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United tates Patent 0 ” 1 3,041,359 2 The novel compounds of the present invention may therefore be illustrated by the following formulas: \ 2,2-DIALKYL ANDROGENIC TYPE HORMONES Howard J. Ringold and Albert Bowers, Mexico City, Mexico, assiguol's to Syntex S.A., Mexico City, Mexico, a corporation of Mexico \ No Drawing. Filed Aug. 29, 1058, Ser. No. 757,908 Claims priority, application Mexico Sept. 3, 1957 21 Claims. (Cl. 260-3973) The present invention relates to cyclopentanophenan 10 threne compounds and to a process for the production thereof. More particularly the present invention relates to novel androgenic type hormones which are 2,2-dialkyl deriva tives of 19-nor-testosterone, 19-nor-dihydrotestosterone, 15 17-lower alkyl-19-nor-testosterone, l7r-lower alkyl-19-nor dihydrotestosterone, 17 - vinyl - 19 - nor-testosterone, 17 vinyl-l9-nor-dihydrotestosterone, 17-ethinyl-19-nor-testos terone and 17-ethinyl-19-nor-dihydrotestosterone. The 20 present invention also relates to active hormones of the androgenic type which are the corresponding S-hydroxy derivatives of the aforementioned compounds. The novel useful 19-nor androgens of the present invention show a marked anabolic effect and practically lack androgenic activity, they inhibit secretion of the gonadotropic by the pituitary gland and have substantial anti-estrogenic activity. It has been discovered in accordance with the present invention that treatment of 19-nor-dihydrotestosterone 30 (19-nor-androstan-17?-oIF3-one) or 17-lower alkyl or l7-'vinyl 19-nor-dihydrotestosterone (17a-lower alkyl-l9 nor-androstan-l7?-ol~3-one or 17a-vinyl-19-nor-andro stan-17/3-ol-3-one) with a lower alkyl iodide in the pres 35 ence of a potassium tertiary alkoxide resulted in the pro duction of the corresponding novel 2,2-di lower‘ alkyl ‘19-ncr-androstan-17/8-ol-3-one, 2,2,17oc-tIi-l0Wer alkyl-l9 nor-androstan—l7l8-ol-3—one and 2,2-di lower alkyl-17a vinyl-19-nor-androstan-17,8-ol-3-one. Further in accord 40 ance with the present invention it has been discovered that monobrornination of the aforementioned compounds gave the corresponding 4-bromo-2,2-di lower alkyl or 2,2, 17a-tri lower alkyl-19-nor-androstan-17/8-olP3-one com pounds which on dehydrobromination gave the corre 4.5 sponding novel 2,2-di lower alkyl or 2,2,17a-t1i lower alkyl-At-19-nor-androsten-17B-ol-3-one compounds. Fur ther 2,2-di lower alkyl-19-nor-androstan-17p3-o1—3-one and 2,2-di lower alkyl-19-nor-A4-androsten-17?-ol-3-one were 50 converted into the corresponding Una-ethinyl compounds by oxidation to the corresponding 17-ket0 compounds followed by reaction with potassium butoxide and acety lene. Partial hydrogenation of the ethinyl compounds gave the same l7-viny1 derivatives previously mentioned and more complete hydrogenation gave the 17a-ethyl derivatives. All of the compounds previously mentioned upon treatment with a reducing agent gave the corre sponding 3-hydroxy derivatives. By conventional esteri ?cation there was also prepared the esters of these com pounds of the nontertiary alcohol groups. 3,041,359 Patented June 26, 1962 60 3,041,359 3 r r 4 OH double bond between 04 and C-5 or a saturated linkage ‘ between C-4 and C-5. -- Q = CH The novel compounds of the present invention may be prepared by a process illustrated in part by the follow- ‘ CTI 70 ing equations: ‘ O//\ JX OH OH in-Ra I-“Ra 1° *1‘ Rlodlde R- I I —___, 0: 15 I \ o- , H H l monobrornlnatlon 20 20 R_ OH OH 1mm 1.03; brginisigltlion .. h - RJ <____— 0_ Br OH R o5 3C0” l potassium acetyllde 0H lm-GEOH R_R / 0: OH 55 l R K' 60 OH /\ i ‘' R_ O_ Q: 0 ethylene ———-—————> I V glycol 1'1 ,, p R RJ 0 [ 1‘1 loxidation 65 H erably a lower alkyl group ‘of less than 7 carbon atoms such as methyl, ethyl and propyl. R1 represents hydro- /\ ‘ I 0 In the above formula R represents an alkyl group pref- I (6“ _ CZCH ‘[3’ gen or an acyl group of the type conventionally found in an esteri?ed steroid alcohol. These are generally 70 R R those derived from a hydrocarbon carboxylic acid of less than 12 carbon atoms such as acetic, propionic, butyric, R | _ ggtgslsilélm valeric, hexanoic, cyclopentylpropionic, benzoic, etc. R2 0_ ii represents a lower alkyl group of less than 7 carbon atoms such as methyl, ethyl or propyl. X represents a 75 : H hydrolysis R O O : H 3,041,359 ard In the above equations R and X represent the same pounds resulting from the ?rst step just referred to are groups as heretofore set forth. R3 represents hydrogen, treated with slightly over 1 molar equivalent of bromine a lower alkyl group of less than 7 carbon atoms (R2) 50 preferably in carbon tetrachloride solution to prepare the or vinyl. R4 represents hydrogen, a lower alkyl group corresponding 4-bromo compound and these compounds of less than 7 carbon atoms, vinyl or ethinyl. were dehydrobrominated with collidine. There were thus Referring to the ?rst equation above the starting com- 7 prepared 2,2-di lower alkyl-l9Fnor-A4-androsten-1713-01 pound which may be, as illustrated, 19-nor-androstan 3-one compounds and their 17-esters or 2,2,17a-t1‘i lower l7B-ol-3-one, or its l7rx-l0Wer alkyl or 17oz-Vinyl deriva 55 alkyl-19-nor-A4-androsten-17/3-ol-3-one compounds a 2,2 tives, in an organic solvent, preferably a tertiary lower di lower alkyl-17u-vinyl-l9-nor-A4-androsten-l7/3-ol-3-one. aliphatic alcohol such as t-butanol, is mixed with a po As indicated in ‘the second equation oxidation of 2,2 tassium t-alkoxide, such as potassium t-butoxide and the di lower alkyl-l9-nor-A4-androsten-l7B-ol-3-one com mixture stirred under nitrogen atmosphere for a'short pounds with preferably chromium trioxide in aqueous “I time such as 1/2_ hour. An excess of a lower alkyl iodide such as methyl, ethyl or propyl iodide is then added and the reaction mixture stirred for a longer period of time acetone gave the corresponding 2,2-di lower alkyl-19 nor-A4Fandrosten-3,l7-dione compounds. Reaction of these last with potassium acetylide gave the correspond i.e. of the order of 3 hours. Water is then added, the ing Wot-ethinyl, 175-01 derivatives. ' , solution is neutralized with acid and the organic solvent The ‘same type of reaction applied to 2,2-di lower is removed by reducing pressure distillation. The residue 65 alkyl-l9-nor-androstan-l7?-ol-3-one compounds with in is then collected by ?ltration and puri?ed to give the re termediate protection of the 3-keto group by formation spective 2,2-di lower alkyl, or 2,2,l7oo-tri lower alkyl or 2,2-di lower alkyl-17a vinyl derivative of l9-nor-andro stan-17/3-ol-3-one. By conventional esteri?cation proce of an ethylene ketal and subsequent hydrolysis of the protective group gave the corresponding 2,2-di lower of the type previously described there is prepared the of the above equations. In the fourth equation above there is illustrated the reaction of the 17¢x-ethinyl derivatives with hydrogen to give the l7a-vinyl derivatives and upon more complete alkyl - 17cc - ethinyl - 19 - nor - androstan - 176 - o1 - 3 dures such as reaction with acid anhydrides or chlorides 70 one compound. This reaction is illustrated in the third corresponding l7-acylates of hydrocarbon carboxylic acids of less than 12 carbon atoms of the 2,2-di lower alkyl compounds. . To prepare the corresponding M-compounds the com 75 hydrogenation the 17a-ethyl derivatives. Preferably the 3,041,359 7 8 partial hydrogenation was in pyridine in the presence of dimethyl - l7a-ethinyl-3-ethylenedioxy-19-nor-androstan a palladium on calcium carbonate catalyst and the more 1718-01. complete hydrogenation of the ethinyl group was in di oxane solution with a palladium on charcoal catalyst. Without further puri?cation, the above precipitate was dissolved in 160 cc. of acetone, mixed with 400 mg. of p-toluenesulfonic acid and allowed to stand overnight at Finally, in the ?fth equation above there is illustrated room temperature. It was then poured into water and the conversion of all of the aforementioned compounds the precipitate was collected, dried under vacuum and to their 3-hydroxy derivatives. In this reaction the 3 recrystallized from acetone-hexane, thus producing 2,2 keto 2,2-dimethyl derivative is treated in an organic sol dimethyl-l7ot-ethinyl-l9-nor-androstan-l7?