Patented Mar. 15, 1949 2.464,203 UNITED STATES PATENT OFFICE 2,464,203 MANUEFACTURE OF DENOESTROL Walace Fraak Short and Gordon van Hobday, Nottingham, England, assignors to Boots Pure Frug Company inited, Nottinghain, England, a coapaay of Great Britain No Drawing. Application May 10, 1944, Serial No. 534,988. In Great Britain May 21, 1943 18 Claims. (C. 260-470) 2 This invention relates to improved processes for an amalgan in an aqueous alkaline solution. the manufacture of y8-bis-(4-hydroxyphenyl)- Preferred anaigans are sodium amalgam and hexane-y&-diol and of the dihydroxy compound potassium amalgam but other amalgams may be ?y8-bis-4-hydroxyphenyl-A56-hexadiene obtained used. from it by dehydration. 5 When the reduction is effected with the use of The latter (known as “Dienoestrol, B. M. J. an analgarin in an alkaline Solution the isolation 1942, 2, page 256) is of importance because it of the pinacol formed may be effected by known possesses oestrogenic propertie5. methods of separation but it is preferred to use It has previously been proposed to reduce the acylation in ethod previously described. p-hydroxypropiophenone to the pinacol, y?-bis O A further object of the invention is to provide (4-hydroxyphenyl)-hexane-yô-diol with the use an improved process for the production of dienoes of aluminium amalgam in moist ether (Dodds, trol from the aforesaid pinacol. Golberg, Lawson and Robinson. Proc. Roy. Hitherto, the pinaco) has been converted into Soc., 1939, B. vol. 127, 140-167) and an electro dienoestrol by treatment with a mixture of acetyl lytic reduction process has also been described in 15 chloride and acetic anhydride (Dodds et al. loc, British patent specification No. 523,515. The cit.), which, while removing the elements of water, above reduction processes are troublesome to produced the diacetyl derivative of dienoestrol carry out and the isolation of the pinaco is Which was then hydrolysed. difficult because in all reduction processes of this According to this part of the invention, the nature the desired pinacol is accompanied by 20 phenolic hydroxy groups of the pinacol are acyl isoners and by the Secondary alcohol correspond ated by means of an aromatic acylating agent, ing to the ketone and possibly by other by-prod the acyl derivative is dehydrated by treatment lucts and separation of the desired pinacol from with a mixture of an aliphatic acid chloride and the accompanying products is slow and incom anhydride, preferably acetyl chloride and acetic plete. 25 anhydride, and the dehydrated product is hydro An object of the present invention is therefore, lysed to yield dienoestrol. firstly, to provide an improved process whereby AS compared with the direct dehydration of the the isolation of the pinacol may be effected more pinacol and separation of dienoestrol, the process easily and a greater yield obtained than with the has the advantages that the dehydration proceeds known processes, and secondly to provide an in 30 more Smoothly, and the diacyl compound, for proved reduction process which is more easily example the dibenzoate, can be isolated more carried out than the processes referred to and conveniently and completely. The subsequent may be followed either by the isolation procers hydrolysis of the diacyl compound and crystal of the present invention or by any other suitable lisation of diencestrol present no difficulties and process of isolation. are carried out almost quantitatively. According to the first part of the invention, An additional advantage of the process also is the separation of the aforesaid pinacol obtained that the crude or only partially purified diacyl by reducing p-hydroxypropiophenone is effected pinacol which is obtained by acylating the mix by acylation of the phenolic hydroxy groups by ture of products obtained in the reduction of means of an aromatic acylating agent, for ex 40 4-hydroxypropiophenone with an alkali metal or ample benzoyl chloride or toluene-p-Sulphon alkaline earth metal amalgam in aqueous alkaline chloride, followed by the separation and purifica Solution can, in accordance also with the inven tion of the 4:4'-acylated compound. The diacyl tion, be used directly for dehydration. compound may then be hydrolysed to yield the Preferably, in carrying out the process, the 45 pinacol obtained as the result of the reduction of required pinacol, or be used in further manufac a 4-hydroxypropiophenone with an alkali metal ture. It has in fact been found that diacy de or alkaline earth metal analgam in aqueous rivatives of the above pinacol lose the elements alkaline solution is converted into it diacyl de of two molecules of Water when treated with rivative Without first being separated from the dehydrating agents and are