Syntheses of 5-amino-2-phenyl-4(3H)-pyrimidinone derivertives starting with glycine

Article abstract of DOI:10.3987/COM-12-12432

N-Cbz derivative of 5-amino-2-phenyl-4(3H)-pyrimidinone was prepared from sodium salt of methyl hydroxymethylene glycinate and benzamidine hydrochloride in good yield. However, the reaction with N-substituted benzamidine did not proceed to give the desired pyrimidinone. In contrast, the reaction of 4-ethoxymethylene-2-phenyl-5(4H)-oxazolone readily prepared from hippuric acid and N-substituted benzamidine proceeded nicely to give 5-(benzoylamino)-6-oxo-2- phenyl-1(6H)-pyrimidineacetic acid in high yield.

Full text of DOI:10.3987/COM-12-12432

HETEROCYCLES, Vol. 85, No. 5, 2012
1089
HETEROCYCLES, Vol. 85, No. 5, 2012, pp. 1089 - 1103. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 19th January, 2012, Accepted, 12th March, 2012, Published online, 22nd March, 2012
DOI: 10.3987/COM-12-12432
SYNTHESES
OF
5-AMINO-2-PHENYL-4(3H)-PYRIMIDINONE
DERIVERTIVES STARTING WITH GLYCINE
Daisuke Takahashi*, Yutaka Honda, and Kunisuke Izawa*
Research Institute for Bioscience Products and Fine Chemicals, Ajinomoto Co.,
Inc., 1780 Hinaga, Yokkaichi, Mie, 510-0885, Japan
E-mail:daisuke_takahashi@ajinomoto.com
Abstract - N-Cbz derivative of 5-amino-2-phenyl-4(3H)-pyrimidinone was
prepared from sodium salt of methyl hydroxymethylene glycinate and
benzamidine hydrochloride in good yield. However, the reaction with
N-substituted benzamidine did not proceed to give the desired pyrimidinone. In
contrast, the reaction of 4-ethoxymethylene-2-phenyl-5(4H)-oxazolone readily
prepared from hippuric acid and N-substituted benzamidine proceeded nicely to
give 5-(benzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid in high yield.
INTRODUCTION
5-Amino-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid (1a) has attracted attention as a core molecule for
the development of novel nonpeptidic enzyme inhibitors. In particular, several drug candidates such as
human leukocyte elastase (also known as human neutrophil elastase) inhibitors for the treatment of COPD
(chronic obstructive pulmonary disease)1 and anti-inflammatory effects,2 chymase inhibitors for the
treatment of heart failure,3 and serine protease inhibitors for anti-malaria action4 have been designed and
are being developed through the use of 1a as peptide mimetics for the P2-P3 scaffold of the enzyme, since
derivatives of 1a are known to show high bioavailability.
N
N
CO2H
RHN
O
1a R=H
1b R=Cbz
1c R=Bz
Figure 1. 5-Amino-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acids.

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HETEROCYCLES, Vol. 85, No. 5, 2012
The first synthesis of 1b was reported by Veale et al.5 using the reaction of methoxymethylenemalonate
(2) with N-(2,2-dimethoxyethyl)benzamidine (3) followed by Curtius rearrangement and subsequent
oxidation of aldehyde with NaClO2 to the corresponding acid 1b (eq.1). So far, this method has been
widely used to synthesize many pharmaceutical candidates. However, there is a risk of explosion
associated with this process on an industrial scale. To avoid dangerous azide chemistry, Nakai et al.
transformed the carboxyl group to an amino group by Lossen rearrangement using hydroxamate.6
Alternatively, Kojima et al. reported an efficient method for the synthesis of 1a consisting of the catalytic
reduction of 5-nitropyrimidinone (8) prepared from 3-methoxy-2-nitroacrylate (6) and benzamidine
derivatives 7a (eq.2).7
NH
• HCl
OMe
N
H
N
O
OMe
N
OMe
3
OMe
OMe
(1)
CO2H
N
N
CbzHN
MeO2C
MeO2C
CO2Me
O
1b
2
4
NH
• HCl
CO2tBu
N
H
OMe
CO2Me
N
N
(MeO)3CH
(2)
7a
O2N
CO2Me
CO2tBu
O2N
O2N
O
6
5
8
Recently, new strategies for the synthesis of 1a were presented in a patent application by Sugiura et al.8
First, they used the reaction of N-protected dimethyl aminomalonate with N-carboxymethyl benzamidine
(7b) to prepare 5-(benzyloxycarbonylamino)-4-hydroxy-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid
(10), which was subjected to chlorination followed by reduction to obtain 1a (eq. 3).
NH
• HCl
CO2H
7b
N
H
1. POCl3
2. H2, Pd-C
N
O
HO
N
NHCbz
CO2Me
(3)
N
CO2H
CO2H
N
MeO2C
CbzHN
H2N
O
10
1a
9
The patent also reported that the reaction of 4-ethoxymethylene-2-phenyl-5(4H)-oxazolone with
N-carboxymethyl benzamidine gave the desired pyrimidinone derivative 1c in good yield. Since, we have
independently developed a method that is very similar to theirs and some of our data are completely novel,
in this report we describe our studies on the synthesis of 1a and 1b aiming at the production of these
compounds on an industrial scale.

