3053(7) 0.0424(9) -0.1598(8) -0.0272)9) -0.3355(8) -0.1683(8) -0.2006(8) -0.3707(7) -0.2100(8) -0.5399(7) 0.126(1) 0.288(1) 0.406(1)
0.3998(2) 0.7272(2) 0.7124(5) 0.8817(5) 0.5636(6) 0.7130(5) 0.8995(5) 0.8221(5) 0.6155(6) 0.5156(7) 0.5004(7) 0.4099(8) 0.5386(7) 0.7303(7) 0.6545(7) 0.8288(6) 1.0196(7) 0.8827(6) 0.5588(9) 0.761(1) 0.625(1)
0.16869(8) 0.11319(7) -0.0104(2) -0.0588(2) 0.2056(2) -0.0094(2) -0.0609(2) -0.0420(2) 0.2495(2) 0.2152(2) 0.1596(2) 0.1361(2) 0.1401(2) 0.0603(3) 0.0116(3) -0.0419(2) -0.0987(3) -0.0586(2) 0.2634(3) 0.2260(3) 0.2937(3)
6.60(5) 5.71(4) 5.4(1) 5.9(1) 4.9(1) 4.2(I) 3.8(1) 4.1(I) 4.7(1) 5.0(2) 4.1(1) 5.1(2) 4.6(1) 5.2(2) 4.6(I) 3.3(1) 5.1(2) 3.6(1) 6.2(2) 8.1(2) 8.0(2)
-0.1938(2) 0.3435(2) 0.7426(5) 0.0484(7) 0.3849(6) 0.2275(5) 0.7158(6) -0.3476(6) -0.1174(8) 0.1230(8) 0.0101(8) 0.3098(8) 0.1729(8) 0.3845(7) 0.2074(8) 0.5491(7) -0.242(1) -0.489(1) -0.231(1)
-0.0572(2) 0.2362(2) 0.2174(5) 0.1356(6) 0.2197(5) 0.4012(5) 0.3252(5) 0.0998(6) 0.1013(7) 0.0349(7) -0.0740(7) 0.0544(7) 0.2442(7) 0.3344(6) 0.5194(7) 0.3843(6) 0.1961(8) 0.179(1) 0.017(1)
0.34389(8) 0.38876(7) 0.5107(2) 0.3162(2) 0.5118(2) 0.5651(2) 0.5432(2) 0.2508(2) 0.3100(3) 0.3499(2) 0.3691(3) 0.3623(2) 0.4454(2) 0.5451(2) 0.6039(3) 0.5600(2) 0.2783(3) 0.2271(3) 0.2107(3)
5.86(4) 5.31(4) 5.4(1) 5.2(1) 3.9(1) 3.7(1) 3.8(1) 4.5(1) 5.0(2) 4.0(1) 4.7(1) 4.6(2) 4.2(1) 3.2(1) 4.8(2) 3.4(1) 6.0(2) 8.6(2) 8.6(3)
Molecule B
S(21) S(27) O(216) N(23) N(210) N(212) N(215) N(23') C(22) C(24) C(25) C(26) C(28) C(211) C(213) C(214) C(22') C(24') C(25')
Anisotropically refined atoms are given in the form of the isotropic equivalent thermal parameter defined as: 4 (a/~ll + b~22 + c/~33 + ab/312cos7 + ac~13cos/3 + bc1323cosa).
3. Discussion Final positional parameters for the non-H atoms for nizatidine are listed in Table 1. Bond lengths are listed in Table 2. An ORTEP-It [14] thermal ellipsoid drawing of the two independent molecules A and B (50% probability of non-H atoms) depicting the numbering scheme is shown in Fig. 1. A stereoscopic view of the molecular packing is shown in Fig. 2. Both molecules have intramolecular hydrogen bonds between a nitro oxygen and the ethylamino group, 2.629(4) ,~ and 2.63(2) ,A ( N . . . O ) for molecules A and B, respectively. Molecules A are related by unit translation along the x-axis, therein forming a continuous chain of intermolecular hydrogen bonds between Ol17 and N l 1 2 with a distance of 2.781(4) ,~. Similarly, B molecules are related by unit translations along the x-axis with intermolecular hydrogen bonds between O217 and N212 with a distance of 2.787(9) ,A,. The crystal structure of nizatidine differs from that of the oxalate salt of ranitidine [15] and the HCI salt of ranitidine [16], Zantac ®, in a number of respects. Spectroscopic investigations of the tautomerism of ranitidine's nitroethenedialkylamine Table 2 Selected bond lengths (A.) Bond O(116) O(117) N(ll0) N(ll2) N(l12) N(ll5) C(lll) H(010) n(012)
N(tI5) N(ll5) C(lll) C(lll) C(113) C(ll4) C(ll4) N(ll0) N(ll2)
Molecule A Bond
Molecule B
1.261(5) 1.275(4) 1.321(7) 1.327(7) 1.432(7) 1.347(6) 1.430(7) 0.717(4) 0.734(4)
1.27(3) 1.28(2) 1.34(6) 1.321(9) 1.444(9) 1.333(9) 1.408(9) 0.84(4) 0.803(9)
O(216) N(215) O(217) N(215) N(210) C(211) N(212) C(211) N(215) C(213) N(215) C(214) C(211) C(214) H(020) N(210) H(022) N(212)
Numbers in parenthesesare estimatedstandard deviationsin the least significantdigits.
