Efficient synthesis of a small molecule, nonpeptide inhibitor of LFA-1

Article abstract of DOI:10.1021/ol101960x

Figure Presented. A three-stage process for the synthesis of LFA-1 inhibitor 1 from amine 4 with an overall yield of 65% is described. The key stage involves a Ph₃PCl₂-induced dehydration/cyclization of urea 6 followed by a regiosele

Full text of DOI:10.1021/ol101960x

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4412-4415
Efficient Synthesis of a Small Molecule,
Nonpeptide Inhibitor of LFA-1
Xiao-jun Wang,* Yibo Xu, Li Zhang, Dhileepkumar Krishnamurthy,
Thomas Wirth,*,† Thomas Nicola,† and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals,
Inc., Ridgefield, Connecticut 06877, and Department of Production and Engineering,
Boehringer Ingelheim GmbH & Co.KG, 55216 Ingelheim am Rhein, Germany
xiao-jun.wang@boehringer-ingelheim.com; thomas.wirth@boehringer-ingelheim.com
Received August 18, 2010
ABSTRACT
A three-stage process for the synthesis of LFA-1 inhibitor 1 from amine 4 with an overall yield of 65% is described. The key stage involves
a Ph3PCl2-induced dehydration/cyclization of urea 6 followed by a regioselective bromination to give 1H-imidazo[1,2-a]imidazol-2-one 9. Br/Mg
exchange of 9 followed by addition to SO2 in THF and subsequent oxidation produces a sulfonyl chloride which is directly reacted with
L-alaninamide using K2CO3 as base in aqueous DMF/THF to give 1 in a one-pot operation. The process was implemented for the production
of 1 on a metric ton scale.
Recently, we described a series of novel and potent 1H-
imidazo[1,2-a]imidazol-2-ones such as compound 1 as the
first small molecule, nonpeptidic inhibitors of lymphocyte
function-associated antigen 1.1 These LFA-1 antagonists have
potential therapeutic application for treatment of inflamma-
tory and immune disorders, and we were interested in
developing an efficient process for 1 on production scale.
We previously reported a first-generation process for the
a]imidazol-2-one derivatives through multiple steps (Scheme
synthesis of analogous LFA-1 inhibitors in which a CuCl-
1).2 The use of stoichiometric CuCl and the long linear
promoted cyclization of thiourea A established the bicyclic
sequence made this process less efficient and cost-effective.
core B which was then transformed to 1H-imidazo[1,2-
A more robust and efficient synthesis was necessary to satisfy
† Department of Production and Engineering.
the need for metric ton production of 1.
10.1021/ol101960x  2010 American Chemical Society
Published on Web 09/10/2010

