Practical large-scale synthesis of the 2-aminomethylpyrrolidin-4-ylthio-containing side chain of the novel carbapenem antibiotic doripenem

Article abstract of DOI:10.1021/op0340412

The first synthesis using an original procedure and a practical large-scale process using an improved procedure for the synthesis of the N-PNZ-protected 2-aminomethylpyrrolidin-4-ylthio-containing side chain of doripenem hydrate (S-4661), a novel parenteral 1β-methylcarbapenem antibiotic, are described, trans-4-Hydroxy-L-proline (4) was converted in an efficient process to (2S,4S)-4-acetylthio-2-(N-sulfamoyl-tert-butoxycarbonylaminomethyl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3) in 55-56% overall yield via a six-step sequence, which includes the two alternative routes to intermediate 13. This process requires no chromatographic purifications, no cryogenic temperatures, no haloalkane solvents, and short operating times and is amenable to a multikilogram-scale preparation. Several kilograms of the side chain 3 were successfully prepared by this process.

Full text of DOI:10.1021/op0340412

Organic Process Research & Development 2003, 7, 649−654
Practical Large-Scale Synthesis of the
2-Aminomethylpyrrolidin-4-ylthio-Containing Side Chain of the Novel
Carbapenem Antibiotic Doripenem
Yutaka Nishino,† Tadafumi Komurasaki, Tetsuya Yuasa,‡ Makoto Kakinuma, Kenji Izumi, Makoto Kobayashi,
Shinichiro Fujiie, Teruhiro Gotoh, Yoshiyuki Masui,* Makoto Hajima, Masayuki Takahira,§ Akira Okuyama, and
Takahiro Kataoka|
Bulk Chemicals Process R&D Department, Manufacturing Technology R&D Laboratories, Shionogi & Co., Ltd.,
Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan
Scheme 1
Abstract:
The first synthesis using an original procedure and a practical
large-scale process using an improved procedure for the
synthesis of the N-PNZ-protected 2-aminomethylpyrrolidin-4-
ylthio-containing side chain of doripenem hydrate (S-4661), a
novel parenteral 1â-methylcarbapenem antibiotic, are de-
scribed. trans-4-Hydroxy-L-proline (4) was converted in an
efficient process to (2S,4S)-4-acetylthio-2-(N-sulfamoyl-tert-
butoxycarbonylaminomethyl)-1-(4-nitrobenzyloxycarbonyl)pyr-
rolidine (3) in 55-56% overall yield via a six-step sequence,
which includes the two alternative routes to intermediate 13.
This process requires no chromatographic purifications, no
cryogenic temperatures, no haloalkane solvents, and short
operating times and is amenable to a multikilogram-scale
preparation. Several kilograms of the side chain 3 were
successfully prepared by this process.
enem skeleton enhances metabolic stability to renal dehy-
dropeptidase-1 (DHP-1) and leads to high antibacterial
potency.7 Doripenem hydrate (S-4661: 1), which was
discovered by Shionogi Research Laboratories, Shionogi &
Co., Ltd., Osaka, Japan, is a novel parenteral 1â-methylcar-
bapenem antibiotic.8 In our previous reports,8,9 its synthesis,
biology, and structure-activity relationships (SAR) have
been reported. Compound 1 exhibits potent, broad, and
well-balanced antibacterial activity against a wide range of
both Gram-positive and Gram-negative bacteria including
Pseudomonas aeruginosa.
According to the conventional retrosynthetic analysis of
a carbapenem, doripenem can be assembled from 4-nitrobenz-
yl-protected 1â-methylcarbapenem enolphosphate 27,10 and
2-aminomethylpyrrolidin-4-ylthio-containing side chain 3
(Scheme 1). Enolphosphate 2 is also used as a starting
material in the synthesis of ertapenem.11 Both the enol-
phophate 2 and aminomethylpyrrolidine 3 are now com-
mercially available. The syntheses of several N-BOC- and
Introduction
Carbapenem compounds are noted for their broad and
potent antibacterial activity.1 Imipenem,2 panipenem,3 mero-
penem,4 biapenem,5 and ertapenem6 have been launched on
the market. In cases of meropenem, biapenem, and ertap-
enem, the introduction of a 1â-methyl group to the carbap-
* Corresponding author. E-mail: yoshiyuki.masui@shionogi.co.jp.
† Current address: Clinical Trial Drugs Producing Unit, Manufacturing
Technology R&D Laboratories, Shionogi & Co., Ltd., Kuise Terajima 2-chome,
Amagasaki, Hyogo 660-0813, Japan.
‡ Current address: Regulatory Affairs Department, Shionogi & Co., Ltd.,
Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan.
§ Current address: Corporate Quality Assurance Department, Shionogi & Co.,
Ltd., Kuise Terajima 2-chome, Amagasaki, Hyogo 660-0813, Japan.
| Current address: Bushu Pharmaceuticals Ltd., 1, Ooaza-Takeno, Kawagoe,
Saitama 350-0801, Japan.
