DE2645527A1 - NEW CHOLESTERINE DERIVATIVES - Google Patents

Description

P Vierer ™ Oct 8, 1976

RAN 4212 / 9K

F. Hofimann-La Roche & Co. Aktiengesellschaft, Basel / Switzerland

New cholesterol derivatives

The isolation and characterization of 24,25-dihydroxycholecalciferol (24,25-dihydroxyvitamin D ₃ ; MF Holick et al., Biochemistry, 11, 4251 [1972]), and the subsequent finding that this second most common metabolite of vitamin D ₃ (JL Omdahl and HF DeLuca, Physiological Reviews, 533, 327 [1973]), preferably stimulates the intestinal calcium transport without mobilizing calcium from the bones at comparable dosages, and that this metabolite in the kidney at the expense of the production of la ^ S-dihydroxycholecalciferol , the powerful and fast-acting natural metabolite of vitamin D ₃ (JL Omdahl and HF DeLuca, LC) is biologically synthesized, prompted in-depth studies of the physiological role this metabolite plays (see, for example, HK Schnoes and HF DeLuca, Vitamins and Hormones , 12, 395 [1974]). These investigations were hindered by the small amounts of substance in which the

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Metabolite was available from natural sources, and that Lack of information regarding the stereochemistry of the hydroxyl group at C-24 and the effect of the configuration this group on the biological activity of 24,25-Dihydroxycholecalciferpls.

Recently, M. Seki et al. (Chem. Pharm. Bull. [Japan], 21, 2783 [1973]) described the non-stereoselective conversion of desmosterol acetate into 24f, 25-dihydroxycholesterol by epoxidation with m-chloroperbenzoic acid and then hydrolysis or by hydroxylation with osmium tetroxide and subsequent reductive hydrolysis. The diol with undefined stereochemistry in C-24 and the epoxide were then used to produce 24R, 25- and 24S, 25-dihydroxycholecalciferol in a process in which the epimeric 24,25-epoxides or diols were separated, whereupon the known steps for the conversion of cholesterol derivatives into vitamin D ₃ metabolite. Shortly thereafter, H.-Y. Lam et al. (Biochemistry, 12 , 4851 [1973]) on a non-stereoselective synthesis of 24f, 25-dihydroxycholecalciferol starting from '3/3-acetoxy-27-nor-5-cholesten-25-one via 24f, 25-dihydroxycholesterol . J. Redel et al. (Compt. Rend. Acad. Sos. [Paris], 278 , 529 [1974]) described a non-stereoselective process for the production of the vitamin D ₃ metabolite. The latter procedure started with desmosterol acetate, proceeded through an indefinite mixture of 24R, 25- and 24S, 25-dihydroxycholesterols and gave in very poor yield (about 1%) an undefined mixture of 24R, 25- and 24S, 25-dihydroxycholecalciferol. A stereospecific synthesis of 24R, 25- and 24S, 25-dihydroxycholecalciferol using 24,25-dihydroxycholesterol derivatives of known stereochemistry at C atom 24, which avoid the shortcomings of the known methods and these important vitamin D ₃ metabolites for biological, clinical and makes therapeutic purposes readily available, thus represents a significant contribution to technical progress in the field of vitamin D.

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The expression "Alky! Group" used in the following refers to straight-chain or branched hydrocarbon radicals with 1-20 C atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl, Octyl. The term "alkylene" denotes a divalent one Hydrocarbon radical with 1-20 carbon atoms of the straight-chain or can be branched and its free valences emanate from two different carbon atoms. Examples of alkylene groups are methylene, ethylene and propylene. Examples of alkoxy groups are methoxy, ethoxy, isopropoxy and tert-butoxy. Examples of phenylalkoxy groups are benzyloxy and 2-phenylethoxy and 4-phenylbutoxy. Examples of alkanyloxy groups are formyloxy, acetoxy, butyryloxy and hexanoyloxy. Of the The term "substituted" in connection with phenyl denotes a phenyl radical with one or more of the following Groups substituted, /: alkyl, halogen (i.e. fluorine, chlorine, Bromine or iodine), nitro, cyano and trifluoromethyl. The term "lower" relates to groups with 1 to 8 carbon atoms.

