Improvements in corticosteroid 21-acetoxy-17α-hydroxy-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione synthesis and its use as common intermediate in the synthesis of some impurities related to dexamethasone and mometasone

Article abstract of DOI:10.1016/j.steroids.2019.04.008

There are quite substantial number of impurities related to dexamethasone or mometasone which cannot be made from respective Active Pharmaceutical Ingredients but from common intermediate 21-acetoxy-17α-hydroxy-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione (12). As such, a robust and economical synthesis of this key intermediate is important for delivering a resilient and economically viable supply chain for these impurities. Therefore, it is critical to have a robust and economically viable process to synthesize the intermediate 12 in good yield and quality. We report here an improved synthesis of 12 and eight impurities related to dexamethasone and mometasone from this common intermediate.

Full text of DOI:10.1016/j.steroids.2019.04.008

Accepted Manuscript
Improvements in corticosteroid 21-acetoxy-17α-hydroxy-16α-methyl-preg-
na-1,4,9(11)-triene-3,20-dione synthesis and its use as common intermediate in
the synthesis of some impurities related to dexamethasone and mometasone
Saibal Kumar Das, Manoj Kumar Dubey, B. Ravinder
PII:
S0039-128X(19)30087-X
https://doi.org/10.1016/j.steroids.2019.04.008
STE 8403
DOI:
Reference:
Steroids
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 February 2019
3 April 2019
23 April 2019
Please cite this article as: Das, S.K., Dubey, M.K., Ravinder, B., Improvements in corticosteroid 21-acetoxy-17α-
hydroxy-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione synthesis and its use as common intermediate in the
synthesis of some impurities related to dexamethasone and mometasone, Steroids (2019), doi: https://doi.org/
10.1016/j.steroids.2019.04.008
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Improvements in corticosteroid 21-acetoxy-17-hydroxy-16-methyl-
pregna-1,4,9(11)-triene-3,20-dione synthesis and its use as common
intermediate in the synthesis of some impurities related to dexamethasone
and mometasone
Saibal Kumar Das*, Manoj Kumar Dubey and Ravinder B.
Integrated Product Development, Dr. Reddy’s Laboratories Ltd, Innovation Plaza,
Bachupally, Qutubullapur, R.R. District 500090, Telangana, India
___________________________________________________________________________
Abstract- There are quite substantial number of impurities related to dexamethasone or
mometasone which cannot be made from respective APIs Active Pharmaceutical Ingredients
but from common intermediate 21-acetoxy-17-hydroxy-16-methyl-pregna-1,4,9(11)-
triene-3,20-dione (12). As such, a robust and economical synthesis of this key intermediate is
important for delivering a resilient and economically viable supply chain for these impurities.
Therefore, it is critical to have a robust and economically viable process to manufacture
synthesize the intermediate 12 in good yield and quality. We report here an improved synthesis
of 12 and eight impurities related to dexamethasone and mometasone from this common
intermediate.
___________________________________________________________________________
1. Introduction
Medicinally important corticosteroids such as dexamethasone (1) and mometasone furoate (2)
(Figure 1) play major role and thus have been widely used to treat inflammation, allergy, and
diseases related to adrenal cortex insufficiency therapies since their introduction to the
worldwide market [1]. The impurities related to dexamethasone and mometasone resemble
close similarities to each other. Their structural similarity presents an opportunity to develop a
general approach to synthesize impurities related to these steroids (Figure 2) from a common
starting material tetraene acetate (11) via triene 12 [2,3]. There are quite a substantial number
Figure 1. Structures of Dexamethasone and Mometasone furoate
1

*Corresponding author, Tel.: +91-40-44346273; email: saibalkumard@drreddys.com
Figure 2. Structures of different impurities
of impurities marketed related to dexamethasone and mometasone which cannot be made from
respective APIs Active Pharmaceutical Ingredients but from a precursor. All of them can be
made from a common intermediate 21-acetoxy-17-hydroxy-16-methyl-pregna-1,4,9(11)-
triene-3,20-dione (12) which is obtained by manipulating C=C double bond in D-ring. As such,
a robust and economical synthesis of this key intermediate is important for delivering a resilient
and economically viable supply chain for these impurities. However, the manufacturing
processes described for 12 or its nearest derivative, as the case may be, in the literature are
having drawbacks such as, reproducibility, difficult to achieve reported yield or lengthy route
of synthesis [2-6]. Therefore, it is critical to have a robust, reproducible and economically
viable process to manufacture synthesize the intermediate 12 in good yield and good quality.
We wish to report here a modified process for the synthesis of intermediate 12 (Scheme 1).
2

Scheme 1. General scheme for synthesis of 12.
2. Results and discussions
In order to pursue our continuous effort to synthesize above eight (3-10) impurities related to
above corticosteroids we decided to start from an easily available and relatively cheaper
material, tetraene acetate (11) (Figure 1). We envisaged that the progression of 11 to 12
required two fundamental changes: conjugated addition of a methyl group to C-16 forming
intermediate 14 [3] followed by oxidation of C-17 of 14 (Scheme 1). The oxidation step was
initially fixed and reagent of choice was m-CPBA [5] since we had observed better results
using m-CPBA than that using peracetic acid [2]. Therefore, our discussion will remain
concentrated mainly on the optimisation of the step-1 (formation of 14) however, the yields
will be reported for the isolated compound 12.
Figure 3. Structure of intermediate 13
We initially chose to examine the copper catalysed addition of the resultant enolate as the
acetylenol ether 13. Literature search revealed a very old US Patent [4] which used a two-step
procedure for similar transformation to get the identical substitution at the D-ring. In step 1,
the authors used MeMgBr for selective -methylation at 16-position. In one vessel, cuprous
o
chloride was added to the steroid in THF at 0-5 C while in the second pot MeMgBr was
complexed with cuprous chloride at ice-cold condition and added to the first pot keeping the
temperature below 5 oC followed by acetyl chloride treatment. In the next step, the acetate (13)
obtained in the first step was reacted with peracetic acid followed by opening of the epoxide
using a base. However, in our hand, implementation of this condition on 11 provided number
3

