CiVentiChem India Presentation - 2012

CiVentiChem (India) Private Limited
(Formerly Known as Indus BioSciences Private Limited)
Global operations in the USA and India with project management, 1 IP control and local solutions at our USA headquarters
Highlights of Presentation
History Business Overview Services and Capabilities Management Experience and Chemistry Expertise Chemistry Specialties & Capabilities Bulk Projects Performed in Plant Chemistry Experience
Examples in Med. Chem & P R&D
Proprietary Building Blocks
Facilities
History
1994 - Founded in RTP, North Carolina 1999 Expanded to Larger Laboratory 2000 Reached 12 Scientists at USA 2001 R&D Laboratories Opened in India with 5 Chemists 2009 Launch of our Plant in Hyderabad, India 2011 cGMP Synthesis lab in RTP, NC, USA
Business Overview
HQ: Services: People: Facilities: RTP, North Carolina Chemistry 80 Experienced Scientists & Admin USA and India
Discovery & Synthetic Chemistry, Process Development, Manufacturing & Analytical Services
RTP, North Carolina and Hyderabad, India 50,000 Sq Ft Total Technical Facilities
Customers: Around 150

including 10 of world Top 20 Pharma; 45 Biotechnology Companies.
Integrated Management Systems ISO-9001-2008 (QMS), 14001-2004 (EMS) and 18001-2007 (OSHA)
Our Role in Drug Development

Biological Target Screening Screening Hits Leads Drug candidate candidate Pre clinical Clinical Clinical Launch
Associated Chemistry
Screening Compounds
Parallel Synthesis
Medicinal Chemistry
Custom Synthesis
Process Scale - up
Pilot Plant
Manufacturing
CiVentiChem USA & India Peakdale Molecular
CiVentiChem India Collaborators
RESEARCH CHEMISTRY
Medicinal Chemistry Focused Libraries Reference Standards & Metabolites Lead Compounds & NCEs Lead Optimization Intermediates and Building Blocks available and in-stock
DEVELOPMENT CHEMISTRY
PRODUCTION CHEMISTRY
Rapid Initial Scale-up to first Kg Pilot Development Process Research & Manufacture Development Process Research & Feasibility Studies Development Pilot Development Manufacture Contract Manufacturing Manufacture Intermediatess & Manufacture Intermediates & APIs APIs cGMP &Global Non-GMP Protocols operations in the USA and India with project management,
5 IP control and local solutions at our USA headquarters
Global Advantages
Flexibility of Choice USA or India or BOTH !! Project Type Deadline Output Scale or Volume Research Requirements Expertise Requirements Communication and Project Control Lowest Cost
Business Overview - Clients

No. of clients 150 No. of Pharma Clients 10 (from world top 20 Pharma Companies) No. of Biotech Clients 10 + No. of Catalogue Companies 5 + No. of Fine Chemical Companies 10 +
Services and Capabilities

Research Chemistry Services

Medicinal Chemistry Synthesis of Focused Libraries & Analogues Synthesis of Reference Standards & Metabolites Synthesis of Lead Compounds & NCEs Lead Optimization & Parallel Synthesis Novel Template Molecules Ready for Purchase
Development/Manufacturing Services
Rapid Initial Scale-up to 1st Kilogram Route Scouting Process Development & Optimization Manufacture of Intermediates API ready starting materials
Management Experience
Management Team
Bhaskar Venepalli, Ph. D
Chief Executive Officer
Professional Experience
Vasu (Srinivas) Chittineni, Ph. D

Chief Technical Officer
25 + Years experience in fine chemicals including 13 20 + Years experience in synthetic organic Yrs experience in R&D, new product development & Business Management at Eastman Kodak-Eastman Chemical Company Expertise in CRAMS & Fine Chemicals Founder of Civentichem in 1994 in USA Education Ph.D. from Osmania University, Hyderabad (IND) Post Doctoral Research at University of Education Ph.D. from Kakatiya University (IICT, Hyderabad, INDIA) Post Doctoral Research at Duke University , NC, USA
chemistry Expertise in Complex Organic Syntheses, Chiral & Carbohydrate Chemistry Co founder of Civentichem in 1994
Southampton (England) & Rockefeller University, New York, (USA)
Management Team
Venkataiah Sunku, Ph. D Managing Director
Venu (Venugopal) Veeramaneni, Ph. D Head R&D and BD&PM