In the formulas, denotes a solid line

() to a substituent on the steroid ring ß-orientation

(i.e. above the molecular level) a broken line

() a bond to a substituent in the α-position

(i.e. below the molecular level) and a wavy line (, ^ • s / va,) a substituent in the α- or / 3-position. the Formulas show the compounds in an absolute stereochemical configuration. Since the starting materials are .from naturally occurring · stigmasterin derive exist these substances in · the individual absolute values shown here Configuration. The inventive method should, however nevertheless on the synthesis of steroids of the unnatural and racemic series, i.e. the enantiomers of those shown here Compounds and mixtures in which formulas are used. So you can do the synthesis using unnatural or racemic starting compounds / to make unnatural ones or to produce racemic products. Optically active compounds can then be cleaved

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- r-

of racemates according to techniques known per se in steroid chemistry can be obtained.

The nomenclature for defining the stereochemistry at the 23/24 double bond and the absolute configuration at the carbon atoms 23 and 24, is in the Journal of Organic Chemistry, 3_5 ^, 2849 (1970) under the title "IUPAC Tentative Rules for the Nomenclature of Organic Chemistry .. Section E. Fundamental Stereochemistry".

In one embodiment, the present invention relates to a method of making a compound the formula

OH

-H ₃

OH

in which R is-, hydroxy, lower-alkoxy, phenyl-lower alkoxy, lower-alkanoyloxy or benzoyloxy,
which is characterized by the fact that one

a compound of the formula

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Il

where R, has the above meaning,

with a lower-alkyl or aryl-lower alkyl hydroperoxide in the presence of a compound of the formula

■ ·? ⁷ ·

CH ₂

HC.

O'

H ₂

III

wherein R- and Rg are hydrogen or lower Are alkyl,

in an inert solvent at reduced temperature to give a compound of the formula

! H ₃

7 0 9 816/1 157

in the R, which has the above meaning,

converts, and the compound of formula IV with a complex metal hydride reducing agent in an inert solvent treated at reduced temperature; or

a compound of the formula II with a borane of the formula

>
^R.

wherein R ₁ - and Rg are independently hydrogen, alkyl or cycloalkyl or together are lower-alkylene,

in an inert organic solvent at reduced temperature to give a compound of the formula

^R 5 ^R 6

Vl

wherein R ₁ , R ₅ and R _{6 have} the above meaning,

reacts, and the compound of formula VI with an oxidizing agent in an inert organic solvent treated; or

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a compound of the formula

CH ₃

H ₃

.CH ₃

VII

where R, has the above meaning,

with osmium tetroxide in an inert organic solvent converts to an osmic acid ester and treats the osmic acid ester with water in the presence of a reducing agent.

According to process variant (a), the 23.24 double bond becomes in a compound of formula II stereospecifically in the presence of a catalytic amount of vanadyl acetylacetonate epoxidized in a suitable inert organic solvent at reduced temperature.

Suitable lower-alkyl hydroperoxides are methyl, ethyl, propyl, 2-propyl, sec-butyl and tert-butyl hydroperoxides. A suitable aryl lower alkyl hydroperoxide is, for example, cumyl hydroperoxide. Branched-chain hydroperoxides, tert-butyl hydroperoxide is particularly preferred. Suitable inert organic solvents are aromatic Solvents such as benzene, toluene and halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. Aromatic hydrocarbons, especially toluene, are preferred.

Of the vanadyl acetylacetonates of the formula III which are suitable for the stereospecific epoxidation, those in which R ₇ and Rg are independently and simultaneously hydrogen or lower-alkyl with up to should be mentioned

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Represent 6 carbon atoms. Compound of formula III / in which R-y

and R _{0 is} simultaneously hydrogen or lower ^{-alkyl ο J sxnd}

in particular vanadyl acetylacetonate are / are particularly preferred.

The amounts of the lower alkyl hydroperoxide and the Vanadyl acetylacetonate of the formula III - based on the Amount of i-cholesteryl olefin of formula II - those in the epoxidation are used are essentially not critical and can be from 1 to about "5 moles of lower alkyl hydroperoxide and 0.01 to about 10 weight percent catalyst vary. The epoxidation is preferably carried out with an approximately 2.5 molar excess Hydroperoxide and about 1 wt.% Vanady! Catalyst carried out.

The vanadylacetylacetonate of the formula III can as described by R. A. Rowe, et al., Inorganic Synthesis, 51, 113 (1957).

Stereospecific epoxidation of the 23,24-double bond in the compound of formula II can be accomplished, for mixing the reagents and the substrate at an initial temperature of about -100 to about -50 ⁰ C and then the reaction temperature slowly to -40 ° to +20 ⁰ C can rise. The starting temperature is preferably about -80 ⁰ C and the final temperature of about -20 ⁰ C.

In the next step of process variant (a) the epoxide of the formula IV region-specific to the i-cholesteryl diol of the formula I split. This conversion is done by reducing the epoxy with a complex metal hydride that is suspended in a suitable inert organic solvent.

Suitable complex metal hydrides for this purpose are alkali metal aluminum hydrides such as lithium aluminum hydride, Mono-, di- or tri- (lower-alkoxy) alkali metal aluminum hydrides such as lithium tris (tert-butoxy) aluminum hydride, Mono-, di- or tri- (lower alkoxy) alkali metal aluminum hydrides

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lazy..,

is

such as sodium bis (2-methoxyethoxy) aluminum hydride, di (lower-alkyl) aluminum hydrides such as, for example, diisobutylaluminum hydride. Lithium aluminum hydride is particularly preferred. Suitable solvents for the cleavage reaction are ethereal solvents such as diethyl ether, dimethoxyethane, dimethoxyethoxyethane, tetrahydrofuran and dioxane. Tetrahydrofuran is particularly preferred. The reductive cleavage of the epoxide is carried out suitably at about -20 to 50 ⁰ C, preferably between about 0 and about 25 ⁰ C.

Obtained by means of the method described above one 24R, 25-dihydroxy-6ß-hydroxy- or substituted 6 (3-hydroxy-3a, 5-cyclo-5a-cholestane the formula

H, -OH

CH ₃

H ₃

where R, has the above meaning,

and the absolute configuration at C atom 24 R is from compound of formula II in which the configuration of the 23,24 double bond ice is. In the preparation of a compound of the formula Ia, a compound of the formula

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- great -

Man

wherein R, has the above meaning, into the i-cholesteryl epoxide of the formula

IVa

where R-, has the above meaning,

and the absolute configuration of the epoxy group is 23R, 24R, and then reductively to form the compound split the formula Ia.

For the production of 24S, 2 5-dihydroxy-6ß-hydroxy- or substituted 6/3-hydroxy-3a, 5-cyclo-5a-cholestanes of the formula

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-4T-

lib

where R, has the above meaning,

and the absolute stereochemistry at carbon atom 24 is S, will a compound of the formula Ha

Ma

stereospecific to a compound of the formula

O · .. CH ₃ '■

IVb

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where R-, has the above meaning,

and the absolute stereochemistry at C-23 and C-24 is R and S, respectively, epoxidized, resulting in the stereospecific reductive cleavage the epoxy group adjoins.

