Union Carbide plans silicones plant - C&EN Global Enterprise (ACS

Oct 13, 1980 - ... mineral fillers, standard and specialty oils, antifoaming agents, volatile silicone lubricants for cosmetic formulations, emulsions...
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maytansine has been reported by a team at Harvard University, Cam­ bridge, Mass., led by organic chem­ istry professor Elias J. Corey [J. Am. Chem. Soc, 102,6613 (1980)]. Maytansine is unusual among cancer drugs because its toxic dose is more than 100 times as great as its therapeutic dose. Most cancer drugs are only slightly less toxic to normal cells than to malignant cells. Side ef­ fects in the central and peripheral nervous and gastrointestinal systems have concerned clinicians, however. Corey's successful synthesis makes large stocks of intermediates available for preparing maytansine analogs that may lack these side effects. The Harvard chemists already have made some analogs that are being tested at the National Cancer Institute. Like a space program, a total syn­ thesis also results in new methods that chemists now can use on other projects. Among methods Corey de­ veloped for maytansine are an aldolbased olefin synthesis, an asymmetric condensation for optically active aldols, and a very mild way to remove methoxyethoxymethoxy (MEM) protecting groups from hydroxyl functions. Corey eventually recruited seven postdoctoral students for the main thrust toward maytansine. The effort took five years. "Many graduate stu­ dents want their own separate projects," Corey explains. "This was a big enough project to need many people." Other members of the winning maytansine team were Mark G. Bock, A. Richard Chamberlin, Hidetsura Cho, David Floyd, Duy H. Hua, A. V. Rama Rao, and Leland O. Weigel. The overall plan of attack was never much of a problem. Corey early settled on the molecular components that had to go together. In a molecule so densely populated with functional groups, however, problems arose continually in finding reactions that would put 35 carbon, 10 oxygen, three nitrogen, and one chlorine atom, to­ gether with the 46 attendant hydro­ gen atoms, in the right positions, controlling configurations at each of eight asymmetric centers, under conditions that would push yields Harvard team over 80% and keep the molecule from synthesizes maytansine falling apart. Corey's olefin synthesis, used twice The antileukemic agent maytansine for maytansine, involved condensa­ has been a target of synthetic organic tion of the anion of an a-trimethylchemists since 1972, when the late S. silyl aldehyde ieri-butylimine with Morris Kupchan, organic chemistry aldehydes. For the asymmetric aldol professor at the University of Vir­ condensation, he developed phenyl ginia, Charlottesville, isolated it from (R)-(+)-a:-p-toluenesulfinylacetate fruit of the Ethiopian shrub May- as a reagent. He closed the 19-memtenus ouatus. Chemists in at least bered lactam on an Af-methylaniline seven laboratories have worked on the moiety via a mixed carboxyl-meproblem. Now, total synthesis of I sitylenesulfonyl anhydride.

The second approach, which EPA appears to favor, is that of using eco­ nomic incentives to reduce use. Under this approach EPA would establish a production ceiling for the industry, measured in "permit pounds," which would allow a producer to vary his mix of products among the various CFC's according to the relative de­ pletion potential of each. These per­ mits could be allocated directly either to producers or users or they could be auctioned off by EPA to the manu­ facturer or user willing to pay the highest price. Whatever rules EPA eventually comes up with will cover chemi­ cals with the general formula CnClxFyH2n+2-x-yX 0, y 0 , and it will take into account the differing ozone depletion potential of the various CFC compounds. EPA admits that unilateral U.S. action to freeze production at, say, 1980 levels would have little impact. It estimates that, even if uncontrolled growth were allowed until 1990 in the domestic CFC industry, the U.S. contribution toward steady-state ozone depletion would be only 7.5% compared to 4.5% with a production freeze. Significant reductions of 70% from 1980 production levels would reduce that contribution to 1.5%. The contribution from the rest of the world in all cases would be 24.5%. But the agency says adoption of a "no-growth" strategy would signal to other CFC producing and using na­ tions that the U.S. is concerned about the risk entailed in depletion of the ozone layer and that it is willing to take serious action on the basis of present knowledge. EPA believes that the only acceptable long-term strat­ egy is "substantial emissions reduc­ tion," but fears that if it implemented this approach immediately it would weaken the U.S. efforts to produce international action of the same magnitude. EPA is allowing three months for comments on the proposals contained in its advanced notice of proposed rule making and expects to propose the rules early next year. D

Maytansine

"We were using up material at a substantial rate just to find proper reaction conditions," Corey says. Toward the end, for example, the Harvard group tried 25 experiments to find the right way to take off the MEM protecting group without ex­ pelling a nearby methoxy group. The methoxy group was filed to a hair trigger by conjugation with two dou­ ble bonds and a benzene ring. The conditions hit upon form a lengthy catalog of precise reagents, solvents, temperatures, times, and modes of addition. In fact, the detailed condi­ tions for almost all reactions in the maytansine synthesis imply a back­ ground of other conditions that did not work nearly so well. Along with successes there also were frustrations. Corey hoped to form an (S)-alcohol at one position by asymmetric reduction of a ketone. The only result was the discovery of 15 reagents that gave clean reduction to (R)-alcohol. Corey devised the asymmetric aldol condensation to solve the problem. Π

Union Carbide plans silicones plant Construction will begin in 1981 on a $150 million silicones plant by Union Carbide at the firm's South Charles­ ton, W.Va., site, with completion scheduled for mid-1983. The compa­ ny has not specified plant capacity, but industry sources suggest that it could be 50 million lb per year. Products will include surfactants for polyurethane formulations, organofunctional silanes for such uses as surface modification of glass fiber and mineral fillers, standard and specialty oils, antifoaming agents, volatile silicone lubricants for cos­ metic formulations, emulsions, and intermediates for gum and elastomer manufacture. Beginning with silicon metal, the Carbide plant will produce chlorotrimethyl-, dichlorodimethyl-, and methyltrichlorosilanes, which are Oct. 13, 1980C&EN

