Modern Methods for the Separation of Enantiomers - from Kilos to - - PowerPoint PPT Presentation

Organic Process Research and Development February 2014

Modern Methods for the Separation of Enantiomers

• from Kilos to Tons -

• Over 80% of drug candidates contain at least
• ne chiral center
• Increasingly complex molecules, requiring

more advanced production methodologies

• Three General Strategies
• Chiral Pool
• Asymmetric Synthesis
• Resolution

Chirality in Drug Pipeline

• Is there an optimal approach to problem?
• No – each stage is driven by different

imperatives, therefore choices are also different

Challenge

• Short-term Focus

–Speed is key –Cost less of an issue

• Pragmatic approach

–Produce racemate then separate –Less effort on asymmetric synthesis, chiral pool (only if quick and easy)

Pre-Clinical

• Long-term focused

–Scalability, cost, efficiency, robustness

• “Tool Box” Approach

– Cannot assume that any approach is invalid – Test all, then run economic feasibility

Clinical

• Used at all stages

– Classical Resolution – Chiral Chromatography

Chiral Separation

• Used at all stages

– Classical Resolution – Chiral Chromatography

• Enabling Chiral Separations

– Developing efficient methods – Small-scale runs (> 100kg) – Technology Transfer for commercial

Chiral Separation

CHIRAL TECHNOLOGIES INC.

West Chester, PA. 23,000 sq ft Labs & Offices

• Chromatography is

considered to be:

– Last Resort – Temporary Solution – Inelegant – Difficult to Use

Perceptions of Chromatography

• Chromatography is;

– Cost effective – Reliable – Scalable

Reality of Modern Chromatography

Scalable Technology

Photo courtesy of AMPAC

Methods are developed on analytical columns

Scalable Technology

Photo courtesy of AMPAC

Ampac Fine Chemicals

• Screen compound

– Chiral Stationary Phase (CSP) – Mobile Phase

• Determine Optimum Combination
• Perform Loading Study
• Run Stability Tests
• Productivity = kg enantiomer/kg CSP/day

Chiral Chromatography Method Development

• Solubility characteristics
• Stability (chemical and stereo)
• Presence of other impurities
• API or intermediate
• Ability to racemize non-target enantiomer

Key Points to Consider

RO O OR OR O n RO O OR OR O n

Amylose-based Cellulose-based

• R

Nature CSP

• R

Nature CSP Immobilized CHIRALPAK IA Immobilized CHIRALPAK IB Immobilized CHIRALPAK IC

N H O CH3 CH3 N H O CH3 CH3 N H O Cl Cl

CHIRALPAK ID Immobilized

N H O Cl

Immobilized CHIRALPAK IE

N H O Cl Cl

Chiral Stationary Phase

Immobilized CHIRALPAK IF

N H O Cl CH3

Screening Study a-Methyl-a-Phenylsuccinimide

EtOAc THF/Hexane MTBE

min 5 10 15 20 25 30 35 mAU 20 40 60 80 100 120

N H O O

Multiple separation opportunities Also separates with conventional

• solvents. Note, zero THF

selectivity CHCl3 ACN:IPA 85:15

CHIRALPAK IA, 250 x 4.6 mm Flow rate 1 ml/min UV detection 254 nm

3.9 8.3 1 2 3 4 5 6 7 8 9 10 Retention Time (min) 0.0 0.1 0.2 0.3 0.4 0.5 Absorbance (AU)

Analytical injection

Dichloromethane/THF 70:30

F = 1 mL/min, 25°C (Column 25 x 0.46 cm, 5 µm CSP)

Solubility in mobile phase: 45 g/L

Chiral Separation of EMD-53986

N H N N H O S EMD-53986 Precursor for Ca-sensitizing drug

3.9 8.3 1 2 3 4 5 6 7 8 9 10 Retention Time (min) 0.0 0.1 0.2 0.3 0.4 0.5 Absorbance (AU)

loading

16mg 20mg 4mg 8mg 12mg

Dichloromethane/THF 70:30

F = 1 mL/min, 25°C (Column 25 x 0.46 cm, 5 µm CSP)

Solubility in mobile phase: 45 g/L

Loading Study for EMD-53986

3.9 8.3 1 2 3 4 5 6 7 8 9 10 Retention Time (min) 0.0 0.1 0.2 0.3 0.4 0.5 Absorbance (AU)

loading

16mg 20mg 4mg 8mg 12mg

Dichloromethane/THF 70:30

F = 1 mL/min, 25°C (Column 25 x 0.46 cm, 5 µm CSP)

Solubility in mobile phase: 45 g/L

Loading Study for EMD-53986

3.9 8.3 1 2 3 4 5 6 7 8 9 10 Retention Time (min) 0.0 0.1 0.2 0.3 0.4 0.5 Absorbance (AU)

loading

16mg 20mg 4mg 8mg 12mg

Dichloromethane/THF 70:30

F = 1 mL/min, 25°C (Column 25 x 0.46 cm, 5 µm CSP)

Solubility in mobile phase: 45 g/L

Loading Study for EMD-53986

3.9 8.3 1 2 3 4 5 6 7 8 9 10 Retention Time (min) 0.0 0.1 0.2 0.3 0.4 0.5 Absorbance (AU)

loading

16mg 20mg 4mg 8mg 12mg

Dichloromethane/THF 70:30

F = 1 mL/min, 25°C (Column 25 x 0.46 cm, 5 µm CSP)

