Structure of alfentanil hydrochloride
a)
b)
Figure 9. The two most stable rotamers of 1a as obtained by the B3LYP/6-31G**‡ computations; (a) ap/Àsc/Àsc (identified as amm in Table 2); (b) ap/À
sc/+sc (identified as amp in Table 2).
rotamers around the C4-CH2. The rotamers of 1B, having the
methoxymethyl group in equatorial position, account only a
16.31%.
NMR details
All experiments were acquired on Bruker spectrometers (Bruker
BioSpin, Rheinstetten, Germany) operating at 400.13 and 500 MHz
for the 1H-NMR spectra, equipped with a 5 mm inverse probe and
a z-axis pulsed field gradient accessory. The spectra were collected
in CDCl3, D2O, and DMSO-D6 as solvents at 298 K.
Experimental
Synthesis of alfentanil hydrochoride, 1, (N-{1-[2-(4-ethyl-5-
oxo-4,5-dihydro-1H-1,2,3,4-tetrazol-1-yl)ethyl]-4-
(methoxymethyl)piperidin-4-yl}-N-phenylpropanamide)
monohydrochloride (1:1)
Major isomer A
1H-NMR (400 MHz, CDCl3), δ: 7.51–7.28 (m, 5H, Har), 4.55
(t, J = 6.6 Hz, 2H, H5), 4.15 (s, 2H, H10), 4.01 (q, J = 7.3 Hz, 2H, H2),
3.44 (s, 3H, H18), 3,40–3,50 (br, 2H, H7e), 3,30–3,40 (br, 2H, H6), 2.98
(dq, J = 12.4, 2.3 Hz, 2H, H7a), 2.58 (d, J = 14.7 Hz, 2H, H8e), 2.42
(dt, J = 14.5, 4.4Hz, 2H, H8a), 1.84 (q, J = 7.4 Hz, 2H, H16), 1.46
(t, J = 7.3Hz, 2H, H1), 0.94 (t, J = 7.4 Hz, 3H, H17).
In a flask connected to a refrigerant and a Dean-Stark distiller, 27.6g
of N-(4-(methoxymethyl)piperidin-4-yl)-N-phenylpropionamide)
and 22.1 g 1-(2-bromoethyl)-4-ethyl-1H-tetrazol-5(4H)-one[12] were
reacted (at 132 °C) in the presence of sodium carbonate (42.4 g)
and 0.7 g of potassium iodide using 1.4 L of methylisobuthylketone
as the solvent. After 12 h was cooled to room temperature, 500 mL
of water added, shaked and phases separated. The organic phase
was dried with anhydrous sodium sulfate and evaporated. The
hydrochloride was obtained by treatment with 100 mL of a solution
(1.0–1.3 M) of hydrogen chloride in isopropanol. Then, it was treated
with 200 mL of n-heptane and 2 mL of water and allowed to crystal-
lize at a temperature of 0 2°C during 12h.
13C-NMR (101 MHz, CDCl3), δ: 175.02 (C15), 150.21 (C3), 139.81
(C11), [131–128] Car, 71.64 (C10), 59.25 (C18), 58.35 (C9), 53.43
(C6), 49.96 (C7), 40.42 (C2), 39.19 (C5), 30.42 (C16), 30.36 (C8),
13.58 (C1), 9.26 (C17).
Minor isomer B
1H-NMR (400 MHz, CDCl3), δ: 7.51–7.28 (m, 5H, H′ar), 4.52
(t, J = 6.5 Hz, 1H, H′5), 4.02 (q, J = 7.4Hz, 2H, H′2), 3.78 (s, 1H, H′10),
3,30–3,40 (br, 4H, H′6 + H′7e), 3.37 (s, 3H, H′18), 2.86 (d, J = 15.8 Hz,
2H, H′8e), 2.77 (t, J = 12.6 Hz, 2H, H′7a), 2.31 (ddd, J = 16.0, 12.2,
4.3 Hz, 2H, H′8a), 1.88 (q, J = 7.3 Hz, 2H, H′16), 1.48 (t, J = 7.3Hz, 2H,
H′1), 0.94 (t, J = 7.4 Hz, 3H, H′17 ).
Computational details
Molecular mechanics calculations have been performed on
Macromodel v.9 program[13] as implemented in Maestro.[14] Force
fields used were MM3*[15] and AMBER*[16] as implemented in the
software used. The conjugate gradient minimization algorithm[17]
from E. Polak and G. Ribiere was used with this force field,
allowing enough cycles to ensure convergence. The GB/SA solva-
tion model[18] was used when modeling solvent effects under
MacroModel. Cutoffs for the van der Waals, electrostatic, and
H-bonds interactions were of 7, 12, and 4 Å, respectively.
Density Functional Theory computations were performed on
Jaguar[19] using the B3LYP hybrid[20] and the 6-31G**‡ basis
set[21] for the study of 1. Model compounds were studied using
B3LYP/6-31G**. Geometry optimization was performed until total
convergence (energy criterion of 5 × 10À5 Hartrees and RMS
matrix change of 5 × 10À6). Computations on continuous solvent
model for water and/or chloroform were performed using the
Poisson-Boltzmann[22] method included in Jaguar.
13C-NMR (101 MHz, CDCl3), δ: 175.87 (C′15), 150.21 (C′3), 140.15
(C′11), [131–128] C′ar, 74.83 (C′10), 59.54 (C′9), 58.93 (C′18), 53.10
(C′6), 48.73 (C′7), 40.42 (C′2), 39.19 (C′5), 30.67(C′16), 28.43 (C′8),
13.58 (C′1), 9.26 (C′17).
Acknowledgements
The ‘Servei de Ressonància Magnètica Nuclear’ of the ‘Universitat
Autònoma de Barcelona’ is gratefully acknowledged for allocating
machine time.
References
[1] CAS registry No: Alfentanil 71195-58-9
[2] Janssen Pharmaceutica Inc. Alfentanil hydrochloride U.S. Patent 6505-
01-265-0009, 1992.
Magn. Reson. Chem. (2014)
Copyright © 2014 John Wiley & Sons, Ltd.
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