Patented Nov. 5, 1946 2,410,463 UNITED STATES PATENT OFFICE 2,410,463 METHODS OF- PREPARING ‘STILBENE DERIVATIVES Otto Schwarzkopf, New York, N. Y., assignor to Burton T. Bush, Incorporated, Delawanna, N. .L, a corporation of New Jersey No Drawing.v Application November 19, 1943, Serial No. 510,976 5 Claims. (Cl. 260-613) 1 2 The invention relates to the preparation of stil~ bene derivatives and particularly hydroxy-stiL. bene compounds of the general formula: dialkyl-stilbene within Formula I above, the hy droxy radicals being in the para positions. no-canl-c=c~c?nl—on R1 R2 (I) The starting material for this invention may be any substance within Formula II. R1, R2, R3, and R4 in all cases represent the same or different» alkyl radicals. Such formula, II, shows that two wherein R1 and R2 are identical or different alkyl radicals, preferably of four or less carbon atoms, diastereo-isomeric racemates may exist, but for this invention itis unimportant which of the two and the hydroxyl radicals are in any positions on is present or whether both are present. ' the benzene nuclei, but preferably the para posi 10 Solutions, containing one or both of such race tion, and including both the cis and the trans mates, have also been used by Braker (U. S._Pat isomers with regard to the positions of the radi ent No. 2,252,696) in the same way as Dodds, also cals R1 and R2, this patent being a continuation by Fieser (U. S. Patent No. 2,248,019). in-part of my application, Serial No. 424,474, ?led Said starting substance may be obtained by the December 26, 1941. ‘ These substances are important because of their estrogenic activity, particularly the highly 15 Dodds process, or by the action of a Grignard reagent, for example methyl-magnesium-iodide, ethyl-magnesium-bromide, etc., upon the carbi-v active form thereof which is trans-4,4'-dihy nol such as obtained by Dodds (whereby, the droxy, alpha,alpha'-diethyl—stilbene, and to Grignard reagent reacts with the hydroxy group which ‘this invention more specially relates. 20 forming methane, ethane, etc.) or it may be pre They are known substances, described by Dodds pared according to said application, Serial No. (Nature, vol. 141, page 248 (1938) and Proc. Royal 424,474, by the action of a Grignard reagent, Society, vol. 127, page 140 (1939)), but the proc such as esses by which they have heretofore been made are expensive to practice and the yields are not 25 high. By this invention these products are more economically obtained by a process which avoids upon a ketonic compound Rs0-—CeH4—CO—Rz. the successive steps of hydrolysis and dehydra- ' In all cases the structural forms of the reagents tion necessary in prior proposals, and yields the selected to make the starting material are prefer more desirable trans isomer in predominating 30 ably such as have their alkoxy radicals in para ratio. ' positions, thereby producing a starting substance, Referring to the Dodds’_ process, the starting Within Formula II, in which such radicals are material was a. ketone of the formula: similarly located and a, ?nal product in which the hydroxy radicals also occupy the para positions, 35 which isdesired. , RI ~ ' Broadly stated the new process comprehends and by reaction with a Grignard reagent the treatment of solutions containing any one or (RzMgHal) was converted to an oxymagnesium more of the-starting substances included within halide compound, of the general formula Formula II above with one or more members of 40 the group consisting of acid halides and» acid anhydrides, organic or inorganic, and then de alkylating the product to substitute hydroxyl for (II) which was hydrolized to a carbinol, of the gen eral formula - Among the inorganic acid halides found’most , practical for the new process are phosphorus tri OH chloride, phosphorus oxychloride, phosphorus tribromide, pentachloride, pentabromide, sul 50 furyl chloride, thionylchloride, etc.; among the R40—C5H4—CH—-b-CaH4-O R3 1 2 and then dehydrated to a dialkoxy-dialkyl-stil bene, viz: ' the alkoxy groups, as by means of an alcoholic solution of an alkali metal hydroxide, as herein 45 explained, or otherwise. " R40—C6H4—~C(R1) =c<Ri> —CsI-I4—OR3 ‘ inorganic acid anhydrides are phosphorus pent oxide, sulfur trioxide, etc. On the organic