methyl 4-(4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoate為抗發炎藥物類似物，試圖發展為顯影劑並用於正電子放射斷層掃描。
經過三種不同路徑的嘗試，最後才得以產生最接近預期的目標物。路徑一經一系列的反應，如Friedel-Crafts reaction、Amide bond coupling、Wohl-Ziegler reaction等步驟合成，基於 4-(4'-(bromomethyl)-[1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide純化困難則不考慮繼續合成；路徑二於Friedel-Crafts reaction前採用保護基的策略也未能產生預期之產物，由於意外的去保護反應導致反應物自我聚合的現象產生，因此更改途徑。
第三途徑是經由兩個單體組合而成，其一單體methyl 4-(4-bromophenyl)-4-oxobutanoate由市售之bromobenzene透過Friedel-Crafts reaction與保護酸基兩步反應合成，產率為70%，另一單體4-hydroxymethylphenyl-1-boronpinacol以市售之4-bromo benzyl alcohol與bis(pinacolato)diboron反應合成產率為81%。最後將兩芳香烴單體以鈀 (0) 進行Suzuki 偶合反應，順利得到所需之化合物methyl 4-(4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoate，總產率為38%。

Methyl 4-(4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoate as a NSAIDs analog was attempted to be prepared for development of imaging agent for positron emission tomography.
Three synthetic routes were designed to approach the desired target compound. As indicated in the first route by staring from Friedel-Crafts reaction, amide bond formation, and Wohl-Ziegler reaction, the difficulty encountered in purification of 4-(4'-(bromomethyl)-[1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide discouraged further exploration. The second route that employed a protective group strategy before the step of Friedel-Crafts reaction also failed to generate the desired product because of an unexpected deprotection that promoted a self-propagation reaction to give a polymer-like product mixtures.
In the third route, the desired product was assembled by two monoarene derivatives. One of the two monomers, 4-(4-bromophenyl)-4-oxobutanoate, was prepared from commercial bromobenzene in two steps via Friedel-Crafts reaction and protection with acetyl group in 70% yield. The other monomer, 4-hydroxymethylphenyl-1-boronpinacol, was prepared from 4-bromo benzyl alcohol with bis(pinacolato)diboron in 81% yield. The final coupling of the two arene monomers using palladium (0) under Suzuki coupling condition was performed smoothly to afford the desired methyl 4-(4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoate in 38% yield.

目錄 1
摘要 5
Abstract 6
縮寫對照表 7
第一章 緒論 9
1.1 藥物發展 9
1.2 非類固醇抗發炎藥物起源 12
1.2.1 芬布芬 (Fenbufen) 12
1.2.2 非類固醇抗發炎藥物 (Non-Steroidal Anti-Inflammatory Drugs，NSAIDs) 13
1.2.3 環氧合酶 (Cyclooxygenases，COX）： 17
1.2.4 前列腺素 (Prostaglandins，PGS) 19
1.2.5 NSAIDs對於COX-1和COX-2選擇性高低的判斷 19
1.3酵素 22
1.3.1 酵素簡介 22
1.3.2 酵素動力學 23
第二章　實驗目的 30
第三章　結果與討論 34
3.1化合物 (3) 合成路徑一之逆合成分析 34
3.1.1 路徑一的合成瓶頸 35
3.1.2 製備4-(4'-(bromomethyl)-[1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide (6) 38
3.2化合物 (3) 合成路徑二之逆分析 47
3.2.1 路徑二的合成瓶頸 48
3.2.2 製備[1,1'-biphenyl]-4-ylmethanol (12) 50
3.2.3製備[1,1'-biphenyl]-4-ylmethyl acetate (11) 51
3.3預期合成之路徑三 55
3.3.1製備methyl 4-(4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoate (17) 56
第四章 實驗步驟 61
4.1實驗方法、材料與儀器 61
4.2 第一條合成路徑 64
4.2.1 製備4-(4'-methyl-[1,1'-biphenyl]-4-yl)-4-oxobutanoic acid (8) 64
4.2.2 製備4-(4'-methyl-[1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide (7) 66
4.2.3製備4-(4'-(bromomethyl)-[1,1'-biphenyl]-4-yl)-N-octyl-4-oxobutanamide (6) 69
4.3 第二條合成路徑 71
4.3.1 製備製備4-(bromomethyl)-1,1'-biphenyl (13) 71
4.3.2製備[1,1'-biphenyl]-4-ylmethanol (12) 73
4.3.3製備[1,1'-biphenyl]-4-ylmethyl acetate (11) 75
4.3.4製備4-(4'-(bromomethyl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoic acid (19) 77
4.3.5製備4-(4'-(acetoxymethyl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoic acid (10) 78
4.4 第三條合成路徑 79
4.4.1製備4-(4-bromophenyl)-4-oxobutanoic acid (18) 79
4.4.2製備methyl 4-(4-bromophenyl)-4-oxobutanoate (14) 81
4.4.3製備(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (15) 83
4.4.5製備methyl 4-(4'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-4-oxobutanoate (17) 85
第五章 結論 87
參考文獻 88
附錄 95

參考文獻
1. Mishra, N. K., Computational modeling of P450s for toxicity prediction. Expert. Opin. Drug. Met. 2011, 7 (10), 1211-1231.
