Organic Process Research & Development
ARTICLE
KHCO (150 mL). The layers were mixed, separated and the
1.45 (s, ∼10H, C(CH ) and OH), 1.63 (m, 1H), 1.76 (m, 1H),
3 3
3
organic layer was washed with 2 M KHCO (150 mL). To the
3.36 (s, 3H, CH O), 3.40 and 3.49 (ABC, J = 9.2 Hz, J = 3.5
3
3
AB
AC
combined aqueous layers, sodium chloride (300 g) and DCM
Hz, JBC = 4.0 Hz, 1H each, CH OCH ), 3.53 (m, 1H), 3.60 (m,
3 2
(
500 mL) was added, the layers were mixed, separated and the
1H), 3.67 (m, 1H), 3.94 (m, 1H, CHN), 4.97 (d br, J ∼8 Hz, 1H,
NH). ESI-MS: calcd for C H NO 219.1475; found 242.1368
aqueous layer was extracted with DCM (500 mL). All the organic
layers were combined, dried over sodium sulfate, filtered, eva-
porated and dried (40 °C/e10 mbar/1 h) to yield 9.5 g (75%) of
crude amino ester 17 as a light yellow oil; GC 99.9%. A sample of
crude 17 (2.3 g) was purified by distillation (75 °C/2-4 mbar)
to yield 2.1 g (89%) of pure 17 as colorless oil; GC 100%; ee
1
0
21
4
þ
þ
þ
(M þ Na) , 220.1551 (M þ H) , 164.0922 [(M þ H) - C H ] .
4
5.7. (S)-3-Hydroxy-1-methoxymethyl-propyl-ammonium
8
Chloride (1 HCl). A solution of 19 (23.87 g, 108.9 mmol) in
3
1.25 M hydrochloric acid in methanol (235 mL, 294 mmol) was
stirred at rt for 5 h. A continuous, slow gas evolution was observed.
The clear solution was further stirred at rt overnight. Evaporation
and drying (20 °C/0.01 mbar/33 h) afforded 17.89 g (105% by
2
0
1
9
9.5%; [R]
= -10.1 (1, CHCl ). H NMR (CDCl , 600
D
3
3
MHz): δ 1.65 (s very br, ∼3H, NH and H O), 2.34 and 2.49
2
2
(
ABX, J = 16.1 Hz, J = 8.7 Hz, J = 4.3 Hz, 1H each,
weight) of hydrochloride1 HCl as glassy oil; GC 96.7%; ee 99.4%;
AB
AX
BX
3
CH CO ), 3.27 and 3.34 (ABC, J = 9.1 Hz, JAC = 6.9 Hz, JBC
=
residual solvents 2.5 wt % methanol, 1.2 wt % water (Karl Fischer);
2
2
AB
1
4
.6 Hz, 1H each, OCH ), 3.37 (s, 3H, CH O), 3.42 (m, 1H,
corrected yield: 98% 1 HCl. H NMR (CDCl
3
, 600 MHz): δ 1.84
2
3
3
CHN), 3.70 (s, 3H, CO CH ). ESI-MS: calcd for C H NO
(m, 1H), 2.08 (m, 1H), ∼2.6 (very br, ∼2H, OH and ∼0.5 equiv
2
3
6
13
3
þ
1
47.0896; found 148.0969 (M þ H) .
.5. (S)-3-tert-Butoxycarbonylamino-4-methoxy-butyric
Acid Methyl Ester (18). A 2-L flask was charged with 17 HOAc
H
2
O), 3.43 (s, 3H, CH OH),
3
O),3.49(s,∼0.8H, ∼0.25 equiv CH
3
5
3.63 (∼dd, J = 9.8 and 4.3 Hz, 1H), 3.68 (m, 1H), 3.72 (m br, 1H,
CHN), 3.84 (m, 1H), 3.97 (m, 1H). Anal. Calcd for C H ClNO
3
5
14
2
(100 g, containing ∼0.3 mol equiv of HOAc, ∼444 mmol) and
(155.62): C 38.59, H 9.07, Cl 22.78, N 9.00; found C 37.88, H 8.98,
DCM (533 mL). The solution was cooled to 5 °C and triethyla-
mine (77.8 mL, 99.5%, 555 mmol) was added resulting in the
formation of a yellowish, slightly turbid solution. A solution of
di-tert-butyl dicarbonate (117.0 g, 99%, 531 mmol) in DCM
Cl total 21.93; N 8.89; H O 1.55 wt % (Karl Fischer).
2
’ AUTHOR INFORMATION
Corresponding Author
*
(200 mL) was added at 5-10 °C within 20 min. The reaction
Author for correspondence. E-mail: rudolf.schmid@roche.com
was slightly exothermic and gas evolution occurred. The reaction
mixture was stirred at rt for 2 h. GC analysis indicated complete
conversion. 4-Dimethylamino-pyridine (1.15 g, 98%, 9.2 mmol)
was added, resulting in strong gas evolution, and the mixture was
stirred at rt for 1 h and then quenched with sat. sodium hydrogen
carbonate solution (160 mL). The phases were separated, and the
organic phase was washed with sat. sodium hydrogen carbonate
solution (160 mL) and 0.1 N hydrochloric acid (330 mL), dried
over sodium sulfate, filtered, evaporated, and dried to provide
’ ACKNOWLEDGMENT
We thank Fabian Degen, Patrick Di Giorgio, Michel Lalonde,
Gerd Schaffner, Daniel Spiess, and Markus Steiner for their
skillful experimental assistance. We also thank Drs. Nicolas Burki,
Andreas St €a mpfli, Josef Schneider, and Jean-Claude Jordan and
their teams for analytical support.
