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INDO-JAPANESE CONFERENCE ON PROCESS CHEMISTRY R & D

30 - 31 January 2014Hotel Ramada Plaza Palm Grove, Juhu Tara Road, Juhu Beach, Mumbai – 400 049 INDIA

Department of Chemicals and Petrochemicals, Government of India

Supported by

Dear Colleagues,

On behalf of ICC as well as on behalf of the Japanese Society for Process Chemistry, I have the pleasure in welcoming you all to this exclusive INDO-JAPANESE CONFERENCE ON PROCESS CHEMISTRY R&D - 2014.

The idea of this joint conference to be organized in Mumbai was first mooted by Prof. T. Shioiri, a member of Hikal's Scientific Advisory Board about a year ago and was enthusiastically supported by Mr. Jai Hiremath, Past President of ICC and Chairman & Managing Director of Hikal Limited. ICC gladly accepted Mr. Jai Hiremath's suggestion to host the conference jointly with the Japanese Society and swung into operation whole heartedly. What we witness today is the successful culmination of these efforts.

The performance of the Japanese Chemical Industry is well-known and the strength of Japanese Chemistry, particularly in Organic Chemistry is outstanding. On the other hand, Indian Chemical Industry has been growing impressively and also has won universal accolades for its ability to deliver Active Pharmaceutical Ingredients, Agrochemical actives, Specialty Chemicals and key chemical intermediates with high quality and at competitive rates. It is expected that the conference will provide participants, a platform to interact with process chemists from different industries and expand the domain knowledge leading to personal improvement and organizational advance.

We are grateful to both Japanese and Indian speakers who have provided valuable assistance in developing topics and archestrating the theme of the Conference. I would like to sincerely thank Japanese Society for Process Chemistry, Department of Chemicals & Petrochemicals, Government of India and Hikal Limited and all sponsors for providing outstanding support.

And a warm thank to all delegates. We hope you find the content to be productive and informative. We welcome your comments on the event. Please communicate your suggestions regarding the program, topics of interest, venue etc.

We hope success of this Conference will lead to very close cooperation between JSPC and ICC in future leading to mutual cooperation in the field of Process Chemistry R&D.

Sincerely,

YOGESH M. KOTHARIPresidentINDIAN CHEMICAL COUNCIL



CONFERENCE LOCATION

SPEAKER PRESENTATIONS

REGISTRATION DESK

Hotel Ramada Plaza Palm Grove

Juhu Tara Road

Juhu Beach

Mumbai – 400 049

Tel: +91 -22-67371600 / 67371603 / 67371605

All the presentations made at this event will be

sent in a CD to each delegate within one week

of the function. Delegates are requested to

drop their Visiting Cards at the Registration

Counter for prompt delivery.

The Registration Desk is open throughout the

conference. ICC staff will be available to

answer questions, assist you and ensure that

your conference experience is rewarding.

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Only registered conference delegates will be

admitted to function and sessions. For security

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Please remove the belongings, including your

conference material, from the meeting room

during lunch and at the end of the day. This

helps prevents lost or stolen items. In addition,

since all books look alike, please write your

Name on the front cover of the book for easy

identification.

In consideration of your fellow attendees and

our speakers, please set your Mobile Phones

and other electronic devices to the Silent Mode.

Your comments and recommendations are an

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PROGRAMME SCHEDULE: DAY-1, 30 JANUARY 2014

08:00 - 09.00 REGISTRATION

09:00 - 09.10 Welcome by: Mr. Yogesh M. Kothari, President, ICC

09:10 - 09.30 Address by: Prof. Kiyoshi Tomioka, President, JSPC

09.30 - 09.50 Inauguration & Address by the Chief Guest:

Dr. A.J.V. Prasad - Jt. Secretary DCPC, Ministry of Chemicals & Fertilizers, Govt. of India

09.50 - 10.45 Keynote Address:

Prof. M. M. Sharma - Former Director, Institute of Chemical Technology, Mumbai

10.45 - 10.50 Vote of Thanks - Mr. Rakesh Bhartia, Vice President, ICC

10.50 - 11.20 TEA BREAK & NETWORKING SESSION

11:20 - 11:50 Development of New Formulation Reaction Using Magnesium Amide : Process Research for a Novel Sodium Channel Blocker E2070

Dr. Katsuya Tagami - Executive Director, API Research Japan, Eisai, Japan

11:50 - 12:20 Challenges in Process Chemistry

Dr. Rajamannar Thennati - R&D, Sun Pharma Advanced Research Company Ltd.

12:20 - 12:50 Asymmetric Reactions Using Bifunctional Hydrogen-Bond-Donor Catalysts

Prof. Yoshiji Takemoto - Graduate School of Pharmaceutical Sciences, Kyoto University, Japan

12:50 - 13.20 Sonocrystallization as a Method to Control the Crystal Size Distribution and Morphology

Prof. Aniruddha B. Pandit - Department of Chemical Engineering, Institute of Chemical Technology, Mumbai

13:20 - 14:20 NETWORKING LUNCH

14:20 - 14:50 Application of PAT in Design, Development and Scale up of Crystallization Process

Ms. Suvarna Choudhary, Asst.Research Scientist - AstraZeneca India Pvt. Ltd.

14:50 - 15:20 Development of Enantio selective Reactions Catalyzed by Chiral Phosphoric Acid

Prof. Takahiko Akiyama, Department of Chemistry, Gakushuin University, Japan

15:20 - 15:50 Development of Specific Functional Group Directed Practical Hydrogenation Methods Using Heterogeneous Catalysts

Prof. Hironao Sajiki, Gifu Pharmaceutical University, Japan

15:50 - 16:20 TEA BREAK & NETWORKING SESSION

16:20 - 16:50 An Efficient Catalytic System for C-H Arylation : A Novel and Practical Synthesis of Angiotensin II Receptor Blockers

Dr. Masahiko Seki - Senior Research Manager, Process R&D Department, API Corporation, Japan

16:50 - 17:20 New Trends in Agrochemical Process Research and Development

Dr. Birja Shanker - Vice President R&D, United Phosphorus Ltd.

17:20 - 18:20 HIGH TEA BREAK & NETWORKING SESSION

18:20 - 19.05 Welcome Address: Mr. Yogesh M. Kothari, President, ICC

Introduction of Consul General: Mr. Jai Hiremath, Chairman & Mg. Director, Hikal Ltd.

Dinner Lecture: Mr. Kiyoshi Asako, Consul General of Japan, Mumbai

Vote of Thanks: Prof. Takayuki Shioiri

19:05 - 20:05 CONFERENCE DINNER

INAUGURAL SESSION

SESSION - I : NOVEL METHODS DIRECTED TO PROCESS CHEMISTRY & DEVELOPMENT - 1

SESSION - II : NOVEL METHODS DIRECTED TO PROCESS CHEMISTRY & DEVELOPMENT - 2

SESSION - III : NOVEL METHODS DIRECTED TO PROCESS CHEMISTRY & DEVELOPMENT - 3

Session Chairman: PROF. G. D. YADAV, Vice Chancellor, Institute of Chemical Technology, Mumbai

Session Chairman : DR. K. NAGARAJAN, Scientific Advisor, Hikal Ltd.

Session Chairman : PROF. SHUJI AKAI, Professor, Graduate School of Pharmaceutical Sciences, Osaka University

CONFERENCE DINNER & LECTURE

SESSION - IV : PROCESS RESEARCH, DEVELOPMENT & SCALE UP

SESSION - V : PROCESS SCALE UP AND ENGINEERING

SESSION - VI : PROCESS SCALE UP AND ENGINEERING & PROCESS SAFETY / PRODUCT SAFETY

SESSION - VII : GREEN PROCESSES INCLUDING BIO-ENERGY

Session Chairman : DR. TOSHIRO KONOIKE, General Manager, R&D Division, Osaka Synthetic Chemistry Laboratories Inc.

Session Chairman: DR. NAOYUKI KISHI, Vice President, Process Technology Research Laboratories,

Pharmaceutical Technology Division, Daiichi Sankyo Co Ltd.

Session Chairman: MR. S. R. LOHOKARE, Chairman - Technology & Energy Expert Committee, ICC

Session Chairman: PROF. G. MEHTA, National Research Professor

09:00 - 09:30 Practical Approach to Prepare Neurokin Receptor Antagonist CS-003 via Asymmetric Oxidation Reactions

Dr. Hiroshi Tomori - Senior Director, Process Technology Research Laboratories,

Pharmaceutical Technology Division, Daiichi Sankyo, Japan

09:30 - 10:00 Catalytic Oxidations

Dr. (Mrs.) M. Lakshmi Kantam - Director, IICT, Hyderabad

10:00 - 10:30 Development of Highly Active Catalyst for Alcohol Oxidation

Mr. Masami Kozawa - Synthesis Research Department, Chemical Research Laboratories, Nissan Chemical Ind. Ltd., Japan

10:30 - 11:00 Research and Development of Amino Acids Derivatives

Dr. Toshihisa Kato - Corporate Vice President, Ajinomoto, Japan


11:30 - 12:00 Process Development for the Large Scale Production of Unnatural Amino Acids

Dr. Masaru Mitsuda - Distinguished Scientist, Head of Research Team, Fine Chemicals Group,

QOL Division, Kaneka Corporation, Japan

12:00 - 12:30 Process Development and Scale up of Generic API

Dr. Vilas Dahanukar - Vice President & Head - Global R&D, Dr. Reddy's Laboratories Ltd., Hyderabad

12:30 - 13:00 Concept to Commercialization of New Process Chemistry: Engineering Aspects

Mr. Gaurav Mediratta & Dr. Utpal Vakil, SABIC Technology Center, Bangalore

13:00 - 14:00 NETWORKING LUNCH

14:00 - 14:30 Process Intensification / Continuous Processes for Fine & Specialty Chemicals

Dr. Vivek Ranade - Dy. Director, Chemical Engineering & Process Development Division, National Chemical Laboratory, Pune

14:30 - 15:00 Relevance of Process & Product Safety in Process Chemistry R & D

Mr. Vijay Bhujle - Head- Expert Services, Intertek India Pvt. Ltd.


15:30 - 16:00 A New Ether Process Solvent: Cyclopentyl Methyl Ether (CPME) for Green Chemistry & Process Innovation

Mr. Mitsuru Sugawara - Sr. Chief Researcher, New Materials Development Lab., R&D Centre, Zeon Corporation, Japan

16:00 - 16:30 Advanced Bio Energy Research - Indian Initiatives

Dr. D. K. Tuli - Executive Director R&D, Indian Oil Corporation Ltd.

16:30 - 17:00 Concluding Remarks & Vote of Thanks - DR. VADIRAJ EKKUNDI, Head-R&D, Hikal Ltd.

PROGRAMME SCHEDULE: DAY-2, 31 JANUARY 2014

ADVISORY COMMITTEE

INDIA

1. Mr. Yogesh M. Kothari, President - ICC &

CMD, Alkyl Amines Chemicals Ltd., Mumbai

2. Mr. Jai Hiremath, CMD, Hikal Limited, Mumbai

3. Prof. G. Mehta, National Research Professor & Lilly-Jubilant Chair,

School of Chemistry, University of Hyderabad

4. Mr. S. Lamba, MD, Eisai Knowledge Centre, Vizag.

5. Prof. G. D. Yadav, VC, Institute of Chemical Technology, Mumbai

6. Mr. V. Shankar, MD & CEO, Rallis India Limited, Mumbai (to be confirmed)

7. Dr. K. Nagarajan, Scientific Advisor, Hikal, Bangalore

8. Mr. S. R. Lohokare, MD, National Peroxide Limited, Mumbai

JAPAN

1. Prof. Kiyoshi Tomioka, Doshisha Women's College of Liberal Arts,

Professor Emeritus of Kyoto University, President of JSPC

2. Dr. Kunisuke Izawa, Advisor, Hamari Chemicals & JSPC

3. Dr. Toshiro Konoike, Advisor, Osaka Synthetic Chemical Laboratories,

Vice President of JSPC

4. Dr. Takayuki Shioiri, Meijo University, Professor Emeritus of

Nagoya City University, Honorary President of JSPC

5. Mr. Shigeru Soda, President of Office Well SODA, Vice President of JSPC

ORGANIZING COMMITTEE

INDIA

1. Dr. S. U. Kulkarni, Director, R & D, Sabic Research & Technology, Bangalore

2. Dr. Mrs. Lakshmi Kantam, Director, IICT, Hyderabad

3. Dr. S. Nambiar, MD, AstraZeneca India Pvt Ltd., Bangalore

4. Mr. S. R. Lohokare, MD, National Peroxide Limited, Mumbai

5. Mr. H. S. Karangale, Director General - ICC, Mumbai

6. Dr. V. S. Ekkundi, Head of R&D, Hikal Limited, Bangalore

JAPAN

1. Prof. Shuji Akai, Graduate School of Pharmaceutical Sciences, Osaka University

2. Dr. Toshihisa Kato, Corporate Vice President, Ajinomoto

3. Dr. Naoyuki Kishi, Vice President, Process Technology Research Laboratories, Pharmaceutical Technology Division, Daiichi Sankyo CO., LTD.

4. Dr. Masaru Mitsuda, Head of Research Team, Fine Chemicals Group, QOL Division, Kaneka Corporation

5. Dr. Hironao Sajiki, Gifu Pharmaceutical University, Vice President of JSPC

6. Dr. Katsuya Tagami, Executive Director, API Research Japan, Eisai Co., Ltd.



SPEAKER PROFILES

ACKNOWLEDGEMENTS

ICC & JSPC would like to give special recognition to those individuals who have so graciously contributed to this Conference program.

Many thanks to those Speakers whose names appear throughout the program for their time and expertise, and for exchanging valuable information with others in the industry.



YOGESH M. KOTHARIPRESIDENT

INDIAN CHEMICAL COUNCIL (ICC)

Mr. Yogesh M. Kothari is a Chemical Engineer having studied his B.Chem.(Engg.) at UDCT (Mumbai) and then

Masters in Chem. Engg. from Lowell Technological Institute, University of Massachusetts. He also studied his

Masters in Management Science from Lowell Technological Institute, University of Massachusetts in 1973. Having

got some project experience with UHDE Gmbh, Germany Mr. Kothari came back to India and worked with ICB India

for a year till 1976.

He gained experience with his family firm of Stock Brokers (D.S. Purbhoodas & Company) and Investment

Bankers (DSP Merrill Lynch Limited) for few years.

In 1978 he founded Alkyl Amines Chemicals Limited and since then looking after Alkyl Amines Chemicals Limited

as CEO. Currently Mr. Kothari is the Chairman & Managing Director of the company.

In the year 1999 Alkyl Amines Chemicals Limited took over Diamines & Chemicals Limited, Baroda along with S.

Amit & Company.

Mr. Kothari is currently:

The President of Indian Chemical Council (ICC).

The Managing Committee Member of Indian Merchants' Chamber (IMC).

