One-pot synthesis of 5-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one

Article abstract of DOI:10.1021/op060207y

An efficient and environmentally benign synthesis of 5-methyl-3H-pyrrolo[2, 3-d]pyrimidin-4(7H)-one is described. An acyl-protected aminoacetone is reacted with cyanoacetamide to give 2-amino-4-methyl-1H-pyrrole-3-carboxamide, which is converted in one-pot to 5-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one in 60% overall yield. This process avoids the use of large excess Raney nickel which is required when known methods are practiced.

Full text of DOI:10.1021/op060207y

Organic Process Research & Development 2007, 11, 86−89
Technical Notes
One-Pot Synthesis of 5-Methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one
Ramanaiah C. Kanamarlapudi, Mark Bednarz, Wenxue Wu,* and Philip Keyes
Process Chemistry, Lexicon Pharmaceuticals, 350 Carter Road, Princeton, New Jersey 08540, U.S.A.
Abstract:
which is prepared from the appropriately substituted cy-
An efficient and environmentally benign synthesis of 5-methyl-
3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one is described. An acyl-
protected aminoacetone is reacted with cyanoacetamide to give
2-amino-4-methyl-1H-pyrrole-3-carboxamide, which is con-
verted in one-pot to 5-methyl-3H-pyrrolo[2,3-d]pyrimidin-
4(7H)-one in 60% overall yield. This process avoids the use of
large excess Raney nickel which is required when known
methods are practiced.
anoacetate 3 in two steps (Scheme 1).3 Due to the lack of
an efficient method for the preparation of the cyanoacetate
3,4 an in-house process was developed during the medicinal
chemistry stage employing desulfurization of 4 as the final
step (Scheme 2).5,6 While this process was sufficient to
support medicinal chemistry, the desulfurization step required
a large excess of Raney nickel and suffered long reaction
times and inconsistent yields during early process develop-
ment.7 We sought to develop a process that is more robust
as well as more environmentally friendly.
Introduction
Results and Discussion
Pyrrolo[2,3-d]pyrimidines have attracted much recent
interest because of their biological importance.1 Due to
presence of multiple reactive sites, 3H-pyrrolo[2,3-d]pyri-
midin-4(7H)-ones are important intermediates for preparation
of pyrrolo[2,3-d]pyrimidines. While there are numerous
synthetic examples for 3H-pyrrolo[2,3-d]pyrimidin-4(7H)-
ones with a heteroatom substitution at the 2-position, only a
limited number of synthetic methods with wide applicability
have been reported for 5-alkyl-3H-pyrrolo[2,3-d]pyrimidin-
4(7H)-ones.2 Recently, we were in need of large quantities
of 5-methyl-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (1) to
support an internal drug development program. Although 1
is known in literature, all reported syntheses utilize the
desulfurization route. One such procedure consists of des-
ulfurization of the 2-thioxopyrrolo[2,3-d]pyrimidinone (2),
While the Discovery synthesis of 1 starts with building
the pyrimidine moiety, literature suggests that building the
pyrrole moiety first may be more effective.2 There are a
number of such methods reported in literature for pyrroles.
For example, pyrrole 5 was prepared from acetamidoacetone
(6) (Scheme 3).8 However, in our hands, the conversion of
5 to 1 using known procedures suffered poor yields. Thus,
heating 5 in formic acid9 gave only 10-15% yield of 1.
Alternatively, treating 5 with formic acid in the presence of
acetic anhydride gave the N-formyl pyrrole 7 in good yield.
However, conversion of 7 to the 1 by heating with concen-
trated phosphoric acid,10 or phosphorus pentaoxide10,11 gave
only trace amounts of 1.
Since the inefficient conversion of 5 to 1 may be due to
the low reactivity of the nitrile in such an electron-rich
pyrrole, we reasoned that replacing the nitrile with a primary
* To
whom
correspondence
should
be
addressed.
E-mail:
wwu@lexpharma.com.
(1) For example: (a) Choi, H.-S.; Wang, Z.; Richmond, W.; He, X.; Yang,
K.; Jiang, T.; Karanewsky, D.; Gu, X.-J.; Zhou, V.; Liu, Y.; Che, J.; Lee,
C. C.; Caldwell, J.; Kanazawa, T.; Umemura, I.; Matsuura, N.; Ohmori,
O.; Honda, T.; Gray, N.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2689-
2692. (b) Choi, H.-S.; Wang, Z.; Richmond, W.; He, X.; Yang, K.; Jiang,
T.; Sim, T.; Karanewsky, D.; Gu, X.-J.; Zhou, V.; Liu, Y.; Ohmori, O.;
Caldwell, J.; Gray, N.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2173-
2176. (c) Smalley, T. L.; Peat, A. J.; Boucheron, J. A.; Dickerson, S.;
Garrido, D.; Preugschat, F.; Schweiker, S. L.; Thomson, S. A.; Wang, T.
