GB1564806A - Cholesterol derivatives - Google Patents
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- C—CHEMISTRY; METALLURGY
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- C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
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- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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Abstract
24,25-Dihydroxycholesterol derivatives which can be used for the stereospecific synthesis of 24R,25- and 24S,25-dihydroxycholecalciferol and have the formula II <IMAGE> in which R9 is lower alkanoyloxy and R10 is hydroxyl or lower alkanoyloxy, or R9 and R10 are hydroxyl, are prepared by retro-i rearrangement of 6 beta -substituted 24,25-dihydroxy-3 alpha ,5-cyclo-5 alpha -cholestane with an acid in a solvolytic medium.
Description
(54) CHOLESTEROL DERIVATIVES (71) We, F. HOFFMANN-LA ROCHE & CO., AKTIENGESELLSCHAFT, a Swiss Company of 124-184 Grenzacherstrasse, Basle, Switzerland, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to cholesterol derivatives. More particularly, the invention is concerned with cholesterol derivatives and a process for the preparation thereof.
The isolation and characterisation of 24,25-dihydroxycholecalciferol (24,25dihydroxyvitamin D3) [M. F. Holick et al., Biochemistry, 11, 4251 [1972]], and the subsequent finding that this second most abundant metabolite of vitamin D3 [J. L.
Omdahl and H. F. DeLuca, Physiological Reviews, 53, 327[197211 preferentially stimulates intestinal calcium transport without, at comparable dosage levels, mobilising bone calcium and is biologically synthesised in the kidney at the expense of the production of la,25-dih droxycholecalciferol, the potent, rapid-acting, natural metabolite of vitamin 3 (J. L. Omdahl and H. F. DeLuca, supra), prompted fairly extensive investigation of the physiological role played by this metabolite [see, for example, H. K. Schnoes and H. . DeLuca, Vitamins and
Hormones, 32 395 [1974]].These investigations have been hampered by the minute amounts of the metabolite available from natural sources, the lack of information concerning the stereochemistry of the metabolic hydroxyl group at C-24 and the effect of the configuration of this group on the biological activity exhibited by 24,25-dihydroxycholecalciferol.
Recently, M. Seki et al. [Chem. Pharm. Bull. [Japan], 21, 2783 [1973]] described the non-stereoselective conversion of desmosterol acetate to 24,25- dihydroxycholesterol by either epoxidation with m-chloroperbenzoic acid followed by hydrolysis or hydroxylation with osmium tetroxide and subsequent reductive hydrolysis. The diol of undefined stereochemical composition at C-24, as well as the epoxide, were subsequently used for the preparation of 24R,25- and 24S,25dihydroxycholecalciferol in a process which involves separation of the epimeric 24,25-epoxides or 24,25-diols followed by the established steps for the conversion of cholesterol derivatives to vitamin D3 metabolites. Shortly thereafter, H.-Y.Lam et al. fBiochemistry, 12, 4 & i li9731] reported a non-suereo-selective synthesis of 245,25-dihydroxycholecalciferol starting from 3p-acetoxy-27-nor-5-cholesten-25one and proceeding via 24,25-dihydroxycholesterol. J. Redel et al. [Compt. rend.
Acad. Sos. [Paris], 278, 529 [1974]] disclosed a non-stereo-selective process for the preparation of the vitamin D3 metabolite. The latter process started with desmosterol acetate, proceeded through an undetermined mixture of 24R, 25-and 24S,25-dihydroxycholesterols and gave an extremely poor (about 1%) yield of an undefined mixture of 24R,25- and 24S,25-dihydroxycholecalciferol. Thus, the stereospecific synthesis of 24R- and 24S,25-dihydroxycholecalciferol using 24,25dihydroxycholesterol derivatives of known stereochemistry at C-24 to overcome the deficiencies of the prior art processes and to make this important metabolite of vitamin D3 readily available for biological, clinical and therapeutic use would represent a major contribution to the advancement of the state of the art in the vitamin D field.
As used in this description and in the claims appended hereto, the term "alkyl" refers to a straight-chain or branched-chain saturated monovalent substituent consisting solely of carbon and hydrogen and containing from 1 to 20 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, tert.butyl, hexyl and octyl. The term "alkylene" refers to a straight-chain or branched-chain saturated divalent substituent consisting solely of carbon and hydrogen and containing from 2 to 20 carbon atoms, the free valences being attached to two different carbon atoms. Examples of alkylene groups are ethylene and propylene.
The term "alkoxy" refers to a monovalent substituent which consists of an alkyl group linked through an ether oxygen atom having its free valence bond from the ether oxygen atom. Examples of alkoxy groups are methoxy, ethoxy, isopropoxy and tert.butoxy. The term "phenyl-alkoxy" refers to an alkoxy group which is substituted by a phenyl group. Examples of phenyl-alkoxy groups are benzyloxy, 2phenylethoxy and 4-phenylbutoxy. The term "alkanoyloxy" refers to the residue of an alkanoic acid formed by removal of the hydrogen atom from the hydroxyl moiety of the carboxyl group. Examples of alkanoyloxy groups are formyloxy, acetoxy, butyryloxy and hexanoyloxy. The term "lower" as applied to any of the aforementioned groups refers to such groups containing from 1 to 8 carbon atoms.
In the formulae given in this description and in the accompanying claims, the various substituents and hydrogen atoms are shown as being joined to the steroid nucleus by one of these notations: namely, a solid line ( ) indicating a substituent or hydrogen atom which has the ,B-configuration (i.e. above the plane of the molecule), a broken line (III1III) indicating a substituent or hydrogen atom which has the a-configuration (i.e. below the plane of the molecule) or, except in the case of general formula II below, a wavy line ( ) indicating a substituent or hydrogen atom which may have the a- or ,8-configuration. The formulae all show the compounds in their absolute stereochemical configurations.Since the starting materials are derived from naturally occurring stigmasterol, the products exist in the single absolute configuration shown herein.
The Greek letter xi () in the name of a vitamin D2 intermediate or metabolite indicates that the stereochemistry of the substituent to which it refers is underlined.
The nomenclature adopted to define the stereochemistry about the 23,24double bond and the absolute configuration ofsubstituents wound to carbon atoms 23 and 24 of the steroid nucleus is described in The Journal of Organic Chemistry, 35, 2849 (1970) under the title "IUPAC Tentative Rules for the Nomenclature of
Organic Chemistry. Section E.Fundamental Stereochemistry."
