38
L. Ribeiro et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 32–40
Synthesis of 3b
N-(Chloromethyloxycarbonyl)proline diethylamide 7c
To a solution of 6c (275.8 mg in 5 mL CH2Cl2) was added chloro-
methyl chloroformate (208.9 mg in 5 mL CH2Cl2) yielding an oil
N-[N-(tert-Butoxycarbonyl)phenylalanyl]-N,N-
diethylamine 5b
1
(170.8 mg, 0.7 mmol). Yield: 40%. H-NMR: 1.12 (3H, t, J = 7.0,
CH3CH2), 1.23 (3H, t, J = 7.0, CH3CH2), 1.71–1.78 (1H, m, CH Pro),
1.85–2.05 (2H, m, CH2 Pro), 2.25–2.32 (1H, m, CH Pro), 3.27–3.44
(6H, m, CH3CH2 and NCH2 Pro), 4.32 (1H, brs, a-CH), 5.95, 5.98 and
6.06 (2H, 36overlapping doublets, J = 5.6, OCH2Cl).
Prepared from BocPheOSuc 4a (906.0, mg, 2.5 mmol) and dieth-
ylamine (182.8 mg, 2.5 mmol). Yield: 78% (624.9 mg, 1.9 mmol).
1H-NMR: 0.99 (3H, t, J = 7.0, CH3CH2), 1.10 (3H, t, J = 7.0, CH3CH2),
1.40 (9H, s, (CH3)3), 2.92–3.14 (5H, m, NCH2 and CH2Ph), 3.5 (1H,
dq, J = 14.0, 6.3, NCH) 4.73 (1H, apparent q, J = 7.5, a-CH), 5.37 (1H,
d, J = 7.5, NH), 7.16–7.24 (5H, m, ArH).
Compound 3c
Prepared from 7c (170.8 mg, 0.7 mmol) and flufenamic acid
(sodium salt) (182.8 mg, 0.7 mmol). Yield: 37% (122.0 mg,
N-(Phenylalanyl)-N,N-diethylamine 6b
1
0.2 mmol). Oil. mmax/cm–1: 3325, 1717, 1687, 1644. H-NMR: 1.01,
1
Yield: 95% (407.6 mg,1.9 mmol). H-NMR: 1.10 (3H, t, J = 7.0,
1.13, 1.21 and 1.28 (6H, 46t, J = 7.0, CH3CH2), 1.85–1.92 (2H, m,
CH2 Pro), 2.05–2.24 (2H, m, CH2 Pro), 3.11–3.74 (6H, m, CH3CH2
and NCH2 Pro), 4.55 and 4.66 (1H, 26dd, J = 8.2, 3.6, a-CH), 5.92,
5.93, 5.98, and 6.08 (2H, 46d, J = 5.8, OCH2O), 6.79–6.84 (1H, m,
ArH), 7.25–7.49 (6H, m, ArH), 8.03-8.06 (1H, m, ArH), 9.42, 9.46
(1H, 26s, NH). EIMS (%): 508.1 (91) [M+]. Calculated for
C25H28N3O5F3 : C, 59.2, H, 5.7, N, 8.3%. Found: C, 59.0, H, 5.7, N,
8.3%.
CH3CH2), 1.15 (3H, t, J = 7.0, CH3CH2), 2.60 (2H, s, NH2), 2.97 (2H,
m, CH3CH2), 3.12 (1H, m, CHHPh), 3.26 (2H, m, CH3CH2), 3.52 (1H,
m, CHHPh), 4.10 (1H, dd, J = 8.7, 7.0, a-CH), 7.20–7.40 (5H, m,
ArH).
N-[2-(Chloromethyloxycarbonylamino)-3-
phenylpropanoyl]-N,N-diethylamine 7b
To a solution of 6b (407.6 mg in 5 mL CH2Cl2) was added chloro-
methyl chloroformate (1.9 mmol, 238.5 mg in 5 mL CH2Cl2)
yielding an oil (309.7 mg, 1.0 mmol). Yield: 54%. H-NMR: 1.01
Synthesis of 3d
1
(3H, t, J = 7.0, CH3CH2), 1.05 (3H, t, J = 7.0, CH3CH2), 2.90–3.15 (5H,
m, NCHH and CH2Ph), 3.50–3.58 (1H, dq, J = 12.5, 8.0, NCHH),
4.78–4.81 (1H, m, a-CH), 5.67 (1H, d, J = 5.8, OCHCl), 5.75 (1H, d, J
= 5.8, OCHCl), 6.09 (1H, d broad, J = 8.0, NH), 7.17-7.29 (5H, m,
ArH).
N-(tert-Butoxycarbonyl)sarcosine diethylamide 5d
Prepared from BocSarOSuc 4c (715.7 mg, 2.5 mmol) and diethy-
lamine (182.8 mg, 2.5 mmol). Yield: 79% (482.6 mg, 2.0 mmol).
1H-NMR: 1.13 (3H, t, J = 7.0, CH3CH2), 1.19 (3H, t, J = 7.0, CH3CH2),
1.43 and 1.47 (9H, 26s, (CH3)3), 2.93 and 2.95 (3H, 26s, NCH3),
3.28-3.32 (2H, m, NCH2CH3), 3.35–3.42 (2H, m, NCH2CH3), 3.94
and 4.05 (2H, 26s, NCH2CO).
