Synthesis of p38 MAP kinase inhibitor BIRB 796 and analogs via copper-mediated N-arylation reaction

Article abstract of DOI:10.1016/j.tetlet.2010.06.109

Direct N-arylation of urea (5) with various arylboronic acids mediated by cupric acetate furnished BIRB796 and a range of N-substituted BIRB796 analogs in good to moderate yields in one step. Urea (5) was readily synthesized from commercially available compounds.

Full text of DOI:10.1016/j.tetlet.2010.06.109

Tetrahedron Letters 51 (2010) 4547–4551
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of p38 MAP kinase inhibitor BIRB 796 and analogs via
copper-mediated N-arylation reaction
*
Zhulin Tan , Jinhua J. Song, Jonathan T. Reeves, Daniel R. Fandrick, Heewon Lee, Scot Campbell ,
Nathan K. Yee
Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road/PO Box 368, Ridgefield, Connecticut 06877-0368, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct N-arylation of urea (5) with various arylboronic acids mediated by cupric acetate furnished
BIRB796 and a range of N-substituted BIRB796 analogs in good to moderate yields in one step. Urea
(5) was readily synthesized from commercially available compounds.
Received 19 May 2010
Revised 17 June 2010
Accepted 21 June 2010
Available online 26 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
Though highly practical and scalable, this method requires the
preparation of amine 3. Normally amine 3 is obtained by reacting
BIRB796 (1, Fig. 1) is the first urea-based small molecule p38
MAP kinase inhibitor from Boehringer Ingelheim that has advanced
as a clinical candidate for the treatment of inflammatory diseases.1
The synthesis of BIRB796 and its derivatives is still being actively
studied in several research laboratories.2
p-tolylhydrazine with pivaloylacetonitrile. Since many arylhydra-
zines and ketonitriles are not commercially available and need to
be synthesized, this approach makes it inconvenient and tedious
The key step of previous syntheses of BIRB796 involved the for-
mation of the urea bond through the reactions of isocyanates3 or
carbamates4 with amines.
For example, the original synthesis of BIRB796 involved the use
of phosgene to generate isocyanate in situ, which would require
special equipment for industrial scale synthesis (Scheme 1).
A scalable synthesis of BIRB796 was later developed through
carbamate 4 generated from amine 3 using trichloroethyl chloro-
formate (Scheme 2).5
H N
O
2
a
N
1
O
2
N
NH
2
N
b
This process obviated the need to use phosgene on large scale
and has been successfully implemented to produce hundreds of
kilograms of BIRB796.
3
Scheme 1. Reagents and conditions: (a) dichloromethane, sodium bicarbonate,
phosgene. 0 °C 15 min. (b) Compound 3, N,N-diisopropylethylamine, THF, rt
overnight.
N
O
O
O
N
N
N
N
H
H
O
a
N
1
O
CCl3
NH
N
2
1
Figure 1. BIRB796.
4
* Corresponding author.
E-mail address: zhulin.tan@boehringer-ingelheim.com (Z. Tan).
Analytical Sciences Department, Boehringer Ingelheim Pharmaceuticals, Inc.
Scheme 2. Reagents and conditions: (a) compound 2, N,N-diisopropylethylamine,
DMSO, 55–60 °C, 1.5 h.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.109

