2-Methyl-4-(4-methyl­piperazin-1-yl)-10H-thieno­[2,3-b][1,5]­benzodiazepine methanol solvate monohydrate

The thienobenzodi­az­epine nucleus of the title compound, olanzapine methanol solvate monohydrate, C₁₇H₂₀N₄S·CH₄O·H₂O, is buckled, with the central seven-membered heterocycle in a boat conformation and the dihedral angle between the planes of the aromatic rings being 118°. The piperazine ring displays an almost perfect chair conformation with the methyl group assuming an equatorial orientation. The relative position of the thienobenzodiazepine and piperazine ring system is controlled by the planarity of the piperazine N in the amidine moiety.

Key indicators

• Single-crystal X-ray study
• T = 123 K
• Mean [sigma](C-C) = 0.003 Å
• R factor = 0.044
• wR factor = 0.092
• Data-to-parameter ratio = 19.2

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT141_ALERT_4_C su on a - Axis Small or Missing (x 100000) .....         20 Ang.
PLAT152_ALERT_1_C Supplied and Calc Volume s.u. Inconsistent .....          ?

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   2 ALERT level C = Check and explain
   0 ALERT level G = General alerts; check

   1 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   0 ALERT type 2 Indicator that the structure model may be wrong or deficient
   0 ALERT type 3 Indicator that the structure quality may be low
   1 ALERT type 4 Improvement, methodology, query or suggestion

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S1. Comment

Schizophrenia is a debilitating mental disorder characterized by the chaotic jumbling and breakdown of internal thought processes. This devastating disease afflicts approximately 1% of the world population. The symptoms of this disease can be divided into two distinct categories, positive (delusions and hallucinations) and negative (social and emotional withdrawal) (Andreasen et al., 1994). Theraputics used to treat this disorder are divided into two clinical classes; typical and atypical (Gerlach, 1991). Typical antipsychotics exhibit efficacy against the positive symptoms of schizophrenia and have a propensity to induce extrapyramidal symptoms (EPS); movement disorders such as parkinsonism, dystonia and motor restlessness. Long-term administration of typical agents can lead to an irreversible condition known as tardive dyskinesia (TD) which is characterized by involuntary facial contortions. Atypical antipsychotics are efficacious against both positive and negative symptoms of schizophrenia, as well as associated cognitive deficits, and are virtually devoid of EPS and TD.

The title compound, olanzapine (ZYPREXA^TM), (I)(Fig. 1), is an atypical antipsychotic by Eli Lilly and Company that obtained approval by the FDA in 1996 for the treatment of schizophrenia and related psychoses. Olanzapine is effective in ameliorating the positive and negative symptoms of schizophrenia and is practically free of movement disorders (Fulton & Goa, 1997). The theraputic action of olanzapine against the symptoms of schizophrenia is thought to be due to its high affinity for dopaminergic D₂ and serotonergic 5-HT_{2 A} receptors (Bever & Perry, 1998); receptor systems implicated in the pathogenesis of this disease state. As a consequence, olanzapine is commonly referred to as a `serotonin-dopamine antagonist' (SDA). Electrophysiologic studies (Stockton & Rasmussen, 1996) have demonstrated olanzipine's preferential affinity for dopaminergic receptors in the mesolimbic area (A10 neurons) of the brain compared to the striatum (A9 neurons). This finding may account for its improved theraputic profile compared to typical antipsychotics, and low incidence of EPS.

Our interest in the structure of (I) was to examine its solid-state conformation and use this information, in conjunction with crystallographic data of other antischizophrenic agents, to design and synthesize novel potential atypical antipsychotics without clinically limited side effects.

