An improved process for the preparation of 4,4-dimethyloxazolidine-2-thione

Article abstract of DOI:10.1021/op6002677

An improved process for the preparation of 4,4-dimethyloxazolidine-2-thione (1), an auxiliary used in the synthesis of (3S,4S)-[(R)-1′-((tert- butyldimethylsilyl)oxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetidinone (2), a key intermediate for carbapenem synthesis is reported.

Full text of DOI:10.1021/op6002677

Organic Process Research & Development 2007, 11, 466−467
Technical Notes
An Improved Process for the Preparation of 4,4-Dimethyloxazolidine-2-thione
Neera Tewari,* Dinesh Nair, Hashim Nizar, Bishwa Prakash Rai, and Mohan Prasad
Chemical Research DiVision, Ranbaxy Research Laboratories, Gurgaon, Haryana-122001, India
Abstract:
preparation of dithiocarbamic acid 4 in benzene followed
by heating of the isolated 4 to result in 1 (Scheme 1).
Benzene being carcinogenic cannot be used on a commercial
scale, and direct heating of solid dithiocarbamic acid 4 is
not recommended on a commercial scale. Another recent
literature method for synthesis of oxazolidine-2-thiones
involves reaction of amino alcohol with carbon disulphide
in the presence of sodium carbonate. However our attempts
to prepare 1 using the above methodology gave poor yields
and quality due to precipitation of sodium carbonate along
with the product.
An improved process for the preparation of 4,4-dimethylox-
azolidine-2-thione (1), an auxiliary used in the synthesis of
(3S,4S)-[(R)-1′-((tert-butyldimethylsilyl)oxy)ethyl]-4-[(R)-1-car-
boxyethyl]-2-azetidinone (2), a key intermediate for carbapenem
synthesis is reported.
1
0
Introduction
Oxazolidine-2-thiones have been used as chiral auxiliaries
for a wide variety of synthetic transformations. These five-
1
membered heterocycles are commonly prepared by the
condensation of carbon disulphide with â-amino alcohols.
Oxazolidine-2-thiones are used in the synthesis of (3S,4S)-
The present process describes the synthesis of 4,4-
dimethyl oxazolidine-2-thione (1) in one step from reaction
of 2-amino-2-methylpropanol (3) in toluene with carbon
disulphide (entry 2). In a typical experiment carbon disul-
phide is added to 2-amino-2-methylpropanol (3) dropwise.
As the reaction proceeds the intermediate 4 separates as a
solid. The solid is dissolved in water and heated in the
presence of aqueous sodium hydroxide (10%) at 95-100
2-4
[
(R)-1′-((tert-butyldimethylsilyl)oxy)ethyl]-2-azetidinone (2),
5-7
a key carbapenem intermediate.
In the course of our
ongoing project for the synthesis of 2, a method for
production of the auxiliary 4,4-dimethyloxazolidine-2-thione
(1) on a multikilogram scale was required. In this report an
efficient and scalable synthesis of 1 is described.
°
C for 1-2 h followed by cooling of the reaction mixture to
yield 1 in 38% yield. During the optimization studies we
have carried out the reaction under different conditions, and
the results are tabulated in Table 1. The preparation of 1
without any organic solvent (entry 1) gives better yields but
can have scale up issues. The preparation of 1 following the
9
reported procedure using toluene instead of benzene as
solvent results in 32% yield (entry 3). However the reaction
carried out in toluene (entry 2) results in better yields (38%).
The reaction using water and a water/toluene mixture as
solvent gave no product (entry 5, 8). Reaction with dichlo-
romethane as solvent also results in lower yields (25%) (entry
Results and Discussion
Literature survey reveals that 1 is prepared from 2-methyl-
2-aminopropanol (3), ammonium hydroxide, carbon disul-
4
).
8
9
phide, and chloroacetic acid. Another method involves the
On a commercial scale, the addition of carbon disulphide
should be carried out under water blanketing and a nitrogen
atmosphere. The rate of addition of carbon disulphide should
be such that the temperature of the reaction mixture does
not rise above 40 °C.
The present method has the following advantages over
the reported methods. The reaction is carried out in one step
without filtration of dithiocarbamic acid 4 which prevents
exposure to carbon disulphide on a commercial scale, and
direct heating of 4 is avoided.
*
Author for correspondence. E-mail: neera.tiwari@ranbaxy.com. Tele-
phone: (91-124) 4011832. Fax: (91-124) 4011832.
1) (a) Velaquez, F.; Olivio, F. H. Curr. Org. Chem. 2002, 6 (4), 303-340.
(
(b) Crimmins, M. T.; Shamszad, M. Org. Lett. 2007, 9, 149-152.
(
(
(
2) Ettlinger, M. G. J. Am. Chem. Soc. 1950, 72, 4792-4796.
3) Rosen, A. A. J. Am. Chem. Soc. 1952, 74, 2994-2997.
4) Chanon, M.; Chanon, F.; Metzger, J. J. Chem. Soc., Chem. Comm. 1974,
4
25.
5) Nakagawa, Y.; Kiyohito, T.; Niigata, I. (Toyama) U.S. Patent 5,731,431,
980.
6) Deziel, R.; Favreau, D. Tetrahedron Lett. 1986, 27, 5687-5690.
7) Tewari, N.; Nizar, H.; Rai, B. P.; Mane, A.; Prasad, M. Org. Process Res.
DeV. 2005, 9, 827-829.
(
1
(
(
(
(
8) Somerville, W. T.; Andersen, C. N. J. Org. Chem. 1960, 25, 656-657.
9) Skulski, M.; Garmais, D. L.; Mckay, A. F. Can. J. Chem. 1956, 34, 815-
(10) Delaunay, D.; Toupet, L.; Le Corre, M. J. Org. Chem. 1995, 60, 6604-
8
20.
6607.
4
66
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Vol. 11, No. 3, 2007 / Organic Process Research & Development
10.1021/op6002677 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/03/2007

