Efficient and practical synthesis of (R)-2-methylpyrrolidine

Article abstract of DOI:10.1021/jo060319n

An efficient, practical, and high yielding synthesis of (R)-2-methylpyrrolidine is described. The sequence allows for the scalable preparation of the target compound in just four synthetic steps and proceeds in 83% overall yield and >99% optical purity from readily available starting materials.

Full text of DOI:10.1021/jo060319n

Efficient and Practical Synthesis of
R)-2-Methylpyrrolidine
the synthesis and preparation of 1 which was closely related to
our own route and that described by Kostyanovsky and
(
7
co-workers (Scheme 1). The Abbott preparation involved a five-
step synthesis beginning with expensive L-prolinol 2, required
the use of a large excess (10 equiv) of costly LiI, and resulted
in the isolation of 1 as an extremely hygroscopic HCl salt in
63% overall yield from 2. The Kostyanovsky route utilized an
N-tosyl-protecting group, required LAH in refluxing THF to
reduce the O-tosyl functionality, and isolated compound 1 by
distillation of the free base in an overall yield of 38% from 2.
It is against this background that we now report our improved
four-step synthesis of (R)-2-methylpyrrolidine 1 that is both
practical and amenable to the large-scale preparation of enan-
tiopure 1.
Dalian Zhao,* Jeffrey T. Kuethe, Michel Journet,
Zhihui Peng, and Guy R. Humphrey
Department of Process Research, Merck & Company, Inc.,
P.O. Box 2000, Rahway, New Jersey 07065
dalian_zhao@merck.com
ReceiVed February 15, 2006
Our synthesis began with inexpensive and readily available
N-Boc-L-proline 7 (Scheme 2). Reduction of 7 with borane,
generated in situ from sodium borohydride and boron trifluoride
etherate, provided prolinol 8 in 97% HPLC assay yield.8
Prolinol 8 was obtained in pure form and in 94% isolated yield
by crystallization of the crude reaction mixture from heptane.
Treatment of 8 with methanesulfonyl chloride in the presence
of Et3N and 5 mol % of DMAP furnished mesylate 3 in 96%
yield. The use of DMAP served to both increase the reaction
rate and improve the overall yield of 3. Interestingly, mesylate
,9
An efficient, practical, and high yielding synthesis of (R)-
2-methylpyrrolidine is described. The sequence allows for
the scalable preparation of the target compound in just four
synthetic steps and proceeds in 83% overall yield and >99%
optical purity from readily available starting materials.
3
was found to be unstable at room temperature as a neat oil
and was found to slowly decompose to mesylate salt 9.
Presumably, the decomposition of 3 to 9 was triggered by trace
amounts of MsOH in the concentrated product. This problem
was completely eliminated by storing 3 as a solution in MTBE
which was stable upon prolonged storage. The reduction of
mesylate 3 to the corresponding N-Boc-2-methylpyrrolidine 4
was routinely achieved by treating 3 with Super-Hydride10 in
Substituted pyrrolidines can be found in numerous natural
products and pharmaceutically active compounds possessing a
wide range of biological activity. Often the type and degree of
1
substitution about the pyrrolidine ring can have a profound effect
on the biological activity of a given substrate. In connection
with an ongoing program, we required an efficient and practical
method for the preparation of kilogram quantities of (R)-2-
methylpyrrolidine 1. Classical resolution of racemic 2-meth-
THF at room temperature for 3-5 h and provided 4 in 95-
9
9
6% HPLC assay yield. Alternatively, reduction of 3 with
LiBH4 (2.0 equiv) in MTBE at 35 °C for 16 h provided 4 in
0-82% HPLC assay yield. The reduction of 3 with NaBH4
2
ylpyrrolidine with L-tartaric acid has been known since 1951.
8
Recently, an optimized large-scale resolution of 1 as its tartrate
was also extensively examined. Aprotic solvents such as DMSO
or DMF were required, and the reactions only gave HPLC assay
yields of 50-70%. When other solvents and conditions were
employed, either no reaction was observed or decomposition
to unidentified byproducts resulted.
