diazomethane

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


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.


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


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

+ +__


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


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


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


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


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


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.


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


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)


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


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.


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


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.


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.


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.


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.


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


HIV Protease Inhibitors (Continued)

O

OHH2N

Phenylalanine

S

ONN

O

OO N

S

OH2N

OH

S-Phenylcysteine

= Extra Carbon

O

O

O

NNH2SO2

NO


Strategy

BocNH COOH BocNH

OH

R

BocNHO

Boc-Phenylalanine Isostere

Approach: Start with existing chiral amino acidAdd one carbonSeparate diastereomers

Key epoxide


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.


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


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.


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


Generation and Handling of Diazomethane in the Plant


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


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.


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.


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


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


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.


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

Documents

diazomethane