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Janssen Research & Development
Chemical Reaction Safety in the Pharmaceutical Research Laboratory
Steve Stefanick
Scientific Director – Technical Integration
API Small Molecules - Reaction Safety Lab
Pharmaceutical Development and Manufacturing Sciences
Janssen Pharmaceutical Companies of Johnson & Johnson
1000 Route 202
Raritan, NJ 08869
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Some Pharma Background
Consumer MDD
Pharma
Johnson & Johnson
Phases of Drug Development
I IIa IIb III IV
Research Development ManufacturingDiscovery Lab Pilot Plant and Plant Commercial and 2nd gen process
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Reaction Safety Lab
NaH/DMF; Hydrazine; DiBAL-H, Peroxides, DMSO, ……
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Famous Last Words
• I didn’t see an exotherm in the lab
• I only saw a little bit of foaming
• It turns brown if you leave it in the oven too long
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Objective
Identify those situations/substances that have the potential for chemical reactions where the reaction energy / products will not be safely absorbed by the reaction environment.
Learn what key tools are available to help identify chemical reactivity hazards in the research laboratory
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Legislative AspectsServeso Directive
1974 - Flixborough England Cylcohexane explosion
1976 - Serveso Italy - Dioxane release
Clean Air Act Ammendment
1984 - Mexico City- LP gas explosion
1984 - Bohpal India - MIC release
1985 - W. Virginia - aldicarb oxime release
1999 – Concept Sciences Inc, Hydroxylamine explosion
OSHA Standard Title 29 CFR 1910.110
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Concept Sciences Inc.
Catastrophichydroxylamine (HA)explosion that occurredon February 19, 1999, atthe Concept Sciences,Inc. (CSI), facility inHanover Township,Lehigh County,Pennsylvania. Four CSIemployees and oneemployee of an adjacentbusiness were killed; 14people were injured.
1. Reaction of HA sulfate and potassium hydroxide to produce a 30 wt-percent HAand potassium sulfate aqueous slurry:HAS + 2 KOH HA + K2SO4 + 2 H2Owhere:HAS = (NH2OH)2*H2SO4HA = (NH2OH).2. Filtration of the slurry to removeprecipitated potassium sulfate solids.3. Vacuum distillation of Hafrom the 30 wt percentsolution to separate it from thedissolved potassium sulfate and producea 50 wt-percent HA distillate.4. Purification of the distillate through ionexchange cylinders.
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Types of Hazards
Chemical reaction hazards
Exothermic reactions - boiling, decomposition and gas evolution
Thermal instability of materials, mixture and product
Mechanical hazards
Fire and explosion
Ignition and grounding
Static
Shock sensitivity
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Incident HistoryPrime causes:
Process Chemistry -No knowledge of the heat of reaction
Reaction mixture decomposed during reaction / workup
Unstable or shock sensitive product
Batch vs semi batch reaction
Too concentrated
Reaction temperature too low – accumulation
Catalysis by equipment materials of construction
Impure starting materials
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Incident History
Prime causes cont’d:
Plant operation and design -
Poor temperature control - loss of cooling, too much heat
Temperature probe placement
Inadequate stirring or failure
Added wrong amount of reactants, solvents, catalyst or added in wrong order
Equipment leaks from reactor jacket / condenser
Human factors and operator error
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Assessment
Chemicals - Literature, calculations, DSC
Reaction rate Equipment
Accelerating Rate Calorimetry Heating/cooling
Reaction calorimetry capacity
Vent sizes
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Assessment - Chemicals
Find reactivity hazard information on MSDS
MSDS Definitions from literature sourcesMSDS: - section 5: fire-fighting measures:
water reactivity + consequences of heating- section 10: Stability + reactivity:
chemical stability, conditions to avoid, incompatibility, decomposition or polymerization
- section 14: Transport:look for the hazardous material description, hazard class, UN/NA id. Number
- section 16: Other information:look for hazard ratings
! MSDS’s often contain incomplete or contradictory information; do not rely on a single source in emergency situations !
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Reactivity Information (Worksheets)
Bretherick’s and other literature
Chemical Reactivity Worksheet http://response.restoration.noaa.gov
CAMEO Chemicals Worksheethttp://cameochemicals.noaa.gov/
Is this substance Reactive?What might happen if these 2 substances are combined?
