Separation of 1,1'-bi-2-naphthol enantiomers by continuous ...
International Conference and Expo on Separation Techniques August 2015 Modern Methods for the...
-
Upload
jason-steven-russell -
Category
Documents
-
view
218 -
download
2
Transcript of International Conference and Expo on Separation Techniques August 2015 Modern Methods for the...
![Page 1: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/1.jpg)
International Conference and Expo on Separation Techniques August 2015
Modern Methods for the Separation of Enantiomers
- from Kilos to Tons -
![Page 2: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/2.jpg)
CHIRAL TECHNOLOGIES INC.
West Chester, PA.
![Page 3: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/3.jpg)
- 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
![Page 4: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/4.jpg)
• Is there an optimal approach to problem?
• No – each stage is driven by different imperatives, therefore choices are also different
Challenge
![Page 5: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/5.jpg)
• 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
![Page 6: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/6.jpg)
• Long-term focused – Scalability, cost, efficiency, robustness
• “Tool Box” Approach– Cannot assume that any approach is invalid– Test all, then run economic feasibility
Clinical
![Page 7: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/7.jpg)
• Used at all stages– Classical Resolution– Chiral Chromatography
Chiral Separation
![Page 8: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/8.jpg)
• Used at all stages– Classical Resolution– Chiral Chromatography
Chiral Separation
![Page 9: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/9.jpg)
• Chromatography is considered to be:
– Last Resort– Temporary Solution– Inelegant– Difficult to Use
Perceptions of Chromatography
![Page 10: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/10.jpg)
• Chromatography is;
– Cost effective– Reliable– Scalable
Reality of Modern Chromatography
![Page 11: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/11.jpg)
Scalable Technology
Photo courtesy of AMPAC
Methods are developed on analytical columns
![Page 12: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/12.jpg)
Scalable Technology
Photo courtesy of AMPAC
Ampac Fine Chemicals
![Page 13: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/13.jpg)
• 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
![Page 14: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/14.jpg)
• Solubility characteristics• Stability (chemical and stereo)• Presence of other impurities• API or intermediate• Ability to racemize non-target enantiomer
Key Points to Consider
![Page 15: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/15.jpg)
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
![Page 16: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/16.jpg)
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
![Page 17: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/17.jpg)
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
![Page 18: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/18.jpg)
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
![Page 19: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/19.jpg)
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
![Page 20: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/20.jpg)
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
![Page 21: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/21.jpg)
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
![Page 22: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/22.jpg)
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
![Page 23: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/23.jpg)
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
![Page 24: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/24.jpg)
• Two Clinical Development Projects
1) Continuous Enantio-Enrichment
2) Stage-Appropriate Technology
Case Studies
![Page 25: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/25.jpg)
• Biogen Idec Alzheimer’s Drug
- BIIB042- Two chiral centers- Continuous process developed
1) Continuous Enantio-Enrichment
![Page 26: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/26.jpg)
BIIB042 Structure
*
*
![Page 27: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/27.jpg)
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.
![Page 28: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/28.jpg)
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
![Page 29: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/29.jpg)
• Screened against matrix of chiral stationary phases/solvents
- Best method; AD CSP with Hexane/IPA
• Determined optimum process parameters- Yield, %ee
Chiral SMB Approach
![Page 30: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/30.jpg)
Continuous SMB Process
Racemic BIM702
Chiral SMB
90 kg
![Page 31: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/31.jpg)
Continuous SMB Process
Racemic BIM702
Chiral SMB
BIM752
>99.5%ee
90 kg
![Page 32: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/32.jpg)
Continuous SMB Process
Racemic BIM702
Chiral SMB
BIM752Non-Target Enantiomer
>99.5%ee
90 kg
![Page 33: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/33.jpg)
Continuous SMB Process
Racemic BIM702
Chiral SMB
BIM752Non-Target Enantiomer
Racemization
>99.5%ee
90 kg
![Page 34: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/34.jpg)
Continuous SMB Process
Racemic BIM702
Chiral SMB
BIM752Non-Target Enantiomer
Racemization
>99.5%ee
90 kg
![Page 35: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/35.jpg)
Lab Scale SMB
![Page 36: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/36.jpg)
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
*
![Page 37: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/37.jpg)
• Development of Armodafinil
• Cephalon (Teva)
2) Stage-Appropriate Technology
![Page 38: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/38.jpg)
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
![Page 39: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/39.jpg)
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
![Page 40: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/40.jpg)
• 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
![Page 41: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/41.jpg)
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
![Page 42: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/42.jpg)
• 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
![Page 43: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/43.jpg)
• 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
![Page 44: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/44.jpg)
• Three different methods employed
• Pre-Clinical – Classical Resolution• Clinical Trials – Chiral HPLC/SMB• Commercial Launch – Asymmetric Synthesis
• Result – Speed to Market
Development of Armodafinil
![Page 45: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/45.jpg)
• Chiral Chromatography can offer advantages– Effective from mgs to MTs– Predictable scale factors– Ability to “dial in” desired %ee
Conclusions
![Page 46: International Conference and Expo on Separation Techniques August 2015 Modern Methods for the Separation of Enantiomers - from Kilos to Tons -](https://reader036.fdocuments.in/reader036/viewer/2022062423/56649f485503460f94c6a2f7/html5/thumbnails/46.jpg)
• Ampac
• Biogen Idec
• Teva (Cephalon)
• Novasep
Acknowledgement to Our Partners