In one aspect, the present invention relates to compounds of the general formula
wherein R, represents a hydroxy, lower alkoxy, phenyl-(lower-alkoxy), lower 'dlkanoyloxy or benzoyloxy group, and to a process for their preparation, which process comprises (a) contacting a compound of the general formula
wherein R, has the significance given earlier, with a lower alkyl or aryl-(lower alkyl)hydroperoxide in the presence of a compound of the general formula
wherein R, and Re each represent a hydrogen atom or a lower alkyl group, in an inert solvent to yield a compound of the general formula
wherein R1 has the significance given earlier, and treating said compound of formula IV with a complex metal hydride reducing agent in an inert solvent; or
(b) contacting a compound of formula II hereinbefore with a borane of the formula
wherein Re and Re each inde endently represent a hydrogen atom or an alkyl or cycloalkyl group or R5 and td together represent a lower alkylene group, in an inert organic solvent to yield a compound of the general formula
wherein R1, Re and Re have the significance given earlier, and contacting said compound of formula VI with an oxidizing agent in an inert organic solvent; or
(c) contacting a compound of the general formula
wherein R, has the significance given earlier, with osmium tetroxide in an inert organic solvent to yield an osmate ester and contacting said osmate ester with water in the presence of a reducing agent.
(The compounds of general formulae II and IV are claimed in our Divisional
Applications Nos. 23139/77 and 23140/77 (Serial Nos. 1564807 and 1564808), respectively.)
In process embodiment (a), the 23,24-double bond in a compound of formula
II is stereospecifically epoxidised in the presence of a catalytic amount of a vanadyl acetylacetonate of formula III in a suitable inert organic solvent at a reduced temperature.
Suitable lower alkyl hydroperoxides include methyl, ethyl, propyl, isopropyl.
sec.butyl and tert.butylhydroperoxides. Suitable aryl-(lower alkyl) hydroperoxides include cumyl hydroperoxide. Branched-chain hydroperoxides are preferred.
Tert.butyl hydroperoxide is most preferred. Suitable inert organic solvents include aromatic solvents such as benzene and toluene and halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. Aromatic hydrocarbons are preferred with toluene being most preferred.
Among the vanadyl acetylacetonates of formula III which are suitable for the stereospecific epoxidation there may be mentioned those in which R, and Re each independently and simultaneously represent a hydrogen atom and a lower alkyl group containing from 1 to 6 carbon atoms. Vanadyl acetylacetonates of formula
III in which R7 and Re simultaneously represent a hydrogen atom or a lower alkyl group are preferred. Vanadyl acetylacetonate is most preferred.
The amounts of lower alkyl hydroperoxide and vanadyl acetylacetonate of formula III. both relative to the amount of i-choiesteryl olefin of formula II, which may be used in the stereospecific epoxidation are not narrowly critical and can vary from 1 to 5 moles of lower alkyl hydroperoxide and from 0.01 to 10 weight per cent of the vanadyl acetylacetonate. The stereospecific epoxidation is preferably carried out using about a 2.5 molar excess of the hydroperoxide and about 1 weight per cent of the vanadyl acetylacetonate.
Vanadyl acetylacetonates of formula III can be prepared by the method described by R. A. Rowe, et al., Inorganic Synthesis, 5, 113 (1957) and references cited therein.
The stereospecific epoxidation of 23,24-double bond of a compound of formula II is conveniently carried out by mixing the reagents and substrate at an initial reaction temperature between -100"C and -50"C and then allowing the temperature to rise slowly to between -40"C and +20 C. An initial temperature of about -80"C and a final temperature of about -20"C is most preferred.
In the next step of process embodiment (a), an epoxide of formula IV is regiospecifically cleaved to the i-cholesteryl diol of formula I. This conversion is accomplished by reduction of the epoxide with a complex metal hydride reducing agent suspended in a suitable inert organic solvent.
Suitable complex metal hydride reducing agents for this purpose include alkali metal aluminium hydrides such as lithium aluminium hydride, mono, di or tri(lower alkoxy) alkali metal aluminium hydrides such as lithium tris(tert.butoxy)aluminium hydride. mono, di or tri(lower alkoxy-lower alkoxy) alkali metal aluminium hydrides such as sodium bis(2-methoxyethoxy)-aluminium hydride; and di(lower alkyl) aluminium hydrides such as diisobutyl aluminium hydride. A particularly preferred complex metal hydride reducing agent is lithium aluminium hydride.
Suitable solvents for the reductive cleavage include ethereal solvents such as diethyl ether, dimethoxyethane, dimethoxyethoxyethane, tetrahydrofuran and dioxane. Tetrahydrofuran is most preferred. The reductive cleavage is conveniently carried out at a temperature between -25"C and 50"C, most preferably between 0 C and 25"C.
24R, 25-Dihydroxy-6p-(hydroxy or substituted-hydroxy)-3a,5-cyclo-5a cholestanes of the general formula
wherein R, has the significance given earlier, in which the absolute configuration at C-24 is R, are prepared by the aforementioned process using a compound of formula II in which the configuration of the 23,24-double bond is cis. In the process for the preparation of a compound of formula Ia, a compound of the general formula
wherein R, has the significance given earlier, is converted into an i-cholesteryl epoxide of the general formula
wherein Rl has the significance given earlier, in which the absolute configuration of the epoxy group is 23R, 24R, and said epoxide is reductively cleaved to give a compound of formula Ia.
In order to prepare a 24S,25-dihydroxy-6A-(hydroxy or substituted-hydroxy) 3a,5-cyclo-5a-cholestane of the general formula
wherein R, has the significance given earlier, in which the absolute stereochemistry at C-24 is !D, a compound of formula II in which the configuration of the 23,24-double bond is trans may be stereospecifically epoxidised to give an epoxide of the general formula
wherein R, has the significance given earlier, in which the absolute stereochemistry at C-23 and C-24 is R and S respectively, followed by stereospecific reductive cleavage of the epoxy system.
The hydroboration in process embodiment (b) may be conveniently carried out by contacting a compound of formula II dissolved in a suitable inert organic solvent with a borane of formula V also dissolved in a suitable organic solvent at a reduced temperature and thereafter allowing the temperature to rise to about ambient temperature. Suitable inert organic solvents for this hydroboration include aromatic solvents such as benzene and toluene, and ethereal solvents such as diethyl ether dimethoxyethane, dimethoxyethoxyethane, tetrahydrofuran and dioxane. Ethereal solvents are preferred. Among the boranes which are useful for the hydroboration there may be mentioned borane, bis(3-methyl-2-butyl)borane (disiamylborane), 2,3-dimethyl-2-butylborane (thexylborane) and dicyclohexylborane. Borane, disiamylborane and thexylborane are preferred.
The temperature at which the hydroboration is carried out is not narrowly critical. It is conveniently carried out by mixing the substrate and reagent at below or about 0 C and then allowing the mixture to warm to about room temperature.
While the molar proportion of the borane to i-steroidyl olefin of formula II is not critical and molar ratios of I to 10 may be used, it is preferable to use 3 to 8 moles of the hydroborating agent for each mole of olefin, especially when the more volatile boranes are used.
Generally, it is most preferred to carry out the hydroboration in tetrahydrofuran at an initial temperature of about 0 C, or even below 0 C, and a final temperature of 25"C using about 4 moles of the borane for each mole of isteroidyl olefin of formula II.
