ORIGINAL ARTICLES
1
3
4
.1.2. Synthesis of compound 1
OCCH CO), 1.55 (s, 3H, 3-CH ), 1.46 (s, 3H, 3- CH ); C NMR (151 MHz): δ 174.7,
2 3 3
1
73.4, 173.2, 170.8, 74.2, 67.2, 64.5, 57.7, 47.8, 31.9, 27.8. ESI-HRMS m/z: calcd for
C H N Na O S [M–2Na] : 333.0387, found: 333.0383.
To a stirred solution of sulbactam (2.33 g, 10 mmol), pyridine (0.5 ml) and Boc O
2
-
(
4.36 g, 20 mmol) in acetonitrile (10 mL), NH HCO (2.37 g, 30 mmol) was added
11 12
2
2
8
4
3
and the mixture was stirred for 3 h. After the reaction was complete, excess NH HCO3
4
was removed by filtration and the filtrate was concentrated. The residue was purified
by flash column chromatography on silica gel with 20 : 1 dichloromethane/methanol
as eluent to give compound 1.
4
.1.6. Synthesis of compounds 6a–d
Compounds 6a–d were synthesized from 6-APA as described for the preparation of
compound 4.
3,3-Dimethyl-7-oxo-6-(3-(m-tolyl)ureido)-4-thia-1-azabicyclo[3.2.0] heptane-2-car-
boxylic acid (6a). White solid (59% yield), m.p. 213.7–214.3 °C. H NMR
(500 MHz): δ 13.39 (s, 1H, COOH), 8.76 (s, 1H, NH), 7.21 (s, 1H, NH), 7.17–7.08
3
,3-Dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxamide 4,4-dioxide
1
(
(
(
1). White solid (25% yield), m.p. 210.5–211.1 °C. H NMR (600 MHz): δ 7.72
s, 1H, CONH ), 7.64 (s, 1H, CONH ), 5.00 (s, 1H, 5-H), 4.00 (s, 1H, 2-H), 3.62–3.52
1
2
2
m, 1H, 6-H), 3.24 (d, J =2.0 Hz, 1H, 6-H), 1.45 (s, 3H, 3-CH ), 1.34 (s, 3H, 3-CH );
3
3
1
3
C NMR (151 MHz): δ 172.7, 168.8, 63.4, 62.9, 60.9, 37.8, 19.9, 18.8. ESI-HRMS
(m, 2H, arom), 6.84–6.76 (m, 2H, arom), 5.59–5.54 (m, 1H, 6-H), 4.29 (s, 1H, 5-H),
3.66 (s, 1H, 2-H), 2.25 (s, 3H, Ar-CH ), 1.62 (s, 3H, 3-CH ), 1.51 (s, 3H, 3-CH ).
-
13
m/z: calcd for C H N O S [M–H] : 231.0445, found: 231.0448.
C
8
12
2
4
3
3
3
NMR (151 MHz): δ 172.0, 170.9, 156.5, 138.7, 132.5, 129.1, 128.9, 127.5, 124.1,
3.4, 66.7, 63.2, 59.9, 27.3, 26.7, 21.3. ESI-HRMS m/z: calcd for C H N O S
7
1
6
19
3
4
-
4
.1.3. Synthesis of compounds 2a–c
[M–H] : 348.1023, found: 348.1021.
