Process for Developing 3β-[4-(S)-Arylacetylamino-4β-(2-(2-furyl) ethyl]azetidin-2-one: A Carbacephem Key Intermediate

Article abstract of DOI:10.1021/op034074h

An optimized process for the stereospecific synthesis of carbacephem key intermediates 3β-[4-(S)-phenoxyacetylamino-4β-[2-(2-furyl)ethyl] azetidin-2-one (1) and 3β-[4-(S)-phenyl-acetylamino-4β-[2(2-furyl) ethyl)]azetidin-2-one] (2) is described. This repo

Full text of DOI:10.1021/op034074h

Organic Process Research & Development 2003, 7, 933−935
Process for Developing
3â-[4-(S)-Arylacetylamino-4â-(2-(2-furyl)ethyl]azetidin-2-one: A Carbacephem
Key Intermediate
Yatendra Kumar,* Neera Tewari, Hashim Nizar, Bishwa Prakash Rai, and Shailendra Kumar Singh
Chemical Research DiVision, Ranbaxy Research Laboratories, Gurgaon 122 001, Haryana, India
Abstract:
other synthetic method reported for the above cleavage makes
use of iodotrimethylsilane.3 Use of lithium/ammonia for the
synthesis of 3â-[4-(S)-phenoxyacetylamino-4â-[2-(2-furyl)-
ethyl]azetidin-2-one (1) and 3â-[4-(S)-phenylacetylamino-
4â-(2-(2-furyl)ethyl]azetidin-2-one (2) from benzyl-3â-[4-
(S)-phenyl-oxazolidine-2-one-3yl]-4â-[2(2-furyl)ethenyl]-
azetidine-2-one (7) affords inconsistent yield and quality of
the desired products. In view of this, an optimized process
is developed for the preparation of 1 and 2 from 7 with the
use of sodium/ammonia in Birch reduction.
An optimized process for the stereospecific synthesis of carba-
cephem key intermediates 3â-[4-(S)-phenoxyacetylamino-4â-[2-
(2-furyl)ethyl]azetidin-2-one (1) and 3â-[4-(S)-phenyl-acetylamino-
4â-[2(2-furyl)ethyl)]azetidin-2-one] (2) is described. This report
provides an efficient and cost-effective process for achieving a
consistent yield and quality of intermediates 1 and 2 via Birch
reduction employing a sodium/ammonia instead of lithium/
ammonia system.
Results and Discussion
Introduction
Intermediate 7 can be readily prepared by the cyclo-
addition of acid chloride of (S)-4-phenyl-oxazolidin-2-one-
3-yl acetic acid (5) with 2-[3-(benzylimino)-1-propenyl]furan
6 in the presence of triethylamine1,4 (Scheme 1). The product
is crystallized from 2-propanol in >99% chromatographic
purity and >99.5% diastereomeric excess. Hydrogenation
of 7 with Pd/C in tetrahydrofuran gives benzyl-3â-(4-(S)-
phenyloxazolidin-2-one-3-yl)-4â-[2-(2-furyl)ethyl]azetidin-
2-one (8). Without isolating intermediate 8, Birch reduction
is carried out using sodium/ammonia followed by insitu
acylation with phenoxyacetyl chloride giving intermediate
1 in an overall yield of 60% compared to the reported yield
of 47% from intermediate 5 (Scheme 1).
The chiral auxiliary (S)-4-phenyl-2-oxazolidinone (3) has
been used for the enantioselective synthesis of carbacephems
employing (2 + 2) cycloaddition.1,2 The first carbacephem
antibiotic loracarbef (4) has been synthesized utilizing this
methodology2.
