One-pot syntheses of 6-mercaptopurines (6MP) from 4,5-diamino-6-chloro- pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2004.01.105

A one-pot synthesis of 6-mercaptopurines from 4,5-diamino-6-chloro- pyrimidine, an aldehyde and elemental sulfur is presented. The key advantage of this procedure is that it utilizes the in situ generated H₂S to convert the chloro to a mercapto group.

Full text of DOI:10.1016/j.tetlet.2004.01.105

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2321–2322
One-pot syntheses of 6-mercaptopurines (6MP) from 4,5-diamino-
6-chloro-pyrimidinesq
Sagun Tandel,a Igor Bliznets,a Katalin Ebinger,b You-An Ma,a Dilip Bhumralkarc
and Mohan Thiruvazhia,*
aDepartment of Chemistry Research, ChemBridge Research Laboratories, 16981 Via Tazon, Suite K, San Diego, CA 92128, USA
bDepartment of Analytical Chemistry, ChemBridge Research Laboratories, 16981 Via Tazon, Suite K, San Diego, CA 92128, USA
cDiscovery Technology, Pfizer Global Research & Development-La Jolla Laboratories, 10770 Science Center Drive, San Diego,
CA 92121, USA
Received 30 December 2003; revised 22 January 2004; accepted 22 January 2004
Abstract—A one-pot synthesis of 6-mercaptopurines from 4,5-diamino-6-chloro-pyrimidine, an aldehyde and elemental sulfur is
presented. The key advantage of this procedure is that it utilizes the in situ generated H2S to convert the chloro to a mercapto
group.
Ó 2004 Elsevier Ltd. All rights reserved.
In the past two decades, 6-mercaptopurine (6MP) and
its analogues have been a synthetic target for SAR
programs in therapeutic areas of cancer,1 viral infec-
tions,2 and in CNS as ligands for benzodiazepine
receptors.3 In one instance, there has been a report of it
being clinically used in the treatment of leukemia.1 In
these reports, thiopurines are obtained by treating
chloropurines with thiourea,1;3;4 NaSH/EtOH,2 and in
some cases with H2S/base.5 These methods can be
undertaken for small scale synthesis (milligram to gram
quantities). However, they may not be very attractive in
larger scales due to the associated problems with stench
in laboratories and surroundings.
R3
Cl
S
N
OMe
NH2
NH
N
N
3-OMe-PhCHO
S8, DMF
N
N
N
°
90-100 C
1a
2a: R3=H (67%)
3a: R3=Me (82%)
Scheme 1.
one-pot conversion, the first step could either be the
formation of dihydro derivatives of imidazopyrimidine8
or a thioamide9 before leading to the chloropurine and
onwards to thiopurine via an SNAr displacement of the
chlorine by the in situ generated H2S.10
We have discovered a simple, one-pot conversion of 4,5-
diamino-6-chloropyrimidines such as 1a to 6-mercapto-
purines such as 2a (Scheme 1).6;7 The reaction consists of
heating a mixture of pyrimidine 1a, 3-methoxybenzal-
dehyde, and an equimolar amount of sulfur in DMF to
90–100 °C for 17 h. Work-up involves addition of water,
and product isolation by filtration and drying. In this
Mercaptopurines were characterized by chemical and
analytical methods. Mercaptopurine 2a was methylated
under standard conditions to afford the thiomethyl-
purine 3a in 82% yield. The LCMS of the mercaptopu-
rine 2a showed a very characteristic MHþ corresponding
to the 34S isotope with the expected intensity to that of
the MHþ of natural 32S.
Keywords: Thiopurines; H2S; One-pot synthesis; 4,5-Diamino-6-
chloro-pyrimidines.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.01.105
The generality of the one-pot conversion of 4,5-
diamino-6-chloropyrimidines to thiopurines was
* Corresponding author. Tel.: +1-858-485-9900x128; fax: +1-858-485-
9922; e-mail: mohan.thiruvazhi@chembridgeresearch.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.105

