Improved process for synthesis of 5-alpha-cholest-8(14)-en-3 beta-ol-15-one and other 15-oxygenated sterols

Abstract: A process for preparing 15-oxygenated sterols, such as 3β-hydroxy-5α-cholest-8(14)-ene-15 one, comprising converting 7-dehydrocholesterol to 3β-benzoyloxycholesta-5,7-diene, converting the 3β-benzoyloxycholesta-5,7-diene to a 3β-benzoyloxy-5-cholesta-7,14-diene, converting the 3β-benzoyloxy-5-cholesta-7,14-diene to a 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene and converting the 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene to a 15-oxygenated sterol. Preferably, the 3β-benzoyloxy-cholesta-5,7-diene is converted to a 3β-benzoyloxy-5-cholesta-7,14-diene by (i) contacting 3β-benzoyloxy-cholesta-5,7-diene, in a solvent at a temperature of at most about -55°C, with HCl at a concentration of at least about 2.0 M for a time sufficient to convert the 3β-benzoyl-­ oxycholesta-5,7-diene to a 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; and (iii) recovering the 3β-benzoyloxy-5-cholesta-7,14-diene.

Description: The present invention relates to a process for preparing 3β-benzoyloxy-5-cholesta-7,14-diene as well as to a process for preparing 3β-hydroxy-5-cholest-8(14)-en-15-one and the intermediate 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene formed in that process. In many instances, the suppression of biosynthesis of sterols is desirable. For example, it is often desirable to suppress the formation of the sterol cholesterol in animals, including humans, whereby the serum cholesterol level in the animal will be lowered. The concentration of cholesterol in blood serum has been correlated with a number of diseases, particularly atherosclerosis. Atherosclerosis is a condition marked by the formation of plaques in the arterial system. Cholesterol and cholesterol esters are major components of these plaques. While the etiology of the disease is not completely known, it appears that an elevated serum cholesterol level contributes to the development and the progression of atherosclerosis. Cholesterol in animals is derived from two sources, firstly the intake and absorption of dietary cholesterol and secondly the biosynthesis of cholesterol from acetate by cells of various organs of the body, e.g., liver, intestines, and skin. The biosynthesis of cholesterol and other sterols from acetate in the body involves a complex sequence of reactions, one of which is the conversion of 3-hydroxy-3-methylglutaryl Coenzyme A into mevalonic acid. This reaction is considered to be a major regulation point in the normal biosynthesis of cholesterol in cells. If the biosynthesis of mevalonic acid can be inhibited in vivo, production of sterols is reduced, and serum cholesterol levels can thereby be lowered. In GB-A-860,303 certain aryloxy carboxylic acid esters, such as the methyl ester of 2-(4'-chloro-phenoxy)isobutyric acid, are proposed for use in suppressing blood cholesterol levels. While this compound has acquired significant importance in the clinical treatment of humans, for various reasons it is not as effective as is desired. Accordingly, more effective compounds for suppressing serum cholesterol levels are of great interest and importance. Obesity is also a serious health problem. The correlation between excess weight and a number of diseases, particularly cardiovascular diseases, is well-known. Many people, often for psychological or other reasons, find it difficult or impossible to adhere to weight control or weight loss diets. For this reason, techniques for safely and effectively suppressing appetite are greatly needed. It is known from US-A-4,202,891, which patent is fully incorporated herein, that certain 15-oxygenated sterols are effective in the inhibition of the biosynthesis of mevalonic acid and of sterols. A number of desirable effects can be derived from the inhibition of the biosynthesis of mevalonic acid, including suppressing the formation of cholesterol in animals, whereby serum cholesterol levels may be lowered. In addition, the growth and proliferation of the cells of higher organisms and certain microorganisms, such as yeast and fungi, involve the formation of sterols. Accordingly, inhibition of the biosynthesis of mevalonic acid, and thus reducing sterol formation, is effective to inhibit the growth of cells, both normal and tumorous. Furthermore, inhibition of the biological synthesis of sterols has the effect of inhibiting the growth of certain microorganisms, thereby combatting fungal and yeast infections. In addition to its role in sterol biosynthesis, mevalonic acid is an important percursor of a number of other important constituents of cells. Thus, while bacteria are generally considered to not contain or need sterols, their growth and proliferation requires synthesis of mevalonic acid and the products derived therefrom. Accordingly, inhibition of mevalonic acid biosynthesis should inhibit bacterial growth. Also the 15-oxygenated sterols and their derivatives are effective to suppress appetite. While the mechanism by which the 15-oxygenated sterols function to suppress appetite is not known, it is believed that this effect is in some way related to the mevalonic acid or sterol biosynthesis inhibiting activity of the 15-oxygenated sterols. The 15-oxygenated sterols of US-A-4,202,891 represent desirable compounds that exhibit a high degree of activity. However, the heretofore known processes for manufacturing the 15-oxygenated sterols have proven costly and time consuming. Often very small yields of the desired products have been obtained or the processes proved difficult to carry out on a large scale for various reasons such as requirements for extensive chromatography. In addition, known processes for the production of 3β-benzoyloxy-5-cholesta-7,14-diene, a key intermediate in the production of 15-oxygenated sterols from 7-dehydrocholesterol, have been unsatisfactory because known procedures are highly variable. On occasion the desired product was obtained in reasonable yield with a reasonable degree of purity; however, frequently the yield and purity were much lower than desired and unknown side products were observed. A process for preparing 15-oxygenated sterols from 7-dehydrocholesterol is known from Y.org. Chem. 1986, 51, pages 4047-4053. The conversion of the 5,7-diene to the 7,14-diene in this process is accomplished by treatment with dilute HCl at low temperatures of -30 to -40°C. FR-A-2 390 960 relates to 