Scheme 1
.
First-Generation Process for LFA-1 Inhibitors
Scheme 3
.
Synthesis of Urea 6 Bearing a Protected Aldehyde
Function
Retrosynthetically (Scheme 2), compound 1 and its
analogues can be disconnected to the key bicyclic imidazole
C which is readily derived from guanidine D bearing a
protected aldehyde function. In the original discovery route,
D was prepared from the condensation of thiohydantoin E
and a potentially explosive azide F. We envisioned that a
urea such as G could be dehydrated and cyclize to D,
presumably through a transient carbodiimide intermediate.2b
Urea G is readily accessible from H.
p-trifluoromethoxybenzyl bromide in THF at 0-5 °C, gave
compound 3 in 93% isolated yield. Cleavage of the protecting
groups was conducted in one-pot by the successive treatment
of 3 with KOH in IPA at 60 °C followed by 3 M sulfuric
acid. Chiral amine 4, as the PTSA salt, was isolated in 87%
yield by crystallization from acetonitrile. Coupling of 4 with
phenylcarbamate 54 in the presence of TEA in DMSO at 60
°C gave urea 6 in 92% yield after crystallization from
methanol.5 While other solvents such as MeOH or CH3CN
significantly slowed the reaction which was in agreement
with the literature report,5 a similar result was achieved using
TEA to replace DMSO as solvent. With the urea 6 in hand,
we next studied the dehydration/cyclization to 7, a central
strategy for the establishment of the 1H-imidazo[1,2-a]imi-
dazol-2-one system.
Scheme 2. Retrosynthetic Analysis of Analogous 1
We initiated the dehydration/cyclization of urea 6 using a
combination of Ph3P, CCl4, and TEA,6 which was proven
to be effective in the synthesis of a similar guanidine
derivative.2b The reaction indeed produced 7 (as a 1:1
mixture of two endo- and exoisomers) in 94% isolated yield.
However, the use of toxic CCl4 as reagent was a drawback
for this reaction. A literature search revealed that the
combination of Ph3P and CCl4 was sometimes used for the
preparation of Ph3PCl2 which is now commercially available,
inexpensive, and often used for N-ylide formation.7 Having
this information, we studied the possibility of applying this
reagent for our dehydration reaction. We were pleased to
find that treatment of a mixture of 6 and 3.5 equiv of TEA
in acetonitrile with 1.7 equiv of moisture-sensitive Ph3PCl2
The synthesis of chiral amine 4 (which is analogous to
intermediate H in the retrosynthetic scheme) began with
template 2 which was prepared using a process based on
Seebach’s principle of self-regeneration of stereocenters
(Scheme 3).3 A highly diastereoselective alkylation, per-
formed by addition of LiN(TMS)2 to a mixture of 2 and
(1) (a) Wu, J.-P.; Emeigh, J.; Gao, D. A.; Goldberg, D. R.; Kuzmich,
D.; Miao, C.; Potocki, I.; Gian, K. C.; Sorcek, R. J.; Jeanfavre, D. D.;
Kishimoto, K.; Mainolfi, E. A.; Nabozny, G., Jr.; Peng, C.; Reilly, P.;
Rothlein, R.; Sellati, R. H.; Woska, J. R., Jr.; Chen, S.; Gunn, J. A.; O’Brien,
D.; Norris, S. H.; Kelly, T. A. J. Med. Chem. 2004, 47, 5356–5366. (b)
Last-Barney, K.; Davidson, W.; Cardozo, M.; Frye, L. L.; Grygon, C. A.;
Hopkins, J. L.; Jeanfavre, D. D.; Pav, S.; Qian, C.; Stevnson, J. M.; Tong,
L.; Zindell, R.; Kelly, T. A. J. Am. Chem. Soc. 2001, 123, 5643–5650. (c)
Kelly, T. A.; Jeanfavre, D. D.; McNeil, D. W.; Woska, J. R., Jr.; Reilly,
P. L.; Mainolfi, E. A.; Kishimoto, K. M.; Nabozny, G. H., Jr.; Zinter, R.;
Bormann, B.-J.; Rothlein, R. J. Immunology 1999, 163, 5173–5177.
(2) (a) Wang, X.-j.; Zhang, L.; Xu, Y.; Krishnamurthy, D.; Varsolona,
R.; Nummy, L.; Shen, S.; Frutos, R. P.; Byrne, D.; Chung, J. C.; Farina,
V.; Senanayake, C. H. Tetrahedron Lett. 2005, 46, 273–276. (b) Frutos,
R. P.; Johnson, M. Tetrahedron Lett. 2003, 44, 6509–6511.
(3) (a) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2708–2748. (b) Frutos, R. P.; Stehle, S.; Nummy, L.;
Yee, N. Tetrahedron: Asymmetry 2001, 12, 101–104. (c) Yee, N. K. Org.
Lett. 2000, 2, 2781–2783.
(4) Carbamate 5 was prepared by the reaction between aminoacetyal-
dehyde dimethyl acetal and phenyl chloroformate in the presence of TEA
in MTBE. After filtration to remove TEA HCl salt, the concentrated solution
(can be stored) was used directly.
(5) Thavonekham, B. Synthesis 1997, 1189–1194.
(6) Appel, R.; Kleinstuck, R.; Ziehn, K. Chem. Ber. 1971, 104, 1335–
1336.
(7) (a) Wamhoff, H.; Schupp, W.; Kirfel, A.; Will, G. J. Org. Chem.
1986, 51, 149–154. (b) Wamhoff, H.; Haffmanns, G.; Schmidt, H. Chem.
Ber. 1983, 116, 1691–1707.
Org. Lett., Vol. 12, No. 19, 2010
4413