Scheme 1
Table 1. Preparation of 4,4-dimethyl oxazolidine-2-thione (1)
under different conditions
Preparation of 4,4-Dimethyloxazolidine-2-thione (1).
Carbon disulphide (1.88 kg, 24.73 mol) was added dropwise
to 2-amino-2-methylpropanol (3) (2.0 kg, 22.47 mol) in
toluene (4.0 L) with vigorous stirring over a period of
entry
solvent (times)
base
yield (%)
40
38
32
1
2
3
4
5
6
7
8
9
neat
-
-
-
-
-
Na
1
-2 h. (The rate of addition of carbon disulphide was
toluene (2T)
toluene (7T)a
maintained in such a way that the reaction temperature does
not exceed 40 °C.) After 1 h, distilled water (4.0 L) was
added and the reaction mixture was stirred until complete
dissolution of the solid in water takes place. The layers were
separated, and to the aqueous layer 10% NaOH (500 mL)
was added; the resulting solution was heated at 95-100 °C
for 1-2 h. The colour of the solution changes from red to
DCM (2T)
waterb
25
no reaction
15
10
no reaction
20
water
2
CO
3
water
toluene + water
DCM
NaOH
-
triethylamine
a
Dithiocarbamic acid is isolated and dissolved in water for further reaction.
Sodium carbonate precipitates out along with the product.
2 2
light green, and evolution of H S gas ceases (H S gas
b
generated is trapped by passing through an aqueous NaOH
solution). The resulting reaction mixture on cooling gave a
crystalline solid which was filtered, washed with cold water
In conclusion, an improved single step scalable process
for the preparation of 4,4-dimethyloxazolidine-2-thione (1)
is reported.
(
2 × 500 mL), and dried to yield 1 (1.12 kg, 38%).
1
Chromatographic purity by HPLC > 99%. H NMR (CDCl
3
)
δ 8.5 (s, 1H, NH), 4.4 (s, 2H, -CH
IR (ν cm , KBr) 3200, 1520. MS (m/e): 131.
2
), 1.4 (s, 6H, 2 × CH
3
).
Experimental Section
-1
General. Reagents are used as such without purification.
HPLC is performed with a Waters instrument using an ACE
C-18 (150 mm × 4.6 mm, 5µ) column with a UV detector
Acknowledgment
We are grateful to the Analytical Division of Ranbaxy
Research Laboratories for their analytical and spectral
support. We are also grateful to Mr. Sanjay Gade and Mr.
Bhupendra Vashisht for reaction calorimetry studies.
(240 nm) and mobile phase phosphate buffer (pH 6.5)/
1
acetonitrile(1:9) with flowrate 1.5 mL/min. H NMR spectra
are recorded using a Bruker 300 MHz instrument. The
chemical shift data are reported as δ (ppm) downfield from
tetramethylsilane which is used as an internal standard.
Infrared spectra are recorded using Perkin-Elmer FTIR
Received for review December 12, 2006.
OP6002677
(Spectrum One) instrument. Mass spectra are recorded using
an API 2000(MDS SCIEX) instrument.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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