Convenient synthesis of 2-substituted 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones

Article abstract of DOI:10.1007/s00706-015-1634-1

A new synthetic route was elaborated at our laboratory providing a convenient access to 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones (diazaoxindoles), a compound family of biological relevance. Treatment of the easily available ethyl 2-(4-chloropyrimidin-5-yl)acetate derivatives with ammonia afforded the corresponding 2-(4-aminopyrimidin-5-yl)acetamides, which were finally cyclized to the target compounds.

Full text of DOI:10.1007/s00706-015-1634-1

Monatsh Chem
DOI 10.1007/s00706-015-1634-1
ORIGINAL PAPER
Convenient synthesis of 2-substituted 5,7-dihydro-6H-pyrrolo-
[2,3-d]pyrimidin-6-ones
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2
Eszter Kokai Jozsef Nagy Tu¨nde Toth Jozsef Kupai Peter Huszthy Gyula Simig2 Balazs Volk
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Received: 26 September 2015 / Accepted: 13 December 2015
Ó Springer-Verlag Wien 2016
Abstract A new synthetic route was elaborated at our
laboratory providing a convenient access to 5,7-dihydro-
Introduction
6H-pyrrolo[2,3-d]pyrimidin-6-ones (diazaoxindoles),
a
5,7-Dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones
(diaza-
compound family of biological relevance. Treatment of the
easily available ethyl 2-(4-chloropyrimidin-5-yl)acetate
derivatives with ammonia afforded the corresponding 2-(4-
aminopyrimidin-5-yl)acetamides, which were finally
cyclized to the target compounds.
oxindoles) represent a class of compounds exerting various
biological activities, such as protein kinase inhibition [1–5]
and soluble guanylate cyclase activation for the treatment
and/or prophylaxis of cardiovascular disorders [6–11].
Several, sometimes rather complicated, syntheses of
diazaoxindoles have been published. The most straight-
forward ones are shown in Scheme 1. The starting
pyrimidines 1 can be routinely synthesized by the reaction
of a 1,3-dicarbonyl compound with a N–C–N fragment
[12]. Chlorination of compounds 1 followed by the reaction
of chloro derivative 2 with various primary amines affor-
ded amino esters 3 [1–3, 13–17].
Graphical abstract
Cyclization of amino esters 3 to diazaoxindoles 4 has
been carried out under various conditions: in refluxing
butanol [13, 14], by heating with aqueous hydrochloric
acid in dioxane [1–3], or under basic conditions, e.g. with
K2CO3 in methanol [16, 17] or with t-BuOK in THF [18,
19] at room temperature. Basic hydrolysis of ester 3
(R1 = Et, R2 = 2-pyridyl) followed by cyclization of the
resulting acid with thionyl chloride in dichloromethane at
25 °C is also described [15].
Keywords Heterocycles Á Cyclization Á Chlorination Á
Elimination
Although the reaction of chloro derivative 2 (X = SEt,
Y = H, R1 = Et) with ethanolic ammonia at 120–130 °C
resulting directly in the corresponding cyclized product 4
(X = SEt, Y = H, R2 = H) was described long ago [20], a
recent study clearly demonstrated the difficulties arising in
the reaction of 2 (X = H, Y = Cl, R1 = Me) with
ammonia under various conditions [21]. Several byprod-
ucts, among others amino amide 6 (Scheme 1) were
formed. This is obviously a common problem of the ami-
nation reaction carried out with ammonia, independently of
the nature of the substituents X and Y of the pyrimidine
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-015-1634-1) contains supplementary
material, which is available to authorized users.
´
& Balazs Volk
volk.balazs@egis.hu
1
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, PO Box 91, 1521
Budapest, Hungary
2
Directorate of Drug Substance Development, EGIS
Pharmaceuticals Plc., PO Box 100, 1475 Budapest, Hungary
123

´
E. Kokai et al.
Scheme 1
ring. The alternative synthesis of amino esters 3 (R2 = H)
via azido derivatives 5 (Scheme 1) looks as if it would
avoid the problems caused by ammonia [8, 9, 22, 23],
nevertheless the synthesis is longer.
of 2-methyl derivative 10b by the ‘‘azide route’’, we treated
chloro derivative 7a [30–33] with sodium azide to give
compound 8a, which latter was subjected to catalytic
hydrogenation on Pd/C (DMF, 60 °C) to afford amino ester
9a in only 46 % yield (Scheme 2), calculated for 7a.
