November 21 st 2006
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Transcript of November 21 st 2006
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November 21st 2006by Isabelle Bonnaventure
Literature Meeting Charette’s Laboratories
Special Issue: Chem. Rev. 2006, vol. 7
An Overview of Process Chemistryor
“Honey, I blew up the baby!”
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Process Chemistry: Contents
I. General Considerations
III. Asymmetric Hydrogenation: behind the scenes
II. High Troughput
IV. Metal Removal
V. Survey
VI. Synthesis of CGS 19755
VII. Synthesis of SB 214857 A
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Process Chemistry: General Considerations
Zhang, T. Y. Chem. Rev. 2006, 106, 2583-95.
General Definition: "Make a defined product available to a given specification, on a given scale, in a defined time-frame"
For the pharmaceutical industry, this means scaling up material for - clinical development - toxicity study - processing knowledge (safety and efficacy of the drugs)
Major criteria:
Safety
Quality
Cost
Time
EnvironmentalImpact
DurabilityRobustness
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Process Chemistry: General Considerations
- Heat and mass transfer controls
- Avoid accumulation of unstable or energetic intermediates
- Explosion hazard of static and organic dust (filtration, drying)
- Containment of potent compounds: workers safety in the exposure and elimination of cross-contamination between different process streams and decision to isolate intermediates.
Safety
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Process Chemistry: Safety Issues
Barker, A. C.; Boardman, K. A.; Broady, S. D.; Moss, W. O.; Patel, B.; Senior, M. W.; Warren, K. E. H. Org. Process Res. Dev. 1999, 3, 253-55.
First route:OH
CH2CONH2
BrCH2CH2Br
Base
BrO
CH2CONH2
Br
+
genotoxicproperties
PhCH2NH21 9% overall yield
Second route:
2
NH
OH SOCl2, NMP, NMM
71%N
OS
O
NaH, NMP, 2
64%1
O
HN
HO
drug candidateZeneca Pharmaceuticals
ZD 2079
O
HN
1
HO2CH2CH2NOCH2C
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Process Chemistry: Safety Issues
First Route:
Second Route:
HO
HN
NH
O
O
O CH2OMe
MMP3 inhibitorPfizer
UK 370,106
OH
O
O
tBuO
Ashcroft, C. P.; Challenger, S.; Derrick, A. M.; Storey, R.; Thomson, M. N. Org. Process Res. Dev. 2003, 7, 362-68.
N
O
O
O
Ph
N
O
O
O
Ph
O
tBuO
NaHMDStBuO2CCH2Br
THF, 78 °C65%
LiOH, H2O2,THF, H2O, 0 °C
85%
OH
O
O
tBuO
OR
O
O
tBuO
Enantioselectivehydrogenation
65%
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- 1994: explosion of a 70 gallon drum of H2O2
Pfizer, Groton
- 2002: explosion of BH3·THF
Process Chemistry: Safety Issues
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Process Chemistry: General Considerations
- Heat and mass transfer controls
- Avoid accumulation of unstable or energetic intermediates
- Explosion hazard of static and organic dust (filtration, drying)
- Containment of potent compounds: workers safety in the exposure and elimination of cross-contamination between different process streams and decision to isolate intermediates.
Safety
- Perfecting analytical methods for their detection
Quality
- Establishing procedures for their removal
- Minimising the introduction and generation of impurities
EnvironmentalImpact
- Solvent usage (limit the use of chlorinated solvents)
- E factor: actual amount of waste produced in the process, defined as everything but the desired product
Sheldon, R. A. Green Chem. 2005, 7, 267-78.