of unwanted by-products affording a very poor yield (~3%) of 12. We thought the higher
reactivity of MeMgBr is the reason for multiple spot formation for our reactive tetraene acetate
11. When we lowered the temperature further, and changed the catalyst to copper(II) chloride
the yield of 12 did not improve much. Even the use of MeMgCl, instead of MeMgBr, and
Ac2O/pyridine combination [4] instead of acetyl chloride, did not yield better result and the
impurity profile was similar to that used for MeMgBr condition (0-5 oC).
Thereafter, we shifted our focus to a slightly expensive procedure [5,6] where the resultant
enolate was trapped as the trimethylsilylenol ether. The tetraene acetate 11 was taken in a THF-
DCM mixed solvent system; and trimethylsilyl imidazole was added and cooled the reaction
o
mixture to -50 C. In another reactor, a mixture of copper(II) propionate, THF and 1,3-
dimethyl-3,4,5,6-tertrahydro-2-(1H)-pyrimidinone was cooled to -50 oC and made the reacting
complex by addition of MeMgCl. The materials of second reactor was then quickly transferred
to the first one followed by additional MeMgCl. The reaction was continued for overnight
giving a stable intermediate 14 (Scheme 1), which was far more stable than the earler
intermediate 13, when acetyl chloride was used (Figure 3). In this case also the yield in our
hand was very poor.
Having met with two setbacks we envisioned that the intricacy of this reaction lies in the
formation and stability of intermediate 13 (Figure 3) or 14 (Scheme 1). Although starting from
moisture, all sorts of precautions were adopted, the yields were poor in our hands. We were
debating if the double bond in the C-ring is a culprit. Hulcoop and Shapland [2] reported a
modest 47% yield of 16 when started from an epoxide 15 on C-ring as shown in Scheme 2. It
is to be noted that our target impurities are of versatile in nature and most of them are devoid
of endo/exo-epoxides. Therefore, we need a more versatile and general method for our target
molecules.
Scheme 2. Reported condition for the synthesis of 16
We decided to use the publication of Hulcoop and Shapland [2] (Scheme 2) as the starting point
of our journey. However, judiciously we wanted to avoid the epoxide and tried the copper(II)
4

chloride, TMSCl method using MeMgCl instead of MeMgBr since, from our earlier experience
we knew that MeMgBr was highly reactive and could lead to low yield.
We followed a two pot three step sequence as shown in scheme 1, where we initially had chosen
to examine the copper-catalyzed addition of a methyl Grignard reagent to 11, followed by
trapping of the resultant enolate as the trimethylsilylenol ether (14) which on m-CPBA
mediated oxidation should furnish the intermediate 12. We started with the similar condition
as that of Hulcoop and Shapland [2] with slight modifications in the amounts of reagents and
solvents. When we tried the whole sequence of reaction at 0 oC (Table 1, entry 1) we could not
detect any product on TLC. On the contrary 80% of tetraene acetate (11) was recovered even
Table 1. Effects of various parameters in the synthesis of Triene 12
Reagents
Time
Temp (°C) (h)
Reaction
Isolated
%Yield
Entry
CH3MgCl (3M CuCl2 LiCl
soln.) ml
TMSCl
(eq)
(eq)
1
2
3
4
0
3.0
0.80 ml
0.80 ml
0.80 ml
0.80 ml
2.5
0.15
0
0
3.0
3.0
-20
-50
-50
2.5
2.5
2.5
0.15
0.15
0.15
0
0
<10
<10
70a
3.0
3.0
0.147
5
-50
0.80 ml
2.2
0.15
0.015
57
6
7
8
9
-52
-55
-55
-55
4.5
2.0
3.0
2.0
0.80 ml
0.80 ml
0.35 ml
0.35 ml
2.2
2.2
2.2
2.2
0.15
0.15
0.15
0.15
0.015
0.015
0.015
0.015
37
60
56
65
a By HPLC, contains multiple close spots
The starting material, tetraene acetate, 1 g (2.73 mmol), solvents anhydrous DCM (5.5 mL)
and anhydrous THF (16 mL), were used in all the entries
after addition of extra amount of copper(II) chloride. Perhaps, the reactivity of the initial
organocopper(I) complex formed by the rapid metathesis was non-compatible with reactivity
of the alkene and time required to reach the activation energy was also too high. By this time
this thermally labile complex, because of poor solution stability, was getting decomposed and
o
therefore desired product could not be observed. When we repeated the reaction at -15 C
(Table 1, entry 2), only ~10% product formation (by TLC) was noticed. We assumed that our
hypothesis of stability of the organocopper(I) complex was working and the stability of the
5

complex would improve if we could further lower the reaction temperature. However, when
we repeated the reaction at -50 oC (Table 1, entry 3), again only ~10% product was observed
on TLC even after 3 h. When we critically examined the physical state of the complex we
noticed that the reaction mixture containing copper(II) chloride and MeMgCl (in THF) was
highly viscous which could be deterrent to complete organocopper(I) complex formation.
Therefore, not only the stability but the solubility of the complex was also poor in this case. To
avoid this, we decided to add LiCl to organocopper(I) complex which resulted in a clear
solution at low temperature (Table 1, entry 4). In this case we could see >70% product
formation by HPLC. However, the product was associated with multiple close impurities and
attempted purification of the mixture failed to generate any single purified product. The
outcome is certainly corroborating the fact that the homogenous nature of the complex is
advantageous as it allows performing this reaction under very mild conditions. However, we
used 0.147 equivalent of LiCl which could have been too much excess and that could be the
reason for the formation of so many close impurities. In order to avoid such kind of situation
we then reduced the amount of LiCl (to 0.015 eq) and conducted the experiment (Table 1, entry
5). Indeed, we achieved good isolated yield of pure compound (HPLC purity >96%). Although
this was significant achievement we wanted to fine tune the reaction condition. We increased
the time to 4.5 h (Table 1, entry 6) however, the yield dropped down to 37%. Since, increase
in reaction time was detrimental to improving the yield, we reduced the reaction time to 2 h
(Table 1, entry 7) which afforded 60% yield. Next we changed the amount of TMSCl but
continued the reaction for 3 h. With 0.35 mL for 1 g of tetraene acetate 13 we could achieve
similar yield (56%) as was achieved using 0.8 mL of TMSCl (57%, Table 1, entry 8). We then
Scheme 3. Synthesis of Triene 12
6