The Executive Committee Member of D.S. Kothari Hospital (Charitable Hospital) at C.P.Tank, Mumbai.

The Managing Committee Member of H.N. Hospital, Mumbai.

The Chairman & Managing Director of Alkyl Amines Chemicals Limited.

The Chairman of Diamines & Chemicals Limited.

The Chairman of Alkyl Speciality Chemicals Limited.

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KIYOSHI TOMIOKAPROFESSOR OF ORGANIC CHEMISTRY, EMERITUS KYOTO UNIV.

Education:

Bachelor 1971, Master 1973: University of Tokyo, Faculty of Pharmaceutical Sciences, Ph.D. 1976: University of Tokyo, Faculty of Pharmaceutical Sciences (Prof. Shun-ichi. Yamada) “Biogenetic-type asymmetric total synthesis of Amaryllidaceae alkaloids” Postdoctoral Fellow: Colorado State University, Department of Chemistry (Prof. A. I. Meyers), 1976-1978 “Total synthesis of Maytansine”

Academic Positions:

Research Associate, University of Tokyo, Faculty of Pharmaceutical Sciences, 1978-1983

Associate Professor, University of Tokyo, Faculty of Pharmaceutical Sciences, 1983-1992

Professor, Osaka University, The Institute of Scientific and Industrial Research, 1992-1996

Professor, Kyoto University, Graduate School of Pharmaceutical Sciences, 1996-2010

Dean, Kyoto University, Graduate School of Pharmaceutical Sciences, 2006-2007

Adjunct Faculty Members, Institute for Integrated Cell-Material Sciences, Kyoto University, 2008-2010

Professor, Doshisha Women's College of Liberal Arts, Faculty of Pharmaceutical Sciences, 2010-2013

Special Appointment Professor, Doshisha Women's College of Liberal Arts, 2013-present

Field of Research: Organic chemistry including synthetic organic chemistry, asymmetric synthesis, organometallic chemistry. Synthesis of natural products and biologically potent compounds. Molecular assembly

Chairperson: The French-Japanese Society of Pharmaceutical and Fine Chemistry 2008-

Membership:

The Japanese Society for Process Chemistry (President 2010)

The Pharmaceutical Society of Japan (Vice President 2011-2013)

International Society of Heterocyclic Chemistry (Advisory board member 2006-2007)

The Chemical Society of Japan, The Japan Cancer Association, The Society of Synthetic Organic Chemistry, Japan, The American Chemical Society, The Royal Society of Chemistry (CChem., MRSC)

Editorial Board: Editor of Chemical & Pharmaceutical Bulletin 1999-2003; Honorary Advisor to the Editorial Board of Heterocycles 2006; Regional Editor of Letters in Organic Chemistry 2006-2007; Tetrahedron Editor 2007; Editorial Advisory Board of ACS Medicinal Chemistry Letters 2010-

Awards:

The Encouraging Award for Scientist, The Research Foundation for Pharmaceutical Sciences, 1983 "Asymmetric Total Synthesis of Antitumor Natural Products Based on the Novel Use of Chiral Synthon with Specific Molecular Structure"

The Pharmaceutical Society of Japan Award for Young Scientists, 1984

"Asymmetric Total Synthesis of Some Biologically Active Natural Products"

The Award of The Research Foundation for Optically Active Compounds, 1991 "Asymmetric Synthesis Controlled by Chiral External Ligands"

The Pharmaceutical Society of Japan Award, 2003

"Asymmetric Reaction Based on Molecular Structure Control and Activation"

Scientific Papers on Chemistry: Original: 260; Review: 70; Books: 20

MR. INDRAJIT PALSECRETARY (C&PC)

MINISTRY OF CHEMICALS AND FERTILIZERS, GOVT. OF INDIA

Mr. Indrajit Pal belongs to the 1977 batch of the Indian Administrative Service – Andhra Pradesh – Cadre.

He is graduate in Chemistry Physics Mathematics, M Phil in Social Sciences and holds Post Gradute Diploma in

Public Admn. He has more than 30 years experience in various department of Andhra Pradesh Government like

Industries, Agriculture & Cooperation, Health & Family Welfare, Social Justice, Energy and Environment & Forests.

He has undergone training in various institutes such as Indian Institute of Management Kolkata, Administrative

Staff College of India - Hyderabad, National Institute of Information Technology, The Energy and Resources

Institute

DR. A. J. V. PRASADJOINT SECRETARY – DCPC

MINISTRY OF CHEMICALS & FERTILIZERS, GOVERNMENT OF INDIA

DR. ADITHELA JAI VARA PRASAD is holding a Doctorate in Agronomy from the Indian Agricultural Research

Institute (I.A.R.I.) PUSA He oined the Indian Administrative Service (I A S) in the year 1986.

In his early years in the Indian Administrative Service, he had worked in the State of Himachal Pradesh in various

capacities, such as Assistant Commissioner (Development) , Jhandutta, Bilaspur District, Sub-Divisional

Magistrate, Arki Sub Division, District Solan, Add tional Deputy Commissioner, Solan, Additional Deputy

Commissioner, Shimla, Settlement Officer, Kangra Division, M D. Kangra Central Cooperative Bank, Deputy

Commissioner, Una, Labour Commissioner, Himachal Pradesh, Director Urban Development, Divisional

Comm ssioner, Kangra Division, Deputy Commissioner, Una, Director, Urban Development Commissioner,

Municipal Corporation, Shimla, Deputy Commissioner Kullu Division n Himachal Pradesh.

He had, Later, worked as Secretary to the Chief Minister (Chhattisgarh) (Hon'ble Shr Ajit Jogi), and also as

Secretary and Commissioner, Higher Education, Technical Education, Science and Technology, I T l s and Man

Power Planning, Secretary and Director, Agriculture, Horticulture, Animal Husbandry, Secretary and Registrar,

Cooperative Societies in the State of Chhattisgarh.

Before joining the Central Government, he had worked as the Divisional Commissioner, Shimla Division, Director,

Himachal Institute of Public Administration (HIPA), D visional Commissioner, Kangra Division, Registrar

Cooperative Societies, Himachal Pradesh, Secretary, Home Principal Secretary, Animal Husbandry, etc. in the

State of Himachal Pradesh

He has acquired vast knowledge and practical experience in development activities in Agriculture, Horticulture,

Animal Husbandry, Agriculture Engineering, Higher Education and Technical Education, Science and Technology,

Man Power Planning, etc. He has also been very active n implementing the work relating to introduction of crop

diversification program organic farming, seed village programs, and introduced Madagaskar system of paddy

cultivation, Jatropha and Pangamia (bio-fuel) crops, setting up of Farm Training Academy, Tissue Culture

Laboratory, setting up of Universities, Engineering Colleges, Regional Science Centre, etc.

He is, at present, working as Joint Secretary (Chemicals) in the Ministry of Chemicals and Fertilizers, Department

of Chemicals and Petrochemicals, Government of India. He is looking after the work of administrative policy and

other aspects of Chemical Industries and Pesticides Industries in addition to the Public Sector Undertakings under

this Department

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PROFESSOR M. M. SHARMAFORMER DIRECTOR

INSTITUTE OF CHEMICAL TECHNOLOGY, MUMBAI

PADMAVIBHUSHAN PROFESSOR M. M. SHARMA is currently Emeritus Professor of Eminence, Institute of Chemical

Technology, Mumbai (formerly UDCT) and has more than 4 decades of experience in chemical industry. He has obtained

B.Chem. Eng., M.Sc. (Tech). (Bombay); Ph.D. (Cambridge); D.Sc. (I.I.T.,Bombay) (I.I.T.,Delhi) (B.H.U.) (Calcutta) (Kanpur)

(Bundelkhand) (Lucknow) (h.c.) D.Eng.(Roorkee) (h.c.) LL.D (Mumbai) (h.c.) FREng, FRS, FNA, FASc, FNASc, FTWAS, C

Chem, FRIC (U.K), C. Eng., FIChE (U.K.), FIIChE, FICS, FBRS.

He has held several positions in academic world. He was-

The First Engineer from India to become a Fellow of Royal Society (1990)

Chairman of Research Council, National Chemical Laboratory, Pune (1998)

Member of Advisory Board, IIT Bombay (2003-2009)

Member, Council, I. I. Sc. Bangalore (2002-2008)

Member, Science Advisory Council of the Prime Minister (2005)

Director, Central Board of Directors, Reserve Bank of India (2006-2010),

Prof. Sharma has won several prestigious awards and recognitions in the past including S.S. Bhatnagar Prize in Engineering

Sciences (1973); Fellow, Indian National Science Academy (INSA)–1976. He has received the Best Teacher Award from

Government of Maharashtra in 1984. He was distinguished visiting Professor. Purdue University, USA.

Prof. Sharma has published 250 research papers in journals like Chemical Engineering Science; Industrial and Engineering

Chemistry Research; Chemical Engineering Research and Design; Canadian Journal of Chemical Engineering; Reactive and

Functional Polymers etc.

He has supervised 71 Doctoral Thesis and 35 M. Chem. Eng. / M. Sc. (Tech.) Thesis.

He has published 2 books:

“Heterogeneous Reactions : Analysis, Examples and Reactor Design”, Volume I and II, Wiley – Interscience, USA, 1984

(with L. K. Doraiswamy)

“Fine Chemicals : Technology and Engineering, Elsevier, The Netherlands” Dec.2001 (with J. A. Moulijn, A. Cybuluski and

R. A. Sheldon)

Prof. Sharma encouraged students to become entrepreneurs and many of his students are running own chemical

manufacturing companies and are leading members of Indian Chemical industry.

Prof. Sharma has immensely contributed towards the growth of Indian Chemical Council. He was member of ICC Awards

Selection Committee for more than a decade and was very judicious in selecting the winners. In fact, during his involvement as

a member of Award Selection Committee, rules and regulations of Awards were refined and fine-tuned. He and other members

of the Awards Selection Committee were used to be in the knowhow of development in R&D fronts and used to advise the

concerned companies to send nomination for ICC Acharya P. C. Ray Award.

He was also member of Editorial Board of CHEMICAL NEWS, the monthly Journal of ICC for many years and was guiding force

for the Journal which has now become of international standard publication.

Prof. Sharma has delivered lectures in the ICC Lecture Series started in memories of its founder Acharya P. C. Ray. He was also

instrumental in starting Dr. G. P. Kane Trust Lecture Series.

He is also an Honorary Member of ICC.

He is a teacher of par excellence and father figure for Indian Chemical industry.

In recognition of his outstanding contributions, Indian Chemical Council is pleased to confer the ICC LIFETIME

ACHIEVEMENT AWARD for the year 2011 on PROFESSOR M. M. SHARMA, Former Director, Institute of Chemical

Technology, Mumbai.

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MR. RAKESH BHARTIA

VICE PRESIDENT - ICC

(CHIEF EXECUTIVE OFFICER INDIA GLYCOLS LIMITED)

Mr. Rakesh Bhartia, is the CEO of India Glycols Limited (IGL) since August 2009, a Rs. 3000 Crores(USD 550

million) company having the distinction of being the largest Company in the world producing a wide variety of Green

Specialty Chemicals from Molasses and Ethanol. In addition, IGL is also engaged in the business of natural gums,

industrial gases and potable alcohol.

Mr. Rakesh Bhartia prior to IGL, was CEO of Bajaj Hindustan Ltd., India's largest manufacturer of sugar and

ethanol.

He started his career in 1992 with ICICI Securities & Finance Company Ltd (a JV between ICICI and JP Morgan).

He has worked in various Banks including Standard Chartered, Grindlays Bank and Bank of America. His career

focus has been in Commercial and Investment Banking.

Mr. Rakesh Bhartia, by qualification is a Chartered Accountant, Company Secretary and Cost Accountant. Mr. Bhartia is currently the Vice President of INDIAN CHEMICAL COUNCIL.

Takayuki Shioiri was born in 1935 and graduated from the Faculty of Pharmaceutical Sciences, University of

Tokyo in 1959. After postgraduate studies at University of Tokyo, he was appointed a Research Associate in 1962

and then promoted to Assistant Professor in 1964 at University of Tokyo. After he obtained Ph. D. degree in 1967,

he worked as a postdoctoral fellow at the Imperial College under the supervision of Professor Sir Derek Barton from

1968 to 1970. He promoted to Associate Professor at University of Tokyo in 1977. In the same year, he was

appointed Professor of Nagoya City University. He retired from Nagoya City University and became Emeritus

Professor in 2001. From 2002 to 2007, he was Professor of Graduate School of Environmental and Human

Sciences, Meijo University. He is now a researcher of Faculty of Agriculture at Meijo University.

Takayuki Shioiri received the PSJ (the Pharmaceutical Society of Japan) Award for Young Scientists in 1974, the

Abbott Prize in 1978, the Aichi Pharmaceutical Society Award in 1981, the PSJ (the Pharmaceutical Society of

Japan) Award in 1993, and the Japanese Peptide Society Award in 1999.

From 1990 to 2007, he was a Japan Regional Executive Editor of Tetrahedron, and a member of the Executive

Board of Tetrahedron Publications. He is now a member of Board of Consulting Editors of Tetrahedron, Tetrahedron

Letters, and International Journal of Peptide Research and Therapeutics. He was President of the Japanese

Peptide Society from 2000 to 2002 and President of the Japanese Society for Process Chemistry (JSPC) from

2001 to July, 2010. He is now Honorary President of JSPC.

TAKAYUKI SHIOIRI

Highly active catalysts for alcohol oxidation;

AZADOLⓇ and pre-MIBSK

Advantages:

High activity (catalytic amount)

AZADOLⓇ is able to oxidize bulky secondary alcohols.

Pre-MIBSK is non-explosive and used as replacement of IBX.

AZADOLⓇ and pre-MIBSK are Ames negative.

Contact Information:

Nissan Chemical Industries, Ltd.