(1) (a) For a brief history: Sunagawa, M.; Sasaki, A Heterocycles 2001, 54,
497-528. (b) Kawamoto, I. Drugs Future 1998, 23, 181-189. (c) Coulton,
S.; Hunt, E. In Progress in Medicinal Chemistry; Ellis, G. P., Luscombe,
D. K., Eds.; Elsevier Science: New York, 1996; Vol. 33, pp 99-145. (d)
Sader, H. S.; Gales, A. C. Drugs 2001, 61, 553-564.
(2) (a) Leanza, W. J.; Wildonger, K. J.; Miller, T. W.; Christensen, B. G. J.
Med. Chem. 1979, 22, 1435-1436. (b) Kropp, H.; Sundelof, J. G.; Kahan,
J. S.; Kahan, F. M.; Birnbaum, J. Antimicrob. Agents Chemother. 1980,
17, 993-1000. (c) Kahan, F. M.; Kropp, H.; Sundelof, J. G.; Birnbaum, J.
J. Antimicrob. Chemother. 1983, 12 (Suppl. D), 1-35.
(3) Miyadera, T.; Sugimura, Y.; Hashomoto, T.; Tanaka, T.; Iino, K.; Shibata,
T.; Sugawara, S. J. Antibiot. 1983, 36, 1034-1039.
(7) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G. Heterocycles 1984,
21, 29-40.
(8) Iso, Y.; Irie, T.; Nishino, Y.; Motokawa, K.; Nishitani, Y. J. Antibiot. 1996,
49, 199-209.
(9) Iso, Y.; Irie, T.; Iwaki, T.; Kii, M.; Sendo, Y.; Motokawa, K.; Nishitani, Y.
J. Antibiot. 1996, 49, 478-484.
(10) (a) There are many efficient approaches to this compound 2, eg. Berks, A.
H. Tetrahedron 1996, 52, 331-375. (b) This is commercially available from
Takasago, Kaneka, and Nisso companies.
(4) Sunagawa, I.; Matsumura, H.; Inoue, T.; Fukasawa, M.; Kato, M. J. Antibiot.
1990, 43, 519-532.
(5) Hiraishi, T.; Miyata, A.; Hara, T.; Araake, M.; Ogawa, H. Jpn. J. Antibiot.
2001, 54, 581-595.
(6) Fuchs, P. C.; Barry, A. L.; Brown, S. D. Antimicrob. Agents Chemother.
2001, 45, 1915-1918 and references therein.
(11) Brands, K. M. J.; Jobson, R. B.; Conrad, K. M.; Williams, J. M.; Pipik, B.;
Cameron, M.; Davies, A. J.; Houghton, P. G.; Ashwood, M. S.; Cottrell, I.
F.; Reamer, R. A.; Kennedy, D. J.; Dolling, U.-H.; Reider, P. J. J. Org.
Chem. 2002, 67, 4771-4776.
10.1021/op0340412 CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/06/2003
Vol. 7, No. 5, 2003 / Organic Process Research & Development
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649

Scheme 2. First-generation process
N-PMZ-protected aminomethylpyrrolidine derivatives have
been reported in our previous papers.8,9 These procedures
facilitated the SAR studies and led to a rapid optimization
of lead derivatives. For the first time, N-PNZ-protected
aminomethylpyrrolidine 3 was prepared by the sequence of
six reaction steps from trans-4-hydroxy-L-proline (4) in
overall yield of 49% using our first-generation process
(Scheme 2), which was a modification of our previously
reported procedure.9 The average yield per reaction was 89%.
However, the first-generation process for the synthesis of
aminomethylpyrrolidine 3 included several undesirable con-
ditions, for instance, cryogenic reaction temperatures, long
operation times, and the use of haloalkane solvents. To
reduce the cost or the processing time and to make the
process more enviromentally suitable, we have developed
an improved process which requires no cryogenic temper-
atures, no haloalkane solvents, and a shorter processing time
than that for the first-generation process. In this contribution,
we describe an efficient and practical synthesis of aminom-
ethylpyrrolidine 3 that is amenable to large-scale produc-
tion.12 The coupling reaction of enolphosphate 2 to give the
protected final intermediate, the deprotection, and the isola-
tion to afford doripenem hydrate (1) will be reported
separately.13
in Scheme 2. This is the first example for the synthesis of
the aminomethylpyrrolidine 3. This first-generation process
was a modification of our previously reported procedure,9
which we described as a medicinal chemical process for the
synthesis of another N-BOC-protected aminomethylpyrro-
lidine derivatives. The hydroxyproline 4 was treated with
4-nitrobenzyl chloroformate (PNZ-Cl) in toluene-water to
give N-protected 4-hydroxyproline 514 in 88% yield. The
hydroxyproline 5 was converted into hydroxymethylpyrro-
lidine 8 in a one-pot procedure in 93% overall yield by a
sequence of three reactions at -45 °C, namely the formation
of mixed anhydride 6 from hydroxyproline 5 with ethyl
chloroformate and triethylamine (Et3N), the O-mesylation
of mixed anhydride 6 with methanesulfonyl chloride (MsCl)
and Et3N, and the reduction of the mixed anhydride 7 with
sodium borohydride (NaBH4). The hydroxymethylpyrrolidine
8 was treated with potassium thioacetate (KSAc) in DMF-
toluene to afford acetylthiopyrrolidine 9 in 74% yield with
the inversion of the C-4 configuration. The conversion of
the hydroxyl group of acetylthiopyrrolidine 9 into the
N-BOC-sulfamoyl group was successfully carried out by the
Mitsunobu reaction to give the target compound 3 in 81%
yield. The overall yield of aminomethylpyrrolidine 3 from
hydroxyproline 4 was 49%. The average yield per reaction
was 89%. This first-generation process required no chro-
matographic purification. We manufactured over 50 kg of
aminomethylpyrrolidine 3 by this first-generation process on
a pilot scale. However, this process for the synthesis of
aminomethylpyrrolidine 3 included some undesirable condi-
tions, for instance, cryogenic reaction temperatures (three
reactions required -45 °C), the use of CH2Cl2 as a solvent
(for the mixed anhydride formation), and long operating
Results and Discussion
The First-Generation Process. For the first time, N-PNZ-
protected aminomethylpyrrolidine 3 was prepared by the
sequence of six reactions from hydroxyproline 4 as shown
(12) A portion of this study was patented. Nishino, Y.; Yuasa, T.; Komurasaki,
T.; Kakinuma, M.; Masui, T.; Kobayashi, M. Patent Application No. JP
2001-140782.
