Synthesis of the intermediate of gemifloxacin by the chemoselective hydrogenation of 4-cyano-3-methoxyimino-1 -(N-tert-butoxycarbonyl)pyrrolidine. Part 1. Screening of metal catalysts

Article abstract of DOI:10.1021/op049913u

A novel synthetic route was devised for 4-aminomethyl-3-Z- methoxyiminopyrrolidine methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime group employing (t-Boc)₂O (BOC) as in situ protecting agent. Over Raney nickel or cobalt catalysts, without in situ BOC protection of amine, the side reaction to 4-aminomethyl-3-amino-1-(N-tert- butoxycarbonyl)pyrrolidine (AABP) was extensive by simultaneous hydrogenation of the methyloxime and cyano groups in CMBP, resulting in over-reduction of the desired intermediate, 4-aminomethyl-3-Z-methoxyimino 1-(N-tert-butoxycarbonyl) pyrrolidine (Z-AMBP) all the way to AABP. When in situ BOC protection was performed, the selectivity to the desired 4-(N-tert-butoxycarbonyl)aminomethyl- 3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-BAMBP) rose to as high as 91 % over Raney cobalt by suppressing the over-reduction of Z-AMBP to AABP. On the basis of these observations, a CMBP hydrogenation process over Raney cobalt was proposed. Among noble metal catalysts, only Pd was found to show a high activity. Over Pd catalyst, 4-cyano-3-amino-1-(N-tert-butoxycarbonyl)-3,4- pyrroline (CABP) was found to be a major byproduct, while the formation of AABP or 4-(N-tert-butoxycarbonyl)aminomethyl-3-(N-tert-butoxycarbonyl)amino-1-(N- tert-butoxycarbonyl)pyrrolidine (BABABP) was greatly suppressed. The byproduct CABP formed by hydrogenolysis of the methyl group in the methyloxime group in CMBP could be recycled to the original substrate, 1-(N-tert-butoxycarbonyl)-4- cyano-pyrrolidine-3-one (BCPO) by an acid-catalyzed hydrolysis.

Full text of DOI:10.1021/op049913u

Organic Process Research & Development 2004, 8, 781−787
Synthesis of the Intermediate of Gemifloxacin by the Chemoselective
Hydrogenation of 4-Cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine.
Part 1. Screening of Metal Catalysts
Hyun Kuk Noh,† Jae Sung Lee,† Yeongdae Kim,‡ Gyohyun Hwang,‡ Jay Hyok Chang,§ Hyunik Shin,§
Do Hyun Nam,§ and Kyung Hee Lee*,†
Department of Chemical Engineering and School of EnVironmental Engineering, Pohang UniVersity of Science and
Technology (POSTECH), San 31 Hyoja-dong, Pohang 790-784, Korea; Corporate R&D, LG Chemical Ltd.,
104-1, Moonji-dong, Yusong-gu, Daejon, 305-380, Korea; and Chemical DeVelopment DiVision, LG Life Sciences,
Ltd./R&D, 104-1, Moonji-dong, Yusong-gu, Daejon 305-380, Korea
Scheme 1. Current process for the synthesis of
4-aminomethyl-3-Z-methoxyiminopyrrolidine
methanesulfonate (AMPM)a
Abstract:
A novel synthetic route was devised for 4-aminomethyl-3-Z-
methoxyiminopyrrolidine methanesulfonate (AMPM), the key
intermediate of gemifloxacin, based on chemoselective hydro-
genation of the cyano group in 4-cyano-3-methoxyimino-1-(N-
tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduc-
tion of the methyloxime group employing (t-Boc)2O (BOC) as
in situ protecting agent. Over Raney nickel or cobalt catalysts,
without in situ BOC protection of amine, the side reaction to
4-aminomethyl-3-amino-1-(N-tert-butoxycarbonyl)pyrrolidine
(AABP) was extensive by simultaneous hydrogenation of the
methyloxime and cyano groups in CMBP, resulting in over-
reduction of the desired intermediate, 4-aminomethyl-3-Z-
methoxyimino 1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP)
all the way to AABP. When in situ BOC protection was
performed, the selectivity to the desired 4-(N-tert-butoxycar-
bonyl)aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbon-
yl)pyrrolidine (Z-BAMBP) rose to as high as 91% over Raney
cobalt by suppressing the over-reduction of Z-AMBP to AABP.
