Improved synthesis of fluticasone propionate

Article abstract of DOI:10.1021/op5001226

A novel process for the preparation of fluticasone propionate (1), a corticosteroid, is reported. In this paper, compound 2 was used as starting material to prepare 6 by using NaClO or NaBrO which was much cheaper than H ₅IO₆ as an oxidizing agent. Furthermore, toxic, expensive, and pollutive BrCH₂F was replaced by AgNO₃ and Selectfluor in decarboxylative fluorination.

Full text of DOI:10.1021/op5001226

Article
pubs.acs.org/OPRD
Improved Synthesis of Fluticasone Propionate
Jiadi Zhou, Can Jin, and Weike Su*
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, Collaborative Innovation
Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, P. R. China
*
S Supporting Information
ABSTRACT: A novel process for the preparation of fluticasone propionate (1), a corticosteroid, is reported. In this paper,
compound 2 was used as starting material to prepare 6 by using NaClO or NaBrO which was much cheaper than H IO as an
5
6
oxidizing agent. Furthermore, toxic, expensive, and pollutive BrCH F was replaced by AgNO and Selectfluor in decarboxylative
2
3
fluorination.
INTRODUCTION
The disadvantages of the above processes include safety
■
issues, high expenses, and environmental problems, such as the
use of costly H IO as an oxidant and BrCH F, XeF , BrF , or
Steroidal glucocorticoid agonists such as fluticasone propionate
1) are anti-inflammatory agents used widely against a broad
spectrum of inflammatory diseases. Fluticasone propionate (1),
synthesized by Glaxo Wellcome and launched in 1993, is a
trifluorinated glucocorticosteroid. It shows good topical anti-
inflammatory activity and is commonly used as a safe and
5
6
2
2
3
(
Deoxo-Fluor as monofluoromethylation reagents. Considering
these drawbacks, we have subjected this synthetic route to
further researches and intended to develop an efficient, eco-
friendly, and commercially feasible process for fluticasone
propionate (1). In this article, we describe an improved process
with an overall yield of 42.3% in method A and 54.5% in
method B (Scheme 3).
1
effective inhaled treatment for asthma and allergic rhinitis. The
previous route for the synthesis of 6 from 2 was in the
commercial scale. Compound 6 was synthesized from
commercial grade flumethasone (5) by H IO oxidation with
5
6
2
a
RESULTS AND DISCUSSION
Preparation of 6α,9α-Difluoro-11β,17α-dihydroxy-
6α-methyl-3-oxoandrosta-1,4-diene-17β-carboxylic
■
a yield of 95.0%. Flumethasone (5) can be prepared from 2 in
3
three steps with a unclear yield (Scheme 1). According to the
2a,3
1
literature, we obtained 6 from 2 in a total yield of 45%.
The compound 7 was synthesized from 6 by propionyl
chloride or propionic anhydride acylation. Compound 7
Acid (6). As one of the oldest known organic reactions, the
haloform reaction can be used to convert a terminal methyl
6
4
ketone into appropriate carboxylic acid. Applying this reaction
reacted with N, N-dimethylthiocarbamoyl chloride in the
presence of an iodide catalyst and Et N to produce 8, followed
by hydrolyzation with K CO , Et NH, or NaSH to obtain
to the synthesis of compound 6 from 2 could shorten reaction
3
7
8
2
a
2b
4a
routes, reduce the cost, and improve the total yield compared
with the traditional method in four steps. Luckily, we found
that using NaClO in the presence of NaOH could successfully
2
3
2
9
(
. Alternatively, the combination of 1,1′-carbonyldiimidazole
2b
CDI) with NaSH can also be used to prepare 9 from 7.
obtain compound 6 in room temperature with a yield of
Fluticasone propionate (1) can be synthesized from 9 by using
9
2
a
5a
6
3.7%, and 11β,17α-dihydroxy and 1,4-diene were tolerated. A
BrCH F, ClCH F, or S-(monofluoromethyl) diarylsulfo-
2
2
5
f,g
series of solvents such as dioxane/H O, THF/H O, dimethoxy-
nium tetrafluoroborate directly. Using BrCH F can get an
ideal yield; however, BrCH F is costly and will destroy to the
ozone layer. In addition, 9 reacted with BrCH Cl or Br CH
and then by an anion exchange with AgF,
tetrabutylammonium fluoride to afford 1 in a low yield.
Fluticasone propionate (1) could be obtained from 10, in the
2
2
2
ethane/H O, and EtOH/H O, were screened in order to find
2
2
2
an optimal solvent. The results showed that all of those mixed
solvents did not work well to afford the desired product 6
2
2
2
2
c,5e
KF, or
5
b
except THF/H O/EtOH, which provided a homogeneous
2
reaction system.