While the intermediate i-cholesteryl borane of formula VI may be isolated from the hydroboration mixture prior to the oxidation, the i-cholesteryl borane is generally oxidised to the carbinol without isolation, after destruction of excess borane by the addition of ice-water. The oxidation is conveniently carried out either by introducing the theoretical amount of oxygen (based on the number of moles of i-cholesteryl borane) at about 0 C or excess aqueous alkaline hydrogen peroxide at a temperature of 0 C to 500 C. Aqueous alkaline hydrogen peroxide is preferred. The hydrogen peroxide is suitably 10 to 50% hydrogen peroxide, especially 30% hydrogen peroxide.
As the alkali for the oxidation, there may be mentioned, inter alia, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, and alkaline earth hydroxides such as calcium hydroxide and barium hydroxide. Alkali metal hydroxides are preferred. Sodium hydroxide is most preferred. The amount (relative to i-cholesteryl borane) of aqueous alkali which may be used is not critical and can vary from 1 to 10 moles of aqueous alkali for each mole of i-cholesteryl borane. A relative amount of aqueous alkali of 2 to 8 moles is preferred and a relative amount of aqueous alkali of about 4 moles is most preferred. The concentration of aqueous alkali is also not critical and can vary from 0.1 to 10 molar. A concentration of aqueous alkali of I to 7 molar is preferred with a concentration of aqueous alkali of about 3 molar being most preferred.
Synthetic applications of hydroboration and oxidation of boranes have been extensively reviewed by H. C. Brown in "Hydroboration", W. A. Benjamin, Inc.,
New York, N.Y., 1962, and "Boranes in Organic Chemistry", Cornell University
Press, Ithaca, N.Y., 1972.
The hydroxylation according to process embodiment (c) is conveniently carried out by treating a compound of formula VII with osmium tetroxide in a suitable inert organic solvent at ordinary temperature followed by reductive hydrolysis of the resulting osmate ester by means of water and a suitable reducing agent added to the original solution at a slightly elevated temperature. This procedure yields a mixture of compounds of formula Ia and Ib.
As suitable inert organic solvents there may be mentioned nitrogen-containing heteroaromatic solvents such as pyridine, lutidine and collidine, ethereal solvents such as diethyl ether, tetrahydrofuran and dioxane and aromatic solvents such as benzene, toluene and xylene. Nitrogen-containing heteroaromatic solvents are preferred with pyridine being most preferred.
It is most convenient to carry out the osmation step in the absence of light.
While the temperature at which the hydroxylation is carried out is not narrowly critical, it is desirable to carry out this reaction at a temperature of from 0 C to 50"C, most desirably at a temperature of from 25"C to 400 C. Similarly, the temperature at which the reductive hydrolysis of the osmate ester is carried out is not narrowly critical, but a slightly elevated temperature within the range of from 30"C to 500C is preferred. A temperature of about 40"C is most preferred for the reductive hydrolysis step.
Among suitable reducing agents are alkali metal sulphites and bisulphites such as sodium or potassium sulphite or bisulphite and hydrogen sulphide. Hydrogen sulphide is preferred. Sodium bisulphite is most preferred. Sugars such as mannitol are also useful to bring about the cleavage of the osmate ester.
The separation of the stereoisomeric diols of formulae Ia and Ib is carried out by means of high pressure liquid chromatography using a solid absorbent column and an inert organic solvent. Suitable inert organic solvents for the separation step include mixtures of hydrocarbons such as n-hexane, isooctane, benzene and toluene and esters such as ethyl acetate and ethyl benzoate. Suitable solid absorbents include PORASIL (trade mark), CORASIL, BIOSIL, ZORBAX,
ZORBAX-SIL and SIL-X. A Waters Associates Chromatograph Model 202 using a 8 foot by 3/8 inch PORASIL A column and a mixture of n-heptane/diethyl ether as the eluent is the preferred high pressure liquid chromatographic system.
In another aspect, the present invention is concerned with a process for the inversion of the 24-configuration in a compound of formula Ia or Ib above, which process comprises
(a) contacting a compound of formula Ia or Ib with a compound of the general formula R2-SO2-X (IX) wherein X represents a chlorine or bromine atom or the group R2SO2O in which.
Re represents a lower alkyl or (lower alkyl)-phenyl group, in a solvent medium comprising an organic solvent and an acid acceptor to afford a compound of the general formula
wherein R1 and Re have the significance given earlier and the configuration at C24 is R or S,
(b) contacting a resulting compound of formula X with a base in an inert solvent to yield a compound of the general formula
wherein R, has the significance given earlier and the absolute configuration at C-.
24 is inverted,
(c) contacting a resulting compound of formula XI with a strong acid in an aqueous medium to yield a compound of formula Ia or Ib having a configuration at
C-24 which is opposite to that of the starting material of formula Ia or Ib.
The compounds of general formula X also form part of the present invention.
Those, of general formula XI are claimed in our Divisional Application No.
23141/77 (Serial No. 1564809).
The sulphonylation (step a) is conveniently carried out by treating a compound of formula Ia or Ib with a lower alkyl or (lower alkyl)-phenylsulphonyl halide or anhydride of formula IX hereinbefore in a suitable solvent medium comprising an organic solvent and an organic acid acceptor
Among the suitable organic solvents which can be used there may be mentioned aromatic solvents such as benzene, toluene and xylene and heteroaromatic solvents, particularly nitrogen containing heteroaromatic solvents such as pyridine, picoline, lutidine and collidine.Among the suitable organic acid acceptors which can be used there may be mentioned acyclic aliphatic amines such as triethylamine and tripropylamine, alicyclic aliphatic amines such as 1,4diazabicyclo[2.2.2]octane and 1,5-diazabicyclo-[3.4.0] non-5-ene, aliphatic aromatic amines such as dimethylaniline and diethylaniline and heteroaromatic amines such as pyridine, picoline, lutidine and collidine. It is preferred to use the same heteroaromatic amine as the organic solvent and acid acceptor. It is most preferred to use pyridine as both solvent and acid acceptor.
Since the C-24 sulphonyloxy group is displaced in the next step of the reaction sequence, the structure of the R2 moiety of the leaving group is not critical.
Nevertheless, it is preferred to use a sulphonyloxy i-steroid in which R2 represents a lower alkyl or (lower alkyl)-phenyl group. It is most preferred to use a sulphonyloxy i-steroid in which Re represents a methyl or para-tolyl group,
Accordingly sulphonylating agents of formula IX in which R2 represents a lower alkyl or (lower alkyl)-phenyl group and X represents a chlorine atom or a methanesulphonyloxy group are preferred. Methanesulphonyl chloride is most preferred.
In order to prevent side reactions such as sulphonylation and/or dehydration of the C-25 hydroxy group, it is preferred to carry out the derivatisation of the C-24 hydroxy group at a temperature of from -25"C to 250 C. The most preferred temperature is about 0 C.
While the molar ratio of sulphonylating agent of formula IX to i-steroidal diol of formula Ia or Ib is not critical, it is preferred to use a molar ratio of about 10:1. A molar ratio of about 6:1 is most preferred.
The cyclisation (step b) is readily carried out by treating a compound of formula X with a metal hydride in a suitable organic solvent at a temperature of from -25"C to 250C, with a temperature of about OOC being preferred.