Chemical Reactivity Worksheet: looking at reactive groups- Only binary combinations- Consequences are predicted for ambient conditions of T and P.- Possible effects of catalysts, contaminants, .. are not included- Reaction products are not predicted, though flammable and toxic
gas generation may be suggested.
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Chemical Reactivity Worksheet• Chemicals in this mixture:
ACETONE mixed with SULFURIC ACID
• Reaction proceeds with explosive violence and/or forms explosive products
• Spontaneous ignition of reactants or products due to reaction heat
• Exothermic reaction. May generate heat and/or cause pressurization
• Combination liberates gaseous products, at least one of which is toxic. May cause pressurization
• Possible Gases: – Nitrogen Oxides– Sulfur Oxides – Halogen Oxides – Carbon Dioxide
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Reactivity Information (Wiser database)
• WISER provides a wide range of information on hazardous substances, including substance identification support, physical characteristics, human health information, and containment and suppression guidance.
• Access to 400+ substances to see detailed information on over 4,700 critical hazardous substances
• Rapid access to the most important information about a hazardous substance
First Responder Hazmat Specialist EMS Specialist
PPE Physical Properties Summary Treatment
Protective Distance PPE Health Effects
Fire Procedures IDLH Toxicity Summary
Reactivities Flammability Limits IDLH
Treatment NFPA 704 Classification NFPA 704 Classification
Download at http://wiser.nlm.nih.gov/about.html
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Classification of Materials
Several types of reactive chemicals: - self reactions- reactions with common environmental
substances- incompatibilities
Some chemicals have many ways they can get involved in out-of-control
situations.
! Whether a chemical hazard actually exists will always depend, not just on the kind of chemical that is present, but whether or not the reaction energy and products will be safely absorbed by the reaction environment.
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Classification of MaterialsReactivity Hazard Definition Examples Measures
UNSTABLE- decomposing- thermally sensitive- shock sensitive- explosive
Has the tendency to break down over time or when exposed to conditions such as heat, sunlight, shock, friction, or a catalyst with the resulting decomposition products often being toxic or flammable. Decomposition can be rapid enough to give an explosive energy release and can generate enough heat and gases for fires/explosions.
TNTdibenzoyl peroxideethylene oxideacetylenepicric acidhydrogen peroxide
- DSC- SS test:*unstable group/stressed rings * oxidant, reductant mixture * DSC (> 1000 J/g)
POLYMERIZING Has the tendency to self-react to form larger molecules, while possible generating enough heat/gases to burst a container
styrene1,3-butadieneacrylic acid
PYROPHORIC Will ignite spontaneously when exposed to air phosphorussilane
See Bretherick’s
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Classification of MaterialsReactivity Hazard Definition Examples Measures
PEROXIDE FORMER Has the tendency to slowly react with oxygen, such as from being exposed to air, to form unstable organic peroxides
isopropyl ether1,3-butadiene
- Note date on opening bottle- Purge N2- Avoid higher temp./concentrate- clean up (dresser dry)+dilute with absorbent
WATER REACTIVE Will react with water or moisture. Some react slowly; others violently. Heat and flammable/toxic gases may be produced.
SodiumSulfuric acidAcetic anhydride
OXIDIZER Will give up oxygen easily or readily oxidize other materials.
