Cases of Green, Sustainable Synthesis in Industrial World

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1 Cases of Green, Sustainable Synthesis in Industrial World
Green Chemistry 綠色化學 工業界綠色永續合成實例 Cases of Green, Sustainable Synthesis in Industrial World 朝陽科技大學 周德璋 2010 綠色/永續合成化學講習會 December 3, 2010, 化學會年會，台灣大學 1 1 1

2 Green Chemistry The design, development, and implementation
工業界綠色永續合成實例 周德璋 Green Chemistry The design, development, and implementation of chemical products and processes to reduce or eliminate the use and generation of substances hazardous to human health and the environment. [為縮減或淘汰對人類健康和環境具有危害性的物質的使用與產生，而進行化學產品和製造過程的設計、開發與執行。] Anastas PT, Warner JC, editors. Green Chemistry: theory and practice. Oxford: Oxford University Press; 1998. Anastas PT, Kirchhoff MM, Origins, Current Status, and Future Challenges of Green Chemistry Acc. Chem. Res. 2002, 2 Introduction December 3, 2010 2

3 The Twelve Principals of Green Chemistry
工業界綠色永續合成實例 周德璋 The Twelve Principals of Green Chemistry Prevent waste 2. Design safer chemicals and products 3. Design less hazardous chemical syntheses Use renewable feedstocks Use catalysts, not stoichiometric reagents Avoid chemical derivatives 7. Maximize atom economy 8. Use safer solvents and reaction conditions 9. Increase energy efficiency Design chemicals and products to degrade after use Analyze in real time to prevent pollution Minimize the potential for accidents Anastas PT, Warner JC, editors. Green Chemistry: theory and practice. Oxford: Oxford University Press; 1998. 3 Introduction December 3, 2010 3

4 is the mechanics of doing sustainable chemistry,”
工業界綠色永續合成實例 周德璋 John C. Warner Research chemist at Polaroid (1988) Professor at the UMass, Boston (1996), -- established first doctoral program in green chemistry Professor at UMass, Lowell (2004) -- founded Center for Green Chemistry Chief technology officer and chairman of the board of Warner Babcock Institute for Green Chemistry (2007) “Green chemistry is the mechanics of doing sustainable chemistry,” Warner: “By focusing on green chemistry, it puts us in a different innovative space. It is a science that presents industries with an incredible opportunity for continuous growth and competitive advantage.” 4 Chemical & Engineering News, 88(40), October 04, 2010 Introduction December 3, 2010 4

5 Paul T. Anastas "Why did you become a chemist?"
工業界綠色永續合成實例 周德璋 Paul T. Anastas Professor of chemistry for the environment at Yale University, Director of Yale's Center for Green Chemistry & Green Engineering, Widely regarded as one of the fathers of "green chemistry,“ The Environmental Protection Agency assistant administrator for the Office of R&D, "Why did you become a chemist?" Some are excited by the intellectual challenges of chemistry. Others want to use chemistry and chemical engineering to solve problems and make the world a better place. Anastas: "The world needs both. Building a sustainable world is the most taxing intellectual exercise we have ever engaged in. It is also the most important for the future of the world." 5 Introduction December 3, 2010 5

6 Introduction December 3, 2010
工業界綠色永續合成實例 周德璋 Robert H. Grubbs, Richard R. Schrock, and France's Yves Chauvin won the 2005 Nobel Award for their development of the metathesis method in organic synthesis. “This represents a great step forward for green chemistry, reducing potentially hazardous waste through smarter production. Metathesis is an example of how important basic science has been applied for the benefit of mankind, society, and the environment,……" 6 Introduction December 3, 2010 6

7 工業界綠色永續合成實例 周德璋 綠色化學 Green Chemistry is focused on the design, manufacture, and the use of chemicals and chemical processes that have little or no pollution potential or environmental risk. Sustainable Chemistry not only includes the concepts of green chemistry, but also expands the definition to a larger system than just the reaction. Also considers the effect of processing, materials, energy, and economics. 永續化學 7 Introduction December 3, 2010 7