By contrast, the usage of NaBrO which has a stronger activity
than NaClO could get a higher yield of 84.5% in a lower
presence of fluorodecarboxylating reagents such as XeF and
2
5
d
BrF3. Unfortunately, XeF is extremely expensive, and BrF3
2
temperature (Scheme 3). To this reaction, dioxane/H O was
which should be stored in Teflon containers is a strong
corrosive toxic liquid, which tends to react very exothermically
with water and release poisonous vapours. Furthermore, the
high toxicities and instabilities of XeF and BrF prevented
2
10
proved to be the best solvent. Other solvents such as THF/
H O, dimethoxyethane/H O, EtOH/H O, and THF/H O/
2
2
2
2
EtOH did not work well, and the reaction did not proceed in
biphasic systems. When the reaction was finished, the
remaining oxidizing agent (NaClO or NaBrO) was destroyed
by the addition of excess sodium sulfite solution, and the
2
3
practical applications of this method. According to the
5
c
literature, Deoxo-Fluor or DAST can also be used as
monofluoromethylation reagent to acquire 1 from 11 at −60
C (Scheme 2). Considering the different literature sources, the
highest overall yield for the previous synthesis of fluticasone
propionate (1) from 2 was close to 30%.
°
Received: April 14, 2014
©
XXXX American Chemical Society
A
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Organic Process Research & Development
Article
Scheme 1. Previous route for the synthesis of 6
a
Scheme 2. Previous method for the synthesis of fluticasone propionate (1)
a
Reactions and conditions: (a) (i) propionic anhydride or propionyl fluoride/Et N; (ii) Et NH; (b) N,N-dimethylthiocarbamoyl chloride/Et N/NaI
3
2
3
or tetrabutylammonium iodide; (c) K CO or Et NH or NaSH; (d) CDI/NaSH; (e) BrCH COOH/Et N; (f) formaldehyde; (g) XeF /BrF ; (h)
2
3
2
2
3
2
3
BrCH F or ClCH F or S-(monofluoromethyl) diarylsulfonium tetrafluoroborate or BrCH Cl/AgF or BrCH Cl/KI/KF; (i) Deoxo-Fluor or DAST.
2
2
2
2
solvent THF/EtOH or dioxane was removed under reduced
pressure. After extraction with ethyl acetate, the aqueous phase
was acidified with hydrochloric acid to furnish a white
precipitate of 6, which was collected by filtration, washed
with water, and dried.
reagents, such as Selectfluor and NFSI, are commercially
available, easy to use, and stable electrophilic fluorinating
reagents that can be used to conduct decarboxylative
11
fluorination. In our improved process, fluticasone propionate
(1) was prepared from 10 with AgNO /Selectfluor (Scheme
3
12
11a
Preparation of 6α,9α-Difluoro-11β-hydroxy-16α-
methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-
4). According to the literature, the combination of AgNO3
(20 mol %) with Selectfluor (2.5 equiv) shows a considerable
decarboxylative fluorination ability (Table 1, entry 1). Other
Ag(I) salts, such as AgOAc and AgOTf, exhibited a weaker
catalytic activity (Table 1, entries 2 and 3), while no reaction
occurred without the presence of a Ag(I) salt (Table 1, entry
4). Switching the electrophilic fluorinating reagent from
Selectfluor to NFSI caused no reaction (Table 1, entry 5). In
addition to Ag(I) ions, water also was turned out to be essential
(Table 1, entry 6). Much of the experimental results was similar
2a,5d
1
7β-carbothioate (10). According to the literature,
the
compound 10 can be synthesized from 6 in four steps including
esterification, acylation, alcoholysis, and alkylation (Scheme 3).
5d
In the original methods, the product 10 was acquired from 9
by BrCH COOH alkylation under the condition of using DCM
2
as the solvent. In our improved process, lower toxic solvent
acetone was used to replace DCM. When the reaction was
finished, the compound 10 could obtained by filtration
conveniently after acidification with 1 mol/L HCl.
Preparation of S-Fluoromethyl-6α,9α-difluoro-11β-
hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-
11a
to the optimization done by the Li group.
