Development of a scalable process for 1-β-methyl azetidinone: A carbapenem key intermediate

Article abstract of DOI:10.1021/op0501085

An optimized process for the stereoselective synthesis of 1-β-methyl carbapenem key intermediate (3S,4S)-[(R)-1′-((tert-butyldimethylsilyl)oxy) ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone (1) and (3R,4R)-4-acetoxy-3-[(R)- 1′-((tert-butyldimethylsilyl)oxy)ethyl]-2-azetidinone has been developed employing commercially available chiral 4-phenyl-2-oxazolidinone. This method provides an efficient and cost-effective process with improved selectivity and higher yield.

Full text of DOI:10.1021/op0501085

Organic Process Research & Development 2005, 9, 827−829
Development of a Scalable Process for 1-â-Methyl Azetidinone: A Carbapenem
Key Intermediate†
Neera Tewari,* Hashim Nizar, Bishwa Prakash Rai, Avinash Mane, and Mohan Prasad
Chemical Research DiVision, Ranbaxy Research Laboratories, Gurgaon, Haryana - 122 001, India
Abstract:
An optimized process for the stereoselective synthesis of 1-â-
methyl carbapenem key intermediate (3S,4S)-[(R)-1′-((tert-
butyldimethylsilyl)oxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidi-
none (1) and (3R,4R)-4-acetoxy-3-[(R)-1′-((tert-butyldimethyl-
silyl)oxy)ethyl]-2-azetidinone has been developed employing
commercially available chiral 4-phenyl-2-oxazolidinone. This
method provides an efficient and cost-effective process with
improved selectivity and higher yield.
tin enolate of 3-propionyl-2-thiazolidine thiones,7b,10 boron
enolate of 3-propionyl-2-thioazolidinone,7a or zirconium
enolate of thiol ester of propionic acid.11 These methods face
difficulties in large scale preparation of 1 as they employ
more than stoichiometric amounts of the precious chiral
sources and/or the expensive or toxic reagents. Different
oxazolidinthione derivatives have been used in the prepara-
tion of 1 resulting in low yield and varying â:R ratio.12 In
Introduction
The â-methyl carbapenem antibiotics exhibit excellent
broad spectrum antibacterial activities with increased chemi-
cal and metabolic stabilities as exemplified by Meropenem1,
addition the stereoselective synthesis of the key intermediate
1 via a Reformatsky type reaction employing different 3-(2-
Biapenem,2 and Ertapenem.3,4 (3S,4S)-[(R)-1′-((tert-Butyldim-
bromopropyl)-2-oxazolidinones using zinc has been re-
ethylsilyl)oxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone (1)
is a key intermediate for the synthesis of â-methyl carbap-
enems. Many synthetic methods have been reported for the
ported.13 However, these oxazolidinone auxiliaries are dif-
ficult to access and expensive. Recently, a commercial
method has been reported for the preparation of 1 employing
synthesis of â-methyl azetidinone derivative 15 of which C-4
a Reformatsky type reaction using nonchiral dihydrooxazi-
alkylation of commercially available (3R,4R)-4-acetoxy-3-
[(R)-1′-((tert-butyldimethylsilyl)oxy)-ethyl]-2-azetidinone5 (2)
none derivatives.14 The best diastereoselectivity reported in
terms of the â:R ratio of the methyl group is 92:8. Another
with different types of enolates derived from propionic acid
diastereoselective synthesis is reported using a titanium
derivatives is the most important method for its commercial
enolate of 2′-hydroxy propiophenone6a which involves ozo-
preparations.6 Different metal enolates of propionic acid
nolysis at -78 °C and column chromatography. Herein we
derivatives having chiral and achiral auxiliary have been
report the process development work for the stereoselective
utilized, including 2-oxazolidinones,7 2-picolyl thiols,8 and
synthesis of (3S,4S)-[(R)-1′-((tert-butyldimethylsilyl)oxy)-
2,3-dihydro-4H-1,3-benzoxazin-4-one9 for improved â-se-
ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone (1) utilizing com-
lectivity in the preparation of 1. Stereoselective introduction
mercially available (S)-4-phenyl-2-oxazolidinone (3).
of the 1-â-methyl substituent in 2 has been achieved using
Results and Discussion
* Author for correspondence. E-mail: neera.tiwari@ranbaxy.com. Tele-
We explored the possibility of using commercially avail-
able chiral (S)-4-phenyl-2-oxazolidinone (3) as an auxiliary
for the synthesis of 1. The reaction of 3 with propionyl
phone: (91-124) 5011832. Fax: (91-124) 5011832.
† A patent application incorporating parts of this report has been filed.