Suitable organic solvents for the cyclisation include ethereal solvents such as diethyl ether, dimethoxyethane, tetrahydrofuran and dioxane and aromatic solvents such as benzene, dimethoxyethoxyethane, toluene and xylene. Ethereal solvents are preferred.Tetrahydrofuran is most preferred.
Metal hydrides suitable for the cyclisation include, inter alia, alkali metal hydrides such as sodium hydride and potassium hydride. Sodium hydride is preferred. A sodium hydride in oil emulsion is most preferred.
The selective cleavage of the epoxy group of compounds of formula Xi without retro-i-rearrangement (step c) is carried out by first treating an epoxide of formula XI with a strong acid in a solvent medium comprising water and an inert organic water-miscible solvent and then isolating the i-steroidal diol of formula Ia or Ib.
Suitable strong acids are mineral acids such as hydrochloric acid, hydrobromic acid and sulphuric acid and organic sulphonic acids such as methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid monohydrate. Sulphuric acid and organic sulphonic acids are preferred. Sulphuric acid is most preferred.
Included among the suitable water-miscible organic solvents which can be used are ethereal solvents such as dimethoxyethane, diethoxyethoxyethane, tetrahydrofuran and dioxane. Tetrahydrofuran and dioxane are the preferred solvents. Tetrahydrofuran is the most preferred solvent for the selective epoxy cleavage.
In order to avoid concommitant retro-i-steroid rearrangement during cleavage of the epoxy group, the cleavage should be carried out at a temperature of from -200C to +100C. An especially preferred temperature range is from -10"C to +5"C, most preferably about 0 C.
The final step of the stereospecific synthesis of 24R, 25-and 24S,25dihydroxycholesterol and the alkanoyl derivatives thereof involves the retro-irearrangement of compounds of formula I to cholesterols of the general formulae
wherein Re represents a hydroxy or lower alkanoyloxy group, and the absolute configuration at C-24 is R,
wherein Rye has the significance given earlier and the absolute configuration at C24 is S;
wherein Re and R10 each represent a lower alkanoyloxy group containing from 1 to 8 carbon atoms and the absolute configuration at C-24 is R,
wherein Re and R10 each represent a lower alkanoyloxy group containing from 1 to 8 carbon atoms and the absolute configuration at C-24 is S.
These conversions and the resultant products are the subject of our Divisional
Application No. 23142/77 (Serial No. 1564810.
The following Examples illustrate the present invention:
Example 1.
23R,24S - Epoxy - 25 - hydroxy - 6A - methoxy - 3,5 - cyclo - 5e - cholestane A mixture of 0.103 g (0.00025 mol) of 25-hydroxy-6ss-methoxy-3α,5-cyclo-5α- cholest-23(E)-ene, 0.001 g of vanadyl acetylacetonate and 3 ml of toluene was cooled to -780C and 0.060 g (0.00060 mol) of 90% tert.butyl hydroperoxide/l0% tert.butyl alcohol in 3 ml of toluene were added dropwise.After completion of the addition, the solution was stirred at -780C for 2 hours and then allowed to warm slowly to'-20"C. The solution was stirred at -200C for 6 hours. 50 ml of methylene chloride were added to the mixture and the solution was washed successively with 25 ml of saturated aqueous sodium bisulphite solution and 25 ml of water. The organic phase was dried over anhydrous magnesium sulphate, filtered and the filtrate was concentrated under reduced pressure. Chromatography of the residue on silica gel gave 0.088 g (81%) of 23R,24S-epoxy-25-hydroxy-6,B-methoxy-3 E,5- cyclo-5a-cholestane (melting point 1120 -- 1130C) by evaporation in the 2% acetone/methylene chloride fractions; [a]26 = +52.9 (c = 1.06 in chloroform).
Example 2.
24S,25 - Dihydroxy - 6A - methoxy - 3a,5 - cyclo - 5a - cholestane To a solution of I ml (0.0010 mol) of l-M borane in tetrahydrofuran at 0 C was added a solution of 0.104 g (0.00025 mol) of 25-hydroxy-6,ss-methoxy-3α,5-cyclo-5α- cholest-23(E)-ene in I ml of tetrahydrofuran and the mixture was stirred overnight at 0 C for I hour and at 250C. The mixture was re-cooled to OOC and 0.10 g of ice was added to destroy the excess borane. 0.3 ml of 3-N aqueous sodium hydroxide solution and 0.3 ml of 30% aqueous hydrogen peroxide were successively added to the mixture. The mixture was stirred for 1 hour, 25 ml of water were added and the solution was extracted with three 25 ml portions of methylene chloride.The combined organic extracts were washed with 25 ml of water, dried over anhydrous magnesium sulphate, filtered and the filtrate was evaporated to dryness. The residue was dissolved in 4 ml of tetrahydrofuran and the solution was cooled to 00C. 1 ml of 0.1-N aqueous sulphuric acid was added dropwise and the mixture was stirred at OOC for 2 hours. 25 ml of water were added and the solution was extracted with three 25 ml portions of methylene chloride. The combined organic extracts were washed with two 25 ml portions of saturated aqueuous sodium bicarbonate solution, dried over anhydrous magnesium sulphate and filtered.Evaporation of the solvent under a vacuum followed by recrystallisation of the residue from benzene gave 0.060 g (55%) of 24S,25-dihydroxy-6p-methoxy-3a,5-cyclo-5 cholestane of melting point l670-l680C; [1Z]26 = +38.2 (c = 0.90 in chloroform).
Example 3.
23R,24R - Epoxy - 25 - hydroxy - 6p - methoxy - 3a,5 - cyclo - 5a - cholestane A mixture of 0.103 g (0.00025 mol) of 25-hydroxy-6/3-methoxy-3a,5-cyclo-5a- cholest-23(Z)-ene, 0.001 g of vanadyl acetylacetonate and 3 ml of toluene was cooled to -780C and 0.060 g (0.00060 mol) of 90% tert.butyl hydroperoxide/l0% tert.butyl alcohol in 3 ml of toluene was added dropwise.After completion of the addition, the solution was stirred at -780C for 2 hours and then allowed to warm slowly to --200C. The solution was stirred at -200C for 6 hours. 50 ml of methylene chloride were added to the mixture and the solution was washed successively with 25 ml of saturated aqueous sodium bisulphite solution and 25 ml of water. The organic phase was dried over anhydrous magnesium sulphate, filtered and the filtrate was concentrated under reduced pressure. Chromatography of the residue on silica gel gave 0.083 g (77%) of 23R,24R-epoxy-25-hydroxy-6-methoxy-3a,5 cyclo-Sa-cholestane.
Example 4.
