PHOENIXCHEMICALS

“Taming Nitrogen”

Industrialisation of Diazomethane -

The Application of Flow Technology Towards

Hazardous Chemistry

Presented to

RSC – Elements of Success Conference

14-15th June 2006

Lee Proctor

Phoenix Chemicals Ltd.

PHOENIXCHEMICALS

Presentation Summary

• Introduction to Phoenix Chemicals

• Introduction to continuous processing

• “Taming nitrogen” – the diazomethane story

PHOENIXCHEMICALS

Introduction to Phoenix

PHOENIXCHEMICALS

Phoenix Chemicals

• Formed in 1991

- engineered solutions to chemical synthesis

• 85 Employees

• Located in NW England

• Customers 100% pharmaceutical

PHOENIXCHEMICALS

Business Model

Technology based company specialising in continuous processing

Develop Technology

Out-licenceApply to

Fine Chemical

Manufacture

‘Sale’ of

Equipment

PHOENIXCHEMICALS

Strengths

• Global leader in developing and utilising continuous technology

to manufacture pharmaceutical intermediates

• Our technology is diverse, economic, sustainable and delivers

high quality products on demand

PHOENIXCHEMICALS

Introduction to Continuous Processing

PHOENIXCHEMICALS

Traditional Chemical Manufacture

Stirred

tanks

16th Century technology for retrieving gold from ore

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Today’s Laboratory Chemists

Stirred tank vessels

PHOENIXCHEMICALS The Continuous Approach

Conventional Batch

Reactor

Plug Flow Continuous

Reactor

PI

PHOENIXCHEMICALS

Advantages of Continuous Processing

• Concentration of reactants/product/intermediates is constant

• Reaction rates can be optimised to maximise throughput

• Low inventory of hazardous materials

• Low-cost plant allowing full containment

• Remote automated plant control

• Continuous monitoring of all process flows and temperatures

• Continuous on-line monitoring of process streams

• Improved product consistency

• Reduced cross-contamination

• Reduced waste

• Reduced environmental emissions

• Reduced energy consumption

PHOENIXCHEMICALS Why Consider

Continuous Processing?

• Oil Industry

• largely continuous processing

• highly efficient

• < 1% output is waste

• Fine Chemical Industry

• largely batch processing

• highly inefficient

• 1mt output produces >25mt waste

• Effect of legislation and competition

• Increasing legislation – eg REACH, IPPC

• Increasing competition – China, India

NEED MORE EFFICIENT AND SUSTAINABLE

MANUFACTURING TECHNOLOGY

PHOENIXCHEMICALS

Continuous Processing

Suitable Chemistry

• Fast energetic reactions are ideal

• Gas liquid reactions

• Reactions involving toxic reactants/intermediates

• Reactions requiring careful process control to achieve high

chemical yield and selectivity

• Hazardous reactions involving unstable intermediates

• Reactions limited by heat transfer

Nearly all chemical reactions

PHOENIXCHEMICALS

Manufacturing Route Selection

TRADITIONAL APPROACH PHOENIX APPROACH

Design suitable plantAvailable plant ?

(batch)

Best chemical

synthesisSuitable chemical

synthesis

PHOENIXCHEMICALS

“Taming Nitrogen”

The Diazomethane Story

PHOENIXCHEMICALS

Diazomethane Chemistry

CH2N2

R OH

O

RN

ON

HX

RX

O

RO

ORR

X

OH

R

O

ROR

O

Acid Diazoketone Halomethylketone

Wolff Rearrangement

Homologated Acid

Reduction Substitution

Halomethylalcohols

Epoxides

PHOENIXCHEMICALS

Diazomethane Chemistry

R

R

R

R N

N

CH2N2

-N2

R

R

isomerise

R

R NH

N

PHOENIXCHEMICALS

Industrialization of Diazomethane

Nelfinavir (Pfizer, Roche)

Saquinavir (Roche)

Amprenavir (GSK)

Atazanavir (BMS)

TMC114 (J&J)

PHN

R

O

PHN

R

OH

Cl

R = SPh

P = Cbz-

R = Ph

P = Boc-

PHN

R

O

R = Ph

P = Boc-

PHOENIXCHEMICALS

Synthetic Route

PHN CO2H

R

PHN

R

O

O

O

OEt

PHN

R

O

CHN2

PHN

R

O

Cl

CH2N2 (DAM)

