Patented Oct 2, 1945 2,385,853 UNITED STATES PATENT OFFICE 2,385,853 PROCESSEs FoE PRODUCING HoRMoNEs Stockton G. Turnbul, Jr., Wilmington, Del, as sinor to E. I. du Pont de Nemours & Company, Wilmington, Del, a corporation of Delaware NoDrawin. Application August 17, 1943, Serial No. 498,984 2 Claims. (CL 260-619) This invention relates to new and inexpensive 150-watt projector flood lamp, a solution of 9.6 processes for producing hormones and in partica parts of bromine in 50 parts by volume of carbon ular synthetic estrogens, tetrachloride was added dropwise over 3.5 hours It is an object of this invention to produce hors in Such a Way that the heat evolved in the reac mones by means of a new and relatively inexpen tion maintained the reaction mixture at a gentle sive process. A further object is to produce syn reflux, Hydrogen bromide was evolved. The thetic estrogens by a simple and easily controlled pale yellow solution was then cooled and ex process. A still further object is to produce hor tracted twice with 5% sodium sulfite and was mones by a process which avoids many of the dis then dried over sodium sulfate and concentrated advantages of the prior art processes. Addi 10 under vacuum. The 20 parts of oil and crystals . tional objects will become apparent from a con thus obtained was slurried in cold acetone which sideration of the following description and gave 7 parts of white crystals. Upon recrystal claims. lization from ethyl acetate the 3,4-di-Cp-anisyl)r These objects are attained in accordance with 3,4-dibromohexane was obtained as white crys the hereinafter described invention wherein a tals tnat darkened sligntly at 115° C. and melted compound having the following general formula 5 sharply with decomposition at 119-121 C. With is sected to the addition of halogen-removing the evolution of hydrogen bromide and the for aeats. nation of a blue-green liquid. CH Calc, for Cao HaO.Bra: C, 52.62; H, 5.30; Br, 35.1 20 Found: C, 52.57; H, 5.17; Br, 35.2 R0-{CX----C)-or EXAMPLE 2 wherein R is hydrogen, an alkyl or an acyl group, 3,4-di-(p-ranisal) 3-dibromioheacane and X is a halogen atom. In a more restricted sense this invention is concerned with the treat To 8 parts of the dimethyl ether of trans ment with halogen-removing agents of a com 25 dietnyl stubestrol in 100 parts by volume of car pound having the above general formula wherein bon busulfide there was added dropwise at 0-5 C. R represents either an alkyl or an acy radical. over 4.5 hours a solution of 4.52 parts of bromine In a still more restricted sense this invention in 45.2 parts by volume of carbon bisulfide. The pertains to the dehalogenation of compounds of 2.8 parts of 3,4-di-(p-anisyl)-3,4-dibromohexane the aforesaid type. In a still more restricted 30 that crystallized had the same behavior on melt sense this invention is concerned with the de ing as that obtained by the method of Example hydrohalogenation of the foregoing and related 1. By concentration of the carbon bisulfide so compounds. In its preferred embodiment this lution, another 3.9 parts of this product was iso invention is directed to the production of a lated. 3,4-discip-hydroxy-phenyl)-hexadiene-24 by de ExAMPLE 3. hydrobrominating with a hydrogen bromide ac Diacetate of 3,4-di-(p-hydroacphenyl)-3,4-di ceptor a compound having the following general bromioheacane formula: To a solution of 7.04 parts of diethyl stilbestrol His Br diacetate in 150 parts by volume of carbon bit sulfide there was added dropwise With agitation Ro-C)---KC)-or at 25 C. over 3.5 hours a solution of 3.36 parts wherein R is hydrogen, an alkyl or an acyl group. of bromine in 20 parts by volume of carbon This invention is also concerned with new com 45 bisulfide. The bromine was only slowly absorbed pounds and the employment of these and related and consequently was added quite slowly. After products in the