8 綠色永續合成 Anastas and Warner: "In virtually every aspect in society,
工業界綠色永續合成實例 周德璋 綠色化學的終極目的是縮減或淘汰對人類健康和環境具有危害性的物質的使用與產生，因此任何化學產品及其相關活動—製造過程的設計、開發、與實行，當然包含化學合成，都要秉持此認知而思考。 Anastas and Warner: "In virtually every aspect in society, it has long been acknowledged that preventing a problem is superior to trying to solve it once it has been created." green chemistry seeks to reduce and prevent pollution at its source. 綠色永續合成 8 Introduction December 3, 2010 8

9 What is the ideal synthesis
工業界綠色永續合成實例 周德璋 What is the ideal synthesis 1. Convenient and practical -- Simple 2. High yield (100%!) 3. Short (1 step! // 1-pot!) 4. Mild conditions (room temperature or 37 oC) 5. Starting materials easy to obtain (natural or commercial) 6. Available controlled stimulus (mild reagents or catalysts) 7. Cheap and safe solvent (water!) 8. Easy isolation of products 9. Isolation of intermediates unnecessary (one-pot reaction) 10. Display novel chemistry or new applications As Mother Nature Does! 9 Introduction December 3, 2010 9

10 Introduction December 3, 2010
工業界綠色永續合成實例 周德璋 高 原子 效率 原料易取 簡便實用 綠色永續 合成 少步驟（一步） 安全 節能 減廢 環境友善 10 Introduction December 3, 2010 10

11 The active ingredient in Januvia™ --
工業界綠色永續合成實例 周德璋 Sitagliptin The active ingredient in Januvia™ -- medication for type 2 diabetes. Disodium iminodiacetate (DSIDA) A key intermediate in the production of Roundup® herbicide Ibuprofen One of core non-steroidal anti-inflammatory medicines Cytovene® [ganciclovir] A prescription medication as “antivirals”. Polyaspartate Biodegradable Alternative to Polyacrylate 11 December 3, 2010 11

12 Greener Synthetic Pathways Award 2006
工業界綠色永續合成實例 周德璋 Case 實例1 sitagliptin US Presidential Green Chemistry Challenge Awards: Greener Synthetic Pathways Award 12 sitagliptin December 3, 2010 12

13 ◆ What is Sitagliptin? ● w w w the active ingredient in Januvia™.
工業界綠色永續合成實例 周德璋 ◆ What is Sitagliptin? (R)-4-oxo-4-[3-(trifluoromethyl)- 5,6-dihydro[1,2,4]triazolo[4,3-a] pyrazin-7(8H)-yl]-1- (2,4,5-trifluorophenyl) butan-2-amine Sitagliptin•H3PO4 ● the active ingredient in Januvia™. w 具效力和選擇性的dipeptidyl peptidase type 4(DPP-4) 抑制劑，治療二型糖尿病（type 2 diabetes）的藥劑。 2006年10月成為第一個通過美國FDA核准的糖尿病藥。 抑制DPP-4對腸泌素激素的水解作用，進而提高glucagonlike peptide-1（GLP-1 )與glucose-dependent insulinotropic polypeptide（GIP )的濃度。 [Review: Drucker, Cell Metab., 2006, 3, 153] w w 13 sitagliptin December 3, 2010 13

14 ◆ synthesis ● (Old process) asymmetric hydrogenation (Noyori)
工業界綠色永續合成實例 周德璋 ◆ synthesis ● first-generation synthesis of sitagliptin (Old process) asymmetric hydrogenation (Noyori) peptide coupling Mitsunobu reaction K. B. Hansen, et. al., Organic Process Research & Development 2005, 9, 14 sitagliptin December 3, 2010 14

15 peptide coupling deprotecting
工業界綠色永續合成實例 周德璋 peptide coupling deprotecting K. B. Hansen, et. al., Organic Process Research & Development 2005, 9, 15 sitagliptin December 3, 2010 15

16 peptide coupling Synthesis of 3-(trifluoromethyl)-5,6,7,8-
工業界綠色永續合成實例 周德璋 Synthesis of 3-(trifluoromethyl)-5,6,7,8- tetrahydro-[1,2,4]triazolo [4,3-a]pyrazine triazolopiperazine peptide coupling D. Kim, et. al., J. Med. Chem. 2005, 48, 16 sitagliptin December 3, 2010 16