The hydroboration in process variant (b) can be carried out by using a compound of the formula II in a suitable inert organic solvent with a borane of the formula V, which is also in a suitable Organic solvent is dissolved, brings together at reduced temperature, and then the reaction temperature can rise to about room temperature. Suitable inert Organic solvents for this conversion are aromatic solvents such as benzene and toluene, ethereal solvents such as diethyl ether, dirnethoxyethane, dimethoxyethoxyethane, tetrahydrofuran and dioxane. Ethereal solvents are preferred. As boranes, bis (3-methyl-2-butyl) borane (disiamylborane), 2,3-dimethyl-2-butylborane (thexylborane), dicyclohexylborane, 9-borobicyclo [3.3.l] nonane may be mentioned. Borane, disiamylborane and thexylborane are preferred.

The reaction temperature is not actually critical in the hydroboration. The hydroboration can be carried out by mixing the substrate and the reagent at a temperature below 0 ^° C. and then allowing the reaction mixture to warm to room temperature.

Although the molar ratio of. Borane to i-steroid olefin of formula II is not critical and molar ratios from about 1 to about 10 can be used, it is preferred to use about 3 to about 8 moles of hydroboration agent to 1 mole of olefin, especially with the more volatile boranes.

Generally, it is preferable to perform the hydroboration in tetrahydrofuran at an initial temperature of about 0 ⁰ C and a final temperature of about 25 ⁰ C, with from about 4 moles to 1 mole of borane-i Steroidylolefin of formula II are used.

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Although the intermediate i-cholesterylborane of the formula VI can be isolated from the hydroboration reaction mixture before the oxidation, the borane is generally oxidized without being isolated after excess borane has been destroyed by adding ice water either the theoretical amount of oxygen (relative to the number of moles of i-Cholesterylboran) introducing at about 0 ⁰ C or preferably characterized in that: aqueous alkaline hydrogen peroxide is added at about 0 to 50 ⁰ C.

Alkali metal hydroxides such as sodium hydroxide come into consideration as alkali in the oxidation reaction or potassium hydroxide, and alkaline earth hydroxides such as calcium hydroxide or barium hydroxide. · Alkali metal hydroxides, in particular Sodium hydroxide are preferred. The amount of aqueous alkali (based on i-cholesterylborane) is not critical and can vary from about 1 to about 10 moles of aqueous alkali to 1 mole of borane. Preferably about 2 to about 8 are used, especially about 4 moles of alkali per mole of borane. The concentration of the aqueous alkali is also not critical and can vary from about 0.1 to about 10 molar. the Concentration is preferably about 1 to about 7, especially about 3 molar.

For the application of the hydroboration and the oxidation of borane in syntheses can refer to a detailed review article 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 variant (c) is expediently by treating a compound of formula VII with osmium tetroxide in a suitable inert organic Solvent at ordinary temperature and subsequent reductive hydrolysis of the osmic acid ester obtained Water and a suitable reducing agent that the

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original solution is added at a slightly elevated temperature, and provides a mixture of compounds of the formulas Ia and Ib.

Suitable inert organic solvents are 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 are mentioned. Nitrogenous aromatic solvents, especially pyridine, are preferred.

The conversion to osmic acid ester is preferably carried out in the absence of light.

Although the temperature is not substantially critical in this reaction, it is desirable to carry out the reaction at a temperature of about 0 ⁰ C to 50 ⁰ C, particularly at about 25 ° C. Similarly, the temperature at which the reductive hydrolysis of the osmic acid ester is carried out is not critical. A slightly elevated temperature is in the range of about 30 ° to about 50 ⁰ C, more preferably 40 ⁰ C, is preferred.

Suitable reducing agents are alkali metal sulfites and bisulfites and hydrogen sulfide be mentioned. Sodium bisulfite is particularly preferred. Sugars, such as mannitol, are also useful in the cleavage bring about the osmic acid ester.

