Application Of Non-swelling
For Parallel
Qunjie Wang, Joseph J. Kirkland, Timothy Langlois.
Lorin A. Thompson. DuPont Pharmaceuticals
Porous Scavengers
Synthesis
Agilent Technologies Inc.
Application Of Non-swelling Porous
Scavengers For Parallel Synthesis
Qunjie Wang, Joseph J. Kirkland, Timothy Langlois. Agilent Technologies
Inc.; Lorin A. Thompson. DuPont Pharmaceuticals
Introduction
• Solid scavengers are increasingly used in parallel organic
synthesis to remove excess reactants or by-products.
However, most of scavengers are based on gel-type polystyrene, which feature: 1) very high swelling in some
solvents - allow only small amount of scavenger in a well,
and cannot be pre-packed and stored in a cartridge or
column format; 2) necessity of swelling - narrow range of
compatible solvents.
• In this research, new macroporous scavengers have been
developed and investigated, based on ultra-pure, spherical
silica and low swelling macroporous polystyrene/DVB.
Volume Restraints
• For Automated Synthesis Using 96 wells Block:
– Blocks hold 2 mL volume: Reaction volume should be
at most half of the volume of the well, scavenger only
around 500 mL
– Collection blocks hold 2.0 mL, but can only safely
concentrate about 1.2 mL
– So: Scavenge with at most 450 mL volume of scavenger
in reaction wells or develop Flow-through method
96-Wells Blocks
Macroporous scavengers
• Based on ultra-pure, spherical silica:
S-monoamine(NH2), S-triamine(NH, NH2),
S-tertiaryamine, S-sulfonic acid, S-aldehyde, S-epoxide,
S-mecaptan, S-diphenylethylphosphine.
• Based on low-swelling macroporous polystyrene/DVB:
MP-isocyanate, MP-aldehyde, MP-mecaptan,
MP-trisamine(NH, NH2), MP-piperidinomethyl,
MP-sulfonyl hydrazide(-NHNH2), MP-sulfonyl chloride
Features and advantages (vs gel-polystyrene
based scavengers)
• Silica-based:
Ultra pure silica - no interference with reactions.
Spherical silica - easy to handle, good through-flow.
No-swelling, high density - larger amount for available volume;
possible incorporation into different format (membrane, column).
Porous structure - solvent independent, good mass transfer of
reactants.
• Low-swelling Macroporous polystyrene/DVB-based:
Low swelling (30% vs 500% for gel)- larger capacity per vol.
easy to handle, possible in different format (membrane, column).
Porous structure - broad solvent compatibility
Types of Silica
Standard Commercial
Silica Gel
HP Ultrapure Silica Gel
CombiZorb (macropolymer-based)
Capacity/v
in THF
(mmol/mL)
Swelling
in THF
Capacity in THF
(mmol/g)
Capacity
in methanol
(mmol/g)
a
a
MP-isocynate
0.4-0.5
Gel
0.1-0.2
MP-aldehyde
0.5-0.7
Gel
0.1-0.2
30%
600%
30%
600%
1-1.3
1-1.5
1.4-1.6
1-1.6
0.5-0.6
0.2
0.7
0.2
a. commercial 1% 0r 2% cross-linked polystyrene gel based scavengers
CombiZorb (silica-based)
S-triamine S-monoamine S-sulfonic acid S-tertiaryamine
Capacity/v
1.6-2.1
0.8- 1.2
0.5-0.8
0.8- 1.2
1.2-1.6
0.6-0.9
0.4-0.6
0.6-0.9
1.2-1.6
0.6-1.0
0.4-0.6
0.5-0.7
in THF
(mmol/mL)
Capacity
(mmol/g)
Capacity
in methanol
(mmol/g)
S: HP ultra pure silica
Scavenging Test of S-monoamine
Electrophile
4-chlorobenzoyl
chloride
2-phenylbutyryl
chloride
Phenyl chloroformate
Chloroacetic anhydride
Cyclohexyl isocyanate
Phenyl isocyanate
Benzaldehyde
Combizorb S1)
triamine (equiv.)
4
Solvent
Conditions
CH2Cl2
1 h, 20 C
4
CH2Cl2
1 h, 20 C
4
4
2
2
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF/MeOH
(1:2)
1 h, 20 C
o
1 h, 20 C
o
1 h, 20 C
o
1 h, 20 C
o
1 h, 60 C
1) Relative to electrophiles without use of additional base
2) Determined by GC
o
Scavenged
2)
(%)
> 99%
o
>99%
o
>99%
> 99%
>99%
> 99%
> 99%
Scavenging Test of S-triamine
Electrophile
4-chlorobenzoyl
chloride
2-phenylbutyryl
chloride
Phenyl chloroformate
Chloroacetic
anhydride
Phenyl isocyanate
Benzaldehyde
Combizorb S-triamine
1)
(equiv.)
4
Solvent
Conditions
CH2Cl2
1 h, 20 C
4
CH2Cl2
1 h, 20 C
4
4
CH2Cl2
CH2Cl2
1 h, 20 C
o
1 h, 20 C
2
3
CH2Cl2
THF/MeOH
(1:2)
1 h, 20 C
o
1 h, 60 C
1) Relative to electrophiles without use of additional base
2) Determined by GC
o
Scavenged
2)
(%)
> 99%
o
>99%
o
>99%
> 99%
o
> 99%
> 99%
Scavenging Test of MP-NCO(2.5 equiv.)