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Process Chemistry: General Considerations
Substrates, reagents, catalysts, solvents, filtering media, transportation = 20 45%
Other costs: - labor (operators, analysts, quality control, other supporting personnel) - capital (equipment, instruments, facility depreciation) - utilities (water, steam, electricity, nitrogen, compressed air) - maintenance, waste treatment, taxes, insurance + overhead charges
These cost categories are directly proportional to concentration (space), duration (time), efficiency (yield) of a process
Cost
DurabilityRobustness
- Constant quality of starting material (suppliers)
- Availability of starting materials, solvents and reagents (transportation restrictions, use restrictions (chemical weapon, narcotics), environmental regulations, natural resource depletion)
- Impact on environment
- Adaptability of the process (advances in chemistry science on engineering technology)
- Flexibility of the process (stability and storage of intermediates, adaptable to different equipments and sites)
- Designed process remains the route of choice as long as the product is on the market
- Reproducibility of the process (different teams involved, quality throughout the batches)
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Route Scouting / Process Screening(early phase)
Process screening
Optimization
Validation
0.1 g
1 g
10 g
100 g 1 4
4 16
8 48
48 96
Single 1 L reactors with full dosageautomation and online analysis
Multiple 50 100 ml reactor stations,independent temperature control
and dosage opportunities
Multiple reaction blocks (5 100 ml)with low to medium automation degree
Workstations with dispenser,racks, analysis automation
Accuracy / Scale Typical parallelreactions throughput
Process Chemistry: Different Phases
Eckert, M.; Notheis, U. in Handbook of Combinatorial Chemistry,vol.2 (Eds: K. C. Nicolaou, R. Hanko, W. Hartwig), Wiley-VCH, Weinheim, 2002, pp.831-63.
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Process Chemistry: Different Phases
Eckert, M.; Notheis, U. in Handbook of Combinatorial Chemistry,vol.2 (Eds: K. C. Nicolaou, R. Hanko, W. Hartwig), Wiley-VCH, Weinheim, 2002, pp.831-63.
Route Scouting / Process Screening(early phase)
Process screening
Optimization
Validation
0.1 g
1 g
10 g
100 g 1 4
4 16
8 48
48 96
Single 1 L reactors with full dosageautomation and online analysis
Multiple 50 100 ml reactor stations,independent temperature control
and dosage opportunities
Multiple reaction blocks (5 100 ml)with low to medium automation degree
Workstations with dispenser,racks, analysis automation
Accuracy / Scale Typical parallelreactions throughput
Route Scouting: "Biocomputers" wanted
Eli Lilly venture Innocentive @ www.innocentive.com You could win a US $ 100 000 reward
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Process Chemistry: High Throughput Equipment
Route scouting: - Set of 48 96 experiments at a time
- Study viable routes
1 5 ml vessel
Chemspeed Accelerator
- 1.5 ml - 2 temperatures - 6 pressures - variability of metal, ligand, solvent - robotic dosing system
BASF: hydroformylation of olefin
DSM: phosphoramidite ligands librariesPremex multireactor
Jäkel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912-42.
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Process Chemistry: High Throughput Equipment
Process screening: - Target parameters: conversion and selectivity
- Variables screened: solvent, temperature, additive, catalyst, PG, stoichiometry, reaction time, etc.
20 50 ml vessel
50 °C < T < 200 °C
Biotage Endeavor multireator
DSM: phosphoramidite screening in hydrogenation
Dow: asymmetric hydroformylation
Jäkel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912-42.
Symyx parallel polymerization reactor PPr 48 - 48 catalysts - 3 substrates
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Process Chemistry: High Throughput Equipment
Helgroup: HP autoMATE
Jäkel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912-42.
Process optimization: - Target parameters: kinetics of the reaction, effects of differing rates of addition, stirring speed, effect of heating and cooling ramps on the reaction rates, impurity spectrum
- Work up development
50-250 ml vessel
mechanical stirrer
independent accurate temperature control
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Process Chemistry: High Throughput Equipment
BASF: Premex miniautoclave
Simple laboratory plant for continuous processing
Jäkel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912-42.
Process validation: Thermodynamic characterization, test of the stability of the process, scale up
1 2 L vessel
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With HTE, 96 experiments at least are set = at least 96 analysis
Need for High Throughput Analytical Instruments
1Infrared Spectroscopy: measure the temperature change in a given reaction usually used for heterogeneous catalysis
Optical Techniques:
2Colorimetric Assays: easiest technique
B A DYE+
B A DYE
+ unreacted material
Wash
Solution
phase
Solid
phase
A DYE
MLn
+ MLn, By products
B A DYE
B
Process Chemistry: High Throughput Analysis
1Reetz, M. T.; Becker, M. H.; Kühling, K. M.; Holzwarth, A. Angew. Chem. Int. Ed. 1998, 37, 2647-50.2Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 2123-32.
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3Reetz, M. T.; Kühling, K. M.; Deege, A.; Hinrichs, H.; Belder, D. Angew. Chem. Int. Ed. 2000, 39, 3891-93.