pursued the combined effect of reduced time (2 h) and reduced TMSCl amount (0.35 mL) in
our next attempt (Table 1, entry 9). Indeed we obtained the best isolated yield so far (Scheme
3). Henceforth, we have used this condition for building up this intermediate 12 and we did not
observe much deviation of the yield in 10 g scale also. It is noteworthy to mention that when
we used 1.5 equivalents of m-CPBA on intermediate 14, we also isolated quite substantial
amount of acetylated dexamethasone-9(11)--epoxide (24) [2] along with 12.
Having suitable method for the preparation of 12 at hand, we focused our attention on the
syntheses of different impurities related to mometasone and dexamethasone. Epoxide 3 (16-
Me) [7,8] is an impurity related to dexamethasone and also the starting material for
mometasone furoate impurity 4 (Mometasone furoate impurity 21-Chloro - (9:11 epoxide))
[8,9] (Scheme 4). Historically, both the impurities were outsourced from a third party vendor.
However, because of the exorbitant price, delay in the supply because of price, long lead time
and an increase in the demand of these two impurities there was an immediate need to
synthesize epoxide 3 and mometasone furoate impurity 4 in-house. The triene 12 was converted
into bromoformate 18 [10] using 1,3-dibromo-5,5-dimethyl hydantoin (DBH) as reagent in
DMF in the presence of perchloric acid. Cyclization of the bromoformate 18 was conducted by
using potassium carbonate, a modified procedure reported by Fu et al [8], followed by
hydrolysis [7] of 21-acetate (19) [2] yielded the desired epoxide 3 in high overall yield (Scheme
4). Epoxide 3 was then treated [9] with methanesulfonyl chloride in pyridine to provide
compound 20 [9,11] which was then reacted with NaCl in DMF [12] to afford mometasone
furoate impurity 4 in good yield (Scheme 4).
Scheme 4. Synthesis of Impurities 3 and 4
Our next target was another expensive impurity 9-desfluoro-11-keto dexamethasone (5) [13].
The triene 12 was converted to hydroxy bromo derivative 21 [14] by the treatment of N-
7

bromoacetamide (NBA) [15]. The compound 21 was debrominated following a slightly
modified patent procedure [16] using CrCl3 by means of converting chromium(III) to the
chromium(II) required for the dehalogination reaction. Chromium(III) chloride hexahydrate
was used less than one equivalent since the catalytic amount chromium(III) present in the DMF
(used as solvent) was actually enough for the dehalogination producing hydroxy acetate 22
[17]. Oxidation of hydroxy to keto compound 23 [18] was performed by well-known Corey
reagent, pyridinium chlorochromate PCC [19]. Finally, hydrolysis [7] of keto acetate 23 using
sodium hydroxide yielded the desired keto compound 5 (Scheme 5).
Scheme 5. Synthesis of Impurity 5
We then switched our attention towards the synthesis of dexamethasone-9(11)--Epoxide (6)
[2]. From triene 12, on treatment with m-CPBA [5] in DCM, we could obtain intermediate 24
which on hydrolysis [5] using potassium carbonate afforded dexamethasone-9(11)--epoxide
(6) in high yield (Scheme 6).
Scheme 6. Synthesis of Impurity 6
Afterwards, we targeted three impurities, icomethasone (7) [20], mometasone sulfonate
impurity (8) [12] and mometasone impurity G (9) [12] from triene 12. Triene 12 was treated
with 1,3-dichloro-5,5-dimethylhydantoin (DDH) [21] to provide chlorohydrin 25 [14] which
on hydrolysis in methanol-DCM [5] afforded icomethasone (7). Mesylation of 7 in pyridine
[12] yielded mometasone sulfonate impurity 8. When sulfonate 8 was treated [12] with sodium
8

chloride at room temperature in DMF mometasone impurity G (9) was obtained in good yield
(Scheme 7).
Scheme 7. Syntheses of Impurities 7, 8 and 9
Finally, we initiated synthesis of mometasone impurity H (10) [14]. The same triene 12 was
furoylated [9,11,22] at the tertiary hydroxyl using DMAP and 2-furoyl chloride at room
temperature to produce compound 26 [22]. Subsequently, the chlorohydrin 27 [21] was
obtained from compound 26 by using DDH in aqueous tetrahydrofuran containing perchloric
acid. During the chlorohydrin formation, we observed some amount of 10 as well which could
be possible because of perchloric acid mediated hydrolysis of acetate. We then tried the
hydrolysis in MeOH-THF mixed solvent system using 70% perchloric acid to obtain impurity
10 in good yield (Scheme 8).
Scheme 8. Synthesis of Impurity 10
In conclusion, an improved general process has been developed for the synthesis of triene 12
based on systematic studies of the deficiencies of the existing processes. The overall yield from
tetraene acetate 11 to triene 12 was improved significantly. The new process was implemented
in the synthesis of eight impurities related to dexamethasone and mometasone through shorter
9

and economically viable routes from triene 12. This intermediate 12 can also be utilised to
synthesise dexamethasone and mometasone as well.
3. Experimental
3.1. General procedures
Unless otherwise indicated, all reactions were carried out with magnetic stirring and in case of
air- or moisture-sensitive compounds reactions were carried out in oven-dried glassware under
nitrogen. Syringes and cannula were used to transfer the reagents and the solvents were purged
with nitrogen before use. Reactions were monitored by thin-layer chromatography (TLC)
analysis using aluminium sheets silica gel 60 F254 TLC plates. Column chromatography was
carried out using silica gel (100-200 mesh) unless stated otherwise. All the reaction solvents
used were of LR grade. The yields reported are not optimized. Purity of all new compounds
1
was determined by HPLC (high performance liquid chromatography) and H NMR
spectroscopy. The 1H NMR spectra were recorded with a Bruker 600 MHz spectrometer and
the 13C NMR spectra were recorded with a Bruker 150 MHz spectrometer in different
deuterated solvents. and the chemical shifts are reported in ppm downfield to TMS (δ = 0) for
1H NMR and 13C NMR. The chemical shifts are reported in ppm () values relative to residual
1
13
un-deuterated solvent used for H NMR and C NMR. The IR spectra were recorded using
Perkin Elmer – Spectrum 1 or 100 FTIR. The electron ionization mass spectra were recorded
using Waters QDA Aquity – ESI (eV 10 or 15).
3.2. Chemical synthesis
3.2.1 General Procedure for the synthesis of 21-acetoxy-17-hydroxy-16-methyl-pregna-
1,4,9(11)-triene-3,20-dione (12)
In a round bottomed flask (RBF-1) tetraene acetate (11; 10 g, 27.3 mmol) was taken and dry
THF (55 mL) was added followed by the addition of dry DCM (55 mL). The solution was
stirred for 5-10 min at room temperature. TMSCl (2.96 g, 27.3 mmol) was added to the reaction
mixture and stirred for further 10 min. The content of RBF-1 was cooled to -55 °C under
nitrogen. In another round bottomed flask (RBF-2), CuCl2 (0.55 g, 4.09 mmol) was taken in
THF (55 mL) and LiCl (17 mg, 0.401 mmol) was added to it. The reaction mixture was stirred
for 15 min at room temperature. The content of RBF-2 was cooled to -55 °C. Then slowly
MeMgCl (3M solution in THF, 4 mL) was added to RBF-2 under nitrogen. The RBF-2 content
was maintained at -55 °C for 30 min. The RBF-2 content was then transferred via a cannula to
10

