tert-Butyl 6-methyl-2-oxo-4-[4-(trifluoro­meth­oxy)anilino]cyclo­hex-3-ene-1-carboxyl­ate

Mariano S Alexander; Henry North; Kenneth R Scott; Ray J Butcher

doi:10.1107/S1600536810046969

. 2010 Nov 20;66(Pt 12):o3229. doi: 10.1107/S1600536810046969

tert-Butyl 6-methyl-2-oxo-4-[4-(trifluoromethoxy)anilino]cyclohex-3-ene-1-carboxylate

Mariano S Alexander ^a, Henry North ^a, Kenneth R Scott ^a, Ray J Butcher ^b,^*

PMCID: PMC3011753 PMID: 21589519

Abstract

In the title compound, C₁₉H₂₂F₃NO₄, the dihedral angle between the benzene ring and the conjugated part of the enaminone ring is 42.5 (1)°. The ester substituent makes a dihedral angle of 81.3 (2)° with this latter moiety. The crystal structure is held together by strong N—H⋯O and weak C—H⋯O intermolecular interactions. The enaminone ring is disordered over two orientations with relative occupancies of 0.794 (4) and 0.206 (4).

Related literature

The title compound posseses significant anticonvulsant properties. For the anticonvulsant properties of enaminones, see: Edafiogho et al. (1992 ▶); Eddington et al. (2003 ▶); Scott et al. (1993 ▶, 1995 ▶).

Experimental

Crystal data

C₁₉H₂₂F₃NO₄
M _r = 385.38
Monoclinic,
a = 13.7896 (3) Å
b = 12.0820 (2) Å
c = 11.0023 (2) Å
β = 91.1978 (18)°
V = 1832.65 (6) Å³
Z = 4
Cu Kα radiation
μ = 1.01 mm⁻¹
T = 123 K
0.48 × 0.18 × 0.08 mm

Data collection

Oxford Diffraction Xcalibur Ruby Gemini diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2007 ▶) T _min = 0.852, T _max = 1.000
7085 measured reflections
3607 independent reflections
3095 reflections with I > 2σ(I)
R _int = 0.018

Refinement

R[F ² > 2σ(F ²)] = 0.058
wR(F ²) = 0.160
S = 1.06
3607 reflections
262 parameters
H-atom parameters constrained
Δρ_max = 0.66 e Å⁻³
Δρ_min = −0.39 e Å⁻³

Data collection: CrysAlis PRO (Oxford Diffraction, 2007 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810046969/hg2750sup1.cif

e-66-o3229-sup1.cif^{(24.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810046969/hg2750Isup2.hkl

e-66-o3229-Isup2.hkl^{(176.9KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1A⋯O2ⁱ	0.88	2.08	2.886 (2)	153
C2—H2A⋯O2ⁱ	0.95	2.58	3.333 (3)	136
C6—H6A⋯O3ⁱⁱ	0.95	2.55	3.385 (3)	147
C9B—H9BA⋯O3ⁱⁱⁱ	0.99	2.44	3.40 (6)	162

Open in a new tab

Symmetry codes: (i) Inline graphic ; (ii) ; (iii) .

Acknowledgments

The authors are indebted to Mr James P. Stables, Epilepsy Branch, Division of Convulsive, Developmental and Neuromuscular Disorders, National Institute of Neurological Disorders and Stroke, for helpful discussions and initial data. The authors wish to acknowledge E. Jeannette Andrews, EdD, Deputy Director of the Center of Excellence at Howard University College of Pharmacy, Nursing and Allied Health Sciences, for her generous assistance in completing this project. RJB wishes to acknowledge the NSF–MRI program (grant CHE-0619278) for funds to purchase the diffractometer.

supplementary crystallographic information

Comment

Our research on enaminones has led to several compounds possessing anticonvulsant properties (Edafiogho et al., 1992; Eddington et al., 2003; Scott et al., 1993, 1995). The present work is part of a structural study of enaminones. Our group has extensively studied the effects of modification of the enaminone with substitutions at the methyl ester, ethyl ester, and without the ester group. We synthesized a series of carbo-tert-butoxy esters to evaluate the effect of added bulk and lipophilicity to the ester functionality. The title compound, tert-butyl-4-(4-trifluoromethoxyphenylamino)-6-methyl-2-oxocyclohex-3-en-1-oate (10) is highly active, with activity at <100 mg kg^-1.

The compound was exclusively active in maximal electroshock seizure evaluation (MES) in mice, indicative of protection against tonic-clonic convulsions in humans (1/4 rats were protected at 15 min then 3/4 rats at 2 h and 4 hrs at post dose 50 mg kg^-1 in rats, orally). The MES test with mice revealed no activity in the 30 minute study, however in the 4 h MES test 1/1 animals were protected at 30 mg kg^-1, 3/3 animals protected at 100 mg kg^-1, and 1/1 at 300 mg kg^-1 with no toxicity. The scMET (subcutaneous phentylenetetrazole assessment), indicative of protection against absence seizures was 0/2 animals protected in doses of 62.5 to 500 mg kg^-1. The compound displayed no toxicity from 62.5 to 500 mg kg^-1 from 15 min to 24 h time range in all doses. A four hour MES test showed 4/16 mice protected at 100 mg kg^-1 dose and maximium protection (7/8 mice protected) at 150 and 200 mg kg^-1. In mice, a MES ED₅₀ (median effective dose) of 121.87 mg kg-1 and TD₅₀ (median toxic dose) of >500 mg kg-1, provided a protective index PI (defined as the ration of the median toxic dose to the median effective dose) at 95% confidence interval.

In view of the therapeutic interest in this compound its structure was determined. The conformation adopted by the molecule is such that the dihedral angle between the phenyl ring and conjugated part of the enaminone ring is 42.5 (1)°. The ester substituent makes a dihedral angle of 81.3 (2)° with this latter moiety. The crystal structure is held together by strong N—H···O and weak C—H···O intermolecular interactions. The enaminone ring is disordered over two conformations with relative occupancies of 0.794 (4)/0.206 (4).

Experimental

4-Carbo-t-butoxy-5-methylcyclohexane-1,3-dione (6.11 g, 27 mmol), mp 145–146°C (lit. mp 130–131.5°C), and 4-trifluoromethoxyaniline (4.428 ml g, 33 mmol) were added to a mixture of absolute EtOH (100 ml) and EtOAc (100 ml), and the solution was refluxed and stirred for 6 h with azeotropic removal of water by Dean-Stark trap. Evaporation under reduced pressure yielded a yellow solid which was recrystallized from 2-PrOH, 47% yield (mp 168–171°C). ).