2005 1Aerojet Custom Chemicals [email protected]
Diazomethane
Commercialization of a Highly Hazardous Chemical
1st International Conference on Organic Process Research and Development
by
Thomas Archibald,* Der-Shing Huang, Jim Barnard, Harlan Reese, Mark Pratton
Aerojet Custom ChemicalsSacramento, California
2005 2Aerojet Custom Chemicals [email protected]
Warning: This Presentation is Rated H for Hazardous
• The information in this presentation contains graphic descriptions of dangerous chemical reactions.
• Diazomethane is both highly toxic and explosive. Adequate protection for personnel and property must be taken before any reaction is conducted.
• The information in this presentation is believed to be correct, and based on our experience we believe diazomethane is a viable reagent for large scale manufacture. However, independent and detailed safety and hazards reviews must be completed for each process and facility before any use of diazomethane is undertaken.
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Overview of the Presentation
• Diazomethane Chemistry– Useful Diazomethane Reactions.– Diazomethane Hazards
• Explosivity• Toxicity
• Overview of Why We Needed Large Scale Diazomethane– Amino Acid Isosteres
• In-Plant Batch Experience
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Diazomethane
• Clean reactant - predictable impurities• High yields • Cost Effective• Variety of reactions (carbanion, dienophile, carbene source):
– Carbanion reactions– Cyclopropanations– Ring expansions– Methylations
C N NH
HC N N
H
H
+ +__
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Examples of Reactions of Diazomethane
CH2N2RCOCl
RCCHN2
O
RC OOH
RC OOCH3
ArOH
ArOCH3
OO
O
OR
O
OR
NN
HCl
RCCH2Cl
O
[H]O
O
RC CH3
O
RC CH2Cl
OH
O
R
[H]
R
O
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Profile of Diazomethane
• Discovered by von Pechmann (Ber. 1894, 27, 1888.)• CAS 334-88-3• Highly toxic and explosive yellow gas (bp -23oC, mp -145oC)• Musty odor (no accepted threshold value)• Vapor Density 1.4 (air=1.0)• Auto-ignition temperature 150oC• Toxicity
– PEL (OSHA) 0.2 ppm (0.4 mg/m3)– TLV-TWA (ACGIH) – 0.2 ppm (0.4 mg/m3)
See: http://www.hhmi.org/science/labsafe/lcss/lcss27.htm
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Diazomethane - A Compound with a Reputation
“Diazomethane is not only toxic, but also potentially explosive... ground joints and sharp surfaces should be avoided... imperative that diazomethane solutions not be exposed to...light......diazomethane should not be distilled......avoid metals......warned against use of Drierite...
Insert in Org Synthesis Col. Vol 2
If True: Diazomethane is Impossible to Scale-up
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CH2N2 CH2 N2n +
Character of Diazomethane as an Explosive
• Thermal decomposition of diazomethane at 220oC gives nitrogen and ethylene, hydrocarbons and polyethylene.
• Temperature accelerates decomposition:– 10% decomposition occurs in 11 sec at 217oC and 24 hours at 135oC
• As little as 5mm of diazomethane in nitrogen gas can detonate at ambient.Steacie, E.W.R. J.Chem.Physics 1931, 35, 1493.
• Heat of Explosion in nitrogen is estimated to be -130 kcal/100 g • Heat of Explosion in oxygen would be -342 kcal/100g • RDX (High Explosive) is -137.5 kcal/100g
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What are the Detonability Hazards of Diazomethane?
• Neat Diazomethane is a very energetic and sensitive material– However it can be handled in vacuum lines with precautions
• Most highly energetic materials are easily desensitized– Examples: nitroglycerine
• Solutions of diazomethane are not detonable.• However, because of the low boiling point, diazomethane concentrates
in the vapor phase.• Diazomethane vapor is very dangerous
– Diazomethane represents unique hazards for scale-up
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Hazards in Ether
• In a reactor, the atmosphere contains:– Diazomethane– Solvent (normally ether or other high heat capacity diluent)– Nitrogen (or other inert gas)
• Historical data suggests the explosive limit of diazomethane should be similar to that of hydrazoic acid (17% explosive limit in gas phase)
• Actual explosive limit in organic solvents is being determined. • Operational conditions can be determined and are dependent on
temperature and boiling points of the solvent used.