Literature method for the preparation of 1 involves
hydrogenation of 7 in dichloromethane and isolation of
intermediate 8 using crystallization in 60% yield.2 Birch
reduction on 8 with lithium/ammonia for removal of chiral
auxiliary, cleavage of the benzyl group from the â-lactam
nitrogen, and acylation with phenoxy acetyl chloride gives
desired amide 1 in 78% yield2 (Scheme 1). However, our
initial attempts to achieve the reported yield with lithium
failed. Hence, we investigated the use of sodium for Birch
reduction. It is found that reduction with sodium/ammonia
drastically improves yield and quality. Further, the manu-
facturing cost of intermediate 1 is also reduced since lithium
is much more expensive than sodium. This one pot synthesis
involves hydrogenation of intermediate 7 in tetrahydrofuran
without isolating intermediate 8 followed by sodium/am-
monia reduction of 8 which affects the following chemical
reactions. The oxazolidone auxiliary is removed to give ethyl
benzene and CO2, and the debenzylation of azetidinone
nitrogen results in toluene. After the reaction, sodium or
Literature survey reveals that Birch reduction using
lithium/ammonia is the most efficient and commonly used
method for cleavage of (S)-4-phenyl-2-oxazolidinone.1 The
* Author for correspondence. E-mail: yatendra.kumar@ranbaxy.com. Tele-
phone: (91-124) 234 2020. Fax: (91-124) 501 1832.
(1) (a) Evans, D. A.; Sjorgren, E. B. Tetrahedron Lett. 1985, 26, 3783. (b)
Evans, D. A.; Sjorgren, E. B. Tetrahedron Lett. 1985, 26, 3787.
(2) Bodurow, C. C.; Boyer, B. D.; Brennan, J.; Bunnell, C. A.; Burks, J. E.;
Carr, M. A.; Doecke, C. W.; Eckrich, T. M.; Fisher, J. W.; Gardner, J. P.;
Graves, B. J.; Hines, P.; Hoying, R. C.; Jackson, B. G.; Kinnick, M. D.;
Kochert, C. D.; Lewis, J. S.; Luke, W. D.; Moore, L. L.; Morin, J. M., Jr.;
Nist, R. L.; Prather D. E.; Sparks, D. L.; Vladuchick, W. C. Tetrahedron
Lett. 1989, 30, 2321.
(3) Fisher, J. W.; Dunigan, J. M.; Hatfield, L. D.; Hoying, R. C.; Ray, J. E.;
Thomas, K. L. Tetrahedron Lett. 1993, 34, 4755.
(4) Evans, D. A.; Sjogren, E. A. (Harvard College) E.P. Patent 209,352, 1986.
10.1021/op034074h CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/02/2003
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Scheme 1
Table 1. Synthesis of Intermediate 1 using Sodium and
Lithium Metal Ammonia Reductions from 5
Experimental Section
General. Reagents are used as such without further
purification. HPLC is performed with Water instrument using
Kromasil C-18 (150 mm × 4.6 mm, 5µ) column.6 1HNMR
spectra are recorded using Bruker 300 MHz. The chemical
shift data is reported as δ (ppm) downfield from tetrameth-
ylsilane which is used as an internal standard.
yield chromatographic purity
reaction
(%)
(% area by HPLC)
reduction with sodium/ammonia ∼60
reduction with lithium/ammonia ∼47
>98.5
95-97
Preparation of 1-Benzyl-3â-[4-(S)-phenyloxazolidin-2-
one-3-yl)-4â-[2-(2-furyl)ethenyl]azetidin-2-one (7).
To a solution of (S)-4-phenyloxazolidin-2-one-3-yl-acetic
acid (100 g, 0.452 mol) in dichloromethane (800 mL) add
N,N-dimethyl formamide (1.2 g) followed by thionyl chloride
(80.7 g, 0.678 mol) at 20-25 °C. The reaction mixture is
refluxed for 4 h and then distilled off the solvent and excess
thionyl chloride under reduced pressure (150-200 mm of
Hg). To the residue toluene (200 mL) is added and recovered
the solvent under vacuum (∼50 mm of Hg) to remove traces
of thionyl chloride. The residue is dissolved in dichlo-
romethane (1.1 L) and then cooled to -70 °C. A solution of
triethylamine (100.5 g, 0.99 mol) in dichloromethane (100
mL) is added slowly by keeping the temperature at -70 to
-65 °C and stirred for ∼30 min at -75 to - 70 °C.
