Organic Process Research & Development
Technical Note
added to quench the reaction, and the pH of the aqueous
solution was adjusted to 7−8; this mixture was extracted with
ethyl acetate (150 mL × 3). The combined organic phase was
washed with brine and dried over anhydrous magnesium
sulfate. After removal of solvent by vacuum distillation, an oily
liquid was obtained (58.0 g, HPLC: 77.73%, yield: 98%), and
the product can be used in the next step without further
purification.
1.26 Hz, 2H), 3.36 (d, J = 4.56 Hz, 1H), 3.32 (s, 3H), 3.25−
3.30 (m, 1H), 2.71−2.72 (d, J = 4.86 Hz, 1H), 2.42−2.50 (m,
1H), 2.06 (t, J = 6.68 Hz, 2H), 1.82−1.84 (m, 1H), 1.62−1.68
(m, 1H), 0.94−0.99 (m, 6H).
(2R,5S)-3,6-Diethoxy-2-isopropyl-5-((S)-2-(4-methoxy-3-
(3-methoxypropoxy)benzyl)-3-methylbutyl)-2,5-dihydropyr-
azine (9). 8 (34.7 g, 0.165 mol) and 160 mL of anhydrous THF
were added to a 500-mL, three-necked bottle, and cooled to
about −78 °C with dry ice/acetone bath. n-BuLi solution (2.5
M, 87.8 mL) was added at this temperature. The mixture was
mechanically stirred for 50 min, and 7 (49.3 g, 0.137 mol) in
240 mL anhydrous THF was added. After addition of 7 was
completed (monitored by TLC, PE/EA = 4/1), saturated
(
R)-2-(4-Methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl-
butanoic Acid (5). H O (95.5 mL of a 30% solution) was
2
2
added to a solution of 300 mL of THF, 200 mL water, and 4
65.8 g, 0.14 mol) in a 1-L, three-necked bottle at 0 °C.
(
Lithium hydroxide monohydrate (11.8 g, 0.28 mol) was added,
and the mixture was mechanically stirred at room temperature.
After reaction with 4 was completed (monitored by TLC, PE/
EA = 8/1), 1.5 M sodium sulfite was added in ice bath until the
Starch-KI did not change color. THF was removed by vacuum
distillation, and a saturated solution of sodium bicarbonate was
added to the aqueous solution to adjust the pH to 9. The
aqueous solution was extracted with dichloromethane (75 mL
NH Cl solution (150 mL) was added to quench the reaction.
4
The mixture was extracted with ethyl acetate (100 mL × 3).
The combined organic layer was washed with brine and dried
over magnesium sulfate. After removal of solvent by vacuum
distillation, oily liquid was obtained (67 g, HPLC: 75.82%,
yield: 99%), and the product can be used in the next step
without further purification.
×
3), and the organic layer was discharged. The pH of the
( 2 S , 4 S ) - E t h y l 2 - a m i n o - 4 - ( 4 - m e t h o x y - 3 - ( 3 -
methoxypropoxy)benzyl)-5-methylhexanoate hydrochloride
(TM10) and (2S,4S)-2-amino-4- (4-methoxy-3- (3-methoxy
propoxy)benzyl)-5-methylhexanoic Acid (11). The mixture of
9 (79 g, 0.161 mol), 150 mL methanol, and 1 N HCl was
mechanically stirred overnight. After 9 was completely
(monitored by TLC, PE/EA = 4/1), removal of methanol by
vacuum distillation, the crude product of 10 was obtained.
NaOH (10 N solution) was added to adjust the pH to 12−13,
and the mixture was mechanically stirred at room temperature.
After the hydrolysis completed (monitored by HPLC), 2 N
HCl was added to adjust the pH to about 9 and was further
acidified with acetic acid to pH 4−5. After cooling to room
temperature and standing for about 2 h, the suspension was
filtered, and the filtered cake was dried by vacuum and
recrystallized from fresh water. Enough pure 11 was obtained
after drying (46.5 g, HPLC: 98.44%; yield: 98% for two steps).
aqueous remains was adjusted to about 3 with 3 N HCl, and
the mixture was extracted with dichloromethane (100 mL × 3).
The combined organic layer was washed with brine and dried
over magnesium sulfate. After removal of the solvent by
vacuum distillation, an oily liquid was obtained (25.6 g, HPLC:
1
9
5.78%, yield: 59%). H NMR (300 MHz, CDCl ) δ 6.68−6.76
3
(
m, 3H), 4.07 (t, J = 12.92 Hz, 2H), 3.80 (s, 3H), 3.55 (t, J =
1
2
2.01 Hz, 2H), 3.34 (s, 3H), 2.76−2.80 (m, 2H), 2.45 (m, 1H),
.03−2.07 (m, 2H), 1.92−1.94 (m, 1H), 0.98−1.04 (m, 6H).