The stereoisomeric diols of the formula Ia and Ib can be separated by means of high pressure liquid chromatography using a solid absorption column and an inert organic solvent. Suitable inert organic solvents for this step are mixtures of hydrocarbons such as ri-hexane, Isooctane, benzene and toluene, and esters such as ethyl acetate and ethyl benzoate. Suitable solid absorbents are

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ΧΓ

Porasil, Corasil, Biosil, Zorbax, Zorbax-Sil and SiI-X. A Waters Associates Chromatograph Model 202 with an 8 feet / 3/8 inch Porasil A column is particularly suitable as a device and a mixture of n-heptane and diethyl ether as eluent.

Another aspect of the present invention relates to stereospecific compounding of the formula Ha and Hb from the compound of the formula VIII. The compounds of the formula VIII can be obtained from the corresponding 25-Tetrahydropyranyläthern (see. US 3,822,254) by treatment with a catalytic amount of a strong acid in one suitable solvent can be obtained. For example, for the preparation of 25-hydroxy-6 £ 3-methoxy-3a, 5-cyclo-5a-cholest-23-yn, the compound of formula VIII with R 1 = methoxy, methanol as solvent and sulfuric acid or sulfonic acids such as benzene acids or p-toluenesulfonic acid can be used as a catalytically active strong acid.

In this regard the invention relates to a process for the preparation of compounds of the formula

Ha

709816/1 157

wherein R _{1 is} hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy or benzyloxy,

and the configuration of the 23,24 double bond is trans, i. wherein the 23,24 double bond has E-configuration, which The method is characterized in that a compound of the formula

VIII

where R, the. has the above meaning

with a complex metal hydride as a reducing agent in an inert organic solvent.

Suitable complex metal hydrides for this purpose are alkali metal aluminum hydrides such as lithium aluminum hydride, mono- and di- (lower alkoxy) alkali metal aluminum hydrides such as lithium mono- (tert-butoxy) aluminum hydride and lithium bis (tert-butoxy) aluminum hydride and sodium bis (2- methoxyethoxy) aluminum hydride. Suitable organic solvents for the reduction are ethereal solvents such as diethyl ether, dimethoxyethane, dimethoxyethoxyethane, tetrahydrofuran and dioxane. The reduction is suitably carried out at temperatures between 50 and 70 ⁰ C.

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Although the amount of complex metal hydride is not essentially critical and between about 1/2 to 10 moles, based on the compound to be reduced, it is generally preferable to be about 1 to 5 moles, especially about 2 moles of complex metal hydride per 1 mole of substrate to use.

The stereospecific reduction of the 23,24-triple bond is a compound of formula VIII in preferably carried out with an alkali metal aluminum hydride in a cyclic ethereal solvent at about 50 to 70 ⁰ C, preferably by means of lithium aluminum hydride in tetrahydrofuran at about 70 ⁰ C.

During the reduction of the acetylene bond in a compound of formula VIII to a double bond in one A compound of the formula Ha can have an alkanoyloxy or benzoyloxy group (R 1) in the 6-position of the i-steroid molecule partially reduced to the corresponding 6-hydroxy group will. The carbinol can continue through the reaction sequence, but the hydroxy group can also be acylated again in a manner known per se.

The invention further relates to a process for the preparation of compounds of the formula

Mb

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wherein R-, hydroxy, lower alkoxy, phenyl-lower alkoxy, represents lower alkanoyloxy or benzyloxy,

and the configuration of the 23,24 double bond is cis, i. wherein the 23,24 double bond has the Z-configuration, which process is characterized by being a compound the formula

VIII

where R-, has the above meaning,

treated with hydrogen in the presence of a hydrogenation catalyst in an inert solvent.

Suitable catalysts for the stereospecific hydrogenation are nickel and noble metal catalysts such as for example platinum, palladium and rhodium, which are free or on a suitable carrier such as carbon, calcium carbonate, Strontium carbonate and aluminum oxide used » can be. Also suitable for the stereospecific hydrogenation are partially deactivated catalysts Precious metals, free or on carriers, poisoned with a heavy metal and an aromatic nitrogen heterocycle are, for example, a Lindlar catalyst made of palladium on calcium carbonate, with lead diacetate and quinoline is poisoned. In general, a palladium catalyst is preferred.

