Macozinone: revised synthesis and crystal structure of a promising new drug for treating drug-sensitive and drug-resistant tuberculosis

Mycobacterium tuberculosis (Mtb), the principal etiological agent of tuberculosis (TB), infects over one-quarter of humanity and is now the leading cause of infectious disease mortality by a single pathogen. Macozinone {2-[4-(cyclo­hexyl­meth­yl)piperazin-1-yl]-8-nitro-6-(tri­fluoro­meth­yl)-4H-1,3-benzo­thia­zin-4-one, C₂₀H₂₃F₃N₄O₃S} is a promising new drug for treating drug-sensitive and drug-resistant TB that has successfully completed phase I clinical trials. We report the complete spectroscopic and structural characterization by ¹H NMR, ¹³C NMR, HRMS, IR, and X-ray crystallography. The cyclo­hexyl moiety is observed to be nearly perpendicular to the core formed by the 1,3-benzo­thia­zin-4-one and piperazine groups. The central piperazine ring adopts a slightly distorted chair conformation caused by sp²-hybridization of the nitro N atom, which donates into the electron-deficient 1,3-benzo­thia­zin-4-one group.

Computing details

Data collection: APEX2 (Bruker, 2013); cell refinement: SAINT (Bruker, 2013); data reduction: SAINT (Bruker, 2013); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

{2-[4-(Cyclohexylmethyl)piperazin-1-yl]-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one

Crystal data

C20H23F3N4O3S	F(000) = 952
Mr = 456.48	Dx = 1.445 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 15.051 (7) Å	Cell parameters from 4036 reflections
b = 5.295 (2) Å	θ = 2.7–27.7°
c = 26.548 (11) Å	µ = 0.21 mm^−1
β = 97.372 (7)°	T = 205 K
V = 2098.3 (15) Å^3	Block, colourless
Z = 4	0.16 × 0.15 × 0.12 mm

Data collection

Bruker D8 Venture diffractometer	3412 reflections with I > 2σ(I)
phi and ω scans	Rint = 0.025
Absorption correction: multi-scan (SADABS; Bruker, 2014/3)	θmax = 27.7°, θmin = 1.9°
Tmin = 0.641, Tmax = 0.746	h = −19→18
11854 measured reflections	k = −6→6
4794 independent reflections	l = −26→34

Refinement

Refinement on F^2	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.047	H-atom parameters constrained
wR(F^2) = 0.122	w = 1/[σ^2(Fo^2) + (0.0422P)^2 + 1.0593P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max = 0.001
4794 reflections	Δρmax = 0.28 e Å^−3
326 parameters	Δρmin = −0.21 e Å^−3
36 restraints