3
salt was reported. However, this procedure required large
reaction volumes and multiple recrystallizations (4×) to achieve
>97% ee and only proceeded in 28% overall yield. Although
there have been a number of methods reported for the synthesis
of enantiomerically pure 1, most suffer from inefficient enzy-
matic resolution protocols of synthetic intermediates or involve
multiple steps employing toxic reagents or costly chiral auxil-
iaries.4 While investigating an enantioselective synthesis of 1,
Removal of the Boc-protecting group of 4 and isolation of 1
as a stable, crystalline, nonhygroscopic solid were examined
,5
6
(5) For racemic syntheses of 1, see: (a) Schlummer, B.; Hartwig, J. F.
Org. Lett. 2002, 4, 1471. (b) Douglass, M. R.; Ogasawara, M.; Hong, S.;
Metz, M. V.; Marks, T. Organometallics 2002, 21, 283-292. (c) Gagne,
M. R.; Nolan, S. P.; Marks, T. J. Organometallics 1990, 9, 1716. (d) Gag n˜ e,
M. R.; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108. (e) Dow Chemical
Co. U.S. Patent US1983/4418201. (f) Pugin, B.; Venanzi, L. M. J.
Organomet. Chem. 1981, 214, 125. (g) Minisci, F.; Galli, R.; Perchinunno,
M. Org. Prep. Proced. 1969, 1, 77. (h) Minisci, F.; Galli, R. Tetrahedron
Lett. 1966, 2532.
a report by Ku and co-workers at Abbott appeared describing
(
1) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435-446. (b) Lewis, J.
R. Nat. Prod. Rep. 2001, 18, 95-128. (c) Daly, J. W.; Spende, T. F. In
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.;
Wiley: New York, 1986; Vol. 4, Chapter 1.
(
2) (a) Karrer, P.; Ehrhart, K. HelV. Chim. Acta 1951, 34, 2202. (b) Kuil,
L. A.; Veldhuizen, Y. S. J.; Grove, D. M.; Zwikker, L. J. W.; Jenneskens,
L. W.; Drenth, W.; Smeets, W. J. J.; Spek, A. L.; Koten, G. Recl. TraV.
Chim. Pays-Bas 1994, 113, 267.
(6) Ku, Y.-Y.; Cowart, M. D.; Sharma, P. N. U.S. Patent US 2004/
0171845 A1.
(
3) (a) Pu, Y.-M.; Grieme, T.; Gupta, A.; Plata, D.; Bhatia, A. V.; Cowart,
M.; Ku, Y.-Y. Org. Process Res. DeV. 2005, 9, 45.
4) For enantioselective syntheses of 1, see: (a) Nguyen, T.; Sherman,
D.; Ball, D.; Solow, M.; Singaram, B. Tetrahedron: Asymmetry 1993, 4,
89. (b) Kim, M.-J.; Lim, I. T.; Choi, G.-B.; Whang, S.-Y.; Ku, B.-C.;
(7) Kostyanovsky, R. G.; Gella, I. M.; Markov, V. I.; Smojlova, Z. E.
Tetrahedron 1974, 30, 39.
(
(8) (a) Brown, H. C. Organic Syntheses Via Boranes; J. Wiley: New
York, 1975. (b) Zweifel, G.; Brown, H. C. Org. React. 1963, 13, 1. (c)
Miller, R. A.; Humphrey, G. R.; Lieberman, D. R.; Ceglia, S. S.; Kennedy,
D. J.; Grabowski, E. J. J.; Reider, P. J. J. Org. Chem. 2000, 65, 1399.
(9) HPLC assay yield refers to quantitative HPLC analysis of reaction
mixtures using an analytically pure standard.
1
Choi, J.-Y. Bioorg. Med. Chem. Lett. 1996, 6, 71. (c) Donner, B. G.
Tetrahedron Lett. 1995, 36, 1223. (d) Gagne, M. R.; Brard, L.; Conticello,
V. P.; Giadello, M. A.; Stern, C. L.; Marks, T. J. Organometallics 1992,
1
1, 2003. (e) Toshimitsu, A.; Fuji, H. Chem. Lett. 1992, 10, 2017.
(10) Krishnamurthy, S.; Brown, H. C. J. Org. Chem. 1976, 41, 3064.
10.1021/jo060319n CCC: $33.50 © 2006 American Chemical Society
4
336
J. Org. Chem. 2006, 71, 4336-4338
Published on Web 05/03/2006

SCHEME 1
SCHEME 2
lization of the stable, nonhygroscopic, and highly crystalline
benzenesulfonic acid salt 1a which was isolated from the
reaction mixture in 95% yield and in greater than 99.5% optical
1
1
purity.