HETEROCYCLES, Vol. 85, No. 5, 2012
1091
RESULTS AND DISCUSSION
Synthetic approach to 1a via N-(benzyloxycarbonyl)-2-(hydromethylene)glycinate.
We began our study by using 2-(hydroxymethylene)glycinate as a starting material instead of
methoxymethylenemalonate (2) or 3-methoxy-2-nitroacrylate (6), which require the transformation of
carboxylate or nitro groups into an amino substituent via Curtius rearrangement using azide or the
reduction of a nitro group in a later step. We considered that our proposed process would be safer by
avoiding these risky reagents and hazardous reactions.
Nemeryuk et al. reported the synthesis of N-formyl ethyl 2-(hydroxymethylene)glycinate 12 by the
reaction of ethyl glycinate (11) with ethyl formate in the presence of sodium methoxide. Compound 12
was then converted to 5-formamido-4(3H)-pyrimidinones (14a and 14b) by the reactions of methyl
amidines 13a (R=Me) and S-ethyl thioisourea 13b (R=Set) in rather poor and excellent yields,
respectively (eq. 4).9
NH2
ONa
OEt
R
NH
N
O
R
H
HCO2Et
NaOMe
13a, 13b
(4)
N
CHONH
CHONH
H2N
CO2Et
O
11
12 (56%)
14a R=Me (21%)
14b R=SEt (90%)
We intended to synthesize 5-(tert-butoxycarbonylamino)-2-phenyl-4(3H)-pyrimidinone 17 in a similar
manner from N-Boc-glycine methyl ester 15, which has a more useful protecting group. The reaction of
15 with ethyl formate in the presence of potassium tert-butoxide gave (hydroxymethylene)glycinate 16 as
a potassium salt, though it was very difficult to isolate as pure crystals in high yield due to high solubility
in aqueous solution. Thus, we reacted 16 formed in situ with benzamidine hydrochloride (13c) to obtain
17 as crystals in 34% isolated yield (eq. 5). We also attempted the synthesis of N-Cbz derivative in the
same manner, but failed, probably due to cleavage of the N-Cbz group under strong basic conditions. As a
result, we abandoned this approach toward the synthesis of 1.
NH2 • HCl
OK
OMe
N
Ph
H
Ph
NH
13c
HCO2Et
-BuOK
(5)
N
BocHN
BocHN
BocHN
CO2Me
tert
O
O
15
16
17 (34%)
To improve the yield in (hydroxymethylene)glycinate formation, we investigated the use of two-step
reaction sequences as follows. According to the method reported by Toplak et al.,10

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HETEROCYCLES, Vol. 85, No. 5, 2012
N-Cbz--(dimethylaminomethylene)glycinate (19) was synthesized from N-Cbz-glycine methyl ester (18)
with tert-butoxy-bis(dimethylamino)methane (Brederick’s reagent) in almost quantitative yield.
Compound 19 has been reported to react with primary alkylamine to give -alkylamino derivatives in
acetic acid.11 Thus, we examined the reaction of 19 with benzamidine hydrochloride (13c) and
N-tert-butoxycarbonylmethyl benzamidine 7a. Unexpectedly, we found that the desired reactions did not
proceed at all in either case. Interestingly, however, sodium salt 21 of methyl
(hydroxymethylene)glycinate, which is readily prepared from 19 by treatment with diluted hydrochloric
acid followed by sodium methoxide, reacted nicely with 13c to give 5-(benzyloxycarbonylamino)-
2-phenyl-4(3H)-pyrimidinone (22) in very good yield (eq. 6).
Me2N
OH
OMe
Brederick's
reagent
aq. HCl
OMe
CbzHN
CO2Me
CbzHN
CbzHN
O
O
18
19 (99%)
20
NH2
Ph
NH • HCl
N
O
Ph
ONa
(6)
NaOMe
13c
N
H
OMe
CbzHN
CbzHN
O
21 (91%)
22
(86%)
In contrast, the reaction of 21 with N-substituted benzamidine 7a under similar reaction conditions did not
proceed to give the desired pyrimidinone 23 (eq. 7).
t
NH
CO2 Bu
Ph
NH • HCl
7a
N
O
Ph
CO2 Bu
ONa
OMe
(7)
t
N
CbzHN
CbzHN
O
23
21
We speculate that the substitution of benzamidine lowered the reactivity of amidine toward the sodium
salt 21. It has been reported that the alkylation of 22 with ethyl bromoacetate occurs with no selectively
to afford the desired ester as a minor product along with the N1- and O-alkylated isomers.5 We also
obtained a very similar result in the reaction of N-Boc pyrimidinone 17 with tert-butyl bromoacetate.12

