A.L. Aguirre, et al.
Bioorganic&MedicinalChemistry28(2020)115439
yield = 206.6 mg; 98%).UIAA-II-068 (8c) (0.207 g, 0.639 mmol) and
triethylamine (0.230 mL, 1.636 mmol) was dissolved in 10 mL of an-
hydrous chloroform and cooled to 0 °C under argon atmosphere. 2,2,2-
trifluoroacetic anhydride (0.130 mL, 0.935 mmol) was added to the
cool solution, dropwise and the reaction mixture was then allowed to
warm to room temperature and consequently stir at room temperature
for 16 h. The reaction mixture was concentrated by rotary evaporation
and purified via silica gel flash chromatography utilizing a gradient
elution from 1:4 to 1:1 ethyl acetate:hexanes to afford pure UIAA-II-
069 (9c). 73% yield. 1H NMR (300 MHz, CDCl3) δ = 8.69 (t,
J = 8.69 Hz, 1H), 7.45 (bs, 1H), 4.32 (m, 2H), 4.03 (d, J = 1.72 Hz,
3H), 3.70 (d, J = 4.87 Hz, 2H), 3.39 (dd, 3.37, 6.88 Hz, 1H), 1.20 (q,
J = 6.68 Hz, 2H), 0.70 (d, J = 3.21, 2H). 19F NMR (282 MHz, CDCl3)
δ = −76.03 (s, 3F), −138.16 (dd, J = 9.29, 21.10 Hz, 1F), −140.84
reaction mixture was allowed to stir at room temperature for 14 h. The
reaction mixture was then concentrated by rotary evaporation. The
residue was then reconstituted in 10 mL of DCM and washed with sa-
turated NaHCO3 and the aqueous layer was back extracted with DCM
5X. All organic layers were pooled, filtered through Na2SO4, and con-
centrated by rotary evaporation. Purified crude product by silica gel
flash chromatography utilizing a gradient elution from 100% ethyl
acetate to 100% DCM, and finally to 10% MeOH in DCM (all eluents
contained 2–3% triethylamine) to afford pure UIAA-II-070 (11a). 84%
yield. 1H NMR (300 MHz, CDCl3) δ = 7.66 (d, J = 13.82 Hz, 1H), 6.63
(d, J = 7.38 Hz, 1H), 4.79 (bs, 1H), 4.12 (bs, 2H), 3.68 (m, 2H), 3.59
(m, 2H), 3.32 (m, 2H), 3.26 (m, 2H), 2.81 (m, 1H), 2.54 (m, 1H), 2.15
(dd, J = 6.78, 13.17 Hz, 1H), 1.82 (dd, J = 6.44, 14.34 Hz, 1H), 1.47
(s, 9H), 1.28 (s, 2H), 0.91 (m, 2H), 0.86 (m, 2H). 19F NMR (282 MHz,
(dd, J = 6.24, 21.25 Hz, 1F). HRMS (ESI) calculated for (M + Na+
)
CDCl3) δ = −134.14 (s, 1F). HRMS (ESI) calculated for (M + H+
)
430.0802,
found
430.0797.
Retention
time
(analytical
462.2511,
found
462.2535.
Retention
time
(analytical
HPLC) = 20.8 min.
HPLC) = 17.4 min.
