Abstract:
An efficient, one-step process for preparing 13-alkyl-17α alkyl, alkenyl, or alkynyl-17β-acyloxy-4-en-3-one steroids from their corresponding 13-alkyl-17α-substituted-3-alkoxygona-2,5(10)-dien-17β-ols is disclosed. Products of the instant process possess, for example, progestational activity.

Description:
BACKGROUND OF THE INVENTION 
     This invention relates to a process for preparing 13-alkyl-17α-substituted- 17β-acyloxy-4-en-3-one steroids, wherein the 17α-substituent may be an alkyl, alkenyl, or alkynyl group. The 17β-hydroxy-precursors of these esters are well-known and in a totally synthetic process are prepared by hydrolysis of suitably substituted 3-alkoxy-2,5(10)-gonadienes (see for example U.K. Pat. Nos. 1,041,279 and 1,111,449). The 13-alkyl-17α-substituted-17β-acyloxy-4-en-3-one steroids are well-known for their pharmaceutical efficacy; thus, for example, norethindrone acetate is currently being marketed as an orally active progestational agent. A process for their synthesis which requires several steps is described in U.K. Pat. No. 1,113,813. 
     In this particular process 13β-ethyl-17α-ethynylgon-4-en-17β-ol-3-one is contacted with an acylating agent such as acetic anhydride producing 3,17β-diacetoxy-13β-ethyl-17α-ethynyl-3,5-diene. This diacylated material must next be selectively deacylated at the 3-position to produce the desired 17β-acetoxy-13β-ethyl-17α-ethynylgon-4-en-3-one. It can be seen that in this process the conditions necessary for the acylation of the 17β-hydroxy group of the 17β-hydroxygon-4-en-3-one are also sufficient to form the 3-enol acylate, which ester must be subsequently hydrolyzed by a carefully controlled preferential deacylation at the 3-position in order to produce the desired 17β-acetoxygon-4-en-3-one (see for example U.S. Pat. No. 2,964,537 and U.K. Pat. No. 1,113,813). It is also known, that the acylation reaction itself, must be carefully controlled in order to prevent dehydration of the tertiary alcohol function at the 17-position. 
     Alternatively, the ketone function of a 17β-hydroxygon-4-en-3-one must be protected by any of the ordinary ketone-protecting groups (e.g. ethylene ketal) prior to the acylation of the 17-alcohol function. The ketone-protecting group must, however, be removed in a subsequent procedure in order to produce the desired 17β-acyloxygon-4-en-3-one. Thus, prior to the discovery of the instant invention the methods available to mono-acylate a 17β-hydroxygon-4-en-3-one required several steps, each of which possibly being accompanied by unwanted side reactions. 
     An additional advantage of the instant process is that the starting materials are 13-alkyl-17α-substituted-3-alkoxygona-2,5(10)-dien-17β-ols, and not the gon-4-en-3-ones derived from them. Those skilled in the art will appreciate the economies inuring to the elimination of each additional step in a synthetic process. 
     The new and practical process of the present invention thus provides a means whereby a 17β-acyloxy-13β-alkyl-17α-substituted-gon-4-en-3-one may be prepared directly from the correspondingly substituted 3-alkoxygona-2,5(10)-dien-17β-ol in an efficient one-step reaction process. 
     SUMMARY OF THE INVENTION 
     The invention sought to be patented resides in the concept of a process for preparing a compound of the structure: ##SPC1## 
     wherein R is alkyl of from 1 to 6 carbon atoms; R 1  is carboxylic acyl of from 1 to 4 carbon atoms; and R 2  is alkyl of from 1 to 6 carbon atoms, alkenyl of from 2 to 6 carbon atoms, or alkynyl of from 2 to 6 carbon atoms; which comprises treating a compound of the structure: ##SPC2## 
     wherein R and R 2  are as defined above and R 3  is alkyl of from 1 to 6 carbon atoms or cycloalkyl of from 3 to 7 carbon atoms; with perchloric acid and a compound of the formula (R 1 ) 2  O wherein R 1  is as defined above, utilizing an ester of formula R 1  OR 4  as solvent wherein R 1  is as defined above and R 4  is alkyl of from 1 to 6 carbon atoms, for from about 1 to about 10 minutes. 