in acetonitrile, by a slow addition at 20-25 °C, gave 7 in
quantitative yield (Scheme 4). Without a workup, the
simplify the process. Table 1 outlines the results of some
typical experiments.
Scheme 4. Ph3PCl2-Induced Dehydration/Cyclization of 6 and
Table 1. Bromination of 8 with NBS to Bromoimidazole 9
Subsequent Bromination of Imidazole 8 to 9
additive
dimerization
isolated
entry (0.1 equiv) derivatives (area, %)a time (h) yield of 9b (%)
1
2c
3
4
5
6
11
11
13
22
2
1
63
64
58
45
83
86
1
PPTS
ZnBr2
TEA
1
0.5
1
K2CO3
1
1
a Area % by HPLC of the reaction mixture. b Crystallization from a
mixture of IPA/water. c Purified 8 used.
A treatment of 8 by slow addition of a suspension of 1.05
equiv of NBS in IPAc produced bromoimidazole 9 in 57%
yield with only a trace amount of regioisomer 10 and <2%
of dibromide 11. A similar result was obtained when purified
8 was used under the same conditions (entry 2, Table 1).
Whereas the regio- and chemoselectivity were promising,
bromide 9 was obtained only in moderate yield because
several byproduct were observed in a combined yield of
>10%. Isolation and identification of these byproduct was
unsuccessful since they rapidly interconverted. On the basis
of preliminary MS data, these byproducts are possibly
products of imidazole dimerization.12 Interestingly, in the
presence of Lewis acids such as PPTS and ZnBr2 for the
bromination, formation of these byproduct significantly
increased up to 22% (entries 3 and 4, Table 1). These
experiments suggested that the proposed dimerization of 8
may be promoted by acids, and there are literature reports
of Lewis acid promoted dimerization of imidazole-related
heterocycles.13 As expected, the same bromination of 8 in
the presence of TEA significantly suppressed the formation
of dimer derivatives (entry 5, Table 1), leading to a much
improved 83% yield of 9. In this case, about 1.4 equiv of
NBS was needed for a complete reaction due to the reaction
between TEA and NBS.14 Subsequently, inorganic base
K2CO3 was used to replace TEA, and indeed, the bromination
of 8 produced 9 in 86% isolated yield with no need of excess
NBS. Ph3PO brought in from the previous step was fully
removed by the same crystallization from IPA/water. In one
instance, the bromination of crude 8 in IPAc gave only 40%
of 9 due to the formation of a byproduct identified as 12.
An investigation revealed that an insufficient azeotropic
resulting mixture was immediately subjected to treatment
with concentrated HCl at 40-50 °C, and bicyclic imidazole
8 was obtained in 95% isolated yield over two steps by
chromatographic purification. Since 8 purified through silica
gel column was still an oily compound, after a simple
aqueous workup the IPAc solution8 of crude 8 containing
Ph3PO was directly used for the subsequent halogenation
and sulfonylation to 1.
Functionalization of 8 by both iodination and bromination
was examined. The expensive NIS with a catalytic amount
of PPTS produced the iodo derivative with the best conver-
sion and chemoselectivity. About 10% of the diiodide
analogous to 11 (Scheme 4) was formed.1a The removal of
this byproduct from the desired monoiodide (analogous to
9) by crystallization was difficult without a large decrease
in the isolated yield of the desired isomer. Bromination of 8
was expected to avoid these issues considering the fact that
bromination of N-alkylimidazoles,9 imidazo[1,2-a]pyrim-
idines10 and imidazo[1,2-a]pyridine derivatives11 is very
regio- and chemoselective.
Bromination of 8 was investigated directly with the IPAc
solution coming from the previous step which would greatly
(8) Amounts of 8 in many batches of IPAc solutions, measured by weight
% HPLC assay, were consistentally corresponding to about 95% yield from
6 over two steps. Therefore, halogenation reagents were charged based on
this number.
(11) For examplex, see: (a) Hua, D. H.; Zhang, F.; Chen, J. J. Org.
Chem. 1994, 59, 5084–5087. (b) Kno¨lker, H.-J.; Hitzemann, R. Tetrahedron
Lett. 1994, 35, 2157–2160.
(9) For examples, see: (a) Choshi, T.; Yamada, S.; Sugino, E.; Kuwada,
T.; Hibino, S. J. Org. Chem. 1995, 60, 5899–5904. (b) Matthews, H. R.;
Rapoport, H. J. Am. Chem. Soc. 1973, 95, 2297–2303. (c) Takeuchi, T.;
Yeh, H. J. C.; Kirk, K. L.; Cohen, L. A. J. Org. Chem. 1978, 43, 3565–
3570.
(12) On the basis of MS data, they are possibly hydrates of imidazole
dimerization. The ring strain of dimers may lead to the addition of
water.
(10) For examples, see: (a) Jensen, M. S.; Hoerrner, R. S.; Li, W.;
Nelson, D. P.; Javadi, G. J.; Dormer, P. G.; Cai, D.; Larsen, R. D. J. Org.
Chem. 2005, 70, 6034–6039. (b) Rival, Y.; Grassy, G.; Michel, G. Chem.
Pharm. Bull. 1992, 40, 1170–1176.
(13) (a) Monguchi, D.; Yamamura, A.; Fujiwara, T.; Somete, T.; Mori,
A. Tetrahedron Lett. 2010, 51, 850–852. (b) Stachel, S. L.; Habeeb, R. L.;
Van Vranken, D. L. J. Am. Chem. Soc. 1996, 118, 1225–1226.
(14) Dunstan, S.; Henbest, H. B. J. Chem. Soc. 1957, 4905–4908.
4414
Org. Lett., Vol. 12, No. 19, 2010