Pharmaceuticals Division, Custom Chemicals Department

E-mail: [email protected]

Phone: +81-3-3296-8005, FAX: +81-3-3296-8210, URL: http://www.nissanchem.co.jp/english/index.html

Session I: NOVEL METHODS DIRECTED TO PROCESS CHEMISTRY & DEVELOPMENT-1

Katsuya Tagami, Ph.D. API Research Japan, Pharmaceutical Science & Technology Function Unit, Eisai Product Creation Systems Eisai Co., Ltd., 22 Sunayama, Kamisu-shi, Ibaraki 314-0255, Japan Phone: 81-479-4982; Fax: 81-479-4983 E-mail: [email protected]

Date of birth: November 28, 1961 Place of birth: Ibaraki, Japan Education: Bachelor of Engineering, Tohoku University, 1984 Master of Engineering, Tohoku University, 1986 PhD of Engineering, Tohoku University (Prof. Michiharu Kato), 1999 Employment History: Apr. 1986 - Mar. 1992: Researcher, Discovery Research Tsukuba Research Laboratories (TRL), Eisai Co., Ltd. Apr. 1992 - Apr. 1994: Research Associate; Department of Chemistry, Harvard University (Prof. Yoshito Kishi) May 1994 - Sep. 1996: Principal Researcher, Discovery Research, TRL, Eisai Co., Ltd. Oct. 1996 - Mar. 1998: Principal Researcher, Tsukuba Process Research Process Research Laboratories (PRL), Eisai Co., Ltd Apr. 1998 - Mar. 2007: Principal Scientist, Tsukuba Process Research, PRL, Eisai Co., Ltd Apr. 2007 - Sep. 2009: Director, Kashima Process Research API Research Laboratories, Eisai Co., Ltd. Oct. 2009 - Present: Executive Director, API Research Japan, Pharmaceutical Science & Technology Function Unit Eisai Product Creation Systems Award Eisai Award for Scientific Achievement, Principal Award, 2004 The Pharmaceutical Society of Japan Award for Drug Research and Development, 2013

DEVELOPMENT OF NEW FORMYLATION REACTION USING MAGNESIUM AMIDE: PROCESS RESEARCH FOR A NOVEL

SODIUM CHANNEL BLOCKER E2070

Katsuya Tagami API Research Japan, Pharmaceutical Science & Technology Function Unit

Eisai Product Creation Systems 22-Sunayama, Kamisu-shi, Ibaraki. 314-0255 Japan

[email protected]

E2070 (1) is a novel selective sodium channel blocker discovered by Eisai Co., Ltd. It targets a drug for the treatment of neuropathic pain. 1) The structure of E2070 and the initial synthetic scheme are depicted in Fig.1.

Synthetic route was simple and suitable for process chemistry, where the two major pieces (4 and 9) are coupled in convergent manner. However, the manufacturing process had some issues to be solved prior to GMP batch production: 1) Low yield; 2) Purification by column chromatography; 3) Use of halogenated solvents. Especially, formylation reaction from 3 to 4 was the biggest problem. The yield was variable and unreproducible even though the reaction was run at cryogenic conditions. Careful investigation of the nature of Li anion of 3 revealed that the anion was unstable even at -78 degree C.

Thus, we embarked on finding alternative anion species which was stable and had enough reactivity toward formylation. After trials and errors, we found that some magnesium amide species were suitable for this transformation (Fig. 2). 2)

We could demonstrate this reaction in a pilot plant on multi kilogram scale and we successfully completed the GMP production of E2070 drug substance. In this talk, the process development of E2070 will be described with focus on this new formylation reaction using magnesium amide.

References

1) F. Ozaki, M. Ono, K. Kawano, Y. Norimine, T. Onogi, T. Yoshinaga, K. Kobayashi, H. Suzuki, H. Minami, K. Sawada, PCT int. Appl. WO 03/084948 (2003).

2) A. Kamada, M. Kubota, PCT int. Appl. WO 05/030714 (2005).

Session I:

Novel Methods Directed to Process Chemistry & Development-1

Dr. Thennati Rajamannar Director &Executive Vice President SUN PHARMA ADVANCED RESEARCH COMPANY LTD. Baroda, India.

Dr. T. Rajamannar was born on the 22nd July 1961, and is currently Director-Executive Vice President of Sun Pharma Advanced Research Company Limited. Dr. Rajamannar has a M.Sc in Chemistry from the University of Madras, a Ph.D in Organic Chemistry from IIT, Madras and did a Post-Doctoral work on Carbohydrate Chemistry (Organic Chemistry) from 1988 to 1990 with Professor Andrea Vasella (currently at ETH, Zuerich) from University of Zurich in Switzerland. Dr. Rajamannar worked from 1990 to 1993 as a Scientist working in Organic Chemistry for SPIC Science Foundation in Chennai, India. He started his career at Sun Pharma Advanced Research Centre in Baroda as Head of Organic Synthesis from 1993, & initiated in 2000 Drug Discovery programme. His group developed Processes for more than 200 APIs, Novel synthetic routes and Polymorphs, with medicinal chemistry in Allergy and Inflammation. Dr. Rajamannar is a Council Member of Chemical Research Society of India (CRSI) and National Organic Symposium Trust (NOST). He delivered several lectures at National and International conferences. He was a Faculty for Ph.D Course work programme in Organic Chemistry at NCL, Pune, also a PAC member of DST-SERB [Science & Engineering Research Board]. Dr. Rajamannar has filed more than 200 patents and has 18 publications in International journals.

CHALLENGES IN PROCESS CHEMISTRY

Dr. Thennati Rajamannar Director &Executive Vice President

SUN PHARMA ADVANCED RESEARCH COMPANY LTD.

SUMMARY In Research a novel and an efficient bond formation process is a pursuit of goal, further chemo, regio and stereo selective out comes are important measures of versatility of inventions.

35 65 (85% Yield)

T Rajamannar et al, JCS Chem Comm., 1994, 25 - 26, & Tet. Lett., 1994, 35(4)637 – 640

In Process Research, amenable for large scale production, high throughput, meeting consistent critical quality attributes and environmentally benign in nature. Gabapentin process described in the patent literature requires removal of large excess of water/solvents. It has been found Gabapentin with low levels of process related impurities, one could isolate the product in solid form from aqueous reaction mixture at its isolelectric point. Development of Gabapentin process with less by products was possible via lactam.

T Rajamannar et al, 62/MUM/2000 A(20.01.2000), & 76/MUM/2000(24.01.2000)

Pharmaceutical substances with chirality often is resolved from its racemic mixture, however molecule containing more than one asymmetric centre leads to isolation of desired product with low yields, hence large amounts of waste is generated. One such product is Sertraline, the unwanted isomers are recycled to obtain sertraline, asymptotically.

CO2HO NH2 N

H O

NH O

NH2 CO2H

Sertraline

(cis-1R,4R-isomer)

(Unwanted isomers, if not recycled, huge environmental burden)

T Rajamannar et al, US 6,506,940 B1

Yet another product viz Citalopram, commercialized with optimal yield, through put and consistent quality

Intermediates

Citalopram Escitalopram

T Rajamannar et a., US 7,019,153 B2, 7,148,364 B2 & 7,989,645 B2

The crystal form attribute is of immense importance in product development. Two forms of Olanzapine are reported, however the form - I is reported to be pharmaceutically non-elegant due to discoloration.

Color stable form –I of Olanzapine T Rajamannar et al., US 6,906,062 B2

NHMe

Cl

Cl

NHMe NHMe

O

Br

NMe2

F

NC

OHNC NC

N

SN

N

N

Me

CH3

H

Session I: NOVEL METHODS DIRECTED TO PROCESS CHEMISTRY & DEVELOPMENT-1

Dr. Yoshiji Takemoto Graduate School of Pharmaceutical Sciences Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan Phone: +81-75 753 4528, Fax: +81-75 753 4569 E-mail: takemoto @pharm.kyoto-u.ac.jp http://www.pharm.kyoto-u.ac.jp/orgchem/

Yoshiji Takemoto was born in Osaka in 1960 and received his B. Sc (1983) and Ph. D.degree (1988) from Osaka University. After working as a postdoctoral fellow with Prof. R. A. Holton at Florida State University from 1988 and with Dr. S. Terashima at Sagami Chemical Research Center from 1989, he joined the Faculty of Pharmaceutical Sciences, Osaka University, as an Assistant Professor in 1990. He moved to the Graduate School of Pharmaceutical Sciences, Kyoto University, as an Associate Professor in 1998 and was promoted to Professor in 2000. Currently, he is a full professor of the Graduate School of Pharmaceutical Sciences at Kyoto University. He was awarded the Takeda Award in Synthetic Organic Chemistry, Japan (1992), the Pharmaceutical Society of Japan (PSJ) Kinki Branch Award for Young Scientists (1994), Thomson Research Front Award (2007), and the PSJ Award for Divisional Scientific Promotions (2008). He was an associate editor of Chemistry Letters (2008-2011) and Chemical & Pharmaceutical Bulletin(2009-2011). His research interests include organocatalysis with hydrogen-bond donor catalysts, the development of transition metal-catalyzed reactions, and the total synthesis of natural products.

Selected Publications (Reviews): 1. Kobayashi, Y.; Inokuma, T.; Takemoto, Y., Development of innovative hydrogen-bond-donor catalysts

based on heterocyclic scaffolds and their applications to asymmetric reactions. J. Synth. Org.Chem. Jpn. 2013, 71, 491-502.

2. Takemoto, Y.; Inokuma, T., Bifunctional Thiourea Catalysts. Wiley-VCH: Weinheim, 2012; p 233-237.

3. Takemoto, Y.; Stadler, M., C-C Bond Formation: Michael Reaction. Elsevier Ltd.: 2012; p 37-68. 4. Inokuma, T.; Takemoto, Y., Bifunctional (Thio)urea & BINOL Catalysts. Thieme: Stuttgart, 2011; p

437-497. 5. Takemoto, Y., Development of Chiral Thiourea Catalysts & Its Appl. to Asymmetric Catalytic

Reactions. Chem. Pharm. Bull. 2010, 58, 593-601. 6. Shindoh, N.; Takemoto, Y.; Takasu, K., Auto-Tandem Catalysis: A Single Catalyst Activating

Mechanistically Distinct Reactions in a Single Reactor. Chem. Eur. J. 2009, 15, 12168–12179. 7. Yanada, R.; Takemoto, Y., Development of Synthetic Methods with Indium. J. Synth. Org. Chem.Jpn.

2009, 67, 239-247. 8. Miyabe, H.; Takemoto, Y., Discovery and Application of Asymmetric Reaction by Multi-functional

Thioureas. Bull. Chem. Soc. Jpn. 2008, 81, 785-795. 9. Yasui, Y.; Takemoto, Y., Intra- and Intermolecular Amidation of C-C Unsaturated Bonds Through

Palladium-Catalyzed Reactions of Carbamoyl Derivatives. Chemcal Record 2008, 8, 386-394 10. Miyabe, H.; Takemoto, Y., Enantioselective Radical Cyclizations: A New Approach to Stereocontrol

of Cascade Reactions. Chem., Eur. J. 2007, 13, 7280-7286. 11. Takemoto, Y.; Miyabe, H., The Amino Thiourea-Catalyzed Asymmetric Nucleophilic Reactions.

Chimia 2007, 61, 269-275. 12. Takemoto, Y., Development of Amino Thiourea Catalysts as an Artificial Enzyme: Their Application to

Catalytic Enantioselective Reactions. J. Synth. Org. Chem. Jpn. 2006, 64, 1139-1147. 13. Takemoto, Y., Recognition and Activation by Ureas and Thioureas: Stereoselective Reactions Using

Ureas and Thioureas as Hydrogen-Bonding Donors. Org. Biomol. Chem. 2005, 3, 4299 - 4306. 14. Miyabe, H.; Takemoto, Y., Regio- and stereocontrolled palladium- or iridium-catalyzed

allylation.Snlett 2005, 1641-1655.

http://www.pharm.kyoto-u.ac.jp/orgchem/

ASYMMETRIC REACTIONS USING BIFUNCTIONAL HB-DONOR CATALYSTS

Yoshiji Takemoto

Graduate School of Pharmaceutical Sciences, Kyoto University [email protected]

[1] Asymmetric reactions with bifunctional thiourea catalysts We designed the bifunctional thiourea catalyst (A) based on the reaction mechanism of serine protease-mediated peptide hydrolysis. So far, it was revealed that the catalyst promoted a wide range of asymmetric reactions described below to give different types of chiral compounds in good yields with high enantioselectivities. In these reactions, the catalyst A, which is commercially available as “Takemoto Catalyst”, activates both nucleophiles and electrophiles concurrently by the tertiary amine and thiourea moieties. In particular, two NH protons of the thiourea play a crucial role as a hydrogen-bond donor (HB-donor) in the deprotonation of various nucleophiles as well as the recognition of the resulting anions. Although only acidic nucleophiles such as malonates, β-keto esters, and nitroalkanes could be used, the obtained chiral products were converted into medicines and biologically active natural products, γ-amino acid (Baclofen), epibatidine, CP-99,994, dysidazirine, and so on.

[2] Development of new powerful HB-donor organocatalysts We also developed several HB-donor catalysts B-E other than thiourea A. The former catalysts B and C are new types of HB-donor catalysts, whose bicyclic structures were introduced to fix the conformation. The latter catalysts possess a primary hydroxy group, which is expected to coordinate to organoboron reagents via a ligand exchange process.

mailto:[email protected]

The quinazoline catalyst B indeed exhibited the excellent performance in hydrazination of cyclic β-keto esters 1, giving the desired product 2 with the highest enantioselectivity.1) In contract, the benzothiadiazine catalyst C, which was proved to have stronger HB-donating ability than A, shows greater activity for a highly enantioselective isomerization of alkynoates 3 into chiral allenoesters 4.2) We have also succeeded in the first asymmetric intramolecular oxa-Michael reaction of α,β-unsaturated amide 5, supposed to have poor reactivity as a Michael acceptor, to furnish chiral isoxazolidine 6 with excellent stereocontrol.3) Similarly, the oxa-Michael addition could be successfully applied to phenol 7 to provide dihydrobenzofuran 8 in 97% with 94% ee. Expectedly, the hydroxy thioureas D and E catalyzed the Petasis reactions of quinolines4) and α-iminoamides5) with organoboronic acids in a good to high stereoselective manner.

REFERENCES:

1. Inokuma, T.; Furukawa, M.; Uno, T.; Suzuki, Y.; Yoshida, K.; Yano, Y.; Matsuzaki, K.; Takemoto, Y.,Chem. Eur. J. 2011, 17, 10470-10477.

2. Inokuma, T.; Furukawa, M.; Suzuki, Y.; Kimachi, T.; Kobayashi, Y.; Takemoto, Y., ChemCatChem2012, 4, 983–985.

3. Kobayashi, Y.; Taniguchi, Y.; Hayama, N.; Inokuma, T.; Takemoto, Y., Angew. Chem. Int. Ed. 2013, 52,11114-11118.

4. Yamaoka, Y.; Miyabe, H.; Takemoto, Y., J. Am. Chem. Soc. 2007, 129, 6686-6687. 5. Inokuma, T.; Suzuki, Y.; Sakaeda, T.; Takemoto, Y., Chem. Asian J. 2011, 6, 2902-2906.