Chlorinenitric acid
INCOMPATIBLE Readily reacts with other chemicals hydrazine+metalAcetone + H2O2
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Highly Energetic Compounds
C-C and C-N triple bonds and metal salts
(acetylenic compounds)
Adjacent N-O atoms (nitro, nitroso compounds)
Adjacent and consecutive O-O pairs (peroxides)
Adjacent and consecutive N-N compounds
(diazo compounds)
Adjacent C atoms bridged by O or N (epoxides)
O-X pairs (perchlorates)
N-metal pairs
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Reactive Chemical Groups
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Reactive Chemical Groups
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Reactive Chemical Groups
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Peroxide Forming SolventsAcetaladehyde Acrylaldehyde Allyl ethel ether 1-Allyloxy-2,3-epoxypropane Bis(2-ethoxyethyl) ether Bis-(2-methoxyethyl) ether 1,3-Butadiene 1,3-Butadiyne 2-Butanol Buten-3-yne Butyl ethyl ether Butyl vinyl ether 2-Chloro-1,3-butadiene Chloroethylene 2-Chloroethyl vinyl ether Cinnamaldehyde Crotonaldehyde Cyclopropyl methyl ether Diallyl ether Dibenzyl ether Dibutyl ether 1,1-Dichloroethylene 1,1-Diethoxyethane 1,2-Diethoxyethane
3,3-Diethoxypropene Diethyl ether Diethylketene 2,3-Dihydrofuran Diisopropyl ether 1,1-Dimethoxyethane 1,2-Diethoxyethane 3,3-Diethoxypropene 1,3-Dioxane 1,4-Dioxane 1,3-Dioxol-4-en-2-one Dipropyl ether Di(2-propynyl) ether Divinyl ether 2-Ethoxyethanol 1-Ethoxy-2-propyne 2-Ethylacrylaldehyde oxime 2-Ethylbutanal 2-Ethylhexanal Ethyl isopropyl ether Ethyl propenyl ether Ethyl vinyl ether 2-Furaldehyde Furan 2,4-Hexadien-2yn-1-ol
2,5-Hexenal 2-Indanecarboxaldehyde 2-Isopropylacrylaldehyde Isobutyraldehyde Isopropyl vinyl ether Isovaleraldehyde Limonene 1,5-p-Menthadiene Methoxy-1,3,5,7-cyclooctatetraene 2-Methoxyethanol 2-Methoxyethyl vinyl ether 4-Methyl-2-pentanone 2-(1-Methylheptyl)-4,6-dinitrophenyl crotonate2-3-Methyl-2-methylenebutanal 2-Methyltetrahydrofuran Methyl vinyl ether Alpha-Pentylcinnamaldehyde Propionaldehyde Sodium 5,8,11,14-eicosatetraenoate Sodium ethoxyacetylide 1,1,2,3-Tetrachloro-1,3-butadiene Tetrahydrofuran
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Minimizing risks in the lab
• Segregated storage: avoid confusion of wrong chemicals:- base / acid- explosives / oxidizers
• Correct labelling of chemicals: avoid abbreviations
• Read the labels !
• Correct use of units (ml - g)
• Systematically look up of the properties of chemicals
• Look up compatibilities of mixtures (catalyst, metals,…)
• Correct use of protective equipment: fume hood, PPE’s
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Strategies
Lab Scale Pilot Plant Manufacturing
Literature Evaluate chemical Evaluate equipment Search reaction hazards hazards
Desktop Define influence of Define critical calculations operating hazards parameters
Laboratory Process Safety Review HAZOPTesting
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Chemical reaction
Desired chemistry Unwanted chemistry
Normal limits Adiabatic Adiabatic temperature temperature
rise of reaction rise of decomposition
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Reaction rate - Laboratory Testing
Property to evaluate Typical Instrumentation
Thermal stability of raw Differential Scanning materials Calorimetry
(DSC)
Normal reaction conditions Reaction Calorimetry (RC-1)
Minimum exothermic Accelerating Rate Calorimetryrunaway temperature (ARC)
Runaway reaction consequences Accelerating Rate Calorimetry (ARC)
Reaction Calorimetry (RC-1 pressure)
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Reaction Safety GuidelinesOperating Guidelines - When and what to test
4 stages of evaluation
Stage 1 - A chemical procedure run at any scale that requires thestorage and use of a key raw material, intermediate, reagent, solventthat contains a known hazardous chemical functionality or is itselfsuspected or known to be hazardous or unstable.
Stage 2 - A chemical procedure that displays any observed thermal orpressure event, unexpected eruption or degassing, venting orspilling, viscosity increase, darkening or polymerization duringlaboratory scale experimentation or initial scale up.
Stage 3 - A chemical procedure that is representative of a final syntheticroute and may not be fully optimized. This chemical procedure hasbeen performed and duplicated minimally on a 500 mL reactionscale.
Stage 4 - A chemical procedure that is optimized at the laboratory scaleand ready for introduction into large scale equipment.
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Reaction Safety Review (RSR)• “HAZOP” - RSR (via in person, phone, or e-mail)
• Formal review of the “mechanics” of the procedure
– Review available data - MSDS, literature, RC-1, DSC, etc.
– What equipment is being used
– How you do things – “mechanics of the procedure”– Heat or cool (Mantle or ice)– Monitor temperature, pressure, etc– Monitor reaction– Work-up reaction (extract, rotovap, filter)– Isolate product– Is additional testing required to scale safely ?