Solubility in mobile phase: 45 g/L

Loading Study for EMD-53986

3.9 8.3 1 2 3 4 5 6 7 8 9 10 Retention Time (min) 0.0 0.1 0.2 0.3 0.4 0.5 Absorbance (AU)

loading

16mg 20mg 4mg 8mg 12mg

Dichloromethane/THF 70:30

F = 1 mL/min, 25°C (Column 25 x 0.46 cm, 5 µm CSP)

Estimated productivity: 2.8kg enantiomer/kg CSP/day Solubility in mobile phase: 45 g/L

Loading Study for EMD-53986

Preparative chromatography

HPLC (batch) SMB (continuous)

Glutethimide

Productivity: > 11 kg enantiomer/kg CSP/day

1 2 3 4 5 6 7 8

min

9 10 11 54 mg 42 mg 36 mg 30 mg 15 mg

Ethyl acetate 100%

F = 1 mL/min, 25°C (Column 25 x 0.46 cm, 20 µm CSP)

Solubility in mobile phase: 300 g/L Productivity demonstrated under SMB conditions

• Two Clinical Development Projects

1) Continuous Enantio-Enrichment 2) Stage-Appropriate Technology

Case Studies

• Biogen Idec Alzheimer’s Drug
• BIIB042
• Two chiral centers
• Continuous process developed

1) Continuous Enantio-Enrichment

BIIB042 Structure

* *

OH BIM-651 N F OH N F OTf N F CF3 BIO-20377 N F CF3 Chiral separation + NH CHO F + Mannich Triflation Suzuki Hydrolysis N F CF3 BIIB042 90% 60-80% 100% 15-18% 70-80% MeO O MeO O MeO O MeO O HO O OH O BIM 702

Initial Drug Discovery Approach

The Mannich reaction established the framework for BIIB042 in the first step producing BIM-702, and chiral chromatography was employed to separate the four stereoisomers.

toluene, 110 oC

OH N CO2Me F

BIM-702

OH CO2Me N H OHC F

+

*

RX Heptane 70-75% diastereomeric salts and enzymatic approaches were not successful SMB, 100%

OH N CO2Me F

BIM-752

Formation of First Chiral Center

• Screened against matrix of chiral stationary

phases/solvents

• Best method; AD CSP with Hexane/IPA
• Determined optimum process parameters
• Yield, %ee

Chiral SMB Approach

Continuous SMB Process

Racemic BIM702 Chiral SMB 90 kg

Continuous SMB Process

Racemic BIM702 Chiral SMB BIM752

>99.5%ee

90 kg

Continuous SMB Process

Racemic BIM702 Chiral SMB BIM752 Non-Target Enantiomer

>99.5%ee

90 kg

Continuous SMB Process

Racemic BIM702 Chiral SMB BIM752 Non-Target Enantiomer Racemization

>99.5%ee

90 kg

Continuous SMB Process

Racemic BIM702 Chiral SMB BIM752 Non-Target Enantiomer Racemization

>99.5%ee

90 kg

Lab Scale SMB

Second Chiral Center

>95% ee via catalytic hydrogenation (Ru)

N C O

2

H C F

3

F R u ( B I N A P ) , H

2

4 0 a t m e n a n t i

• s

e l e c t i v e

*

*

N C O

2

M e F

B I M

• 7

5 7

C F

3

N C O

2

H F

B I M

• 7

9 5 *

C F

3

B I I B 4 2

S

• d

i u m t r i m e t h y l s i l

• n

a t e

*

• Development of Armodafinil
• Cephalon (Teva)

2) Stage-Appropriate Technology

S O O NH2

Stage-Appropriate Technology

• Modafinil (Provigil)

– Approved for treatment of apnea, narcolepsy, shift work disorder – Racemic API

• Armodafinil (Nuvigil)

– (R)-Enantiomer – Second generation therapy

S O O NH2

Pre-Clinical Phase

• aq. NaOH
• aq. HCl, acetone

Na2CO3, Me2SO4

• aq. acetone

NH3, MeOH

DMSAM Modafinil Modafinic Acid

• Modafinic Acid was the best candidate for classical resolution
• Easily converted to R-Modafinil

• 85 kgs prepared via crystallization
• ~98% ee
• Conversion to R-Modafinil
• Non-ideal system due to
• Product degradation
• Cost inputs
• High labor component

Pre-Clinical Phase

S O O NH2

Clinical Phase

• Chiral HPLC/SMB study on Modafinil

– Screened CSPs – HPLC and SMB methods developed

• 60kg of Phase I material produced

– Single column HPLC – >99.0%ee

S O O NH2

HPLC

• 550kg Phase II/III material produced
• Chiral SMB
• Optical purity >99.2%ee
• Chemical purity >99.7%
• Over 10 MT of racemate processed via SMB
• Novasep operation
• Process ran on 300mm and 450mm systems
• Stabile, robust process

Clinical Phase

• Asymmetric Oxidation Results
• 75% isolated yield
• >99.5% optical purity
• Significantly longer development than chromatography
• Favorable economics
• Launch of Armodafinil was accelerated due to stage-

appropriate technologies

Commercial Launch

• Three different methods employed
• Pre-Clinical – Classical Resolution
• Clinical Trials – Chiral SMB
• Commercial Launch – Asymmetric Synthesis
• Result – Speed to Market

Development of Armodafinil

• Chiral Chromatography can offer advantages

– Effective from mgs to MTs – Predictable scale factors – Ability to “dial in” desired %ee

Conclusions

• Biogen Idec
• Teva (Cephalon)
• Novasep

Acknowledgements

Thank You Partners

Chiral Technologies

49

move easily … move quickly …

move ahead

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