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Vapor Composition of Diazomethane-Ether Solution
Weight % Diazomethane in Vapor vs Liquid Concentration and Temperature
0
10
20
30
40
50
60
-30 -20 -10 0 10 20 30
Temperature (C)
% D
iazo
met
han
e in
Vap
or
1098765432.52
wt-% of Diazomethanein Ether Solution
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Operational Temperature Limits Safe Concentration
Temperature at Which Diazomethane in Vapor Reaches 15 Wt. %
-40
-30
-20
-10
0
10
20
30
0 2 4 6 8 10
Weight % Diazomethane in Liquid Ether
Tem
per
atu
re (
C)
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Implication: Safety is Related to Equipment Design
• All parts of the equipment must be closely analyzed for potential places for diazomethane to concentrate.
• High vapor phase concentrations of diazomethane must be avoided.• Temperature control is critical.• Zones in which large temperature variations can occur should be
avoided.
• All reactions should be run remotely
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Explosivity of the Diazomethane System
• Use a high volatility solvent at low processing temperatures to stay below explosive limits. Solvents must boil below 40oC
• Use a high heat capacity solvent such as diethyl ether rather thanmethylene chloride.
• Pressure rise in reactor can be calculated in the event of a vapor phase detonation.– For example, decomposition of vapor above a 3% diazomethane solution
in a 200 gallon Pfaudler reactor yields only a 6 psi pressure increase
• It is a good idea to limit equipment head space.
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Comments on Toxicity
• OSHA Permitted Exposure Limits of 0.2 ppm is similar to bromine– Exposure exceeding limits may result in
• Irritation of the respiratory system, eyes, skin• Chest discomfort, headache, weakness, possible collapse• Allergic reaction
– Similar to isocyanate in hypersensitivity– Asthmatic symptoms– Delayed onset
• One (1) documented fatality (due to ingestion)
• Aerojet considers toxicity to represent the most serious threat in the use of diazomethane.– Pale yellow gas– Insignificant odor– Insidious
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Chemical Reactivity
• Diazomethane hydrolyzes in water slowly (t1/2 approx. 24 h) to give methanol.
• Diazomethane reacts rapidly with acids. Aqueous hydrochloric acid gives methyl chloride. Acetic acid gives methyl acetate and is an excellent choice for scrubbers.
• Most reactions of diazomethane are fast and extremely exothermic.• Presence of water in the diazomethane is generally not detrimental• Diazomethane does not appear to react with Drierite, however any
place in which neat diazomethane can collect should be avoided.• As diazomethane is produced, it should be reacted immediately.
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The Sharp Edge Issue
• If ground glass or sharp edges causes diazomethane to explode, it would be very difficult, if not impossible, to run large scale reactions in Pfaudlers.
• There is no evidence that ground glass joints cause a problem directly. However, decomposition of diazomethane gives polyethylene that builds up on the joint and prevents a tight fit. Improperly fitting joints give a source of leakage and a place to allow diazomethane to collect.
• We have run over 250 runs in 12 l, 22 l and 50 l ground glass jointed flasks with normal condensers and other fittings without a single incident.
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Strategy for Handling Diazomethane
• Precautions:– Make & use immediately: DO NOT STORE– Detailed hazard analysis conducted including FMEA– Run reactions remotely in restricted facilities.– Safety interlocks on additions and critical process controls– Decontaminate all equipment before personnel return to building.– Scrub exit points (or potential exit points) with “killer” solutions– Supervise (medically) all operators– Equip operators with respirators, protective coats, gloves
• Results:– No incidents or safety problems after more than 500 runs in batches up to
750 gallon reactor size.
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Why We Needed Diazomethane
• We needed a synthetic tool to extend amino acids by one carbon• The targets containing multiple chiral centers and a central
hydroxyethylamine group.• In early clinical work, diazomethane was the only reagent that could
make clean product with few side products. • As other routes have been developed, the diazomethane route remains
cost competitive and gives the best quality product.
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Representative HIV Protease Inhibitors
NN
N
O
O
ON
N
N
O
O
Saquinavir (Roche)
O
N
O
NO
O
N O
O
BMS-182193
O
OHH2N
Phenylalanine
= Extra Carbon
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HIV Protease Inhibitors (Continued)
O
OHH2N
Phenylalanine
S
ONN
O
OO N
S
OH2N
OH
S-Phenylcysteine
= Extra Carbon
O
O
O
NNH2SO2
NO
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Strategy
BocNH COOH BocNH
OH
R
BocNHO
Boc-Phenylalanine Isostere
Approach: Start with existing chiral amino acidAdd one carbonSeparate diastereomers
Key epoxide
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Selected Routes:
Bn2N
OH
ClBrCH2Cl-50 to -35oC
Bu Li or Li Metal
Bn2NH
O
Ng, J.S., et. al. Organic Process Research and Development 1997,1, 46.Beaulieu, P.L. et. al. J. Org. Chem. 1997, 62, 3441.
