brochure - Asymchem

ASYMCHEM
CMC Solutions
CMC
CMC
Solu
utions
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Sales office
Asymchem Inc.
600 Airport Blvd Morrisville, NC 27560 USA
Tel: +1 (919) 468-3884
Fax: +1 (919) 468-3916
Asymchem shanghai representative office
Gu Mei Road, Caohejing Modern Service Complex, Shanghai, 200233
P. R. China
Tel: 021-54452037
Fax: 021-64956008
China R&D and Manufacturing sites
Asymchem Laboratories (Tianjin) Co. Ltd.
6 Dongting 3rd St. TEDA Tianjin, 300457
P.R. China
Asymchem Life Science (Tianjin) Co. Ltd.
No. 71, 7th St. TEDA Tianjin, 300457
P.R. China
Asymchem Laboratories (Fuxin) Co. Ltd.
8E Rd. Fuxin Economic Area, Liaoning, 123000
P.R. China
Jilin Asymchem Laboratories Co., Ltd.
Economic Development Zone Dunhua, Jilin, 133700
P.R. China
Tianjin Asymchem Pharmaceuticals Co., Ltd.
Economic Development Zone TEDA Tianjin, 30000
P.R. China
Liaoning Asymchem Laboratories Co.,Ltd.
Fluorine chemical industry park Fuxin, Liaoning,123129
P.R. China
Tianjin Asymchem Pharma Analytical Testing Service Co., Ltd.
No. 71, 7th St. TEDA Tianjin, 300457
P.R. China
Integrate, Optimize, Succeed
01-02
Asymchem Overview of Facilities
03-04
Introduction
05-06
Asymchem Overview of Manufacturing
Capabilites
07-08
Asymchem Overview of R&D Capabilites
09-10
Discovery Chemistry
11-14
CMC Solution
15-16
Pharmaceutical Service
17-18
High Potency
19-20
Biotechnologies
21-22
Flow Chemistry
23-28
Technologies
02
ASYMCHEM OVERVIEW
OF FACILITIES
Asymchem is a leading custom synthesis manufacturer of pharmaceutical intermediates and API’s,
with over 1200 employees worldwide. We offer fully integrated services for our global customers
ranging from discovery to commercialization. Since its founding in 1995, Asymchem has built up a
broad technical expertise with a proven track record of high quality services and on-time deliveries,
providing practical and cost-effective outsourcing solutions. Asymchem is committed to science
excellence, flexibility and customer-centric service.
Tianjin
Asymchem Inc. (USA) 1995
Jilin Asymchem Laboratories Co., Ltd. 2007
♦ Business & Marketing, technical support
♦ Back integration of RM and RSM
♦ cGMP intermediate and API manufacturing
Asymchem Laboratories (Tianjin) Co., Ltd. 1998
♦ Dedicated for High Potency R&D and
manufacturing
Tianjin Asymchem Pharmaceuticals Co., Ltd. 2010
Tianjin
Personnel: >1200, PhD: 40
Master:85 Bachelors: 443
Tianjin
♦ cGMP API & drug product manufacturing
(under construction)
Asymchem Laboratories (Fuxin) Co. Ltd. 2001
♦ Dedicated for cGMP production of beta lactams
Liaoning Asymchem Laboratories Co.,Ltd. 2013
Asymchem Life Science (Tianjin) Co., Ltd. 2005
♦ Back integration of RM & RSM
(Under Construction)
QP Inspected 2013
♦ New technologies development
♦ cGMP API & drug product manufacturing
♦ Pharmaceutical Research
♦ Analytical Research
♦ Long-term stability testing
♦ Process engineering/safety
♦ Biotransformation
Fuxin
Jilin
Fuxin
Beijing
Asymchem Shanghai representative office 2013
Fuxin
Tianjin
♦ Business development & customer reception
Tianjin Asymchem Pharma Analytical Testing Service Co., Ltd. 2013
♦ Analytical testing service
Jilin
Shanghai
USA
600 Airport Blvd Morrisville, NC 27560 USA
Tel: +1 (919) 468-3884
Fax: +1 (919) 468-3916
04
INTRODUCTION
Benefits
An integrated solution from a CRO/CMO is the
most efficient way to bring more drug candidates
to your R&D pipeline and commercialization
through:
Asymchem is a custom synthesis CRO/CMO for the development and manufacturing of intermediates,
API’s and Drug Products. We strive to deliver innovative processes at every stage of your new product
pipeline, providing practical and cost-effective scale-ups from route development, through pilot scale to
launch.