(1) Sunagawa, M.; Matsamura, H.; Takaasi, I.; Fukasawa, M.; Kato, M. J.
Antibiot. 1990, 43, 519-532.
(2) Malonski, G. J.; Collins, I.; Wiennerstein, C.; Moellering, R. C.; Eliopoulos,
chloride in the presence of triethylamine results in the
G. M. Antimicrob. Agents Chemother. 1993, 37, 2009-2016.
formation of N-propionyl oxazolidinone derivative 4 (Scheme
(3) Sunagawa, M.; Sasaki, A. Heterocycles 2001, 54, 497-528.
1). This derivative is treated with titanium tetrachloride in
the presence of a tertiary amine base followed by reaction
with 2. After workup the condensed product 5 obtained is
(4) Cunha, B. A. Drugs Today 2002, 38, 195-213.
(5) Berks, A. H. Tetrahedron 1996, 52, 331-375.
(6) (a) Lee, Y. S.; Choung, W. K.; Kim, K. H.; Kang, T. W.; Ha, D. C.
Tetrahedron 2004, 60, 867-870. (b) Kondo, K.; Seki, M.; Kuroda, T.;
Yamanaka, T.; Iasaki, T. J. Org. Chem. 1995, 60, 1096-1097. (c) Ito, Y.;
Sasaki, A.; Tamato, K.; Sunagawa, M.; Terashima, S. Tetrahedron 1991,
47, 2801-2820.
(7) (a) Fuentes, L. M.; Shinkai, I.; Salzmann, T. N. J. Am. Chem. Soc. 1986,
108, 4675-4676. (b) Nagao, Y.; Kamagai, T.; Tamai, S.; Abe, T.;
Kuramoto, Y.; Taga, T.; Aoyagi, S.; Nagase, Y.; Ochaiai, M.; Inoue, Y.;
Fujita, E. J. Am. Chem. Soc. 1986, 108, 4673-4675.
(8) Martel, A.; Daris, J. P.; Bachand, C.; Corbeil, J.; Menard, M. Can. J. Chem.
1988, 66, 1537-1539.
(9) (a) Kondo, K.; Seki, M.; Kuroda, T.; Yamanaka, T.; Iwasaki, T. J. Org.
Chem. 1977, 62, 2877-2884.
(10) Deziel, R.; Favreau, D. Tetrahedron Lett. 1986, 27, 5687-5690.
(11) Kim, C. U.; Luh, B.; Partyka, R. A. Tetrahedron Lett. 1987, 28, 507-510.
(12) Nakagawa, Y.; Kiyohito, T.; Niigata, I. (Toyama) U.S. Patent 5,731,431,
1980.
(13) (a) Ito, Y.; Terashima, S. Tetrahedron Lett. 1987, 28, 6625-6628. (b)
Terashima, S.; Ito, Y.; Kawabata, T.; Sakai, K.; Hiyama, T.; Kimura, Y.;
Sunagawa, M.; Tomoto, K.; Sasaki, A. (Sumitomo) U.S. Patent 5,231,-
179, 1993.
(14) Lu, X.; Xu, Z.; Yang, G.; Fan, R. Org. Process Res. DeV. 2001, 5 (2),
186-188.
10.1021/op0501085 CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/10/2005
Vol. 9, No. 6, 2005 / Organic Process Research & Development
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827

Scheme 1
Table 1. . Hydrolysis of 5 with H2O2/Base
reaction
temp
entry
base
(°C)
solvent
yield (%)
62
1
2
3
4
5
6
LiOH
LiOH
LiOH
NaOH
NaOH
NaOH
5-8
20-25
0-5
5-10
20-25
20-25
acetone/water
acetone/water
methanol/water
acetone/water
acetone/water
methanol/water
55
a
63b
65
a
a Reaction incomplete. b Reaction is slow and requires longer time (4-5 h).
hydroxide requires low temperatures (0-5 °C), whereas with
sodium hydroxide the reaction is better optimized at 20-25
°C (Table 1). This optimized process is further scaled up to
the 1 kg scale (Experimental Section).
The advantage of this method over the other existing
methods are high stereoselectivity, better yield, and use of
commercially available and inexpensive (S)-4-phenyl-2-
oxazolidinone (3) auxiliary which is recovered (∼80%
recovery) and reused.
In conclusion, a scalable process for the preparation of
(3S,4S)-[(R)-1′-((tert-butyldimethylsilyl)oxy)ethyl]-4-[(R)-1-
carboxyethyl]-2-azetidinone (1) using a highly diastereose-
lective condensation of (3R,4R)-4-acetoxy-3-[(R)-1′-((tert-
butyldimethylsilyl)oxy)ethyl]-2-azetidinone (2) with com-
mercially available (S)-4-phenyl-2-oxazolidinone (3) has been
developed. This method is cost-effective and affords the
product in better selectivity and yield.
