Simple and convenient synthesis of 21-thioalkylether derivatives of methyl 16-prednisolone carboxylates

Article abstract of DOI:10.1080/00397910601038954

The antedrug approach for corticosteroids has been described as a fundamentally sound approach for the development of safer anti-inflammatory and anti-asthmatic therapy. However, the derivatization of prednisolone and its congeners have been considered to be major pitfalls, because their syntheses are complicated by the presence of numerous carboxylate esters and hydroxyl functions in the steroid nucleus. A simple and direct synthesis of 21-thioalkylether derivatives of methyl 16-prednisolonecarboxylates is described. The 21-mesylate of the methyl 16-prednisolonecarboxylate and 9-fluoro-17-dehydro methyl 16-prednisolonecarboxylate were reacted with Na-thioalkoxides to furnish the desired thioethers in good yields. A previously published method for the methanolysis of 16-cyanoprednisolone to methylcarboxylate has been reexamined, and the conditions are explained clearly. The reaction conditions for all these reactions were critical. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601038954

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Simple and Convenient Synthesis of
21‐Thioalkylether Derivatives of Methyl
16‐Prednisolone Carboxylates
M. Omar F. Khan a & Henry J. Lee a
a College of Pharmacy and Pharmaceutical Sciences , Florida A & M
University , Tallahassee, Florida, USA
Published online: 06 Feb 2007.
To cite this article: M. Omar F. Khan & Henry J. Lee (2007) Simple and Convenient Synthesis of
21‐Thioalkylether Derivatives of Methyl 16‐Prednisolone Carboxylates, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:3, 409-415, DOI:
10.1080/00397910601038954
To link to this article: http://dx.doi.org/10.1080/00397910601038954
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Synthetic Communicationsw, 37: 409–415, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601038954
Simple and Convenient Synthesis of
21-Thioalkylether Derivatives of Methyl
16-Prednisolone Carboxylates
M. Omar F. Khan and Henry J. Lee
College of Pharmacy and Pharmaceutical Sciences, Florida A & M
University, Tallahassee, Florida, USA
Abstract: The antedrug approach for corticosteroids has been described as a funda-
mentally sound approach for the development of safer anti-inflammatory and anti-
asthmatic therapy. However, the derivatization of prednisolone and its congeners
have been considered to be major pitfalls, because their syntheses are complicated
by the presence of numerous carboxylate esters and hydroxyl functions in the
steroid nucleus. A simple and direct synthesis of 21-thioalkylether derivatives of
methyl 16-prednisolonecarboxylates is described. The 21-mesylate of the methyl
16-prednisolonecarboxylate and 9-fluoro-17-dehydro methyl 16-prednisolonecarboxy-
late were reacted with Na-thioalkoxides to furnish the desired thioethers in good
yields. A previously published method for the methanolysis of 16-cyanoprednisolone
to methylcarboxylate has been reexamined, and the conditions are explained clearly.
The reaction conditions for all these reactions were critical.
Keywords:
21-thioethers
antedrug,
methanolysis,
16-methylcarboxylates,
prednisolone
In our continued effort to synthesize anti-inflammatory steroids on the basis of
the antedrug concept,[1–3] metabolically labile groups at various strategic
positions of potent corticosteroids, for example, prednisolone (1), were intro-
duced.[4–6] An antedrug is a designed locally active drug that undergoes a
predictable metabolic inactivation upon entry into the systemic circulation
Received in the USA April 19, 2006
Address correspondence to M. Omar F. Khan, College of Pharmacy, Southwestern
Oklahoma State University, Weatherford, OK 73096, USA. E-mail: drkhan_99@
yahoo.com
409