     DESCRIPTION OF THE INVENTION 
     Starting materials for the process of the instant invention are 13-alkyl-17α-substituted-3-alkoxy-2,5(10)-dien-17β-ol steroids, whose 17α-substituent may be either an alkyl, alkenyl, or alkynyl group. Those skilled in the art will recognize that these compounds are, for example, intermediates in the total synthesis of non-aromatic &#34;A&#34;-ring steroid molecules, and are best prepared by Birch Reduction of the corresponding aromatic A-ring steroids (see for example, Fieser and Fieser, Steroids, Reinhold Publishing Corp., New York, 1959, page 591, and U.S. Pat. No. 3,547,909). 
     In carrying out the process of the instant invention, the steroid starting material is contacted for a brief period, less than 10 and preferably less than 5 minutes, with a lower alkanoic anhydride and perchloric acid using an ester as solvent for the reaction. The acyl portion of the ester should preferably be derived from the same alkanoic acid as the anhydride, to avoid the possibility of any ester exchange during the reaction. 
     In a preferred embodiment of the invention, a starting material such as dl-13-ethyl-17α-ethynyl-3-methoxygona-2,5(10)-dien-17β-ol is added either as a solid or in solution to a solution of acetic anhydride and 70% aqueous perchloric acid in ethyl acetate and the mixture is rapidly swirled for about 1.5 minutes at which time it becomes a clear solution. 
     The reaction is next quenched, for example, by the addition of a base, such as a saturated aqueous sodium bicarbonate solution. 
     The product of the reaction may next be separated and purified by procedures which will be familiar to those skilled in the art. For example, the organic solvent may be washed with saturated sodium bicarbonate and brine solutions, dried over anhydrous sodium or magnesium sulfate, filtered and evaporated. The residue may next be treated with a base such as pyridine in a solvent such as methanol to decompose any residual anhydride, which treatment may be followed by evaporation of the solvents and recrystallization of the residue. Those skilled in the art will recognize that variations in the above-described methods, or various other methods, such as chromatography, may be used to separate and purify the product of the instant process, and the proper choice of these methods and variations is within the skill of the art. 
     It has been observed that the instant process works particularly well and efficiently when the amounts of the various reagents and reactants utilized are in the following proportions: 
     1. steroid substrate (1.0 g.) 
     2. lower alkanoic anhydride (9.6 ml.) 
     3. perchloric acid (0.02 ml.) 
     4. ester (100 ml.) 
     However, the choice of quantities of reactants and reagents utilized in the instant process is not a critical aspect of the invention, and the variation of these quantities for example to optimize a particular yield is within the skill of the art. 
     While the process may be utilized to prepare a variety of lower alkanoic acid esters, it has been found to work particularly well for the preparation of acetates. This particular aspect of the invention would thus require, in addition to the steroid substrate, the use of acetic anhydride, perchloric acid, and any of the various lower alkyl acetates as solvent, for example ethyl acetate. 
     The reaction has been observed to proceed very rapidly and efficient yields are obtained when reaction times of from 1 to 3 minutes are utilized. Reaction times of longer than 10 minutes should be avoided as these longer times would increase the likelihood of competing side reactions with concomitant reduction in yield of the desired product. Because of the short reaction times involved it may be advantageous, when performing a large scale reaction, to predissolve the steroid reactant in the ester of choice and add this solution to the anhydride/perchloric acid solution dissolved in the same ester. In small scale reactions, addition of the steroid substrate to the anhydride/perchloric acid solution in either solution or in solid form has been found to produce efficient results. 
