Synthesis of a series of carbon-14 labeled tetrahydropyrido[4,3-d] pyrimidin-4(3H)-ones

Article abstract of DOI:10.1002/jlcr.3110

A series of tetrahydropyrido[4,3-d]pyrimidin-4(3H)-ones labeled with carbon-14 in the 2-position of pyrimidinone moiety were prepared as part of a 3-step sequence from benz[amidino-¹⁴C]amidine hydrochloride as a key synthetic intermediate. Copyright

Full text of DOI:10.1002/jlcr.3110

Research Article
Received 5 May 2013,
Revised 6 July 2013,
Accepted 12 July 2013
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3110
Synthesis of a series of carbon-14 labeled
tetrahydropyrido[4,3-d]pyrimidin-4(3H)-ones
a
b
a
*
Omid Khalili Arjomandi, Nader Saemian, Ross P. McGeary,
and Gholamhossein Shirvanib
A series of tetrahydropyrido[4,3-d]pyrimidin-4(3H)-ones labeled with carbon-14 in the 2-position of pyrimidinone
moiety were prepared as part of a 3-step sequence from benz[amidino-14C]amidine hydrochloride as a key synthetic
intermediate.
Keywords: piperidine derivatives; piperidine-pyrimidone fused skeleton; carbon-14
Introduction
Results and discussion
The fused skeleton piperidine-pyrimidones have been a rich In this approach, according to the synthetic pathway shown in
source of biologically active molecular entities and are related to Scheme 1, after conversion of potassium [14C]cyanide 3 to zinc
a wide family of compounds with well-known pharmacological [14C2]cyanide 5 in the presence of an aqueous solution of zinc
properties.1–5 Among the different substitution patterns that are chloride, benzo[cyano-14C]nitrile 7 was derived from reaction of
known, tetrahydropyrido[4,3-d]pyrimidines are important iodobenzene 6 with zinc [14C2]cyanide 5 in the presence of
because of their potential biological and pharmaceutical tetrakis(triphenylphosphine)palladium(0) in dry DMF, with good
activities. The tetrahydropyridopyrimidine core is
a
key yield.13–15 The latter product 7 could then be converted to
pharmacophore in several reported preclinical drug candidates, methyl benz[imido-14C]imidate 8 by treatment with sodium
including selective P2X7 receptor antagonists, inhibitors of platelet methoxide in anhydrous methanol under N2-atmosphere during
aggregation, gastric anti-lesion agents, and phosphor diesterase 10 24 h.16 In the next step, benz[amidino-14C]amidine hydrochloride
inhibitors. These compounds also show anti-inflammatory, diuretic, 1 was achieved by reaction of 8 with ammonium chloride in
and coronary dilator effects.6–10 A series of novel tetrahydropyrido methanol solution.17 Methyl 1-benzyl-4-oxopiperidine-3-carboxylate
[4,3-d]pyrimidin-4(3H)-ones as possible effective MBL(metallo-β- part of the molecule (2a-d) has been synthesized as part of a 2-step
lactamase) enzymes inhibitors were introduced by Peter Vella and sequence from methyl acrylate 10 and benzyl amine 9.18 Then
coworkers.11
6-benzyl-2-phenyl-[2-14C]-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-
To further elucidate the mechanism of action and investigate 4(3H)-one 13 was produced via the coupling of methyl
the pharmacokinetics and drug metabolism of these compounds, 1-benzyl-4-oxopiperidine-3-carboxylate 12 with benz[amidino-14C]
the preparation of suitable metabolically stable carbon-14 labels amidine hydrochloride 1 in the presence of a solution of sodium
were required.12 In this paper, we present a convenient synthetic ethoxide in dry ethanol in 62% yield. The latter product 13 could
pathway for the synthesis of a series of tetrahydropyrido[4,3-d] then be converted to 2-phenyl-[2-14C] -5,6,7,8-tetrahydropyrido
pyrimidines 2a-d labeled with carbon-14 via benz[amidino-14C] [4,3-d]pyrimidin-4(3H)-one 14 in quantitative yield by treatment
amidine hydrochloride 1 as a key synthetic intermediate which with hydrogen gas in anhydrous ethanol in the presence of Pd/C
have been synthesized as part of a 4-step sequence from 5% under reflux condition during 48 h.19 In the final step, the coupling
potassium [14C]cyanide. Figure 1
of 14 with acyl chloride 15a-d was carried out in the presence of
aSchool of Chemistry & Molecular Biosciences, The University of Queensland,
Brisbane, Australia
bNuclear Science Research School, Nuclear Science & Technology Research
Institute, Tehran, Iran
*Correspondence to: Nader Saemian, Nuclear Science Research School, Nuclear
Science & Technology Research Institute, Tehran, Iran.
