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Transcript of International Conference and Expo on Separation Techniques August 2015 Modern Methods for the...
International Conference and Expo on Separation Techniques August 2015
Modern Methods for the Separation of Enantiomers
- from Kilos to Tons -
CHIRAL TECHNOLOGIES INC.
West Chester, PA.
- Over 80% of drug candidates contain at least one 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
Chiral Separation
• 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
OOR
ORO n RO
O
OR
OR
O
n
Amylose-based Cellulose-based
-RNatureCSP -RNatureCSP
ImmobilizedCHIRALPAK IA
ImmobilizedCHIRALPAK IB
ImmobilizedCHIRALPAK IC
NH
O CH3
CH3
NH
O CH3
CH3
NH
O Cl
Cl
CHIRALPAK ID Immobilized NH
O Cl
ImmobilizedCHIRALPAK IE NH
O Cl
Cl
Chiral Stationary Phase
ImmobilizedCHIRALPAK IF NH
O Cl
CH3
Screening Study a-Methyl-a-Phenylsuccinimide
EtOAc
THF/Hexane
MTBE
min0 5 10 15 20 25 30 35
mAU
0
20
40
60
80
100
120
NH
OO
Multiple separation opportunitiesAlso separates with conventional solvents. Note, zero THF selectivity
CHCl3
ACN:IPA 85:15
CHIRALPAK IA, 250 x 4.6 mmFlow rate 1 ml/minUV detection 254 nm
3.9
8.3
0 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 70:30F = 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
NH
N
NH
O
S
EMD-53986Precursor for Ca-sensitizing drug
3.9
8.3
0 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 70:30F = 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
0 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 70:30F = 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
0 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 70:30F = 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
0 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 70:30F = 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
0 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 70:30F = 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
Glutethimide
Productivity:> 11 kg enantiomer/kg CSP/day
0 1 2 3 4 5 6 7 8
min
9 10 11
54 mg42 mg36 mg30 mg15 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
Chiralseparation
+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 oCOH
N
CO2Me
F
BIM-702
OH
CO2Me
NH
OHC
F
+*
RX Heptane 70-75%
diastereomeric salts andenzymatic approacheswere 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
BIM752Non-Target Enantiomer
>99.5%ee
90 kg
Continuous SMB Process
Racemic BIM702
Chiral SMB
BIM752Non-Target Enantiomer
Racemization
>99.5%ee
90 kg
Continuous SMB Process
Racemic BIM702
Chiral SMB
BIM752Non-Target Enantiomer
Racemization
>99.5%ee
90 kg
Lab Scale SMB
Second Chiral Center
>95% ee via catalytic hydrogenation (Ru)
N
CO2H
CF3
F
Ru(BINAP), H2
40 atmenantioselective
*
*N
CO2Me
F
BIM-757
CF3
N
CO2H
F
BIM-795
*
CF3
BIIB042
Sodiumtrimethylsilonate
*
• 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. NaOHaq. HCl, acetone
Na2CO3, Me2SO4 aq. acetoneNH3, MeOH
DMSAM ModafinilModafinic 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
NH2HPLC
• 550kg Phase II/III material produced- Chiral SMB- Optical purity >99.2%ee- Chemical purity >99.7%
• Over 10 MT of processed pre-launch via SMB- Process ran on 300mm and 450mm systems- Stable, 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 HPLC/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
• Ampac
• Biogen Idec
• Teva (Cephalon)
• Novasep
Acknowledgement to Our Partners