30 + Years experience in pharma including 8

Yrs experience as Director R&D at Aurobindo Pharma (India) Expertise in Process Development & Plant Scale operations Developed processes for 22 bulk drugs & Transferred to Mfg Plants
18 Years experience in Drug Discovery

(Medicinal &Synthetic Organic Chemistry. Including 11 yrs at Dr. Reddys Discovery Research. Expertise in Synthesis of NMEs & Complex Organic Syntheses
Education Education Ph.D. in Chemistry from Osmania University, Hyderabad (INDIA). 6 Publications & Patents Ph.D. in Chemistry from JNTUniversity (DRF, Hyderabad, INDIA) 25 Publications, Patents & Presentations
Research Team @ Civentichem India

Hari Prasad Chittineni, Ph.D. Section Head, Process Development 14 Yrs Experience in Carbohydrate, Heterocyclic Chemistry including 4 Yrs in AVRA Synthesis Expertise in Process Development M.Sc. From Osmania University Ph.D. from JNT University 7 Publications & Patents Venkat Laxman Rao Cilamkoti, Ph.D. Section Head, Medicinal Chemistry 16 Yrs experience in Multi Step Organic Synthesis including 8 Yrs in Dr Reddys Discovery Research Expertise in Medicinal & Small scale Chemistry M.Sc. From Osmania University Ph.D. from Osaka University, Japan 9 Publications & Patents Shyam Group Leader 8 Yrs Exp in Med. Chem. & Small Scale M.Sc. from Osmania University RC Sekar Group Leader 8 Yrs Exp in Med. Chem. & Small Scale M.Sc. from Osmania University Rajitha Group Leader 8 Yrs Exp in New Building Blocks M.Sc. from Osmania University
Vineel, Ph.D Group Leader 5 Yrs Exp in Sugar & Chiral Chemistry. Ph.D. from JUNTU
Mamatha Group Leader 8 Yrs Exp in Azaindole & Indazole Chemistry M.Sc. from Osmania University
Gopal Group Leader 8 Yrs Exp in Process & Scale Up Chemistry M.Sc. from Osmania University

Venkataiah, Ph.D. MD Venugopal Rao Veeramaneni, Ph.D. Head R&D and PM
Hari Prasad Chittineni, Ph.D. Section Head, Process Chemistry Vineel Group Leader PR&D Gopal Group Leader PR&D Mamatha Group Leader PR&D Shyam
Venkat Laxman Rao C, Ph. D.
Section Head, Med. Chem

RC Sekar Group Leader Med. Chem. Rajitha Group Leader Med. Chem.
Group Leader Med. Chem.
2 SRA
1 RA
2 SRA
2 RA
2 SRA
1RA
2 SRA
1RA
2SRA
1RA
2SRA
1RA
Global operations in the USA and India with project management, IP control and local solutions at our USA headquarters

Venkataiah, Ph.D. MD
Analytical R&D (6 AR&D Chemists) Vinay Kumar GM, Plant Operations Admin & Finance (6 Persons)
Manager, Maintenance (9 Persons)
Plant Production In-Charge
Stores
Purchase
Safety
Shift in-Charge & Chemists/Operator (9 Persons)

Chemistry Expertise & Performance Matrix

Chemistry Specialties
Sugar Molecules Chiral Catalysts and Reagents
Reagents for peptide formation

Novel Hetero cyclic compounds for supporting all the stages in drug discovery. Pyrazoles, Isoxazole, Oxazoles, Pyrazines, Pyridazines, Pyrimidines, Pyrrolopyrimidine, Azaindoles, Indazoles,
Piperidinopyrimidines and Heterocycles having Spiro group