RBF-1 in 10 min and the RBF-2 was rinsed with THF (50 mL) and transferred to RBF-1. The
reaction mixture was stirred for 30 min and slowly MeMgCl (3M solution in THF, 18 mL) was
added to RBF-1 under nitrogen at least for 30 min. The reaction was continued at -55 °C for 1
h. After completion the reaction was quenched by adding 30% ammonium chloride solution.
The reaction temperature was raised to 25-35 °C. The neat organic layer was separated. The
aqueous layer was extracted with EtOAc (2x50 mL). Combined organic layer was washed with
15% sodium chloride solution. The organic layer was dried (Na2SO4) and evaporated under
reduced pressure in a rotavapor below 40 °C to obtain 14 (crude weight 14 g) which was used
in the next step without further purification.
o
To a cooled (-5 C) solution of the crude intermediate 14 (14 g) in DCM (124 mL) m-
chloroperbenzoic acid (m-CPBA) (55% w/w, 7.06 g, 22.5 mmol) was added slowly. The
o
o
reaction was maintained at -5 C to 0 C for 1.5 h. We observed appearance of a new
intermediate 17 but conversion was incomplete. Then another batch of m-CPBA (55% w/w,
2.355 g, 7.5 mmol) was added and the reaction was continued for 30 min. The TLC revealed
the absence of compound 14. The reaction mass was quenched with 10% hydrochloric acid
solution (124 mL) and the stirring was continued for 3 h at room temperature. The intermediate
17 disappeared. The organic layer was separated and the aqueous layer was extracted with
dichloromethane. The combined organic layer was successively washed with water, 20%
sodium bicarbonate solution and 10% sodium chloride solution. The organic layer was dried
(Na2SO4) and evaporated to dryness under reduced pressure to afford 11 g of crude title
compound 12. The crude mass was stirred in EtOAc (40 mL) at room temperature for 2 h to
provide pure compound 12 (3.2 g, 29.4%) as white solid. The mother liquor was evaporated to
dryness and column purified using a gradient of 20-30% ethyl acetate in hexane to afford 3.78
g of 12 (combined yield was 6.98 g, 64.2%, HPLC purity >95%).
IR (KBr) in cm-1: 3396 (-OH stretching), 2939 (C-H stretching), 1747, 1723 and 1660 (C=O
stretching), 889 (=C-H bending). 1H NMR (600 MHz, CDCl3):  7.15 (d, J=10.2 Hz, 1H), 6.24
(dd, J=10.2 and 1.8 Hz, 1H), 6.02 (s 1H), 5.51 (d, J=5.4 Hz, 1H), 4.96 (d, J=17.4 Hz, 1H), 4.77
(d, J=17.4 Hz, 1H), 3.08-3.03 (m, 1H), 2.63-2.58 (m, 2H), 2.48 (brs, 1H), 2.40-2.36 (m, 1H),
2.27-2.23 (m, 1H), 2.14 (s, 3H), 2.11-2.07 (m, 1H), 1.84-1.66 (m, 3H), 1.41-1.36 (m, 1H), 1.38
(s, 3H), 1.18-1.17 (m, 1H), 0.90 (d, J=7.2 Hz, 3H), 0.72 (s, 3H). 13C NMR (150 MHz, CDCl3):
205.1, 186.4, 170.6, 166.9, 154.7, 142.5, 127.2, 123.7, 120.7, 91.0, 68.1, 48.0, 47.7, 45.9,
36.7 (2C), 34.8, 33.0, 32.3, 32.1, 26.7, 20.5, 14.4 (2C). m/z (EIMS): 399.2 (M+1).
11

