rapid compound production...boronic acids mp-deam ps-tosylhydrazide aldehydes, ketones mp-carbonate...

Rapid Compound Production:Microwave-Assisted Synthesis, Workup and Purification

Farah Mavandadi, Ph.D.Product Manager

Topics

• Microwave Assisted Organic Synthesis – Advantages

• Role of Solid-Supported Reagents & Scavengers in Solution Phase Chemistry

• Advantages of Solid-Supported Reagents & Scavengers

• Supported Reagents/Scavengers in Microwave Assisted Multi-step Synthesis:

Sulfahydantoin & Unsymmetrical Sulfamides

Substituted Biaryls

Microwave Assisted Organic Synthesis (MAOS)

Uses Less Energy

Uses Less Solvent

Enables Difficult Compound Synthesis

Increases Reaction Rate

Rapid Reaction Optimization

Rapid Analog Synthesis

Microwave Assisted Sulfonylation of7-Azaindolyl-1-yl acetonitriles

N N

N

ArSO OCl N N

N

S ArOO

+

Conventional: 125 oC / 18-20 h /11-18% yield

tmw = tconv x 0.5[(Tmw-Tconv)/10 oC]

tmw = 1440 min x 0.5[(200 oC - 120 oC)/10 oC]

tmw = 5.6 min

Microwave: 200oC / 5 min / 30-40% yield

S. Haydar et al. 33rd Microwave Symposium, Philadelphia, PA, Oct 2006Bioorg. Med. Chem. Lett. In Press


N N

N

ArSO OCl

N N

N

S ArOO

+


Traditional: 125 oC/ 18-20h / 11-18%

Microwave: 200 oC / 5 min / 30-40%


N N

N

ArSO OCl N N

N

S ArOO

+200oC / 5 min


PhNO2

DMA(CH3)2CHCN

Sc(OTf)3

Sn(OTf)2

Fe(mont)Y(OTf)3Cu(OTf)2

FeCl3Sm(OTf)3La(OTf)3

AlCl3Dy(OTf)3Yb(OTf)3

InBr3Zn(OTf)2Bi(OTf)3

In(OTf)3Ho(OTf)3AgOTf

FailedNot IsolatedSucceed

Reagents

Solvents



• Rapid Optimization of Reaction Conditions

• 45 sulfonylations in ~ 4 h (vs 18-20 h)

• Moderate 18-76% Yields vs 11-18% conventional

What slows down drug discovery?

1. Target and Synthesis Design2. Reaction

J. C. Hodges, Pfizer Inc. ACS Spring Meeting, San Diego, 2001

3. Work-up - usually extraction & evaporation4. Purification - usually chromatography

5. Spectral Analysis Registration

Bottlenecks (3) and (4) become greater with microwave chemistry

Purification Techniques

Flash Chromatography

HPLC

Solid phase extraction (SPE)

Solid-supported liquid extraction

Solid-bound reagents

Solid-bound scavengers

Solid Supported Organic Synthesis

A-B M M A M A-B

M

Filter

B (XS)

B Filter Filter

A (XS)

A

• Excess reagents help drive reactions to completion

• Minimal workup is needed, usually by filtration

• Extra steps of anchoring and cleaving the target molecule to the resin

• Difficulty in real time monitoring of the reaction progress

• Slow reaction kinetic

Solid-Bound Reagents & ScavengersMode of Action

Rgt1.5eq S1 + S2

R gt-sp e nt

P + 0 .5 e q S 1

Scvngr

ScvngrRgt-spent S1

Product

Solution Phase Synthesis• Conventional• Microwave-assisted

• Filtration• Flash Chromatography

Biotage Resin Reagents

Catch & Releasep-toluenesulfonic acidMP-TsOH

Catch & Releasep-toluenesulfonyl chloridePS-TsCl

ApplicationSolution AnalogBound Reagent

Catalyst, Catch & ReleaseDMAPPS-DMAP

Strong BaseTBDPS-TBD

Base, Catch & ReleaseAmmonium carbonateMP-Carbonate

Non-benzylic baseN-methyl morpholinePS-NMM

Amine baseHindered tertiary aminePS-DIEA

Reducing agentSodium triacetoxy borohydrideMP-Triacetoxyborohydride

Reducing agentSodium cyanoborohydrideMP-Cyanoborohydride

Reducing AgentSodium borohydrideMP-Borohydride

Oxidizing AgentTEMPOMP-TsO-TEMPO

Coupling agentHOBtPS-HOBt (HL)