The Ag(II)- or Ag(III)-mediated decarboxylation of
1
3
carboxylic acids is well-documented. According to the
11a
1
,4-diene-17β-carbothioate (1). Recently reported N−F
literature,
a tentative mechanism of the decarboxylative
B
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Organic Process Research & Development
Article
a
Scheme 3. Improved process for the synthesis of fluticasone propionate (1)
a
Reactions and conditions: (a) NaClO/NaOH, THF/EtOH/H O, 25 °C, 63.7%; (b) NaBrO/NaOH, dioxane/H O, 0−5 °C, 84.5%; (c) (i)
2
2
propionic anhydride/Et N, acetone, 15−25 °C; (ii) Et NH, 15−25 °C, 97.3%; (d) N,N-dimethylthiocarbamoyl chloride/Et N/NaI, acetone/H O,
3
3
2
3
2
0 °C, 96.0%; (e) K CO , CH OH, 25 °C, 95.0%; (f) BrCH COOH/Et N, acetone, 15−25 °C, 97.1%; (g) AgNO /Selectfluor, acetone/H O, 45
2
3
3
2
3
3
2
°C, 92.7%.
Scheme 4. Decarboxylative fluorination for the synthesis of 1
Table 1. Screening of Ag(I) catalyst and N−F reagent of
a
decarboxylative fluorination of 10
Figure 1. Proposed mechanism of silver-catalyzed decarboxylative
fluorination.
N−F
b
c
catalyst
entry (equiv)
reagent
(equiv)
time yield
purity
(%)
solvent
(h)
(%)
1
2
3
4
5
6
AgNO3
AgOAc
AgOTf
Selectfluor
Selectfluor
Selectfluor
Selectfluor
NFSI
acetone/H O
3
8
8
8
8
8
92.7
64.2
48.8
0
92.6
74.2
79.5
2
reaction was performed at 55 °C (Table 2, entry 3).
Unfortunately, using AgNO3 (10 mol %)/Selectfluor (2.5
acetone/H O
2
acetone/H O
2
equiv) or AgNO (20 mol %)/Selectfluor (2.0 equiv) as
3
acetone/H O
2
fluorodecarboxylating reagents provided 1 in only 75.2% and
AgNO3
AgNO3
acetone/H O
0
2
7
0.3% yields, respectively (Table 2, entries 4 and 5).
The activity of decarboxylative fluorination was proved to be
Selectfluor
acetone
trace
a
Reagents and conditions: 1.0 equiv 10, 0.2 equiv catalyst, 2.5 equiv
N−F reagent, 45 °C, under nitrogen. The isolated yield was
calculated with 10. The purity was monitored by HPLC.
solvent-dependent, the mixed solvent of acetone/H O (2:1,
b
2
v:v) exhibited the best activity (Table 2, entry 2). By contrast, a
higher reaction temperature was needed in CH CN/H O (2:1,
c
3
2
v:v) solution that led to more impurity 12 (Table 2, entry 6).
fluorination with AgNO /Selectfluor was proposed. The
No fluorodecarboxylation occurred in THF/H O (2:1, v:v)
3
2
oxidation of Ag(I) by Selectfluor generates an Ag(III)−F
intermediate, which initiated the decarboxylative fluorination of
carboxylic acids (Figure 1).
Further optimization of the decarboxylative fluorination was
carried out by screening of a range of temperatures, and of
solution (Table 2, entry 7) or other biphasic systems.
The optimized reaction conditions (Table 2, entry 2), 10 was
treated with AgNO (20 mol %) and Selectfluor (2.5 equiv) in
3
acetone/H O (2:1, v:v) solution at 45 °C for 3 h under a
2
nitrogen atmosphere giving the expected product fluticasone
propionate 1. Dilution with water upon completion of the
reaction and collection of the product by filtration followed by
washing with water gave 1 in 92.7% isolated yield.
reagent stoichiometries, using AgNO and Selectfluor (Table
3
2
). As shown in (Table 2, entry 1), 10 was treated with AgNO3
(20 mol %) and Selectfluor (2.5 equiv) at 30 °C for 8 h under a
nitrogen atmosphere giving 1 in 80.1% yield, when raising the
temperature to 45 °C improved the yield of 1 to 92.7% (Table
2, entry 2). However, more impurities were generated when the
The major impurity 12 was obtained by preparative HPLC,
the process of impurity formation was studied (Scheme 5). We
suspected that fluticasone propionate (1) could be hydrolyzed
C
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Organic Process Research & Development
Article
Table 2. Optimisation of decarboxylative fluorination of 10
a
b
entry
AgNO (equiv)
Selectfluor (equiv)
solvent
temp (°C)
time (h)
yield (%)
purity (%)
3
1
2
3
4
5
6
7
0.2
0.2
0.2
0.1
0.2
0.2
0.2
2.5
2.5
2.5
2.5
2.0
2.5
acetone/H O
30
45
55
45
45
55
55
8
3
3
8
8
8
8
80.1
92.7
92.0
75.2
70.3
80.5
0
85.0
92.6
79.7
80.2
83.1
67.0
2
acetone/H O
2
acetone/H O
2
acetone/H O
2
acetone/H O
2
MeCN/H O
2
2.5
THF/H O
2
a
b
The isolated yield was calculated with 10. The purity was monitored by HPLC.
