Transcript Application of Porous Scavengers for High Throughput

Application of Porous Scavengers for
High Throughput Purification
Cory Szafranski, Qunjie Wang, Joseph J. Kirkland, Timothy Langlois
Agilent Technologies Inc.
Lorin A. Thompson
DuPont Pharmaceuticals
APPLICATION OF POROUS SCAVENGERS FOR HIGH
THROUGHPUT PURIFICATION
Cory Szafranski, Qunjie Wang, Joseph J. Kirkland and Timothy
Langlois, Agilent Technologies Inc., 2850 Centerville Road,
Wilmington, DE 19808;
Lorin A. Thompson, DuPont Pharmaceuticals, Wilmington, DE
19880-0500
ABSTRACT
To overcome practical difficulties related to gel-type polystyrenebased scavengers, i.e. large wet volume, significant swelling,
solvent incompatibilities, and low flow-through efficiencies, we
have recently developed silica and macroporous polymer based
scavengers (CombiZorb). This presentation describes the advantages
and usefulness of these scavengers, and applications of them in
various reaction protocols.
Introduction
• Solid scavengers are increasingly used in parallel organic
synthesis to remove excess reactants or by-products.
However, most scavengers are based on gel-type polystyrene, which features: 1) very high swelling in some
solvents - cannot be pre-packed and stored in a cartridge or
column format; 2) necessity of swelling - narrow range of
compatible solvents.
• New macroporous scavengers - CombiZorb has been
developed based on ultra-pure, spherical silica and low
swelling macroporous polystyrene/DVB, to overcome
these drawbacks.
Macroporous Scavengers
• Based on ultra-pure, spherical silica:
S-Monoamine(NH2), S-Triamine(NH, NH2),
S-TertiaryAmine, S-Sulfonic Acid, S-Aldehyde, SEpoxide, S-Mercaptan, S-Diphenylethylphosphine.
• Based on low-swelling macroporous polystyrene/DVB:
MP-Isocyanate, MP-Aldehyde, MP-Mercaptan,
MP-Trisamine(NH, NH2), MP-Piperidinomethyl,
MP-Sulfonyl Hydrazide(-NHNH2), MP-Sulfonyl Chloride
Features and Advantages (vs. gel-type
polystyrene based scavengers)
• Silica-based:
Ultra pure silica - no interference with reactions.
Spherical silica - easy to handle, good flow-through properties.
No-swelling, high density - larger amount for available volume;
possible incorporation into different formats (membrane, column).
Porous structure - solvent independent, good mass transfer of
reactants.
• Low-swelling macroporous polystyrene/DVB-based:
Low swelling (30% vs. 500% for gels) - larger capacity per vol.,
easy to handle, possible in different formats (membrane, column).
Porous structure - broad solvent compatibility.
Performance Comparison
Capacity/v
Capacity /w
(mmol/mL)
(mmol/g)
(THF)
(THF)
Trisamine MP
3
25%
1.4
PS
500%
0.3-0.5
3-4
Piperidino MP
2
25%
0.8
PS
400%
0.4
3
Hydrazide MP
1.6
40%
0.5
PS
400%
0.1-0.2
1-2
Sulfonyl.
1.8
MP
30%
0.6
Chloride
PS
500%
0.1-0.2
1-2
Isocyanate MP
1.3
30%
0.5
PS
500%
0.1-0.2
1-1.5
Aldehyde MP
1.5
30%
0.6
PS
600%
0.1-0.2
1-1.6
PS: gel-type polystyrene based products. na: not applicable.