E-mail: nsaemian@aeoi.org.ir
Figure 1. The key synthetic intermediate 1 for 14C-labelling of tetrahydropyrido
[4,3-d]pyrimidines 2a-d.
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O. K. Arjomandi et al.
triethylamine and DMAP in THF, and 6-acyl-2-phenyl-[2-14C] -5,6,7,
8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one 2a-d were achieved in
good yield.20
ethyl acetate (200 mL), and washed twice with ammonium hydroxide
(2N, 40 mL). The ethyl acetate solution was then washed with brine
(20 mL). The organic phase was dried over Na2SO4, filtered, and
concentrated in vacuo, and the residue was purified by silica gel
chromatography by using ethyl acetate: Hexane (15%) as eluant to
give the title compound 7 (567 mg, 1269 MBq, 230.53 MBq/mmol) in
88.3% yield. IR(KBr): 3092, 2240,1600, 1490, and 1450 cm-1.
Experimental
Barium [14C] carbonate ( 235.9 MBq/mmol) was converted to potassium
[
14 C]cyanide according to the standard procedure.21 Infrared (IR) spectra
Benz[amidino-14C]amidine hydrochloride 1
were recorded on a Nicolet IR 550 spectrometer (USA) and all 1H-NMR
spectra were recorded on Bruker AVANCE 500, 400, or 300 MHz
spectrometers (Germany). HPLC: equipment consisted of: a Waters 1525
Binary HPLC pump (USA), a Waters 2487 Dual λ Absorbance Detector, a
A catalytic amount of sodium metal (15 mg, 0.65 mmol) was dissolved in
10 mL dry methanol and benzo[cyano-14C]nitrile 7 (550 mg, 1230.9 MBq,
230.53 MBq/mmol) was added, and the reaction was allowed to stir
under N2-atmosphere for 24 hours at 35-40°C. Ammonium chloride
(300 mg) was added, and stirring was continued for an additional
24 hours at 35-40°C. The reaction mixture was concentrated under
reduced pressure and the crude residue was washed with Et2O
(3 × 15 mL), dissolved in ethanol (15 mL), and filtered. The organic solvent
was removed under reduced pressure to give the product 1 (457 mg,
672 MBq, 230.13 MBq/mmol) as white solid in 54.6% yield.
Waters Breeze Data processing system, Column:
μ Bondapak18
(150 × 4.6 mm), and 5 μm diameters and uv detection at λ = 254 nm.
The isocratic elution was used for chromatographic separation in room
temperature. The eluent was CH3CN: H2O: triethylamine (600 : 400 : 0.75 )
with flow rate: 1 mL/min. Radioactivity was determined using a Beckman
LS6500 (USA) liquid scintillation spectrometer. Mass spectra were
obtained on a Finnigan TSQ-70 instrument (USA).
1H NMR (400 MHz, DMSO): δ 8.40 (4H, sb, NH.HCl, NH2), 7.87 (2H, d,
J = 7.6 Hz, ArH), 7.72 (1H, t, J = 7.3 Hz, ArH), 7.59 (2H, t, J = 7.7 Hz, ArH),
Zinc[14C2]-cyanide 5
MS (70 eV): m/z = 123 [M+H] +
.
To a solution of zinc chloride 4 (710 mg) in water (2 mL) was added
dropwise an aqueous solution of potassium [14C]cyanide 3 (450 mg,
1630 MBq, 235.45 MBq/mmol) in water (4 mL) at room temperature.
Precipitation of the white zinc [14C2]cyanide 5 started immediately.
The reaction mixture was stirred at room temperature for 5 min and
then centrifuged. The supernatant was removed and the remaining
solid was washed with water (4 × 3 mL) and diethyl ether (2 × 3 mL).
The obtained white crystals were dried overnight by using high vacuum,
affording the desired product 5 (391 mg, 1561 MBq, 468.7 MBq/mmol) in
95.7% yield.
3-[(2-Methoxycarbonylethyl) benzyl amino]propionic acid
methyl ester 11
To a stirred solution of methyl acrylate 10 (3.2 mL, 35.5 mmol) in methanol
(8 mL) was slowly added a solution of benzylamine 9 (1 mL, 9.2 mmol) in
methanol (8 ml) and was heated under reflux overnight. The residue were
concentrated under reduced pressure to give the product 11 (2.54 g) as
yellow oil in 99% yield.