Session I:

Novel Methods Directed to Process Chemistry & Development-1

Dr. Aniruddha B. PANDIT FNA, FASC, FNASc, FNAE, FMASc Dept. of Chemical Engineering Institute of Chemical Technology Mumbai. Aniruddha B. Pandit was born on 7th December 1957 in Mumbai, Maharashtra. He earned his B. Tech (Chem) degree from Institute of Technology, Banaras Hindu University in 1980 and joined for his Ph.D. (Tech) degree in University Department of Chemical Technology (now UICT), University of Mumbai. During his Ph.D. (Tech) work from 1980-1984, he also worked as an Associate Lecturer in the same department and earned his Ph.D. (Tech) in 1984 under the guidance of Prof. J. B. Joshi. From 1984 till 1990 he worked in the Department of Chemical Engineering, University of Cambridge, United Kingdom as a Research Assistant & then as a Research Associate with Prof. J. F. Davidson, working in the area of bubble break-up and design of multiphase reactors, on project sponsored by Imperial Chemical industries & Agricultural and Food Research Council. He developed many novel designs of gas-liquid contactors and also developed new impeller designs. ACADEMIC & RESEARCH CONTRIBUTION: After returning to India in 1990,he joined UICT as a UGC Research Scientist ‘B’ and was subsequently promoted Scientist ‘C’ (Professor’s Grade) in 1996. He was instrumental in starting a major activity & program in the area of Hydrodynamic Cavitation. Dr. Pandit has been singularly responsible to propose, promote and apply the phenomena of Hydrodynamic cavitation for intensification of physical and chemical processing applications. He has successfully exploited the cavitation phenomena for a variety of operations such as crystallization, emulsification, nano-particle synthesis and processes such as esterification, oxidation etc. His work on microbial cell disruption for water disinfection has been recognized by International Maritime Organization (IMO) as a most probable technique for Ballast Water Treatment among other seven developed by the scientists in Japan, Germany, USA etc. Prof. Pandit has authored over 200 publications, 3 books and over 10 chapters and has 5 patents & is on Editorial board of several International Scientific Journals. He has guided 25 PhD’s and 45 master’s students so far. OTHER CONTRIBUTIOIN: Prof. Pandit has contributed to innovation in teaching, at graduate and undergraduate levels, demonstration experiments for elaborating the physical principles of many chemical engineering operations. He is actively involved in the area of harnessing solar energy & with tribal population in extending the chemical engineering principles for drying of farm/ forest product & water disinfection for potable water. He is currently involved in setting up of cavitational application centre to exploit the phenomena of cavitation for physical/ chemical/ biological transformations in UICT Mumbai. AWARDS: Prof. Pandit was elected to the fellowship of INSA in 2008. He is also a fellow of Indian Academy of Sciences, Indian National Academy of Sciences Indian National Academy of Engineering & Maharashtra Academy of Sciences. Among the several honors & prizes that he received were ISTE, Outstanding research award (1992) VASVIK award (1996), IIChE – Herdilia award (2002), UAA distinguished alumnus award (2008) and UICT Best teacher award on 7 occasions in the past 15 years.

SONOCRYSTALLIZATION AS A METHOD TO CONTROL THE CRYSTAL SIZE DISTRIBUTION AND MORPHOLOGY

Dr. Aniruddha B. PANDIT

FNA, FASC, FNASc, FNAE, FMASc

The controlled application of ultrasound at the various stages of crystallization has been used to modify the product properties to meet specified requirements. Ultrasonic irradiation at an initial stage will induce primary nucleation, and will assist crystallization process to be carried out in moderate metastable zone widths. These conditions are usually associated with the production of large, well-formed crystals with minimum fines. Continuous irradiation will reduce crystal size and result into imperfect crystals. Ultrasound may also be applied in the final stages to break up agglomerates. Sonocrystallization has been used to change the crystal size, distribution, morphology, and structure of Gemfibrozil crystals [1].Judicious selection of process conditions and combinations of polymer and surfactants were also identified experimentally for the ultrasound precipitation of ultrafine particles of griseofulvin (GF) with a narrow particle size distribution (PSD) as compared to other non-ultrasonic processes[2]. Ultrasound irradiation has been used to reduce induction time and narrow the width of metastable zone which resulted into finer and more uniform crystals of BaSO4, K2SO4, TiO2 [3]. Effect of ultrasonic irradiation parameters such as sonication time, ultrasound power on crystal habit and crystal size distribution of lactose crystals has been widely studied [4, 5]. Stoltz et al. [6]presented a method for generating RDX crystals with controlled particle size and morphology using ultrasonic irradiation and slow evaporation rates. Thus, sonication has been widely used method for controlling the crystallization process as well as influencing the crystal size distribution and the crystal habit[7]. References:

1. R. Ambrus, et al., "Effect of Sonocrystallization on the Habit and Structure of Gemfibrozil Crystals," Chemical Engineering & Technology, vol. 33, pp. 827-832, 2010.

2. S. V. Dalvi and R. N. Dave, "Controlling Particle Size of a Poorly Water-Soluble Drug Using Ultrasound and Stabilizers in Antisolvent Precipitation," Industrial & Engineering Chemistry Research, vol. 48, pp. 7581-7593, 2009/08/19 2009.

3. J. Dodds, et al., "The Effect of Ultrasound on Crystallisation-Precipitation Processes: Some Examples and a New Segregation Model," Particle & Particle Systems Characterization, vol. 24, pp. 18-28, 2007.

4. E. Kougoulos, et al., "Lactose particle engineering: Influence of ultrasound and anti-solvent on crystal habit and particle size," Journal of Crystal Growth, vol. 312, pp. 3509-3520, 2010.

5. S. R. Patel and Z. V. P. Murthy, "Effect of process parameters on crystal size and morphology of lactose in ultrasound-assisted crystallization," Crystal Research and Technology, vol. 46, pp. 243-248, 2011.

6. C. Stoltz, et al., "Sonocrystallization as a tool for controlling crystalline explosivemorphology and inclusion content," AIP Conference Proceedings, vol. 1426, pp. 641-644, 2012.

7. G. Ruecroft, et al., "Sonocrystallization: The Use of Ultrasound for Improved Industrial Crystallization," Organic Process Research & Development, vol. 9, pp. 923-932, 2005/11/01 2005.

Session II:

Novel Methods Directed to Process Chemistry & Development - 2

Ms. Suvarna Choudhari AstraZeneca India Pvt. Ltd. Bangalore, India Suvarna Choudhari has completed her Post Graduation in Chemical Engineering from Visveswaraya Technological University. After a brief stint as a lecturer in one of the Engineering colleges in Karnataka, post her Bachelors’ Degree, she went back to school to get her Masters’ Degree in 2007. Ever since, she has been with AstraZeneca in Bangalore, starting off as a Research Associate & presently serving as an Assistant Research Scientist. In the last 6.5 years she has been with Astra, Suvarna has worked on a diverse area of Crystallisation, Process Analytical Techniques, Process Engineering; scale up, Technology Transfer, Process Safety etc. Her other areas of expertise include Cost of goods estimation, Process Mass Intensity estimation, Troubleshooting of scale up bottlenecks’, Commissioning of Chromatography lab, Containment Facility, Equipment qualification / validation, Process Simulation Softwares. A recipient of several team and individual awards at Astra Zeneca, Suvarna is actively involved in very regular collaboration with her counterparts in the UK on advanced topics pertaining to various ongoing campaigns. She has co-authored a Paper titled “Observations of Solid-Liquid Systems in Anchor Agitated Vessels” published in ‘Chemical Engineering Research and Design’ Vol 9 0 (2 0 1 2)750–756. Additionally she has authored publications within AstraZeneca.

APPLICATION OF PAT IN DESIGN, DEVELOPMENT AND SCALE UP OF CRYSTALLISATION PROCESSES

Ms. Suvarna Choudhari AstraZeneca India Pvt. Ltd.

Bangalore

Purification of solids by Crystallisation is one of the important activity in most pharmaceuticals, agrochemicals and fine chemicals industries. It is the final step of isolation of pure drug substance in Pharmaceutical industry. However, it is often challenging since there are many competing issues of physical and chemical characteristics to be addressed, e.g. purity yield, particle size distribution, polymorph, crystal shape, bulk density etc. and they can affect downstream unit operations, e.g. filtration, drying and secondary processing (milling) and manufacture (tablets, suspension stability). Over the last decade new process analytical tools and techniques have been developed to have a greater understanding and control on the crystallisation process to obtain substances with specific physical and chemical attributes consistently In recent years, Lasentec focused beam reflectance measurement (FBRM) has emerged as a widely used technique for the in situ characterization of high-concentration particulate slurries. It offers the advantage that it can characterize crystal behaviour after the nucleation event, giving an indication, for instance, of growth or agglomeration or the complex effects of micro- and meso-mixing on a precipitation process. FBRM is widely used as a tool for batch and continuous crystallization development and scale-up, crystallization control, and the troubleshooting and optimization of downstream processing problems. This contribution reviews typical problems encountered in production crystallization, with case studies, advice & strategies to understand and avoid these problems through the use of in situ crystallization characterization tools. Specifically benefits of FBRM probe will be discussed during the conference with case studies. References:

1. Barrett, P, et.al, Organic Process Research & Development, 2005, 9, 348-355 2. Lasentec® D600L with FBRM® Technology, Source; Mettler Toledo International Inc.

Session II:


Dr. Takahiko Akiyama Department of Chemistry Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan Phone: +81-3-3986-0221 Fax: +81-3-5992-1029 E-mail: [email protected] http://www-cc.gakushuin.ac.jp/~940020/akiyama_site/index_E.html Takahiko Akiyama received his PhD in 1985 from the University of Tokyo under the guidance of Professor Teruaki Mukaiyama. After working at the Shionogi Research Laboratories, Shionogi & Co., Ltd, as a research chemist, he was appointed as an Assistant Professor at Ehime University (1988). He worked as a visiting scholar with Professor Barry M. Trost at Stanford University in 1992-1993 and moved to Gakushuin University as an Associate Professor in 1994. He has been a Professor of Chemistry at Gakushuin University (Tokyo, Japan) since 1997. He is the recipient of the Chemical Society of Japan Award for Creative Work (2009), Daiichi-Sankyo Award for Medicinal Organic Chemistry (2009), and Nagoya Silver Medal (2012). His current research interests are focused on the development of new and useful synthetic methodologies based on the design of novel chiral Brønsted acid catalysts as well as the utilization of transition metal catalysts.

DEVELOPMENT OF ENANTIOSELECTIVE REACTIONS CATALYZED BY CHIRAL PHOSPHORIC ACID

Takahiko Akiyama

Department of Chemistry, Faculty of Science, Gakushuin University

Mejiro, Toshima-ku, Tokyo 171-8588, JAPAN

Development of highly efficient chiral catalyst continues to be one of the most

important topics in synthetic organic chemistry as well as process chemistry.

Although biocatalysts and metal catalysts have been extensively employed for the

preparation of chiral compounds, organocatalysts have recently emerged as the third

catalysts and a range of organocatalysts have been developed. Advantages of

organocatalysts follow: (1) due to the absence of metal, contamination of metals in

the products is obviated. (2) because weak interactions such as hydrogen bonding are

the dominant factor to control stereochemistry, domino reaction and relay catalysis

combining with other catalysts are feasible.

We paid attention to the electrophilic activation of carbonyl group and imines

by use of proton as a catalyst, and designed chiral phosphoric acid 1, derived from

(R)-BINOL, as a chiral Brønsted acid, and demonstrated its catalytic activity for the

Mannich-type reaction of ketene silyl acetal

with aldimines, leading to the formation of

-amino esters with excellent enantioselectivities

(Scheme 1).1 Phosphoric acid hydrogen atom

activated the imine moiety by acting as a

Brønsted acid and phosphoryl oxygen formed a

hydrogen bond with the o-hydroxy group of

N-aryl group, acting as a Lewis basic site (Fig. 1).2,3

The asymmetric reduction of ketimines is an

important method for the preparation of amines

in optically pure form. Recently, chiral

phosphoric acid catalyzed transfer hydrogenation

of ketimine by use of Hantzsch ester as hydrogen

donor has attracted much attention for the

preparation of chiral amines.4 We envisaged

that benzothiazoline would be a novel hydrogen

donor for the transfer hydrogenation of ketimines

by means of chiral phosphoric acid for the

following reasons: (1) benzothiazoline could be

O

Ar

O

Ar

PO

O H Brønsted acidic site

Lewis basic site

Stereocontrolling site

1

Figure 1

R1 R2

NPMP

R1 R2

NHPMP

S

HN

ArS

NAr

cat

Ar CF3

HNPMP

95-98% ee

Ar CO2Me

HNPMP

93-99% ee

Ar CH3

HNPMP

95-98% ee

Scheme 2

synthesized easily starting from o-aminobenzenethiol with aldehyde, (2) both

hydrogen donating ability and enantioselectivity could be controlled by the proper

choice of the 2-substituent of benzothiazoline. Transfer hydrogenation of ketimines

-imino ester, and CF3-substituted ketimines underwent

transfer hydrogenation smoothly to give the corresponding amines with excellent

enantioselectivities (Scheme 2).5 Interestingly, benzothiazoline exhibited higher

enantioselectivity than Hantzsch ester in the transfer hydrogenation by tuning the

2-substituent.

Alkyl methyl ketones underwent reductive amination with anisidine and

2-phenylbenzothiazoline to furnish the corresponding amines in high yields and with

excellent enantioselectivities (Scheme 3).3

Next, we compared the reactivity of benzothiazoline and indoline as a hydrogen

donor. Indoline also proved to be efficient hydrogen donor and the amines were

obtained with excellent enantioselectivities. Furthermore, prominent kinetic

resolution was observed. Chiral 2-aryl- and 2-alkyl-substituted indolines were

obtained with excellent enantioselectivities (Scheme 4). It was found that

(R)-2-substituted indoline reacted exclusively in the presence of the (S)-isomer.

References 1) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566-1568. 2) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129, 6756-6764. 3) For reviews, see: Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999-1010. Akiyama, T. Chem.

Rev. 2007, 107, 5744-5758. Terada, M. Synthesis 2010, 1929-1982. 4) For reviews, see: Rueping, M.; Sugiono, E.; Schoepke, F. R. Synlett 2010, 852-865. Zheng, C.; You, S.-L. Chem.

Soc. Rev. 2012, 41, 2498-2518. 5) Zhu, C.; Akiyama, T. Org. Lett. 2009, 11, 4180-4183. Zhu, C.; Akiyama, T. Adv. Synth. Catal. 2010, 352,

1846–1850. Henseler, A.; Kato, M.; Mori, K.; Akiyama, T. Angew. Chem. Int. Ed. 2011, 50, 8180–8183. Sakamoto, T.; Mori, K.; Akiyama, T. Org. Lett. 2012, 14, 3312–3315. Saito, K.; Akiyama, T. Chem. Commun. 2012, 48, 4573-4575. Sakamoto, T.; Horiguchi, K.; Saito, K.; Mori, K.; Akiyama, T. Asian J. Org. Chem. 2013, 2, 943–946.

6) Saito, K.; Shibata, Y.; Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2013, 135, 11740–11743.