(13) Nishino, Y.; Kobayashi, M.; Izumi, K.; Yonezawa, H.; Shinno, T.; Kobayashi
T.; Masui, Y.; Hajima, M.; Takahira, M.; Okuyama, A.; Kataoka, T.
Manuscript in preparation.
(14) Hadfield, P. S.; Galt, R. H. B.; Sawyer, Y.; Layland, N. J.; Page, M. I. J.
Chem. Soc., Perkin Trans. 1 1997, 503-509.
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Scheme 3. Improved process
times (numerous separations of biphasic layers in extractions
and four isolation steps of the crystalline intermediates 5, 8,
9, and the product 3). A cryogenic reaction temperature
confines equipment and significantly increases the cost of
production. It is difficult to recover CH2Cl2 completely,
mainly due to its low boiling point. Unless CH2Cl2 can be
100% recovered, its use should be avoided due to the effect
on the environment. The longer operating times lead to lower
productivity and to higher manufacturing cost. Therefore,
we have developed an improved process which requires no
cryogenic temperatures, no haloalkane solvents, and operat-
ing times shorter than those for the first-generation process.
The Improved Process. We then developed the efficient
process for the synthesis of aminomethylpyrrolidine 3 which
is shown in Scheme 3. After the intermediate 13,15 the
improved process is identical to the first-generation process.
There are two alternative routes to afford 13 in the improved
process. In Route A, hydroxyproline 4 was converted into
mesylate 1415 in 91% yield by a sequence of three reactions,
namely the esterification with methanol in the presence of
HCl or SOCl2 to give methyl ester hydrochloride 12, the
N-protection with PNZ-Cl to give methyl ester 13, and the
O-mesylation with MsCl and Et3N without isolation of the
two intermediates 12 and 13. Acetylthiopyrrolidine 9 was
prepared from mesylate 14 in 76% yield without isolation
of hydroxymethylpyrrolidine 8. The target compound 3 was
prepared from acetylthiopyrrolidine 9 in 81% yield. The
overall yield of 3 from 4 by Route A was 56%. In Route B,
hydroxyproline 4 was treated with PNZ-Cl in toluene-water
to give N-PNZ-protected carboxylic acid hydrate 1516 in 95%
yield. The carboxylic acid hydrate 15 was converted into
acetylthiopyrrolidine 9 in 71% overall yield by a sequence
of four reactions, namely the esterification of hydroxyproline
4 with methanol in the presence of H2SO4, the O-mesylation
with MsCl and Et3N, the reduction of the methyl ester with
NaBH4, and the substitution of the C-4 position with KSAc
without isolation of the three intermediates 13, 14, and 8.
The target compound 3 was prepared from acetylthiopyrro-
lidine 9 in 81% yield. The overall yield of 3 from 4 by Route
B was 55%, which was quite similar to that by Route A
(56%). The improved process provided 6-7% larger yields
than the first-generation process and provides the flexibility
of two routes to 13. The average yield per reaction in each
route was 91%. Route B is preferable because expensive
PNZ-Cl is used in the later step. However, if PNZ-Cl is
produced in-house cheaply, Route A can be chosen.
Because of instability of the intermediates 6 and 7 in the
first-generation process, -45 °C was necessary for the
reactions. Significantly, in the improved process, we suc-
(15) The synthesis of the esters 13 and 14 from hydroxyproline 4 was
described: The overall yield of ester 14 from 4 was 80%, which was 11%
lower than that by our process (Route A). This process contained
chromatographic purification of ester 13. CH2Cl2 was used as a solvent for
the reactions to give the both esters 13 and 14: Oh, C.-H.; Lee, S. C.;
Park, S.-J.; Lee, I.-K.; Nam, K. H.; Lee, K.-S.; Chung, B.-Y.; Cho, J.-H.
Arch. Pharm. Pharm. Med. Chem. 1999, 332, 111-114.
(16) (a) Carpenter, F. H.; Gish, D. T. J. Am. Chem. Soc. 1952, 74, 3818-3821.