In summary, an effective four-step synthesis of (R)-2-
methylpyrrolidine 1 as its benzenesulfonate salt has been
demonstrated. This synthetic sequence utilized readily available,
inexpensive starting materials and reagents, required no chro-
matographic purifications, and proceeded in an excellent 83%
overall yield providing 1b in >99% optical purity. The
efficiency and practicality of the protocol should also be
applicable to the synthesis of the corresponding (S)-enantiomer
of 1 and now represents the most practical synthesis of 1 to
date.
Experimental Section
General Methods. Melting points are uncorrected. All solvents
and reagents were used as received from commercial sources.
Analytical samples were obtained by silica gel chromatography
using an ethyl acetate-hexane mixture as the eluent unless specified
otherwise. Water content (KF) was determined by Karl Fisher
titration on a Metrohm 737 KF Coulometer.
next. Although deprotection could be accomplished with
anhydrous HCl or HBr, the resulting workup of these reactions
absolutely required decanting the liquors several times to obtain
Preparation of 2-(S)-Hydroxymethylpyrrolidine-1-carboxylic
Acid tert-Butyl Ester (8). To a heterogeneous mixture of sodium
borohydride powder (37.94 g, 1.00 mol) in isopropyl acetate (540
mL) was added N-Boc-L-proline 7 (135 g, 0.627 mol), at -5 to 0
°C in one portion. A gentle evolution of hydrogen gas was observed
after the addition. After the reaction mixture was stirred at -5 to
6
a crystalline solid. Furthermore, both the HCl and HBr salts
of 1 are extremely hygroscopic and become amorphous syrups
or thick oils when exposed to air for even short periods of time.
Although the L-tartrate salt of 1 is highly crystalline and
nonhygroscopic, its direct preparation from 4 was not straight-
forward. Not surprisingly, reaction of 4 with L-tartaric acid
resulted in no detectable reaction even at refluxing temperatures.
Therefore, an alternative procedure was developed whereby the
Boc group of 4 was removed by treatment with 5 N HCl in
0
°C for 1 h, boron trifluoride etherate (178 g, 1.254 mol) was
added via an addition funnel over 1.5 h maintaining the internal
temperature between -5 and 5 °C. The resulting reaction slurry
was stirred for an additional 1-2 h at the same temperature and
was quenched by the addition of 0.5 N NaOH (800 mL) over 30
min at 0-10 °C. The resulting mixture was heated to 45 °C with
vigorous stirring for 10 min to give two clear separated layers which
were separated. The lower aqueous layer was back extracted with
isopropyl acetate (150 mL). The combined organic extracts were
washed with 5% NaCl (200 mL) and saturated NaCl (200 mL).
The organic solution was azeotropically concentrated, and the
solvent was switched to heptane. The final volume was adjusted
to approximately 230-250 mL. The solution was seeded with
analytically pure 8 while stirring at 35-40 °C, and the product
gradually crystallized. The resulting white slurry of the product
was stirred at room temperature for 2 h and then at -5 to 0 °C for
2
-propanol (2.5 equiv). Neutralization with NaOEt and filtration
of the resulting sodium salts gave a solution of the freebase of
in 2-propanol. Addition of L-tartaric acid and azeotropic
distillation to remove water afforded the crystalline tartrate salt
b in 83% yield which was contaminated with a number of
1
1
sodium salts (i.e., NaCl and sodium tartrate). Although the
tartrate salt 1b could be used uneventfully in subsequent
transformations, a more practical procedure for the preparation
of 1 in highly pure form was desired. After considerable
experimentation, it was discovered that reaction of crude 4 in
MTBE with benzenesulfonic acid (1.4 equiv) at room temper-
ature resulted in smooth deprotection and concomitant crystal-
(11) The optical purity of 1a and 1b was determined by chiral HPLC by
derivitization with Cbz-valine; see ref 3.
(12) The compound is also available from Aldrich Chemical Company.
J. Org. Chem, Vol. 71, No. 11, 2006 4337

2
h and was filtered. The wet cake was dried at room temperature
under vacuum/N sweep to afford 8 (120 g, 99.2 wt %, 94% yield)
as a white solid.12
Additional LiBH
was stirred at 35 °C for 15 h. The reaction was quenched by
transferring the mixture into a mixture of 1 M H PO (10 mL),
4
(99 mg, 4.55 mmol) was added, and the mixture
2
3
4
Preparation of 2-(S)-Methanesulfonyloxymethylpyrrolidine-
-carboxylic Acid tert-Butyl Ester (3). To a solution of prolinol
(120 g, 99.2 wt %, 0.591 mol) in MTBE (600 mL) was added
water (5 mL), and MTBE (10 mL) at 0 °C with vigorous stirring.