4.5.4. Preparation of (S)-tert-butyl ((1-(1-cyclopropyl-6-fluoro-2,4-dioxo-
3-(2-(2,2,2-trifluoroacetamido)ethyl)-1,2,3,4-tetrahydroquinazolin-7-yl)
pyrrolidin-3-yl)methyl)carbamate (10a) (UIAA-II-066)
4.5.7. Preparation of (S)-tert-butyl ((1-(3-(2-aminoethyl)-1-cyclopropyl-6-
fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-
3-yl)methyl)carbamate (11c) (UIAA-II-074)
To a stirring solution of UIAA-II-063 (9a) (0.080 g, 0.212 mmol)
and (R)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate (0.111 g,
0.554 mmol) in 1.0 mL of anhydrous DMSO, triethylamine (0.090 mL,
0.640 mmol) was added, dropwise, at room temperature and under
argon atmosphere. The reaction mixture was then heated to 55 °C for
16 h. The product was then precipitated out with cold nanopure water
and filtered. The crude product was then purified via silica gel flash
chromatography utilizing an isocratic elution consisting of only ethyl
acetate to afford pure UIAA-II-066 (10a). 91% yield. 1H NMR
(300 MHz, CDCl3) δ = 7.83 (bs, 1H), 7.65 (d, J = 13.75 Hz, 1H), 6.64
(d, J = 7.31 Hz, 1H), 4.78 (bs, 1H), 4.34 (dd, J = 3.82, 6.27 Hz, 2H),
3.67 (m, 4H), 3.36 (t, J = 7.21 Hz, 1H), 3.26 (m, 2H), 2.83 (m, 1H),
2.55 (m, 1H), 2.16 (dd, J = 5.16, 11.56 Hz, 1H), 1.81 (dt, J = 7.58,
19.77 Hz, 1H), 1.71 (s, 9H), 1.29 (m, 2H), 0.92 (m, 2H). 19F NMR
(282 MHz, CDCl3) δ = −76.02 (s, 3F), −133.54 (s, 1F). HRMS (ESI)
calculated for (M + Na+) 580.2159, found 580.2228. Retention time
(analytical HPLC) = 21.8 min.
UIAA-II-072 (10c) (0.284 g, 0.483 mmol) was dissolved in 15 mL of
a 6 N NH4OH MeOH solution at room temperature. The resulting re-
action mixture was allowed to stir at room temperature for 14 h. The
reaction mixture was then concentrated by rotary evaporation. The
residue was then reconstituted in 10 mL of DCM and washed with sa-
turated NaHCO3 and the aqueous layer was back extracted with DCM
5X. All organic layers were pooled, filtered through Na2SO4, and con-
centrated by rotary evaporation. Purified crude product by silica gel
flash chromatography utilizing a gradient elution from 100% ethyl
acetate to 100% DCM, and finally to 10% MeOH in DCM (all eluents
contained 2–3% triethylamine) to afford pure UIAA-II-074 (11c). 98%
yield. 1H NMR (300 MHz, CDCl3) δ = 7.47 (d, J = 13.55 Hz, 1H), 4.74
(bs, 1H), 4.13 (bs, 2H), 3.66 (m, 3H), 3.51 (s, 3H), 3.45 (m, 1H), 3.33
(m, 2H), 3.27 (dd, J = 6.74, 13.08 Hz, 2H), 3.03 (m, 2H), 2.46 (m, 2H),
2.10 (dd, J = 7.97, 14.26 Hz, 2H), 1.70 (dd, J = 7.97, 11.87 Hz, 2H),
1.47 (s, 9H), 1.08 (m, 2H), 0.62 (m, 2H). 19F NMR (282 MHz, CDCl3)
δ = −127.04 (s, 1F). HRMS (ESI) calculated for (M + H+) 492.2617,
found 492.2594. Retention time (analytical HPLC) = 18.5 min.