Special details

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

Refinement. Single-crystal X-ray diffraction measurements were carried out on a Bruker SMART APEXII CCD diffractometer at 205.0 K using graphite-monochromated Mo Kα radiation (λ = 0.71070 Å). Absorption correction was performed with Multi-scan BRUKER SADABS. All structures were solved by direct methods and refined by full-matrix least squares on F² using the OLEX 2-1.2 computer program package.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
S1	0.52703 (3)	0.65072 (11)	0.42522 (2)	0.04694 (16)
F1	0.8552 (9)	−0.1746 (17)	0.4930 (6)	0.108 (3)	0.54 (2)
F1A	0.8725 (9)	−0.143 (3)	0.4794 (5)	0.111 (4)	0.46 (2)
F2	0.9241 (6)	0.170 (3)	0.4874 (6)	0.128 (4)	0.54 (2)
F2A	0.9244 (7)	0.184 (2)	0.5097 (9)	0.125 (5)	0.46 (2)
F3	0.8780 (7)	0.076 (3)	0.5547 (4)	0.102 (3)	0.54 (2)
F3A	0.8502 (11)	−0.052 (4)	0.5517 (5)	0.129 (5)	0.46 (2)
O1	0.63947 (12)	0.0187 (4)	0.34831 (6)	0.0694 (5)
O2	0.5728 (11)	0.832 (3)	0.5164 (5)	0.070 (4)	0.5
O3	0.6875 (10)	0.755 (3)	0.5709 (6)	0.081 (4)	0.5
N1	0.54185 (11)	0.3384 (4)	0.34317 (6)	0.0487 (4)
N2	0.63712 (12)	0.7050 (4)	0.53079 (7)	0.0526 (5)
N3	0.43493 (11)	0.6421 (4)	0.33536 (6)	0.0515 (5)
N4	0.26569 (10)	0.7797 (3)	0.28300 (6)	0.0434 (4)
C1	0.50279 (12)	0.5254 (4)	0.36293 (7)	0.0425 (5)
C2	0.61018 (13)	0.2030 (5)	0.36797 (7)	0.0464 (5)
C3	0.65155 (12)	0.2764 (4)	0.42019 (7)	0.0413 (5)
C4	0.61939 (12)	0.4688 (4)	0.44857 (7)	0.0372 (4)
C5	0.66502 (12)	0.5100 (4)	0.49754 (7)	0.0410 (5)
C6	0.73970 (13)	0.3740 (4)	0.51622 (8)	0.0468 (5)
H6	0.769070	0.407636	0.548954	0.056*
C7	0.77130 (13)	0.1896 (4)	0.48713 (8)	0.0479 (5)
C8	0.85604 (17)	0.0546 (6)	0.50615 (10)	0.0662 (7)
C9	0.72686 (13)	0.1392 (5)	0.43980 (8)	0.0486 (5)
H9	0.747755	0.009301	0.420233	0.058*
C10	0.41082 (14)	0.5820 (6)	0.28127 (8)	0.0603 (7)
H10A	0.439959	0.424089	0.273247	0.072*
H10B	0.431976	0.716647	0.260462	0.072*
C11	0.31140 (14)	0.5553 (5)	0.26915 (7)	0.0493 (5)
H11A	0.296009	0.523696	0.232706	0.059*
H11B	0.291271	0.409934	0.287546	0.059*
C12	0.28611 (15)	0.8181 (5)	0.33727 (7)	0.0543 (6)
H12A	0.266122	0.671138	0.355248	0.065*
H12B	0.253750	0.966621	0.347326	0.065*
C13	0.38519 (16)	0.8555 (5)	0.35200 (9)	0.0615 (7)
H13A	0.404235	1.010959	0.336436	0.074*
H13B	0.398081	0.873235	0.388956	0.074*
C14	0.16929 (13)	0.7631 (5)	0.26748 (8)	0.0508 (5)
H14A	0.139390	0.893787	0.285327	0.061*
H14B	0.148037	0.598650	0.277928	0.061*
C15	0.14244 (13)	0.7943 (4)	0.21079 (7)	0.0431 (5)
H15	0.174017	0.663337	0.193265	0.052*
C16	0.16959 (17)	1.0481 (5)	0.19249 (9)	0.0625 (6)
H16A	0.235041	1.062146	0.198156	0.075*
H16B	0.144881	1.180598	0.212410	0.075*
C17	0.1376 (2)	1.0897 (6)	0.13692 (10)	0.0831 (9)
H17A	0.152016	1.262774	0.127726	0.100*
H17B	0.169625	0.974292	0.116704	0.100*
C18	0.0386 (2)	1.0477 (6)	0.12409 (11)	0.0823 (9)
H18A	0.006208	1.179663	0.140110	0.099*
H18B	0.022299	1.060636	0.087238	0.099*
C19	0.01126 (18)	0.7948 (6)	0.14168 (10)	0.0745 (8)
H19A	0.036229	0.662908	0.121730	0.089*
H19B	−0.054178	0.780856	0.135811	0.089*
C20	0.04285 (15)	0.7530 (6)	0.19717 (9)	0.0645 (7)
H20A	0.028111	0.580029	0.206253	0.077*
H20B	0.010587	0.868432	0.217269	0.077*
O3A	0.6660 (9)	0.690 (3)	0.5751 (5)	0.063 (2)	0.5
O2A	0.5785 (13)	0.850 (4)	0.5140 (6)	0.080 (4)	0.5