HETEROCYCLES, Vol. 85, No. 5, 2012
1093
To achieve efficient pyrimidinone formation, we further investigated the electronic effect of a
-substituent on the reactivity of the olefin bond by changing hydroxymethylene group to
methoxymethylene compound 24, which is readily achieved in 85% yield by the treatment of 21 with
dimethyl sulfate.
t
NH
CO2 Bu
OMe
OMe
ONa
OMe
Ph
NH • HCl
N
O
Ph
7a
Me2SO4
MeCN
(8)
t
N
CO2 Bu
CbzHN
CbzHN
CbzHN
aq. Na2CO3
toluene
O
O
21
24 (85%)
23
(31%)
Methyl ester 24 was allowed to react with the free form of benzamidine 7a at 80 °C in toluene to give the
desired compound 23 in 31% yield (eq. 8), while the acetoxy compound obtained by acetylation of 21
gave only a trace amount of 23.
As noted above, the synthetic approach using methyl N-Cbz (hydroxymethylene)glycinate (21) efficiently
gave N3 non-substituted pyrimidinone 22, but was not applicable to the industrial-scale synthesis of 23
due to the low yield of cyclization.
Synthesis of 1a via 4-hydroxymethylene-5-oxazolone.
To improve the yield of cyclization of hydroxymethylene glycinate with amidine derivatives, it was
considered that the activation of olefin might be essential. We anticipated that 4-alkoxymethylene-
5-oxazolone (25) may be one of the most suitable intermediates for this purpose.
NH • HCl
BnS
NH2
EtO
N
O
SBn
NH
26
O
(9)
N
BzHN
O
Ph
27
25
Mukerjee et al. reported that the oxazolone 25 reacted with S-benzyl isothiouronium hydrochloride salt
(26) to give 5-benzoylamino-2-benzylsulfanyl-4(3H)-pyrimidinone (27) in 74% yield (eq. 9).13
Encouraged by this report, we examined the reaction of 25 with benzamidine derivative, with particular
focus on N-substituted benzamidine 7a. Since there have been several reports on the addition-elimination
reactions of 25 to replace a -ethoxy group with a-amino group,14 we expected that the risk of a
ring-opening reaction by amine attack was low. The oxazolone 25 that was easily prepared from hippuric

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HETEROCYCLES, Vol. 85, No. 5, 2012
acid by the Erlenmeyer method was heated with benzamidine derivative 7a in toluene after treatment with
base to make a free form. To our delight, the desired pyrimidinone 28a was obtained in 97% yield (eq.
10). The use of N-(carboxymethyl)benzamidine 7b instead of 7a gave a lower yield (58%) of the
product 1c, while it does not require deprotection of the ester group. 15
t
HN
Ph
CO2 Bu
NH • HCl
EtO
N
N
O
7a
(EtO)3CH
Ac2O
t
O
(10)
N
CO2 Bu
Ph
N
H
CO2H
BzHN
aq. Na2CO3
toluene
O
O
Ph
hippuric Acid
28a
(97%)
25
(70%)
HN
Ph
CO2H
N
O
NH • HCl
N
CO2H
7b
BzHN
1c (58%)
The cyclization reactions using other oxazolones prepared from ring-substituted hippuric acids gave
similar results in each case: p-Cl 28b; 96%, p-Me 28c; 95%, p-OMe 28d; 82%, and o-Cl 28e; 76%. The
reaction could also be applied to the syntheses of 2-(p-fluorophenyl) derivative (29; 89%) using the
corresponding amidine.
N
O
N
O
N
O
O
O
O
t
t
t
N
CO2 Bu
N
CO2 Bu
N
CO2 Bu
N
N
N
H
H
H
MeO
Cl
28b
28d
(82%)
(96%)
28c (95%)
F
N
O
N
Cl
O
O
t
N
CO2 Bu
t
N
N
CO2 Bu
N
H
H
O
28e (76%)
29 (89%)
The resulting t-butyl ester 28a was treated with trifluoroacetic acid at ambient temperature to achieve the
selective and complete deprotection of t-butyl ester followed by recrystallization from ethyl acetate to
give pure product 1c in 85% yield (eq. 11). When we carried out the deprotection reaction by treatment

