Ⅵ CLASSIC PAPERS REVISITED David S. Warner, M.D., Editor Anesthesiology 2008; 108:531–3 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. The Invention and Development of Enflurane, Isoflurane, Sevoflurane, and Desflurane Ross C. Terrell, Ph.D.* Reprinted with permission from: Terrell RC, Speers L, Szur AJ, Eleven of the ethers were too unstable to test, Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/108/3/531/366681/0000542-200803000-00025.pdf by guest on 25 September 2021 Treadwell J, Ucciardi TR: General anesthetics: 1. Halogenated and, of the remaining 25, 13 had promising an- methyl ethyl ethers as anesthetic agents. J Med Chem 1971; esthetic properties in mice and are suitable for 14:517–9. Copyright 1971 American Chemical Society. study in larger animals. Those ethers having one H with at least 2 halogens other than F or 2 or Thirty-six halogenated Me Et ethers have been more H with at least one Br or Cl were the best synthesized for evaluation as volatile anesthetics. anesthetics. THE anesthetic properties of several fluorinated hydro- came the market leader. Fluoroxene and methoxyflurane carbons were reported by Robbins1 in 1946. In the were less successful because fluoroxene was borderline period 1946–1959, three fluorinated compounds, two flammable and caused serious postoperative nausea and ethers, and one hydrocarbon were introduced into clin- vomiting. The high boiling point (102°C) and high lipid ϭ ical practice: fluoroxene (CF3CH2OCH CH2) by Ohio solubility of methoxyflurane resulted in long recovery Medical Products (Cleveland, OH) in 1951, halothane times, and some renal toxicity probably due to a high (CF3CHClBr) by Ayerst Laboratories (New York, NY) and degree of metabolism. Imperial Chemical Industries, PLC (London, England) in This was the “state of the art” around 1960 when Ohio 1955, and methoxyflurane (CH3OCF2CHCl2) by Abbott Medical Products (a small division of Airco, Inc.) initi- Laboratories (Abbott Park, IL) in 1959. Although several ated a research project, the goal of which was to syn- other fluorinated ethers and hydrocarbons were re- thesize a new volatile anesthetic at least equal to, but ported to have anesthetic properties, none were success- hopefully better than, halothane, the market leader at fully marketed.2 Halothane was an immediate success the time. This was a logical project for Ohio Medical because it was potent and nonflammable with a very Products because they were already in the anesthetic acceptable anesthetic syndrome. It was especially useful market with nitrous oxide, cyclopropane, medical oxy- for mask inductions in children. There were, however, gen, the somewhat unsuccessful fluoroxene, and some three problems associated with halothane, less than ideal other anesthesia-related hardware. A new improved in- cardiovascular properties, the occurrence of rare but halation anesthetic would have been a valuable addition serious hepatic toxicity, and a substantial degree of me- to the product line. Ohio Medical Products assigned two tabolism. Despite these problems, halothane rapidly be- senior chemists, Louise Speers Croix, Ph.D. (1920–1992), and me to the project. I remember that at the time, several of our colleagues told us that we didn’t have a chance to Additional material related to this article can be found on the compete with the large companies, Abbott Laboratories, ANESTHESIOLOGY Web site. Go to http://www.anesthesiology .org, click on Enhancements Index, and then scroll down to find Imperial Chemical Industries, or Ayerst, who probably had the appropriate article and link. Supplementary material can also done or were doing considerable research on new anes- be accessed on the Web by clicking on the “ArticlePlus” link thetics. History shows that they had not and were not. either in the Table of Contents or at the top of the Abstract or We were not discouraged, and over the next 10 or 15 yr, HTML version of the article. we synthesized several hundred new fluorinated com- pounds, four of which—enflurane (CHF2OCF2CHFCl), * Vice President (Retired). Current position: Research Associate. isoflurane (CF3CHClOCHF2), sevoflurane (CF3)2CHOCH2F, Received from Minrad, Inc., Orchard Park, New York. Submitted for publica- and desflurane (CF3CHFOCHF2)—are currently used in tion July 20, 2007. Accepted for publication November 20, 2007. The research clinical practice. Some of the most important work on the for and preparation of this revisited article were supported solely by the author’s personal funds. synthesis of fluorinated methyl ethyl ethers and fluorinated Address correspondence to Dr. Terrell: Minrad, Inc., 50 Cobham Drive, Or- methyl isopropyl ethers, which resulted in the discovery of chard Park, New York 14127-1421. [email protected]. This article may be enflurane, isoflurane, sevoflurane, and desflurane, has been accessed for personal use at no charge through the Journal Web site, www 3–6 .anesthesiology.org. published. Most of the other work on fluorinated hydro- Anesthesiology, V 108, No 3, Mar 2008 531 532 ROSS C. TERRELL carbons, fluorinated diethyl ethers, and