To the above reaction mixture was slowly added the Schiff
base (6) solution [prepared from furyl acrolien (61 g, 0.50
mol) and benzylamine (53.5 g, 0.50 mol)] in dichloromethane
(800 mL) at -75 to -65 °C in 15 to 20 min. The temperature
of the mixture was allowed to raise to -10 °C in ∼60 min,
and the mixture was stirred for an additional 30 min at -10
to -5 °C. Water (1.5 L) is added, and we adjusted the pH
to ∼3.5 with 6 N HCl. The reaction mixture is allowed to
settle and separate into layers. The organic layer is washed
with 3% aqueous NaHCO3 solution (600 mL) and then with
sodamide is decomposed with ammonium chloride resulting
in the dischargement of blue coloration of the reaction
mixture.5 Ammonia is evaporated from the reaction mixture,
and the white slurry is dissolved in water followed by
acidification with hydrochloric acid. In situ acylation with
phenoxy acetyl chloride in the presence of NaHCO3 gives
the intermediate 1.
We compared Birch reduction with lithium/ammonia and
sodium/ammonia, and the following observations are made.
(1) Sodium/ammonia is superior to lithium/ammonia for
Birch reduction in terms of cost, yield, and quality (Table
1). (2) Experiments with lithium/ammonia results in thicken-
ing of the reaction mixture during removal of ammonia.
Excess ammonia is trapped in the system due to this
thickening, and excess acid is required for neutralization.
This phenomenon is not observed in the case of sodium/
ammonia reduction.
Thus, we found that the optimal reaction condition is the
use of sodium with 12 to 15 times dilution volume of liquid
ammonia of input 7. Liquid ammonia less than 10 times by
volume results in lower yield.
In conclusion, a scalable process using sodium for Birch
reduction is described. This method is cost effective and
affords the desired product in consistently good yield and
quality.
(6) HPLC analysis of intermediate 7 and 8: mobile phase, methanol/phosphate
buffer (pH 3.5) 60:40. Flow rate: 1.5 mL/min. UV detection at 210 nm.
Retention time of 7 is ∼9.0 min, and that of 8 is 11.30 min. HPLC analysis
of intermediate 1: mobile phase, acetonitrile/phosphate buffer (pH 2.5, KH2-
PO4 1.36 g/L; adjust pH with orthophosphoric acid). Flow rate: 2 mL/min
(gradient acetonitrile: buffer 5:95 to 50:50 in 30 min and 75:25 in 45 min).
UV detection at 210 nm. Retention time: 14.5 min.
(5) If required, add more ammonium chloride until blue colour discharges.
Liquid ammonia should be in excess to dissolve sodium metal completely;
add sodium metal in portions.
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5% aqueous sodium chloride solution (500 mL). The
resulting organic solution is concentrated under vacuum to
recover the solvent and added 2-propanol (1.0 L). The
reaction mixture is cooled to 10 °C and stirred for 60 min at
5-10 °C. The solid is filtered, washed with cold 2-propanol
(300 mL), and dried to yield 141 g (75.4%) of 7. Chromato-
graphic purity (by HPLC) > 99%. 1H NMR (CDCl3) δ 7.45-
7.07 (m, 11, ArH), 6.36 (dd, 1H, J ) 1.8, 3.3 Hz, OCHd
CH), 6.25 (d, 1H, J ) 16 Hz, NsCHsCHdCH), 6.20 (d,
1H, J ) 3.3 Hz, OsCdCH), 5.75 (dd, 1H, J ) 16, 8.9 Hz,
NsCHsCHdCH), 4.90 (dd, 1H, J ) 8.8, 7.4 Hz, OCH2CH),
4.65 (t, 1H, J ) 8.9 Hz, 1 × OCH2CH), 4.60 (d, 1H, J ) 15
Hz, 1H × ArCH2), 4.50 (d, 1H, J ) 4.8 Hz, C-3H), 4.20
(dd, 1H, J ) 7.4, 8.8 Hz, 1 × OCH2CH), 4.11 (dd, 1H, J )
4.8, 8.9 Hz, Cs4H), 4.00 (d, 1H, J ) 15 Hz, 1H × ArCH2).