HETEROCYCLES, Vol. 85, No. 5, 2012
1095
with NaOMe/MeOH followed by aqueous NaOH solution, we obtained 1a in only 70% yield along with
impurity after conventional acid workup. However, simultaneous cleavage of the N-benzoyl and t-butyl
groups was achieved by refluxing methanol solution of 28a in the presence of NaOH (3 equiv.) to give 1a
in 90% yield after acid workup.
N
O
N
TFA
t
N
CO2 Bu
N
CO2H
BzHN
BzHN
O
28a
1c
(85%)
NaOH/MeOH
NaOMe/MeOH
(11)
aq. NaOH
N
N
O
N
CO2Me
N
CO2H
H2N
H2N
O
30
1a
(90%)
The pyrimidinone 1a was treated with benzyl chloroformate under basic conditions using a two-phase
reaction to give N-Cbz pyrimidinone 1b in 77% yield. Formylation of 1a was also efficiently performed
by a conventional method to give 1d in 97% yield.
N
N
Cbz-Cl
N
CO2H
(9)
N
CO2H
CbzHN
H2N
toluene-
aq. NaOH
O
O
1a
1b (77%)
N
N
O
HCO2H
Ac2O
(10)
N
CO2H
N
CO2H
OHCHN
H2N
O
1a
1d (97%)
The precise mechanism for the cyclization reaction of ethoxymethylene oxazolone 25 with
benzamidinoacetate 7a is not yet clear. If the nucleophilic attack of an amidine derivative to the

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HETEROCYCLES, Vol. 85, No. 5, 2012
carbonyl carbon at the 5-position occurred, N1-alkylated pyrimidinone 33 should be formed via the
intermediate 32. However, only a trace amount of the product 33 was observed in the reaction mixture.
Therefore, the initial attack of the amidine 7a should occur at the -position of the exo-olefin bond. This
phenomenon is consistent with the result that the ethoxy group of the oxazolone could be changed to an
amino group (Scheme 1).
EtO
7a
N
O
N
N
t
N
CO2 Bu
NH
BzHN
O
t
CO2 Bu
Ph
O
N
O
O
25
Ph
28a
31
t
t
CO2 Bu
CO2 Bu
OEt
NH
N
N
O
N
BzHN
BzHN
O
33
32
Scheme 1. A possible reaction mechanism for cyclization
Meanwhile, 2-methyl-4-alkoxymethylene-5-oxazolone (35) could also be prepared by the treatment of
N-acetylglycine (34) with triethyl orthoformate and acetic anhydride. However, the oxazolone 35 is an
oily compound and difficult to obtain in a satisfactory yield. Thus, we attempted to carry out the reaction
without the isolation of 35, and obtained the N-acetyl pyrimidinone derivative 36 in 19% overall yield (eq.
13).
t
NH
CO2 Bu
EtO
Ph
NH • HCl
N
HC(OEt)3
Ac2O
7a
t
(13)
N
CO2 Bu
AcHN
CO2H
O
N
AcHN
aq. Na2CO3
toluene
O
O
Me
34
35
36
Notably, the N-acetyl group of 36 can be deacetylated under remarkably mild conditions. Therefore, the
N-acetyl group should be a very good protecting group if a facile and efficient method for the synthesis of
35 can be developed in the future.16

HETEROCYCLES, Vol. 85, No. 5, 2012
1097
CONCLUSION
Versatile methods for the synthesis of 5-(benzyloxycarbonylamino)-2-phenyl-4(3H)-pyrimidinone 22 and
its N3-carboxymethyl derivative 1b were developed using glycine as a starting material. The processes do
not require hazardous reaction conditions or reagents such as azide and nitro compounds. It should be
straightforward to scale-up these processes to an industrial scale.
EXPERIMENTAL
All reagents were purchased and used without further purification. Thin-layer chromatography (TLC) was
conducted on precoated TLC plates (Merck 60F250). High-performance liquid chromatography (HPLC)
was performed with a Hitachi L-6000 pump and an L-4000 UV detector system using an Inertsil ODS-2
column. Melting points were measured with a Büchi B-545 or a Yanaco melting point apparatus MP
model and are uncorrected. NMR spectra were obtained on a Varian XL-300 spectrometer. All proton
NMR spectra were measured in CDCl3 or DMSO-d6 solvent, and chemical shifts are reported as  values
in parts per million relative to tetramethylsilane ( 0.00) or CHCl3 ( 7.26) as an internal standard. Data
are reported as follows: chemical shift (integrated intensity or assignment, multiplicity, coupling constants
in hertz, assignment). All carbon NMR spectra were measured in CDCl3 or DMSO-d6 solvent, and
chemical shifts are reported as  values in parts per million relative CDCl3 ( 77.0) or DMSO-d6 ( 39.5)
as an internal standard. Infrared (IR) spectra were recorded on a SHIMADZU IR Prestige-21 Fourier
transform infrared spectrophotometer equipped with a Smith Dura Sample IR II ATR unit and are
reported in wave number (cm-1). Mass spectra (MS) were obtained with a ThermoQuest TSQ700 or a
JEOL JMS-HX110 instrument with ESI (electrospray) or FAB (fast atom bombardment) ionization.
High-resolution mass spectra (HRMS) were obtained with a JEOL MS700V (JEOL Datum Ltd.).
5-(tert-Butoxycarbonylamino)-2-phenyl-4(3H)-pyrimidinone (17).
To a THF suspension (10 mL) of potassium t-butoxide (0.59 g, 5.3 mmol) were added dropwise a THF
solution (10 mL) of N-Boc-glycine methyl ester (1.00 g, 5.3 mmol) and methyl formate (0.35 g, 6.5
mmol) on an ice bath. After the mixture was stirred for 3 h at the same temperature, benzamidine
hydrochloride 13c (0.82 g, 5.2 mmol) was added. The reaction mixture was stirred at 40 °C for an
additional 14 h and concentrated under reduced pressure. The residue was washed with water. The
resulting precipitate was triturated with ether, collected and dried to give compound 17 as a white solid
(0.52 g, 34%).
Mp 227.5-227.8 °C, IR (neat): 1720, 1647, 1519, 1477, 1153, 711, 617, 565 cm-1, 1H-NMR (CDCl3) δ
13
1.62 (9H, s), 7.25 (1H, s), 7.52 (3H, m), 8.02 (2H, d, J = 3.0 Hz), 8.82 (1H, s), 11.74 (1H, s), C-NMR
(CDCl3) δ 28.3, 125.8, 126.7 129.1, 131.4, 132.1, 137.2, 148.5, 152.2, 158.7, HRMS: Calcd for

