Synthesis of new TGX-221 analogs

Article abstract of DOI:10.5560/ZNB.2014-4081

TGX-221 is a potent phosphoinositide 3-kinase (PI3K)β inhibitor that has great therapeutic potential to treat prostate cancer. Chemical modification of TGX-221 at positions 2 and 9 was made. Five new TGX-221 analogs with different heterocyclic substituent

Full text of DOI:10.5560/ZNB.2014-4081

Synthesis of New TGX-221 Analogs
Chunjing Liua, Benyi Lib and Lester Mitscherc
a
Higuchi Biosciences Center, The University of Kansas, Lawrence, KS66045, USA
Department of Urology, The University of Kansas Medical Center, 3901 Rainbow Bouleward,
b
Kansas City, KS66160, USA
Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS66045, USA
c
Reprint requests to Dr. Chunjing Liu. E-mail: cjliu2@gmail.com
Z. Naturforsch. 2014, 69b, 817 – 822 / DOI: 10.5560/ZNB.2014-4081
Received March 31, 2014
TGX-221 is a potent phosphoinositide 3-kinase (PI3K)β inhibitor that has great therapeutic poten-
tial to treat prostate cancer. Chemical modification of TGX-221 at positions 2 and 9 was made. Five
new TGX-221 analogs with different heterocyclic substituents of morpholine, 1-methylpiperazine,
aniline, and thiazole-2-amine at positions 2 and 9 were synthesized. Parallel synthetic methods were
employed in SN2 replacement reactions at positions 2 and 9 of TGX-221.
Key words: TGX-221, Heterocyclic Substituent, Parallel Synthesis, SN2 Reaction, Microwave
Reaction
Introduction
TGX-221 {7-methyl-2-morpholino-9-(1-(phenyl-
amino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one} is
a potent phosphoinositide 3-kinase (PI3K)β in-
hibitor [1 – 4]. Its key chemical features include
a pyridopyrimidinone nucleus (I), a morpholinyl
substituent at position 2 (II) and a 1-phenylaminoethyl
moiety at position 9 (III) as shown in Fig. 1 [2].
Following on earlier reports of the PI3Kβ-inhibiting
ability of TGX-221, structural modifications on
TGX-221 were carried out. On the core structure of
TGX-221, replacement of the pyridopyrimidinone
Fig. 1. Chemical structure of TGX-221.
nucleus was made [5 – 8]. Two families of imid- new TGX-221 analogs were synthesized. Parallel syn-
azopyrimidinones and triazolopyrimidinones were thetic methods were employed in SN2 replacement re-
generated [5, 6]. Both series of the compounds were actions.
found to display high clearance in metabolism [7, 8].
Therefore two series of pyrazolopyrimidines and Results and Discussion
thiazolopyrimidinones were synthesized in an attempt
to improve clearance [7, 8]. On the side fragment of
TGX-221, a hydroxyethyl moiety was added to the from 2-amino-3-bromo-5-methylpyridine and mal-
aniline group at position 9 to produce analogs [9, 10]. onyl dichloride to generate the scaffold of 9-bromo-
The synthesis of TGX-221 analogs was initiated
In this paper chemical modifications of TGX-221 at 2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
positions 2 and 9 were undertaken. The group at po- (1). The hydroxyl group at position 2 of com-
sition 2 was replaced by 1-methylpiperazine and mor- pound 1 was substituted with morpholine or 1-me-
pholine. The moiety at position 9 was substituted with thylpiperazine. Subsequent replacement at position 9
thiazole-2-amine, 1-methylpiperazine and aniline. Five of the resulting compounds was made with 1-methyl-
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C. Liu et al. · Synthesis of New TGX-221 Analogs
piperazine, aniline or thiazole-2-amine. The synthetic
procedures are illustrated in Scheme 1.