Solution: Integrated Development
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Reduction of handoffs to multiple suppliers
Eliminate time gaps in drug development
Access to flexible resource when needed
Reduce R&D cost through integrated prining
Effectively manage the risk of drug development
Since our beginning in 1995, Asymchem has built up a broad in-house technical expertise with a proven track
record of on-time deliveries with high quality products. Solid fiscal growth since our beginning has gone hand
in hand with the level of satisfied repeat customers year after year, including receiving supplier awards from
Pfizer, Merck and Roche to name a few.
At the forefront of Asymchem’s Technical Development Team is the senior management group, which can
focus resources quickly to develop and implement solutions before obstacles can affect cycle times or
cost. The R&D base of Asymchem’s integrated Chemical Development team consists of over 500
scientists experienced in the most challenging syntheses.
Asymchem’s current four R&D and manufacturing sites offer innovative research and process
development at every stage, from preclinical to commercial, running under either non-cGMP or cGMP
conditions in labs, kilo labs, pilot plants, commercial scale cGMP production from Asymchem’s facilities in
P.R. China. Projects are handled at high standards of safety and environmental responsibility.
Asymchem R&D and Manufacturing Facilities (P.R. China)
Multipurpose, meets ICH Q7A and ICH Q10 guidelines
Commercial Production
Clinical Phase Projects Service
Drug Discovery Service
Medicinal
Chemistry
Asymchem Laboratories (Tianjin) Co., Ltd
Asymchem Life Science (Tianjin) Co., Ltd
Synthesis
process R&D
Formulation
Development
Tianjin Asymchem Pharmaceuticals Co., Ltd
Liaoning Asymchem Laboratories Co.,Ltd
RM/RSM
cGMP
Intermediates
√
√
HiPo API
API
√
√
√
√
√
√
√
√
√
√*
Drug
Products
√*
√
√
Asymchem Laboratories (Fuxin) Co. Ltd
Jilin Asymchem Laboratories Co., Ltd
Analytical
Service
√
√
√
√*
√*
√*
* Expansion Plan
06
ASYMCHEM OVERVIEW OF
MANUFACTURING CAPABILITES
CMC
Solution
Asymchem Laboratories
(Tianjin)Co.,Ltd
TJ1
Internal
Supply Chain
HiPo API
HiPo Drug Products *
（CMO）
Asymchem Life Science
(Tianjin)Co.,Ltd
TJ2
Liaoning Asymchem
Laboratories Co.,Ltd
FX2 *
Jilin Asymchem
Laboratories Co.,Ltd
DH
RSM
RM/RSM *
RM/RSM
RM/RSM
cGMP Intermediates
cGMP Intermediates
cGMP Intermediates
API
API
Drug Products（CMO）*
Tianjin Asymchem
Pharmaceuticals Co., Ltd
TJ3 *
Asymchem Laboratories
(Fuxin)Co.,Ltd
FX1
API *
Drug Products（CMO）*
( * : Under construction）
cGMP Kilo Plant
HiPo Klio Plant
20~80L, 0.22m3
<0.01μg/m3,-20~180℃
Pilot/Bulk Plant
200~8,000L,122m3
cGMP-like Plant
cGMP Plant
API Kilo Plant
20~50L,0.2m3
HiPo Plant
500~1,000L,5 m3
<0.01μg/m3,-20~180℃
cGMP Pilot Plant
200~3,000L, 8.4 m3
Pilot/Bulk Plant
100~8,000L,163.1m3
AutoClaves，
200~3,000L,6m3
Flow Chemistry
Plant
one continuous
diazomethane system
2 Liquid-Liquid reactors,
3 Gas-Liquid reactors
500~1,000L, GL
Fermentation
Plant
500L×4,200L×2,
Fermenters
Formulation
Plant
Oral dosage,
HiPo Production
Pilot Plant：Oral solid dosage form
The typical batch is a few kilograms.