2. Hughes, J. P.; Rees, S.; Kalindjian, S. B.; Philpott, K. L., Principles of early drug discovery. Brit. J. Pharmacol. 2011, 162 (6), 1239-1249.
3. Rudin, M.; Weissleder, R., Molecular imaging in drug discovery and development. Nat. Rev. Drug. Discov. 2003, 2 (2), 123-131.
4. Ghulaxe, C. ; Verma, R., A review on transdermal drug delivery system. J. Pharm. Innov. 2015, 4 (1), 37-43.
5. Drüeke, T. B.; Massy, Z.A., Oral or intravenous iron for anemia correction in chronic kidney disease? Kidney. Int. 2015, 88 (2015), 673–675.
6. Srinivas, C.; Raju, C. M. H.; Acharyulu, P. V. R., A simple procedure for the isolation of gamma-oxobenzenebutanoic acid derivatives: Application to the synthesis of fenbufen. Org. Process. Res. Dev. 2004, 8 (2), 291-292.
7. Wehling, M., Non-steroidal anti-inflammatory drug use in chronic pain conditions with special emphasis on the elderly and patients with relevant comorbidities: management and mitigation of risks and adverse effects. Eur. J. Clin. Pharmacol. 2014, 70 (10), 1159-1172.
8. Husain, A.; Ahmad, A.; Alam, M. M.; Ajmal, M.; Ahuja, P., Fenbufen based 3-[5-(substituted aryl)-1,3,4-oxadiazol-2-yl]-1-(biphenyl-4-yl)propan-1-ones as safer antiinflammatory and analgesic agents. Eur. J. Med. Chem. 2009, 44 (9), 3798-3804.
9. Hsu, C. C.; Wang, H. J.; Hsu, Y. H.; Chuang, S. Y.; Huang, Y. W.; Chang, Y. K.; Liu, J. S.; Hsiung, C. A.; Tsai, H. J., Use of Nonsteroidal Anti-Inflammatory Drugs and Risk of Chronic Kidney Disease in Subjects With Hypertension Nationwide Longitudinal Cohort Study. Hypertens. 2015, 66 (3), 524-533.
10. Lone, A. M.; Tasken, K., Proinflammatory anc immunoregulatory roles of eicosanoids in T cells. Front. Immunol. 2013, 4, 1-15.
11. Schmid, V. B.; Seewald, W.; Lees, P.; King, J. N., In vitro and ex vivo inhibition of COX isoforms by robenacoxib in the cat: a comparative study. J. Vet. Pharmacol. Ther. 2010, 33 (5), 444-452.
12. Hegazy, G. H.; Ali, H. I., Design, synthesis, biological evaluation, and comparative COX1 and COX2 docking of p-substituted benzylidenamino phenyl esters of ibuprofenic and mefenamic acids. Bioorg. Med. Chem. 2012, 20 (3), 1259-1270.
13. Renard, J. F.; Lecomte, F.; Hubert, P.; de Leval, X.; Pirotte, B., N-(3-Arylaminopyridin-4-yl)alkanesulfonamides as pyridine analogs of nimesulide: Cyclooxygenases inhibition, anti-inflammatory studies and insight on metabolism. Eur. J. Med. Chem. 2014, 74, 12-22.
14. Chandna, N.; Kumar, S.; Kaushik, P.; Kaushik, D.; Roy, S. K.; Gupta, G. K.; Jachak, S. M.; Kapoor, J. K.; Sharma, P. K., Synthesis of novel celecoxib analogues by bioisosteric replacement of sulfonamide as potent anti-inflammatory agents and cyclooxygenase inhibitors. Bioorg. Med. Chem. 2013, 21 (15), 4581-4590.
15. Chaiamnuay, S.; Allison, J. J.; Curtis, J. R., Risks versus benefits of cyclooxygenase-2-selective nonsteroidal antiinflammatory drugs. Am. J. Health. Syst. Ph. 2006, 63 (19), 1837-1851.