-ol-3-one. vent such as aqueous dioxane with a reducing agent such as lithium borohydride.- For the preparation of the 3 l0 Example III esters of these compounds they were conventionally re When in the method of Example I the 17a-methyl-l9 acted with acid anhydrides or chlorides of hydrocarbon nor-dlhydrotestosterone was substituted by its 170:, -ethyl, carboxylic acids of less than 12 carbon atoms preferably -propyl or -vinyl analogue, there were obtained the 2,2 in pyridine. The following speci?c examples serve to illustrate but 15 dimethyl derivatives of these 17tx-alkyl or vinyl substituted are not intended to limit the present invention. l9-nor-dihydrotestosterones. Example IV When in the methods of the previous examples the A solution of 4 g. of l7u-methyl-19-nor-dihydro methyliodide was substituted by ethyl iodide, there were testosterone (Nat-methyl-19-nor-androstan-l75-ol-3-one) 20 obtained the corresponding 2,2-diethyl derivatives instead in 50 cc. of ‘anhydrous t-butanol was added to a cooled of the 2,2-dimethyl derivatives. 1 solution of potassium t-butoxide prepared by dissolving Example V 2.2 g. of potassium in 75 cc. of anhydrous t-butanol. The ‘Example I mixture was cooled to 0° C. and treated with 7 cc. of methyl iodide; it was then stirred for 3 hours under an atmosphere of nitrogen, diluted with water and the precipitate was collected by ?ltration and puri?ed by chromatography on a column of 200 g. of neutral alumina, thus giving 3.4 g. of 2,2,l7a-trimethyl-l9—nor dihydrotestosterone of M.P. 128-130° C. Recrystalliza tion from acetone-hexane yielded the pure compound, M.P. l40-142° C., ]; +102“ (chloroform). To a solution of 750 mg. of 2,2,l7a-trimethyl-l9-nor dihydrotestosterone, prepared as described in Example I, in 25 cc. of dioxane there was added a solution of 500 mg. of sodium borohydride in 5 cc. of aqueous dioxane (9:1) and the mixture was kept for 3 hours at room tem perature. It was then acidi?ed with a few drops of acetic acid and diluted with water. The precipitate was ?ltered and washed with water, to give 680 mg. of 2,2,17a-tri Example [I methyl-l9-nor-androstan-3B,l7B-diol, M.P. 171-l73° C., [0L1]; +28° (chloroform). Similarly, there was prepared 2,2-di lower alkyl By'the method of the previous example, 19-nor-di (methyl or ethyl) 19-nor-androstan-3B,l7?-diol from 2,2 di lower alkyl-(methyl or ethyl)-IQ-nor-dihydrostestoster hydrotestosteroue was converted into 2,2-dimethyl-19 nor-dihydrotestosterone. 5 g, of this 2,2-dimethyl-19-nor-dihydrotestosterone was mixed with 350 cc. of benzene, 35 cc. of ethylene glycol and 250 mg. of p-toluenesulfonic acid and the mix ture was boiled under re?ux for 48 hours with the use of an adapter for the continuous removal of the water formed during the reaction. 100 cc. of 2 normal sodium vcarbonate solution ‘and 100 cc. of water were added to the 45 cooled mixture and the benzene layer was separated, washed with water and evaporated to dryness. Recrystal lization from acetone-hexane afforded 2,2-dimethyl-3 one, as well as well as the corresponding 2,2-di lower alkyl-17a-methyl, ethyl, propyl, vinyl or ethinyl-19-nor androstan-3?,l7B-diols from the corresponding 17a methyl, ethyl, propyl, vinyl or ethinyl-substituted 2,2-di ' alkyl-l9-nor-dihydrotestosterone. Example VI A solution of l g, of 2,2-dimethyl-19-nor-dihydro testosterone in 20 cc. of carbon tetrachloride was mixed with a