Phase 1: 500 ~10,000 units / batch
Phase 2: 2,000 ~ 150,000 units / batch
Drug Product manufacturing center
Line 1: up to 25 kg/batch and
50 MM units/year
Line 2: 150~300kg/batch and
500MM units/year
Bulk Plant
first-stage construction
3,000~8,000L, 260m3
second-stage construction
8,000~20,000L, 300m3
Bulk Plant,
50~8,000L,313m3
Autoclaves,
500~3,000L,6.5m3
-20~300℃
Bulk Plant
3,000~20,000L, ,219m3
Bulk Plant
3,000~20,000L,219m3
Bulk Plant
first-stage construction
3,000~8,000L 200m3
second-stage construction
5,000~12,500L 200m3
Oral Solid Dosage,
lyophilized Powder
injection,
Injection
Annual Output:
100~300MM units/year
Bulk Plant
500~8,000L,321m3
Dedicate for β-lactam
Production
Capacities
Notes:
1. Light blue boxes : production
capacity that has been put into
use
2. Light grey boxes : expansion
plan or under construction
08
ASYMCHEM OVERVIEW OF
R&D CAPABILITES
R&D Capabilites
Discovery
Chemistry
Process
Research
● Discovery medicinal
chemistry and discovery
chemistry synthesis
● Chemical process
development
● New process
development
Within the last decade, Asymchem has developed significant expertise in
chemistries involving boronic acids, cross coupling reactions, asymmetric
syntheses, and heteroaromatics containing nitrogen, oxygen and sulfur.
Asymchem accumulate the experience and developed it R&D force to more
aspect. The key servies of Asymchem are listed as following:
● Synthetic route design and evaluation
● Optimization of reaction conditions and process development
● Key process parameters
● Cost of goods
● Process safety assessment
● Catalyst screening and optimization
● Impurity profile assessment
● Development of robust and scalable processes
● Crystallization procedures
● Reference standard preparation
Process
Development
● Process development for
validation and
commercialization
● Process development and
optimization
● Process safety
assessment
Chemical
Engineering
● Flow chemistry
Formulation
● Preformulation and
formulation
development
● Long/ short term
stability testing
Biotechnologies
● Enzyme Engineering
● Bioorganic Chemistry
10
DISCOVERY CHEMISTRY
Asymchem offers Discovery chemistry
capabilities from Hit identification to lead
optimization. These new capabilities at
Asymchem has been initiated and grown by
proven industry leadership with over 15 years
of experience. Asymchem discovery chemists
are highly skilled and efficient synthetic and
medicinal chemists. Utilizing the principles of
medicinal chemistry, our goal is your goal: the
identification of novel, targeted compounds
suitable for scale up and further development.
With strong IP Protection, we ensure that every
request from the client is achieved and that the
data produced is confidential. Our international
chemical shipping & handling expertise is a big
plus to shorten the delivery time.
Discovery Medicinal
Chemistry Services
● Design synthetic route and synthesize target
compounds
● Co-pilot drive project to develop SAR
● Hit assessment
● Hit to lead
● Lead optimization
● Library generation
Discovery Chemistry
Synthesis Services
Customer synthesis from milligrams to kilograms
Provide scale up support for discovery medicinal
chemistry at various stages
● Any target compound
● Advanced intermediates and building blocks
● API
● Reference compounds
● Stable isotope-labeled compounds
● Light sensitive compounds
State of the art modern
medicinal chemistry facility
● 22,000 sq. ft. labs and offices space
● 107 fume hoods with house vacuum,
house nitrogen and house waste disposal
State of the art kilo lab facility
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20,000 sq. ft. kilo lab facility
50 walk-in hoods
10-72L reactors
Access to current facilities such as
autoclaves and pilot plant
Capability
● Rapid and cost-effective execution of
collaboration tasks
● Medicinal chemistry expertise in major
target classes and disease areas
● Integrated drug discovery services through
our strategic alliances and partners
● Experience in all type of chemistry and
synthesis
● Low temperature chemistry
● High temperature and high pressure
chemistry
● Asymmetric synthesis
● Transition metal catalyzed reactions
● Continuous flow chemistry
● Biotransformation
● Synthesis of high potency API
● Chiral separation (SFC)
Advantage
● >15 years of service with a proven track
record of success
● Exceptional management team
supported by skilled scientists
● Medicinal chemistry leaders with global
pharma/biotech and CRO/CMO
experience
● Routine employee training programs
so that each FTE members can meet
or exceed our stringent
performance/productivity requirement
● International chemical shipping &
handling expertise
● Strict IP controls
CMC SOLUTION
Client Technology
Transfer (TT) Approach
For those projects that have been more developed,
the technical transfer of our Clients’ methodology
and the subsequent development and validation of
those processes for development and scaleup is
necessary:
Manufacturing
Campaign
● Raw Material sourcing, quality control, and release
● Site visits by our Clients are encouraged and
welcomed
● Campaign updates on a regular basis, agreed upon in
advance
● Delivery of final product with CofA and supporting
analytical data
● Support of internal compliance and controls such as
BSE/TSE, TSCA, etc.
