G Model
CCLET 3861 No. of Pages 6
X.-Y. Wu et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
5
a 2D0
ꢄ
+ 138 (c 1, CHCl3). 1H NMR (400 MHz, CDCl3):
CH3), 0.89 (s, 3H, 19-CH3), 2.02–2.11 (m, 1H, 16 -H), 2.41–2.65 (m,
6H, 16 -H and 2
-H and 2-NCH2 ꢃ 2), 3.36 (s, 1H, OH), 3.66–3.74
(m, 4H, 2-OCH2 ꢃ 2), 3.85–3.90 (m, 1H, 3 -H). HRMS: (ESI+) calcld.
for C23H37NO3Na+ [M+Na]+ 398.2666, found 398.2670.
d 0.86 (s, 3H, 18-
the solvent was removed to afford compound 6 (27.8 mg, 92.7%) as
white solid without further purification. Mp: 215–218 ꢁC (Lit. [13]
½
a
212–219 ꢁC); ½a D
1H NMR (400 MHz, CDCl3):
CH3), 2.42–2.76 (m, 9H, 16-NCH2 ꢃ 2, 2
2.95 (m, 1H,16 -H), 3.38–3.40 (m, 1H,17
OCH2 ꢃ 2), 3.83–3.89 (m, 1H, 3 -H). HRMS: (ESI+) calcld. for
27H46N2O3Na+ [M+Na]+ 469.3401, found 469.3398.
ꢄ
20 + 86.2 (c 0.5, CHCl3) (Lit. [13] +87.9, c 1.02, CHCl3).
0.70 (s, 3H, 18-CH3), 0.86 (s, 3H, 19-
-H and 2-NCH2 ꢃ 2), 2.91–
-H), 3.65–3.74 (m, 4H, 2-
b
a
d
b
a
a
a
4.4. Synthesis of 3
androstan-17-one (4)
a
-hydroxy-2
b
-(4-morpholinyl)-16
a
-bromo-5
a-
b
C
To a solution of compound 3 (550 mg, 1.46 mmol) in anhydrous
methanol (20 mL) at a dried 50 mL round-bottom flask was added
CuBr2 (1.31 g, 5.84 mmol) in portions. The mixture was heated to
reflux for 30 h under argon. Then the mixture was cooled to room
temperature and concentrated in vacuum. The residue was
dissolved in 12.5% ammonia solution (40 mL) and stirred for
10 min, and then extracted with EtOAc (30 mL). The organic layer
was separated and washed with another 12.5% ammonia solution
(40 mL), water (3 ꢃ 40 mL) and brine (30 mL), after that dried over
Na2SO4. The solvent was evaporated in vacuum and the residue
was purified by recrystallization with petroleum ether and acetone
to afford compound 4 (616 mg, 92.8%) as white solid. Mp: 141–
4.7. Rocuronium bromide
According to the method of literatures [12,13], compound 6 was
used as material to provide rocuronium bromide as white solid.
Mp: 162–166 ꢁC (Lit. [13] 161–169 ꢁC); ½a D
[13] +18.7, c 1.03, CHCl3). 1H NMR (600 MHz, CDCl3):
18-CH3), 0.85 (s, 3H, 19-CH3), 2.21 (s, 3H, OCH3), 2.56 and 2.68
(br ꢃ 2, 5H, 2 -H and 2-NCH2 ꢃ 2), 3.73–3.92 (m, 9H, 16-NCH2 ꢃ 2,
2-OCH2 ꢃ 2 and -H), 4.10–4.19 and 4.29–4.33 (m ꢃ 2, 2H,
CꢂꢂCH2), 4.53 (br, 1H, OH), 5.21 (d, 1H, J = 8.4 Hz, 17 -H),
5.68–5.72 (m, 2H, C CH2), 6.12–6.22 (m, 1H, C
CH). 13C NMR
(150 MHz, CDCl3):
ꢄ
20 + 18.9 (c 0.5, CHCl3) (Lit.
0.79 (s, 3H,
d
a
3
b
C¼
a
¼
¼
d
13.71, 16.45, 20.84, 21.40 (C ꢃ 2), 24.52, 27.75,
145 ꢁC; ½a 2D0
ꢄ
+ 101 (c 0.5, CHCl3). 1H NMR (400 MHz, CDCl3):
-H), 2.52–
-H and 2-NCH2 ꢃ 2), 3.39 (br, 1H, OH),
3.74 (s, 4H, 2-OCH2 ꢃ 2), 3.90–3.93 (m, 1H, 3 -H), 4.09 (t, 1H, 16
H, J = 8.8 Hz). 13C NMR (150 MHz, CDCl3):
14.20, 16.68, 20.44,
d 0.90
28.25, 31.30, 33.27, 33.77, 34.57, 35.96, 37.71, 38.43, 43.27, 45.36,
46.90 (C ꢃ 2), 49.38, 52.20, 54.99 (C ꢃ 2), 61.13, 63.83 (C ꢃ 2), 65.36,
66.62, 77.98, 125.89, 128.80, 168.80.