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HETEROCYCLES, Vol. 85, No. 5, 2012
C15H17N3O3 [M+M]+: 288.1348, Found: 288.1335.
Methyl N-benzyloxycarbonyl-2-(hydroxymethylene)glycinate sodium salt (21).
Methyl N-Cbz-2-(dimethylaminomethylene)glycinate (19)10 (2.38 g, 8.55 mmol) was dissolved in MTBE
(20 mL). Into the solution was poured aqueous 1M HCl (15 mL) on an ice bath. After the mixture was
stirred for 2 h at rt, the organic layer was separated, washed with brine and added dropwise to a 28%
NaOMe/MeOH solution (1.50 g, 8.00 mmol). The mixture was concentrated under reduced pressure. The
resulting precipitate was triturated with Et2O, collected and dried to give compound 21 as a white solid
(2.12 g, 91%).
Mp 105.8-106.4 °C. IR (neat) 1668, 1556, 1520, 1438, 1278, 1186, 1124, 1055, 734, 694 cm-1.
1H-NMR(DMSO-d6) δ 3.40 (3H, s), 4.96 (2H, s), 6.83 (1H, s), 7.32-7.37 (5H, m), 8.75 (1H, s), 13C-NMR
(DMSO-d6) δ 48.7, 65.0, 97.2, 126.5, 127.6, 128.3, 137.5, 155.6, 168.7, 172.0., HRMS: Calcd for
C12H13NO5Na [M+M]+: 274.0691, Found: 274.0667.
5-(Benzyloxycarbonylamino)-2-phenyl-4(3H)-pyrimidinone (22).
To a solution of sodium salt 21 (1.54 g, 5.62 mmol) in MeCN (19 mL) was added benzamidine
hydrochloride 13c (0.88g) and the mixture was stirred at 70 °C for 14 h. The reaction mixture was
concentrated under reduced pressure. To the residue was added water (15 mL) and the mixture was stirred
for 1 h. The resulting precipitate was triturated with Et2O, collected and dried to give compound 22 as a
white solid (1.54 g, 86%).
Mp 217.1-218.9 °C, IR (neat); 3315, 1651, 1533, 1502, 1230, 1217, 1049, 949, 765, 687, 600, 569 cm-1.
1H-NMR (DMSO-d6) δ 5.18 (2H, s), 7.32-7.57 (8H, m), 8.06-8.09 (2H, m), 8.46 (1H, s), 8.79 (1H, s),
13.0 (1H, brs). 13C-NMR (DMSO-d6) δ 66.1, 124.8, 127.3, 127.6, 127.9, 128.3, 128.6, 131.1, 132.1, 136.3,
150.9, 153.4, 158.8, 158.9. HRMS: Calcd for C18H15N3O3 [M+M]+: 322.1191, Found: 322.1163.
Methyl N-Cbz-methoxymethylene glycinate (24).
Sodium salt of 21 (300 mg, 1.10 mmol) was suspended in MeCN (5 mL) and dimethyl sulfate (0.105 mL,
1.04 mmol) was added dropwise. The mixture was stirred at 40 °C for 17 h. The resulting precipitate was
filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica
gel chromatography (hexane-EtOAc) to give 24 as colorless oil (248 mg, 85%).
IR (neat): 3325, 2951, 1701, 1653, 1496, 1249, 1226, 1122, 1053,736, 696 cm-1. 1H-NMR (CDCl3) δ 3.76
(3H, s), 3.93 (3H, s), 5.10 (1H, s), 5.20 (2H, s), 5.78 (1H, s), 7.28-7.33 (5H, m). 13C-NMR (CDCl3) δ 51.8,
62.1, 67.3, 107.6, 128.2, 128.5, 128.6, 136.2, 155.2, 165.7. HRMS m/z Calcd for C13H15NO5 [M+M]+:
266.1028, Found: 266.1031.