side, among the acid halides, are acetyl chloride, stearyl chloride, benzoyl chloride, propionyl chlo which was dealkylated to form a’ dihydroxy- 5s ride, and the like, and among the organic acid 3 4 anhydrides, are propionic anhydride, acetic an hydride, phthalio anhydride, etc. I am aware that acid halides as well as acid anhydrides have been used in the prior art proc esses, but they were there used only for dehy drating carbinols and not for'direct conversion (without hydrolysis and subsequent dehydration) of any such oxymagnesium halide compound as is represented by Formula II above. ' It can be assumed that the primary result of ' the reaction of the selected agent on a substance of Formula II is the formation of an ester of the formula 220 cc. This is a solution of an oxymagnesium halide compound within Formula II, being ‘ wherein Ac is the radical of the acid derivative employed. . temperature between 0° C. and 35° C. to a Gris? nard reagent prepared in known way from 3.5 g. magnesium covered with 70 cc. of ether and 15.6 gr. of ethyl bromide (or corresponding amount of other halide) dissolved in 90 cc. of ether. The solution was allowed to stand over night and then decanted from the unreacted magnesium. The volume was then brought to ' These esters are transitory and decompose im mediately to yield the stilbene derivative v"To 220 cc. of a solution prepared as above there was added at room temperature a solution of 11 g. phosphorus oxychloride, POC13, in 25 cc. ether. The mixture remained over night and the ether was then distilled on and after standing for a day at room temperature, 90-100 cc. of ethanol was added while stirring the batch. After cool _ If organic acid halides are used, it is possible ing, trans-4,4’—dimethoxy-alpha,alpha’-diethyl under vappropriate conditions-such as low re stilbene (21-25 g.) crystallized and was ?ltered, action temperature, use of equimolecular quan washed and dried (yield ‘72%-86%) melting titles of the acid halide and short reaction time, point 122° C. The dealkylation was made by to isolate these esters from the reaction mixture heating this substance with a solution of KOH (which in any event will contain some of the (41-50 g.) in diethylene glycol (180-220 g.) at compound of Formula IV). They can be subse 30 180-215” C. for twenty hours atmospheric pres quently converted, as intermediates, to the stil sure. Before heating the air was displaced by bene derivative (IV) by different ways, accord nitrogen. After the dealkylation was completed, ing to the stability of the particular ester. Some of_ them, by simply standing at room temperature crude trans-4,4’ - dihydroxy - a1pha,alpha’ - di ethylstilbene was precipitated with HCl (150 cc. will be split and others must be heated to tem 35 conc. I-ICl diluted With 150 cc. H2O). The pre peratures between ISO-200° C., or be distilled at cipitate was ?ltered, redissolved in a solution of this temperature, to yield the stilbene derivative. 20 g. KOH in 100 cc. H20 which solution was ?l The isolation of these intermediates and their tered and the substance was again precipitated subsequent conversion to the stilbene is included with HCl as before. The material was then dis in this invention although the direct conversion 40 solved in ether, washed with sodium bicarbonate is preferred and is generally su?’iciently accom (saturated solution), the other solution was plished ‘by using moderate temperature and some dried, the ether distilled OE and the residue re excess, say 30% of the acid halide or the anhy . crystallized from 5 times its weight of 50% eth dride, disposing of the excess afterwards by anol. 16-17 g. pure trans-4,4'-dihydroxy,alpha, treatment with ethanol, for example. al'pha'-diethylsti1behe (M. P. 169-171° C.) were The alkoxy substance of Formula IV is next thus obtained, yield 80 %. dealkylated to yield the product dihydroxy-di In. another case trans-4,4’dimethoxy,alpha alkyl-stilbene of Formula I, and this is preferably alpha'-diethylstilbene, prepared as above (29.6 done by reacting it with a solution of alkali g. ) was added to a solution of 60 g. KOH in 240 metal hydroxide in one of the polyhydric also~ cc. of ethylene glycol and heated to 180-2150 C. 50 hols at a temperature between 180° and. 250° C. for 20 