We developed a synthetic procedure for TGX-221
analogs which is different from the previous synthetic
Compound 1 was formed through a nucleophilic cy- method for a series of pyridopyrimidinone in Jackson‘s
clization reaction by treatment of malonyl dichloride patent [1]. In our work, a microwave synthesizer was
with a solution of 2-amino-3-bromo-5-methylpyridine used to speed up the SN2 replacement reactions from
in dichloromethane (CH2Cl2). The hydroxyl group in compound 1 to compounds 2 and 5. We employed
compound 1 was substituted with morpholine and 1- two reaction steps to achieve the formation of the fi-
methylpiperazine through parallel synthesis to produce nal compounds via compounds 3 and 6, which made
compounds 2 and 5, respectively. The bromo group in methylation and SN2 replacement reactions to proceed
compound 2 was transformed to an acetyl group to af- easily. Our synthesis is facile, proceeds from commer-
ford compound 3 through an intramolecular Heck re- cially available materials, is easily scaled up, and very
action. Using the same method compound 6 was gener- manageable in relation to the synthesis of analogs.
ated from compound 5. The ketone group in compound Morpholine and 1-methylpiperazine groups at position
3 was reduced to the secondary alcohol by sodium 2 are installed by a nucleophilic displacement reaction.
borohydride (NaBH4) to afford compound 4. Com- 1-Methylpiperazine, aniline and thiazole-2-amine moi-
pound 7 was obtained in the same manner from com- eties at position 9 are installed by a SN2 reaction.
pound 6.
Parallel synthesis was employed for the SN2 reac-
Conclusion
tion to replace the secondary alcohol in compounds 4
and 7 with thiazole-2-amine, 1-methylpiperazine and
Chemical modification of TGX-221 was carried
aniline to yield five compounds of TGX-221 analogs,
out. 9-Bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]-
as shown in Scheme 1. Analogs TGX-221a and TGX-
pyrimidin-4-one was synthesized as the scaffold. Five
new TGX-221 analogs were synthesized. Parallel syn-
thetic methods were developed for SN2 replacement of
the hydroxyl group at positions 2 and 9 of the scaffold.
221b were generated from compound 4; analogs TGX-
221c, TGX-221d and TGX-221e were synthesized
from compound 7. The new TGX-221 analogs were
1
characterized by H and 13C NMR spectra and high-
resolution mass spectrometry.
Experimental Section
A series of pyridopyrimidinone was reported in
the patent by Jackson and co-workers [1]. In their
patent, pyridinyl and morpholino groups were used
as substituents at position 2 of the pyridopyrimidi-
none nucleus [1]. Some substituents, such as ben-
zyl, 4-hydroxyphenylamino, pyridin-4-yl-ethyl and
thiophene-2-yl-methyl were employed at position
9 [1]. The hydroxylethyl moiety was added to the
aniline group at position 9 of TGX-221 [9, 10]. In
our work, modifications of TGX-221 at positions 2
and 9 were undertaken. All analogs contain amino-
substituted heterocyclic moieties as substituents. 1-
Methylpiperazine and morpholine rings were used
as substituents at position 2. Thiazole-2-amine, 1-
methylpiperazine and aniline were selected as sub-
stituents at position 9. Combination of the substituents
generated five new TGX-221 analogs. Four analogs
with the 1-methylpiperazine group are particularly at-
tractive, since 1-methylpiperazine possesses a proto-
natable nitrogen atom which will enable the formation
of more water-soluble acid addition salts, such as hy-
drochlorides.
Reactions that required an inert atmosphere were car-
ried out under argon with flame-dried glassware. Column
chromatography was carried out by employing silica gel
(230 – 400 mesh). Thin-layer chromatography (TLC) was
performed on a silica gel w/uv254 uniplateTM. Parallel syn-
thesis was conducted on Mettler Toledo MiniBlock and
MiniBlock XT. Anhydrous organic solvents were purchased.
Melting points were determined using a Barnstead Inter-
national MET-TEMP® capillary Melting Point Apparatus,
Model 1001D-120VAC. IR spectra were measured with
a Perkin ElmerTM Spectrum One FT-IR spectrometer. 1H and
13C NMR spectra were recorded on a 400 MHz spectrometer
(400 and 100 MHz, respectively), or a 500 MHz spectrome-
ter (500 and 125.5 MHz, respectively). Abbreviations are as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, mul-
tiplet. High-resolution mass spectra (HRMS) were obtained
on a double-focusing mass spectrometer.