HETEROCYCLES, Vol. 85, No. 5, 2012
1099
5-(Benzyloxycarbonylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid tert-butyl ester (23).
To a suspension of 7a (675 mg, 2.5 mmol) in toluene (10 mL) was added 10% aqueous solution (8 mL) of
sodium carbonate with vigorous stirring. After separation of the organic layer, the aqueous layer was
extracted with toluene (5 mL). The combined organic layer was washed with brine and dried over Na2SO4.
To the organic layer was added 24 (500 mg, 1.9 mmol). The mixture was stirred at 80 °C for 17 h and
washed with 1M HCl and brine. After concentration, the residue was purified by silica gel column
chromatography (hexane-EtOAc, 10:1 to 2:1) to give 23 as a white solid (246 mg, 31%).
Mp 108.7-108.9 °C; IR (neat) 3265, 1734, 1656, 1514, 1489, 1365, 1213, 1151, 1091, 771, 696 cm-1.
1H-NMR (DMSO-d6) δ 1.43 (9H, s), 4.53 (2H, s), 5.17 (2H, s), 7.26-7.54 (10H, m), 8.77 (1H, s).
13C-NMR (DMSO-d6) δ 27.9, 48.8, 67.5, 83.1, 125.1, 128.1, 128.2, 128.4, 128.6, 128.9, 130.3, 134.1,
134.8, 135.7, 152.7, 153.0, 157.7, 166.1. HRMS: Calcd for C24H25N3O5 [M+M]+: 436.1872, Found:
436.1875.
5-(Benzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid tert-butyl ester (28a).
To a suspension of 7a (5.00 g, 18.5 mmol) in toluene (70 mL) were added sodium carbonate (8.0 g) and
water (70 mL) with vigorous stirring. After phase separation, the aqueous layer was extracted with
toluene (70 mL). The combined organic layer was washed with brine and dried over Na2SO4. The organic
layer was added dropwise to a solution of 2-phenyl-4-ethoxymethylene 5-(4H)-oxazolone17 (25) (3.09 g,
14.2 mmol) in MeCN (5 mL). The mixture was stirred at 80 °C for 17 h and washed with 1M HCl,
saturated aqueous NaHCO3 solution and brine. After concentration, the residue was added dropwise to
hexane and stirred. The resulting crystals were collected by filtration and dried under reduce pressure to
give the desired pyrimidinone 28a as pale yellow crystals (5.59 g, 97%).
1
Mp 188.5-190.1 °C. IR (neat): 1734, 1649, 1512, 1485, 1365, 1238, 1149, 771, 698, 597 cm-1. H-NMR
(DMSO-d6) δ 1.31 (9H, s), 4.57 (2H, s), 7.51-7.65 (8H, m), 797-8.00 (2H, m), 8.79 (1H, s), 9.58 (1H, s).
13C-NMR (CDCl3) δ 27.9, 49.0, 83.3, 125.2, 125.3, 127.3, 128.2, 128.9, 128.9, 129.0, 130.5, 132.3, 133.7,
153.4, 158.4, 165.6, 166.2. MS(ESI) m/z; [M+M]+: 406.2. Anal. Calcd for C23H23N3O4: C, 68.13; H, 5.72;
N, 10.36. Found: C, 68.20; H, 5.65; N, 10.30.
5-(p-Chlorobenzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid tert-butyl ester (28b).
1
Yield: 96%; Mp 165.6-168.1 °C. H-NMR (CDCl3) δ 1.46 (9H, s), 4.58 (2H, s), 7.42-7.55 (6H, m),
13
7.86-7.89 (2H, m), 8.76 (1H, s), 9.24(1H, s). C-NMR (CDCl3) δ 28.3, 49.4, 83.7, 125.5, 128.5, 129.1,
129.3, 129.5, 130.9, 132.4, 134.4, 137.2, 139.1, 154.0, 158.6, 164.8, 166.5. Anal. Calcd for
C23H22ClN3O4: C, 62.80; H, 5.04; N, 9.55. Found：C, 62.85; H, 5.01; N, 9.48.

