An unusual dienone-phenol rearrangement product formed during the synthesis of mometasone furoate (Sch 32088).

Article abstract of DOI:10.1016/S0039-128X(97)00155-4

The structure of an unusual dienone-phenol rearrangement product 4 obtained during the synthesis of mometasone furoate (Sch 32088) was assigned on the basis of NMR and x-ray crystallographic data. The mechanism of formation is discussed.

Full text of DOI:10.1016/S0039-128X(97)00155-4

An unusual dienone-phenol
rearrangement product formed during
the synthesis of mometasone furoate
(Sch 32088)
Richard W. Draper,* Mohindar S. Puar,* Eugene J. Vater,* and
Andrew T. McPhail†
*
Chemical Process Development Department, Schering-Plough Research Institute,
Kenilworth, New Jersey, USA, and †Department of Chemistry, P. M. Gross Chemical Laboratory,
Duke University, Durham, North Carolina, USA
The structure of an unusual dienone-phenol rearrangement product 4 obtained during the synthesis of mometa-
sone furoate (Sch 32088) was assigned on the basis of NMR and x-ray crystallographic data. The mechanism of
formation is discussed. (Steroids 63:135–140, 1998) © 1998 by Elsevier Science Inc.
Keywords: mometasone furoate; dienone-phenol rearrangement; mechanism; NMR; x-ray
Introduction
Experimental
Discovered in our laboratories, mometasone furoate, 9␣,21-
9␣,21-Dichloro-11␤,17␣-dihydroxy-16␣-methyl-
pregna-1,4-diene-3,20-dione 17-(2Ј-furoate) 2 and
11␣,21-dichloro-3,17␣-dihydroxy-16␣-methyl-
9(10)-secopregna-1,3,5(10)-triene-9,20-dione 17-
(2Ј-furoate) 4
dichloro-11␤,17␣-dihydroxy-16␣-methylpregna-1,4-diene-
1
3
,20-dione 17-(2Ј-furoate), Sch 32088, Elocon௡, 2 is a
medium potency synthetic corticosteroid anti-inflammatory
agent, indicated for the treatment of various steroid respon-
2
3
sive dermatoses, such as psoriasis and dermatitis. The
drug is characterized by its low potential for systemic ac-
tivity as measured by its effect on the hypothalamic-
Hydrogen chloride gas was slowly bubbled through a solution
of 21-chloro-9␤,11␤-epoxy-17␣-hydroxy-16␣-methylpregna-
1,4-diene-3,20-dione 17-(2Ј-furoate) 2 (49.39 g, 0.102 mol) in
4
,5
methylene chloride (300 mL) at R for 90 min. The solvent was
pituitary-adrenal axis when applied topically.
A synthesis of mometasone furoate from commercially
t
removed under vacuum and the residue was crystallized from
6
methanol to give pure compound 3 (33.24 g, 62.6%). The
6
,7
available intermediate has been described but we have
mother liquors were concentrated to dryness and the residue
column chromatographed (silica-gel, 60 mesh, hexane/ethyl
acetate gradient, 250-mL fractions). The contents of fractions 4,
5, and 6 were combined and crystallized from ethyl acetate to
afford compound 4 (125 mg), m.p. ϭ 240–242°C, decomp.,
also prepared mometasone furoate from the 9,11 epoxide 1
8
as shown in Scheme 1. During the course of hydrogen
chloride induced ring opening of the 9,11 epoxide, we
observed the formation of a byproduct 3 (Figure 1) whose
2
D
Ϫ1
3°C
8
[␣]
cm
ϭ ϩ6° [c ϭ 0.18, CHCl ]. IR (nujol): 1712 & 1695
structure was reported previously, arising via a carbonium
3
(CAO). Analysis calculated for C H Cl O : Cl,
27 30 2 6
ion promoted rearrangement involving the C and D rings. In
this paper, we describe the formation, isolation, and char-
acterization of a second unusual byproduct 4, which ema-
nates from a dienone-phenol rearrangement involving the A
and B rings.
1
3.60%. Found: Cl, 13.49%. Mass calculated for C H Cl O :
27 30 2 6
5
20. Found: m/z 520 [EIMS] and 521 [FABMS]. Fraction 12
8
from the same chromatography contained compound 3.
Figure 2 shows the reverse phase HPLC (Supelcosil LC-8
column; mobile phase, MeOH/H O [77 : 43]; flow rate 1.2 mL/
min; UV detection at 254 nM) profile of a mixture of compounds
, 2, 3, and 4.
2
1
Results and discussion
Address reprint requests to Richard W. Draper, Ph.D., Chemical Process
Development Department, Schering-Plough Research Institute, 2015 Gal-
loping Hill Road, Kenilworth, NJ 07033-0539, USA.
NMR analysis of 4
1
1
Table 1 presents the analysis of 2D ( H– H) COSY, HMBC
and other NMR data. By comparison of this NMR data with
Received September 18, 1997; accepted October 28, 1997.
Steroids 63:135–140, 1998
©
1998 by Elsevier Science Inc. All rights reserved.
0039-128X/98/$19.00
6
55 Avenue of the Americas, New York, NY 10010
PII S0039-128X(97)00155-4

