United States Patent (19) [11] 3,956,348 Hilscher (45) May 11, 1976 54 STERODETHER SPLTTING 58 Field of Search....................... 260/.397.4, 397.5 75 Inventor: Jean-Claude Hilscher, Berlin, Germany 56 References Cited (73) Assignee: Schering Aktiengesellschaft, Berlin UNITED STATES PATENTS & Bergkamen, Germany 3,818,056 6/1974 Pierdet ct al.................. 260/.397.45 3,845,084 i0/1974 Stein................................ 260/.397.5 22 Filed: Feb. 25, 1975 (21 Appl. No. 552,960 Primary Examiner-Elbert L. Roberts Attorney, Agent, or Firm-Millen, Raptes & White (30) Foreign Application Priority Data 57 ABSTRACT Feb. 27, 1974 Germany............................ 240999 Ethers of aromatic steroids are cleaved to regenerate 52 U.S. Cl........................... 260/397.5; 260/.397.4; i.E. it is hydride dialkylalu 260/239.55 C 51 Int. Cl.’............................................. C07J 1100 10 Claims, No Drawings 3,956,348 2 1 group is in the 1, 2 or 3-position thereof, especially the STEROD ETHER SPLTTING 3-position. Specific examples of alkyl aluminum compounds of BACKGROUND OF THE INVENTION the formula AlR,R,Rs are triisobutylaluminum, diethyl This invention relates to a process for cleaving aro 5 aluminum hydride, di-n-butylaluminum hydride, and matic steroid ethers. diisobutylaluminum hydride. Aluminum hydride is also The splitting of ethers of aromatic alcohls requires, as suitable. is known, more vigorous conditions and reagents than The reaction is conducted in an inert solvent in which the splitting of purely aliphatic ethers. Frequently, alkyl the starting steroid is at least partially soluble. Solvents ethers are utilized in steroid syntheses for the protec 10 which can be used for the process of this invention are tion of hydroxy groups, because this grouping with those which are inert with respect to the reactants and stands almost all reactions. However, precisely because which have a boiling point below 160° C. Examples are of this great resistance displayed by these ethers against aromatic hydrocarbons, such as benzene, toluene, and reagents, difficulties are often encountered in the liber xylene; aliphatic hydrocarbons, such as hexane; cyclic ation of the hydroxy groups protected by such etherifi 15 hydrocarbons such as cyclopentane and cyclohexane; cation after the synthesis, without affecting other groups of the molecule during this step. The aromatic and their mixtures, as well as, for example, ligroin and steroid ethers are particularly resistant. They are split benzine. only under extreme reaction conditions, such as, for The exact nature of ether group to be cleaved is not example, by treatment with strong acids, such as hydro 20 critical. The ether group is preferably an alkyl ether of gen bromide in glacial acetic acid (See German Unex an alkanol of 1-4 carbons, preferably a methyl or ethyl amined Laid-Open Application DOS 1,924,222) or ether. However, all other ethers conventional in steroid with a hydrochloric acid-pyridine complex at high tem chemistry can be employed, including those more peratures. See J. Chem. Soc. (London), 1963, 5072; readily cleaved than alkyl ethers, e.g., benzyl ethers. Ann. Chem. 705 (1967) 211. However, many steroid 25 Specific examples of ether groups are methoxy, ethoxy, ethers are sensitive to acids, for example, those wherein isopropoxy, n-butoxy, benzyloxy and cyclopentyloxy. acids can cause rearrangements or shifting of double The ether group or groups can be at any possible bonds. The only known method for splitting of aro position of the steroid molecule, such as, for example in matic steroid ethers which is not conducted in an acidic the 1-, 2-, 3-, 6-, 7-, 11-, 16- and 17-positions. medium employs Grignard reagents at temperatures of 30 The steroid ethers employed as the starting material about 160 C. See Tetrahedron 26 (1970) 1917. have an ether substituent on an aromatic ring, prefer Accordingly, it is an object of this invention to pro ably an aromatic A-ring. Preferred are those having at vide a process for splitting of ethers of aromatic steroid least one further double bond in the steroid molecule alcohols, particularly those with at least one additional which can be conjugated or non-conjugated with re double bond in the steroid molecule which can be con 35 spect to the aromatic A-ring, such as, for example, in ducted under non-acidic, gentle conditions, and thus the 6-, 7-, 8-, 9(11)-, 14-and/or 16-position. Moreover, which does not have the aforedescribed disadvantages. the rings of the steroid molecule can be substituted in Other objects will be apparent to those skilled in the the usual manner, such as, for example, with lower art. alkyl groups, preferably methyl, e.g., in the 1-, 2-, 4-, 40 6-, 7-, 13-, 16- and 17-positions and free or esterified SUMMARY OF THE INVENTION