410
M. O. F. Khan and H. J. Lee
from the applied site. Thus, a true antedrug acts locally and is devoid of
systemic toxicities. Various structural and pharmacological classes of
antedrugs have been developed.[7] The synthesis of 16-cyanoprednisolone in
five steps from prednisolone and its conversion to corresponding methyl-
16a-prednisolonecarboxylates by methanolysis procedures have been
reported by our group.[8–13] In methanolysis of 16-cyanoprednisolone, the
conversion of the 16-cyano function to the corresponding 16-methylcarboxy-
late needs careful thermodynamic control of the reaction to suppress the
mattox rearrangement[14,15] and or the side reaction leading to the amide
(5).[16] The temperature for the reaction was described to be 2208C.[13]
In the present study, we have examined the reaction further to reveal that
the saturation of the methanol solution of the nitrile with HCl gas should be
done at 2208C, then allow the temperature to reach and maintain 2108C
overnight and then reach at 08C slowly (over 5 h) to force the reaction to
the completion, before pouring the solution into water and neutralizing with
sodium carbonate powder to pH 3–4. Pouring the mixture in water for
hydrolysis to occur at the final stage of the reaction at low temperature
(220 to –108C) leads to the formation of a higher amount of amide (5)
whereas allowing the temperature to be more than 08C before pouring it
into water causes the mattox rearrangement, furnishing compound 4, and a
careful balance of temperature is important to furnish the desired methyl
ester (3) (Scheme 1). The same method was used to synthesize compound 6
from isofluprednisolone acetate in seven steps. The synthesis of 9-fluoro-17-
dehydroprednisolone 16-methylcarboxylate (7) was performed in six steps
employing the procedure described earlier.[17]
Scheme 1.

21-Thioalkylether Derivatives of Prednisolone
411
In an attempt to increase the potency of the methyl-16-carboxylates of
prednisolone and analogs, we sought the substitution of 21-OH with
thioalkyl ether to examine whether increased lipophilicity has any effect on
localization of pharmacological activity and/or glucocorticoid receptor binding
affinity. Compounds 3, 6, and 7 were used to synthesize the new 21-thioether
derivatives according to the Scheme 2. In general, the mesylation of 21-OH
was done using methyl sulfonylchloride and triethylamine as the base at 08C
for 2 h to furnish 70% isolated yields of compounds 8, 9, and 10, respectively,
after purification by column chromatography using ethylacetate–hexane (1:1).
The substitution of a methyl sulfonate group with the desired thioalkyl group
was critical in terms of reaction condition. At elevated temperature (708C) using
5.0 or 2.0 equivalents of the Na-thioalkoxide for 2 h[18] in freshly distilled
anhydrous methanol as solvent gave a very low yield of the product accompanied
by several side products, which are supposed to be the hydrolytic products at the
16-ester linkage (as shown by highly polar products at the base of the thin-layer
chromatography, TLC, plates) and some disubstituted products resulting from
the formation of 21-thioalkylether with or without the 16-thioesters. A mild
reaction condition, using 1.5 equivalents of the Na-thioalkoxide and 1.0 equival-
ent of the mesylate in anhydrous methanol at 358C for 1 h loading the reaction
mixture onto a silica-gel column, and eluting with 1:1 ethylacteate/hexane,
furnished 60–75% of the pure thioethers as colorless crystals (Table 1) (11–
19).[19] These conditions could lead to ꢀ90% conversion to the desired
product based on the TLC of the reaction mixture before column chromato-
1
graphy. The compounds were characterized by H NMR and 13C NMR, and
the purity was checked by HPLC and C, H analyses. The HPLC system
consisted of a Varian auto-sampler (9100), pump (9012), and UV detector
(9050) set at a wavelength of 254 nm. The column was a Discovery-C18
(5 mm, 4.0 mm  15 cm I.D.), coupled with a Pelliguard-C18 guard column
(4.6 mm  5 cm I.D.). The initial solvent conditions were set at 60% of water,
40% of methanol. After sample injection, there was a 10 min linear gradient
change to 10% of water, 90% of methanol. Flow rate was maintained at
1.0 ml/min.
In conclusion, a new convenient process for the synthesis of 21-thioalk-
ylether derivatives has been described. This provides a very facile method
Scheme 2.