The conformation of olanzipine shows the buckled nature of the thienobenzodiazepine nucleus with the central seven-membered heterocycle in a boat conformation. The dihedral angle between the planes of the aromatic rings is 117.67 (5)°, which is similar to the 115° observed for the prototypical atypical antipsychotic, colozapine (Petcher & Weber, 1976). Interestingly, molecular modelling of olanzapine with HYPERCHEM predicts an interplanar angle of 135° between the benzene and thiophene rings (Lien et al., 1996). The dihedral angles between the plane of the four C atoms in the piperazine ring and the methyl-substituted thiophene ring and unsubstituted benzene ring are 29.7 (1) and 33.9 (1)°, respectively, a consequence of the planarity of the piperizine N in the amidine moiety and the partial double bond character of N3—C12. The piperazine ring adopts an almost perfect chair conformation with the methyl group assuming an equatorial orientation.

S2. Experimental

The title compound was patented by Chakrabarti et al. (1991). We greatfully acknowledge Eli Lilly and Company, West Rhyde, New South Wales, Australia, for supplying a sample of (I) as a pale-yellow powder·(I) was recrystallized by the diffusion method, from a methanol solution of the compound layered onto water, as bright yellow prisms.

S3. Refinement

Most H atoms were included in the riding-model approximation [C—H(methylene) = 0.99 Å, C—H(methyl) = 0.98 Å, C—H(aromatic) = 0.95 Å and O—H(methanol) = 0.84 Å] with U_iso(aromatic-H and methylene-H) = 1.2U_eq(C). The H atoms on O2 and N1 were refined.

Computing details

Data collection: COLLECT (Nonius BV, 1997-2000); cell refinement: HKL SCALEPACK (Otwinowski & Minor, 1997); data reduction: HKL DENZO (Otwinowski & Minor, 1997) and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX publication routines (Farrugia, 1999).

Figures

Fig. 1. View of (I) (50% probability displacement ellipsoids).

(I)

Crystal data

C17H20N4S·CH4O·H2O	F(000) = 1552
Mr = 362.49	Dx = 1.283 Mg m^−3
Monoclinic, C2/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -C 2yc	Cell parameters from 21650 reflections
a = 25.3587 (2) Å	θ = 2.6–28.3°
b = 11.9729 (2) Å	µ = 0.19 mm^−1
c = 15.6010 (2) Å	T = 123 K
β = 127.582 (1)°	Prismatic, yellow
V = 3753.77 (8) Å^3	0.15 × 0.14 × 0.14 mm
Z = 8

