Examples of Industrial Biotechnology in the

Chemistry-using Industries
 Peptides: Hydrolases

ASPARTAME – artificial sweetener: using Proteases

NH2
DL
NHZ H2N COOMe 1. Thermolysin H L
+ HOOC N COOMe
HOOC 2. H2 / Cat. L
L COOH CH2Ph
O CH2Ph
ASPARTIC ACID PHENYL ALANINE ASPARTAME

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
 Antibiotics : Hydrolases

D-HYDROXYPHENYLGLYCINE : Two steps – Two enzymes

‘DYNAMIC RESOLUTION’
• 100% conversion to a single isomer
• Intermediate for β-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 Omega oxidation of alkanes

• C11 Undecanedioc acid

CH3 – (CH2)n – CH3
• C12 Dodecanedioic acid
• C13 Brasyllic acid
• C14 Tetradecanedioic acid FERMENTATION

• C15 Pentadecanedioic acid

• C16 Hexadecanedioic acid HOOC – (CH2)n – COOH

• Trial production n = C9 – C14

FATTY ACIDS DIACIDS
Various applications
 ‘Natural’ Vanillin

From ‘natural’ Ferulic acid & ‘natural’ biocatalysts

CO2H

CHO 2% w/w in vanilla beans

0.2% w/w in vanilla extract

Natural vanillin : ~ $4,000 / kg

OMe OMe
Synthetic : ~ $25 / kg
OH OH

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 BIO-1,4-BUTANEDIOL

Spandex
Automotive parts
Running shoes
GENOMATICA (BIO June 2010) 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 SYNGAS BIOETHANOL

Renewable
Feedstock power
flexible
Bioethanol

Fermentation

Gasification
 C2 Platform - Ethanol

Ethyl tert-butyl ether Ethylene Bio-POLYETHYLENE / PVC / PVA

Braskem / Dow / Solvay / Wacker

Ethyl esters

Ethyl ethers
Acetaldehyde

Glycol ethers
Ethylamine
 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