converted into the accompanying by-products and the acyl deriva acyl derivatives of dienoestrol. tive is then dehydrated, which has the double The process has the advantage that the acylated advantage that the separation of the diacyl com compound crystallises quickly and almost com pound from the accompanying acylated products pletely out of the mixture of acyl derivatives of the reduction process can be carried out more formed, and upon hydrolysis the pinacol sepa 5 5 easily and more completely than the separation rates very rapidly in a crystalline and practically of the pinacol from the other reduction products pure condition. themselves and that the dehydration of the diacyl According to the second part of the invention, compound obtained proceeds very Smoothly. the reduction of the p-hydroxypropiophenone to It is of course also possible, though it would the aforesaid pinacol is effected by the use of 60 not usually be advantageous, first to isolate the 2,464,208 3 4. pinacol and then to convert it into the acyl deriva a small amount of insoluble material, dienoestrol tive. The pinacol to be treated may be produced is precipitated from the alkaline solution by treat either by the reduction process previously de ment With carbon dioxide. It is filtered off, scribed or by a known reduction proceSS. washed with water and recrystallised from dilute In order that the invention may be clearly 5 alcohol after which it melts at 233-234°C. (Dodds, understood and readily carried into effect, the loc. cit, records a melting point of 227-228 C.). following examples are given: EXAMPLE 3 EXAMPLE Preparation of dienoestrol Preparation of yö-bis-(4-hydroacylphenyl)- 10 A potassium amalgam is prepared containing heacane-ya-diol 10 gms. of potassium and 400 gms. of mercury A sodium amalgam is prepared containing 6 and covered with a solution of 20 gms. of p-hy gms. of sodium and 400 g. of mercury. The droxypropiophenone in a mixture of 30 mls. amalgam is covered with a solution of 20 gms. of 5-N-potassium hydroxide and 220 mls. of water. 4-hydroxypropiophenone in a mixture of 30 mls. 15 The mixture is stirred until no further reaction of 5-N-sodium hydroxide solution and 220 mls. takes place and the dibenzoyl derivative is isolated of water and the mixture is heated to 28-30° C. as in Example 1. Dienoestrol is then produced by and stirred gently. The reduction is accom dehydration and hydrolysis as in Example 2. panied by development of heat and the tempera ture of the solution rises to 34-35° C., and then 20 EXAMPLE 4 falls slowly. After 5 hours the alkaline solution Preparation of y&-bis-(4-hydroacylphenyl)- is separated from the mercury and diluted with heacane-yô-diol 3 or 4 times its volume of water, when, in order An amalgam is made by shaking 5.6 gms. cal to form the benzoyl derivatives of the products, cium with 400 gms. of mercury for a considerable the solution is vigorously stirred, while it is being time and it is then stirred with a solution of cooled, with 20 mls. of benzoyl chloride, the solu 20 gms. of p-hydroxypropiophenone in 50 mls. tion being kept at a temperature of 15-20° C. 5-N-caustic soda and 250 mls, water during 24 When the reaction is completed, the benzoyl de hours. The mercury is then separated and the rivatives are filtered off, washed with water and 3) aqueous layer is filtered and benzoylated and the recrystallised from a mixture of benzene and crude product is recrystallised from alcohol after alcohol, when a product with a melting point of which the benzoate which has a melting point 195-215 is obtained. This product is sufficiently about 200° C. is hydrolysed in the usual manner pure, for instance, for conversion into the afore and the pinaco separated as in Example 1. said pinacol or for treatment by dehydrating agents. (When purified by Several recrystallisa 3 5 ExAMPLE 5 tions, the dibenzoate has a melting point of235 Preparation of dienoestrol C.) In order to isolate the pinacol 14.5 gms. of 20 parts of p-hydroxypropiophenone are re the benzoate are hydrolysed with alcoholic potash duced with sodium amalgam as in Example 1 and (150 gms., containing 10 gms. of the alkali) after 4. which the solution is diluted with Water and the alkaline Solution is diluted with an equal saturated with carbon dioxide. The pinacol is volume of water and shaken with 51 parts of extracted With ether and after removal of the toluene-p-suiphon-chloride at room temperature ether the residue is recrystallised from acetic for 30 hours. The product is separated from the acid. When it melts at 203-5° C. alkaline liquid by filtration and after recrystal 45 lisation from benzene the ditolueine-p-Sulphonate If the pinacol dibenzoate is to be used for con of the pinacol has a melting point of 203 C.