Nucleophile
Solvent
benzylamine
CH2Cl2
benzylamine
acetonitrile
benzylamine
i-PrOH
benzylamine
MeOH
morpholine
THF
1-methyl piperazine
THF
tryptamine
THF
phenyl hydrazine
THF
aniline
THF
1) Determined by GC
o
Temp C
20
20
20
20
20
20
20
20
50
1)
Time (h) Scavenged (%)
0.5
>99
0.5
>99
0.5
92
0.5
91
1
>99
1
>99
1
94
1
>99
1
75
Scavenging Test of MP-CHO (3 equiv.)
o
Nucleophile
Solvent
Additive
Temp ( C)
phenylhydrazine
phenylhydrazine
phenylhydrazine
phenylhydrazine
p-toluene
sulfonylhydrazide
4-methoxyphenyl
hydrazine
hydrochloride
Benzylamine
THF
Toluene
i-PrOH
MeOH
THF
none
none
none
none
MeOH
MeOH
THF
Tryptamine
THF
Determined by GC
50-60
50-60
50-60
50-60
50-60
Time
(h)
2
2
2
2
2
Scavenged
1)
(%)
95
>99
93
> 99
> 99
none
50-60
2
>99
Acetic
acid
MeOH
50-60
2
>99
20
3
97
Example 1
O
O
Cl
O 2N
NH 2
100 mMol
N
H
DIEA
100 mMol
50 mMol
200 uL of Water
16 h rt
50 mMol
O
N
H
50 mMol
O
NO 2
O 2N
50 mMol
50 mMol
O
O 2N
50 mMol
OH
DIEA HCl
NO 2
Cl
DIEA HCl
50 mMol
• Rxn run in 2 mL of Ethyl Acetate, THF, or DMF. Added 200 mL of
water, stirred 16 h at rt.
• The solution is forced with a pipet bulb through a plug of 450 mL
of scavenger in a 2.0 mL tube, and the scavenger is then rinsed
with 1.0 mL of solvent.
• The eluents are concentrated, redissolved in 4.0 mL of solvent and
analyzed by HPLC
Flow-Through Method
Reaction Block
Filter Block prepacked
with scavenger
(Polyfiltronics)
Vaccuum
Collection Block
Aqueous Cosolvent Sequestering
Aqueous Cosolvent Sequestering
O
120
N
H
100
80
% Acid
Remaining 60
Ethyl Acetate
Methanol
DMF
40
DIEA HCl
O
P-NMM
P-DIEA
OH
P-Tris
AP Silica
HP silica
Control
0
Control
20
NO 2
O 2N
50 uMol each
Example 2
NH2HCl
O
Cl C
Cl
NMe2
NH2
O
Cl C
NMe2HCl
(1.2 meq)
Cl
O
NH C
(0.6meq)
O
PhCH2NH C
(0.6 mmol)
+
+
PhCH2NH2
(0.4 mmol)
O
PhCH2NH C
Cl
Cl
Purity > 99 %
Yield = 95%
NMe2
: S-tertiaryamine, 0.8meq/g;
NH2
: S-triamine, 1.4 meq/g.
- Benzylamine, chlorobenzoyl chloride and S-tertiaryamine were mixed with 2 mL
CH2Cl2 at RT and shaken for 1 hour.
- S-triamine plus 1 mL acetonitrile was added to the mixture and shaken for 1 h, the
solid was filtered off and washed with CH2Cl2 (twice, 0.5 mL each).
- Benzyl chlorobenzamide was obtained as a pure product upon solvent
evaporation.
Cl
Example 3
O
PhNCO
(0.2 mmol)
NCO
PhNCO
NHCNHCH2Ph
(0.3 mmol)
O
+
+
O
PhCH2NH2
(0.3 mmol)
PhNHCNHCH2Ph
PhNHCNHCH2Ph
Purity > 99 %
Yield = 87 %
NCO
: MP-isocyanate, 1mmol/g.
- Benzylamine and phenyl isocyanate was mixed with 1.5 mL dichloromethane and
shaken for 1 hour at RT.
- MP-isocyanate and 1 mL MeOH were added to the reaction mixture, shaken for
two more hours; the solid was filtered off and washed with 1 mL MeOH.
- Phenyl benzyl urethane was obtained as a pure product upon solvent evaporation.
Example 4
Synthesis of Pyrazoles
R
H
N
O
NH2
1.0 eq.
O
N
+
SO2NHNH2
2 eq
N
MeOH
1.5 eq
R
RT 1h
+
O
MeOH
RT 2h
O
N
N
R
Yield > 80%
Purity > 95%
R = phenyl, 4- methoxyphenyl, m-tolyl;
*
Unlike the gel-type polystyrene based scavengers, the macroporous
scavengers can be used in the alcohols with good efficiency.
Summary
• Two types of porous scavengers (ultra pure silica, low-swelling
polystyrene) have been developed with a variety of functionality.
• The preliminary studies demonstrate the major advantages of
the new scavengers:
- higher capacity for available volume;
- broad solvent compatibility;
- compatible with different application format.
Stability of Silica-based scavengers
References
For general application of scavengers
[1] R. J. Booth & J. C. Hodges J. Am. Chem. Soc., 1997, 119, 4882.
[2] D. L. Flynn, et al. J. Am. Chem. Soc., 1997, 119, 4874.
[3] L. A. Thompson, et al. at Lake Tahoe Symposium on Molecular
Diversity, Lake Tahoe, CA. 1999, Jan. 28.
[4] S. W. Kaldor et al. Tetrahedron Lett.,1996, 37, 7193
[5] J. M. Frechet et al. J. Am. Chem. Soc., 1971, 93, 492