720
S. Scapecchi et al. / Il Farmaco 58 (2003) 715Á722
/
11), was added with an excess of appropriate amine, and
a catalytic amount of NH4Cl, in a steel bomb at 110 8C
for 24 h. The solvent was eliminated under reduced
pressure and the residue treated with water and ex-
tracted with CHCl3. The organic layer was made
anhydrous and evaporated under reduced pressure to
give a mixture that was purified by column chromato-
graphy with the suitable eluent.
mixture was refluxed under stirring for 3 h. Then the
reaction was cooled and a solution of 5% NaHCO3 was
added. The solid formed was filtered off and re-crystal-
lised from EtOH; 63% yield. m.p. 109Á
/
111 8C. 1H NMR
7.4 Hz), 3.03 (q,
7.4 Hz), 3.88 (s, 3H, OCH3), 6.98 (d,
1
(CDCl3) d 1.21 (t, 3H, CH2CH3, Jꢀ
/
2H, CH2CH3, 1Jꢀ
/
2
2H, CH arom., Jꢀ
2Jꢀ8.8 Hz) ppm. 13C NMR (CDCl3) d 8.73 (q,
CH3CH2, Jꢀ
127.45 Hz), 31.53 (t, CH2CH3, 1Jꢀ
124.75 Hz), 55.95 (q, OCH3, 1Jꢀ
143.9 Hz), 114.48
(dd, CH arom., 1Jꢀ161 Hz, 2Jꢀ
4.55 Hz), 125.25 (t, C
arom.), 130.26 (dd, CH arom., Jꢀ159.3 Hz, Jꢀ7.3
/
8.8 Hz), 7.85 (d, 2H, CH arom.,
/
/
/
5.2.1. N-Carbamoylmethylpropionamide (2)
/
1
30% yield. m.p. 137Á
(D2O) d 0.96 (t, 3H, CH3CH2, Jꢀ
CH3CH2, Jꢀ
8.0 Hz), 3.70 (s, 2H, NHCH2) ppm. 13C
NMR (D2O) d 8.99 (q, CH3CH2, 1Jꢀ
127.1 Hz), 28.6 (t,
CH3CH2, 1Jꢀ130 Hz), 41.86 (t, NHCH2, 1Jꢀ
138.4
/
141 8C. Eluent WE4. H NMR
/
/
1
2
/8.0 Hz), 2.17 (q, 2H,
/
/
/
Hz), 163.82 (s, C arom.), 165.35 (s, CH2CONH), 177.86
(s, PhCONH) ppm. Anal. C9H8NO3.
/
/
/
Hz), 174.22 (s, CH2CO), 178.48 (s, CONH2) ppm. Anal.
C5H10N2O2.
5.4. 4-Methoxy-N-methyl-N-propionylbenzamide (7)
A mixture of N-methylamide of anisic acid (1.47 g,
8.9 mmol) and propionic anhydride (5 ml) was warmed
at 165 8C for 5 h and worked up as reported in Ref. [22].
The residue was submitted to four chromatographic
separations (column chromatography eluent WE2,
CH2Cl2, CHCl3:MeOH, 99:01 and finally preparative
TLC using as eluting system CHCl3:MeOH, 99:01) to
5.2.2. N-[(2-
Diisopropylaminoethylcarbamoyl)methyl]propionamide
(3)
26% yield. m.p. 45Á
/
49 8C. Eluent WE4. 1H NMR
1
(CDCl3) d 0.95 (d, 12H, CH(CH3)2, Jꢀ
/
6.0 Hz), 1.12
1
(t, 3H, CH3CH2, Jꢀ
/
8.0 Hz), 2.23 (q, 2H, CH2CH3,
Jꢀ
/
8.0 Hz), 2.52 (t, 2H, CH2CH2N, Jꢀ
/
6.0 Hz), 2.90Á
/
obtain compound 7; 10% yield. m.p. 34Á
/
39 8C. 1H
3.00 (m, 2H, CH(CH3)2), 3.18 (t, 0.5 2H, CH2NH), 3.20
(t, 0.5 2H, CH2NH), 3.86 (s, 0.5 2H, NHCH2CO), 3.88
(s, 0.5 2H, NHCH2CO), 7.80 (bs, 1H, NH) ppm. 13C
1
NMR (CDCl3) d 1.14 (t, 3H, CH2CH3, Jꢀ
2.58 (q, 2H, CH2CH3, 1Jꢀ
7.4 Hz), 3.22 (s, 3H, NCH3),
3.88 (s, 3H, OCH3), 6.95 (d, 2H, CH arom., Jꢀ
Hz), 7.63 (d, 2H, CH arom., 2Jꢀ8.8 Hz) ppm. 13C
NMR (CDCl3) d 10.10 (q, CH2CH3, Jꢀ
31.24 (t, CH2CH3, 1Jꢀ128.4 Hz), 34.95 (q, NCH3, 1Jꢀ
140.2 Hz), 55.93 (q, OCH3, 1Jꢀ
143.85 Hz), 114.36 (dd,
CH arom., 1Jꢀ161 Hz, 2Jꢀ
4.55 Hz), 127.53 (t, C
arom., 2Jꢀ8.2 Hz), 131.43 (dd, CH arom., 1Jꢀ
160 Hz,
2Jꢀ
6.4 Hz), 163.53 (s, C arom.), 174.18 (s, NCOCH2),
/7.4 Hz),
/
2
/8.8
1
NMR (CDCl3) d 10.08 (q, CH3CH2, Jꢀ
/127.45 Hz),
/
21.12 (q, CH(CH3)2, 1Jꢀ
1Jꢀ125.65 Hz), 39.07 (t, CH2NH, 1Jꢀ
(t, CH2CH2NH, Jꢀ
1Jꢀ
/
124.75 Hz), 29.65 (t, CH3CH2,
1
/127.5 Hz),
/
/
138.4 Hz), 43.53
/
/
1
/
138.4 Hz), 48.34 (d, CH(CH3)2,
/
/
132 Hz), 169.23 (s, CH3CH2CO), 174.62 (s,
/
/
CONH) ppm. Anal. C13H27N3O2.