1H NMR (300 MHz, CDCl3): δ 7.29-7.17 (5H, m, ArH), 3.61 (6H, s, OCH3),
3.55 (2H, s, NCH2Ph), 2.76 (4H, t, J=7.2 Hz, NCH2), 2.43 (4H, t, J=7.2 Hz,
COCH2). 13C NMR (300 MHz, CDCl3): δ 172.87 (CO), 138.99 (Ar), 128.67
(Ar), 128.18 (Ar), 127 (Ar), 58.30 (NCH2Ph), 51.47 (OCH3), 49.17(NCH2),
32.58 (COCH2).
Benzo[cyano-14C]nitrile 7
Iodobenzene 6 (1.3 g) , zinc [14C2]-cyanide 5 (360 mg, 1437.2 MBq,
468.7 MBq/mmol), and tetrakis(triphenylphosphine) palladium(0)
(352 mg) were weighed in a dry flask charged with argon. Freshly
deoxygenated DMF (20 mL) was added and yellow slurry was heated
Methyl 1-benzyl-4-oxopiperidine-3-carboxylate 12
to 80°C under argon until HPLC showed no starting material remaining The amine 11 (2.4 g, 8.6 mmol) was added dropwise under stirring to a
(1-2 h). The mixture was cooled to room temperature, diluted with suspension of fresh sodium methoxide* (698 mg, 12.90 mmol) in dry
Scheme 1. a) Pd(PPh3)4, DMF; b) NaOMe, MeOH; c) NH4Cl, MeOH; d) MeOH, Heat; e) NaOMe, Toluene; f) NaOEt, EtOH; g) Pd/C 5%, EtOH, H2(g); h) DMAP, Et3N, THF.
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J. Label Compd. Radiopharm 2013

O. K. Arjomandi et al.
toluene (520 mL). The mixture was stirred for 48 hours under reflux (8H, m, ArH), 4.57 (2H, sb, CONCH2C), 3.92 (2H, sb, CONCH2CH2C), 2.89
condition then cooled to 0°C and poured into water. The mixture was (2H, s, CONCH2CH2C). MS (70 eV): m/z = 333 (M+).
stirred until the ketone sodium salt dissolved completely, the organic
6-(Cyclohexanecarbonyl)-2-phenyl-[2-14C]-5,6,7,8-
tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one 2b
phase was separated and the aqueous phase was neutralized with acetic
acid and extracted with toluene (85 mL). The combined toluene phases
were dried over Na2SO4 and evaporated under reduced pressure to give
the pure product 12 (960 mg, 3.9 mmol) as yellow solid in 45% yield. *
The 2b was prepared according to the described procedure in the earlier
Sodium methoxide: Sodium (300 mg, 13 mmol) dissolved in dry texts for 2a, by stirring 14 (80 mg, 78.35 MBq, 222.17 MBq/mmol),
methanol (50 mL), after complete dissolving under nitrogen, the organic cyclohexanecarbonyl chloride 15b (100 mg, 0.68 mmol), triethylamine
solvent evaporated under reduced pressure to give the fresh sodium (148 μl) and DMAP (4 mg) in THF (40 mL) at room temperature during
methoxide (704 mg, 13 mmol).
12 h. The title compound 2b (85 mg, 55.39 MBq, 219.61 MBq/mmol ) was
1H NMR (300 MHz, CDCl3): δ 7.71-7.60 (dd, 2H, J1 = 2.5 Hz, J2 = 7.5 Hz, obtained in 71% yield. (Rt = 2.69min from HPLC analysis according to
ArH), 7.48-7.38 (m, 3H, ArH), 4.34-4.16 (m, 2H, PhCH2N), 4.01-3.88 (db, aforementioned condition), 1H NMR (300 MHz, CDCl3, 298 K): δ 8.00-8.13
1H), 3.75 (s, 3H, OCH3), 3.58-3.44 (m, 2H), 3.35-3.17 (m, 1H), 3.07-2.91 (2H, m, ArH), 7.47-7.60 (3H, m, ArH), 4.60 (1H, s, CONCH2C), 4.50 (1H, s,
(m, 1H), 2.49 (dt, 1H, J1 = 18.6 Hz , J2 = 4.6 Hz). 13C NMR (300 MHz, CDCl3): CONCH2C), 3.88 (1H, t, J = 5.2Hz, CONCH2CH2C), 3.77 (1H, sb,
δ 169.42 (CH2COCH), 167.97 (CHCOOCH3), 131.33 (Ar), 130.37 (Ar), 129.44 CONCH2CH2C), 2.75-2.90 (2H, m, CONCH2CH2C), 2.5-2.68 (1H, m, NH),
(Ar), 127.86 (Ar), 91.54 (NCH2Ph), 59.19 (CHCH2N), 52.13 (COCHCO), 46.92 1.62-1.88 (5H, m, cyclohexane), 1.10-1.40 (5H, m, cyclohexane). 1H NMR
(CH2CH2N), 46.53 (OCH3), 25.36 (CH2CO).
