R2CO ------Pd > Al(OR) 2 CHO HO / OE (Fro N S O O O CH-N CH3-N

Patented Oct. 6, 1953 2,654,756 UNITED STATES PATENT OFFICE 2,654,756 PROCESS OF PREPARING CODENONE, DI PHNONEHYDROCODENONE, AND DIHYDROMOR August H. Homeyer, Webster Groves, and George B. De La Mater, St. Louis County, Mo., assign ors to Mallinckrodt Chemical Works, St. Louis, Mo., a corporation of Missouri No Drawing. Application October 20, 1949, Serial No. 122,587 Claims. (C. 260-285) This invention relates to the production of 2 narcotics and more particularly to a proceSS for able value for the alleviation of coughs, being the manufacture of morphine derivatives. more active than codeine in this respect. Until This application is a continuation-in-part of now, dihydrocodeinone has been obtained prin our Copending application Serial No. 76,855, filed cipally by the catalytic hydrogenation of the February 16, 1949, now abandoned. naturally occurring opium alkaloid thebaine, but Briefly this invention provides an effective Supplies of this natural alkaloid are limited and method for the preparation of dihydrocodeinone a Satisfactory and economical Synthesis from a from dihydrocodeine, of codeinone from codeine more readily obtainable starting material has not and of dihydromorphinone from dihydromor been available. phine by oxidation with a ketone in the presence O Codeine On the other hand is readily avail of an aluminum alkoxide. able and can be converted to dihydrocodeine al Among the objects of this invention are the most quantitatively by catalytic hydrogenation, provision of an improved process for the manu but the known methods for effecting the trans facture of morphine derivatives Such as dihydro formation of dihydrocodeine to dihydrocodeinone codeinone, dihydromorphinone and codeinone; 5 give very poor yields and the processes are beset the provision of a process of the type set forth with So many difficulties as to be impracticable. which employs readily available starting mate Similar problems are encountered in the pro rials; the provision of a process of the type re duction of codeinone and dihydromorphinone. ferred to which gives good yields of dihydro Although these are valuable pharmaceuticals a codeinone, dihydromorphinone or codeinOne 20 Satisfactory method for the production of co Without Simultaneous formation of Substantial deinone from codeine and dihydromorphinone amounts of accompanying by-products; and the from dihydromorphine has not been available. provision of a proceSS of the type indicated which We have discovered that if the oxidation of permits the recovery of unreacted starting ma dihydrocodeine to dihydrocodeinone, of codeine terial from the reaction mixture. Other objects 25 to codeinone and of dihydromorphine to dihy Will be in part apparent and in part pointed out dromorphinone is effected by certain ketones in hereinafter. the presence of aluminum alkoxides, dihydro The invention accordingly comprises the Steps codeine, codeine and dihydromorphine can be and sequence of steps, and features of manipula Converted respectively to dihydrocodeinone, co tion, which will be exemplified in the methods 3. deinone and dihydromorphinone in good yield. hereinafter described, and the Scope of the ap The unoxidized dihydrocodeine, codeine or dihy plication of which Will be indicated in the follow dromorphine can be conveniently and substan ing claims. tially completely recovered, thus making the over Dihydrocodeinone is a starting material in the all conversion virtually complete. manufacture of the valuable new analgesic drug 35 equations:The reactions are represented by the following CH3-N- CH-N- CH3-N

------ms- -ms-R2CO ------Pd > Al(OR) 2 CHO HO / OE (fro N S O O O CH-N CH3-N-

R2CO Al(OR) HO OE EO N nO O O CEs-N- CE-N-w Cis-N-