Coupling AgentDCCPS-CarbodiimidePalladium CatalystTriphenylphosphine Pd(0)PS-PPh3-Pd

Mitsunobu/Wittig/HalogenationTriphenylphosphinePS-Triphenylphosphine

Biotage Polymeric Scavengers

Pd (0)MP-TMTMetal

Amines, AnilinesMP-Tosic acid

Anilines, AlcoholsPS-Tosyl chloride

1o aminesPS-Benzaldehyde

1o, 2o amines, hydrazinePS-IsocyanateMP-Isocyanate

Nucleophile

Alkyl halidesPS-Triphenylphosphine

Alkylating agentsPS-Thiophenol

Ti(IV), Sn(IV), Boronic acids

MP-DEAM

Aldehydes, KetonesPS-Tosylhydrazide

Carboxylic acids, PhenolsMP-Carbonate

Acyl halides, Sulfonylhalides, Isocyanates

PS-TrisamineMP-Trisamine

Electrophile

NCO

H

O

S ClO O

S OHO O

NH

N

NH2

NH2

NEt3+ (CO3

2- )0.5

S NHNH2

O O

NH

OSH

P

S N

NN

SH

SH

NOHOH

Solution Phase Resins: Introductory Kit

Contains resin samples for:

AmidationPS-Carbodiimide (3g; 1.1-1.3 mmol/g)PS-HOBt(HL) (3g; (0.9-1.0 mmol/g)Rgt-ACTU (3g)MP-TsOH(65) (3g; 3.5-4.5 mmol/g)MP-Carbonate (3g, 2.5-2.8 mmol/g)

Reductive AminationMP-Triacetoxyborohydride (3g; 1.8-2.0 mmol/g)MP-Cyanoborohydride (3g; 2.0-2.3 mmol/g)MP-TsOH(65) (3g; 3.5-4.5 mmol/g)PS-Isocyanate (3g, 1.1-1.4 mmol/g)MP-Isocyanate (3g, 0.9-1.3 mmol/g)PS-Benzaldehyde (3g, 1.1-1.3 mmol/g)

CouplingPS-Triphenylphosphine (3g; 1.8-2.2 mmol/g); PS-PPh3-Pd (1g, 0.08-0.1 mmol/g)MP-TsOH(65) (3g; 3.5-4.5 mmol/g)MP-Carbonate (3g, 2.5-2.8 mmol/g) PS-DEAM (3g; 1.5-1.8 mmol/g)

OxidationMP-TsO-TEMPO (3g; 0.8-1.0 mmol/g)

NEW! Launched Sept 18, 2006NEW! Launched Sept 18, 2006

ISOLUTE® Si-Triamine

BIOTAGE INTRODUCESBIOTAGE INTRODUCESSilicaSilica--supported Reagents/Scavengerssupported Reagents/Scavengers

ISOLUTE® Si-Carbonate

ISOLUTE® Si-Ts-Hydrazine

ISOLUTE® Si-Thiol

ISOLUTE® Si-Propylsulfonic acid (SCX-2)

ISOLUTE® Si-EthylPhenyl sulfonic acid (SCX-3)

N+ (CO3)-20.5Si

SHSi

NH

HN

NH2Si

S

O

O

NHNH2

Si

SSiO

O

O-

S

O

O

O-Si

NEW!NEW!

In the Laboratory

•Use standard lab equipment

•Shaking, overhead or magnetic

Advantages of Solid-supported Reagents/Scavengers

Drive reaction to completion using excess reagents

Remove spent and excess reagent by filtration

Perform one-pot multi-step reactions

Mix “incompatible” functionalities

R1 R2

ON

NH

R2

R11) NH2NH2

70 °C, 3h2) PS-CHO

N-Substituted Pyrazoline Libraries

Chalcones used as templates for pyrazoline library

Bauer, U. et al. Tetrahedron Lett. 2000, 41, 2713-2717

Synthesis1, R3COCl, PS-DIEA; 2, R3NCO; 3, R3SO2Cl, PS-DIEA; 4, R3OCOCl, PS-DIEA

PurificationPS-Trisamine, PS-Isocyanate cocktail

NN

R2

R1

NN

R2

R1

NNS

R2

R1

NN

R2

R1

R3

HN

O

O

O R3

O R3

OO

R3

1

2

3

4





Real time reaction progress monitoring (TLC/LC-MS)