1
17.9 g of a light-yellow oil. The material was dissolved in heptane/
’
REFERENCES
ethyl acetate 2:1 (50 mL) and filtered over silica gel (200 g) using
(
1) Yata, S.; Ozeki, H.; Wakitani, K. (Japan Tabacco). Eur. Pat. Appl.
EP 0717040 A1, 1996.
2) Le Grand, D. M.; McCarthy, C.; Walker, C. V.; Woods, J. J.
heptane/ethyl acetate 2:1 (2.0 L). Evaporation (45°C/g15 mbar/
2
h) provided 99.32 g (90% by weight) of Boc-amino ester 18 as
(
1
colorless oil; GC 98.4%. H NMR (CDCl , 600 MHz): δ 1.44 (s,
3
(Novartis AG). PCT Int. Appl. WO 2003/077907 A1, 2003.
9
H, C(CH ) ), 2.60 (m, 2H, CH CO ), 3.34 (s, 3H, CH O), 3.45
3 3 2 2 3
(3) For Rh-catalyzed asymmetric enamine hydrogenation see:
(m, 2H, OCH ), 3.68 (s, 3H, CO CH ), 4.11 (m br, 1H, CHN),
2 2 3
(a) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.; Njolito, E.; Wang,
F.; Sun, Y.; Armstrong, J. D., III; Grabowski, E. J. J.; Tillyer, R. D.;
Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918. (b) For a
review see: Shultz, C. S.; Krska, S. W. Acc. Chem. Res. 2007, 40, 1320.
4
.76 and5.12 (m br, 0.15 and0.85H, NH, rotamers). ESI-MS: calcd
þ
for C H NO 247.14211; found 270.1313 (M þ Na) , 248.1492
11
21
5
þ
(M þ H) .
(
4) For Ru-catalyzed asymmetric enamine hydrogenation see:
5.6. (S)-3-Hydroxy-1-methoxymethyl-propyl)carbamic Acid
Matsumura, K.; Zhang, X.; Saito, T. (Takasago Int. Corp.). Eur. Pat.
Appl. EP 1386901 A1, 2004.
tert-Butyl Ester (19). To a solution of 18 (92.0 g, 372 mmol)
in 2-methyltetrahydrofuran (850 mL) was added at rt lithium
borohydride (227 mL 2 M solution in THF, 435.8 mmol, 1.22
equiv). Methanol (30 mL, 748 mmol, 2.0 equiv) was added
dropwise to the clear solution within 40 min (exothermic). During
the addition the temperature was held in the range of 20-24 °C by
occasional cooling. GC analysis after 1.5 h reaction time indicated
complete conversion. The reaction mixture was stirred for an
additional 1.5 h, then quenched by addition within 5 min of acetone
(
5) For asymmetric reductive amination of β-keto esters see:
a) Matsumura, K.; Saito, T. (Takasago Int. Corp.). PCT Int. Appl.
WO 2005/028419, 2005. (b) Bunlaksananusorn, T.; Rampf, F. Synlett
005, 2682. (c) Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.;
(
2
Saito, T. Acc. Chem. Res. 2007, 40, 1385. (d) For asymmetric reductive
amination of β-keto amides see: Steinhuebel, D.; Sun, Y.; Matsumura,
K.; Sayo, N.; Saito, T. J. Am. Chem. Soc. 2009, 131, 11316.
(6) (a) Kinugawa, M.; Arai, H.; Nishikawa, H.; Sakaguchi, A.; Ogasa,
T.; Tomioka, S.; Kasai, M. J. Chem. Soc., Perkin Trans. 1 1995, 2677.
(102 mL, exothermic!) followed by addition within 10 min of 2 N
(
b) Oi, S.; Maezaki, H.; Suzuki, N. (Takeda Pharm. Comp. Ltd.). PCT
Int. Appl. WO 2005/042488 A1, 2005.
7) Iwanami, M.; Shibanuma, T.; Fujimoto, M.; Kawai, R.; Tamazawa,
K.; Takenaka, T.; Takahashi, K.; Murakami, M. Chem. Pharm. Bull. 1979, 27,
426.
8) Further methods tested to prepare 14 included NH OAc/
NaOH (900 mL). The mixture was stirred for 30 min, and the
clear phases were separated. The aq phase was extracted with
MTBE (2 ꢀ 350 mL). The combined organic phases were
washed with sat. sodium chloride solution (2 ꢀ 290 mL), dried
over sodium sulfate, filtered, evaporated, and dried to constant
(
1
(
4
weight (45 °C/10 mbar) to yield 71.67 g (88% by weight) of 19
HOAc/toluene/reflux and NH gas/cat. TsOH/toluene/reflux, both
3
1
as colorless oil; GC 98.65%. H NMR (CDCl , 600 MHz): δ
involving azeotropic removal of water. The former protocol turned out
3
3
58
dx.doi.org/10.1021/op1002775 |Org. Process Res. Dev. 2011, 15, 353–359