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5-(p-Methylbenzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid tert-butyl ester (28c).
1
Yield 95%; Mp 161.6-163.9 °C. H NMR (CDCl3) δ 1.46 (9H, s), 2.43 (3H, s), 4.58 (2H, s), 7.24-7.31
(2H, dd, J = 6.5, 1.7 Hz), 7.45-7.54 (6H, m), 7.82-7.85 (2H, dd, J = 6.5, 1.7 Hz), 8.79 (1H, s), 9.27 (1H, s).
13C-NMR (CDCl3) δ 21.9, 28.3, 49.4, 83.6, 125.7, 127.7, 128.5, 129.3, 129.9, 130.8, 131.2, 134.5, 136.9,
143.4, 153.6, 158.7, 165.9, 166.6. Anal. Calcd for C24H25N3O4: C, 68.72; H, 6.01; N, 10.02. Found C,
68.92; H, 5.99; N, 9.92.
5-(p-Methoxybenzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid tert-butyl ester (28d).
1
Yield 82%; Mp 160.9-163.6 °C, H-NMR (CDCl3) δ 1.46 (9H, s), 3.84 (3H, s), 4.58 (2H, s), 6.96-7.00
(2H, d, J = 9.8 Hz), 7.45-7.54 (6H, m), 7.89-7.92 (2H, d, J = 9.8 Hz), 8.74 (1H, s), 9.26 (1H, s). 13C-NMR
(CDCl3) δ 28.3, 49.4, 55.9, 83.6, 114.4, 125.8, 126.3, 128.6, 129.3, 129.6, 130.8, 134.5, 136.8, 153.5,
158.7, 163.3, 165.5, 166.6. Anal. Calcd for C24H25N3O5: C, 66.19; H, 5.79; N, 9.65. Found C, 66.23; H,
5.73; N, 9.57.
5-(o-Chlorobenzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid tert-butyl ester (28e).
1
Yield 76%; H-NMR (CDCl3) δ 1.48 (9H, s), 4.57 (2H, s), 7.32-7.55 (8H, m), 7.89-7.92 (1H, d, J = 6.0
13
Hz), 8.89 (1H, s), 9.27(1H, s). C-NMR (CDCl3) δ 27.9, 48.9, 83.2, 125.2, 127.2, 128.2, 128.9, 130.4,
130.5, 130.6, 131.1, 132.1, 134.1, 134.2, 137.2, 153.8, 158.1, 164.7, 166.1. HRMS: Calcd for
C23H22ClN3O4 [M+M]+ 440.1377, Found: 440.1368.
5-(p-Fluorobenzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid tert-butyl ester (29).
Yield 89%; 1H-NMR (CDCl3) δ 1.46 (9H, s), 4.56 (2H, s), 7.16 (2H, dd, J = 8.5 Hz), 7.45-7.56 (4H, m),
13
7.91 (2H, d, J = 7.3 Hz), 8.81 (1H, s), 9.22 (1H, s). C-NMR (CDCl3) δ 28.0, 49.0, 83.4, 116.0, 116.3,
125.4, 127.3, 128.9, 130.2, 130.3, 130.4, 132.4, 133.7, 136.5, 152.4, 158.3, 162.2, 165.6, 166.2. HRMS:
Calcd for C23H22FN3O4 [M+M]+: 424.1672, found: 424.1692.
5-(Benzoylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid (1c).
i
To a suspension of N-carboxymethyl benzamidine (7b)8 (300 mg, 1.68 mmol) in PrOH (5 mL) were
added 21% NaOEt (631 mg) and 4-ethoxymethylene-2-phenyl-5-oxazolone (25) (364 mg, 1.68 mmol),
and the mixture was stirred at 80 °C overnight. The solution was concentrated and washed by the addition
of water (6 mL) and MTBE (6 mL), and the aqueous layer was adjusted to pH 8 with aqueous NaOH. The
aqueous layer was acidified with hydrochloric acid. The precipitate was filtered and dried to give 1c as
pale yellow crystals (324mg, 58%).
Mp 247.0-248.7 °C (lit.,8 244.0-245.3 °C). IR (neat) 1728, 1656, 1516, 1487, 1227, 1199, 773, 704, 592