15-oxygenated sterols and their use for inhibiting the biosynthesis of mevalonic acid and lowering the serum cholesterol level. It is the object underlying the present invention to provide a procedure for production, on a large scale, of high quality 15-oxygenated sterols in consistent high yields, the 15-oxygenated sterols obtained therewith having corresponding effectiveness and efficiency as the 15-oxygenated sterols known in the state of the art. In accordance with the present invention this object is accomplished with a process for converting 3β-benzoyloxycholesta-5,7-diene to 3β-benzoyloxy-5-cholesta-7,14-diene comprising: (i) forming a first reaction mixture by contacting 3β-benzoyloxycnolesta-5,7-diene, in a solvent at a temperature of at most -55°C, with HCl at a concentration in said solvent of at least about 2.0 M for a time sufficient to convert said 3β-benzoyloxycholesta-5,7-diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; and (iii) recovering said 3β-benzoyloxy-5-cholesta-7,14-diene; and with a process for converting 3β-benzoyloxycholesta-5,7-diene to 3β-hydroxy-5-cholest-8(14)-en-15-one comprising the steps: (i) forming a first reaction mixture by contacting 3β-benzoyloxycholesta-5,7-diene, in a solvent at a temperature of at most -55°C, with HCl at a concentration in said solvent of at least about 2.0 M for a time sufficient to convert said 3β-benzoyloxycholesta-5,7-diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; (iii) forming a solution of 3β-benzoyloxy-5-cholesta-7,14-diene and diethyl ether and subsequently cooling said solution; (iv) forming a second reaction mixture by adding a mixture comprising MCPBA and NaHCO₃ to said solution, and cooling said second reaction mixture to form 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene; and (v) converting said 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene to said 3β-hydroxy-5-cholest-8(14)-en-15-one. Further, the present invention provides the intermediary compound 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene. Preferred embodiments of the present invention are set forth in the dependent claims. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents a schematic flow chart of a reaction sequence according to the present invention along with corresponding structural formulae. Figure 2 represents a more detailed schematic flow chart or the reaction sequence, showing intermediates and by products produced by the process of the present invention. Figure 3 represents detailed structural formulae of certain compounds discussed in the present specification. The 15-oxygenated sterol compound obtained according to the present invention is useful for inhibiting the biosynthesis of mevalonic acid, including all effects derived from inhibition of biosynthesis of mevalonic acid. Effects derived from inhibition of the biosynthesis of mevalonic acid include supression of the biosynthesis of sterols with a resultant reduction in serum cholesterol levels, in animals, and the inhibition of microorganism and cell growth. The 15-oxygenated sterol is also effective to suppress appetite, which effect is believed to be related to its inhibitory activity on the biosynthesis of mevalonic acid and products derived therefrom, most especially cholesterol. The compounds discussed herein are each assigned a reference number, which reference numbers are correlated in Figures 1 and 3 to the corresponding structural formulae. The present invention relates to an improved synthesis technique for preparing 3β-hydroxy-5α-cholest-8(14)-en-15-one ( 1a ) from 7-dehydrocholesterol( 2 ). Such a process is generally disclosed in Parish et al., Chemistry and Physics of Lipids, 18 , 233-239, 1977; Schroepfer et al., Journal of Biological Chemistry, 252 , 8975-8980, 1977. However, the present improved process is more suitable for use an a large-scale and is more capable of consistently producing a high yield of a relatively pure product. Development of the process of the present invention has involved, inter alia , the isolation and identification of intermediates and side products produced in the various process steps as well as appreciation of their implications. The present invention involves the conversion of 7-dehydrocholesterol ( 2 ) to 3β-benzoyloxycholesta-5,7-diene ( 3 ), conversion of 3β-benzoyloxycholesta-5,7-diene to 3β-benzoyloxy-5-cholesta-7,14-diene ( 4 ), conversion of the 3β-benzoyloxy-5-cholesta-7,14-diene to a 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene ( 5 ), and, finally, conversion of said 3β-benzoyloxy-14α, 15α,-epoxy-5-cholest-7-ene to a 15-oxygenated sterol, preferably, 3β-hydroxy-5α-cholest-8(14)-en-15-one ( 1a ). In accordance with the present invention, 3β-benzoyloxy-cholesta-5,7-diene is converted to a 3β-benzoyloxy-5-cholesta-7,14-diene by a process comprising: (i) contacting 3β-benzoyloxy-cholesta-5,7-diene, in a solvent at a temperature of at most -55°C, with HCl at a concentration of at least about 2.0 M for a time sufficient to convert the 3β-benzoyloxycholesta-5,7- diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene ( 8a and 8b ); and (iii) recovering the 3β-benzoyloxy-5-cholesta-7,14-diene. Preparation of Benzoate (Step 1). Conversion of 7-dehydrocholesterol ( 2 ) to the Δ 5,7 benzoate ( 3 ) can be accomplished by known techniques, such as reacting ( 2 ) with benzoyl chloride. The reactants may be refluxed in a solvent, such as pyridine and the product recovered by filtration after cooling the reaction mixture. A high purity product can be obtained in a high yield by washing ( e.g. , with water and dilute carbonate) and recrystallization ( e.g. , in hot CHCl₃). Diene Isomerization (Step 2). Prior techniques for conversion of the Δ 5,7 diene ( 3 ) to the 5α-Δ 7,14 isomer ( 4a ) have proven to produce highly variable results. Yields varied from 30% (or less) to 70%. Furthermore, despite attempts to maintain constant reaction conditions, the desired product 4a was often contaminated with variable amounts of several different compounds. Even more complexity with respect to the product composition was observed in attempts to obtain a second crop of the product from the initial crystallization. Moderate variation of such factors as reaction temperature, purity of the starting material and solvents, duration of reaction, and temperature of quenching of the reaction had little or no discernable effect on the product composition. Isolation and identification of the major