(300MHz, CDCl3, 313 K): δ 8.37 (2H, b, ArH), 7.48-7.60 (3H, m, ArH), 4.53
(2H, sb, CONCH2C), 3.86 (2H, sb, CONCH2CH2C), 2.82 (2H, sb, CONCH2CH2C),
2.60 (1H, sb, NH), 1.55-1.90 (6H, m, cyclohexane), 1.15-1.40 (4H, m,
cyclohexane). MS (70 eV): m/z = 339 (M+).
6-Benzyl-2-phenyl-[2-14C]-5,6,7,8-tetrahydro-pyrido[4,3-d]
pyrimidin-4(3H)-one 13
6-(3-Nitrobenzoyl) -[2-14C] -2-phenyl-5,6,7,8-tetrahydropyrido
[4,3-d]pyrimidin-4(3H)-one 2c
To
a solution of methyl 1-benzyl-4-oxopiperidine-3-carboxylate 12
(645 mg, 2.61 mmol) and benz[amidino-14C]amidine hydrochloride 1
(400 mg, 588 MBq, 230.13 MBq/mmol) in dry ethanol (2.1 mL) was
added a solution of sodium (188 mg) in dry ethanol (2.1 mL). The
mixture was heated under reflux for 24 h then evaporated to dryness
under reduced pressure. The residue was suspended in water
overnight until appearing solid crystal was filtered off and washed with
water. The residue was recrystallized from ethanol to give the product
13 (505 mg, 363 MBq, 227.90 MBq/mmol) as white solid in 62% yield.
(Rt = 3.18 min from HPLC analysis according to the aforementioned
condition), 1H NMR (300 MHz, CDCl3): δ 7.99 (2H, d, , J = 8.2 Hz, ArH),
7.55-7.26 (8H, m, ArH), 3.73 (2H, s, PhCH2N(CH2)CH2), 3.51 (2H, s,
BnNCH2C), 2.89-2.82 (2H, m, NCH2CH2C), 2.82-2.73 (2H, m, NCH2CH2C).
MS (70 eV): m/z = 319 (M+).
The 2c was prepared according to the described procedure mentioned
earlier in the texts for 2a, by stirring 14 (80 mg, 78.35 MBq, 222.17 MBq/
mmol), 3-nitrobenzoyl chloride 15c (135 mg, 0.73 mmol), triethylamine
(148 μl) and DMAP (4 mg) in THF (40 mL) at room temperature during
12 h. The title compound 2c (93 mg, 54.39 MBq, 219.90 MBq/mmol) was
obtained in 69.4 % yield. (Rt = 2.81 min from HPLC analysis according
to the aforementioned condition), 1H NMR (400 MHz, DMSO, 298 K):
δ 8.38-8.23 (m, 2H, ArH), 8.06 (sb, 2H, ArH), 7.96 (1H, d, J = 7.6 Hz,
ArH), 7.78 (1H, t, J = 7.9 Hz, ArH), 7.60-7.46 (3H, m, ArH), 4.51 (1H, s,
CONCH2C), 4.25 (1H, s, CONCH2C), 3.94 (1H, s, CONCH2CH2C), 3.60
(1H, s, CONCH2CH2C), 2.78 (2H, s, CONCH2CH2C). 1H NMR (400 MHz,
DMSO, 353K): δ 8.34-8.23 (2H, m, ArH), 8.13-8.03 (m, 2H, ArH), 7.93 (dt,
1H, J1 = 4.0Hz, J2 = 1.3Hz, ArH), 7.78 (1H, t, J = 8.4Hz, ArH), 7.60-7.44 (m,
3H, ArH), 4.41 (s, 2H, CONCH2C), 3.78 (s, 2H, CONCH2CH2C), 2.80 (2H, t,
J = 8.4Hz, CONCH2CH2C). MS (70 eV): m/z = 378 (M+).
