Organic Process Research & Development
Article
Scheme 4. Demonstration on a 200 g Scale
was noticed, improved mass balance was indeed obtained,
likely because of less decomposition (entry 2 vs entry 1). With
a prolonged reaction time (65 h), high conversion and a good
reaction yield were retained at the reaction temperature of 125
°C (entry 3). Further reduction of the reaction temperature led
to incomplete conversion (entry 4). Notably, there was no
significant impact on the reaction performance when the
number of equivalents of base was reduced to as low as 9
(entries 3, 5, and 6), which also improved the volume
productivity by reducing the reaction volume from 20 to 5
volumes (vol). We ultimately found that the optimal balance to
achieve high conversion, a clean profile, and an acceptable
reaction rate was the use of 9 equiv of ammonium hydroxide at
125 °C (entry 6).
After identifying conditions to enable efficient access to AIC,
we focused our efforts on developing a highly efficient isolation
process. The high aqueous solubility of AIC prevented any
aqueous workup processes, so a direct isolation process was
developed. The use of ammonium hydroxide as both the base
and the solvent allowed us to isolate the AIC free base with
high purity by filtration after cooling the reaction mixture to
ambient temperature. Under this optimized reaction proto-
col,12 a 200 g scale reaction was successfully demonstrated to
afford a 75% assay yield of AIC, proving the robustness and
scalability of the process (Scheme 4). The AIC free base was
directly isolated via filtration in 68% yield with high purity. To
further improve the purity and color, subsequent active carbon
treatment and HCl salt formation in MeOH led to the
isolation of AIC·HCl in 58% overall yield with 99.7% purity
from the readily available and low-cost commodity chemical
hypoxanthine.
in experiments. IR spectra were measured on Thermo Fisher
1
Nicolet iS5 FT-IR spectrometer. H and 13C NMR spectra
were recorded on a Bruker AVANCE 3HD-400 NMR
spectrometer. Chemical shifts are reported in parts per million
relative to the residual deuterated solvent. Reactions were
monitored by reversed-phase HPLC on an Agilent 1260 HPLC
instrument and LC−MS on an Agilent 1260 HPLC with 6120
mass spectrometer system. High-resolution mass spectrometry
was performed on a Xevo G2-XS QTof (Waters MS
Technologies) mass spectrometer by electrospray ionization.
1,3,9-Tribenzyl-3,9-dihydro-1H-purine-2,6-dione (Tri-
benzylxanthine, 4). In a 100 mL three-neck round-bottom
flask, 3,9-dihydro-1H-purine-2,6-dione (5 g, 1.0 equiv) was
dissolved in DMF (50 mL, 10 vol). NaOH (5.3 g, 4.0 equiv)
was added at 25 °C, and the mixture was stirred for 0.5 h.
Benzyl bromide (19.6 g, 3.5 equiv) was added, and the mixture
was stirred for another 16 h at 25 °C while being monitored by
LC−MS. The mixture was diluted with EtOAc (200 mL) and
washed with water (200 mL × 3). The organic phase was
concentrated, and the residue was purified by silica gel
chromatography, eluting with a gradient of ethyl acetate in
petroleum ether ranging from 0% to 20% to yield 7.1 g (51%
yield) of 1,3,9-tribenzyl-3,9-dihydro-1H-purine-2,6-dione (4)
as a white solid. Mp = 126 °C. 1H NMR (400 MHz, CDCl3): δ
(ppm) 7.55−7.48 (m, 5H), 7.42−7.35 (m, 5H), 7.35−7.25
(m, 6H), 5.51 (s, 2H), 5.29 (s, 2H), 5.23 (s, 2H). 13C NMR
(101 MHz, CDCl3): δ (ppm) 155.2, 151.4, 148.7, 140.9, 137.3,
136.4, 135.1, 129.1, 128.7, 128.7, 128.7, 128.5, 128.4, 128.3,
127.8, 127.5, 107.2, 50.4, 46.7, 44.5. HRMS MS (m/z): [M +
H]+ calcd for [C26H22N4O2H] 423.4955, found 423.1826.
FTIR (neat): 3031, 1706, 1668, 696, 519 cm−1.
N,1-Dibenzyl-4-(benzylamino)-1H-imidazole-5-car-
boxamide (9). In a 40 mL sealed tube, compound 4 (0.5 g,
1.0 equiv) was dissolved in EtOH (5 mL). NaOH (3 N, 5 mL)
was added. The mixture was stirred at 80 °C for 16 h, and the
desired product was detected by LC−MS. The combined
mixture was diluted with EtOAc (40 mL) and washed with
water (40 mL × 2). The organic phase was concentrated, and
the residue was purified by reversed-phase combi-flash
chromatography (C18 column with a gradient of MeCN in
H2O (0.05% TFA) ranging from 0% to 60%) to yield 54 mg
(11% yield) of N,1-dibenzyl-5-(benzylamino)-1H-imidazole-4-
CONCLUSION
■
We have reported the design and details behind the
development of a highly efficient one-step synthesis of 5-
amino-1H-imidazole-4-carboxamide (AIC, 1), an important
intermediate for the antitumor drug temozolomide. The new
synthesis achieves a major yield improvement and significant
reduction in materials, labor, and overhead costs compared
with existing syntheses through the use of readily available
commercial reagents. In addition, we have developed this into
a robust and scalable manufacturing process to eliminate
hazardous and highly toxic reagents and significantly reduce
the process mass intensity (PMI = 9 for AIC and 26 for AIC·
HCl) and environmental impact.
1
carboxamide (9) as a white semisolid. H NMR (400 MHz,
CDCl3): δ 7.76 (s, 1H), 7.34 (dd, J = 5.0, 2.0 Hz, 3H), 7.31−
7.26 (m, 4H), 7.25 (d, J = 2.8 Hz, 1H), 7.19 (dd, J = 7.1, 2.5
Hz, 2H), 7.13 (ddt, J = 7.5, 6.0, 2.1 Hz, 4H), 6.98 (d, J = 6.0
Hz, 1H), 5.48 (s, 2H), 4.41 (d, J = 5.5 Hz, 2H), 4.34 (s, 2H).
13C NMR (101 MHz, CDCl3): δ 159.5, 147.3, 137.7, 137.5,
134.2, 133.8, 129.5, 129.1, 128.8, 128.7, 127.9, 127.8, 127.7,
127.5, 109.9, 52.1, 50.7, 43.3. HRMS MS (m/z): [M + H]+
EXPERIMENTAL SECTION
■
General Information. All of the experiments described
herein were carried out under a nitrogen atmosphere. All of the
reagents were stored under a nitrogen atmosphere prior to use
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Org. Process Res. Dev. 2021, 25, 591−596