24R,25 - Dihydroxy- 6P -methoxy- 3a,5 - cyclo - 5xr- cholestane To a solution of 1 ml (0.0010 mol) of l-M borane in tetrahydrofuran at OOC was added a solution of 0.104 g (0.00025 mol) of 25-hydroxy-6,B-methoxy-3a,5-cyclo-5a- cholest-23(Z)-ene in I ml of tetrahydrofuran and the mixture was stirred at OOC for I hour and at 259C overnight. The mixture was re-cooled to 0 C and 0.10 g of ice was added to destroy the excess borane. 0.3 ml of 3-N aqueous sodium hydroxide solution and 0.3 ml and 30% aqueous hydrogen peroxide were successively added to the mixture. The mixture was stirred for 1 hour, 25 ml of water were added and the solution was extracted with three 25 ml portions of methylene chloride.The combined organic extracts were washed with 25 ml of water, dried over anhydrous magnesium sulphate, filtered and the filtrate was evaporated to dryness. The residue was dissolved in 4 ml of tetrahydrofuran and the solution was cooled to OOC. 1 ml of 0.1-N aqueous sulphuric acid was added dropwise and the mixture was stirred at 0 C for 2 hours. 25 ml of water were added and the solution was extracted with three 25 ml portions of methylene chloride.
The combined organic extracts were washed with two 25 ml portions of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulphate and filtered. Evaporation of the solvent under a vacuum followed by recrystallisation of the residue from ethyl acetate gave 0.057 g (52%) of 24R,25 dihydroxy-6fi-methoxy-3a,5-cyclo-5a-cholestane of melting point 142"--143"C; [a]205 = +62.10 (c = 1.14 in chloroform).
Example 5.
24S,25 - Dihydroxy - tA - methoxy - 3a5 - cyclo - Sa - cholestane A mixture of 0.046 g (0.00011 mol) of 23 R,24S-epoxy-25-hydroxy-6p-methoxy- 3a,5-cyclo-5a-cholestane, 0.038 g (0.0010 mol) of lithium aluminium hydride and 2 ml of tetrahydrofuran was stirred at 0 C for 1 hour and at 250C for 1 hour and then cooled to 0 C and diluted with 4 ml of ether. 0.08 ml of water and 0.06 ml of 10% aqueous sodium hydroxide solution were successively added and the mixture was stirred at 25"C for 1 hour. The mixture was filtered and the filtrate was evaporated.
The residue was triturated with three 10 ml portions of methylene chloride, filtered and the combined filtrates were evaporated to dryness. Purification of the residual product by preparative thin layer chromatography on silica gel (1:1 benzene/ethyl acetate) gave 0.022 g (47%) of 24S,25-dihydroxy-6-methoxy-3a-cyclo-5a- cholestane of melting point 167"--168"C; [a]2D = +39.0 (c = 0.88 in chloroform).
Example 6.
24R,25 - Dihydroxy - 6ss - methoxy - 3a,5 - cyclo - 5 - cholestane A mixture of 0.072 g (0.00017mol) of 23R,24R-epoxy-25-hydroxy-6ss-methoxy- 3a,5-cyclo-5a-cholestane, 0.100 g (0.0026 mol) of lithium aluminium hydride and 4
ml of tetrahydrofuran was stirred at 0 C for 1 hour and at 250C for 1 hour. The
mixture was diluted with 8 ml of ether and cooled to 0 C. 0.20 ml of water and 0.16
ml of 10% aqueous sodium hydroxide solution were successively added and the
mixture was stirred at 250C for I hour. The mixture was filtered, the filtrate was
evaporated and the residue was triturated with three 10 ml portions of methylene
chloride and filtered. The combined filtrates were evaporated to dryness.
Recrystallisation from ethyl acetate gave 0.062 g (86%) of 24R,25-dihydroxy-6p- methoxy-3a,5-cyclo-5a-cholestane of melting point 142"--143"C; [a]25 = +62.5 (c
= 0.96 in chloroform).
Example 7.
24R- and 24S,25 - dihydroxy - 6ss - methqxy - 3a,5 - cyclo - Sa - cholestane
To a solution of 1.49 g (0.0037 mol) of 6 -methoxy-3,5-cyclo-5a-cholest-24-: ene and 20 ml of dry pyridine was added a solution of 1.00 g (0.0039 mol) of osmium tetroxide in 10 ml of pyridine and the mixture was stirred at 250C for 20 hours in the dark. A solution of 1.66 g (0.0160 mol) of sodium bisulphite in 25 ml of water was
added and the mixture was stirred at 40"C for 3 hours. The mixture was diluted with 100 ml of water and extracted with three 100 ml portions of ethyl acetate.The
combnined organic extracts were washed with two 100 ml portions of 10% aqueous
sulphuric acid, two 100 ml portions of saturated aqueous sodium bicarbonate
solution and two 100 ml portions of saturated sodium chloride solution. The
organic layer was dried over anhydrous magnesium sulphate and the drying agent
was collected on a filter. Evaporation of the filtrate gave 1.40 g (87%) of a 1:1
mixture of diols.
The product obtained according to the preceding paragraph was separated on
a Waters Associate Chromatography Model 202 using an 8 ft by 3/8 in PORASIL A
and a mixture of n-heptane and diethyl ether.
In a second experiment using the same conditions, the 1:1 mixture of diols was
dissolved in hot benzene and seeded with previously prepared authentic 24S,25 dihydroxy-6ss-methoxy-3α,5-cyclo-5α-cholestane to give 0.60 g (37%) of pure 24S
isomer of melting point l670-l680C; [a12D = +39.00 (c = 1.04 in chloroform).
The benzene filtrate was evaporated and the residue was dissolved in hot ethyl
acetate and seeded with authentic 24R,25-dihydroxy-6-methoxy-3a,5-cyclo-5a- cholestane to give 0.54 g (33%) of pure 24R-isomer of melting point 1420--1430C; [ < r]2D = +63.20 (c = 1.11 in chloroform).
Example 8.
25 - Hydroxy - 6ss - methoxy - 24R - methylsulphonyloxy - 3(z,5 - cyclo - Sa - cholestane
To a solution of 0.050 g (0.000116 mol) of 24R,25-dihydroxy-6p-methoxy-3a,5- cyclo-5a-cholestane in 0.5 ml of dry pyridine cooled to 0 C was added 0.05 ml (0.00066 mol) of methanesulphonyl chloride and the mixture was stirred at 0 C for 0.5 hour. 0.10 g of ice was added to destroy excess methanesulphonyl chloride and the mixture was stirred for a short period. The solution was washed with two:
10 ml portions of 10% aqueous sulphuric acid and two 10 ml portions of saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous
magnesium sulphate and, after removal of the drying agent by filtration, the filtrate was evaporated to dryness to yield 0.59 g (100%) of 25-hydroxy-6ss-methoxy-24R- methylsulphonyloxy-3a,5-cyclo-5a-cholestane; [α]D25 = +44.70 (e = 1.03 in chlorform).
Example 9.
25 - Hydroxy - 6ss - methoxy - 24S - methylsulphonyloxy - 3a,5 - cyclo - 5a- cholestane
25 - Hydroxy - 6ss - methoxy - 24S - methylsulphonyloxy - 3a,5 - cyclo cholestane [[a]25 = +39,50 (c = 0.80 in chloroform)] was prepared in 100% yield analogously to the procedure described in Example 8.