Experimental Section
General. Reagents are used as such without further
1
purification. H NMR spectra are recorded using a Bruker
300 MHz spectrometer. The chemical shift data are reported
as δ (ppm) downfield from tetramethylsilane which is used
as an internal standard. Chiral HPLC analysis was performed
on a Waters instrument with a UV detector (205 nm) using
a Kromasil C18, 3.5 µm (100 mm × 4.6 mm) column (oven
temperature 40 °C) and mobile phase phosphate buffer (pH
3.5)/acetonitrile gradient (Buffer/Acetonitrile: 75:25 in 0 min
to 60:40 in 20 min; 25 min 60:40 to 25:75 in 30 min; 35
min 25:75 to 75:25 in 40 min) with a flow rate of 1.1 mL/
min.
Preparation of (S)-4-Phenyl-3-propionyl-2-oxazolidi-
none (4). To a suspension of (S)-4-phenyl-2-oxazolidinone
(3) (100 g, 0.613 mol) in toluene (500 mL), propionyl
chloride (96.4 g, 1.04 mol) was added at 20-25 °C.
Triethylamine (111.5 g, 1.10 mol) was then added (exother-
mic) dropwise in 30 min at 25-50 °C and stirred for 1 h at
40-50 °C. After completion of the reaction, the reaction
mixture was cooled to 25 °C, treated with 5% aqueous
sodium bicarbonate solution (500 mL) and then washed with
water (500 mL). The organic layer was concentrated under
reduced pressure. To the residue isopropyl alcohol (200 mL)
was added, and the precipitate thus obtained was stirred at
0-5 °C for 3 h, filtered, washed with isopropyl alcohol (100
mL), and dried to give 4 (110 g, 82%) as crystalline material.
1H NMR (CDCl3): 1.11 (t, 3H, CH3), 2.95 (q, 2H, -CH2),
directly taken for hydrolysis with lithium hydroxide/H2O2.
The synthesis of 5 is reported in the literature by the
condensation of N-propyl oxazolidinone 4 with (3R,4R)-4-
acetoxy-3-[(R)-1′-((tert-butyldimethylsilyl)oxy)ethyl]-2-aze-
tidinone (2) in the presence of alkylmagnesium chloride.15
Adjusting the pH of the reaction mixture to 8.5-9.0, the
chiral auxiliary 4-phenyl-2-oxazolidinone (3) is precipitated
and recovered (∼80% recovery) for reuse. Further adjusting
the pH to 2.5 yielded â-methyl azetidinone 1. From our
experiments, we found that the S-isomer of 3 selectively gave
the â-isomer with overall 65% yield (â:R ratio 99.5:0.5)
compared to the earlier best reported method14 of 55% yield.
Similarly the R-isomer of 3 gave the R-isomer of 1 selectively
(100:0 ratio) in 63% yield.
During the process optimization, we have studied the
effect of triethylamine and diisopropyl ethylamine as base
during enolate formation. The use of diisopropylethylamine
results in 65% yield of 1 (â:R ratio 99.5:0.5) and triethy-
lamine in 52% yield (â:R ratio 99.5:0.5). Similarly the effects
of base, lithium hydroxide and sodium hydroxide, during
the hydrolysis of 5 have been studied. The yield and quality
of the product 1 did not have much effect, but lithium
(15) Takao, S.; Toshiyuki, M.; Takaji, M.; Miura, T. (Takasago) U.S. Patent
6,340,751, 2004.
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Vol. 9, No. 6, 2005 / Organic Process Research & Development

4.28 (dd, 1H), 4.68 (dd, 1H, H-4), 5.42 (dd, 1H), 7.26-7.39
(m, 5H, Ph-H).
ethyl]-2-azetidinone (2). The condensation reaction was
scaled up as in the above procedure. The residue of the
condensed product 5 obtained by the above process was
dissolved in acetone (7 L), diluted with deionized water (3.5
L), and cooled to 15 °C. Cooled aqueous hydrogen peroxide
solution (30% w/w, 1.18 kg, 10.4 mol) was added to the
above solution in 10 min at 15-18 °C. Then a cold solution
of sodium hydroxide (420 g, 10.5 mol) in deionized water
(3 L) was added slowly by keeping the temperature 20-25
°C in 45 min by circulating the jacket of the reactor with
brine of temperature -15 to -10 °C. The reaction mixture
was stirred for 1 h at 20-25 °C and then diluted with
deionized water (20 L), and the pH was adjusted with 6 N
HCl to 8.5 at 15-20°C. The precipitate was filtered, washed
with water, and dried to give (S)-4-phenyl-2-oxazolidinone
(3) (recovery 79%, chromatographic purity by HPLC 98.9%).
