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