Data collection

KappaCCD diffractometer	3683 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.041
Horizonally mounted graphite crystal monochromator	θmax = 28.3°, θmin = 2.6°
Detector resolution: 9 pixels mm^-1	h = −33→33
CCD rotation images in ϕ and ω, thick slices scans	k = −15→15
20806 measured reflections	l = −20→20
4643 independent reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.044	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.092	H atoms treated by a mixture of independent and constrained refinement
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0341P)^2 + 3.6138P] where P = (Fo^2 + 2Fc^2)/3
4643 reflections	(Δ/σ)max = 0.001
242 parameters	Δρmax = 0.40 e Å^−3
0 restraints	Δρmin = −0.32 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
C1	0.10965 (8)	0.94868 (13)	0.18536 (13)	0.0206 (3)
H1A	0.0731	0.9262	0.1113	0.031*
H1B	0.1257	1.0228	0.1845	0.031*
H1C	0.0937	0.9511	0.2289	0.031*
C2	0.16534 (7)	0.86597 (12)	0.23344 (12)	0.0150 (3)
C3	0.18515 (7)	0.78810 (12)	0.31062 (11)	0.0139 (3)
H3	0.1640	0.7781	0.3436	0.017*
C4	0.24083 (7)	0.72199 (12)	0.33826 (11)	0.0127 (3)
C5	0.26366 (7)	0.75393 (12)	0.28198 (11)	0.0131 (3)
C6	0.37941 (7)	0.73079 (12)	0.40753 (11)	0.0130 (3)
C7	0.43267 (7)	0.79212 (13)	0.42741 (12)	0.0170 (3)
H7	0.4299	0.8221	0.3684	0.020*
C8	0.48943 (7)	0.80978 (13)	0.53202 (13)	0.0200 (3)
H8	0.5253	0.8519	0.5447	0.024*
C9	0.49376 (7)	0.76580 (13)	0.61843 (12)	0.0178 (3)
H9	0.5322	0.7789	0.6905	0.021*
C10	0.44164 (7)	0.70256 (12)	0.59891 (12)	0.0150 (3)
H10	0.4456	0.6706	0.6583	0.018*
C11	0.38359 (7)	0.68461 (12)	0.49437 (11)	0.0126 (3)
C12	0.27225 (7)	0.62998 (12)	0.41716 (11)	0.0124 (3)
C13	0.25732 (7)	0.48180 (13)	0.50978 (12)	0.0156 (3)
H13A	0.3013	0.5069	0.5745	0.019*
H13B	0.2634	0.4095	0.4860	0.019*
C14	0.20989 (7)	0.46729 (13)	0.53773 (12)	0.0180 (3)
H14A	0.2276	0.4097	0.5947	0.022*
H14B	0.2066	0.5384	0.5665	0.022*
C15	0.11731 (7)	0.51950 (13)	0.35793 (13)	0.0193 (3)
H15A	0.1130	0.5914	0.3845	0.023*
H15B	0.0726	0.4970	0.2933	0.023*
C16	0.16359 (7)	0.53390 (13)	0.32756 (12)	0.0164 (3)
H16A	0.1658	0.4633	0.2968	0.020*
H16B	0.1461	0.5930	0.2720	0.020*
C17	0.09905 (9)	0.41697 (15)	0.47150 (16)	0.0281 (4)
H17A	0.1178	0.3599	0.5281	0.042*
H17B	0.0554	0.3924	0.4076	0.042*
H17C	0.0942	0.4872	0.4983	0.042*
C18	0.45804 (8)	0.39384 (15)	0.60240 (14)	0.0266 (4)
H18A	0.4761	0.4585	0.5895	0.040*
H18B	0.4342	0.3454	0.5385	0.040*
