Synthesis of celecoxib via 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2006.08.138

A regioselective 1,3-dipolar cycloaddition reaction between a nitrile imine and an enamine is described for the preparation of celecoxib. Nitrile imines are generated in situ from the corresponding hydrazonoyl benzenesulfonates.

Full text of DOI:10.1016/j.tetlet.2006.08.138

Tetrahedron Letters 47 (2006) 7943–7946
Synthesis of celecoxib via 1,3-dipolar cycloaddition
Lynette M. Oh*
Synthetic Chemistry, Chemical Development, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA
Received 12 July 2006; revised 28 August 2006; accepted 31 August 2006
Available online 25 September 2006
Abstract—A regioselective 1,3-dipolar cycloaddition reaction between a nitrile imine and an enamine is described for the prepara-
tion of celecoxib. Nitrile imines are generated in situ from the corresponding hydrazonoyl benzenesulfonates.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
crucial in ensuring both reactivity and regioselectivity.3
Herein is described a completely regioselective synthesis
of celecoxib via nitrile imine 4 and enamine 5 (Scheme
2).
The 1,3,5-trisubstituted pyrazole structural motif is
found in numerous drug targets including the widely
prescribed COX-2 inhibitor CELEBREX (celecoxib) 1.
A common approach into these systems, including the
commercial process, is to react 4-sulfamidophenylhydr-
azine 2 with diketone 3 (Scheme 1). However, a regioiso-
meric mix of both pyrazoles is often produced, requiring
the development of a crystallization protocol to obtain a
2. Results and discussion
Nitrile imine dipoles, such as 4, can be generated in a
variety of ways including the oxidation of aldehyde
1
4
5
regiopure material. In another strategy, phenyl hydr-
hydrazones, thermolysis of 2,5-disubstituted tetrazoles
6
azines are reacted with trifluoromethyl butynones in a
one pot 1,4-conjugate addition/cyclization protocol.
Whilst only one regioisomer can be produced, the syn-
thesis of intermediates requires a number of steps
including palladium catalysis), many of which rely on
column chromatography to generate a clean material.
or oxadiazolin-5-ones and by the photochemical degra-
dation of sydnones. One of the more practical and
7
scalable methods is the dehydrohalogenation of hyd-
razonoyl halides (via NBS/NCS treatment of the corre-
8
(
sponding hydrazones) such as 9. The dipole is
2
generated in situ using a base such as triethylamine.
However, in the case of celecoxib synthesis, the triflu-
oroacetaldehyde (or its derivatives) required for the
formation of hydrazonoyl chloride 9 is expensive and
in a limited supply. Previous reports have shown more
economical ways around this problem by utilizing
1
,3,5-Trisubstituted pyrazoles can also be assembled via
a 1,3-dipolar cycloaddition between a nitrile imine
dipole and a dipolarophile. The appropriate electronic
pairing of the dipole precursor and dipolarophile is
F3C
Ar
N
N
CF3
NHNH2
N
N
O
O
Me
+
CF3
+
Me
2
SO NH2
3
SO NH2
SO NH2
2
2
2
1, celecoxib
regioisomer
Scheme 1.
*
0
Tel.: +1 610 2705492; fax: +1 610 2704829; e-mail: lynette.m.oh@gsk.com
040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.138