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Reaction Safety Testing Protocol
2-5 mg of materialQuick screening test
25°C to 300°C
DSC TestEvaluate the thermal stability
of all raw mateirals used
3-5 grams of materialMore sensitive than DSC
Time to Maximum Rate/pressuresRunaway reaction potential
ARC TestEvaluate the thermal stability
of raw materials, reaction mixturesunder adiabatic conditions
1.0 L scale"Any chemistry" can be tested-90°C to 250°C, under pressure
ReactIR, kinetics, "optimization"
RC-1 CalorimetryEvaluate the Heat of Reaction
and worst case temperature riseunder actual reaction conditions
* Any Reaction to be run onequal/greater than 5L scale that
requires ice bath cooling(other than for chemical quality)
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Differential Scanning Calorimetry DSC
Typical sample size = 1-10 mgScanning rate = 5οC/min to 300οC
100o/50o ruleTMR24AKTS
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DSC Example
FastSmall sample sizeBroad temperature range
Representative sample ?No mixing (heterogeneous)No pressure data
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DSC Example
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Accelerating Rate Calorimeter
Typical sample size = 3- 5 gramsHeat / wait / search to 400οC
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ARC Example
TBAP salt TBAP reaction mixture
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EasyMax and MultiMax
Preliminary chemistry screening, observing Tr-Tj behaviorSmall scale, easy and fastCrystallization study and optimization
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Reaction Calorimeter (RC-1)
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RC-1 iCSafety
R OH
O
R OCH3
O
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Reactor heat transfer specific cooling specific ΔT needed on jacketcoëfficiënt area heat transfer to cool 30 W/L
U (W/m2K) (m2/m3) U . A / V (W/lK)
500 ml flask 200 86 17.2 2RC1 1L vessel 150 40 6 5250 L reactor 250 6,8 1,70 16
1000 L reactor 250 4,6 1,15 266300 L reactor 250 2,6 0,65 44
Cooling capacities for different reaction vessels
** ALWAYS OBSERVE AND REPORTTEMPERATURE CHANGES
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Typical Heat of Reaction Values
Bromination: < 50kJ/moleFriedel-Crafts: 53 kJ/moleAcid/Base Neutralization: 56 kJ/moleEsterification: 67 kJ/moleNaBH4 Reduction: 150 kJ/moleOxidation: 300kJ/moleGrignard: 400 kJ/moleHydrogenation (NO2): 560 kJ/moleNitration: 130 kJ/moleEpoxidation: 96 kJ/moleAmination: 120 kJ/moleDiazotization: 117 kJ/mole
0-50 kJ = Weak50-100 kJ = Medium150-300 kJ = Strong300 kJ = Very Strong
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Mettler FTIR Model iC10
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Reaction Calorimeter and ReactIR
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We have the information
Now what ??
Some Examples
Chemical Reaction Hazards
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Example # 1
A Critical Parameter in the Development of a
Scaleable Synthesis of 2,3-Bis-chloromethylpyridine Hydrochloride
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Reaction Safety Issues
1. Potential runaway chemical reaction2. Reaction done in neat thionyl chloride3. Difficult temperature control on larger reaction scale4. “Troublesome” isolation of product5. Waste disposal
Reaction Scheme
N
OH
N
Cl
Cl
x HCl
SOCl2OH
N
OH
Cl
SOCl2
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Dosing loop
Charge reactor at set temperaturethen add thionyl chloride via dosing loop or manually
Reaction Flow Diagram
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Heat Flow Curve - MTBE at 25°C
Issues: ExothermicInduction period, accumulation of SOCl2En-mass reaction, uncontrolled out-gassing
Add thionyl chloride at 25oC over 40 minutes
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Issues: ExothermicStill did not initiate, accumulationSimilar to MTBE reaction at 25 CSO2 and isobutylene (CRC90e at 40 C)
Heat Flow Curve - MTBE at 45°C
Add thionyl chloride at 45oC over 30 minutes
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Re-think our Strategy
Issues:
Reaction will not initiate in MTBE at 25oC and 45oC
Serious accumulation of thionyl chloride
Uncontrolled outgassing – SO2
Solvent decomposition issues – Isobutylene
Action Plan:
Evaluate new solvent / conditions
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Heat Flow Curve - Toluene at 25°C
Issues: ExothermicInduction period, accumulation of SOCl2En-mass reaction, uncontrolled out-gassing
Add thionyl chloride at 25oC over 40 minutes
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Heat Flow Curve - Toluene at 45°C
Issues: ExothermicStill did not initiate, accumulationSpontaneous reaction as 2nd equivalent of SOCl2 is added
Add thionyl chloride at 45oC over 40 minutes
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Heat Flow – MTBE/DMF at 25°C
Issues: Exothermic, feed controlledReaction initiates, controlled out-gassingPossible isobutylene formation from MTBE
Add thionyl chloride portion-wise at 25oC over 40 minutes
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Heat Flow – Toluene/DMF at 25°C
Issues: Exothermic, feed controlledReaction initiates, controlled out-gassingIsobutylene formation not possible
Add thionyl chloride portion-wise at 25oC over 45 minutes
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Why the Chemistry is DifferentChlorination via "Vilsmeier Intermediates"
N CH2Cl
CH2
N CH2Cl
CH2Cl
3.