On the basis of these observations, a CMBP hydrogenation
process over Raney cobalt was proposed. Among noble metal
catalysts, only Pd was found to show a high activity. Over Pd
catalyst, 4-cyano-3-amino-1-(N-tert-butoxycarbonyl)-3,4-pyrro-
line (CABP) was found to be a major byproduct, while the
formation of AABP or 4-(N-tert-butoxycarbonyl)aminomethyl-
3-(N-tert-butoxycarbonyl)amino-1-(N-tert-butoxycarbonyl)pyr-
rolidine (BABABP) was greatly suppressed. The byproduct
CABP formed by hydrogenolysis of the methyl group in the
methyloxime group in CMBP could be recycled to the original
substrate, 1-(N-tert-butoxycarbonyl)-4-cyano-pyrrolidine-3-one
(BCPO) by an acid-catalyzed hydrolysis.
a Conditions: reagent: (a) Raney Ni, H2, IPA-H2O, 40 °C; (b) (t-Boc)2O,
KOH, DME-H2O, 0 °C; (c) Pd/C, H2, THF-H2O, room temperature; (d)
MeONH2‚HCl, NaOAc, EtOH-THF, 40 °C; (e) methanesulfonic acid, MeOH,
0 °C.6,7
Science Co. and approved by the U.S. Food and Drug
Administration (FDA) in 2003. The drug possesses extremely
potent antimicrobial activity against Gram-positive organisms
and shows an excellent in vivo and in vitro efficacy and
pharmacokinetic profile.1-5
At present, AMPM is manufactured by a five-step process
starting from 1-(N-tert-butoxycarbonyl)-4-cyano-pyrrolidine-
3-one (BCPO) (Scheme 1).6,7 Hydrogenation of BCPO over
Raney nickel catalyst yields mainly 1-(N-tert-butoxycarbon-
yl)-4-aminomethylene-pyrrolidine-3-one (1) by selective
hydrogenation of the cyano group with subsequent double
bond migration. Consequently, the enamine group should be
protected (and activated) by (t-Boc)2O (BOC) in a strong
alkali medium to give 1-(N-tert-butoxycarbonyl)-4-(N-tert-
butoxycarbonyl)aminomethylene-pyrrolidine-3-one (2) for
subsequent hydrogenation of the double bond over Pd/C. The
final product, AMPM, can be produced without difficulty
by introducing the methyloxime group on the ketone group
in 1-(N-tert-butoxycarbonyl)-4-(N-tert-butoxycarbonyl)ami-
1. Introduction
(1) Oh, J. I.; Paek, K. S.; Ahn, M. J.; Kim, M. Y.; Hong, C. Y.; Kim, I. C.;
Kwak, J. H. Antimicrob. Agents Chemother. 1996, 40, 1564.
(2) Hong, C. Y.; Kim, Y. K.; Chang, J. H.; Kim, S. H.; Choi, H.; Nam, D. H.;
Kim, Y. Z.; Kwak, J. H. J. Med. Chem. 1997, 40, 3584.
(3) Hong, C. Y.; Kim, Y. K.; Kim, S. H.; Chang, J. H.; Choi, H.; Nam, D. H.;
Kim, A. R.; Lee, J. H.; Park, K. S. U.S. Patent 5,633,262, 1998.
(4) Hong, C. Y.; Kim, Y. K.; Kim, S. H.; Chang, J. H.; Choi, H.; Nam, D. H.;
Kim, A. R.; Lee, J. H.; Park, K. S. U.S. Patent 5,869,670, 1999.
(5) Hong, C. Y. Farmaco 2001, 56, 41.
4-Aminomethyl-3-Z-methoxyiminopyrrolidine (AMP) and
its methanesulfonate salt (AMPM) are key intermediates in
synthesizing gemifloxacin. Gemifloxacin (Factive) is a novel
quinolone antibacterial drug developed by the LG Life
* To whom correspondence should be addressed. Telephone: 82-54-279-
2263. Fax: 82-54-279-5528. E-mail: kyunglee@postech.ac.kr.
† Pohang University of Science and Technology (POSTECH).
‡ LG Chemical Ltd..
(6) Moon, K. Y.; Kim, W. S.; Lee, T. H.; Chang, J. H. U.S. Patent 6,307,059,
1999.
(7) Grinter, T. J.; Howie, S. WO 0117961, 2000.
§ LG Life Sciences, Ltd./R&D.
