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. version into dienoestrol, recrystallisation is not 8.5 parts of the ditoluenesulphonate are treated necessary, and it is sufficient to wash the product with a mixture of 25 parts of acetic anhydride on the filter with Water, sludge Well With 250 cc. and 25 parts of acetyl chloride. The product of cold S. W. M. and finally filter off With Suction 50 which crystallises on cooling may be recrystallised and dry in air. The crude pinacol dibenzoate is from a mixture of alcohol and benzene and the thereby obtained as a practically white, coarse dienoestrol ditoluene-p-sulphonate thus obtained powder having a melting point of 180-200° C. melts at 233 C. EXAMPLE 2 8.4 parts of the dienoestrol ditoluene-p-sul Preparation of dienoestrol 55 phonate are hydrolysed by the action of 100 parts of a ten per cent alcoholic solution of potassium In order to obtain dienoestrol, 14.6 gms. of the hydroxide. The solution is diluted with water dry 4:4'-dibenzoate of Example 1, with a melting and dienoestrol is precipitated by the addition of point of 195-215° C., or of the crude dibenzoate a small excess of dilute hydrochloric acid. with a melting point of 180-200° C., are refluxed 60 Warious modifications of the process may be with a mixture 40 mls. Of acetic anhydride and made. Thus concentration, temperatures, times 40 mls. acetylchloride by heating in an oil-bath of reaction and the nature of the acylating agent at about 90° C. for 6 hours after which the bath and dehydrating agent may be varied as may be temperature is increased to 120° C. and heating desirable in any particular case. continued for a further 18 hours, after which time 65 We cairn: the evolution of hydrogen chloride practically 1. A process for the manufacture of the pinacol ceases. The mixture is allowed to cool for sev nyà-bis-(4-hydroxyphenyl)-hexane-y-diol which eral hours and the crystals which separate are Comprises reducing p-hydroxypropiophenone with filtered off and recrystallised from an alcohol an amalgam of a metal of the group consisting of benzene mixture when the product melts at 70 alkali and alkaline earth metals in an aqueous 210°-222° C. This product is converted into alkaline solution, acylating the phenolic hydroxy dienoestrol by adding 10.8 gms. of it to 100 mls. of groups of the reduction product with an aromatic 10% (W/W) alcoholic potassium hydroxide solu acylating agent, recovering the acylated material tion and then refluxing during 1 hour. After from the reaction mixture and hydrolysing it to dilution. With 200 ml. of water and filtration from 5 yield the aforesaid pinacol. 2,464,208 5 6 2. In a process for the manufacture of dieno and alkaline earth metals in an aqueous alkaline estrol, the steps which comprise dehydrating, by Solution, benzoylating the phenolic hydroxy groups treatment with a mixture of an aliphatic acid of the reduction product, recovering the benzoyl chloride and anhydride, the pinacol y&-bis-(4- ated product from the reaction mixture dehydrat hydroxyphenyl)-hexane-ya-diol in which the ing the benzoylated material by treatment with a phenolic hydroxy groups have been acylated with mixture of an aliphatic acid chloride and anhy an aromatic acylating agent, and recovering the dride, recovering the dehydrated product from the dehydrated product from the reaction mixture. reaction mixture and hydrolysing the dehydrated 3. A process for the manufacturing of dieno benzoylated product. estrol, which comprises the steps of reducing 10. In a process for the manufacture of dieno p-hydroxypropiophenone to the corresponding estrol, the steps which comprise dehydrating by pinacol with an amalgam of a metal of the group treatment with a mixture of acetyl chloride and consisting of alkali and alkaline earth metals in acetic anhydride the pinacol ya-bis-(4-hydroxy an aqueous alkaline solution, acylating the phe phenyl)-hexane-yô-diol in which the phenolic nolic hydroxy groups of the reduction product hydroxy groups have been benzoylated, and re With an aromatic acylating agent, recovering the covering the dehydrated product from the reac acylated material from the reaction mixture, de tion mixture. hydrating the acylated material by treatment 11. A process as claimed in claim 1 in Which with a mixture of an aliphatic acid chloride and the acylating agent is toluene-p-sulphonchloride. anhydride, recovering the dehydrated acylated O 12. A process as claimed in claim 2 in which the product from the reaction mixture and hydrolys acylating agent is toluene-p-sulphonchloride. ing the dehydrated acylated product. 