-(3-(3-Methoxyphenyl)ureido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]
6
Sulbactam (10 mmol) was added to a solution of triethylamine (2.6 mL) in anhydrous
DMF (10 mL), and the resulting mixture was stirred for 1 h at room temperature. After
the solid was dissolved, 3-bromo-N-tritylpropanamine or benzyl bromide (12 mmol)
in anhydrous DMF (10 mL) was added dropwise slowly and then the mixture was
stirred for 16 h at room temperature. After the reaction was completed, the mixture
was extracted with ethyl acetate (30 mL) and brine (30 mL). The organic layer was
dried over Na SO and evaporated. The residue was purified by flash column chro-
1
heptane-2-carboxylic acid (6b). White solid (62% yield), m.p. 206.2–206.8 °C. H
NMR (600 MHz): δ 11.62 (s, 1H, COOH), 9.11 (s, 1H, NH), 7.15 (s, 1H, NH), 7.13
(
1
d, J = 8.2 Hz, 1H, arom), 6.94 (d, J = 8.9 Hz, 1H, arom), 6.87 (dd, J = 8.0, 2.0 Hz,
H, arom), 6.51 (dd, J = 8.2, 2.5 Hz, 1H, arom), 5.48–5.45 (m, 2H, 5-H and 6-H), 4.02
1
3
(s, 1H, 2-H), 3.71 (s, 3H, Ar-OCH ), 1.59 (s, 3H, 3-CH ), 1.51 (s, 3H, 3-CH ); C
3
3
3
NMR (151 MHz): δ 175.4, 170.7, 160.1, 154.1, 141.5, 130.0, 110.5, 107.5, 104.0,
3.2, 68.2, 64.7, 59.0, 55.3, 32.5, 27.6. ESI-HRMS m/z: calcd for C H N O S
2
4
7
matography on silica gel with 3 : 1 petroleum ether/ethyl acetate as eluent to give the
target compounds 2a–c.
16 19
3
5
-
[M–H] : 364.0972, found: 364.0976.
6
-(3-(3-Cyanophenyl)ureido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]
2
-(Tritylamino)ethyl 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-car-
1
1
heptane-2-carboxylic acid (6c). White solid (61% yield), m.p. 213.5–213.8 °C.
NMR (600 MHz): δ 13.03 (s, 1H, COOH), 8.80 (s, 1H, NH), 7.98–7.91 (m, 1H, NH),
7
2
1
H
boxylate 4,4-dioxide (2a). Light yellow solid (52% yield), m.p. 56.8–57.3 °C.
H
NMR (600 MHz): δ 7.96 (s, 1H, NH), 7.47–7.35 (m, 6H, arom), 7.28 (t, J = 7.6
Hz, 6H, arom), 7.18 (t, J = 7.3 Hz, 3H, arom), 5.10 (dd, J = 4.6, 1.7 Hz, 1H, 5-H),
.83–7.61 (m, 4H, arom), 5.10–4.96 (m, 1H, 6-H), 4.34 (s, 1H, 5-H), 3.77 (s, 1H,
13
-H), 1.58 (s, 3H, 3-CH ), 1.22 (s, 3H, 3-CH ); C NMR (151 MHz): δ 171.6, 170.8,
4
.29–4.20 (m, 2H, COOCH ), 3.64 (dd, J = 16.5, 4.6 Hz, 1H, 2-H), 3.24 (dd, J =
3
3
2
55.7, 133.4, 131.8, 131.5, 130.8, 129.9, 118.4, 112.2, 73.3, 66.5, 63.4, 59.9, 27.3,
1
6.5, 1.7 Hz, 1H, 6-H), 2.83 (m, 1H, 6-H), 2.16–2.00 (m, 2H, CH CH NH), 1.85 (m,
2
2
-
13
26.7. ESI-HRMS m/z: calcd for C16
,3-Dimethyl-7-oxo-6-(3-(4-(trifluoromethyl)phenyl)ureido)-4-thia-1-azab-
icyclo[3.2.0]heptane-2-carboxylic acid (6d). White solid (61% yield), m.p.
H N O S [M–H] : 359.0819, found: 359.0825.
16 4 4
2
H, CH CH NH), 1.31 (s, 3H, 3-CH ), 1.23 (s, 3H, 3-CH ); C NMR (151 MHz): δ
2
2
3
3
3
1
3
72.5, 167.5, 146.3 (3), 128.9 (6), 128.2 (6), 126.6 (3), 70.7, 66.3, 62.7, 61.0, 42.7,
+
7.9, 20.1, 18.3 (3). ESI-HRMS m/z: calcd for C H N O S [M + H] : 533.2104,
30
32
2
5
1
2
(
13.1–213.6 °C. H NMR (600 MHz): δ 13.00 (s, 1H, COOH), 8.79 (s, 1H, NH), 7.87
d, J = 8.3 Hz, 2H, arom), 7.61 (d, J = 8.3 Hz, 2H, arom), 5.10–5.02 (m, 1H, 6-H),
4.39–4.32 (m, 1H, NH), 4.23 (s, 1H, 5-H), 3.79 (s, 1H, 2-H), 1.59 (s, 3H, 3-CH ),
.21 (s, 3H, 3-CH ); C NMR (151 MHz): δ 171.6, 170.8, 155.8, 136.2, 128.3, 127.1
found: 533.2107.
