Crystal structure and synthesis of 17α-Acetoxy-pregn-4,6-diene-3,20- dione

Article abstract of DOI:10.1007/s10870-010-9805-8

17α-Acetoxy-pregn-4,6-diene-3,20-dione (1), C₂₃H ₃₀O₄, was synthesized from the commercially available 17α-acetoxyprogesterone. X-ray diffraction analysis of (1) demonstrated that it consists of four rings, three six-membered rings (A, B and C) and one-five-membered ring (D). A, B, C and D rings occur in an envelope; half chair and chair; and half chair conformations, respectively. The crystal of 17α-acetoxy-pregn-4,6-diene-3,20-dione is in orthorhombic crystal system with space group P2₁2₁2₁, lattice constants: a = 10.843(1), b = 11.744(1), c = 15.815(2)A, V = 2013.9(4) A³, Dx = 1.222 g/cm³ and Z = 4. The molecules in the crystal are stabilized by C-H???O interactions and van der Waals forces. Graphical Abstract: 17α-acetoxy-pregn-4,6-diene-3,20-dione (1) was synthesized. Compound 1 exhibited a high antiandrogenic effect and could be considered as a potential drug for the treatment of prostate cancer. The crystal structure of (1) was obtained by determination of X-ray diffraction from suitable single crystals. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s10870-010-9805-8

J Chem Crystallogr (2010) 40:1115–1118
DOI 10.1007/s10870-010-9805-8
ORIGINAL PAPER
Crystal Structure and Synthesis of 17a-Acetoxy-pregn-4,6-diene-
3,20-dione
•
Manuel Soriano-Garcıa Armando Zambrano
•
´
Marisa Cabeza Eugene Bratoeff
•
Received: 16 October 2009 / Accepted: 20 May 2010 / Published online: 5 June 2010
Ó Springer Science+Business Media, LLC 2010
Abstract 17a-Acetoxy-pregn-4,6-diene-3,20-dione (1),
C23H30O4, was synthesized from the commercially available
17a-acetoxyprogesterone. X-ray diffraction analysis of (1)
demonstrated that it consists of four rings, three six-mem-
bered rings (A, B and C) and one-five-membered ring (D). A,
B, C and D rings occur in an envelope; half chair and chair;
and half chair conformations, respectively. The crystal of
17a-acetoxy-pregn-4,6-diene-3,20-dione is in orthorhom-
bic crystal system with space group P212121, lattice con-
treatment for androgen mediated diseases such as: prostate
cancer, hirsutism, acne, seborrhea, androgenic alopecia and
benign prostatic hyperplasia [1]. Although surgery pres-
ently represents the usual treatment for prostate cancer,
there are several other alternative modalities currently
available for the treatment of these androgen-dependent
afflictions [2, 3].
At the present time, the most common therapy for the
treatment of prostate cancer and benign prostatic hyper-
plasia is blockage of the androgen receptor by androgen
antagonists or inhibition of the conversion of testosterone
to the more active androgen, dihydrotestosterone by the
enzyme 5a-reductase [4–6].
˚
stants: a = 10.843(1), b = 11.744(1), c = 15.815(2)A,
3
3
˚
V = 2013.9(4)A , Dx = 1.222 g/cm and Z = 4. The mol-
ecules in the crystal are stabilized by C–HꢀꢀꢀO interactions
and van der Waals forces.
In this article we describe the synthesis and X-ray deter-
mination of one steroidal derivative, 17a-acetoxypregn-4,6-
diene-3, 20-dione 1. This compound was prepared from the
commercially available 17a-acetoxyprogesterone. Com-
pound 1 exhibited a high antiandrogenic effect and could be
considered as a potential drug for the treatment of prostate
cancer.