Eliminate problems with the free reagent

Amide Coupling Reagents

Use:One-step amide synthesis

Advantage over DCCUrea Byproduct Resin bound and easily removed

Use:Two-step amide synthesisAmine = limiting reagent in acylation

Advantage over HOBt:Active Ester intermediate resin bound; Isolatable & Storable

NN

O2S

NH

NOH

PS-HOBt

O N=C=N

PS-Carbodiimide

PS-Triphenylphosphine-Pd(0)

Use:Palladium catalyzed C-C couplingPd catalyzed reductive cleavage of protecting groups eg Alloc

Advantage over Tetrakis palladiumStable to air, light and moistureNo “Hot Spot” – minimizes vial breakage in MAOSShelf-stable at room temperature Simplified product isolationLow Pd levels in product (< 100ppm)

P PdLn

PS-Triphenylphosphine

P

R2

R3 R1

R1 O R2CN

R

ClO

Cl

R1

R2

P R

Wittig Chemistry Alkene Synthesis

Mitsunobu Chemistry Ether Synthesis

Palladium Catalyzed ReactionsC-C coupling

Pd(OAc)2

DEAD, DIAD

ChlorinationFormation of acid chlorides & alkyl halides

Cl3CCN or CCl4

Scavengingof Alkyl Halides+ X-

Advantage over Triphenylphosphine:

Phosphines and oxide byproducts are resin bound

and easily removed

Use:Reductive amination under ‘Neutral’ conditions

Advantage over Na(OAc)3BHDoes not require acid catalyst; can be used with acid-sensitive groups: ketals, acetalsWorkup = Filtration; eliminates aqueous extraction

NEt3 (OAc)3BH

2 mmol/ g

Bound Reagents Reductive Amination

MP-Triacetoxyborohydride

NEt3 (CN)BH3

2-3 mmol/ g

Use:Reductive amination under acidic conditions

Advantages over NaCNBH3:Eliminates Aqueous extractions post-reactionMasked toxicityVery little pressure build up with MAOS

MP-Cyanoborohydride

SO O

OH

Bound Acid: MP-TsOHISOLUTE® Si-TsOH

Scavenger for amines & basic compoundsCatch and Release purifications

UseAcid catalystCleavage of acid sensitive groups eg BOC-

S

O

O

O-Si

MP-TsOH ISOLUTE® Si-TsOH

Advantages over p-Toluenesulfonic acid:

Eliminates Aqueous extractions post-reactionCan perform Catch-and-Release purification of amines via filtrationSilica bound form compatible with Flash Chromatography



Slow reaction kinetics



Real time reaction progress monitoring (TLC/LC-MS)


Eliminate problems with the free reagent

Supported Reagents in Microwave-Assisted

Multi-Step Organic Synthesis

• Sulfahydantoin compounds have broad biological activity

O NH

SO2N

R1 R

I

Pka comparable to carboxylic

acid ~ 4

Sulfahydantoin

• General scheme for sulfahydantion1. Reductive alkylation (1 day)2. Sulfamide synthesis (2 days)3. Cyclitive cleavage (1 day)

Total time: ~4 Days

• These conditions are not convenient for rapid High Throughput Synthesis

Two-Step One-PotMicrowave-Assisted Reductive Amination

Step I

O NH2

O

OMe

HO

DIEA, MeOH+ µW

90 ºC / 2 minImine

O

N

O

OMe

Total time for synthesis: 5 min Total time for synthesis + purification: 10-15 mins (vs 1 day)

Ghassemi, S. 2005 ACS, San Diego

Amine

O

NH

O

OMe

µW80 ºC / 3 min

(CN)BH3

MeOH is important for stereoselectivityEtOH or CH3CN result in racemization

Microwave-Assisted Reductive AminationRacemization study

• Extent of racemization was studied by comparing 1H-NMR (500 MHz) of the LL and DL diastereomers