3.2.2 Synthesis of -methyl epoxide (3)
o
To a cooled (0 C) solution of triene 12 (1.5 g, 3.76 mmol) in DMF (6 mL) perchloric acid
(70% v/v in water, 57 mg, 0.4 mmol) was added slowly and stirred for 30 min. DBH (915 mg,
3.2 mmol) was added slowly to the reaction mixture and the mixture was stirred for 2 h at 0-5
oC. Methanol (2.1 mL) and water (30 mL) were added to the reaction mixture and stirred for
2.5 h at room temperature. Precipitated solids were filtered and washed with water to obtain
bromoformate 18. The cake was suck dried for 30 min and then was taken in a mixture of
acetone (22.5 mL) and water (6.75 mL). Anhydrous potassium carbonate (1.56 g, 11.29 mmol)
was added to the reaction mixture and was heated to 47 oC for 50 h. Acetone was evaporated
under reduced pressure and the reaction mixture was cooled to room temperature and diluted
with water (15 mL). The aqueous layer was extracted with ethyl acetate two times. The
combined organic layer was washed with 10% sodium chloride solution, dried (Na2SO4) and
evaporated to dryness under reduced pressure to provide crude 19 (1.2 g) which was taken to
next step without further purification.
The crude mass was taken in a mixture of methanol (3.75 mL) and dichloromethane (12 mL)
o
and stirred for 10 min. The reaction mixture was cooled to -5 C and a solution of sodium
hydroxide (0.45 g) in water (0.9 mL) was added to the reaction mixture. The reaction was
maintained at -5 to 0 oC for 3 h. The reaction mixture was quenched with 50% acetic acid (10
mL) and stirred for 30 min. The reaction mixture was extracted with dichloromethane, washed
with saturated sodium bicarbonate solution, dried (Na2SO4) and evaporated to dryness under
reduced pressure to provide crude 3 (650 mg). The crude mass was taken in ethyl acetate (4
mL) and stirred for 45 min at room temperature. The solids separated were filtered to obtain
510 mg of pure solid epoxide 3. The mother liquor was evaporated to dryness and purified
through a column using 45% ethyl acetate in hexane to afford further 70 mg of 3 (combined
yield was 580 mg, 41.3% over three steps, HPLC purity >92.4%).
IR (KBr) in cm-1: 3396 (-OH stretching), 2939 (C-H stretching), 1717 (aliphatic C=O
1
stretching), 1656 (Conjugated C=O stretching), 889 (=C-H bending). H NMR (600 MHz,
CDCl3):  6.57 (d, J=10.2 Hz, 1H), 6.16 (d, J=9.6 Hz, 1H), 6.12 (s, 1H), 4.58 (d, J=19.8 Hz,
1H), 4.19 (d, J=19.8 Hz, 1H), 3.19 (s, 1H), 3.05-2.98 (m, 1H), 2.67-2.62 (m, 1H), 2.55 (brs,
1H), 2.48-2.44 (m, 1H), 2.35-2.30 (m, 1H), 2.27-2.19 (m, 2H), 1.83-1.78 (m, 1H), 1.66-1.59
(m, 2H), 1.44 (s, 3H), 1.43-1.35 (m, 2H), 1.34-1.31 (m, 1H), 0.90 (s, 3H), 0.87 (d, J=7.2 Hz,
12

3H). 13C NMR (150 MHz, CDCl3): 211.8, 186.2, 165.2, 152.4, 128.1, 125.2, 90.0, 67.7, 66.3,
62.9, 48.3 (2C), 44.3, 35.8, 34.4, 33.5, 30.6, 30.1, 29.3, 23.8, 17.9, 14.8. m/z (EIMS): 395.3
(M+Na).
3.2.3 Synthesis of mometasone furoate impurity 21-chloro - (9:11 epoxide) (4)
o
To a cooled (-5 C) solution of epoxide 3 (0.4 g, 1.07 mmol) in pyridine (2.5 mL)
methanesulfonyl chloride (221 mg, 1.93 mmol) was added drop wise and stirred for 5 h
maintaining same temperature. The reaction mixture was poured into cold 10% hydrochloric
acid solution and stirred for 1 h. The aqueous layer was extracted with ethyl acetate two times.
The combined organic layer was washed with 10% sodium chloride solution, dried (Na2SO4)
and evaporated to dryness under reduced pressure to provide crude 20 (450 mg) which was
taken to the next step without further purification.
Crude compound 20 (450 mg) was dissolved in DMF (4.5 mL) and NaCl (486 mg, 8.32 mmol)
was added and the reaction mixture was heated to 65 oC for 5 h. The reaction mixture was
poured into water and stirred for 15 min. Solid separation was observed. Ethyl acetate was
added to it and stirred for 15 min. Organic layer was separated and the aqueous layer was
extracted with ethyl acetate once. The combined organic layer was washed with 10% sodium
chloride solution, dried (Na2SO4) and evaporated to dryness under reduced pressure to afford
crude 4. The crude mass was column purified using 20% ethyl acetate in hexane to afford
mometasone furoate impurity 4 (270 mg, 64.4%, HPLC purity >97%).
IR (KBr) in cm-1: 3393 (-OH stretching), 2932 (C-H stretching), 1732 (aliphatic C=O
1
stretching), 1662 (Conjugated C=O stretching), 883 (=C-H bending). H NMR (600 MHz,
CDCl3):  6.57 (d, J=10.2 Hz, 1H), 6.17 (dd, J=10.2 & 1.8 Hz, 1H), 6.12 (d, J=0.6 Hz, 1H),
4.54 (d, J=16.2 Hz, 1H), 4.17 (d, J=16.2 Hz, 1H), 3.20 (s, 1H), 3.11-3.07 (m, 1H), 2.67-2.62
(m, 1H), 2.51-2.44 (m, 2H), 2.36-2.31 (m, 2H), 2.23-2.19 (m, 1H), 1.81-1.76 (m, 1H), 1.65-
1.59 (m, 2H), 1.44-1.39 (m, 1H), 1.41 (s, 3H), 1.34-1.29 (m, 1H), 0.90 (s, 3H), 0.87 (d, J=7.2
Hz, 3H). 13C NMR (150 MHz, CDCl3): 202.7, 186.2, 165.1, 152.4, 128.2, 125.2, 91.3, 66.3,
62.8, 48.3, 47.9 (2C), 44.3, 35.6, 34.4, 33.4, 30.9, 30.2, 29.4, 23.9, 18.0, 14.7. m/z (EIMS):
391.3 (M+1).
3.2.4 Synthesis of 9-desfluoro-11-keto dexamethasone (5)
Triene 12 (5 g, 12.55 mmol) was taken in acetone (80 mL) and water (4 mL) was added to the
reaction mixture and was stirred at room temperature for 30 min. The reaction mixture was
13