Scheme 5. Process of impurity 12 generated
The UV detector was set at 239 nm to analyze the column
1
13
19
effluent. H (400 MHz) NMR, C (101 MHz) NMR, and
F
(
376 MHz) NMR spectra were recorded on a Varian
spectrometer in CDCl or DMSO-d using tetramethylsilane
3
6
(
TMS) as internal standards.
6
α,9α-Difluoro-11β,17α-dihydroxy-16α-methyl-3-ox-
oandrosta-1,4-diene-17β-carboxylic Acid (6). Method A.
NaOH (25.0 g, 0.625 mol) was dissolved in H O (0.040 L), the
2
mixture was diluted with 0.500 L of THF and 0.500L of EtOH.
Into the solution, 2 (50.0 g, 0.126 mol) was added, then 10%
NaClO (0.500 L) was added gradually at 25 °C. The reaction
was kept at 25−30 °C for 6 h. When the reaction was finished,
the remaining oxidizing agent (NaClO) was destroyed by the
addition of excess 10% Na SO solution. The solvent THF/
2
3
EtOH was removed under reduced pressure. Ethyl acetate
0.500 L) was added to the solution; the layers were separated,
and then acidification of the aqueous phase to pH = 1.0−2.0 by
mol/L HCl furnished a white precipitate of 6 (32.0 g), which
was collected by filtration, washed with water, and dried. Yield:
63.7%; HPLC purity 96.0%.
(
3
to 7 which might generate 12 through decarboxylative
fluorination rapidly. The C-17 stereochemistry of compound
1
2 was established by X-ray crystallography. In order to confirm
Method B. Br (140.0 g, 0.875 mol) was added slowly to a
2
the speculation, we successfully using 7 as material to obtain 12
with AgNO /Selectfluor in acetone/H O solution at 45 °C.
vigorously stirred solution of 130.0 g of NaOH in 1.170 L of
H O while cooling in an ice-salt-bath. When all of the Br had
dissolved, the mixture was diluted with 0.600 L of cold dioxane,
and the ice-cold NaBrO was added slowly to a stirred solution
of 100.0 g of 2 in 1.400 L of dioxane which was maintained at a
temperature below 8 °C throughout the oxidation. After 5 h,
the remaining oxidizing agent (NaBrO) was destroyed by the
3
2
2
2
CONCLUSION
■
In conclusion, an efficient, eco-friendly, and commercially
viable process for the synthesis of fluticasone propionate (1)
has been developed. In this method, compound 2 was used as
the starting material, which was transformed to 1 in six steps
including oxidation, esterification, acylation, alcoholysis,
alkylation, and fluorodecarboxylation. Especially, compared to
traditional flumethasone oxidation with H IO , application of
addition of excess 10% Na SO solution. The solvent dioxane
2 3
was removed under reduced pressure. Ethyl acetate (1.000 L)
was added to the solution; the layers were separated, then
acidification of the aqueous phase to pH = 1.0−2.0 by 3 mol/L
HCl furnished a white precipitate of 6 (85.0 g), which was
5
6
haloform reaction to the synthesis of compound 6 for the first
time could shorten reaction routes, reduce the cost, and
improve the total yield dramatically. Furthermore, the usage of
collected by filtration, washed with water, and dried. Yield:
1
84.5%; HPLC purity 95.6%; H NMR (400 MHz, DMSO-d ) δ
6
toxic, extremely costly, and pollutive BrCH F was replaced by
12.45 (s, 1H), 7.24 (d, J = 10.3 Hz, 1H), 6.27 (dd, J = 10.2 Hz,
2
1
an efficient method with AgNO and Selectfluor in a good
yield.