Papers
Scheme 1
Figure 1 Byproducts 3 & 4 of mometasone furoate synthesis.
8
that of compounds 3 and 2 (not listed), it is evident that the
original A-ring dienone system has been replaced by a
methyl substituted phenolic ring and a new ketone function
at ␦ 202.2. The proton resonance of the 19-methyl group
new ketone function at C . These observations led us to
(9)
assign the 9-keto-11␣-chloro-9,10-seco structure 4, which
was confirmed unequivocally by x-ray crystallographic
analysis.
1
was shifted significantly downfield to ␦ 2.20. The 2D ( H–
H) COSY spectrum provided important structural informa-
1
tion about ring C; an A X pattern (C(11)–C(12)) at ␦ 5.20
2
X-ray crystal structure analysis of 4
(
CH) and ␦ 2.41 (center, m, CH ) and a correlation of the ␦
2
2
.71 (CH) resonance with the ␦ 1.45 and ␦ 1.80 multiplets
Crystal data. C H Cl O , M ϭ 521.44, orthorhombic,
2
7
30
2 6
(
CH ) (C –C ) and ␦ 2.46 (CH) resonance (C –C(14)).
D NOE NMR data gave positive NOE’s between 18-CH3
a ϭ 12.167(1) Å, b ϭ 27.947(3) Å, c ϭ 7.580(1) Å, V ϭ
2
(8)
(7)
(8)
3 Ϫ3
calcd
1
2577.4(8) Å , Z ϭ 4, D
ϭ 1.344 g cm , ␮(Cu–K␣
Ϫ1
and 12␤-H, as well as between 11␤-H and 18-CH and
radiation, ␭ ϭ 1.5418 Å) ϭ 26.2 cm . Space group
3
4
1
1␤-H and 12␤-H. A phase sensitive 2D NOE experiment
P2 2 2 (D ) uniquely from the Laue symmetry and sys-
1
1 1
2
indicated many cross-peaks depicting through space inter-
actions. HMBC correlation confirmed the position of the
tematic absences: h00 when h Þ 2n, 0k0 when k Þ 2n, 00l
when l Þ 2n. Crystallographic calculations were performed
Figure 2 High-performance liquid chroma-
tography profile of a mixture of compounds 1,
2, 3, and 4.
1
36 Steroids, 1998, vol. 63, March