Chiral Binaphthols & Boronic Acids
General Reactions - mg to Kg scale Grignard Reactions Up to 50 kg of Mg charge Bromination mg to multi Kg scale Hydrogenation Reactions 350L SS, 30 kg/cm Transition Metal Reactions Suzuki coupling (0.5Kg, 1Kg to 25Kg Scale)
Buchwald-Hartwig Coupling (5g & 500g Scale) Negishi coupling (150g & 250g) Sonogashira reaction (1Kg Scale) Stille coupling (10g Scale)
Chemistry Capabilities
Enzymatic Resolutions Reactions in Aqueous medium Phosgenations using triphosgene

Bulk Projects Performed in Plant

S.No. Project Code 1 2 3 4 5 6 7 8 IB-205/151 IB-205/284 IB-150/011 IB-111/280 IB-111/291 IB-150/214 IB-206/263 IB-080/319 Quantity 45Kg 120Kg 425Kg & 415Kg 15Kg & 27Kg 15Kg & 27Kg 5Kg & 7Kg 10Kg 6Kg & 12Kg No. of Steps 2 2 4 3 3 7 1 2 Month of completion Oct, 2009 Nov, 2009 Jan & Oct 2010 Jan, 2010 Jan, 2010 Feb & Nov 2010 Feb, 2010 March, 2010 Remarks/Key Chemistries Iodination & amide formation Indole Acylation Methylsulfonation & chlorination Bromination & Phosphonate Chemistry Bromination & Phosphonate Chemistry Cyclopropanation & Protection of Amine Hydroxymethylation Formyl pyrazoles

S.No. 9 10 11 12 13 14 15 16 Project Code IB-206/320 IB-323/282 IB-323/086 IB-206/263 IB-313/275 IB-150/333 IB-213/338 IB-150/014 Quantity 21Kg/ 35Kg 5Kg/30Kg 7Kg 10Kg/ 100Kg 3X100Kg 15Kg 75Kg 24Kg No. of Steps 4 10 5 1 1 2 2 9 Month of completion March & July 2010 April & Nov 2010 April 2010 April & june 2010 3 Times in 2010 June, 2010 June, 2010 Sept, 2010 Remarks/Key Chemistries Amino acid Chemistry Benzofuran formation, Suzuki coupling & Reduction Azaindole Chemistry & Catalytic hydrogenation Hydroxymethylation Preparation Phase Transfer Catalyst Nitration & etherification Cyclopropanation Nitration, Reduction and Migration

S.No. 17 18 19 20 21 22 23 24 Project Code IB-080/293 IB-266/267 IB-036/206 IB-372/266 BAL-PH IB-398/404 IB-079/176 IB-373/399 Quantity 10Kg 45Kg 10Kg / 100Kg 5Kg , 35Kg & 35Kg 186Kg 10Kg 35Kg 48Kg No. of Steps 7 3 4 2 2 3 1 1 Month of completion Oct, 2010 Oct, 2010 Oct, 2010 Dec, 2010 & Feb, 2011 Jan, 2011 Feb, 2011 Feb, 2011 Feb, 2011 Remarks/Key Chemistries Azaindole Chemistry, Nitration & Bromination Bromination & Selective Reduction Grignard Reaction Bromination & Thiazole formation Critical Reduction Phosphonate Chemistry Pyrazole formation Cyclization

S.No. Project Code Quantity No. of Steps Month of completion Remarks/Key Chemistries
25
26
IB-416-2053595
IB-426-427025 IB-147-1503988 IB-455-1505025 IB-407-1505628 IB-232-4504062
76Kg
60Kg
3
4
April, 2011
June, 2011
Cyclization
Modified Reduction method to avoid expensive Pd Charcoal Synthesized Starting Material instead of buying expensive KSM Synthesized Starting Material instead of buying expensive KSM Benzofuran formation, Suzuki coupling & Reduction
27
60Kg
July, 2011
28
16Kg
July, 2011
29 30
45Kg 6Kg
10 5
July, 2011 July, 2011
Target is Very Useful KSM for Anti Viral APIs. And process is Global operations in the USA and India with project performed inmanagement, water
IP control and local solutions at our USA headquarters

