Utility of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine. An efficient solid-phase synthesis of olomoucine

Article abstract of DOI:10.1016/S0040-4039(02)01953-6

4,6-Dichloro-2-(methylthio)-5-nitropyrimidine has been utilized as a building block for an efficient nine-step synthesis of olomoucine. The methodology reported herein is applicable to the regiocontrolled solution and solid-phase synthesis of libraries of highly substituted purines, as well as other related scaffolds.

Full text of DOI:10.1016/S0040-4039(02)01953-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8071–8073
Utility of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine.
An efficient solid-phase synthesis of olomoucine
Lars G. J. Hammarstro¨m, David B. Smith,* Francisco X. Talama´s,* Sharada S. Labadie and
Nancy E. Krauss
Roche Bioscience, Inflammatory and Viral Diseases Unit, 3401 Hillview Avenue, Palo Alto, CA 94304-1397, USA
Received 27 August 2002; revised 3 September 2002; accepted 10 September 2002
Abstract—4,6-Dichloro-2-(methylthio)-5-nitropyrimidine has been utilized as a building block for an efficient nine-step synthesis
of olomoucine. The methodology reported herein is applicable to the regiocontrolled solution and solid-phase synthesis of libraries
of highly substituted purines, as well as other related scaffolds. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2.3,4 This synthesis serves as a specific example of a
general methodology that can deliver highly substituted
purine libraries 3 with complete regiocontrol (Fig. 1).
Due to interest in multi-substituted purines as media-
tors of biological process, including their activity as
ATP competitive kinase inhibitors, a number of solid-
phase methods for their library synthesis have recently
been advanced.1 In general, these protocols fall into
two classes. In one class, primarily pioneered by Schultz
and co-workers, a pre-formed purine with displaceable
functionality is loaded onto resin, and after further
manipulation, cleavage is conducted to afford final
products.1a–o This method has the advantage of allow-
ing the synthesis of highly substituted compounds, but
requires a fixed substitution at position 8 and can suffer
from poor regiocontrol in N-9 functionalization. Also,
certain N-9 substituents could not be efficiently pre-
pared using the reported alkylation or Mitsunobu pro-
cedures (e.g. t-butyl and phenyl).
2. Results and discussion
Our synthesis of olomoucine is shown in Scheme 1.
Argogel MB-CHO resin5 (loading: 0.4 mmol/g) was
subjected to a standard reductive amination6 protocol
using benzyl amine. Loading of the pyrimidine 1 was
next carried out in THF at ambient temperature. After
a
second displacement using methylamine,7 the
thiomethyl moiety was converted to the sulfone by
treatment with oxone®. The final displacement was then
carried out using t-butyldiphenylsilyl protected
The second class utilizes substituted pyrimidines as
precursors to the purine scaffold, which is built up on
resin prior to cleavage.1p An advantage here is higher
flexibility with respect to substitution at the 6, 8 and 9
positions, with the possibility for complete regiocontrol
with respect to N-9 functionalization. Reports to date
using this on-resin de novo purine synthesis have not
realized the potential for complete purine substitution.
In this preliminary report, we describe our use of the
versatile scaffold 4,6-dichloro-2-(methylthio)-5-nitro-
pyrimidine2 1 in a solid-phase synthesis of olomoucine
* Corresponding author. E-mail: dave.smith@roche.com
Figure 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01953-6

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L. G. J. Hammarstro¨m et al. / Tetrahedron Letters 43 (2002) 8071–8073
ethanolamine. Reduction of the nitro functionality was
required next. In exploring this nitro reduction, we were
initially frustrated in applying various literature8 condi-
tions, however, the method of Miller proved superior in
carrying out this transformation without concomitant
cleavage.9 Purine formation was then smoothly effected
by treatment of the system with trimethylorthoformate
in the presence of catalytic methanesulfonic acid. After
fluoride treatment, cleavage under standard conditions
using aqueous TFA then provided the final product 2.
Olomoucine formed directly in this manner showed
good purity (89%, LC/MS), and the product was
purified for comparison of physical characteristics with
literature data.3,10 The overall isolated yield for the
nine-step sequence leading to olomoucine, after purifi-
cation, was 76% (182 mg isolated from 2 g of resin).
This corresponds to an average yield per step of
approximately 97%.
allow an efficient displacement of the sulfone with
amines from this fully formed purine scaffold. This
observation is similar to that reported by Schultz in a
related system.1c At best, olomoucine of about 25%
purity could be produced using this protocol under
highly forcing conditions.
3. Conclusion
In summary, we have presented an efficient solid-phase
synthesis of the kinase inhibitor olomoucine. By varia-
tion of the individual amines used in each displacement
and the orthoester used in the purine cyclization, the
methodology outlined in this paper can be utilized to
prepare libraries of such purines 3.11 To our knowledge,
this is the first example of a general methodology for
preparing purine libraries with complete regiocontrol
and full flexibility for substitution at every position. In
consideration of the general and mild conditions used
and the acceptable purity and yield of the final cleaved
products, we expect to show further utility through the
synthesis of highly diverse arrays of purine and purine
related libraries. Using the highly substituted pyrim-
idine scaffold 4,6-dichloro-2-(methylthio)-5-nitropyrim-
idine 1, we have also investigated solution-based
strategies for library synthesis.11
In working out the proper order of events for the
successful approach shown in Scheme 1, we initially
attempted the sequence shown in Scheme 2. In this
variation, the nitro reduction and purine cyclization
were carried out prior to sulfone oxidation and
attempted displacement. Unfortunately, although the
2-methanesulfonyl purine itself could be cleaved from
the resin in good yield and with high purity (>90%,
LC/MS), no conditions could be found that would
Scheme 1.
Scheme 2.

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8073
References
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7. In our optimizations of this step, we found reduced
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We found it advantageous to add a protic solvent
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10. Olomoucine was purified using flash column chromato-
graphy (80/10/1 ethyl acetate/methanol/triethylamine).
Recrystallization (ethyl acetate/methanol/hexanes) then
afforded material of 100% purity (LC/MS). This material
gave 1H NMR spectra identical to that reported in the
literature, and had mp 129.4–130.3°C (lit.3 125–126°C).
Using commercially available olomoucine (Sigma), we
found mp 120.9–125.8°C. A 1:1 mixture of commercial
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123.7–126.4°C and showed a single compound by TLC,
2. Syntheses of 4,6-dichloro-2-(methylthio)-5-nitropyrim-
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1
LC/MS, and H NMR.
11. Further work using pyrimidine 1, including applications
to library synthesis, has been completed and will be
reported in detail shortly.