17 ● (New process – Green route)
工業界綠色永續合成實例 周德璋 ● second-generation synthesis of sitagliptin (New process – Green route) Meldrum’s adduct One-pot, three-component reaction to key b-enamino amide intermediate 17 K. B. Hansen, et. al., J. Am. Chem. Soc. 2009, 131, 8798–8804 sitagliptin December 3, 2010 17

18 ferrocenyl phosphine ligands
工業界綠色永續合成實例 周德璋 Enantioselective hydrogenation of unprotected b-enamine amide recrystallized as the phosphoric acid salt JOSIPHOS ferrocenyl phosphine ligands [Rh(COD)Cl]2 tBu JOSIPHOS 18 K. B. Hansen, et. al., J. Am. Chem. Soc. 2009, 131, 8798–8804 sitagliptin December 3, 2010 18

19 The “greener” features
工業界綠色永續合成實例 周德璋 The “greener” features Fewer steps (4 vs 8): elimination Mitsunobu reaction elimination one peptide coupling No protection-deprotection of the amine nitrogen ● Increases yield (65% vs 52%) ● Waste reduction (>80%): Eliminate 60 L of aqueous waste per kg of product (prevent formation of 150,000 metric tons of solid and aqueous process waste over the lifetime of Januvia) ● Unprecedented efficient hydrogenation of an unprotected enamine. an excellent example of a scientific innovation resulting in benefits to the environment! ● 19 sitagliptin December 3, 2010 19

20 How is the Meldrum’s adduct formed?
工業界綠色永續合成實例 周德璋 How is the Meldrum’s adduct formed? 20 sitagliptin December 3, 2010 20

21 How is the b-ketoamide formed?
工業界綠色永續合成實例 周德璋 How is the b-ketoamide formed? 21 sitagliptin December 3, 2010 21

22 J Biocatalytic Transamination
工業界綠色永續合成實例 周德璋 Biocatalytic Transamination C K Savile et al. Science 2010;329: Presidential Green Chemistry Challenge Award Greener Reaction Conditions Award 2010 J 22 December 3, 2010 22

23 Disodium iminodiacetate (DSIDA) Greener Synthetic Pathways Award 1996
工業界綠色永續合成實例 周德璋 Case 實例2 Disodium iminodiacetate (DSIDA) US Presidential Green Chemistry Challenge Awards: Greener Synthetic Pathways Award 23 December 3, 2010 Disodium iminodiacetate 23

24 ◆ What is Disodium iminodiacetate (DSIDA)?
工業界綠色永續合成實例 周德璋 ◆ What is Disodium iminodiacetate (DSIDA)? sodium 2,2'-azanediyldiacetate disodium 2-[(2-oxido-2-xoethyl)amino]acetate a key intermediate in the production of Monsanto’s Roundup® herbicide Glyphosate: N-(phosphonomethyl)glycine in the form of its isopropylamine salt (41%) Roundup® agricultural herbicides are the flagship of Monsanto’s agricultural chemicals business. 24 December 3, 2010 Disodium iminodiacetate 24

25 ● Strecker amino acid synthesis Aldehydes (or Ketones)
工業界綠色永續合成實例 周德璋 ● Strecker amino acid synthesis Aldehydes (or Ketones) Traditionally, the Strecker process has been used to manufacture DSIDA. It requires formaldehyde, ammonia, hydrogen cyanide, and hydrochloric acid. 25 December 3, 2010 Disodium iminodiacetate 25

26 x N N M The Strecker process for synthesizing DSIDA hydrogen cyanide:
工業界綠色永續合成實例 周德璋 x The Strecker process for synthesizing DSIDA N hydrogen cyanide: extremely toxic; requires special handling M exothermic reaction generating potentially unstable intermediates. N waste: 1 kg for every 7 kg of product. 26 December 3, 2010 Disodium iminodiacetate 26

27 Greener Synthetic Pathways Award
工業界綠色永續合成實例 周德璋 y Green process for synthesizing DSIDA copper-catalyzed dehydrogenation of diethanolamine Greener Synthetic Pathways Award 1996 27 December 3, 2010 Disodium iminodiacetate 27

