Diazomethane

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 Chemicals Sacramento, California
Aerojet Custom Chemicals
2005
1 Chemistry@thomasarchibald.com
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.
2005
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
2005
Diazomethane
H C H

+ _ N N
H _ C H
+ N N
Clean reactant - predictable impurities High yields Cost Effective Variety of reactions (carbanion, dienophile, carbene source):
Carbanion reactions Cyclopropanations Ring expansions Methylations
2005
Examples of Reactions of Diazomethane

O N O R
O R O
O N RCCH 2 Cl
[H]
OH RC CH 2 Cl
HCl
O O
O
O
RC OCl
CH 2 N 2
O
RCCHN 2
[H]
RC OOH
ArOH
O
O R
O RC CH 3
ArOCH 3
RC OOCH3
2005
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
2005
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

2005 7 Chemistry@thomasarchibald.com
Character of Diazomethane as an Explosive

CH2N 2 CH2 n + N2
Thermal decomposition of diazomethane at 220 oC 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
2005
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
2005
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.
2005
Vapor Composition of Diazomethane-Ether Solution
Weight % Diazomethane in Vapor vs Liquid Concentration and Temperature wt-% of Diazomethane in Ether Solution
60 50 40 30 20 10 0 -30 -20 -10 0 Temperature (C) 10 20 30 % Diazomethane in Vapor 10 9 8 7 6 5 4 3 2.5 2
2005
Operational Temperature Limits Safe Concentration

Temperature at Which Diazomethane in Vapor Reaches 15 Wt. %
30 20 Temperature (C) 10 0 -10 -20 -30 -40 Weight % Diazomethane in Liquid Ether 0 2 4 6 8 10
2005
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
2005
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 than methylene 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.
2005
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
2005
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.
2005
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.
2005
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.
2005
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.
2005
Representative HIV Protease Inhibitors
O N O O Saquinavir (Roche)
H2N O OH
N N O
N O N
= Extra Carbon
O O N O BMS-182193 N O N O O
Phenylalanine
2005
HIV Protease Inhibitors (Continued)
H2N O
OH
O O N O N SO2 NH2
Phenylalanine
= Extra Carbon
S
S OH H2N O
O O
N O
N O N
S-Phenylcysteine
Strategy
Approach: Start with existing chiral amino acid Add one carbon Separate diastereomers
BocNH
COOH
BocNH OH
R Isostere
Boc-Phenylalanine
BocNH
Key epoxide
2005
Selected Routes:
Bn2N O
Bu Li or Li Metal Bn2N BrCH2Cl -50 to -35oC
Cl OH
R2N
Ng, J.S., et. al. Organic Process Research and Development 1997,1, 46. Beaulieu, P.L. et. al. J. Org. Chem. 1997, 62, 3441.
TMSO Cl O
OTMS OH OTMS R2N O COOH
R2N
R2N O Parkes, K.E.B. et. al. J. Org. Chem. 1994, 59, 3656. R2N
OH O
2005
Metallation: Complete Route

[H] Bn2N COOH Bn2N OH [O] Bn2N O H
Li Metal Bn2N O H BrCH2Cl -50oC Bn2N OH Cl
de 89% 38-45% Yield
[H] Bn2N OH Cl
Cl
1. Boc2O BocNH Cl 2. Base OH O
H3N
2005
Aerojets Process to BOC Epoxide
Et3N ROCOCl BocNH COOH BocNH O O O O
CH2N 2 R BocNH O
N2
HCl BocNH O
One Pot Reaction to chloroketone
[H] BocNH Cl OH Cl
Base BocNH O
Yield 70% overall 80% d.e.

Comparison of Routes
Route
Metallation
Yields % (key step) 25-35 (60) 13 30
TrisTMS ethene Hydroxy ester
Scale Problems Feasible per ? batch 200 low temp, Yes kg starting material >kg Very low Yes yield Barton decarboxylation Sharpless azide diazomethane No
Company
Boehringer Ingelheim; Serles Roche Roche
Azido Diol Diazomethane
67 60-70 (80-90)
100 kg
No Yes
Roche Aerojet
Based on Published Literature
2005
Generation and Handling of Diazomethane in the Plant
2005
Traditional Diazomethane Generation

NH2CH3 CH3 PTSC NaNO 2 CH3 SO2 NHCH3 AcOH DIAZALD NO CH3 SO 2 NCH3 KOH CH2N2 / Et2O ROH/Et2O CH3 SO2Cl CH3 SO2 NHCH3
NO SO 2 NCH3
Yields: 70-80%
Requires distillation
Lots of waste
2005
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.
2005
Plant Experience (Continued)

Reaction is exothermic but requires an excess of diazomethane to reach 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 form chloromethylketone 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.
2005
Other Sources of Diazomethane

NaNO2 CH3NHCONH2 HNO3 NO CH3NCONH2 KOH
CH2N2
Methyl urea is an inexpensive starting material Nitrosation proceeds rapidly at 15 oC 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
2005
Aerojets 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
2005
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.
2005
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
2005

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Diazomethane

Aerojet Custom Chemicals

Warning: This Presentation is Rated H for Hazardous

Aerojet Custom Chemicals

Overview of the Presentation

Overview of Why We Needed Large Scale Diazomethane

In-Plant Batch Experience

Aerojet Custom Chemicals

Aerojet Custom Chemicals

Examples of Reactions of Diazomethane

Aerojet Custom Chemicals

Aerojet Custom Chemicals

Diazomethane - A Compound with a Reputation

If True: Diazomethane is Impossible to Scale-up

Character of Diazomethane as an Explosive

Aerojet Custom Chemicals

What are the Detonability Hazards of Diazomethane?

Most highly energetic materials are easily desensitized

Aerojet Custom Chemicals

Aerojet Custom Chemicals

Vapor Composition of Diazomethane-Ether Solution

Aerojet Custom Chemicals

Operational Temperature Limits Safe Concentration

Aerojet Custom Chemicals

Implication: Safety is Related to Equipment Design

Aerojet Custom Chemicals

Explosivity of the Diazomethane System

It is a good idea to limit equipment head space.

Aerojet Custom Chemicals

One (1) documented fatality (due to ingestion)

Aerojet Custom Chemicals

Aerojet Custom Chemicals

The Sharp Edge Issue

Aerojet Custom Chemicals

Strategy for Handling Diazomethane

Aerojet Custom Chemicals

Why We Needed Diazomethane

Aerojet Custom Chemicals

Representative HIV Protease Inhibitors

Aerojet Custom Chemicals

HIV Protease Inhibitors (Continued)

Aerojet Custom Chemicals

Bu Li or Li Metal Bn2N BrCH2Cl -50 to -35oC

OTMS OH OTMS R2N O COOH

Aerojet Custom Chemicals

Metallation: Complete Route

Li Metal Bn2N O H BrCH2Cl -50oC Bn2N OH Cl

de 89% 38-45% Yield

1. Boc2O BocNH Cl 2. Base OH O

Aerojet Custom Chemicals

Aerojets Process to BOC Epoxide

Et3N ROCOCl BocNH COOH BocNH O O O O

Yield 70% overall 80% d.e.

Aerojet Custom Chemicals

Yields % (key step) 25-35 (60) 13 30

TrisTMS ethene Hydroxy ester

Boehringer Ingelheim; Serles Roche Roche

Azido Diol Diazomethane

Based on Published Literature

Aerojet Custom Chemicals

Generation and Handling of Diazomethane in the Plant

Aerojet Custom Chemicals