R2NCl
O
TMSO OTMS
OTMSR2N
O
COOH
OH
OH
O
R2NR2N O
R2N O
Parkes, K.E.B. et. al. J. Org. Chem. 1994, 59, 3656.
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Metallation: Complete Route
Bn2N COOH Bn2NOH
Bn2NH
O
Bn2NH
O
[H] [O]
Li Metal
BrCH2Cl-50oC
Bn2N
OH
Cl
Bn2N
OH
Cl
[H]
38-45% Yieldde 89%
H3N+
OH
Cl
Cl-Boc2O
2. Base
1.
BocNHO
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One Pot Reaction to chloroketone
Aerojet’s Process to BOC Epoxide
BocNH COOH
BocNH
OH
Cl BocNHO
BocNH
O
O
O
OR
Et3N
ROCOCl
CH2N2
BocNH
ON2
BocNH
OCl
HCl [H] Base
Yield 70% overall80% d.e.
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Comparison of Routes
Route Yields%
(key step)
Scaleper
batch
Problems Feasible?
Company
Metallation 25-35(60)
200kg
low temp,startingmaterial
Yes BoehringerIngelheim;
SerlesTrisTMSethene
13 >kg Very lowyield
Yes Roche
Hydroxy ester 30 - Bartondecarbox-ylation
No Roche
Azido Diol 67 - Sharplessazide
No Roche
Diazomethane 60-70(80-90)
100kg
diazo-methane
Yes Aerojet
Based on Published Literature
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Generation and Handling of Diazomethane in the Plant
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CH3 SO2ClNH2CH3
CH3 SO2 NHCH3
PTSC
CH3 SO2NHCH3
NaNO2
AcOHCH3 SO2NCH3
NO
DIAZALD
CH3 SO2NCH3
NO KOH
ROH/Et2OCH2N2 / Et2O
Yields: 70-80% ? Requires distillation ? Lots of waste
Traditional Diazomethane Generation
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Batch Diazomethane• Batch process - Essentially a large lab generator using production
equipment..• Diazald in ether is added at 45-55oC to a 35-40% potassium hydroxide
solution with phase transfer catalyst.• Reactor equipped with interlock to prevent Diazald solution addition
below the boiling point of ether or above 70C.• Design of condensors is important to avoid local concentrations.• Vent lines require special scrubbing capacity• Ether containing 3 wt-% of diazomethane is distilled into mixed
anhydride at -30oC.
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Plant Experience (Continued)
• Reaction is exothermic but requires an excess of diazomethane toreach completion. Diazomethane is rinsed out of the generator with excess ether.
• Excess diazomethane is reacted with acetic acid. All reactors are blown clean with nitrogen into scrubbers for 30 minutes.
• The diazoketone solution is reacted with HCl to formchloromethylketone which in turn is washed with water and held for further reaction.
• After initial start up conditions, yields vary less than 3% from run to run.
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Other Sources of Diazomethane
• Methyl urea is an inexpensive starting material• Nitrosation proceeds rapidly at 15oC• Diazomethane formation is rapid at 0oC without phase transfer catalyst• By-products are sodium nitrate and sodium cyanate• Reactions are done in water BUT:• N-nitrosomethyl urea is a listed carcinogen with limited thermal
stability
CH3NHCONH2
NaNO2
HNO3CH3NCONH2
NOKOH
CH2N2
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Aerojet’s Continuous Diazomethane Process• Advantages:
– Yields exceed 80% – Allows control of process variables to give consistent quality– Lowest cost operation– Small amounts of diazomethane present at any time– Demonstrated at rates of 0.8 kg per hour of diazoketone– Small-scale setup, occupying .2 cubic meters of space, can produce 3,800
kg of product per year– Plant implementation in static mixers to limit head space.
• Details to follow
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Conclusions
• Diazomethane is a clean, versatile reagent.• Diazomethane can used be in chemical production.• Appropriate facilities, safety equipment, training and hazards analysis
are mandatory.• Because of toxicity and explosivity, engineering controls must be
carefully implemented.• Operational discipline is a requirement.
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Acknowledgments
• Scale-up of Diazomethane is a joint Chemistry & Engineering Effort• Chemists:
– Aslam Malik– Steve Backlund– Kiren Dirken
• Engineers– Joe Campbell– Lee Howell– Mike Mugnaini– Jeff Robinson– Greg McParland