intermediates and side products in the reaction were undertaken in an attempt to develop optimum reaction conditions. In preparing the 5α-Δ 7,14 isomer by contacting the Δ 5,7 diene with HCl at a low temperature, the principal intermediate was found to be 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene ( 7 ), along with minor amounts of species 8a and 9a . The principal side product was found to be the 5β-Δ 8,14 isomer 9b . The 3β-benzoyloxy-5β-cholesta-7,14-diene isomer 4b was also isolated as a minor side product. The structures were determined by conventional analytical techniques, such as NMR and x-ray crystallography, familiar to those having skill in the art. Although chloro intermediates in the diene isomerization of sterols were proposed by D.H.R. Barton, Journal Chemical Society, 512-522 (1946), over forty years ago, such an intermediate has not previously been isolated or identified. Additionally, while 5β-isomers have been previously reported in sterol diene isomerizations, see, for example, D.H.R. Barton, Journal Chemical Society, 1116-1123 (1946), the formation of 5β-dienes by low-temperature addition of HCl to a Δ 5,7 system has not previously been reported. A proposed pathway for the diene isomerization depicted in Figure 1 (3→4) is shown in Figure 2 with the principal intermediates and side products indicated. Isomerization of the 5β-dienes appears to follow a pathway similar to that for the 5α-dienes. However, as discussed below, the reaction rates appear to be different for the 5α and 5β systems, and no chloro intermediate corresponding to 7 has been observed in the 5β-sterol pathway. Analysis of the total reaction product indicated that approximately 20% of the initial protonation of the Δ 5,7 systems occurred so as to give 5β-sterols. Since the 5β-dienes constitute the bulk of the impurities in the isomerization reaction, any attempts to further increase the yield of the desired product 4a would require modifications of conditions to further favor the initial addition of HCl to the α face of the sterol. For purposes of producing 5 α sterols, it is advantageous to reduce the principal side product 4b . However, 15-oxygenated 5 β -sterols are also potent inhibitors of sterol biosynthesis. Thus, production of both the key intermediate 4a and the side product 4b is advantageous. Accordingly, both are within the scope and spirit of the present invention. Further, it should be apparent that although the discussion focuses on the production of 5 α -sterols, processes for producing 5 β -sterols from the side product 4b are the same as those for producing 5 α -sterols from 4a . Accordingly, the process disclosed herein with regard to 5 α -sterols applies equally as well to 5 β -sterols and the use of either the 4a or 4b intermediate is within the scope and spirit of the invention. Once the various species in the diene isomerization have been identified and characterized by conventional techniques, such as ¹H and ¹³C NMR, TLC and HPLC, the course of the reaction can be followed by periodically analyzing aliquots of the reaction. The results of this analysis indicate that the Δ 5,7 isomer reacts very rapidly to form 7 . This 1,2 addition of HCl to the Δ 5,7 system contrasts with the 1,4 addition proposed by Barton, J. Chem. Soc. 1946, 512-522, and with the preferred Markovnikov addition of HCl to Δ⁵ steroids. See, e.g., Barton, Experientice, Suppl. II, 1955, 121-136. The slow step of the reaction appears to be the dehydrohalogenation of 7 , which bears a pseudo -equatorial chlorine. It has been found that, at low temperatures, this elimination requires a rather high concentration of HCl, suggesting the intermediacy of the pseudo -axial 6β-epimer of 7 . Consistently low levels of the 5α-Δ 6,8(14) isomer 8a were observed as the reaction progressed, suggesting that conversion of 8a to the 5α-Δ 7,14 diene 4a is much faster than the dehydrohalogenation of 7 . The isomerization of 4a to the 5α-Δ 8,14 isomer 9a appears to be somewhat slower than the dehydrohalogenation of 7 , since it was discovered that the reaction can be quenched at an optimal time when 7 has completely reacted yet only minor amounts of the 9a isomer have formed. Based on these observations, a procedure was developed for consistently obtaining good yields and high product purity in the isomerization reaction, i.e. , the process for preparing 4a . Generally, the reaction was carried out at a low temperature (no more than -55°C and preferrably between -65° and -75°C). Low temperature promotes the solubility of HCl in the solvent and retards formation of the 5α-Δ 8,14 isomer 9a , thereby insuring that the time period for optimal quenching of the reaction is not too short. By adding CH₂Cl₂ to a CHCl₃ solvent, it is possible to lower the freezing point without adversely affecting solubility of the Δ 5,7 isomer 3 . A solvent mixture of CHCl₃ and CH₂Cl₂ in a weight ratio of about 3:1 has proven to be satisfactory. Of course, other solvents or solvent mixtures that have a low freezing point and good solubility for HCl and the Δ 5,7 isomer may be used. To counteract the tendency of the starting material to crystallize out at low temperature, HCl gas is preferably introduced rapidly until a concentration of about 2.0-2.5 M is obtained. After the flow of HCl is shut off, the conversion of 7 to 4a is allowed to proceed at no more than -55°C, and preferably between -65° to -70°C. The reaction can be monitored periodically, such as by chromatography (e.g., TLC) on a aliquot of the reaction mixture, to determine the optimal quenching time. After the Δ 5,7 diene ( 3 ) has been isomerized to the Δ 7,14 intermediate ( 4a ), but prior to the production of any significant amount of Δ 8,14 byproduct ( 9a ), the reaction solution is quenched (neutralized) with a base such as NH₄OH. Subsequent to quenching and extraction of the product, an additional base such as pyridine may be added to the CHCl₃ solution to neutralize any additional HCl released from the dehydrohalogenation of 7 , thus preventing HCl-catalyzed isomerization of the 5α-Δ 7,14 isomer 4a to the 5α-Δ 8,14 isomer 9a . Partial evaporation of the CHCl₃ extracts followed by addition of a polar solvent such as acetone produces a precipitate composed of about 90% 4a and about 10% 9a and 9b (combined). Using this procedure, twelve consecutive reactions (700-1000 g scale) gave 77-84% (average 82%) yields of 4a of 83-91% purity (average 88%). The 5β-isomers produced