few drops of a saturated solution of hydrogen bromide in carbon tetrachloride, followed by the addition of 0.6 g. of bromine in 5 cc. of carbon tetrachloride, with A suspension of'3 g. of chromium trioxide in 25 cc. of 50 stirring, and in the course of approximately 5 minutes, while the temperature of the mixture was maintained pyridine was added to a solution of 3 g, of the above ketal in 20 cc. of anhydrous Pyridine. The suspension was below 18° C.; it was then kept for 1 hour at room tem ethylenedioxy-19-nor-androstan-17B-ol. prepared by adding the powdered chromium trioxide in 4 portions to the pyridine, maintaining the temperature perature, diluted with water, mixed with 100 cc. of ether and the organic layer was separated, washed with water, below 35° C., until the dark red color characteristic of 55 dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue consisted chromium trioxide disappeared. The mixture of the of the crude 4 - bromo - 2,2 - dimethyl-l9-nor-dihydro steroid solution and the oxidizing reagent was kept for 24 testosterone. ~ hours at room temperature, diluted with ethyl acetate The above bromo compound was mixed with 5 cc. of and ?ltered through celite; the solution was washed with water until the washings were coloreless, dried over anhy 60 collidiue and the mixture was boiled under re?ux for 1 drous sodium sulfate and evaporated to dryness under hour. It was poured into dilute sulfuric acid and ice and the precipitate was extracted with ether. The ether reduced pressure. There was thus obtained 2,2-dimethyl 3-ethylene-dioxy-19-nor-audrostan-l7-one. solution was washed with dilute sulfuric acid and water, dried over anhydrous sodium sulfate and evaporated to 2 g. of 2,2-dimethyl-3-ethylenedioxy-19-nor-androstan l7-one was dissolved in 80 cc. of anhydrous benzene 65 dryness. The residue was puri?ed by chromatography and added under nitrogen to a cooled solution of potas in a column of ‘alumina, thus a?ording the pure 2,2-di sium t-butoxide prepared by dissolving 2 g. of potassium methyl-l9-nor-testosterone. Similarly, there were prepared the corresponding 2,2 dimethyl-l7a-rnethyl or ethyl-19-nor-testosterones from phere of nitrogen. The stream of nitrogen was substituted by a slow stream of dried purified acetylene and this 70 the corresponding l7a-ethyl or methyl substituted 2,2 metal in 100 cc. of anhydrous t-butanol, under ‘an atmos stream was allowed to pass through the solution for 40 hours. The mixture was then poured into 400 cc. of dilute hydrochloric acid, the organic solvents were re moved by steam ‘distillation, the residue was cooled and the precipitate was ?ltered; there was thus obtained 2,2 75 dimethyl-19-nor-dihydrotestosterones. The 2,2-diethyl lQ-nor-dihydrotestosterones, with or without a methyl or ethyl substitutent at C-17a in a similar manner gave 2,2 diethyl-l9-nor-testosterone or 2,2-diethyl-17m-methyl or ethyl-19-nor—testosterones, respectively. 3,041,359 9 l0 , Example XI By the method of Example X, 2,2-dimethyl-17a-ethinyl Example VII In other experiments the bromination of Example VI 19-nor-testosterone was hydrogenated until the equivalent was carried out in glacial acetic acid instead of carbon tetrachloride, with the same ?nal result. of 2 mols of hydrogen was absorbed. There was thus obtained 2,2—dimethyl-17a-ethyl-19-nor-testosterone, iden Example VIII tical to the one obtained in accordance with the previous example. An oxidizing solution was prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to a total volume of 100 cc. 1 g. of 2,2-dimethyl-19-nor-testosterone, obtained by any of the methods of Examples VI and VII, was dis Example XII '10 When in the method of Example VIIl 2,2-dimethyl-19 nor-testosterone was substituted by 2,2-diethyl-19-nor testosterone; there was obtained as an intermediate 2,2-kdi ethyl-19-nor-A4-androsten-3,17-dione and as ?nal product solved in 120 