Improved Synthesis of Buprenorphine from Thebaine and/or Oripavine
then quenched with water (10 mL) and the products were
extracted with dichloromethane (2ꢂ5 mL). A saturated so-
lution of NH4Cl (1.5 mL) was added to the aqueous layer,
which was extracted with dichloromethane (2ꢂ5 mL). The
addition of saturated solution of NH4Cl followed by extrac-
tion was repeated twice, the pH of water layer was strongly
basic, and the mixture turned into a suspension. TLC analy-
sis of the aqueous layer indicated that no product remained.
The combined organic layers were washed with water, brine,
dried over Na2SO4 and concentrated. The products were iso-
lated by column chromatography (eluent EtOAc to di-
chloromethane+20% MeOH), providing 12 and 11 in the
yields shown in Table 2.
ACHTUNGTRENNUNG[5a,7a]-17-Acetyl-a-(1,1-dimethylethyl)-4,5-epoxy-18,19-
dihydro-6-methoxy-a-methyl-6,14-ethenomorphinan-7-meth-
anol amide (12): mp >2408C (MeOH); Rf =0.45 (ethyl ace-
1H), 2.26–2.10 (m, 2H), 1.97–1.78 (m, 2H), 1.55 (m, 1H),
1.37 (s, 3H), 1.27 (m, 1H), 1.18 (m, 1H), 1.09 (s, 9H), 0.88
(m, 1H), 0.76 (m, 1H); 13C NMR (150 MHz, DMSO): d=
146.2, 139.6, 131.0, 124.1, 120.2, 118.1, 93.8, 80.2, 79.1, 53.0,
52.5, 44.8, 41.9, 40.5, 35.7, 34.2, 31.7, 31.6, 29.6, 28.7, 26.7,
20.5, 18.7; MS (EI+): m/z (%)=43 (70), 57 (60), 324 (100),
338 (75), 356 (45), 381 (22), 395 (13), 413 (6); HR-MS:
m/z=413.2572, calcd. for C25H35NO4: 413.2566.
[O-Methylnorbuprenorphine cyclopropylcarbox-
amide], [5a,7a(R)]-17-(Cyclopropylcarbonyl)-a-(1,1-
dimethylethyl)-4,5-epoxy-18,19-dihydro-3,6-
dimethoxy-6,14-ethenomorphinan-7-methanol (13)
tate); IR (CHCl3): n=3583, 3390, 3000, 2981, 2876, 1626,
1504, 1457, 1370, 1310, 1159, 1090 cmÀ1; ratio of isomers
1:1.5; HR-MS: m/z=455.2663, calcd. for C27H37NO5:
455.2672.
Major isomer: 1H NMR (600 MHz, CDCl3): d=6.77 (d,
J=8.1 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 5.81 (s, 1H, OH),
4.87 (d, J=7.1 Hz, 1H), 4.46 (s, 1H), 3.65 (dd, J=14.2,
5.5 Hz, 1H), 3.55 (s, 3H), 3.36 (ddd, J=13.5, 13.5, 3.8 Hz,
1H), 2.88 (m, 1H), 2.74 (d, J=18.6 Hz, 1H), 2.17 (s, 3H),
2.09 (m, 1H), 1.99 (m, 1H), 1.94–1.75 (m, 5H), 1.54 (dd, J=
13.1, 9.2 Hz, 1H), 1.34 (s, 3H), 1.25–1.19 (m, 1H), 0.99 (s,
9H), 0.76–0.69 (m, 1H); 13C NMR (150 MHz, CDCl3): d=
169.0, 145.7, 138.0, 131.1, 126.2, 120.2, 117.3, 96.66, 80.4,
79.4, 52.7, 49.7, 46.4, 43. 8, 40.3, 38.8, 35.5, 34.9, 32.6, 32.1,
28. 6, 26.4, 21.6, 20.1, 17.8.