28 C J C C C C C the dehydrogenation reaction is endothermic;
工業界綠色永續合成實例 周德璋 C the dehydrogenation reaction is endothermic; avoid the use of cyanide and formaldehyde; fewer process steps, higher overall yield; no purification or waste cut is necessary; recover catalyst by filtration, ready for subsequent use in the manufacture of Roundup; This catalysis technology is applicable in the production of other amino acids and becomes a general method for conversion of primary alcohols to carboxylic acid salts. C C C C 1. Prevent Waste 2. Increase Atom Economy 3. Design Less Hazardous Chemical Syntheses 4. Design Safer Chemicals 9. Use Catalysts C J 28 December 3, 2010 Disodium iminodiacetate 28

29 Greener Synthetic Pathways Award 1997
工業界綠色永續合成實例 周德璋 Case 實例3 Ibuprofen US Presidential Green Chemistry Challenge Awards: Greener Synthetic Pathways Award 29 ibuprofen December 3, 2010 29

30 工業界綠色永續合成實例 周德璋 ◆ What is ibuprofen? (S)-2-(4-isobutylphenyl)propanoic acid, (S)-ibuprofen, is active form both in vitro and in vivo. marketed as racemic mixtures. 30 ibuprofen December 3, 2010 30

31 消炎藥) in the World Health Organization's "Essential Drugs List",
工業界綠色永續合成實例 周德璋 ● One of core non-steroidal anti-inflammatory medicines (非類固醇 消炎藥) in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system ---- Over-the-Counter (不需處方可出售的) medicine. [others: aspirin, paracetamol (acetaminophen)] ● Discovered by S. Adams, with J. Nicholson, A. R. M. Dunlop, J. B. Wilson & C. Burrows (Boots Company), and was patented in 1961. Dr. Adams initially tested the drug on a hangover (宿醉). 31 ibuprofen December 3, 2010 31

32 rheumatoid arthritis [風濕性關節炎] in the UK and in 1974 in the USA.
工業界綠色永續合成實例 周德璋 ● It was launched in 1969 as a medication for the treatment of rheumatoid arthritis [風濕性關節炎] in the UK and in 1974 in the USA. ● The Boots Group was awarded Queen's Award for Technical Achievement for the development of ibuprofen in 1987. ● 具解熱、消炎和鎮痛的作用，可治療發燒、疼痛和發炎。 ● 減輕關節炎(arthritis) ，原發型痛經( primary dysmenorrhea) ， 發燒 (fever)，等症狀；作為止痛劑（analgesic)； 具抑制血小板凝集效應（antiplatelet effect）。 ● Active ingredient in “Motrin”, “Advil”, Medipren”….， “炎熱消”(水液) , “普服芬” (錠劑),宜痛炎錠, 伊普®鎮痛,…. 32 ibuprofen December 3, 2010 32

33 ◆ synthesis and patented by Boots Company of
工業界綠色永續合成實例 周德璋 ◆ synthesis ● The industrial synthesis was developed and patented by Boots Company of England in brown synthesis ● A new greener industrial synthesis was developed and implemented by the BHC Company (now BASF Corporation) in green synthesis ● BHC won Presidential Green Chemistry Challenge Awards (USA) ---- Greener Synthetic Pathways Award in 1997. BHC = Boots + Hoechst Celanese 33 ibuprofen December 3, 2010 33

34 Boots synthesis of ibuprofen
工業界綠色永續合成實例 周德璋 Boots synthesis of ibuprofen --- brown synthesis developed and patented by Boots Company of England in the 1960s 34 ibuprofen December 3, 2010 34

35 Table 1. Atom economy in the Boots’ synthesis of ibuprofen
工業界綠色永續合成實例 周德璋 Reagent Used in ibuprofen Unused in ibuprofen Formula Mw 1 C10H14 134 C10H13 133 H C4H6O3 102 C2H3 24 C2H3O3 75 2 C4H7ClO2 122.5 CH 13 C3H6ClO2 109.5 C2H5ONa 68 3 H3O 19 4 NH3O 33 6 H4O2 36 HO2 Total Ibuprofen Waste products C20H42NO10ClNa 514.5 C13H18O2 206 C7H24NO8ClNa 308.5 ► = (206)/(514.5) x 100 = 40% Table 1. Atom economy in the Boots’ synthesis of ibuprofen 35 ibuprofen December 3, 2010 35