cc. of acetone and cooled to 10—,15° C. in an ice bath. There was then added 1.6 cc. of the oxi 2,2-diethyl-17a-ethinyl-19-noratestosterone, which was in dizing solution, with stirring, in the course of 5 minutes, 15 turn hydrogenated to 2,2-diethyl-l9-nor-17a-vinyl~testos terone, in accordance withthe method of Example IX. while the temperature was kept below 15° C. After 2 more minutes the mixture was diluted with water to ‘a Example XIII volume of approximately 500 cc. and the white precipitate formed was ?ltered, well washed with water, dried under vacuum and recrystallized from acetone-hexane. There was thus obtained 2,2-dimethyl-A4-19-nor-androsten-3,17 dione. A solution of potassium t-butoxide was prepared by dissolving 1 g. of potassium metal in 14 cc. of t-butanol, A mixture of 1 g. of 2,2-dimethyl-19-nor—testosterone, 10 cc. of pyridine and 1 cc. of acetic anhydride was kept overnight at room temperature, poured into water ‘and . heated on the steam bath for ‘half an hour. The mixture was cooled and the precipitate was collected, washed, dried and recrystallized from acetone-hexane. There was the solution was cooled and the ‘air in the apparatus was 25 thus obtained 2,2-dimethyl-l9~nor~testosterone acetate. substituted by nitrogen. To this solution there was ‘added Example XIV ‘a solution of 1 g. of 2,2-dimethyl-l9-nor-n4eandrosten-3, By the same conventional method of Example Xlli, there was esteri?ed the secondary hydroxyl groups of all of the 2,2-dimethyl-‘androstanes described; instead of an 17-dione in 10 cc. of toluene, with stirring under nitrogen and in the course of 2 minutes. The stirring under nitro gen was continued for a further half hour, when a acid vanhydride there, can also be used the acid chloride. homogeneous brown solution was obtained. The nitro The ‘anhydride or chloride were those derived from a gen was then substituted for a slow stream of dried hydrocarbon carboxylic acid of to 12 ‘carbon atoms. puri?ed acetylene which was allowed to pass for 16 There was thus prepared 1a great variety of esters, and hours, at room temperature with stirring. The mixture was acidi?ed with dilute hydrochloric'acid to Congo red 35 more speci?cally, C—17 acetates, prop-ionates, cyclopentyl propionates and benzoates of 2,2-methyl or ethyl-19-nor paper ‘and the reaction product was extracted with toluene. testosterone and 2,2-dialkyl-19-nor-dihydrotestosterone, The toluene was washed with water to neutral, dried over thesame C—3 esters of the Not-substituted 2,2-dia1kyl-l9 anhydrous sodium sulfate, ?ltered ‘and concentrated under vacuum to approximately 15 cc. nor-androstan-3?,17,6-diols previously described, as well It was then passed through a short column of alumina, washing the column 40 as C—3,17 idiesters of these diols without substituent at ‘Cl-17a. with ‘a little toluene. Evaporation of the solution under We claim: ' reduced pressure afforded 2,2-dimethyl-17a-eminyl-19— l. 2,2,17a-trimethy1-19-nor-A4-androsten-17,8-01-3-one. 2. A compound of the following formula: nor-testosterone, which was puri?ed by recrystallization from acetone-hexane. Example IX 45 0 ll A suspension of 300 mg. of 2% palladium on calcium carbonate in 30 cc. of pure pyridine was pre-hydrogenated at room temperature for 3 hours. There was then added 1 g. of 2,2-dimethyl-17a-ethinyl-19-nor-testosterone, pre 50 pared as described in Example VIII, and the mixture was stirred under hydrogen at room temperature until the equivalent of 1 mol of hydrogen had been absorbed. The catalyst was removed by ?ltration and washed with a little pyridine and the combined ?ltrate and washings was 55 wherein R is a lower alkyl group and both R’s are the evaporated to dryness under vacuum. The residue was same and X is selected from the group consisting of a dou dissolved in ether, washed with dilute hydrochloric acid, ble bond between C—4 and C—5 and a saturated linkage water, 5% sodium carbonate solution and again with between C—4 and C—5. water to neutral. Recrystallization of the residue from 3. 