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 poly- styrene, 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 L

– Collection blocks hold 2.0 mL, but can only safely concentrate about 1.2 mL

– So: Scavenge with at most 450 L 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 CommercialSilica Gel

HP Ultrapure Silica Gel

CombiZorb (macropolymer-based)

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

CombiZorb (silica-based)

S-triamine S-monoamine S-sulfonic acid S-tertiaryamine

Capacity/vin THF

(mmol/mL)

1.6-2.1 0.8- 1.2 0.5-0.8 0.8- 1.2

Capacity(mmol/g)

1.2-1.6 0.6-0.9 0.4-0.6 0.6-0.9

Capacityin methanol(mmol/g)

1.2-1.6 0.6-1.0 0.4-0.6 0.5-0.7

S: HP ultra pure silica

Scavenging Test of S-monoamine

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 anhydride 4 CH2Cl2 1 h, 20 oC > 99%Cyclohexyl isocyanate 2 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 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)

VaccuumCollection 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 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

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

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

[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 MolecularDiversity, 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

For general application of scavengers