7944
L. M. Oh / Tetrahedron Letters 47 (2006) 7943–7946
5
O
F3C
F3C
F3C
N
N
N +
N
N
O
N
-
N
N
Me
Me
Me
6
1
SO NH2
SO NH
SO NH
2
2
2
2
2
4
Scheme 2.
trifluoroacetylated hydrazines as intermediates in nitrile
imine preparations. The acylation of 4-sulfon-
celecoxib, with 100% regioselectivity. In order to con-
firm the regiochemistry, 1,2-disubstituted enamine 12
was employed as the dipolarophile producing only
1,3,4-pyrazole isomer 14, albeit in a more sluggish, low
yielding reaction (Scheme 4). None of the 1,3,5-regio-
isomer was detected by LC, thus indicating that regio-
control during the cycloaddition is governed entirely
by the enamine substitution and that the reactivity of
1,2-disubstituted enamines is less than the correspond-
9
amidophenylhydrazine 7 with trifluoroacetic anhydride
affords the trifluoroacetylated hydrazine 8. From 8,
9
either the hydrazonoyl chloride 9 (an oil) or the
hydrazonoyl benzenesulfonate 10 (a crystalline, air and
moisture stable solid) can be prepared (Scheme 3). Both
precursors were evaluated for their reactivity with
potential dipolarophiles.
1
1
ing 1,1-disubstituted version.
Typical dipolarophiles in a 1,3-dipolar cycloaddition are
3
,10,11
substituted alkynes or olefins.
Since this is a
In conclusion, the preparation of celecoxib was accom-
plished via a 1,3-dipolar cycloaddition with complete
regioselectivity, between a nitrile imine dipole, generated
in situ from hydrazonoyl benzenesulfonate 10, and 1,1-
disubstituted enamine 5. The protocol is simple and
practical, employing economical and readily available
reagents. In the three steps, the overall yield from 4-sul-
fonamidophenylhydrazine 2 is 52%.
LUMO-dipole, HOMO-dipolarophile controlled reac-
tion, a number of electron-rich olefins (which raise the
HOMO) such as TMS enol ether 11, 1,1-disubstituted
enamine 5 and 1,2-disubstituted enamine 12 were
prepared. The commercially available 4-methylphenyl-
acetylene 13 was also screened as a dipolarophile
3
b
1
0
12
(
Fig. 1). Hydrazonoyl chloride 9 proved to be an unre-
active partner with all the dipolarophiles screened,
requiring extended reactions times and affording low
yields. In the same manner, potential dipolarophiles
such as TMS enol ether 11 and 4-methylphenylacetylene
3. Experimental
1
3 produced very little of pyrazole product even at ele-
3.1. 4-[2-(Trifluoroacetyl)hydrazino]benzenesulfonamide
(8)
vated temperatures with either hydrazonoyl chloride 9
or benzenesulfonate 10 as the dipole precursor.
Sulfonamidophenylhydrazine
hydrochloride
(25 g,
On the other hand, when benzenesulfonate 10 is utilized
in conjunction with 1,1-disubstituted enamine 5, a fast
and clean reaction ensued to generate the 1,3,5-pyrazole,
0.11 mol) is slurried in acetonitrile (125 mL) and cooled
to 5–10 °C. Trifluoroacetic acid anhydride (17.3 mL,
0.12 mol) is added dropwise and the reaction mixture
O
F3C OH
F3C
HN
X
F3C
F3C
HN
NH .HCl
N
+
2
NH
N
N
HN
-
N
HN
TFAA
Et N
3
SO NH
SO NH
2
2
SO NH
SO NH
SO NH
2
2
2
2
2
2
2
2
7
8
4
9
) X = Cl
1
0) X = OSO Ph
2
Scheme 3.
O
TMSO
N
N
O
Me
Me
Me
Me
11
5
12
13
Figure 1.