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- primal

The amount of catalyst is not essentially critical and, including carrier, can be from about 0.01 to 2% by weight, based on the compound to be reduced. In general, from 0.05 to 0.5 weight percent of the catalyst is preferred.

Suitable solvents for the hydrogenation are, for example, ethers such as diethyl ether, tetrahydrofuran, Dioxane, dimethoxyethane, dimethoxyethoxyethane; Alcohols like Ethanol, methanol, 2-propanol; Esters such as methyl acetate, Ethyl acetate; organic carboxylic acids such as acetic acid. Methanol is preferably used as the solvent for hydrogenation.

Although the temperature and pressure conditions for the partial catalytic hydrogenation of the acetylene bond are not particularly critical, the hydrogenation is expediently carried out at a hydrogen pressure between about 1 and 5 atmospheres and at about 0 ^° C. to about 100 ^° C., depending on which solvent and which Pressure to be applied. In general, it is preferable to hydrogenate at about 1 to 3 atmospheric hydrogen pressure and at 0 ^° C. to 50 ^° C.

The partial stereospecific hydrogenation of the acetylene bond of compounds of formula VIII to olefins of the formula Hb with Z configuration is best carried out in the presence of a Lindlar catalyst (H. Lindlar and R. Dubuis in "Organic Syntheses", Coll., Vol. V, John Wiley and Sons, New York, N.Y., 1973, pp. 880-883).

Another aspect of the present invention relates to a method for converting the 24 configuration in a compound of formula Ia or Ib

709816/1157

2ΤΓ -

.OH

lib

wherein R-, hydroxy, lower-alkoxy, phenyl-lower-alkoxy, represents lower-alkanoyloxy or benzoyloxy, characterized in that one

a) a compound of a formula Ia or Ib with a compound of the formula

R o 'S Op X

IX

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wherein X is chlorine, bromine or R ₂ SO ₂ O and R ₂

represents lower-alkyl or lower-alkylphenyl,

Reacts in a solvent that includes an organic solvent and an acid acceptor to a compound of formula

CH ₃

O SO ₂ -R ₂

CH ₃

wherein R has the above meaning and the configuration at C-24 is R or S, to obtain,

b) the compound of formula X obtained with a base in an inert solvent at reduced Temperature to a compound of the formula

Xl

709816/1157

where R, has the above meaning,

and the absolute configuration on the C-24 is reversed, converts, and

c) the compound of formula XI obtained with a strong acid in an aqueous medium at reduced Temperature converts to a compound of one of the formulas Ia or Ib, in which the configuration at C-24 in opposite to that in the starting compound of the formula Ia or Ib.

The sulfonylation (a) is suitably carried out by using a compound of the formula Ia or Ib with a lower alkyl or lower alkylphenylsulfonyl halide, lower alkyl or lower alkylphenylsulfonic anhydride of the formula

wherein X is bromine, chlorine or R ₂ ^SO 2 and R _{2 has} the above meaning,

at a reduced temperature in a medium which comprises an organic solvent and an organic acid acceptor contains.

Suitable organic solvents are, for example, aromatic solvents such as benzene, toluene and xylene and heteroaromatic solvents, in particular nitrogen-containing heteroaromatic solvents such as pyridine, picoline, Lutidine and collidine. Suitable organic acid acceptors are, for example, acyclic aliphatic amines such as Triethylamine and tripropylamine, alicyclic aliphatic amines such as 1,4-diazobicyclo [2.2.2] octane, 1,5-diazabicyclo [3.4.0] non-5-en, aliphatic aromatic amines such as dimethyl and diethyla.niline and heteroaromatic amines such as pyridine, Picoline, lutidine and collidine. Preferably one uses

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one and the same heteroaromatic amine as organic Solvent and as an acid acceptor. Pyridine is particularly preferred as a solvent and acid acceptor.

