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Malawska and co-workers
added to the crude residue. The aqueous layer was extracted with AcOEt
portions. The combined extracts were dried and evaporated in vacuo to give
a crude oil which generally crystallized on standing at room temp. Recrys-
tallization of the residue from an appropriate solvent or purification by
column chromatography afforded the pure N-substituted amides 3–16.
N-(3,4-Dimethoxybenzylamide) of α-(N-Benzylamino)-γ-hydroxybutyric
Acid (9)
Mp 78–81 °C (from toluene). TLC: Rf = 0.76 (S2), Rf = 0.35 (S4). MS
(70 eV); m/z (%) = 358.2 (0.47) [M+], 253.4 (6.82), 235.5 (9.84), 202.5
(1.97), 193.3 (1.12), 164.6 (100), 151.5 (34.07), 136.2 (4.21), 132.3 (2.81),
1
124.3 (1.36), 106.0 (7.26), 91.3 (46.03), 65.3 (3.07). H NMR (CDCl3) δ
N-Benzylamide of α-(N-Benzylamino)-γ-hydroxybutyric Acid (3)
(ppm) = 1.85 (m) CH2 (3), 3.30 (t) (C-2) J = 6.7 Hz, 3.70 (m) CH2 (4, 12),
3.82 (s), 3.85 (s) (-OCH3)2, 4.38 (d) CH2 (5) J = 5.9 Hz, 6.80 (s), 7.25 (m)
8H aromatic protons, 7.55 (t) N-H J = 5.7 Hz. Formula C20H26N2O4, MW =
358.438.
Mp 77.5–78.4 °C (from ethyl acetate and n-hexane). TLC: Rf = 0.79 (S2),
Rf = 0.35 (S4). MS (70 eV); m/z (%) = 299.0 (0.19) [M+], 253.3 (0.25), 219.2
(0.16), 204.9 (0.41), 192.9 (4.01), 175.2 (4.98), 164.2 (100) [M+ – (Ph-CH2-
NH-CO)], 132.0 (2.37), 106.4 (10.74), 91.1 (89.6) [M+ -CH2-Ph], 77.1 (1.6),
65.3 (5.71). 1H NMR (CDCl3) δ (ppm) = 1.84 (m) CH2 (3), 3.32 (t) (C-2) J
= 6.8 Hz, 3.62–3.77 (m) CH2 (4, 12), 4.43 (d) CH2 (5) J = 5.9 Hz, 7.19–7.36
(m) 10H aromatic protons, 7.53 (t) N-H. Formula C18H22N2O2, MW =
298.385. Anal. C, H, N.
N-Benzylamide of α-(2-Phenylethylamino)-γ-hydroxybutyric Acid (10)
Mp 93.2–93.8 °C (from ethyl acetate and cyclohexane). TLC: Rf = 0.78
(S2), Rf = 0.40 (S4). MS (70 eV); m/z (%) = 312.9 (0.28) [M+], 221.3 (7.64),
203.0 (3.28), 178.1 (100), 175.2 (4.95), 160.3 (3.00), 147.9 (1.03), 132.0
(1.08), 120.5 (3.28), 105.1 (36.16), 91.2 (19.29), 79.2 (4.55), 77.3 (3.35). 1H
NMR (CDCl3) δ (ppm) = 1.76 (m) CH2 (3), 2.66–2.92 (m) CH2 (12, 13), 3.26
(t) (C-2) J = 6.7 Hz, 3.69 (t) CH2 (4) J = 5.4 Hz, 4.23 (dd) 1H (C-5) 3J = 6.6
Hz, Jgem = 14.7 Hz, 4.29 (dd) 3J = 5.8 Hz, 4.33 (dd) 1H (C-5) 3J = 5.8 Hz,
Jgem. = 14.7 Hz,, 4.40 (dd) 3J = 6.18 Hz, 7.05–7.35 (m) 10 H aromatic protons,
7.63 (t) N-H J =5.7 Hz. Formula C19H24N2O4, MW = 312.412
N-(2-Chlorobenzylamide) of α-(N-Benzylamino)-γ-hydroxybutyric Acid (4)
Mp 80.7–81.6 °C (from ethyl acetate and cyclohexane). TLC: Rf = 0.78
(S2), Rf = 0.39 (S4). MS (70 eV); m/z (%) = 333.1 (0.19) [M+], 287.2 (0.18),
227.1 (2.65), 209.0 (1.25), 196.1 (1.66), 174.3 (3.08), 164.4 (100), 146.2
(1.01), 132.1 (1.74), 125.3 (5.12), 106.5 (6.22), 91.3 (72.3), 77 (1.39), 65.3
(3.89). 1H NMR (CDCl3) δ (ppm) = 1.84 (m) CH2 (3), 3.31 (t) (C-2) J = 6.8
Hz, 3.62–3.79 (m) CH2 (4, 12), 4.54 (d) CH2 (5) J = 6.1 Hz, 7.21–7.40 (m)
9H aromatic protons, 7.61 (t) N-H. Formula C18H21N2O2Cl , MW = 332.83.
Anal. C, H, N.
N-(2-Chlorobenzylamide) of α-(2-Phenylethylamino)-γ-hydroxybutyric
Acid (11)
Mp 108.0–108.7 °C (from ethyl acetate and n-hexane). TLC: Rf = 0.78
(S2), Rf = 0.44 (S4). MS (70 eV); m/z (%) = 347.1 (0.26) [M+], 257.1 (2.31),
255.2 (6.48), 237.2 (3.16), 211.2 (2.01), 208.9 (3.52), 178.2 (100), 160.4
(2.78), 148.2 (1.03), 139.9 (2.23), 125.3 (15.94), 114.2 (5.17), 105.2 (36.11),
91.3 (3.18), 79.1 (3.88), 77.1 (3.79). 1H NMR (CDCl3) δ (ppm) = 1.83 (m)
CH2 (3), 2.69–2.94 (m) CH2 (12, 13), 3.34 (t) (C-2) J = 6.7 Hz, 3.72 (m) CH2
(4) J = 5.4 Hz, 4.18 (dd) 1H (C-5), 4.25 (dd) 3J = 56.7 Hz, 4.28 (dd) 1H (C-5)
3J = 6.6 Hz, 4.37 (dd), 7.13 (m), 7.25 (m) 9 H aromatic protons, 7.56 (t) N-H
J =5.9 Hz. Formula C19H23N2O2Cl, MW = 346.857.
N-(4-Chlorobenzylamide) of α-(N-Benzylamino)-γ-hydroxybutyric Acid (5)
Mp 78–80 °C (from ethyl acetate and cyclohexane). TLC: Rf = 0.78 (S2),
Rf = 0.34 (S4). MS (70 eV); m/z (%) = 333.4 (0.19) [M+], 227.6 (1.75), 209.5
(3.6), 196.6 (1.31), 164.9 (100), 146.3 (1.83), 132.3 (1.66), 125.3 (6.03),
106.5 (5.7), 91.5 (45.35), 65.3 (2.38). 1H NMR (CDCl3) δ (ppm) = 1.83 (m)
CH2 (3), 3.31 (t) (C-2) J = 6.7 Hz, 3.65–3.79 (m) CH2 (4, 12), 4.36 (d) CH2
(5) J = 6.0 Hz, 7.13–7.29 (m) 9H aromatic protons, 7.67 (t) N-H J =5.8 Hz.
Formula C18H21N2O2Cl, MW = 332.83. Anal. C, H, N.
N-(4-Chlorobenzylamide) of α-(2-Phenylethylamino)-γ-hydroxybutyric
Acid (12)
N-(4-Fluorobenzylamide) of α-(N-Benzylamino)-γ-hydroxybutyric Acid (6)
Mp 101–105 °C (from ethyl acetate and cyclohexane). TLC: Rf = 0.79 (S2),
Rf = 0.40 (S4). MS (70 eV); m/z (%) = 347 (0.26) [M+], 255.1 (8.70), 237.0
(3.1), 209.1 (3.43), 178.3 (100), 160.0 (2.83), 140.0 (1.12), 125.2 (8.97),
105.0 (23.94), 91.2 (2.12), 79 (2.51), 77 (2.25). 1H NMR (CDCl3) δ (ppm)
= 1.79 (m) CH2 (3), 2.7 (m), 2.88 (m) CH2 (12, 13), 3.24 (t) (C-2) J = 6.6
Hz, 3.70 (t) CH2 (4) J = 5.9 Hz, 4.15 (dd) 1H (C-5) 3J = 6.2 Hz, Jgem = 15.1
Hz, 4.23 (dd) 3J = 6.4 Hz, 4.28 (dd) 1H (C-5) 3J = 6.6 Hz, Jgem. = 15.04 Hz,,
4.35 (dd) 3J = 6.2 Hz, 7.07–7.29 (m) 9 H aromatic protons, 7.46 (t) N-H J =
6.1 Hz. Formula C19H23N2O2Cl, MW = 346.857
Mp 78–80 °C (from ethyl acetate and cyclohexane). TLC: Rf = 0.78 (S2),
Rf = 0.32 (S4). MS (70 eV); m/z (%) = 316.1 (0.16) [M+], 272.0 (0.63), 211.1
(3.08), 193.2 (1.29), 180.0 (1.42), 164.2 (100), 132 (1.46), 124 (1.76), 109.0
1
(12.1), 106 (7.87), 91.2 (81.91), 65.1 (3.92). H NMR (CDCl3) δ (ppm) =
1.84 (m) CH2 (3), 3.31 (t) (C-2) J = 6.7 Hz, 3.65–3.75 (m) CH2 (4, 12), 4.37
(d) CH2 (5) J = 5.9 Hz, 6.99 (m), 7.26 (m) 9H aromatic protons, 7.63 (t) N-H
J =5.7 Hz. Formula C18H21N2O2F, MW = 316.376. Anal. C, H, N.
N-(4-Methylbenzylamide) of α-(N-Benzylamino)-γ-hydroxybutyric Acid (7)
N-(4-Fluorobenzylamide) of α-(2-Phenylethylamino)-γ-hydroxybutyric Acid
(13)
Mp 70–71 °C after purification by column chromatography using
CHCl3/(CH3)2CO (1:1) as a solvent system. TLC: Rf = 0.79 (S2), Rf = 0.35
(S4). MS (70 eV); m/z (%) = 312.2 (0.11) [M+], 272.1 (0.14), 207.0 (5.97),
176 (2.0), 164.1 (100), 146 (0.97), 132 (1.46), 120 (2.97), 105.2 (14.53), 91.1
(56.87), 79 (1.89), 77 (2.58). 1H NMR (CDCl3) δ (ppm) = 1.83 (m) CH2 (3),
2.95 (s) CH3, 3.31 (t) (C-2) J = 6.7 Hz, 3.61–3.78 (m) CH2 (4, 12), 4.38 (d)
CH2 (5) J = 5.9 Hz, 7.13–7.32 (m) 9H aromatic protons, 7.49 (t) N-H J = 5.5
Hz. Formula C19H24N2O2, MW = 312.412. Anal. C, H, N.
Mp 86–88 °C. TLC: Rf = 0.70 (S2), Rf = 0.42 (S4). MS (70 eV); m/z (%) =
331.6 (0.37) [M+], 239.4 (10.68), 237.3 (0.58), 221.2 (3.31), 193.5 (3.84),
178.6 (100), 160.4 (3.26), 109.0 (12.8), 105.3 (24.05), 91.3 (2.07), 79.3
1
(2.71). H NMR (CDCl3) δ (ppm) = 1.80 (m) CH2 (3), 2.71 (m) CH2 (12,
13), 3.22 (t) (C-2) J = 6.6 Hz, 3.69 (t) CH2 (4) J = 5.8 Hz, 4.16 (dd) 1H (C-5)
3J = 6.05 Hz, Jgem = 15.14 Hz, 4.23 (dd) 3J = 6.59 Hz, 4.28 (dd) 1H (C-5) 3J
= 6.59 Hz, Jgem. = 15.02 Hz,, 4.37 (dd) 3J = 6.23 Hz, 6.97 (m), 7.14 (m) 9 H
aromatic protons, 7.48 (t) N-H J = 5.9 Hz. Formula C19H23N2O2F, MW =
330.402
N-(4-Methoxybenzylamide) of α-(N-Benzylamino)-γ-hydroxybutyric Acid
(8)
N-(4-Methylbenzylamide) of α-(2-Phenylethylamino)-γ-hydroxybutyric Acid
(14)
Mp 51–53 °C after purification by column chromatography using
CHCl3/MeOH/NH3 (9:1:0.1) as a solvent system. TLC: Rf = 0.78 (S2), Rf =
0.35 (S4). MS (70 eV); m/z (%) = 329 (0.1) [M+], 255 (0.1), 223.5 (6.52),
205.6 (6.76), 164.6 (100), 136.2 (4.61), 121.4 (23.22), 106 (5.31), 91.3 (51.4),
77.6 (2.14), 65.3 (2.91). 1H NMR (CDCl3) δ (ppm) = 1.83 (m) CH2 (3), 3.30
(t) (C-2) J = 6.7 Hz, 3.60–3.75 (m) CH2 (4, 12), 3.77 (s) -OCH3, 4.34 (d)
CH2 (5) J = 5.9 Hz, 6.85 (m), 7.22 (m) 9H aromatic protons, 7.49 (t) N-H J
= 5.6 Hz. Formula C19H24N2O3, MW = 328.411
Mp 100–104 °C (from ethyl acetate and cyclohexane). TLC: Rf = 0.73 (S2),
Rf= 0.45 (S4). MS (70 eV); m/z (%) = 327.1 (0.49) [M+], 235.5 (8.57), 217.12
(1.98), 189.2 (2.83), 178.5 (100), 160.3 (2.07), 134.1 (1.11), 120.1 (1.24),
105.3 (36.06), 91.2(2.69), 79.4(3.44), 77.4(2.73). 1H NMR (CDCl3) δ (ppm)
= 1.80 (m) CH2 (3), 2.34 (s) CH3, 2.73 (m) CH2 (12, 13), 3.26 (t) (C-2) J =
6.6 Hz, 3.72 (t) CH2 (4) J = 5.7 Hz, 4.21 (dd) 1H (C-5) 3J = 6.04 Hz, Jgem
=
Arch. Pharm. Pharm. Med. Chem. 332, 167–174 (1999)