36 Problems with Boots synthesis of ibuprofen
工業界綠色永續合成實例 周德璋 Problems with Boots synthesis of ibuprofen aluminium trichloride, AlCl3, is not a true catalyst. it is changed into a hydrated form, Al(OH)3/H2O, that has to be disposed of – usually in landfill sites. atom economy = 74.5% atom economy = 71.6% 36 ibuprofen December 3, 2010 36

37 atom economy = 92% atom economy = 67.6% atom economy = 91%
工業界綠色永續合成實例 周德璋 atom economy = 92% atom economy = 67.6% dehydration atom economy = 91% hydrolysis atom economy = 92.4% 37 ibuprofen December 3, 2010 37

38 thus every 1 kg of ibuprofen produced is accompanied
工業界綠色永續合成實例 周德璋 ● 6 steps! If 90% yield for each step, then overall yield is 53%. ● atom economy is 40%! thus every 1 kg of ibuprofen produced is accompanied with more than 1.5 kg of waste. ● UK market for ibuprofen is about 3,000,000 kg per year! ● about 4,500,000 kg of waste are produced. ● a typical tablet contains 200 mg of ibuprofen, then 15,000,000,000 (1.5 x 1010) tablets are produced. World population on November 2010 is estimated by the United States Census Bureau to be billion (6,884,000,000). 38 ibuprofen December 3, 2010 38

39 BHC synthesis of ibuprofen --- green synthesis
工業界綠色永續合成實例 周德璋 BHC synthesis of ibuprofen --- green synthesis (USA) Presidential Green Chemistry Challenge Awards Greener Synthetic Pathways Award in 1997 developed and implemented by the BHC Company in 1991 39 ibuprofen December 3, 2010 39

40 Table 2. Atom economy in the BHC synthesis of ibuprofen
工業界綠色永續合成實例 周德璋 Reagent Used in ibuprofen Unused in ibuprofen Formula Mw 1 C10H14 134 C10H13 133 H C4H6O3 102 C2H3O 43 C2H3O2 59 2 H2 3 CO 28 Total Ibuprofen Waste products C15H22O4 266 C13H18O2 206 C2H4O2 60 atom economy = (206)/(266) x 100 = 77.4% Table 2. Atom economy in the BHC synthesis of ibuprofen 40 ibuprofen December 3, 2010 40

41 Economic and Environmental Advantages of BHC Synthesis
工業界綠色永續合成實例 周德璋 Economic and Environmental Advantages of BHC Synthesis ● Greater overall yield (three steps vs. six steps) ● Greater atom economy (uses less feedstocks) ● Fewer auxiliary substances (products and solvents separation agents) ● Less waste: greater atom economy, catalytic vs. stoichiometric reagents, recovery of byproducts and reagents, recycling, and reuse, lower disposal costs. The BHC ibuprofen process is an innovative, efficient technology that has revolutionized bulk pharmaceutical manufacturing. J 41 ibuprofen December 3, 2010 41

42 The Cytovene® [ganciclovir] Greener Synthetic Pathways Award 2000
工業界綠色永續合成實例 周德璋 Case 實例4 The Cytovene® [ganciclovir] US Presidential Green Chemistry Challenge Awards: Greener Synthetic Pathways Award 42 Cytovene (gancyclovir) December 3, 2010 42

43 ◆ What is ganciclovir [“更昔洛韋”]?
工業界綠色永續合成實例 周德璋 ◆ What is ganciclovir [“更昔洛韋”]? ● IUPAC name: 2-amino-9-{[(1,3-dihydroxypropan-2-yl)oxy] methyl}-6,9-dihydro-3H-purin-6-one ● Ganciclovir is a prescription medication that belongs to the family of drugs known as “antivirals” [“更昔洛韋”是屬於抗病毒的處方藥劑] 43 Cytovene (gancyclovir) December 3, 2010 43