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
S1	0.0422 (3)	0.0577 (4)	0.0374 (3)	0.0079 (2)	−0.00828 (19)	−0.0052 (2)
F1	0.092 (5)	0.053 (3)	0.168 (8)	0.019 (3)	−0.029 (5)	−0.001 (3)
F1A	0.079 (5)	0.132 (8)	0.107 (5)	0.066 (5)	−0.043 (4)	−0.058 (6)
F2	0.040 (3)	0.164 (8)	0.183 (8)	0.031 (3)	0.020 (4)	0.080 (6)
F2A	0.048 (4)	0.091 (5)	0.221 (12)	0.001 (3)	−0.047 (6)	−0.023 (7)
F3	0.090 (4)	0.129 (7)	0.074 (3)	0.048 (4)	−0.042 (3)	−0.010 (4)
F3A	0.124 (7)	0.174 (11)	0.085 (5)	0.080 (7)	−0.001 (5)	0.042 (6)
O1	0.0746 (11)	0.0853 (13)	0.0458 (9)	0.0258 (10)	−0.0022 (8)	−0.0171 (9)
O2	0.072 (6)	0.100 (10)	0.035 (4)	0.050 (6)	−0.008 (4)	−0.016 (4)
O3	0.073 (7)	0.091 (9)	0.070 (6)	0.017 (5)	−0.031 (5)	−0.043 (5)
N1	0.0419 (9)	0.0666 (13)	0.0354 (8)	0.0050 (9)	−0.0031 (7)	−0.0064 (9)
N2	0.0508 (10)	0.0619 (13)	0.0419 (10)	0.0087 (10)	−0.0067 (8)	−0.0093 (9)
N3	0.0428 (9)	0.0688 (13)	0.0390 (9)	0.0082 (9)	−0.0094 (7)	−0.0053 (9)
N4	0.0404 (9)	0.0533 (11)	0.0337 (8)	0.0026 (8)	−0.0065 (6)	−0.0019 (8)
C1	0.0327 (9)	0.0573 (14)	0.0354 (9)	−0.0037 (9)	−0.0033 (7)	0.0010 (9)
C2	0.0411 (10)	0.0625 (15)	0.0353 (10)	0.0037 (10)	0.0037 (8)	−0.0052 (10)
C3	0.0338 (9)	0.0532 (13)	0.0362 (10)	−0.0008 (9)	0.0014 (7)	0.0007 (9)
C4	0.0305 (9)	0.0463 (12)	0.0337 (9)	−0.0029 (8)	−0.0002 (7)	0.0025 (8)
C5	0.0369 (10)	0.0489 (13)	0.0357 (10)	−0.0004 (9)	−0.0018 (7)	−0.0031 (9)
C6	0.0384 (10)	0.0585 (14)	0.0405 (10)	−0.0007 (10)	−0.0066 (8)	−0.0007 (10)
C7	0.0365 (10)	0.0575 (14)	0.0474 (11)	0.0065 (10)	−0.0032 (8)	0.0002 (11)
C8	0.0518 (14)	0.0741 (19)	0.0668 (16)	0.0172 (13)	−0.0144 (12)	−0.0065 (14)
C9	0.0382 (10)	0.0606 (15)	0.0463 (11)	0.0061 (10)	0.0029 (8)	−0.0055 (11)
C10	0.0479 (12)	0.098 (2)	0.0328 (10)	0.0152 (13)	−0.0042 (9)	−0.0019 (12)
C11	0.0487 (11)	0.0646 (15)	0.0319 (10)	0.0043 (11)	−0.0056 (8)	−0.0067 (10)
C12	0.0557 (12)	0.0663 (16)	0.0369 (10)	0.0179 (11)	−0.0095 (9)	−0.0117 (10)
C13	0.0616 (14)	0.0593 (15)	0.0552 (13)	0.0123 (12)	−0.0248 (11)	−0.0148 (12)
C14	0.0394 (10)	0.0706 (16)	0.0403 (11)	0.0025 (10)	−0.0025 (8)	0.0004 (10)
C15	0.0428 (10)	0.0447 (12)	0.0386 (10)	0.0037 (9)	−0.0070 (8)	−0.0023 (9)
C16	0.0654 (15)	0.0550 (15)	0.0618 (14)	−0.0078 (12)	−0.0122 (11)	0.0056 (12)
C17	0.098 (2)	0.081 (2)	0.0654 (17)	−0.0008 (17)	−0.0073 (15)	0.0278 (16)
C18	0.100 (2)	0.0721 (19)	0.0639 (16)	0.0223 (17)	−0.0313 (15)	0.0081 (15)
C19	0.0699 (16)	0.078 (2)	0.0659 (16)	0.0025 (14)	−0.0305 (13)	−0.0043 (14)
C20	0.0483 (12)	0.0796 (18)	0.0602 (14)	−0.0067 (13)	−0.0136 (10)	0.0029 (13)
O3A	0.062 (5)	0.082 (7)	0.039 (2)	0.011 (4)	−0.018 (3)	−0.016 (3)
O2A	0.090 (8)	0.060 (6)	0.080 (8)	0.026 (5)	−0.027 (6)	−0.020 (5)

