Optimized Synthesis of Fentanyls
1H NMR (600 MHz, D2O) d 7.6527.44 (m, 3H), 7.3327.30 (m,
2H), 7.2727.24 (m, 1H), 7.2327.20 (m, 4H), 4.7724.61 (m, 1H)
(overlaps with HOD), 3.6023.54 (m, 2H), 3.3023.24 (m, 2H),
3.1323.10 (m, 2H), 3.0722.90 (m, 2H), 2.0922.04 (m, 2H), 1.72
(s, 3H), 1.6021.53 (m, 2H); 13C NMR (150 MHz, D2O) d 174.1,
137.6, 136.2, 129.8, 129.7, 129.3, 129.1, 128.8, 127.4, 57.6, 52.1,
50.0, 29.9, 27.4, 22.5; TOF-MS (ESI) m/z calcd for C21H27N2O
[M+H+]: 323.2118; found 323.2124; Anal. Calcd for
C21H27ClN2O: C, 70.28; H, 7.58; N, 7.81. Found: C, 69.97; H,
7.72; N, 7.91.
brine (NaCl/H2O, 3650 mL), saturated NaHCO3 (2650 mL),
dried over Na2SO4 and concentrated in vacuo to give a yellow oil.
The oily mixture was purified by flash column chromatography
(1:1 R 7:3 EtOAc/hexanes) to give 20 as a light yellow oil (2.7 g,
90%). Rf = 0.25 (1:1 EtOAc/hexanes); 1H NMR (600 MHz,
CDCl3) d 7.14 (dd, J = 5.4, 1.2, 1H), 6.92 (dd, J = 5.4, 3.6, 1H),
6.84 (dq, J = 3.6, 1.2, 1H), 3.04 (t, J = 7.2, 2H), 2.82 (t, J = 6.0,
4H), 2.77 (t, J = 7.2, 2H), 2.48 (t, J = 6.0, 4H); 13C NMR (150
MHz, CDCl3) d 209.0, 142.4, 126.6, 124.7, 123.7, 60.4, 53.0,
41.3, 28.3; HRMS (CI) m/z calcd for C11H15NOS [M+]: 209.0874;
found 209.0872; Anal. Calcd for C11H15NOS: C, 63.12; H, 7.22;
N, 6.69; Found: C, 63.01; H, 7.16; N, 6.77.
Acetylfentanyl citrate (18)
Acetylfentanyl (9) (150 mg, 0.46 mmol) was dissolved in MeOH
(4 mL) in a 20 mL scintillation vial and treated with citric acid
(90 mg, 0.46 mmol). The clear solution was stirred at ambient
temperature for 2 hours. The methanol was removed in vacuo at
50uC to obtain a glassy solid that upon scrapping from the surface
of the vial yielded a white solid that was placed under vacuum
overnight. Fentanyl citrate (18) was obtained as a white solid
(225 mg, 95%). 1H NMR (600 MHz, D2O) d 7.5327.47 (m, 3H),
7.3627.33 (m, 2H), 7.3027.26 (m, 1H), 7.2627.22 (m, 4H),
4.7724.61 (m, 1H) (overlaps with HOD), 3.6223.58 (m, 2H),
3.3123.28 (m, 2H), 3.11 (td, J = 13.2, 2.4, 2H), 2.9922.96 (m,
2H), 2.87 (d, J = 15.6, 2H), 2.73 (d, J = 15.6, 2H), 2.1222.10 (m,
2H), 1.74 (s, 3H), 1.58 (qd, J = 14.4, 3.0, 2H); 13C NMR (150
MHz, D2O) d 178.3, 174.5, 174.1, 137.6, 136.3, 129.8, 129.7,
129.3, 129.1, 128.8, 127.4, 73.7, 57.6, 52.1, 49.9, 48.9, 43.6, 29.8,
27.4, 22.5; TOF-MS (ESI) m/z calcd for C21H27N2O [M+H+]:
323.2118; found 323.2127; Anal. Calcd for C27H34N2O8: C,
63.02; H, 6.66; N, 5.44. Found: C, 63.38; H, 6.69; N, 5.78.
N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine (21)
Aniline (0.53 mL, 5.7 mmol) was taken up in methylene
chloride (50 mL) in a 250 mL round-bottom flask equipped with
a stir bar. The light brown solution was placed on an ice bath and
treated dropwise with acetic acid (0.32 mL, 5.7 mmol). To the
mixture, N-[2-(2-thienyl)ethyl]-4-piperidinone (20) (1.2 g,
5.7 mmol) was added as a solution in methylene chloride
(30 mL), followed by the careful, slow addition of sodium
triacetoxyborohydride (1.8 g, 8.6 mmol, 1.5 equiv.) in small
portions. The reaction mixture was stirred at ambient temperature
for 14 h. After this time, methanol (40 mL) was added to the
mixture and all contents transferred to a separatory funnel. The
mixture was partitioned (CH2Cl2//saturated NaHCO3). Once
neutralized, the organic phase was washed with brine (NaCl/H2O,
3650 mL), dried over Na2SO4 and concentrated in vacuo to give
a light brown oil. The oily mixture was purified by flash column
chromatography (1:1 R 9:1 EtOAc/hexanes) to give 21 as a light
yellow oil (1.42 g, 87%). Rf = 0.33 (7:3 EtOAc/hexanes); 1H NMR
(600 MHz, CDCl3) d 7.1827.15 (m, 2H), 7.13 (dd, J = 5.4, 1.2,
1H), 6.92 (dd, J = 5.4, 3.6, 1H), 6.8426.82 (m, 1H), 6.69 (tt,
J = 7.2, 0.6, 1H), 6.6226.58 (m, 1H), 3.52 (br, 1H), 3.3423.31 (m,
1H), 2.13 (t, J = 6.6, 2H), 2.9522.93 (m, 2H), 2.68 (t, J = 6.6, 2H),
2.22 (td, J = 13.2, 2.4, 2H), 2.1022.07 (m, 2H), 1.5421.51 (m,
2H); 13C NMR (150 MHz, CDCl3) d 147.1, 142.9, 129.3, 126.6,
124.6, 123.5, 117.2, 113.3, 60.0, 52.4, 49.9, 32.6, 28.0; HRMS
(CI) m/z calcd for C17H22N2S [M+]: 286.1504; found 286.1503;
Anal. Calcd for C17H22N2S: C, 71.29; H, 7.74; N, 9.78; Found: C,
71.16; H, 7.75; N, 9.66.