S.No. 31 Project Code Quantity 30Kg No. of Steps 1 Month of completion August, 2011 Remarks/Key Chemistries Salt preparation as per clients typical specifications Salt preparation as per clients typical specifications Salt preparation as per clients typical specifications
CVI-429-4287024
32 CVI-476-428092 33 CVI-431-4287026 15Kg 1 August, 2011 30Kg 1 August, 2011
34
CVI-431-4287025 35 IB-471-472-088 36 CVI-432-1505025
15Kg
August, 2011
Salt preparation as per clients typical specifications

Handling of use amount of TFA (which is minimized to 30%)
10Kg & 25Kg 40Kg
August, 2011 & Jan 2012
November, Synthesized Starting Material 2011 instead of buying expensive Global operations in the USA and India with project management, KSM IP control and local solutions at our USA headquarters
Performance of our Research Team

2007 2008 2009 2010 2011
No. of Steps Vs Compounds

162 336 236 164 2009 2010 2011
136
108 35 50 6-10 Steps
9 20 21 11-15 Steps
22 16 5 15 and above
113 95 80 72 66 60 99 93 84 85
1-5 Steps
75
62
41 30 35 28 22 22 15 9 19 19 18 8 23 12 14
2 4
Up to 1g
1.1g to 10g
11g to 100g
101g to 1000g
1.1Kg to 10Kg
11Kg to 50Kg
51Kg to 100Kg & above
Quality and Integrated Management Systems
ISO Certifications
CiVentiChem India has successfully obtained the following certifications
Currently follow Integrated Management Systems

ISO-9001-2008 certification for Quality Management Systems ISO-14001-2004 certification for Environmental Management Systems ISO-18001-2007 certification for Occupational, Health and Safety
Management Systems (OSHA)
Chemistry Experience - Case Studies
Route Scouting and Discovery Support Erlotinib Analogue

Client wanted a compound with a reactive functional group Re-designed the synthesis and delivered the product
Med Chem Support/Route Scouting
C-imatinib analogue
Client wanted analog with a reactive functional group Re-designed the synthesis with a new route and delivered the product with NH2 and maleimido groups
Med Chem Support-Focus Libraries
Reference Standards for Med Chem Support
Reference Standards for Med Chem Support
New Route & Process Development Hexahydrofuro[2,3-b]furan-3-ol moiety

Bis-THF alcohol -A Key intermediate in many antiviral drugs Our goal: Develop a new route for use in Med Chem Then develop a process for manufacturing
NCE
Reported synthetic route
Problems with enantiomeric purity Scalability


New Route Development to make chiral alchol
Process Development
Initial Goal: Make small quantity to make 100 gm of API After this is delivered, client wanted to file for IND, hence needed 10 Kg No luxury of time as it was needed urgently Brute forced the synthesis and delivered the product Two enantiomers were separated by column chromatography

Process Development Objectives
Eliminate hazardous radical reactions Avoid column purification of resolution mixture Improve economics of API route- 12 step synthesis Avoided column chromatography by developing a solid derivative that can be separated by filtration from resolution mixture
Redesigned API route where this expensive chiral piece comes at penultimate step In earlier synthesis it was used in second step-Thus improving economies by several fold Made 500 gm of API with the route which is being used now
New Route & Process Development for a key intermediate for API
Piperidine-4-acetic acid is a key intermediate
Inhibition of Cholesterol Synthesis by Inhibiting Squalene Synthase potent farnesyl protein transferase (FPT) inhibitor
New Route & Process Development

Piperidine-4-acetic acid is a key intermediate Lonarfanib
Process Development 4-(4-Chloro-pyrimidin-2-ylamino)-benzonitrile for Anti Viral drugs

N N N H N N H
N H N N N N H N
Depivirin (TMC 120)
N N Cl N N H
Br O N HN N NH2 N
Rilpivirine (TMC 278)
Etravirine (TMC 125)

N Global operations in the USA and India with project management, IP control and local solutions at our USA headquarters
Process Development Synthesis of di-tert-butyl chloromethyl phosphate for The Synthesis of Prodrugs
Innovative Chemistry
- (+) Lactacystine
Isolated in 1991 by Omura et. Al from Steptomyces sp. First non-protein neurotropic factor Highly useful pharmacological tool Lactone is key active component and acts by acylation of threonine residue
Innovative Chemistry
Organic synthesis in Aqueous medium
Water as a solvent: 3,4-dihydro-2H-benzo[b]thiazine-3-ones 1,2,3,4-tetrahydro-2-quinoxalinones 2,6-dialkyl-3,5-dicarboxyl-1,4-dihydropyridines & others
Summary of Chemistry Expertise

