Examples of Industrial Biotechnology in the

Chemistry-using Industries

Peptides: Hydrolases
ASPARTAME artificial sweetener: using Proteases

NHZ
+

H2N

DL

NH2
COOMe

HOOC
L

COOH

ASPARTIC ACID

1. Thermolysin
2. H2 / Cat.

CH2Ph
PHENYL ALANINE

200 TIMES SWEETER THAN SUCROSE

Great example of Regio- and Enantioselectivity

DSM / TOSOH (HOLLAND SWEETNER CO) : multi thousand t/a

Old chemical method by Searle protection / deprotection
more expensive

H
N

HOOC

COOMe

O
ASPARTAME

CH2Ph

Antibiotics : Hydrolases
D-HYDROXYPHENYLGLYCINE : Two steps Two enzymes

DYNAMIC RESOLUTION
100% conversion to a single isomer
Intermediate for -Lactam antibiotics - Amoxicillin / Cephadroxil
KANEGAFUCHI / DSM / SNAM Progetti / GSK : > 8,000 t/a

Pharma: Ligases / Synthetases

L-EPHEDRINE : Chiral condensation / C-C bond formation

A natural alkaloid - anti-asthmatic and for blood circulation disorders

Reaction discovered in 1921

Industrial production by KNOLL, Malladi (India) etc.

Speciality Chemicals: Cosmetics

Myristyl myristate : Emollients - Simple Esterification

Energy consumption reduced by

60%
Emission of pollutants reduced by
60-90%
Emission of greenhouse gases reduced by 62%
Chemical process:

5 purification steps:

temp: up to 240OC

Biocatalytic process:

0 purification steps:

temp: up to 60OC

IFSCC Congress 2006, Degussa & Novozymes

Bulk Chemicals: Nitrile hydratase

Acrylamide : Bulk Chemical Production

Mitsubishi Rayon (formerly Nitto Japan) and Others : ca. 300,000 t/a (of total 500,000 t/a)
Single largest commodity chemical manufacture through Biocatalysis

Sulfuric acid hydration process 1950s - 1970s

Copper catalyst process

1970s - 1980s

Enzymatic process

since 1985

Cleaner Cheaper Chemistry

Replacement of Pd catalyst, used at 70oC, in organic solvent, in a high
pressure hydrogenation.
Lotrafiban scale-up;
GSK

Increased yield
Reduced environmental impact
Replacement of hazardous operations
Reduced cost (No organic solvent, ambient temp)
Reduced reactor time

On a manufacturing scale,

3 tons of palladium catalyst per year

replaced with 150 kg of immobilised enzyme.

Chiral Alcohols
Enzymes in Organic Solvents!
A groundbreaking discovery!!

Lipase catalysed Kinetic resolution

A well-established platform now

Several major applications

Intermediates in Pharma, Agchem, Fragrance etc

Fatty Dicarboxylic acids

CATHAY INDUSTRIAL BIOTECH

C11 Undecanedioc acid

C12 Dodecanedioic acid
C13 Brasyllic acid
C14 Tetradecanedioic acid
C15 Pentadecanedioic acid
C16 Hexadecanedioic acid

Trial production
FATTY ACIDS
DIACIDS

Omega oxidation of alkanes

CH3 (CH2)n CH3
FERMENTATION

HOOC (CH2)n COOH

n = C9 C14

Various applications

Natural Vanillin
From natural Ferulic acid & natural biocatalysts
CO2H

2% w/w in vanilla beans

0.2% w/w in vanilla extract

CHO

OMe

OMe
OH

OH

Natural vanillin : ~ $4,000 / kg

Synthetic
: ~ $25 / kg

Made by Givaudan, Rhodia, SAFISIS and others

Natural Ferulic acid available from rice, maize etc and cheaper than vanillin.
Oxidative cleavage : enzymatic hydration and retro-aldol.

Occurs in whole cells bacteria & fungi

Corn to Polyesters
1,3 Propanediol

DuPONT-GENENCOR VENTURE

Renewable resource content of Sorona : 37%

Corn to Polylactic acid

DOW-CARGILL VENTURE

First large scale production by NatureWorks

First plant - 14,000 t/a in NEBRASKA (US) in 2000-01 / $300 M

investment

Produced by several other companies now

Several applications now in place
Though more expensive than petroleum derived commodity plastics

Sugar cane to tyres......

Genencor, a Division of Danisco, has developed technology for manufacturing
isoprene from sugar cane, corn, corn cobs, switchgrass or other biomass,
Process involves
Microbial strain development
Large scale fermentation
Recovery and purification

The vision is that all Goodyear tyres will be manufactured from this bio-isoprene

Manufacturing a conventional tyre requires 7 gallons of petroleum feedstock per tyre.

Using bio-isoprene will reduce that down to close to zero

Bio-succinic acid
From glucose / renewable resources, not maleic acid

Bio-amber

started production

DSM + Roquette

pilot scale 2010, commercial 2011

Market for succinic acid estimated at 2.5 billion

Uses: in antifreeze liquids, coolants, solvents, pigments, polyesters, butanediol
and its derivatives, plasticizers, etc.

Bio-1,4-Butanediol
Gen. Eng. E. Coli
Sucrose

Single step

GENOMATICA (BIO June 2010)

BIO-1,4-BUTANEDIOL

Spandex
Automotive parts
Running shoes
Cheaper & Greener Bio-Butadiene?

Replacing Acetylene + Formaldehyde ---> 1,4-Butynediol ---> 1,4-Butanediol

Claims: reduction of 25% of GHG emissions and 30% reduction in direct energy
Estimated current global BDO market: $3billion
3000L scale tried at Michigan Biotechnology Institute
Plans : demonstration facility 20-50kL by 2011, and commercial production 2013-2014
Use cellulosic biomass and syngas as future feedstock

Rubbish to bio-ethanol

Convert low cost biomass & wastes (MSW) to clean fuel and energy

Deliver a step change in green house gas emissions

Achieve both in a safe, reliable, cost effective & sustainable way

BIOMASS

Feedstock
flexible

SYNGAS

BIOETHANOL

Renewable
power
Bioethanol
Fermentation
Gasification

C2 Platform - Ethanol
Ethyl tert-butyl ether

Ethylene

Bio-POLYETHYLENE / PVC / PVA

Braskem / Dow / Solvay / Wacker

Ethyl esters

Ethyl ethers

Acetaldehyde

Ethylamine

Glycol ethers

C3 Platform - Glycerol
1,2-propanediol

1,3-Propanediol

Glyceric acid
Epichlorohydrin

Acrolein
Mono-, di- and tri-esters

Polyglycerols & Polyglycerol esters

C4 Platform Succinic acid

Tetrahydrofuran

1,4-Butanediol

Polyesters
N-Methyl-2-pyrrolidone (NMP)

Polyamides

-Butyrolactone

Di-esters

Arrange a visit from the Industrial Biotechnology Sector

Expert Dr Yvonne Armitage to see how IB can help you
and your business
yvonne.armitage@biosciencektn.com

_connect up with the Industrial Biotechnology Special

Interest Group online
https://ktn.innovate.org/web/industrial-biotechnology