Cyclization of intermediate 9a with methanolic sodium
methoxide (0 °C to rt, 10 min) resulted in target compound
10a in 56 % yield. After all, the ‘‘azide route’’ gave
unsatisfactory yields in our case.
Now, we have aimed at elaborating an efficient syn-
thesis of diazaoxindoles 10 (Scheme 2). The synthesis of
2-methyl derivative 10b has been described in patent
applications starting from amino ester 9b, either by heating
in Dowtherm A at 230 °C for 3 h [22, 23], or by cycliza-
tion with t-BuOK in THF [18, 19, 24, 25], in 70 and 91 %
yields, respectively (Scheme 2); the preparation of com-
pound 10b is mentioned also in an earlier publication,
however, the structure assignment is doubtful [26]. Com-
pound 9b was obtained via azide 8b, starting from chloro
ester 7b with 90 % overall yield [22, 23, 27, 28].
Next, we turned our attention to the direct amination
reaction of chloro ester 7a with ammonia. In some pre-
liminary experiments, compound 7a was reacted with
alcoholic ammonia in an autoclave under various condi-
tions of ammonia excess and temperature. We observed, in
addition to minor amounts of diazaoxindole 10a, the for-
mation of several products, among others chloro amide 12,
amino ester 9a and amino amide 11a, nevertheless with
poor reproducibility (Scheme 3).
Diazaoxindoles 10c and 10d are, to the best of our
knowledge, unknown in the literature. For compound 10a,
Cheung et al. [29] have described an extremely compli-
cated synthesis, however, neither experimental details nor
characterization of the compound were presented.
These results demonstrated that, when treating chloro
ester 7a with ammonia, amidation of the ester group
competes with the substitution of the chloro substituent.
However, when carrying out the reaction in alcoholic
ammonia in an autoclave, we could not find appropriate
reaction conditions resulting in diazaoxindole 10a as a
single product. On the other hand, treatment of compound
7a with excess ammonia in ethanol in an autoclave
(60–70 °C, 2 days) afforded the corresponding amino
Results and discussion
First we checked the feasibility of the synthetic routes to
our target compound 10a on analogies found in the liter-
ature. Motivated by the published high-yielding synthesis
Scheme 2
123

Convenient synthesis of 2-substituted 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones
Scheme 3
amide 11a in 68 % yield. Presumably, the ammonia
applied in the reaction was disadvantageous for the ring
closure reaction of the primarily formed amino amide 11a
to give 10a in a one-pot reaction.
82, 77, and 74 % for R = H, Me, Ph, and SMe,
respectively).
Isolation of 11a from the above reaction led us to the
conclusion that amino amides 11 might be the appropriate
intermediates for a simple and high-yielding synthesis of
diazaoxindoles 10 (Scheme 4). Nevertheless, the cycliza-
tion of amino amides 11 to compound 10 (a transamidation
reaction) was expected to require markedly harsher reac-
tion conditions than that of amino esters 9 (an ester
amidation reaction).
Conclusion
In conclusion, a new synthetic route was elaborated at our
laboratory providing a convenient access to diazaoxindoles
10. Treatment of the easily available ethyl 2-(4-chloropy-
rimidin-5-yl)acetate derivatives 7 (R = H, Me, Ph, SMe)
with alcoholic ammonia afforded the corresponding 2-(4-
aminopyrimidin-5-yl)acetamides 11, which were finally
cyclized to target compounds 10 (R = H, Me, Ph, SMe),
members of a family of biological relevance.
Compounds 11b [27, 34–37] and 11c [38, 39] are known
in the literature, they were obtained by long heating of
chloro derivatives 7 with alcoholic ammonia in an auto-
clave at high temperature (120–130 °C). In our hands,
treatment of compounds 7 with excess ammonia in ethanol
in an autoclave at 60–70 °C for 2 days afforded the cor-
responding amino amides 11 in good (68–94 %) yields
(Scheme 4).
Experimental
Melting points were determined on a Boetius micro-melt-
ing point apparatus and on an OptiMelt Automated Melting
Point System by Stanford Research Systems. Infrared
spectra were obtained on a Bruker Alpha-T FT-IR spec-
trometer. NMR spectra were recorded on a Bruker DRX-
First we attempted cyclization of amino amides 11
simply by heating at 225–255 °C until the evolution of
ammonia stopped (15–20 min). The yields of compounds
10 obtained using this procedure were unsatisfactory
(46–56 %). It was expected that heating of compounds 11
in a solvent at a similar temperature could lead to better
results. The mixture of diphenyl ether and biphenyl seemed
a good choice since it is widely used as a heat transfer
medium around 250–260 °C, among others in ring closure
reactions [22, 23, 40].