Session II: Novel Methods Directed to Process Chemistry & Development–2

Dr. Hironao Sajiki Professor of Organic Chemistry Gifu Pharmaceutical University Education Gifu Pharmaceutical University, Japan, B.Sc. (Prof. Yoshifumi Maki), 1983 Gifu Pharmaceutical University, Japan, M.Sc. (Prof. Yoshifumi Maki), 1985 Gifu Pharmaceutical University, Japan, Organic Chemistry, Ph.D.(Prof.Yoshifumi Maki),1989 State University of New York at Albany, USA, Postdoctoral Fellow (Prof. Frank M. Hauser), 1990-1991 Massachusetts Institute of Technology, USA, Postdoctoral Fellow (Prof. Satoru Masamune), 1991-1992 Job Experiences Kotobuki Pharmaceutical Co. Ltd., Japan, Researcher, 1986-1989 Metasyn Inc. (EPIX Pharmaceuticals Inc.), USA, Group Leader, 1992-1995 Gifu Pharmaceutical University, Japan, 1995-Present Principal Academic Appointments Vice President, the Japanese Society for Process Chemistry Executive Board Member, the Society of Synthetic Organic Chemistry, Japan Tokai District Leader, the Society of Synthetic Organic Chemistry, Japan Part-time Professor, Graduate School of Engineering, Gifu University, Japan Awards 2013 The Pharmaceutical Society of Japan Award for Divisional Scientific Contributions 2012 The Society of Synthetic Organic Chemistry, Japan Nissan Chemical Industries Award for Novel Reaction & Method 2003 The Japanese Society for Process Chemistry Awards for Excellence 1999 The Pharmaceutical Society of Japan Tokai Branch Award for Young Scientists Research fields Development of Selective and Heterogeneous Transition Metal Catalysts, Development of Convenient Deuterium Labeling Methods, Creation of Practical and Useful Functional Materials for Synthetic and Medicinal Chemistry

Pd/CPd/HP20

Pd/C(en)

Pd/C（Ph2S）

Reducible Functionalities

R-O-TBDMS (TES) Benzyl alcohol Alkyl-O-Bn

Alkyl-N-Cbz

R-CO2BnArCOR

Epoxide

Ar-X Aromatic-N-Cbz

Pd/C+amine Ar-O-Bn

Pd/MS3APd/BN

R-CN

Ar-NO2

Os/C

Pd/Fib

Pd/PEIPd/BN

+pyridine

R-N3

Alkyne

Alkene

Pd/WA30

Figure. The overall comparison of the catalyst activities against hydrogenation

DEVELOPMENT OF PD CATALYSTS FOR CHEMOSELECTIVE HYDROGENATION

Hironao Sajiki

Laboratory of Organic Chemistry, Gifu Pharmaceutical University 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan, e-mail: [email protected]

Catalytic hydrogenation using a heterogeneous catalyst has been a powerful tool for the functional group transformation in both laboratory and industrial scale reaction processes. Especially, Pd on charcoal (Pd/C), the most frequently used heterogeneous hydrogenation catalyst, has many advantages over homogeneous catalysts, such as stability, ease of separation, recyclability, cost performance, and so on.1 However, the high catalytic activity of Pd/C makes it difficult to achieve the chemoselective hydrogenation among some reducible functionalities. On the other hand, chemoselective hydrogenation is one of the most desirable reactions in organic synthesis, such as the total synthesis of complex molecules bearing many reducible functional groups.In this presentation, I would like to introduce the development of a way to suppress of the Pd/C-catalyzed hydrogenation of benzyl ethers by the addition of nitrogen-containing bases and six practical and novel heterogeneous catalysts as well as the catalyst properties and significance for the chemoselective hydrogenation in synthetic and process chemistries. During the course of the investigation of a chemoselective hydrogenation, we found that the addition of an amine or sulfideeffectively works as a partial catalyst poison to control the catalytic activity of Pd/C. As a result, we developed Pd/C-catalyzed chemoselective hydrogenation methods between various reducible functions using the appropriate catalyst poison. As an extension of these methods, we prepared the isolatable amine- and sulfur-poisoned catalysts; i.e., Pd/C-ethylenediamine complex [Pd/C(en)],2

Pd/C-diphenylsulfide complex [Pd/C(Ph2S)],3 and Pd-polyethyleneimine complex (Pd/PEI),4 for the chemoselective hydrogenations. Furthermore, we also developed a silk fibroin, a protein produced by silkworms possessing very few residues of sulfur containing amino acids, molecular sieve, and boron nitride supported Pd-catalyst; i.e., Pd/fibroin (Pd/Fib),5 Pd/molecular sieve 3A(Pd/MS3A),6 andPd/boron nitride (Pd/BN).7 These catalysts activities werecontrolled by means of the properties of supports.


The overall comparison of the catalyst activities against hydrogenation among Pd/C, Pd/C plus a nitrogen containing base, Pd/C(en), Pd/C(Ph2S), Pd/PEI, Pd/Fib, Pd/MS3A and Pd/BN is summarized in Figure (reducible functionalities within the framework could be hydrogenated by the use of each catalyst).8 By the use of these catalyst on the basis of synthetic demands, a wide variety of chemoselective hydrogenation methods, which meet the criteria of green and process chemistry, become available. Pd/C(en), Pd/C(Ph2S), Pd/Fib and Pd/PEI are now commercially available from Wako Pure Chemical Industries and N.E. Chemcat Corporation. Selected References 1. (a) P. N. Rylander, in Catalytic Hydrogenation in Organic Synthesis; Academic Press, New York, 1979,

175. (b) S. Nishimura, in Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis, John Wiley & Sons, Inc, New York, 2001, pp. 414. (c)Y. Monguchi, H. Sajiki, J. Synth. Org. Chem., Jpn,2012, 70, 711(review).

2. (a) H. Sajiki, Tetrahedron Lett., 1995, 36, 3465.(b) H. Sajiki, K. Hattori, K. Hirota, J. Org. Chem., 1998, 63, 7990. (c) H. Sajiki, K. Hirota,J. Synth. Org. Chem., Jpn,2001, 59, 109(review).

3. (a) A. Mori, Y. Miyakawa, E. Ohashi, T. Haga, T. Maegawa, H. Sajiki, Org. Lett., 2006, 8, 3279. (b) A. Mori, T. Mizusaki, Y. Miyakawa, E. Ohashi, T. Haga, T. Maegawa, Y. Monguchi, H. Sajiki, Tetrahedron, 2006, 62, 11925. (c) A. Mori, T. Mizusaki, M. Kawase, T. Maegawa, Y. Monguchi, S. Takao, Y. Takagi, H. Sajiki, Adv. Synth. Catal.,2008, 350, 406.

4. (a) H. Sajiki, S. Mori, T. Ohkubo, T. Ikawa, A. Kume, T. Maegawa, Y. Monguchi, Chem. Eur. J.2008, 14, 5109. (b) S. Mori, T. Ohkubo, T.Ikawa, A.Kume, T.Maegawa, Y.Monguchi, H.Sajiki, J. Mol. Catal. A, 2009, 307, 77.

5. (a) H. Sajiki, T. Ikawa, H. Yamada, K. Tsubouchi, K. Hirota, Tetrahedron Lett., 2003, 44, 171. (b) H. Sajiki, T. Ikawa, K. Hirota, Tetrahedron Lett., 2003, 44, 8437. (c) T. Ikawa, H. Sajiki, K. Hirota, Tetrahedron, 2005, 61, 2217. (c) T. Ikawa, H. Sajiki, K. Hirota,J. Synth. Org. Chem., Jpn, 2005, 63, 1218(review).

6. (a) T. Maegawa, T. Takahashi, M. Yoshimura, H. Suzuka, Y. Monguchi, H. Sajiki, Adv. Synth. Catal., 2009, 351, 2091. (b) T. Takahashi, M. Yoshimura, H. Suzuka, T. Maegawa, Y. Sawama, Y. Monguchi, H. Sajiki, Teterahedron, 2012, 68, 8293.

7. (a) Y. Yabe, T. Yamada, S. Nagata, Y. Sawama, Y. Monguchi, H. Sajiki, Adv. Synth. Catal., 2012, 354, 1264. (b) Y. Yabe, Y. Sawama, T. Yamada, S. Nagata, Y. Monguchi, H. Sajiki, ChemCatChem., 2013, 5, 2360. (c) Chem. Eur. J., 2013, 19, 484.(d) Catal. Sci. Technol. in press, DOI: 10.1039/C3CY00650F (review).

8. H. Sajiki, J. Synth. Org. Chem., Jpn, in press (review).

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Session III:


Dr. Masahiko Seki Senior Research Manager, Process R&D Department, Healthcare Business Division II, API Corporation, Japan Masahiko Seki was born in Kyoto, Japan. He received his M.S. degree in 1982 from Kyoto University and, in the same year, joined Tanabe Seiyaku, a former company of Mitsubishi Tanabe Pharma Corporation, where he became a senior scientist in 1999. He has been conducting research on both medicinal and process chemistry at research laboratories of the company. He received Ph.D. degree from Kyoto University in 1988. From 1993, he spent a year as a postdoctoral fellow at Colorado State University under the direction of professor Albert I. Meyers. He received 1996 Incentive Award in Synthetic Organic Chemistry, Japan from The Society of Synthetic Organic Chemistry, Japan in 1997. Recently he received a gold medal of CPhI Pharma Award 2013 as the best Innovation in Process Development from CPhI Worldwide Frankfurt where 34,000 delegates from 140 countries were recorded. He is the author of 80+ scientific papers and an inventor on 40+ patent applications in the field of organic synthesis. As of February 1, 2011, he relocated to API Corporation, a group company of Mitsubishi Chemical Holdings and has conducted process research on drug intermediates and APIs. His collaboration has extended to companies outside Japan especially India’s CROs & CMOs. Actually he visits India every month.

AN EFFICIENT CATALYTIC SYSTEM FOR C-H ACTIVATION: A NOVEL AND PRACTICAL SYNTHESIS OF ANGIOTENSIN II

RECEPTOR BLOCKERS

Masahiko Seki Process R&D Department, Healthcare Division II, API Corporation, Tokyo, Japan

E-mail:[email protected]

The C-H activation provided access to a wide variety of highly functionalized biaryls involving drugs and other commercially significant compounds. However, the previous procedures need high loading of expensive catalysts, which inevitably prevent their commercial application. We have developed a quite efficient catalytic system which required an unprecedentedly low catalyst loading. In this presentation will be presented the efficient protocol using a practical synthesis of an important class of pharmaceuticals, angiotensin II receptor blockers (ARBs), as an example.1-7

[1] Seki, M. WO2011061996A1, 2010.

[2] Seki, M. ACS Catal. 2011, 1, 607.

[3] Seki, M. Nagahama, J. Org. Chem. 2011, 76, 10198.

[4] Seki, M. Synthesis 2012, 3231.

[5] Seki, M. J. Syn. Org. Chem. Jpn. 2012, 70, 1295.

[6] Kocienski, P. Synfacts 2013, 9, 0006.

[7] Seki, M. Science of Synthesis 2014.

Session III:


Dr. Birja Shanker Vice President R&D United Phosphorus Limited Thane, India Dr. Birja Shanker has a Ph.D. in chemistry with 38 years of experience in Industrial R&D. He has worked in diverse areas of technology in the field of agrochemicals, pharmaceuticals and perfumery chemicals. He has expertise in organic synthesis, product and process development, technology transfer, regulatory and administration of R&D. Currently he is working as Vice President – R&D in United Phosphorus Ltd (UPL) based at Thane. Prior to joining UPL, he has worked at Rallis India Ltd, Mumbai & MaltiChem Research Centre at Vadodara. He has been instrumental in the development and commercialization of number of agrochemicals and perfumery chemicals. Dr. Birja Shanker has published 2 research papers in leading chemistry journals and has 12 patents to his credit. He is also referee for M.Sc. and Ph.D. students for various universities.

NEW TRENDS IN AGROCHEMICAL

PROCESS RESEARCH AND DEVELOPMENT

Dr. Birja Shanker Vice President R&D

United Phosphorus Limited Thane, India

Agrochemicals have contributed immensely to improve the world food production. They have also contributed in eradication of vector borne diseases like malaria, dengue, plague, etc. The discovery, development and introduction of a new agrochemical molecule require considerable effort, time and money. There have been, of late, considerable regulatory pressures which havealso caused escalation in the time and cost. Due to these, the introduction of new patented molecules has been very feeble in the last one decade. It is understood that generic molecules command almost two third of the total agrochemical sales. The inventor companies have been giving utmost importance and protection of their generic molecules by process innovations and cost reduction. The generic companies are also finding space in this area by cost competitive process development. These process innovations have led to very efficient synthesis routes which have made possible the manufacture of generic molecules in much cost effective way. The effort will be made in the presentation to elaborate these process innovations and how they have changed the overall scenario in the manufacturing technologies of agrochemicals.

Session IV:

Process Research, Development & Scale up

Dr. Hiroshi Tomori Senior Director Process Technology Research Laboratories Pharmaceutical Technology Division Daiichi Sankyo, Japan

Hiroshi Tomori received a master’s degree and a PhD from the Chiba University, Japan

(supervision by Prof. Katsuyuki Ogura). In 1990, he joined Sankyo, a former company of

Daiichi Sankyo and he has been working in the field of process development over the last

couple of decades.

From September 1998 to March 2000, he stayed in Prof. Stephen L. Buchwald’s group at

Massachusetts Institute of Technology, USA as a postdoctoral scholar, where he worked on

Buchwald-Hartwig amination. From April 2010 to March 2012, he worked for Ranbaxy

Laboratories in Gurgaon as an expatriate from Daiichi Sankyo to promote collaboration

projects on API research & manufacturing between two companies.

PRACTICAL APPROACH TO PREPARE NEUROKININ RECEPTOR ANTAGONIST CS-003 VIA ASYMMETRIC OXIDATION REACTIONS

Dr. Hiroshi Tomori

Senior Director, Process Technology Research Laboratories Pharmaceutical Technology Division, Daiichi Sankyo, Japan

SUMMARY A practical and competitive process for manufacturing neurokinin receptor antagonist CS-003 was developed, where diisopropyl D-tartrate (D-DIPT), one of the most affordable chiral sources, is used as a ligand for asymmetric oxidation reactions to introduce chirality in to two key intermediates, i.e., chiral sulfoxide (S)-1 and chiral morpholine (R)-2, see Figure 1.

Figure 1: Synthetic Route of CS-003

Process Development of Chiral Sulfoxide (S)-1 In the discovery to early clinical phase, there were two synthetic methods to prepare (S)-1: the 1st generation synthesis via asymmetric oxidation of cyclic sulfide 3 by using stoichiometric amount of Davis reagent and the 2nd generation synthesis via optical resolution of (RS)-1 with (S)-mandelic acid [(S)-MA]. Although the 2nd generation synthesis was useful for pilot-scale synthesis, it was not considered suitable for commercial use in terms of cost and throughput. Toward the development of more practical synthesis, catalytic asymmetric sulfoxidation of 3 was investigated. After close scrutiny, we found the most active catalyst for this reaction[Ti(OiPr)4, D-DIPT and iPrOH in a molar ratio of 1:4:4], by which (S)-4 was obtained in 87% with 10 mol% catalyst loading, see Figure 2.