along with the 5α-isomers can be easily separated from the 5α-isomers by recrystallization from CHCl₃-acetone (1:2), but the 5α-isomers, especially the 5α-Δ 7,14 and 5α-Δ 8,14 isomers 4a and 9a , are not, on a preparative scale, readily separated by recrystallization or chromatography. ¹³C NMR provides the most useful approach for compositional analysis of reaction mixtures derived from the treatment of the Δ 5,7 diene 3 with HCl since all of the known components can be resolved without decomposition. Most of the diene species could be resolved by ¹H NMR, capillary GC, and reversed-phase HPLC; however, the chloro intermediate 7 was unstable upon chromatography. Compositional analysis of mixtures of any pair of dienes (including 7 ) could be carried out by ¹H NMR by examination of either the 3α-H, vinyl, or methyl ¹H NMR resonances, but in more complex mixtures, overlap of these peaks precluded quantitation. Decomposition of the sterol benzoates was a major impediment to quantitation by capillary GC. This problem can be overcome by using a very clean column. However, even under these conditions, the 5α-Δ 7,14 and 5α-Δ 8,14 peaks (for 4a and 9a ) are barely resolved. Reversed-phase HPLC gave fairly good resolution of all dienes except for 4a and 9a . Normal-phase HPLC of sterol benzoates is unsatisfactory because of excessive peak tailing. The isolation of 5β-dienes has not been reported previously in low-temperature isomerizations of Δ 5,7 dienes. From the isomerization of a 5β-Δ 6,8(14) acetate, Windaus et al., Justus Liebigs Ann. Chemistry , 536 , 204-216 (1938) isolated a new diene which was later identified by D.H.R. Barton, Journal Chemical Society , 1946, 1116-1123 as the 5β-Δ 8,14 diene acetate 9f . Saponification and acetylation of the 5β-Δ 8,14 species 9b gave a diene acetate 9f virtually identical in melting point, UV spectrum, and optical rotation with the Windaus diene. A more recent example of a 5β-diene is the reported isolation in the ergosterol series of a 5β-Δ 6,8(14) diene, which was unexpectedly resistant to acid isomerization to other dienes under refluxing with aqueous HCl/ethanol. See J. Andrieux, D.H.R. Barton, H. Patin, Journal of the Chemical Society , Perkin Transactions 1, 359-363 (1977). Surprisingly, no 5β-Δ 8,14 species was observed when ergosterol was subjected to the Fieser conditions. See Fieser et al., Journal American Chemical Society , 74 , 5397-5403 (1952). Although the major side product of diene 3 isomerizations in CHCl₃ is 9b , the major side product of one reaction in CH₂Cl₂ was the 5β-Δ 7,14 species 4b . Apparently, 4b was converted to the 5β-Δ 8,14 species 9b more slowly in CH₂Cl₂ than in CHCl₃/CH₂Cl₂ (4:1). Another major side product of this reaction in CH₂Cl₂ was found to be 3β-benzoyloxy-5α-cholest-8(14)-en-7α-ol ( 10a ). The structure of 10a was established by hydrolysis to the known diol 10b . Compound 10a probably arose during workup from a cationic or chloro intermediate formed by protonation or addition of water to either the 5α-Δ 6,8(14) or 5α-Δ 7,14 species ( 8a or 4a ). No 5β-epimer of chloro intermediate 7 has been detected. If 1,2 addition of HCl occurs in a syn manner, then the resulting 6β-chloro substituent would be pseudo -axial and, unlike 7 , capable of facile elimination to the 5β-Δ 6,8(14) species 8b . Diene 8b is believed to be an intermediate, isolated in impure form. In dilute (1%) solution in ethyl acetate or benzene, 7 was demonstrated to be stable for 12 days. In methanol or ethanol or in concentrated CHCl₃ solution, 7 decomposed within 5 hours to a mixture of dienes 3 , 8a , and a component which probably represents 3β-benzoyloxy-5α-cholesta-6,8-diene( 11 ). Little dehydrohalogenation was observed after 3 hours for 2% solutions of 7 in CHCl₃ or in CHCl₃ containing 10% triethylamine or pyridine. Upon slow heating (10 min) in a capillary tube, 7 melted as low as 135°C. At a normal heating rate for melting point determination, 7 melted at 154-155°C. These combined observations suggest that HCl promotes the decomposition of 7 ; the HCl released then further accelerates the decomposition. The rapid decomposition of 7 in alcohols may stem from catalytic release of HCl by nucleophilic substitution by the alcohol. Epoxidation and Hydrolysis to Ketone 1 (Steps 3 and 4). The Δ7,14 diene 4a can be epoxidized to 5a following known modifications shown in Parish et al., Chem. Phys. Lipids 18 , 233-239 (1977), i.e. , treatment of 4a with m -chloroperbenzoic acid (MCPBA). The known process could not be readily scaled up because of the limited solubility of 4a in ether. The known epoxidation procedure can be improved by the addition of solid NaHCO₃ to the reaction mixture to neutralize 3-chlorobenzoic acid (present both as a contaminant in m -chloroperbenzoic acid and as a product of the epoxidation reaction) and thereby prevent the acid-catalyzed decomposition of the epoxide product. In addition, it has been found desirable to add the MCPBA to the reaction mixture at a higher temperature than shown in Parish, id ., in order to prevent precipitation of the starting material. From 164 epoxidation reactions carried out on a 140 g scale, yields of 57-68% (average 63%) were obtained, or 65-81% (average 72%) assuming 88% purity for the starting diene 4a . The purity of the epoxide 5 was judged by melting point (mp) since techniques such as ¹H NMR, TLC and HPLC did not reveal any impurities for samples of 5 melting 12°C lower than the normal mp of 211°C. Lower-melting samples of 5 gave significantly lower yields (50% vs. 65%) in the subsequent conversion to 1 . Epoxide 5 can be hydrolyzed to 6 in just 5 min and, on a 5 g scale, afforded an 82% yield. However, on a 200 g scale, purification of the intermediate 6 consumes vast amounts of time and solvent, and typical yields were only about 50%. Scaling up the existing procedure for converting 6 to 1 is also hampered by the limited solubility of 6 in the hydrolysis solvent: using a 5 liter flask, this reaction could be carried out on only a 30-40 g scale. In accordance with the known procedure, intermediate 6 is subsequently hydrolyzed to 1 . However, the reagent for both steps is mineral acid in an organic solvent (milder conditions being used in the first step), and it has been found that the two steps may be combined. Specifically, it was found that the conditions for transforming 6 to 1 were also sufficient for transforming 5 to 1 . In order to carry out 120 g scale reactions in