Procedures for the synthesis of intermediates 1–7
Compounds 1, 2, and 3 were synthesized following the
procedures given in refs. [1, 2].
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C. Liu et al. · Synthesis of New TGX-221 Analogs
819
Entry
R1H
R2H
Yield (%)
67
TGX-221a
TGX-221b
TGX-221c
TGX-221d
69
75
72
TGX-221e
55
Scheme 1. Synthesis of TGX-221 analogs.
9-Bromo-2-hydroxy-7-methyl-4H-pyrido[1,2-a]pyrimidin-
9-Bromo-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyr-
4-one (1)
imidin-4-one (2)
To a solution of 2-amino-3-bromo-5-methylpyridine
To a suspension of compound 1 (1.275 g, 5 mmol)
(2.25 g, 12 mmol) in CH2Cl2 (25 mL) was added malonyl in CH2Cl2 (30 mL) were added triethylamine (1.4 mL,
dichloride (1.25 mL, 12.5 mmol) at 0 ◦C. The mixture was 10 mmol) and methanesulfonyl chloride (0.54 mL, 7 mmol)
stirred at room temperature for 48 h. The yellow solid was at 0 ◦C. The mixture was stirred at room temperature for
collected by filtration, washed with CH2Cl2 (3 × 25 mL), 30 min. Morpholine (1.25 mL, 12.5 mmol) was added, and
and dried under reduced pressure. Compound 1 was ob- the mixture was heated in a microwave synthesizer at 90 ◦C
tained as a yellow solid with a yield of 88% (2.75 g). M. p. for 45 min. The mixture was diluted with water (30 mL) and
209 – 211 ◦C. – 1H NMR ([D6]DMSO, 400 MHz): δ = 8.74 extracted with CH2Cl2 (3 × 100 mL). The organic layer was
(s, 1H, 8-CH), 8.29 (s, 1H, 6-CH), 5.55 (s, 1H, 3-CH), 2.35 washed with water and dried over Na2SO4. After concen-
(s, 3H, 7-CH3) ppm. – HRMS ((+)-ESI): m/z = 254.9793 tration under reduced pressure, the dark-yellow residue was
(calcd. 254.9769 for C9H8BrN2O2, [M+H]+).
purified through a silica flash column using EtOAc/hexane
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C. Liu et al. · Synthesis of New TGX-221 Analogs
2 : 1 as an eluent to give compound 2 as a pale-yellow solid 100 MHz): δ = 160.21 (4-C=O), 158.69 (2-C), 147.45 (10-
with a yield of 45% (0.65 g). M. p. 198 – 199 ◦C. – 1H NMR C), 137.22 (8-C), 135.47 (6-C), 129.77 (9-C), 117.80 (7-
(CDCl3, 400 MHz): δ = 8.69 (s, 1H, 8-CH), 7.85 (s, 1H, 6- C), 81.39 (3-CH), 66.57 (O-CH2), 49.23 (O-CH), 44.63 (N-
CH), 5.59 (s, 1H, 3-CH), 3.82 (m, 4H, 2 O-CH2), 3.75 (m, CH2), 22.11 (CH3), 18.29 (7-CH3) ppm. – HRMS ((+)-
4H, 2 N-CH2), 2.33 (s, 3H, 7-CH3) ppm. – HRMS ((+)- ESI): m/z = 290.1513 (calcd. 290.1505 for C15H20N3NO3,
ESI): m/z = 324.0348 (calcd. 324.0348 for C13H15BrN3O2, [M+H]+).
[M+H]+).