44 [“更昔洛韋”是用於治療免疫損害患者中的巨細胞病毒 (CMV) 視網膜炎，包括獲得性免疫缺陷綜合征 (愛滋病）或化療病人。]
工業界綠色永續合成實例 周德璋 ● Ganciclovir works by inhibiting cellular DNA polymerase that is associated with viral infections. ● Ganciclovir is used to treat for cytomegalovirus (CMV) retinitis infections in immunocompromised patients, including patients with acquired immunodeficiency syndrome (AIDS) or patients undergoing chemotherapy. [“更昔洛韋”是用於治療免疫損害患者中的巨細胞病毒 (CMV) 視網膜炎，包括獲得性免疫缺陷綜合征 (愛滋病）或化療病人。] ● Cytovene®, the registered trade name by the Roche Pharmaceuticals, contains ganciclovir sodium as the medicinal ingredient. 44 Cytovene (gancyclovir) December 3, 2010 44

45 工業界綠色永續合成實例 周德璋 ◆ synthesis ● In 1974, scientists at Wellcome discovered the potent antiviral agent acyclovir (Zovirax®) for the treatment of various viral infections including herpes viruses HSV-1 and HSV-2. ● In 1980, Dr. Kelvin Ogilvie and his research team at McGill University discovered Ganciclovir [CAN. J. CHEM. 1982, 60, 3005.], and developed by Verheyden and Martin at Syntex Research in 1980. ● The first commercially viable process for the manufacture of ganciclovir was developed by Roche Colorado Corporation, formerly known as Syntex Chemicals, in the early 1990s. ● The 1st generation process is known as Persilylation Process. 45 Cytovene (gancyclovir) December 3, 2010 45

46 Persilylation Process --- Brown process
工業界綠色永續合成實例 周德璋 Persilylation Process --- Brown process U.S. Patent 4, 621,140, November 4, 1986. U.S. Patent 4,803,271, February 7, 1989. 46 Cytovene (gancyclovir) December 3, 2010 46

47 Cytovene (gancyclovir) December 3, 2010
工業界綠色永續合成實例 周德璋 47 Cytovene (gancyclovir) December 3, 2010 47

48 Problems with Persilylation Process
工業界綠色永續合成實例 周德璋 Problems with Persilylation Process ● A six-step process, in which 4-steps are protection-deprotection reactions. ● Involved 28 reagents and intermediates, and required the purification and isolation of 5 discrete intermediates. ● Involved at least 8 different kinds of solvents. ● Afforded specification grade ganciclovir in 54% yield. ● Involved a potentially hazardous palladium catalyzed hydrogenation step, which is needed to remove dibenzyl ether protecting group. ● Poor selectivity of key alkylation reaction, affording the desired N-7 isomer as minor product (N-7:N-9 = 1:10) and requiring costly and tedious chromatographic separation. 48 Cytovene (gancyclovir) December 3, 2010 48

49 The Guanine TriEster (GTE) Process.
工業界綠色永續合成實例 周德璋 In 1993, the Boulder Technology Center of Roche Colorado Corporation completed the demonstration of a new and expedient process for the production of ganciclovir by (1) leveraging the basic principles of molecular conservation to minimize the creation and disposal of undesired wastes, and (2) formulating efficient process engineering design for streamlining process operation and the recycling of raw materials. The new (2nd generation) process is called The Guanine TriEster (GTE) Process. This technology was awarded the Presidential Green Chemistry Challenge Award [Greener Synthetic Pathways Award] in the U.S. in 2000. 49 Cytovene (gancyclovir) December 3, 2010 49

50 The Guanine TriEster (GTE) Process
工業界綠色永續合成實例 周德璋 The Guanine TriEster (GTE) Process --- Green process Isolated by selective crystallization 50 Cytovene (gancyclovir) December 3, 2010 50

51 The “greener” features of the GTE process
工業界綠色永續合成實例 周德璋 The “greener” features of the GTE process ● Fewer process steps: ￭ The process demonstrates the potential for a “one step” process for the production of ganciclovir. ● Waste quantity reduction/elimination: ￭ Reduced the number of chemical reagents and intermediates from 28 to 11. ￭ Eliminated 2 hazardous solid waste streams (SiO2-AlO2 & Pd(OH)2). ￭ Eliminated 11 different byproducts from the liquid waste streams. ￭ Efficiently recycled and reused 4 of the 5 raw materials not incorporated into the final product. [U.S. Patent 5, 565, 565, October 15, 1996.] 51 Cytovene (gancyclovir) December 3, 2010 51