a 5 liter flask, the reaction was allowed to begin with large amounts of undissolved 5 , which went into solution as the reaction progressed. In the two-step reaction, the first step produced side products generally less polar than 6 , and the second step gave side products generally more polar than 1 . In the one-pot reaction, 1 had to be separated from both more and less polar side products. This separation was achieved by using a two-phase recrystallization from hexane/methanol/water: the polar impurities remained in the methanol/water phase, the non-polar impurities remained in the hexane phase, and 1 , being soluble in neither phase, crystallized out at the interface in long, large needles. After two such recrystallizations, samples of 1 contained less than 1% non-polar impurities and approximately 5% polar impurities. Filtration through silica gel using a relatively nonpolar solvent (CH₂Cl₂ or CHCl₃) afforded 1 of greater than 99% purity. Using the procedure of the present invention, 101 hydrolyses of 5 on a 120-140 g scale gave greater than 99% pure 1 in 58-71% yield (average 65%). The major side products of the one pot conversion of 5 to 1 were the benzoate ester 6 and the aromatic ring C sterol 12 . The configuration of 12 at C-17 was established to be 17α(H) by comparison of the NMR chemical shifts (17-H and 21-H₃) with those reported for 12 and its epimer at C-17. Three minor side products were also isolated: 9α-hydroxy derivatives of 1 and 6 ( 13a and 13b ) and a keto-diol. When 1 or 6 was subjected to the hydrolysis conditions for converting 5 to 1 , the recovered 1 was found to contain several impurities. Conducting the reaction under argon reduced the amount of impurities somewhat compared to reactions in air. The absence of 12 in these impurities indicates that neither 1 nor 6 is an intermediate in the formation of 12 . The formation of 12 from α,β-unsaturated sterol epoxides has been previously studied and appears to involve a 7,9 (11),14-triene intermediate. In summary, there has been described significant improvements in the synthesis of ketone 1 from 7-dehydrocholesterol 2 so that the reactions can be carried out on a large scale in a reasonably short period of time. The synthesis has been shortened to four steps, for which the average yields for the individual steps were 97%, 82% (88% purity), 63%, and 65%. The overall average yield for conversion of 7-dehydrocholesterol to 1 was 33%. The highest yields for the individual steps were 97%, 84%, 68% and 71%, giving an overall best yield of 39%, which is at least 40% higher than previously reported for the syntheses of 1 . The present invention also provides for a much-improved large-scale synthesis of epoxide 5 , which is a key intermediate not only in the synthesis of 1 but also in the synthesis of a number of other 15-oxygenated sterols. In the course of optimizing the conditions for each step in this synthetic scheme, major side products of these reactions have been isolated and identified. In addition, new intermediates and side products in the diene isomerization reaction have been discovered, findings which have significant implications with respect to the mechanism and use of this reaction. For example, the reason high HCl concentrations are required for the diene isomerization at low temperature is to promote the dehydrohalogenation of the chloro intermediate 7 , the slow step in the overall conversion of 3 to 4a . Furthermore, under conditions developed herein, the 5α-Δ 7-14 diene 4a can be obtained with only minor amounts of the 5α-Δ 8,14 isomer 9a ; the 5-15% Δ 8,14 contaminant observed is mainly the 5β-Δ 8,14 isomer 9b , which can be removed by recrystallization. With reference to the following Examples, the invention will now be described in further detail. EXAMPLE I 3β-Benzoyloxycholesta-5,7-diene (3) . In a 5 l round bottom flask are placed 1000.0 g (2.60 moles) 7-dehydrocholesterol (Chemical Dynamics, containing 3.3% methanol), 2.4 l dry pyridine (Aldrich Gold Label, 0.05% water), and 550 mℓ (4.74 mol) benzoyl chloride (Aldrich, 99%). The contents are swirled briefly, heated rapidly (15 min) to boiling, and refluxed for 5 min. A small (approximately 200 mℓ) bottom layer of pyridinium chloride (composition by ¹H and ¹³C NMR analysis) normally forms and solidifies when the reaction mixture is cooled. After 30 min of cooling in air, the dark reaction mixture is poured over ice, swirled, and allowed to stand at 20°C for 1-2 hours. The precipitate which forms is collected by suction filtration. The filter cake is washed successively with 7 l of water, 4 l of dilute sodium carbonate, 7 l of water, and 4 times with 500 mℓ of acetone. The filter cake is pulverized and allowed to dry in air overnight. The crude product (97-105% yield) shows a single spot by TLC (silica gel eluted with toluene/hexane 1:1, R f 0.58) and melts at 140-144°C, clearing at 191°C. It appeared to be pure by ¹H and ¹³C NMR except for a trace (less than 1 mole %) of methyl benzoate. The excess mass (up to 8%) of some samples is apparently water. Although the crude product gives satisfactory results in the subsequent diene isomerization, this material is normally recrystallized by dissolving it in 2 l of hot CHCl₃ (the small aqueous phase which forms is ignored) and precipitating the sterol by addition of 5 l of acetone. After cooling and subsequent storage overnight at -20°C, the crystals are filtered, washed twice with 300 mℓ of cold acetone, and dried to constant mass. The yield of white crystals was 1193 g (97% yield). In one run, no impurities were detected at the 1% level by ¹H or ¹³C NMR, and a single spot was observed on TLC at R f 0.58 (solvent, toluene/hexane 1:1). Two recrystallizations of 5.00 g of this material from hot acetone/CHCl₃ gave an analytical sample (2.7 g of colorless needles). Values obtained by standard analytical methods conform well to previously reported values. Four consecutive reactions carried out on a 700 g scale gave similar results with yields of 836, 838, 836, and 827 g (average, 834 g; 97% yield, based on 3.3% methanol in the starting 7-dehydrocholesterol) and virtually identical physical constants. A sterol material balance carried out for this reaction showed that the acetone washings contained only pyridine and methyl benzoate and that the filtrate from recrystallization contained a mixture of sterols (1.9% of total sterol mass). EXAMPLE II 3β-Benzoyloxy-5α- cholesta-7,14-diene (4a), large-scale