● Final production campaign summary
● Review of technical packages
● Client teleconferences and f2f meetings for
smooth technical gathering
● Coordination and development of analytical
methods with both QC departments (internal and
Client)
● Direct manufacturing support by TT team
Process Research and Development
12
World class process R&D is fundamental to robust, reliable drug development and commercial processes.
Asymchem has invested heavily and wisely in this expertise, through areas such as:
● Process characterization and validation
● Reaction optimization to reduce costs and maximize output
● Catalysts screening and optimization
● Statistical Design of Experiments (DOE) utilizing Quality by Design (QBD) and Multivariate Data Analysis principles
● Crystallization studies
● Salt selection and polymorph screening
● Cryogenic (-90° C), high temperature, and high pressure (40 atm, 587 psi) capacities
● API synthesis to support from GLP toxicology to clinical studies
● Capable of handling highly potent compounds with OEL < 0.1 ug/m3
● Critical process parameter assessment
● Impurity profiling and isolation
● FTE Services for utilizing Lab, Kilo and/or Pilot Plant facilities
Process Development Approach
Raw Material Back Integration
Custom Manufacturing
Asymchem recognizes that having the ability to
guarantee the RM supply for quality and timeliness is
key in controlling not only downstream impurity profiles,
but also cost and lead-times. Since operations began
at the Asymchem Fuxin site in 2003 for Bulk production
of RM and RSM’s, Asymchem has consistently
maintained a track record of on-time delivery by being
able to guarantee raw material supply through our
in-house production.
Asymchem’s 15 years of proven success have
given us an enviable reputation for technical
expertise, flexibility, and an outstanding
commitment to our customers. Our joint focus is the
advancement of lead compounds through the drug
development process, from bench scale to
commercial production.
Due to stricter enforcement of environmental
regulations many suppliers of raw materials have been
closed down by the government. As a result, some raw
material supply shortages are being observed.
Asymchem is constructing a new faility in Liaoning
which will be dedicated to the production of RM's and
RSM's to guarantee the supply chain.
Asymchem is able to meet our Clients’ needs and
expectations with our focus on complex chemistry
allied with our commitment to the development of
new technologies such as chiral catalysis and flow
chemistry, continuous process optimization, and
developing cost efficient green chemistries
in-house.
Since we have a history of the synthesis and
development of building blocks, should the starting
material needed for your synthesis not be commercially
available in China, chances are that we can make it
efficiently ourselves. Asymchem has an excellent
environmental protection track record and are fully
committed to retaining our leading position in this area.
Under Asymchem’s project management model, chemists in
R&D follow their individual projects through to pilot plant,
thereby minimizing the risk of delays due to internal technical
transfers. This ensures smooth operation through multiple
campaigns into large scale production.
Process Safety Control Group
Asymchem’s Process Safety Control Group evaluates potential
hazards of each stage of synthesis, and all unit operations, then
defines critical parameters for inclusion as part of a final
campaign summary, or as a process FTE service.
Advanced process safety evaluations using:
● RC-1
● DSC
● Super CRC
● TSU
Asymchem is dedicated to developing safe, practical and cost-effective routes for
scale-up to commercial production.
Module 2 in TJ2 cGMP Pilot Plant
AC Labs
Analytical In house capabilities and services
Environmental Health & Safety (EHS)
Asymchem provides analytical research and development services for a wide
range of chemical and pharmaceutical programs, incorporating full quality control
and quality assurance support for all GMP and non-GMP manufacturing.
● Process Safety: precautions to prevent flammable dusts and vapors in solvent
storage, charging, and solvent transfers
● Material Management system to control chemical transfers and inventory
● Emergency response plan for firefighting, first aid, chemical spills, accidents, etc.
● Waste treatment and disposal
The expansion of Asymchem's Analytical Center (AC) went hand in hand with the
increase of the R&D and manufacturing capacity.
Ministry of Environmental Protection (MEP)
Compliance
Asymchem's MEP office, formerly known as the SEPA office, is responsible for
compliance with CRC-MEP (Chemical Registration Center of MEP), from working with
domestic Chinese accredited testing agencies to generate required data, to
communicating with the governmental Environmental Bureau throughout the application
process. Asymchem offers MEP registrations as a CRO service, handling applications
for compounds to be manufactured or imported into China.