2-Phenyl-[2-14C] -5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4
(3H)-one 14
The compound 13 (475 mg, 341 MBq, 227.90 MBq/mmol) was dissolved
in 50 mL ethanol. The catalyst Pd/C 5% (100 mg) was added and the
resulting suspension was hydrogenated under reflux for 48 h. After
removal of the catalyst by filtering, the organic solvent was evaporated
under reduced pressure. The product 14 was obtained as a white solid
(329 mg, 322 MBq, 222.17 MBq/mmol) in 94 % yield. (Rt = 3.46 min from
HPLC analysis according to aforementioned condition), 1H NMR
(300 MHz, CDCl3): δ 8.06-7.99 (2H, m, ArH), 7.45-7.43 (3H, m, ArH), 3.87
6-(4-Nitrobenzoyl)-2-phenyl-[2-14C]-5,6,7,8-tetrahydropyrido
[4,3-d]pyrimidin-4(3H)-one 2d
The 2d was prepared according to the described procedure mentioned
earlier in the texts for 2a, by stirring 14 (60 mg, 58.76 MBq, 222.17 MBq/
mmol), 4-nitrobenzoyl chloride 15d (99 mg, 0.53 mmol), triethylamine
(111 μl) and DMAP (3 mg) in THF (30 ml) at room temperature during
12 h. The title compound 2d (67 mg, 39.01 MBq, 218.92 MBq/mmol) was
obtained in 66.4% yield. (Rt = 2.85 min from HPLC analysis according to
aforementioned condition), 1H NMR (400 MHz, DMSO, 298 K): δ8.35-8.15
(4H, m, ArH), 7.72 (2H, t, J = 9 Hz, ArH), 7.30 (3H, sb, ArH), 4.38 (1H, s,
CONCH2C), 4.07 (1H, s, CONCH2C), 3.88 (1H, t, J = 5.9 Hz, CONCH2CH2C),
3.46 (1H, t, J = 5.4 Hz, CONCH2CH2C), 2.68-2.54 (2H, m, CONCH2CH2C).
(2H, s, NHCH2C), 3.16 (2H, t, J = 5.8 Hz, NHCH2CH2C), 2.74 (2H, t,
+
J = 5.8 Hz, NHCH2CH2C), MS (70 eV): m/z = 230 [M + H]
.
6-Benzoyl-2-phenyl-[2-14C]-5,6,7,8-tetrahydropyrido[4,3-d]
pyrimidin-4(3H)-one 2a
A mixture of 14 (100 mg, 97.94 MBq, 222.17 MBq/mmol), benzoyl chloride 1H NMR (400 MHz, DMSO, 353 K): δ 8.35-8.05 (4H, m, ArH), 7.69 (2H,
15a (125 mg, 0.88 mmol), triethylamine (185 μl) and DMAP (5 mg) in THF
d, J = 8.7 Hz, ArH), 7.36-7.22 (3H, m, ArH), 4.24 (2H, sb, CONCH2C),
3.72 (2H, sb, CONCH2CH2C), 2.61 (2H, t, J = 10.9 Hz, CONCH2CH2C). MS
(50 mL) was stirred vigorously at room temperature for 12 h, then the
organic solvent evaporated under reduced pressure and the reaction (70 eV): m/z = 378 (M+).
mixture was quenched by addition of potassium hydroxide (50 mL, 1 M)
and extracted with ethyl acetate, the solvent and triethylamine
evaporated under reduced pressure to give the product 2a (115 mg,
Conclusion
76.49 MBq, 220.16 MBq/mmol) as white solid in 78.1%yield. (Rt = 2.75 min
from HPLC analysis according to the aforementioned condition), 1H NMR
(400 MHz, CDCl3, 298 K): δ 8.06 (2H, d, J = 6.9 Hz, ArH), 7.58-7.40 (8H, m,
ArH), 4.74 (1H, sb, CONCH2C), 4.48 (1H, sb, CONCH2C), 4.06 (1H, sb,
CONCH2CH2C), 3.70 (1H, sb, CONCH2CH2C) 2.91 (2H, sb, CONCH2CH2C).
In this paper, we have presented a convenient synthetic pathway
for labeling of a series of 6-acyl-2-phenyl-5,6,7,8-tetrahydropyrido
[4,3-d]pyrimidin-4(3H)-ones with carbon-14 in the 2-position
of pyrimidinone moiety by using benz[amidino-14C]amidine
1H NMR (400 MHz, CDCl3, 313 K): δ 8.06 (2H, d, J = 7.5 Hz, ArH), 7.57-7.38 hydrochloride as a key synthetic intermediate.
J. Label Compd. Radiopharm 2013
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O. K. Arjomandi et al.
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Acknowledgement
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The authors would like to express their acknowledgement to
Dr. Tri Le and Mr. Graham MacFarlane for 1H-NMR and the
high resolution mass spectroscopy of synthesized samples,
respectively. The authors are also grateful to Mr. Waleed
M. Hussein and Mr. Jedd Burn for their invaluable assistance.
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Conflict of Interest
The authors did not report any conflict of interest.
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