- sm-- ed Pd H TH H. Y OE O it. R metopon, and is itself an analgesic of consider where R and R are organic residues, 2,654,756 4. 3 The crude dihydrocodeinone was purified by For this reaction, a ketone having a sufficiently high oxidation potential is necessary, but the precipitation as the acid tartrate, and decompo ketone must not contain other functional groups Sition of the salt yielded 1.10 g. (22%) of mate which will destroy or condense with dihydro rial melting at 190°-197° C. codeinone, dihydrocodeine, codeine, codeinone, The caustic mother liquor was extracted with dihydromorphinone or dihydromorphine. Qui two 15 ml. portions of chloroform which When none, for example, possesses a very high oxidation evaporated to dryness yielded 3.38 g. Of a yellow potential, but when it was used as the oxidizing oil, that was shown to be crude dihydrocodeine agent in these reactions, the product was a by conversion to an acid tart rate. dark, insoluble substance from which no oxidized O Eacample 2 product could be isolated. It has been found In a 500 ml. fiask were placed anhydrous di that cyclohexanone and alkoxy cyclohexanones hydrocodeine (10 g.; 0.033 mole), a-imethoxycy are capable of oxidizing dihydrocodeine, dihy clohexanone (25.6 g.: 0.2 mole), and dry toluene dromorphine and codeine without simultaneous (250 ml.). Toluene (50 ml.) was distilled from formation of troublesome by-products. Mixtures 5 the reaction mixture and to the clear solution of such cyclohexanones may likeWise be en Was added aluminum tertiary-butoxide (1 g.; ployed. 0.004 mole). The mixture was then refluxed for While many aluminum alkoxides will serve in 17 hours. this reaction, those alkoxides derived from alco The Solution was cooled, shaken with Rochelle hols which are not themselves oxidized under the 2) Salt Solution (50 ml.) and filter aid (5 g.) and conditions of this reaction are preferred. Such filtered. The clear, orange organic layer was alkoxides are the aluminum tertiary alkoxides. Shaken. With 2% hydrochloric acid solution (100 If the aluminum alkoxide is not freshly pre ml.). The aqueous layer was shaken with one pared or if an excess of it is used, it has been 25 ml. portion of chloroform and two 50 ml. por found that the unreacted dihydrocodeine is trans 2 5 tions of ether. The clear aqueous layer was formed to its stereoisomer, dihydroisocodeine, cooled and stirred mechanically and sodium hy without affecting the quality or yield of the de droxide was added dropwise. When a permanent sired ketone. This does not affect the over-all turbidity appeared, sodium hydrosulfite (0.1 g.) conversion to dihydrocodeinone, since the isoner Was added to prevent discoloration and a seed is oxidized under the same conditions as dihydro 30 Crystal of dihydrocodeinone was added. Depo codeine itself. If dihydrocodeine is reacted with Sition of a crystalline product began and the an aluminum alkoxide without the ketone, it is substantially converted to dihydroisocodeine. addition of Sodium hydroxide was continued un This is a simple and convenient method for pre til the Solution was strongly alkaline to phenol paring the latter compound which heretofore 3 5 phthalein. The dense, finely crystalline precipi could be prepared only by involved and difficult tate of crude dihydrocodeinone was filtered off, procedures. Dihydroisocodeine is an analgesic Washed with water and dried. The yield of di which, so far as is known, possesses properties hydrocodeinone was 3.75 g. (37%). generally quite similar to those of dihydrocodeine. Extraction of the alkaline mother liquor with The reaction should be carried out in a suit 40 two 30 mi. portions of chloroform, and evapora able solvent. Any of the inert solvents, such as tion of the chloroform extract to dryness yielded benzene, toluene or xylene, may be employed. 6.64 g. of crude dihydrocodeine. The following examples illustrate specific en Eacample 3 bodiments of this reaction: In a 1 liter flask were placed dihydrocodeine Eacample 1 (25 g.), methoxycyclohexanone (42.5 ml.), cyclo hexanone (35 ml.) and toluene (450 ml.). Tolu In a 250 ml. flask were placed dry toluene ene (50 ml.) was distilled off and to the remain (150 ml.), cyclohexanone (15 ml.; 0.145 mole) and ing Solution was added aluminum tertiary-butox anhydrous dihydrocodeine (5 g.; 0.0166 mole). 