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Z. Tan et al. / Tetrahedron Letters 51 (2010) 4547–4551
to prepare a series of analogs of BIRB796 that vary only at the N(1)-
position of the pyrazole (Fig. 2). A more flexible synthesis was re-
quired by our Drug Discovery program for SAR studies and metab-
olite synthesis.
From retrosynthetic analysis of 1, we envisioned that it might
be possible to prepare 1 by the selective N-arylation of urea 5,
which should be readily accessible from the commercially avail-
able 3-(tert-butyl)-1H-pyrazol-5-amine 66 and naphthalene amine
27 through the carbamate process (Scheme 3).
N
O
O
NH
2
N
+
6
N
O
N
H
CCl
N
H
3
O
Cl C
3
7a
7%
7b
32%
We now wish to report a new synthesis of BIRB796 and its
derivatives via the copper-mediated N-arylation of urea 5 with
arylboronic acids which is suitable for drug discovery SAR studies
and metabolite synthesis.8
Scheme 4. Reagents and conditions: THF, N,N-diisopropylethylamine, 2,2,2-
trichloroethyl chloroformate (0.9 equiv). ꢀ10 °C, 10 min.
in 88% yield after simple workup. The subsequent reaction be-
tween carbamate 7c and amine 6 afforded urea 5 in 84% yield as
the single product without the need for chromatographic purifica-
tion (Scheme 5).10
With this key urea intermediate in hand, we turned our atten-
tion to copper-mediated arylation reactions.11 Lam and Chan first
reported that N–H and O–H containing compounds can be arylated
at room temperature with arylboronic acids in the presence of cup-
ric acetate.12 Specifically, pyrazole was found to react with differ-
ent arylboronic acids to give N-arylated products in good to
moderate yields (Scheme 6).
Buchwald also reported a very general CuI-catalyzed N-aryla-
tion of amide and nitrogen heterocycles with aryl halides.13a Most
recently, Sreedhar reported N-arylation of pyrazole in high yield
with arylboronic acids using catalytic copper(I) oxide at room tem-
perature without a base.13b
2. Results and discussions
On the basis of our experience with urea formation, we began our
study on urea 5 by treating 3-(tert-butyl)-1H-pyrazol-5-amine 6
with 2,2,2-trichloroethyl chloroformate in the presence of N,
N-diisopropylethylamine in THF. Even at ꢀ10 °C, two major prod-
ucts (7a and 7b) were obtained from this reaction and the selectivity
of the reaction favored the undesired by-product 7b (Scheme 4).9
Although the desired product could be isolated by chromatogra-
phy, this approach suffered from a low yield early in the synthesis.
On the other hand, when 4-(2-morpholin-4-yl-ethoxy)-naphtha-
len-1-ylamine 2 was treated with 2,2,2-trichloroethyl chlorofor-
mate under the same conditions, the desired trichloroethyl
carbamate 7c was formed as the major product and was isolated
O
N
O
N
O
O
O
O
N
N
N
H
N
H
N
H
N
H
N
N
NH
2
9
OH
Figure 2. Pyrazole N(1)-substituted BIRB796 derivatives.
N
O
O
O
N
O
N
O
N
H
N
H
O
N
N
N
H
N
H
N
H
1
5
N
O
O
N
H N
NH
2
2
N
H
6
2
Scheme 3. Retrosynthetic analysis of BIRB796.

Z. Tan et al. / Tetrahedron Letters 51 (2010) 4547–4551
4549
N
O
O
O
a
2
O
N
H
Cl C
3
88%
7c
b
84%
N
O
O
O
N
N
H
N
N
H
H
5
Scheme 5. Reagents and conditions: (a) 2,2,2-trichloroethyl chloroformate, N,N-diisopropylethylamine, THF, ꢀ10 °C, 40 min. (b) Compound 6, N,N-diisopropylethylamine,
DMSO, 80 °C, 14 h.
etric amount of copper(I) oxide, urea 5 and p-tolylboronic acid
failed to give any detectable BIRB796.
N
N
+
R
R
B(OH)2
N
HN
By subjecting urea 5 and p-tolylboronic acid to the copper ace-
tate conditions, we were pleased to find that BIRB796 was formed
as the major product and was isolated in 91% yield from the reac-
tion after column chromatography (Scheme 7). Gratifyingly, no
urea N-arylation product was detected by LC/MS. The major by-
product was 4,40-dimethylbiphenyl formed by homo-coupling of
the p-tolylboronic acid. A small amount of the unreacted urea 5
was also recovered.14
R = CF3 45%
CH3 76%
CH3O 64%
Scheme 6. Reagents and conditions: Cu(OAc)2, pyridine, dichloromethane, MS, rt,
2 days.
One major concern for arylation of urea 5 was that the two urea
N–H’s might also react with the boronic acid under the same con-
ditions to give two potential by-products (Fig. 3).
Using urea 5 as a substrate, we explored all the three previously
mentioned N-arylation methods. Multiple products were obtained
with CuI-catalyzed method, probably resulting from N-arylation on
the urea N–H’s of the compound. In our hand, even with stoichiom-
Encouraged by this result, we then applied these conditions to a
variety of commercially available arylboronic acids to explore the
scope of this reaction in making N-aryl analogs of BIRB796. The
results are listed in Table 1.15
As can be seen from Table 1, this arylating reaction tolerates a
variety of functional groups. Simple arylboronic acids such as 4-to-
lyl, 4-tert-butyl, and biphenyl boronic acids gave 91%, 69%, and 70%
N
O
N
O
O
O
O
O
N
N
N
N
H
N
N
N
N
H
H
H
Figure 3. Two potential by-products.
O
N
O
N
HO
OH
O
B
O
O
O
+
N
N
N
N
N
H
N
H
N
H
H
N
91%
H
5
1
Scheme 7. Reagents and conditions: Cu(OAc)2, pyridine, dichloromethane, MS, rt, 17 h.