Preparation of 3â-(4-(S)-Phenoxyacetylamino-4â-[2-
(2-furyl)ethyl]acetidin-2-one (1). To a solution of 7 (100
g, 0.24 mol) in tetrahydrofuran (800 mL), 2.5% Pd/carbon
(50% wet, 30 g) is added under nitrogen at 20-25 °C and
H2 gas is bubbled for ∼3 h. The reaction is monitored by
HPLC. After completion of reaction, the catalyst is filtered
and washed with THF (200 mL) and the combined THF
solution containing 8 is used as such after adding tert-butyl
alcohol (100 mL).
Small pieces of sodium (45.5 g, 1.98 mol) are slowly
added in ∼30 min to liquid ammonia (∼1.5 L) at -70 to
-75 °C and allowed to stir for 30 min at the same
temperature until the metal pieces dissolve. To this blue
coloured solution, the above-mentioned THF solution of 8
is added in 30-40 min at -75 to -60 °C, and stirring is
continued for additional 30 min at -65 to -60 °C.
Ammonium chloride (100 g, 1.88 mol) is added in portions
in 10-15 min. (Blue colour discharged.) The temperature
was slowly raised from 30 to 35 °C to remove ammonia
completely from the reaction mixture. To the resulting white
slurry water (1.0 L) is added, and we adjusted the pH with
concentrated HCl (∼100 mL) to ∼4.0 at 10-20 °C. Sodium
bicarbonate (71 g, 0.84 mol) is added and stirred for 10-15
min. The reaction mixture is diluted with THF (400 mL),
and we added a solution of phenoxy acetyl chloride (41 g,
0.24 mol) in THF (100 mL) in 30-40 min at 15-20 °C.
Stirring is continued for 5-6 h at 25-30 °C and monitored
by HPLC for reaction completion. The reaction mixture is
allowed to settle and separate into layers. The organic layer
is collected and evaporated under reduced pressure (60-
100 mmHg). To the resulting white slurry isopropyl alcohol
is added, and we recovered ∼100 mL solvent under vacuum
(60-100 mmHg). The mixture was stirred for 30 min at
room temperature and then cooled to 5 °C. After stirring for
3 h at 5-8 °C, the mixture was filtered and washed with
cold IPA (200 mL). We air dried the wet material at 40-45
°C for 6 h to yield the titled compound 1 in 80% (60.3 g)
yield.
Chromatographic purity (By HPLC): >98.5%; 1H NMR
(DMSO-d6) 1.70 (m, 2H, NsCHsCH2sCH2), 2.57 (m, 2H,
CH2sCH2sOsCH), 3.62 (m, 1H, H-4), 4.57 (s, 2H, Os
CH2), 5.10 (m, 1H, H-3), 6.05 (dd, 1H, OsCdCH), 6.35
(dd, 1H, OsCHdCHs), 6.94 (m, 3H, ArH), 7.24 (m, 2H,
ArH), 7.50 (d, 1H, J ) 3.1 Hz, OsCHdCHs), 8.43 (br,
1H, NH), 8.93 (d, 1H, COsNH).
Preparation of 3â-[4-(S)-Phenylacetylamino-4â-(2-(2-
furyl)ethyl]azetidin-2-one (2). The titled compound is
prepared following the above method using phenyl acetyl
chloride (37.4 g, 0.24 mol) instead of phenoxy acetyl chloride
in 62% yield. Chromatographic purity (HPLC) >98.5%; 1H
NMR (DMSO-d6) 1.64 (m, 2H, NHsCHsCH2sCH2), 2.50
(m, 2H, sCHsCH2sCH2sCsO), 3.48 (s, 2H, CH2sPh),
3.60 (m, H, H-4), 5.04 (m, 1H, H-3), 6.00 (dd, 1H, sOs
CdCH), 6.35 (dd, 1H, OsCHdCH), 7.22 (m, 5H, ArH),
7.50 (d, 1H, OsCHdCH), 8.41 (br 1H, NH), 8.87 (m, 1H,
COsNH).
Acknowledgment
We are grateful to the Analytical Division of Ranbaxy
Research Laboratories for their analytical and special support.
Received for review June 13, 2003.
OP034074H
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