Keywords Androgen receptor ꢀ
5-alpha-reductase inhibitors ꢀ Binding ꢀ Prostate
Introduction
Prostate cancer is now the most common malignancy and
the second leading cause of cancer death in North Ameri-
can males. Androgen antagonists offer a potentially useful
Experimental
Synthesis
´
M. Soriano-Garcıa (&)
´
Instituto de Quımica, Universidad Nacional Autonoma de
Mexico, Circuito Exterior, Ciudad Universitaria, 04510 Mexico,
´
´
´
A solution of 17a-acetoxyprogesterone (1 g, 2.69 mmol),
chloranil (0.7 g, 2.8 mmol) in toluene (2 ml) and glacial
acetic acid (8 ml) was allowed to reflux for 4 h. The pre-
cipitated tetrachlorohydroquinone was filtered. The filtrate
was washed with a 10% aqueous sodium hydroxide solu-
tion, water and dried over anhydrous sodium sulfate; the
solvent was removed in vacuum. The crude product was
recrystallized from ethyl acetate. Yield 0.7 g, (1.8 mmol),
70.4%, mp 224–226 °C. UV (nm) 282 (e = 27,400). IR
´
D.F., Mexico
e-mail: soriano@servidor.unam.mx
A. Zambrano ꢀ E. Bratoeff
´
Facultad de Quımica, UNAM, Ciudad Universitaria,
04510 Mexico, D.F., Mexico
´
´
M. Cabeza
Departamento de Sistemas Biologicos, Universidad Autonoma
´
Metropolitana Unidad Xochimilco, Mexico, D.F., Mexico
´
´
´
123

1116
J Chem Crystallogr (2010) 40:1115–1118
(KBr) cm-1: 2978, 1730, 1700, 1675. 1H-NMR (CDCl3) d:
0.7 (3H, s, H-18), 1.1 (3H, s, H-19), 2.0 (3H, s, acetoxy),
2.1 (3H, s, H-21), 5.7 (1H, q, J = 2 Hz and J = 4 Hz,
H-6), 6.0 (1H, s, H-4), 6.2 (1H,d, J = 10 Hz, H-7).
13C-NMR (CDCl3) d: 14.3 (C-18), 16.3 (C-19), 21.2
(C-21), 123.9 (C-4), 128.3 (C-6), 130.3 (C-7), 170.6 (ester
carbonyl), 199.9 (C-3), 203.8 (C-20).
software package [7] and refined on F2 by full-matrix least-
squares with anisotropic displacements parameters for all
non-hydrogen atoms [8]. All hydrogen atoms were geo-
metrically fixed and allowed to ride on the parent C atoms.
The crystals data and pertinent details of the experimental
conditions are summarized in Table 1.
Crystal Structure Determination
˚
Table 2 Bond distances (A) and angles (°) for compound 1
˚
Bond lengths (A)
X-ray data were collected on a Bruker Smart APEX AXS
CCD area detector with a graphite monochromator and Mo
O1–C3
1.222(3)
1.347(2)
1.193(2)
1.531(3)
1.438(3)
1.442(3)
1.322(3)
1.528(2)
1.527(3)
1.533(3)
1.531(3)
1.539(3)
1.524(3)
1.534(3)
1.497(3)
O2–C20
O3–C17
C1–C10
C2–C3
1.206(2)
1.464(2)
1.527(3)
1.493(3)
1.339(3)
1.512(3)
1.491(3)
1.536(3)
1.554(3)
1.537(3)
1.531(2)
1.559(2)
1.540(3)
1.531(3)
1.488(3)
O3–C22
˚
Ka radiation (k = 0.71073 A) by the x-scan method. The
O4–C22
observed reflections were corrected for Lorentz and
polarization effects, but not for X-ray absorption. The
structure was solved using direct methods with SHELXTL
C1–C2
C3–C4
C4–C5
C5–C6
C5–C10
C7–C8
C6–C7
C8–C14
C8–C9
Table 1 Crystal data, collection parameters and refinements for
compound 1
C9–C11
C9–C10
C11–C12
C13–C14
C13–C17
C15–C16
C17–C20
C22–C23
C10–C19
Compound
1
C12–C13
CCDC deposit no.