J = 1.6 Hz, 1H), 6.08 (s, 1H), 5.70−5.54 (2m, 1H), 5.32 (s,
3
2
1H), 4.69 (s, 1H), 4.12 (d, J = 11.7 Hz, 1H), 2.88−2.80 (m,
1
2
H), 2.50−2.35 (m, 2H), 2.25−1.96 (m, 3H), 1.70−1.50 (m,
H), 1.49 (s, 3H), 1.12−1.05 (m, 1H), 0.99 (s, 3H), 0.86 (d, J
EXPERIMENTAL SECTION
■
13
Compound 2 was provided by Zhejiang Xianju Junye
Pharmaceutical Co., Ltd., and all other chemicals were
purchased from commercial sources and were used without
further purification. HPLC analysis for fluticasone propionate
= 7.0 Hz, 3H); C NMR (101 MHz, DMSO-d ) δ 184.14 (s),
6
174.35 (s), 162.86 (d, J = 13.7 Hz), 151.86 (s), 128.85 (s),
119.23 (d, J = 12.9 Hz), 100.13 (d, J = 176.0 Hz), 86.83 (d, J =
178.0 Hz), 85.34 (s), 70.61 (d, J = 36.0 Hz), 48.14 (d, J = 19.5
Hz), 47.31 (s), 42.23 (s), 35.42 (s), 35.19 (s), 33.91 (d, J = 18.8
Hz), 32.30 (m), 31.99 (s), 22.86 (s), 16.93 (s), 15.45 (s);
(1) was carried out on an Agilent HPLC system (series 1200,
Agilent Technologies, Germany) equipped with Agilent
ZORBAX SB-C18 reversed-phase column (250 mm × 4.6
mm, 5 μm). A mobile phase of methanol, acetonitrile, and
buffer with 1.2 g/L of monobasic ammonium phosphate, a pH
of 3.5 adjusted with phosphoric acid, (50:15:35) was used at a
flow rate of 1.5 mL/min and a column temperature of 40 °C.
+
MS(ESI-) m/z 395.2 [M − H] .
6α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-propio-
nyloxy-3-oxoandrosta-1,4-diene-17β-carboxylic Acid
(7). To a suspension of 6 (85.0 g, 0.215 mol) in acetone
(0.425 L) at 10−15 °C was added sequentially Et N (65.1 g,
3
D
dx.doi.org/10.1021/op5001226 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
.645 mol) and propionic anhydride (83.8 g, 0.645 mol). After
Article
0
(m, 1H), 3.67 (s, 2H), 3.25 (m, 1H), 2.56−2.45 (m, 1H), 2.33
(q, J = 7.4 Hz, 2H), 2.24 (m, 1H), 2.08 (m, 2H), 1.91−1.86 (m,
2H), 1.48 (m, 4H), 1.24 (m, 1H), 1.02 (s, 3H), 1.00 (t, J = 7.6
Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H); 13C NMR (101 MHz,
stirring for 4 h at 25 °C, Et NH (31.4 g, 0.430 mol) was added
2
dropwise at 10−15 °C and then stirred at 25 °C for 1 h.
Thereafter, the reaction mixture was acidified to pH 1.0−1.5
with 1 mol/L HCl at 0 °C. The precipitated product 7 (93.3 g)
DMSO-d ) δ 194.93 (s), 184.01 (s), 171.81 (s), 169.19 (s),
6
was obtained by filtered, washed with water, and dried. Yield
1
1
8
(
1
1
62.49 (d, J = 13.4 Hz), 151.46 (d, J = 8.1 Hz), 128.90 (s),
19.25 (d, J = 12.8 Hz), 99.84 (d, J = 176.4 Hz), 95.63 (s),
6.68 (d, J = 180.7 Hz), 70.00 (d, J = 35.0 Hz), 48.65 (s), 47.90
d, J = 19.9 Hz), 42.71 (s), 35.75 (s), 35.07 (s), 33.78 (d, J =
9.3 Hz), 33.40 (s), 31.98 (m), 31.47 (s), 27.09 (s), 22.77 (s),
7.03 (s), 15.83 (s), 9.10 (s); MS(ESI−) m/z 525.0 [M − H] .
S-Fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-
methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-
7β-carbothioate (1). A solution of 10 (95.0 g, 0.180 mol),
Selectfluor (159.3 g, 0.450 mol), and AgNO (6.1 g, 0.036 mol)
in acetone (1.900 L) and water (0.950 L) was stirred at 45 °C
for 3 h under a blanket of nitrogen. Then water (1.900 L) was
added to the solution; the resultant was cooled to 0 °C and
stirred for 1 h. The precipitated product 1 (83.5 g) was
collected by filtered, washed with water, and dried. Yield 92.7%;
HPLC purity 92.6%.