methyl-n-propyl well be as good an anesthetic as sevoflurane. Stability to ethers has not been published except in the patent litera- soda lime should be similar and possibly better because ture, although many compounds were synthesized in these the –OCHF2 group should be more stable than the areas. –OCH2F group in sevoflurane. This structure may be The research project was unique in several ways. There related to the decomposition of sevoflurane caused by were four general requirements. First, volatility was neces- iron oxide and aluminum oxide.12 There has been one sary. This limited syntheses, with few exceptions, to com- product recall of sevoflurane because of decomposition pounds having no more that four carbon atoms. Second, caused by iron oxide. nonflammability. This limited the number of hydrogen at- There are several other compounds that were not devel- oms. Fortunately, hydrogen could be substituted with chlo- oped by Ohio Medical Products, not because of instability to rine or fluorine and still retain some anesthetic properties. soda lime but rather because of low potency resulting from Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/108/3/531/366681/0000542-200803000-00025.pdf by guest on 25 September 2021 Third, stability, especially to soda lime. This requirement low solubility. There are four compounds of possible interest, 2 3 2 3 effectively excluded groups such as CH2ClO–, generally CHF2OCF2CF2Cl, CHF2OCF2CF2H, CF2ClOCF CHF2, and 3 known to be unstable to base, as well as some other CH2FOCF2CHF2, which is claimed to have good analgesia at groups. Fourth, a synthesis that could be used to manufac- subanesthetic concentrations.13 ture relatively large quantities at a reasonable price. This is There were also many other compounds, diethyl ethers, in contrast to the usual pharmaceutical product where the methyl propyl ethers, and assorted hydrocarbons, which active ingredient is usually measured in pounds. For anes- were volatile and stable to soda lime. None had acceptable thetics, the quantity is measured in tons. Current annual anesthetic properties. The data on most of these have not production of volatile anesthetics is estimated to be well been published. over 2,000 tons. Following this fourth guideline, much of Data on the large number of fluorinated compounds the work was done using readily available starting materi- synthesized allow some general structure–activity rela- ϭ als, such as CF2 CFCl, the starting material for enflurane; tions to be deduced. For example, fully halogenated CF3CH2OH and CF2HCl (freon 22), the starting materials compounds are usually poor anesthetics or are convul- for isoflurane and desflurane; and (CF3)2CH–OH, the start- sants. Other correlations can be made, but there are no ing material for sevoflurane. The most valuable synthetic really definite structure–activity relations that can be route used was photochemical chlorination, followed by used to accurately predict whether a compound will be replacement of the chlorine by fluorine. The Swarts reac- a good anesthetic. It is fortunate and somewhat amazing, tion, discovered around 1895, which used SbF3 or HF at least to me, that there is any correlation at all between 7 catalyzed by SbCl5, was the most useful. Chorine could pharmacologic activity and a structural formula as writ- also be substituted using potassium fluoride or other fluo- ten on paper. ride salts, also a well-known reaction.7 Predictions of activity based on structural formulae It would have been simpler to replace hydrogen di- often fail. A striking example of this is hexafluorodiethyl rectly using elemental fluorine rather than first chlorinat- ether, CF3CH2OCH2CF3, which might be predicted to be ing and then replacing the chlorine with fluorine. How- anesthetic because the structure is similar to that of ever, elemental fluorine is so reactive that the reaction is diethyl ether. It is not and is, in fact, a potent convulsant exceedingly difficult to control. Some research was done marketed by Ohio Medical Products as an alternative to on this method, and the first sample of desflurane was electroshock therapy. synthesized by this method.8 We also produced several Are there other compounds possible that have not yet fires, and this synthetic route was soon abandoned. been synthesized and tested? To possibly answer this Even with the somewhat strict guidelines and the lim- question, I did the following study, which I believe is ited synthetic methods available, it was possible to syn- unique to the anesthetic project because one can calcu- thesize several hundred fluorinated compounds for test- late the total number of compounds possible, both ing as anesthetic agents. Most of the compounds failed ethers and hydrocarbons having four carbon atoms or when tested in mice, but three did not—enflurane, less and any combination of hydrogen, fluorine, chlo- isoflurane, and desflurane.9,10 These three were all pat- rine, and bromine. This could never be done for any ented as anesthetics and are currently approved and other group of pharmaceutical products.