Vous êtes sur la page 1sur 34

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.

Aerojet Custom Chemicals

2005

2 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

3 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

4 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

5 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

6 Chemistry@thomasarchibald.com

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


Aerojet Custom Chemicals
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

Aerojet Custom Chemicals

2005

8 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

9 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

10 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

11 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

12 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

13 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

14 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

15 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

16 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

17 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

18 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

19 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

20 Chemistry@thomasarchibald.com

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
Aerojet Custom Chemicals
2005 21 Chemistry@thomasarchibald.com

Strategy
Approach: Start with existing chiral amino acid Add one carbon Separate diastereomers

BocNH

COOH

BocNH OH

R Isostere

Boc-Phenylalanine

BocNH

Key epoxide
22 Chemistry@thomasarchibald.com

Aerojet Custom Chemicals

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

Aerojet Custom Chemicals

2005

23 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

24 Chemistry@thomasarchibald.com

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.


2005 25 Chemistry@thomasarchibald.com

Aerojet Custom Chemicals

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

Aerojet Custom Chemicals

2005

26 Chemistry@thomasarchibald.com

Generation and Handling of Diazomethane in the Plant

Aerojet Custom Chemicals

2005

27 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

28 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

29 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

30 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

31 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

32 Chemistry@thomasarchibald.com

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.

Aerojet Custom Chemicals

2005

33 Chemistry@thomasarchibald.com

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

Aerojet Custom Chemicals

2005

34 Chemistry@thomasarchibald.com