An unusual dienone-phenol rearrangement product: Draper et al.
1
3
1
Table 1
C and H NMR Spectral Data of Compound 4 in
atoms were then located in a difference Fourier synthesis
and incorporated at their calculated positions in the sub-
sequent iterations. A secondary extinction correction, g,
was included as a variable during the later iterations
a
DMSO-d6
1
3
1
C
C, ␦ (ppm)
H, ␦ (ppm), J (Hz)
which converged at R ϭ 0.047 [R ϭ 0.065, GOF ϭ
w
C-1
130.6
112.6
155.1
115.2
141.4
33.0
6.90 (d, 8)
Ϫ6
C-2
6.49 (dd, 8, 1)
1.77, g ϭ 1.1(2) ϫ 10 ], where R ϭ ⌺ʈF ͉–͉F ʈ/⌺͉F ͉;
o
c
o
2
2 1/2
2
C-3
Rw ϭ [⌺w(͉F ͉–͉F ͉) /⌺w͉F ͉ ] ; GOF ϭ [⌺w⌬ /
o
c
o
C-4
6.58 (d,1)
1/2
(
Nobservations–N
)] . No unusual features were
parameters
C-5
present in a final difference Fourier synthesis (⌬␳: max
C-6
2.41 (m), 2.60 (m)
1.45 (m), 1.80 (m)
2.71 (m)
3
C-7
30.6
0.30; min Ϫ0.28 e/Å ). For all structure–factor calcula-
C-8
48.1
tions, neutral atom scattering factors and their anomalous
C-9
202.2
125.3
62.5
9
dispersion corrections were taken from the literature.
C-10
C-11
C-12
C-13
C-14
C-15
C-16
C-17
C-18
C-19
C-20
C-21
C-22
C-23
C-24
C-25
C-26
C-27
A view of the solid-state conformation, with the crystal-
lographic atom numbering scheme, is provided in Figure 3.
5.20 (t, 11, 8.5)
2.41 (m)
41.5
49.1
Bond lengths all lie close to expected values. The aromatic
10
48.6
2.46 (m)
1.35 (m), 1.95 (m)
3.45 (m)
ring atoms are strictly coplanar (⌬ Ϯ 0.001–0.002 Å) while
those of the directly bonded substituents lie close to the
least-squares plane through the ring atoms [⌬(Å): C(6)
0.034, C(19) Ϫ0.015, O(23) 0.020]; the C(6)-C(7) bond is
oriented approximately perpendicular to the ring plane
36.1
38.5
94.8
16.3
1.12 s
2.20 s
17.8
196.8
47.3
[C(10)-C(5)-C(6)-C(7) torsion angle ϭ 81.0(5)°]. Endocy-
4.63 s
0.88 (d, 6.5)
14.1
clic torsion angles, ␻ (␴ Ϯ 0.3–0.5Њ), about the bonds
ij
157.4
142.3
120.3
112.4
148.6
between atoms i and j in the cyclohexanone moiety [␻8,9
7.55 (m)
6.74 (m)
8.05 (m)
a
Assignments based upon APT, selective INEPT, 2D (H–H)COSY
and HMBC experiments. ␦ 3-OH ϭ 9.0.
on PDP11/44 and Micro VAX computers by use of the
Enraf-Nonius Structure Determination Package.
Crystallographic measurements. Oscillation and Weis-
senberg photographs yielded preliminary unit-cell parame-
ters and space group information. One octant of intensity
data was recorded on an Enraf-Nonius CAD-4 diffractom-
eter (Cu–K␣ radiation, graphite monochromator; ␻-2␪
scans, ␪max ϭ 75°) from a crystal of dimensions 0.25 ϫ
0
.32 ϫ 0.56 mm. The intensities of four strong reference
reflections, remeasured every 2 h during data collection,
showed insignificant variation (Ͻ1% overall). In addition to
the usual corrections for Lorentz and polarization effects,
an empirical absorption correction, [Tmax : Tmin (relative)
ϭ
1
.00 : 0.80] based on the ␾ dependency of the intensities of
several reflections with ␹ ca. 90°, was also applied to the
data. From a total of 3,029 nonequivalent measurements,
those 2,290 reflections with I Ͼ 3.0␴(I) were retained for
the analysis. Refined unit-cell parameters were derived from
the diffractometer setting angles for 25 reflections (35° Ͻ ␪
Ͻ 40°) widely separated in reciprocal space.
Structure analysis. The crystal structure was solved by
direct methods. Initial non-hydrogen atom coordinates
were obtained from an E-map. Positional and thermal
parameters (first isotropic and then anisotropic) were
adjusted by means of several rounds of full-matrix least-
Figure 3 ORTEP diagram (40% probability elipsoids) showing
the atom numbering scheme and solid state conformation of 4;
small filled circles represent hydrogen atoms.
2
squares calculations during which ⌺w⌬ [w
ϭ
2
1
/␴ (͉F ͉); ⌬ ϭ (͉F ͉–͉F ͉)] was minimized. Hydrogen
o
o
c
Steroids, 1998, vol. 63, March 137

