Transcript Application Of Macroporous Scavengers and Solid Reagents

Application Of Macroporous 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 - 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 have been
developed based on ultra-pure, spherical silica and low
swelling macro-porous 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, S-epoxide,
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-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
Performance Comparison
Swelling
(by THF)
Trisamine
Piperidino
Hydrazide
Sulfonyl.
Chloride
Phosphine
Mercaptan
MP
PS
MP
PS
MP
PS
MP
PS
Si
PS
Si
25%
500%
25%
400%
40%
400%
30%
500%
0
300%
0
Capacity/v
(mmol/mL)
(THF)
1.4
0.3-0.5
0.8
0.4
0.5
0.1-0.2
0.6
0.1-0.2
0.8
0.2-0.4
1.0
(THF/EtOH)
PS
400%
0.2-0.3
PS: gel-type polystyrene based products. na: not applicable.
Capacity /w
(mmol/g)
(THF)
3
3-4
2
3
1.6
1-2
1.8
1-2
0.4
1-1.8
0.5
Capacity/w
(mmol/g)
(MeOH)
1.8
<0.3
1.3
<0.3
1.1
na
na
0.5
Capa.(MeOH)
-
-
_________
Capa. (THF)
60%
<10%
60%
<10%
70%
20%
na
na
>95%
(THF/EtOH)
1-1.5
Performance comparison (cont’d)
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
Performance comparison (cont’d)
Scavenging aldehyde/ketones by polymerSO2NHNH2 (3 eq., 2h, RT).
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 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
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)
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
NH2
100 Mol
N
H
DIEA
100 Mol
50 Mol
200 uL of Water
16 h rt
50 Mol
O
N
H
50 Mol
O
NO2
O 2N
50 Mol
50 Mol
O
O 2N
50 Mol
OH
DIEA HCl
NO2
Cl
DIEA HCl
50 Mol
• 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 with a pipet bulb through a plug of 450 L
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)
Vacuum
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
NO2
O 2N
50 uMol each
Example 2
NH2HCl
O
Cl C
Cl
NMe 2
NH2
O
Cl C
NMe 2HCl
(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%
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-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
NCO
PhNCO
(0.2 mmol)
PhNCO
NHCNHCH 2Ph
(0.3 mmol)
O
+
+
O
PhCH2NH2
(0.3 mmol)
Ph NHCNHCH 2Ph
Ph NHCNHCH 2Ph
Purity > 99 %
Yield = 87 %
NCO
: MP-isocyan ate , 1m m ol /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 weres 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
+
SO 2NHNH2
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.
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
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.
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