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1101
cm-1. 1H-NMR (DMSO-d6) δ 4.56 (2H, s), 7.53-7.65 (8H, m), 7.97 (2H, d, J = 5.1 Hz), 8.81 (1H, s), 9.55
(1H, s). 13C-NMR (DMSO-d6) δ 48.6, 124.8, 128.0, 128.4, 129.0, 130.7, 132.5, 133.8, 134.4, 140.2, 155.3,
158.1, 165.8, 169.1. Anal. Calcd for C, 65.32; H, 4.33; N, 12.03. Found: C, 65.12; H, 4.18; N, 11.88.
5-Amino-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid (1a).
To a solution of 28a (1.00 g 2.5 mmol) in MeOH (8 mL) was added NaOH (0.40 g, 10 mmol), and the
mixture was stirred under reflux for 17 h. To the reaction mixture was added water (5 mL), and the
solution was concentrated under reduced pressure. The residue was poured into MTBE (3 mL) and
acidified to pH 3.0 with 6M hydrochloric acid. The resulting precipitates were washed with water/MTBE
and dried under reduced pressure to give 1a as white crystals (585 mg, 96%).
Mp. 202.4-204.7 °C. IR (neat); 2580, 1691, 1616, 1516, 1427, 1382, 1298, 1182, 773, 715, 686, 547 cm-1.
1H-NMR (DMSO-d6) δ 4.46 (2H, s), 5.22 (2H, brs), 7.34 (1H, s), 7.41-7.49 (5H, m). HRMS: Calcd for
C12H11N3O3 [M+M]+: 246.0878, Found: 246.0882.
5-(Benzyloxycarbonylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid (1b).
Sodium salt of compound 1a (0.56 g, 2.1 mmol) was dissolved in water (6 mL), and benzyl chloroformate
(0.43 mL, 2.5 mmol) was added dropwise for 1 h while the pH was maintained at 6-8 by the addition of
saturated aqueous NaHCO3 solution. After the mixture was stirred for 2 h, it was washed with toluene.
The aqueous layer was acidified to pH 1 with 6M hydrochloric acid and extracted twice with EtOAc. The
combined organic layers were washed with brine and concentrated. After the addition of hexane, the
resulting precipitate was collected by filtration and dried under reduced pressure to give 1b (0.61 g, 77%).
Mp 183.6-185.9 °C. IR (neat); 3298, 1734, 1658, 1516, 1491, 1213, 1182, 1086, 986, 767, 748, 694 cm-1.
1H-NMR (DMSO-d6) δ 4.52 (2H, s), 5.20 (2H, s), 7.34-7.55 (10H, m), 8.47 (1H, s), 9.01 (1H, s), 13.3
(1H, br). 13C-NMR(DMSO-d6) δ 48.0, 66.3, 124.7, 127.7, 128.0, 128.4, 128.6, 130.1, 134.1, 136.4, 137.4,
153.4, 153.8, 157.2, 168.7, 169.7. HRMS: Calcd for C20H17N3O5 [M+M]+: 380.1246, Found: 380.1262.
5-(Formylamino)-6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid (1d).
Formic acid (1.5 mL) was added dropwise to acetic anhydride (0.5 mL) at room temperature for 1 h,
and 1a (0.1 g, 0.41 mmol) was then added to the mixture, which was stirred for 2 h. Toluene was added
and the mixture was concentrated under reduced pressure. The residue was washed with EtOAc and the
resulting crystals were collected by filtration and dried under reduced pressure to give 1d (0.11 g, 97%).
Mp 218-220 °C. IR (neat): 3282, 1643, 1604, 1512, 1487, 1232, 1186, 1141, 777, 723, 700, 696 cm-1.
1H-NMR (DMSO-d6) δ 4.53 (2H, s), 7.49-7.58 (5H, m), 8.14 (1H, s), 8.39 (1H, s), 8.89 (1H, s), 10.05
(1H, s). 13C-NMR (DMSO-d6) δ 48.5, 124.8, 128.4, 129.0, 130.6, 134.4, 137.2, 154.3, 157.2, 161.2, 163.4,

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169.0. HRMS: Calcd for C13H11N3O4 [M+M]+: 274.0828, Found: 274.0809.
5-(Acetylamino)–6-oxo-2-phenyl-1(6H)-pyrimidineacetic acid tert-butyl ester (36).
To a suspension of N-acetylglycine 34 (0.2 g, 1.7 mmol) in EtOAc (1.5 mL) were added triethyl
orthoformate (0.76 g, 5.1 mmol) and acetic anhydride (1.74 g, 16.4 mmol). After the reaction mixture was
stirred at 95 oC for 14 h, it was cooled to room temperature, and washed with saturated aqueous NaHCO3
solution and brine. After evaporation with toluene, the residue was added to a solution of the free form of
benzamidine 7a (2.22 mmol) and stirred at 80 °C for 15 h. The mixture was washed with 1M
hydrochloric acid, saturated aqueous NaHCO3 solution, and brine, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give
pyrimidineacetic acid tert-butyl ester 36 (0.11 g, 19%) as a pale yellow solid.
Mp; 150-152 °C. IR (neat): 3329, 1735, 1645, 1508, 1354, 1226, 1147, 771, 667, 590 cm-1. 1H-NMR
13
(CDCl3) δ 1.45 (9H, s), 2.23 (3H, s), 4.54 (2H, s), 7.48 (5H, m), 8.03 (1H, s), 9.09 (1H, s). C-NMR
(DMSO-d6) δ 24.4, 27.9, 49.0, 94.1, 125.1, 128.1, 128.9 130.0, 134.0, 136.6, 153.3, 158.0, 166.1, 168.8.
HRMS: Calcd for C18H21N3O4 [M+M]+: 344.1610, Found: 344.1584.
ACKNOWLEDGEMENT
We would like to thanks Mrs. Naoko Hirose for taking analytical data.
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