production of pharmaceutical standing overnight, some crystals had deposited. materials, All was dissolved in chloroform and the solvent The invention may be more readily understood mixture was removed under vacuo. The crystal by a consideration of the following illustrative 50 line residue was treated with alcohol, which gave examples wherein the quantitles are stated in the crude 3,4-die (p-hydroxyphenyl)-3,4-dibror parts by weight. Inohexane diacetate. Upon purification with ethyl acetate the pure product was obtained. It ExAPLE 1. melted sharply at 156-156.5 C, with the evolu 3,4-di-(p-anisyl)-3,4-dibromoheane tion of gas. A solution of 8.9 parts of hexestrol dimethyl ether in 100 parts by volume of carbon tetra Calc. for Ca2H24O4Br2: C, 51,55; H, 4.73; Br, 31.20 chloride was heated to 65 C. and approximately Found: C, 51.60; H, 4.76; Br, 31.42 0.025 part of benzoyl peroxide was added. While Bromination in glacial acetic acid gave the irradiating the solution with actinic light from a 60 same product. The rate of bromination in acetic 2 2,885,858 - acid was more rapid than in carbon bisulfide, but tained by crystallization from alcohol, and the the product was more stable in the latter solvent. caustic washes on acidification, extraction into Bromination of hexestrol diacetate in carbon ether and crystallization from benzene and 50% tetrachloride under the conditions of Example 1 ethanol gave hexestrol of melting point 184.5- gave the same diacetate of 3,4-di-(p-hydroxy 1870 C. phenyl)-3,4-dibromohexane. 5 ExAMPLE 8 EXAMPLE 4 When the process of Example 1 was repeated using a trace of iodine as a catalyst, rather than To 0.50' part of the dibromo product of Example . benzoyl peroxide, there. Was formed a new 3 in 50 parts of alcohol there was added a solu 0. dibromo-3,4-di-(p-anisyl)-hexane in which the tion of 2 parts of potassium iodide in 50 parts of bromine atoms are attached to the benzene alcohol. The solution was heated at reflux for an nuclei. In contrast to the product of Example 1, hour, and was then poured into water. The pro this material melted clear without signs of de duct was extracted into ether which was washed composition at i79-181 C., indicating the two with dilute Na2SO3 and water. After drying and 5 concentration, 0.16 part of crystalline product bromine atoms to be firmly bound in the benzene was obtained from alcohol. After two recrystal nuclei. lizations from alcohol, it melted at 117-119 C. Calc. for CaoH24O2Bra: Br, 35.1 The melting point when mixed with authentic Found: Br, 33.4 transdiethyl stilbestrol diacetate of melting point 20 ExAMPLE 9 121-23° C. Was 107-108 C. When the 3,4-di-(p-anisyl)-3,4-dibromohexane Calc. for 3,4-di-(p-hydroxyphenyl)-hexadiene of Example 1 was treated with potassium iodide 2,4-diacetate: C, 75.4; H, 6.3 in acetone or with zinc dust in alcohol, acetic Found: C, 75.2; H, 6.5 acid, carbon tetrachloride or benzene, there was The mother liquors from the crystallizations 25 apparently formed in all cases hexestrol dimethyl above were joined and freed of solvent. After ether... No explanation for this is readily appar saponification by heating at reflux in 5% meth ent. Evidently reduction in addition to de anolic potassium hydroxide for 0.5 hour, there bromination occurred. was obtained 0.08 part of white crystals that 30 It is to be understood that the above examples melted at 220-223° C. when crystallized from are representative merely of a few of the many ethylene dichloride. It corresponds to the 3,4- embodiments of this invention. They may be di-(p-hydroxy-phenyl)-hexadiene-2,4 described varied widely with respect to the individual re by Dodds as melting at 227-228 C. The latter is actants, the amounts thereof and the conditions an estrogen comparable in activity to diethyl 35 of reaction without departing from the scope stilbestrol. hereof. EXAMPLE: 5 The compounds