500 (at 500 MHz for H and at 125 MHz for 13C spectra)
1
or on a Bruker 300 Avance spectrometer (at 300 MHz for
1H and at 75 MHz for 13C spectra). CDCl3 or DMSO-d6
was used as solvent. Chemical shifts (d) and coupling
constants (J) are given in parts per million and in Hertz.
The electron ionization (EI) mass spectra were recorded on
a Clarus 560 D mass spectrometer coupled with a Clarus
500 gas chromatograph. The ESI ? mass spectra were
recorded on a Thermo LTQ XL mass spectrometer coupled
with an AcquityTM UPLC. Elemental analyses were
Finally, compounds 11 were successfully cyclized to
diazaoxindoles 10, by heating in a mixture of diphenyl
ether and biphenyl at 260 °C for 4–8 h, in high yields (91,
Scheme 4
123

´
E. Kokai et al.
Ethyl 2-[4-hydroxy-2-(methylthio)pyrimidin-5-yl]acetate
(1, X = SMe, Y = H, R1 = Et)
performed on a Perkin-Elmer 2400 analyzer. The reactions
were followed by analytical thin layer chromatography on
silica gel 60 F254. Starting materials were purchased from
Sigma-Aldrich Co., Molar Chemicals Kft or Merck.
This compound was prepared according to the general
procedure I using 2.44 g sodium ethoxide (34 mmol),
20 cm3 ethanol, 4.02 g diethyl 2-formylsuccinate
(20 mmol), 7.30 g 2-methylisothiouronium iodide
(34 mmol), 3 cm3 aqueous hydrogen chloride solution
(5 %), and 10 cm3 water. The crude product was filtered
off and recrystallized from ethanol using charcoal to give 1
(X = SMe, Y = H, R1 = Et; 2.37 g, 52 %) as colorless
General procedure I for the synthesis of compounds 1
(X = H, Me, Ph, SMe; Y = H, R1 = Et)
A solution of sodium ethoxide in ethanol was cooled to
0 °C under argon atmosphere. Diethyl 2-formylsuccinate
was added under stirring. After 5 min, the corresponding
amidine was added at 0 °C and stirring was continued at rt
for 3 days. Aqueous hydrogen chloride solution (5 %) was
added and it was stirred for 30 min. After addition of water
the ethanol was removed in vacuo at 30 °C. The precipitate
was filtered off to give compound 1 (X = H, Me, Ph, SMe;
Y = H, R1 = Et).
crystals.
Rf = 0.70
(DCM/MeOH = 10:1);
m.p.:
189–190 °C (EtOH) (Ref [41] 188–189 °C).
General procedure II for the synthesis of compounds 7
A mixture of compound 1 (X = H, Me, Ph, SMe; Y = H,
R1 = Et) and phosphoryl chloride was refluxed for 2 h.
Phosphoryl chloride was then evaporated. Dichloro-
methane (DCM) and water was added to the dark oily
residue. It was cooled to 5–10 °C and ammonium hydrox-
ide solution was added until pH 9–10. The layers were
separated and the aqueous layer was extracted with DCM.
The combined organic layer was washed with aqueous
NaHCO3 solution (10 %) and brine. It was dried and
evaporated to give compounds 7.
Ethyl (4-hydroxypyrimidin-5-yl)acetate (1, X = H, Y = H,
R1 = Et)
This compound was prepared according to the general
procedure I using 167.8 g sodium ethoxide (2.34 mol),
500 cm3 ethanol, 253.4 g diethyl 2-formylsuccinate
(1.26 mol), 219.0 g formamidine acetate (2.10 mol), and
1000 cm3 aqueous hydrogen chloride solution (5 %). The
crude product was suspended in 300 cm3 diethyl ether,
filtered off, and recrystallized from ethanol using charcoal
to give 1 (X = H, Y = H, R1 = Et; 126.2 g, 55 %) as
colorless crystals. Rf = 0.40 (DCM/MeOH = 10:1); m.p.:
161–162 °C (EtOH) (Ref [30] 158–160 °C).
Ethyl (4-chloropyrimidin-5-yl)acetate (7a)
This compound was prepared according to the general
procedure II using 12.95 g 1 (X = H, Y = H, R1 = Et;
71.1 mmol) and 143.1 g phosphoryl chloride (87 cm3,
0.93 mol) to give 7a (11.23 g, 79 %) as a pale yellow oil
(Ref [32, 33]).
