Application of Porous Scavengers for High Throughput Purification

Cory Szafranski, Qunjie Wang, Joseph J. Kirkland, Timothy LangloisAgilent Technologies Inc.

Lorin A. ThompsonDuPont 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

ABSTRACTTo overcome practical difficulties related to gel-type polystyrene-based 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 poly- styrene, 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, 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-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

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 naMP 30% 0.5 1.3 0.6 45%IsocyanatePS 500% 0.1-0.2 1-1.5 0.2 14%MP 30% 0.6 1.5 0.8 54%AldehydePS 600% 0.1-0.2 1-1.6 0.2 13%

PS: gel-type polystyrene based products. na: not applicable.

Performance Comparison (cont’d)

05

101520253035404550

Ben

zald

ehyd

e

Cyc

lohe

xano

ne

Pen

tane

dion

eMP-SO2NHNH2Gel-SO2NHNH2

Scavenging aldehyde/ketones by polymer-SO2NHNH2 (3 eq., 2h, RT, in MeOH).

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-Isocyante

(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

Sequestering of Carboxylic Acids

Co

ntr

ol

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

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 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.

Acylation of Benzylamine

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-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.

Synthesis of Pyrazoles

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

2 eq

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

[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

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