A practical large-scale synthesis of (3R,4R)-4-(Hydroxymethyl)pyrrolidin-3- ol via asymmetric 1,3-dipolar cycloaddition

Article abstract of DOI:10.1021/op049768k

(3R,4R)-4-(Hydroxymethyl)pyrrolidin-3-ol (1), which is a useful intermediate for the synthesis of various bioactive molecules, has been synthesized in 51% overall yield by 1,3-dipolar cycloaddition reaction from the dipolarophile, (E)-3-benzyloxypropenoyl-(2′S)-bornane-10,2-sultam (5), and the achiral ylide precursor, N-(benzyl)-N-(methoxymethyl)-N- (trimethylsilylmethyl)amine (6), without using chromatography and the subsequent reduction with LAH and catalytic hydrogenation. The diastereomers 7 and 8 were separated by crystallization, and efficient procedures were developed for the subsequent reactions to afford 1.

Full text of DOI:10.1021/op049768k

Organic Process Research & Development 2005, 9, 193−197
A Practical Large-Scale Synthesis of (3R,4R)-4-(Hydroxymethyl)pyrrolidin-3-ol
via Asymmetric 1,3-Dipolar Cycloaddition
Pravin L. Kotian, Tsu-Hsing Lin, Yahya El-Kattan, and Pooran Chand*
Department of Medicinal Chemistry, BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake DriVe,
Birmingham, Alabama 35244, U.S.A.
Abstract:
The first synthesis of the pure enantiomer (3R,4R)-4-
(hydroxymethyl)pyrrolidin-3-ol was reported by Filichev11,12
from glucose and xylose in very low yields, requiring several
steps, which is not practical for synthesis of kilogram
quantities of 1.
Karlsson and Hogberg13 reported the preparation of this
compound via asymmetric 1,3-dipolar cycloaddition using
camphor sultam as a chiral auxiliary. In this synthesis, the
chiral ylide used was generated from phenethylamine and
the intermediates obtained were oils requiring flash chro-
matography for the separation of isomers.
These reported methods are considered unsuitable for
various reasons. We needed kilogram quantities of this
starting material to synthesize one of our lead PNP inhibitors,
BCX-4208. Therefore a practical synthesis was needed for
1 using a suitable procedure. Reinvestigation of the 1,3-
dipolar cycloaddition using the achiral ylide prepared from
benzylamine instead of phenethylamine provides a crystalline
intermediate. On the basis of this methodology, we now
report the practical synthesis of the single enantiomer of
(3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol (1) as a starting
material for BCX-4208 (2) which is currently in phase-I
clinical trials.
(3R,4R)-4-(Hydroxymethyl)pyrrolidin-3-ol (1), which is a useful
intermediate for the synthesis of various bioactive molecules,
has been synthesized in 51% overall yield by 1,3-dipolar cyclo-
addition reaction from the dipolarophile, (E)-3-benzyloxy-
propenoyl-(2′S)-bornane-10,2-sultam (5), and the achiral ylide
precursor, N-(benzyl)-N-(methoxymethyl)-N-(trimethylsilyl-
methyl)amine (6), without using chromatography and the
subsequent reduction with LAH and catalytic hydrogenation.
The diastereomers 7 and 8 were separated by crystallization,
and efficient procedures were developed for the subsequent
reactions to afford 1.
Introduction
Racemic and nonracemic 4-(hydroxymethyl)pyrrolidin-
3-ols have been prepared and found to have an inhibitory
effect on certain enzymes1-3and on glial GABA uptake.4
These pyrrolidines have also been used as building blocks
for the synthesis of some compounds having antibacterial
activity5,6 and also for some nucleoside analogues. The very
first aza C-nucleoside incorporating this compound was
reported by Sorensen.3 Recently, (3R,4R)-4-(hydroxymethyl)-
pyrrolidin-3-ol was used for the synthesis of a highly potent
purine nucleoside phosphorylase (PNP) inhibitor.7,8
The first synthesis of 3-hydroxy-4-hydroxymethylpyrro-
lidine (1) was reported by Jaeger9 starting from N-benzyl-
glycinate and ethyl acrylate and was obtained as a mixture
of cis/trans isomers. The trans-racemic compound was
prepared by Makino,10 starting from fumaric acid methyl
ester.