(s, 3H,18-CH3),1.07 (s, 3H,19-CH3), 2.11–2.24 (m,1H,15
a
2.69 (m, 6H, 15b-H and 2a
b
a-
d
Acknowledgment
27.77, 29.65, 30.27, 32.37, 32.55, 33.99, 34.20, 34.29, 35.91, 38.43,
46.29, 47.79, 47.85, 55.72 (C ꢃ 2), 63.64, 64.92, 67.24 (C ꢃ 2), 213.30.
HRMS: (ESI+) calcld. for C23H36BrNO3Na+ [M+Na]+ 476.1771, found
476.1768.
We are grateful for support from the National Natural Science
Foundation of China (No. 81373259 & No. 81573286).
Appendix A. Supplementary data
4.5. Synthesis of 3
a-hydroxy-2b-(4-morpholinyl)-16b-(1-
pyrrolidinyl)-5 -androstan-17-one (5)
a
Supplementary data associated with this article can be found, in
Under argon protection, pyrrolidine (185 mL, 2.2 mmol) was
taken into to a dried 25 mL two-neck round bottom flask in the
stirred solution of compound 4 (200 mg, 0.44 mmol) in anhydrous
acetonitrile (10 mL). The entire mixture was heated under reflux
for 8 h. Then the reaction was cooled to room temperature and
concentrated in vacuo. The residue was added with 2% HCl aqueous
solution (15 mL) and extracted with EtOAc (20 mL). The pH value of
the aqueous layer was adjusted with saturated sodium carbonate
solution to pH 9–10 and then filtered to remove the solid. EtOAc
(20 mL) was added into the aqueous layer. After stirring for 10 min,
organic layer was separated and washed with deionized water
(3 ꢃ 20 mL) and brine (20 mL) followed by drying over Na2SO4. The
solvent was removed in vacuum and the residue was purified by
flash column chromatography to afford compound 5 (164 mg,
83.7%) as light yellow solid. Mp: 177–183 ꢁC (Lit. [36] 185 ꢁC);
References
20 + 78.6 (c 0.5, CHCl3) (Lit. [36] +79, c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): 0.86 (s, 3H, 18-CH3), 0.99 (s, 3H,19-CH3), 2.40–
2.49 (m, 5H,16-NCH2 ꢃ 2, 2 -H), 2.66 (br, 4H, 2-NCH2 ꢃ 2), 3.72 (br,
5H, 2-OCH2 ꢃ 2 and 16 -H), 3.86–3.92 (m, 1H, 3 -H). HRMS: (ESI+)
calcld. for C27H44N2O3Na+ [M+Na]+ 467.3244, found 467.3241.
½ ꢄ
a D
[10] J.A. Mendez, M.A. De La Mora, A. Guillen, et al., Processes for the synthesis of
rocuronium bromide, U.S. Patent US20070117975 (issued May 24, 2007).
[11] E. Adar, D. Sondack, O. Friedman, et al., Processes for the preparation of
rocuronium bromide and intermediates thereof, U.S. Patent US20050159398
(issued July 21, 2005).
d
a
a
b
4.6. Synthesis of 2
androstan-3 ,17 -diol (6)
b-(4-morpholinyl)-16b-(1-pyrrolidinyl)-5a-
[12] T. Sleigh, D.S. Savage, I.C. Carlyle, Novel
2b-morpholino-androstane
a
b
derivatives, U.S. Patent US4894369 (issued June 16, 1990).
[13] J.A. Mendez, M.A. De La Mora, A.A. Rodriguez, et al., Process for the synthesis of
rocuronium bromide, WIPO Patent WO2007033348A3 (issued March 22,
2007).
[14] G. Nadamuni, C.S. Venkatesan, P.M. Senthilkumar, Process for the preparation
of rocuronium bromide and intermediate thereof, WIPO Patent
WO2009016648A (issued February 5, 2009).
To a solution of compound 5 (30.0 mg, 0.0675 mmol) in
methanol (2 mL) at a 10 mL round-bottom flask was added NaBH4
(8 mg, 0.21 mmol) carefully at ꢂ3 ꢁC. The mixture was stirred for
2 h at the temperature. CH2Cl2 (10 mL) and deionized water (15 mL)
was added, and the mixture was stirred for another 10 min to
quench the reaction. The organic layer was separated and washed
with water (3 ꢃ10 mL) and brine (10 mL). After drying over Na2SO4,
Please cite this article in press as: X.-Y. Wu, et al., A new and efficient method for the synthesis of rocuronium bromide, Chin. Chem. Lett. (2016),