Crystal size (mm)
Color/shape
699041
C13–C18
0.28 9 0.24 9 0.22
Colorless/prism
C14–C15
C16–C17
Empirical formula
Formula weight
Crystal system
Space group
C23H30O4
C20–C21
370.47
Bond angles (°)
C22–O3–C17
C3–C2–C1
O1–C3–C2
C5–C4–C3
C4–C5–C10
C7–C6–C5
C7–C8–C14
C14–C8–C9
C11–C9–C10
C5–C10–C1
C1–C10–C19
C1–C10–C9
C9–C11–C12
C14–C13–C12
C12–C13–C18
C12–C13–C17
C15–C14–C8
C8–C14–C13
C17–C16–C15
O3–C17–C16
O3–C17–C13
C16–C17–C13
O2–C20–C17
O4–C22–O3
O3–C22–C23
Orthorhombic
P212121
117.81(15)
113.3(2)
C10–C1–C2
O1–C3–C4
113.96(18)
121.5(2)
Unit cell dimensions
121.3(2)
C4–C3–C2
117.2(2)
˚
a (A)
10.843(1)
11.744(1)
15.815(2)
2013.9(4)
4
125.0(2)
C4–C5–C6
120.42(19)
118.09(17)
122.9(2)
˚
b (A)
121.43(19)
123.7(2)
C6–C5–C10
C6–C7–C8
˚
c (A)
3
˚
Volume (A )
113.49(16)
108.26(14)
115.09(15)
108.87(17)
110.80(18)
110.02(15)
112.50(15)
108.64(15)
109.95(17)
117.38(15)
120.35(15)
112.81(15)
107.11(16)
109.94(15)
105.04(14)
104.18(14)
120.01(18)
123.91(19)
110.65(19)
C7–C8–C9
110.91(16)
110.37(16)
113.01(15)
107.77(15)
108.26(15)
111.03(16)
111.51(16)
112.53(15)
100.42(14)
107.69(15)
104.16(15)
103.94(16)
109.40(14)
114.39(16)
113.40(15)
120.67(19)
119.06(17)
125.4(2)
Z
Density (calculated) (mg/m3)
Absorption coefficient (mm-1
F(000)
1.222
C11–C9–C8
C8–C9–C10
C5–C10–C19
C5–C10–C9
C19–C10–C9
C13–C12–C11
C14–C13–C18
C14–C13–C17
C18–C13–C17
C15–C14–C13
C14–C15–C16
O3–C17–C20
C20–C17–C16
C20–C17–C13
O2–C20–C21
C21–C20–C17
O4–C22–C23
–
)
0.082
800
h range for data collection (°)
Index ranges
2.16–25.37
-13 B h B 13, -14 B k B 14,
-19 B l B 19
Reflections collected/unique
16773/3692
Observed reflections (I [ 2r(I))a
Data/restraints/parameters
Goodness-of-fita on F2
3692(Rint = 0.0449)
2748/0/248
0.915
Final R indices [(I) [ 2r(I)]a
R indices (all data)a
R1 = 0.0412, wR2 = 0.0782
R1 = 0.0571, wR2 = 0.0827
Largest diff. peak and hole (e A-3) 0.167 and -0.125
P
P
jFo2 ꢁ ðFo2Þj
jjFoj ꢁ jFcjj
a
P
P
Rint
¼
; R1 ¼
;
Fo2
jFoj
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
P
P
2
2
wðFo2 ꢁ Fc2Þ
wðFo2 ꢁ Fc2Þ
wR2 ¼
; S ¼
P
2
–
wðFo2Þ
m ꢁ n
123

J Chem Crystallogr (2010) 40:1115–1118
1117
˚
compound 1 are 1.518(3), 1.406(2), 1.207(2) A, respec-
tively. These bond lengths values are comparable to the
theoretical values as reported by Allen et al. [14] although
some bonds show significant deviation from the mean
value.