412
M. O. F. Khan and H. J. Lee
Table 1. Structures of the 21-thioalkylether derivatives of methyl 16-prednisolone
carboxylates
Yield
(%)
Mp
(8C)
Compound X1 X2
R
11
12
13
14
15
16
17
18
19
H
H
H
F
OH CH3
OH C2H5
OH C(CH3)3
60
72
66
60
73
65
65
61
75
169–71
128–30
142–4
H
H
H
CH3
C2H5
C(CH3)3
138–40
108–10
118–20
178–80
126–8
F
F
F
OH CH3
OH C2H5
OH C(CH3)3
F
F
149–50
to synthesize numerous thioalkylether derivatives of various novel steroidal
antedrugs in search of more potent yet safer anti-inflammatory and anti-
asthmatic therapeutic agents.
EXPERIMENTAL
The chemicals and reagents were of high quality, purchased from Acros
Organics and/or Aldrich. The procedures for each compound series are
explained next.
Methanolysis of Nitrile
Compound 2 (1 g, 2.34 mmol) in 50 ml of dry anhydrous methanol was
dissolved under stirring, cooled to 2258C, and then bubbled with HCl gas
until completely saturated (as indicated by cloudy smoke or volume doubles).
The temperature was adjusted to 2202108C overnight. The mixture was
allowed to warm up to 08C over 5 h, poured into 250 ml of water, and slowly
neutralized with sodium carbonate powder (ꢀ40 g) to pH 3–4. The methyl
ester product was then extracted into ethyl acetate. The product was purified
by column chromatography over silica gel using benzene–acetone (4:1) as
the mobile phase to yield 420 mg of the pure ester (3) (43%).
21-Mesylation
The 21-OH derivative of isofluoprednisolone (3) (1.5 g, 3.58 mmol) was
dissolved in 30 ml of dry CH2Cl2 and 3.0 ml (21 mmol) of triethylamine.
The mixture was stirred on cooling to 258C under N2, and CH3SO2Cl

21-Thioalkylether Derivatives of Prednisolone
413
(0.65 g, 5.67 mmol) was added to it slowly over 10 min. The mixture stirred
for 1 h, more CH2Cl2 (200 ml) and was added. The mixture was taken to a sep-
arating funnel, washed consecutively with water, 2N HCl, saturated NaHCO3,
and brine; dried with Na2SO4; and evaporated to yield the crude product. The
product was purified by column chromatography over silica gel using ethyl
acetate–hexane (6:4) to yield 1.2 g of compound 8 (68%).
21-Thioalkylation
Compound 8 (150 mg, 0.30 mmol) and 30 mg (0.44 mmol) of Na-ethanethioate
in 1 ml of methanol was warmed to 358C and stirred for 1 h. The mixture was
diluted with ethyl acetate, loaded onto the silica-gel column, and eluted with
ethyl acetate–hexane (6:4) to yield 100 mg (72%) of the pure thialkylated
product (12).
Chemical Data
Compound 11: 1H NMR (dppm, CDCl3): 1.0 (s, 3H, 10-CH3), 1.46 (s, 3H, 13-
CH3), 2.14 (s, 3H, S-CH3), 3.70 (s 3H, COOCH3), 3.96–4.01 (bm, 1H, 11-
CH), 4.49–4.68 (m, 2H, 21-CH2), 6.02 (d, 1H, 4-CH), 6.27 (dd, 1H, 2-CH),
7.25 (d, 1H, 1-CH); 13C NMR (dppm, CDCl3): 204, 187, 176, 170, 156, 128,
123, 70, 64, 56, 55, 52, 48, 45, 44(2), 42, 34, 32, 31, 29, 21, 17, 16; anal.
(C24H32O6S: C, calc. 64.26, found 64.04; H, calc. 7.19, found 7.28).
Compound 12: 1H NMR (dppm, CDCl3): 1.0 (s, 3H, 10-CH3), 1.46 (s, 3H, 13-
CH3), 2.60 (q, 2H, S-CH2), 1.27 (t, 3H, S-CH2CH3), 3.69 (s 3H, COOCH3),
3.94–4.00 (bm, 1H, 11-CH), 4.49–4.70 (m, 2H, 21-CH2), 6.02 (d, 1H,
4-CH), 6.27 (dd, 1H, 2-CH), 7.26 (d, 1H, 1-CH); 13C NMR (dppm, CDCl3):
205, 187, 176, 170, 146, 128, 123, 91, 70, 55, 52, 51, 48, 46, 44, 40, 37, 34,
32, 31, 28, 26, 21, 17, 14; anal. (C25H34O6S: C, calc. 64.91, found 64.78;
H, calc. 7.48, found 7.76).
Compound 13:1HNMR(dppm, CDCl3): 1.0(s, 3H, 10-CH3), 1.45 (s, 3H, 13-CH3),
1.34 (s, 9H, S-C(CH3)3), 3.69 (s 3H, COOCH3), 3.93–3.98 (bm, 1H, 11-CH),
4.45–4.55 (m, 2H, 21-CH2), 6.02 (d, 1H, 4-CH), 6.27 (dd, 1H, 2-CH), 7.27
(d, 1H, 1-CH); 13C NMR (dppm, CDCl3): 205, 184, 173, 168, 154, 126, 120, 88,
68, 53, 50, 49, 46, 43, 42, 40, 38, 34, 31, 30, 29, 28(3), 26, 18, 15; anal.
(C27H38O6S: C, calc. 66.09, found 65.83; H, calc. 7.81, found 7.87).
1
Compound 14: H NMR (dppm, CDCl3): 0.97 (s, 3H, 10-CH3), 1.46 (s, 3H,
13-CH3), 2.06 (s, 3H, S-CH3), 3.64 (s 3H, COOCH3), 4.09–4.14 (bm,
1H, 11-CH), 4.43–4.45 (m, 2H, 21-CH2), 6.02 (d, 1H, 4-CH), 6.27
(dd, 1H, 2-CH), 7.27 (d, 1H, 1-CH); anal. (C24H32FO5S: C, calc. 63.98,
found 64.22; H, calc. 6.93, found 7.04.