Y. Bioorg. Med. Chem. Lett. 2006, 16, 2091-2094. (d) Gangjee, A.; Jain,
H. D.; Phan, J.; Lin, X.; Song, X.; McGuire, J. J.; Kisliuk, R. L. J. Med.
Chem. 2006, 49, 1055-1065. (e) Seela, F.; Peng, X. J. Org. Chem. 2006,
71, 81-90 and references therein. (f) Foloppe, N.; Fisher, L. M.; Howes,
R.; Kierstan, P.; Potter, A.; Robertson, A. G. S.; Surgenor, A. E. J. Med.
Chem. 2005, 48, 4332-4345. (g) Kempson, J.; Pitts, W. J.; Barbosa, J.;
Guo, J.; Omotoso, O.; Watson, A.; Stebbins, K.; Starling, G. C.; Dodd, J.
H.; Barrish, J. C.; Felix, R.; Fischer, K. Bioorg. Med. Chem. Lett. 2005,
15, 1829-1833. (h) Traxler, P.; Bold, G.; Buchdunger, E.; Caravatti, G.;
Furet, P.; Manley, P.; O’Reilly, T.; Wood, J.; Zimmermann, J. Med. Res.
ReV. 2001, 21, 499-512.
(3) West, R. A. J. Org. Chem. 1961, 26, 4959-4961.
(4) Luepke, U.; Seela, F. Chem. Ber. 1979, 112, 799-806. Okuma, K. J.
Antibiot. 1961, 14, 343-52.
(5) For annulation of similarly substituted pyrimidines, see: Noell, C. W.;
Robins, R. K. J. Heterocycl. Chem. 1964, 1, 34-41. Williams, D. M.;
Loakes, D.; Brown, D. M. J. Chem. Soc., Perkin Trans. 1 1998, 3565-
3570.
(6) For desulfurization of 2-(methylthio)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-
one, see: Gerster, J. F.; Hinshaw, B. C.; Robins, R. K.; Townsend, L. B.
J. Heterocycl. Chem. 1969, 6, 207-213.
(7) It should be noted that this process was eventually optimized and scaled
up by a contract research organization to produce about 500 g of 1 to support
preclinical studies. The key to a reproducible desulfurization was to start
with a large excess of Raney nickel.
(8) Wamhoff, H.; Wehling, B. Synthesis 1976, 51.
(9) Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.; Lydon, N.
J. Med. Chem. 1996, 39, 2285-2292. El-Bayouki, K. A. M.; Basyouni,
W. M.; Hosni, H.; El-Deen, A. S. J. Chem. Res., Synop. 1995, 314-315.
(10) Girgis, N. S.; Joergensen, A.; Pedersen, E. B. Synthesis 1985, 101-104.
(11) Hess, S.; Mueller, C. E.; Frobenius, W.; Reith, U.; Klotz, K.-N.; Eger, K.
J. Med. Chem. 2000, 43, 4636-4646.
(2) For a review on synthesis of pyrrolopyrimidines, see: Amarnath, V.;
Madhav, R. Synthesis 1974, 837-859.
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10.1021/op060207y CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/13/2006

Scheme 1
Scheme 5
to carry out the two annulation reactions in one pot. Although
acetamidoacetone (6) can be prepared by the Dakin-West
reaction,13 the reaction and isolation is somewhat tedious.14
We decided to use phthalimidoacetone (9),15 which is easier
to monitor during the reaction due to the presence of a
chromophore, as the aminoacetone surrogate.16
Scheme 2
Since the pyrimidinone-formation step requires an alkox-
ide, such as sodium ethoxide, as the base, it was chosen as
the base for the pyrrole-formation step as well. Thus, the
cyanoacetamide was treated with sodium ethoxide followed
by 9 at 40-50 °C. Upon consumption of 9, ethyl formate
was added along with additional sodium ethoxide. After
heating at 50-60 °C for 4 h, HPLC showed the disappear-
ance of 8. The reaction mixture was then quenched with
water, and solvent was removed. The product 1 was isolated
by adjusting the pH to 7-8. Although this procedure gave
about 30-35% yield at 10-g scale, the yield fell dramatically
to about 10% when the procedure was scaled up to 50-g
scale. It is noteworthy that the product 1 isolated from this
low-yielding experiment was still very clean by HPLC and
NMR.