(
R)-2-(4-Methoxy-3-(3-methoxypropoxy)benzyl)-3-methyl-
butan-1-ol (6). 5 (29.8 g, 96 mmol) in 120 mL THF was added
to a solution of NaBH (3.7 g, 96 mmol), 30% BF .Et O 21.8 g
and 60 mL THF under nitrogen atmosphere. The mixture was
mechanically stirred at room temperature for 5 h. Saturated
NH Cl solution 120 mL was added to quench the reaction, and
THF was removed by vacuum distillation. The aqueous was
extracted with ethyl acetate (50 mL × 3). The combined
organic layer was washed with brine and dried over magnesium
sulfate. After removal of the solvent by vacuum distillation, oily
liquid was obtained (26.5 g, HPLC: 87.56%, yield: 93%), and
the product can be used in the next step without further
purification. An analytical sample of 6 was purified by SiO2
4
3
2
4
Further purification may be achieved by repeating the same
1
recrystallization. H NMR (300 MHz, DMSO-d ) δ 6.70−6.83
6
(
m, 3H), 3.96 (t, J = 6.63, 2H), 3.70 (s, 3H), 3.46 (t, J = 6.60
Hz, 2H), 3.23(3H, s), 2.56−2.60 (t, J = 4.52 Hz, 1H), 2.28 (s,
H), 2.08 (s, 1H), 1.90−1.98 (m, 2H), 1.80 (s, 1H), 1.58−1.60
m, 3H), 0.73−0.79 (m, 6H). MS (ESI, m/z) calculated for
1
(
+
1
C H NO ([M + H] ) 354.2279, found 354.2275.
column chromatography (PE/EtOAc = 8/1). H NMR (300
19 32
5
MHz, CDCl ) δ 6.68−6.77 (m, 3H), 4.08 (t, J = 6.12 Hz, 2H),
3
AUTHOR INFORMATION
Corresponding Author
Notes
3
1
1
.81 (s, 3H), 3.51−3.57 (m, 4H), 3.33 (s, 3H), 2.58−2.60 (m,
H), 2.40−2.47 (m, 1H), 2.03−2.09 (m, 2H), 1.82−1.83 (m,
H), 1.58−1.61 (m, 2H), 0.92−1.95 (m, 6H).
■
(
R)-4-(2-(Bromomethyl)-3-methylbutyl)-1-methoxy-2-(3-
methoxypropoxy)benzene (7). PBr (8.2 g, 30 mmol) in 60
3
The authors declare no competing financial interest.
mL dichloromethane was added to a three-necked bottle and
cooled to 0 °C with an ice bath. 6 (25.5 g, 86 mmol) in 100 mL
of dichloromethane was added at this temperature, and the
mixture was mechanically stirred. After addition of 6 was
completed (monitored by TLC, PE/EA = 4/1), 100 mL water
was added to quench the reaction. The organic layer was
separated, washed with water twice, and dried over sodium
sulfate. After removal of the solvent by vacuum distillation and
recrystallization from hexane (250 mL), 28.2 g of white solid
was obtained (HPLC: 90.38%; yield: 91%). An analytical
ACKNOWLEDGMENTS
■
This project was financially supported by Hisoar Pharmaceut-
icals Co., Ltd., Zhejiang, China and also Chinese Academy of
Sciences.
REFERENCES
■
(
1) (a) Maibaum, J.; Feldman, D. L. Annu. Rep. Med. Chem. 2009, 44,
1
05−127. (b) Jensen, C.; Herold, P.; Brunner, H. R. Nat. Rev. Drug
Discovery 2008, 7, 399−410. (c) Siragy, H. M.; Kar, S.; Kirkpatrick, P.
Nat. Rev. Drug. Discovery 2007, 6, 779−780.
sample of 7 was obtained by SiO column chromatography
2
1
(
(
PE/EtOAc = 4/1). H NMR (300 MHz, MeOD) δ 6.69−6.77
m, 3H), 4.08 (t, J = 6.52 Hz, 2H), 3.79 (s, 3H), 3.54 (t, J =
(2) (a) Herold, P.; Stutz, S.; Spindler, F. WO Pat. Appl. 2002/
002508A1, 2002. (b) Herold, P.; Stutz, S. WO Pat. Appl. 2002/
1
461
dx.doi.org/10.1021/op400205k | Org. Process Res. Dev. 2013, 17, 1458−1462