Synthetic studies on a nonsteroidal progesterone metabolite: Regioselective N-alkylation of an activated pyrazole

Article abstract of DOI:10.1055/s-0029-1219535

This paper describes the large-scale synthesis of a progesterone receptor metabolite. The key step in this sequence was the regioselective pyrazole N-alkylation. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1219535

LETTER
873
Synthetic Studies on a Nonsteroidal Progesterone Metabolite: Regioselective
N-Alkylation of an Activated Pyrazole
R
egioselective
a
N
-Alkylat
u
c
l
d
Pyrazo
A
le . Bradley, Pieter D. de Koning, Karl R. Gibson, Yann C. Lecouturier, Malcolm C. MacKenny, Inaki Morao,
Cedric Poinsard, Toby J. Underwood*
Pfizer Ltd., Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
E-mail: toby.underwood@pfizer.com
Received 14 December 2009
umn chromatography. Subsequent NaBH4 reduction of al-
dehyde 4 then gave the desired hydroxymethyl compound
6 in excellent yields (Scheme 2).
Abstract: This paper describes the large-scale synthesis of a
progesterone receptor metabolite. The key step in this sequence was
the regioselective pyrazole N-alkylation.
This route proved to have poor reproducibility, and larger-
scale preparation of compound 6 proved problematic. Our
initial attempts to oxidize enzymatically or halogenate
compound 1A failed.
Key words: regioselective pyrazole alkylation, iodination, carbon-
ylation
In this letter we wish to describe the practical large-scale
preparation of compound 6 a metabolite of compound 1A
a progesterone receptor antagonist previously described
by these laboratories (Scheme 1).1
We quickly identified pyrazole 12 as a key intermediate
towards a number of alternate synthetic routes to the tar-
get compound 6 (Scheme 3).
Bromination of cyclopropylmethyl ketone 7 proceeded
smoothly under standard conditions to furnish the bro-
mide 8 in a yield of 98%.4 Subsequent nucleophilic dis-
placement of this bromide with the phenol 9, using cesium
carbonate as a base gave the ether 10 in a high yield. Pyra-
zole 12 was then prepared by treating ether 10 with DMF–
DMA to give compound 11. Cyclization of 11 with hydra-
zine hydrate then gave pyrazole 12 in 84% yield over the
two steps.5–7
The initial route towards compound 6 is outlined in
Scheme 2 and started from the advanced intermediate 1.
Oxidation of thioether 1 with Oxone® proceeded smooth-
ly to give the corresponding sulfone as indicated by thin-
layer chromatography and mass spectrometry.2 However,
when the crude reaction mixture was partitioned between
dichloromethane and water an emulsion formed. In an at-
tempt to break this emulsion, NaCl was added. This re-
sulted in an immediate green color discharge to the
organic phase. Purification of the resulting extract re-
vealed that the sulfone had undergone an unexpected
chlorination reaction to give a mixture of the mono- and
dichloro derivatives 2 and 3. Based on literature precen-
dent,3 we hypothesize that NaCl reacts with excess Ox-
one® in the reaction, to provide a mild source of chlorine,
which then acts as a chlorinating agent.
Having developed an efficient route to the pyrazole core,
we explored different strategies to deliver target com-
pound 6 on a five-gram scale.
The initial strategy was to N-alkylate pyrazole 12 with
chloromethyl methyl sulfide 13, and then oxidize to deliv-
er sulfone 15. Subsequent pyrazole iodination, carbonyla-
tion, and reduction of 15 should furnish 6.
The alkylation of pyrazole 12 with chloromethyl methyl
sulfide 13 proceeded smoothly (Scheme 4). Regioselec-
tivity was poor (1:1) indicating minimal steric influence
by the neighboring cyclopropyl group. Attempted iodina-
The crude mixture of the halogenated compounds 2 and 3
proved inseparable by column chromatography, but when
treated with dimethylamine in THF gave the aldehyde 4
and amine 5, respectively. These were separable by col-
CN
CN
CN
human
liver
microsomes
OH
Oxone®
O
MeOH–H2O
25 °C, 6 h
90%
O
O
N
N
N
N
N
N
SO2Me
SMe
SO2Me
1
6
1A
Scheme 1
SYNLETT 2010, No. 6, pp 0873–0876
x
x.
x
x.