Since the C-24 sulfonyloxy group is removed, the structure of the residue R ~ of the leaving group is not of critical importance. A sulfonyloxy-i-steroid in which Rp is lower-alkyl or lower-alkylphenyl and in particular methyl is preferably used. Accordingly, preferred sulfonylating agents of the formula IX are those in which R _{2 is} lower-alkyl or lower-alkylphenyl and X is chlorine or methanesulphonyloxy. Methanesulfonyl chloride is particularly preferred.

To side reactions such as sulfonylation and / or dehydrogenation of the C-25 hydroxy group to avoid, it is preferred that derivatization of the C-24 hydroxy group at a reduced temperature of about -25 ° to + 25 ⁰ C to make. The preferred reaction temperature is 0 ^° C.

Although the molar ratio of sulfonylating agent of formula IX to i-steroid diol of formula Ia or Ib is not is critical, a molar ratio of about 10: 1, in particular 6: 1, is preferably used.

The cyclization of (b) is carried out by simple treatment of a compound of formula X with a metal hydride in a suitable organic solvent at a .Temperature from about -25 ° C to +25 ⁰ C, preferably at 0 ⁰ C.

Suitable organic solvents for the cyclization are ethereal solvents such as diethyl ether, dimethoxyethane, Tetrahydrofuran and dioxane, and aromatic solvents such as benzene, dimethoxyethoxyethane, toluene and xylene. Ethereal Solvents, especially tetrahydrofuran, are preferred.

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Suitable metal hydrides for the cyclization include alkali metal hydrides such as sodium hydride and Potassium hydride, especially sodium hydride. A sodium hydride / oil emulsion is particularly preferred.

The selective cleavage of the epoxy group of compound of formula XI without retro-i rearrangement (step c) is carried out by first the epoxide of the formula XI at reduced temperature with a treated strong acid in a solvent, the water and an inert organic, water-miscible solvent and the i-steroid diol of the formula Ia or Ib is isolated.

Strong mineral acids such as hydrochloric acid, Hydrobromic acid and sulfuric acid and organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid are suitable. Organic sulfonic acids and, in particular, sulfuric acid are preferred.

Suitable water-miscible organic solvents are ethereal solvents such as dimethoxyethane, diethoxyethoxyethane, Tetrahydrofuran and dioxane. Preferred solvents are tetrahydrofuran and dioxane. Tetrahydrofuran is the most preferred solvent for selective epoxy cleavage and dioxane is particularly preferred for the reaction sequence: epoxy cleavage-retro-i-rearrangement.

In order to prevent simultaneous retro-i-ümlagerung Epoxyspaltung during the reaction at reduced temperature of from about -20 ° to +10 ⁰ C should, to + 5 / preferably be carried out -10 ° ° Cj · especially 0 ⁰ C.

The final step in stereospecific synthesis of 24R, 25- and 24S, 25-dihydroxycholesterol and its Alkanoyl derivatives consist in a retro-i rearrangement of compounds of the formula I into cholesterols of the formula

709816/1157

- -JXi -

Xllia

wherein R _{g is} hydroxy or lower-alkanoyloxy,
and the absolute configuration at the C atom 24 is R,

XiIb

where R _{g has} the above meaning and the absolute configuration at C atom 24 is S j

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3t

H..

Xl I la

where R _g and R, _{Q represent} lower alkanoyloxy with 1 to 8 carbon atoms and the absolute configuration at the carbon atom 24 is R,

Xl I Ib

where R _g and R, _{Q represent} lower alkanoyloxy with 1 to 8 carbon atoms and the absolute configuration at the carbon atom 24 is S.

These conversions can be accomplished by treating the i-cholesteryl diols with an acid treated in a suitable solvolytic medium.