H18C	0.4946	0.3519	0.6650	0.040*
N1	0.32099 (6)	0.71296 (11)	0.29962 (10)	0.0145 (3)
N2	0.33596 (6)	0.61103 (10)	0.48370 (9)	0.0133 (3)
N3	0.23026 (6)	0.56443 (10)	0.42333 (9)	0.0143 (3)
N4	0.14363 (6)	0.43402 (10)	0.44242 (10)	0.0178 (3)
S1	0.216496 (18)	0.86312 (3)	0.19364 (3)	0.01644 (10)
O1	0.41373 (6)	0.43087 (10)	0.62292 (9)	0.0248 (3)
H1	0.3881	0.4796	0.5771	0.037*
O2	0.14343 (7)	0.24120 (11)	0.33951 (10)	0.0287 (3)
H2A	0.1438 (11)	0.298 (2)	0.3743 (18)	0.053 (7)*
H2B	0.1264 (11)	0.187 (2)	0.3499 (17)	0.046 (6)*
H1N	0.3263 (8)	0.7280 (15)	0.2524 (14)	0.022 (5)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0186 (8)	0.0173 (8)	0.0257 (8)	0.0051 (6)	0.0134 (7)	0.0060 (7)
C2	0.0123 (7)	0.0149 (7)	0.0174 (7)	−0.0013 (6)	0.0088 (6)	−0.0017 (6)
C3	0.0126 (7)	0.0137 (7)	0.0159 (7)	−0.0030 (5)	0.0089 (6)	−0.0020 (6)
C4	0.0112 (7)	0.0130 (7)	0.0121 (7)	−0.0015 (5)	0.0062 (6)	0.0002 (6)
C5	0.0134 (7)	0.0124 (7)	0.0118 (7)	0.0001 (5)	0.0068 (6)	−0.0002 (6)
C6	0.0125 (7)	0.0132 (7)	0.0146 (7)	0.0020 (5)	0.0090 (6)	−0.0011 (6)
C7	0.0187 (8)	0.0181 (8)	0.0206 (8)	0.0013 (6)	0.0152 (7)	0.0029 (6)
C8	0.0152 (7)	0.0213 (8)	0.0274 (8)	−0.0035 (6)	0.0149 (7)	−0.0010 (7)
C9	0.0122 (7)	0.0203 (8)	0.0179 (7)	−0.0004 (6)	0.0077 (6)	−0.0023 (6)
C10	0.0144 (7)	0.0157 (7)	0.0146 (7)	0.0014 (6)	0.0087 (6)	0.0017 (6)
C11	0.0126 (7)	0.0098 (7)	0.0183 (7)	0.0013 (5)	0.0109 (6)	−0.0004 (6)
C12	0.0146 (7)	0.0125 (7)	0.0126 (7)	−0.0017 (5)	0.0096 (6)	−0.0022 (6)
C13	0.0149 (7)	0.0167 (7)	0.0161 (7)	−0.0004 (6)	0.0099 (6)	0.0033 (6)
C14	0.0213 (8)	0.0170 (8)	0.0214 (8)	−0.0023 (6)	0.0160 (7)	0.0003 (6)
C15	0.0129 (7)	0.0171 (8)	0.0274 (8)	−0.0004 (6)	0.0120 (7)	0.0001 (7)
C16	0.0126 (7)	0.0156 (7)	0.0179 (7)	−0.0025 (6)	0.0077 (6)	0.0000 (6)
C17	0.0281 (9)	0.0266 (9)	0.0450 (11)	−0.0043 (7)	0.0302 (9)	−0.0010 (8)
C18	0.0215 (8)	0.0323 (9)	0.0270 (9)	0.0021 (7)	0.0152 (8)	0.0015 (8)
N1	0.0140 (6)	0.0200 (7)	0.0125 (6)	0.0008 (5)	0.0096 (5)	0.0006 (5)
N2	0.0129 (6)	0.0135 (6)	0.0148 (6)	−0.0011 (5)	0.0092 (5)	0.0011 (5)
N3	0.0121 (6)	0.0149 (6)	0.0144 (6)	−0.0013 (5)	0.0074 (5)	0.0033 (5)
N4	0.0183 (7)	0.0155 (6)	0.0270 (7)	−0.0029 (5)	0.0176 (6)	0.0000 (6)
S1	0.01615 (18)	0.01826 (19)	0.01590 (18)	0.00254 (15)	0.01028 (15)	0.00547 (16)
O1	0.0251 (6)	0.0236 (6)	0.0308 (6)	0.0069 (5)	0.0197 (6)	0.0114 (5)
O2	0.0514 (8)	0.0197 (6)	0.0378 (7)	−0.0064 (6)	0.0389 (7)	−0.0043 (6)