The mixture of intermediate
6
(88 mg, 0.20 mmol),
Cu(OAc)2 (2 mg,
Pd(OAc)2 (2.2 mg, 0.01 mmol),
G
ACHTUNGTRENNUNG
0.01 mmol), cyclopropylcarboxylic acid anhydride (210 mg,
1.40 mmol) and dioxane (1 mL) was stirred under an oxygen
atmosphere at 1008C for 39 h. Then the mixture was evapo-
rated to a thick oil and diluted with dichloromethane
(10 mL). The resulting mixture was washed with a saturated
solution of NaHCO3 (10 mL) and after separation the aque-
ous layer was extracted with dichloromethane (3ꢂ5 mL).
Combined organic layers were washed with water, brine,
dried over Na2SO4 and concentrated. Column chromatogra-
phy (eluent EtOAc:hexane=1:1) afforded amide 13; yield:
98 mg (95%); ratio of isomers 1:1.5; mp 103–1058C
(MeOH, mixture of isomers); Rf =0.70 (ethyl acetate); IR
(CHCl3): n=3397, 3002, 2957, 2841, 1628, 1503, 1453, 1440,
1162, 944 cmÀ1; MS (EI+): m/z (%)=41 (68), 56 (55), 69
(100), 86 (89), 124 (19), 167 (15), 406 (29), 438 (25), 495 (1);
HR-MS: m/z=495.2990, calcd. for C30H41NO5: 495.2985.
Major isomer: 1H NMR (600 MHz, CDCl3): d=6.76 (d,
J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 5.77 (s, 1H), 4.85
(d, J=7.1 Hz, 1H), 4.44 (s, 1H), 4.06 (dd, J=14.1, 5.0 Hz,
1H), 3.89 (s, 3H), 3.55 (s, 3H), 3.38 (ddd, J=13.7, 13.7,
3.6 Hz, 1H), 2.91 (m, 1H), 2.77 (d, J=18.6, 1H), 2.06 (dd,
J=9.8, 9.8 Hz, 1H), 2.01–1.92 (m, 2H), 1.92–1.81 (m, 3H),
1.77 (m, 1H), 1.47 (d, J=12.6, 1H), 1.32 (s, 3H), 1.20 (m,
1H), 1.10 (m, 1H), 0.97 (s, 9H), 0.86 (m, 1H), 0.73–0.83 (m,
Minor isomer: 1H NMR (600 MHz, CDCl3): d=6.78 (d,
J=8.1 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 5.81 (s, 1H, OH),
4.57 (dd, J=13.9, 5.6 Hz, 1H), 4.46 (s, 1H), 3.85 (d, J=
6.8 Hz, 1H), 3.56 (s, 3H), 3.00–2.88 (m, 2H), 2.81 (ddd, J=
13.4, 13.4, 4.0 Hz, 1H), 2.15 (m, 2H), 2.13 (s, 3H), 1.94–1.75
(m, 5H), 1.44 (m, 1H), 1.36 (s, 3H), 1.19–1.14 (m, 1H), 0.99
(s, 9H), 0.81–0.76 (m, 1H); 13C NMR (150 MHz, CDCl3):
d=168.9, 145.7, 138.1, 131.1, 125.4, 120.1, 117.4, 96.3, 80.3,
79.3, 56.1, 52.7, 46.3, 43.3, 40.4, 36.1, 33.9, 33. 6, 32.8, 32.7,
29.0, 26.4, 21.7, 20.1, 18.0; MS (+EI) m/z (%): 43 (100), 57
(48), 84 (82), 366 (68), 380 (78), 398 (51), 423 (6), 455 (3).
Norbuprenorphine (11): mp 227–2308C (EtOH); Rf =
0.24 (DCM+20% methanol); [a]2D0: À80.1 (c 1.0, MeOH);
IR (CHCl3): n=3587, 3397, 2957, 2848, 1598, 1460,
1124 cmÀ1 1H NMR (600 MHz, CDCl3): d=6.79 (d, J=
;
8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 5.75 (s, 1H, OH), 4.49
(s, 1H), 3.55 (s, 3H), 3.52 (m, 1H), 3.33 (m, 1H), 3.21 (m,
1H), 3.07 (m, 1H), 2.93 (dd, J=18.8, 6.3 Hz, 1H), 2.85 (m,
Adv. Synth. Catal. 2012, 354, 613 – 626
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
621