Results and Discussion
The synthesis reported by Karlsson and Hogberg13 using
(S)-N-(1-phenylethyl)-N-(methoxymethyl)-N-(trimethylsilyl-
methyl)amine as the precursor for chiral azomethine ylide
and (E)-3-benzyloxypropenoyl-(2′S)-bornane-10,2-sultam as
the dipolarophile for 1,3-dipolar cycloaddition gave a mixture
of diastereomers in a 83:17 ratio with the desired diastere-
omer predominant. These diastereomers were separated by
flash chromatography on silica gel and were found to be
semi-crystalline and oily in nature.
* To whom correspondence should be addressed: Department of Medicinal
Chemistry, BioCryst Pharmaceuticals, Inc., 2190 Parkway Lake Drive, Birming-
ham, AL 35244. Telephone: (205) 444-4627. Fax: (205) 444-4640. E-mail:
pchand@biocryst.com.
(1) Hansen, S. U.; Bols, M. Acta. Chem. Scand. 1998, 52, 1214.
(2) Godskesen, M.; Lundt, I. Tetrahedron Lett. 1998, 39, 5841.
(3) Sorensen, M. D.; Khalifa, N. M.; Pedersen, E. B. Synthesis 1999, 1937.
(4) Thorbek, P.; Hjeds, H.; Schaumburg, K. Acta. Chem. Scand., Ser. B 1981,
35, 473.
(5) Jacquet, J. P.; Bouzard, D.; Kiechel, J.-R.; Remuzon, P. Tetrahedron Lett.
1991, 32, 1565.
(6) Bouzard, D.; Di Cesare, P.; Essiz, M.; Jacquet, J. P.: Kiechel, J.-R.;
Remuzon, P.; Weber, A.; Oki, T.; Masuyoshi, M.; Kessler, R. E.; Fung-
Tomc, J.; Desiderio, J. J. Med. Chem. 1990, 33, 1344.
(7) Lewandowicz, A.; Shi, W.; Evans, G. B.; Tyler, P. C.; Furneaux, R. H.;
Basso, L. A.; Santos, D. S.; Almo, S. C.; Schramm, V. L. Biochemistry
2003, 42, 6057.
Since it has been reported that the use of chiral ylides on
acyclic alkenoic substrates has a small effect on diastereo-
selectivity,15 the use of achiral benzylamine instead of chiral
(8) Evans, G. B.; Furneaux, R. H.; Lewandowicz, A.; Schramm, V. L.; Tyler,
P. C. J. Med. Chem. 2003, 46, 5271.
(9) Jaeger, E.; Biel, J. H. J. Org. Chem. 1965, 30, 740.
(10) Makino, K.; Ichikawa, Y. Tetrahedron Lett. 1998, 39, 8245.
(11) Filichev, V. V.; Pederson, E. B. Tetrahedron 2001, 57, 9163.
(12) Filichev, V. V.; Brandt, M.; Pederson, E. B. Carbohydr.. Res. 2001, 333,
115.
(13) Karlsson, S.; Hogberg, H.-E. Tetrahedron: Asymmetry 2001, 12, 1977.
10.1021/op049768k CCC: $30.25 © 2005 American Chemical Society
Published on Web 02/17/2005
Vol. 9, No. 2, 2005 / Organic Process Research & Development
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193

Scheme 1
phenethylamine was adopted, which also aided in reducing
hydrogenation time in the last step. We attempted the
cycloaddition of (E)-3-benzyloxypropenoyl-(2′S)-bornane-
10,2-sultam with N-(1-benzyl)-N-(methoxymethyl)-N-(trim-
ethylsilylmethyl)amine in dichloromethane. The diastereo-
selectivity was found to be 82:18, comparable to that
obtained using chiral ylide. Initially the diastereomers were
separated by flash chromatography, with the desired isomer
a crystalline solid and the undesired isomer an oil. Therefore,
crystallization of the desired isomer from the crude reaction
mixture was attempted using a mixture of ethyl acetate and
hexane. The undesired isomer ratio was ca. 5% after the first
crystallization and negligible after the second crystallization
with recoveries of >90% of the desired isomer after both
crystallizations.