96
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
,~
CJ,4'
~
~'J
17
Fig. 1. Thermal ellipsoid (51)% probability of non-H atoms) depiction of molecule A (top) and molecule B (bottom) showing the numbering scheme.
group have shown that in solution there exists rapid equilibrium between enediamine tautomers through a low barrier of rotation about the carbon-carbon double bond [5]. In the crystal structure of the oxalate salt of ranitidine, the conformation around the ethene double bond is such that the nitro and methylamino groups are cis, whereas the ethylamino group carrying the rest of
o/N_
H
I4~N~N,~.CH3
I
~ ~
I
R
H trans
Scheme 2.
O
R~N,~,,,N/H
I
H cis
Fig. 2. Molecular packing diagram showing H-bond (thin line) between molecule A and molecule B.
H~N~
I
CH3
G.A. Stephenson et aL/Journal of Molecular Structure 380 (1996) 93-100
97
Table 3 Selected torsion angles (degrees) Molecule A N(13) C(14)C(16) S(17) C(14')N(13') C(12') C(12) C(15')N(13') C(12') C(12)
72.47 (0.66) 71.43 (0.72) -166.58 (0.60)
Molecule B N(23) C(24) C(26) S(27) C(24' ) N(23' ) C(22' ) (C22) C(25') N(23') C(22') C(22)
55.96 (0.67) 170.25 (0.56) 67.71 (0.72)
Numbers in parentheses are estimated standard deviations in the least significant digits.
the molecule is trans with respect to the nitro group, Scheme 2. In the crystal structure of the hydrochloride salt of ranitidine, there is an equal population of cis and trans conformers in the unit cell. Nizatidine represents the opposite situation, with its nitro group trans with respect to the methylamino group and cis with respect to the rest of the molecule. Molecules A and B have similar molecular conformations, except for the orientation of the N,N-dimethylamino groups with respect to the aromatic ring. There is also a 16.5 ° deviation in the torsion angle N13-C14C16-S17 as compared with N23-C24-C26-$27 (see Table 3). All bond lengths and angles are in
agreement with the given atom type and hybridization with the exception of the N-ethyl-N'-methylaminonitroethylene/'esidue. The planarity of this group, the lengthening of the double bonds of molecules A and B to 1.41 ,~, and 1.43 .~, and also the shortening of the C - N bonds to an average distance of 1.33 ,~ provide evidence o f extended conjugation. Because of the high degree of conformational similarity of molecules A and B, there is little evidence of the two independent molecules in the 13C solid-state N M R spectrum. The resonances at 151.2 and 150.2 ppm, Fig. 3, are assigned to the ipso carbon of the thiazolyl ring and provide spectroscopic evidence of chemical inequivalence
PPM
I 180. O0
i
I 120. O0
I 80. O0
i
I
40. O0
i
I -O. O0
Fig. 3. The ~3C CP/MAS solid-state NM R spectrum of nizatidine shows evidence of multiple chemical environments of the ipso carbon, CI4 (and C24), thereby confirming that two independent molecular conformations exist in the crystallographic unit cell (13C 6: 173.4, 156.7, 151.2, 150.2, 119.7, 98.7, 88.7, 61.4, 46.2, 39.4 and 29.6 ppm).