Diazald®

Stage 1

Stage 3

Stage 4

Stage 2

Protected amino acid Mixed Anhydride (MA) Diazoketone (DAK)

Chloroketone(CK)

PHOENIXCHEMICALS

Synthetic Route

PHN

R

Cl

O

PHN

R

OH

Cl

(2R,3S) Chloroalcohol

PHN

R

O

(2R,3S) Epoxide

PHN

R

OH

Cl

(2S,3S) Chloroalcohol

PHN

R

O

(2S,3S) Epoxide

PHOENIXCHEMICALS

Project Aims

• Develop process technology capable of making >200mt

of CK products per annum :

• This requires:

- Handling unstable intermediates

- Generating >60mt diazomethane

• Safe, non-flammable system

• Continuous system

PHOENIXCHEMICALS

The Process and its Development

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PHOENIXCHEMICALS

Solvent Store

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Mixer Area

upper floor

PHOENIXCHEMICALS

Mixer Area

ground floor

PHOENIXCHEMICALS Stage 1

Mixed anhydride

PHN CO2H

RNMM

PHN

R

O

O

O

OEtPHN

R

O

O

O

OEtECF/MDC, 0°C

+ NMM.HCl

Water wash

Phase Separate

• Yield >98%

• Conditions 4 seconds / 5-10°C

• By-product NMM.HCl

- high velocities prevent blocking

- removed by countercurrent extraction with water

• Stability Stable

- No decomposition or racemisation

PHOENIXCHEMICALS

4s

PHOENIXCHEMICALS MA Reactor

MA mixer tee

Centrifugal

extractors

Residence tube

PHOENIXCHEMICALS

Stage 2

Diazomethane Introduction

• Highly toxic and explosive gas (bpt. = -23°C)

• Explosive properties:

LEL has not been reported in the literature

“5mm of DAM in nitrogen can explode at ambient”

Widely reported that explosive decomposition can occur

in the presence of ground glass joints, rough surfaces,

metals, metal salts and exposure to light

PHOENIXCHEMICALS

Diazomethane

PHOENIXCHEMICALS

Diazomethane

PHOENIXCHEMICALS

Diazomethane

Methods of Manufacture

Examples:

• Aldrich Diazald® kit - generates up to 300mmol DAM in ether (1)

• Large scale batch manufacture - Aerojet-General Corporation (2)

Methodology/Limitations:

• Procedures generate DAM solutions using volatile/flammable solvents

• Reactions are bi-phasic and require PTC to achieve high yields

• Distillation of DAM solutions is required

(1) Black Aldrichchimica Acta 16(1) 3-10 (1983)

(2) US patent 5,817,778

PHOENIXCHEMICALS

Phoenix’ Diazomethane Process

Design Aims

• Non-flammable system

• Continuous process to minimize hazard

• “Purify” DAM before carrying out subsequent chemistry

• Define the safe operating envelope by determining the LEL

• Carry out full scale explosion testing on the final reactor design

• Develop methods for continually monitoring the concentration of DAM

Phoenix’

Diazomethane – Process

(GB2357501)

PHOENIXCHEMICALS

N2

Drain

Diazald/DMSOKOH/water

CH2N2/N2

S

O

O

N

NO

CH3H3C CH2N2

KOH/H2O

DMSOSOK

O

O

H3C+

PHOENIXCHEMICALS

Phoenix Diazomethane

Process Advantages

• Homogenous/single-phase reaction mixture

• Rapid reaction generating DAM in high yield (>95%) without

the need for PTC

• High purity DAM produced essentially free of solvents

• Non-flammable and low-volatility solvent system

• The reactor is simple and has no moving parts and therefore no

moving seals

• Safe operating envelope defined by determination of the LEL

PHOENIXCHEMICALS

LEL Testing (1)

Experiment Design

Spark gapPneumatic valve

Pressure gauge 2 Pressure gauge 1

0.5m 0.235m Gas flow in

(1) Testing carried out in conjunction with Centre for Explosion Studies - University of Wales Aberystwyth

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7

P1 Max (psi)

P2 Max (psi)

LEL = 3.9% (v/v)

P Max Air

% DAM in Air

Ma

xP

ressure

Ri s

e(p

si )

PHOENIXCHEMICALS

Lower Explosive Limit (Air)

PHOENIXCHEMICALS

Explosive Limit (Nitrogen)