2
0
1
0
Advanced online publication: 23.02.2010
DOI: 10.1055/s-0029-1219535; Art ID: D36009ST
© Georg Thieme Verlag Stuttgart · New York

874
P. A. Bradley et al.
LETTER
CN
CN
O
CN
O
i) Oxone
MeOH–H2O
25 °C, 6 h
Cl
Cl
Cl
+
O
ii) NaCl, H2O
16%
SMe
SO2Me
SO2Me
N
N
N
N
N
N
1
3
2
Me2NH, THF
70 °C, 16 h
CN
CN
O
CN
O
NaBH4, THF
NMe2
CH2OH
CHO
+
25 °C, 1 h
91%
O
SO2Me
SO2Me
SO2Me
N
N
N
N
N
N
4
6
5
35%
37%
Scheme 2
t-BuOK, DME
MeS Cl
13
tion of compounds 14 or 15 provided a complex mixture
of products, with iodide incorporation seen a to the sulfide
group.
H
MeS
N
CN
CN
N
N
N
25 °C, 16 h
66%
O
12
O
In light of these results we decided to switch the order of
steps and iodinate the pyrazole 12 first (Scheme 5). We
were then intrigued as to the steric effect of the incorpo-
rated iodide group in relation to the subsequent N-alkyla-
tion. Pleasingly the iodination step proceeded smoothly to
give compound 17.8 Alkylation of compound 17 with
chloromethyl methyl sulfide 13 provided regiomeric
products 18 and 19 in a 1:1 ratio. Unfortunately, these two
lipophilic regioisomers were not readily separated by col-
umn chromatography.
14
NIS,
MeCN
Oxone®
X
MeOH–H2O
25 °C, 6 h
90%
Me
O
N
NIS,
S
CN
R
MeCN
X
N
CN
O
N
N
O
O
I
16
15
We postulated that installation of a polar group prior to N-
alkylation might facilitate separation of the resultant re-
gioismers (Scheme 6). Carbonylation of 17 in EtOH gave
Scheme 4
the ethyl ester 20 in an acceptable yield. Subsequent N-
alkylation with KOt-Bu gave a mixture of regioisomers in
a 3:2 ratio in favor of the undesired isomer 22. At this
stage we postulated that this could be due to anion stabili-
zation by the ester in the reactive intermediate 21 in which
full deprotonation occurs. Fortunately, the resulting regio-
isomers 22 and 23 could be easily separated by column
chromatography.
CN
CN
HO
O
O
O
Br2, MeOH
9
Br
O
25 °C, 16 h
98%
Cs2CO3, MeCN
50 °C, 3 h
91%
8
10
7
DMF–DMA
100 °C, 1 h
93%
We hypothesized that we might be able to achieve selec-
tive N-alkylation by using a weaker noncoordinating base.
We are pleased to report that using a relatively weak or-
ganic base such as 2,6-lutidine N-alkylation proceeded
smoothly with excellent selectivity to afford compound
23 in a ratio of 20:1 over the undesired the regioisomer 22
(Table 1).
Me2N
O
HN
N
NH2NH2
AcOH
25 °C, 16 h
90%
O
O
CN
CN
12
11
Scheme 3
Synlett 2010, No. 6, 873–876 © Thieme Stuttgart · New York

LETTER
Regioselective N-Alkylation of an Activated Pyrazole
875
H
H
O
Me
O
H
H
H
CN
CN
N
I
S
H
H
HN
N
NIS
O
HN
CN
CN
H
N
N
R
H
MeCN
82 °C, 3 h
70%
S
Me
O
O
N
N
O
17
O
O
12
H
R
S
Me
Cl
15a
KOt-Bu, DME
25 °C, 16 h
15b
13
Figure 1
MeS
CN
CN
N
I
N
I
MeS
With these results in hand we retrospectively used compu-
tational analysis to further investigate our hypothesis.
N
N
+
O
O
Indeed, the observed regioselectivity is in agreement with
the computational analysis of this reaction carried out at
B3LYP/6-31G** level of theory.10 If R = Me, no signifi-
cant energy differences were found between the two re-
gioisomeric transition structures (Figure 2). Accordingly,
no regioselectivity is seen during N-alkylation if R = Me.