98
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
0 O
g Q
F
0
O
tt%
J "i:: 0
I-
z O cxl
o
O 0 qo t'o
oo
.< ¢y
0 0 0
o
~
~
~
~o
,~
~
~
~
-
o
~
~
,~
~
~
~"
~
,~
-
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
99
Table 4 Spectral assignments from the Fourier-transform infrared and Raman spectra of nizatidine HCI . IR (cm-I)
Raman (cm-I)
Assignment
3280,3210 3107 3094 2945, 2860, 2829,2784 1622 1587
3143 3108 3091 2949, 2916, 2826, 2780 1617 1578
1521 1470, 1458, 1 4 3 5 , 1 4 2 2 1377, 1359
1518,1487 1472,1429,1415
NH stretch; two groups CH stretch in NO,-CHCH stretch thiazole ring CH stretches in NCH3, CH,.CH_, C=C, conjugated with NO_, Asym. NO, stretch, conjugated with C=C; thiazole ring also, weak contribution Thiazole ring CH deformation in NCH 3, CH_,; CH stretch Thiazole ring for one frequency and sym. NO.,, H-bonded, conjugated H-bonded NO., H..... O
1262, 1246, 1196, 1159
o f C14 and C24 in the two independent molecules. There is considerable b r o a d e n i n g in m a n y o f the resonances in the N M R spectra, attributable to carb o n a t o m s being b o n d e d to 14N q u a d r u p o l a r nuclei. 3.1. Fourier-transform infrared and R a m a n spectroscopy T h e infrared a n d R a m a n spectra are consistent with the m o l e c u l a r structure o f nizatidine, see Fig. 4. T h e I R s p e c t r u m has N H stretches at 3280 a n d 3210 cm - l , w h e r e a s the R a m a n s p e c t r u m has c o r r e s p o n d i n g stretches at 3143 c m - I . T h e I R s p e c t r u m has two a b s o r p t i o n s a s s o c i a t e d with the c o n j u g a t e d d o u b l e b o n d at 1622 a n d 3107 c m -1, a n d the R a m a n s p e c t r u m shows an a b s o r p t i o n at 3108 c m - l . A n NO2 stretch is o b s e r v e d at 1587 in the I R a n d 1578 cm - l in the R a m a n spectra. T h i a z o l e ring stretches are o b s e r v e d at 1521 cm - I in the I R a n d 1518 a n d 1487 c m - l in the R a m a n spectra. T a b l e 4 p r o v i d e s a listing o f the spectral a s s i g n m e n t s m a d e for nizatidine.
Acknowledgments The
authors
thank
Dr.
P.E.
Fanwick,
D e p a r t m e n t o f C h e m i s t r y , P u r d u e University, for his g u i d a n c e a n d the use o f the E n r a f - N o n i u s C A D 4 diffractometer. T h e a u t h o r s also t h a n k Eli Lilly a n d C o m p a n y for the g e n e r o u s gift o f nizatidine a n d Jim O s b o r n e for p r o v i d i n g the infrared a n d R a m a n spectra.
References [I] D.C. Evan, R.R. Ruffolo, M.W. Warrick and T.M. Lin, Fed. Proc., 43 (1984) Abstr. 4618. [2] T.M. Lin, D.C. Evans, M.W. Warrick, R.P. Pioch and R.R. Ruffolo, Gastroenterology, 84 (1983) 1231. [3] C.G. Meredith, K.V. Speeg and S. Schenker, Clin. Res., 31 (1983) 765A. [4] U. Klotz, W.R. Gonlieb, P.P. Keohane and H.G. Dammann, J. Clin. Pharmacol., 27 (1987) 210. [5] T.J. Cholerton, J.H. Hunt, G. Klinkert and M. MartinSmith, J. Chem. Soc. Perkin Trans. 2, (1984) 1761. [6] B.A. Frenz, The Enraf-Nonius CAD4 soy - - a real-time system for concurrent X-ray data collection and crystal structure determination, in Computing in Crystallography, H. Schenk, R. Olthof-Hazelkamp, H. vanKonigsvelt and G.C. Bassi (Eds.), Delft University Press, Delft, 1978, p. 64. [7] N. Walker and D. Stuart, Acta Crystallogr. Sect. A, A39 (1983) 158. [8] M.C. Burla, M. Camalli, G. Cascarano, C. Giacovazzo,
100
G.A. Stephenson et al./Journal o f Molecular Structure 380 (1996) 93-100
G. Polidori, R. Spagna and D. Viterbo, sms8 program for crystal structure determination. J. Appl. Crystallogr., 22 (1989) 389. [9] G.M. Sheldrick, SHELX?6 program for crystal structure determination, University of Cambridge, UK, 1976. [10] R.C.G. Killean and J.L. Lawrence, Acta Crystallogr. Sect. B, B25 (1969) 1750. [11] International Tables for X-ray Crystallography, VoI.IV, Kynoch Press, Birmingham, UK (present distributor Kluwer Academic Publishers, Dordrecht), 1974, Table 2.2B, p. 99 and Table 2.3.1, p. 149.