preparation . A solution of 1000 g of 3 in a mixture of CHCl₃ (3000 mℓ) and CH₂Cl₂ (800 mℓ) is prepared in a 5 l round bottom flask fitted with a thermometer, a gas dispersion tube, an outlet port, and a mechanical stirrer. The flask is rapidly cooled to -55°C, and HCl gas is bubbled through the partially crystallized reaction mixture at a flow rate of 50 on a Gilmont size 2 flowmeter (Gilmont Instruments, Great Neck, NY). The reaction mixture is further cooled as rapidly as possible to -65° to -70°C over the next 30-60 min, and then the HCl flow is increased to 100 on the flowmeter. These flow and temperature conditions are maintained until the HCl concentration is 2.0-2.5 M (determined by titration of a reaction aliquot with standard base). The HCl flow is then shut off, and the reaction monitored every 15-30 min by TLC (silica gel spotted with a neutralized, washed aliquot or the reaction mixture and developed with toluene/hexane 1:1). The reaction is considered complete when, instead of 3 overlapping spots at R f 0.50, 0.55, and 0.60, only a single spot at R f 0.55 is observed. Most of the HCl is then evaporated in vacuo over the next 40-60 min by drawing the HCl vapors through a sodium hydroxide trap using a water aspirator. The reaction mixture is neutralized by pouring (with vigorous swirling) 600 mℓ portions of the cold, dark reaction mixture into a 2 l Erlenmeyer flask containing 500 g of ice and 150 mℓ of concentrated NH₄OH. The neutralized mixtures are combined in a 6 l separatory funnel, the aqueous phase discarded, the organic phase washed twice with 2.5 l of water, and the lower phase immediately drained into 120 mℓ of pyridine. The cloudy organic layer becomes clear after a few minutes, and the solution is drawn into the continuous feed tube of a rotary evaporator, typically leaving behind a small aqueous layer. The (often turbid) solution is concentrated from about 5 l to 3.0 l and divided into two portions. Acetone (total 3.0 l) is then added rapidly with swirling. Crystallization is allowed to proceed for a few minutes, an additional 3.0 l of acetone is added, and the mixture is stored overnight at 4°C. The crystals are collected by suction filtration, washed twice with 100 mℓ of acetone, pressed very dry, pulverized, and dried to constant mass. A white powder (815-841 g) containing Δ 7,14 diene 4a in 83-88% purity is obtained. The impurities are a mixture of sterol benzoates principally 9a and 9b ). The former (but not the latter) impurity can be removed by recrystallization from acetone/CHCl₃ (2:1) as described above. The yield and purity ranges given above are based on six 1000 g scale reactions. The best reaction gave 836 g (84% crude yield) of material which assayed at 88% purity. (A second crop obtained from concentration of the filtrate consisted of 4a and 9b in a 1:4 ratio.) This 88% pure product was assayed by ¹H NMR (comparison of the intensities of the Δ 7,14 vinyl peaks at δ5.76 and δ5.52 with the height of the 5α-Δ 8,14 /5β-Δ 8,14 peak at δ5.4), HPLC (comparing the intensity of the 4a / 9a peak with that of the 9b peak), by capillary GC (comparing the intensity of the partially resolved 4a / 9a peak with that of the 9b peak), by TLC (single spot at R f = 0.53 on silica gel developed with toluene/hexane 1:1 and R f 0.35 on silica gel coated with AgNO₃ developed with toluene/hexane 1:1), and by mp (151-153°C; 98% pure 4a melts at 154.4-156°C, vide infra ). EXAMPLE III 3β-Benzoyloxy-5α- cholesta-7,14-diene (4a), analytical sample . A diene isomerization was carried out on a 450 g scale using the procedure described above. The first crop of 269 g (60% yield) of white solid (assayed by ¹H NMR at 94% 4a , contaminated mainly with 9b ) was recrystallized by dissolving it in 700 mℓ of hot CHCl₃ containing 1 mℓ pyridine and adding 1.0 l of hot acetone. The product was collected after 24 hr to give 220 g of colorless crystals of 4a of 95% purity (¹H NMR). Two additional recrystallizations gave 181 g (98% purity) and 127.8 g (98% purity). The structure and purity were confirmed by standard analytical techniques. Because no impurities could be detected by HPLC analysis, the 2% Δ 8,14 impurity observed in the ¹H NMR spectrum was judged to be 9a . Concentrations of diene intermediates as the reaction progresses . A diene isomerization was carried out as described above but using 20 g of 4a in 120 mℓ of CHCl₃/CH₂Cl₂ (4:1). The reaction was cooled to -55°C, a saturated solution of HCl in CHCl₃ (30 mℓ, -55°C) was added, and HCl was allowed to bubble through the reaction mixture for 20 min. Then the HCl was shut off, and the reaction was held at -65°C. At various times (2, 6, 17, 26 55, 75, 115, 160, 220, and 300 min) approximately 10 mℓ aliquots were removed from the reaction and poured into cold concentrated NH₄OH. The resulting organic layer was washed with water, rotary evaporated to an oil or solid, and dissolved in CDCl₃ (deuterated chloroform, C²HCl₃) immediately prior to ¹H and ¹³C NMR analysis. The results of the NMR analysis appear in Table I. An analogous experiment carried out on a 200 g scale gave similar results. EXAMPLE IV 3β-Benzoyloxy-6α-chloro-5α-cholest-7-ene (7) . To a solution of 1.6 M HCl in 100 mℓ CHCl₃ (ethanol-free) at -65°C is added with stirring a solution of 10.0 g of 3 in 100 mℓ of CHCl₃ (ethanol-free) at -5 C. The resulting amber solution is stirred at -62 C for 70 s and poured into a mixture of 50 mℓ of concentrated NH₄OH and 50 g of ice. The neutralization mixture is swirled vigorously and placed in a separatory funnel. The cold organic layer is drained into 5 mℓ of pyridine and washed with 2 x 150 mℓ of water. After addition of another 5 mℓ of pyridine, the organic layer is rotary evaporated to a moist solid and dried overnight in vacuo . A sample of the resulting solid (10.74 g) obtained by the above procedure was analyzed by ¹H NMR and found to contain 50% 7 , 25% 4a , 5% 3 , and 20% of a substance believed to be the 5β-Δ 6,8(14) isomer 8b . After dissolving the crude sample (10.74 g) in 30 mℓ of CHCl₃, addition of 60 mℓ of acetone yields a slowly forming precipitate, which is collected after 30 min by suction filtration. This product (3.38 g) is subjected to five additional recrystallizations to give an analytical sample of 7 (0.37 g) melting over a 2°-3° range at 135° (slow heating) or 155°C (fast heating). Upon melting, gas was evolved and the product decomposed mainly to 8a (analysis of melted material by ¹H NMR). The structure