10.1021/op049913u CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/03/2004
Vol. 8, No. 5, 2004 / Organic Process Research & Development
•
781

Scheme 2. Novel process for synthesizing
4-aminomethyl-3-Z-methoxyiminopyrrolidine
methanesulphonate (AMPM)
Table 1. Operating conditions of HPLC
column
mobile phase
symmetry C18, 5.0 um, 4.6 mm × 150 mm
A: acetonitrile (HPLC grade, Baker)
B: water (0.1% trifluoroacetic acid)
1.0 mL/min
total flow rate
detection (UV)
197 nm
column temperature ambient
Table 2. Gradient elution composition of HPLC (A:
acetonitrile, B: water (0.1% trifluoroacetic acid))
time
% A
% B
0
3
5
11
13
19
21
24
20
50
50
80
50
50
30
0
0
80
80
nomethylpyrrolidine-3-one (3) and subsequent deprotection
with MSA.
70
Many attempts have been made for the direct chemose-
lective full hydrogenation of the cyano group in BCPO to
the aminomethyl group without much success thus far. The
reason for the only partial hydrogenation of the cyano group
in BCPO is not clear yet, but it may be due to the highly
stable six-membered ring structure of 1-(N-tert-butoxycar-
bonyl)-4-aminomethylene-pyrrolidine-3-one by intramolecu-
lar hydrogen bonding between the hydrogen atom in the
aminomethylene group and the oxygen atom in the ketone
group. This partial hydrogenation is the major reason for
the requirement of two hydrogenation steps and BOC
protection step for transformation of the cyano group to the
aminomethyl group.
100
100
20
20
reactions; higher amines may be formed by coupling between
the produced amine and the imine in the same way as in the
nitrile hydrogenation. In the presence of water, hydrolysis
of imines may lead to formation of carbonyl compounds
which can be reduced further to alcohols.8,9,11-12 Additionally,
hydroxylamines and O-alkylhydroxylamines can be produced
in the hydrogenation of oximes and O-alkyloximes especially
over platinum catalyst.
If we could reduce the number of these reaction steps,
the overall AMPM process would become greatly simplified,
resulting in an improved efficiency and a reduced production
cost. In search for this type of improved process for AMPM
manufacture, we have invented a novel process which
comprises only one hydrogenation step (Scheme 2). In this
new process, the methyloxime group is introduced first,
yielding 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)-
pyrrolidine (CMBP), and this compound is subjected to
hydrogenation and subsequent deprotection with MSA to
complete a three-step process including a single hydrogena-
tion step.
There exists, however, a great challenge in this new
process that the methyloxime group in CMBP is also apt to
be hydrogenated over ordinary hydrogenation catalysts as
well as the cyano group, and it is therefore expected that
the chemoselectivity toward 4-aminomethyl-3-Z-methoxy-
imino-1-(N-tert-butoxycarbonyl)pyrrolidine (Z-AMBP) or
4-(N-tert-butoxycarbonyl)aminomethyl-3-Z-methoxyimino-
1-(N-tert-butoxycarbonyl)pyrrolidine (Z-BAMBP) may be
low.8
Thus, we can expect that countless side products may be
generated in CMBP hydrogenation and that achieving a high
chemoselectivity toward Z-AMBP or Z-BAMBP would be
a great challenge. There has been almost no research on the
chemoselective hydrogenation of the cyano group in a
R-methoxyiminonitrile compound keeping methyloxime in-
tact. This contribution deals with heterogeneous catalytic
chemoselective hydrogenation of CMBP in liquid phase with
BOC as an in situ protecting agent of amine that can be
applied to the manufacture of 4-aminomethyl-3-Z-methoxy-
iminopyrrolidine methanesulfonate (AMPM), the novel
pharmaceutical intermediate especially for gemifloxacin.
