Synthesis of metapristone through an efficient: N -demethylation of mifepristone

Article abstract of DOI:10.1039/c5ra26557f

Accumulating evidence demonstrates that mifepristone (RU486) exhibits potent anti-proliferative effects on various cancer cell lines. Our recent work shows that its major metabolite metapristone (RU42633) is a good drug candidate for cancer metastatic che

Full text of DOI:10.1039/c5ra26557f

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Synthesis of metapristone through an efficient N-
demethylation of mifepristone†
Cite this: RSC Adv., 2016, 6, 7195
Jianlei Wu,‡ Xuemei Yu,‡ Jian Liu, Yuqin Lin, Yu Gao, Lee Jia and Haijun Chen*
Received 12th December 2015
Accepted 24th December 2015
DOI: 10.1039/c5ra26557f
www.rsc.org/advances
3–5
Accumulating evidence demonstrates that mifepristone (RU486) mifepristone. Blood concentrations of metapristone are equal
6,7
exhibits potent anti-proliferative effects on various cancer cell lines. to or even higher than those of mifepristone. In addition,
Our recent work shows that its major metabolite metapristone metapristone showed the AUC (area under the curve) level
8,9
(
RU42633) is a good drug candidate for cancer metastatic chemo- higher than mifepristone. Recent extensive studies indicated
prevention. However, lack of an efficient method for synthesizing that mifepristone exhibited potent anti-proliferative effects on
1
0–12
metapristone limited its further clinical development. Herein, an various cancer cell lines.
Notably, the solubility and stability
13
improved and efficient condition of N-demethylation of mifepristone of metapristone are both higher than mifepristone. Consid-
with an excellent yield is described. The procedure presented here has ering its relative safety and distinctive pharmacological effects,
several advantages including one-pot preparation, ease of synthesis, our recent work indicated that metapristone was suitable for
14
and large-scale feasibility.
cancer metastatic chemoprevention. Therefore, an easy and
efficient method for synthesis of metapristone is essential for
preclinical studies and further chemical optimization. Despite
the availability of three conditions for N-demethylation of
mifepristone, they are not applicable for large-scale preparation
Fig. 1). For example, Schramm et al. reported that a one-step
procedure for N-demethylation of mifepristone to prepare
metapristone by using CaO (base) and iodine in methanol
resulted in a yield of 28%. The extremely low yield limited its
As one of the essential medicines on the WHO model list,
mifepristone (RU486, Fig. 1) with potent antiglucocorticoid and
antiprogestogen was widely used clinically for medical termi-
nation of pregnancy. Pharmacokinetic studies have shown
that N-monodemethyl mifepristone (RU42633, metapristone) is
the most predominant metabolite aer oral administration of
(
1,2
15
16,17
further application.
Geldern et al. developed a two-step
procedure for the N-demethylation of mifepristone by using
TPAP/NMO (tetra-n-propylammonium perruthenate/N-methyl
morpholine-N-oxide) to provide the desired product for the total
18
yield of about 50%. However, TPAP is a very expensive and rare
19
metal reagent. In addition, harsh conditions and the complex
purication process made this method inaccessible to obtain
sufficient quantities of the desired compound for further
preclinical studies. Goldrick et al. also reported that the desired
Fig. 1 Major metabolic pathway of mifepristone in vivo and general product could be obtained by reacting mifepristone with
reagents and conditions for synthesis of metapristone from mifepris-
20
2
PhI(OAc) in a 10% yield.
ꢀ
tone. Method A: CaO, I
NMO, CH Cl
CH CN/CH Cl
2
, MeOH/THF, 0 C, 28%; method B: (i) TPAP,
To overcome this obstacle, our group aimed at developing
a suitable N-demethylation condition for large-scale prepara-
tion of metapristone. We rst examined several available and
2
2
, 63%; (ii) aq. HCl, MeOH, 86%; method C: PhI(OAc)
2
,
3
2
2
, room temperature, overnight, 10%.
mild conditions for N-demethylation including NIS/CH CN and
3
2
1,22
TiCl /CH Cl .
However, these methods resulted in a complex
mixture. We then turned our attention to the previous reported
). As shown in Table 1,
mifepristone treating with 10 eq. of CaO and 3 eq. of I in
College of Chemistry, Fuzhou University, Fuzhou, Fujian 350116, China. E-mail:
chenhaji@gmail.com; Fax: +86 591 22866227; Tel: +86 591 22866234
4
2
2
1
13
†
Electronic supplementary information (ESI) available: Copies of H, C NMR relative cost-effective condition (CaO/I
