P. Borowiecki et al.
Molecular Catalysis 504 (2021) 111451
3
1
364, 3112, 1697, 1656, 1601, 1548, 1449, 1410, 1318, 1283, 1232,
185, 1159, 1132, 1080, 1060, 1000, 978, 936, 882, 841, 812, 764, 752;
VIS: λmax = 274 nm (EtOH); HPLC [n-hexane-2-PrOH (78:22, v/v); f =
◦
1.0 mL/min; λ = 273 nm; T = 25 C (Chiralpak AD-H)]: t
isomer) and 12.99 min (R-isomer).
R
=10.12 (S-
+
+
MS (ESI-TOF) m/z: [M+H] Calcd for C13
H
21
N
4
O
3
m/z: 281.1609,
+
+
Found 281.1387, [2M+H]
C
26
H
41
N
8
O
6
m/z: 561.3144, Found
ꢀ
–
5
2
3
61.3820; MS (ESI-TOF) m/z: [Mꢀ H] Calcd for C13
H
19
N
4
O
O
3
–
3
m/z:
2.3.3. 6-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)
hexan-2-yl decanoate (lisofylline decanoate, rac-3c)
–
79.1462, Not Found, [M+2Na–H] Calcd for C13
H
19
N
4
Na
2
m/z:
–
–
25.1258, Found 325.1687, [2M+2Na–H] Calcd for C26
H
39
N
8
Na
2
O
6
Yield 36 % (56 mg); yellowish oil; R
f
[CHCl
3
/MeOH (95:5, v/v)]
+
1
m/z: 605.2793, Found 605.3885; FTMS (ESI-TOF) m/z: [M+H] Calcd
0.47; H NMR (500 MHz, CDCl
3
): δ 0.82–0.92 (m, 3 H), 1.17–1.21 (m, 3
+
for C13
H
21
N
4
O
3
m/z: 281.1609, Found 281.1605; GC [240–260 (10
H), 1.23–1.31 (m, 12 H), 1.32–1.47 (m, 2 H), 1.51–1.70 (m, 6 H),
2.21–2.29 (m, 2 H), 3.57 (s, 3 H), 3.96–4.02 (m, 5 H), 4.89 (dd, J = 12.8,
◦
C/min)]: t
R
=11.99 min or GC [260 (const.)]: t = 8.77 min; UV/VIS:
R
λ
max = 273 nm (EtOH); HPLC [n-hexane-EtOH (90:10, v/v); f = 0.3
6.2 Hz, 1 H), 7.50 (s, 1 H); 13C NMR (126 MHz, CDCl
): δ 14.2, 20.1,
3
◦
mL/min; λ = 273 nm; T = 25 C (Chiralcel OD-H)]: t
R
= 112.23
22.8, 23.0, 25.2, 28.0, 29.3, 29.4, 29.6, 29.8, 32.0, 33.7, 34.9, 35.8,
(
R-isomer) and 119.04 min (S-isomer); HPLC [n-hexane-2-PrOH (78:22,
41.3, 44.8, 70.7, 107.8, 141.5, 148.9, 151.6, 155.4, 173.7; IR (nujol):
◦
v/v); f = 1.0 mL/min; λ = 273 nm; T = 25 C (Chiralpak AD-H)]: t
R
=
ν
max = 3513, 3116, 1706, 1664, 1604, 1548, 1490, 1414, 1360, 1328,
+
3
0.59 (R-isomer) and 33.37 min (S-isomer).
1280, 1239, 1181, 1127, 1111, 764, 752; FTMS (ESI-TOF) m/z: [M+H]
+
Calcd for C23
H
39
N
4
O
4
m/z: 435.29658, Found 435.29607; GC [260
2
.3. General procedure for the synthesis of racemic esters of lisofylline
(const.)]: Not Found; UV/VIS: λmax = 273 nm (EtOH); HPLC [n-hexane-
◦
rac-3a–d
2-PrOH (78:22, v/v); f = 1.0 mL/min; λ = 273 nm; T = 25 C (Chiralpak
AD-H)]: t
R
=7.75 (S-isomer) and 9.70 min (R-isomer).
