Patented Feb. 22, 1938 2,109,400 UNITED STATES PATENT OFFICE 2,109,400 ESTERS OF TESTOSTERONE AND PROCESS OF MAKING SAME Karl Miescher, Riehen, near Basel, and Albert Wettstein and Caesar Scholz, Basel, Switzer land, assignors to the firm of Society of Chem ical Industry in Basle, Basel, Switzerland No Drawing. Application September 8, 1936, Se rial No. 99,856. In Switzerland October 5, 1935 16 Claims. (C. 260-106) This invention relates to the manufacture of The new esters are applicable in therapeutics. new esters of Saturated or unsaturated oxyke The following examples illustrate the inven tOnes of the type of androstane-3-one-17-ol by tion, the parts being by weight:- s treating the oxyketone with an acylating agent having more than two carbon atoms and con Eacample 1 taining in addition to the acylating group no 1 part of testosterone is dissolved in 4 parts group having a tendency to form salt or group of dry pyridine and the solution is heated with capable of conversion into a salt-forming group. 1.5 parts of propionic acid anhydride for 1% AS compared with testosterone and testoster hours at 125 C. The whole is then poured into 10 One-acetate the new esters are characterized by Water and allowed to stand for some time during their protractive effect. Esters derived from me which crystallization occurs. The crystalline 10 dium fatty acids, from propionic acid onwards, mass is filtered by suction, washed with water, have proved to have a particularly strong effi dried over phosphorous pentoxide and re-crys cacy in tests on rats. tallized from hexane; colourless testosterone 5 For the acylation either the free acid itself propionate is thus obtained of melting point Or its anhydride, halide or ester derived from a 21-23 C. 15 lower alcohol may be used. Suitable acid com The reaction may occur in the presence of an 'ponents are, for instance, propionic acid, butyric other tertiary base or even in the absence of such acids, Valerianic acids, capric acid, benzoic acid, a base. 20 Crotonic acid or the like. w The following oxyketones are examples of the Eacample 2 parent materials: testosterOne (A5-androstene A Solution of 1 part of testosterone in 4 parts 3-one-17-ol), dihydrotestosterone (androstene of pyridine is heated with 2 parts of n-butyric 3-one-17-ol), 17-methyl-testosterone (A4,5-17 acid anhydride in an oil bath at 125° C. for 1% 25 methyl-androstene-3-one-17-ol), 17-methyldihy hours. Water is then added and the mixture al drotestosterOne (17-methyl-androstane-3-one lowed to stand for a long time during which . 25 17-ol). Crystallization occurs. The crystals are filtered The new products have been tested biologi by Suction, washed with water and dried over Cally by the following methods:- phosphorus pentoxide. When re-crystallized 30 (A) Castrated rats received on the 1st an from hexane or dilute methanol the product 6th experimental days each 1 mg. of the com yields testosterone-n-butyrate in the form of 30 pound to be investigated. On the 16th or 21st slender needles which melt at 111-113° C. day the rates were killed and the weight of the Seminal vesicles Were ascertained. Eacample 3 (B) Castrated rats received on the 1st exper 1 part of testosterone is dissolved in 3 parts imental day 2 mgs. Of the compound to be in of dry pyridine and the solution is heated to vestigated. On the 6th and 11th days the rats gether with 2 parts of iso-butyric acid anhydride were killed and the weights of the seminal vesi at 125 C. for 2% hours. The mass is then cles were ascertained. poured into warm water and stirred somewhat; 40 The following table shows the particularly high after a short time crystallization begins. The activity of the new products as compared with crystals are filtered by suction, washed with 40 the known testosterone, its acetate and the di water and dried over phosphorus pentoxide. hydrotestosterOne:- After recrystallization from hexane or dilute ace 45 Weight of seminal vesicle of the tone testosterone-iso-butyrate is obtained in the rat in mg. form of thick needles of melting point 134-136 C. 45 Compounds investigated Method. A MethodB Eacample 4 16 days 21 days 6 days 11 days A solution of 1 part of testosterone in 3 parts of dry pyridine is mixed in the cold with part Testosterone.------15 14 18 14 Dihydrotestosterone.--- 15 4 18 14 of n-valerianic acid chloride and the whole is 50 17-methyl-testosterone- 16 14 27 17 1-methyl-dihydrotestostcronc 6 14 25 6 allowed to remain at room temperature for a long Testosterone-formate.------61 46 86 35 time. The mass, which is partially solidified, is Testosterone-acetate----- 89 33 93 4. Testosterone-propionate- 285 106 0. 265 then poured into strongly diluted sulfuric acid, Testosterone-n-butyrate- 375 320 130 306 extracted with ether and the ethereal solution is Testosterone-iso-butyrate------334 135 50 32 washed with dilute sulfuric acid, sodium car 55