50 ide (10 g.). The mixture was refluxed for two Toluene (50 ml.) was distilled from the flask hours, cooled and extracted with a total of 350 through a short column and to the resulting clear ml. of 2% hydrochloric acid. The acid layer was solution in the flask was added aluminum ter Separated and extracted with two 50 ml. portions tiary-butoxide (2 g.; 0.0081 mole). The resulting of chloroform and two 50 ml. portions of ether mixture was heated under reflux for 17 hours. SS to remove non-basic organic material. After the The turbid solution was cooled and shaken with addition of a saturated aqueous solution of Ro 50 ml. of a saturated aqueous Solution of potas chelle Salt (120 ml.), the acid solution was cooled sium sodium tartrate (Rochelle Salt) and after and Stirred and made alkaline by the slow addi the addition of filter aid (5 g.), the resulting tion of Sodium hydroxide, whereupon a crystal emulsion was filtered through a bed of the filter 60 line precipitate of dihydrocodeinone was formed. aid. The pale yellow organic layer was separated The yield of dihydrocodeinone melting at 182 and was extracted with a total of 50 ml. Of 191° C. was 16.2 g. (65%). 2% aqueous hydrochloric acid. The acid extract was shaken with two 20 ml. portions of ben Eacample 4 zene to remove cyclohexanone and then was made 65 In a 200 ml. flask were placed dihydroisoco alkaline with excess sodium hydroxide. The deine (2.37 g.), alpha-methoxycyclohexanone (8 solution deposited a small amount of oil and g.) and toluene (75 ml.). Solvent (25 ml.) was upon stirring and scratching a precipitate formed distilled off and to the remaining solution was and the initially deposited oil Solidified. The added aluminum tertiary-butoxide (1 g.). The Solids were removed from the clear liquid by fil 70 mixture was refluxed for 3 hours, cooled and tration and after Washing with Water and dry shaken With a total of 50 ml. of 2% hydrochloric ing weighed 1.96 g. (39.2%) and melted at 162° acid. The combined acid layers were extracted 190° C. The mixed melting point with an With two 10 ml. portions of chloroform and two authentic sample of dihydrocodeinone (M. Pt. 20 ml. portions of ether. Saturated Rochelle salt 197° C.) was 173°-191° C. 75 2,654,756 5 solution (15 ml.) was added to the acid Solution S which was then heated on a steam bath to expel 183.8° C. With decomposition. More codeinone ether. The solution was then cooled and stirred could be recovered from the mother liquors. The and slowly made alkaline, whereupon there was purified codeinone gave an oxime melting at precipitated 1.8 g. (76%) of material which 217-218° C., and a picrate melting at 208.6-210.6 proved to be crude dihydrocodeinone. 5 With decomposition. Crystallographic compari SOn Of these derivatives With those obtained from Eacample 5 codeinone prepared by chronic acid oxidation showed them to be identical, and further proof Dihydromorphine hydrate (10 g.), methoxy of the identity of the product was afforded by cyclohexanone (26 ml.) and toluene (250 ml.) O its catalytic hydrogenation to dihydrocodeinone were placed in a flask and a part of the toluene melting at 196.5-197.5°. (80 ml.) was distilled off. A solution of alumi Many variations and modifications of this in nunn tertiary-butoxide (4 g. in 30 ml. toluene) vention will be apparent to those skilled in the was added over a period of ten minutes and the art. For example, the particular aluminum mixture was then refluxed for two hours. The 5 tertiary-alkoxide employed is not critical, alu cooled mixture was shaken with diluted hydro minum tertiary-butoxide being preferred because chloric acid (5 ml. concentrated acid and 70 ml. of its availability. water) and the acid extract was washed with Attention is directed to our copending appli two successive 25-mil, portions of chloroform and cation Serial No. 269,121, filed January 30, 1952, two successive 25-ml. portions of ether. A 30% 20 and our Patent 2,628,962. solution of potassium sodium tartrate (20 ml.) In view of the above, it will be seen that the was added to the acid extract; the resulting S0 Several objects of the invention are achieved lution was heated to expel ether and then made and other advantageous results attained. alkaline with ammonium hydroxide. When the As many changes could be made in the above sides of the container were scratched, a crys 25 methods without departing from the scope of talline precipitate formed. This precipitate of the invention, it is intended that all matter con crude dihydromorphinone was filtered off and tained in the above description shall be inter dried. It weighed 9 g. and melted Over a range preted as illustrative and not in a limiting sense. from 143° C. to over 200° C. The crude product We claim: was dissolved in hot 90% alcohol (90 ml.) and 30 1. The process for preparing a substance se an excess of oxalic acid was added. When the lected from the group consisting of