RESEARCH
Another Steroid Synthesis May Go Commercial Industrial feasibility of its synthesis claimed by France's Roussel-Uclaf Another total synthesis of steroids shows commercial promise, according to its developers at Roussel-Uclaf, Paris, France (C&EN, Feb. 24, page 39). So far, the synthesis has been scaled up to produce 1000-kilogram amounts of steroids. The process is an adaptation of a steroidal total synthesis worked out earlier by the Paris firm's Dr. Leon Velluz, Dr.
Gerard Nomine, Dr. J. Mathieu, and Dr. G. Armiand [Angew. Chem., 72, 725 (1960); Compt. Rend., 257, 3086 (1963)] to give the optically active isomers. Last summer, scientists at Wyeth Laboratories, Philadelphia, Pa., made public a commercially feasible total synthesis of steroids, some of which look promising in clinical trials
Roussel-Uclaf s Total Synthesis Leads Directly to 19-Nortestosterone, Estradiol Compounds £ o
Methyl-5-exe6-hepteneate
2-AlkyM,3-diexecyclopentane
(C&EN, Aug. 26, 1963, page 32). The Wyeth synthesis is based on one originated several years earlier by Dr. Herchel Smith and Dr. Gordon A. Hughes at England's Manchester University [Proc. Chem. Soc. 74, (1960); Chem. Ind. {London), 1022 ( I 9 6 0 ) ] . Dr. Smith and Dr. Hughes have since left Manchester, and are now working at Wyeth. The attraction of Dr. Velluz's total synthesis, Roussel-Uclaf says, lies in its ability to produce 19-norsteroids directly (hydrogen atom instead of an angular methyl group at the junction of the steroid molecule's A and B rings) and compounds in the estradiol series (aromatic A ring). It's among these compounds that the successful commercial oral contraceptives are found, as are some of the anabolic and
Resolved by fractional crystallization of ephedrine salts from benzene Dextrorotatory compound (less soluble) PROCESS. Top photo shows processing area used by Roussel-Uclaf for its scaled-up total synthesis of steroids; 1000-kilogram amounts of product have been made. Developers of the process (lower photo) are Dr. Gerard Nomine
tfo^c j (CH 8 CO),0
Ketonic ethylenic acid
WcHCOONa
Tricyclic hydroxydione 4-Ethylenedioxy-lmagnesium bromide, then KOH (in CHaOH), then CHsCOOH
O'
O'
M£ Additional StepiC^
Lactone
19-Nortestosterone derivatives
42
C&EN
MAR.
2,
1964
Estradiol derivatives
progestational drugs in use today, the company notes. Some 19-nor compounds made by Roussel-Uclaf's process (and the areas of biological activity, including clinical) under study are: • 17a-Ethynyl-17/?-hydroxy-estra5 (10) ,9 (11) -diene-3-one, a possible oral contraceptive. • 17a-Methyl-17/?-hydroxy-4,9,llestratriene-3-one and a trienic counterpart of 19-norprogesterone. • 130- (n-propyl) -17a-ethynyl-17/?hydroxy-4-gonen-3-one, a progestomimetic agent. Natural. All of the steroid drugs currently being sold around the world are made from naturally occurring starting materials that already contain the steroid nucleus. The various steroidal starting materials are put through a variety of transformations to the finished product. Total synthesis on a commercial scale, according to its proponents such as Wyeth and Roussel-Uclaf, could be more economical
and Dr. R. Joly (standing, left to right), and Dr. R. Boucourt, Dr. J. Warnant, and Dr. G. Amiard (seated, left to right). Not shown is Dr. Leon Velluz
than the route now being used by steroid drug makers. The compounds produced by its process, for instance, would more than compete with other such compounds on a cost per unit dose basis, Wyeth says. For a total synthesis to be commercially successful, a basic position has to be obtained in both process and products. Wyeth feels it is well on its way in these respects. Patents covering its process and products have been issued or are now pending in about 50 countries, and a new drug application covering an anabolic agent has been filed with the Food and Drug Administration. Roussel-Uclaf at this time doesn't plan to market in the U.S. any drugs that may result from its total synthesis. But the company will make the process available for licensing in this country. The Roussel-Uclaf total synthesis is being developed to an industrial process by Dr. R. Joly and Dr. J. Warnant. In the process, methyl-5-oxo-6heptenoate is condensed with a 2-alkylcyclopentanedione (such as the methyl, ethyl, or n-propyl compound) by refluxing in the presence of pyridine. Treatment with hydrochloric acid (5N) forms a double bond and hydrolyzes the ester to give a racemic diketonic ethylenic acid. Resolution of this racemic acid to its optical antipodes is done by fractional crystallization of the ephedrine salts from benzene. The dextrorotary enantiomorph is the least soluble of the salts. It corresponds to what Roussel-Uclaf terms the "natural" configuration, thus gives its process an advantage over other total syntheses, the company feels. The diketonic acid will make up the C and D rings of the eventual steroid nucleus. Next, selective and stereospecific reduction with sodium borohydride leads to a ketolic ethylenic acid. The acid is then hydrogenated over palladium (in aqueous ethanol), and the product having the trans configuration is heated in acetic anhydride in the presence of sodium acetate to produce a lactone. The lactone is condensed with a magnesium derivative of brominated ethylenedioxypentane and the condensate treated with methanolic potassium hydroxide to close the B ring. Acetic acid hydrolysis of the ketal gives a hydroxydione, which can then be easily converted to 19-norsteroid or estradiol derivatives, Roussel-Uclaf says.
&>ScbuellC°' Carl
MEW
S&S
S ^
i n
announ^
Brochure on
THIN LAYER CHROMATOGRAPHY Every chemist interested in chromatography will find this new authoritative S&S brochure on Thin Layer Chromatography valuable in his work. Advantages include superior separation of enzymes, proteins, hormones, lipids, and nucleic acids. Even materials such as hemoglobin may be separated into fractions by this method. CONTENTS: Included is a background on the benefits of ion exchange celluloses, the advantages of thin layer chromatography; the types of ion exchangers available; their uses,- prices of Selectacel® TLC Ion Exchange Celluloses; and a bibliography.
S&S TLC
Advantages: Briefly,
Selectacel TLC Ion Exchangers offer chemists two outstanding advantages over all known materials for thin layer chromatography work.
1 2
SAYINGS IN TIME. Quality control techniques result in extremely uniform particle size, outstandingly smooth TLC layers. BETTER ADHERENCE TO THE PLATE. Superior, extremely sharp separations even of closely related substances.
Selectacel Ion Exchange Celluloses are available in a complete range of types (DEAE, ECTEOLA, CM and P). Get full data. TEAR OFF
COUPON AND
MAIL TODAY!
Carl Schleicher & Schuell Co. Keene, New Hampshire-Dept. CE432 Please send free the new Selectacel brochure on Thin Layer Chromatography. Name
i| Company, • Address Zone
t City
State
Selectacel is produced by Brown Company and exclusively packaged and distributed for laboratory use by Carl Schleicher & Schuell Co.
MAR.
2, 196 4 C & E N
43
