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SOLUTION PHASE PARALLEL SYNTHESIS & PURIFICATION OF

2-ACETAMIDO THIOMORPHOLIN-3-ONES.

Santosh R Nandan; M.N. Harishkumar; P.M. Ramanujulu


AstraZeneca R&D Bangalore, India.
ABSTRACT

The reaction of vicinal aminothiols with substituted


maleimides has been developed for parallel
synthesis. Application of this reaction to the
synthesis of an array of 2-acetamido-thiomorpholin-
3-ones using commercially available vicinal
aminothiols and maleimides is presented.
H
O N O
NH2
R SOLVENT
N + BASE S
SH
O H N O
R
Parallel synthesis has become an important tool in the
medicinal chemist’s arsenal; specially when applied to
lead optimisation1. The last few years have witnessed
the explosive growth of Solid Phase Organic Chemistry
(SPOC) and its application to combinatorial and parallel
synthesis2. Solution phase organic chemistry as
applied to parallel and combinatorial synthesis has
received step-motherly treatment despite the fact that
the number of synthetic protocols and chemistries
available is far superior. One of the major contributing
factors is the task of purification / removal of
byproducts. In the past two years both academic and
industrial researchers have presented quite a few
elegant approaches for solving this problem3. We would
like to suggest that parallel chromatography can be a
solution to the above problem4.
We were interested in generating a series of
thiomorpholines for evaluation in our antibacterial
assays. In this paper we would like to present the
development of a general synthetic method for the
parallel synthesis of 2-acetamido-thiomorpholin-3-one
and application of parallel chromatography for
purification of the library.
The synthesis of 2-acetamido-thiomorpholin-3-
one using the ring opening of maleimides by a tandem
Michael -Ring opening sequence (Scheme 1) is known
in the chemical literature 5. However the reaction has
not been studied with respect to the reactivity of the
aminothiol component or nonaromatic maleimides.
H
O N O
NH2 O
DMF, heat
N + H
S N
SH
O

Scheme 1
Preliminary experiments revealed that the reaction
conditions would have to be optimized before the
reaction could be applied in a parallel fashion. The
parameters selected for optimization were solvent,
base, and the reactivity of the maleimide / aminothiol.
Our experiments also suggested that a temperatures
ranging from 800C to 1000C would be required for the
ring-opening of the initially formed Michael adduct.
Optimization of the reaction conditions were
performed using solvents (Pyridine, Toluene
Dimethylformamide) and bases (Triethylamine, 4-
Dimethylamino-pyridine, and Pyridine) that are
commonly used. The maleimides and aminothiols
shown in Scheme 2 were chosen in an attempt to
cover the entire spectrum of reactivity.
OPTIMIZATION OF REACTION CONDITIONS

Br H2N N
O O
NH2
N
N N SH HS
N N
M1 O M2 O ALAT ARAT

S
c
h
e
m
e
2
M2 M1 M1 M1 M1 M2 TEMP
ARAT ALAT ALAT ARAT ARAT ALAT PROBE
Excess Pyridine 2eqDMAP, DMF Excess Pyridine 2eq DMAP Excess Pyridine Excess Pyridine
DMF
M1 M2 M2
ALAT ARAT ARAT ALAT ALAT ARAT ARAT
2eq Pyridine Excess TEA 2eq Pyridine 2eq Pyridine 2eq DMAP 2eq Pyridine 2eq DMAP
DMF DMF DMF DMF DMF DMF DMF
M1 M2 M2 M2 M2 M1 M1
ARAT ALAT ALAT ARAT ARAT ALAT ALAT
2eq Pyridine 2eq Pyridine Excess TEA 2eq Pyridine Excess TEA 2eq Pyridine Excess TEA
Toluene Toluene DMF Toluene DMF Toluene DMF
M2 M2 M1 M1
ALAT ARAT ALAT ARAT
Excess TEA Excess TEA Excess TEA Excess TEA
Toluene Toluene Toluene Toluene
A typical reaction procedure involved mixing the
maleimide(1eq) and the aminothiol(0.8eq) in solvent and
heating to 1000C for 16 hours. The best solvent and
base for this reaction was found to be toluene and
triethylamine (Scheme2).
NH2 SH
NH2 Bu
NH SH
SH N
SH N NH2
N
NH2 CF3

SH NH2
SH
N

O
O O
Br N
N N
O
O O
Scheme 3
Using the modified procedure an array of 18
compounds was synthesized and purified using 3
maleimides and 6 commercially available
aminothiols (Scheme 3)
Our parallel chromatography system6 consists of a
solvent delivery system (HPLC pumps and a flow
splitter), and a multiple fraction collector which
collects the output from 6 chromatographic columns
at the same time. In a typical run purification is
completed in 2 hours. All the compounds exhibited
satisfactory NMR and MS spectrums (purity > 95%).
The yield of purified compounds ranged from 30% to
80%. The isolation of pure products from the low
yielding reactions testify to the effectiveness of the
parallel purification protocol used.
2-acetamido-thiomorpholin-3-ones synthesized
O R H
N H S N
N S R
S N N
H R
N O
O N O
N N O
H H Bu
N O

H H H
S N S N S N
R R R
O O O
N O CF3 N O N O
H H H

R= Br

Scheme 4
Shown above is the equipment7 used for agitating and heating reactions.
Salient features of this instrument are interchangeable blocks(49, 16, 9, 4
reactors), solution or solid phase reactions, variable agitation and a maximum
temperature of 1500C.
Shown above is the equipment6 used for parallel chromatography. This system can
run six separations simultaneously. Solvent delivery is achieved using a Waters HPLC
system. The solvent is delivered to a splitter which divides the flow into six equal
streams which is then connected to the chromatography columns. The output from
the columns is collected by the multiple fraction collector.
Conclusion

We succeeded in establishing a general synthetic


method for the parallel synthesis of thiomorpholino-
acetamides. We have also demonstrated that parallel
chromatography can be successfully applied to the
purification of multiple reaction mixtures
simultaneously; thus enhancing the throughput
possible. The synthetic route used is capable of
enormous diversity, as the building blocks are easily
accessible.
Acknowledgements : We are grateful to Astra Research Center
(India) for financing the development of the multiple fraction
collector used in this work.

References
1) For review see Terret N. A. Combinatorial Chemistry, John
Wiley,1998.
2) For Review see Bunnin B.A. The Combinatorial Index, Academic
San Diego 1998.
3) For Review see Coe, M Diane and Storer Richard Molecular
diversity 4 1999 p31-38.
4) Recently Dyax Corporation, Jones chromatography and Isco have
introduced systems for parallel chromatography.
5) a. Kirchner Alexander; J. Am. Chem Soc. 81, 1959, p1721
b. Balasubramanian Y; Balasubramanian P; Shaikh A. S.;
Tetrahedron 42 1986 p2731
6) The multiple fraction collector and splitter were built to our
specifications by Tensil glassworks and Eltel Corporation.
7) All the reactions were carried out in a agitated heating block built
for us by Lead Instruments Bangalore.