Purification. The crude product 1 (83.5 g) was dissolved in
ethyl acetate (0.835 L) and ethanol (3.340 L). The suspension
was refluxed for 30 min, gradually cooled to 0 °C, and stirred
for 1 h, and the soild was collected by filtration and dried at 40
1
9
6.0%; HPLC purity 97.0%; H NMR (400 MHz, DMSO-d ) δ
6
7.24 (d, J = 10.3 Hz, 1H), 6.27 (dd, J = 10.1, 1.9 Hz, 1H), 6.09
(
s, 1H), 5.70−5.54 (2m, 1H), 5.46 (s, 1H), 4.16 (m, 1H), 3.14
(m, 1H), 2.50 (m, 1H), 2.30 (q, J = 7.2 Hz, 2H), 2.23 (m, 1H),
2
.05 (m, 2H), 1.82−1.68 (m, 2H), 1.49 (m, 4H), 1.18 (m, 1H),
.01 (t, J = 7.2 Hz, 3H), 1.00 (s, 3H), 0.84 (d, J = 7.2 Hz, 3H);
+
1
1
3
C NMR (101 MHz, DMSO-d ) δ 184.03 (s), 171.96 (s),
6
1
1
8
2
1
1
69.79 (s), 162.59 (d, J = 13.5 Hz), 151.64 (s), 128.88 (s),
19.24 (d, J = 12.1 Hz), 99.96 (d, J = 175.9 Hz), 91.13 (s),
6.69 (d, J = 180.8 Hz), 70.23 (d, J = 36.1 Hz), 47.96 (d, J =
2.2 Hz), 47.64 (s), 42.63 (s), 35.41 (s), 35.30 (s), 33.86 (d, J =
8.9 Hz), 33.08 (s), 32.19 (m), 27.02 (s), 22.77 (s), 16.44 (s),
6.43 (s), 9.26 (s); MS(ESI+) m/z 475.4 [M + Na] .
6
1
3
+
α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-propio-
nyloxy-3-oxoandrosta-1,4-diene-17β-carbothioic Acid
9). A solution of 7 (93.3 g, 0.206 mol) and N,N-
dimethylthiocarbamoyl chloride (50.8 g, 0.449 mol) in acetone
1.866 L) at room temperature was cooled to 10−15 °C. It was
sequentially treated with Et N (41.3 g, 0.413 mol), NaI (15.0 g,
(
(
3
0
.080 mol), and water (9.330 mL, 10% w/w with 7) at 10−15
°
(
°
C. The solution was stirred for 6 h at 30 °C, then added DMF
0.466 L) and water (3.000 L). The resultant was cooled to 0
C and stirred for 1 h. The precipitated product 8 (106.6 g)
°
C under vacuum to provide 69.5 g (83%) of product 1. HPLC
14
purity 99.2%; residual silver content 0.04633 (μg/g).
1
H NMR (400 MHz, DMSO-d ) δ 7.23 (d, J = 10.0 Hz, 1H),
6
was obtained by filtration, washed with water, and dried. Yield
6
2
1
(
1
(
(
1
.28 (dd, J = 10.1, 1.6 Hz, 1H), 6.10 (s, 1H), 5.92 (J = 50.0 Hz,
H), 5.70−5.54 (2m, 1H), 5.58 (d, J = 3.2 Hz, 1H), 4.20 (m,
H), 3.28 (m, 1H), 2.36 (q, J = 7.2 Hz, 2H), 2.23 (m, 1H), 2.09
m, 2H), 1.86 (m, 2H), 1.53 (m, 1H), 1.48 (s, 3H), 1.26 (m,
H), 1.05 (m, 1H), 1.01 (t, J = 7.2 Hz, 3H), 0.99 (s, 3H), 0.89
9
6.0%; HPLC purity 96.5%.
A suspension of 8 (106.6 g, 0.196 mol) and K CO (54.1 g,
2
3
0.392 mol) in methanol (0.530 L) was stirred at 25 °C for 5 h
under a blanket of nitrogen. Thereafter, water (0.530 L) was
added to the reaction mixture, and the resultant clear solution
was washed twice with toluene (0.212 L). The aqueous layer
was acidified with 1 mol/L HCl until pH is 1.5 to 2.0. The
precipitated product was filtered, washed with water, and dried
1
3
d, J = 7.1 Hz, 3H); C NMR (101 MHz, DMSO-d ) δ 192.87
s), 183.98 (s), 172.07 (s), 162.43 (d, J = 13.5 Hz), 151.54 (s),
6
28.91 (s), 119.25 (d, J = 12.1 Hz), 99.72 (d, J = 176.3 Hz),
95.94 (s), 86.62 (d, J = 178.0 Hz), 80.92 (d, J = 211.8 Hz),
9.97 (d, J = 37.2 Hz), 48.40 (s), 47.84 (d, J = 22.4 Hz), 42.84
(s), 35.74 (s), 35.10 (s), 33.73 (d, J = 19.4 Hz), 33.37 (s), 31.93
1
to obtain 9 (87.1 g). Yield 95.0%; HPLC purity 96.0%; H
6
NMR (400 MHz, DMSO-d ) δ 7.25 (d, J = 11.2 Hz, 1H), 6.30
6
(dd, J = 10.1, 1.8 Hz, 1H), 6.11 (s, 1H), 5.80 (d, J = 5.0 Hz,
1
9
1
2
1
1
H), 5.72−5.55 (2m, 1H), 4.27 (m, 1H), 3.30 (m, 1H), 2.64−
.54 (m, 1H), 2.40 (q, J = 7.5 Hz, 2H), 2.30−2.09 (m, 4H),
.92−1.88 (m, 1H), 1.51 (m, 4H), 1.26 (m, 1H), 1.13 (s, 3H),
.03 (t, J = 7.5 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H); 13C NMR
(m), 26.94 (s), 22.73 (s), 16.95 (s), 16.08 (s), 9.05 (s);
F
NMR (376 MHz, CDCl ) δ −165.35 (dd, J = 27.5, 8.5 Hz),
−187.00 (dd, J = 48.3, 13.8 Hz), −191.35 (t, J = 49.6 Hz);
3
+
MS(ESI+) m/z 501.0 [M + H] .