However, when R = CO2Et a significant energy differ-
ence is observed (Figure 2) predicting selective N-alkyla-
tion to give compound 23 in the presence of a
noncoordinating base. Additionally, calculations on the
N-alkylation in which coordinating metallic bases such as
KOt-Bu are used predict formation of compound 22 as the
N2 nitrogen is masked by coordination with the metal, and
the reactivity of the substrate anion comes mainly through
the more accessible N1 atom (Figure 3). Both of these
models rationalize the experimental outcome by assuming
a standard SN2 mechanistic pathway.
1:1
19
18
Scheme 5
N
N
Pd(OAc)2, CO
Et3N, EtOH
HN
HN
CN
CN
100 °C, 100 psi
16 h
I
O
EtO2C
O
20
90%
17
KOt-Bu
N
N
K+
base (see Table1)
DME
25 °C, 16 h
CN
O
O
MeS
Cl
OEt
21
13
MeS
MeS
N
Oxidation of sulfide 23 to the sulfone 24 with Oxone®
proceeded in a good yield. Subsequent LiBH4 reduction of
the ester functionality afforded the desired alcohol 6
(Scheme 7).11
N
N
N
CN
EtO2C
O
+
CN
EtO2C
O
23
22
In summary we have developed a regioselective synthesis
of the progesterone receptor antagonist metabolite 6 in
nine steps (22% overall yield) from commercial starting
materials. The key step in this sequence was a regioselec-
tive pyrazole N-alkylation using 2,6-lutidine as a base.
Scheme 6
Table 1 Synthesis of Isomers 22 and 23
Base
Isomer ratio 22/23
Overall isolated yield (%)
KOt-Bu
Et3N
3:2
67
56
0
1:1
pyridine
EtN(i-Pr)2
2,6-lutidine
no reaction
1:5
67
84
1:20
The regiochemistry was determined by 1H NMR through
the effect of the relative freedom of rotation of the cyclo-
propyl group on the multiplicity of the attached protons
(Figure 1).9 This was further confirmed by NOE experi-
ments.
Figure 2 The two most stable regioisomeric transition structures
Synlett 2010, No. 6, 873–876 © Thieme Stuttgart · New York

876
P. A. Bradley et al.
LETTER
and their corresponding relative energies (in kcal/mol) associated to
the studied N-alkylation for both substituents (R = Me, CO2Et).
a preferential stability of N2–H tautomer in the gas phase
(5.9 kcal/mol). In solution, however, the most polar N1–H
tautomer becomes nearly isoenergetic (only 0.3 kcal/mol
differences).
(8) Tong, Y.; Claiborne, A.; Pyzytulinska, M.; Tao, Z.; Stewart,
K. D.; Kovar, P.; Chen, Z.; Credo, R. B.; Guan, R.; Merta,
P. J.; Zhang, H.; Bouska, J.; Everitt, E. A.; Murry, B. P.;
Hickman, D.; Stratton, T. J.; Wu, J.; Rosenberg, S. H.; Sham,
H. L.; Sowin, T. J.; Lin, N. Bioorg. Med. Chem. Lett. 2007,
17, 3618.
(9) 4-(5-Cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-
4-yloxy)-2,6-dimethylbenzonitrile (15a)
1H NMR (400 MHz, CDCl3): d = 0.75 (m, 2 H), 0.90 (m, 2
H), 1.80 (m, 1 H), 2.45 (s, 6 H), 3.05 (s, 3 H), 5.35 (s, 2 H),
6.65 (s, 2 H), 7.40 (s, 1 H).
4-(3-Cyclopropyl-1-methanesulfonylmethyl-1H-pyrazol-
4-yloxy)-2,6-dimethylbenzonitrile (15b)
Figure 3 The most stable transition structure found for the potassi-
1H NMR (400 MHz, CDCl3): d = 0.85 (m, 4 H), 1.65 (m, 1
H), 2.45 (s, 6 H), 2.90 (s, 3 H), 5.10 (s, 2 H), 6.70 (s, 2 H),
7.45 (s, 1 H).
(10) All the calculations reported in this paper have been
performed within density functional theory,using the hybrid
three-parameter functional customarily denoted as B3LYP.