In all essential details, the molecular geometry of (1) in
terms of the bond lengths and angles are in good agreement
with standard values. However, the C11–C9–C10 and
C12–C13–C17 bond angles of 115.1(2) and 117.4(2)° have
been increased to minimize the steric interactions between
the double bond at C6–C7 and the methyl group at C10;
and the interaction between the methyl group at C13 and
the O atoms of the acetoxy group at C17, respectively. The
molecule is comprised of a quadricyclic skeleton consisting
of three-six-membered rings (A, B and C) and one-five-
membered ring (D). The molecule consists of three-six-
membered rings and one-five-membered ring, all trans
fused. For the puckering-parameters values (/2, h2 and Q)
[15]. The six-membered rings A, B, and C occur in an
envelope (1E), half chair (5H6), and chair (1C4) confor-
mations, respectively. Ring D occurs in a half chair
conformation.
Fig. 1 Molecular structure of 1, with displacement ellipsoids at the
50% probability level. Hydrogen atoms are drawn as circles with an
arbitrary radius
Results and Discussion
Table 2 gives the bond distances and bond angles of non-
hydrogen atoms, respectively. ORTEP views of the title
compounds with atomic labeling are shown in Figs. 1 and 2
[9]. The geometry of the molecule was calculated using the
WinGX [10] and PARST [11, 12] softwares.
Although the absolute configuration of 1 could not be
determined from the diffraction data alone, it was established
based on the structure of 17a-acetoxy-6,7-epoxypregn-
4-ene, 3,20-dione compound [13]. The stereochemistry of
the title compound is as follows: C8–bH is trans to C9–aH;
C9–aH is trans to C10–bCH3; C13–bCH3 is trans to
The bond distances and bond angles are in good agree-
ment with the corresponding values obtained in case of
17a-acetoxy-6,7-epoxypregn-4-ene,3,20-dione [13]. Mean
bond lengths [C(sp3)–C(sp3), C(sp3)=O and C(sp2)=O, for
Fig. 2 The packing diagram for
1 projected along the b-axis
123

1118
J Chem Crystallogr (2010) 40:1115–1118
of charge via www.ccdc.cam.ac.uk/cgi-bin/catreq.cgi, by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK, fax; ?44(0)1223-336033.
References
1. Cabeza M, Zambrano A, Heuze I, Carrizales E, Palacios A,
Segura T, Valencia N, Bratoeff E (2009) Steroids 74:793
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I, Cabeza M (2009) J Enzym Inhib Med Chem 2009(24):655
3. Bratoeff E, Cabeza M, Perez V, Recillas S, Heuze IJ (2008)
Steroid Biochem Mol Biol 111:275
Scheme 1 Structure of compound 1
´
4. Cabeza M, Bratoeff E, Gomez G, Heuze I, Rojas A, Ochoa M,
C14–aH; C13–bCH3 is cis to C17–a(COCH3); and C13–bH
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Figure 2 shows the unit-cell packing arrangement for 1
along the b-axis. There are four intramolecular C–HꢀꢀꢀO
interactions, which are due to their length, and could be
considered as significant ones [16] [C2ꢀꢀꢀO4, C7ꢀꢀꢀO1,
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Cruz A, Cabrera O, Perez V (2008) Steroids 73:838
´
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˚
C19ꢀꢀꢀO2, C23ꢀꢀꢀO1 3.464(3), 3.368(3), 3.348(3), 3.443(3)A;
H2BꢀꢀꢀO4, H7ꢀꢀꢀO1, H19CꢀꢀꢀO2, H23CꢀꢀꢀO1 2.693(2),
˚
2.817(2), 2.801(2), 2.522(2)A and C2–H2BꢀꢀꢀO4, C7–
H7ꢀꢀꢀO1, C19–H19CꢀꢀꢀO2, C23–H23CꢀꢀꢀO1 136.8(1),
119.1(1), 117.1(1), 161.0(1)8]. The molecules in the crystal
are packed at normal van der Waals distances.
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Supplementary Materials
CCDC-699041 contains the supplementary crystallo-
graphic data for this article. These data can be obtained free
123