13. A process as claimed in claim 3 in which the 4. In a process for the manufacture of dieno acylating agent is toluene-p-sulphonchloride. estrol, the steps which comprise dehydrating by 14. A process as claimed in claim 4 in Which the treatment with a mixture of acetyl chloride and 25 acylating agent is toluene-p-Sulphonchloride. acetic anhydride the pinacol ya-bis-(4-hydroxy 15. A process for the manufacture of dieno phenyl)-hexane-ys-diol in which the phenolic estrol, which comprises reducing p-hydroxypro hydroxy groups have been acylated with an aro piophenone to the corresponding pinacol with an matic acylating agent and recovering the dehy amalgam of a metal of the group consisting of drated product from the reaction mixture. 30 alkali and alkaline earth metals in an aqueous 5. A process for the manufacture of dieno alkaline solution, acylating the phenolic hydroxy estrol which comprises reducing p-hydroxypropio groups of the reduction product with an aromatic phenone to the corresponding pinacol with an acylating agent, dehydrating the acylated product amalgam of a metal of the group consisting of with a mixture of an aliphatic acid chloride and alkali and alkaline earth metals in an aqueous 35 anhydride, recovering the dehydrated acylated alkaline solution, acylating the phenolic hydroxy product from the reaction mixture and hydrolys groups of the reduction product With an aromatic ing the dehydrated acylated product. acylating agent, recovering the acylated material 16. A process for the production of the pinacol from the reaction mixture, dehydrating the acyl ?y8-bis-(4-hydroxyphenyl)-hexane-ya-diol which ated material by treatment with a mixture of 40 comprises the step of reducing p-hydroxypropio acetyl chloride and acetic anhydride recovering phenone by treatment with Sodium amalgam in the dehydrated product from the reaction mix an aqueous alkaline solution. ture, and hydrolysing the dehydrated acylated 17. A process for the production of the pinacol product. ty8-bis-(4-hydroxyphenyl)-hexane-ya-diol which 6. A process for the production of the pinacol comprises the step of reducing p-hydroxypropio y8-bis-(4-hydroxyphenyl)-hexane-yô-diol which phenone by treatment with potassium amalgam comprises the step of reducing p-hydroxypropio in an aqueous alkaline Solution. phenone by treatment with an amalgam of a 18. In a process for the production of a purified metal of the group consisting of alkali and alka pinacol compound from p-hydroxypropiophenone line earth metals in an aqueous alkaline Solution. 50 by a method including the reduction of such phe 7. A process for the manufacture of the pinacol none with an amalgam of a metal of the group ?y6-bis-(4-hydroxyphenyl)-hexane-ya-diol which consisting of alkali and alkaline earth metals in comprises reducing p-hydroxypropiophenone with an aqueous alkaline solution, the steps which an amalgan of a metal of the group consisting comprise reacting with an aromatic acylating of alkali and alkaline earth metals in an aqueous agent the pinacol yá-bis-(4-hydroxyphenyl)-hex alkaline solution, acylating the phenolic hydroxy ane-yô-diol together with the by-products ob groups of the reduction product with benzoyl tained in the reduction of p-hydroxypropiophe chloride, recovering the benzoylated material from none and recovering the acylated pina Col from the reaction mixture and hydrolysing it to yield the reaction mixture. the aforesaid pinacol. 60 WALACE FRANK SEIORT. 8. In a process for the manufacture of dieno GORDON IVAN HOBDAY. estrol the steps which comprise dehydrating by treatment with a mixture of an aliphatic acid REFERENCES CTED chloride and anhydride, the pinaco y&-bis-(4- hydroxyphenyl)-hexane-yö-diol in which the The following references are of record in the phenolic hydroxy groups have been benzoylated file of this patent: and recovering the dehydrated product from the UNITED STATES PATENTS reaction mixture. Number Name Date 9. A process for the manufacture of dienoestrol, 2,349,770 Tendick ------May 23, 1944 which comprises reducing p-hydroxypropiophe 70 2,385,853 Turnbull ------Oct. 2, 1945 none to the corresponding pinacol with an amal gam of a metal of the group consisting of alkali 2,395,934 Miescher et al. ------Mar. 5, 1946