Example 10.
24S,25 - Epoxy - 6p - methoxy - 3zz,5 - cyclo - 5a - cholestane
To a suspension of 0.024 g (0.0010 mol) of sodium hydride in 1 ml of tetrahydrofuran cooled to 0 C was added dropwise with stirring a solution of 0.059 g (0.000116 mol) of 25-hydroxy-6,B-methoxy-24R-methylsulphonyloxy-3Q,5-cyclo- Sa-cholestane in 0.5 ml of tetrahydrofuran. After 0.5 hour, the mixture was diluted with 10 ml of water and the solution was extracted with three 10 ml portions of methylene chloride. The combined organic extracts were washed with two 10 ml portions of water, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness.Recrystallisation of the solid residue from methyl ethyl ketone gave 0.041 g (91%) of 24S,25-epoxy-6p-methoxy-3a,5-cyclo-5-cholestane of melting point l000-1020C; [a]25 = +42.2 (c = 0.97 in chloroform).
Example 11.
24R,25 - Epoxy - 6p - methoxy - 3a,5 - cyclo - 5- cholestane 24R,25-Epoxy-6-methoxy-3a,5-cyclo-5a-cholestane was prepared in 93 O yield from 25-hydroxy-6ss-methoxy-24S-methylsulphonyloxy-3α,5-cyclo-5α-chol- estane analogously to the procedures described in Example 19; melting point l260-l270C; [C1]25 = +58.00 (c =1.08 in chloroform).
24S,25 - Dihydroxy - 6p - methoxy - 3a,5-cyclo - 5a - cholestane
A solution of 0.200 g (0.00049 mol) of 24S,25-epoxy-6p-methoxy-3a,5-cyclo- Sa-cholestane, 8 ml of tetrahydrofuran and 2 ml of 1.0-N aqueous sulphuric acid was stirred at 0 C for 3 hours. The mixture was diluted with 25 ml of water and extracted with three 25 ml portions of methylene chloride. The combined organic layers were washed with 25 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulphate, filtered and evaporated.
Recrystallisation of the residue from benzene gave 0.153 g (73%) of 24S,25 dihydroxy-6p-methoxy-3a,5-cyclo-5-eholestane of melting point 1670--1680C; [a]205 = +38.7 (c = 0.96 in chloroform).
Example 13.
24R,25 - Dihydroxy - 6p - methoxy - 3a,5 - cyclo - 5a - cholestane A solution of 0.104 g (0.00025 mol) of 24R,25-epoxy-6p-methoxy-3a,5-cyclo- Sa-cholestane, 8 ml of tetrahydrofuran and 2 ml of l-N aqueous sulphuric acid was stirred at 0 C for 4 hours. 25 ml of water were added to the mixture and the solution was extracted with three 25 ml portions of methylene chloride. The combined organic layers were washed with 25 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulphate, filtered and evaporated. Recrystallisation of the residue frm ethyl acetate gave 0.090 g (83%) of 24,25-dihydroxy-6p-methoxy-3a,5-eyclo-5cr-eholestane of melting point l420-l430C; [a]205 = +63.00 (e = 1.08 in chloroform).
WHAT WE CLAIM IS:
1. A compound of the general formula
wherein R1 represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower alkanoyloxy or benzoyloxy group.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (75)
1. A compound of the general formula
wherein R1 represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower alkanoyloxy or benzoyloxy group.
2. A compound of formula I given in claim 1, wherein R, represents a lower
alkoxy group and the absolute configuration of the C-24 hydroxyl group is R or S.
3. The compound as set forth in claim 2, wherein R, represents a methoxy group and the absolute configuration of the C-24 hydroxyl group is R.
4. The compound as set forth in claim 2, wherein R, represents a methoxy group and the absolute configuration of the C-24 hydroxyl group is S.
5. A process for the preparation of a compound of formula I given in claim 1, which process comprises
(a) contacting a compound of the general formula
wherein Rj has the significance given in claim 1, with a lower alkyl or aryl-(lower alkyl) hydroperoxide in the presence of a compound of the general formula
wherein R7 and Re each represent a hydrogen atom or a lower alkyl group, in an inert solvent to yield a compound of the general formula
wherein R1 has the significance given in claim 1, and treating said compound of formula IV with a complex metal hydride reducing agent in an inert solvent; or
(b) contacting a compound of formula II given earlier in this claim with a borane of the general formula
wherein R5 and Re each independently represent a hydrogen atom or an alkyl or cycloalkyl group or R5 and Re together represent a lower alkylene group, in an inert organic solvent to yield a compound of the general formula
wherein R, has the significance given in claim I and R5 and R6 have the significance given earlier in this claim, and contacting said compound of formula VI with an oxidising agent in an inert organic solvent; or
(c) contacting a compound of the general formula
wherein R, has the significance given in claim 1, with osmium tetroxide in an inert organic solvent to yield an osmate ester and contacting said osmate ester with water in the presence of a reducing agent.
6. A process according to claim 5, wherein a compound of formula II is contacted with a lower alkyl or aryl-(lower alkyl) hydroperoxide in the presence of a compound of formula III in an inert solvent at a reduced temperature to yield a compound of formula IV and said compound of formula IV is treated with a complex metal hydride reducing agent in an inert solvent at a reduced temperature; or a compound of formula II is contacted with a borane of formula V in an inert organic solvent at a reduced temperature to yield a compound of formula VI and said compound of formula VI is contacted with an oxidising agent in an inert organic solvent.
7. A process according to claim 5, wherein a compound of formula VII is contacted with osmium tetroxide in an inert organic solvent to yield an osmate ester and said osmate ester is contacted with water in the presence of a reducing agent.
8. A process according to any one of claims 5 to 7 inclusive, wherein R, represents a lower alkoxy group.
9. A process according to claim 8, wherein R, represents a methoxy group.
10. A process according to any one of claims 5, 6, 8 and 9, wherein the configuration of the 23,24-double bond in a compound of formula
II is cis (denoted by the symbol Z).
I I. A process according to any one of claims 5, 6, 8 and 9, wherein the configuration of the 23,24-double bond in the compound of formula II is trans (denoted by the symbol E).
12. A process according to claim 5 or claim 6, wherein the lower alkyl hydroperoxide is a lower tertiary alkyl hydroperoxide.
13. A process according to claim 12, wherein the lower tertiary alkyl hydroperoxide is tert.butyl hydroperoxide.
14. A process according to claim 5 or claim 6, wherein the aryl-(lower
alkyl) hydroperoxide is cumyl hydroperoxide.
15. A process according to claim 5 or claim 6, wherein R7 and Re each represent a hydrogen atom.
16. A process according to claim 5 or claim 6, wherein the inert organic solvent
used in the reaction of a compound of formula II with the lower alkyl or aryl-(lower
alkyl) hydroperoxide is an aromatic solvent.
17. A process according to claim 16, wherein said aromatic solvent is toluene.
18. A process according to claim 5 or claim 6, wherein the temperature in the reaction of a compound of formula II with the lower alkyl or aryl-(lower alkyl) hydroperoxide is initially from -100"C to -500C and then from -40"C to 20"C.