2,2-dimethyl-19-nor~A4-androsten-3,17-dione. 4. A compound of the following formula: acetone-hexane yielded 2,2-dimethyl-17a-vinyl-l9-n0r testosterone. Example X A solution of 1 g. of 2,2-dimethyl-17a-vinyl-19-nor 65 testosterone, obtained as described in Example IX, in 75 cc. of dioxane was mixed with 0.4 g. of previously re duced 5% palladium on charcoal catalyst and the mix ture was hydrogenated ‘at room temperature with stirring until the equivalent of one mol of hydrogen was ‘absorbed. It was then ?ltered through celite, washing the ?lter with dioxane, and the combined ?ltrate and washings was evaporated to dryness under reduced pressure. The resi , due ‘crystallized from acetone-hexane to give 2,2-dimethyl Not-ethyl-1-9-nor-testosterone. wherein R is a lower alkyl group and both R’s are the 75 same and X is selected from the group consisting of a dou 3,041,359 12 ble bond between (3-4 and C-5 and a saturated linkage between C-4 and C-5. 5. 2,2-dirnethy1 - 17oz - vinyl-19-nor-androstan-1718-01 3-one. 6. 2,2,-climethyl - 17a - vinyl-l9-nor-A4-androsten-17,8 ol-3-one. 7. A compound of the following formula: ' ‘ wherein R is a lower alkyl group and both R’s are the same, R2 is a lower alkyl group, X is selected from the group consisting of a double bond between 0-4 and C—5 and a saturated linkage between C-4 and C-5 and R1 is 5 selected from the group consisting of hydrogen and a hy drocarbon carboxylic acyl group of less than 12 carbon atoms. 16. 2,2,17a-trimethyl - 19 - nor - androstan - 35,1713 on diol. “wQECLH 17. The 3-hydrocarbon carboxylic esters of less than 12 carbon atoms of 2,2,17a-trlmethyl-19-nor-androstan— ’ 35,17?-diol. 18. A compound of the following formula: 15 J. wherein R is ‘a lower alkyl group and both R’s are the same and X is selected from the group consisting of a dou ble bond between C-4 and C-5 and a saturated linkage between C54 and C-5. 8. 2,2-dirnethyl - 17a - ethinyl-l9-nor-androstan-17/3-ol 3-one. 25 e10 9. 2,2-dlmethy1 - 17oz - ethinyl-l9-nor-A4-androsten-1718 ol—3-one. wherein R is a lower alkyl group and both R’s are the same, X is selected from the group consisting of a double bond between 0-4 and C-5 and a saturated linkage be tween C-4 and C-5 and R1 is selected from the group 10. A compound of the following formula: consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms. 19. 2,2-dimethyl - 17a - vinyl-19-nor-androstan-3,B,17;3 diol. 20. A compound of the following formula: 35 OH @‘0 wherein R is a lower alkyl group and both R’s are the same, X is selected from the group consisting of a dou ble bond between 0-4 and C—5 and a saturated linkage between C—4 and C-5 and R1 is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms. 45 1 1. 2,2-dimethyl-19-nor-androstan-3?,1718-diol. 12. The hydrocarbon carboxylic esters of less than 12 carbon atoms of 2,2-dimethyl-19-nor—androstan—313,175 diol. wherein R is a lower alkyl group and both R’s are the same, X is selected from the group consisting of a double bond between 0-4 and C-5 and a saturated linkage be tween C-4 and C-5 and R1 is selected from the group 13. 2,2Pdimethyl-l9-uor-A4-androsten~3;3,17,8-diol. 14. The hydrocarbon carboxylic esters of less than 12 carbon atoms of 2,2-dirnethyl-19-nor-A4-androsten-3/3,17,8 diol. consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms. . 21. 2,2-climethyl - 17a - ethinyl - l9 - nor-androstan 15. A compound of the following formula: 35,1713-(11‘01. References Cited in the ?le of this patent UNITED STATES PATENTS 2,813,880 2,845,381 2,852,537 65 Campbell et al. ______ .._ Nov. 19, 1957 Tindall ______________ __ July 29, 1958 Ringold et al. ________ __ Sept. 16, 1958 OTHER REFERENCES Ringold et al.: Journal of Organic Chemistry (1956), vol. 21, pp. 1333-1334.