(
101 MHz, DMSO-d ) δ 189.76 (s), 184.00 (s), 172.36 (s),
6α,9α,17α-Trifluoro-11β-hydroxy-16α-methyl-17β-
propionyloxy-3-oxoandrosta-1,4-diene (12). H NMR
400 MHz, CDCl ) δ 7.11 (d, J = 10.1 Hz, 1H), 6.41 (s,
6
1
1
1
8
62.45 (d, J = 13.5 Hz), 151.38 (d, J = 10.9 Hz), 128.92 (s),
19.27 (d, J = 12.5 Hz), 99.73 (d, J = 176.4 Hz), 96.90 (s),
6.63 (d, J = 174.0 Hz), 69.85 (d, J = 36.1 Hz), 48.34 (s), 47.87
(
1
(
2
1
1
1
9
3
3
H), 6.35 (dd, J = 10.1, 1.2 Hz, 1H), 5.45−5.29 (2m, 1H), 4.35
(d, J = 24.4 Hz), 42.90 (s), 36.63 (s), 35.44 (s), 33.76 (d, J =
m, 1H), 2.58−2.46 (m, 1H), 2.35 (q, J = 7.6 Hz, 2H), 2.28−
1
8.8 Hz), 33.51 (s), 32.01 (m), 27.07 (s), 22.84 (s), 17.08 (s),
.23 (m, 1H), 2.05−1.68 (m, 6H), 1.52 (s, 3H), 1.35−1.28 (m,
+
15.51 (s), 9.05 (s); MS(ESI−) m/z 467.1 [M − H] .
13
H), 1.18−1.07 (m, 9H); C NMR (101 MHz, CDCl ) δ
3
6
α,9α-Difluoro-11β-hydroxy-16α-methyl-17α-propio-
85.20 (s), 171.28 (s), 160.94 (d, J = 13.8 Hz), 150.23 (s),
30.10 (s), 121.93 (d, J = 250 Hz), 121.08 (d, J = 9.7 Hz),
8.53 (d, J = 177.4 Hz), 86.47 (d, J = 181.1 Hz), 71.76 (d, J =
5.1 Hz), 48.05 (d, J = 22.6 Hz), 47.08 (d, J = 20.6 Hz), 42.09
nyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (10).
A solution of 9 (87.1 g, 0.186 mol), Et N (28.2 g, 0.279 mol),
3
and BrCH COOH (28.2 g, 0.205 mol) in acetone (0.871 L)
2
was stirred at 25 °C for 5 h. Thereafter, water (0.871 L) was
added, and the reaction mixture was acidified to pH 1.0−1.5
with 1 mol/L HCl at 0 °C. The precipitated product 10 (95.0
(
(
s), 39.58 (s), 39.36 (s), 37.79 (s), 33.21 (m), 32.08 (s), 28.13
1
9
s), 23.25 (s), 16.44 (s), 15.32 (d, J = 13.1 Hz), 9.04 (s);
F
NMR (376 MHz, CDCl ) δ −129.60 (d, J = 17.3 Hz), −165.39
g) was obtained by filtered, washed with water, and dried. Yield
3
1
9
7
7.1%; HPLC purity 97.0%; H NMR (400 MHz, DMSO-d ) δ
(dd, J = 27.5, 8.3 Hz), −187.05 (dd, J = 48.3, 13.7 Hz);
6
+
.24 (d, J = 10.6 Hz, 1H), 6.28 (dd, J = 10.0, 1.6 Hz, 1H), 6.10
HRMS(ESI+): C23
found: 427.2089.
