Removal of pinanol via continuous steam distillation

Article abstract of DOI:10.1021/op010209c

A practical procedure for the efficient removal of pinanol from the reaction mixture has been developed. The process was based on the observation that pinanol can be easily removed by steam distillation in the laboratory. On-scale, a continuous countercurrent column stripper was implemented to remove pinanol.

Full text of DOI:10.1021/op010209c

Organic Process Research & Development 2002, 6, 301−303
Removal of Pinanol via Continuous Steam Distillation
Atul S. Kotnis,* Dale Vanyo, Sushil Srivastava, Ambarish K. Singh, Joseph Bush, J. Siva Prasad, Donald C. Kientzler,
Edward J. Delaney, and San Kiang
Process Research and DeVelopment, Bristol-Myers Squibb Pharmaceutical Research Institute, One Squibb DriVe,
P.O. Box 191, New Brunswick, New Jersey 08903-0191, U.S.A.
Abstract:
Table 1. Preparation of crude I
A practical procedure for the efficient removal of pinanol from
the reaction mixture has been developed. The process was based
on the observation that pinanol can be easily removed by steam
distillation in the laboratory. On-scale, a continuous counter-
current column stripper was implemented to remove pinanol.
mol of
CpNa
crude oil
amount of I by
(I) kg
HPLC quantitation kg
14.3
9.5
159
138
1.7
15.6
14.5
1
1
19.7
08.6
Table 2. Pinanol removal and isolation of I
The chiral hydroboration-oxidation sequence developed
by the Brown group is one of the most powerful and
commonly used protocols to prepare chiral alcohols from
before pinanol
after pinanol
removal oil/HPLC time spent removal oil/HPLC overall
quantitation
kg/kg
in pinanol
removal h
quantitation
kg/kg
yield
%
1
olefins. Although this protocol has been used extensively,
the major limitation to this approach, especially on-scale, is
the generation of undesired chiral pinanol as the byproduct.
Pinanol, a high boiling liquid (bp 219 °C), can be removed
by steam distillation, but the process is Wery tedious and slow
and is often a serious pratical problem which hinders the
application of this protocol on-scale. In connection with our
efforts to prepare clinical supplies of entecavir, a novel
carbocylic 2′-deoxyguanosine analogue with potent and
selective anti-HBV activity, the need arose to remove pinanol
on scale. This report describes a practical procedure to
remove pinanol by continuous steam distillation. Entecavir
has been asymmetrically synthesized in 10 steps in 18%
overall chemical yield and >99% optical purity.2
a,c
9.5/1.7a
16
91
32
3.3/1.3
24.2/12.1
16.3/13d
45
a
c
1
1
59/15.6
49
38/14.5a
a,b
59
c
a
The ratio of pinanol to I at the beginning of the distillation was 17:1, and
b
it was lowered to a final ratio of 1:16 at the end of the distillation. In this
batch, a 12-in. diameter Schott column was used, compared to a 3-in. column in
the previous two runs, thereby significantly reducing the removal time. The
operating parameters are as follows:
c
In these batches, crude oil of I was subjected to Darco G-60 treatment after
pinanol removal. The quality of isolated I was dependent on two factors. The
quality of the supplied CpNa from the vendor and the efficiency of the continuous
steam distillation. The quality of the CpNa for the last batch was the best, and
the use of the larger-diameter column with specialized Pro-pak packing greatly
improved the efficiency of the column in the steam distillation and hence resulted
in a better quality product (I) in the last run.
d
starting from readily available sodium cyclopenadienide
(CpNa). The synthesis of epoxide (III) from sodium cylco-
pentadienide is outlined below in Scheme 1.
The first intermediate I is prepared by alkylation of CpNa
with benzyloxymethyl chloride (BOMCl), followed by chiral
hydroboration-oxidation of the alkylated BOMCp (Scheme
The synthesis of entecavir uses the known chiral cyclo-
pentyl epoxide (III), which is prepared in a few steps
3
2
). Intermediate I possesses two of the three chiral centers
*
To whom correspondence should be addressed. E-mail: atul.kotnis@bms.
com. Telephone: (732) 519-3259. Fax: (732) 519-2531.
of entecavir and also sets up the introduction of the desired
epoxide, which affords the final chiral center.
(1) (a) Brown, H. C.; Pelter, A.; Smith, K. Borane Reagents; Academic Press:
1988. (b) Brown, H. C. Organic Synthesis Via Boranes; Wiley-Interscience
Publication, 1975. (c) Brown, H. C. Boranes in Organic Chemistry; Cornell
University Press: 1972 and references therein. (d) Brown, H. C.; Zweifel,
G. J. Am. Chem. Soc. 1964, 86, 393 (e) Brown, H. C.; Zweifel, G.;
Ayyangar, N. R. J. Am. Chem. Soc. 1964, 86, 397.
2) Bisacchi, G. S.; Caho, S. T.; Bachard, C.; Daris, P.; Innaimo, S.; Jacobs,
G. A.; Kocy, C.; Lapointe, P.; Martel, A.; Merchant, Z.; Slusarchyl, W.
A.; Sundeen, J. E.; Young, M. G.; Colonno, R.; Zahler, R. Bioorg. Med.
Chem. 1997, 127.
The asymmetric hydroboration followed by oxidation
gives a crude reaction mixture which contains the desired
alcohol (I), pinene, benzyl alcohol, and chiral pinanol. The
optimum amount of the chiral hydroborating agent used for
hydroboration of BOMCp was 1.5 equiv, thereby generating
nearly 3 equiv of chiral pinanol as an unwanted byproduct.
The presence of such high levels of pinanol interferes in the
successful epoxidation of I. Thus, the pinanol had to be
removed or its levels lowered significantly prior to the
epoxidation-esterification step, which affords II as the first
solid isolated intermediate in the synthesis (see Table 1).
(
(
3) (a) Biggadike, K.; Borthwick, A. D.; Evans, D.; Exall, A. M.; Kirk, B. E.;
Roberts, S. M.; Stephenson, L.; Youds, P. J. Chem. Soc., Perkin Trans. 1
1
988, 549. (b) Altmann, K.-H.; Kesselring, R. Synlett 1994, 853. (c)
Ezzitouni, A.: Barchi, J. M., Jr.; Marquez, V. E. J. Chem. Soc., Chem.
Commun. 1995, 1345. The methodology outlined to prepare I was originally
developed by Partridge, J. J.; Chadha, N. K.; Uskokovic, M. R. J. Am.
Chem. Soc. 1973, 95, 532.
1
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Published on Web 04/27/2002