9-Bromo-7-methyl-2-(4-methylpiperazin-1-yl)-4H-pyrido-
9-Acetyl-7-methyl-2-morpholino-4H-pyrido[1,2-a]pyr-
[1,2-a]pyrimidin-4-one (5)
imidin-4-one (3)
To a suspension of compound 2 (600 mg, 2.35 mmol)
Compound
was mixed with N,N-diisopropylethylamine (1.5 mL), 7.06 mmol), followed by methanesulfonyl chloride (0.4 mL,
butyl vinyl ether (1.6 mL) and
dichloro-1,10- 4.7 mmol) at 0 ◦C. The mixture was stirred at room temper-
2 (650 mg, 2 mmol) in DMF (10 mL) in CH2Cl2 (30 mL) was added triethylamine (1.5 mL,
bis(diphenylphosphino)ferrocene palladium(II) (70 mg, ature for 1 h. 1-Methylpiperazine (1.1 mL, 7.06 mmol) was
0.066 mmol) at room temperature under argon for 30 min added, and the mixture was heated in a microwave synthe-
until a homogeneous solution was formed. The solution sizer at 90 ◦C for 45 min. The mixture was diluted with water
was heated to 120 ◦C for 16 h. After cooling, the solution (30 mL) and extracted with CH2Cl2 (3 × 100 mL). The or-
was poured into 100 mL of 1 M HCl aqueous solution at ganic layer was washed with water and dried over Na2SO4.
0 ◦C. The mixture was stirred at room temperature overnight After concentration under reduced pressure, the dark-yellow
and extracted with CH2Cl2 (2 × 100 mL). The combined residue was purified through a silica flash column using 1%
organic phases were washed with water and dried over MeOH/CH2Cl2 as an eluent to give compound 5 as a pale-
Na2SO4. Removal of the solvent under reduced pressure yellow solid with a yield of 43% (0.45 g). M. p. 201 – 202 ◦C.
followed by purification of the resulting residue through – 1H NMR (CDCl3, 400 MHz): δ = 8.70 (s, 1H, 8-CH), 7.84
a silica flash column using EtOAc/hexanes 3 : 1 as an (s, 1H, 6-CH), 5.62 (s, 1H, 3-CH), 3.76 (m, 4H, 2 N-CH2),
eluent afforded compound 3 as a yellow solid with a yield 2.53 (s, 3H, N-CH3), 2.37 (s, 3H, 7-CH3), 2.33 (m, 4H, 2
of 60% (389 mg). M. p. 207 – 208 ◦C. – 1H NMR (CDCl3, N-CH2) ppm. – HRMS ((+)-ESI): m/z = 337.0637 (calcd.
400 MHz): δ = 8.88 (s, 1H, 8-CH), 7.86 (s, 1H, 6-CH), 5.65 337.0664 for C14H18BrN4O, [M+H]+).
(s, 1H, 3-CH), 3.84 – 3.79 (m, 4H, 2 O-CH2), 3.67 – 3.62 (m,
9-Acetyl-7-methyl-2-(4-methylpiperazin-1-yl)-4H-pyrido-
[1,2-a]pyrimidin-4-one (6)
4H, 2 N-CH2), 2.75 (s, 3H, CH3), 2.35 (s, 3H, 7-CH3) ppm.
–
13C NMR (CDCl3, 100 MHz): δ = 199.17 (11-C=O),
160.17 (4-C=O), 158.21 (2-C), 147.30 (10-C), 141.07 (8-C),
133.29 (6-C), 128.40 (9-C), 121.98 (7-C), 81.37 (3-C), 66.56
(O-CH2), 44.55 (N-CH2), 31.35 (CH3), 17.87 (7-CH3) ppm.
– HRMS ((+)-ESI): m/z = 288.1347 (calcd. 288.1348 for
C15H18N3O3, [M+H]+).
Compound 5 (328 mg, 1.0 mmol) in DMF (10 mL)
was mixed with N,N-diisopropylethylamine (0.8 mL),
butyl vinyl ether (0.4 mL, 4 mmol) and dichloro-1,10-
bis(diphenylphosphino)ferrocene palladium(II) (70 mg,
0.05 mmol) at room temperature under argon for 30 min
until a homogeneous solution was formed. The solution
was heated to 120 ◦C for 1 h in a microwave synthesizer.