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raw materials for silicone manufacture. Company spokesmen say the plant will use technology based on Carbide's research to approach the maximum practical efficiency of the polymerization reaction. This may mean that the firm has found ways to reduce the reject rate, which can be 40% for some silicone products, and which adds so much to the cost of each pound. Silicone fluids and resins are made by four U.S. producers. Of the $900 million or so domestic and export market, about 50% goes to Dow Corning, with plants at Carrollton, Ky., and Midland, Mich.: 25% to General Electric, which produces at Waterford, N.Y.; 15% to Carbide, which already has a plant at Sistersville, W.Va.; and 10% to SWE Silicones, owned jointly by Stauffer Chemical and Wacker Chemical, whose plant is in Adrina, Mich. Carbide says the new plant will serve the firm's marketing needs through 1990. One new market in which Carbide and other producers hope to make inroads is automobile brake fluids. With cars and brake systems becoming smaller, operating temperatures will rise, making heat resistance of silicone oils attractive despite their relatively high costs. The Army, Navy, and Postal Service have demonstration projects under way to evaluate contribution of silicone brake fluids to lower maintenance and part replacement costs. The new capacity also may serve to discourage entry by such European competitors as Rhône-Poulenc and Bayer. Competitors would have to contend both with plentiful existing capacity and the need to set up elaborate marketing organizations to serve an estimated 30,000 to 40,000 ultimate customers. D

Antibodies target cancer radiotherapy A strategy for directing radiation specifically by biochemical means to kill cancer cells wherever they're growing in the body is being tested in cancer patients on a limited basis at Johns Hopkins Comprehensive Cancer Center in Baltimore. The technique depends on antibodies, directed against proteins on tumor cells, to deliver highly radioactive iodine there. Patients "experience no sensations from the radiation" when it's delivered in this manner, according to Stanley E. Order, who directs the Johns Hopkins team. Thus, antibody-directed radiation therapy avoids many of the 6

C&EN Oct. 13, 1980

side effects associated with conventional radiotherapy. So far, the new technique has been used only on patients whose tumors could not be removed surgically. For example, patients with inoperable liver cancer have survived as long as two years when they were expected to live for only three to seven months. Extended life spans also are accompanied by reductions in the relative size of tumors, the Johns Hopkins team notes. Patients whose cancer has not reached such an advanced stage have not undergone this type of treatment, for several reasons. Principal among them is that high doses of radiation—up to 150 millicuries—are injected into patients. This considerably complicates ordinary clinical procedures, making it necessary for hospital staff members to quarantine these temporarily highly radioactive patients.

This strategy for therapy exploits the specificity of antibody proteins for directing the powerful killing activity of radiation. Antibody proteins used so far have been obtained from rabbits, primed by injection with proteins from the tumors of patients. Head of the Hopkins team Order anticipates that improved purification procedures soon will provide more potent antibodies that, in turn, can deliver higher doses of radiation to tumor cells. Use of a purer form of antibody would permit intensifying the dose without adding more to the total burden of radiation to which the body is exposed, he notes. In a variation of this strategy, scientists at Wistar Institute in Philadelphia and the University of California, Los Angeles, recently used antibodies carrying chemical toxins (instead of radioactive iodine) to kill cancer cells in vitro (C&EN, Sept. 29, page 31). D

U.S. chemical firms to k ep cost advantage Although many U.S. chemical producers doubt that their notable hydrocarbon raw material cost advantage over foreign producers of the past few years will hold up after completion of federal decontrol of hydrocarbon prices in October 1981, a leading consultant thinks otherwise. In a wide-ranging study of the worldwide chemical industry in the early 1980's, Arthur D. Little Inc. of Cambridge, Mass., concludes that U.S. companies will retain their hydrocarbon cost advantage through this period. That means a continuation of U.S. producers' enhanced competitive position in export markets.'However, ADL cautions that relatively few companies will have the resources and skills needed to compete worldwide as the chemical industry continues to mature and become more international in scope. All but the largest companies must concentrate their efforts on specific product and geographic market segments to prosper in the decade ahead. ADL's overall picture for U.S. and non-U.S. chemical companies in the early 1980's is one of somewhat slower growth than in the already slowed 1970's. It puts the industry's annual growth rate at an average of one and a half times growth in gross national product. In commodity chemicals, ADL says that U.S. producers will benefit from the upcoming cyclical rebound after the recession, favorable plant capacity, raw material availability, and international trade conditions. The

study predicts that both commodity sales growth and after-tax return on investment will average about 15% per year through 1985. This sort of sales growth will bring pressure for more production capacity. But trouble could be ahead in the mid-1980's leading to a cyclical dip in commodity profits. The reason will be new capacity coming on stream during a general economic downswing similar to what happened in 1970, 1975, and this year. Outside the U.S., ADL expects rapid commodity chemical growth from a relatively small base in newly industrialized countries in Latin America, Asia, and the Middle East. Among industrialized areas, ADL predicts that U.S. commodity growth probably will parallel that of Europe while trailing growth in Japan. In specialty chemicals, the report projects after-tax return on equity at an annual average of 17% through 1985, higher than in the more cyclical commodities. This favorable comparison will help extend a high level of acquisition activity in chemical specialties. ADL expects European and Japanese companies to be particularly active in the takeover scene. Such heightened interest by major chemical companies in specialties will lead to more intense competition in this area. Still, ADL concludes that there will continue to be significant opportunities worldwide for new entrants. Particular specialties singled out by ADL as among the most attractive are lube oil and fuel additives, and oil field chemicals. D