Analytical services
● Analytical Method Development and
Validation
● Stability Testing
● Force degradation studies
● Stability testing to support clinical
studies
● Stability testing under ICH guidelines
● API Reference Standard Qualification
and Maintenance
● Spectroscopic Structure Confirmation
● Release testing
● Identification product and pathway
● Cleaning validation
● Physical property characterization
Major analytical equipment
● HPLC, LC-MS, GC, GC-MS, High resolution LC-MS,
Headspace GC-MS, TOF-LCMS, Triple Q LC-MS
● Prep HPLC, UPLC, ICP(Trace Metals)
● Hot stage poloarzied microscope
● 300, 400 & 500MHz NMR
● Stability chambers
● Dissolution apparatus
● XRPD, DSC, TGA, FTIR, SFC, Hotstage microscope
● Particle size analyzer
● Flash Purification
● Ion-chromatographic analyzer
● Coulometric KF, Volumetric KF
● Metter Toledo DL31 Karl Fischer Titrator
● TOC analyzer, Melting point detector, polarimeter,
Potentiometric titrator
Regulatory Filings
Asymchem’s CMC project teams are managed by scientists with thorough understanding of drug R&D processes and
regulation and many years experience at major pharmaceutical companies. Our CMC teams work closely with our
clients to ensure regulatory strategy alignment. We generate the complete CMC data package for regulatory filings
including:
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API synthesis flow chart
Process control, raw material acceptance criteria and API specifications
API batch analysis
API pKa, logP, and pH dependant solubility
API GMP clinical batch stability
Spectroscopic structure confirmation: NMR, MS, FTIR, UV, Raman
API and drug product analytical method validation
Drug Master Files
16
PHARMACEUTICAL SERVICE
Asymchem’s Integrated Approach to Formulation Design
Our scientists approach each formulation project with unique characteristics of your compound in mind.
We take into account multiple factors such as quality, speed, cost constraints and availability of API
during formulation development. With a full range of preformulation, formulation and analytical
development capabilities, along with a CFDA approved pilot scale cGMP facility, we can accelerate your
molecule through development to market.
Pharmaceutical Development Services
Preformulation and Formulation
Drug Product Manufacturing
Asymchem can use existing formulations and processes to manufacture clinical supplies or
develop a robust and bioavailable product based on phyisochemical, mechanical and
biopharmaceutical properties of a drug molecule.
Asymchem’s goal is to develop and manufacture quality products with
competitive pricing and rapid turnaround time. The drug product
facility has received the manufacturing certificates from CFDA.
Preformulation and
Formulation Development
Determining the physicochemical, mechanical and
biopharmaceutical properites of drug substances is
critical to successful formulation development. The
following services are offered by Asymchem for this:
●
●
●
●
●
Dynamic vapor sorption
Surface area and porosity tester
Salt selection
Polymorph screen
Solubility screen
Solution and solid state stability testing
Characterization of physicochemical properties:
dissociation constant and partition coefficient(pKa and
LogP tester), hygroscopicity(DVS),particle size(PSA),
surface area(BET) and IDR(Intrinsic Dissolution Rate)
Processing Capabilities
● Blending
● Encapsulation – powder/pellet/liquid fill
● Granulation – wet granulation, roller compaction and
fluid bed granulation
● Fluid bed drying
● Particle coating
● Tablet compression
● Tablet film coating – immediate and modified released
film coat
Oral Solid Dosage cGMP Batch Size
● Clinical Supply: 500~150,000 units/batch
● Large scale and Commercial Manufacturing:
15~300kg/batch and 50MM~500MM units/year
(Expansion Plan in 2014)
● Obatained CFDA manufacturing certificate for
oral formulations
● Able to handle potent and cytotoxic compounds
Long Term Stability Study Services
Dissolution tester(RC806D)
Asymchem provides many types of Stability Studies Services to support all phases of Drug
Development. We have expertise and experience in managing International Stability Studies. We have
the infrastructure to carry out these studies efficiently and in full compliance with current regulations
Prototype formulation development
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Drug excipient compatibility testing
Mechanical property characterization
Solid dispersion preparation(Mini Spray Dryer)
Particle size control and characterization (Jet mill, Dyno-mill, Co-mill
and Granumill)
● Tablets, capsules, solution and suspension
● Functional testing: Long / short term stability testing, dissolution,
content uniformity,assessing processability
Chambers Capabilities
Stability chambers are computer controlled to maintain
humidity and temperature with a 100% backup system and
redundancies for each critical system to ensure uninterrupted
maintaining of conditions throughout the study.
Asymchem can generate the stability indicating method
development and validation, provide the study protocol,
and produce the report and support documentation
at wrap-up for your filing (IND, NDA, ANDA, etc.) needs.