cooled to 5 oC and NBA (2.6 g, 18.82 mmol) was added. The reaction temperature was raised
to room temperature in 30 min and was stirred for 5 h when TLC revealed the completion of
the reaction. The organic solvent was completely evaporated under reduced pressure. Water
(50 mL) was added and the reaction mass was stirred for 30 min when solid separated. The
solids were filtered and washed with cold water and oven dried for 6 h to obtain 4.2 g of crude
compound 21.
The crude compound 21 (4 g, 8.07 mmol) was dissolved in DMF (12.8 mL) and nitrogen gas
was purged to make inert atmosphere. The solution was cooled to -10 oC followed by addition
of DMF (2.5 mL) and DMSO (1.8 mL). Then chromium trichloride hexahydrate (0.31 g, 1.16
mmol) and zinc dust (0.371 g, 5.68 mmol) were added followed by the addition of thioglycolic
o
acid (1.321g, 14.34 mmol). The reaction mixture was stirred for 5 h at 0 C. Water (60 mL)
was added, and the temperature was raised to room temperature. The solids appeared were
filtered, washed with cold water and the cake was oven dried to afford compound 22 (3.2 g,
95.4%).
To a solution of compound 22 (3 g, 7.2 mmol) in DCM (30 mL) PCC (2.33 g, 10.8 mmol) was
added and the reaction mixture was stirred for 3 h at room temperature. Diethyl ether (600 ml)
was added to the mixture which resulted in solid precipitation which was filtered and washed
with ether. The mother liquor was distilled off under reduced pressure to yield compound 23
(1.8 g, 60.2%).
The crude compound 23 (1.7 g, 4.1 mmol) was taken in a mixture of methanol (0.85 mL) and
o
DCM (10.2 mL) and stirred for 10 min. The reaction mixture was cooled to -10 C and a
solution of NaOH (0.328 g, 8.2 mmol) in water (1.0 mL) was added to the reaction mixture.
The reaction was maintained at -10 oC for 1 h. The reaction was incomplete. Again a solution
of NaOH (0.3 g, 7.5 mmol) in water (0.5 mL) was added to the reaction mixture and was
maintained at -10 oC for 1.5 h. The reaction mixture was quenched with 50% acetic acid (20
mL) and stirred for 30 min. The reaction mixture was extracted with dichloromethane, washed
with saturated sodium bicarbonate solution, dried (Na2SO4) and evaporated to dryness under
reduced pressure to provide crude 5 (1 g). The crude mass was taken in ethyl acetate (6 mL)
and stirred for 45 min at room temperature. The solids separated were filtered to obtain 540 mg
of pure solid keto compound 5. The mother liquor was evaporated to dryness and column
purified using 35% ethyl acetate in hexane to afford further 270 mg of 5 (combined yield was
810 mg, 53%, HPLC purity 92.5%).
IR (KBr) in cm-1: 3592.5 (-OH stretching), 2942.2 (C-H stretching), 1703.2 (aliphatic C=O
stretching), 1654.7 (Conjugated C=O stretching), 1609.8 (C=O stretching), 892.5 (=C-H
14

bending). 1H NMR (600 MHz, DMSO-d6):  6.59 (d, J=10.2 Hz, 1H), 6.10 (d, J=10.2 Hz, 1H),
6.01 (s, 1H), 5.30 (s, 1H), 4.70 (s, 1H), 4.43 and 4.06 (2d, J=19.2 Hz, 2H), 2.97-2.93 (m, 1H),
2.89 (d, J=12.0 Hz, 1H), 2.40-2.34 (m, 2H), 2.11 (d, J=11.4 Hz, 1H), 2.00-1.93 (m, 3H), 1.69
(d, J=12.0 Hz, 1H), 1.35 (s, 3H), 1.25-1.11 (m, 3H), 0.83 (d, J=7.2 Hz, 3H), 0.57 (s, 3H). 13C
NMR (150 MHz, DMSO-d6): 211.15, 209.96, 185.03, 167.20, 155.05, 126.99, 123.73, 89.55,
66.55, 59.24, 51.38, 50.10, 47.87, 41.94, 36.22, 35.68, 33.05, 31.51, 31.39, 18.73, 15.86, 15.23.
m/z (EIMS): 373.33 (M+1), 395.3 (M+Na).
3.2.5 Synthesis of dexamethasone-9(11)--epoxide (6)
To a solution of triene 12 (2.8 g, 7.028 mmol) in dichloromethane (30 ml) m-CPBA (70% w/w,
1.82 g, 7.035 mmol) was added at room temperature and the reaction mixture was stirred for 3
h. The reaction was quenched with 5% sodium bicarbonate solution (30 mL) followed by
separation of organic layer. The organic layer was washed with 10% sodium chloride solution
(30.0 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure to obtain crude
product 24 (2.1 g, 72.1%).
To a cooled (0 °C) solution of compound 24 (2.0 g, 4.83 mmol) in a mixture of methanol (8
mL) and DCM (4 mL) 1M KOH (0.667 g, 4.83 mmol) in water was added and the reaction
was continued at 0-5 °C for 3 h. The pH of the reaction mass was adjusted to 7-8 with 10%
hydrochloric acid solution. The reaction mass was distilled off completely under reduced
pressure to obtain crude compound 6. This crude product was taken in dichloromethane (20
mL), washed the organic layer with water (10 mL), saturated sodium chloride solution, dried
(Na2SO4) and evaporated to dryness under reduced pressure. The crude mass was column
purified using 45% ethyl acetate in hexane to obtain pure compound 6 (0.9 g, 50.3%, HPLC
purity >96%).
IR (KBr) in cm-1: 3439.9 (-OH stretching), 2966.1 (C-H stretching), 1708.4 (aliphatic C=O
stretching), 1665.6 (Conjugated C=O stretching), 817.9 (=C-H bending). 1H NMR (600 MHz,
DMSO-d6):  6.91 (d, J=10.2 Hz, 1H), 6.07-6.05 (m, 2H), 4.44 (d, J=19.2 Hz, 1H), 4.04 (d,
J=19.8 Hz, 1H), 3.49 (d, J=5.4 Hz, 1H), 3.34 (brs, 1H), 2.82-2.79 (m, 1H), 2.70-2.66 (m, 1H),
2.44-2.42 (m, 1H), 2.29-2.23 (m, 2H), 1.91-1.83 (m, 2H), 1.65-1.59 (m, 1H), 1.45-1.41 (m,
4H), 1.25-1.10 (m, 3H), 0.75 (d, J=7.2 Hz, 3H), 0.66 (s, 3H). 13C NMR (150 MHz, DMSO-d6):
211.4, 185.2, 165.8, 152.0, 128.6, 125.0, 90.0, 68.4, 66.4, 54.6, 46.7, 45.2, 40.2, 36.2, 34.2,
31.8, 31.4, 30.2, 29.9, 22.5, 17.2 and 14.8. m/z (EIMS): 373.0 (M+1).
15