Attention was then focused on the earlier steps of the
reaction sequence to further improve the synthesis of the
desired pyrrolidine 1.
First, the synthesis of ylide precursor, N-(1-benzyl)-N-
(methoxymethyl)-N-(trimethylsilylmethyl)amine (6), was
investigated, resulting in a slightly better procedure compared
to those in literature reports. N-(Trimethylsilylmethyl)-
benzylamine16 was prepared from benzylamine and chlo-
romethyltrimethylsilane and was reacted with formaldehyde
and methanol to give the desired ylide precursor 6.17,18
Initially, 6 was purified by distillation and used for dipolar
cycloaddition. However, on a larger scale, distillation led to
decomposition of the product. Experiments using crude 6
revealed that purification was not needed and that 6 could
be used as such without purification.
Next, the large-scale synthesis of (1R)-(+)-2,10-camphor
sultam (3) was studied. Although camphor sultam is com-
mercially available, it is very expensive; hence, a kilogram-
scale method was developed from (-)-camphor sulfonic acid
based upon the literature reports.19,20 The reaction of camphor
sulfonic acid with 1.2 equiv of thionyl chloride in chloroform
or dichloromethane gave the acid chloride which was
quenched with ammonium hydroxide to give the correspond-
ing amide, which was used without further purification.
Dehydration of the amide was accomplished in toluene under
acidic conditions (H+ resin) to yield the corresponding imine,
isolated on cooling of the toluene layer after removal of the
resin by hot filtration. The imine was pure enough to advance
to the hydrogenation with Raney nickel.19 This route afforded
optically pure (1R)-(+)-2,10-camphor sultam with the same
optical rotation value as reported in the literature and required
no crystallization steps.
The most appropriate conditions for this reaction were
identified after several series of experiments were conducted
at different temperatures and varying molar ratios of the
reactants. The best set of conditions was obtained when the
reactions were carried out at temperatures between -35 and
-40 °C with 1 equiv of (E)-3-benzyloxyacrylic acid chloride,
0.85 equiv of camphor sultam, and 0.9 equiv of methylmag-
nesium bromide to reduce the formation of side products.21
The resulting mixture was concentrated and crystallized from
ethyl acetate and hexanes to remove impurities,21 critical for
the next step of cycloaddition.
The cycloaddition was carried out by the addition of (E)-
3-benzyloxypropenoyl-(2′S)-bornane-10,2-sultam (5) and N-
(benzyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)-
amine (6) in the presence of trifluoroacetic acid. After the
cycloaddition reaction, the desired isomer 7 was isolated by
two crystallizations from the crude reaction mixture. The
resultant product 7 was then reduced (LAH) to give (3R,4R)-
(1-benzyl-4-benzyloxy-pyrrolidin-3-yl)methanol (9), and sub-
sequent hydrogenation of 9 with 10% Pd/C at 100 psi
afforded (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol (1). The
use of benzylamine instead of phenethylamine reduced the
time required for hydrogenation from 15 to 2 days, which is
again important for the large-scale preparations.
Summary
The preparation of the dipolarophile, (E)-3-benzyloxypro-
penoyl-(2′S)-bornane-10,2-sultam (5) was accomplished from
(1R)-(+)-2,10-camphor sultam (3) and (E)-3-benzyloxypro-
penoyl chloride (4)13 (Scheme 1).
In this contribution, a large-scale synthesis of (3R,4R)-
4-(hydroxymethyl)pyrrolidin-3-ol (1), a useful intermediate
for a number of bioactive compounds, is described. This
synthesis has permitted the preparation of kilogram quantities
(14) Karlsson, S.; Hogberg, H.-E. Org. Lett. 1999, 1, 1667.