(b) DeWald, H. A.; Behn, D. C.; Moore, A. M. J. Am. Chem. Soc. 1959,
81, 4364-4366.
Vol. 7, No. 5, 2003 / Organic Process Research & Development
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651

cessfully avoided the cryogenic temperature conditions in
the original process by changing the intermediates 6 and 7
into the stable intermediates 13 and 14, thereby, eliminating
the need for a cryogenic reaction. In addition, CH2Cl2 was
removed from the process by employing toluene as the
reaction solvent. The process throughput (product produced
per unit time)17 of the improved process was 3-fold higher
than that of the first-generation process. A total production
period is the sum of an operation time for the reactions,
extractions, concentrations, crystallizations, drying, cleaning
up the equipment, quality control, and so on. According to
our simulation, the total production period for 1 MT of 3
from 4 by the improved process on a commercial scale would
be almost one-third of that required by the first-generation
process. The operation time was shortened by reducing the
number of phase cuts in the extractions from 13 times to 4
times, by reducing the number of isolated crystalline products
from 4 (5, 8, 9, and 3) to 3 (14 or 15, 9, and 3), and by
reducing the amounts of solvent concentrated during the
workup after the reactions or extractions. For example, the
weight of solvent for the Mitsunobu reaction was reduced
from 18- to 7-fold of the weight of 3.
trans-4-hydroxy-L-proline (4) (36.0kg, 275 mol) and NaOH
(24.2 kg) in water (240 L) at 5 °C. The reaction mixture
was stirred for 1 h at 5 °C. After the addition of toluene
(100 L), the layers were separated. The aqueous layer was
washed with toluene (90 L). Each organic layer was back-
extracted with aqueous 2% NaOH (67.5 kg). EtOAc (360
L) was added to the combined aqueous extracts. The pH was
adjusted to 2.0 by slow addition of concentrated HCl (ca.
36 kg). Extraction with EtOAc (144 L) followed by crystal-
lization from toluene gave N-protected proline 514 (75.06 kg,
88%) as a colorless crystalline powder: mp 182-183 °C
1
(lit. 181.6-182.6 °C). H NMR (300 MHz, DMSO-d6) δ
1.85-2.25 (m, 2H, H-3), 3.30 (br s, 1H, -OH), 3.40 (m,
2H, H-5), 4.28 (m, 2H, H-2 and H-4), 5.20 (m, 2H, -OCH2-
Ar), 7.60 (m, 2H, meta-H of nitrophenyl), 8.20 (m, 2H,
ortho-H of nitrophenyl), 12.65 (br s, 1H, -CO2H).
One-Pot Preparation of (2S,4R)-2-Hydroxymethyl-4-me-
thylsulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (8)
from 5. Ethyl chloroformate (11.9 kg, 1.1 equiv) and Et3N
(12.1 kg, 1.2 equiv) were added to a solution of N-protected
proline 5 (31.0 kg, 99.9 mol) in CH2Cl2 (250 L) at 0 °C.
The reaction mixture was stirred for 0.5 h at 0 °C and then
was cooled to -45 °C. MsCl (12.6 kg, 1.1 equiv) and Et3N
(12.1 kg, 1.2 equiv) were added dropwise to the reaction
mixture at -45 °C. After the reaction mixture was stirred
for 0.5 h at -45 °C, 2-propanol (78 kg) was added dropwise
at -45 °C, followed by the dropwise addition of a solution
of NaBH4 (5.7 kg, 1.5 equiv) in water (23 L) to the reaction
mixture at -45 °C. The reaction mixture was stirred for 0.5
h at -45 °C and then was poured into aqueous 2.4% HCl
(234 kg). After the layers were separeted, the organic layer
was washed with aqueous 2% NaHCO3 and 3% NaCl. Each
aqueous layer was back-extracted with CH2Cl2. The com-
bined extracts were concentrated to 50 L. EtOAc (250 L)
was added to the concentrate, and the mixture was concen-
trated to 110 L. Crystallization by addition of hexane (62
L) to the concentrate gave 8 (34.9 kg, 93%) as a colorless
crystalline powder: mp 113-116 °C. A thermal equilibrium
of the single C-N bond rotation in a solution of CDCl3 at
0 °C to give a 5:2 mixture of cis and trans isomers was
Since the improved process does not require chromato-
graphic purification, cryogenic temperature, or haloalkane
solvent and provides shorter operation time, it is a practical,
efficient, and enviromentally friendly process. This new
process has been scaled up in the pilot plant to produce the
compound 3 in over 50 kg scale.
Conclusions
We described the first example for the synthesis of
(2S,4S)-4-acetylthio-2-(N-sulfamoyl-tert-butoxycarbonylami-
nomethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3), which
is the side chain of the new parenteral carbapenem antibiotic
doripenem hydrate (1). Further, we developed the process
including the two alternative routes to intermediate 13 and
demonstrated its use for the practical multikilogram-scale
synthesis of 3. The improved process can provide 3 from 4
in overall yield of 55-56% (by six reactions with an average
of yield of 91%), and requires no chromatographic purifica-
tion, no cryogenic temperature, no haloalkane solvent, and
short operation time. This makes it practical, efficient, and
industrial. In fact, this new process has been scaled up in
the pilot plant to produce over 50 kg of the compound 3.
1
observed. H NMR (600 MHz, CDCl3) δ 2.05 (m, 1H, one
of H-3 of pyrrolidine), 2.42 (m, 1H, one of H-3 of
pyrrolidine), 3.07 (minor) and 3.09 (major) (s, 3H, Ms-), 3.60
(minor) and 3.64 (major) (m, 1H, one of -CH2OH), 3.65
(minor) and 3.72 (major) (m, 1H, one of H-5 of pyrrolidine),
3.89 (major) and 3.95 (minor) (m, 1H, one of -CH2OH),
3.90-4.10 (br, 1H, -OH), 4.04 (m, 1H, one of H-5 of
pyrrolidine), 4.21 (m, 1H, H-2 of pyrrolidine), 5.23 (d, 1H,
J ) 13.7 Hz, one of -CH2-Ar of minor isomer), 5.26 (s,
2H, -CH2-Ar of major isomer), 5.27 (major) and 5.30
(minor) (m, 1H, H-4 of pyrrolidine), 5.30 (d, 1H, J ) 13.7
Hz, one of -CH2-Ar of minor isomer), 7.54 (minor) and
7.67 (major) (d, 2H, J ) 9.1 Hz, meta-H of nitrophenyl),
8.24 (d, 2H, J ) 9.1 Hz, ortho-H of nitrophenyl). 13C NMR
(150 MHz, CDCl3) δ 35.1 (major) and 35.4 (minor) (C-3 of
pyrrolidine), 38.8 (minor) and 38.9 (major) (Ms-), 53.7
(minor) and 53.8 (major) (C-5 of pyrrolidine), 57.5 (minor)
and 59.3 (major) (C-2 of pyrrolidine), 63.2 (minor) and 65.1
Experimental Section
Materials and Instrumentation. All commercially avail-
able materials and solvents were used as received. Melting
points are uncorrected. NMR experiments were conducted
by using a Mercury 300 or a Unity 600 NMR spectrometer
(Varian). IR spectra were obtained on a Magna 560 FT-IR
spectrophotometer (Nicolet).
The First-Generation Process (Scheme 2). Preparation
of (2S,4R)-4-Hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-
2-carboxylic Acid (5). A 50% solution of PNZ-Cl (130.0 kg,
1.1 equiv) in toluene was added dropwise to a solution of
(17) Anderson, N. G. Practical Process Research & DeVelopment; Academic
Press: San Diego, 2000; pp 46-50.
652
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Vol. 7, No. 5, 2003 / Organic Process Research & Development

(major) (-CH2OH), 66.3 (major) and 67.2 (minor) (-CH2-
Ar), 78.3 (major) and 79.0 (minor) (C-4 of pyrrolidine), 124.1
(ortho-C of nitrophenyl), 128.3 (major) and 128.4 (minor)
(meta-C of nitrophenyl), 143.6 (major) and 143.7 (minor)
(para-C of nitrophenyl), 147.7 (ipso-C of nitrophenyl), 155.9
(CdO of PNZ-). IR (KBr) 3439, 1699, 1684, 1523, 1342,
1169 cm-1. MS (Ion Mode: FAB+) m/z 375 [M + H]+, 749
[2M + H]+. Anal. Calcd for C14H18N2O8S: C, 44.92; H,
4.85; N, 7.48; S, 8.57. Found: C, 44.82; H, 4.68; N, 7.50;
S, 8.40.
2.0. The resulting precipitate was collected by filtration,
washed with water, and dried to give 119 (78.4 kg, 90%) as
a colorless crystalline powder: mp 131-133 °C (lit. 130-
131 °C). 1H NMR (300 MHz, DMSO-d6) δ 1.43 (s, 9H, tert-
Bu-), 7.27 (s, 2H).
Preparation of (2S,4S)-4-Acetylthio-2-(N-sulfamoyl-tert-
butoxycarbonylaminomethyl)-1-(4-nitrobenzyloxycarbonyl)-
pyrrolidine (3). A solution of diisopropyl azodicarboxylate
(DIAD) (16.7 kg, 1.2 equiv) in EtOAc (24 L) was added
dropwise to a mixture of 9 (24.3 kg, 68.6 mol), triph-
enylphosphine (21.9 kg, 1.2 equiv), N-BOC-sulfamide 11
(20.2 kg, 1.5 equiv), and EtOAc (560 L) at 20 °C. The
reaction mixture was stirred at 20 °C for 2 h. After the
reaction was completed, the reaction mixture was concen-
trated to 110 L, and the residual EtOAc was exchanged into
MeOH by evaporation to give the concentrate (160 L). Water
(19 L) was added to the concentrate at 65 °C. After addition
of seed cryatal (40 g), the mixure was stirred at 50 °C for 2
h and then was stored at room temperature overnight. The
resultant precipitate was collected by filtration, washed with
85% aqueous MeOH, and dried to give 3 (29.6 kg, 81%) as
Preparation of (2S,4S)-4-Acetylthio-2-hydroxymethyl-1-
(4-nitrobenzyloxycarbonyl)pyrrolidine (9) from 8 Using
DMF-Toluene as Reaction SolVents. A mixture of 8 (40.0
kg, 107 mol), potassium thioacetate (16.0 kg, 1.3 equiv),
DMF (80 L), and toluene (120 L) was stirred at 65 °C for 4
h. After the reaction was completed, the reaction mixture
was added to a mixure of EtOAc (600 L) and water (300
L). The layers were separated, and the organic layer was
washed with aqueous 5% NaCl (200 kg × 2). Each aqueous
layer was back-extracted with EtOAc (120 L). The combined
organic extracts were concentrated to 290 L. Toluene (340
L) was added to the concentrate. The mixture was concen-
trated to 290 L. The mixture was stored at room temperature
overnight. The resultant precipitate was collected by filtra-
tion, washed with EtOAc-toluene, and dried to give 9 (27.9
kg, 74%) as a slightly yellow crystalline powder: mp 132-
133 °C. 1H NMR (600 MHz, CDCl3) δ 1.66 (m, 1H, H-3 of
pyrrolidine), 2.33 (s, 3H, Ac-), 2.50 (m, 1H, H-3 of
pyrrolidine), 3.26 (dd, 1H, J ) 7.6 and 11.2 Hz, H-5 of
pyrrolidine), 3.74 (m, 2H, CH2-OH), 3.88 (m, 1H, H-4 of
pyrrolidine), 4.07 (m, 1H, H-2 of pyrrolidine), 4.14 (dd, 1H,
J ) 8.8 and 11.2 Hz, H-5 of pyrrolidine), 4.42 (dd, 1H, J )
3.5 and 8.6 Hz, -OH), 5.22 (s, 2H, CH2-Ar), 7.53 (d, 2H,
J ) 9.1 Hz, meta-H of nitrophenyl), 8.28 (d, 2H, J ) 9.1
Hz, ortho-H of nitrophenyl). 13C NMR (150 MHz, CDCl3)
δ 30.8 (Me- of Ac-), 34.0 (C-3 of pyrrolidine), 38.5 (C-4
of pyrrolidine), 52.9 (C-5 of pyrrolidine), 60.9 (C-2 of
pyrrolidine), 66.2 (CH2-Ar), 66.5 (-CH2OH), 124.0 (ortho-
C of nitrophenyl), 128.4 (meta-C of nitrophenyl), 143.5
(para-C of nitrophenyl), 147.6 (ipso-C of nitrophenyl), 156.2
(CdO of PNZ-), 195.5 (CdO of Ac-). IR (KBr) 3419,
1693, 1670, 1604, 1519, 1429, 1340, 1126 cm-1. MS (Ion
Mode: FAB+) m/z 355 [M + H]+, 709 [2M + H]+. Anal.
Calcd for C15H18N2O6S: C, 50.84; H, 5.12; N, 7.90; S, 9.05.
Found: C, 50.88; H, 4.82; N, 7.97; S, 8.87.
1
a slightly yellow crystalline powder: mp 139-142 °C. H
NMR (600 MHz, CDCl3) δ 1.48 (s, 9H, tert-Bu-), 1.57-
1.61 (ddd, 1H, J ) 14.1, 5.4 and 3.6 Hz, H-3â of
pyrrolidine), 2.35 (s, 3H, AcS-), 2.59 (dt, 1H, J ) 14.1
and 8.6 Hz, H-3R of pyrrolidine), 3.27 (dd, 1H, J ) 12.1
and 6.5 Hz, H-5â of pyrrolidine), 3.62 (dd, 1H, J ) 14.9
and 2.7 Hz, one of -CH2N(BOC)SO2-), 3.96 (m, 1H, H-4
of pyrrolidine), 4.02 (dd, 1H, J ) 14.9 and 8.5 Hz, one of
-CH2N(BOC)SO2-), 4.27 (dd, 1H, J ) 12.1 and 7.8 Hz,
H-5R of pyrrolidine), 4.55 (m, 1H, H-2R of pyrrolidine),
5.18 (ABq, 2H, J ) 13.4 Hz, -OCH2-Ar), 5.86 (br, 2H,
-SO2NH2), 7.49 (A2B2, 2H, J ) 8.7 Hz, meta-H of
nitrophenyl), 8.24 (A2B2, 2H, J ) 8.7 Hz, ortho-H of
nitrophenyl). 13C NMR (150 MHz, CDCl3) δ 28.1 (Me- of
tert-Bu-), 30.5 (Me- of AcS-), 34.5 (C-3 of pyrrolidine),
39.2 (C-4 of pyrrolidine), 49.9 (-CH2NSO2-), 52.2 (C-5
of pyrrolidine), 56.7 (C-2 of pyrrolidine), 66.1 (-OCH2-
Ar), 84.2 (quat-C of tert-Bu-), 123.9 (ortho-C of nitrophe-
nyl), 128.2 (meta-C of nitrophenyl), 143.1 (para-C of
nitrophenyl), 147.8 (ipso-C of nitrophenyl), 151.8 (CdO of
BOC-), 155.1 (CdO of PNZ-), 194.9 (CdO of AcS-).
IR (KBr) 3361, 3226, 2978, 1708, 1692, 1523, 1381, 1336,
1187,1149 cm-1. MS (Ion Mode: FAB+) m/z 533 [M + H]+,
555 [M + Na]+. Anal. Calcd for C20H28N4O9S2: C, 45.10;
H, 5.30; N, 10.52; S, 12.04. Found: C, 45.00; H, 5.27; N,
10.52; S, 11.99.
The Improved Process (Scheme 3). Preparation of
Methyl (2S,4R)-4-Methylsulfonyloxy-1-(4-nitrobenzyloxycar-
bonyl)pyrrolidin-2-carboxylate (14) from 4. SOCl2 (10.0 g,
1.0 equiv) was added dropwise to a mixture of hydroxypro-
line 4 (10.0 g, 76.3 mmol) and MeOH (50 mL) at 0 °C. The
reaction mixture was then stirred at 40 °C for 2 h. After
cooling the reaction mixture to 0 °C, a 48% aqueous solution
of NaOH (7.0 g) was added dropwise at 0 °C. After addition
of water (30 mL), K2CO3 (15.8 g) was added slowly below
20 °C by controlling the amount of gaseous CO2 evolution.
A solution of PNZ-Cl (16.4 g, 1.0 equiv) in toluene (17 mL)
Preparation of N-tert-Butoxycarbonylsulfamide (11) Ac-
cording to the Literature Method.9 Chlorosulfonyl isocyanate
(10) (62.5 kg, 442 mol) was added to a solution of tert-
butyl alcohol (32.7 kg) in EtOAc (626 L) at -40 °C. The
reaction mixture was stirred at -40 °C for 40 min, and then
was cooled to -65 °C. After dry liquid ammonia (NH3, 45.1
kg) was added dropwise to the reaction mixture at -60 °C,
and the reaction mixture was warmed to 15 °C. Aqueous
22% H2SO4 (ca. 150 kg) was added to the reaction mixture
to adjust the pH to 9.5 with cooling. Water (100 L) was
added to the mixture. The layers were separated. The aqueous
layer was washed with EtOAc (230 L) and then was acidified
with aqueous 22% H2SO4 (ca. 170 kg) to adjust the pH to
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was added dropwise to the mixture at 5 °C. The reaction
mixture was stirred for 1 h at 2 °C and then was concentrated
to remove MeOH. After addition of EtOAc (100 mL) and
water (60 mL) to the concentrate, the layers were separated.
The organic layer was concentrated to replace EtOAc into
toluene. Et3N (9.3 g, 1.2 equiv) was added to the residue.
MsCl (9.6 g, 1.1 equiv) was added dropwise to the mixture
at room temperature. After the reaction mixture was stirred
at room temperature for 20 min, water (60 mL) was added.
The precipitate was collected and dried to give 1415 (27.8 g,
91%) as a colorless crystalline powder: mp 87-90 °C (lit.
78.0-80.0 °C). A thermal equilibrium of the single C-N
bond rotation in a solution of CDCl3 at 0 °C to give a 1:1
at 10 °C, concentrated HCl (4.6 g) was added to the
suspension. Filtration followed by drying gave 1516 (23.8 g,
95%) as a colorless crystalline powder: mp 136-138 °C
(lit. 133-135 °C). 1H NMR (300 MHz, DMSO-d6) δ 1.85-
2.25 (m, 2H, H-3), 3.30 (br s, 1H, -OH), 3.40 (m, 2H, H-5),
4.28 (m, 2H, H-2 and H-4), 5.20 (m, 2H, -OCH2-Ar), 7.60
(m, 2H, meta-H of nitrophenyl), 8.20 (m, 2H, ortho-H of
nitrophenyl), 12.65 (br s, 1H, -CO2H).
Preparation of Hydroxymethylpyrrolidine 9 from 15.
H2SO4 (98%, 0.6 g) was added to a solution of 15 (10.0 g,
30.4 mmol) in MeOH (50 mL). The reaction mixture was
stirred at 60 °C for 7 h. After cooling the mixture below 10
°C, the reaction mixture was neutralized with aqueous 5%
NaOH to adjust the pH to 5 and then was concentrated. The
residue (17.8 g) was poured into a mixture of EtOAc (50
mL) and aqueous 10% NaCl (50 mL). The layers were
separated. The organic layer was concentrated to remove
water. After the residual organic solution cooled to 0 °C,
MsCl (3.8 g, 1.1 equiv) and Et3N (3.7 g, 1.2 equiv) were
added to the solution. After the reaction was completed, the
reaction mixture was washed with aqueous 5% H2SO4 and
water. The organic layer was concentrated to remove water.
EtOAc (48 mL) and MeOH (7.5 mL) were added to the
residue (14.5 g). NaBH4 (0.46 g × 5, 2.0 equiv) was added
slowly to the solution at 0 °C. After the reaction was
completed, the reaction mixture was washed with aqueous
5% H2SO4 and water. The organic layer was concentrated.
DMF (23 mL), EtOAc (34 mL), and potassium thioacetate
(4.5 g) were added to the residue (11.8 g). The reaction
mixture was stirred at 65 °C for 7 h. After cooling the
mixture below 40 °C, aqueous 1% H2SO4 (24 mL) was added
to the mixture. After removal of EtOAc, the aqueous mixture
(60.0 g) was stirred at room temperature for 1 h. The
precipitate was collected and dried to give 9 (7.62 g, 71%)
as a slightly yellow crystalline powder.
1
mixture of cis and trans isomers was observed. H NMR
(600 MHz, CDCl3) δ 2.30 and 2.35 (m, 1H, H-3 of
pyrrolidine), 2.67 and 2.76 (m, 1H, H-3 of pyrrolidine), 3.10
(s, 3H, Ms-), 3.68 and 3.79 (s, 3H, CH3OCO-), 3.83 (m,
1H, H-5 of pyrrolidine), 3.88 (m, 1H, H-5 of pyrrolidine),
4.55 and 4.57 (t, J ) 8.1 Hz, H-2 of pyrrolidine), 5.14-
5.35 (s and 2d, 2H, J ) 13.7 Hz, -CH2-Ar), 5.31 and 5.33
(m, 1H, H-4 of pyrrolidine), 7.48 and 7.54 (d, 2H, J ) 9.0
Hz, meta-H of nitrophenyl), 8.24 (d, 2H, J ) 9.0 Hz, ortho-H
of nitrophenyl). 13C NMR (150 MHz, CDCl3) δ 36.4 and
37.7 (C-3 of pyrrolidine), 38.8 and 38.9 (Ms-), 52.8 and
53.2 (C-5 of pyrrolidine), 52.9 and 53.1 (MeO-), 57.3 and
57.6 (C-2 of pyrrolidine), 66.2 (-CH2-Ar), 77.7 and 78.1
(C-4 of pyrrolidine), 124.0 (ortho-C of nitrophenyl), 128.1
and 128.3 (meta-C of nitrophenyl), 143.6 (para-C of nitro-
phenyl), 147.6 and 147.7 (ipso-C of nitrophenyl), 153.6
and 154.2 (CdO of PNZ-), 172.2 and 172.4 (CdO of
-CO2Me). IR (KBr) 1745, 1707, 1523, 1440, 1345. MS (Ion
Mode: FAB+) m/z 403 [M + H]+, 805 [2M + H]+. Anal.
Calcd for C15H18N2O9S: C, 44.77; H, 4.51; N, 6.96; S, 7.97.
Found: C, 44.79; H, 4.34; N, 7.05; S, 7.78.
Preparation of Hydroxymethylpyrrolidine 9 from 14. After
dissolving 14 (27.6 g, 68.6 mmol) in a mixture of EtOAc
(120 mL) and MeOH (16.5 mL) at 34 °C, the solution was
cooled to 0 °C. NaBH4 (13.2 g, 5.1 equiv) was added slowly
to the solution, maintaining the temperature at 5 °C. The
reaction mixture was stirred at 5 °C for 3 h and then was
poured into aqueous 5% H2SO4 (138 mL). The layers were
separated. The organic layer was washed with aqueous 5%
NaCl (55 mL × 2) and then was concentrated. Potassium
thioacetate (10.2 g), DMF (50 mL), and EtOAc (66 mL) were
added to the residue. The mixture was stirred at 65 °C for 8
h. After cooling the mixture below 30 °C, water (44 mL)
and aqueous 5% H2SO4 (11 mL) were added to the mixture.
After removal of EtOAc, the precipitate was collected and
dried to give 9 (18.4 g, 76%) as a slightly yellow crystalline
powder.
Preparation of Aminomethylpyrrolidine 3. DIAD (68.3
g, 1.2 equiv) was added dropwise to a mixture of 9 (100.0
g, 282 mmol), triphenylphosphine (90.2 g, 1.2 equiv),
N-BOC-sulfamide 11 (83.0 g, 1.5 equiv), and EtOAc (1 L)
at 20 °C. The reaction mixture was stirred at 20 °C for 7 h.
After the reaction was completed, the reaction mixture was
concentrated, and the residual EtOAc was replaced into
MeOH by evaporation to give the concentrate (700 g). Water
(75 mL) was added to the concentrate at 65 °C. The mixure
was stirred at 50 °C for 2 h. After cooling, it was stored at
room temperature overnight. The resultant precipitate was
collected by filtration, washed with 85% aqueous MeOH,
and dried to give 3 (121.7 g, 81%) as a slightly yellow
crystalline powder.
Acknowledgment
We are grateful to Dr. K. Yoshikawa, Ms. S. Sekimoto,
Mr. T. Toya, Mr. K. Hamada, Ms. M. Hiura, Dr. J. Kikuchi,
and their co-workers for analytical data. We also thank Mr.
K. Kishimoto, Mr. Y. Okumura, Mr. M. Toyoda, Mr. I.
Nanjo, and their co-workers for scale-up operations.
Preparation of (2S,4R)-4-Hydroxy-1-(4-nitrobenzyloxy-
carbonyl)pyrrolidin-2-carboxylic Acid Hydrate (15) from 4.
A solution of PNZ-Cl (16.4 g, 1.0 equiv) in toluene (17 mL)
was added dropwise to a solution of hydroxyproline 4 (10.0
g, 76.3 mmol) and K2CO3 (19.0 g) in water (50 mL) at 5
°C. After stirring the reaction mixture for 1 h at 2 °C, the
layers were separated. Concentrated HCl (15.4 g) was added
to the aqueous layer. After the mixture was stirred for 0.5 h
Received for review March 24, 2003.
OP0340412
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