distillation of the IPAc solution of 8 after an aqueous workup
led to the cleavage of the imidazole ring by NBS/water as
rationalized in Scheme 5.
Table 2. One-Pot Operation to LFA-1 Inhibitor 1 from 9
Scheme 5
.
Proposed Cleavage of Bicyclic Imidazole 8 to 12
with NBS in the Presence of Water
cosolventb
yield of 1d
entry basea
(vol % to THF)c time (h) (%) (wt % of 16)e
1
2
3
4
5
6
7
8
TEA
TEA
py
/
20
17
15
20
6
<10
DMF (10)
DMF (10)
45 (23)
40 (25)
51 (20)
64 (13)
85 (6)
86 (5)
72 (11)
K2CO3 DMF (10)
TEA
DMF (10)/H2O (10)
K2CO3 DMF (10)/H2O (10)
Cs2CO3 DMF (10)/H2O (10)
K2CO3 H2O (10)
6
6
24
The final stage of the elaboration of 9 to 1 followed a
process that had been previously applied to the synthesis of
LFA-1 inhibitors.1a,2 Br/Mg exchange of 9 was performed
by addition of i-PrMgCl (1.05 equiv) in THF at <-5 °C.
Upon completion of the charge of i-PrMgCl, successive
addition of SO2 (1.1 equiv) as a THF solution and a
suspension of NCS (1.1 equiv) in THF to the reaction mixture
at <-5 °C produced sulfonyl chloride 15. Without workup,
coupling of 15 with L-alaninamide was carried out. A
screening of conditions revealed that the choices of solvents
and bases had a significant impact on the reaction as shown
in Table 2. Without a cosolvent, the coupling of 15 with
L-alaninamide in the presence of TEA was sluggish, probably
due to the poor reactivity and solubility of L-alaninamide in
THF (entry 1). Addition of a mixture of L-alaninamide and
TEA or pyridine in DMF (as cosolvent) to the reaction
mixture of 15 produced 1 in only 40-50% yield due to the
formation of a large amount of sulfonic acid 16 over the
prolonged reaction time (entries 2 and 3). Inorganic base
K2CO3 under the same conditions gave a similar result (entry
4). While the coupling reaction using a combination of DMF
and water as cosolvent and TEA as base gave an improved
yield of 1 (entry 5), the use of either K2CO3 and Cs2CO3
significantly reduced the formation of 16 with a complete
reaction in 6 h resulting in 85-86% yield of 1 after
crystallization from ethanol/water (entries 6-7). In the
a 3 equiv for TEA and pyridine and 1.5 equiv for K2CO3 and Cs2CO3.
b Added as L-alaninamide HCl salt solution. c Volume % to all THF used
in the first three chemical transformations. d Isolated by crystallization from
EtOH/water. e Weight % assay of the reaction mixture by HPLC.
absence of DMF, the reaction was drastically slowed down
and 24 h was required for a complete reaction. Under these
conditions, more hydrolysis of the sulfonyl chloride was
observed (entry 8).
In summary, we have developed a concise, robust process
for the production of LFA-1 inhibitor 1 on a metric ton scale.
The synthesis features a new methodology for dehydration
of urea with Ph3PCl2 and a regioselective bromination of
imidazo[1,2-a]imidazol-2-one derivatives. Furthermore, an
efficient one-pot process for the preparation of sulfonamide
from bromoimidazole was also developed involving four
chemical transformations.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of H/13C NMR
1
spectra for 1, 3-12, 15, and 16. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL101960X
(15) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley-Interscience:
Hoboken, NJ, 1992; pp 613-615.
Org. Lett., Vol. 12, No. 19, 2010
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