3
,4-Dichlorobenzyl 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-car-
1
3
boxylate 4,4- dioxide (2b). Light yellow solid (45% yield), m.p. 64.2–64.7 °C.
H
13
1
NMR (500 MHz): δ 7.58 (d, J = 8.0 Hz, 2H, arom), 7.52-7.45 (m, 1H, arom), 5.45
3
(2), 126.4, 125.3, 123.5, 73.4, 66.6, 63.3, 60.0, 27.3, 26.6. ESI-HRMS m/z: calcd for
(
d, J = 2.7 Hz, 2H, COOCH ), 5.20 (dd, J = 4.7, 1.7 Hz, 1H, 5-H), 4.51 (s, 1H, 2-H),
2
-
C H F N O S [M–H] : 402.0740, found: 402.0739.
3
3
1
.69 (dd, J = 16.5, 4.6 Hz, 1H, 6-H), 3.26 (dd, J = 16.5, 1.7 Hz, 1H, 6-H), 1.42 (s,
16 16
3
3
4
13
H, 3-CH ), 1.35 (s, 3H, 3-CH ); C NMR (151 MHz): δ 172.5, 167.0, 136.5, 132.6,
3
3
30.4, 129.3 (3), 62.9, 62.7, 62.6, 61.0, 37.8, 20.0, 18.0. ESI-HRMS m/z: calcd for
+
4.1.7. Synthesis of compounds 6e–g
C H Cl NO S [M + H] : 389.9980, found: 389.9949.
15
15
2
5
2
-Nitrobenzyl 3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptanes-2-carbox-
6-APA (10 mmol) was added to a solution of triethylamine (2.6 mL) in dichloro-
methane (20 mL), and the resulting mixture was stirred for 1 h at room temperature.
After the solid was dissolved, isocyanate (12 mmol) was added dropwise slowly
and then the mixture was stirred for 3 h at room temperature. After the reaction was
completed, the precipitate was collected by filtration and washed with dichloro-
methane (50 mL) to give the target compounds 6e–g.
1
ylate 4,4-dioxide (2c). Light yellow solid (46% yield), m.p. 72.1–72.9 °C. H NMR
500 MHz): δ 8.16–8.14 (m, 1H, arom), 7.90–7.76 (m, 2H, arom), 7.67 (m, 1H, arom),
.57 (s, 2H, COOCH ), 5.21 (dd, J = 4.6, 1.7 Hz, 1H, 5-H), 4.62 (s, 1H, 2-H), 3.70
(
5
2
(
dd, J = 16.5, 4.6 Hz, 1H, 6-H), 3.28 (dd, J = 16.5, 1.7 Hz, 1H, 6-H), 1.47 (s, 3H,
13
3
1
-CH ), 1.36 (s, 3H, 3-CH ); C NMR (151 MHz): δ 172.5, 167.0, 162.7, 148.1,
3 3
34.7, 130.8, 130.3, 125.4, 64.7, 62.8, 62.7, 61.0, 37.8, 20.0, 18.0. ESI-HRMS m/z:
Triethylammonium 6-(3-(tert-butyl)ureido)-3,3-dimethyl-7-oxo-4- thia-1-azabicyclo
+
1
calcd for C H N O S [M + H] : 367.0599, found: 367.0594.