4550
Z. Tan et al. / Tetrahedron Letters 51 (2010) 4547–4551
Table 1
N
O
N
O
O
O
O
O
R-B(OH)2
N
N
N
H
N
H
N
H
N
H
N
H
N
R
5
8
Entry
1
R-B(OH)2
Product
Yielda (%)
Entry
7
R-B(OH)2
Product
Yielda (%)
B(OH)2
B(OH)2
1
91
8g
55
O
B(OH)2
B(OH)2
2
3
8a
8b
76
66
8
9
8h
8i
49
66
O
CN
B(OH)2
B(OH)2
S
B(OH)2
B(OH)2
4
5
8d
69
10
8j
71
O
O
B(OH)2
B(OH)2
8e
8f
70
64
11
12
8k
8l
25
51
B(OH)2
Cl
B(OH)2
6
Br
a
Isolated yield. Reaction conditions are not optimized.
yields, respectively (entries 1, 4, and 5). Cyanophenyl, acetylphe-
nyl, and chlorophenyl boronic acids all worked well and gave the
desired products (entries 6–8). Vinylphenyl boronic acid was also
successfully utilized for this reaction (entry 9). Both ortho- and
meta-substituted arylboronic acids were suitable substrates,
though ortho-substituted arylboronic acids gave lower yields (en-
tries 11 and 12). A slight electronic effect was observed, as more
electron-deficient boronic acids gave reduced yields (entries 7
and 8). It is worth noting that 4-methoxycarbonylphenyl- boronic
acid worked well to give compound 8j in 71% yield (entry 10). This
compound proved to be a very useful intermediate that can be
readily reduced with NaBH4/MeOH to give compound 9, which is
O
N
O
N
O
O
O
O
N
O
N
H
N
N
N
H
N
N
H
N
H
93%
8j
9
O
OH
Scheme 8. Reagents and conditions: NaBH4, methanol, rt, 1 h.