Process Chemistry: High Throughput Analysis
HighVoltage
anode cathode
capillary
detector
Buffersolutions
3Chiral Capillary Electrophoresis: >7000 ee separation per day
Common Techniques: HPLC, GCMS and NMR
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Process Chemistry: Ligand Synthesis
Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348, 23-39.
Me
PCy2
Me2N
PCy2iPr
PCy2
iPr
iPr
Ligands for C N coupling reactions:
1 2 3
Me
MgBr
Br
Cl
MgBr
Me
+Cy2PH
CuCl (cat.), 60 °C
Me
PCy2
Mg turnings were used instead of powder
Mg was added in 2 batches
Slow addition of the reagentsRq: the addition of aryl bromide to Mg could, theoretically, produced the heat to evaporate 93% of the initial THF
50%
10 kg / batch(Rhodia)
For 1 and 2:
1
Mg
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Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348, 23-39.
Process Chemistry: Ligand SynthesisFor ligand 3:
Cl
NH2
Cl
NMe2
Methylation
Methylation attempts:
CH2O, HCO2H, NaBH3CN: good on small scale but polymeric by products observed on large scale
Me2SO4 in alkaline soln: - good on both small and large scale
- but tedious aqueous work up: addition of an excess of SM to the RM solved that problem
- but monomethylated and product were not separable by distillation (1 °C difference) which was solved by addition of Ac2O to transform the monomethylated product into acetanilide
MgCl
NMe2
Grignardformation
Grignard formation: - aryl halide was added slowly (analytical checks)
- took 8 12 h to go to completion
MgCl
Me2N
Biphenylformation
Biphenyl formation: Wurtz type coupling products observed for long reaction times and if excess of reagent is used
Me2N
PCy2
C P coupling
C P coupling: CuI / LiBr was preferred to CuCl (more homogeneous, easier work up)
63%
3
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Process Chemistry: Ligand Synthesis
Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348, 23-39.
250 L vessel for pilotscale production of ligand 1 and 2
150 L vessel for pilotscale production of ligand 3
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Process Chemistry: Ligand Library
de Vries, J. G.; de Vries, A. H. M. Eur. J. Org. Chem. 2003, 799-811.
Homogeneous Catalysis
Key success factors: - the rate of the reaction expressed as the TOF (TurnOver Frequency) TOF = moles of product / moles of catalyst x hour
- the stability of the catalyst expressed as the TON (TurnOver Number) TON = moles of product /moles of catalyst
Economics = decisive factor in the choice of production methods
But ... some metals may be quite expensive as well as ligands
screening of a reaction usually involves screening of a broad spectrum of ligand types
Necessity to define ligand libraries
For example, chiral bis(phosphane) ligands will cost 45 000 150 000 / kg
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Process Chemistry: Ligand Library
Gao, X.; Kagan, H. B. Chirality 1998, 10, 120-24.
Supported catalysts under heterogeneous or homogeneous conditions
Ligand Metal
Anchoringagent
1heterogeneous
2homogeneous
Solid Support
CatalystSolid Support
Drawbacks: - Few viable processes, very substrate specific, metal leaching, less active,
- Optimization necessary, loss of their activity and selectivity on separation, re use difficult
1Gilbertson, S. R.; Wang, X. Tetrahedron 1999, 55, 11609-618.2Augustine, R. L.; Goel, P.; Mahata, N.; Reyes, C.; Tanielyan, S. K. J. Mol. Catal. A: Chem. 2004, 216, 189-97.
Multi-substrate screening procedure
Substrates (up to 7)
Catalyst
Reagent
Requirements: - SM, products peaks should not overlap with each other
- Substrates and products should not interfere during the reaction (e.g. autocatalysis)
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Process Chemistry: Ligand Library
O
OMe
NHAc
Ph
LRh(COD)2BF4
H2, DCM
O
OMe
NHAc
Ph
96 ligands tested within 1 day
hits
Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G. Org. Lett. 2004, 6, 1733.