[12] J.A. lbers and W.C. Hamilton, Acta Crystallogr., 17 (1964) 781.. [13] D.W.J. Cruickshank, Acta Crystallogr., 2 (1949) 154. [14] C.K. Johnson, ORTEP-H, a FORTRAN thermal-ellipsoid plot program for crystal structure illustrations, Rep. ORNL-5138 (3rd revision of ORNL-3794), Oak Ridge National Laboratory, Oak Ridge, TN, 1976. [15] B. Kojic-Podic and Z. Ruzic-Toros, Acta. Crystallogr. Sect. B, B38 (1982) 1837. [16] T. Ishida, Y. In and M. Inoue, Acta Crystallogr. Sect. C, C46 (1990) 1893.
MOLECULAR STRUCTURE
Journal of Molecular Structure 380 (1996) 93-100
Nizatidine, N-[ 2-[[[ 2-[ (dime th ylamin o )m e th yl]-4- thiazo l yl]me th yl ]thi o ]e th yl]N'-methyl-2-nitro- 1,1-ethenediamine Gregory A. Stephenson *'a, Timothy J. Wozniak a, Joseph G. Stowell b, Stephen R. Byrn b aLilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA bDepartmenrof Medicinal Chemistry and Pharmacognosy, Purdue University, West Lafayette, IN 47907-1333, USA
Received 3 October 1995; accepted in final form 1 December 1995
Abstract
CI2H21NsS202, Mr=331.46, triclinic, P1, a=7.3645(5), b=8.8785(9), c=25.678(4) A, a = 8 9 . 3 5 ( 1 ) °, 13 = 82.49(I) °, ? = 87.46(1) °, V = .1662.9(5) ,~3, Z = 4, D x = 1.324 g cm -3, A(Cu Ka) = 1.54184 ,A, # = 29.57 cm -t, F(000) = 704.0, T = 293 K, final R = 0.057 for 4830 observed reflections. Nizatidine, Axid ®, is a selective H2-receptor antagonist used in the treatment of duodenal ulcers. The pharmaceutical nizatidine crystallizes with two independent molecules in the asymmetric unit. The two molecules have similar conformations, with the exception of the dimethylamino group. The bisalkylamino-2-nitroethene moiety differs from the structurally related hydrogen oxalate salt form of ranitidine in that the nitro group of nizatidine is the cis geometrical isomer with respect to the ethylamino group. Keywords: Axid®; Nizatidine; Solid-state; Structure; Tautomer
I. Introduction
Nizatidine is a specific H2-receptor antagonist [1,2]. Unlike cimetidine, which contains an imidazole ring, or ranitidine, which contains the furan ring, nizatidine has a thiazolyl ring structure. T h e molecule is m o r e p o t e n t than cimetidine at inhibiting the secretion o f gastric acid and lacks m a n y of cimetidine's anti-androgenic and hepatic m i c r o s o m a l enzyme inhibiting effects [3,4]. Nizatidine has been effective in the t r e a t m e n t of duodenal ulceration, and joins cimetidine and ranitidine in this very i m p o r t a n t class of p h a r m a ceuticals. Nizatidine and ranitidine each contain
the N-ethyl-N'-methylnitroethenediamine moiety. This functionality has been shown to undergo rapid tautomerization in solution. The barrier to rotation, as given by the difference in Gibbs free
* Corresponding author. 0022-2860/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0022-2860(96)09216-2
(CH3)2NCH2 N~S,,,~
IL
Nizatidine
NCH2SCH2CH2I~r'I~CH3 CHNO 2 II
(CH3)2NCH2
Scheme 1.
94
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
energy, has been estimated to be approximately 15.7 kcal mol -l [5]. The following article reports the crystal structure of nizatidine and many of its spectroscopic properties.