0

0.2

0.4

0.6

0.8

1

1.2

0 5 10 15 20 25 30

P1 Max (psi)

P2 Max (psi)

P Max Nitrogen

% DAM in Nitrogen

Max P

ressure

Ris

e (

psi) Explosive Limit = 14.7% (v/v)

PHOENIXCHEMICALS

Reactor Testing (1)

• 17% DAM/Air Explosion propagated into 1L Pilot reactor

equipped with a full bore 2 bar bursting disk

Peak pressure = 3.45bar before disk failure

• Full scale testing on 160L reactor using mimic gas (7% ethylene/air)

Reactor equipped with a full-bore 3.4bar bursting disk

Peak pressure = 3.57bar before disk failure (Rate = 35.7bar/s)

(1) Testing carried out in conjunction with Centre for Explosion Studies - University of Wales Aberystwyth

PHOENIXCHEMICALS

Reactor Testing

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Production

• Continuous monitoring of gas-phase DAM concentration is

linked to plant control system

• Maximum DAM inventory <80g at full scale production rate

• Personnel monitoring of DAM levels <0.2ppm

• Thoroughly investigated the stability of Diazald®, defined shipping and

handling characteristics (1)

• Full-scale DAM plant has been in operation for over 6 years

(1) In conjunction with Chilworth Technology Ltd.

PHOENIXCHEMICALS Stage 3

Diazoketone

PHN

R

O

O

O

OEt

PHN

R

O

CHN2

MeO

O

OEt

PHN

R

O

OMe

+

2 x CH2N2

• Yield >98%

• Conditions 5-10°C / 4 minutes

• By-products carbonate (1 Eq.) / methyl ester (<1% HPLC area)

Process IR-MP

PHOENIXCHEMICALS

Stage 4

Chloroketone

PHN

R

O

CHN2

PHN

R

O

Cl

+ N2

HCl (g)

• Yield >96%

• Reaction temperature 5°-10°C

PHOENIXCHEMICALS

Process IR-MP

PHOENIXCHEMICALS Stages 1, 3 and 4

PAT Monitoring by FT-IR

PHOENIXCHEMICALS

On-Line PAT using FT-IR

Diazoketone

Mixed anhydride

PHOENIXCHEMICALS

Continuous Evaporator

& Environmental abatement

PHOENIXCHEMICALS Phase I & II

Process Operation

PHOENIXCHEMICALS

Downstream Process

(2S,3S-chloroalcohol)

PHN

R

OH

Cl

(2S,3S) Chloroalcohol

PHN

R

Cl

O

Achiral reduction

Chloroalcohol

• Yield >80%

• Purity >98%

• Selectivity >99:1 (SS:RS)

PHOENIXCHEMICALS

Downstream Process

(2R,3S-chloroalcohol)

PHN

R

OH

ClPHN

R

Cl

O

Cat* / solvent

Novel chiral transfer hydrogenation technology accesses

other diastereoisomer with a de >97%

PHOENIXCHEMICALS

PHOENIXCHEMICALS

Downstream Process

(Epoxidation)

PHN

R

O

PHN

R

Cl

OH

Epoxidation under PTC conditions

Epoxide

• Yield >90-95%

• Purity >99%

• Selectivity >99:1 (>98%de)

PHOENIXCHEMICALS

Summary

• The plant can produce 200mt of chloroketone per annum

• To achieve this the plant produces over 60mt of diazomethane per annum.

• Continuous processing technology ensures the maximuminventory of diazomethane at full the scale production rate is <80g

• Chloroalcohol and Epoxide Intermediates are produced in high yield and high puritywithout the need for any additional purification

PHOENIXCHEMICALS

4 Continuous Steps “In One”

PROTECTED AMINO ACID

MIXED ANHYDRIDE

CHLOROKETONE

CHLOROALCOHOL

DIAZOKETONE

DIAZOMETHANE

4 seconds

240 seconds

9 seconds

10 seconds

YIELD >90%

EPOXIDE

PHOENIX PRODUCTS2 BATCH STEPS

- PHASE II 12 hrs

16 hrs

PHOENIXCHEMICALS

Continuous processing and flow technology

is the future of fine chemical and pharmaceutical manufacturing

Phoenix is recognised as a world leader

in developing and successfully applying this technology

PHOENIXCHEMICALS

Change your thinking …

…improve your chemistry