414
M. O. F. Khan and H. J. Lee
Compound 15: 1H NMR (dppm, CDCl3): 0.97 (s, 3H, 10-CH3), 1.46 (s, 3H, 13-
CH3), 2.51 (q, 2H, S-CH2), 1.24 (t, 3H, S-CH2CH3), 3.64 (s 3H, COOCH3),
3.62–3.70 (bm, 1H, 11-CH), 4.43–4.47 (m, 2H, 21-CH2), 6.02 (d, 1H,
4-CH), 6.27 (dd, 1H, 2-CH), 7.27 (d, 1H, 1-CH); 13C NMR (dppm, CDCl3):
204, 186, 176, 170, 156, 128, 123, 70, 64, 56, 55, 52, 48, 45, 44, 41(2), 34,
32, 31, 29, 26, 21, 17, 14; anal. (C25H33FO5S: C, calc. 64.63, found 64.89;
H, calc. 7.16, found 7.15).
Compound 16: 1H NMR (dppm, CDCl3): 1.0 [s, 3H, 10-CH3], 1.45 (s, 3H, 13-CH3),
1.34 (s, 9H, S-C(CH3)3), 3.69 (s 3H, COOCH3), 3.93–3.98 (bm, 1H, 11-CH),
4.45–4.55 (m, 2H, 21-CH2), 6.02 (d, 1H, 4-CH), 6.27 (dd, 1H, 2-CH), 7.27
(d, 1H, 1-CH); 13C NMR (dppm, CDCl3): 205, 187, 176, 170, 156, 128, 122, 70,
65, 56, 55, 52, 48, 45, 44, 43, 42, 40, 34, 32, 31, 30(3), 29, 21, 17; anal.
(C27H37FO5S: C, calc. 65.83, found 65.81; H, calc. 7.57, found 7.77).
Compound 17: 1H NMR (dppm, CDCl3): 1.00 (s, 3H, 10-CH3), 1.55 (s, 3H, 13-
CH3), 2.14 (s, 3H, S-CH3), 3.70 (s 3H, COOCH3), 4.09–4.14 (bm, 1H, 11-CH),
4.35–4.68 (m, 2H, 21-CH2), 6.12 (d, 1H, 4-CH), 6.33 (dd, 1H, 2-CH), 7.20
(d, 1H, 1-CH); 13C NMR (dppm, CDCl3): 205, 186, 175, 166, 152, 130, 126,
91, 73, 72, 52, 48, 47, 44, 39, 37, 34, 31, 30, 27, 23, 17, 17, 14; anal.
(C24H31FO6S: C, calc. 61.78, found 61.87; H, calc. 6.70, found 6.94).
Compound 19:1HNMR(dppm, CDCl3): 1.0 (s, 3H, 10-CH3), 1.55(s, 3H, 13-CH3),
1.33 (s, 9H, S-C(CH3)3), 3.69 (s 3H, COOCH3), 3.09–3.14 (bm, 1H, 11-CH),
4.38–4.87 (m, 2H, 21-CH2), 6.12 (d, 1H, 4-CH), 6.33 (dd, 1H, 2-CH), 7.23
(d, 1H, 1-CH); 13C NMR (dppm, CDCl3): 207, 187, 176, 167, 152, 130, 126, 91,
73, 72, 53, 48, 46, 44, 43, 37, 36, 34, 31(4), 30, 27, 23, 17, 14;anal.
(C27H37FO6S: C, calc. 63.76, found 63.81; H, calc. 7.33, found 7.37).
ACKNOWLEDGMENTS
This research was supported in part by National Institute of Health Grants
RO1 AM 21627, MBRS GM 008111, and RCMI G12 RR003020.
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