L. M. Oh / Tetrahedron Letters 47 (2006) 7943–7946
7945
F3C
5
N
N
N
Me
O
Me
1
F3C OSO Ph
2
SO NH
72%
2
2
N
Et N, THF/EtOAc
HN
3
o
5
-10 C
Me
10
SO NH2
F3C
2
O
12
N
H
N
N
14
Me
SO NH
47%
2
2
Scheme 4.
is allowed to warm up to room temperature over 4 h.
The slurry is concentrated in vacuo to approximately
mately 2–3 h), it is cooled to 5–10 °C and filtered. The
cake is washed with toluene, which is added to the
filtrate. The combined filtrates are concentrated until
morpholine is <10 mol % (via GC) with respect to 5. THF
(40 mL) is added to the crude morpholine enamine 5
followed by triethylamine (13.5 mL, 96.7 mmol) and
stored cold until further use.
1
/3 of the original volume and tbme–heptane
(
60:60 mL) is added to precipitate the product out.
The slurry is cooled to 0–5 °C, held for 1 h, filtered
and washed with heptanes. The cake is collected and
dried in vacuo at 50 °C. Yield = 26.5 g (90%).
1
1
H NMR (400 MHz, DMSO-d ): d 11.56 (1H, s), 8.80
H NMR (300 MHz, CDCl ): d 7.38 (2H, d, J = 8.0 Hz),
6
3
(
1H, br s), 7.66 (2H, d, J = 8.0 Hz), 7.12 (2H, br s),
7.16 (2H, d, J = 8.0 Hz), 4.32 (1H, s), 4.17 (1H, s), 3.78
6
.81 (2H, d, J = 8.0 Hz).
(4H, t, J = 8.0 Hz), 2.85 (4H, t, J = 8.0 Hz), 2.38 (3H, s).
3.2. N-[4-(Aminosulfonyl)phenyl]-2,2,2-trifluoro-
ethanehydrazonoyl benzenesulfonate (10)
3.4. Celecoxib (1)
Hydrazonoyl benzenesulfonate 10 (12.1 g, 28.6 mmol) is
dissolved in 60 mL THF and cooled to 5–10 °C. The
solution of morpholine enamine 3 solution (33 g of the
Trifluoroacetylated hydrazine 8 (11.0 g, 41.4 mmol) is
slurried in ethyl acetate (88 mL) and cooled to 5–10 °C
in an ice bath. Benzenesulfonyl chloride (6.4 mL,
THF/Et N solution, 30.0 mmol) is added dropwise over
3
4
9.6 mmol) is added, followed by dropwise addition of
10 min. The reaction is complete once the addition is fin-
ished. HCl (20 mL, 4 N) is added and stirred for 0.5–1 h
after which ethyl acetate (60 mL) is added and a phase
cut is performed. The organic layer is washed with water
N-methylmorpholine (4.8 mL, 43.3 mmol). The reaction
mixture is held for 1 h at 5–10 °C after which water
(
44 mL) is added and the mixture is stirred for 0.5 h.
The organic layer is separated from the aqueous layer
and washed with brine (44 mL). After a phase cut, the
(60 mL) and dried over MgSO . After concentrating to
4
25 mL, heptanes (50 mL) are added and the resulting
slurry is filtered to produce 10.9 g of crude celecoxib.
The crude product is recrystallized in a mixture of hot
isopropanol–water (60:60 mL) to generate an off-white
solid. Yield = 8.7 g (72%). DSC = 159.7–162.2 °C,
organic layer is dried over MgSO and concentrated to
4
approximately 45 mL. Heptane (45 mL) is added at
room temperature to triturate out the product which is
dried in a vacuum oven at 50 °C. Yield = 14.1 g (80.6%).
DH = 92.03 J/g (ramp 10 °C/min).
f
1
H NMR (400 MHz, DMSO-d ) 10.97 (1H, s), 8.13 (2H,
6
1
d, J = 4.0 Hz), 7.86 (1H, t, J = 8.0 Hz), 7.73 (4H, m),
H NMR (300 MHz, DMSO-d ): d 7.88 (2H, dt, J = 8.7,
6
7
.22 (4H, m).
.3. 4-[1-(4-Methylphenyl)vinyl]morpholine (5)
2.4 Hz), 7.54 (dt, 2H, J = 8.7, 2.4 Hz), 7.52 (s, 2H),
7
.29–7.13 (5H, m), 2.32 (3H, s).
References and notes
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1
3
3
Morpholine (40 mL, 450.0 mmol) is added to a slurry of
toluene (80 mL) and sodium sulfate (50 g) at 5 °C.
Titanium tetrachloride (8.2 mL, 74.4 mmol) is added
dropwise to form a light green slurry (Ti–morpholine
complex). Diisopropylethylamine (28.0 mL, 370.0
mmol) is added, followed by 4-methylacetophenone
1
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2
3
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3
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h. Once the reaction is deemed complete (approxi-

7946
L. M. Oh / Tetrahedron Letters 47 (2006) 7943–7946
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4
2
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(
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Æpyr,
CH
2
Cl
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1
O
1
1
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˚
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