Easily tunable ligands:
P N
O
O R2
R1
P
O
O
Cl HN
R2
R1
+
Phosphoramidite type ligands: - Highly tunable
- SM commercially or easily available
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Process Chemistry: Ligand LibraryBuy them from suppliers: Solvias, JM catalysts, Chiral Quest
BINAP analogs DuPHOSanalogs
Ferrocenyl-basedLigands
P-chiralLigands
Monodentate Ligands
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Process Chemistry: Legendary Example
Blaser, H-U. Adv. Synth. Catal. 2002, 344, 17-31. Blaser, H-U.et al in Asymmetric Catalysis on Industrial Scale,(Eds: H. U. Blaser, E. Scmidt), Wiley-VCH, Weinheim, 2004, pp.55-70.
Behind the scenes ....
Milestones in the history of metolachlor:
NO
O
Cl
(S) metolachlor (Dual®)
Syngenta most important herbicide>10 000 tons / year
16 years study
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Process Chemistry: Legendary Example
Blaser, H-U. Adv. Synth. Catal. 2002, 344, 17-31. Blaser, H-U.et al in Asymmetric Catalysis on Industrial Scale,(Eds: H. U. Blaser, E. Scmidt), Wiley-VCH, Weinheim, 2004, pp.55-70.
Behind the scenes ....
Milestones in the history of metolachlor:
NO
O
Cl
(S) metolachlor (Dual®)
Syngenta most important herbicide>10 000 tons / year
16 years study
4 stereoisomers: - 1 atropisomerism - 1 stereogenic center
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Process Chemistry: Legendary Example4 routes were defined
- Enamide hydrogenation
"Selective synthesis for one particular enamide isomers was judged to be difficult"
NO
O
Cl
- Nucleophilic substitutionO
OMe
OTs
OMe
NH R
+1. Enantioselective H2
2. TsX(S) metolachlor
- Pt cinchona catalyzed hydrogenation on methoxyacetone ??
- Nucleophilic substitution: weak nucleophile, no activation of the leaving group
- Imine hydrogenationN
O
MEA imine
H2(S) metolachlor
H2(S) NAA
Only 1 example of imine hydrogenation (22% ee)
Catalyst
Nucleophilic
substitution
Catalyst
- Direct catalytic alkylation
OH
OMe
NH2
+Chiral
Catalyst(S) NAA
Based on N alkylation of aliphatic amines with alcohols using Ru phosphine catalyst
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Process Chemistry: Legendary Example- Enamide hydrogenation
- Nucleophilic substitution
- Imine hydrogenation
- Direct catalytic alkylation
3 isomers prepared with >95% purity
No conversion with 7 different Rh-diphosphine catalysts (50 °C, 1 bar)
O
OMe *OH
OMe
cinchonidine modified Pt / CH2
12% ee
NO
MEA imine
(S) NAA
cinchonidine modified Pt / CH2
0% ee
Not tested
J. P. Kutney from UBC: 69% ee ( 25 °C), TOF = 15h 1, TON = 1000 (65 bar, rt) on DMA with Rh cycphos
cycphos:PPh2
PPh2
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Process Chemistry: Legendary Example
First Major breakthrough (1985): Ir catalyzed imine hydrogenations
- 84% ee reached (original goal) with Ir bdpp but TOF < 150h 1
- TON = 10 000 (goal was 40 000) with Ir diop but 63% ee
But catalyst deactivation during the reaction
1987: End of project, results were patented and published
Philosophy: "Try the impossible and succeed or fail with grandeur"
Second Major breakthrough (1992): Xyliphos
Fe PPh2
P
Me
2
s/c = 800, 73% ee, 6h
no catalyst deactivation"S DUAL Breakthrough Party"
Third Major breakthrough (1993): AcOH and I2
TON > 600 000, 76% ee, 50h
Xyliphos
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Process Chemistry: Legendary ExampleFrom laboratory procedure to the first production batch
- MEA imine: multi step continuous distillation process (recovery of solvent and non reacted SM)
80 bar, 50 °C, 4h s/c > 1 000 000, TOF = 1 800 000h 1, 79% ee
- Xyliphos was synthesized on a 100 kg scale in 2500 L reactors
- Catalyst formulation: liquid, highly active catalyst formulation stable over several months
addition of the catalyst was safer and easier
- Reactor technology: loop reactor
The reaction mixture is pumped via a heat exchanger through a nozzle where H2 is fed into the reaction solution (good mixing and exchange surface)
- Optimization of reaction medium and conditions:
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Process Chemistry: Legendary Example
- Scale up of the process:
1. Laboratory procedure developped in a 300 ml reactor2. Production of 100 kg of enriched metolachlor in a stirred tank 50 L autoclave3. (2.) was reproduced on a loop reactor of the same size4. First tons were produced in a dedicated 1000 L loop reactor
- Work up:
1. Continuous aqueous extraction (neutralization and elimination of acid from the crude)2. Flash distillation (residual water removal)3. Catalyst separation from the (S) NAA by distillation on a thin film evaporator
- Ir is recovered- Xyliphos is lost
In the end
November, 16th 1996: 10 tons of (S) NAA (79% ee) are produced with 34 g of Ir, 70 g of Xilyphos in 2 h, 99.6% conversion
No major changes needed for the plant
Sandmeyer Prize 1999 of the New Swiss Chemical Society
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Process Chemistry: Metal Removal
1Note for Guidance on Specification Limits for Residues of Metal Catalysts, The European Agency for the Evaluation of Medicinal Products, Evaluation of Medicines for Human Use; London, 17 December 2002; http://www.emea.eu.int
Absorption of palladium is highly dependent on its chemical form:
PdCl2 (i.v. administration): 3 mg / kg body weight
PdO (oral administration): >4900 mg / kg body weight
Element Oral PDE (g/kg/day) Parenteral PDE (g/kg/day)
Pt, Pd, Ir, Rh, Ru, Os
Mo
V
Cu
Ni
Cr
Mn
Zn
Fe
2.6
5
10
50
20
25
100
300
250
0.25
2.5
0.5
10
2
2.5
5
30
25
PDE = Permitted Daily Exposure
1Specification limits for residues of metal catalysts:
LD50 (rats, mice, rabbits):
Concentration (ppm) =(y / 100) x PDE x Body weight
Dose
y = % of PDE apportioned to drug substancePDE = permitted daily exposure (g / kg / day)Dose = daily intake of the drug substance in g / dayBody weight expressed in kg (standard is 60 kg)
Element Oral concentration Limit (ppm) Parenteral Concentration Limit (ppm)
Pt, Pd, Ir, Rh, Ru, Os
Mo, V, Ni, Cr
Cu, Mn
Zn, Fe
5
10
15
20
0.5
1
1.5
2
Procedure for determining limits
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Process Chemistry: Metal Removal
MS
Garrett, C. E.; Prasad, K. Adv. Synth. Cat. 2004, 346, 889-900.
How to detect such low level of metal in a given sample?
- USP metal test (visual) MH2S
buffer solnMS
coloured precipitateppm level
- Atomic Absorption Spectroscopy
Measure the concentration of gas-phase atoms using their absorption of light
ppb level
- ICP-MS
Samples are decomposed to neutral elements in a high temperature argon plasma and analyzed by MS
ppt level
Usually used to analyse several metal in one analysis
Usually used to analyse one metal at a time
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Process Chemistry: Metal Removal
Garrett, C. E.; Prasad, K. Adv. Synth. Cat. 2004, 346, 889-900.
Heterogeneous catalysis: simple filtration except when metal leaching into the medium
Homogeneous catalysis:
- Adsorbents
- Distillation
- Extraction
- Crystallization
Optimization needs to be done on the solvent wash
Requires at least 24h
N N
NHS
SH
SH
TMT(and supported TMT)
NH
N
NH2
NH2
PS
PS bound EDA
Activated carbon(carbon cartridges available)
Glass Bead sponges
SmopexTM (polyethylene or cellulose based fibers with FG)
Silica bound scavengers
SHSi
Usually to remove the last traces of metal
N acetylcysteineHO
O
NHAc
SH
N acetylcysteine / L cysteine
PBu3 / lactic acid
PBu3
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Process Chemistry: Survey
General data:
Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2004, 4, 2337-47.
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Process Chemistry: Survey
Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2004, 4, 2337-47.
Summary of reaction categories:
C-C bond forming reactions: Pd catalysis (Suzuki, Heck)
Ester condensation
Organometallic (Aryl-Met,Directed lithiation, Grignard)Friedel-Crafts
Other
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Process Chemistry: Survey
Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2004, 4, 2337-47.
Protections
Amino (Boc, Bn, Cbz)
Hydroxyl (Bn, SiR3, Ac)
Carboxylic acid
other
Deprotections
Amino (Boc, Bn, Cbz)
Carboxylic acid
Bn, SiR3, phenol
Thiol
Other
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Process Chemistry: Survey
Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2004, 4, 2337-47.