x HCl
x HCl
H NMe2
OSOCl2
H NMe2 + Cl-
OSO2Cl
H NMe2 + Cl-
Clor
"Vilsmeier Intermediate"
N CH2OH
CH2OH
2.
x HCl
N CH2
CH2OHx HCl
N CH2Cl
CH2OHx HCl
H NMe2
O+
H NMe2 + Cl-
X X = Cl or OSO2Cl
"monochloro"
+
H NMe2
O
O
NMe2+
H
Cl-
O H
NMe2+Cl-
-HCl, -SO2
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Conclusions
• Reaction in Toluene with catalytic DMF is SAFE
• Optimized thionyl chloride• Simplified product isolation• Minimal Waste Disposal concerns
Chemical reaction safety testing in tandem with reaction optimization has led to a safe, acceptable and environmentally friendly synthesis able to produce >3.0 kg of material for use in the preparation of final product.
N
OH
N
Cl
Cl
x HCl
SOCl2OH
N
OH
Cl
SOCl2
Source: Stephen Stefanick et al, Organic Process Research and Development, 2002, 6, 938-942
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Improved Reductive Cyclization Procedure for the Preparation of 3,4-
Dihydro-1H-[1,4]oxazino[3,4-c][1,4]benzodiazepine-6,12(11H, 12aH)-
dione with Iron in Acetic Acid
Example # 2
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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IntroductionFor an ongoing project, we needed toprepare kilograms of 3,4-dihydro-1H-[1,4]-oxazino[3,4-c][1,4]benzodiazepine-6,12(11H,12aH)-dione
Our original procedure involved thereductive cyclization of 4-(2-nitrobenzoyl)morpholine-3-carboxylatemethyl ester 1 by simply adding iron powderto 1 in glacial acetic acid and refluxing.
NH
N OO
O
Fe (powder)HOAc, reflux
21
N
OH
O
CO2MeNH2
N
OH
O
CO2MeNO2
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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Results
A brief examination of the original procedure presented several challenges to scale-up……
• Dilute reaction concentration [5% w(g)/v(mL)] required a large volume of glacial acetic acid
• The use of 6.3 equivalents of iron pellets resulted in a significant agitation problem.
• The reaction needed 20 hours to achieve completion.• A prolonged workup and silica gel chromatographic purification
was necessary to isolate the product.• The mass yield was only 62%.
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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Our Initial Process Work Resulted In Several Improvements…..
• Double reaction concentration [10% w(g)/v(mL)] therefore cut the use of glacial acetic acid.
• Reduce the amount of Fe powder (2.5 equivalent, 325 mesh size).
• Shorten the reaction time to 1.5 hours.• The product is precipitated from water after removal of acetic
acid.• The HPLC assay yield is increased to 84%.• Low iron content (50-100 ppm) in the product is crucial for the
subsequent reactions.
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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However We Observed…
…An uncontrollable exotherm: after heating to 50-60 °C, the reaction temperature increased to reflux in less than 1 minute (115-116 °C)!
…The reaction mixture thickened - almost stopping the agitation.
…After 5-10 minutes, the reaction mixture thinned out to a more stirrable suspension.
…A potential chemical reaction hazard!!
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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Evaluation Using Reaction Calorimetry; How About Portion-wise Addition of Iron
powder?
Adding iron powder in fourportions to a heated solution of 1in acetic acid resulted in thefollowing heat flow curve.
• Heat flow curve from RC-1 reaction calorimeter.
• Red = Heat flow
• Blue = Tj Jacket temperature
• Green = Iron addition
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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From Portion-wise Addition, We Observed…
• Each iron addition step is exothermic.
• Thickening of reaction mixture and poor agitation were observed.
• Large calculated temperature rise (198 °C) existed.