/
/
/
5.2.3. N-(2-Oxo-2-piperidin-1-yl-ethyl)propionamide
177.72 (s, COC arom.) ppm. Anal. C12H15NO3.
(11)
50% yield. m.p. 84Á
(CDCl3) d 1.13 (t, 3H, CH3CH2, Jꢀ
(m, 6H, CH2 piper.), 2.24 (q, 2H, CH2CH3, Jꢀ
3.30 (t, 2H, CH2 piper., Jꢀ6.0 Hz), 3.35 (t, 2H, CH2
/
86 8C. Eluent WE1 1H NMR
8.0 Hz), 1.53Á1.62
8.0 Hz),
/
/
5.5. 4-Amino-N-benzylbutyramide (8) [25]
/
/
The hydrolysis of compound 16 was performed under
different conditions from that reported in literature [25].
In fact 16 (1.5 g, 8.6 mmol) was dissolved in H2O and to
this solution was added 1 equiv. of NaOH (0.35 g, 8.6
mmol), the mixture obtained was warmed at 80 8C for 5
days. The crude product was purified by flash chroma-
piper., Jꢀ6.0 Hz), 3.98 (s, 0.5 2H, CH2NH), 3.99 (s, 0.5
/
2H, CH2NH), 6.69 (bs, 1H, NH) ppm. 13C NMR
1
(CDCl3) d 10.23 (q, CH3CH2, Jꢀ
/
127.45 Hz), 24.74
128.5 Hz), 25.80 (t, CH2 piper., 1Jꢀ
127.7 Hz), 29.87 (t,
(t, CH2 piper., 1Jꢀ
/
/
127.8 Hz), 26.54 (t, CH2 piper., 1Jꢀ
/
1
1
CH3CH2, Jꢀ
/
126.5 Hz), 41.6 (t, CH2 piper., Jꢀ
134.7 Hz), 45.82 (t,
135.3 Hz), 166.46 (s, CONH), 174.18 (s,
/140
tography using WE2 as eluting system. 20% yield. m.p.
1
Hz), 43.53 (t, CH2 piper., 1Jꢀ
/
118Á
NMR (CDCl3) d: 1.52 (bs, 2H, NH2), 1.76Á
CH2CH2CH2NH2), 2.3 (t, 2H, CH2CO, Jꢀ
2.74 (t, 2H, CH2NH2, Jꢀ7.0 Hz), 4.42 (s, 0.5 2H,
PhCH2), 4.44 (s, 0.5 2H, PhCH2), 6.30 (bs, 1H, NH),
7.27Á
7.32 (m, 5H, CH arom.) ppm. 13C NMR (D2O) d:
/
121 8C. IR n(cmꢁ1): 3300 (NH), 1650 (CO). H
1
CH2NH, Jꢀ
/
/1.83 (m, 2H,
CON) ppm. Anal. C10H18N2O2.
/7.0 Hz),
/
5.3. 4-Methoxy-N-propionylbenzamide (6)
/
An excess of propionic anhydride and a catalytic
amount of H2SO4 concentrated were added to 1 equiv.
of commercially available 4-methoxybenzamide. The
26.31 (t, CH2CH2CH2NH2), 32.92 (t, CH2CO), 39.45 (t,
CH2NH2), 42.84 (t, CH2NH), 127.02 (d, CH arom.),
127.24 (d, CH arom.), 128.57 (d, CH arom.), 137.74 (s,