Papers
Scheme 2
Scheme 3
Ϫ47.9, ␻9,11 47.1, ␻11,12 Ϫ51.0, ␻12,13 58.5, ␻13,14 Ϫ65.3,
␻14,8 57.5°] show that the ring has a chair conformation
flattened around C(9); the ␣-oriented Cl substituent is equa-
torial. Torsion angles (␴ Ϯ 0.3–0.5°) in the cyclopentane
ring [␻13,14 46.4, ␻14,15 Ϫ34.3, ␻15,16 7.9, ␻16,17 20.9,
Mechanistic considerations
The products of steroid 1,4-diene-3-one-phenol rearrange-
ments are A-ring aromatized compounds, bearing a methyl and
phenolic hydroxyl group, either meta or para to each other
which arise through various 1,2 carbon bond shifts, from the
carbonium ion 6 produced by protonation of the 3-carbonyl
␻13,17
Ϫ41.4°] indicate that it lies intermediate between an
envelope form, with C(13) as the out-of-plane atom, and a
11
oxygen (Scheme 2). Migration of C(9) to C(5) leads to the
spiro cation 7, which in turn gives rise to the ‘para’ phenols 9
and 11 by migration of C(9) to C(4) or C(6) to C(4) respectively,
followed by deprotonation. The ‘meta’ phenol 16 is generated
from cation 6 by migration of the C-19 methyl, from C(10) to
C(1) affording cation 12 which aromatizes by loss of a proton.
half-chair form in which the C -symmetry axis passes
2
through C(16) and bisects the C(13)-C(17) bond. The furan
ring atoms are coplanar (⌬ Ϯ 0.003–0.007 Å), and C(6Ј) lies
in the ring plane (⌬ 0.001 Å). The dihedral angle between
the least-squares plane through C(2Ј), C(6Ј), O(7Ј), O(25) of
the ester group at C(17) (⌬ 0.319 Å) and that through the
furan ring atoms is 10.8°; torsion angles characterizing the
arrangement around the O(25)-C(6Ј) and C(2Ј)-C(6Ј) bonds
are: C(17)-O(25)-C(6Ј)-O(7Ј) Ϫ14.7(6)°, O(1Ј)-C(2Ј)-
C(6Ј)-O(7Ј) Ϫ11.4(8)°. In crystals of 4, molecules related
Conversely, shift of the 19-methyl group from C(10) to C(5)
affording 13, followed by a migration of C(6) to C(10) generates
a new spiro cation 14 which on suffering a C(9) to C(1) reor-
ganization yields a second ‘meta’ phenol 15. In cation 14,
migration of C(6) to C(1) leads to the ‘meta’ phenol 16A which
although structurally identical to 16 has a different ordering of
by the 2 screw axis along a are linked by an O-H . . . O
1
hydrogen bond [O(23) . . . O(24) ϭ 2.931(5) Å].
1
38 Steroids, 1998, vol. 63, March

An unusual dienone-phenol rearrangement product: Draper et al.
Scheme 4
Scheme 5
Scheme 6
the original carbon atoms. The particular mechanistic pathway
mediate carbocations 23 and 24 (Scheme 5) were pro-
posed to justify the formation of the aromatic 9␣-chloro-
9,10-secosteroid 25.
followed in the dienone–phenol rearrangement is dependent
upon reaction conditions and the nature of substituents in the
substrate.
1
5
We are not aware of any examples of dienone-phenol
rearrangements of 9␤,11␤-epoxysteroids, which are normally
protonated on the epoxide oxygen, leading in this case to a
chlorohydrin. However, competitive protonation at the
3-carbonyl oxygen would generate carbocation 26 (Scheme 6).
By analogy to the precedents cited above, ion 26 can be
quenched by chloride attack at C-9␣ with consequent rupture
of the C(9,10) bond to give chloroepoxide 27. Carbonium ion 26
may undergo bond reorganization via a spirocation of type 7
followed by a C(9) to C(4) shift prior to C(9,10) bond scission
which would also lead to the same chloro-epoxide 27. Steroid
Steroid carbocations of type 6 and 7 can also be
quenched by scission of the C(9,10) bond to produce 9,10-
secosteroids. This mechanistic variant is rare, although frag-
mentation of this bond with concomitant aromatization of
the A ring is often observed in certain reductive rearrange-
1
1,12
1
2
ments. The rearrangement of the ⌬
-1,4-diene-3-one
1
7 with acetic anhydride in acetic acid gave the aromatic
9
,11
1
2␣-acetoxy-⌬ -9,10-secosteroid 19 by the mechanism
1
3
suggested in Scheme 3 and microbiological reduction of
9
␣-hydroxyandrost-4-ene-3,17-dione was reported14 to
16
give the aromatic 9,17-diketo-secosteroid 22 via the pu-
tative corresponding 1,4-dien-3-one intermediate 20
chloroepoxides have been reported to readily undergo rear-
rangement to ␣-chloroketones by migration of chlorine, with
the intermediate being considered an ␣-ketocarbonium ion
chloride in the form of an ion pair.
1
,4
(
Scheme 4). Interestingly, in the reaction of a ⌬ -3-
ketosteroid with phenyl(trichloromethyl)mercury, inter-
Steroids, 1998, vol. 63, March 139