(15) Karlsson, S.; Hogberg, H.-E. Tetrahedron: Asymmetry 2001, 12, 1975.
(16) Carey, J. S. J. Org. Chem. 2001, 66, 2526.
(21) The impurities were identified as the following probable structures:
(17) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117.
(18) Padwa, A.; Dent, W. Org. Synth. 1988, 67, 133.
(19) Shriner, R. L.; Shotton, J. A.; Sutherland, H. J. Am. Chem. Soc. 1938, 60,
2794.
(20) Weismiller, M. C.; Towson, J. C.; Davis; F, A. Org. Synth. 1990, 69, 154.
194
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Vol. 9, No. 2, 2005 / Organic Process Research & Development

of the desired product used to prepare the lead PNP inhibitor,
BCX-4208, currently in phase I clinical trials.
NMR (CDCl3): δ 0.94 (s, 3H), 1.13 (s, 3H), 1.32 (m, 1H),
1.46 (m, 1H), 1.82-2.04 (m, 5H), 3.12 (m, 2H), 3.43 (m,
1H), 4.10 (bs, 1H); 13C NMR (CDCl3): δ 20.41, 26.72,
Experimental Section
31.78, 35.98, 44.63, 47.38, 50.29, 54.90, 62.75. [R]25
D
General. Unless otherwise stated, all reagents and sol-
vents were purchased from Aldrich and used as received.
(-)-Camphor sulfonic acid was purchased from Senn
Chemicals, and chloromethyltrimethylsilane was purchased
form Gelest, Inc. 1H NMR and 13C NMR were recorded on
a Bruker 300 MHz instrument. Chemical shifts (δ) are
reported in parts per million (ppm) and referenced to TMS
or the respective deuterated solvent peak. Coupling constants
(J) are reported in hertz. FT-IR spectra were obtained on a
Biorad FTS-3500 GX model using KBr pellets or NaCl cells
with a scan range of 4000-500 cm-1. Mass spectra data were
acquired on a Waters ZMD with a Waters LC system 2695
either in positive or negative mode. Optical rotations were
determined on an Autopol III automatic polarimeter. The
elemental analyses (C, H, and N) were performed by Atlantic
Microlab in Norcross, Georgia, U.S.A. The TLC solvent
systems CMA-80 and CMA-50 refer to chloroform/methanol/
concentrated NH4OH (80:18:2) and chloroform/methanol/
concentrated NH4OH (50:40:10), respectively. The non-UV
active compounds were visualized by charring TLC plates
sprayed with ammonium molybdate cesium sulfate spray
prepared by dissolving concentrated H2SO4 (22.4 mL),
CeSO4 (45 mg), (NH4)6Mo7O24‚4H2O (7 g) in water in a 100-
mL volumetric flask. The unsaturated compounds 4 and 5
were visualized by using KMnO4 spray.
(1R)-(+)-2,10-Camphor Sultam (3). To a solution of
(-)-camphor sulfonic acid (1.45 kg, 6.25 mol) in chloroform
(7 L) under reflux conditions was added thionyl chloride
(0.896 kg, 7.5 mol) over a period of 1 h. The reaction mixture
was refluxed for 16 h and then cooled to 4 °C using an ice
bath. This cooled reaction mixture was added slowly to
concentrated NH4OH (15 L), maintaining temperature below
15 °C during the addition. After addition, the mixture was
stirred for 4 h at room temperature. The organic layer was
separated, and the aqueous layer was extracted with chlo-
roform (2 × 2 L). The combined organic extracts were
washed with brine (4 L) and dried over MgSO4. After
filtration, the filtrate was concentrated under vacuum and
dried to give 1.2 kg (83%) of camphor sulfonamide. In one
experiment at 145-g scale of camphor sulfonic acid, the use
of dichloromethane instead of chloroform for the reaction
and extraction gave comparable yields.
+32.07° (c ) 2.37, chloroform), Aldrich catalog [R]20D +32°
(c ) 5, chloroform). The total quantity of product obtained
in 10 batches was 0.98 kg (97%) from 1 kg of the imine.