Geometric parameters (Å, º)

S1—C1	1.776 (2)	C9—H9	0.9400
S1—C4	1.739 (2)	C10—H10A	0.9800
F1—C8	1.262 (10)	C10—H10B	0.9800
F1A—C8	1.305 (11)	C10—C11	1.496 (3)
F2—C8	1.342 (9)	C11—H11A	0.9800
F2A—C8	1.229 (11)	C11—H11B	0.9800
F3—C8	1.293 (9)	C12—H12A	0.9800
F3A—C8	1.347 (10)	C12—H12B	0.9800
O1—C2	1.216 (3)	C12—C13	1.506 (3)
O2—N2	1.200 (16)	C13—H13A	0.9800
O3—N2	1.253 (14)	C13—H13B	0.9800
N1—C1	1.296 (3)	C14—H14A	0.9800
N1—C2	1.353 (3)	C14—H14B	0.9800
N2—C5	1.455 (3)	C14—C15	1.516 (3)
N2—O3A	1.203 (14)	C15—H15	0.9900
N2—O2A	1.211 (18)	C15—C16	1.504 (3)
N3—C1	1.330 (2)	C15—C20	1.512 (3)
N3—C10	1.470 (3)	C16—H16A	0.9800
N3—C13	1.455 (3)	C16—H16B	0.9800
N4—C11	1.444 (3)	C16—C17	1.508 (3)
N4—C12	1.449 (2)	C17—H17A	0.9800
N4—C14	1.459 (2)	C17—H17B	0.9800
C2—C3	1.496 (3)	C17—C18	1.501 (4)
C3—C4	1.390 (3)	C18—H18A	0.9800
C3—C9	1.390 (3)	C18—H18B	0.9800
C4—C5	1.407 (3)	C18—C19	1.494 (4)
C5—C6	1.373 (3)	C19—H19A	0.9800
C6—H6	0.9400	C19—H19B	0.9800
C6—C7	1.368 (3)	C19—C20	1.505 (3)
C7—C8	1.492 (3)	C20—H20A	0.9800
C7—C9	1.372 (3)	C20—H20B	0.9800
C4—S1—C1	100.61 (10)	N4—C11—H11B	109.4
C1—N1—C2	124.30 (17)	C10—C11—H11A	109.4
O2—N2—O3	121.8 (11)	C10—C11—H11B	109.4
O2—N2—C5	119.3 (6)	H11A—C11—H11B	108.0
O3—N2—C5	118.3 (9)	N4—C12—H12A	109.5
O3A—N2—C5	116.8 (9)	N4—C12—H12B	109.5
O3A—N2—O2A	123.7 (11)	N4—C12—C13	110.69 (18)
O2A—N2—C5	118.8 (7)	H12A—C12—H12B	108.1
C1—N3—C10	120.85 (19)	C13—C12—H12A	109.5
C1—N3—C13	125.62 (17)	C13—C12—H12B	109.5
C13—N3—C10	113.11 (17)	N3—C13—C12	110.48 (19)
C11—N4—C12	108.74 (16)	N3—C13—H13A	109.6
C11—N4—C14	111.55 (17)	N3—C13—H13B	109.6
C12—N4—C14	111.45 (16)	C12—C13—H13A	109.6
N1—C1—S1	127.78 (15)	C12—C13—H13B	109.6
N1—C1—N3	119.23 (18)	H13A—C13—H13B	108.1
N3—C1—S1	112.98 (16)	N4—C14—H14A	108.8