Ethyl 2-(4-hydroxy-2-methylpyrimidin-5-yl)acetate
(1, X = Me, Y = H, R1 = Et)
Ethyl 2-(4-chloro-2-methylpyrimidin-5-yl)acetate (7b)
This compound was prepared according to the general
procedure II using 7.79 g 1 (X = Me, Y = H, R1 = Et;
39.7 mmol) and 131.60 g phosphoryl chloride (80 cm3,
0.86 mol) to give 7b (6.37 g, 75 %) as a slowly solidifying
pale brown oil (Ref [27] m.p.: 40–41 °C).
This compound was prepared according to the general
procedure I using 8.02 g sodium ethoxide (0.12 mol),
70 cm3 ethanol, 12.07 g diethyl 2-formylsuccinate
(0.06 mol),
10.09 g
acetamidine
hydrochloride
(0.10 mol), 12 cm3 aqueous hydrogen chloride solution
(5 %), and 10 cm3 water. The colorless crystals were
filtered off and dried to give 1, (X = Me, Y = H, R1 = Et;
8.08 g, 69 %). The product thus obtained was of high
purity as indicated by the elemental analysis. Rf = 0.44
(DCM/MeOH = 10:1); m.p.: 184–185 °C (Ref. [27]
179 °C, [28] 179–180 °C).
Ethyl 2-(4-chloro-2-phenylpyrimidin-5-yl)acetate (7c)
This compound was prepared according to the general
procedure II using 2.50 g 1 (X = Ph, Y = H, R1 = Et;
10.9 mmol) and 41.13 g phosphoryl chloride (25 cm3,
0.27 mol) to give 7c (2.51 g, 9.0 mmol, 83 %) as pale
orange crystals (Ref [42, 43] m.p.: 78–80 °C).
Ethyl 2-(4-hydroxy-2-phenylpyrimidin-5-yl)acetate
(1, X = Ph, Y = H, R1 = Et)
Ethyl 2-[4-chloro-2-(methylthio)pyrimidin-5-yl]acetate (7d)
This compound was prepared according to the general
procedure II using 2.39 g 1 (X = SMe; Y = H, R1 = Et;
10.0 mmol) and 32.9 g phosphoryl chloride (20 cm3,
0.22 mol) to give 7d (2.29 g, 93 %) as a pale beige oil
(Ref [41] m.p.: 38–39 °C).
This compound was prepared according to the general
procedure I using 2.12 g sodium ethoxide (30.0 mmol),
20 cm3 ethanol, 5.03 g diethyl 2-formylsuccinate
(25.0 mmol), 3.79 g benzamidine (30.0 mmol), 19.5 cm3
aqueous hydrogen chloride solution (5 %), and 30 cm3
water to give 1 (X = Ph, Y = H, R1 = Et; 5.93 g, 92 %).
The product thus obtained was of high purity as indicated
by the elemental analysis. Rf = 0.55 (DCM/
MeOH = 10:1); m.p.: 177–178 °C (Ref [38, 39] 179 °C).
General procedure III for the synthesis of compounds 11
A solution of compound 7 in ethanol was added to liquid
ammonia in an autoclave (250 cm3) at -50 °C. The
123

Convenient synthesis of 2-substituted 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones
mixture was heated to 60–70 °C, the pressure increased to
15–16 bar. It was stirred for 2 days under these conditions.
The volatile components were removed and the residue
was suspended in water, filtered, and dried.
diphenyl ether and biphenyl, filtered, washed with water,
and dried to give product 10.
General procedure IVB
Compound 11 was heated at 225–255 °C until the evolu-
tion of ammonia stopped (15–20 min). Product 10 was
obtained by recrystallization from the appropriate solvent.
2-(4-Aminopyrimidin-5-yl)acetamide (11a, C6H8N4O)
This compound was prepared according to the general
procedure III using 10.03 g 7a (50.0 mmol) in 100 cm3
ethanol and 160 g NH3 (9.41 mol) to give 11a (5.21 g,
68 %) as off-white crystals. Rf = 0.05 (DCM/
MeOH = 10:1); m.p.: 244–245 °C (H2O); 1H NMR
(500 MHz, DMSO-d6): d = 8.24 (s, 1H, ArH), 7.94 (s,
1H, ArH), 7.79 (s, 1H, CONH2), 7.06 (s, 1H, CONH2), 6.79
(s, 2H, ArNH2), 3.26 (s, 2H, CH2) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 171.9, 162.7, 157.1, 155.4,
5,7-Dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one
(10a, C6H5N3O)
According to the general procedure IVA, 0.50 g compound
11a (2.8 mmol) was heated in a mixture of 1.50 g biphenyl
(9.7 mmol) and 4.54 g diphenyl ether (4.23 cm3,
26.7 mmol) to give 10a (0.33 g, 91 %) as yellow crystals.