Papers
Intermediate 27 might also arise by an alternative mecha-
ointment and cream 0.1 percent in treatment of psoriasis: comparison
with ointment and cream formulations of flucinolone acetonide 0.025
percent and triamcinolone acetonide 0.1 percent. Cutis 42:480–485.
Bressinck R, Williams J, Peets EA (1988). Comparison of the effect
of mometasone furoate ointment 0.1% and hydrocortisone ointment
1.0%, on adrenocorticoid function in psoriasis patients. Today Ther
Trends 5:25–35.
Shapiro EL, Gentles MJ, Tiberi RL, Popper TL, Berkenkopf J,
Lutsky BL, Watnick AS (1987). 17-Heteroaroyl esters of cortico-
steroids. 2. 11␤-hydroxy series. J Med Chem 30:1581–1588.
Popper TL, Gentles MJ, Kung TT, Berkenkopf J, Lutsky BL,
Watnick AS, and Shapiro EL (1987). Structure-activity relation-
ships of a series of novel topical corticosteroids. J Steroid Biochem
nism from mometasone furoate 2. Protonation of the
-carbonyl oxygen of 2 would lead to a new carbocation 28
Scheme 6) which could gain aromaticity by intramolecular
3
5
.
(
attack of the 11␤ hydroxyl at C(9) to afford the same chloro-
epoxide 27. Indeed when mometasone furoate 2 was treated
with hydrogen chloride in methylene chloride, a small amount
of the same chloroseco compound 4 was observed. We cannot
distinguish which or whether both of these mechanisms are
operating. It may also be true, that under the conditions of the
reaction, an equilibrium exists between chlorohydrin 2 and its
precursor epoxide 1 and the chloroseco compound 4 arises
only from the latter.
6
.
.
7
2
7:837–843.
8
.
.
Puar MS, Thompson PA, Ruggeri M, Beiner D, McPhail AT (1995).
An unusual rearrangement product formed during production of
mometasone furoate (Sch 32088). Steroids 60:612–614.
Ibers JA, Hamilton WC (eds) (1974), International Tables for X-Ray
Crystallography, Vol. IV. The Kynoch Press, Birmingham, United
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Allen FH, Kennard O, Watson DG, Brammer L, Orpen AG, Taylor
R (1987). Tables of bond lengths determined by x-ray and neutron
diffraction. Part 1. Bond lengths in organic compounds. J Chem Soc
Perkin Trans 2 S1–S19.
9
Acknowledgment
The authors wish to thank Dr. T. M. Chan for the acquisition
of some of the NMR data.
1
0.
Note
1
1.
2.
Whiting DA (1991). Dienone-phenol rearrangements and related
reactions. In: Trost BM ed. Comprehensive Organic Chemistry, Vol.
Tables of atomic positional and thermal parameters, bond
lengths and angles for compound 4 have been deposited at
the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK.
3
. Pergamon Press, New York, pp. 803–820.
1
Ananthanarayan TP, Magnus P, Norman W (1983). Reductive
cleavage of the 9,10 bond in 11-oxygenated steroids: a new method
for the partial synthesis of the Vitamin D skeleton. J Chem Soc
Chem Commun 1096–1098.
1
1
3.
4.
Takeda K, Tanida H, Horiki K (1975). Preparation of the steroidal
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