2-(Thiophen-2-yl)ethyl methanesulfonate (19) [32]
2-Thiophene ethanol (5.0 g, 39 mmol) was taken up in
methylene chloride (50 mL) in a 250 mL round bottom flask
and treated with triethylamine (TEA, 6.5 mL, 46.8 mmol). The
resulting dark brown solution was cooled with an ice bath and
treated with mesyl chloride (MsCl, 3.7 mL, 46.8 mmol, 1.2
equiv.). The ice bath was removed and the resulting brown
solution was allowed to warm to ambient temperature where it was
stirred overnight. The brown solution was transferred to a
separatory funnel and partitioned (CH2Cl2//H2O). The organic
phase was washed with brine (NaCl/H2O, 3650 mL), satd.
NaHCO3 (1650 mL), dried over anhydrous Na2SO4 and
evaporated in vacuo at 50uC to give a brown oil that was purified
by flash column chromatography (hexanes R 3:7 EtOAc/
hexanes) to furnish thiophene mesylate 19 as a light brown oil
(6.76 g, 84%). Rf = 0.54 (3:7 EtOAc/hexanes); 1H NMR (600
MHz, CDCl3) d 7.91 (dd, J = 4.8, 0.6, 1H), 6.95 (dd, J = 5.4, 3.6,
1H), 6.9126.90 (m, 1H), 4.42 (t, J = 6.6, 2H), 3.27 (t, J = 6.6, 2H),
2.92 (s, 3H); 13C NMR (150 MHz, CDCl3) d 138.1, 127.1, 126.2,
124.5, 69.7, 37.4, 29.8; HRMS (CI) m/z calcd for C7H10O3S2
[M+]: 206.0071; found 206.0070.
Thiofentanyl (10)
N-phenyl-1-(2-(thiophen-2-yl)ethyl)piperidin-4-amine
(21)
(2.21 g, 7.74 mmol) was dissolved in methylene chloride (50 mL)
in a 100 mL round bottom flask equipped with a stir bar and was
treated with diisopropylethylamine (DIPEA, 2.0 mL, 1.5 g,
11.6 mmol, 1.5 equiv.). The solution was cooled with an ice bath
and treated dropwise with propionyl chloride (0.99 mL,
11.6 mmol). The resulting mixture was stirred for 2 h at ambient
temperature. The mixture was transferred to a separatory funnel
and partitioned (CH2Cl2//H2O). The organic phase was washed
with brine (NaCl/H2O, 1650 mL), satd. NaHCO3 (1650 mL),
dried over anhydrous Na2SO4 and evaporated in vacuo at 40uC to
give a yellow oil that was purified by flash column chromatogra-
phy (3:7 R 7:3 EtOAc/hexanes) to furnish thiofentanyl (10) as a
N-[2-(2-thienyl)ethyl]-4-piperidinone (20)
4-piperidone monohydrate hydrochloride (12) (2.22 g,
14.5 mmol) was dissolved in acetonitrile (80 mL) in a 250 mL
round-bottom flask equipped with a stir bar and a condenser. The
colorless solution was treated sequentially with cesium carbonate
(Cs2CO3, 10.4 g, 31.9 mmol, 2.2 equiv.) and 2-(thiophen-2-
yl)ethyl methanesulfonate (19) (3.0 g, 14.5 mmol) at ambient
temperature. The resulting suspension was vigorously stirred and
refluxed at 80uC for 5 h. After 5 hours, the mixture was cooled to
ambient temperature, transferred to a separatory funnel and
partitioned (CH2Cl2//H2O). The organic phase was washed with
1
light yellow oil (2.57 g, 97%). Rf = 0.28 (1:1 EtOAc/hexanes); H
NMR (600 MHz, CDCl3) d 7.3827.33 (m, 3H), 7.0927.06 (m,
2H), 6.88 (dd, J = 4.8, 3.0, 1H), 6.7726.75 (m, 1H), 4.67 (tt,
J = 12.0, 4.2, 1H), 2.9722.92 (m, 4H), 2.6122.58 (m, 2H), 2.17
(td, J = 12.0, 1.8, 2H), 1.91 (q, J = 7.8, 2H), 1.8121.78 (br s, 1H),
1.40 (qd, J = 11.4, 3.6, 2H), 1.00 (t, J = 7.8, 3H); 13C NMR (150
MHz, CDCl3) d 173.5, 142.6, 138.8, 130.4, 129.3, 128.3, 126.6,
124.5, 123.4, 60.0, 53.0, 52.1, 30.5, 28.5, 27.8, 9.6; HRMS (CI) m/
6
September 2014 | Volume 9 | Issue 9 | e108250