N-(Benzyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)-
amine (6). To a solution of chloromethyltrimethylsilane (1.34
kg, 10.96 mol) in acetonitrile (17.0 L) was added benzyl-
amine (2.34 kg, 21.92 mol), and the reaction mixture was
heated at reflux for 16 h. The reaction mixture was cooled
to room temperature, and the precipitate of benzylamine
hydrochloride was removed by filtration. The filtrate was
concentrated under vacuum to about 5 L and then diluted
with water (5 L). The reaction mixture was extracted with
hexane (2 × 5 L). The organic extracts were combined and
washed with brine (5 L) and dried over MgSO4. The filtrate
was concentrated under vacuum to give 1.77 kg (83%) of
N-(trimethylsilylmethyl)benzylamine.
The above amine (1.77 kg, 9.14 mol) was added to a
mixture of 37% formaldehyde (0.89 kg, 10.96 mol) and
methanol (0.35 kg, 10.96 mol) at 0 °C over a period of 30
min. The reaction mixture was further stirred at 0 °C for 1
h and at 10-15 °C for 3 h. To the reaction mixture was
then added anhydrous K2CO3 (1 kg), and this mixture stirred
for 2 h. The oily layer was decanted onto 100 g of K2CO3
and stirred for 15 min and again decanted. The remaining
residual material from the K2CO3 was recovered by washing
all the solid K2CO3 with ether. Ether washings were mixed
with the decanted oily product and concentrated on the rotary
evaporator to give 2.10 kg (82%) of the desired product 6,
deemed pure enough to be used in the next step.
(E)-3-Benzyloxypropenoyl-(2′S)-bornane-10,2-sultam
(5). To a solution of (E)-3-benzyloxyacrylic acid14 (1.74 kg,
9.88 mol) and dichloromethane (20 L) was added thionyl
chloride (1.75 kg, 14.7 mol) over a period of 30 min. The
reaction mixture was heated at reflux and the SO2 and HCl
generated were scrubbed through a solution of aqueous
1
NaOH. After 4 h (reaction progress was monitored by H
NMR analysis), the solvent was removed under vacuum and
the residual thionyl chloride was removed under vacuum
overnight to give 2.00 kg (104%) of the desired acid chloride
4.
To a solution of camphor sultam 3 (1.72 kg, 7.98 mol) in
THF (16 L) at -40 °C was added methylmagnesium bromide
(2.79 L, 8.38 mol; 3M solution in ether) dropwise at a rate
maintaining the internal temperature between -30 °C and
-40 °C. The reaction mixture was stirred for an additional
hour at -40 °C. To the anion at -40 °C was added slowly,
acid chloride 4 (1.92 kg, 96% purity based upon the use of
acid, 9.4 mol) in THF (8 L) maintaining the internal
temperature below -25 °C. The reaction mixture was further
stirred between -30 °C and -40 °C for 1 h and allowed to
warm to +10 °C over a period of 5-6 h. The reaction
mixture was then quenched with saturated aqueous NH4Cl
(16 L). The aqueous layer was separated and extracted twice
with ethyl acetate (10 L). The combined organic layers were
To a suspension of the camphor sulfonamide (1.2 kg, 5.2
mol) in toluene (15 L) was added Amberlyst H+ resin (150
g), and the mixture was heated at reflux for 4 h with the
water formed removed azeotropically using a Dean-Stark
water separator. The reaction mixture was filtered hot to
remove the resin. On cooling, the filtrate gave a white solid
which was collected by filtration to give 1.02 kg (92%) of
the desired imine.
To the above imine (100 g, 0.47 mol) in ethanol (0.75 L)
was added Raney nickel (100 g), and the mixture was
hydrogenated at 40 psi for 2 h. The catalyst was removed
by filtration and the filtrate concentrated under vacuum to
1
give the product 3 as a white solid: mp 182-186 °C; H
Vol. 9, No. 2, 2005 / Organic Process Research & Development
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195

washed with saturated aqueous sodium carbonate (20 L) and
brine (20 L). The organic layer was filtered through a pad
of anhydrous MgSO4 and concentrated under vacuum to
dryness to furnish 3.12 kg of the crude product 5.