After cooling, the solution was poured into 100 mL of
9-(1-Hydroxyethyl)-7-methyl-2-morpholino-4H-pyrido-
[1,2-a]pyrimidin-4-one (4)
Sodium borohydride (52.2 mg, 1.38 mmol) was added to a 1 M HCl aqueous solution at 0 ◦C. The mixture was
a suspension of compound 3 (198 mg, 0.69 mmol) in CH2Cl2 stirred at room temperature overnight and extracted with
(5 mL) and methanol (10 mL) at 0 ◦C. The reaction mixture CH2Cl2 (2 × 100 mL). The combined organic phases were
was stirred for 2 h at room temperature. Water was added and washed with water and dried over Na2SO4. Removal of the
the mixture extracted with chloroform (3 × 30 mL). The or- solvent under reduced pressure followed by purification of
ganic layer was washed with water and dried over Na2SO4. the resulting residue through a silica flash column using
After concentration under reduced pressure, the residue was 1% MeOH/CHCl3 as an eluent afforded compound 6
crystallized in EtOAc/hexane (1:1) to obtain compound 4 as a yellow solid with a yield of 60% (192 mg). M. p.
as a colorless solid with a yield of 75% (150 mg). M. p. 206 – 208 ◦C. – 1H NMR (CDCl3, 400 MHz): δ = 8.89 (s,
218 – 219 ◦C. – 1H NMR (CDCl3, 400 MHz): δ = 8.57 (s, 1H, 8-CH), 7.86 (s, 1H, 6-CH), 5.68 (s, 1H, 3-CH), 3.70
1H, 8-CH), 7.51 (d, J = 2 Hz, 1H, 6-CH), 5.58 (s, 1H, 3- (m, 4H, 2 N-CH2), 2.81 (m, 3H, N-CH3), 2.53 (s, 4H, 2
CH), 5.22 (q, J = 6 Hz, 1H, O-CH), 4.66 (s, 1H, OH), 3.80 N-CH2), 2.38 (s, 3H, 7-CH3), 2.37 (s, 3H, CH3) ppm. –
(m, 4H, 2 O-CH2), 3.59 (m, 4H, 2 N-CH2), 2.29 (s, 3H, 7- HRMS ((+)-ESI): m/z = 301.1654 (calcd. 301.1664 for
CH3), 1.57 (d, J = 6 Hz, 3H, CH3) ppm. – 13C NMR (CDCl3, C16H21N4O2, [M+H]+).
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821
2925 (CH3), 1728 (C=O), 1667 (C=C), 1641 (N=C) cm−1
9-(1-Hydroxyethyl)-7-methyl-2-(4-methylpiperazin-1-yl)-
4H-pyrido[1,2-a]pyrimidin-4-one (7)
.
–
1H NMR (CDCl3, 400 MHz): δ = 8.69 (s, 1H, 8-CH),
7.58 (s, 1H, 6-CH), 7.12 (d, J = 4.6 Hz, 1H, thiazole-CH),
6.75 (d, J = 7.3 Hz, 1H, NH), 6.48, (d, J = 4.6 Hz, 1H,
thiazole-CH), 5.66 (s, 1H, 3-CH), 5.27 (m, 1H, N-CH), 3.82
(t, J = 4.0 Hz, 4H, 2 O-CH2), 3.66 (t, J = 4.0 Hz, 4H, 2
N-CH2), 2.31 (s, 3H, CH3), 1.69 (d, J = 6.8 Hz, 3H, 7-CH3)
ppm. – 13C NMR (CDCl3, 100 MHz): δ = 169.31 (thiazole-
2-C), 160.13 (4-C=O), 158.87 (2-C), 147.47 (10-C), 139.02
(thiazole-5-C), 135.97 (thiazole-4-C), 135.39 (8-C), 124.38
(6-C), 122.24 (9-C), 107.06 (7-C), 81.49 (3-C), 66.52
(O-CH2), 52.62 (N-CH), 44.67 (N-CH2), 21.33 (CH3),
18.21 (7-CH3) ppm. – HRMS ((+)-ESI): m/z = 372.1442
(calcd. 372.1494 for C18H22N5O2S, [M+H]+).