2. Experimental 2.1. Single crystal X-ray diffraction Nizatidine, a highly active H2-receptor antagonist, was provided by Eli Lilly and Company. A colorless plate (dimensions 0.25 x 0.19 x 0.06 mm) was obtained from a methanol solution. The solution was cooled from 50°C to 10°C at a rate of I°C h -l. The data were collected on an EnrafNonius CAD4 diffractometer, using SDP [6], with graphite monochromated Cu Ka radiation at 20 ° + 1° using the w-20 scan technique (w 2-16 ° min -1) to a 20 maximum of 120.0 °. A total number of 4830 unique reflections was measured within the range - 8 < h < 7 , -9
agreement factor wR of 0.07, and (A/if)max of 0.13. The standard deviation of an observation of unit weight was 1.63. There was one correlation coefficient greater than 0.50 which was between parameters 92 and 383. The final difference Fourier map showed no significant residual electron density and the highest peak had a maximum p of 0.37 e ,~-3 with an estimated error based on a A F of 0.06 [131. Plots of r~w(I I Fo [ - l Fc II) 2 versus [ F o 1, reflection order in data collection, sin0/A, and various classes of indices showed no unusual trends.
2.2. 13C CP/MAS solid-state N M R CP/MAS laC solid-state N M R spectra were recorded at 50.19 MHz on a Chemagnetics M200 F T N M R spectrometer. Approximately 250-300 mg of powdered sample were placed in a Kel-F rotor and spun at approximately 3.3 kHz. Free induction decays were defined typically by 8 K over a 3 kHz sweep width and were accumulated over 3000 transients with a recycle delay of 5 s for an acceptable signal-to-noise ratio. A proton decoupling field of 199.58 M H z and a contact time of 2.00 ms were used. Chemical shifts were measured relative to a hexamethylbenzene external standard with a methyl resonance at 17.36 ppm relative to tetramethylsilane.
2.3. FT-Raman spectroscopy Fourier-transform Raman spectroscopy was carried out using a Nicolet Raman 950 spectrometer equipped with a liquid nitrogen-cooled germanium detector. Nizatidine was placed in a 5 mL quartz N M R tube and its spectrum was acquired. Each spectrum was the result of 100 coadded double sided interferograms obtained at 4 cm -l resolution. The interferograms were apodized with a H a p p - G e n z e l function prior to transformation.
2.4. FT-infrare'd spectroscopy A Nicolet 5 SXC F T I R spectrometer with a D T G S detector was used to record the IR spectra. Solid nizatidine samples were gently ground with
95
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
Table 1 Fractional coordinatesof non-H atoms and equivalentisotropic temperature factors x
y
z
B (~2)
KB/" and pressed into 13 mm pellets. All spectra were from 128 coatided double sided interferograms obtained at 2.0 cm -1 resolution and apodized with a H a p p - G e n z e l function prior to transformation.
Molecule A
S(II) S(17) O(I 16) O(117) N(13) N(110) N(112) N(II5) N(13') C(12) C(14) C(l 5) C(16) C(18) C(19) C(lll) C(113) C(114) C(12') C(14') C(15')
0.1600(2) -0.3532(3) -0.7183(5) -0.8441(5) -0.1200(7) -0.3617(6) -0.2210(5) -0.7019(6) 0.3053(7) 0.0424(9) -0.1598(8) -0.0272)9) -0.3355(8) -0.1683(8) -0.2006(8) -0.3707(7) -0.2100(8) -0.5399(7) 0.126(1) 0.288(1) 0.406(1)
