Synthetic Studies Towards Fluconazole Analogues
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SYNTHETIC STUDIES TOWARDS FLUCONAZOLE ANALOGUES BY SULEMAN RIYAJSAHEB MAUJAN DR. H. B. BORATE (RESEARCH GUIDE) ORGANIC CHEMISTRY DIVISION NATIONAL CHEMICAL LABORATORY DR. HOMI BHABHA ROAD PUNE–411008 (India) MAY–2010 SYNTHETIC STUDIES TOWARDS FLUCONAZOLE ANALOGUES A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY (IN CHEMISTRY) TO UNIVERSITY OF PUNE BY Mr. SULEMAN RIYAJSAHEB MAUJAN Dr. H. B. BORATE (RESEARCH GUIDE) ORGANIC CHEMISTRY DIVISION NATIONAL CHEMICAL LABORATORY DR. HOMI BHABHA ROAD PUNE–411008 MAY–2010 Dr. H. B. Borate Telephone: +91-20-25902546 Sc. F Telefax : +91-20-25902629 Division of Organic Chemistry E mail: [email protected] CERTIFICATE This is to certify that the work presented in this thesis entitled “SYNTHETIC STUDIES TOWARDS FLUCONAZOLE ANALOGUES” submitted by Mr. Suleman R. Maujan, has been carried out by the candidate at National Chemical Laboratory, Pune, India, under my supervision. Such materials as obtained from other sources have been duly acknowledged in the thesis. This work is original and has not been submitted for any other degree or diploma of this or any other university. MAY 2010 Dr. H. B. BORATE CANDIDATE’S DECLARATION I hereby declare that the research work presented in the thesis entitled “SYNTHETIC STUDIES TOWARDS FLUCONAZOLE ANALOGUES” was carried out by me at the National Chemical Laboratory, Pune, India, under the supervision of Dr. H. B. BORATE, Sc. F, Division of Organic Chemistry, National Chemical Laboratory, Pune, India and submitted for the degree of Doctor of Philosophy in Chemistry to the University of Pune. This work is original and has not been submitted in part or full by me for any other degree or diploma of this or any other university. MAY 2010 SULEMAN R. MAUJAN Acknowledgements It gives me a great pleasure to express my deep sense of gratitude to my mentor and guide Dr. H. B. Borate for his constant and generous support and guidance. I am grateful to him for giving me a great opportunity to develop my potential to contribute in organic chemistry and motivating me to carry out research in medicinal chemistry. I am fortunate enough to have Dr. (Mrs.) R. D. Wakharkar in achieving this entire endeavor. I am grateful to her for her help in my initial period at NCL. I am very much grateful to Dr. S. P. Chavan, Dr. U. R. Kalkote and Dr. A. G. Gaikwad for their advice, guidance, support and encouragement during every stage of this research work. Discussion with them was really a great pleasure and fetched me a lot of learning experience. I take this opportunity to thank staff at microbial testing laboratory of FDC Ltd., Mumbai for screening of biological activity of new molecules. Without their help, it would have been an incomplete research. My thanks are due to Dr. M. K. Gurjar, (former Head, OCT Division) for his constant support. It is my privilege to thank Dr. G. Pandey, Head, OCD and Dr. S. Sivaram (Director, NCL) for permitting me to work in NCL. I sincerely thank CSIR, New Delhi, for the Fellowship. I am also grateful to Dr. M. N. Deshmukh, Dr. J. M. Gajbhiye, Dr. D. D. Sawaikar, Dr. R. G. Kelkar, Dr. S. R. Bhide, Dr. (Mrs.) V. S. Pore and Dr. (Mrs.) B. Chanda for their help and encouragement. I would also like to acknowledge all the staff members of GC, HPLC, IR, NMR, Mass, Microanalysis, X-ray analysis, Library, Administration and Technical divisions of NCL for their valuable assistance. I wish to express a great sense of gratitude for Prof. B. P. Bandgar (Vice-Chancellor, University of Solapur, former HOD, School of Chemical Sciences, SRTM University, Nanded) for his inspirational teaching. Also I thank my teachers, Prof. P. K. Zubaidha, Dr. Kamble, Dr. Karde, Dr. Tale, Dr. (Mrs.) Makone, S. R. T. M. University (Campus) Nanded, during my M. Sc. Studies and Dr. Salunke, Dr. Birajdar, Dr. Chandrawanshi, Mr. Dhawale, Mr. Sanap, Mr. Palkhe and Mrs. Gore (Shahu College, Latur) during my B. Sc. Studies, for their encouragement and motivation. It is my great pleasure to thank my beloved friends Abasaheb and Manmath for their continuous encouragement, discussion and advice and with whom I shared golden moments. I would like to extend my thanks to Omprakash, Jaman, Kotalwar, Dandge and Narladkar for making my stay in Pune comfortable and memorable. Most importantly, I am very much thankful to my labmates Vishal, Shinde, Vinod, Mrs. Vasudha, Navnath, Vilas, Milind, Mrs. Deepa, Mrs. Shubhada, Lahore, Bhole and Amit for helping me in various capacities throughout my work and maintaining cheerful atmosphere in the lab. Thanks are also due to Santosh, Vaibhav, Talha, Maqsood, Pravin, Sandeep, Ravi, Suresh, Lakshman, Suleman, Jamil, Sachin, Seema, Pradnya, Ashfaq, Mahesh, Dhiraj, Pratap, Prem, Jayant, Gopi, Rohit