    
    
     The following non-limiting examples further illustrate the best mode contemplated by the inventor for carrying out the process of the invention. 
     EXAMPLE 1 
     dl-13-Ethyl-17α-ethynyl-17-hydroxygon-4-en-3-one, acetate 
     Prepare a fresh solution of acetic anhydride (9.6 ml.) and 70% aqueous perchloric acid (0.02 ml.) in ethyl acetate (100 ml.) then add dl-13-ethyl-17α-ethynyl-3-methoxygona-2,5(10)-dien-17-ol (1.00 g.) as a solid, [Note, on larger scale reactions it may be advantageous to dissolve the substrate in ethyl acetate first to complete the reaction rapidly ] swirl for 1.5 minutes (clear) then quench the reaction by adding saturated aqueous sodium bicarbonate solution. Wash the ethyl acetate layer with saturated bicarbonate, brine and dry over anhydrous sodium sulfate. Filter, evaporate in vacuo then add methanol with a trace of pyridine and let stand for 2 hours. Evaporate in vacuo, pump dry then treat the residue in ether with decolorizing charcoal. Filter, evaporate and crystallize the residue from methanol to obtain 326 mg. of dl-13-ethyl-17α-ethynyl-17-hydroxygon-4-en-3-one, acetate; m.p. 163°-165°; λ max .sup. KBr 3.10, 4.77, 5.68, 6.03 and 6.20 μ; λ max .sup. EtOH 239 mμ (ε 16,700). 
     EXAMPLE 2 
     d-13-Ethyl-17α-ethynyl-17-hydroxygon-4-en-3-one, acetate 
     Prepare a fresh solution of acetic anhydride (9.6 ml.) and 70% aqueous perchloric acid (0.02 ml.) in ethyl acetate (100 ml.) then add d-13-ethyl- 17α-ethynyl-3-methoxygona-2,5(10)-dien-17-ol (1.00 g.) as a solid or as a solution in ethyl acetate then swirl for 1 minute (clear). Quench by adding 1.5 ml. of water then saturated aqueous sodium bicarbonate solution. Wash the ethyl acetate layer with saturated bicarbonate, brine and dry over anhydrous sodium sulfate. Filter, evaporate in vacuo and cover the residue with methanol (40 ml.) and pyridine (0.2 ml.). Warm briefly on the steam-bath, cool and evaporate the solvent in vacuo. Pump dry then pass the residue in benzene through a short column of Florex, treat the eluate with decolorizing charcoal, filter and evaporate the solvent in vacuo. Crystallize the residue from isopropanol and recrystallize the solid obtained again from the same solvent to obtain 400 mg. of d-13-ethyl-17α-ethynyl-17-hydroxygon-4-en-3-one, acetate, m.p. 200°-202°C.; 
     λ max .sup. KBr 3.10, 4.76, 5.68, 6.02 and 6.19 μ. [α] D .sup. 26 - 26.58°  (c, 1% in chloroform). 
     EXAMPLE 3 
     dl-13-Methyl-17α-ethynyl-17-hydroxygon-4-en-3-one, acetate 
     Prepare a fresh solution of acetic anhydride (4.8 ml.) and 70% aqueous perchloric acid (0.01 ml.) in ethyl acetate (50 ml.) then add dl-13-methyl-17α-ethynyl-3-methoxygona-2,5(10)-dien- 17-Ol (0.5 g.) as a solid, swirl for 1.5 minutes then quench the reaction by adding saturated aqueous sodium bicarbonate solution. Wash the ethyl acetate layer with saturated bicarbonate, brine and dry over anhydrous sodium sulfate. Filter, evaporate in vacuo then add methanol with a trace of pyridine and let stand for 2 hours. Evaporate in vacuo, pump dry then treat the residue in ether with decolorizing charcoal. Filter, evaporate and crystallize the residue from methanol to obtain dl-13-methyl-17α-ethynyl-17-hydroxygon-4-en-3-one, acetate.