52 ￭ Involved virtually no protection-deprotection steps, and thus
工業界綠色永續合成實例 周德璋 ￭ Involved virtually no protection-deprotection steps, and thus eliminated a potentially hazardous palladium catalyzed hydrogenation step. ￭ The process thus reduced air emissions by ∼66% and liquid/solid waste generation by ∼89%. ● Yield improved: The process provides more than a 25% increase in overall yield and a 100% increase in production throughput. ● Greener: The process achieves applying the principles of 1. Prevent Waste Increase Atom Economy Design Less Hazardous Chemical Syntheses 52 Cytovene (gancyclovir) December 3, 2010 52

53 工業界綠色永續合成實例 周德璋 ● The process designed and used a 4-carbon triester coupling reagent, which generated innocuous byproduct (EtCOOH) via simple hydrolysis. ● The process demonstrated the novel design of the direct silylation of guanine, that gives rise to a highly regioselective alkylation and thus less unwanted alkylated byproduct. For a review of synthetic approaches to N-9 substituted guanies. ● F. P. Clausen and J. Juhl-Christensen, Organic Prep. & Proced. Intl., 1993, 25, 375. ● V. V. N. K. V. Prasada Raju, et. al. ARKIVOC 2009 (xii) ● K. Izawa* and H. Shiragami, Pure & Appl. Chem.,1998, 70, For the study describing a possible approach to selective alkylation of guanines. ● D. Sing, M.J. Wani and A. Kumar, J. Org. Chem. 1999, 64, 4664. ● J. Boryski and B. Golankiewicz, Synthesis, 1999, 625. ● United States Patent , Issued on July 18, 2006. 53 Cytovene (gancyclovir) December 3, 2010 53

54 工業界綠色永續合成實例 周德璋 References ● Development of an Environmentally Friendly, Cost Effective Process for the Production of cytovene® Antiviral Agent. ● Biologically active acyclonucleoside analogues. 11. The synthesis of 9-[[2-hydroxy-1-(hydroxymethyl)ethoxy]methyl]guanine (BIOLF-62). K. Ogilvieu, et. al., Can. J. Chem. 1982, 60, 3005. ● Synthesis of acyclovir, ganciclovir and their prodrugs: A review [Review], Gao, H.; Mitra, A. K. Synthesis, 2000, 2000. ● Regioselective synthesis of various prodrugs of ganciclovir, Gao, H.; Mitra, A. K. Tetrahedron Letters, 2000, 41, 1131. A Facile Synthesis of 9-(1,3-Dihydroxy-2-propoxymethyl) guanine (Ganciclovir) from Guanosine, Boryski, et al., Synthesis, 1999, 625. ● J 54 Cytovene (gancyclovir) December 3, 2010 54

55 Polyaspartate Biodegradable Alternative to Polyacrylate Case 5. 實例5
工業界綠色永續合成實例 周德璋 Case 實例5 Polyaspartate Biodegradable Alternative to Polyacrylate US Presidential Green Chemistry Challenge Awards: Award in the small business category 1996 55 Polyaspartate December 3, 2010 55

56 Polyaspartic acid Polyacrylic acid
工業界綠色永續合成實例 周德璋 Aspartic acid Acrylic acid 天冬氨酸 壓克力酸 Polyaspartic acid Polyacrylic acid 聚天冬氨酸 聚丙烯酸 poly(succinimide) 2-Aminobutanedioic acid 2-氨基丁酸 propenoic acid 丙烯酸 56 Polyaspartate December 3, 2010 56

57 Polyaspartate Polyacrylate 聚天冬氨酸鹽 聚丙烯酸鹽
工業界綠色永續合成實例 周德璋 Polyaspartate Polyacrylate 聚天冬氨酸鹽 聚丙烯酸鹽 What are polyaspartate and polyacrylate in common? Polyanion, Hydrophilic, Water soluble 57 Polyaspartate December 3, 2010 57

58 Polyelectrolytes Examples polypeptides (proteins), DNA,
工業界綠色永續合成實例 周德璋 Polyelectrolytes ● polymers whose repeating units bear an electrolyte group, dissociating in aqueous solution (water) to generate positive or negative charge. ● also called macroions or polyions or polysalts. ● can be polyanions or polycations. ● generally water soluble polymers if their structure is linear. ● the polymer will be highly expanded in aqueous solution. ● can be modified to function as antiscalant (抗垢劑) and dispersant (分散劑). Examples polypeptides (proteins), DNA, poly(sodium styrene sulfonate, PSS), polyacrylic acid (PAA). 58 Polyaspartate December 3, 2010 58