which are subjected to treat When 1 part of the dibromo compound of Ex ment with halogen-removing agents, as previously , ample 3 was heated with 40 parts by volume of mentioned, conform to the following general dry pyridine under nitrogen, there was obtained 40 formula: the diacetate of 3,4-di-(p-hydroxyphenyl)-hex adiene-2,4 described in Example 4. - Y" i? Y-or ExAMPLE 6 no-(D-KD 2.5 parts of the Crystalline 3,4-di-(p-hydroxy 45 wherein R is hydrogen, an alkyl or an acyl group, phenyl)-3,4-dibromohexane diacetate obtained and X is a halogen atom. In this formula R may in Example 3 was agitated in a solution of 100 represent practically any alkyl, aralkyl or acyl parts by volume of alcohol with 10 parts of zinc radical, among which may be mentioned ethyl, dust at 25° C. for 20 hours. After filtration from propyl, isopropyl, butyl, propionate, palmitate, Zinc dust and concentration, a green oil was ob 50 laurate, stearate, benzoate, etc. tained that was crystallized from benzene to yield Numerous halogen-removing agents are known a compound of melting point:141-142 C. sapon and described in the literature, and it is contem ification of the acetate groups had occurred. plated that any of them may be used in practic Upon esterification with acetic anhydride in ing this invention. For purposes of illustration pyridine the cisdiethyl stilbestrol diacetate was 55 a few of the many dehalogenating and dehydro apparently obtained. The compound of M. P. halogenating agents coming within this category 141-142 C. is apparently the mixture first re may be mentioned. Dehalogenating agents are, ported by Dodds (Proc. Roy. Soc, 127B, 153 in general, metals in solvents. For instance, (1939), who thought it to be an isomer of still metals such as sodium, calcium, and the like, bestrol. It was later shown by Walton and 60 may be used. Dehydrohalogenating agents or Brownlee Nature, 151, 306 (1943) to be a hydrogen halide acceptors are, for example, in eutectic mixture containing 60% psi-stilbestrol organic bases, inorganic Salts, and organic amines, and 40% stilbestrol. such as, for instance, metallic hydroxides, retal lic oxides, metallic carbonates, pyridine, piperi- - ExAP dine, trimethyl ammonium hydroxide, andline, The mother liquor from the isolation of the dimethyl aniline, quinoline, metallic salts of material of melting point 156-156.5° C. described organic acids, such as sodium acetate, lead ace in Example 3 was concentrated to obtain the steroisomeric 3,4-di-(p-hydroxyphenyl)-3,4-di tate, etc. w bromohexane diacetate, an oil. This was agitated 70 By means of the present invention a new and in 100 parts of alcohol with 10 g. of zinc dust for relatively inexpensive process for obtaining hor 20 hours. After filtration and concentration, the mones has been made available. This process is oil obtained was dissolved in ether, which was of particular value in the production of synthetic extracted several times with dilute caustic. From estrogens, such as 3,4-di-(p-hydroxyphenyl)- 5 hexadiene-24 and its diacetate. Likewise, syne - the ether solution hexestrol diacetate was obn 2,885,858 3. thetic estrogens of the same order of activity as of 3,4-di-(p-hydroxyphenyl)-3,4-dibromohexane. diethyl stilbestrol have been attained. with a solution of potassium iodide in alcohol, and As many widely different embodiments of this then saponifying the resulting product. invention may be made without departing from 2. A process which comprises heating the di the Spirit and scope thereof, it is to be undero acetate of 3,4 - di - (p-hydroxyphenyl)-3,4-di stood that the invention is not limited to the bromohexane with a solution of potassium iodide Specific embodiments thereof except as defined in in alcohol, and then 8aponifying the resulting the appended claims. product. s I claim: 1. A process which comprises heating a diester 10 STOCKTON G, TURNBULL, Jr.