Compound 3b
Prepared from 7b (309.67 mg, 0.99 mmol) and flufenamic acid
(sodium salt) (278.4 mg, 1.0 mmol). Yield: 39% (217.5 mg,
0.4 mmol). Oil. mmax/cm–1: 3323, 3275, 1736, 1699, 1633. 1H-NMR:
0.99 (3H, t, J = 7.0, CH3CH2) and 1.04 (3H, t, J = 7.0, CH3CH2), 2.90–
3.11 (5H, m, NCH2 and CH2Ph), 3.49–3.57 (1H, m, NCH), 4.78 and
4.80 (1H, ddd, J = 8.53, 8.35, 6.18, a-CH), 5.83 (1H, d, J = 8.7, NH),
5.94 (1H, d, J = 5.81, OCHO), 5.97 (1H, d, J = 5.81, OCHO), 6.80–
6.83 (1H, m, ArH), 7.17–7.50 (11H, m, ArH), 8.01–8.04 (1H, m,
ArH), 9.46 (1H, s, NH). EIMS (%): 558 (100) [M+]. Calculated for
C29H30N3O5F3 : C, 62.5, H, 5.4, N, 7.5%. Found: C, 62.4; H, 5.4; N,
7.5%.
Sarcosine diethylamide 6d
Yield: 90% (257.0 mg, 1.8 mmol). Oil 1H-NMR: 1.10 (3H, t, J = 7.0,
CH3CH2), 1.20 (3H, t, J = 7.0, CH3CH2), 2.54 (3H, s, NCH3), 3.26 (2H,
q, J = 7.0, CH3CH2), 3.39 (2H, q, J = 7.0, CH3CH2), 3.58 (2H, s, NCH2),
3.86 (1H, brs, NH).
N-(Chloromethyloxycarbonylsarcosine diethylamide 7d
To a solution of 6d (257.0 mg in 5 mL CH2Cl2) was added chloro-
methyl chloroformate (1.8 mmol, 229.5 mg in 5 mL CH2Cl2)
yielding an oil (421.3 mg, 1.8 mmol). Yield: 100% (syn/anti ratio
= 0.5) [29, 30]. 1H-NMR: 1.13 (3H, t, J = 7.0, CH3CH2), 1.22 (3H, t, J =
7.0, CH3CH2), 3.04 (3H, s, NCH3), 3.29 (2H, q, J = 7.2, NCH2), 3.39
(2H, q, J = 7.0, NCH2), 4.05 and 4.11 (2H, 26s, COCH2N), 5.76 and
5.79 (2H, 26s, OCH2Cl).
Synthesis of 3c
N-(tert-Butoxycarbonyl)proline diethylamide 5c
Prepared from BocProOSuc 4b (780.8 mg, 2.5 mmol) and diethy-
lamine (182.8 mg, 2.5 mmol). Yield: 68% (459.6 mg, 1.7 mmol).
1H-NMR: 1.10 and 1.14 (3H, 26t, J = 7.0, CH3CH2), 1.23 and 1.25
(3H, 26t, J = 7.0, CH3CH2), 1.41 and 1.45 (9H, 26s, (CH3)3), 1.64–
2.22 (4H, m, 26CH2 pro), 3.20–3.66 (6H, m, NCH2 and CH2 Pro),
4.44 and 4.60 (1H, 26dd, J = 4.0, 8.3, a-CH).
Compound 3d
Prepared from 7d (421.3 mg) and flufenamic acid (sodium salt)
(500.5 mg, 0.7 mmol). Yield: 37% (317.8 mg, 0.7 mmol). Oil. mmax
/
cm–1: 3335, 1727, 1697, 1663. 1H-NMR: 1.13, 1.17, 1.21, 1.26 (6H,
46t, J = 7.1, CH3CH2), 3.03 and 3.04 (3H, 26s, NCH3), 3.21, 3.28,
3.29, 3.38 (4H, 46q, J = 7.0, CH3CH2), 4.02 and 4.10 (2H, 26s,
NCH2), 5.98 and 6.03 (2H, 26s, OCH2O), 6.79–6.84 (1H, m, ArH),
7.25–7.49 (6H, m, ArH), 8.04–8.06 (1H, m, ArH), 9.41 and 9.45
(1H, 26s, NH). EIMS (%): 482.1 (100) [M+]. Calculated for
C23H26N3O5F3 : C, 57.4, H, 5.4, N, 8.7%. Found: C, 56.7; H, 5.6; N,
8.7%.
Proline diethylamide 6c
Yield: 95% (275.8 mg, 1.6 mmol). 1H-NMR: 1.12 (3H, t, J = 7.0,
CH3CH2), 1.23 (3H, t, J = 7.0, CH3CH2), 1.71–1.78 (1H, m, CH Pro),
1.85–2.05 (2H, m, CH2 Pro), 2.25–2.32 (1H, m, CH Pro), 3.15 (1H,
brs, NH), 3.27–3.44 (6H, m, CH3CH2 and NCH2 Pro), 4.32 (1H, brs,
a-CH).
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim