DOI: 10.3109/14756366.2015.1088840
Role of –COOH group in NSAIDs
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(s, 3H, CH3O), 3.88 (q, J: 6.69 Hz, 1H, CHCH3), 3.53 (m, 1H, ammonium salt, washed it twice with ether, and dried it under
prolinyl), 3.30 (m, 1H, prolinyl), 2.47 (m, 1H, prolinyl), 1.97–1.84 vacuum in a desiccator for 18 h. To generate HCl gas, we
(m, 3H, prolinyl), 1.54 (d, J: 7.32 Hz, 3H, CH3CH).
2-(4-Isobutylphenyl)-1-(pyrrolidin-1-yl)propan-1-one
produced it in situ by adding (dropwise) conc. H2SO4 to a
(8a): commercial 37% solution of HCl under vigorous magnetic
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87% yield; H-NMR (CDCl3) ꢀ 7.18 (d, J: 7.95 Hz, 2H, phenyl stirring. Then we transferred the HCl gas produced in this
H-2, H-6), 7.07 (d, J: 7.95 Hz, 2H, phenyl H-3, H-5), 3.71 (q, J: reaction using Teflon tubing connected to a CaCl2 trap. While
6.72 Hz, 1H, CHCH3), 3.43 (br, 4H, pyrrolidinyl H-2, H-5), 2.43 passing the HCl gas, we isolated the system (three-necked
(d, J: 7.32 Hz, 2H, CH2Ar), 1.86 (m, 5H, CH(CH3)2 and round bottom flask) by using a septum inlet adapter with
pyrrolidinyl H-3, H-4), 1.43 (d, J: 6.72 Hz, 3H, CH3CH), 0.89 stopcock, to which we had attached a balloon to store any excess
(d, J: 6.72 Hz, 6H, (CH3)2CH).
of HCl gas.
1-(2-(6-Methoxynaphthalen-2-yl)propyl)pyrrolidinium chlor-
N-(2-Hydroxyethyl)-2–(4-isobutylphenyl)propanamide (8b):
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85% yield; H-NMR (CDCl3) ꢀ 7.19 (d, J: 7.95 Hz, 2H, phenyl ide (13a): 89.36% yield; m.p. 197–198 ꢀC; 1H-NMR (D2O) ꢀ
H-2, H-6), 7.11 (d, J: 7.95 Hz, 2H, phenyl H-3, H-5), 6.04 (br, 1H, 7.88 (m, 3H, naphthyl), 7.52 (dd, J: 8.55 Hz, 1.83 Hz, 1H,
NH), 3.64 (t, J: 5.49 Hz, 2H, CH2OH), 3.58 (q, J: 7.32 Hz, 1H, naphthyl), 7.38 (d, J: 2.43 Hz, 1H, naphthyl), 7.25 (dd, J: 8.55 Hz,
CHCH3), 3.34 (m, 2H, CH2N), 3.08 (s, 1H, OH), 2.44 (d, 2.43 Hz, 1H, naphthyl), 3.95 (s, 3H, CH3O), 3.62 (m, 2H, CH2N),
J: 7.32 Hz, 2H, CH2Ar), 1.84 (m, 1H, CH(CH3)2), 1.51 (d, 3.4 (m, 1H, CHCH3), 3.28 (br, 4H, pyrrolidinyl), 1.95 (br, 4H,
J: 7.32 Hz, 3H, CH3CH), 0.90 (d, J: 6.69 Hz, 6H, (CH3)2CH).
1-[2-(4-Isobutylphenyl)-1-oxo-1-propyl]proline (8c): 91% 156.4, 136.4, 132.9, 128.6, 128.1, 127.2, 125.4, 124.9, 118.1,
pyrrolidinyl), 1.38 (d, J: 6.72 Hz, 3H, CH3CH). 13C-NMR (D2O):
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yield; m.p. 113–114 ꢀC; H-NMR (CDCl3) ꢀ 7.24 (d, J: 7.95 Hz, 105.5, 60.5, 54.7, 53.9, 36.1, 21.8, 18.3. ESI-MS (m/z); 292
2H, phenyl H-2, H-6), 7.09 (d, J: 7.95 Hz, phenyl H-3, H-5), 4.72 [M + Na]+(100%), 269 [M + H]+.
(m, 1H, prolinyl H-2), 3.53 (q, J: 7.32 Hz, 1H, CHCH3), 3.41–
N-(2-Hydroxyethyl)-2–(6-methoxynaphthalen-2-yl)propan-1-
3.16 (m, 2H, prolinyl), 2.45 (d, J: 7.32 Hz, 2H, CH2Ph), 1.94–1.69 ammonium chloride (13b): 85.0% yield; m.p. 230–231 ꢀC;
(m, 5H, prolinyl and CH(CH3)2), 1.43 (d, J: 6.72 Hz, 3H, 1-NMR (D2O): ꢀ 7.91–7.81 (m, 3H, naphthyl), 7.51 (dd, J:
CH3CH), 0.88 (d, J: 6.72 Hz, 6H, (CH3)2CH).
8.55 Hz, J: 1.23 Hz, 1H, naphthyl), 7.38 (d, J: 2.43 Hz, 1H,
naphthyl), 7.23 (dd, J: 9.15 Hz, J: 2.43 Hz, 1H, naphthyl), 3.95
2-[4-(Phenyl)-3-fluorophenyl)-1-(pyrrolidin-1-yl)propan-1one
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(9a): 98% yield; m.p. 86–87 ꢀC; H-NMR (CDCl3) ꢀ 7.55–7.33 (s, 3H, CH3O), 3.77 (t, J: 5.49 Hz, 2H, CH2OH), 3.39 (m, 1H,
(m, 6H, phenyl), 7.16–7.11 (m, 2H, phenyl), 3.79 (q, J: 6.72 Hz, CHCH3), 3.35 (m, 2H, CH2NH), 3.15 (q, J: 5.49 Hz, CH2NH),
1H, CHCH3), 3.48 (br, 4H, pyrrolidinyl H-2, H-5), 1.86 (br, 4H, 1.41 (d, J: 6.72 Hz, 3H, CH3CH). 13C-NMR (D2O): 156.3, 136.4,
pyrrolidinyl H-3, H-4), 1.49 (d, J: 6.72 Hz, 3H, CH3 CH).
2 -(4-Phenyl-3-fluorophenyl)-N-(2-hydroxyethyl)propanamide
132.8, 128.6, 128.1, 127.1, 125.2, 125.0, 118.1, 105.5, 55.5, 54.6,
52.5, 48.5, 36.1, 18.3. ESI-MS (m/z); 296 [M + Na]+(100%), 273
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(9b): 92% yield; m.p. 82–83 ꢀC; H-NMR (CDCl3) ꢀ 7.55–7.36 [M + H]+.
(m, 6H, phenyl), 7.17–7.11 (m, 2H, phenyl), 6.00 (br, 1H, NH), 2-(Hydroxyethyl)-1-[2-(6-methoxynaphtalen-2-yl)-1-propyl]-
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3.69 (t, 2H, J: 4.8 Hz, CH2OH), 3.64 (q, J: 7.32 Hz, 1H, CHCH3), pyrrolidinium chloride (13c): 85.0% yield, m.p. 153–154 ꢀC; H-
3.39 (m, 2H, CH2N), 2.33 (br, 1H, OH), 1.55 (d, J: 7.32 Hz, 3H, NMR (D2O) ꢀ 7.91–7.83 (m, 3H, naphthyl), 7.51 (dd, J: 8.55 Hz,
CH3 CH).
J: 1.23 Hz, 1H, naphthyl), 7.37 (d, J: 2.44 Hz, 1H, naphthyl), 7.24
1-[2-(4-Phenyl-3-fluorophenyl)-1-oxo-1-propyl]proline (9c). (dd, J: 8.55 Hz, J: 2.44 Hz, 1H, naphthyl), 3.94 (s, 3H, CH3O),
66% yield; 1H-NMR (CDCl3) ꢀ 7.55–7.34 (m, 5H, phenyl), 3.87 (m, 2H, CH2OH), 3.66 (m, 1H, CHCH3), 3.59 (m, 2H,
7.14–7.09 (m, 3H, phenyl), 4.61 (m, 1H, CH prolinyl, 3.84 (q, J: CH2N), 3.42 (m, 2H, pyrrolidinyl), 3.28 (m, 1H, pyrrolidinyl),
7.32 Hz, CHAr), 3.69 (m, 1H, pyrrolidin-1-yl), 3.35 (m, 1H, 2.15 (m, 2H pyrrolidinyl), 1.90–1.67 (two m, 2H, pyrrolidinyl),
prolinyl), 2.09–1.91 (m, 4H, prolinyl), 1.53 (d, J: 7.32 Hz, 3H, 1.36 (d, J: 6.81 Hz, 3H, CH3CH). 13C-NMR (D2O): 156.4, 136.0,
CH3 CH).
132.9, 128.6, 128.1, 127.3, 125.4, 124.8, 118.1, 105.5, 69.2, 58.3,
54.6, 53.6, 53.5, 35.9, 24.7, 21.1, 19.5. ESI-MS (m/z); 322
[M + Na]+ (100%), 299 [M + H]+.
General procedure for the preparation of amines
(10a–c to 12a–c)
1-(2-(4-Isobutylphenyl)propyl)pyrrolidinium chloride (14a):
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90.9% yield; m.p. 187–188 ꢀC; H-NMR (D2O) ꢀ 7.33–7.27 (m,
We added (dropwise) a solution of the corresponding amide (7–9,
1 eq.) in dry THF (5 mL), to a suspension of lithium aluminum
hydride (2–4 eq.) in dry THF (15 mL). Then we stirred the
reaction mixture at about 25 ꢀC for 3–4 h (except for compounds
10b, 11b, and 12b, in which case we stirred the mixture under
reflux for 3 h). In all cases, we monitored the reaction progress by
TLC. After completion, we quenched the reaction by adding water
(dropwise), 1 N NaOH solution, and ethyl acetate. After stirring
for about 2 min, we separated the organic layer and dried it with
sodium sulfate. Finally, we evaporated the solvent under vacuum,
and we purified the corresponding amines by flash chromatog-
raphy. All products (10–12) were used immediately after purifi-
cation to obtain the corresponding ammonium salts (13–15)
described below.
4H, phenyl), 3.59 (m, 4H, pyrrolidinyl), 3.15 (m, 2H, CH2N), 2.98
(m, 1H, CHAr), 2.49 (d, J: 6.69 Hz, 2H, CH2Ar), 2.07–1.80 (two
m, 4H, pyrrolidinyl), 1.81 (m, 1H, CH(CH3)3, 1.30 (d, J: 6.72 Hz,
3H, CH3CH), 0.87 (d, J: 6.09 Hz, 6H, (CH3)2CH). 13C-NMR
(D2O): 141.1, 138.3, 129.3, 126.3, 60.6, 54.5, 53.2, 43.4, 35.7,
28.9, 21.8, 20.8, 18.9. ESI-MS (m/z); 268 [M + Na]+(100%), 245
[M + H]+.
N-(2-Hydroxyethyl)-2-(4-isobutylphenyl)propan-1-ammonium
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chloride (14b): 89.6% yield; m.p. 137–138 ꢀC; H-NMR (D2O) ꢀ
7.32–7.26 (m, 4H, phenyl), 3.78 (t, J: 4.89 Hz, 2H, CH2OH), 3.32
(d, J: 7.32 Hz, 2H, CH2N), 3.22–3.09 (m, 3H, CH2N and CHAr),
2.49 (d, J: 7.32 Hz, 2H, CH2Ar), 1.85 (m, 1H, CH(CH3)2), 1.32 (d,
J: 7.32 Hz, 3H, CH3), 0.87 (d, J: 6.72 Hz, 6H, (CH3)2CH).
13C-NMR (D2O): 141.1, 138.2, 129.3, 126.3, 55.5, 52.7, 48.5,
43.4, 35.7, 28.9, 20.8, 18.3. ESI-MS (m/z); 258 [M + Na]+(100%),
235 [M + H]+.
General procedure for the preparation of ammonium salts
(13–15)
2-(Hydroxymethyl)-1-[2-(4-isobutylphenyl)-1-propyl]pyrrolidi-
We passed dry HCl gas through a solution of the corresponding nium chloride (14c): 67.5% yield; m.p. 145–146 ꢀC; 1H-NMR
amine (10–12; 2 mmol) dissolved in diethyl ether (20 mL), under (D2O) ꢀ 7.35–7.25 (m, 4H, phenyl), 3.88 (m, 2H, CH2OH), 3.77
magnetic stirring until we did not observe any more precipitate (m, 2H, CH2N) 3.42–3.21 (m, 3H, pyrrolidinyl), 2.99 (m, 1H,
coming out of solution. We filtered the resulting insoluble CHAr), 2.49 (d, J: 6.72 Hz, 2H, CH2Ar), 2.22–2.11