2. Experimental Section
2.1. Analytical Methods. The reaction mixtures were
analyzed in the course of the reaction with HPLC (Waters
1525) with a UV detector (Waters 2487). The operating
conditions and gradient elution composition of HPLC are
shown in Tables 1 and 2. Reaction products such as
4-aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbon-
yl)pyrrolidine (Z-AMBP), 4-(N-tert-butoxycarbonyl)ami-
nomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyr-
rolidine (Z-BAMBP), 4-cyano-3-amino-1-(N-tert-butoxy-
carbonyl)-3,4-pyrroline (CABP), 4-aminomethyl-3-amino-
1-(N-tert-butoxycarbonyl)pyrrolidine (AABP), and 4-(N-tert-
butoxycarbonyl)aminomethyl-3-(N-tert-butoxycarbonyl)amino-
1-(N-tert-butoxycarbonyl)pyrrolidine (BABABP) were iden-
tified by HPLC and LC-MS (Finnegan LCQ(067-MS-05))
Actually hydrogenation of oximes and O-alkyloximes
proceeds in a very similar way to that of nitriles.9,10 Like
nitrile hydrogenation, amines are produced in the hydrogena-
tion of oximes and O-alkyloximes mainly via imine inter-
mediate which is formed by hydrogenolysis of the N-O
bond. The imine intermediate is responsible for various side
(8) Bellefon, C.; Fouilloux, P. Catal. ReV. Sci. Eng. 1994, 36, 459.
(9) Nishimura, S. Handbook of Heterogeneous Catalytic Hydrogenation for
Organic Synthesis; John Wiley & Sons: New York, 2002.
(10) Rylander, P. N. Hydrogenation Methods; Academic Press Inc.: New York,
1985.
(11) Odo, K.; Ichikawa, E.; Shirai, K.; Sugino, K. J. Org. Chem. 1957, 22, 1715.
(12) Albert, H.; Taguchi, H. J. Chem. Soc., Perkin Trans. 1 1973, 1629.
782
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Vol. 8, No. 5, 2004 / Organic Process Research & Development

Figure 1. A sample chromatogram in CMBP hydrogenation with in situ BOC protection.
Table 3. List of the relative HPLC retention times for the
compounds in the report
pyridine (99%, Aldrich) was introduced thereto as a base.
Without bases, both reaction rate and CMBP yield were
found to be lower than in the presence of base. Subsequently
1.2 equiv of MeONH2‚HCl (98%, Aldrich) was added, and
the mixture was agitated at ambient temperature for about
5 h to obtain CMBP by introducing the methyloxime group.
After completion of the reaction, 25 mL of water was
added to the solution, and MeOH was removed in vacuo.
The 25 mL of CH2Cl2 (Baker) was poured into the obtained
solution, and the layers were separated. The organic layer
was thoroughly washed, first with saturated NaHCO3 (2 ×
25 mL) and then with saturated NaCl solution (2 × 25 mL)
thoroughly, and CH2Cl2 was removed by vacuum distillation
to obtain yellowish, oily CMBP with 95% yield. From HPLC
analysis, the product was found to consist of E- and
Z-isomers with a 1:4 ratio.
compound
retention time [min]
CMBP
AABP
E-isomer: 7.5, Z-isomer: 8.1
1.21
BABABP
Z-AMBP
Z-BAMBP
CABP
BCPO
BOC
11.3
3.01
10.5
5.4
4.37-6.33 (broad)
12.2
by comparison with the standard samples obtained from the
LG Life Science Co. Because Z-isomer is the desired product,
the selectivity to Z-AMBP or Z-BAMBP was calculated on
the basis of the amount of Z-isomers.13 A list of the relative
HPLC retention times for the compounds in the report is
shown in Table 3 and a sample chromatogram included in
Figure 1.
2.2. Preparation of 4-Cyano-3-methoxyimino-1-(N-tert-
butoxycarbonyl)pyrrolidine (CMBP). CMBP, the substrate
for chemoselective hydrogenation, was prepared as fol-
lows: 5.25 g of 1-(N-tert-butoxycarbonyl)-4-cyano-pyrro-
lidine-3-one (BCPO) received from the LG Life Science Co.
was dissolved in 50 mL of MeOH (Baker) and 1.2 equiv of
1
Spectral data for CMBP: H NMR (500 MHz, CDCl3) δ
4.12 (2H, s), 3.99 (0.8H, s), 3.96 (2.2H, s), 4.15-3.95 (1H,
hidden proton), 3.86 (1H, broad t, J ) 7.2 Hz), 3.71 (1H,
dd, J ) 7.2, J2 11.2 Hz), 1.5 (9H, s); 13C NMR (100 MHz,
CDCl3) δ 153.6, 152.6, 116.1, 81.2, 63.0, 47.6, 45.2, 31.6,
28.3; IR 2249.8, 1694.3 cm-1.