To a solution of lisofylline (rac-2, 100 mg, 0.36 mmol) in CH
2
Cl
2
(5
mL), Et
3
N (54 mg, 0.54 mmol, 75
μ
L, 1.5 equiv) and DMAP (10 mg) were
2.3.4. 6-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)
hexan-2-yl hexadecanoate (lisofylline palmitate, rac-3d)
◦
added. The mixture was cooled to 0–5 C in ice bath. Next, one of the
appropriate acyl chlorides (1.5 equiv) was dissolved in dry CH
Cl
2
(2.5
Yield 48 % (89 mg); yellowish oil (rac-3d); white solid [(R)-(+)-3d]:
2
◦
1
mL) and added dropwise to the reaction mixture by using syringe. Af-
terwards, the resulting mixture was continuously stirred at cooling bath
temperature and left to warm at room temperature for next 24 h. The
Mp 39–42 C (CHCl
3 f 3
/MeOH); R [CHCl /MeOH (95:5, v/v)] 0.49; H
NMR (500 MHz, CDCl
3
): δ 0.83–0.90 (m, 3 H), 1.19 (d, J = 6.1 Hz, 3 H),
1.21–1.32 (m, 24 H), 1.32–1.46 (m, 2 H), 1.49–1.69 (m, 6 H), 2.24 (t, J =
7.6 Hz, 2 H), 3.56 (s, 3 H), 3.92–4.03 (m, 5 H), 4.88 (d, J = 6.6 Hz, 1 H),
crude mixture was diluted with CH
with H O (20 mL), the water phase was extracted with CH
mL), and the combined organic layer was washed with saturated
aqueous solution of NaHCO (40 mL), brine (40 mL), and dried over
anhydrous MgSO . After filtration of the drying agent under suction and
2
Cl
2
(10 mL), subsequently quenched
7.49 (s, 1 H); 13C NMR (126 MHz, CDCl
): δ 14.2, 20.1, 22.8, 23.0, 25.2,
3
2
2
Cl
2
(3 × 10
28.0, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8 (6C), 32.0, 33.7, 34.9, 35.8, 41.3,
70.7, 107.8, 141.5, 148.9, 151.6, 155.4, 173.7; IR (nujol):
ν
max = 3405,
3
+
1735, 1712, 1668, 1554, 1538; FTMS (ESI-TOF) m/z: [M+H] Calcd for
4
+
subsequent evaporation of the residuals of solvent under reduced pres-
sure the crude product was purified by column chromatography on silica
C
29
H
51
N
4
O
4
m/z: 519.39048, Found 519.38994; GC [260 (const.)]: Not
Found; UV/VIS: λmax = 273 nm (EtOH); HPLC [n-hexane-2-PrOH (78:22,
◦
gel, using gradient of CHCl
3
/MeOH (99:1, 98:2, 95:5 v/v) mixture, thus
v/v); f = 1.0 mL/min; λ = 273 nm; T = 25 C (Chiralpak AD-H)]: t
(S-isomer) and 7.06 min (R-isomer).
R
=5.86
obtaining desired esters rac-3a–d.
2
.3.1. 6-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)
hexan-2-yl acetate (lisofylline acetate, rac-3a)
2.4. General procedure for the synthesis of racemic lisofylline levulinate
(rac-3e)
Yield 40 % (46 mg); colorless oil (rac-3a); white solid [(R)-(+)-3a]:
◦
3 f 3
/MeOH); R [CHCl H
/MeOH (95:5, v/v)] 0.51; 1
Mp 82–85 C (CHCl
NMR (500 MHz, CDCl
3
): δ 1.20 (d, J = 5.9 Hz, 3 H), 1.30–1.47 (m, 2 H),
To a solution of lisofylline (rac-2, 100 mg, 0.36 mmol), levulinic acid
1
4
2
1
1
1
.49–1.69 (m, 4 H), 2.01 (s, 3 H), 3.56 (s, 3 H), 3.92–4.06 (m, 5 H),
.79–4.97 (m, 1 H), 7.49 (s, 1 H); C NMR (126 MHz, CDCl
1.5, 22.9, 28.0, 29.8, 33.7, 35.7, 41.3, 71.0, 110.2, 141.5, 148.9, 151.6,
55.4, 170.9; IR (nujol):
(83 mg, 0.72 mmol), and DMAP (15 mg) in CH
2
Cl
2
(5 mL), EDCI hy-
1
3
◦
3
): δ 20.0,
drochloride (150 mg, 0.78 mmol) was added in one portion at 0–5 C.