Sodium borohydride (100 mg, 1.32 mmol) was added to
a suspension of compound 6 (200 mg, 0.66 mmol) in CH2Cl2
(5 mL) and methanol (10 mL) at 0 ◦C. The reaction mixture
was stirred for 3 h at room temperature. Water was added and
extracted with chloroform (3 × 30 mL). The organic layer
was washed with water and dried over Na2SO4. After con-
centration under reduced pressure, the residue was purified
by column chromatography with 2% MeOH/CHCl3 as an
eluent to obtain compound 7 as a colorless solid with a yield
of 78% (156 mg). M. p. 215 – 216 ◦C. – IR: ν = 3423 (HN),
2925 (CH3), 1667 (C=C), 1643 (N=C) cm−1. – 1H NMR
(CDCl3, 400 MHz): δ = 8.64 (s, 1H, 8-CH), 7.48 (s, 1H, 6-
CH), 5.64 (s, 1H, 3-CH), 5.20 (q, J = 6.0 Hz, 1H, 11-CH),
3.65 (t, J = 4.0 Hz, 4H, 2 N-CH2), 2.50 (t, J = 4.2 Hz, 4H, 2
N-CH2), 2.35 (s, 3H, N-CH3), 2.33 (s, 3H, 7-CH3), 1.62 (d,
J = 6.4 Hz, 3H, CH3) ppm. – 13C NMR (CDCl3, 100 MHz):
δ = 159.09 (4-C=O), 158.13 (2-C), 147.45 (10-C), 137.13
(8-C), 135.33 (6-C), 129.25 (9-C), 117.69 (7-C), 81.42 (3-
CH), 66.56 (O-CH), 54.66 (N-CH2), 46.11 (N-CH2), 44.22
(N-CH3), 22.22 (CH3), 18.29 (7-CH3) ppm. – HRMS ((+)-
ESI): m/z = 303.1910 (calcd. 303.1921 for C16H23N4O2,
[M+H]+).
7-Methyl-9-(1-(4-methylpiperazin-1-yl)ethyl)-2-morpho-
lino-4H-pyrido[1,2-a]pyrimidin-4-one (TGX-221b)
Compound
4
(35 mg, 0.121 mmol), triethylamine
(0.47 mL, 3.63 mmol), methanesulfonyl chloride (0.05 mL,
0.609 mmol), 1-methylpiperazine (242 mg, 2.42 mmol), and
CH2Cl2 (5 mL). TGX-221b: a pale-yellow solid. Yield:
69% (24 mg). M. p. 210 – 211 ◦C. – IR: ν = 3286 (HN),
2925 (CH3), 1666 (C=C), 1645 (N=C) cm−1. – 1H NMR
(CDCl3, 400 MHz): δ = 8.68 (s, 1H, 8-CH), 7.70 (s, 1H,
6-CH), 5.65 (s, 1H, 3-CH), 4.37 (m, 1H, 11-CH), 3.81 (t,
J = 4.0 Hz, 4H, O-CH2), 3.64 (t, J = 4.0 Hz, 4H, N-CH2),
2.59 (m, 8H, N-CH2), 2.43 (s, 3H, N-CH3), 2.30 (s, 3H,
CH3), 1.36 (d, J = 6.4 Hz, 3H, 3-CH3) ppm. – 13C NMR
(CDCl3, 100 MHz): δ = 160.23 (4-C=O), 158.17 (2-C),
146.68 (10-C), 137.22 (8-C), 123.39 (6-C), 122.24 (9-C),
113.28 (7-C), 81.49 (3-C), 66.52 (O-CH2), 54.62 (N-CH2),
49.23 (N-CH), 46.10 (N-CH2), 44.23 (N-CH2), 42.22
(N-CH3), 21.33 (CH3), 18.21 (7-CH3) ppm. – HRMS ((+)-
ESI): m/z = 372.2301 (calcd. 372.2400 for C20H30N5O2,
[M+H]+).