of 7 was confirmed by various analytical techniques. EXAMPLE V Stability of 7 under various conditions . Solutions of 7 were prepared in EtOAc (1% w/v), anhydrous ether (1%), benzene (1%), and acetone (0.5%). Aliquots of the solutions were removed after 0.5 h, 24 h, and 12 days, evaporated to dryness in a stream of nitrogen, dissolved in CDCl₃, and immediately analyzed by ¹H NMR. Any Δ 5,7 and Δ 6,8(14) impurities ( 3 , 8a , 8b ) could be detected at the 5% level, and Δ 7,14 and Δ 8,14 impurities ( 4a , 4b , 9a , 9b ) could be detected at the 2% level. No impurities were detected after 0.5 h or 24 h in any of the solvents. After 12 days, no decomposition was observed for the EtOAc or benzene solutions. However, 7 had decomposed completely to 8a in ether solution and partially to a mixture including 8a and 3 in the acetone solution. In other experiments, a 0.13% solution of 7 in cyclohexane stored at 20°C for 6 weeks showed no decomposition to 8a or any other sterol (2% detection limit). A 0.06% solution of 7 in hexane (Burdick and Jackson) stored at 20°C for 30 h showed decomposition to 8a (admixed with 5-10% each of 11 and 7 ). Solutions of 50 mg of 7 in 6 mℓ of CHCl₃/methanol (1:1) or CHCl₃/ethanol (1:1) each containing 0.1 mℓ pyridine decomposed completely after 1 h at 20°C to a mixture of 3 , 8a , and 11 . A 20% solution of 7 decomposed rapidly in CDCl₃ solution (contained 5% 8a after 1 h, decomposed completely to 9a and unidentified sterols after 5 h) whereas a dilute (2%) solution in CDCl₃ decomposed more slowly (approximately 10% each of 8a and 11 after 11 h). At -20°C, a 2% solution of 7 in CDCl₃ was stable for a month. In CHCl₃ solution in the absence of base, 7 decomposed to 9a and lesser amounts of unidentified substances. A stirred solution of 7 in CHCl₃ containing solid Na₂CO₃ or pyridine was found after 48 h to consist primarily of 11 and less than 20% each of 8a and 3 . A 2% solution of 7 in CDCl₃ containing 10% pyridine or triethylamine showed no detectable decomposition products (<10%) after 3 h at 20°C. Stirring a solution of 7 in tetrahydrofuran containing solid AgNO₃ resulted in a mixture of 3 , 8a , and 11 . Heating 7 at 80-120°C for 10 min in an unsealed tube did not lead to detectable (more than 10%) decomposition (¹ H NMR analysis). EXAMPLE VI 3β-Benzolyoxy-14α,15α-epoxy-5α-cholest-7-ene (5) . A solution of 140 g (0.29 mol, 90% pure) of 4a in 5.3 l of diethyl ether is prepared by gentle warming on a steam bath. This solution is placed in an ice bath and cooled to 24°C, at which time a mixture of 118 g (0.69 mol, 80-85% pure, Aldrich) of MCPBA, 60 g (0.60 mol) of NaHCO₃, and 400 mℓ of diethyl ether is added with vigorous stirring during a 3 min period in 100 mℓ portions. The resulting mixture remains in the ice bath at 5°C for 1 h while crystallization proceeds. The needle-like crystals of 5 and solid NaHCO₃ are collected together by suction filtration and the filter cake dissolved in 1 l of hot THF. The solution is decanted carefully from the NaHCO₃, 2 l of hexane are added, and the solution is allowed to crystallize overnight at -15°C. Filtration affords 105.0 g of colorless crystals (81% yield). The structure of 5 was confirmed by various analytical techniques (mp, IR, and NMR). Analogous to the above reaction, but on a 1.0 g scale (2.0 mmol) and using 50 mℓ of solvent (except 100 mℓ of diethyl ether), reactions were carried out in the following solvents with the isolated yields in parentheses: dibutyl ether (88%), tert -butyl ethyl ether (83%), diisopropyl ether (86%), tert -butyl methyl ether (80%), diethyl ether (76%), CH₂Cl₂ (77%), and CHCl₃ (75%). A similar reaction using 100 mℓ of diethyl ether and 25 mℓ of 0.5 M NaHCO₃ gave a 75% yield. Use of 99% pure MCPBA instead of 80-85% pure MCPBA did not affect the yield of 5 . A series of reactions using 1.0 g of 4a , 40 mℓ of tert -butyl methyl ether, 0.8 g of MCPBA, and 0.37 g of NaHCO₃ was carried out by adding the MCPBA solution when the diene solution had cooled to 28°, 24° and 20°C; yields of 83%, 80%, and 80% were obtained. EXAMPLE VII 3β-Hydroxy-5α-cholest-8(14)-ene-15-one (1) . A mixture of 120 g (0.238 mol) of 5 , 3.0 l of 95% ethanol, and 350 mℓ or water in a 5 l round bottom flask is cooled to 5°C in an ice bath for 30 min. Concentrated H₂SO₄ (650 mℓ) is added to this mixture over a period of 10 min in 50 mℓ portions. Any large chunks of suspended material are broken up mechanically. The mixture is heated under reflux for 20-24 h. The brownish reaction mixture is cooled to 20°C using an ice bath and then poured into 7 kg of ice in a 12 l carboy. The paste-like precipitate is collected on a Büchner funnel using either polypropylene filter cloth (Aldrich) or three layers of Whatman #1 filter paper, which is occasionally scratched to facilitate filtration. The pale-yellow cake is washed three times with 1 l of cold water and dissolved in 1 l of hot methanol, to which 1 l of hexane and 500 mℓ of hot water are added. The resulting two-phase system is heated on a steam bath until all solid material is dissolved. This mixture is allowed to cool for 2-3 h to 20°C; at this point crystals begin to form at the solvent interface. The mixture is then cooled overnight at -15°C to give a brown upper hexane phase, a lower light yellow aqueous phase, and white crystalline material. The crystals (roughly 90% pure by TLC) are collected by suction filtration and recrystallized again from methanol/hexane/water (2:2:1) as described above. The resulting material (greater than 95% pure by TLC) is passed through silica gel (200 g, 60-200 mesh, Baker), in a 3 l glass Büchner funnel with a medium porosity glass frit by eluting with CHCl₃. The CHCl₃ solution is rotary evaporated to dryness, and the residue is recrystallized from methanol/water to give 66.6 g (70%) of colorless needles. The structure of a product produced by such a process was confirmed as 1 by known analytical techniques. Samples of 1 stored under nitrogen at 25°, 4°, and -17°C showed no decomposition (analysis by TLC and HPLC) after two years. Samples of 1 (in both air and argon), 6 , (in argon), and 5 (in both air and argon) were subjected to the above hydrolysis conditions on a small scale. TLC analyses of the crude reaction mixtures showed major spots at R f 0.70, 0.65 (same R f as 6 ), and 0.31. In the case of 5 (but not 1 and 6 ), an additional major spot at R f 0.36 (same R f as 12 ) was observed. GC and HPLC analyses gave analogous results.