2
and HRMS spectra of metapristone, and photographic guide for synthesis of
2
metapristone. See DOI: 10.1039/c5ra26557f
ꢀ
MeOH/THF at 0 C for 8 h afforded the desired product in 29%
‡
These authors contributed equally to this work.
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a
Table 1 Optimization of reaction conditions of metapristone
b
ꢀ
c
Entry
Base
I
2
Temperature ( C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
CaO (10 eq.)
DBU (10 eq.)
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
3 eq.
2 eq.
1 eq.
0.5 eq.
3 eq.
0
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
8
24
5
29
3
3
CaCl
2
(10 eq.)
LiF (10 eq.)
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
10
18
10
25
20
37
61
60
79
82
2
93
97
90
75
45
30
92
K
2
HPO
KH PO
KHCO
Cs CO
Na CO
Li CO
CO
4
(10 eq.)
(10 eq.)
(10 eq.)
(10 eq.)
(10 eq.)
2
4
3
2
3
2
3
10
11
12
13
14
15
16
17
18
19
20
21
2
3
(10 eq.)
(10 eq.)
K
2
3
NaOAc (10 eq.)
KOAc (10 eq.)
NaOCOCF (10 eq.)
3
LiOAc (10 eq.)
LiOAc (5 eq.)
LiOAc (3 eq.)
LiOAc (5 eq.)
LiOAc (5 eq.)
LiOAc (5 eq.)
LiOAc (5 eq.)
d
a
b
ꢁ1
c
d
Concentration was 0.044 M in THF/MeOH. Concentration was 100 mg mL in MeOH. Isolated yield. Gram scale.
yield (entry 1). Note that about 70% of the starting material was amounts of LiOAc were further evaluated (Table 1, entries 16–17).
recovered. We also noticed that most of CaO was insoluble in Upon reducing the amount of LiOAc (5 eq., 3 eq.), the yields of
MeOH/THF, indicating that a large amount of CaO did not the desired product were 97% and 90%, respectively. Also, no
participate in the reaction.
visible LiOAc was observed in the reaction mixture. Thus, 5 eq.
Based on the above precedents, we hypothesized that judi- of LiOAc was the best amount for this reaction. It is worth
cious choice of a suitable base might play an important role in mentioning that the solubility of LiOAc in MeOH is the highest
N-demethylation. Therefore, various bases were evaluated at in all three metal acetates (LiOAc: 30.37 g/100 g MeOH, KOAc:
ꢀ
23
room temperature in order to improve efficiency and potential 24.24 g/100 g MeOH, NaOAc: 16.00 g/100 g MeOH at 15 C),
large-scale application (Table 1, entries 2–15). Our efforts were further indicating that the solubility of an inorganic base in
quickly rewarded, as metapristone was obtained at a higher organic solvents is quite important for N-demethylation. Different
yield when we used Na
Table 1, entries 9–11). The use of DBU, CaCl
KH PO , KHCO or Cs CO as a base only provided the desired yield of metapristone was decreased. Hence, the condition of
2
CO
3
or K
2
CO
3
or Li
2
CO
3
as a base amounts of I
2
were also evaluated (Table 1, entries 18–20).
(
2
, LiF, K
2
HPO However, reducing the amount of I
4
,
2
(2 eq., 1 eq., 0.5 eq.), the
2
4
3
2
3
product at a low yield (Table 1, entries 2–8). Notably, metapri- entry 16 (5 eq. of LiOAc and 3 eq. of I ) should be used as the
2
stone was isolated in a signicantly higher yield (79%) when best reaction condition. Gratifyingly, this improved condition
using NaOAc as a base (Table 1, entry 12). Other similar bases was employed on the gram scale to afford metapristone at
(
KOAc, NaOCOCF
3
and LiOAc) were further examined (Table 1, a 92% yield (entry 21; see also Fig. S1–S5†).
In summary, the concise and efficient synthetic approach to
entries 13–15). To our delight, LiOAc was found as the best base
to provide metapristone at a 93% yield (Table 1, entry 15). We access metapristone was achieved for the rst time at a high
also noticed that only a small part of LiOAc was visible as yield by using the improved condition. We determined that
a white solid in the reaction mixture. Therefore, diverse LiOAc is a superior base for N-demethylation of mifepristone.
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The established condition facilitated ongoing preclinical eval-
uation of metapristone for cancer metastatic chemoprevention.
The synthesis of new mifepristone analogues as novel anti-
cancer agents as well as potential cancer metastatic chemo-
preventive agents is currently underway.
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(
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4-(methylamino)phenyl)-17-(prop-1-yn-1-yl)-
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14
1
(
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2
This work was supported by the National Natural Science
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Technology Development Foundation of Fuzhou University.
2
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