2322
S. Tandel et al. / Tetrahedron Letters 45 (2004) 2321–2322
Supplementary data available Spectral data (1H, 13C and
LCMS-ELSD) for 2a. The supplementary data is
available online with the paper in ScienceDirect.
Table 1. Yields of thiopurines
Cl
SH
N
NH2
R2CH=O
S8, DMF
N
N
N
N
R2
N
NH
R1
°
90-100 C
R1
Acknowledgements
Entry
R1
R2
Ph
Yield (%)a
M.T. acknowledges Dr. Larry Truesdale at Pfizer Glo-
bal Research & Development-La Jolla Laboratories,
San Diego for helpful discussions.
1
C6H13
82
2
Ph
70
References and notes
3
4
Ph
Ph
65
81
1. Banerjee, S.; Dutta, S.; Chakraborti, S. K. J. Indian Chem.
Soc. 1982, 59(3), 417–418, and references cited therein.
2. Murakami, K.; Shirasaka, T.; Yoshioka, H.; Kojima, E.;
Aoki, S.; Ford, H.; Driscoll, J. S.; Kelley, J. A.; Mitsuya,
H. J. Med. Chem. 1991, 34, 1606–1612.
N
O
3. Kelley, J. L.; McLean, E. W.; Ferris, R. M.; Howard, J. L.
J. Med. Chem. 1990, 33, 1910–1914.
5
6
7
Ph
Ph
89
89
70
ꢀ
ꢁꢀ
ꢀ
4. Holy, A.; Rosenberg, I.; Dvorakova, H. Collect. Czech.
Chem. Commun. 1989, 54(9), 2470–2501, and references cited
therein.
H
5. Chun, B. K.; Olgen, S.; Hong, J. H.; Newton, M. G.; Chu,
C. K. J. Org. Chem. 2000, 65, 685–693.
N
6. Sulfur has been used for the synthesis of 2-arylim-
idazo[4,5-b]- and 2-arylimidazo[4,5-c]-pyridines from o-/m-
diaminopyridines and aromatic aldehydes. See: Yutilov,
Y. M.; Shcherbina, L. I. Chem. Heterocycl. Compd. 1987,
23(5), 529–535.
8
93
N
7. All new compounds were characterized by analytical
methods such as NMR and LCMS. Typical procedure:
A solution of 1a (923 mg, 5 mmol), 3-methoxybenzalde-
hyde (681 mg, 5 mmol) and sulfur (177 mg, 5.5 mmol) in
DMF (20 mL) was heated at 100 °C for 17 h. The cooled
reaction mixture was slowly added to vigorously stirred ice
cold water (200 mL). The brown solid that separated was
filtered, dried in the vacuum to afford pure 2a (980 mg,
67%) as a brown solid. An analytically pure sample was
obtained as a brown solid by silica gel purification, mp:
9
45
18
F3C
10
H
a Crude yields after isolation.
1
98–100 °C. H NMR (DMSO-d6) d 13.70 (s, 1H), 8.22 (s,
1H), 7.47–7.55 (m, 3H), 7.22–7.06 (m, 1H), 3.86 (s, 3H),
3.81–3.69 (m, 1H), 1.21–0.93 (m, 2H), 0.92–0.63 (m, 2H):
13C (DMSO-d6) d 175.06, 158.94, 152.54, 147.02, 144.59,
134.36, 130.79, 129.46, 121.39, 115.79, 114.20, 55.32,
demonstrated by synthesizing thiopurines from a variety
of chloropyrimidines and aldehydes, respectively, as
shown in Table 1. From the table, it is clear that the
yields in the synthesis depend only on the type of alde-
hyde independent of whether N-9 was substituted or
39.51,
26.14,
8.40.
MS
(ESI)
m=z:
299.2
[C15H14N4OS+Hþ].
8. Dubey, P. K.; Ratnam, C. V. Proc. Indian Acad. Sci. 1977,
85A, 204.
not, as in entry
6
(R1 ¼ H) versus entries 1–5
(R1 ¼ alkyl). Thiopurines derived from aliphatic alde-
hydes (entries 9 and 10) were obtained in low yields
possibly due to the inherent inefficiency of imidazole
formations from aliphatic aldehydes.
9. When aniline was treated with benzaldehyde and sulfur in
hot DMF, N-phenylbenzenecarbothioamide was obtained
in high yields. For similar published results, see: Pelova,
R.; Kozhukharova, A. Nauchni, Trudove Plovdivski Uni-
versitet Paisii Khilendarski 1982, 20(3, Khim), 79–90.
10. No chlorine displacement is observed on performing a
1.0 mmol scale reaction under a constant stream of N2 to
displace the generated H2S. An additional proof for the in
situ produced H2S is from the observation that when
phenylenene diamine, m-hydroxybenzaldehyde and 6-
chloro-9-cyclopentyl-9H-purine were subjected to the
reaction conditions, the expected 3-(1H-benzimidazol-2-
yl)phenol and 9-cyclopentyl-9H-purine-6-thiol were
obtained. However, no mercapto product was obtained
in the absence of the diamine and benzaldehyde.
Our discovered method uses an in situ generated H2S
for the conversion of the chloro to the mercapto
group thereby avoiding any offensive odor in the
laboratory. In conclusion, we have discovered a sim-
ple one-pot conversion of 4,5-diamino-6-chloropyr-
imidines to 6-mercaptopurines in good to high
chemical yields. We are currently exploring further
utility of this methodology and the results will be
reported in due course.