Scheme 3
We suspected that self reactions of cyanoacetamide and
9 under the reaction conditions were responsible for the scale-
up issues since longer addition times may allow self reactions
to proceed to a greater extent. Indeed, 9 is known to undergo
a Gabriel-Coleman-type rearrangement in the presence of
alkoxide bases to give 3-acetyl-4-hydroxyisoquinolin-1(2H)-
one (10, Scheme 5).17,18 It is also reported in the literature
that cyanoacetamide undergoes self-condensation to give 11
in the presence of sodium methoxide.19 Indeed, when
cyanoacetamide was heated with 0.8 equiv of sodium
methoxide in methanol for 6 h at 40 °C and then 5 h at
60 °C, a yellow solid was formed and isolated cleanly by
filtration. This compound accounted for about 55% of the
reaction mixture by HPLC area. The structure of the solid
product was determined to be 12 based on HPLC/MS as well
as NMR analysis. Further proof of the structure of 12 came
Scheme 4
(13) Dakin, H. D.; West, R. J. Biol. Chem. 1928, 78, 91-105 and 745-756.
For a review on the Dakin-West reaction, see: Buchanan, G. L. Chem.
Soc. ReV. 1988, 17, 91-109.
(14) Hepworth, J. D. Organic Syntheses; Wiley & Sons: New York, 1973;
Collect. Vol. V, pp 27-29. Wiley: R. H.; Borum, O. H. J. Am. Chem. Soc.
1948, 70, 2005-2006. Yuan, C.; Chen, D. Synthesis 1992, 531-532.
Fadnavis, N. W.; Vadivel, S. K.; Bhalerao, U. T. Tetrahedron: Asymmetry
1997, 8, 2355-2359.
(15) Phthalimidoacetone (9) is commercially available from TCI America,
Portland, Oregon. For a convenient preparation from chloroacetone, see:
Lei, A.; Wu, S.; He, M.; Zhang, X. J. Am. Chem. Soc. 2004, 126, 1626-
1627.
(16) A similar strategy was employed by Yumoto, M.; Kawabuchi, T.; Sato,
K.; Takashima, M. Jpn. Kokai Tokkyo Koho, JP 10316654 A2, 1998.
(17) Howe, R.; Johnson, D. J. Chem. Soc., Perkin Trans. 1 1972, 977-981.
Nan, F.; Li, J.; Chen, Y.; Zhang, Y.; Gu, M.; Zhang, H. PCT Int. Appl.
WO 2004111010 A1, 2004.
amide could ease the construction of the pyrimidinone ring.
Indeed, when 2-amino-4-methyl-1H-pyrrole-3-carboxamide
(8) was prepared from 6 using similar conditions, it
underwent annulation with ethyl formate to 1 in about 80%
yield (Scheme 4). However, the yield of 8 was low, and the
pyrrole was found to be unstable.12 Consequently, we decided
(12) For a review on aminopyrroles, see: Cirrincione, G.; Almerico, A. M.;
Aiello, E.; Dattolo, G. in Chemistry of Heterocyclic Compounds; Chich-
ester: United Kingdom, 1992; Vol. 48 (Pyrroles, Pt. 2), pp 299-523.
(18) Gabriel, S.; Colman, J. Ber. 1900, 33, 980-995.
(19) Fahmy, S. M.; Mohareb, R. M. Synthesis 1985, 1135-1137.
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Scheme 6
Scheme 7
from NMR comparison of its protonated form 13 with that
reported in literature.20 We suspect that compound 11
reported in the literature19 may be a secondary product
produced during workup from 12. A possible mechanism
for this reaction is presented in Scheme 6.
Having established the reaction conditions for conversion
Since both side reactions proceed under strongly basic
conditions, lower basicity should be beneficial to the desired
reaction. We decided to investigate the efficiency of the
pyrrole formation vs strength of the base. Weak amine bases,
such as triethylamine, gave only the ethanolysis product 14a
even after heating at reflux overnight. Some pyrrole 8 (about
10% by HPLC area) was observed when potassium carbonate
was used as the base and the reaction mixture was heated at
reflux overnight. In this case, the ethanolysis product 14a
and hydrolysis product 14b predominated. With sodium
hydroxide as the base, we were surprised to observe the aldol
condensation product 15. Thus, when a mixture of 9 and
cyanoacetamide (1.5 equiv) was treated with 50% sodium
hydroxide (1.5 equiv) at room temperature in DMF, 9 was
converted within 30 min to aldol 15 and hydrolysis product
14b in about 2:1 ratio. Aldol 15 was found to be unstable
under reaction conditions and was gradually converted to
pyrrole 8 upon heating. However, hydrolysis product 14b
resisted further reaction. To minimize hydrolysis, solid
sodium hydroxide or lithium hydroxide was used, resulting
in improved yields. After conversion to the pyrrole was
complete, excess ethyl formate was added along with sodium
methoxide to form the product in about 60% yield. Although
reactions using lithium hydroxide gave similar yields to that
using solid sodium hydroxide on small scale, they are more
reproducible on larger scale (e.g., 100 g).