Z. Tan et al. / Tetrahedron Letters 51 (2010) 4547–4551
4551
an important human metabolite of BIRB796 (Scheme 8).16 The pre-
vious synthesis of 9 required a multi-step synthesis starting from
4-hydrazinobenzoic acid ethyl ester.17
10. 1-(3-tert-Butyl-1H-pyrazol-5-yl)-3-(4-(2-morpholino
ethoxy)naphthalen-1-yl)
urea (5). A solution of 2,2,2-trichloroethyl 4-(2-morpholinoethoxy)naphtha-
len-1-yl carbamate (7c) (4.5 g, 10 mmol), 5-tert-Butyl-2-aminopyrazole (1.4 g,
10 mmol), and N,N0-diisoproplyethylamine (1.8 mL, 10 mmol) in DMSO
(100 mL) was heated at 80 °C for 14 h. The mixture was cooled to room
temperature. Ethyl acetate (100 mL) and water (100 mL) were added. The
organic layer was washed with brine, dried over magnesium sulfate, filtered,
and concentrated under vacuum to give the crude product. The crude product
was triturated with ether, filtered, washed with hexane, and dried to give 3.7 g
urea (5) as a beige solid. Yield (84%). Mp 206–207 °C. 1H NMR (DMSO-d6,
500 MHz) d 12.08 (br s, 1H), 9.70 (br s, 1H), 9.21 (br s, 1H), 8.22 (d, J = 8.30 Hz,
1H), 8.09 (d, J = 8.40 Hz, 1H), 7.86 (d, J = 8.15 Hz, 1H), 7.61 (t, J = 7.35 Hz, 1H),
7.57 (t, J = 7.65 Hz, 1H), 6.98 (d, J = 8.45 Hz, 1H), 5.90 (br s, 1H), 4.26 (t,
J = 5.55 Hz, 2H), 3.60 (t, J = 4.50 Hz, 4H), 2.85 (t, J = 5.55 Hz, 2H), 2.55 (br s, 4H),
1.28 (s, 9H). 13C NMR (DMSO-d6, 125 MHz) d 153.0, 152.9, 150.3, 148.2, 127.5,
127.2, 126.5, 125.3, 125.3, 122.1, 121.4, 118.8, 105.2, 90.2, 66.2, 57.0, 53.6, 30.6,
29.9. MS(ES) m/z = 438 [M+H]+.
In conclusion, we have described a new method for the expedi-
ent and facile access to BIRB796 and its N-arylated analogs in good
to moderate yields. Direct cross-coupling of arylboronic acids with
urea 5 in the presence of cupric acetate and base gave the
corresponding products in one step. Key intermediate 5 was
readily prepared from commercially available materials in good
yield. This method uses inexpensive reagents and readily available
starting materials under mild conditions. We believe that this new
method should prove to be a useful alternative for the synthesis of
BIRB796 and its derivatives.
11. For
a recent review on copper-mediated C–O, C–N, C–S bond formation
chemistry, see: Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
and references cited therein.
Supplementary data
12. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941.
13. (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001,
7727; (b) Sreedhar, B.; Venkanna, G. T.; Kuma, K. B. S.; Balasubrahmanyam, V.
Synthesis 2008, 795.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.109.
14. The reaction solution was analyzed by LC/MS. Among the few by-products
formed, none had a mass matching those of urea N-arylation isomers.
15. General N-arylation procedure. A mixture of 1-(3-tert-butyl-1H-pyrazol-5-yl)-3-
(4-(2-morpholinoethoxy) naphthalen-1-yl) urea (5) (200 mg, 0.457 mmol),
arylboronic acid (0.914 mmol, 2.0 equiv), copper(II) acetate (125 mg,
0.686 mmol, 1.5 equiv), pyri0dine (0.07 mL, 0.914 mmol, 2.0 equiv), and
molecular sieves (300 mg, 4 ÅA, activated) in dichloromethane (10 mL) was
stirred in a dry flask open to air at 21 °C for 17 h. The crude product mixture
was purified by silica gel chromatography (0–10% ethanol/ethyl acetate) to
give the product in the yields reported in Table 1. Copies of 1H and 13C NMR
spectra of isolated products are provided as Supplementary data to
demonstrate the homogeneity of samples. 1-(3-tert-Butyl-1-(4-methylphenyl)-
1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen -1-yl) urea (1): mp 144–
146 °C 1H NMR (DMSO-d6, 500 MHz) d 8.79 (s, 1H), 8.59 (s, 1H), 8.21 (d,
J = 7.95 Hz, 1H), 7.93 (d, J = 8.30 Hz, 1H), 7.66 (d, J = 8.35 Hz, 1H), 7.59–7.53 (m,
2H), 7.46 (d, J = 8.25 Hz, 2H), 7.37 (d, J = 8.20 Hz, 2H), 6.97 (d, J = 8.45 Hz, 1H),
6.39 (s, 1H), 4.26 (t, J = 5.55 Hz, 2H), 3.60 (t, J = 4.55 Hz, 4H), 2.85 (t, J = 5.55 Hz,
2H), 2.55–2.51 (m, 4H), 2.40 (s, 3H), 1.30 (s, 9H). 13C NMR (DMSO-d6, 125 MHz)
d 160.5, 152.6, 150.9, 137.5, 136.7, 136.2, 129.7, 128.4, 126.6, 126.3, 125.3,
125.2, 124.3, 122.0, 121.9, 120.5, 105.0, 94.9, 66.2, 57.0, 53.6, 32.0, 30.2, 20.6.
MS(ES) m/z = 528 [M+H]+.
References and notes
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5. Zhang, L.-H.; Zhu, L. PCT Int. Appl., WO 200104115, 2001.
6. 3-(tert-Butyl)-1H-pyrazol-5-amine
kilogram quantities from several vendors.
7. Amine 2 is commercially available in gram quantities and can be prepared by
following the procedures from Refs. 1 or 5.
6 is commercially available in multi-
16. 4-Hydroxymethylphenylboronic acid is commercially available. Unfortunately,
no desired product was detected when it was used in the copper-mediated
arylation reaction with urea 5.
17. Cirillo, P. F.; Dinallo, R.; Regan, J. R.; Riska, P. S.; Swinamer, A. D.; Tan, Z.;
Walter, B. A. US Patent 6525046, 2003.
8. Part of this work has been described in a patent, see: Tan, Z.; Song, J. J. PCT Int.
Appl., WO 2002066442, 2002.
9. Structures of 7a and 7b were established by 1H NMR and LC/MS. See
Supplementary data for details.