3.2.6 Synthesis of icomethasone (7)
To a cooled (0 °C) solution of triene 12 (1.0 g, 2.51 mmol) in THF (20 ml) perchloric acid
(70% v/v in water, 0.5 mL, 5.82 mmol) was added followed by water (1.5 mL) and DDH (0.346
g, 1.78 mmol). The reaction temperature was raised to room temperature. The reaction was
continued at room temperature for 8 h. The reaction mixture was quenched with saturated
sodium bicarbonate solution (50 mL) followed by addition of ethyl acetate (50 mL) to the
reaction mass. The organic layer was separated and the aqueous layer was extracted with ethyl
acetate. The combined organic layer was distilled under reduced pressure to obtain crude
product 25 which was chromatographed using 5% ethyl acetate in hexane to afford pure 25
(0.7 g, 62%).
To a cooled (0 °C) solution of compound 25 (0.5 g, 1.109 mmol) in a mixture of methanol (5
mL) and DCM (1 mL) K2CO3 (0.153 g, 1.109 mmol) in water (1.1 mL) was added and the
reaction mixture was stirred at 0-5 °C for 2 h. The pH of the reaction mass was adjusted to 7-
8 with 10% hydrochloric acid solution. The reaction mass was distilled off completely under
reduced pressure to obtain crude compound 7. This crude product was taken in ethyl acetate
(10 mL) and washed the organic layer with water (5 mL), saturated sodium chloride solution,
dried (Na2SO4) and evaporated to dryness under reduced pressure. The crude mass was
chromatographed using 35% ethyl acetate in hexane to obtain pure icomethasone (7, 0.22 g,
48.5%, HPLC purity 94.6%).
IR (KBr) in cm-1: 3407 (-OH stretching), 2926 (C-H stretching), 1707 (aliphatic C=O
stretching), 1662 (Conjugated C=O stretching), 823 (=C-H bending), 753 (C-Cl stretching). 1H
NMR (600 MHz, DMSO-d6):  7.30 (d, J=9.6 Hz, 1H), 6.22 (dd, J=9.9 and 1.5 Hz, 1H), 5.97
(s, 1H), 5.45 (d, J=4.8 Hz, 1H), 5.00 (s, 1H), 4.67 (t, J=6.0 Hz, 1H), 4.50 (dd, J=19.2 and 6.0
Hz, 1H), 4.35 (d, J=1.8 Hz, 1H), 4.09-4.04 (m, 1H), 2.96-2.94 (m, 1H), 2.64-2.47 (m, 3H),
2.38-2.31 (m, 2H), 1.75-1.64 (m, 2H), 1.59 (s, 3H), 1.51-1.49 (m, 1H), 1.41-1.39 (m, 1H), 1.07-
1.03 (m, 1H), 0.88 (s, 3H), 0.79 (d, J=7.2 Hz, 3H). 13C NMR (150 MHz, DMSO-d6): 211.1,
185.2, 166.7, 152.8, 128.6, 124.0, 90.0, 85.6, 74.2, 66.2, 49.7, 47.9, 43.3, 35.2, 34.8, 34.3, 31.6,
29.9, 27.3, 24.3, 17.1, 15.3. m/z (EIMS): 431.2 (M+Na).
3.2.7 Synthesis of mometasone sulfonate impurity (8)
To a cooled (-5 to 0 °C) solution of icomethasone 7 (0.2 g, 0.489 mmol) in pyridine (6 ml)
methanesulfonyl chloride (0.07 mL, 0.929 mmol) was added and the reaction mixture was
16

stirred at -5 - 0 °C for 4 h. The reaction mass was poured into a precooled 10% hydrochloric
acid solution with stirring while solid separated out. The solids were filtered and washed with
cold water and dried at 70-75 °C under vacuum to obtain pure mometasone sulfonate impurity
8 (0.19 g, 79.8%, HPLC purity 92.9%).
IR (KBr) in cm-1: 3456 (-OH stretching), 2947 (C-H stretching), 1732 (aliphatic C=O
stretching), 1661 (Conjugated C=O stretching), 1364 (sulfonate S=O stretching), 891 (=C-H
bending), 753 (C-Cl stretching). 1H NMR (600 MHz, CDCl3):  7.34 (d, J=10.2 Hz, 1H), 6.22
(d, J=10.2 Hz, 1H), 5.98 (s, 1H), 5.62 (brs, 1H), 5.35 (d, J=18.0 Hz, 2H), 4.91 (d, J=17.4 Hz,
1H), 4.37 (brs, 1H), 3.24 (s, 3H), 2.93-2.90 (m, 1H), 2.67-2.51 (m, 3H), 2.40-2.32 (m, 2H),
1.76-1.67 (m, 2H), 1.60 (s, 3H), 1.54-1.45 (m, 2H), 1.09-1.05 (m, 1H), 0.91 (s, 3H), 0.83 (d,
J=7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3): 203.7, 185.2, 166.7, 152.8, 128.5, 124.0, 90.4,
85.5, 73.9, 72.8, 49.7, 48.4, 43.3, 37.8, 35.3, 35.1, 34.3, 31.6, 29.9, 27.3, 24.4, 17.0, 15.2. m/z
(EIMS): 487.0 (M+1).
3.2.8 Synthesis of mometasone impurity G (9)
a solution of mesylate compound 8 (0.18 g, 0.370 mmol) in DMF (2 mL) NaCl (0.24 g,
4.07 mmol) was added at room temperature and the reaction mass was stirred at 65-70 °C for
5 h. The reaction mixture was poured in cold water with stirring while solid precipitated out.
The solids were filtered and washed with water and dried the solid at 50-55 °C under vacuum
to obtain mometasone impurity G (9, 0.13 g, 82.4%, HPLC purity 91.8%).
IR (KBr) in cm-1: 3491 (-OH stretching), 2966 (C-H stretching), 1707 (aliphatic C=O
stretching), 1659 (Conjugated C=O stretching), 1295 (C-H wag, terminal alkyl chloride), 888
(=C-H bending), 785 (C-Cl stretching). 1H NMR (600 MHz, DMSO-d6):  7.30 (d, J=10.2 Hz,
1H), 6.22 (d, J=10.2 Hz, 1H), 5.97 (s, 1H), 5.46 (d, J=4.2 Hz, 1H), 5.31 (s, 1H), 4.76 (d, J=16.8
Hz, 1H), 4.41 (d, J=17.4 Hz, 1H), 4.36 (s, 1H), 2.96-2.94 (m, 1H), 2.63-2.53 (m, 3H), 2.39-
2.32 (m, 2H), 1.75-1.65 (m, 2H), 1.59 (s, 3H), 1.51-1.43 (m, 2H), 1.09-1.05 (m, 1H), 0.88 (s,
13
3H), 0.80 (d, J=7.2 Hz, 3H). C NMR (150 MHz, DMSO-d6): 202.8, 185.2, 166.7, 152.7,
128.6, 124.0, 90.9, 85.4, 74.1, 49.7, 49.0, 48.0, 43.1, 35.2, 35.0, 34.3, 31.5, 29.9, 27.2, 24.3,
17.2 & 15.2. m/z (EIMS): 427.2 (M+1).
3.2.9 Synthesis of mometasone impurity H (10)
To a solution of triene 12 (0.40 g, 1.004 mmol) in DCM (24 ml) 4-(dimethylamino)pyridine
(1.23 g, 10.04 mmol) was added and stirred for 5-10 min. The reaction mass was cooled to 5-
17