16. Uddin, M. J.; Crews, B. C.; Blobaum, A. L.; Kingsley, P. J.; Gorden, D. L.; McIntyre, J. O.; Matrisian, L. M.; Subbaramaiah, K.; Dannenberg, A. J.; Piston, D. W.; Marnett, L. J., Selective visualization of cyclooxygenase-2 in inflammation and cancer by targeted fluorescent imaging agents. Cancer. Res. 2010, 70 (9), 3618-3627.
17. Frungieri, M. B.; Calandra, R. S.; Mayerhofer, A.; Matzkin, M. E., Cyclooxygenase and prostaglandins in somatic cell populations of the testis. Reprod. 2015, 149 (4), 169-180.
18. Chopade, A. R.; Sayyad, F. J.; Naikwade, N. S., Pharmacological characterization of carrageenan induced heat muscle hyperalgesia in rats using non-selective, preferential and selective COX-2 inhibitors. Pharmacol. Rep. 2014, 66 (3), 353-362.
19. Warner, T. D.; Mitchell, J. A., COX-2 selectivity alone does not define the cardiovascular risks associated with non-steroidal anti-inflammatory drugs. Lancet. 2008, 371 (9608), 270-273.
20. Everts, B.; Wahrborg, P.; Hedner, T., COX-2-specific inhibitors - the emergence of a new class of analgesic and anti-inflammatory drugs. Clin. Rheumatol. 2000, 19 (5), 331-343.
21. Gierse, J. K.; Koboldt, C. M.; Walker, M. C.; Seibert, K.; Isakson, P. C., Kinetic basis for selective inhibition of cyclo-oxygenases. Biochem. J. 1999, 339, 607-614.
22. Krohn, K. A.; Link, J. M., Interpreting enzyme and receptor kinetics keeping it simple, but not too simple. Nucl. Med. Biol. 2003, 30 (8), 819-826.
23. Timson, D. J., Quantitative enzymology. Current. Enzym. Inhib. 2015, 11 (1), 20-31.
24. Bearne, S. L., Illustrating enzyme inhibition using gibbs energy profiles. J. Chem. Educ. 2012, 89 (6), 732-737.
25. Antuch, M.; Ramos, Y.; Alvarez, R., Simulated analysis of linear reversible enzyme inhibition with SCILAB. J. Chem. Educ. 2014, 91 (8), 1203-1206.
26. Walsh, R.; Martin, E.; Darvesh, S., Limitations of conventional inhibitor classifications. Integr. Biol. Uk. 2011, 3 (12), 1197-1201.
27. (a) Lin, K. I.; Yang, C. H.; Huang, C. W.; Jian, J. Y.; Huang, Y. C.; Yu, C. S., Synthesis and structure-activity relationships of fenbufen amide analogs. Mol. 2010, 15 (12), 8796-8803.
(b) Huang, H. L.; Yeh, C. N.; Lee, W. Y.; Huang, Y. C.; Chang, K. W.; Lin, K. J.; Tien, S. F.; Su, W. C.; Yang, C. H.; Chen, J. T.; Lin, W. J.; Fan, S. S.; Yu, C. S., [I-123]Iodooctyl fenbufen amide as a SPECT tracer for imaging tumors that over-express COX enzymes. Biomaterials 2013, 34 (13), 3355-3365.
28. Zervas, L.; Dilaris, I., Dealkylation and debenzylation of triesters of phosphoric acid - phosphorylation of hydroxy and amino compounds. J. Am. Chem. Soc. 1955, 77 (20), 5354-5357.
29. Hariharan, M.; Neelakandan, P. P.; Ramaiah, D., Encapsulation of electron donor-acceptor dyads in beta-cyclodextrin cavity: Unusual planarization and enhancement in rate of electron-transfer reaction. J. Phys. Chem. B. 2007, 111 (41), 11940-11947.
30. Djerassi, C., Brominations with N-bromosuccinimide and related compounds - the Wohl-Ziegler reaction. Chem. Rev. 1948, 43 (2), 271-317.
31. (a) Schultz, E. M.; Mickey, S., Alpha, alpha-diphenylacetone - 2-propanone, 1,1-diphenyl. Org Synth 1949, 29, 38-42.
(b) Kwok, R.; Chamberlain, B.; Mutha, S. C., Friedel-Crafts reaction with 1-bromo-1-phenyl-2-propanone. J. Org. Chem. 1972, 37 (8), 1275-1276.
32. Gogoi, N.; Boruwa, J.; Barua, N. C., A concise total synthesis of antifungal antibiotic (+)-preussin. Eur. J. Org. Chem. 2006, 2006 (7), 1722-1725.
33. Rueping, M.; Nachtsheim, B. J., A review of new developments in the Friedel-Crafts alkylation - from green chemistry to asymmetric catalysis. Beilstein J. Org. Chem. 2010, 6 (6), 1-24.