Figure 1.
Scheme 1
Earlier efforts to isolate intermediate I as a golden-colored
a nearly colorless solution of I with <1% loss, during the
Darco treatment. The methanolic solution of I was solvent-
exchanged into water for the epoxidation-esterification
sequence.
oil involved distillation of the low-boiling components on a
rotary evaporator, followed by repeated short-path distillation
of the enriched material at 0.01-0.001 mm at 128 °C. The
scale-up of this approach requires the purchase of specialized
short-path wiped-film distillation equipment with a long lead
time.
In the laboratory, it was observed that the levels of pinanol
were significantly lowered by a simple steam distillation of
the crude reaction mixture by continuously charging water
to the reaction mixture and distilling water at 86-90 °C
under a vacuum of ∼50 mmHg. This protocol would
routinely generate a dark oil with pinanol levels of at 3-7%.
These levels of pinanol were well tolerated in the epoxida-
tion-esterification step. The crude oil I was dissolved in
methanol, and the methanol solution was refluxed in the
presence of Darco G-60 for 1 h. This procedure resulted in
Although steam distillation was successful on laboratory
scale, it was not practical for scale-up, and hence an efficient
process using a continuous-counter current steam distillation
was developed (Figure 1). Attempts to remove pinanol in a
single pass were tried in a 3-in. i.d. Scott glass column but
proved unfeasible due to the high amounts of pinanol present
in the crude oil (See note 1). A 12-in. i.d. Schott glass column
was packed with Pro-Pak 0.24-in. protruded stainless steel
random packaging. Steam was introduced from the bottom
of the column, and the column was maintained constantly
at ∼90 °C prior to the charge of the reaction mixture. Crude
reaction mixture from a feed tank was continuously intro-
duced from the top of the Schott column. The feed rate of
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Scheme 2
the crude mixture was adjusted to maintain good turbulence
and avoid any channeling during the steam distillation. This
counter-current mixing allowed for removal of volatiles
which were condensed and collected in the distillate receiver
Summary of Pilot Plant Results to Prepare I
Notes. (1) To obtain a high turbulence in the column we
had the feed ratio higher than we needed for a single pass,
and hence we recirculated the crude oil. Building constraints
prevented us from building a taller column.
(See note 2). The order of removal of the volatiles was
pinene, followed by benzyl alcohol, and finally pinanol. The
enriched crude reaction mixture was collected at the bottom
of the Schott column and was continuously recycled to the
feed tank. The process was performed until the desired level
of 3-7% of pinanol was attained in the crude oil of I.
Removal of all the volatiles was monitored by periodically
analyzing the enriched crude reaction mixture using a GC
assay. The removal of volatiles increased the viscosity of
the reaction mixture, and hence, constant adjustment by
lowering the feed rate of the crude mixture was done to
prevent the column from flooding. The formation of a dark
oil indicated some degradation of product due to long
distillation times. Use of a wider column reduced the dis-
tillation time (see distillation times and yields, for example,
(
2) Greater than 90% of pinanol was recovered from the
receiver. The condensor was maintained at a higher tem-
perature to avoid freezing of the pinanol. The receiver was
kept at 0-5 °C to trap the pinanol, although some pinanol
was evident in the vacuum line.
Acknowledgment
We appreciate the assistance of Dr. Melanie Miller and
Mr. David J. Kacsur during the on-scale implementation of
the steam distillation. We also thank Mr. Min Lin and the
New Brunswick Pilot plant Operations group for the suc-
cessful implementation of I to II in the pilot plant.
2
and 3 in Table 2 below). This protocol efficiently provides
improved recovery and cleaner quality of I, which is easily
transformed to II as a white solid. The overall yield of II
from CpNa was about 55%.
Received for review February 28, 2001.
OP010209C
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