19. A process according to claim 18, wherein the temperature is initially about -80 C and then about -20"C.
20. A process according to claim 5 or claim 6, wherein the complex metal hydride reducing agent is an alkali metal aluminium hydride.
21. A process according to claim 20, wherein the alkali metal aluminium hydride is lithium aluminium hydride.
22. A process according to claim 5 or claim 6, wherein the inert organic solvent in the treatment of a compound of formula IV with a complex metal hydride reducing agent is an ethereal solvent.
23. A process according to claim 22, wherein said ethereal solvent is tetrahydrofuran.
24. A process according to claim 5 or claim 6, wherein the temperature used for the treatment of a compound of formula IV with a complex metal hydride reducing agent is from -25"C to +500 C.
25. A process according to claim 24, wherein the temperature is from 0 C to 25"C.
26. A process according to claim 5 or claim 7, wherein a compound of formula
VII is contacted with osmium tetroxide in a heteroaromatic, ethereal or aromatic solvent.
27. A process according to claim 26, wherein the heteroaromatic solvent is pyridine.
28. A process according to claim 5 or claim 7, wherein a compound of formula
VII is contacted with osmium tetroxide at a temperature of from 0 C to 50"C.
29. A process according to claim 28, wherein the temperature is from 250C to 40"C.
30. A process according to claim 5 or claim 7, wherein the osmate ester is reduced using an alkali metal sulphite or bisulphite.
31. A process according to claim 30, wherein the alkali metal bisulphite is sodium bisulphite.
32. A process according to claim 5 or claim 6, wherein Re and R, each independently represent a hydrogen atom or an alkyl or cycloalkyl group.
33. A process according to claim 32, wherein R5 and Re each independently represent a hydrogen atom.
34. A process according to claim 5 or claim 6, wherein the inert organic solvent in the reaction of a compound of formula II with a borane of formula V is an ethereal solvent.
35. A process according to claim 34, wherein the ethereal solvent is tetrahydrofuran.
36. A process according to claim 5 or claim 6, wherein the temperature in the reaction of a compound of formula II with a borane of formula V is from below 0 C to +250C.
37. A process according to claim 5 or claim 6, wherein the oxidizing agent with which a compound of formula VI is contacted is oxygen.
38. A process according to claim 5 or claim 6, wherein the oxidising agent with which a compound of formula VI is contacted is aqueous-alkaline hydrogen peroxide.
39. A process according to claim 38, wherein the alkali is an alkali metal hydroxide.
40. A process according to claim 39, wherein the alkali metal hydroxide is sodium hydroxide.
41. A process according to claim 40, wherein the hydrogen peroxide is 10% to 50% hydrogen peroxide.
42. A process according to claim 41, wherein the hydrogen peroxide is 30% hydrogen peroxide.
43. A process according to any one of claims 38 to 42 inclusive, wherein the temperature is from 0 C to +500C.
44. A process for the inversion of the 24-configuration in a compound of formula Ia or Ib
wherein R1 represents a hydroxy, lower alkoxy, phenyl-(lower alkoxy), lower
alkanoyloxy or benzoyloxy group, which process comprises
(a) contacting a compound of one of the formulae Ia or Ib with a compound of
the general formula R2-SO2-X (IX) wherein X represents a chlorine or bromine atom or the group R2SO2O in which Re represents a lower alkyl or (lower alkyl)-phenyl group, in a solvent medium comprising an organic solvent and an acid acceptor to yield a compound of the general formula
wherein R1 has the significance given earlier in this claim and the configuration at
C-24 is R or S,
(b) contacting the resulting compound of formula X with a base in an inert solvent to yield a compound of the general formula
wherein R, has the significance given earlier in this claim and the absolute configuration at C-24 is inverted, and
(c) contacting the resulting compound of formula XI with a strong acid in an aqueous medium to yield a compound of formula Ia or Ib having a configuration at
C-24 which is opposite to that of the starting material of formula Ia or Ib.
45. A process according to claim 44, wherein R, represents a lower alkoxy group.
46. A process according to claim 45, wherein R1 represents a methoxy group.
47. A process according to any one of claims 44 to 46 inclusive, wherein the configuration of the C-24 hydroxyl group in the starting material is R.
48. A process according to any one of claims 44 to 46 inclusive, wherein the configuration of the C-24 hydroxyl group in the starting material is S.
49. A process according to any one of claims 44 to 48 inclusive, wherein R2 represents a lower alkyl group.
50. A process according to claim 49, wherein R2 represents a methyl group.
51. A process according to any one of claims 44 to 48 inclusive, wherein R2 represents a (lower alkyl)-phenyl group.
52. A process according to claim 51, wherein R2 represents aparatolyl group.
53. A process according to any one of claims 44 to 52 inclusive, wherein X represents a chlorine atom or the group R2SO2O.
54. A process according to claim 53, wherein X represents the group R2SO2O.
55. A process according to any one of claims 44 to 54 inclusive, wherein the organic solvent and the acid acceptor in step (a) are the same heteroaromatic compound.
56. A process according to claim 55, wherein the heteroaromatic compound is pyridine.
57. A process according to any one of claims 44 to 56 inclusive, wherein the base used in step (b) is a metal hydride.
58. A process according to claim 57, wherein the metal hydride is an alkali metal hydride.
59. A process according to claim 58, wherein the alkali metal hydride is sodium hydride.
60. A process according to any one of claims 44 to 59 inclusive, wherein the inert solvent used in step (b) is an ethereal solvent.
61. A process according to claim 60, wherein the ethereal solvent is tetrahydrofuran.
62. A process according to any one of claims 44 to 61 inclusive, wherein step (b) is carried out at a temperature of from -25"C to +250 C.
63. A process according to claim 62, wherein the temperature is about 0 C.
64. A process according to any one of claims 44 to 63 inclusive, wherein the strong acid used in step (c) is sulphuric acid or an organic sulphonic acid.
65. A process according to claim 64, wherein the organic sulphonic acid is paratoluenesulphonic acid monohydrate.
66. A process according to any one of claims 44 to 65 inclusive, wherein step (c) is carried out at a temperature of from -20"C to +lO0C.
67. A process according to claim 66, wherein the reduced temperature is about O"C.
68. A process according to any one of claims 44 to 67 inclusive, wherein the aqueous solvent medium used in step (c) comprises a water-miscible ethereal solvent.
69. A process according to claim 68, wherein the water-miscible ethereal solvent is tetrahydrofuran.
70. A process according to claim 68, wherein the water-miscible ethereal solvent is dioxane.
71. A compound of the general formula
wherein R1 represents a hydroxy, lower alkoxy, pnenyl-(lower alkoxy), lower alkanoyloxy or benzoyloxy group and R2 represents a lower alkyl or (lower alkyl)phenyl group.
72. A compound according to claim 71, wherein R, represents a lower alkoxy group, Re represents a lower alkyl group and the absolute configuration at C-24 is
R or S.