Figure 2 3rd Generation Synthesis of (S)-1, Hybrid of Catalytic Asymmetric Sulfoxidation and Optical Resolution

(S)-4 was deprotected in situ with hydrochloric acid and then treated with (S)-MA to afford (S)-1 (S)-MA with >99% de in 82% isolated yield from 3. It is noteworthy that a small amount of water plays a crucial role in the formation of the active Ticatalyst. In the presence of MS 4A (1 wt/wt based on 3), the enatioselectivity drastically dropped to 9% ee.

Process Development of Chiral Morpholine(R)-2 In the discovery stage, the 1st generationsynthesis via Sharpless dihydroxylation reaction was used to prepare (R)-2, see Figure 3. For preclinical to early clinical studies, the route was changed to the 2nd generation synthesis via classical optical resolution in order to avoid AD-mix- , a root cause of cost and safety issues of the 1st generation synthesis. The 2nd generation synthesis was robust and straightforward but not considered suitable for further scale up due to its high cost and low throughput.

Figure 3 1st and 2nd Generation syntheses of (R)-2

The 3rd generation synthesis was developed by taking advantage of the process knowledge that 2 is conglomerate and the desired enantiomer is effectively enriched by crystallization, see Figure 4. Zirconium-catalyzed asymmetric epoxidation of homoallyl alcohol 8 gave (R)-9 with 89% ee in 91% yield, which was converted to optically pure (R)-2in 64% isolated yield from 9 through amination, salt formation, chemoselective N-acylation, and regioselective cyclization via disulfonylated intermediate. It should be noted that no protection/deprotection steps are required for the 3rd generation synthesis of (R)-2.

Figure 4 3rd Generation Synthesis of (R)-2via Catalytic Asymmetric Epoxidation

Session IV: Process Research, Development & Scale up

Dr. (Mrs.) M. Lakshmi Kantam Director CSIR-Indian Institute of Chemical Technology Uppal Road, Hyderabad -500607 Phone: 27193030(O); Fax: 27160387 Email: [email protected] Current Interests: Development of specially designed homogeneous / heterogeneous catalysts for green chemical processes. In particular utilization of nanomaterials, hydrotalcites and hydroxyapatites as supports and catalysts for asymmetric catalysis , C-C / C-N coupling and oxidation reactions . Education: M.Sc 1976, Kurukshetra University, India Ph.D 1982, Kurukshetra University, India Publications: 290 Patents granted: US 43, Indian 43 Ph.D students guidance : 27 (awarded) and 17 (continuing) Honours and Awards:

1. Fellow of Royal Society of Chemistry, 2013. 2. Vasvik award, 2011. 3. Adjunct Professor, RMIT University, Melbourne, Australia. 4. Lifetime Achievement Award, Indian Chemical Society, 2011. 5. Fellow of the National Academy of Sciences, India, 2008. 6. BD Tilak Visiting Fellow, 2008, UICT, Mumbai. 7. Fellow of AP Akademi of Sciences, 2006. Member: 1. Chairperson, Subject Expert Committee, Women Scientists Scheme, Department of

Science and Technology, Government of India. 2. Editorial Board Member, The Chemical Record (TCR), Wiley-VCH 3. Editorial Board Member, Journal of Chemical Sciences, Springer 4. Past President, Catalysis Society of India (CSI).


CATALYTIC OXIDATIONS

M. Lakshmi Kantam Director

CSIR-Indian Institute of Chemical Technology Hyderabad-500 007 India

E-mail: [email protected], [email protected]

The eco-friendly and energy efficient processes at affordable cost is the prime requirement of bulk & fine chemical manufactures today. Both homogenous and heterogeneous catalytic oxidations are being used for the conversion of hydrocarbon feedstocks to industrially important oxygenated derivates, however, heterogeneous catalytic oxidation is preferred for the large-scale production of organic chemicals. Earlier stoichiometric quantities of classical inorganic oxidants such as potassium dichromate and potassium permanganate were used for the production of fine chemicals and were suitable for small scale requirement. In the bulk production , these classical oxidation approaches have found less acceptability due to strict environmental regulations. In this context, very important role is being played by the catalytic chemists today and the protection of the environment is being prompted by the development of eco-economic processes. Variety of metal complexes of porphyrin, salen, and phthalocyanines etc have been used as homogeneous oxidation catalysts for the synthesis of different oxygenated products however the complicated synthetic procedure, separation and associated environmental issues limits its use. In recent years, heterogeneous catalysts have been widely used for the production of fine and bulk chemicals due to its advantages such as ease of separation of reactants, minimization of metal traces in product, ease of handling, process control and reusability of catalyst. In this presentation, a number of systems, including selective oxidation of olefins and alcohols, asymmetric oxidation of sulphides, oxidation of amines and selective aerobic epoxidation of olefins will be discussed.




Mr. Masami Kozawa Chemical Research Laboratories, Synthesis Research Dept., Nissan Chemical Industries, Ltd. 2-10-1, Tsuboi-nishi, Funabashi, Chiba 274-8507, Japan [email protected] 1989-1993: The Department of Energy and Hydrocarbon Chemistry, Faculty of Engineering, Kyoto University 1993-1995: The Department of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Master degree 1995-now Nissan Chemical Industries, Ltd. 1998–1999 the Noyori Molecular Catalyst Development Project He has worked in the field of process chemistry at Nissan Chemical Industries.


DEVELOPMENT OF HIGHLY ACTIVE CATALYST FOR ALCOHOL OXIDATION

Masami Kozawa

Chemical Research Laboratories Synthesis Research Dept., Nissan Chemical Industries, Ltd.

2-10-1, Tsuboi-nishi, Funabashi, Chiba 274-8507, Japan [email protected]

Alcohol oxidation is a fundamental reaction in organic chemistry. In particular, oxidation catalyzed by 2,2,6,6-tetramethylpiperizine N-oxyl (TEMPO) is one of the most useful methods in industrial fine chemistry. Professor Iwabuchi reported that 2-azaadamantane N-oxyl (AZADO) is a superior oxidation catalyst.1 Both turn over number and turn over frequency of AZADO are greater than those of TEMPO. In addition, AZADO can oxidize sterically hindered secondary alcohols such as menthol, which cannot be easily oxidized by TEMPO (Figure 1).

Nissan Chemical Industries developed this highly efficient catalyst in collaboration with Iwabuchi’s group and introduced it in the world market.

Preparation of AZADO We studied the practical 4 steps synthetic route of AZADO.2 Before our study, AZADO was synthesized by 11 steps. After further development, 5 steps manufacturing process was finally built (Scheme 1).3 In addition, the hydroxylamine form (AZADOL®) was selected as a product because of its better stability. AZADOL® has the same catalytic ability as AZADO because both are precursors of the

oxoammonium ion (AZADO+), which is the active species (Scheme 2). Now AZADOL® is available at kg-scale It can be purchased as a reagent from Wako Pure Chemical Industries, Ltd. and Tokyo Chemical Industries, co. Ltd. and as kg amount from us.

Scheme 1. Developed manufacturing synthetic route to AZADOL®

Figure 1. AZADO oxidation of menthol

compared with TEMPO

0

20

40

60

80

100

0 2 4 6 8

tim e(h)

GC area (%) of menthone

A ZADO

TEM PO

Scheme 3. kg-scale synthesis

Figure 2. Conversion of substrate with various paddle stir at 300mL flask

How to use AZADO Bleach is the most useful co-oxidant for AZADO oxidation as well as TEMPO oxidation because of its high availability and low cost. For most substrates, AZADO is so active that even 0.1 mol% amount of catalyst can accelerate the reaction without any Br sources. However, TEMPO oxidation usually needs a Br additive such as tetra-butylammonium bromide and potassium bromide. AZADO/bleach oxidation is biphasic system. So, it needs vigorous stirring (Figure 2). We achieved the demonstration batch at the 300L plant vessel before applying it to the pharmaceutical intermediate production. In this demonstration, 2.7 kg of menthol were oxidized with enough stirring (Scheme 3).

Other co-oxidants Aside from bleach, other many co-oxidants can be used as same as TEMPO. Especially oxygen gas is a valuable co-oxidant at the view of atom-economy. Prof. Iwabuchi reported useful aerobic oxidations with AZADOs.4, 5 I will also introduce them and discuss as a manufacturing method. References

1. Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y., J. Am. Chem. Soc. 2006, 128, 8412 - 8413. 2. Shibuya, M.; Sasano, Y.; Tomizawa, M., Hamada, T.; Kozawa, M.; Nagahama, N.; Iwabuchi, Y.,

Synthesis, 2011, 21, 3418-3425. 3. WO2010/123115 4. Shibuya, M.; Osada, Y.; Sasano, Y.; Tomizawa, M.; Iwabuchi, Y., J. Am. Chem. Soc. 2011,

133, 6497–6500.

5. Sasano, Y.; Nagasawa, S.; Nishiyama, T.; Shibuya, M.; Iwabuchi, Y. , the Japanese Society for Process Chemistry 2013 Summer Symposium, 2P-13.

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10

tim e (h)

conv. (%)

100rpm

200rpm

300rpm

400rpm

Scheme 2. Catalytic mechanism of

AZADO/bleach

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Dr. Toshihisa KATO Corporate Vice President AJINOMOTO CO., INC. & General Manager Institute for Innovation Education: 1976 B.Sc., Faculty of Engineering, Kyoto University 1978 M.Sc., Graduate School of Engineering, Kyoto University Employment History: 1978 AJINOMOTO CO., INC. Tokai Plant 1980 Central Research Lab. Chemist 1990 Central Research Lab. Chief Chemist 1996 Central Research Lab. Associate General Manager 1998 Head Quarter R&D Planning Dept. Associate General Manager 2000 Tokai Plant 1st Production Dept. General Manager 2006 Tokai Plant Manager 2007 Corporate Executive Officer Tokai Plant Plant Manager 2010 Corporate Executive Officer Material Development &

Application Lab. General Manager 2011 Corporate Vice President, Deputy Chief Technology Officer 2013 Corporate Vice President, General Manager, Institute for Innovation

RESEARCH AND DEVELOPMENT OF AMINO ACIDS DERIVATIVES

Toshihisa KATO

1-1, SUZUKI-CHO, KAWASAKI-KU, KAWASAKI-SHI 210-8681, JAPAN Telephone: 044-210-5887, Fax; 044-244-9617

Email: [email protected]

ABSTRACT

Ajinomoto Co. has developed a business based on amino acids utilizing both technology of biotransformation and chemical synthesis. By combination of these technologies (so called hybrid process), we have developed various amino acids including unnatural amino acids and their derivatives as well as long chain peptides. Herein, I wish to present the already industrialized examples of them.

1. Aspartame and a new high-intensity sweetener “Advantame”

We have synthesized hundreds derivatives of Aspartame to find higher-intensity sweetener. By performing the study on structure-sweetness relationship, it was found that the “arylpropyl” substitution on N-terminus amino group of Aspartame play a fundamental role in enhancing the sweetness potency. Among them, “Advantame” having 3-hydroxy-4-methoxy-phenylpropyl group was chosen as a candidate for a new sweetener and developed as commercial product. It has the sweetening potency of 20,000 times more than that of sucrose.

2. L-DOPA (3,4-Dihydroxyphenylalanine for the treatment of Parkinson disease) We have found a unique enzymatic synthesis of L-DOPA using Tyrosine phenol-lyase by collaboration with Yamada group at Kyoto University in early 1970. However, it has long been very difficult to scale up and requires 20 years for industrialization due to the substantial formation of side products. Around 1990, we could eventually overcome the problem by controlling the reaction conditions. Since then, we are producing more than hundreds tons of L-DOPA annually. 3. L-Alanyl-L-Glutamine We have also developed a unique enzymatic synthesis of L-Alanyl-L-Glutamine using L-alanine methyl ester hydrochloride and L-glutamine as substrates. This dipeptide shows high solubility and stability in aqueous solution. A recombinant E.coli expressing L-amino acid ligase was used in this method. 4. Enzymatic Production of L- and D-Amino Acids We have been developing enzymatic hydantoin hydrolysis since early 1970’s. Hydantoins can be hydrolysed to the corresponding D-amino acids using D-hydantoinase and D-carbamoylase. Since the hydantoin racemase can convert L-hydantoin to D-hydantoin and vice versa, combination of this racemase with the enzymes above gives quantitative yield from racemic hydantoins to the amino acids with desired chirality.


5. “Ajiphase” and “Corynex” Recently, Ajinomoto successfully developed a very unique solution phase peptide synthesis named “Ajiphase”. The method can also be applied to oligonucleotide synthesis. For peptide and protein production by fermentation, we developed novel expression system using specially developed gram positive bacterium (Corynebacterium glutamicum). Using “Corynex”, particular target proteins are not only secreted directly into the growth media as an active form, but also formed correct disulphide bonds. Other topics will be presented. References

1. Y. Amino et al., In: Sweetness and Sweeteners; 2008 D. K. Weerasinghe and G. E. DuBois, Eds; ACS Symposium Series 979, American Chemical Society: 463-480.

2. K.Yokozeki et al., Agric. Biol. Chem., 1987, 51, 355. 3. I.Kira et al., Biosci.Biotechnol. Biochem.,2013, 77, 618-623. 4. I. Kira et al., (Ajinomoto Co.), EP 1275723 (2003), WO 2003085108. 5. D. Takahashi et al., Org. Letters, 2012, 14, 4514-4517.