Relative induction Asymmetric
synthesis
ResolutionPurchased
Where does chirality come from?
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Process Chemistry: Synthesis of CGS 19755
Giannousis, P.; Carlson, J.; Leimer, M. in Process Chemistry in the Pharmaceutical Industry,(Ed: K. G. Gadamasetti), Marcel Dekker Inc., New York, 1999, pp.173-88.
NH
CO2H
P(O)(OH)2
CGS 19755
Antiischemic agent in the treatment of stroke and head trauma
Discovered in 1985
Challenges: - Not a thermally recrystallizable solid
- Polyionic nature and low solubility in organic solvents
- Hydrochloride salt generated esterification by products from crystallization from alcohols
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Process Chemistry: Synthesis of CGS 19755
N
OH
N
Cl
N
P(O)(OEt)2
N
P(O)(OEt)2
CN
N
P(O)(OEt)2
CONH2NH
P(O)(OEt)2
CONH2 NH
P(O)(OH)2
COOH
SOCl2
DCM
93%
1. NaOH / toluene
2. NaH, HP(O)(OEt)2
1. m CPBA, DCM
2. TMSCN, Et3N
91%
1. H2SO4
2. H2O
71%
H2 / PtO2, AcOH
100%
1. 6N HCl
2. EtOH, H2OO
74%( ) CGS 19755
Medicinal Route:
- cis:trans = 95:5 ratio
- Use of m CPBA, TMSCN, propylene oxide, 2 is highly irritating
·HCl
100g, 200$ (Aldrich)
1 2 3 4
5 6cis:trans = 95:5
Drawbacks:
88%
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Process Chemistry: Synthesis of CGS 19755
N
P(O)(OEt)2
N
P(O)(OEt)2
CN N
P(O)(OEt)2
CONH2
NH
P(O)(OEt)2
CONH2 NH
P(O)(OH)2
COOH
1. m CPBA, DCM 77%2. TMSCN, Et3N 88%
1. H2SO42. H2O 71%
H2 / PtO2, AcOH100%
1. 6N HCl2. EtOH, H2O
O
74%
2. i. (CH3O)2SO2 MeCN ii. NaCN / H2O 84%
1. NaOEt / EtOH2. HCl / H2O 65%
COOEt
COOEt
65% 0. i. NaOH / EtOH ii. HCl / MeCN 65%1. 50%, >99.5% purity2. NaHCO3 / H2O 84%
First scale up:
Objective: avoid the presence of the trans isomer
too exothermic
300 g, 6.3% yield
intermediates purification difficult due to not recrystallizable solids
3 4
6
5
cis:trans = 95:5
( ) CGS 19755
Drawback:
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Process Chemistry: Synthesis of CGS 19755
N
OH
N
P(O)(OEt)2
N
P(O)(OEt)2
CONH2 N
P(O)(OH)2
COOH
NH
P(O)(OH)2
COOH NH
P(O)(OH)2
COOH NH
P(O)(OH)2
COOH
1. SOCl2, DCM then1. NaOH / toluene2. NaH, HP(O)(OEt)2 85%
1. SOCl2, DCM2. NaOH / toluene3. HP(O)(OEt)24. t AmOK / toluene 11% of by product5. Distillation 57%
Cyanation followedby hydrolysis
1. HCONH2, H2SO4, (BzO)22. DCM3. n BuOAc 44%
6N HCl,reflux
1. H2 / 5% Rh / C NaOH / H2O2. HCl / H2O Acetone 90%
H2 / PtO2, AcOH65%
PiperidineH2O / EtOH
77%
6N HCl50%
1. HCl / H2O / IPA2. NaOH / H2O3. HCl / H2O 89%
crude <1% trans isomerdifficult to monitor by analytical techniques
Advantages: - 5 and 7 are stable and recrystallizable solids