[3.2.0]heptane-2-carboxylate (6e). White solid (65% yield), m.p. 205.4–205.9 °C. H
15
16
2
7
NMR (600 MHz): δ 6.31 (s, 1H, NH), 6.25 (s, 1H, NH), 5.40–5.37 (m, 2H, 5-H and
6
-H), 3.96 (s, 1H, 2-H), 2.90 (q, J = 7.3 Hz, 6H, (CH CH ) N), 1.55 (s, 3H, 3-CH ),
2
3
3
3
4
.1.4. Synthesis of compound 4
1.48 (s, 3H, 3-CH ), 1.22 (s, 9H, (CH ) C), 1.12 (t, J = 7.3 Hz, 9H, (CH CH ) N);
3 3 3 2 3 3
13
C NMR (151 MHz): δ 176.6, 170.8, 155.8, 73.2, 68.5, 64.6, 58.9, 49.7, 45.4 (3),
Compound 3 (Sandanayaka et al. 2003) (10 mmol) was added to a solution of triethyl-
amine (2.6 mL) in dichloromethane (20 mL), and the resulting mixture was stirred
for 1 h at room temperature. After the solid was dissolved, isocyanate (12 mmol) was
added dropwise slowly and then the mixture was stirred for 3 h at room temperature.
After the reaction was complete, the mixture was adjusted with 2 N HCl to reach the
pH 1.5–2.0 and washed with brine (30 mL). The organic layer was dried over Na SO
-
3
3
2.2, 29.5 (3), 27.7, 9.4 (3). ESI-HRMS m/z: calcd for C H N O S [M–Et NH] :
14.1180, found: 314.1179.
19 36
4
4
3
Triethylammonium 6-(3-ethylureido)-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]
1
heptane-2-carboxylate (6f). White solid (64% yield), m.p. 200.6–201.3 °C. H NMR
(500 MHz): δ 6.51–6.42 (m, 1H, NH), 6.35–6.33 (m, 1H, NH), 5.43–5.31 (m, 2H,
2
4
5-H and 6-H), 3.95 (s, 1H, 2-H), 3.06–2.97 (m, 2H, CH CH ), 2.91 (q, J = 7.3 Hz,
2
3
and evaporated. The residue was purified by flash column chromatography on silica
gel with 20 : 1 dichloromethane/methanol as eluent to give the target compound 4.
6
H, (CH CH ) N), 1.56 (s, 3H, 3-CH ), 1.48 (s, 3H, 3-CH ), 1.12 (t, J = 7.3 Hz, 9H,
2 3 3 3 3
13
2 3 3 2 3
(CH CH ) N), 0.99 (t, J = 7.2 Hz, 3H, CH CH ); C NMR (151 MHz): δ 176.2, 171.1,
6
-(3-(3-Chlorophenyl)ureido)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]
1
56.7, 73.4, 68.4, 64.5, 59.1, 45.3 (3), 34.5, 32.1, 27.7, 15.9, 9.2 (3). ESI-HRMS m/z:
-
heptane-2-carboxylic acid 4,4- dioxide (4). White solid (50% yield), m.p. 205.1–
calcd for C H N O S [M–Et NH] : 286.0867, found: 286.0868.
1
17 32
4
4
3
2
05.9 °C. H NMR (600 MHz): δ 13.82 (s, 1H, COOH), 9.50 (s, 1H, NH), 7.67–7.66
m, 1H, NH), 7.31–7.28 (m, 1H, arom), 7.20–7.18 (m, 1H, arom), 7.08–6.97 (m, 2H,
arom), 5.99 (dd, J = 10.3, 4.6 Hz, 1H, 6-H), 5.46 (d, J = 4.6 Hz, 1H, 5-H), 4.42
Triethylammonium 6-(3-Isopropylureido)-3,3-dimethyl-7-oxo-4-thia- 1-azabicyclo
(
[
3.2.0]heptane-2-carboxy late (6g). White solid (65% yield), m.p. 208.2–208.9 °C.