• If loss of cooling/agitation and mischarge of all the iron powder, vigorous reflux and spewing of reaction mixture from reaction vessel might occur.
• A potential chemical reaction hazard still existed.
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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How About Reverse Addition?
A solution of 1 in acetic acid was added slowly to a stirring mixture of iron powder (325 mesh) and acetic acid at 75 °C.
• Heat flow curve from RC-1 reaction calorimeter.
• Yellow = Thermal conversion to product
• Red = Heat flow
• Blue = Tj Jacket temperature
• Green = Starting nitro ester 1 addition
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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From Reverse Addition, We Observed…
• The reaction is still exothermic but feed controllable.
• No thickening or poor agitation was observed.
• Large calculated temperature rise (158°C) existed.
• If loss of cooling/stirring and mischarge of all solution of 1 in acetic acid , vigorous reflux and spewing of reaction mixture from reaction vessel might occur.
• A chemical reaction hazard existed; however,…...
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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The Reverse Addition Is Our Choice
• Feed controlled addition with metering pumps of the acetic acid solution of 1 prevents accidental full mischarge of 1 thus minimizing the reaction hazard.
• The “continuous” heat flow resulting from the reverse addition is far more controllable than the “portion-wise” heat flow.
• No thickening or poor agitation leads to a much improved heat transfer.
• The reverse addition method offers a substantial improvement compared to other conditions.
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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SummaryThrough the use of RC-1 reaction calorimetry, we evaluated reaction safety and our scale-up process.
The improved reverse addition conditions allows us to safely prepare multi kilograms of 3,4-dihydro-1H-[1,4]-oxazino[3,4-c][1,4]benzodiazepine-6,12(11H,12aH)-dione 2 in high yield and high purity.
NH
N OO
O
Fe (powder)HOAc, reflux
21
N
OH
O
CO2MeNH2
N
OH
O
CO2MeNO2
Source: Stephen Stefanick et al, Organic Process Research and Development, 2003, 67 1067-1070
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Oxidation of 4-Halo-2-nitrotoluene with Tetrabutylammonium Permanganate in Pyridine:
Development and SafetyEvaluation
Introduction- RC1e used for safety assessment of
modified conditions that resulted in an improved and safer procedure
Target molecule needed in multigram quantities for a drug discovery projectTypical KMnO4 oxidation in water not satisfying Variations of conditions did not yield good enough resultsTBAP more soluble, relatively stable, gives better results
Source: Xiaohu Deng, Stephen Stefanick et al, Organic Process Research and Development, 2006, 10, 1287-1291
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Scale-Up Difficulties
- Induction period from hours to days- Very fast reaction once initiated- Cause of induction unclear- DSC and ARC test run before
increasing temperature to 60⁰C
Source: Xiaohu Deng, Stephen Stefanick et al, Organic Process Research and Development, 2006, 10, 1287-1291
Implemented changes and safety study- Slow addition of a cold
TBAP/pyridine solution to a 60°C solution of bromonitrotoluene
- Still induction period- Feed controlled exotherm- Reaction complete in 2.5 h, 80%
isolated yield- Reaction enthalpy: 575kJ/mol; worst
case temperature rise 72°CConclusion
- Unpredictable induction period- Reaction vigorously exothermic- Pose a serious safety concern- Safe for multigram- Not recommended for larger scale
Source: Xiaohu Deng, Stephen Stefanick et al, Organic Process Research and Development, 2006, 10, 1287-1291
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Thermal Safety of Chemical Processes by Francis Stoessel
Chemical Reaction Hazards, John Barton and Richard Rogers, Institution of Chemical Engineers, 1993
•Guidelines for Chemical Reactivity Evaluation and Application to Process Design, Center for Chemical Process Safety of the American Institute of Chemical Engineers,1995
•Bretherick’s Handbook of Reactive Chemical Hazards
•Chilworth Technology
Acknowledgements
Dr. Cynthia A. MaryanoffDr. Kirk SorgiDr. Dave Palmer Mr. Mitul PatelDr. Xini Zhang
Dr. Fuqiang LiuMr. Jeff GrimmXiaohu DengDan PippelNeelakandha Mani
References:
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Conclusions
Find reactivity hazard information.
Know the existence of databases - programs to search for safety information.
Know when Lab Testing of chemicals & mixtures is needed.
Know how to minimize risks in the lab.
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THANK YOU FOR YOUR ATTENTION
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