59 PAC can function as both
工業界綠色永續合成實例 周德璋 Polyacrylate (PAC) Synthesis Polyacrylic Acid Polyacrylate PAC can function as both an antiscalant (抗垢劑 ) and a dispersant (分散劑).  59 Polyaspartate December 3, 2010 59

60 PAC and the Environment
工業界綠色永續合成實例 周德璋 PAC and the Environment PAC is nontoxic and environmentally benign, but it is not biodegradable. Because it is widely used for many applications, it poses an environmental problem from a landfill perspective. When PAC is used as an antiscalant or a dispersant, it becomes part of wastewater. PAC is nonvolatile and not biodegradable, so the only way to remove it from the water is to precipitate it as an insoluble sludge. The sludge must then be landfilled. Feedstocks are made from fossil fuels. ● ● ● ● ● ● 60 Polyaspartate December 3, 2010 60

61 工業界綠色永續合成實例 周德璋 Polyaspartate Polyaspartate has similar properties to the polyacrylates and so it can be used as a dispersant, or an antiscalant, or a superabsorber. Polyaspartate is nontoxic, biodegradeable (可生物分解的), and environmentally safe. Biodegradation results in decomposition of TPA to environmentally benign products such as carbon dioxide and water.  The Donlar Corporation developed an economic way to produce “thermal polyaspartate (TPA)” in high yield (~97%), that eliminates use of organic solvents, cuts waste, and uses less energy. Polyaspartate is a biopolymer synthesized from L-aspartic acid, a natural amino acid. ● ● ● ● ● 61 Polyaspartate December 3, 2010 61

62 Synthesis of thermal polyaspartate (TPA)
工業界綠色永續合成實例 周德璋 Synthesis of thermal polyaspartate (TPA) 60 °C 62 Polyaspartate December 3, 2010 62

63 Green Chemistry in ACTION
工業界綠色永續合成實例 周德璋 Green Chemistry in ACTION In April 1997, Donlar opened the world's largest manufacturing facility for biodegradable polyaspartates, in Peru, Illinois, with a production capacity of more than 30 million pounds a year. The opening of this facility resulted in commercial availability of TPA. TPA is marketed and sold as a corrosion and scale inhibitor, a dispersing agent, a waste water additive, a superabsorber, and also as an agricultural polymer. As an agricultural polymer, TPA is used to enhance fertilizer uptake by plants. Less fertilizer is added to the soil and the environmental impact from fertilizer run-off is reduced. ● ● ● ● 63 Polyaspartate December 3, 2010 63

64 工業界綠色永續合成實例 周德璋 ● British Petroleum Exploration and others have achieved success with a TPA additive that helps to sustain the flow of crude from oil wells in North Sea offshore oil fields. TPA is a green alternative to Polyacrylate and other currently used water soluble polymers! References 1.  Low, K.C., Atencio, A.M., Meah, A. R., Anderson, D.E., Batzel, D.A., Vallino, B., Rico, B., Ross, R.J., Harms, D., Spurrier, E., Below, F.  "Production and Use of Thermal Polyaspartate Polymers", a proposal submitted to the Presidential Green Chemistry Challenge Awards program, 1996. 2.  Wood, A.  "Acrylics:  Versatile Chemistry Adapts to Growth Market Emulsions and Superabsorbents Take the Lead",  Chemical Week,1994, (Dec 22), 22. 3. Wheeler, A.P., Koskan, L.P. "Large Scale Thermally Synthesized Polyaspartate as a Substitute in Polymer Applications", Mat. Res. Soc. Symp. Proc., 1993, 292, 277. 4. R. A. Gross and B. Kalra, “Biodegradable Polymers for the Environment”, SCIENCE VOL AUGUST 2002, 803, J 64 Polyaspartate December 3, 2010 64

65 工業界綠色永續合成實例 周德璋 感謝您的聆聽，請指教 朝陽科技大學 周德璋 65 65