2.3. Liquid-Phase Hydrogenation of CMBP To Pre-
pare 4-Aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxy-
carbonyl)pyrrolidine (Z-AMBP) and 4-(N-tert-Butoxy-
carbonyl)aminomethyl-3-Z-methoxyimino-1-(N-tert-
butoxycarbonyl)pyrrolidine (Z-BAMBP). Raney-type
(13) Over both Raney metal and Pd catalysts, the hydrogenation rates of Z- and
E-CMBP were actually same.
Vol. 8, No. 5, 2004 / Organic Process Research & Development
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783

Table 4. Liquid-phase CMBP hydrogenation over
Raney-type catalyst system: without in situ BOC protection
of amine produceda
conversion of
CMBP [%]
selectivity to
Z-AMBP [%]
catalyst
time [h]
1
7
1
7
1
7
1
7
1
7
1
7
31
98
29
95
2
13
11
68
9
27
17
38
20
87
76
79
58
83
58
-
Raney Ni
Raney Ni (Mo)b
Raney Co
Raney Coc
Raney Co (Ni, Cr)d
Raney Cu
56
0
0
-
Figure 2. CMBP hydrogenation without in situ BOC protec-
tion. Reaction conditions: T ) 313 K, H2 500 psi, IPA 30 mL,
H2O 20 mL, CMBP 0.5 mmol, Raney Cobalt (doped with Ni,
Cr) 0.03 g.
a The following reaction conditions were used unless otherwise stated. CMBP
0.5 mmol; IPA 30 mL; H2O 20 mL; Raney metal 50 mol % of CMBP; H2 500
psi; T ) 313 K. b Mo (2.5 wt %)-doped Raney nickel; 20 mol % of CMBP.
c Raney cobalt of 300 mol % of CMBP. d Ni-, Cr-doped Raney cobalt (Co:
94.8 wt %, Ni: 2.9 wt %, Cr: 2.3 wt %).
poor. The major byproduct was 4-aminomethyl-3-amino-1-
(N-tert-butoxycarbonyl)pyrrolidine (AABP) which was formed
by complete reduction of the methyloxime group as well as
the cyano group. The 2.5 wt % Mo-promoted Raney nickel
increased the reaction rate greatly, and thus the catalyst
loading was reduced to 20 mol % to obtain the data in Table
4. However, the selectivity to Z-AMBP was almost invariant.
Among Raney-type catalysts, Raney cobalt showed the
highest selectivity toward Z-AMBP, although the hydrogena-
tion rate was very slow. When Raney cobalt catalysts were
employed, AABP was also observed as the major byproduct
as over Raney nickel. Doping Raney cobalt with Ni and Cr
gave a dramatic increase in activity in comparison with
undoped Raney cobalt, while the high selectivity to Z-AMBP
was maintained almost the same. Raney Cu showed no
activity at all in the hydrogenation of CMBP.
Representative time vs conversion and selectivity curves
in CMBP hydrogenation over Raney Co (Ni, Cr) catalyst
are shown in Figure 2. The drop of the selectivity to Z-AMBP
with time was accompanied by the increase in the proportion
of AABP. The reduction continued even after 100% conver-
sion of CMBP, and the proportion of Z-AMBP decreased
while that of AABP increased. These observations indicate
that the formed Z-AMBP is further reduced by hydrogenation
of the methyloxime group in Z-AMBP to the amine group.
On the basis of these observations, a hydrogenation
pathway of CMBP without in situ BOC protection may be
proposed as shown in Scheme 3. In this case, the pathway
from CMBP to AABP via Z-AMBP is dominant. The
reaction pathway could be more complex than this in a real
situation, because there may exist various side reactions due
to active species such as imine. However, other side products
were found in negligible amounts, with the exception of the
compounds specified in Scheme 3. Thus, AABP is expected
to be formed via this serial-parallel hydrogenation pathway.
3.1.2. Effect of in Situ BOC Protection. To suppress
the over-hydrogenation of Z-AMBP, CMBP hydrogenation
with in situ protection of amine with BOC was carried out
as shown in Table 5. In this case, the desired product was
4-(N-tert-butoxycarbonyl)aminomethyl-3-Z-methoxyimino-
catalysts that are immersed in water were purchased from
Grace Co. and utilized as received unless otherwise stated.
The composition of Ni- and Cr-doped Raney cobalt analyzed
by ICP was 94.8 wt % Co, 2.9 wt % Ni, and 2.3 wt % Cr.