11.5 Hz, 1H), 4.54 (d, J ) 11.5 Hz, 1H), 4.64 (m, 1H), 7.30
(m, 10H); 13C NMR (CDCl3): δ 14.07, 19.72, 20.57, 20.92,
26.33, 32.61, 38.19, 44.04, 47.62, 48.29, 51.09, 52.89, 57.73,
59.28, 59.76, 60.26, 64.99, 71.25, 79.07, 99.45, 126.82,
127.40, 127.76, 128.07, 128.16, 128.53, 137.91, 138.32,
172.10; IR (KBr): 2776, 1698, 1311, 1215 cm-1; MS
The crude product was taken up in ethyl acetate (8.3 L)
and heated to 60 °C to dissolve the crude residue. The
homogeneous solution was diluted slowly with hexanes (30
L) while maintaining the solution at reflux. The reaction
mixture was kept in a cold room for 16 h at 4 °C. The
crystalline material that separated was collected by filtration
and washed with hexanes to give 1.906 kg (60%) of the
desired product 5. The filtrate also contained the product,
but no attempts were made to recover this material from the
filtrate. 1H NMR (DMSO-d6): δ 0.97 (s, 3H), 1.17 (s, 3H),
1.40 (m, 2H), 1.89 (m, 3H), 2.10 (m, 2H), 3.47 (d, J ) 6.0
Hz, 2H), 3.92 (dd, J ) 5.0 and 7.5 Hz, 1H), 4.95 (s, 2H),
6.05 (d, J ) 12.0 Hz, 1H), 7.37 (m, 5H), 7.78 (d, J ) 12.0
Hz, 1H); 13C NMR (DMSO-d6): δ 19.92, 20.78, 26.56,
32.78, 38.55, 44.68, 47.81, 48.31, 53.08, 65.07, 73.25, 97.64,
99.61, 127.98, 128.64, 128.71, 134.92, 163.04, 164.77; IR
(KBr): 2964, 2885, 1673, 1319, 1132 cm-1; MS (ES+):
(ES+): 509.36 (M + H)+. [R]25 +86.9 (c ) 0.86,
D
chloroform). Anal. Calcd for: C29H36N2O4S: C, 68.47; H,
7.13; N, 5.51; S, 6.30. Found: C, 68.58; H, 7.25; N, 5.51;
S, 6.22.
1
For the minor isomer 8, H NMR (CDCl3): δ 0.79 (s,
3H), 1.01 (s, 3H), 1.17 (m, 2H), 1.70 (m, 3H), 1.87 (m, 2H),
2.40 (dd, J ) 9.5 and 7.4 Hz, 1H), 2.57 (dd, J ) 10.0 and
6.2 Hz, 1H), 2.69 (dd, J ) 10.0 and 3.2 Hz, 1H), 3.10 (t, J
) 9.0 Hz, 1H), 3.25 (d, J ) 13.9 Hz, 1H), 3.34 (d, J ) 5.3
Hz, 1H), 3.39 (d, J ) 4.5 Hz, 1H), 3.52 (d, J ) 13.0 Hz,
1H), 3.62 (m, 1H), 3.70 (t, J ) 6.2 Hz, 1H), 4.17 (m, 2H),
4.38 (d, J ) 11.5 Hz, 1H), 7.10 (m, 10H); 13C NMR
(CDCl3): δ 14.61, 20.25, 21.37, 26.80, 33.33, 39.02, 45.16,
48.17, 48.75, 51.68, 53.58, 58.05, 60.15, 60.28, 60.79, 65.73,
71.62, 83.40, 127.37, 128.01, 128.19, 128.53, 128.63, 128.73,
129.21, 138.26, 138.84, 173.88; MS (ES+): 509.36 (M +
376.34 (M + H)+. [R]25 +71.15 (c ) 0.52, chloroform);
D
Anal. Calcd for C20H25NO4S: C, 63.97; H, 6.71; N, 3.73; S,
H)+. [R]25 +29.6 (c ) 1, ethanol).