0.3998(2) 0.7272(2) 0.7124(5) 0.8817(5) 0.5636(6) 0.7130(5) 0.8995(5) 0.8221(5) 0.6155(6) 0.5156(7) 0.5004(7) 0.4099(8) 0.5386(7) 0.7303(7) 0.6545(7) 0.8288(6) 1.0196(7) 0.8827(6) 0.5588(9) 0.761(1) 0.625(1)
0.16869(8) 0.11319(7) -0.0104(2) -0.0588(2) 0.2056(2) -0.0094(2) -0.0609(2) -0.0420(2) 0.2495(2) 0.2152(2) 0.1596(2) 0.1361(2) 0.1401(2) 0.0603(3) 0.0116(3) -0.0419(2) -0.0987(3) -0.0586(2) 0.2634(3) 0.2260(3) 0.2937(3)
6.60(5) 5.71(4) 5.4(1) 5.9(1) 4.9(1) 4.2(I) 3.8(1) 4.1(I) 4.7(1) 5.0(2) 4.1(1) 5.1(2) 4.6(1) 5.2(2) 4.6(I) 3.3(1) 5.1(2) 3.6(1) 6.2(2) 8.1(2) 8.0(2)
-0.1938(2) 0.3435(2) 0.7426(5) 0.0484(7) 0.3849(6) 0.2275(5) 0.7158(6) -0.3476(6) -0.1174(8) 0.1230(8) 0.0101(8) 0.3098(8) 0.1729(8) 0.3845(7) 0.2074(8) 0.5491(7) -0.242(1) -0.489(1) -0.231(1)
-0.0572(2) 0.2362(2) 0.2174(5) 0.1356(6) 0.2197(5) 0.4012(5) 0.3252(5) 0.0998(6) 0.1013(7) 0.0349(7) -0.0740(7) 0.0544(7) 0.2442(7) 0.3344(6) 0.5194(7) 0.3843(6) 0.1961(8) 0.179(1) 0.017(1)
0.34389(8) 0.38876(7) 0.5107(2) 0.3162(2) 0.5118(2) 0.5651(2) 0.5432(2) 0.2508(2) 0.3100(3) 0.3499(2) 0.3691(3) 0.3623(2) 0.4454(2) 0.5451(2) 0.6039(3) 0.5600(2) 0.2783(3) 0.2271(3) 0.2107(3)
5.86(4) 5.31(4) 5.4(1) 5.2(1) 3.9(1) 3.7(1) 3.8(1) 4.5(1) 5.0(2) 4.0(1) 4.7(1) 4.6(2) 4.2(1) 3.2(1) 4.8(2) 3.4(1) 6.0(2) 8.6(2) 8.6(3)
Molecule B
S(21) S(27) O(216) N(23) N(210) N(212) N(215) N(23') C(22) C(24) C(25) C(26) C(28) C(211) C(213) C(214) C(22') C(24') C(25')
Anisotropically refined atoms are given in the form of the isotropic equivalent thermal parameter defined as: 4 (a/~ll + b~22 + c/~33 + ab/312cos7 + ac~13cos/3 + bc1323cosa).
3. Discussion Final positional parameters for the non-H atoms for nizatidine are listed in Table 1. Bond lengths are listed in Table 2. An ORTEP-It [14] thermal ellipsoid drawing of the two independent molecules A and B (50% probability of non-H atoms) depicting the numbering scheme is shown in Fig. 1. A stereoscopic view of the molecular packing is shown in Fig. 2. Both molecules have intramolecular hydrogen bonds between a nitro oxygen and the ethylamino group, 2.629(4) ,~ and 2.63(2) ,A ( N . . . O ) for molecules A and B, respectively. Molecules A are related by unit translation along the x-axis, therein forming a continuous chain of intermolecular hydrogen bonds between Ol17 and N l 1 2 with a distance of 2.781(4) ,~. Similarly, B molecules are related by unit translations along the x-axis with intermolecular hydrogen bonds between O217 and N212 with a distance of 2.787(9) ,A,. The crystal structure of nizatidine differs from that of the oxalate salt of ranitidine [15] and the HCI salt of ranitidine [16], Zantac ®, in a number of respects. Spectroscopic investigations of the tautomerism of ranitidine's nitroethenedialkylamine Table 2 Selected bond lengths (A.) Bond O(116) O(117) N(ll0) N(ll2) N(l12) N(ll5) C(lll) H(010) n(012)
N(tI5) N(ll5) C(lll) C(lll) C(113) C(ll4) C(ll4) N(ll0) N(ll2)
Molecule A Bond
Molecule B
1.261(5) 1.275(4) 1.321(7) 1.327(7) 1.432(7) 1.347(6) 1.430(7) 0.717(4) 0.734(4)
1.27(3) 1.28(2) 1.34(6) 1.321(9) 1.444(9) 1.333(9) 1.408(9) 0.84(4) 0.803(9)
O(216) N(215) O(217) N(215) N(210) C(211) N(212) C(211) N(215) C(213) N(215) C(214) C(211) C(214) H(020) N(210) H(022) N(212)
Numbers in parenthesesare estimatedstandard deviationsin the least significantdigits.
