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 poly- styrene, 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 CommercialSilica Gel
HP Ultrapure Silica Gel
Performance Comparison
Swelling(by THF)
Capacity/v(mmol/mL)
(THF)
Capacity /w(mmol/g)
(THF)
Capacity/w(mmol/g)(MeOH)
Capa.(MeOH)_________
Capa. (THF)
MP 25% 1.4 3 1.8 60%TrisaminePS 500% 0.3-0.5 3-4 <0.3 <10%
MP 25% 0.8 2 1.3 60%PiperidinoPS 400% 0.4 3 <0.3 <10%
MP 40% 0.5 1.6 1.1 70%HydrazidePS 400% 0.1-0.2 1-2 - 20%
MP 30% 0.6 1.8 na naSulfonyl.Chloride PS 500% 0.1-0.2 1-2 na na
Si 0 0.8 0.4 - -PhosphinePS 300% 0.2-0.4 1-1.8 - -
Si 0 1.0(THF/EtOH)
0.5(THF/EtOH)
0.5 >95%Mercaptan
PS 400% 0.2-0.3 1-1.5 - -
PS: gel-type polystyrene based products. na: not applicable.
Performance comparison (cont’d)
MP-isocynate Gela MP-aldehyde Gela
Capacity/vin THF
(mmol/mL)
0.4-0.5 0.1-0.2 0.5-0.7 0.1-0.2
Swellingin THF
30% 600% 30% 600%
Capacity in THF(mmol/g)
1-1.3 1-1.5 1.4-1.6 1-1.6
Capacityin methanol(mmol/g)
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)
05
101520253035404550
Ben
zald
ehyd
e
Cyc
lohe
xano
ne
pent
aned
ione
MP-SO2NHNH2Gel-SO2NHNH2
Scavenging aldehyde/ketones by polymer-SO2NHNH2 (3 eq., 2h, RT).
MP-: Macroporous CombiZorb ScavengersGel-: Gel polystyrene based Scavengers
residue (%)
Scavenging Test of S-triamine
Electrophile Combizorb S-triamine(equiv.)1)
Solvent Conditions Scavenged(%) 2)
4-chlorobenzoylchloride
4 CH2Cl2 1 h, 20 oC > 99%
2-phenylbutyrylchloride
4 CH2Cl2 1 h, 20 oC >99%
Phenyl chloroformate 4 CH2Cl2 1 h, 20 oC >99%Chloroacetic
anhydride4 CH2Cl2 1 h, 20 oC > 99%
Phenyl isocyanate 2 CH2Cl2 1 h, 20 oC > 99%Benzaldehyde 3 THF/MeOH
(1:2)1 h, 60 oC > 99%
1) Relative to electrophiles without use of additional base2) Determined by GC
Scavenging Test of MP-NCO(2.5 equiv.)
Nucleophile Solvent Temp oC Time (h) Scavenged (%)1)
benzylamine CH2Cl2 20 0.5 >99benzylamine acetonitrile 20 0.5 >99benzylamine i-PrOH 20 0.5 92benzylamine MeOH 20 0.5 91morpholine THF 20 1 >99
1-methyl piperazine THF 20 1 >99tryptamine THF 20 1 94
phenyl hydrazine THF 20 1 >99aniline THF 50 1 75
1) Determined by GC
Scavenging Test of MP-CHO (3 equiv.) Nucleophile Solvent Additive Temp (oC) Time
(h)Scavenged
(%) 1)
phenylhydrazine THF none 50-60 2 95phenylhydrazine Toluene none 50-60 2 >99phenylhydrazine i-PrOH none 50-60 2 93phenylhydrazine MeOH none 50-60 2 > 99
p-toluenesulfonylhydrazide
THF MeOH 50-60 2 > 99
4-methoxyphenylhydrazine
hydrochloride
MeOH none 50-60 2 >99
Benzylamine THF Aceticacid
50-60 2 >99
Tryptamine THF MeOH 20 3 97
Determined by GC
Example 1
O2N
Cl
O
NH2100 Mol
DIEA
NH
O
100 Mol 50 MolNO2
DIEA HCl
50 MolO2N
Cl
O
50 Mol
200 uL of Water
16 h rt
NH
O
NO2
DIEA HCl
50 MolO2N
OH
O
50 Mol50 Mol
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 prepackedwith scavenger(Polyfiltronics)
VacuumCollection Block
Aqueous Cosolvent SequesteringC
on
tro
l
Co
ntr
ol
HP
sil
ica
AP
Sil
ica
P-T
ris
P-D
IEA
P-N
MM
0
20
40
60
80
100
120
Aqueous Cosolvent Sequestering
Ethyl Acetate
Methanol
DMF
% Acid Remaining
NH
O
NO2
DIEA HCl
O2N
OH
O
50 uMol each
Example 2
ClC
O
ClNMe2
NMe2
NH2NMe2HCl
(0.4 mmol)
Cl
PhCH2NH2
C(0.6 mmol)
O
+
Cl
+
NH2
(1.2 meq)
ClCO
NH
NH2HCl
(0.6meq)
ClC
O
PhCH2NH
ClC
O
PhCH2NH
Purity > 99 %
Yield = 95%
: S-tertiaryamine, 0.8meq/g; : 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.
Example 3
NCO
(0.3 mmol)
PhCH2NH2
PhNCO(0.2 mmol)
+
NHCNHCH2Ph
NCO
(0.3 mmol)PhNCO
+
O
NHCNHCH2Ph
O
Ph
NHCNHCH2Ph
O
Ph
: MP-isocyanate, 1mmol/g.
Purity > 99 %
Yield = 87 %
- 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
HN
NH2
O O NN
R
SO2NHNH2
RN
N+
+R1.0 eq. 1.5 eq
MeOH MeOH
R = phenyl, 4- methoxyphenyl, m-tolyl;
Yield > 80%Purity > 95%
RT RT1h 2h
Unlike the gel-type polystyrene based scavengers, the macroporous scavengers can be used in the alcohols with good efficiency.
*
O O
Synthesis of Pyrazoles
2 eq
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
[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
For general application of scavengers