D
8.54. Found: C, 63.68; H, 6.78; N, 3.87; S, 8.66.
(3R,4R)-(1-Benzyl-4-benzyloxypyrrolidin-3-yl)metha-
nol (9). To a stirred mixture of lithium aluminum hydride
(344 g, 8.6 mol) in THF (8.6 L) under a nitrogen atmosphere
was added dropwise compound 7 (1.46 kg, 2.87 mol) in THF
(3.5 L) at 0 °C over a period of 2 h. The reaction mixture
was stirred at 0 °C for 1 h and allowed to warm to room
temperature over a period of 2.5 h (TLC analysis showed
complete reduction). The reaction mixture was cooled to 0
°C and quenched by careful addition of water (750 mL) and
diluted with ethyl acetate (15 L). The solid cake was filtered
through Celite and the cake washed with ethyl acetate (4 ×
2.5 L). The filtrate was extracted with 2 N HCl (6 × 3 L).
The organic layer was discarded, the aqueous layer was
cooled to 0 °C, and the pH was adjusted to 13 using solid
NaOH (3.64 kg). The basified aqueous layer was extracted
with ethyl acetate (3 × 8 L). The organic layers were
combined, washed with brine (4 L), filtered through a pad
of MgSO4, and the filtrate was concentrated under vacuum
to dryness giving 756 g of the desired product 9 (89%) as a
N-[[3S,4R)-4-Benzyloxy-1-(benzyl)pyrrolidin-3-yl]car-
bonyl]-(2′S)-bornane-10,2-sultam (7). To a solution of 5
(1.83 kg, 4.88 mol) in dichloromethane (29 L) and trifluo-
roacetic acid (42 mL) was added 6 (2.32 kg, 9.76 mol) over
a period of 30 min at room temperature. The reaction mixture
was stirred for 15 min (reaction monitored for disappearance
of starting materiel by NMR analysis of an aliquot). The
reaction mixture was washed with 10% aqueous Na2CO3 (20
L) and brine (16 L). The reaction mixture was filtered
through a pad of MgSO4, and the filtrate was concentrated
under vacuum. To the oily residue was added hexanes (10
L), and the mixture was stirred at room temperature
overnight. The resulting solids were collected by filtration,
washed with hexanes (4 L), and then air-dried for 3 h to
furnish 2.26 kg product (NMR analysis shows the desired
isomer comprises 91% of the mixture). Ethyl acetate (4.5
L) was added, and the mixture was heated at reflux to
dissolve the product. Hexanes were added while maintaining
reflux (13.5 L, added at 1-L increment each). The mixture
was then allowed to cool to room temperature with stirring
for 16 h. The resulting solid obtained was collected by
filtration and washed with 10% ethyl acetate in hexanes (5
L), affording 1.67 kg of desired isomer as a white solid
(NMR analysis showed a trace of the minor isomer). The
solid was again subjected to recrystallization from ethyl
acetate and hexanes as described above; the purified product
was collected by filtration, washed with 10% ethyl acetate
in hexanes, and dried to furnish 1.46 kg (57.5%) of the
desired isomer 7 as a white solid, mp 108-109 °C. 1H NMR
(CDCl3): δ 0.94 (s, 3H), 1.02 (s, 3H), 1.37 (m, 2H), 1.88