Thus, cyanoacetamide and 9 are treated with lithium
hydroxide in methanol at room temperature to form 15.
Sodium methoxide solution in methanol is then added, and
the reaction mixture is heated to convert 15 to 8. The
pyrrolopyrimidinone 1 is formed by heating the reaction
mixture with ethyl formate and additional sodium methoxide
(Scheme 7). After quenching with water and removal of
organic solvent, 1 is isolated by precipitation at pH 7.5 to
8.0. This process consistently produced 1 at 60% overall
yield on 100-g (9) scale with purity greater than 99% by
HPLC.
of phthalimidoacetone (9) to 1, we repeated the process using
acetamidoacetone (6). The one-pot procedure gave an overall
yield of 55% yield of 1. If the preparation procedure for 6
can be streamlined, the process starting with 6 should be
more attractive due to its higher atom efficiency.
In summary, we have developed a one-pot process for
the preparation of 5-methyl-3H-pyrrolo[2,3-d]pyrimidin-
4(7H)-one (1). This process avoids the use of hazardous
Raney nickel and eliminates the resulting heavy metal waste
stream. The process produces 1 in 60% yield from readily
available starting material 9.
Experimental Section
Reagents and solvents were obtained from commercial
sources and used as received. All solvents used were of
HPLC grade. NMR spectra were recorded with a Bruker
ARX 300, Bruker DPX 400 or Varian Mercury 400. HPLC
analysis was performed on a Shimadzu instrument with a
PDA detector. HPLC/MS analysis was carried out on a
Waters ZQ or Shimadzu instrument.
Representative Procedure To a solution of LiOH (17.25
g, 1.5 equiv) in anhydrous methanol (600 mL) was added
cyanoacetamide (63 g, 1.5 equiv) under nitrogen atmosphere.
The resulting mixture was stirred for 20 min at room
temperature. To this was added a solution of phthalimidoac-
etone (101.5 g, 0.5 mol) in 700 mL of THF (anhydrous)
over a period of 30 min. The resulting reaction mixture was
stirred for 2 h at room temperature and then heated at 55 °C
for 1 h. To this was added sodium methoxide solution (25%
solution, 172 mL, 1.5 equiv) at 55 °C over a period of 40
min. After 3 h HPLC/MS indicated starting material and
intermediates were converted to the pyrrole 8. A crude
sample of 8 was obtained by extractive aqueous workup.
1
MS: MH+ ) 140.1. H NMR (DMSO-d6): δ 9.71 (br s,
1H), 6.08 (br s, 2H), 5.84 (s, 1H), 5.64 (s, 2H), 2.07 (s, 3H).
13C NMR (DMSO-d6): δ 169.2, 146.7, 113.8, 108.0, 95.5,
13.4. To the above reaction mixture was added ethyl formate
(200.8 mL, 5 equiv) over a period of 20 min followed by
(20) Junek, H.; Sarhan, E. T.; Sterk, H. Monatsh. Chem. 1988, 119, 717-726.
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sodium methoxide (25% solution, 324 g, 3 equiv). The
resulting reaction mixture was heated for 7 h at 55 °C at
which time HPLC/MS indicated that the pyrrole 8 was
converted to the pyrrolopyrimidinone 1. The reaction mixture
was diluted with 1.5 L water, heated at 60 °C for 1 h, and
then concentrated to small volume (∼1.5 L). Solution assay
indicated that pyrrolopyrimidinone 1 was formed in 75%
solution yield. This solution was neutralized to pH ≈ 7.5
with 6 N aq HCl, cooled to about 5 °C, and held at this
temperature for 30 min. Solids were filtered, washed with
water, dried at 50 °C under vaccum overnight to give the
pyrrolopyrimidinone 1 as a light brown solid (45.8 g, 61%
yield, purity: 99.0% by HPLC area). MS: MH+ ) 150.1.
1H NMR (DMSO-d6): δ 2.27(s, 3H), 6.74(s, 1H), 7.74(s,
1H), 11.53 (br s, 2H). 13C NMR (DMSO-d6): δ 11.6, 107.0,
113.8, 117.8, 143.5, 148.2, 159.6.
Acknowledgment
We thank Lisa Imbrogno and Leonard Hargiss for their
assistance in HPLC and HPLC/MS, respectively. Royce
Groff and Hugh Burgoon are also acknowledged for prepara-
tion of large batches of phthalimidoacetone (9).
Received for review October 6, 2006.
OP060207Y
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