Testosterone-n-walerianate------400 140 235 Testosterone-caprinate--- 58 7 bonate solution and water. On evaporation of Testosterone-benzoate.-- 70 75 Dihydrotestosterone-formate.-- 75 40 the solution and crystallization of the residue Dihydrotestosterone-acetate------85 35 from hexane and dilute acetone there is obtained Dihydrotestosterone-propionate.------90 230 testosterone-n-valerianic acid ester of melting 60 point 109-111° C. 2 2,109,400 Instead of Valerianic acid chloride another What we claim is:- halide of the acid may be used, for instance 1. The 3-keto-cyclopentanopolyhydrophenan bromide, , threnes containing in 17-position the group In like manner, one can obtain the iso-vale R rianic acid ester of melting point 138-139.5° C. N Eacample 5 O-Ac wherein R is a member of the group consisting Equal parts of testosterone and capric acid are of hydrogen and a lower aliphatic hydrocarbon 10 heated together in an atmosphere of nitrogen for radical, and AC stands for an unsubstituted mon O 3 hours at 200° C. The mass is then taken up Ocarboxylic acid radical containing more than with ether, the ethereal solution being washed - two carbon atoms. with Sodium carbonate solution and water and 2. The 3-keto-cyclopentanopolyhydrophenan then evaporated. The residue which crystallizes threnes containing in 17-position the group " 15 after standing for some time is re-crystallized from absolute alcohol or aqueous methyl alcohol SO as to obtain the testosterone capric acid ester N of melting point 55-57 C. O-Act In quite analogous manner for example the wherein R is a member of the group consisting 20 esters of capronic acids, oenanthic acids, caprilic of hydrogen and a lower aliphatic hydrocarbon 20 acids, pelargonic acids and the like may also be radical, and Ac stands for an unsubstituted all obtained. phatic monocarboxylic acid radical containing Eacample 6 more than two carbon atoms. 3. The 3-keto-cyclopentanopolyhydrophenan 25 1.44 parts of testosterOne is dissolved in abso 25 lute pyridine and to this solution 1 part of benzoyl threnes containing in 17-position the group chloride is added. The mixture is allowed to R stand for several hours and then poured into / dilute sulfuric acid; the mass is then extracted 30 with ether and the ethereal extract is washed 30 repeatedly with dilute acid, dilute caustic SOda wherein R is a member of the group consisting solution and finally water. The residue of the of hydrogen and a lower aliphatic hydrocarbon dried ether solution is purified by re-crystalliza radical. tion from hexane or by sublimation in a high vac 4. The 3-keto-cyclopentanopolyhydrophenan uum or by both methods of purification, whereby threnes containing in 17-position the group the testosterone benzoate of melting point 198 R 200° C. is obtained. 1 17-alkyl-testosterones such as, for example, c the 17-methyl compound or the 17-ethyl com O-CO-CE pound are esterified in analogous manner, for ex wherein R is a member of the group consisting 40 ample the propionates, butyrates, Valerianates, of hydrogen and a lower aliphatic hydrocarbon benzoates and the like are produced as crystalline radical. compounds. 5. The 3-keto-cyclopentanopolyhydrophenan Eacample 7 threnes containing in 17-position the group 45 5 parts of dihydrotestosterone are mixed with R 15 parts of dry pyridine and 5 parts of propionic N acid anhydride and the mixture is heated for 1% O-CO-CH hours at about 100° C., the solution remaining nearly colourless. The whole is then poured into wherein R is a member of the group consisting 50 water and allowed to stand for some time during of hydrogen and a lower aliphatic hydrocarbon which crystallization immediately sets in. The radical. crystalline mass is filtered by suction, washed 6. The testosterone propionate of the formula With Water and dried over phosphorus pentOxide, CBs CH whereafter by re-crystallization from hexane di 55 55 hydrotestosterone-propionate is obtained of melt O-CO-OH-CH ing point 120-121 C. . Instead of pyridine another tertiary base, for instance dimethylaniline may be used. In quite analogous manner the butyric acid O-Q2 ester of melting point 91-92 C., and the n-vale rianic acid ester and other esters may be ob of melting point 121-123 C. tained. 7. A process for the manufacture of esters of 17-alkyl-dihydrotestosterones such as, for ex the 3-keto-cyclopentanopolyhydrophenanthrenes 85 65 ample, the 17-methyl compound or the 17-ethyl containing in 17-position the group compound are esterified in analogous manner, for R example the propionates, butyrates, vallerianates, benzoates and the like are produced as crystalline compounds. : Yoh 70 70 wherein R is a member of the group consisting In like manner there may be made, for in of hydrogen and a lower aliphatic hydrocarbon stance androstane - 3 - one-17-trans-ol-hexa-hy radical, consisting in treating the said 3-keto drobenzoateandrostane-3-one-17-cis-ol-hexahydrobengoate of melting point 165-166° C. and cyclopentanopolyhydrophenanthrenes with agents 5. of melting point 136-137° C., capable of introducing unsubstituted monocar- is 2,109,400 3 boxylic acid radicals containing more than two carbon atoms, 13. The testosterone-n-butyrate of the formula 8. A proress for the manufacture of esters of His OH the 3-keto-cyclopentanopolyhydrophenanthrenes containing in 17-position the group O-CO-CE-CH-CH R