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Session V: Process Scale Up and Engineering

Dr. Masaru Mitsuda Distinguished Scientist Head of Research Team, Fine Chemicals Group, QOL Division Kaneka Corporation [email protected] +81-(0)50-3133-6943 Education 1987 B. Sc. Kwansei Gakuin University 1989 M. Sc. Graduate School of Osaka City University 2008 Ph.D. Graduate School of Nagasaki University Work Experience 1989 – Present Kaneka Corporation 1997 Assistant Manager 2003 Manager 2012 Senior Manager and Distinguished Scientist 2013 Head of Research Team, Fine Chemicals Group Social Activities 2008 – Present Board of Director, The Japanese Society for Process Chemistry 2012 - Kansai branch Vice Chair, The Society of Synthetic Organic Chemistry, Japan 2013 – Present Board Member, The Society of Synthetic Organic Chemistry, Japan Award: 2010 - JSPC Award for Excellence 2010 Interest: Organic Synthesis, Asymmetric Synthesis, Process Chemistry

PROCESS DEVELOPMENT FOR THE LARGE SCALE PRODUCTION OF UNNATURAL AMINO ACIDS

Masaru Mitsuda

Kaneka Corporation, Japan

A number of the new chemical entities approved by FDA for the recent years contain an -amino acid moiety in their structure. Especially, unnatural amino acids have attracted a great deal of attention as a key component of peptide mimetic agents, which improve efficacy, bioavailability and stability due to the resistance toward metabolic degradation of the new drug candidates. From the view point of process chemistry, a variety of efficient methods -amino acids have been established. In particular, recent remarkable progress in asymmetric synthesis has provided a wide range of accesses to -amino acids. Biotransformation is one of the most powerful methodologies for large scale production of optically active unnatural amino acids. We have been developing large scale process for diverse unnatural amino acids applied with enzymatic conversions as shown below.1-2)

The organo-catalyst, called as “The third catalyst” follows metal and bio catalyst, is paid great attention to advance into a new frontier of process chemistry. The remarkable advantage of organo-catalysis would be simple operational handling and easy scale up of the synthetic protocols. (2R, 3R)-N-Boc-3-cyclohexylserine was attracted as a key intermediate of a new potent CCR5 receptor antagonist APLAVIROK. We achieved to develop a scale-up process of this

R

HN

CO2H

HNNH

RO

O

aminoacylase

R

HN

CO2H

O

NH2

hydantoinase

HNNH

RO

O

+R

NH2

CO2H

D-amino acid

R'

O

R

HN

CO2H

R'

O

R

NH2

CO2H

L-amino acid

+

R CO2H

O NH3

dehydrogenase R

NH2

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L-amino acid

Kinetic resolution by Hydantoinase

Kinetic resolution by amino acylase

Reductive amination by dehydrogenase

unnatural amino acid utilizing a simple organocatalyst D-proline reported by Barbas III in 2004.3)

At the beginning of our investigations, a large excess amount of cyclohexane aldehyde was required to avoid self-condensation of amino acetaldehyde. In order to establish an economical process, we had to minimize the cost of two aldehydes, which accounted 70 to 80 % of the total material cost. I would like to discuss how we developed an efficient and robust process for large scale synthesis of (2R, 3R)-N-Boc-3-cyclohexylserine in detail. References:

1) Takahashi, S. et al Org. Proc. Res. Dev.2007, 11, 503-508. 2) Yasohara, Y. et al Specialty Chemicals Magazine, 2012(9), 14. 3) R. Thayumanavan, F. Tanaka, C.F. Barbas III Org. Lett. 2004,6, 3541.

N CHO

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catalyticD-Proline

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OH

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OH

NOO

HO-TEMPO

NaBr, NaHCO3, NaClO

2) Boc2O

NaOHaq

CO2H

OH

NHBoc

1) Na2S2O5

/ THF

AcOEt


Dr. Vilas H. Dahanukar Vice President & Head Global R&D Dr. Reddy’s Laboratories Ltd. Hyderabad, India. Vilas H. Dahanukar currently is Vice President, Global Process Research and Development head at Dr. Reddy’s Laboratories. He has been working with DRL since 2003 and headed process R&D teams in custom pharmaceutical services and generics development. Over the years he has successfully worked on several projects in areas of heterocyclic chemistry, carbohydrate chemistry, prostaglandins, biocatalysis and chemocatalysis. Earlier, Vilas worked at the Schering-Plough Research Institute, New Jersey as a Senior Principal Scientist in process research and development group. He handled several projects in development of new chemical entities. He served on various drug development teams and has comprehensive knowledge of drug development activities. He has coauthored over 50 publications and patents in areas of medicinal and process chemistry. He holds a M.Pharm degree from UDCT and a Ph.D. in Medicinal chemistry from University of Kansas, USA. He worked as a postdoctoral research fellow in synthetic organic chemistry at University of Minnesota and University of California, Irvine.

PROCESS DEVELOPMENT AND SCALE UP OF GENERIC API

Dr. Vilas H. Dahanukar Vice President & Head Global R&D

Dr. Reddy’s Laboratories Ltd.

Generic Active Pharmaceutical Ingredients (API) has the same quality, strength, purity and stability as that of brand-name drugs. They provide an affordable option and enhance accessibility of drug to needy patients across the globe. Generic process development strategy should entail competitive pricing and address any intellectual property as well as regulatory challenges. This presentation will describe application of biocatalysis in generic industry through examples of Miglitol and synthon B of Aliskiren. Miglitol (1) and Miglustat (2) are derivatives of the azasugarDeoxynojirimycin (DNJ, 1).1Miglitol is a glycosidase inhibitor that is used to treat non-insulin dependent diabetes. Miglustat is primarily used for the treatment of Gaucher’s and other hereditary diseases.

HN

HO

HO

OH

OH

NHO

HO

OH

OH

NHO

HO

OH

OH

OHCH3

Deoxynojirimycin (DNJ) Miglitol Miglustat

1 2 3

Several synthetic methods are available for the synthesis of iminosugars.2 A majority of methods described for the chemical synthesis of DNJ and its congeners involves in-situ preparation of keto-aldehyde by oxidation of Glucitol using Swern condition or biooxidation and then a reductive amination.3 We herein describe two D-Glucose based approaches, namely, chemical and a whole cell bio-oxidationroutes towards cost effective and scalable synthesis of Miglitol. References:

1. Afrinkia, K.; Bahar, A.; Tetrahedron: Asymmetry2005, 16,1239.(a) Barili, P. L.; Berti, G.; Catelani, G.; D’Andrea, F.; D’Rensis, F.; Puccioni, L. Tetrahedron, 1997, 53, 3407–3416. (b) Baxter, E. W.; Reitz, A. B. J. Org. Chem. 1994, 59, 3175–3185. (c) Diot, J.; Garcia-Moreno, M. I.; Gouin, S. G.; Mellet, C. O.; Haupt, K.; Kovensky, J.Org. Biomol. Chem. 2009, 7, 357–363.(c) Wennekes, T.; Lang, B.; Leeman, M.; Marel, G. A. v. d.; Smits, E.; Weber, M.; Wiltenburg, J. v.; Wolberg, M.; Aerts, J. M. F. G.; Overkleeft, H. S. Org. Process Res. Dev. 2008, 12, 414–423.


Mr. Gaurav Mediratta SABIC Technology Center Chikkadunnasandra Village Off Sarjapur-Attibele Road Bangalore – 562125 Gaurav Mediratta completed his M.Tech. in Polymer Technology from IIT Delhi. He has over 12 years of experience in the field of polymer product and process development. His areas of interest include specialty polymers, flame retardant materials and monomer process development. Mr. Mediratta is currently Lab Manager with SABIC Technology Center, Bangalore.

CONCEPT TO COMMERCIALIZATION OF NEW PROCESS CHEMISTRY: ENGINEERING ASPECTS

Gaurav Mediratta, Dr. Utpal Vakil, , Anup Krishnan

Sabic Research & Technology Pvt. Ltd.

Commercialization is termed as a process by which an innovation or research idea gets converted into marketable products at a larger scale without losing its original functionality. In the current scenario of increasing competition and public demand, it is imperative to find ways to make products in an efficient, cost competitive, safe and environmentally friendly way without compromising the quality of the product. Thus challenges for a process engineer are to identify those factors which can lead to sub-optimal process and poor cost position. This requires learning and experience from multiple cycles of process design where inputs from one cycle go to the next. “Engineering” the laboratory chemistry thus involves multi stage, multi generation iterative approach. The present paper is a summary of our learnings from multiple such translations of lab processes to manufacturing scale. Understanding the constraints in large chemical plants and constant improvements based on process data has been found to be critical to successful commercialization. These activities are best handled by cross functional teams with experts from Marketing, Technology, Sourcing, Supply Chain and Manufacturing playing a critical role.

Session VI:

Process Scale Up & Engineering and Process Safety/ Product Safety

Dr. Vivek V. Ranade

Deputy Director & Chair, Chemical Engineering Division National Chemical Laboratory, Pune, India Email: [email protected] Current Interests

Multiphase flows (with phase change), chemical reactor engineering, industrial flow modeling

Process development/ intensification, converting batch processes to continuous ones, scale-up Education

PhD, Chemical Engineering, University of Bombay (UDCT), 1988. B. Chem. Eng., University of Bombay (UDCT), 1984 [University Rank # 3]

Experience Since July 2010: Scientist H at National Chemical Laboratory; leads research on sustainable chemical

industry, process intensification and multiphase flows with phase change; also has a responsibility as Deputy Director

Member and Chairman of the Board of Directors of Tridiagonal Solutions Pvt. Ltd. June 2008 - May 2010: CEO and CTO of Tridiagonal Solutions Pvt Ltd. (TSPL); led a dynamic team of

30+ professionals for building computational products and for providing engineering solutions to a wide range of manufacturing industry.

1990 - 2008: Scientist at National Chemical Laboratory. Successfully completed several industrial research & consultancy assignments from the leading multinational and Indian industries.

Since 2003: Adjunct Professor of Chemical Engineering at UDCT/ UICT/ ICT, Mumbai 1997 - 98: Guest Researcher at Twente University of Technology, The Netherlands. Worked on dynamics

of gas-liquid reactors. 1993 - 94: Guest Researcher at Delft University of Technology, The Netherlands. Worked on

computational modeling of gas-liquid reactors. 1988 - 90: Research Associate at Swiss Federal Institute of Technology, Zurich, Switzerland. Worked on modeling of turbulent reactive mixing.

Achievements CHEMTECH CEW Outstanding Achievement Award (R&D Individual Excellence) 2013 RPG Life Sciences Professor MM Sharma Medal, IIChE, 2011 UAA Distinguished Alumnus Award 2011 Member of the editorial board of Sadhana – Academy Proceedings in Engg. Sciences Fellow of Indian Academy of Sciences, Bangalore, 2011 Selected as ‘Outstanding scientist’ by CSIR in July 2010 Co-founded a technology company ‘Tridiagonal Solutions Pvt. Ltd.’ in July 2006 Associate Editor of Asia Pacific Journal of Chemical Engineering, since Nov 2006 CHEMTECH “Outstanding Contribution” Award (Chemical Engineering), 2005 Fellow of Indian National Academy of Engineering, 2005 Shanti Swarup Bhatnagar Prize in Engineering Sciences, 2004 Herdillia Award for Excellence in Basic Research in Chemical Engineering, 2004 AVRA Young Scientist Award, 2003 DST Swarnajayanti Fellowship, 1999 INAE Young engineer award, 1996; CSIR Young Scientist award, 1992 Publications in peer-reviewed international journals: > 125; Conferences: > 100 [citations: >2000;

h index: 27]; international patents: 2 Books: 3 (CFM for CRE, Academic Press, London, 2002; Rotary Kiln, VDM, 2009; Trickle Bed Reactors,

Elsevier, 2011)


PROCESS INTENSIFICATION / CONTINUOUS PROCESSES FOR FINE & SPECIALTY CHEMICALS

Vivek V. Ranade

Chemical Engineering and Process Development Division CSIR – National Chemical Laboratory

Pune - 411008, INDIA [email protected]

Fine and specialty chemical industry caters to several key applications required for maintaining and enhancing quality of life. It is interesting to note that most of the fine and specialty chemicals are still manufactured in stirred batch reactors (devised centuries ago) operated as batch or semi-batch processes. A paradigm shift is necessary to transform this into new age, efficient and continuous processes and plants. An ambitious program called Indus MAGIC (Innovate, develop and up-scale modular, agile, intensified and continuous processes) has been initiated by CSIR – NCL and other CSIR laboratories (see www.indusmagic.org for more information). The structure of the program is shown in Figure 1.

Figure 1: Structure of Indus MAGIC program of CSIR Chemical Cluster Laboratories

The Indus MAGIC processes and plants are based on using variety of new concepts and technologies to transform the way fine and specialty chemicals are manufactured today (some of which are listed in the following table): Conventional way MAGIC way Batch or semi-batch processes Continuous processes Stirred reactors Compact, intensified reactors Less flexible plants, clumsy cleaning Modular, agile and reconfigurable plants Use of stoichiometric reagents Use of catalysts & catalytic processes Generate significant waste per unit product Intensified processes/ operation to maximize atom efficiency Large water foot print Reduced water foot print via water recycle and reuse Use hazardous solvents Conduct reactions in water/ benign solvents Reactions limited by transport limitations Reactions at intrinsic rates without any transport limitations Separate unit operations: reactors, separations Integrated processes with multi-functional reactors/ process

equipment Cabled process instrumentation & control Wireless process instrumentation & control/ new paradigms for

process optimization

Licensing/

Commercialization/

Spinout companies

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Indian Chemical Council &

other industry contacts

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Process Intensification

www.indusmagic.org

Indus MagicInnovate, Develop & Up Scale Modular, Agile,

Intensified & Continuous Processes & Plants

©


http://www.indusmagic.org/

Modular, agile, intensified and continuous concepts underlying MAGIC processes and plants are briefly discussed by Ranade (2012). The foundation for such recent developments of process intensification and MAGIC reactors/ processes is our ability to manipulate rates of relevant transport processes so as to enhance process performance and to design effective reactors/ process equipment. There is a long history of chemical engineers deciphering the interaction between hydrodynamics/ transport and process performance. Engineering of reactors and processes include all the activities necessary to evolve best possible hardware and operating protocol of reactor/ process equipment to carry out the desired transformation of raw materials (or reactants) into value added products. Any reactor has to carry out several functions like bringing reactants into intimate contact with the active sites on catalyst (to allow chemical reactions to occur), providing an appropriate environment (temperature and concentration fields) for adequate time and allowing for removal of products from catalyst surface. A reactor engineer has to ensure that the evolved reactor hardware and operating protocol satisfy various process demands without compromising safety, environment and economics. Naturally, successful reactor/ process engineering requires bringing together better chemistry [thermodynamics, catalysis (replace reagent based processes), improved solvents (supercritical media, ionic liquids), improved atom efficiency, prevent waster - leave no waste to treat] and better engineering (fluid dynamics, mixing and heat and mass transfer, new ways of process intensification, computational models and real time process monitoring and control). The present talk will cover key concepts in developing MAGIC processes and will summarize recent results obtained at CSIR - NCL. References: Ranade, V.V. (2012), MAGIC (Modular, Agile, Intensified and Continuous) Processes and Plants for Specialty Chemicals, Chemical News, June issue, 52.

Session VI:

Process Scale Up & Engineering and Process Safety/Product Safety

Mr. Vijay Bhujle Head Expert Services Intertek India Pvt. Ltd. Mumbai, India Job roles and Experience: He is currently heading the business line Chemicals and Pharma (Expert services) of Intertek in India since 2010. He had various responsibilities during carrier of more than 35 years in process development, scale up and technology transfer. He has worked in pharma API manufacturing &formulation, polymer additives, soaps& detergent formulation, food and crop protection chemicals. He has over 20 years of experience in powder and process safety and hazard assessment. He joined Ciba in 1993 and was General Manager, Research and Technology. His main responsibilities were process development, scale up and technology transfer. Process safety data generation and assessment was a part of scale up activity. He was involved in transferring many products and processes on plant scale. He had training on process safety, powder handling safety and audits at Ciba, Switzerland. His previous professional experience includes working as senior manager, chemical engineering at Atul Products Ltd (4 years). Work involved scale up and tech transfer for dyes, intermediates and natural product extraction. During the tenure as Process development engineer at Hindustan Lever Research Centre, Mumbai (12 years) worked on process development and scale up of synthetic fatty acids, soaps and detergent formulations as well as new processing routes. . Presently he is heading business line Chemicals & Pharma (Expert services) India which provides consultancy services mainly in process safety, environmental services and regulatory services for pharma, food and chemical industries. CP also provides analytical testing and material testing services. Publications, Associations: He has two patents and published papers on process development and process safety aspects. He is a member of Indian Institute of Chemical Engineers. He was a member of COA of Chemexcil and currently member of technical committee on chemical inventory. He is visiting faculty at Institute of Chemical Technology, Mumbai. Qualification: He received degree B.E. in Chemical Engg. from KREC Surathkal, Mysore university and Master of Chemical Engineering from Institute of Chemical Technology (formerly UDCT) Mumbai University in 1977. e-mail: [email protected] Office address: Head, Business line-Chemicals & Pharma

INTERTEK INDIA PVT. LTD. F-wing, Tex Centre, Chandivali Farm Road Andheri (East), Mumbai- 400072


RELEVANCE OF PROCESS AND POWDER SAFETY IN PROCESS R&D

Vijay Bhujle

Intertek India Pvt. Ltd., Mumbai

Safety assessment of a chemical process is to be based upon specific hazard test data for both desired & undesired, chemistry and unit operations. The data has to be generated using appropriate experiments and testing techniques. This data is then interpreted and transformed into safe operating conditions (or safe operating window) for a given process. The testing scope will depend upon quantities to be handled and the development stage of the product. Overview of various testing techniques and their implication is elaborated. The tests can be divided into two categories viz. 1)for chemical reaction and 2)for unit operations 1) Thermal hazard during a chemical reaction is the risk of loss of control of the reaction or

of triggering a runaway reaction. The risk assessment requires the knowledge of severity and probability of occurrence of runaway. This can be evaluated from heat of reaction of desired reaction, onset of undesired reactions and kinetics. Many of these questions can be answered using experimental techniques using various types of calorimetric testing like Differential Scanning Calorimeter, Carius tube, ARC and Reaction Calorimeter.

ISO-IEC 17025 accreditated laboratory at Intertek, Mumbai

1) The chemicals, which are undergoing various unit operations like drying, milling and distillation are undertaken for different tests depending upon the unit operation involved. The screening tests have been evolved over a period of time mostly based on the EU and US chemical industry efforts. The screening tests are mainly to identify whether the chemical (product) can undergo an exothermic decomposition and the temperature range of its occurrence. Also tests are carried out to know whether the powder (chemical) is resistive and its dust explosion properties.

Some of the main tests are: Minimum Ignition energy, Minimum Ignition temperature, Powder resistivity, dust explosion ( Pmax and Kst values), Impact sensitivity test, Burning class test, Grewer oven. The test results give an idea of hazards involved during the unit operation. Based on these test results and their implication, safe operating parameters are arrived at. This would help in arriving at inherently safer manufacturing process. This will be illustrated with a few case studies.

Session VII: Green Processes Including Bio-Energy

Mr. Mitsuru Sugawara Senior Chief Researcher New Materials Development Laboratory Research & Development Center ZEON CORPORATION, Japan

Mitsuru Sugawara was born in 1968, Japan. He received his bachelor’s degree in 1992 from

Kyoto University, faculty of engineering, under the direction of Professor Yoshihiko Ito, and

master’s degree in 1994 from Graduate School of Hokkaido University under the direction of

Professor Tamio Hayashi.

He joined in Zeon Corporation, 1994, and worked as a chemical researcher, production

technology development engineer.

A NEW ETHER PROCESS SOLVENT: CYCLOPENTYL METHYL ETHER

(CPME) FOR GREEN CHEMISTRY & PROCESS INNOVATION

Mitsuru Sugawara New Materials Development Laboratory

Research & Development Center, Zeon Corporation, Japan

Introduction In the recent process chemistry for pharmaceutical and other fine chemical industries, scientists’ demand for greener solvents has been increasing day by day. In view of the circumstances, typical ether solvents, such as tetrahydrofuran (THF), 2-methyl tetrahydrofuran (MeTHF), Diisopropylether (IPE), 1,4-dioxane and methyl t-butyl ether (MTBE), have some inherent properties which are incompatible with Green Chemistry. For example, THF easily forms explosive peroxides and is difficult to recover because of its infinite miscibility with water. In order to solve this problem, ZEON CORPORATION developed Cyclopentyl methyl ether (CPME)and started commercialization in November, 2005, with its unique C5 feedstock and synthetic technologies. CPME has been found to be an alternative solvent and has many preferable characteristics for Green Chemistry. Because it is free from drawbacks including easy peroxide formation and water miscibility, the demand for CPME has steadily been growing in the pharmaceutical industry as well as in the electronic and fragrance industries. Also, CPME has been registered or listed in the corresponding legislations for new chemical substances of United States of America, Canada, European Union, Japan, South Korea, China and Chinese Taipei, and is commercially available in these countries and regions as well as others including India.

Table1

Comparison with CPME and other Ethers

CPME THF MeTHF Et2O Dioxane MTBE

Density (20°C) [g/cm3] 0.86 0.89 0.85 0.71 1.03 0.74

Vapor specific gravity (air = 1) 3.45 2.49 2.97 2.56 3.3 3.03

Boiling point [°C] 106 65 80 34.6 101 55

Melting point [°C] <-140 -108.5 -136 -116.3 11.8 -108.7

Viscosity (20°C) [cP] 0.55 0.55 0.6 (25 C) 0.2448 1.31 0.35

Surface tension (20°C) [mN/m] 25.17 26.4 Unknown 17.3 33.74 19.8

Vaporization energy (bp) [Kcal/kg] 69.2 98.1 89.7 86.08 98.6 81.7

Specific heat (20°C) [Kcal/kg∙K] 0.4346 0.469 Unknown 0.5385 0.41 0.51

Refractive index (20°C) 1.4189 1.407 1.406 1.353 1.422 1.369

Solubility parameter [cal/ml] 8.4 9.5 8.52 7.4 Unknown Unknown

Dielectric constant (25°C) 4.76 7.58 7 4.197 2.227 2.6

Dipole moment [D] 1.27 (calcd.) 1.7 Unknown 1.12 0.45 1.4

Azeotropic temperature with water [°C] 83 (a) 64 71 (b) 34.2 87.8 52.9 (c)

Solubility of solvent in water (23°C) ［g/100g］ 1.1 Infinite 14 6.5 Infinite 4.8

Solubility of water in solvent (23°C) ［g/100g］ 0.3 Infinite 4.4 1.2 Infinite 1.5

Flash point [°C] -1 -14.5 -11 -45 12 -28

Auto Ignition Temperature [°C] 180 205 270 180~190 180 224

LogPow 1.59 0.47 Unknown 0.89 -0.42 0.94

Explosion range [vol%] Lower limit 1.1 1.84 1.5 1.85 2 1.6

Upper limit 9.9 11.8 8.9 48 22 8.4

General Properties of CPME As is shown in Table 1, CPME is asymmetric aliphatic ether having a cyclopentyl moiety, and has unique features. 1. Extremely low miscibility with water 2. Lower peroxide formation 3. Higher stability under acidic conditions 4. Higher boiling point and lower melting point 5. Lower latent heat of vaporization 6. Higher efficiency for azeotropic dehydration 7. Medium polarity 8. Lower solubility of salt in CPME CPME for Green Chemistry& Process Innovation CPME meets eight definitions out of “the 12 Principles of Green Chemistry” at the point of physical properties and manufacturing.

Prevention Atom Economy Safer Solvents and Auxiliaries Design for Energy Efficiency Reduce Derivatives Catalysis Real-time Analysis for Pollution Prevention Inherently Safer Chemistry for Accident Prevention

For example of Green Chemistry & Process Innovation, we would like to introduce “Improved Pinner Reaction” (Figure1). The solvent requirements for the process in single solvent are stability to acid, solubility of raw material and insolubility of product. In this case, 4M-HCl in CPME is used because CPME is stable to gaseous HCl. The raw materials, nitrile and methanol are soluble in CPME. After reaction, white crystalline product is precipitated because of the insolubility in CPME. The product is easily isolated only by filtration and washing. In comparison with the original process, the process has been obviously shortened and simplified by CPME without dangerous solvents such as diethylether and dioxane. The original process, which consists of 9 steps, is not recommended for scalable preparation of Pinner products, which are often sensitive to moisture and prone to decomposition. The quick work-up sequence with CPME is thus very valuable in handling such sensitive products. As a result, in the case, CPME contributes to Green Chemistry due to reduction of total amount of solvent used, waste disposal and energy without unfavorable solvents, and to Process Innovation due to simplification of the total process as well as fixed and variable cost reduction.

Figure 1 Improved Pinner Reaction

R OCH3

NH4M-HCl solution, CH3OH

solvent, 0oC, 1 h, then 0-5 oC, 48 h

solution solvent Yield (%)

CPME CPME 89b)

a) U.S.Pat.No.: US 6806380 B2b) Work-up of CPME process is only filtration and washing.

R CN

R

CH3

H3CO

1,4-Dioxane Et2O 86a)

CPME CPME 90b)

CPME CPME 91b)

HCl

1. Reaction: CPME

2. Cooling

3. Filtration

4. Drying

Product

TelescopingSteps: 9 to 4Solvents: 2 to 1

Greener ProcessWithout:Dangerous Solvents

CPME Process4 steps without dangerous solvents

Original Process9 steps with dangerous solvents

　　　Waste

1. Reaction: Et2O - Dioxane

2. Cooling:

3. Warmed at 40℃

4. N2 Bubbling

5. Removal of

solvent in vacuo

6. Precipitated by cooling

7. Addition of Et2O

8. Filtration

9. Drying

Product

Et2O

Dioxane

HCl

Et2O

Session 8:

Green Processes Including Bio-Energy

Dr. D. K. Tuli Executive Director R&D IndianOil Corporation Ltd. Faridabad, India

Dr. D. K. Tuli holds Ph.D. followed by over two decades of rich and varied experience in Research & Development in the hydrocarbon industry with a special interest in Synthetics and Biotics. Dr. Tuli, has to his credit, 14 US patents, two European patents and over 20 Indian patents. He has also published over 65 research papers in professional journals. Dr. Tuli did his post-doctoral research at university of Liverpool in 1978-81. He was also UK SERC senior research fellow at Robert Robinson labs during 1986-88. He was the Chief Executive Officer of IndianOil Technologies Limited (ITL), a subsidiary of Indian Oil Corporation. Dr. Tuli had been in-charge of bio energy, solar , nanotechnology divisions of IOC(R&D). Presently, Dr. Tuli is Executive Director & Centre Coordinator of DBT-IOC Centre at IOC (R&D) in Faridabad. This centre for advanced bio-energy research is funded equally by department of biotechnology & Indian Oil Corporation .

ADVANCED BIO-ENERGY RESEARCH –INDIAN INITIATIVES

Dr. D. K. Tuli Executive Director & Centre Co-coordinator

DBT-IOC centre for Advanced Bio-Energy Research Indian Oil R&D centre , Faridabad 121007

[email protected]

India depends heavily on imports for petroleum crude and this dependence is likely to increase in near future. Many alternate energy sources are being explored and solar, nuclear and wind are the one which have started making some impact. However, these alternates do not substitute for the liquid transport fuels (Diesel and Petrol) and without finding alternate to these , crude imports would continue to grow. Bio-energy, energy derived from biomass, has been considered seriously as this can provide liquid transport fuels or additives components like ethanol. Ethanol has been in use in our country for last few years as a blend component for gasoline. 5-10 % of ethanol is legally allowed and now becoming mandatory for blending in petrol. However, since all the ethanol in India is based on sugarcane molasses as the source feed, it has limited availability. Biodiesel, Fatty acid methyl esters, were promoted as a blend component of diesel during last decade. However, the feedstock for this i.e Jatropha could not give the promised and economical yields and this programme suffered a serious setback. Meanwhile Govt. of India announced its national bio-fuel policy which mandates 20 % blending of biofuels in all transport fuels. There are certain inherent differences with our biofuel programme vis a vis US of European programmes. We have limited farm land which needs to support nation on producing food and hence this land or the food crops cannot be diverted to fuels. Recent global successes in producing ethanol and other fuels from agricultural wastes has prompted every nation to investigate this option. Lignocellulosic materials offer a window of opportunity for conversion into fuels / ethanol by adopting thermo-chemical or bio-chemical routes. There are several plants, both commercial and demo, which are producing ethanol priced almost equivalent to corn ethanol. In India Department of Biotechnology (DBT) took a lead about five years ago and established a centre for advanced biofuel research at Institute of Chemical Technology (ICT) , Mumbai in 2007. This centre has carried out extensive R&D in cellulosic ethanol production and set up a large demo plant at IGL, Kashipur. Later in 2012, DBT established two more centres , one at Indian Oil R&D in Faridabad and second at ICGEB, New Delhi. All these centres have specific mandates and work in a network for sustainable technology development. There are other researchers in private sector e.g Praj Industries, Nagarjuna and several academic institutes which have carried out extensive R&D. Some of the Indian efforts in advanced biofuels will be discussed.


Thank You

About the organizers ……

INDIAN CHEMICAL COUNCIL (ICC) was established in the year 1938 to promote the interests of the nascent Indian chemical industry. Pioneers of the chemical industry in India such as Acharya P. C. Ray brought together a group of industrialists including Rajmitra B. D. Amin and founded this national body.

What began as a vision, emerging from foresight and aspirations of the founding members became the Indian Chemical Manufacturers Association and was subsequently rechristened as Indian Chemical Council (ICC). Today, ICC has become the representative body of all sectors of chemical industry in India and includes members both Indian companies as well as multinational companies operating in India. Home Page: http:// www.indianchemicalcouncil.com The Japanese Society for Process Chemistry (JSPC) was founded in 2001, after several symposia and sincere discussions between process chemistry directors of industries and university professors. JSPC aims to promote and encourage the development of process chemistry in various directions among members. Process chemistry includes synthetic chemistry, analytical chemistry, chemical technology, solid state chemistry, environmental science, regulations, patent problems and so on, to mention a few. JSPC has regular symposia twice a year, summer and winter, after the foundation commemorative symposium was held in 2002. Members of JSPC belong to industries, especially pharmaceutical ones, manufacturers of intermediates, universities and so on. Process chemistry now occupies an important hub position between substance creative chemistry and commercial production. Without its strong activity, no useful compounds would be produced in an efficient manner on a large industrial scale. JSPC believes that the society will have a key feature to advance and improve process chemistry in this century. Home Page: http://www.jspc-home.com/process/index.html

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http://www.jspc-home.com/process/index.html

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