Spray dryer
DYNO-MILL
Reach-in stability chamber
Stability conditions
Total volume
25℃/60% RH
>40,000 L
30℃/65% RH
>40,000 L
40℃/75% RH
>40,000 L
5±3℃
>42,000 L
6±2℃(For CFDA)
>40,000 L
-20±5℃
400 L
Back-up chamber
>42,000 L
18
HIGH POTENCY
Elements of Asymchem’s
High Potency Program:
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Prominent features of Asymchem’s
potent compound program :
● A well-developed program to
eliminate contamination vectors,
such as pressurization, primary
decontamination stations within
suites, and qualification of facilities
and processing equipment
Medicinal chemistry
API manufacturing
Drug product manufacturing
Analytical development
Environmental health and safety
● Ongoing facilities performance
monitoring, including dust testing of
isolators and air monitoring
● Rigorous worker training for potent
compounds specific practices
relating to PPE, decontamination,
and incident response
High Potency Facility
Asymchem operates dedicated potent compound production
facilities in both cGMP and non-GMP configurations. We have
specialized facilities for common potent compounds classes
(cytotoxics, b-lactams) and offer the following scales:
Overview of HP Capabilities
Site
Asymchem has the facility to handle compounds with an
occupational exposure limit (OEL) of less than 0.01 ug/m3. This
is equivalent to Safebrige category 4, which covers the most
potent compounds. Equipment trains are designed for maximum
flexibility – after dispensing solids in a controlled area, solutions
are transferred to glass reactors fitted to the process, then
Nutsche is used for filtration/drying.
Function
High Potency
R&D Labs
Asymchem
HiPo DP
( Depending on
individual project
requirements, the
plant can be ready
from anywhere
between
3~6 months)
Work parameters
/OEL Rating
Lab 1 :2 labs, 4 fume hoods,
Lab 2 :2 labs, 4 fume hoods, 1 QC lab
Module 1: 5-80L Glass flex system
HiPo API Mfg
Laboratories
(TJ1)
Equipment/Capability
< 0.01 μg/m3
Module 2: 500-1000L GL/SS reactors
-20 to 180°C
Encapsulation, Compression, Blending,
Granulation for oral dosage
< 1.0 μg/m3
20
All enzymatic functions performed in-house:
Enzyme Discovery
BIOTECHNOLOGIES
Enzyme Screening
Application in chemical process
Enzyme Production
Substrate Production
Biocatalysis
Available Enzyme families currently
being developed and produced:
Enzyme Production- from DNA to protein
● Aminotransferases
● Ketoreductases
Over 400 enzymes from multiple families, including ketoreductases, transaminases, lipases/esterases, etc., were developed and
produced in Asymchem. The gene coding for target enzyme was cloned, transformed, and expressed in E.coli, pichia yeast, or bacillus
subtilis, depending on the enzyme character. Appropriate post-modification technologies, for example, affinity purification, lyophilization,
immobilization, were developed and applied to the enzymes. Customizable enzyme evolution techniques were readily available to
improve enzyme characterizations. 7 sets of fermenters in the size of 5L, 200L, and 500L were used for fermentation process
optimization, as well as enzyme production.
O
Biotransformation
Resolutions
To reduce market share of specialty enzyme producers by developing in-house enzymatic transformations for process chemistry, we
put our efforts on Biotransformation.
To quickly screen biotransformation reactions for specific substrate, 40 scientists, including 6 Ph.D. 30 masters, and 4 bachelors, are
dedicated to the establishment of enzyme library, in-house enzyme production, as well as development and application of
biotransformation.
OH
R
OH
R
R'
R'
R
NH2
NH2
R
O
R
R'
R
H2O
O
NAD+
NADH
HCOOH
CO2
FDH
R represents aliphatic or aromatic derivatives, for example, t-butyl group.
O
C7H15
R
R'
OH
X
OR'
R
R'
R
O
O
R'
NH3
Bioreductions
O
O2CC7H15
OH
R
O
● Esterases
● Amino acid dehydrogenases
We have developed conversions of alpha-keto
acids to unnatural amino acids for several cases of
interest, including t-leu as illustrated righthand.
NH2
LeuDH or PDH
OH
R
X
NH2
OR'
R
O
O
O
Substrate
OH
R
R=cycloalkyl
R=Heteroaryl
R
R=Heterocyc
n
N
R1
N
X
n
R1
R2
n
X
n=0-4
X=O, N
X=O, S
Product
OH
OH
R
Enzyme
Chiral ee
Fermentation
capacity
Enzyme in stock
NH2
OH
NH2
O
Phenylalanine
Dehydrogenase,
D-amino acid
Dehydrogenase,
Glucose
Dehydrogenase,
Formate
Dehydrogenase.