Medicinal Chemistry Support New Route Development Process Optimization Innovative Chemistry Reference Standards for Med Chem Support
Chemistry Experience Proprietary Building Blocks Developed at CiVentiChem

Key building blocks for NCEs 7-Azaindoles
Selective, ATP-competitive inhibitors of the mTOR
Selective Inhibitor of Aurora B/C Kinase Active potent VEGFR-2 inhibitor
Selective B-Raf inhibitors
Key building blocks for NCEs 1H-Indazoles
Potent TRPV1 Antagonist for Pain Management (ABT-102)
Potent and Selective Inhibitors of Factor Xa
Potent CDC7 inhibitors
Novel 5-HT6 Receptor Antagonists
Azaindoles & (1H)-Indazoles
Drug Intermediates in Bulk
Aryl -Keto & Diketo esters
Pyrimidines
Pyrazole Derivatives
Isoxazole Derivatves
2-Naphthol Derivatives (R & S Isomers)
Reagents & Catalysts
Facilities
Facilities - India
Hyderabad, India
Four Synthetic Laboratories
6 Fume hoods in each lab
Analytical Capabilities (HPLC, GC, LC-MS) Provide Competitive Large-Scale Production Provide Chemists (FTEs) Access to Modern Library & Exceptional Scientific Talent from National Labs
Facilities - India
Plant - Equipment Configuration
Stainless Steel Reactors: 2000 L(1); 1600 L(2); 1000 L(1); 500 L(2); 350 L(4) & 250 L (4) GL Reactors: 2000 L(1); 1000 L(2); 630 L(1) &250 L(1) Autoclave (Hydrogenation) 350 L(1) Yet to be installed and 2.0 L(1) & 0.5 L(1) Auxiliary Filtration, Drying and Milling Separate QC Laboratory and Documentation Center
Manufacturing Equipment
Production Block
SS316 Reactor SS316 Reactor Glass Lined Reactor SS316 Reactor SS316 Reactor SS316 Reactor SS316 Reactor Glass Lined Reactor Glass Lined Reactor Glass Lined Reactor Glass Lined Reactor Centrifuze SS316 Centrifuze SS316 Centrifuze SS316 Rotocone GL dryer Rotocone SS316 dryer Tray dryer Vacuum Tray dryer Tray dryer Sifter Multi mill Sifter Multi mill Cooling tower Cooling tower Vacuum Pumps 1200L 1000L 1000L 250L 350L 2000L 500L 160L 250L 500L 1600L 36 24" 18" 250 L 50 L 12 trays 6 Tray 24Tray 24 25 Kg/Hr 12 10 Kg/Hr 70 TR 30 TR 300M3/Hr
R&D , Stores and QC

2 No's R&D Labs: 1 No Fume Hoods 27 Nos 1 No Cooling Tower 30TR 2 Nos 2 No's Vacuum Pumps 120M3/Hr 4 Nos 2 No's 1 No Analytical Equipment: 1 No HPLC (Quartanery & Gradient) 2 Nos 2 No's Preparative HPLC, LCMS & GC 1 No Each 1 No 1 No Utility Block 1 No Diesel Generator 180 KVA 1 No 1 No Oil Fired Boiler 1 Ton/Hr 1 No 1 No N2 Generator 99.5 %, 5 m3/h 1 No 1 No 3 DM Plant (with RO) 40 m /Reg 1 No 1 No Air Compressor 70 CFM 1 No 1 No 1 No Corrosive Block 1 No FRP Reactor 2000L 1 No 1 No Glass Lined Reactor 1600 L 1 No 1 No Glass Lined Reactor 630L 1 No 1 No Glass Lined Reactor 100L 1 No 2 No's Hydrogenator -SS316 -350L (25 Kg) 1 No 2 No's Brine Compressor (-20 DEG) 15 TR 1 No 1 No Cooling in tower 165and TR India with project 1 No 1No Global operations the USA management, Centrifuze SS316 & halar coat 36 1 No 4 Nos IP control and local solutions at our USA headquarters
Analytical Facilities CiVentiChem, India