According to the general procedure IVB, 76 mg com-
pound 11a (0.5 mmol) was heated at 240–250 °C for
20 min. Recrystallization of the crude product from water
gave 10a (37 mg, 54 %) as yellow crystals. Rf = 0.36
(DCM/MeOH = 10:1); m.p.: ca. 205 °C, decomp. (H2O);
1H NMR (500 MHz, DMSO-d6): d = 11.43 (br s, 1H, NH,
disappears by shaking with D2O), 8.65 (s, 1H), 8.32 (s,
1H), 3.61 (s, 2H) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 175.7, 164.9, 156.7, 148.7, 118.6, 33.3 ppm; IR
112.7, 35.7 ppm; IR (KBr):m = 3381, 1654 cm-1; MS
ꢀ
(ESI?): m/z = 152.96.
2-(4-Amino-2-methylpyrimidin-5-yl)acetamide (11b)
This compound was prepared according to the general
procedure III using 6.31 g 7b (29.4 mmol) in 60 cm3
ethanol and 95 g ammonia (4.35 mol) to give 11b (3.41 g,
70 %) as colorless crystals. Rf = 0.10 (DCM/
MeOH = 10:1); m.p.: 250–251 °C (EtOH:H2O = 3:1)
(Ref [27] 250 °C).
(KBr):m = 1737, 1703 cm-1; MS (ESI): m/z = 136.12
ꢀ
([M?1]?).
2-(4-Amino-2-phenylpyrimidin-5-yl)acetamide (11c)
This compound was prepared according to the general
procedure III using 4.38 g 7c (15.8 mmol) in 40 cm3
ethanol and 51 g ammonia (2.34 mol) to give 11c (3.40 g,
94 %) as colorless crystals. Rf = 0.22 (DCM/MeOH =
10:1); m.p.: 224–225 °C (EtOH) (Ref [38, 39] 177 °C).
5,7-Dihydro-2-methyl-6H-pyrrolo[2,3-d]pyrimidin-6-one
(10b)
According to the general procedure IVA, 2.50 g compound
11b (15.0 mmol) was heated in a mixture of 9.00 g
biphenyl (58.4 mmol) and 29.0 g diphenyl ether (27.0 cm3,
170.4 mmol) to give 10b (1.84 g, 82 %) as yellow crystals.
According to the general procedure IVB, 175 mg
compound 11b (1.0 mmol) was heated at 250–255 °C for
15 min. Recrystallization of the crude product from ethanol
gave 10b (68 mg, 46 %) as yellow crystals. Rf = 0.40
(DCM/MeOH = 10:1); m.p.: ca. 230 °C, decomp. (EtOH).
2-[4-Amino-2-(methylthio)pyrimidin-5-yl]acetamide
(11d, C7H10N4OS)
This compound was prepared according to the general
procedure III using 3.20 g 7d (13.0 mmol) in 40 cm3
ethanol and 41 g NH3 (2.45 mol) to give 11d (2.11 g,
82 %) as off-white crystals. Rf = 0.10 (DCM/
MeOH = 10:1); m.p.: 230–231 °C (EtOH:H2O = 3:1);
1H NMR (300 MHz, DMSO-d6): d = 7.79 (s, 1H, ArH),
7.46 (s, 1H, CONH2), 7.04 (s, 1H, CONH2), 6.79 (s, 2H,
ArNH2), 3.17 (s, 2H, CH2), 2.39 (s, 3H, CH3) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 172.0, 168.7, 162.6,
5,7-Dihydro-2-phenyl-6H-pyrrolo[2,3-d]pyrimidin-6-one
(10c, C12H9N3O)
According to the general procedure IVA, 1.36 g compound
11c (6.0 mmol) was heated in a mixture of 4.00 g biphenyl
(25.9 mmol) and 16.80 g diphenyl ether (15.7 cm3,
98.7 mmol) to give 10c (0.97 g, 77 %) as ochre crystals.