1
8
The organic layer was washed with saturated NaHCO (10 mL)
3
and saturated NaCl (10 mL). The organic solution was azeotropi-
DMAP (3.6 g, 29.5 mmol) and triethylamine (119.6 g, 1.182 mol)
at room temperature. The mixture was stirred at the same temper-
ature for 10 min until all the solids were dissolved. The reaction
solution was cooled to -5 to 0 °C, and a solution of methane-
sulfonyl chloride (88 g, 0.768 mol) in MTBE (300 mL) was added
via an addition funnel over 1.5 h maintaining the internal reaction
temperature between -5 and 0 °C. An off-white slurry was formed
during the addition. The reaction mixture was stirred for an
additional 1-2 h at the same temperature and was quenched by
cally concentrated and filtered through a pad of Solka Floc (filter
agent) to provide 4 (1.37 g, 81% HPLC assay) as a solution in
MTBE.
Preparation of (R)-2-Methylpyrrolidine Benzenesulfonic Acid
Salt (1a). To a solution of benzenesulfonic acid (121.8 g, 0.77 mol)
in MTBE (400 mL) was added N-Boc-(R)-2-methylpyrrolidine 4
(102 g, 0.55 mol) in MTBE (140 mL) at room temperature over 1
h. Gas was evolved during the addition. The reaction mixture was
seeded with 1a (150-200 mg) after about 75% of 4 was added,
and the product 1a crystallized during the course of the rest of the
addition of 4. The reaction mixture was stirred at room temperature
for 12-16 h. The solid product was isolated by filtration, and the
wet cake was washed with MTBE (300 mL). The solid was dried
under vacuum at 35 °C under a nitrogen sweep to afford 1a (130
the addition of 1 M H
vigorous stirring. The organic layer was sequentially washed with
saturated NaHCO (200 mL), 5% NaCl (200 mL), and saturated
3 4
PO (500 mL) over 20 min at 5-15 °C with
3
NaCl (200 mL). The organic solution was azeotropically concen-
trated and filtered through a pad of Solka Floc (filter agent) to obtain
5
(160 g, 96% HPLC assay) as an MTBE (∼800 mL) solution
12
1
g, 95%, 99.6% ee ) as a white solid: mp 119-120 °C. H NMR
(KF ) 125 µg/mL). The solution was used directly in the next
(
400 MHz, DMSO-d
m, 2H), 7.35 (m, 3H), 3.49 (m, 1H), 3.16 (m, 2H), 2.04-1.79 (m,
H), 1.45 (m, 1H), 1.24 (d, 1H, J ) 6.63 Hz). 13C NMR (100 MHz,
): δ 147.9, 129.4, 128.3, 125.9, 55.8, 44.7, 31.5, 23.3,
7.3. Anal. Calcd for C11 S: C, 54.30; H, 7.04; N, 5.76.
6
): δ 8.82 (br s, 1H), 8.35 (br s, 1H), 7.67
step reaction without further purification.
(
3
Preparation of 2-(S)-Methanesulfonyloxymethylpyrrolidine
Methanesulfonic Acid Salt (9). Mesylate salt 9 was formed from
the concentrated oil of mesylate 4 after standing at room temperature
DMSO-d
6
1
H17NO
3
for several days and was isolated as a crystalline white solid
Found: C, 54.29; H, 6.96; N, 5.75.
Preparation of (R)-2-Methylpyrrolidine Tartrate Salt (1b).