Next, the reaction mixture was slowly warmed to room temperature and
stirred for additional 48 h. After this time, content of the flask was
νmax = 3507, 3112, 2948, 2867, 1729, 1706,
657, 1604, 1552, 1487, 1456, 1417, 1372, 1321, 1248, 1191, 1130,
diluted with CH
aqueous layer was back-extracted with CH
bined organic phases were washed again with H
(20 mL), dried over anhydrous MgSO , filtered, and the permeate was
concentrated in vacuo. The residue was purified by silica gel column
chromatography using gradient of mixture of CHCl /MeOH (100:0,
98:2, 95:5, v/v) to provide the corresponding lisofylline levulinate (rac-
3e, 53 mg, 0.14 mmol, 40 %) as a colorless oil. R [CHCl /MeOH (95:5,
v/v)] 0.44; 1H NMR (500 MHz, CDCl
2
Cl
2
(5 mL), washed with H
2
O (4 × 10 mL), and the
(3 × 15 mL). The com-
O (20 mL) and brine
+
086, 1019, 952, 764; MS (ESI-TOF) m/z: [M+H] Calcd for
2
Cl
2
+
C
15
H
23
N
4
O
4
m/z: 323.1714, Found 323.1614; FTMS (ESI-TOF) m/z:
2
+
+
[
[
M+H] Calcd for C15
H
23
N
4
O
4
m/z: 323.17138, Found 323.17089; GC
4
◦
240–260 (10 C/min)]: t
R
= 11.99 min or GC [260 (const.)]: t = 8.77
R
min; UV/VIS: λmax = 273 nm (EtOH); HPLC [n-hexane-2-PrOH (78:22,
3
◦
v/v); f = 1.0 mL/min; λ = 273 nm; T = 25 C (Chiralpak AD-H)]: t
R
=
1
3.98 (S-isomer) and 17.26 min (R-isomer).
f
3
3
): δ 1.19 (d, J = 6.4 Hz, 3 H),
2
.3.2. 6-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)
1.28–1.45 (m, 2 H), 1.49–1.57 (m, 1 H), 1.58–1.69 (m, 3 H), 2.17 (s, 3 H)
2.50–2.56 (m, 2 H), 2.72 (td, J = 6.6, 3.4 Hz, 2 H), 3.56 (s, 3 H),
hexan-2-yl butanoate (lisofylline butanoate, rac-3b)
Yield 43 % (54 mg); colorless oil; R [CHCl /MeOH (95:5, v/v)] 0.45;
H NMR (500 MHz, CDCl
1
3
f
3
3.94–4.02 (m, 5 H), 4.82–4.93 (m, 1 H), 7.49 (d, J = 0.5 Hz, 1 H);
C
1
3
): δ 0.92 (t, J = 7.5 Hz, 3 H), 1.18 (d, J = 6.4
NMR (126 MHz, CDCl
38.2, 41.3, 71.4, 107.8, 110.2, 141.5, 148.9, 151.6, 155.4, 172.5, 206.8;
IR (nujol):
max = 3513, 3109, 2940, 2867, 1706, 1656, 1601, 1552,
3
): δ 20.0, 22.9, 28.0, 28.5, 29.8, 30.0, 33.7, 35.7,
Hz, 3 H), 1.30–1.46 (m, 2 H), 1.49–1.71 (m, 6 H), 2.23 (t, J = 7.5 Hz, 2
H), 3.55 (s, 3 H), 3.93–4.02 (m, 5 H), 4.88 (dd, J = 12.7, 6.1 Hz, 1 H),
ν
7
2
1
1
8
.49 (s, 1 H); 13C NMR (126 MHz, CDCl
3
): δ 13.8, 18.7, 20.1, 23.0, 28.0,
1464, 1360, 1229, 1188, 1159, 1124, 1083, 1019, 978, 940, 847, 812,
+
+
5
m/
9.8, 33.7, 35.8, 36.7, 41.3, 70.7, 107.8, 141.5, 148.9, 151.6, 155.4,
764, 746, 656; FTMS (ESI-TOF) m/z: [M+H] Calcd for C18
H
27
4
N O
73.5; IR (nujol):
ν
max = 3113, 2960, 2867, 1709, 1656, 1605, 1548,
z: 379.19760, Found 379.19692; GC [260 (const.)]: t
R
= 39.88 min; UV/
485, 1453, 1352, 1241, 1187, 1140, 1089, 1007, 982, 950, 881, 849,
VIS: λmax = 274 nm (EtOH); HPLC [n-hexane-2-PrOH (78:22, v/v); f =
02, 760, 653; FTMS (ESI-TOF) m/z: [M+H]+ Calcd for C17
H
N
4
O
4
m/
1.0 mL/min; λ = 273 nm; T = 25 C (Chiralpak AD-H)]: t
isomer) and 29.28 min (R-isomer).
◦
=22.98 (S-
27
R
z: 351.20268, Found 351.20213; GC [260 (const.)]: t
R
= 15.84 min; UV/
4