O O wherein R is a member of the group consisting in hydrogen and a lower aliphatic hydrocarbon 10 radical, consisting in treating the said 3-keto of melting point 111-113 C. cyclopentanopolyhydrophenanthrenes with all 14. The testosterone-n-valerianate of the for phatic agents capable of introducing unsubsti mula 5 tuted monocarboxylic acid radicals containing C CE more than two carbon atoms. 5 9. A process for the manufacture of propi 40-co-ch-ca-ch-UE, onates of the 3-keto-cyclopentanopolyhydrophen 20 anthrenes containing in 17-position the group R 20 / C YoH of melting point 109-111° C. 25 wherein R is a member of the group consisting of hydrogen and a lower aliphatic hydrocarbon 15. A process for the manufacture of testo 25 radical, consisting in treating the said 3-keto sterone-n-butyrate of the formula cyclopentanopolyhydrophenanthrenes with pro pionylating agents. Cas C 30 10. A process for the manufacture of butyrates 4-co-oh-oh-oh, of the 3-keto-cyclopentanopolyhydrophenan 30 -- threnes containing in 17-position the group

35 Yoh O-Q2 wherein R is a member of the group consisting of hydrogen and a lower aliphatic hydrocarbon wherein testosterone of the formula radical, consisting in treating the said 3-keto C CB 40 cyclopentanopolyhydrophenanthrenes with buty rylating agents. 4. 40 11. A process for the manufacture of Valeri anates of the 3-keto - cyclopentanopolyhydro phenanthrenes containing in 17-position the 45 group R 45 / O-Q2 C is treated with a n-butyrylating agent. YoH 16. A process for the manufacture of testo 50 Wherein R is a member of the group consisting sterone-n-valerianate of the formula of hydrogen and a lower aliphatic hydrocarbon 50 radical, consisting in treating the said 3-keto CH CH B cyclopentanopolyhydrophenanthrenes with vale rianylating agents. |-4-co-ch-oh-oh-oh, 55 12. A process for the manufacture of testo sterone-propionate of the formula 55 CH C '' B Q/N/ 60 Of O-CO-C-CH wherein testosterone of the formula O 2 y CH, CH, 4r 65 wherein testosterone of the formula 65

CH

70 O-Q2 is treated with a ni-Valerianylating agent. 70 KAR MESCHER. 75 is treated with a propionylating agent. ALBERT WETSTEIN. CAESAR SCOLZ. 75