General procedure for the parallel synthesis of TGX-221a–e
Parallel synthesis was carried out in five reactors on
a Mettler Toledo MiniBlock for the SN2 reaction to re-
place the secondary alcohol in compounds 4 and 7 with
thiazole-2-amine, 1-methylpiperazine and aniline. Triethyl-
amine and methanesulfonyl chloride were added to the so-
lution of compounds 4 and 7 in CH2Cl2 at 0 ◦C, respec-
tively. The mixtures were stirred at room temperature for 1 h.
When the methylation reactions were completed, thiazole-2-
amine, 1-methylpiperazine and aniline were added to the ob-
tained solutions of methylated compounds 4 and 7, respec-
tively. After the mixtures were refluxed for 24 h, the solu-
tions were diluted with CH2Cl2 (30 mL). The organic layer
was washed with water and dried over Na2SO4. Removal
of the solvent under reduced pressure followed by purifica-
tion of the resulting residue through a silica flash column us-
ing MeOH/CH2Cl2 as an eluent produced the five analogs
TGX-221a–e.
7-Methyl-2-(4-methylpiperazin-1-yl)-9-(1-(phenylamino)-
ethyl)-4H-pyrido[1,2-a] pyrimidin-4-one (TGX-221c)
Compound 7 (150 mg, 0.5 mmol), triethylamine (0.4 mL,
3 mmol), methanesulfonyl chloride (0.2 mL, 2.2 mmol), ani-
line (1.0 mL, 10.0 mmol), and CH2Cl2 (20 mL). TGX-
221c: a pale-yellow solid. Yield: 75% (120 mg). M. p.
214 – 215 ◦C. – IR: ν = 3269 (HN), 2925 (CH3), 1728
(C=O), 1665 (C=C), 1645 (N=C) cm−1. – 1H NMR
(CDCl3, 400 MHz): δ = 8.67 (s, 1H, 8-CH), 7.60 (s, 1H,
6-CH), 7.15 (d, J = 6.6 Hz, 2H, aniline-CH), 6.68 (d, J =
7.3 Hz, 1H, aniline-CH), 6.48, (d, J = 6.6 Hz, 2H, aniline-
7-Methyl-2-morpholino-9-(1-(thiazol-2-ylamino)ethyl)-
4H-pyrido[1,2-a]pyrimidin-4-one (TGX-221a)
Compound
4
(35 mg, 0.121 mmol), triethylamine CH), 5.68 (s, 1H, 3-CH), 5.15 (m, 1H, 11-CH), 3.81 (m, 4H,
(0.47 mL, 3.63 mmol), methanesulfonyl chloride (0.05 mL, 2 N-CH2), 2.72 (m, 4H, 2 N-CH2), 2.41 (s, 3H, N-CH3), 2.28
0.609 mmol), thiazole-2-amine (242 mg, 2.42 mmol), and (s, 3H, 7-CH3), 1.59 (d, J = 6.0 Hz, 3H, CH3) ppm. – 13C
CH2Cl2 (5 mL). TGX-221a: a pale-yellow solid. Yield: NMR (CDCl3, 100 MHz): δ = 159.88 (4-C=O), 159.09 (2-
67% (22 mg). M. p. 212 – 213 ◦C. – IR: ν = 3274 (HN), C), 147.45 (10-C), 146.77 (Ar-C), 137.13 (8-C), 135.33 (Ar-
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C. Liu et al. · Synthesis of New TGX-221 Analogs
C), 129.25 (Ar-C), 123.79 (6-C), 122.20 (9-C), 117.69 (7-C), (7-C), 81.49 (3-C), 54.68 (N-CH2), 49.28 (N-CH), 46.19 (N-
113.24 (Ar-C), 81.42 (3-C), 54.66 (N-CH2), 49.28 (N-CH), CH2), 44.27 (N-CH3), 22.13 (CH3), 18.22 (7-CH3) ppm.