and Sanil for maintaining cheerful atmosphere in our laboratory. I take this opportunity to thank my present labmates Sangamesh, Shankar, Pankaj, Ananda, Jaydeep, Mrs. Manisha and Sandip. They made working in the lab enjoyable and memorable. No words will be sufficient to express my thanks to my friends Shriram, Amol, Nagendra, Kulbhushan, Namdev, Sharad, Nilkanth, Pandurang, Awadhut, Ganesh, Abhijit, Sudhir, Taterao, Shafi, Sambhaji, Ashok, Dushyant, Lalit, Kishor, Sumanta, Nilesh, Pradeep, Prakash, Harshali, Ravi, Sutar, Satish, Arvind, Selukar, Majid, Manish, Harbindu, Ankush, Kedar, Vinay, Ram, Ismail and all other friends at NCL as well as out of NCL, who helped me whenever it was needed; be it personal or research related. I owe my deepest gratitude and affection to my Father “ABBAJAN”. He inspired me to become a DOCTOR. No words would suffice to express my gratitude and love to AMMIJAN, my brother (Bhaijan) AEJAZ (The Right Man In The Right Place), adored sisters (Aapa) NAZNEEN and MUMTAJ, uncle Sd. ABDULLAH and brother-in-law KHALED and JAWED and all family members for their continuous showering of boundless affection on me and supporting me in whatever I chose or did. It is my parent’s prayer, constant struggle and relentless hard work to overcome the odds of life, which has inspired me to pursue life with a greater optimism. The moral values of my parents guided me throughout my life and I would always look up to them for strength no matter what I have to go through. This thesis is a result of the extraordinary wills, efforts and sacrifices of my parents. My successes are dedicated to them now and always. The love and support from my wife SADIYA who walked along with me, sharing every ups and downs is unparalleled and I am highly indebted to her for the sacrifice, help and encouragement for the healthy and inspiring environment. I thank my son SHAYAN (GOLU) for making my life more beautiful than it was. Finally, my acknowledgement would not be completed without thanking Almighty ALLAH, for giving me the strength and the determination to overcome the hardship faced in my life. Suleman R. Maujan CONTENTS Page No. * General remarks i * Abbreviations ii * Abstract iv Chapter 1: Synthesis of fluconazole analogues containing substituted thieno[2,3-d]pyrimidin-4(3H)-one and their bioevaluation Section I: Synthesis of fluconazole analogues containing substituted thieno[2,3-d]pyrimidin-4(3H)-one 1.1.1 Abstract 3 1.1.2 Introduction 3 1.1.3 Review of literature 4 1.1.4 Present work 26 1.1.4.1 Objective 26 1.1.4.2 Results and discussion 27 1.1.5 Conclusion 48 1.1.6 Experimental section 49 1.1.7 Selected spectra 115 1.1.8 References 135 Section II: Bioevaluation of fluconazole analogues containing substituted thieno[2,3-d]pyrimidin-4(3H)-one 1.2.1 Introduction 140 1.2.2 Present work 140 1.2.3 Results and discussion 140 1.2.4 Conclusion 149 1.2.5 References 150 Chapter 2: Synthesis of dimeric fluconazole analogues containing substituted thieno[2,3-d]pyrimidin-4(3H)-one and their bioevaluation 2.1 Abstract 152 2.2 Introduction 152 2.3 Review of literature 153 2.4 Present work 164 2.4.1 Objective 164 2.4.2 Results and discussion 165 2.5 Conclusion 176 2.6 Experimental section 177 2.7 Selected spectra 193 2.8 References 200 Chapter 3: Synthesis of fluconazole analogues containing 2H-1,4-benzothiazin- 3(4H)-ones or 2H-1,4-benzoxazin-3(4H)-ones and one-step preparation of α-chlorostyrenes Section I: Synthesis of fluconazole analogues containing 2H-1,4-benzothiazin- 3(4H)-ones or 2H-1,4-benzoxazin-3(4H)-ones 3.1.1 Abstract 204 3.1.2 Introduction 204 3.1.3 Review of literature 205 3.1.4 Present work 214 3.1.4.1 Objective 214 3.1.4.2 Results and discussion 215 3.1.5 Conclusion 224 3.1.6 Experimental section 225 3.1.7 Selected spectra 238 3.1.8 References 245 Section II: One-step preparation of α-chlorostyrenes 3.2.1 Abstract 249 3.2.2 Introduction 249 3.2.3 Review of literature 250 3.2.4 Present work 256 3.2.5 Conclusion 261 3.2.6 Experimental section 262 3.2.7 Selected spectra 271 3.2.8 References 279 List of publications 282 GENERAL REMARKS 1H NMR spectra were recorded on Bruker AC–200 MHz, Bruker AC–400 MHz and DRX–500 MHz spectrometer using tetramethylsilane (TMS) as an internal standard. Chemical shifts have been expressed in ppm units downfield from TMS. 13C NMR spectra were recorded on Bruker AC–200, Bruker AC–400 and DRX–500 instruments operating at 50 MHz, 100 MHz and 125 MHz respectively. EI Mass spectra were recorded on Finngan MAT–1020 spectrometer at 70 eV using a direct inlet system and applied Biosystems API QSTAR Pulsar Mass Spectrometer (Electrospray ionization, direct infusion method, solvents used were acetonitrile/methanol).