Swelling
(by THF)
Capacity/w
(mmol/g)
(MeOH)
1.8
<0.3
1.3
<0.3
1.1
na
na
0.6
0.2
0.8
0.2
Capa.(MeOH)
_________
Capa. (THF)
60%
<10%
60%
<10%
70%
20%
na
na
45%
14%
54%
13%
Performance Comparison (cont’d)
Scavenging aldehyde/ketones by polymerSO2NHNH2 (3 eq., 2h, RT, in MeOH).
residue (%)
MP-: Macroporous CombiZorb
Scavengers
Gel-: Gel polystyrene based
Scavengers
Pentanedione
Cyclohexanone
MP-SO2NHNH2
Gel-SO2NHNH2
Benzaldehyde
50
45
40
35
30
25
20
15
10
5
0
Scavenging Test of S-Triamine
Electrophile
4-chlorobenzoyl
chloride
2-phenylbutyryl
chloride
Phenyl chloroformate
Chloroacetic
anhydride
Phenyl isocyanate
Benzaldehyde
Combizorb STriamine (equiv.)1)
4
Solvent
Conditions
CH2Cl2
1 h, 20 oC
Scavenged
(%) 2)
> 99%
4
CH2Cl2
1 h, 20 oC
>99%
4
4
CH2Cl2
CH2Cl2
1 h, 20 oC
1 h, 20 oC
>99%
> 99%
2
3
CH2Cl2
THF/MeOH
(1:2)
1 h, 20 oC
1 h, 60 oC
> 99%
> 99%
1) Relative to electrophiles without use of additional base
2) Determined by GC
Scavenging Test of MP-Isocyante
(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
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
1)
•
Sequestering of Carboxylic Acids
O
O
Cl
O 2N
NH2
100 Mol
N
H
DIEA
100 Mol
50 Mol
16 h rt
NO2
50 Mol
O
NO2
O 2N
50 Mol
O 2N
•
50 Mol
OH
DIEA HCl
50 Mol
Cl
DIEA HCl
50 Mol
O
N
H
200 uL of Water
O
50 Mol
•
Aqueous Cosolvent Sequestering
120
O
100
N
H
80
60
Ethyl Acetate
Methanol
DMF
40
20
NO2
DIEA HCl
O
P-NMM
O 2N
P-DIEA
P-Tris
AP Silica
HP silica
OH
Control
0
Control
% Acid
Remaining
Rxn run in 2 mL of Ethyl
Acetate, THF, or DMF.
Added 200 L of water,
stirred 16 h at RT.
The solution is forced
through a plug of 450 L
of scavenger in a 2.0 mL
tube, and is then rinsed
with 1.0 mL of solvent.
Eluents are conc.,
redissolved in 4.0mL
solvent, and analyzed by
HPLC.
50 uMol each
Acylation of Benzylamine
NH2HCl
O
Cl C
Cl
NMe 2
NH2
O
Cl C
NMe 2HCl
(1.2 meq)
Cl
O
PhCH2NH C
+
PhCH2NH2
(0.4 mmol)
O
PhCH2NH C
Cl
(0.6meq)
(0.6 mmol)
+
O
NH C
Cl
Purity > 99 %
Yield = 95%
NMe 2
: S-te rti aryam in e , 0.8m e q/g;
NH2
: S-tri am in e , 1.4 me q/g.
- Benzylamine, chlorobenzoyl chloride and S-Tertiary Amine 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
Synthesis of Pyrazoles
R
H
N
O
NH2
1.0 eq.
O
N
+
SO 2NHNH2
2 eq
N
MeOH
1.5 eq
R
RT 1h
+
O
MeOH
N
N
R
RT 2h
O
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
functionalities.
• The preliminary studies demonstrate the major advantages of
the new scavengers:
- higher capacity for available volume;
- broad solvent compatibility;
- compatible with different application formats.
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] D. L. Flynn, et al. Med. Chem. Res. 1998, 8, 219.
[4] A. T. Merritt. Comb. Chem. High Throughput Screening 1998, 1, 57
[5] R.J. Booth and J.C.Hodges. Acc. Chem. Res.1999. 32, 18
Stability of Silica-based Scavengers
safety zone
- Non-aqueous solution: 1< pH<14 , >24 h
- 10% H2O:
1<pH<10, >5h
- > 50% H2O:
1<pH<10, >2h