A 50 L flask was charged with N-Boc-(R)-2-methylpyrrolidine 4
1
(
9
(
2
(
3
hygroscopic): mp 53-54 °C. H NMR (400 MHz, CDCl
3
): δ
.37 (br, 1H), 8.94 (br, 1H), 4.56 (dd, 1H, J ) 11.1, 4.1 Hz), 4.50
dd, 1H, J ) 11.1, 6.5 Hz), 4.08-3.95 (m, 1H), 3.52-3.37 (m,
H), 3.22 (s, 3H), 2.78 (s, 3H), 2.28-2.00 (m, 2H), 1.98-1.82
(2.54 kg HPLC assay, 13.7 mol) in EtOH (13 L) and 5 N HCl
m, 1H). 1 C NMR (100 MHz, CDCl
3
(6.86 L, 34.3 mol). The resulting solution was heated to 50 °C,
aged for 1 h, and cooled to 5 °C. To the cooled solution was added
slowly phenolphthalein (2.54 g) and NaOEt (21 wt % in EtOH)
3
): δ 67.6, 58.4, 46.3, 39.4,
7.5, 26.6, 23.7. Anal. Calcd for C H17NO S : C, 30.53; H, 6.22;
7 6 2
N, 5.09. Found: C, 30.49; H, 6.21; N, 5.11.
Preparation of 2-(R)-Methylpyrrolidine-1-carboxylic tert-
Butyl Ester (4). Method A. To a solution of mesylate 3 (160 g,
(
temp <25 °C) until the solution turned pale pink (ca. 10.2 L, 27.3
mol). The slurry was filtered with the receiving pot cooled in a
dry ice/acetone bath. The wet cake (NaCl) was washed with EtOH
0
.573 mol) in MTBE (∼800 mL) was added LiEt
3
BH (Super-
(
2 L). The filtrate was transferred to a 50 L flask, and L-tartaric
acid (2.26 Kg, 15.1 mol) was added. The mixture was stirred at 50
C for 3 h and cooled to room temperature. The slurry was
Hydride, 1.146 L, 1.146 mol, 1 M in THF) over 1 h at -5 to 0 °C.
The reaction mixture turned hazy during the addition. The reaction
mixture was allowed to warm to room temperature and was stirred
for an additional 3-5 h. The reaction was inversely quenched into
a biphasic mixture of MTBE (360 mL) and water (360 mL) at 0-10
°
azeotropically concentrated under reduced pressure with addition
of IPA (at a constant total volume of ∼30 L and a temperature of
∼
30 °C; a total of ∼38 L of IPA was needed). The slurry was
°
C with vigorous stirring over 20 min. The organic layer was
sequentially washed with 1 M H PO (800 mL), saturated NaHCO
250 mL), 5% NaCl (250 mL), and saturated NaCl (250 mL). The
cooled to room temperature, stirred for 2 h, and filtered. The wet
cake was washed with IPA (4 L) and dried at 40 °C under vacuum
for 48 h to give 1b (2.87 kg, 83 wt %, 2.38 Kg assay, >99.6%
3
4
3
(
organic solution was azeotropically concentrated and filtered
through a pad of Solka Floc (filter agent) to obtain product 4 (102
g, 96% HPLC assay) as an MTBE (140 mL) solution. The solution
was used directly in the next step without further purification. A
small amount of product was distilled under reduced pressure to
12
1
ee ) as an off-white solid: mp 129-130 °C. H NMR (400 MHz,
CD OD): δ 4.38 (s, 2H), 3.63 (m, 1H), 3.27 (m, 2H), 2.17 (m,
1H), 2.02 (m, 2H), 1.62 (m, 1H), 1.37 (d, 3H, J ) 6.6 Hz).
NMR (100 MHz, CD
3
1
3
C
3
OD): δ 175.8, 72.9, 55.9, 44.7, 31.4, 23.1,
1
give 4 as a colorless oil: bp 75 °C (7.7 mmHg). H NMR (400
16.2.
MHz, CDCl ): δ 3.99-3.77 (br, 1H), 3.42-3.26 (br, 2H), 2.05-
3
1
5
3
.72 (m, 3H), 1.61-1.47 (br, 1H), 1.46 (s, 9H), 1.16 (d, 3H, J )
Acknowledgment. We thank Robert Reamer and Lisa
DiMichele for valuable NMR assistance. We also thank Mirlinda
Biba, Magareta Figus, and Scott Thomas for the optical and
chemical purity analysis.
.2 Hz). 13C NMR (100 MHz, CDCl
3.0, 28.6, 23.3, 20.5.
): δ 154.5, 78.8, 52.8, 46.3,
3
Method B. To a solution of mesylate 3 (2.54 g, 9.1 mmol) in
MTBE (25 mL) was added LiBH (297 mg, 13.65 mmol) at room
temperature. The reaction mixture was heated to 35 °C for 3 h.
4
JO060319N
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338 J. Org. Chem., Vol. 71, No. 11, 2006