According to the general procedure IVB, 205 mg
compound 11c (0.9 mmol) was heated at 225–240 °C for
15 min. Recrystallization of the crude product from a
mixture of DMF and water (1:1) gave 10c (106 mg, 56 %)
as ochre crystals. Rf = 0.53 (DCM/MeOH = 10:1); m.p.:
ca. 235 °C decomp (DMF:H2O = 2:1); 1H NMR
(500 MHz, DMSO-d6): d = 11.51 (s, 1H, NH), 8.43 (s,
1H, ArH), 8.32 (dq, J = 7.8, 4.1 Hz, 2H, ArH), 7.53–7.48
(m, 3H, ArH), 3.64 (s, 2H, CH2) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 175.9, 165.6, 161.9, 149.1, 137.4, 130.5,
ꢀ
155.5, 108.7, 35.3, 13.7 ppm; IR (KBr):m = 3368,
1648 cm-1; MS (EI?): m/z = 198 (M?), 181, 154, 152,
137, 108, 106, 81.
General procedures IVA and IVB for the synthesis of
compounds 10: General procedure IVA
Compound 11 was added to a mixture of diphenyl ether
and biphenyl, and it was heated to 260 °C for 4–8 h. After
cooling to rt, hexane was added and it was stirred for
30 min. The crystalline precipitate was filtered off. The
crystals were suspended in hexane again in order to remove
123

´
E. Kokai et al.
128.5, 127.5, 116.6, 33.2 ppm; IR (KBr):mꢀ = 1754 cm-1
MS (EI?): m/z = 211 (M?), 168, 141, 104, 103, 77.
;
stirring, dropwise at 0 °C. After 15 min at 0 °C, 3.5 cm3
acetic acid (61 mmol) was added to the reaction mixture
and the solvents were removed in vacuo at 30 °C. The
residue was dissolved in 9 cm3 water and the pH was
adjusted to 7 with acetic acid. After being kept at 0 °C for
1 day, the precipitate was filtered off and recrystallized
from water to give 10a (1.66 g, 56 %) as yellow crystals.
The product was identical with the compound obtained by
cyclization of amino amide 11a.
2-(Methylthio)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-
one (10d, C7H7N3OS)
According to the general procedure IVA, 1.00 g compound
11d (5.0 mmol) was heated in a mixture of 3.6 g biphenyl
(23.3 mmol) and 11.60 g diphenyl ether (10.81 cm3,
68.2 mmol) to give 10d (0.67 g, 74 %) as beige crystals.
According to the general procedure IVB, 100 mg com-
pound 11d (0.5 mmol) was heated at 250 °C for 15 min.
Recrystallization of the crude product from EtOH gave 10d
(45 mg, 50 %) as beige crystals. Rf = 0.80 (DCM/
MeOH = 10:1); m.p.: ca. 196 °C, decomp. (EtOH); 1H
NMR (300 MHz, DMSO-d6): d = 11.41 (s, 1H, NH), 8.16
References
1. Shepherd TA, Dally RD, Joseph S (2010) Akt and p70 S6 kinase
inhibitors. US Patent Appl. US 2010120801, 13 May 2010
2. Shepherd TA, Dally RD, Joseph S (2010) Akt and p70 S6 kinase
inhibitors. PCT Int. Pat. Appl. WO 2010056563, 20 May 2010
(s, 1H, ArH), 3.53 (s, 2H, CH2), 2.46 (s, 3H, CH3) ppm; 13
C
3. Shepherd TA, Dally RD, Joseph
152:568154
S (2010) Chem Abstr
NMR (75 MHz, DMSO-d6): d = 175.9, 169.1, 165.1, 148.8,
113.8, 32.9, 13.5 ppm; IR (KBr):m = 1758 cm-1; MS (ESI):
ꢀ
4. Mitchell IS, Spencer KL, Stengel P, Han Y, Kallan NC, Munson
M, Vigers GPA, Blake J, Piscopio A, Josey J, Miller S, Xiao D,
Xu R, Rao C, Wang B, Bernacki AL (2005) Akt protein kinase
inhibitors. PCT Int. Patent Appl. WO 2005051304, 9 June 2005
5. Mitchell IS, Spencer KL, Stengel P, Han Y, Kallan NC, Munson
M, Vigers GPA, Blake J, Piscopio A, Josey J, Miller S, Xiao D,
Xu R, Rao C, Wang B, Bernacki AL (2005) Chem Abstr
143:40007
6. Follmann M, Stasch J-P, Redlich G, Lang D, Vakalopoulos A,
Wunder F, Tersteegen A (2014) Trifluoromethyl-substituted
fused pyrimidines and their use. US Patent Appl. US
2014249168, 4 Sep 2014
7. Follmann M, Stasch J-P, Redlich G, Lang D, Vakalopoulos A,
Wunder F, Tersteegen A (2014) Chem Abstr 161:404656
8. Follmann M, Stasch J-P, Redlich G, Ackerstaff J, Griebenow N,
Knorr A, Wunder F, Li VM-J, Kroh W, Baerfacker L (2012)
Ring-fused pyrimidines and triazines and use thereof for the
treatment and/or prophylaxis of cardiovascular diseases. PCT Int.
