modern methods for the separation of enantiomers - from...
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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 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
• Enabling Chiral Separations
– Developing efficient methods
– Small-scale runs (> 100kg)
– Technology Transfer for commercial
Chiral Separation
• Chromatography is considered to be:
– Last Resort
– Temporary Solution
– Inelegant
– Difficult to Use
Perceptions of Chromatography
• 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
Chiral Stationary Phase
RO
O
OR
ORO 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
NH
O CH3
CH3
NH
O CH3
CH3
NH
O Cl
Cl
CHIRALPAK ID Immobilized NH
O Cl
Immobilized CHIRALPAK IE NH
O Cl
Cl
Screening Study a-Methyl-a-Phenylsuccinimide
EtOAc
THF/Hexane
MTBE
min 0 5 10 15 20 25 30 35
mAU
0
20
40
60
80
100
120
NH
OO
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
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 70:30 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
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 70:30 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
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 70:30 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
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 70:30 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
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 70:30 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
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 70:30 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
Glutethimide
Productivity: > 11 kg enantiomer/kg CSP/day
0 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
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
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
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 o 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 0 4 2
S o d i u m t r i m e t h y l s i l o n a t e
*
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
NH2HPLC
• 550kg Phase II/III material produced - Chiral SMB
- Optical purity >99.2%
- 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