In all cases the standard 6-31G** basis set was used as
implemented in Jaguar package (Schrodinger, LLC,
Portland, Oregon). This level (B3LYP/6-31G**) has been
shown to be a convenient method for the computational
study of these types of reactions in terms of computational
cost and accuracy. Reactants and intermediates were
characterized by frequency calculations and have positive
definite Hessian matrixes. Transition structures (TS) show
only one negative eigenvalue in their diagonalized force
constant matrixes, and their associated eigenvectors were
confirmed to correspond to the motion along the reaction
coordinate under consideration. Nonspecific solvent effects
were partially taken into account by means of the standard
Poisson–Boltzmann continuum solvation model, where he
solvent is represented as a polarizable continuum (with
dielectric e) surrounding the molecular complex at an
interface constructed by combining atomic van der Waal
radii with the effective probe radius of the solvent. In several
cases molecular mechanics computations were performed on
several stationary points in order to determine the minimum
energy conformations. These calculations were performed
using the AMBER* force field as implemented in the
MacroModel package (Schrodinger, LLC, Portland,
Oregon). The different possible conformers were optimized
and then Monte Carlo simulations were performed on 1000
structures. All geometries are available on request to the
authors.
(11) 4-(3-Cyclopropyl-5-hydroxymethyl-1-methanesulfonyl-
methyl-1H-pyrazol-4-yloxy)-2,6-dimethylbenzonitrile (6)
Lithium borohydride (0.66 mL, 2 M in THF, 1.32 mmol)
was added dropwise to a solution of compound 24 (250 mg,
0.6 mmol) in THF (6 mL), under nitrogen, and the resulting
mixture was stirred for 30 min. The solvent was removed in
vacuo, and the residue was azeotroped with MeOH (25 mL).
The resulting solid was purified by flash chromatography
(silica gel) eluting with 70% EtOAc in pentane to afford
compound 6 as a white foam (180 mg, 80%). 1H NMR (400
MHz, CDCl3): d = 0.80 (m, 4 H), 1.60 (m, 1 H), 2.40 (t, 1 H),
2.45 (s, 6 H), 3.00 (s, 3 H), 4.60 (d, 2 H), 5.35 (s, 2 H), 6.65
(s, 2 H). Anal. Calcd for C18H21N3O4S·0.66H2O: C, 55.82; H,
5.81; N, 10.85. Found: C, 55.80; H, 5.76; N, 10.87.
CN
N
MeS
N
O
Oxone®
MeOH–H2O
EtO2C
23
O
CN
Me
25 °C, 6 h
N
S
N
O
O
LiBH4, THF
25 °C, 16 h
EtO2C
24
80%
O
CN
Me
N
S
N
O
O
HO
6
Scheme 7
References and Notes
(1) Bradley, P. A.; De Koning, P. D.; Johnson, P. S.;
Lecouturier, Y. C.; McManus, D. J.; Robin, A.; Underwood,
T. J. Org. Process Res. Dev. 2009, 13, 848.
(2) Narsaiah, A. V. Synlett 2002, 1178.
(3) Shinkre, B. A.; Velu, S. S. Synth. Commun. 2007, 37, 2399.
(4) Calverley, M. J. Tetrahedron 1987, 43, 4609.
(5) Del Carmen Cruz, M.; Tamariaz, J. Tetrahedron 2005, 61,
10061.
(6) Lebedev, A. V.; Lebedeva, A. B.; Sheludyakov, V. D.;
Kovaleva, E. A.; Ustinova, O. L.; Kozhevnikov, I. B. Russ.
J. Org. Chem. 2005, 75, 412.
(7) The pyrazoles can exit in two tautomeric forms, that is, the
hydrogen atom may be bound to either the N1 or N2 atom.
This tautomeric equilibrium has not been experimentally
studied in this manuscript, and the corresponding schemes
herein only show an arbitrary tautomer. The stability of both
pyrazole tautomers was computational analyzed for
compounds 12 and 20 in both gas phase and water solution
as the extreme media in terms of dielectric constant. In the
unsubstituted case 12, the tautomers are almost equally
stable in both media (0.7 and 0.0 kcal/mol, respectively, in
favor of N2–H tautomer). On the other hand, in the case of
compound 20, the stabilizing electrostatic interaction
between N2–H and lone pair of the carbonyl group involves
Synlett 2010, No. 6, 873–876 © Thieme Stuttgart · New York