+

• No racemization was detected

NHBoc

O

NH

O

Et

LL

NHBoc

O

NH

O

Et

DL


Microwave-Assisted Reductive AminationComparison of Cyanoborohydide reagents

O

ONH

NH

OO

O

NHO

O

NH

O

CF3

O

NHO

O

O

NH

O

ClCl

NHO

O

OMe

NH

CF3

O

OBrNHO

ONH

Cl

O

O

Cl

Method A 84% 68%83%79%

75%88%88%89%85%Method A

Method A: 2 eq. 1 M NaCNBH3

Method B 79%74% 85% 63%

73%78%80%84%79%Method B

Method B: 2 eq. Silica-CNBH3

Method C: 2 eq. Polymer-CNBH3

Method C 80%72% 73% 59%

65%81%77%80%80%Method C


Microwave-Assisted Sulfamide Synthesis

Step II

H OH

O+ S

O

OCl NH2S

O

OCl NCO µW

90 ºC / 1 min

Total time for synthesis: 5 min Total Synthesis+Purification: 25-30 mins (vs 2 days)

O

N

O

OMeSO2NH2

Et3N, DCM

µW 80 ºC / 4 min

O

NH

O

OMe


Microwave-Assisted Cyclitive CleavageStep III

Total time for synthesis: 5 min Total Synthesis + Purification: 25-30 mins (vs 1 day)

O

N SO2

NH

MeO

O

N

O

OMeSO2NH2

NaOMe / MeOH

µW

100 ºC / 5 min


SulfahydantoinIn Summary

Conventional Synthesis

4 days

Microwave-assisted organic synthesis+ Solid Supported reagents

+ Flash Chromatography

1 – 1.5 hours

Unsymmetrical Sulfamides

Amine or

Aniline

µW80 °C,5 min

SOO

NO

O

R1

NR

H

R3-OHPh3PDEAD

SOO

NO

O

R1

NR

R3

THF µW80 °C

1-4 min

SO

OO

-SOO

NR1

N+R

R3

H HSi

µW

100 °C / 5 min

MeCN:DCM

SiSO

OO

H

NH3/MeOH

SOO

NR1

NR

R3

H

* Ghassemi, S. et al. Molecular Diversity, 2005, 9, 295-299

SCl

OO

NCO DCM0° C

SCl

O O

NH O

OOH Helium

Substituted Biaryls

COOHN

O

R2R1

R1NHR2

BrBr

BOH

OH R3N

O

R1

R2

R3

Ghassemi, S. ACS, Atlanta, GA, March 2006

Step I: Amide Coupling Step II: Suzuki Coupling

Step I: AmidationPS-DIEA, Si-Carbonate, Si-TsOH

COOHBrN

O

R2R1

BrR1NHR2

+PS-DIEA, HATU

µW, 110-150 oC 6-12 min

NiPr

iPrPS


N+ (CO3)-20.5Si

57-99% yield>97 % Purity

N

O

R2R1

Br

SO O

O-

Si

Catch & Release

59150oC, 12 min6

57150oC, 12 min5

90110oC, 6 min4

97110oC, 6 min3

91110oC, 6 min2

99110oC, 6 min1

% YieldConditionR1NHR2

NH

NH

N NH

NH

O

EtO

NH

NH

R1NHR2

+

Step II: Suzuki Coupling PS-PPh3-Pd, Si-Carbonate


N

O

R2R1

Br

BOH

OH R3N

O

R1

R2

R3

PPh3-Pd CsCO3

µW 130 oC, 10 min

EtOH:DME (1:1)

N+ (CO3)-20.5Si

85-99% yield>97 % Purity

O

NO2N

O

NNO2N

O

NCH3O2N O

OEt

O

NO2N

O

NO2N

O

NO2N

O

N

MeO

O

NN

CH3

99 %

89 %

85 %

96 %

99 %

99 %

97%

95%

SUMMARY

• MAOS is a versatile tool for accelerating synthesis

• Solid bonded Reagents and Scavengers significantly reduces the work-up and purification bottleneck

• Combining MAOS with Solid bonded Reagents and Scavengerscan accelerate total compound production time

Thank You for Your Attention!

rapid compound production...boronic acids mp-deam ps-tosylhydrazide aldehydes, ketones mp-carbonate...

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