Patent Appl. WO 2012004258, 12 Jan 2012
9. Follmann M, Stasch J-P, Redlich G, Ackerstaff J, Griebenow N,
Knorr A, Wunder F, Li VM-J, Kroh W, Baerfacker L (2012)
Chem Abstr 156:175315
10. Raghavan S, Stelmach JE, Smith CJ, Li H, Whitehead A, Wad-
dell ST, Chen Y-H, Miao S, Ornoski OA, Garfunkle J, Liao X,
Chang J, Han X, Guo J, Groeper JA, Brockunier LL, Rosauer K,
Parmee ER (2011) Soluble guanylate cyclase activators. PCT Int.
Patent Appl. WO 2011149921, 1 Dec 2011
11. Raghavan S, Stelmach JE, Smith CJ, Li H, Whitehead A, Wad-
dell ST, Chen Y-H, Miao S, Ornoski OA, Garfunkle J, Liao X,
Chang J, Han X, Guo J, Groeper JA, Brockunier LL, Rosauer K,
Parmee ER (2011) Chem Abstr 155:11159
12. Joule JA, Mills K (2000) Heterocyclic chemistry, 4th edn.
Blackwell Science Ltd, Oxford, p 218
13. Sun CL, Li X, Zhu Y (2009) Bioactive compounds for treatment
of cancer and neurodegenerative diseases. PCT Int. Patent Appl.
WO 2009139834, 19 Nov 2009
m/z = 181.95 ([M?1]?).
Synthesis of 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-
one (10a) via the ‘‘azide route’’: Synthesis of ethyl
(4-aminopyrimidin-5-yl)acetate (9a, C8H11N3O2)
To a vigorously stirred solution of 9.72 g chloro ester 7a
(48.4 mmol) in 120 cm3 acetonitrile was added 10.5 g
sodium azide (162 mmol) under Ar at rt. The reaction
mixture was heated and stirred at 80 °C for 36 h. The
solvent was removed in vacuo at rt and the residue was
dissolved in a mixture of 80 g ice, 50 cm3 water, and
100 cm3 dichloromethane. The layers were separated, the
aqueous layer was extracted with dichloromethane
(2 9 50 cm3). The combined organic layer was dried
(MgSO4), filtered, and the solvent was removed at rt under
reduced pressure to give crude ethyl 2-(4-azidopyrimidin-
5-yl)acetate (8a). Azide 8a was dissolved in 300 cm3 ethyl
acetate, treated with 4.0 g charcoal and hydrogenated in the
presence of 1.5 g Pd/C (10 %) catalyst at atmospheric
pressure at rt. The catalyst was filtered off and washed with
ethyl acetate (3 9 30 cm3). The solvent was evaporated.
The crude product was triturated with 20 cm3 toluene,
filtered off, dried, and recrystallized from water to give 9a
(4.03 g, 46 %) as off-white crystals. Rf = 0.42 (isopropyl
1
alcohol/hexane 1:1); m.p.: 130–131 °C (water); H NMR
(300 MHz, CDCl3): d = 8.48 (s, 1H), 8.10 (s, 1H), 5.68 (br
s, 2H, NH2), 4.16 (q, J = 7.1 Hz, 2H), 3.43 (s, 2H), 1.25 (t,
J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d = 170.6, 162.4, 158.0, 156.3, 110.9, 61.9, 35.9,
14.2 ppm; IR (KBr):m = 3341, 1724 cm-1; MS (ESI): m/
14. Sun CL, Li X, Zhu Y (2009) Chem Abstr 151:571128
15. Choi H-S, Wang Zh, Richmond W, He X, Yang K, Jiang T, Sim
T, Karanewsky D, Gu X, Zhou V, Liu Y, Ohmori O, Caldwell J,
Graya N, Hea Y (2006) Bioorg Med Chem Lett 16:2173
16. Neelamkavil SF, Boyle CD, Harris JM, Stamford AW, Hao J,
Neustadt BR, Chackalamannil S, Xia Y, Greenlee WJ (2010)
Bicyclic heterocycle derivatives and their use as GPCR modu-
lators. PCT Int. Patent Appl. WO 2010009207, 21 Jan 2010
ꢀ
z = 182.06 ([M?1]?).