hours in the protection of nitrogen. After and at atmospheric pressure, and then liberating cooling, the solution was acidi?ed with 200 cc. the hydroxy-compound from the alkaline solu of hydrochloric acid diluted with 200 cc. of water. tion by treatment ‘with any acid stronger than Trans-44' - dihydroxy,alpha,alpha’ - diethylstil the hydroXy-compound, e. g. HCl, vH2804, CO2 bene precipitated and was ?ltered, redissolved etc. The polyhydric alcohols suitable for this 55 and again ?ltered and 18-20 grams were ?nally purpose are those in which the alkali metal hy crystallized from ethylene dichloride (M P. droxide is soluble either at room or elevated tema 167-169“ 0.). perature and which have boiling points above Example 2 150° C. and preferably above; 180° 0., for ex— ample, ethylene glycol, diethylene glycol, propyl ene glycol, glycerol.v Such alkaline dealkylation is equally effective whether the alkoxy group occurs in only one or both sides of theformula and it is also possible to obtain dealkylation of only one of the two alkoxy groups, which can be done by simply I terminating the treatment at the appropriate point, as indicated by test of samples. In further explanation of the invention, the following illustrative examples are given: To prepare the starting material used in the following examples, 28.4 g. ethyl de'soxyanisoin <oH3o-o@Hl—co-<:H(c2H51) -——C6H4-——OCH3) To 220 cc. of the solution as above, there were added 19 g. of p-nitro benzoyl chloride at room temperature. The mixture stood for twenty-four hours, andwas then poured into 100 cc. of cold water. The water was extracted with ether, and 65 the ether washed with sodium carbonate and wa ter. The solution was then dried, the ether re moved, the, residue crystallized from ethanol yielding the ester,’ p-nitrobenzoate' of 3,4-di ,anisyl-hexane-3-ol, of melting point 122‘0 C. which is convertible by heating into dimethoxy diethylstilbene, as above pointed out. Example 3 To 220 cc. of the solution as above, there was dissolved in 50 cc. of ethyl ether was added at a 75 added dropwise a solution of 18 g. sulfuryl chlo 3144.02.46? ride dissolved in 100 cc. of ;ether. The mixture stood over night at room temperature. Then the ether was distilled off and the residue stood for one day. Then 120 cc. of ethanol were added with stirring until the mass cooled'to room tem-_ perature. Trans - 4,4’ 4 dimethoxy,alpha,alpha’ diethylstilbene crystallized and was ?ltered, and ?nally dried (yield 15 g._, M. P. 122-4° C., 50%) being convertible to trans-4,4’ dihydroxy,alpha,i alpha-diethylstilbene by dealkylation as before. 10 ' ' Example-4 ' ' , ' 6 g.’ of trans-4,4’-dimethoxyealpha,alpha’-dieth£ 'ylstilb'ene’ crystallized out. After. evaporating the alcohol, the liquid ‘ residue contained essentially the acetate of 3,4-dianisyl-hexane-3-ol. This was converted into trans-4,4’-dimethoxy-alpha, alpha'-diethylstilbene by prolonged standing, also by distillation in vacuo, and thereafter de methylated. In a similar way other esters, stearates, for example, can be formed and then converted into'the desired stilbene derivative. ' From the above examples it'will be apparent that the members of the group referred to are effective reagents for producing the unsaturated To 220 cc. of the solution as above was added at stilbene form from a starting material of the room temperature dropwise a solution of 16 g. acetyl chloride in 50 cc. of ether. The mixture 15 kind mentioned, and that they tend to yield the trans isomer in preference to the other. The stood for 4 days at the same temperature. Then reaction is found to be indifferent to the par the ether was distilled off; the residue kept for ticular positions on'the benzene nuclei of the 1 day. Then 120 cc. of ethanol were added. methoxy (or alkoxy) groups in the starting ma stilbene crystallized (yield 21 g., M. P. 122-4° C‘. 20. terial, and as might be expected, the original position persists through to the stilbene product. 72%) and was dealkylated and worked up as de Also, and as the case with other stilbene processes scribed above. ’ the reaction pattern is the same regardless of the ‘Example 5 identity of the alkyl groups (R1, R2‘, R3, and R4) , To 220 cc. of the above solution was added the‘ same" or different.’ Thus, 4,4’ dropwise a solution of 20 g. of benzoyl chloride 25 whether dimethoxy-alpha,alpha"-dimethylstilbene (M. P. (CeHsCOC'l) in 100 cc. of ether. After standing 128° C.) can be produced according to this inven Trans - 4,4’ - dimethoxy - alpha,alpha' - diethyl for 1 hour at room temperature, the ether was distilled o?. The residue stood over night, then 100 cc. of ethanol were added. Trans-4,4’-di— methoxy - alpha,alpha’-diethylstilbene crystal lized (yield 21 g., M. P. 122~3° C., ‘72%) and was dealkylated and worked up as described above. Example 6 tion from a solution containing the homolog prepared by the reaction of methyl magnesium iodide and methyl desoxyanisoin, to be then de methylated as above described to the correspond ing dihydroxy compound (M.YP. 195° 0.); and 4,4’-dimethoxy - alpha - methyl,alpha’-ethylstil bene (B. P. 160° C./0.1 mm.) can be produced To 220 cc. of the above solution was added a 35 from the homolog prepared from ethyl magne sium iodide and methyl desoxyanisoin, and other solution of 24 g. propionic anhydride in 200 cc. alkyl radicals such as propyl-, isopropyl, butyl, xylene, at room temperature. The ether was dis isobutyl, etc. can be introduced in the side chain tilled off until the boiling point rose to 130° G. in positions R1, R2 in the stilbene derivative if Then the liquid was re?uxed for 1 hour. Then the xylene and the propionic acid formed were 40 that should be desired, or in the positions R3 distilled off. To the residue was added 100 cc. of ethanol, and trans-4,4'-dimethoxy-alpha,alpha’ diethylstilbene was crystallized (M. P. 121-4° C.) and was dealkylated as before. and R4. ’ I claim as my invention: 1. The process for preparing the trans-com pound having the structural formula: Example 7 To 25 g. of P205 with 300 cc. of xylene, there was added 220 cc. of the above solution. The ether was distilled off and suspension heated to 130° C. under vigorous stirring for 4 hours. Then the xylene was distilled off and the residue stood over night. 100 cc. of ethanol were then added , and after cooling trans-4,4’-dimethoxy-alpha, CHsO which comprises mixing the compound having the structural formula: . 0 M gHalogen H l alpha’-diethylstilbene crystallized and was ?l OCH; tered and treated as said before (M. P. 122-4° C.) . Example 8 To 220 g. of the solution as above was added a solution of 17 g. of thionyl chloride in 100 cc. of - with a compound selected from‘ the group con sisting of acid halides and acid anhydrides; and isolating the said trans-compound thus produced. ether. It stood over night, the ether was distilled 60 2. The process for preparing the trans-com o? and to the residue were added immediately pound having the structural formula: 100 cc. of ethanol. Trans-4,4’-dimethoxy,alpha, alpha'-diethylstilbene was obtained (M. P. 122-3° C.) . Example 9 CzHn OMOaEQOOH. which comprises mixing the compound having To 220 cc. of the above solution there was the structural formula: ‘ added dropwise in 2 hours a solution of 11 g. of OMgBr acetyl chloride in 100 cc. of ether at room tem perature. After 30 min. standing, the mass was poured into 200 cc. of a 5% solution of sodium bicarbonate. The ether layer was separated, C2Hs 02115 washed with water and dried over sodium sul with a compound selected from the group con fate. The ether was then distilled off leaving a residue to which was added 100 cc. of ethanol, 4 75 sisting of acid halides and acid anhydrides; and i‘ i isolating the said trans-compound thus produced. , 8 _ which comprises mixing the compound having 3. The process for preparing the 'trans-com-i the structural formula: pound having-the structural formula: OMgBr III (L y . C1115 C2115 with phosphorus oxychloride; and isolating the said trans-compound thus produced. which comprises mixing the eompoundhaving the structural formula: ' . 5. The process for preparing the trans-com pound having the structural formula: OCH: 15 which comprises mixing the compound having the structural formula: with acetyl chloride; and isolating the said trans compound thus produced.v 51,, The process for preparing the pound having the structural‘ tormula:trans-com5 20 CaHa C 2H5 I? ' 0M Br i g (llsHa (12H; with sulfuryl chloride; and isolating the said trans-compound thus produced. 25 OTTO SCHWARZKQPF.