73. 25 - Hydroxy - 6p - methoxy - 24S - methylsulphonyloxy - 3a,5 - cyclo cholestane.
74. 25 - Hydroxy - 6A - methoxy - 24R - methylsulphonyloxy - 3a,5 - cyclo - 5a- cholestane.
75. A process for the preparation of cholesterol derivatives, substantially as hereinbefore described with reference to any one of the Examples.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/621,319 US3994878A (en) | 1975-10-10 | 1975-10-10 | Syntheses of 24R,25- and 24S,25-dihydroxycholesterol and alkanoyl derivatives thereof |
US05/623,859 US4038272A (en) | 1975-10-20 | 1975-10-20 | Stereospecific syntheses of 24r,25- and 24s,25-dihydroxycholesterol and alkanoyl derivatives thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
GB1564806A true GB1564806A (en) | 1980-04-16 |
Family
ID=27088923
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB4193876A Expired GB1564806A (en) | 1975-10-10 | 1976-10-08 | Cholesterol derivatives |
GB2314177A Expired GB1564809A (en) | 1975-10-10 | 1976-10-08 | 24,25-epoxy-cholestane derivatives |
GB2314277A Expired GB1564810A (en) | 1975-10-10 | 1976-10-08 | Cholesterol derivatives |
GB2314077A Expired GB1564808A (en) | 1975-10-10 | 1976-10-08 | 23,24-epoxy-25-hydroxycholestane derivatives |
GB2313977A Expired GB1564807A (en) | 1975-10-10 | 1976-10-08 | Cholestene derivatives |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB2314177A Expired GB1564809A (en) | 1975-10-10 | 1976-10-08 | 24,25-epoxy-cholestane derivatives |
GB2314277A Expired GB1564810A (en) | 1975-10-10 | 1976-10-08 | Cholesterol derivatives |
GB2314077A Expired GB1564808A (en) | 1975-10-10 | 1976-10-08 | 23,24-epoxy-25-hydroxycholestane derivatives |
GB2313977A Expired GB1564807A (en) | 1975-10-10 | 1976-10-08 | Cholestene derivatives |
Country Status (8)
Country | Link |
---|---|
JP (1) | JPS5246061A (en) |
AT (1) | AT355236B (en) |
CH (1) | CH628907A5 (en) |
DE (1) | DE2645527A1 (en) |
FR (2) | FR2407941A1 (en) |
GB (5) | GB1564806A (en) |
IT (1) | IT1068692B (en) |
NL (1) | NL7611155A (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11104701B2 (en) | 2013-03-13 | 2021-08-31 | Sage Therapeutics, Inc. | Neuroactive steroids and methods of use thereof |
US11117924B2 (en) | 2015-07-06 | 2021-09-14 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11149056B2 (en) | 2016-09-30 | 2021-10-19 | Sage Therapeutics, Inc. | C7 substituted oxysterols and methods of use thereof |
US11279730B2 (en) | 2016-07-07 | 2022-03-22 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11407782B2 (en) | 2016-05-06 | 2022-08-09 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11851457B2 (en) | 2016-10-18 | 2023-12-26 | Sage Therapeutics | Oxysterols and methods of use thereof |
US11884697B2 (en) | 2016-04-01 | 2024-01-30 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CH644873A5 (en) * | 1980-02-12 | 1984-08-31 | Hoffmann La Roche | METHOD FOR PRODUCING CHOLESTEROL DERIVATIVES. |
US10696712B2 (en) * | 2015-07-06 | 2020-06-30 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2219943B1 (en) * | 1973-03-02 | 1976-04-30 | Eisai Co Ltd | |
US3822254A (en) * | 1973-05-21 | 1974-07-02 | Hoffmann La Roche | Synthesis of 25-hydroxycholesterol |
-
1976
- 1976-09-28 CH CH1224676A patent/CH628907A5/en not_active IP Right Cessation
- 1976-10-08 DE DE19762645527 patent/DE2645527A1/en not_active Ceased
- 1976-10-08 GB GB4193876A patent/GB1564806A/en not_active Expired
- 1976-10-08 GB GB2314177A patent/GB1564809A/en not_active Expired
- 1976-10-08 JP JP12050076A patent/JPS5246061A/en active Pending
- 1976-10-08 NL NL7611155A patent/NL7611155A/en not_active Application Discontinuation
- 1976-10-08 AT AT751376A patent/AT355236B/en not_active IP Right Cessation
- 1976-10-08 GB GB2314277A patent/GB1564810A/en not_active Expired
- 1976-10-08 IT IT2816476A patent/IT1068692B/en active
- 1976-10-08 GB GB2314077A patent/GB1564808A/en not_active Expired
- 1976-10-08 GB GB2313977A patent/GB1564807A/en not_active Expired
- 1976-10-11 FR FR7630450A patent/FR2407941A1/en active Granted
-
1977
- 1977-04-22 FR FR7712223A patent/FR2351998A1/en active Granted
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11104701B2 (en) | 2013-03-13 | 2021-08-31 | Sage Therapeutics, Inc. | Neuroactive steroids and methods of use thereof |
US11905309B2 (en) | 2013-03-13 | 2024-02-20 | Sage Therapeutics, Inc. | Neuroactive steroids and methods of use thereof |
US11117924B2 (en) | 2015-07-06 | 2021-09-14 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11732000B2 (en) | 2015-07-06 | 2023-08-22 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11884697B2 (en) | 2016-04-01 | 2024-01-30 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11407782B2 (en) | 2016-05-06 | 2022-08-09 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11878995B2 (en) | 2016-05-06 | 2024-01-23 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11279730B2 (en) | 2016-07-07 | 2022-03-22 | Sage Therapeutics, Inc. | Oxysterols and methods of use thereof |
US11149056B2 (en) | 2016-09-30 | 2021-10-19 | Sage Therapeutics, Inc. | C7 substituted oxysterols and methods of use thereof |
US11926646B2 (en) | 2016-09-30 | 2024-03-12 | Sage Therapeutics, Inc. | C7 substituted oxysterols and methods of use thereof |
US11851457B2 (en) | 2016-10-18 | 2023-12-26 | Sage Therapeutics | Oxysterols and methods of use thereof |
Also Published As
Publication number | Publication date |
---|---|
IT1068692B (en) | 1985-03-21 |
FR2351998B1 (en) | 1980-04-25 |
ATA751376A (en) | 1979-07-15 |
NL7611155A (en) | 1977-04-13 |
AT355236B (en) | 1980-02-25 |
FR2407941A1 (en) | 1979-06-01 |
FR2351998A1 (en) | 1977-12-16 |
FR2407941B1 (en) | 1980-05-16 |
GB1564810A (en) | 1980-04-16 |
DE2645527A1 (en) | 1977-04-21 |
GB1564808A (en) | 1980-04-16 |
GB1564809A (en) | 1980-04-16 |
JPS5246061A (en) | 1977-04-12 |
GB1564807A (en) | 1980-04-16 |
CH628907A5 (en) | 1982-03-31 |
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