hydroxy groups in the 1-, 2-, 3-, 4-, 6-, 7-, 8-, 1 1-, 16-, According to this invention, ethers of aromatic ste 17- 20- and/or 21-position. roid alcohols, including those which contain at least The starting steroid ethers can be ethers of steroids one further double bond in the steroid molecule and of, e.g., the estrane, the 18-lower-alkyl-estrane, and the which are thus especially sensitive to acids and which 45 19-norpregnane series. do not withstand excessively high temperatures, are Preferred as starting steroids are A-ring aromatic cleaved to regenerate the aromatic hydroxy group by steroids, e.g., of the formula reaction with an alkyl aluminum compound or alumi num hydride of the formula AlRRR wherein R, R. and Ra are alike or different and are hydrogen or 50 straight-chain or branched-chain alkyl. It was surprising that further double bonds in the steroid molecule, i.e., those which are not part of the aromatic ring system, are not concomitantly reduced. A reduction of non-aromatic double bonds would have 55 to be expected, in accordance with the published work of Ziegler et al. (liebigs Ann. Chemie, 589, 105, 159), since alkyl aluminum compounds, such as diethylalu minum hydride, attack cyclic olefins. 60 DETAILED DISCUSSION Preferred aluminum compounds of the formula AlRRR are those wherein R and R are alike and are alkyl of 1-4 carbon atoms and Ra is Hor R, especially wherein R is lower-alkyl, preferably methyl, or benzyl; those wherein R, and R, are ethyl, n-butyl or isobutyl, 65 Rand Reach are hydrogen or lower-alkyl, preferably particularly those wherein R, and R are isobutyl. methyl; R is hydrogen or o- or 6-methyl; R" is hydro Preferred starting steroids are those wherein the A gen or lower-alkyl, preferably methyl or ethyl; X is ring is aromatic, particularly those wherein the ether C=O or CHOH and Y is C=O, CR", 3,956,348 4. num compound. After the reaction is terminated, the OH ORF OR ORF excess aluminum compound is decomposed, for exam 1. 1 / / ple, with alcohol, and then with aqueous alcohol. c C y Thereafter, the steroid product is isolated from the N H H . YCH, CH, CH, reaction mixture, e.g., by distillation of the solvents and precipitation into water, drying the precipitate and CCH i-chor extraction with an organic solvent. In case of steroid 6 O alcohols stable with respect to dilute acids at lower t temperatures, the reaction mixture, after the excess oR YoRr 10 aluminum compound has been decomposed, can im mediately be precipitated into dilute acid, e.g., 2% wherein R” is hydrogen, the acyl radical of an organic strength hydrochloric acid, and then washed neutral carboxylic acid, preferably containing one to 20, most with water after filtration. The further working-up op preferably one to eight carbon atoms, and A is a double eration and purification take place according to con bond optionally present in one or more of the 6-, 7-, 8-, 5 ventional methods, such as, for example, recrystalliza 8(14)-, 9(11)-, 14-, 5- or 16-positions. tion and chromatography. By the process of this invention, it is possible to split Without further elaboration, it is believed that one aromatic steroid ethers which do not withstand high skilled in the art can, using the preceding description, temperatures and are sensitive to acids, since the pro utilize the present invention to its fullest extent. The cess of this invention is gentler and also simpler in its 20 following preferred specific embodiments are, there conductance as compared to the conventional steroid fore, to be construed as merely illustrative, and not ether splitting process using Grignard reagents. limitative of the remainder of the disclosure in any way While carbon-to-carbon double bonds present in the whatsoever. steroid molecule are not attacked, carbonyl oxygen 25 EXAMPLE 1. atoms are reduced to hydroxy groups. As will be appar 10.0 g of 3-methoxy-1,3,5(10),7-estratetraen-17B-ol ent, any such reducible groups in the starting steroid, is suspended in 100 ml. of dry toluene. Within 20 min e.g., ester, ketone, ketalized ketone, aldehyde, epoxide, utes, 125 ml. of a 20% diisobutylaluminum hydride etc., are susceptible to being and probably will be re solution in toluene is added dropwise thereto under duced concurrently with the cleavage of the ether 30 nitrogen purging and agitation at 20° C. Under further group. Accordingly, if any such groups are present in nitrogen purging and agitation, the reaction mixture is the molecule, a correspondingly larger amount of alu heated for 6 hours under reflux. Then, the mixture is minum compound may be required to both reduce such cooled to about 0°C. Under ice cooling and while con reducible group and cleave the ether group. tinuing the nitrogen purging, 25 ml. of ethanol and then Surprisingly, if an attempt is made to block a keto 35 25 ml.