O1—C2—N1	120.73 (19)	N4—C14—H14B	108.8
O1—C2—C3	118.38 (19)	N4—C14—C15	113.72 (17)
N1—C2—C3	120.89 (19)	H14A—C14—H14B	107.7
C4—C3—C2	124.04 (17)	C15—C14—H14A	108.8
C9—C3—C2	115.71 (19)	C15—C14—H14B	108.8
C9—C3—C4	120.25 (18)	C14—C15—H15	107.9
C3—C4—S1	122.06 (14)	C16—C15—C14	111.66 (18)
C3—C4—C5	116.85 (17)	C16—C15—H15	107.9
C5—C4—S1	121.09 (16)	C16—C15—C20	110.74 (19)
C4—C5—N2	121.74 (18)	C20—C15—C14	110.58 (18)
C6—C5—N2	116.08 (17)	C20—C15—H15	107.9
C6—C5—C4	122.16 (19)	C15—C16—H16A	109.1
C5—C6—H6	120.1	C15—C16—H16B	109.1
C7—C6—C5	119.89 (18)	C15—C16—C17	112.4 (2)
C7—C6—H6	120.1	H16A—C16—H16B	107.9
C6—C7—C8	119.7 (2)	C17—C16—H16A	109.1
C6—C7—C9	119.47 (19)	C17—C16—H16B	109.1
C9—C7—C8	120.8 (2)	C16—C17—H17A	109.1
F1—C8—F2	108.5 (8)	C16—C17—H17B	109.1
F1—C8—F3	110.5 (7)	H17A—C17—H17B	107.8
F1—C8—C7	112.9 (6)	C18—C17—C16	112.6 (2)
F1A—C8—F3A	101.1 (8)	C18—C17—H17A	109.1
F1A—C8—C7	114.4 (5)	C18—C17—H17B	109.1
F2—C8—C7	108.4 (5)	C17—C18—H18A	109.3
F2A—C8—F1A	105.8 (9)	C17—C18—H18B	109.3
F2A—C8—F3A	108.2 (7)	H18A—C18—H18B	108.0
F2A—C8—C7	115.5 (7)	C19—C18—C17	111.5 (2)
F3—C8—F2	102.6 (5)	C19—C18—H18A	109.3
F3—C8—C7	113.2 (4)	C19—C18—H18B	109.3
F3A—C8—C7	110.6 (5)	C18—C19—H19A	109.2
C3—C9—H9	119.3	C18—C19—H19B	109.2
C7—C9—C3	121.3 (2)	C18—C19—C20	111.9 (2)
C7—C9—H9	119.3	H19A—C19—H19B	107.9
N3—C10—H10A	109.6	C20—C19—H19A	109.2
N3—C10—H10B	109.6	C20—C19—H19B	109.2
N3—C10—C11	110.19 (17)	C15—C20—H20A	109.0
H10A—C10—H10B	108.1	C15—C20—H20B	109.0
C11—C10—H10A	109.6	C19—C20—C15	113.1 (2)
C11—C10—H10B	109.6	C19—C20—H20A	109.0
N4—C11—C10	111.31 (19)	C19—C20—H20B	109.0
N4—C11—H11A	109.4	H20A—C20—H20B	107.8
S1—C4—C5—N2	0.2 (3)	C6—C7—C8—F2A	−67.1 (12)
S1—C4—C5—C6	−177.98 (16)	C6—C7—C8—F3	18.7 (9)
O1—C2—C3—C4	−174.1 (2)	C6—C7—C8—F3A	56.3 (13)