dihydroco solution cooled and the sides of the Wessel Were deinone, dihydromorphinone and codeinone scratched, a crystalline acid oxalate Salt formed. Which comprises reacting the corresponding hy This was filtered off and recrystallized from 90% droxy compound selected from the group con alcohol. The purified salt was dissolved in Wate' sisting of dihydrocodeine, dihydroisocodeine, and converted to the free base with ammonium codeine and dihydromorphine, in the presence hydroxide. The purified dihydromorphinone of an aluminum tertiary-alkoxide and a solvent, weighed 3.4 g. and melted at 262.5-263 C. This With a ketone from the group consisting of cy material and an authentic sample of dihydro clohexanone and alkoxy-Substituted cyclohexa morphinone were compared and found to be 40 OCS. identical. 2. The process for preparing dihydrocodeinone Eacample 6 which comprises reacting dihydrocodeine with Cyclohexanone in the presence of an aluminuri) Dihydromorphine hydrate (10 g.) was treated tertiary-alkoxide and a solvent. with cyclohexanone (34 ml.), toluene (250 3. The process for preparing dihydrocodeinone ml.) and aluminum tertiary-butoxide following Which comprises reacting dihydrocodeine with the procedure described in Example 5 above, a-methoxycyclohexanone in the presence of an except that the mixture was refluxed for two aluminum tertiary-alkoxide and a solvent. and one-half hours. Pure dihydromorphinone 4. The process for preparing dihydrocodeinone Was obtained. Which comprises reacting dihydrocodeine with Eacample 7 50 an a-alkoxycyclohexanone in the presence of an aluminum tertiary-alkoxide and a solvent. Codeine hydrate (25 g.), toluene (550 ml.) 5. The process for preparing dihydromorphis and methoxycyclohexanone (65 ml.) were placed none which comprises reacting dihydromorphine in a flask and toluene (100 ml.) was distilled off. With cyclohexanone in the presence of an au Then 60 ml. of a solution of aluminum tertiary 55 minum tertiary-alkoxide and a Solvent. butoxide in toluene (0.15 g. per ml.) was added 6. The process for preparing dihydromorphi and the solution was refluxed for two hours. none which comprises reacting dihydromorphine When the catalyst was added the color of the with a-methoxycyclohexanone in the presence of solution changed from a very pale yellow to a an aluminum tertiary-alkoxide and a solvent. deep orange. After the reaction mixture had 60 7. The process for preparing dihydroinorphi cooled, it was extracted with 5% sulfuric acid none which comprises reacting dihydromorphine (250 ml.). The acid extract was then washed with an a-alkoxycyclohexanone in the presence with two 50-ml. portions of chloroform followed of an aluminum tertiary-alkoxide and a solvent. by two 50-ml. portions of ether. Next, a 30% 8. The process for preparing codeinone which aqueous solution of Rochelle Salt (100 ml.) was 65 comprises reacting codeine with a-methoxycy added to the acid solution, and it was made al clohexanone in the presence of an aluminum kaline with sodium hydroxide, whereupon a pre tertiary-alkoxide and a solvent. cipitate formed. After the solution and precip 9. The method of preparing dihydrocodeinone itate stood overnight in an ice-box, the precipi which comprises reacting dihydrocodeine with tate, which was a mixture of codeinone and 70 cyclohexanone in the presence of aluminum codeine, was filtered off and dried. It Weighed tertiary-butoxide and toluene. 23 g. and melted at 170-176° C. with decompo 10. The method of preparing dihydrocodeinone sition. Fifteen grams of this crude material which comprises reacting dihydrocodeine with when twice recrystallized from ethyl alcohol a-methoxycyclohexanone in the presence of alu yielded 7.5 g. of codeinone melting at 1833 75 minum tertiary-butoxide and toluene. 2,854,758 7 8 11. A process for oxidizing dihydrocodeine Number Name Date to dihydrocodeinone which comprises reacting 2,384,335 Oppenauer ------Sept. 4, 1945 dihydrocodeine with cyclohexanone and alu FOREIGN PATENTS minum tertiary-butoxide in an inert Solvent. 5 Number Country Date AUGUST H. HOMEYER. 415,097 Germany ------June 13, 1925 GEORGE. B. DE LA MATER. OTHER REFERENCES References Cited in the file of this patent Baker et al.: J. Am. Chem. Soc., vol. 65, pp. UNITED STATES PATENTS 10 1675-1676 (1943). Number Name Date 2,379,832 Serini ------July 3, 1945