CL-170923
Received: September 30, 2017 | Accepted: October 20, 2017 | Web Released: November 1, 2017
Improved Synthesis of Fluocinolone Acetonide and Process Research of 6α,9α-Fluorination
Jie Tang,1,2 Chunling Zeng, Longyong Xie, Jinghua Wang, Mi Tian, and Cancheng Guo*
2
2
2
1
1
1
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, Hunan, P. R. China
2
Hunan Norchem Pharmaceutical Co., Ltd., Changsha 410205, Hunan, P. R. China
E-mail: ccguo@hnu.edu.cn
2
OH
O
An efficient and improved synthetic route of fluocinolone
acetonide with combination of bio-fermentation was developed
from 21-acetyloxy-17α-hydroxy-4,9(11)-diene-3,20-dione (1a).
Process of the 6α and 9α fluorination steps was studied, and it
was observed that the stereoselectivity of 6α fluorination is
highly substrate dependent. After an extensive screening on the
fluorinating reagents and activation reagents, 6α-F was intro-
duced in 85% yield with 98.9% stereoselectivity. Instead of HF
gas, aqueous HF solution was applied in 9α fluorination step to
provide the desired product in 89% yield. Starting from 1a,
fluocinolone acetonide was prepared in 9 steps with an overall
R
O
HO
O
R2
=
β-sitosterol
F
F
HO
stigmasterol
campesterol
cholesterol
O
phytosterol
fluocinolone
acetonide
fermentation
step
OAc
1
O
20
O
21
OH
5
steps
12
9
6
6.5% yield
11
OH
1
4
17
16
2
1
5
7
O
O
9
αOH-AD
6
1a
Scheme 1. The new raw materials of fluocinolone acetonide.
Table 1. 6α-Fluorination of different substrates via 3,5-dienol
3
8.5% yield.
Keywords: Fluocinolone acetonide
| Fluorination |
a
acetate
Bio-fermentation
1)
2)
1
Fluocinolone acetonide (8), firstly reported in 1960, is a
potent glucocorticoid used typically as an anti-inflammatory
agent for the treatment of skin disorders such as eczema and
seborrhoeic dermatitis. It also has been used in the treatment of
O
AcO
O
1a-1f
F
2a-2f
OAc
OH
OAc
OH
OAc
O
O
O
2
facial melasma, diabetic retinopathy, and non-infectious uveitis.
Due to its wide applications and recent discoveries, chemists
were always searching for efficient ways to improve its
synthesis. Traditionally, most glucocorticoids, including fluo-
O
O
O
F
2a
yield: 76%
F
2b
yield: 65%
6α selectivity: 72%
F
2c
3
yield: 79%
6
α selectivity: 62%
6α selectivity: 65%
cinolone acetonide, were semi-synthesized from natural steroid
derivatives, such as diosgenin, tigogenin, and hecogenin. These
OAc
OAc
OAc
O
O
O
4
OH
raw materials were firstly converted to intermediate 11α-hydro-
cortison (epicortisol) or 16,17α-epoxy-11-hydroxyprogesterone
in several steps, and then fluocinolone acetonide was produced
with a total yield of 5.2% or 2.8%, respectively, via each
O
O
O
O
O
F
2d
yield: 80%
α selectivity: 66%
F
2e
yield: 82%
6α selectivity: 93%
F
2f
yield: 82%
6α selectivity: 92%
6
5
intermediate. Although some steps in those established syn-
aReaction condition: 1) 0.01 mol of substrate, 32 mL of
isopropenyl acetate, 0.12 g of p-Ts, 60 °C, 3 h; 2) 20 mL of
thetic protocol were improved so far, they still face several
problems: 1) low stereoselectivity of 6α-fluorination, 2) extra
TM
6
CH CN, 3.6 g of Selectfluor , ¹510 °C, 58 h.
bioconversion to introduce 11-OH lead low efficiency, 3) these
3
raw materials, which themselves are extracted from a specific
plant with low extraction efficiency, are getting obsolete because
their production tends to suffer from pollution, expensive cost,
and limited source. Hence, efforts are directed toward the use of
new starting materials and routes for their syntheses.
In this paper, we demonstrated a new and efficient synthesis
of fluocinolone acetonide from 1a, as an important intermediate
for many glucocorticoids, compound 1a could be readily pre-
prepared from 17α-OH via an olefin intermediate. Our study
centered on the 6α and 9α fluorination steps. 6α-F can be
introduced via the reaction of the corresponding 3,5-dienol
7
1
4
esters with electrophilic fluorinating reagents. However, due
to low stereoselectivity of this transformation, a mixture of both
stereoisomers is typically obtained and pure 6α-fluorosteroids
have to be prepared by selective crystallization or another
1
5
pared in 66.5% yield in 5 steps starting from 9α-hydroxyandrost-
transformation step. Our strategy to tackle this problem was
based on the following assumptions: stereoselective 6α-fluori-
8
4
-ene-3,17-dione (9αOH-AD), which could be prepared via
1
6
simple bio-fermentation of phytosterol on a large scale
nation of steroids may be substrate dependent.
Consequently, we prepared six steroids with different groups
9
(
Scheme 1). Analysis on its structure, compound 1a, is an
1
7
ideal platform for the synthesis of fluocinolone acetonide: (a)
at specific positions, which were easily derivatized from 1a,
and subjected them to the fluorination reaction using Select-
1
0
11
direct bio-fermentation or DDQ oxidation could introduce
1
(2)
TM
¦
. (b) 6α-F could be introduced via electrophilic fluorination
at activated C6. (c) 9α-F and 11β-OH can be obtained from
fluor as the fluorinating reagent. The results are summarized
1
2
in Table 1; different stereoselectivities were obtained under
the identical reaction conditions with various acetyl 3,5-dienol
9
(11) 13
¦
.
(d) Vicinal hydroxy groups at 16, 17C could be
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