Geometric parameters (Å, º)

C1—C2	1.499 (2)	C13—N3	1.4628 (19)
C1—H1A	0.9800	C13—C14	1.519 (2)
C1—H1B	0.9800	C13—H13A	0.9900
C1—H1C	0.9800	C13—H13B	0.9900
C2—C3	1.354 (2)	C14—N4	1.4647 (19)
C2—S1	1.7469 (14)	C14—H14A	0.9900
C3—C4	1.437 (2)	C14—H14B	0.9900
C3—H3	0.9500	C15—N4	1.469 (2)
C4—C5	1.3683 (19)	C15—C16	1.520 (2)
C4—C12	1.472 (2)	C15—H15A	0.9900
C5—N1	1.3936 (18)	C15—H15B	0.9900
C5—S1	1.7402 (14)	C16—N3	1.4639 (18)
C6—C7	1.396 (2)	C16—H16A	0.9900
C6—C11	1.406 (2)	C16—H16B	0.9900
C6—N1	1.4255 (18)	C17—N4	1.4667 (19)
C7—C8	1.384 (2)	C17—H17A	0.9800
C7—H7	0.9500	C17—H17B	0.9800
C8—C9	1.388 (2)	C17—H17C	0.9800
C8—H8	0.9500	C18—O1	1.4144 (19)
C9—C10	1.386 (2)	C18—H18A	0.9800
C9—H9	0.9500	C18—H18B	0.9800
C10—C11	1.395 (2)	C18—H18C	0.9800
C10—H10	0.9500	N1—H1N	0.846 (18)
C11—N2	1.4204 (18)	O1—H1	0.8400
C12—N2	1.3014 (18)	O2—H2A	0.86 (3)
C12—N3	1.3726 (18)	O2—H2B	0.85 (2)
C2—C1—H1A	109.5	H13A—C13—H13B	108.2
C2—C1—H1B	109.5	N4—C14—C13	111.02 (12)
H1A—C1—H1B	109.5	N4—C14—H14A	109.4
C2—C1—H1C	109.5	C13—C14—H14A	109.4
H1A—C1—H1C	109.5	N4—C14—H14B	109.4
H1B—C1—H1C	109.5	C13—C14—H14B	109.4
C3—C2—C1	128.69 (13)	H14A—C14—H14B	108.0
C3—C2—S1	110.46 (11)	N4—C15—C16	110.13 (12)
C1—C2—S1	120.83 (11)	N4—C15—H15A	109.6
C2—C3—C4	114.19 (13)	C16—C15—H15A	109.6
C2—C3—H3	122.9	N4—C15—H15B	109.6
C4—C3—H3	122.9	C16—C15—H15B	109.6
C5—C4—C3	112.11 (13)	H15A—C15—H15B	108.1
C5—C4—C12	121.38 (13)	N3—C16—C15	109.92 (12)
C3—C4—C12	126.50 (12)	N3—C16—H16A	109.7
C4—C5—N1	125.00 (13)	C15—C16—H16A	109.7
C4—C5—S1	111.27 (10)	N3—C16—H16B	109.7
N1—C5—S1	123.45 (10)	C15—C16—H16B	109.7
C7—C6—C11	119.91 (13)	H16A—C16—H16B	108.2
C7—C6—N1	120.59 (13)	N4—C17—H17A	109.5
C11—C6—N1	119.50 (13)	N4—C17—H17B	109.5
C8—C7—C6	120.80 (14)	H17A—C17—H17B	109.5
C8—C7—H7	119.6	N4—C17—H17C	109.5
C6—C7—H7	119.6	H17A—C17—H17C	109.5
C7—C8—C9	119.78 (14)	H17B—C17—H17C	109.5
C7—C8—H8	120.1	O1—C18—H18A	109.5
C9—C8—H8	120.1	O1—C18—H18B	109.5
C10—C9—C8	119.59 (14)	H18A—C18—H18B	109.5
C10—C9—H9	120.2	O1—C18—H18C	109.5
C8—C9—H9	120.2	H18A—C18—H18C	109.5
C9—C10—C11	121.74 (14)	H18B—C18—H18C	109.5
C9—C10—H10	119.1	C5—N1—C6	112.83 (12)
C11—C10—H10	119.1	C5—N1—H1N	117.1 (12)
C10—C11—C6	118.14 (13)	C6—N1—H1N	113.2 (12)
C10—C11—N2	116.64 (12)	C12—N2—C11	122.59 (12)
C6—C11—N2	124.88 (13)	C12—N3—C13	120.23 (12)
N2—C12—N3	118.89 (13)	C12—N3—C16	122.25 (12)
N2—C12—C4	124.95 (12)	C13—N3—C16	111.88 (11)
N3—C12—C4	116.05 (12)	C14—N4—C17	110.31 (12)
N3—C13—C14	109.49 (12)	C14—N4—C15	109.49 (11)
N3—C13—H13A	109.8	C17—N4—C15	111.13 (12)
C14—C13—H13A	109.8	C5—S1—C2	91.94 (7)
N3—C13—H13B	109.8	C18—O1—H1	109.5
C14—C13—H13B	109.8	H2A—O2—H2B	107 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···N2	0.84	2.00	2.835 (2)	172
O2—H2A···N4	0.86 (3)	1.95 (3)	2.810 (2)	175 (2)
O2—H2B···O1^i	0.85 (2)	1.93 (2)	2.779 (2)	177 (2)
N1—H1N···O2^ii	0.85 (2)	2.00 (2)	2.834 (2)	167 (2)

Symmetry codes: (i) −x+1/2, −y+1/2, −z+1; (ii) −x+1/2, y+1/2, −z+1/2.