10 °C and furan-2-carbonyl chloride (0.2 ml, 2.008 mmol) was added slowly. The reaction
temperature was raised to room temperature. The reaction mass was stirred at room temperature
for 48 h. The reaction mixture was quenched with 15% hydrochloric acid solution (20 mL) and
stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with
dichloromethane. The combined organic layer was distilled under reduced pressure to obtain
crude product 26. This crude product was column purified using 2% acetone in
dichloromethane to afford pure 26 (0.4 g).
To a cooled (0 °C) solution of intermediate 26 (0.40 g, 0.81 mmol) in THF (10 ml) perchloric
acid (70% v/v in water, 0.3 mL, 3.49 mmol) was added followed by addition of water (0.6 mL)
and DDH (0.11 g, 0.568 mmol). The reaction temperature was raised to room temperature and
the mixture was stirred for 10 h. The reaction mixture was quenched with saturated sodium
bicarbonate solution (20 mL) followed by addition of ethyl acetate (10 mL) to the reaction
mass. The organic layer was separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layer was washed with water, dried (Na2SO4) and distilled under
reduced pressure to obtain crude product 27 (0.45 g) which was used in the next step without
purification.
To a solution of the above compound 27 (0.45 g, 0.826 mmol) in methanol (20 mL) THF (3.2
mL) was added followed by addition of perchloric acid (70% v/v in water, 1.0 mL, 11.63 mmol)
at room temperature. The reaction was continued at room temperature for 24 h. The pH of the
reaction mass was adjusted to 8 with saturated sodium bicarbonate solution. The reaction mass
was distilled off completely under reduced pressure to obtain crude compound 10 which was
chromatographed using 6% acetone in DCM to obtain pure mometasone impurity H (10, 0.2
g, 39.6% over three steps, HPLC purity >93%).
IR (KBr) in cm-1: 3420 (-OH stretching), 2928 (C-H stretching), 1724 (aliphatic C=O
1
stretching), 1661 (Conjugated C=O stretching), 884 (=C-H bending). H NMR (600 MHz,
CDCl3): 7.64 (s, 1H), 7.30 (s, 1H), 7.25 (d, J=15.0 Hz, 1H), 6.56-6.54 (m, 1H), 6.39 (dd,
J=10.2 and 1.8 Hz, 1H), 6.16 (s, 1H), 4.67 (s, 1H), 4.44 and 4.40 (2d, J=18 Hz, 2H), 3.29-3.27
(m, 1H), 2.90 (dd, J=14.4 and 3.6 Hz, 1H), 2.69-2.64 (m, 3H), 2.46 (dd, J=14.1 and 3.3 Hz,
1H), 2.38 (s, 1H), 1.99-1.68 (m, 5H), 1.71 (s, 3H), 1.40-1.38 (m, 1H), 1.13 (s, 3H), 1.09 (d,
J=7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3): 205.3, 186.5, 165.7, 157.9, 151.9, 147.4, 143.3,
129.6, 125.1, 119.3, 112.2, 94.4, 82.9, 75.1, 67.6, 49.9, 49.3, 43.3, 36.3, 35.3, 34.4, 33.4, 30.6,
27.2, 24.4, 17.1 and 17.0. m/z (EIMS): 525.2 (M+Na).
18

Acknowledgements
The authors are thankful to the management of Dr. Reddy’s Laboratories for providing full
support to this work. The contribution from analytical laboratory is thankfully acknowledged
for providing the spectral and HPLC data.
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20

Improvements in corticosteroid 21-acetoxy-17-hydroxy-16-methyl-
pregna-1,4,9(11)-triene-3,20-dione synthesis and its use as common
intermediate in the synthesis of some impurities related to dexamethasone
and mometasone
Saibal Kumar Das*, Manoj Kumar Dubey and Ravinder B.
Integrated Product Development, Dr. Reddy’s Laboratories Ltd, Innovation Plaza,
Bachupally, Qutubullapur, R.R. District 500090, Telangana, India
Graphical abstract
21

Improvements in corticosteroid 21-acetoxy-17-hydroxy-16-methyl-
pregna-1,4,9(11)-triene-3,20-dione synthesis and its use as common
intermediate in the synthesis of some impurities related to dexamethasone
and mometasone
Saibal Kumar Das*, Manoj Kumar Dubey and Ravinder B.
Integrated Product Development, Dr. Reddy’s Laboratories Ltd, Innovation Plaza,
Bachupally, Qutubullapur, R.R. District 500090, Telangana, India
Highlights –
1. There are quite substantial number of impurities related to dexamethasone or
mometasone which cannot be made from respective Active Pharmaceutical Ingredients.
Therefore, a common intermediate 21-acetoxy-17-hydroxy-16-methyl-pregna-
1,4,9(11)-triene-3,20-dione was synthesized which led to all reported impurities
2. The starting material was chosen keeping the availability and cost in mind
3. An improved, robust and economically viable process was developed to synthesize the
intermediate.
4. All the synthesized impurities were fully characterised using mass, IR and NMR
spectroscopy and the purity was checked by HPLC.
22