The filtrate was collected, and its pH was adjusted to 2.5
with 6 N HCl. The crystalline solid thus obtained was
filtered, washed with water (4 L) followed by ethyl acetate
(1 L), and dried at 40-45°C to give 1 in 64.5% (675 g)
yield (â:R ratio 99.6:0.4).
Preparation of (3S,4S)-[(R)-1′-((tert-Butyldimethylsi-
lyl)oxy)ethyl]-4-[(S)-1-carboxyethyl]-2-azetidinone. The
titled compound was synthesized from (R)-4-phenyl-3-
propionyl-2-oxazolidinone [prepared from (R)-4-phenyl-2-
oxazolidinone and propionyl chloride by the above method]
and 2 by following the above procedure in 63% yield (â:R
ratio 0:100). 1H NMR (CDCl3): 0.06 (s, 6H, CH3sSi), 0.79
(s, 9H, SisCsCH3), 1.18 (dd, 3H, CH3sCH), 1.20 (dd, 3H,
CH3sCH), 2.48 (m, 1H, CH3sCHsCdO), 2.72 (dd, 1H,
H-3), 3.60 (dd, 1H, H-4), 4.11 (m, 1H, CH3sCHsO), 6.54
(br s, NH).
Preparation of (3S,4S)-[(R)-1′-((tert-Butyldimethylsi-
lyl)oxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone (1). To
a solution of (S)-4-phenyl-3-propionyl-2-oxazolidinone (4)
(92 g, 0.42 mol) in dichloromethane (700 mL) TiCl4 (86 g,
0.45 mol) was added dropwise in ∼30 min at -20 to -25
°C. After stirring of the mixture for 30 min at -20 to -25
°C diisopropyl ethylamine (56 g, 0.434 mol) was added
dropwise, and stirring continued for ∼60 min at the same
temperature. The reaction mixture was diluted with dichlo-
romethane (300 mL), and (3R,4R)-4-acetoxy-3-[(R)-1′-((tert-
butyldimethylsilyl)oxy)ethyl]-2-azetidinone (2) (100 g, 0.348
mol) added at -15 to -10 °C. The temperature was raised
to 20-25 °C in ∼60 min, and then the mixture was stirred
at this temperature for ∼3 h. After completion of the reaction,
deionized water (1.0 L) was added after cooling to ∼10 °C.
The layers were separated, and the organic layer was again
washed with deionized water (1.0 L) and concentrated under
vacuum to give a residue of intermediate 5. The residue was
dissolved in acetone (700 mL) and added deionized water
(350 mL). Cooled aqueous hydrogen peroxide (30% w/w,
118 g, 1.04 mol) solution (the solution is corrosiVe and can
cause skin burns) was added followed by dropwise addition
of aqueous sodium hydroxide solution (42 g, 1.05 mol) in
water (300 mL) at 20-25 °C in 30 min (slightly exothermic).
After stirring for 1 h the reaction was diluted with deionized
water (2.0 L), and the pH was adjusted with 6 N HCl to
∼8.5. The precipitated (S)-4-phenyl-2-oxazolidinone (3) was
collected after filtration (81% recovery, chromatographic
purity >98.0%). The filtrate was collected, and its pH was
further adjusted to 2.5 with 6 N HCl. The solid thus obtained
was filtered (the aqueous stream is peroxide free, checked
with starch iodide paper and potassium iodide solution) and
washed with water (400 mL) and ethyl acetate (100 mL)
which on drying at 40-45 °C yielded 68 g (65%) of 1 as
Acknowledgment
1
We are grateful to the Analytical Division of Ranbaxy
Research Laboratories for their analytical and spectral
support.
white crystalline material (â:R ratio 99.5:0.5). H NMR
(CDCl3): 0.05 (s, 6H, CH3sSi), 0.81 (s, 9H, SisCsCH3),
1.13 (d, 3H, CH3sCsH), 1.18 (d, 3H, CH3sCH), 2.67 (m,
1H, CH3sCHsCdO), 2.96 (dd, 1H, H-3), 3.88 (dd, 1H,
H-4), 4.14 (m, 1H, CH3sCHsO), 6.36 (br s, NH).
The above process was scaled up to 1.0 kg input of
(3S,4R)-4-acetoxy-3-[(R)-1′-(tert-butyldimethylsilyl)oxy)-
Received for review June 29, 2005.
OP0501085
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