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G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
,~
CJ,4'
~
~'J
17
Fig. 1. Thermal ellipsoid (51)% probability of non-H atoms) depiction of molecule A (top) and molecule B (bottom) showing the numbering scheme.
group have shown that in solution there exists rapid equilibrium between enediamine tautomers through a low barrier of rotation about the carbon-carbon double bond [5]. In the crystal structure of the oxalate salt of ranitidine, the conformation around the ethene double bond is such that the nitro and methylamino groups are cis, whereas the ethylamino group carrying the rest of
o/N_
H
I4~N~N,~.CH3
I
~ ~
I
R
H trans
Scheme 2.
O
R~N,~,,,N/H
I
H cis
Fig. 2. Molecular packing diagram showing H-bond (thin line) between molecule A and molecule B.
H~N~
I
CH3
G.A. Stephenson et aL/Journal of Molecular Structure 380 (1996) 93-100
97
Table 3 Selected torsion angles (degrees) Molecule A N(13) C(14)C(16) S(17) C(14')N(13') C(12') C(12) C(15')N(13') C(12') C(12)
72.47 (0.66) 71.43 (0.72) -166.58 (0.60)
Molecule B N(23) C(24) C(26) S(27) C(24' ) N(23' ) C(22' ) (C22) C(25') N(23') C(22') C(22)
55.96 (0.67) 170.25 (0.56) 67.71 (0.72)
Numbers in parentheses are estimated standard deviations in the least significant digits.
the molecule is trans with respect to the nitro group, Scheme 2. In the crystal structure of the hydrochloride salt of ranitidine, there is an equal population of cis and trans conformers in the unit cell. Nizatidine represents the opposite situation, with its nitro group trans with respect to the methylamino group and cis with respect to the rest of the molecule. Molecules A and B have similar molecular conformations, except for the orientation of the N,N-dimethylamino groups with respect to the aromatic ring. There is also a 16.5 ° deviation in the torsion angle N13-C14C16-S17 as compared with N23-C24-C26-$27 (see Table 3). All bond lengths and angles are in
agreement with the given atom type and hybridization with the exception of the N-ethyl-N'-methylaminonitroethylene/'esidue. The planarity of this group, the lengthening of the double bonds of molecules A and B to 1.41 ,~, and 1.43 .~, and also the shortening of the C - N bonds to an average distance of 1.33 ,~ provide evidence o f extended conjugation. Because of the high degree of conformational similarity of molecules A and B, there is little evidence of the two independent molecules in the 13C solid-state N M R spectrum. The resonances at 151.2 and 150.2 ppm, Fig. 3, are assigned to the ipso carbon of the thiazolyl ring and provide spectroscopic evidence of chemical inequivalence
PPM
I 180. O0
i
I 120. O0
I 80. O0
i
I
40. O0
i
I -O. O0
Fig. 3. The ~3C CP/MAS solid-state NM R spectrum of nizatidine shows evidence of multiple chemical environments of the ipso carbon, CI4 (and C24), thereby confirming that two independent molecular conformations exist in the crystallographic unit cell (13C 6: 173.4, 156.7, 151.2, 150.2, 119.7, 98.7, 88.7, 61.4, 46.2, 39.4 and 29.6 ppm).
98
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
0 O
g Q
F
0
O
tt%
J "i:: 0
I-
z O cxl
o
O 0 qo t'o
oo
.< ¢y
0 0 0
o
~
~
~
~o
,~
~
~
~
-
o
~
~
,~
~
~
~"
~
,~
-
G.A. Stephenson et al./Journal of Molecular Structure 380 (1996) 93-100
99
Table 4 Spectral assignments from the Fourier-transform infrared and Raman spectra of nizatidine HCI . IR (cm-I)
Raman (cm-I)
Assignment
3280,3210 3107 3094 2945, 2860, 2829,2784 1622 1587
3143 3108 3091 2949, 2916, 2826, 2780 1617 1578
1521 1470, 1458, 1 4 3 5 , 1 4 2 2 1377, 1359
1518,1487 1472,1429,1415
NH stretch; two groups CH stretch in NO,-CHCH stretch thiazole ring CH stretches in NCH3, CH,.CH_, C=C, conjugated with NO_, Asym. NO, stretch, conjugated with C=C; thiazole ring also, weak contribution Thiazole ring CH deformation in NCH 3, CH_,; CH stretch Thiazole ring for one frequency and sym. NO.,, H-bonded, conjugated H-bonded NO., H..... O
1262, 1246, 1196, 1159
o f C14 and C24 in the two independent molecules. There is considerable b r o a d e n i n g in m a n y o f the resonances in the N M R spectra, attributable to carb o n a t o m s being b o n d e d to 14N q u a d r u p o l a r nuclei. 3.1. Fourier-transform infrared and R a m a n spectroscopy T h e infrared a n d R a m a n spectra are consistent with the m o l e c u l a r structure o f nizatidine, see Fig. 4. T h e I R s p e c t r u m has N H stretches at 3280 a n d 3210 cm - l , w h e r e a s the R a m a n s p e c t r u m has c o r r e s p o n d i n g stretches at 3143 c m - I . T h e I R s p e c t r u m has two a b s o r p t i o n s a s s o c i a t e d with the c o n j u g a t e d d o u b l e b o n d at 1622 a n d 3107 c m -1, a n d the R a m a n s p e c t r u m shows an a b s o r p t i o n at 3108 c m - l . A n NO2 stretch is o b s e r v e d at 1587 in the I R a n d 1578 cm - l in the R a m a n spectra. T h i a z o l e ring stretches are o b s e r v e d at 1521 cm - I in the I R a n d 1518 a n d 1487 c m - l in the R a m a n spectra. T a b l e 4 p r o v i d e s a listing o f the spectral a s s i g n m e n t s m a d e for nizatidine.