Noble metal catalysts such as Pd, Pt, Ru, and Rh on supports
and their precursors were purchased from Aldrich. Most of
the Pd catalysts were used as received, but if necessary, they
were utilized after reduction in H2 stream at 473 K for
1-2 h. Supported Pt, Ru, and Rh catalysts were activated
in H2 stream at 573 K for 3 h before CMBP hydrogenation.
The liquid-phase hydrogenation of CMBP was conducted
in a 100-mL Hastelloy-C autoclave reactor (Autoclave
Engineers). Typically CMBP, a solvent, a catalyst, and an
additive, e.g., (t-Boc)2O (99%, Aldrich) were introduced in
the reaction vessel. Typical solvent was 30 mL of isopropyl
alcohol (IPA) and 20 mL of water. After the purge of the
reactor with hydrogen twice, the reactor was pressurized to
60-500 psi with H2. The reaction was conducted typically
at 283-323 K with agitation at 1000 rpm to minimize the
external mass transfer limitation.
1
Spectral data for Z-AMBP: H NMR (400 MHz, CDCl3)
δ 4.19 (2H, broad, s), 3.89 (3H, s), 3.87 (1H, broad, s), 3.77
(1H, broad, m), 3.36 (1H, broad, s), 2.89 (2H, broad, s), 1.49
(9H, s); 13C NMR (100 MHz, CDCl3) δ 157.3, 151.0, 76.6,
-1
58.7, 45.1, 44.5, 42.9, 40.8, 25.0; IR 1694.5 cm
.
1
Spectral data for Z-BAMBP: H NMR (500 MHz, CDCl3)
δ 4.98 (1H, broad, NHCO2-t-Bu, s), 4.08 (2H, s), 3.81 (3H,
s), 3.75 (1H, broad t, J ) 8.0 Hz), 3.50 (1H, broad, s), 3.41
(1H, broad, s), 3.28 (1H, broad, s), 3.00 (1H, broad t, J ) 8
Hz), 1.40 (18H, s); IR 1709.3, 1687.6 cm-1.
3. Results and Discussion
3.1. Raney-Type Catalyst System. 3.1.1. Hydrogenation
Without in Situ BOC Protection. In Table 4, the results of
hydrogenation with Raney-type catalysts are presented with
no in situ protection of amine with BOC. When Raney nickel
was employed as the catalyst, the CMBP conversion was
very high, while the selectivity toward Z-AMBP was very
784
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Vol. 8, No. 5, 2004 / Organic Process Research & Development

Scheme 3. CMBP hydrogenation pathway with no in situ
protection over Raney cobalt catalyst
Table 5. Liquid-phase CMBP hydrogenation over
Raney-type catalyst system with in situ BOC protectiona
selectivity [%]
conversion of
catalyst
CMBP [%]
Z-BAMBP BABABP
Figure 3. CMBP hydrogenation with in situ BOC protection.
Reaction conditions: T ) 298 K, H2 500 psi, IPA 30 mL, H2O
20 mL, BOC 4 equiv of CMBP, CMBP 0.5 mmol, Raney Cobalt
(doped with Ni, Cr) 0.03 g.
Raney Ni
85
81
51
40
34
18
15
27
42
26
32
83
86
87
83
91
89
85
70
63
13
10
10
12
4
Raney Ni (Mo)b
Raney Coc
Raney Co (Ni, Cr)
Raney Co (Ni, Cr)d
Raney Coc,e
Scheme 4. CMBP hydrogenation pathway with in situ
BOC protection over Raney cobalt catalyst
Raney Co (Ni, Cr)e
Raney Co (Ni, Cr)f
Raney Co (Ni, Cr)g
7
10
a The following reaction conditions were used unless otherwise stated. CMBP
0.5 mmol; IPA 30 mL; H2O 20 mL; BOC 4 equiv of CMBP; Raney metal
50 mol % of CMBP; H2 500 psi; T ) 298 K; time ) 7 h. b 20 mol % of CMBP.
c Raney cobalt 300 mol % of CMBP. d BOC 100 equiv. e IPA 40 mL + H2O
10 mL. f T ) 278 K. g P ) 1000 psi.
1-(N-tert-butoxycarbonyl)pyrrolidine (Z-BAMBP), and the
major byproduct was 4-(N-tert-butoxycarbonyl)aminomethyl-
3-(N-tert-butoxycarbonyl)amino 1-(N-tert-butoxycarbonyl)-
pyrrolidine (BABABP). When Mo-promoted Raney nickel
was employed as a catalyst, the Z-BAMBP selectivity was
32% with in situ BOC protection. Note that the Z-AMBP
selectivity was 20% at 7 h without the protection as shown
in Table 4. When Ni-, Cr-promoted Raney cobalt catalyst
was employed with in situ BOC protection, the selectivity
toward Z-BAMBP increased greatly to as high as 91% with
the much lower content of BABABP although CMBP
conversion was reduced somewhat relative to the case with
no in situ BOC protection.
The representative time vs conversion and selectivity
curves over Ni-, Cr-doped Raney Co catalyst with in situ
BOC protection are shown in Figure 3. It is evident that
decrement of the selectivity of Z-BAMBP is much slower
than that in Figure 2. Thus, Z-BAMBP is transformed into
BABABP in a much lower rate with the in situ BOC
protection than that without the protection. However, even
though the amount of BOC was increased as high as 100
equiv relative to that of CMBP, the selectivity toward
BABABP was almost invariant, indicating that 4 equiv of
BOC was enough for the protection of Z-AMBP from further
hydrogenation. From these observations, we can understand
that in situ protection of the amine group in Z-AMBP with
BOC hinders the serial hydrogenation of Z-AMBP to AABP
and that adsorption of Z-AMBP via its amine group on the
catalytic surface is responsible for the serial reaction. A
plausible hydrogenation pathway of CMBP with in situ BOC
protection is proposed on the basis of these observations in
Scheme 4. In this scheme, the reaction pathway from CMBP
to Z-BAMBP via Z-AMBP is dominant, and hydrogenation
of Z-BAMBP to BABABP is negligible.
A certain amount of water was found to be essential for
high rates in CMBP hydrogenation. The data in Table 5 were
obtained with 30 mL of IPA and 20 mL of H2O as solvent.
As the volume of water was reduced to 10 mL with 40 mL
of IPA, the rate decreased abruptly (seventh entry). It is
known that carbonyl compound may be formed via hydroly-
sis of imine intermediate in nitrile or oxime hydrogenation
in the presence of water. However, a few hydrolysis products
were found, and the selectivity to Z-BAMBP was almost
invariant with an increase in the amount of water. Therefore,
the addition of a proper amount of water was found to be
beneficial in view of the reaction rate with no significant
side reaction caused by it. To achieve still higher selectivity
to Z-BAMBP, reaction temperature (eighth entry), pressure
(ninth entry), and organic solvents (not shown) were varied,
but they gave no marked effects on the selectivity.
3.2. Pd Catalyst System. Liquid-phase CMBP hydroge-
nation over Pd catalysts was carried out using BOC as the
in situ protecting agent (Table 6). The side reaction to 4-(N-
tert-butoxycarbonyl)aminomethyl-3-(N-tert-butoxycarbonyl)-
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Table 6. Liquid-phase CMBP hydrogenation over Pd
catalyst; screening test with various supported Pd catalysts
with in situ BOC protectiona
Raney metal catalysts. However, over Pd catalysts, a new
byproduct became the major byproduct that did not appear
in CMBP hydrogenation over Raney nickel and Raney cobalt
systems. This new byproduct was found highly stable and
was not hydrogenated further over Pd catalyst. The new
byproduct has been identified as 4-cyano-3-amino-1-(N-tert-
butoxycarbonyl)-3,4-pyrroline (CABP), which is formed by
hydrogenation of the methyloxime group in CMBP. The
byproduct was converted to the initial starting substrate, 1-(N-
tert-butoxycarbonyl)-4-cyano-pyrrolidine-3-one (BCPO) when
acid was added. The plausible reaction pathway of CMBP
to CABP over Pd catalyst was proposed as in Scheme 5.
First the N-O bond in CMBP is hydrogenolyzed, and the
resulting imine intermediate is tautomerized to the enamine
structure of CABP.
The transformation of CABP to BCPO in the presence
of acid is considered to be owing to hydrolysis of CABP.
Thus, it is known that imines are liable to be converted to
ketones or aldehydes by hydrolysis in the presence of
water,9,11-13 and the acid added may take part in the
hydrolysis reaction as catalyst to change CABP to its imine
structure. The stability of CABP may probably come from
a six-membered ring hydrogen-bonding structure like the one
in 1-(N-tert-butoxycarbonyl)-4-aminomethylene-pyrrolidine-
3-one(1).
selectivity [%]
conversion of Z-BAMBP
BABABP
catalyst
CMBP [%] (or Z-AMBP) CABP (or AABP)
5% Pd/C
1% Pd/C
72
83
78
57
85
67
26
74
71
61
75
70
73
78
20
21
22
22
23
23
19
2
3
9
1
3
2
1
1% Pd/Cb
1% Pd/Cc
1% Pd/Cd
5% Pd/Al2O3
1% Pd/Ce
a The following reaction conditions were used unless otherwise stated. CMBP
0.5 mmol; IPA 30 mL; H2O 20 mL; BOC 4 equiv of CMBP; Pd 5 mol % of
CMBP; H2 500 psi; T ) 298 K; Time ) 7 h. b No BOC. c T ) 278 K. d H2
1000 psi. e IPA 45 mL, water 5 mL.
Scheme 5. Proposed reaction pathway to CABP in
hydrogenation of CMBP over Pd catalyst
amino-1-(N-tert-butoxycarbonyl)pyrrolidine (BABABP) was
suppressed to a great extent over Pd catalysts compared with
Scheme 6. Glossary
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Table 7. Liquid-phase CMBP hydrogenation over noble
However, the reaction rate was poor with a low selectivity
to Z-BAMBP (Table 7), and they did not show better results
than Pd. It was remarkable that CABP was also found as
the main side product over these catalysts as it was in the
Pd catalytic system, suggesting these noble metals behave
in a similar way in the hydrogenation of CMBP.
metal catalyst systemsa
conversion of
CMBP [%]
selectivity to
Z-BAMBP [%]
catalyst
1 wt % Pt/C
PtO2
5 wt % Ru/Al2O3
5 wt % Ru/C
5 wt % Rh/Al2O3
21
28
18
20
35
72
69
73
75
60
4. Conclusions
Over Raney nickel or cobalt catalysts, without in situ BOC
protection of initially formed amine, the side reaction to
AABP by hydrogenation of the methyloxime group as well
as the cyano group in CMBP was extensive, together with
serial hydrogenation of Z-AMBP to AABP. When in situ
BOC protection was performed, the selectivity to Z-BAMBP
rose as high as 91% over Raney cobalt by suppressing the
over-reduction of Z-AMBP to AABP. Among noble metal
catalysts, Pd showed reasonable activity and selectivity.
CABP was found to be a major byproduct over Pd catalyst,
while the formation of AABP or BABABP was substantially
reduced. CABP appeared to be formed by hydrogenolysis
of the methyl group in the methyloxime group in CMBP
and could be recycled to the original substrate, 1-(N-tert-
butoxycarbonyl)-4-cyano-pyrrolidine-3-one (BCPO) by an
acid-catalyzed hydrolysis.
a The following reaction conditions were used unless otherwise stated. CMBP
0.5 mmol; IPA 30 mL; H2O 20 mL; BOC 4 equiv of CMBP; metallic species
5 mol % of CMBP; H2 500 psi; T ) 298 K; time ) 24 h.
Similar to the Raney metal catalytic system, a certain
amount of water was also found essential for an acceptable
reaction rate over Pd catalyst system in CMBP hydrogena-
tion, and the selectivity to Z-BAMBP was not affected by
water added. Reduction in water content of solvent decreased
the reaction rate significantly (seventh entry of Table 6). In
anhydrous conditions, the reaction did not proceed signifi-
cantly.
At 100% conversion of CMBP, the selectivity to Z-
BAMBP over 1% Pd/C was about 65% with in situ BOC
protection. Various attempts were made to increase the
selectivity by suppressing side reaction to CABP such as a
change of reaction temperature, pressure, and organic
solvents, but they were of no avail. However, Pd catalyst
systems gave good Z-BAMBP yields with a higher reaction
rate than Raney cobalt catalysts. Furthermore, considering
CABP could be recycled back to BCPO, the advantage of
Pd catalyst systems becomes even greater.
Acknowledgment
We are grateful for the financial support provided by the
Brain Korea 21 project of the Ministry of Education in 2003,
Korea, and by the LG life Science Co., Korea.
Received for review April 28, 2004.
OP049913U
3.3. Other Noble Metal Catalysts. Pt, Ru, and Rh
catalysts were tried as catalysts for CMBP hydrogenation.
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