R
O
OH
OH
R
Leucine Dehydrogenase,
Phenylalanine Dehydrogenase,
D-amino acid Dehydrogenase,
Glucose Dehydrogenase.
Valine Dehydrogenase,
Glutamate Dehydrogenase,
Aspartate Dehydrogenase,
OH
R
NH2
R
R'
OH
R
Carbonyl Reductases.
Alcohol Dehydrogenases
R1
R
N
R-transaminase from
Arthrobacter sp.,
Pyruvate transaminase,
ω-Transaminase from ArS,
ω-Transaminase from CV,
Branched-chain
Aminotransferases.
Aspartate transaminase,
TBAD,
ReADH,
DADH,
TeSADH,
ReAADH,
Phenylacetaldehyde
Reductase,
R-specific ADH,
SSCR,
ScCR.
O
n R2
R'
O
O
Alcohol
Dehydrogenases
Carbonyl
Reductases,
Nitrilases,
X
X
X
X
n=1,2
n=1-5
N
R2
R'
N
H
X
X
O
R'
R=alkyl
N
O
n R2
R
O
R=Aryl
R1
O
n=1,2
Monoamine Oxidase
(MAO) from
Aspergillus niger,
MAO-A from rat,
MAO-B from rat.
OH
R'
chiral center formation
Lipase A Candida Antarctica,
Lipase B Candida Antarctica,
Lipase from Candida rugosa,
Lipase from Pseudomonas
fluorescens.
95-99.5%
93-99%
95-99.5%
94-98%
90-99.5%
95-99.5%
85-98%
90-99%
15,000L
25,000L
25,000L
25,000L
35,000L
50,000L
1,000L
20,000L
100Kg
200Kg
200Kg
200Kg
300Kg
600Kg
10Kg
500Kg
Green represents in-house developed enzymes, while blue represents the enzymes that will be developed in the near future.
HO
22
FLOW CHEMISTRY
Continuous diazomethane reaction
R
OH
Cbz
R
CH2N2
R
HX
Cbz
Cbz
N2
O
X
O
R
O3
R
Continuous
ozonolysis
O
R
O
OH
R
O O
O
OH
O
R
Continuous curtius rearrangement
R1 COOH
When batch processing is inappropriate for the
intended chemistry, Asymchem will design and
set up a flow reactor.
Why flow chemistry
● Safety
● Waste reduction
Recent examples include flow
chemistry for the generation of
diazomethane and flow chemistry for
safe handling and use of ethyl
diazoacetate.
Flow chemistry is more safety to
handle the energetic reactions or
hazardous reagents.
DPPA
O
R1
N3
R1
-N2
O
● Continuous Ozonolysis-Pilot/Commercial Scale
N
H
O
R2
Continuous catalytic hydrogenation
O
R1
Cat. 1
O
Cat. 1
O
R1
OH
R1
O
Cat. 2
O
R1
Flow chemistry can enhance the efficiency of the reaction and control the cost.
Continuous nitration
R2
HNO 3
R1
N
R2
R1
R3
NO2
R3
N
Continuous oxidation
● Continuous Curtius Rearrangement-Pilot Scale
● Continuous Nitration-Commercial Scale
● Continuous Diazomethane Reaction-Pilot/Commercial Scale
O
R1
N
● Capital cost avoidance
Active development areas
at Asymchem
R2-OH
O
B
R1
H 2O 2
OH
R1
O
● Continuous Catalytic Hydrogenation-Lab Scale
Continuous low temperature reaction
R2
Br
N
R1
R2
B(OH)2
triisopropylborate
n-Buli
N
R1
24
TECHNOLOGIES -1
Large-scale cyclopropanation
Asymchem specializes in multi-step processes involving a wide range of chemical expertise. A strong
technical portfolio together with a proven track record of managing complex projects ensures the
highest quality product with communication a priority at every step of the process.
R
X
Asymmetric Synthesis
Reduction of ketones and olefins
Sample of Chiral enolate additions
● Large-scale asymmetric
cyclopropanation
● Asymmetric reduction of ketones and
olefins
● Catalytic asymmetric hydrogenation
● Enzymatic transformation
● Epichlorohydrin derivatives
● Auxiliary-controlled enolate and
cycloaddition chemistry
O
R
OM
+
R'
X
R
R'
O
O
X
R
R
O
Rh(I),CO/H2
Ru*lig
N
O
H2/RuL'*
OEt
R
O
N
B O
H3C
OEt
NHAc
R
H2
N
OH
O
R
Cl
Ph
Ph /BH3
OH
R
Cl
Functionalized chiral building blocks
Asymchem is adept at preparing small, densely functionalized chiral alcohols and related synthons through a
variety of technologies. Ask us for a proposal on your target.