Acknowledgments The
authors
thank
Dr.
P.E.
Fanwick,
D e p a r t m e n t o f C h e m i s t r y , P u r d u e University, for his g u i d a n c e a n d the use o f the E n r a f - N o n i u s C A D 4 diffractometer. T h e a u t h o r s also t h a n k Eli Lilly a n d C o m p a n y for the g e n e r o u s gift o f nizatidine a n d Jim O s b o r n e for p r o v i d i n g the infrared a n d R a m a n spectra.
References [I] D.C. Evan, R.R. Ruffolo, M.W. Warrick and T.M. Lin, Fed. Proc., 43 (1984) Abstr. 4618. [2] T.M. Lin, D.C. Evans, M.W. Warrick, R.P. Pioch and R.R. Ruffolo, Gastroenterology, 84 (1983) 1231. [3] C.G. Meredith, K.V. Speeg and S. Schenker, Clin. Res., 31 (1983) 765A. [4] U. Klotz, W.R. Gonlieb, P.P. Keohane and H.G. Dammann, J. Clin. Pharmacol., 27 (1987) 210. [5] T.J. Cholerton, J.H. Hunt, G. Klinkert and M. MartinSmith, J. Chem. Soc. Perkin Trans. 2, (1984) 1761. [6] B.A. Frenz, The Enraf-Nonius CAD4 soy - - a real-time system for concurrent X-ray data collection and crystal structure determination, in Computing in Crystallography, H. Schenk, R. Olthof-Hazelkamp, H. vanKonigsvelt and G.C. Bassi (Eds.), Delft University Press, Delft, 1978, p. 64. [7] N. Walker and D. Stuart, Acta Crystallogr. Sect. A, A39 (1983) 158. [8] M.C. Burla, M. Camalli, G. Cascarano, C. Giacovazzo,
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G.A. Stephenson et al./Journal o f Molecular Structure 380 (1996) 93-100
G. Polidori, R. Spagna and D. Viterbo, sms8 program for crystal structure determination. J. Appl. Crystallogr., 22 (1989) 389. [9] G.M. Sheldrick, SHELX?6 program for crystal structure determination, University of Cambridge, UK, 1976. [10] R.C.G. Killean and J.L. Lawrence, Acta Crystallogr. Sect. B, B25 (1969) 1750. [11] International Tables for X-ray Crystallography, VoI.IV, Kynoch Press, Birmingham, UK (present distributor Kluwer Academic Publishers, Dordrecht), 1974, Table 2.2B, p. 99 and Table 2.3.1, p. 149.
[12] J.A. lbers and W.C. Hamilton, Acta Crystallogr., 17 (1964) 781.. [13] D.W.J. Cruickshank, Acta Crystallogr., 2 (1949) 154. [14] C.K. Johnson, ORTEP-H, a FORTRAN thermal-ellipsoid plot program for crystal structure illustrations, Rep. ORNL-5138 (3rd revision of ORNL-3794), Oak Ridge National Laboratory, Oak Ridge, TN, 1976. [15] B. Kojic-Podic and Z. Ruzic-Toros, Acta. Crystallogr. Sect. B, B38 (1982) 1837. [16] T. Ishida, Y. In and M. Inoue, Acta Crystallogr. Sect. C, C46 (1990) 1893.