Organic Process Research & Development
TECHNICAL NOTE
Table 4. Comparison of Diastereomeric Ratio of 15R-Isomer
2 with DEANB from Different Vendors
organic layer was washed with 1.5 N hydrochloric acid (2 Â 1 L),
water (2 Â 1 L) and saturated sodium chloride solution (1 L),
dried using anhydrous sodium sulphate, filtered, and evaporated
under vacuum. The crude product obtained gave a 95:5 epimeric
mixture of 15S-isomer and 15R-isomer 2. The epimers were
separated by flash column chromatography on silica gel of 230À400
mesh using ethyl acetate and petroleum ether solvents. This
purification step provided 15R-isomer 2 as a solid (315 g) in 63%
scale (g)
vendor
dr
100
200
500
S-A
95:5
95:5
96:4
BASF
BASF
yield with mp 130À133 °C and [α]25 À93.8° (c 1.0 in
D
1
Sigma-Aldrich and BASF and used for scale-up studies that
showed no much difference in the selectivity using that reagent
from either source.
The diastereomeric ratio and chemical purities of scale-up
batches are shown in Table 4.
acetonitrile). NMR (400 MHz, CDCl3) δ 2.30 (m, 1H), 2.44
(s, 1H), 2.59 (m, 2H), 2.84 (m, 3H), 3.88 (m, 2H), 4.57 (m, 1H),
5.10 (m, 1H), 5.32 (m, 1H), 5.76 (m, 2 H); 7.03 (dd, J = 8 Hz, 2
Hz, 1H), 7.13 (s, 1H), 7.23 (d, J = 8 Hz, 1H), 7.36 (m, 4H), 7.61
(m, 4H), 8.06 (d, J = 8 Hz, 2H).
’ CONCLUSION
’ AUTHOR INFORMATION
We have demonstrated that the use of DEANB/(R)-Me CBS
as reducing agent in a process for the manufacture of Travoprost
intermediate 15R-isomer 2 provides high selectivity with good
yields. The results from numerous multigram batches have proved
that DEANB is a superior source of boron in the reduction
reactions than DMSB.
Corresponding Author
*Tel: +91 2808 2438. Fax: +91 2808 2303. E-mail: chandrashekar.
’ ACKNOWLEDGMENT
We thank Dr. P. V. Srinivas for his continued advice and M/s.
Biocon Ltd. for technical and analytical support.
’ EXPERIMENTAL SECTION
General. All the reagents, raw materials, and solvents were
purchased from commercial suppliers and used without further
purification. All of the reactions were conducted under atmo-
sphere of nitrogen unless noted otherwise. Reactions were mon-
itored for completion by removing a small sample from the re-
action mixture and analyzing by TLC or HPLC. TLC was per-
formed using one of the following systems: 2:1 or 1:1 ethyl
acetate/hexane visualized under UV or with Dragendrorff re-
agent. HPLC analysis was performed at an ambient temperature
on a reversed phase stable bond Zorbax SB C8 5 μm column
using a mobile phase consisting of 20 mM ammonium acetate
and acetonitrile with 70% of ammonium acetate for the first
5 min, changing to 30% ammonium acetate in 17 min and 10%
ammonium acetate in 22À25 min at a flow rate of 1.2 mL. The
detector was set at 220 nm. The normal phase chromatogrphic
separation was performed at ambient temperature on a silica
5 μm column using a mobile phase consisting of 900 mL of
n-hexane and 100 mL aof bsolute alcohol at a flow rate of 1.0 mL.
The detector was set at 220 nm.
Synthesis of 15R-Isomer (3aR,4R,5R,6aS)-4-((R,E)-3-Hydro-
xy-4-(3-(trifluoromethyl)phenoxy)but-1-enyl)-2-oxohexa-
hydro-2H-cylopenta[b]furan-5-yl Biphenyl-4-carboxylate 2.
Detailed description of the process on 500 g scale is as follows.
(R)-Me CBS (181 mL, 1 M solution in toluene) was charged
along with tetrahydrofuran (5 L) under nitrogen atmosphere,
and the mixture was stirred at 25 ( 5 °C. N,N-Diethylaniline-
boarane (370 g) was added in a slow stream and stirred for 30
min at 25 ( 5 °C. The contents were cooled to À15 ( 5 °C, and
to this mixture was added enone 1 solution (500 g dissolved in
1 L of THF) in about 30 min. The temperature of the reaction
mass was increased to 0 ( 5 °C, and the mixture was stirred at
that temperature for 1 h. The reaction completion was monitored
by TLC. The reaction was quenched with methanol (2 L) at
0 ( 5 °C and stirred at 25 ( 5 °C for 10 min. To the above mass
was added 1.5 N hydrochloric acid (2 L), the mixture was stirred
at 25 ( 5 °C for 10 min, diluted with ethyl acetate (5 L) and
water (5 L), and stirred, and the layers were separated. The
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