(m, 3H), 2.04 (m, 2H), 2.57 (dd, J ) 9.5 and 5.6 Hz, 1H),
2.69 (dd, J ) 9.7 and 4.0 Hz, 1H), 2.92 (dd, J ) 9.7 and 6.5
Hz, 1H), 3.20 (t, J ) 9.0 Hz, 1H), 3.46 (m, 2H), 3.52 (m,
1H), 3.73 (m, 2H), 3.91 (t, J ) 6.0 Hz, 1H), 4.36 (d, J )
1
colorless oil that solidified on standing, mp 62-64 °C. H
NMR (CDCl3): δ 2.31 (m, 1H), 2.42 (dd, J ) 4.5 and 10.0
Hz, 1H), 2.62 (dd, J ) 9.2 and 3.0 Hz, 1H), 2.74 (dd, J )
9.0 and 7.0 Hz, 1H), 3.11 (dd, J ) 9.8 and 6.5 Hz, 1H),
3.45 (bs, 1H), 3.61 (m, 3H), 3.67 (dd, J ) 10.0 and 4.5 Hz,
1H), 4.03 (m, 1H), 4.46 (s, 2H), 7.30 (m, 10H); 13C NMR
(CDCl3): δ 26.44, 46.97, 47.22, 57.26, 60.90, 61.25, 66.65,
72.17, 74.42, 82.10, 128.04, 128.50, 128.54, 129.01, 129.21,
129.25, 129.55, 139.03, 139.09; IR (KBr): 3224, 3030, 1456,
1351, 1143, 1094 cm-1; MS (ES+): 298.46 (M + H)+. [R]25
D
+16.7 (c ) 0.52, chloroform). Anal. Calcd for: C19H23-
NO2: C, 76.73; H, 7.80; N, 4.71; Found: C, 76.84; H, 7.95;
N, 4.76.
(3R,4R)-4-(Hydroxymethyl)pyrrolidin-3-ol Hydrochlo-
ride (1). To a solution of 9 (70 g, 0.235 mol) in ethanol
(700 mL) was added a 4 M solution of HCl in dioxane (59
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mL, 0.235 mol) and palladium on carbon (10%, 50 g). The
resulting slurry was hydrogenated at 100 psi for 2 days. The
catalyst was removed by filtration through Celite and
concentrated under vacuum and dried to furnish 38 g (100%)
of 1, homogeneous by TLC analysis (75% CMA-50 in CMA-
80). This compound was pure enough for the synthesis of
the clinical candidate, BCX-4208. 1H NMR (DMSO-d6): δ
2.21 (m, 1H), 2.96 (dd, J ) 5.0 and 12.0 Hz, 1H), 3.19 (dd,
J ) 12.0 and 5.0 Hz, 1H), 3.29 (dd, J ) 7.7 and 3.8 Hz,
1H), 3.38 (m, 3H), 4.15 (m, 1H), 4.94 (t, J ) 5.0 Hz, 1H),
5.44 (d, J ) 3.8 Hz, 1H), 9.15 (bs, 2H); 1H NMR (D2O): δ
4.44-4.40 (m, 1H), 3.67-3.57 (m, 3H), 3.43 (dd, J ) 5.1
and 12.6 Hz, 1H), 3.27 (dd, J ) 12.6 and 2.5 Hz, 1H), 3.16
(dd, J ) 5.7 and 12.3 Hz, 1H), 2.53-2.43 (m, 1H); 13C NMR
(D2O): 46.54, 47.86, 52.07, 60.83, 71.82; IR (KBr) 3835,
2955, 1616, 1396, 1050 cm-1; MS (ES+): 118.71 (100%;
literature reports.13 An analytical sample was prepared by
purifying 0.5 g on a silica gel column (10 g), eluting with
CMA-80/CMA-50 to furnish product as an oil. The product
obtained was dissolved in methanol (5 mL), and 1 mL
concentrated HCl was added. This was stirred at room
temperature for 5 min and concentrated under vacuum to
dryness to furnish desired product 1 as hydrochloride salt.
Anal. Calcd for C5H11NO2‚HCl‚0.5 H2O: C, 36.92; H, 8.06;
N, 8.68. Found: C, 37.32; H, 8.00; N, 8.52. [R]25 +17.53
D
(c ) 1.175, methanol).
Acknowledgment
We thank Drs. Charlie Bugg, Claude Bennett, and
Yarlagadda S. Babu for their encouragement throughout this
work.
Received for review December 13, 2004.
OP049768K
1
M+1). H NMR and 13C NMR data are consistent with the
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