34. Wetter, H.; Oertle, K., Thexyldimethylsilyl chloride, an easily accessible reagent for the protection of alcohols. Tetrahedron. Lett. 1985, 26 (45), 5515-5518.
35. Magoulas, G. E.; Kostopoulou, O. N.; Garnelis, T.; Athanassopoulos, C. M.; Kournoutou, G. G.; Leotsinidis, M.; Dinos, G. P.; Papaioannou, D.; Kalpaxis, D. L., Synthesis and antimicrobial activity of chloramphenicol-polyamine conjugates. Bioorg. Med. Chem. 2015, 23 (13), 3163-3174.
36. Dupre, B.; Bui, H.; Scott, I. L.; Market, R. V.; Keller, K. M.; Beck, P. J.; Kogan, T. P., Glycomimetic selectin inhibitors: (alpha-D-mannopyranosyloxy)methylbiphenyls. Bioorg. Med. Chem. Lett. 1996, 6 (5), 569-572.
37. Lennox, A. J. J.; Lloyd-Jones, G. C., Selection of boron reagents for Suzuki-Miyaura coupling. Chem. Soc. Rev. 2014, 43 (1), 412-443.
38. Valeur, E.; Bradley, M., Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 2009, 38 (2), 606-631.
39. Birkeland, S.; Daub, G. H.; Hayes, F. N.; Ott, D. G., Liquid Scintillators .9. Synthesis of some aryl substituted phenanthrenes and dihydrophenanthrenes, and related p-terphenyls and p-quaterphenyls. J. Org. Chem. 1961, 26 (8), 2662-2667.
40. Chittiboyina, A. G.; Mizuno, C. S.; Desai, P. V.; Patny, A.; Kurtz, T. W.; Pershadsingh, H. A.; Speth, R. C.; Karamyan, V.; Avery, M. A., Design, synthesis, and docking studies of novel telmisartan-glitazone hybrid analogs for the treatment of metabolic syndrome. Med. Chem. Res. 2009, 18 (7), 589-610.
41. Tao, B.; Boykin, D. W., Simple amine/Pd(OAc)(2)-catalyzed Suzuki coupling reactions of aryl bromides under mild aerobic conditions. J. Org. Chem. 2004, 69 (13), 4330-4335.
42. Holland, H. L.; Morris, T. A.; Nava, P. J.; Zabic, M., A new paradigm for biohydroxylation by Beauveria bassiana ATCC 7159. Tetrahedron 1999, 55 (24), 7441-7460.
43. Bly, R.S.; Tse, K.-K.; Bly, R.K., The preparation and acetolysis of some [π-phenylchromium tricarbonyl]benzyl p-toluenesulfonates and their noncomplexed analogs. a search for σπ delocalization. J. Org. Chem. 1976, 117 (1), 35-54.
44. Sonpatki, V. M.; Herbert, M. R.; Sandvoss, L. M.; Seed, A. J., Troublesome alkoxythiophenes. A highly efficient synthesis via cyclization of gamma-keto esters. J. Org. Chem. 2001, 66 (22), 7283-7286.
45. Lutz, R. E.; Scott, G. W., Cis and trans beta-aroylacrylic acids and some derivatives. J. Org. Chem. 1948, 13 (2), 284-296.
46. Quin, C.; Robertson, L.; McQuaker, S. J.; Price, N. C.; Brand, M. D.; Hartley, R. C., Caged mitochondrial uncouplers that are released in response to hydrogen peroxide. Tetrahedron 2010, 66 (13), 2384-2389.
47. de Filippis, A.; Morin, C.; Thimon, C., Synthesis of some para-functionalized phenylboronic acid derivatives. Synth. Commun. 2002, 32 (17), 2669-2676.
48. Lee, J. C.; Bae, Y. H.; Chang, S. K., Efficient alpha-halogenation of carbonyl compounds by N-bromosuccinimide and N-chlorosuccinimde. B. Kor. Chem. Soc. 2003, 24 (4), 407-408.
49. Huang, Y. C.; Huang, H. L.; Yeh, C. N.; Lin, K. J.; Yu, C. S., Investigation of brain tumors using F-18-fluorobutyl ethacrynic amide and its metabolite with positron emission tomography. Oncotargets. Ther. 2015, 8, 1877-1885.
50. Grobben, B.; De Deyn, P. P.; Slegers, H., Rat C6 glioma as experimental model system for the study of glioblastoma growth and invasion. Cell Tissue Res. 2002, 310 (3), 257-270.
51. Kuchar M.; Mamat C., Methods to increase the metabolic stability of 18F-radiotracers. Molecules 2015, 20, 16186-16220.