1
H NMR (600 MHz) δ 6.34 (d, J = 9.9 Hz, 1H, NH), 6.27 (d, J = 7.4 Hz, 1H, NH),
1
3
(
s, 1H, 2-H), 1.52 (s, 3H, 3-CH ), 1.40 (s, 3H, 3-CH ); C NMR (151 MHz): δ 176.3,
3
3
5.39–5.38 (m, 2H, 5-H and 6-H), 3.96 (s, 1H, 2-H), 3.66–3.63 (m, 1H, CH), 2.91
1
1
68.5, 153.8, 141.4, 133.7, 130.9, 122.2, 117.8, 116.8, 66.3, 64.6, 63.7, 57.2, 19.9,
7.6. ESI-HRMS m/z: calcd for C H ClN O S [M–H] : 400.0375, found: 400.0370.
(
q, J = 7.3 Hz, 6H, (CH CH ) N), 1.55 (s, 3H, 3-CH ), 1.48 (s, 3H, 3-CH ), 1.12
2 3 3 3 3
13
-
15
16
3
6
(t, J = 7.3 Hz, 9H, (CH CH ) N), 1.03 (m, 6H, (CH ) CH); C NMR (151 MHz): δ
2
3
3
3
2
1
76.3, 170.8, 156.0, 73.3, 68.5, 64.6, 59.1, 45.3 (3), 41.5, 32.3, 27.7, 23.5 (2), 9.4
-
(3). ESI-HRMS m/z: calcd for C H N O S [M–Et NH] : 300.1023, found: 300.1024.
18 34 4 4 3
4
.1.5. Synthesis of compound 5
Compound 3 (10 mmol) was added to a solution of N, O-bis(trimethylsilyl)acetamide
20 mmol) in ethyl acetate (20 mL), and the resulting mixture was stirred overnight at
(
4.1.8. Synthesis of compounds 7a–c
room temperature. After the solid was dissolved, the anhydride or Meldrum’s acid (11
mmol) was added and the mixture was stirred for an additional 3 h. After the reaction
Compounds 7a–c were synthesized from 6- APA as described for the preparation of
compound 5.
was completed, the mixture was adjusted with NaHCO to reach the pH 7.0–8.0 and
Sodium 6-(2-carboxylatoacetamido)-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]
3
1
extracted with water (20 mL). The combined aqueous layers were adjusted with 2 N
HCl to reach the pH 1.5–2.0 and extracted with ethyl acetate (20 mL). The organic
layer was washed with brine (30 mL), and added sodium 2-ethylhexanoate (22 mmol)
in ethyl acetate (10 mL). The precipitate formed was collected by filtration. The
product was purified by recrystallization in ethanol to give the target compound 5.
Sodium 6-(2-carboxylatoacetamido)-3,3-dimethyl-7-oxo-4-thia-1- azabicyclo[3.2.0]
heptane-2-carboxylate (7a). White solid (56% yield), m.p. 136.3–137.1 °C.
H
NMR (500 MHz): δ 10.33 (s, 1H, NH), 5.47 (dd, J = 8.8, 4.1 Hz, 1H, 6-H), 5.38
(d, J = 4.1 Hz, 1H, 5-H), 3.91 (s, 1H, 2-H), 2.87 (s, 2H, OCCH CO), 1.55 (s, 3H,
2
13
3-CH ), 1.46 (s, 3H, 3-CH ); C NMR (126 MHz): δ 175.1, 171.5, 170.8, 169.5,
3
3
74.1, 67.4, 64.8, 57.9, 44.0, 32.0, 27.9. ESI-HRMS m/z: calcd for C H N Na O S
1
1
12
2
2
6
-
[M–2Na] : 301.0499, found: 301.0501.
heptane-2-carboxylate 4,4-dioxide (5). White solid (54% yield), m.p. 213.1–213.6
Sodium 6-(3-carboxylatopropanamido)-3,3-dimethyl-7-oxo-4-thia- 1-azabicyclo
[3.2.0]heptane-2-carboxylate (7b). White solid (53% yield), m.p. 213.5–213.8 °C. H
1
1
°
C. H NMR (500 MHz): δ 10.17 (s, 1H, NH), 5.41 (s, 1H, 6-H), 5.36 (d, J = 4.1
Hz, 1H, 5-H), 3.86 (s, 1H, 2-H), 3.46–3.42 (m, 1H, OCCH CO), 2.81–2.74 (m, 1H,
NMR (500 MHz): δ 9.29 (s, 1H, NH), 5.32–5.28 (m, 2H, 5-H and 6-H), 3.83 (s, 1H,
2
4
36
Pharmazie 73 (2018)