- recrystallization of adduct 9
- one pot conversion (3 to 5)
7
13.8%, 51 kg
Second scale up:
Objective: rapidity and cost
3 51
( ) CGS 197558 9
·Pip
cis:trans = 90:10
Drawbacks: - isolation of 3 lengthy
- low yield in the one pot conversion
- cis:trans ratio
89%
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Process Chemistry: Synthesis of CGS 19755
N
P(O)(OEt)2
N
O
1. HP(O)(OEt)2 LiNH2, toluene2. EtOAc3. H3PO4, EtOH 64%
from corresponding alcohol: 57%
N
P(O)(OEt)2
CONH2
1. HCONH2, H2SO4, (BzO)22. DCM3. n BuOAc 44%
1. HCONH2, H2O (NH4)2S2O82. DCM, extraction
Solvent exchange /6N HCl, reflux
56%
N
P(O)(OH)2
COOH
1. Piperidine H2 / 4.5% Pd 0.5% Rh / C, MeOH
2. i PrOH3. EtOH 79% N
H
P(O)(OH)2
COOH NH
P(O)(OH)2
COOH
1. HCl / H2O / IPA2. NaOH / H2O3. HCl / H2O 89%
Advantages: - cheaper SM (100 g, 96$ (Aldrich))
- 3 isolated as a solid
23% overall yield
Optimal scale up:
3 5
( ) CGS 197557
·Pip
·H3PO4
9
cis:trans = 97:3
- one pot conversion 3 to 7
- only 4 isolations
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Process Chemistry: Synthesis of SB214857A
NH
NMe
O
MeO2C
N
O
HN ·HCl
Lotrafiban SB 214857 AGSK
Potent non peptidic glycoprotein IIb/IIIa receptor antagonist to prevent platelet aggregation and thrombus formation
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Process Chemistry: Synthesis of SB214857A
NH
NMe
O
MeO2C
NH
NMe
O
MeO2C
N
O
HN ·HCl
NO2
Lotrafiban SB 214857 AGSK
Potent non peptidic glycoprotein IIb/IIIa receptor antagonist to prevent platelet aggregation and thrombus formation
NH
NMe
O
MeO2C
N
O
HN ·HCl
OH
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Miller, W. H.; Ku, T. W. et al Tetrahedron Lett. 1995, 36, 9433-36.
Process Chemistry: Synthesis of SB214857A
BrMg Me
F
t-BuO2C Me
F
t-BuO2C
F
NHMe
t-BuO2C
F
NMe
O
CO2Me
NH2
NH
NMe
O
CO2Me
t-BuO2C
t-BuO2C
F
NMe
O
CO2Me
+
NH
NMe
O
CO2Me
HO2C
NH
MeN O
CO2MeN
O
BocN
1. CO2, THF 77%
2. isobutylene TfOH (5 mol%)
Et2O, 78 °C to rt sealed pressure bottle
94%
1. NBS, (PhCO)2O2, CCl4, reflux
2. MeNH2 (40% H2O) THF 70%
1. Cbz-L-Asp--Me-ester DCC, HOBt·H2O, DMF
86%
2. H2, 10% Pd / C, MeOH 98%
DMSO (0.1M)125 °C
6:4 ratio
47%
anisoleDCM / TFA (1:1)
95%
1-Boc-4,4'-piperidineEDC, DIPEA, DMF
94%
1. 2N NaOH (2 equiv) MeOH / THF (1:1) then AcOH, 81%2. 4M HCl, CHCl3 then 1N KOH / EtOH 75%
3. precipitation from aqueous soln (pH 6.8) 83%
> 99:1 ratio (S:R)
Discovery route:
50 ml, 67$ (Aldrich)
SB 214857 A
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Process Chemistry: Synthesis of SB214857A
Morgan, D. O.; Wells, A. S. Org. Process Res. Dev. 2003, 7, 655-62.