H
30
F
O
3
4
[M + H] ; calculated: 427.2091,
(s, 1H), 5.60 (d, J = 4.4 Hz, 1H), 5.70−5.53 (2m, 1H), 4.19
E
dx.doi.org/10.1021/op5001226 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
ASSOCIATED CONTENT
■
*
S
Supporting Information
Safety assessment for the NaClO oxidation and fluorodecarbox-
1
13
ylation, H and C NMR copies for compounds 6, 7, 9, 10, 1,
and 12, 19F NMR copies for compounds 1 and 12, and X-ray
crystallographic data for compound 12. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*
Telephone/fax: (+86)57188320899. E-mail: pharmlab@zjut.
edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from National
Natural Science Foundation of China (No. 21176222) and
Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals.
(
8) We have checked the prices for NaClO, Br , and H IO on a
2
5
6
tonne scale. 10% NaClO (96 $ per ton), Br (288 $ per ton), and
REFERENCES
2
■
NaBrO could be prepared by Br on the spot. H IO needs 136085 $
2
5
6
(
1) (a) Barnes, P. J. Pharmaceuticals 2010, 3, 514−540. (b) Rhen, T.;
Cidlowski, J. A. New Engl. J. Med. 2005, 353, 1711−1723.
2) (a) Jadav, K. J.; Kambhampati, S.; Chitturi, T. R.; Thennati, R.
per ton, and it was not friendly to the environment.
(9) The yield of NaClO oxidation (63.7%) was higher than previous
synthesis in four steps (45%), even if it was lower than NaBrO
oxidation (84.5%). Furthermore, the NaClO oxidation system was
more environmentally friendly and suitable for industrialization.
(
World Patent WO 2004/001369, 2004. (b) Phillipps, G. H.; Bailey, E.
J.; Borella, R. A.; Buckton, J. B.; Clark, J. C.; Doherty, A. E.; English, A.
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water in the recycled dioxane has no significant influence for the next
halogen reaction.
(11) (a) Yin, F.; Wang, Z. T.; Li, Z. D.; Li, C. Z. J. Am. Chem. Soc.
2
012, 134, 10401−10404. (b) Ruedabecerril, M.; Sazepin, C. C.;
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(
(
WO 01/62722 A2, 2001. (b) Qin, G. R. China Patent CN
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(d) Mizuta, S.; Stenhagen, I. S. R.; O’Duill, M.; Wolstenhulme, J.;
1
(
Kirjavainen, A. K.; Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore,
P. R.; Huiban, M.; Luthra, S. K.; Passchier, J.; Solin, O.; Gouverneur,
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Paquin, J. F. J. Am. Chem. Soc. 2014, 136, 2637−2642.
(
12) In the previous routes, BrCH F is used as the major
2
2
004. (d) Leitao, E. P. T.; Heggie, W. World Patent WO 2011/151625
A1, 2011. (e) Zhu, D. J.; Zhang, D. F. China Patent CN 100560598C
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electrophilic monofluoromethylation reagent. However, BrCH F is
2
costly (2500 $ per kg) and toxic and will destroy the ozone layer. The
cost of Selectfluor (170 $ per kg)/AgNO (500 $ per kg) is lower than
2
3
BrCH F. Furthermore, Selectfluor/AgNO is more environmentally
2
3
Org. Lett. 2008, 10, 557−560. (g) Leitao, E. P. T.; Turner, C. R. World
Patent WO 2011/151624 A1, 2011.
friendly than BrCH F.
2
(13) (a) Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970, 92,
(
(
6) Djerassi, C.; Staunton, J. J. Am. Chem. Soc. 1961, 83, 736−743.
1
9
651−1659. (b) Anderson, J. M.; Kochi, J. K. J. Org. Chem. 1970, 35,
7) Compound 13, acquired by chemical degradation of Saponin, is a
86−989. (c) Kouadio, I.; Kirschenbaum, L. J.; Mehrotra, R. N.; Sun,
basic raw material for the synthesis of steroidal glucocorticoid drugs.
Compound 14 (17-keto), acquired by biological selective degradation
phytosterol side chain, is a basic raw material for the synthesis of sex
hormones. It is difficult to synthesize 21-desoxy from 17-keto.
Compound 2 could be prepared from 13 in several steps, and
flumethasone (5) was prepared from 2. In our improved process,
applying haloform reaction to the synthesis of compound 6 from 2
could shorten reaction routes, reduce the cost, and improve the total
yield (see scheme below).
Y. J. Chem. Soc., Perkin Trans. 2 1990, 12, 2123−2127.
(14) According to the ICH Q3D, we calculated the USP Inhalation
Limit of Silver was close to 0.69 (μg/g). The residual silver content of
compound 1 was 0.04633 (μg/g) by ICP-MS detection. In addition,
the silver salts in the aqueous waste stream could be recycled. Silver
salts reacted with HCl or NaCl could generate the AgCl precipitation
which could be collected by filtration.
F
dx.doi.org/10.1021/op5001226 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX