Novel synthetic route of a pivotal intermediate for the synthesis of 1β-methyl carbapenem antibiotics

Article abstract of DOI:10.1021/op0600714

A novel synthetic method using an original and practical procedure for the preparation of the N-PNZ protected 2-amino-methylpyrrolidin-4-ylthio-containing side chain of doripenem hydrate (S-4661), a new parenteral 1β- methylcarbapenem antibiotic, is described. trans-4-Hydroxy-L-proline was converted through an efficient process to (2S,4S)-4-acetylthio-2-(N-sulfamoyl-4- nitro-benzyloxycarbonyl-aminomethyl)-1-(4-nitrobenzyl-oxycarbonyl) pyrrolidine with 60-70% overall yield via a two-step sequence. This procedure requires no Chromatographic purifications, no cryogenic temperatures, no haloalkane solvent, and shorter operating times and avoids the side reaction brought by acid hydrolysis. Furthermore, the product was obtained as a crystal rather than an oil, which made it to be an advantage for quantization in the pilot-scale manufacture. Several kilograms of the side chain were prepared by using this method.

Full text of DOI:10.1021/op0600714

Organic Process Research & Development 2006, 10, 829−832
Technical Notes
Novel Synthetic Route of a Pivotal Intermediate for the Synthesis of
1â-Methyl Carbapenem Antibiotics
Yuan Yu,†,‡,§ Wu-Chun Zhou,‡ Ji Zhang,† Mei Zhang,‡ Da-Yong Xu,‡ Yun Tang,‡ Bo-Gang Li,*,‡,§ and Xiao-Qi Yu*,†,|
Department of Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education), Sichuan
UniVersity, Chengdu, Sichuan 610064, P.R. China, Chengdu Di-Ao Pharmaceuticals Company, Chengdu 610041,
Sichuan, P.R. China, Chengdu Institute of Biology, The Chinese Academy of Science, Chengdu 610041, P.R. China,
and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan UniVersity,
Chengdu, Sichuan 610041, P.R. China
Abstract:
Osaka, Japan) is a novel parenteral 1â-methylcarbapenem
antibiotic.8 Compound 1 is superior to meropenem against
Gram positive bacteria and, meanwhile, is superior to
imipenem against Gram negative bacteria. Furthermore, 1
has an antibacterial potency against Pseudomonas aeruginosa
which is up to twice as strong as that of imipenem or
meropenem. With its potent, broad, and well-balanced
antibacterial activity against a wide range of both Gram-
positive and Gram-negative bacteria, doripenem is now under
phase 3 clinical trials for the treatment of serious infections
such as pneumonia, pyelonephritis, and respiratory tract
infections.
A novel synthetic method using an original and practical pro-
cedure for the preparation of the N-PNZ protected 2-amino-
methylpyrrolidin-4-ylthio-containing side chain of doripenem
hydrate (S-4661), a new parenteral 1â-methylcarbapenem anti-
biotic, is described. trans-4-Hydroxy-L-proline was converted
through an efficient process to (2S,4S)-4-acetylthio-2-(N-sulfa-
moyl-4-nitro-benzyloxycarbonyl-aminomethyl)-1-(4-nitrobenzyl-
oxycarbonyl) pyrrolidine with 60-70% overall yield via a two-
step sequence. This procedure requires no chromatographic
purifications, no cryogenic temperatures, no haloalkane solvent,
and shorter operating times and avoids the side reaction
brought by acid hydrolysis. Furthermore, the product was
obtained as a crystal rather than an oil, which made it to be an
advantage for quantization in the pilot-scale manufacture.
Several kilograms of the side chain were prepared by using
this method.
According to the conventional retrosynthetic analysis of
a carbapenem, doripenem can be assembled from 4-nitro-
benzyl-protected 1â-methylcarbapenem enolphosphate 27,10
and 2-aminomethyl-pyrrolidin-4-ylthio-containing side chain
3 (Scheme 1). SAR studies revealed that the acylation and
sulfamoylamination of the side chain pyrrolidine would
benefit the enhancement of the antibacterial activity.
Several papers have been published regarding the syn-
thesis of the side chain aminomethylpyrrolidine deriva-
tives,8,9,11a,11b among which two are important. In 1996, Iso
and co-workers reported the synthesis of N-p-methoxybenzyl
(PMZ)-protected aminomethylpyrrolidine 3a (R2 ) PMZ)
1. Introduction
Members of the carbapenem family are important among
the â-lactam antibiotics for their broad and potent antibac-
terial activity and their relatively high resistance to most
clinically encountered â-lactamases.1 So far many products,
such as imipenem,2 panipenem,3 meropenem,4 biapenem,5
and ertapenem,6 have been put into market. The introduction
of a 1â-methyl group to the carbapenem skeleton in
meropenem, biapenem, and ertapenem enhances metabolic
stability to renal dehydropeptidase-1 (DHP-1) and leads to
high antibacterial potency.7 Doripenem hydrate (S-4661, 1,
Shionogi Research Laboratories, Shionogi & Co., Ltd.,
or N-BOC-protected aminomethylpyrrolidine 3b (R2
)
(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.
(4) Sunagawa, I.; Matsumura, H.; Inoue, T.; Fukasawa, M.; Kato, M. J. Antibiot.
1990, 43, 519-532.
* Corresponding author. E-mail: xqyu@tfol.com,libg@cib.ac.cn.
† Department of Chemistry, Key Laboratory of Green Chemistry and
Technology (Ministry of Education), Sichuan University.
(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.
(7) Shih, D. H.; Baker, F.; Cama, L.; Christensen, B. G. Heterocycles 1984,
21, 29-40.
‡ Chengdu Di-Ao Pharmaceuticals Company.
§ Chengdu Institute of Biology, The Chinese Academy of Science.
| State Key Laboratory of Biotherapy, Sichuan University.
(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. (e) Neu, H. C. Why
carbapenems? Curr. Opin. Infect. Dis. 1994, 7, 3-10.
(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) Ohtani, M.; Watanabe, F.; Narisada, M. J. Org. Chem. 1984, 49, 5271-
5272.
10.1021/op0600714 CCC: $33.50 © 2006 American Chemical Society
Published on Web 06/29/2006
Vol. 10, No. 4, 2006 / Organic Process Research & Development
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Scheme 1. Retrosynthetic analysis of a carbapenem
pyrrolidine 3d. In this contribution, we describe the prepara-
tion of the new pyrrolidine derivative 3d and its coupling
with enolphosphate 2b (Scheme 2). This process avoided
the side reaction brought by deprotection of the tert-
butoxycarbonyl group and made it easier for purification.
Furthermore, the product was obtained as a crystal rather
than an oil, which made it an advantage for quantization in
the pilot-scale manufacture.
2. Experimental Section
2.1. Materials and Instrumentations. ESI-MS spectral
data were measured on a Finnigan LCQDECA mass spectrom-
1
eter. H NMR and 13C NMR experiments were measured
on a Bruker Avance 600 spectrometer. Chemical shifts are
reported in ppm (δ scale) using tetramethylsilane as an
internal standard. Melting points were determined with a
micromelting point apparatus and are uncorrected. All
commercially available materials and solvents were used as
received without any further purification. 4-Nitrobenzyl
(4R,5S,6S)-3-[(diphenylphosphono)oxy]-6-[(1R)-1-hydroxy-
ethyl]-4-methyl-7-oxo-1-azabicyclo[3, 2, 0]hept-2-ene-2-car-
boxylate (2b) is commercially available.
BOC),8 after coupling with the diphenylmethyl-protected
enolphosphate 2a, compound 1 was prepared by deprotection
with AlCl3-anisole.
Although this route facilitated the SAR studies and led
to rapid optimization of the lead derivatives, it had several
drawbacks for multikilogram-scale preparation of compound
1. The two most serious problems resided in the isola-
tion and deprotection steps. Compound 1 was isolated as a
foam, which needed further purification on a Diaion HP-20.
Later, a modified process was developed, and compound 1
was obtained as a crystalline monohydrate.9 However, the
process still required chromatographic purification, and the
yield of compound 1 through the deprotection, purifica-
tion, and crystallization steps on a pilot scale (49%) was
lower than that through the deprotection and purification
steps on a bench scale (72%). During the column chroma-
tography and concentration of the eluents, decomposition of
the target compound 1 was observed, resulting in a 16% yield
decrease due to longer operating times on scale-up. Further-
more, this process included several severe conditions such
as cryogenic reaction temperatures (three reactions required
-45 °C), long operation times, and the use of haloalkane
solvent (CH2Cl2). To reduce the cost of processing time and
to make the process more environmentally suitable, Nishino
and co-workers11b reported N-PNZ-protected aminomethyl-
pyrrolidine (R2 ) Boc) 3c, which was prepared from trans-
4-hydroxy-L-proline. But the deprotection of the tert-
butylcarbonyl group by 98% H2SO4 results in an oily product
at room temperature, and the carbonium ion brought many
side reactions, while scavenger usage will increase the
producing cost.
2.2. Preparation of the Compounds. 2.2.1. Preparation
of the N-PNZ-Protected Pyrrolidine Derivative 3d. 2.2.1.a.
Preparation of N-4-Nitrobenzyloxycarbonyl-sulfonamide
(5). To a solution of 4-nitrobenzyl alcohol (38.25 g, 250
mmol) in THF, chlorosulfonyl isocyanate (21.75 mL, 250
mmol) was added dropwise at -40°C, and the mixture was
stirred at -40 °C for 30 min. After cooling the mixture to
-60°C, gaseous amine was bubbled into the reaction with
stirring. After bubbling, the mixture was stirred for 30 min
at 15 °C and then acidified with 1 N HCl until no more
precipitation was generated. The precipitate was collected
by filtration and dissolved in EtOAc, washed with water and
brine, dried over anhydrous Na2SO4, and evaporated in a
vacuum. The residue was crystallized from EtOAc-hexane
to give 55 g of N-4-nitrobenzyl sulfonamide as a colorless
crystal (80%). Mp: 160-162 °C (dec). FT-IR (KBr, cm-1):
3348, 3258, 3223, 1721, 1610, 1473, 1454, 1348, 1260, 1156,
1
847. H NMR (600 MHz, DMSO-d6) δ 5.29 (2H, s, sOs
CH2sAr), 7.54 (br, 2H, sSO2NH2), 7.64 (A2B2, 2H, J )
8.7 Hz, sArH), 8.26 (A2B2, 2H, J ) 8.7 Hz, -ArH), 11.38
(br, 1H, sCOsNHsSO2s). 13C NMR (600 MHz, DMSO-
d6) δ 65.6 (sOsCH2sAr), 124.1 (o, sArsNO2), 128.8 (m,
sArsNO2), 144.3 (p, sArsNO2), 147.6 (sArsNO2 in
situ), 152.0 (CdO, PNZs). ESI-MS: 298 [M + Na]+, 314
[M + K]+. FTICR/MS: Calculated for [C8H9N3Na1O6S1],
298.0110; found, 298.0104.
2.2.1.b. Preparation of Acetylthiol-pyrrolidine Deriva-
tive (3d). A solution of diisopropyl azodicarboxylate (DIAD,
22 mL, 130 mmol) in EtOAc was added dropwise to a
mixture of (2S,4S)-4-acetylthio-2-hydroxymethyl-1-(4-nitro-
benzyl-oxycarbonyl)pyrrolidine (6, 35.5 g, 100 mmol), N-4-
nitrobenzylsulfamide (5, 41.25 g, 150 mmol), triphenyl
phospine (34.125 g, 130 mmol), and THF (1000 mL) at 0 °C.
The reaction mixture was stirred at 20 °C for 2 h. After the
reaction was completed, the reaction mixture was concen-
trated to 200 mL, and 500 mL of anhydrate alcohol were
then added. The solution was stored in a refrigerator over-
To increase the yield and to avoid the chromatographic
purification, we developed an improved process. Compound
1 was synthesized from PNB-protected enolphophate 2b and
N-[p-nitrobenzyloxycarbonyl] (PNZ)-protected aminomethyl-
(11) (a) A portion of this study was patented. Nishino, Y.; Yuasa, T.;
Komurasaki, T.; Kakinuma, M.; Masui, T.; Kobayashi, M. Patent Applica-
tion No. JP 2001-140782. (b) Nishino, Y.; Komurasaki, T.; Yuasa, T.;
Kakinuma, M.; Izumi, K.; Kobayashi, M.; Fujiie, S.; Gotoh, T.; Masui,
Y.; Hajima, M.; Takahira, M.; Okuyama, A.; Kataoka, T. Org. Process
Res. Dev. 2003, 7, 649-654.
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Scheme 2. Improved method for the preparation of 1
1
night and resulted in 54 g of amorphous yellowish powder
(88%). FT-IR (KBr, cm-1): 3383, 3082, 2960, 1695, 1607,
1522, 1430, 1395, 1296, 1267, 1181, 1154, 1114, 850. H
1268, 1181, 1154, 1112, 850. H NMR (600 MHz, CDCl3)
δ 1.52 (m, 1H, H-3â of pyrrolidine), 1.83 (d, 1H, J ) 6.12
Hz, H of HSs), 2.62 (m, 1H, H-3R of pyrrolidine), 3.13
(dd, 1H, J ) 11.64 and 7.68 Hz, H-5â of pyrrolidine), 3.39
(m, 1H, H-4 of pyrrolidine), 3.75 (d, 1H, J ) 15.3 Hz, one
of sCH2N(PNZ)SO2s), 4.10 (dd, 1H, J ) 11.64 and 7.26
Hz, H-5R of pyrrolidine), 4.27 (dd, 1H, J ) 15.3 and 10.32
Hz, one of sCH2N(PNZ)SO2s), 4.48 (m, 1H, H-2R of
pyrrolidine), 5.15 (ABq, 2H, J ) 13.74 Hz, sOCH2sAr),
5.26 (ABq, 2H, J ) 13.74 Hz, sOCH2sAr), 5.84 (br, 2H,
sSO2NH2), 7.45 (A2B2, 2H, J ) 8.22 Hz, meta-H of
nitrophenyl), 7.51 (A2B2, 2H, J ) 8.40 Hz, meta-H of
nitrophenyl), 8.21 (m, 4H, ortho-H of nitrophenyl). 13C NMR
(600 MHz, CDCl3) δ: 34.5 (pyrrolidine C-3), 39.4 (pyrro-
lidine C-4), 50.9 (sCH2N(PNZ)SO2s), 55.3 (pyrrolidine
C-5), 57.2 (pyrrolidine C-2), 66.1 (sOCH2sAr), 67.3
(sOCH2sAr), 123.9 and 124.0 (nitrophenyl ortho-C), 128.0
and 128.5 (nitrophenyl meta-C), 141.9 and 143.2 (nitrophenyl
para-C), 147.8 and 148.0 (nitrophenyl ipso-C), 152.8 and
155.3 (CdO of PNZs). ESI-MS: 592.1 [M + Na]+, 608.1
[M + K]+. FTICR/MS: Calculated for [C21H23N5Na1O10S2],
592.0784; found, 592.0779.
2.2.2.b. Preparations of 8. To a DMF solution (250 mL)
of (1R,5S,6S)-2-diphenoxy-phosphonyloxy-6-[(1R)-1-hydroxy-
ethyl]-1-methylcarbapen-2-em-3-carboxylic acid-4-nitro-
benzyl ester (7, 17.82 g, 30 mmol) and the corresponding
mercaptopyrrolidine (2b, 22 g, 38.66 mmol), diisopropyl-
ethylamine (7.23 mL, 42.5 mmol) was added with an ice
bath. After stirring for 2 h, the mixture was diluted with 500
mL of EtOAc and washed with 1 N HCl, saturated Na2CO3,
and saturated brine, dried over anhydrous Na2SO4, and
evaporated in a vacuum. Toluene was added to deposit the
product. After filtration, the product was obtained as a
yellowish amorphous powder (27 g, 98.5%). FT-IR (KBr
cm-1): 3405, 2969, 1771, 1716, 1607, 1522,1433, 1392,
1347, 1276, 1181, 1141, 1111, 850.1H NMR (600 MHz,
CDCl3) δ 1.26 (d, 3H, J ) 7.14 Hz, CH3s on 4-position),
1.37 (d, 3H, J ) 6.18 Hz, CH3CHOHs), 1.64 (m, 1H, H-3â
of pyrrolidine), 2.62 (m, 1H, H-3R of pyrrolidine), 3.27 (m,
1
NMR (600 MHz, CDCl3) δ 1.60 (1H, m, pyrrolidine, H-3â),
2.33 (3H, s, AcSs), 2.59 (dt, 1H, J ) 14.0, 8.7 Hz, pyr-
rolidine, H-3R), 3.17 (dd, 1H, J ) 11.9, 6.24 Hz, pyrrolidine
H-5â), 3.71 (dd, 1H, J ) 14.9 Hz, sCH2N(PNZ)SO2s),
3.92 (1H, m, pyrrolidine H-4), 4.10 (dd, 1H, J ) 15.3,10.2
Hz, sCH2N(PNZ)SO2s), 4.20 (dd, 1H, J ) 11.7, 7.5 Hz,
pyrrolidine H-5R), 4.52 (1H, m, pyrrolidine H-2R), 5.16
(ABq, 2H, J ) 13.4 Hz, sOsCH2sAr), 5.25 (br, 2H,
sOsCH2sAr), 5.86 (br, 2H, sSO2NH2), 7.47 (A2B2, m,
2H, J ) 8.46 Hz, sArNO2), 7.51 (A2B2, m, 2H, J ) 8.46
Hz, sArNO2), 8.21 (A2B2, 2H, o, J ) 8.52 Hz, sArNO2),
8.23 (A2B2, 2H, o, J ) 8.28 Hz, sArNO2). 13C NMR (600
MHz, CDCl3) δ 30.5 (Mes, AcSs), 34.7 (pyrrolidine C-3),
39.1 (pyrrolidine C-4), 50.6 (sCH2NSO2s), 52.2 (pyrroli-
dine C-5), 56.7 (pyrrolidine C-2), 66.1 (sOCH2sAr), 74.0
(sOCH2sAr), 123.9 (o, sArNO2), 124.0 (o, sArNO2),
128.0 (m, sArNO2), 128.5 (m, sArNO2), 141.7 (p, sArNO2),
143.1 (p, sArNO2), 147.8 (sArNO2, in situ), 148.0 (sArNO2,
in situ), 152.7 (CdO, PNZs), 155.4 (CdO, PNZs), 194.6-
(CdO, AcSs). ESI-MS: 610.2 [M - H]-. FTICR/MS:
Calculated for [C23H25N5O11S2Na], 634.0890; found, 634.0884.
2.2.2. Preparation of Doripenem (S-4661). 2.2.2.a.
Preparation of Thiol-pyrrolidine Derivative (2S,4S)-1-tert-
Nitrobenzyl-oxycarbonyl-2-4S)-1-tert-nitrobenzyloxycar-
bonyl-2-(N-4-nitrobenzyloxycarbonylbenzyl-N-sulfamoul-
aminomethyl)-4-mercaptopyrrolidine (7). To a solution of
50 g (81.8 mmol) of (2S,4S)-1-tert-nitrobenzyl-2-(N-tert-
nitrobenzylcarbonyl-N-aminosulfamide)methyl-4-acetylthio-
pyrrolidine (3d) in 200 mL of THF, 6 g of lithium hydroxide
in 20 mL of water were added with an ice bath. After stirring
for 2 h, the mixture was acidified with 6 N HCl and gave a
sticky solid. The solid was collected by filtration, was
dissolved with EtOAc and alcohol, and then stored in a
refrigerator overnight. The product was precipitated as a
yellowish amorphous powder (32 g, 68.8%). FT-IR (KBr,
cm-1): 3381, 2959, 1717, 1607, 1521, 1432, 1393, 1347,
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1
1H, H-4R), 3.27 (m, 1H, H-6), 3.27 (m, 1H, H-5â of
pyrrolidine), 3.73 (m, 1H, one of sCH2N(PNZ)SO2s), 3.73
(m, 1H, H-4 of pyrrolidine), 4.10 (m, 1H, H-5R of pyrroli-
dine), 4.25 (m, 1H, H-5), 4.25 (m, 1H, sCH(OH) CH3), 4.25
(m, 1H, one of sCH2N(PNZ)SO2s), 4.54 (m, 1H, H-2R of
pyrrolidine), 5.12-5.48 (m, 6H, sOCH2sAr), 5.85 (br, 2H,
sSO2NH2), 7.47 (m, 4H, meta-H of nitrophenyl), 7.63 (A2B2,
2H, J ) 8.70 Hz, meta-H of nitrophenyl), 8.16 (A2B2, 2H,
J ) 8.28 Hz, ortho-H of nitrophenyl), 8.20 (m, 4H, ortho-H
of nitrophenyl).13C NMR (600 MHz, CDCl3) δ 16.9 (Mes
of 4-position), 22.0 (Mes of CH3CHOHs), 34.7 (pyrrolidine
C-3), 40.5 (pyrrolidine C-4), 44.0 (C-4), 50.7 (C of sCH2N-
(PNZ)SO2s), 54.0 (pyrrolidine C-5), 56.2 (C-5), 56.8
(pyrrolidine C-2), 59.8 (C-6), 65.5 (sCHs of CH3CHOHs),
66.2 and 67.4 and 68.4 (sOCH2sAr), 123.8 and 123.9 and
124.0 (ortho-C of nitrophenyl), 125.8 (C-2), 128.3 and 128.4
(meta-C of nitrophenyl), 141.8 and 142.6 and 143.0 (para-C
of nitrophenyl), 147.7 and 147.8 and 148.0 (ipso-C of
nitrophenyl), 148.2 (C-3), 152.7 and 155.0 (CdO of PNZs),
160.0 (CdO of PNBs), 172.4(CdO of C-7). FTICR/MS:
Calculated for [C38H39N7Na1O16S2], 936.1792; found,
936.1787.
2.2.2.c. Deprotection and Preparation of Doripenem
(S-4661, 1). To a solution (180 mL) of (1R,5S,6S)-2-[(3S,5S)-
1-p-nitrobenzyloxycarbonyl-5-(N-p-nitrobenzyloxycarbonyl-
N-aminosulfonyl-amide)methylpyrrolidine]-sulfur-6-[(1R)-1-
hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid-4-
nitrobenzyl ester (8, 10 g, 10.95 mmol), 120 mL of water
and 10 g of 10% Pd/C (contents 54% H2O) were added, and
the reaction mixture stirred under 0.5 mpa H2 pressure for
4 h and then was filtered to remove the catalyst. Then 4 g
of MgCl2‚H2O were added followed by partitioning with 300
mL of THF. 2-Propanol was added to the separated aqueous
layer, which was then stored in a refrigerator overnight. The
product S-4661 was precipitated and collected by filtration
and dried in a vacuum as a white powder (2.269 g, 49%).
FT-IR(KBr cm-1): 3532, 3391, 3261, 3080, 2949, 2922,
2853, 1713, 1630, 1567, 1455, 1378, 1350, 1321, 1278, 1264,
1162, 1092, 1071, 930, 764. H NMR (600 MHz, D2O) δ
1.11 (d, J ) 7.26 Hz, 3H), 1.18 (d, J ) 6.48 Hz, 3H), 1.62-
1.67 (m, 1H), 2.60-2.65 (m, 1H), 3.25-3.35 (m, 3H), 3.36
(dd, J ) 2.58, 6 Hz, 1H), 3.43 (dd, J ) 4.77, 10.11 Hz,
1H), 3.60 (dd, J ) 6.96, 12.48 Hz, 1H), 3.8-3.84 (m, 1H),
3.92-3.96 (m, 1H), 4.12-4.16 (m, 2H). 13C NMR (600
MHz, D2O) δ 15.76, 20.05, 32.67, 39.22, 42.42, 43.06, 52.15,
55.88, 58.08, 59.57, 65.03, 133.69, 138.11, 167.63, 176.60.
ESI-MS: 421.1 [M + H]+. FTICR/MS: Calculated for
[C15H24N4Na1O6S2], 443.4940; found, 443.1029. The data are
coincident with literature.
3. Conclusions
We developed and described a practical multikilogram
scale synthesis of doripenem hydrate (1) by deprotection of
compound 8, which was prepared from enolphosphate 2b
and N-PNZ protected aminomethylpyrrolidine 3d. We found
effective extraction conditions to remove p-toluidine and
most other organic impurities using THF/water and MgCl2.
The reported process requires no chromatographic purifica-
tion and affords compound 1 as a sterile crystalline mono-
hydrate in satisfactory yield. This process is practical and
efficient. In fact, this process is now under pilot-scaled study
to make compound 1 for clinical studies.
Acknowledgment
We acknowledge the useful help from Di-Ao Pharma-
ceutical Company for its financial support. This work was
also financially supported by the National Natural Science
Foundation of China (Nos.: 20372051, 20471038), Program
for New Century Excellent Talents in University, Specialized
Research Fund for the Doctoral Program of Higher Educa-
tion, and Scientific Fund of Sichuan Province for Outstanding
Young Scientist.
Received for review March 31, 2006.
OP0600714
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