O
+
Br
R
*R
N
O
O
R
OEt
OH
O
LDA
OH
NH3Cl
OH
SBz
O
R
HO
R
NH
NR2
CbzHN
O
OH
OH
Cl
R
OtBu
Cl
R
O
O
OMe
O
Xc
Et 2 AlCl
OH
OH
CbzHN
Xc
R
R'
H
R
Sample of Auxiliary-controlled enolate
and cycloaddition chemistry
R
OH
OP
Me
R
O
H2/RuL'*
With pressure reactors up to 3000 L, Asymchem scientists are not limited to kilo size preparations
OP
Me
N
R"
EtO2 C
H
O
NHAc
OR'
R
*R
R
R
OEt
X
O
R'
N2
OH O
O
R
+
R"
R'
Ru(II) pybox
catalyst
O
R'
MeO
R
OH
Cl
O
Nuc1
Cl
OH
Nuc1
Nuc2
TECHNOLOGIES -2
Transition Metal Catalyzed Reactions
Notable Capabilities
Low temperature Chemistry
Our staff is adept at scaling up
chemistry requiring temperatures as
low as -90°C, including metal/halogen
exchange, directed metallation,
enolate chemistry, and others. And
with multiple low temperature
production modules, alkylmetal
reagents in stock, and liquid nitrogen
on site, lead times are kept short.
● Metal/halogen exchange
● Enolate Chemistry
CH3
CH2R
sec-BuLi
RBr
Cl
N
26
N
sec-BuLi
Cl
Asymchem develops proprietary technology
for important chiral transformations and takes
advantage of patent-free methodology. Our
analytical chemists work with the synthetic
teams for accurate detection of enantiomers
and diastereomers.
Why stop at a boronic acid?
Asymchem has years of experience in the design and scale
up of metal-catalyzed reactions, and not only Suzuki
couplings. By selecting the optimal coupling partners and
catalyst, Asymchem chemists will develop efficient and low
cost processes to complex target molecules.
O
R'
OH
Swern
oxidation
NHR
R'
CHO
NHR
Br
R'
Pd(PPh3)4
N
R
N
N
R
O
NHR
O
F3C
F3C
● Directed metallation
● Others
Br
+
TMS
TMS
F3C
F3C
COOMe
High Pressure and High Temperature Chemistry
+
Asymchem handles hydrogen, carbon monoxide,
acetylene, and a variety of other reactive gases.
Pressure reactors range in size from lab scale to 3000 L.
Asymchem also has facilities and experience running
reactions over 200 degrees C.
EtO 2C
CO 2Et
O
X
CH2I2
Br
R
M
N
B(OH)2
Pd(OAc)2
P(Cy)3
R
TECHNOLOGIES -3
Asymchem scientists have prepared hundreds of complex boronic acids. Ask us about the
heterocyclic boronic acid needed for your synthesis. We can also make pinacolate esters or other
derivatives whenever the parent boronic acid is not suitable for your application.
B(OH)2
Cl
X
O
R
O
Heterocyclic Boronic Acids
Other carbene transformations
M
COOMe
R
N
RCM
R
O
CO2Et
Macrocycles via olefin metathesis
NH
N
B(OH) 2
R
N
H
O
Cl
Ni cat.
R
N
H
O
N
MeO
N
O
B
O
S
R'
CHO
N
R
N
R'
(HO)2B
(HO)2B
27
TECHNOLOGIES -3
Heterocyclic Chemistry
Starting with over 600 substituted pyridines and extending through a wide array of other N,
O, and S ring systems, heterocycles have long been a core area of expertise for Asymchem.
PYRIDINES
Br
Br
N
F
N
F
N
O
O
EtO
N
F
CO2Et
CN
O
OEt
OH
F
NH2
NC
O
Br
CHO
CO2Et
OEt
O
H3C
O
N
H
O
H3C
N
Cl
PYRIMIDINES
X
X
EtO2C
HO2C
N
CO2Et
HO
F
F
N
N
N
Cl
OH
Cl
F
F
PYRROLES
O
O
O
R
O
OEt
R
EtOOC
R
EtOOC
OEt
OEt
OEt
N
H
N
H
O
N
H
O
THIOPHENES
CO2Et
EtO2C
HO
HO
SH
S
CO2Et
Br
CO2Et
S
PYRAZINES
R
O
R
OH
NH2
HN
O
R
R
O
R
Cl
N
X
N
N
N
NH
R
R

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