O1—C2—C3—C9	6.2 (3)	C6—C7—C9—C3	1.7 (3)
O2—N2—C5—C4	1.0 (11)	C8—C7—C9—C3	−175.3 (2)
O2—N2—C5—C6	179.3 (11)	C9—C3—C4—S1	178.49 (16)
O3—N2—C5—C4	−170.4 (7)	C9—C3—C4—C5	−1.7 (3)
O3—N2—C5—C6	7.9 (8)	C9—C7—C8—F1	−37.8 (9)
N1—C2—C3—C4	5.9 (3)	C9—C7—C8—F1A	−13.4 (11)
N1—C2—C3—C9	−173.8 (2)	C9—C7—C8—F2	82.5 (9)
N2—C5—C6—C7	−179.0 (2)	C9—C7—C8—F2A	109.9 (12)
N3—C10—C11—N4	56.2 (3)	C9—C7—C8—F3	−164.3 (8)
N4—C12—C13—N3	−56.6 (3)	C9—C7—C8—F3A	−126.7 (13)
N4—C14—C15—C16	−61.0 (3)	C10—N3—C1—S1	173.83 (17)
N4—C14—C15—C20	175.2 (2)	C10—N3—C1—N1	−7.3 (3)
C1—S1—C4—C3	−2.88 (19)	C10—N3—C13—C12	51.9 (3)
C1—S1—C4—C5	177.31 (17)	C11—N4—C12—C13	61.2 (2)
C1—N1—C2—O1	174.7 (2)	C11—N4—C14—C15	−73.9 (2)
C1—N1—C2—C3	−5.3 (3)	C12—N4—C11—C10	−61.4 (2)
C1—N3—C10—C11	135.4 (2)	C12—N4—C14—C15	164.3 (2)
C1—N3—C13—C12	−135.5 (2)	C13—N3—C1—S1	1.8 (3)
C2—N1—C1—S1	0.1 (3)	C13—N3—C1—N1	−179.3 (2)
C2—N1—C1—N3	−178.6 (2)	C13—N3—C10—C11	−51.6 (3)
C2—C3—C4—S1	−1.2 (3)	C14—N4—C11—C10	175.31 (17)
C2—C3—C4—C5	178.66 (19)	C14—N4—C12—C13	−175.5 (2)
C2—C3—C9—C7	179.5 (2)	C14—C15—C16—C17	−175.9 (2)
C3—C4—C5—N2	−179.62 (18)	C14—C15—C20—C19	177.0 (2)
C3—C4—C5—C6	2.2 (3)	C15—C16—C17—C18	53.5 (3)
C4—S1—C1—N1	3.8 (2)	C16—C15—C20—C19	52.7 (3)
C4—S1—C1—N3	−177.46 (16)	C16—C17—C18—C19	−53.5 (4)
C4—C3—C9—C7	−0.2 (3)	C17—C18—C19—C20	53.2 (3)
C4—C5—C6—C7	−0.8 (3)	C18—C19—C20—C15	−53.7 (3)
C5—C6—C7—C8	175.8 (2)	C20—C15—C16—C17	−52.2 (3)
C5—C6—C7—C9	−1.2 (3)	O3A—N2—C5—C4	163.6 (6)
C6—C7—C8—F1	145.3 (9)	O3A—N2—C5—C6	−18.1 (7)
C6—C7—C8—F1A	169.7 (10)	O2A—N2—C5—C4	−7.0 (11)
C6—C7—C8—F2	−94.5 (8)	O2A—N2—C5—C6	171.2 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—O2···H12B	0.98 (1)	2.68 (1)	3.311 (3)	123 (1)
N2—O3···H13B	0.98 (1)	2.94 (1)	3.844 (15)	153 (1)