Synthesis of 10a by cyclization of amino ester 9a
Sodium metal (1.40 g, 61 mmol) was dissolved in 60 cm3
methanol. To this solution was added 4.00 g amino ester 9a
(22 mmol) dissolved in 60 cm3 methanol under vigorous
123

Convenient synthesis of 2-substituted 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-ones
17. Neelamkavil SF, Boyle CD, Harris JM, Stamford AW, Hao J,
Neustadt BR, Chackalamannil S, Xia Y, Greenlee WJ (2010)
Chem Abstr 152:192137
18. Leftheris K, Barrish J, Hynes J, Wrobleski ST (2002) Methods of
treating p38 kinase-associated conditions and pyrrolotriazine
compounds useful as kinase inhibitors. PCT Int. Patent Appl. WO
2002040486, 23 May 2002
19. Leftheris K, Barrish J, Hynes J, Wrobleski ST (2002) Chem Abstr
136:386144, also published as: EP 1363910
20. Johnson TB, Peck HT, Ambler JA (1911) J Am Chem Soc 33:758
21. Vaid RK, Spitler JT, Boini S, May SA, Hoying RC (2012)
Synthesis 44:2396
22. Hennequin LFA, Ple P, Lohmann JM, Thomas AP (1999)
Oxindolylquinazoline derivatives as angiogenesis inhibitors. PCT
Int. Patent Appl. WO 1999010349, 3 Mar 1999
23. Hennequin LFA, Ple P, Lohmann JM, Thomas AP (1999) Chem
Abstr 130:209715
24. Hunt JT, Bhide RS, Borzilleri RM, Qian L (2000) Pyrrolotriazine
inhibitors of kinases. PCT Int. Patent Appl. WO 2000071129, 30
Nov 2000
25. Hunt JT, Bhide RS, Borzilleri RM, Qian L (2000) Chem Abstr
134:17506
26. Biggs J, Sykes P (1959) J Chem Soc 1849
27. Andersag H, Westphal K (1937) Chem Ber 70:2035
28. Cereced LR, Pickel FD (1937) J Am Chem Soc 59:1714
29. Cheung M, Harris PA, Lackey KE (2001) Tetrahedron Lett
42:999
30. Massaroli GG, Signorelli G (1966) Boll Chim Pharm 105:400
31. Zymalkowski F, Reimann F (1966) Arch Pharm 299:362
32. Holmes IP, Bergman Y, Lunniss GE, Nikac M, Choi N, Hemley
CF, Walker SR, Foitzik RCh, Ganame D, Lessene R (2012) FAK
inhibitors. PCT Int. Patent Appl. WO 2012110773, 23 Aug 2012
33. Holmes IP, Bergman Y, Lunniss GE, Nikac M, Choi N, Hemley
CF, Walker SR, Foitzik RCh, Ganame D, Lessene R (2012)
Chem Abstr 157:382910
34. Gravin AI (1943) Zhurnal Prikladnoi Khimii. Russian Federation,
Sankt-Petersburg, p 105
35. Gravin AI (1944) Chem Abstr 38:8327
36. Andersag H, Westphal K (1945) Pyrimidine derivatives and
process of preparing the same. US Patent 2,377,395, 5 June 1945
37. Andersag H, Westphal K (1946) Chem Abstr 40:570
38. Verma SD, Dey AN (1963) J Indian Chem Soc 40:283
39. Verma SD, Dey AN (1963) Chem Abstr 59:41697
40. Hermecz I, Kereszturi G, Vasvari-Debreczy L (1992) Advances
in heterocyclic chemistry. Academic Press Inc, San Diego, p 141
41. Peters E, Minnemeyer HJ, Spears AW, Tickelmann H (1960) J
Org Chem 25:2137
42. Partyka RA (1965) N,N0-Bis(pyrimidine-5-acetyl)ethylene dia-
mines. US Pat. US 3,225,047, 21 Dec 1965
43. Partyka RA (1966) Chem Abstr 64:35926
123