NO2 NO2
Br
NH
CO2Me
NMeBoc
MeO2C
NH
NMe
O
MeO2C
OH
NO2
NHMe
NH2
NMeBoc
NH
CO2Me
NMeBoc
MeO2C
NH
CO2Me
NHMe
MeO2C
Bromination Amination 1. Protection
2. Hydrogenation
Michael reaction Reduction Deprotection
Cyclization
- lengthy route
- oily intermediates
- lachrymatory material
- by products
Drawbacks:
+ by products
First scaleup route:
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Process Chemistry: Synthesis of SB214857A
NO2 NO2
OMs
NH
NMe
O
MeO2C
OH
NO2
NHMe
NO2
NMe
MsCl, Et3NTHF
MeNH2 aq.12 equiv
92%
EtOAc
100%
Pd / C, NaBH4,MeOH, H2O
93%
- lengthy route
- too much extraction steps
- by products
Drawbacks:
+ by products
CO2Me
CO2Me
NH2
NMe
CO2Me
CO2Me
Pd / Ccyclohexene
5 equiv
92%NH
NMe
O
MeO2C
NH
NMeCO2Me
CO2Me
AcOHMeOH
94%
NaOMeMeOH
95%
MeOCO OCOMe
Scaleup route:
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Process Chemistry: Synthesis of SB214857A
Never subjected to scaleup (clinical programme was halted at phase III)
Alternative scaleup route:
CHO
NO2 NH2
NHMe
NH
NMe
O
MeO2C
NH
NMe
O
MeO2C
1. MeNH2, NaBH4 MeOH, H2O
2. H2, Pd / C, MeOH 97%
1. MeOH,2. AcOH, MeOH
3. NaOMe, MeOH 68%
MeOCO OCOMe NH4CO2HPd / C, MeOH
93%
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Process Chemistry: Synthesis of SB-214857-A
Carey, J. S.; Wells, A. S. Org. Process Res. Dev. 2003, 7, 663-75.
NH
NMe
O
MeO2C
NH
NMe
O
MeO2C
NH
NMe
O
HO2C
NH
NMe
O
HO2C
I
NH
NMe
O
HO2C
N
O
N
NH
NMe
O
HO2C
N
O
HN
Novozym 435,t BuOH, H2O,
NH3, pH 7
NaOMe, MeOH(MeO)2CO, 38%
Py ICl, H2ONaOH, pH 7
38%
PdCl2(PPh3)2, COanisole,86%
N
NH
1. H2, Pd / C, i PrOH2. Py·HCl, IMS DCM, H2O 78%
·HCl
+
25% overall yield
End of the synthesis:
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Process Chemistry: Conclusion
Process Chemistry:
- The link between medicinal chemistry and drug manufacturing (pharmaceutical industry)
- Major factors: Safety, Quality, Environmental impact, Cost, Durability / Robustness
TIME
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Process Chemistry: Conclusion
Process Chemistry:
- The link between medicinal chemistry and drug manufacturing (pharmaceutical industry)
- Major factors: Safety, Quality, Environmental impact, Cost, Durability / Robustness
TIME
Chemical Transformations:
- Think simple and practicle
- Chiral Compounds: - Buy chirality
- Asymmetric Hydrogenations
- Resolution (diastereomeric crystallization or enzymatic) - Enzymatic processes
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Process Chemistry: Bulk Chemistry vs Fine Chemistry
Variable/Constraint Basic Chemicals Fine Chemicals
Scale of the process
Plant
Time line
Ratio material costs per total costs
Budget for process screening
1000 100 000 tons 0.01 1000 tons
Continuous
Dedicated
Batch
Multipurpose
1 10 years 10 days to 2 years
High Low
LowHigh
Eckert, M.; Notheis, U. in Handbook of Combinatorial Chemistry,vol.2 (Eds: K. C. Nicolaou, R. Hanko, W. Hartwig), Wiley-VCH, Weinheim, 2002, pp.831-63.
Bulk chemicals: priority = cost of the product radical new approaches are often pursued to effect the large reduction in cost (an improvement in the reaction selectivity of less than 1% saves several million $)
Fine chemicals: priority = time to market much smaller quantities and shorter lifetime (generics) strict quality requirements
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Process Chemistry: High Throughput Experimentation
de Vries, J. G.; de Vries, A. H. M. Eur. J. Org. Chem. 2003, 799-811.
High throughput experimentation = Screen all parameters to their full extent in a reasonable amount of time
1999: the cost and time to develop a new drug averaged $500 million and 15 years
Parameters for HTE in homogeneous catalysis:
Requirements for HTE in homogeneous catalysis:
Hardware (robots), Software and data handling,
Libraries of ligands and catalysts, Fast analysis
Metal, Counterion, Ligand, Metal/Ligand ratio, Method of catalyst preparation, Substrate/catalyst ratio, Reactant,
Solvent, Temperature, Pressure, Substrate/reactants ratio, Concentrations of catalyst, substrate and reactants,
Order of mixing catalyst and reactants, Rate of addition of one or more reactants, pH, Additives (acids, bases, R4N+X )