4.5.5. Preparation of (S)-tert-butyl ((1-(1-cyclopropyl-6-fluoro-8-methoxy-
2,4-dioxo-3-(2-(2,2,2-trifluoroacetamido)ethyl)-1,2,3,4-
4.5.8. Preparation of (S)-tert-butyl ((1-(1-cyclopropyl-6-fluoro-3-(2-bis-
(tert-butylguanidine-carbamate)ethyl)-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl)methyl)carbamate (10c) (UIAA-
II-072)
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl)methyl)carbamate (12a) (UIAA-
II-077)
To a stirring solution of UIAA-II-069 (9c) (0.190 g, 0.466 mmol)
and (R)-tert-butyl (pyrrolidin-3-ylmethyl)carbamate (0.232 g,
1.158 mmol) in 2.0 mL of anhydrous DMSO, triethylamine (0.197 mL,
1.401 mmol) was added, dropwise, at room temperature and under
argon atmosphere. The reaction mixture was then heated to 55 °C for
4 days. The product was then precipitated out with cold nanopure
water and filtered. The crude product was then purified via silica gel
flash chromatography utilizing an isocratic elution consisting of only
ethyl acetate to afford pure UIAA-II-072 (10c). Quantitative yield. 1H
NMR (300 MHz, CDCl3) δ = 7.78 (bs, 1H), 7.49 (d, J = 13.53 Hz, 1H),
4.72 (bs, 1H), 4.32 (d, J = 3.82 Hz, 2H), 3.66 (m, 3H), 3.51 (d,
J = 7.05 Hz, 3H), 3.46 (s, 1H), 3.33 (m, 2H), 3.26 (m, 2H), 2.47 (m,
1H), 2.11 (dd, J = 8.09, 14.10 Hz), 1.71 (dd, 8.12, 12.04 Hz, 2H), 1.47
(s, 9H), 0.90 (m, 2H), 0.63 (m, 2H). 19F NMR (282 MHz, CDCl3)
δ = −76.01 (s, 3F), −126.41 (d, J = 12.14 Hz, 1F). HRMS (ESI)
calculated for (M + H+) 588.2440, found 588.2861. Retention time
(analytical HPLC) = 22.2 min.
UIAA-II-070 (11a) (0.0745 g, 0.161 mmol) and N,N’-bis-Boc-gua-
nylpyrazole (0.0767 g, 0.247 mmol) was dissolved in 3 mL of chloro-
form (anhydrous) at room temperature and under argon atmosphere.
The reaction mixture was then heated to 40 °C for 72 h. The reaction
mixture was then cooled to room temperature and concentrated by
rotary evaporation. The resulting residue was then purified via flash
chromatography, utilizing a gradient elution from 0 to 50% ethyl
acetate in cyclohexane to afford pure UIAA-II-077 (12a). 52% yield. 1H
NMR (300 MHz, CDCl3) δ = 11.44 (bs, 1H), 8.49 (bs, 1H), 7.65 (d,
J = 13.63 Hz, 1H), 6.62 (d, J = 7.39 Hz, 1H), 4.8 (bs, 1H), 4.28 (dd,
J = 9.41, 15.19 Hz, 2H), 3.74 (dd, J = 5.48, 10.81 Hz, 2H), 3.58 (d,
J = 7.48 Hz, 2H), 3.32 (dd, J = 6.97, 14.55 Hz, 2H), 3.24 (m, 2H), 2.79
(m, 1H), 2.53 (m, 1H), 2.14 (dd, J = 7.87, 12.40 Hz, 1H), 1.48 (s, 9H),
1.46 (s, 18H), 0.95 (m, 2H), 0.86 (m, 2H). 19F NMR (282 MHz, CDCl3)
δ = −134.31 (s, 1F). HRMS (ESI) calculated for (M + H+) 704.3778,
found 704.3807. Retention time (analytical HPLC) = 29.6 min.
4.5.6. Preparation of (S)-tert-butyl ((1-(3-(2-aminoethyl)-1-cyclopropyl-6-
fluoro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl)methyl)
carbamate (11a) (UIAA-II-070)
4.5.9. Preparation of (S)-tert-butyl ((1-(1-cyclopropyl-6-fluoro-3-(2-bis-
(tert-butylguanidine-carbamate)ethyl)-8-methyl-2,4-dioxo-1,2,3,4-
tetrahydroquinazolin-7-yl)pyrrolidin-3-yl)methyl)carbamate (12b) (UIAA-
II-081)
UIAA-II-066 (10a) (0.108 g, 0.194 mmol) was dissolved in 6 mL of
a 6 N NH4OH MeOH solution at room temperature. The resulting
To a stirring solution of UIAA-II-065 (9b) (0.118 g, 0.301 mmol)
12