46.10 (N-CH2), 44.22 (N-CH3), 22.12 (CH3), 18.28 (7-CH3) – HRMS ((+)-ESI): m/z = 385.1497 (calcd. 385.1811 for
ppm. – HRMS ((+)-ESI): m/z = 378.1951 (calcd. 378.2224 C19H25N6OS, [M+H]+).
for C22H28N5O, [M+H]+).
7-Methyl-2-(4-methylpiperazin-1-yl)-9-(1-(4-methylpiper-
azin-1-yl)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one
(TGX-221e)
7-Methyl-2-(4-methylpiperazin-1-yl)-9-(1-(thiazol-
2-ylamino)ethyl)-4H-pyrido[1,2-a]pyrimidin-4-one
Compound 7 (80 mg, 0.27 mmol), triethylamine (1.0 mL,
8.1 mmol), methanesulfonyl chloride (0.1 mL, 1.35 mmol),
(TGX-221d)
Compound 7 (150 mg, 0.5 mmol), triethylamine (0.4 mL, 1-methylpiperazine (0.54 mL, 5.4 mmol), and CH2Cl2
3.0 mmol), methanesulfonyl chloride (0.2 mL, 2.2 mmol), 2- (10 mL). TGX-221e: a pale-yellow solid. Yield: 55%
aminothiazole (960 mg, 9.6 mmol), and CH2Cl2 (20 mL). (42 mg). M. p. 217 – 219 ◦C. – IR: ν = 1728 (C=O), 2930
TGX-221d: a pale-yellow solid. Yield: 72% (106 mg). M. p. (CH3), 1668 (C=C), 1640 (N=C) cm−1. – 1H NMR (CDCl3,
210 – 211 ◦C. – IR: ν = 3269 (HN), 1728 (C=O), 2925 400 MHz): δ = 8.67 (s, 1H, 8-CH), 7.73 (s, 1H, 6-CH), 5.67
(CH3), 1665 (C=C), 1645 (N=C) cm−1. – 1H NMR (CDCl3, (s, 1H, 3-CH), 4.39 (m, 1H, 11-CH), 3.75 (m, 4H, N-CH2),
400 MHz): δ = 8.71 (s, 1H, 8-CH), 7.61 (s, 1H, 6-CH), 7.12 2.96 (s, 3H, N-CH3), 2.52 (s, 3H, N-CH3), 2.37 (m, 12H,
(d, J = 6.6 Hz, 1H, thiazole-CH), 6.68 (t, J = 6.6 Hz, 1H, N-CH2), 2.31 (s, 3H, 7-CH3), 1.65 (m, 3H, CH3), ppm. –
thiazole-CH), 6.48, (s, 1H, NH), 5.68 (s, 1H, 3-CH), 5.15 13C NMR (CDCl3, 100 MHz): δ = 160.22 (4-C=O), 159.13
(m, 1H, N-CH), 3.81 (m, 4H, N-CH2), 3.17 (m, 4H, N- (2-C), 147.45 (10-C), 135.33 (8-C), 122.27 (6-C), 117.60
CH2), 2.64 (s, 3H, N-CH3), 2.36 (s, 3H, 7-CH3), 1.69 (d, (9-C), 113.28 (7-C), 81.32 (3-C), 56.69 (N-CH2), 54.67 (N-
J = 6.6 Hz, 3H, CH3) ppm. – 13C NMR (CDCl3, 100 MHz): CH2), 49.23 (N-CH), 46.18 (N-CH2), 44.69 (N-CH2), 42.23
δ = 168.52 (thiazole-2-C), 160.17 (4-C=O), 158.87 (2- (N-CH3), 22.11 (CH3), 18.30 (7-CH3) ppm. – HRMS ((+)-
C), 147.49 (10-C), 139.09 (thiazole-4-C), 135.97 (8-C), ESI): m/z = 385.2558 (calcd. 385.2716 for C21H33N6O,
135.39 (thiazole-5-C), 124.38 (6-C), 122.24 (9-C), 107.06 [M+H]+).
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