S. No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Name of the Instrument HPLC With PDA detector HPLC With VWD detector HPLC with PDA Detector Preparative HPLC GC with FID Detector LCMS Analytical Balance Ultrasonicator Digital PH-Meter Microprocessor PH-Meter Conductivity & TDS Meter Melting Range Apparatus Karl Fischer Apparatus Milli-Q Water purification system No. of instruments Make 2 Agilent 1 Agilent 1 Agilent 1 Agilent 2 Agilent 2 Agilent & Schimadzu 2 Denver, Sartorius 2 PCi 2 POLOMON & GLOBAL 1 GLOBAL 1 GLOBAL 2 POLOMON 2 POLOMON 2 Millipore
For inquiries, please contact: Dr. Venugopal Rao Veeramaneni CiVentiChem India Limited [Formerly known as Indus BioSciences (P) Ltd.,] Plot No. 72/A, Part 2, Phase-I, I.D.A., Jeedimetla, Hyderabad, A.P. , India.. Tel : +91-40-23197766/67/68 Ext: 228; Fax : +91-40-23091692 Mobile: +91-9030026010; e-mail : venu@civentichem.com www.civentichem.com

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CiVentiChem (India) Private Limited

(Formerly Known as Indus BioSciences Private Limited)

Proprietary Building Blocks

Customers: Around 150

Our Role in Drug Development

CiVentiChem USA & India Peakdale Molecular

CiVentiChem India Collaborators

Business Overview - Clients

Services and Capabilities

Research Chemistry Services

Vasu (Srinivas) Chittineni, Ph. D

Southampton (England) & Rockefeller University, New York, (USA)

Venu (Venugopal) Veeramaneni, Ph. D Head R&D and BD&PM

30 + Years experience in pharma including 8

18 Years experience in Drug Discovery

Research Team @ Civentichem India

Research Team @ Civentichem India

Venkat Laxman Rao C, Ph. D.

Section Head, Med. Chem

Group Leader Med. Chem.

Research Team @ Civentichem India

Manager, Maintenance (9 Persons)

Plant Production In-Charge

Shift in-Charge & Chemists/Operator (9 Persons)

Chemistry Expertise & Performance Matrix

Reagents for peptide formation

Piperidinopyrimidines and Heterocycles having Spiro group

Enzymatic Resolutions Reactions in Aqueous medium Phosgenations using triphosgene

Bulk Projects Performed in Plant

Bulk Projects Performed in Plant

Bulk Projects Performed in Plant

Bulk Projects Performed in Plant

July, 2011 July, 2011

Bulk Projects Performed in Plant

Salt preparation as per clients typical specifications

10Kg & 25Kg 40Kg

August, 2011 & Jan 2012

Performance of our Research Team

No. of Steps Vs Compounds

108 35 50 6-10 Steps

51Kg to 100Kg & above

Quality and Integrated Management Systems

Currently follow Integrated Management Systems

Management Systems (OSHA)

Chemistry Experience - Case Studies

Route Scouting and Discovery Support Erlotinib Analogue

Med Chem Support/Route Scouting

Med Chem Support-Focus Libraries

Med Chem Support-Focus Libraries

Med Chem Support-Focus Libraries

Reference Standards for Med Chem Support

Reference Standards for Med Chem Support

New Route & Process Development Hexahydrofuro[2,3-b]furan-3-ol moiety

New Route & Process Development Hexahydrofuro[2,3-b]furan-3-ol moiety

Reported synthetic route

Problems with enantiomeric purity Scalability

New Route & Process Development Hexahydrofuro[2,3-b]furan-3-ol moiety

New Route & Process Development Hexahydrofuro[2,3-b]furan-3-ol moiety

New Route & Process Development

Process Development 4-(4-Chloro-pyrimidin-2-ylamino)-benzonitrile for Anti Viral drugs

Depivirin (TMC 120)

Rilpivirine (TMC 278)

Etravirine (TMC 125)