Claims: A process for converting 3β-benzoyloxycholesta-5,7-diene to 3β-benzoyloxy-5-cholesta-7,14-diene comprising: (i) forming a first reaction mixture by contacting 3β-benzoyloxycholesta-5,7-diene, in a solvent at a temperature of at most -55°C, with HCl at a concentration in said solvent of at least about 2.0 M for a time sufficient to convert said 3β-benzoyloxycholesta-5,7-diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; and (iii) recovering said 3β-benzoyloxy-5-cholesta-7,14-diene. The process according to claim 1, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5α-cholesta-7,14-diene. The process according to claim 1, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5β-cholesta-7,14-diene. The process according to claim 1, wherein said HCl concentration is from 2.0 M to 2.5 M. The process according to claim 4, wherein said temperature is from -65°C to -75°C. The process according to claim 1, wherein said HCl is introduced as a gas into said reaction mixture to a concentration of from 2.0 to 2.5 M. The process according to claim 1, wherein said solvent comprises a mixture of CHCl₃ and CH₂Cl₂. The process according to claim 7, wherein said solvent mixture consists of CHCl₃ and CH₂Cl₂ in approximately a 3:1 ratio. The process according to claim 1, further comprising the step of removing HCl from said reaction mixture through a sodium hydroxide trap prior to said neutralizing step. The process according to claim 1, wherein said base is concentrated NH₄OH. The process according to claim 1, wherein prior to obtaining said 3β-benzoyloxy-5-cholesta-7,14-diene, said 3β-benzoyloxycholesta-5,7-diene is converted to 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene. The process according to claim 1, further comprising the step of monitoring said first reaction mixture to determine when to neutralize said reaction mixture. The process according to claim 12, wherein said monitoring is accomplished by chromatography. 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene. A process for converting 3β-benzoyloxycholesta-5,7-diene to 3β-hydroxy-5-cholest-8(14)-en-15-one comprising the steps: (i) forming a first reaction mixture by contacting 3β-benzoyloxycholesta-5,7-diene, in a solvent at a temperature of at most -55°C, with HCl at a concentration in said solvent of at least about 2.0 M for a time sufficient to convert said 3β-benzoyloxycholesta-5,7-diene to said 3β-benzoyloxy-5-cholesta-7,14-diene; (ii) neutralizing the resultant reaction mixture with a base to prevent formation of a significant amount of 3β-benzoyloxy-5-cholesta-8,14-diene; (iii) forming a solution of 3β-benzoyloxy-5-cholesta-7,14-diene and diethyl ether and subsequently cooling said solution; (iv) forming a second reaction mixture by adding a mixture comprising MCPBA and NaHCO₃ to said solution, and cooling said second reaction mixture to form 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene; and (v) converting said 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene to said 3β-hydroxy-5-cholest-8(14)-en-15-one. The process according to claim 15, wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5α-cholesta-7,14-diene. The process according to claim 15 wherein said 3β-benzoyloxy-5-cholesta-7,14-diene is 3β-benzoyloxy-5β-cholesta-7,14-diene. The process according to claim 15, wherein said HCl concentration is from 2.0 M to 2.5 M. The process according to claim 18, wherein said temperature is from -65°C to -75°C. The process according to claim 15, wherein said HCl is introduced as a gas into said reaction mixture to a concentration of from 2.0 to 2.5 M. The process according to claim 15, wherein said solvent comprises a mixture of CHCl₃ and CH₂Cl₂. The process according to claim 21, wherein said solvent mixture consists of CHCl₃ and CH₂Cl₂ in approximately a 3:1 ratio. The process according to claim 15, further comprising the step of removing HCl from said reaction mixture through a sodium hydroxide trap prior to said neutralizing step. The process according to claim 15, wherein said base is concentrated NH₄OH. The process according to claim 15, wherein said 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene is 3β-benzoyloxy-14α,15α-epoxy-5α-cholest-7-ene. The process according to claim 15, wherein said 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene is 3β-benzoyloxy-14α,15α-epoxy-5β-cholest-7-ene. The process according to claim 15, wherein said second mixture further comprises diethyl ether. The process according to claim 15, wherein prior to obtaining said 3β-benzoyloxy-5-cholesta-7,14-diene, said 3β-benzoyloxy-cholesta-5,7-diene is converted to 3β-benzoyloxy-6α-chloro-5α-cholest-7-ene. The process according to claim 15, further comprising the step of monitoring said reaction mixture to determine when to neutralize said reaction mixture. The process according to claim 29, wherein said monitoring is accomplished by chromatography. The process of claim 15, wherein said 3β-benzoyloxy-14α, 15α-epoxy-5-cholest-7-ene is converted to 5-cholest-8(14)-en-3β-ol-15-one by reacting said 3β-benzoyloxy-14α,15α-epoxy-5-cholest-7-ene with a mineral acid in an organic solvent.

Inventors: KISIC ALEMKA, SCHROEPFER GEORG J JR, WANG KER-SHI, WILSON WILLIAM K, KISIC, ALEMKA, SCHROEPFER, GEORG J., JR., WANG, KER-SHI, WILSON, WILLIAM K.
Applicants: UNIV RICE WILLIAM M, WILLIAM MARSH RICE UNIVERSITY
Application year: 1989
Main classification: C07J9
IPC codes: C07J71, C07J75, C07J9