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-yr-

For example, for the production of 24R- and 24S, 25-dihydroxycholesterol the compounds of formulas XIIa and XIIb, in which R “is hydroxy, with a strong acid in one aqueous medium containing a miscible cosolvent, solvolyzed. Suitable strong acids for this purpose are mineral acids such as hydrochloric acid, hydrobromic acid and Sulfuric acid; organic sulfonic acid such as benzenesulfonic acid and p-toluenesulfonic acid. Sulfuric acid is preferred. as suitable miscible cosolvents can include ethereal solvents such as tetrahydrofuran, dioxane, and ketones such as acetone and Methyl ethyl ketone are mentioned. Ethereal solvents, especially dioxane, are particularly preferred.

Although the retro-steroid rearrangement proceeds readily over a wide temperature range, it is preferable to carry out the reaction at temperatures from about 25 ° C. to the boiling point of the reaction medium. A temperature of 80 ^° C. is best for most solvent systems.

If you want to prepare a 3-lower-alkanoyloxy derivative, ie a compound of the formula XIIa or XIIb, in which Rg is lower-alkanoyloxy, the retro-i rearrangement is carried out in a solvent system which contains an alkanecarboxylic acid which corresponds to that shown in the 3 Position corresponds to the desired alkanoyloxy group. For example, glacial acetic acid is used as a solvent to make 24R, 25- or 24S, 25-dihydroxycholesteryl-3-acetate. In this case, a strong acid is not required since the alkanecarboxylic acid is strong enough to serve as a solvent source. Sodium acetate is preferably added to promote solvolysis. The reaction may be at an elevated temperature between about 40 ⁰ C and the boiling point of the reaction mixture, preferably at 60 ° C, Duch performed.

If you have a 3,24-di- (lower-alkanoyloxy) derivative wants to produce, i.e. a compound of formula XIIIa or XIIIb, the reaction is carried out in a solvent medium

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which contains the lower alkanecarboxylic acid and a lower alkanecarboxylic anhydride which corresponds to the alkanoyloxy group to be introduced in the 3- and 24-positions. For example, glacial acetic acid and acetic anhydride are used as solvents and sodium acetate is added to promote solvolysis to produce 24R, 25- or 24S, 25-dihydroxycholesteryl-3,24-diacetate. Elevated reaction temperatures, between 40 ^° C. and the boiling point of the solvent, can also be used in order to achieve the retro-i rearrangement. A solvolysis reaction ^{temperature of 60 °} C. is particularly preferred.

24R, 25- and 24S, 25-dihydroxycholesterol and alkanoyl derivatives thereof are useful as intermediates for the preparation of C-24 stereoisomers of the biologically important vitamin D ₃ metabolite, namely 24R, 25-dihydroxycholecalciferol and the unnatural 24S stereoisomer. This conversion can be achieved in a manner known per se by introducing a Δ double bond (generally by halogenation-dehydrohalogenation) followed by photolysis of the diene, thermal isomerization of the previtamin and hydrolysis of the alkanoyloxy groups (J. Redel, et al., And H. .-Y. Lam, et al., LC).

The following examples explain the process according to the invention.

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example 1

A mixture of 5 g of 63-methoxy-25- (2-tetrahydropyranyloxy) -3a, 5-cyclo-5a-cholest-2 3-yn _f 0.01 g of p-toluenesulfonic acid monohydrate and 250 ml of methanol were stirred at 0 ° for 1 hour . Then 1 g of potassium carbonate was added and the mixture was stirred at 0 °. After half an hour the solvent was evaporated off under reduced pressure, 200 ml of water were added and the mixture was extracted twice with 100 ml of ethyl acetate. The combined organic layers were washed with 100 ml of water and 100 ml of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure and filtration of the drying agent, 4.1 g (99%) of 25-hydroxy-63-methoxy-3a, 5-cyclo-5acholest-23-yne were obtained.
[a] ^ ⁵ = + 49.7 ° (c = 0.99 in CHCl ₃ ).

Example 2

A mixture of 1.2 g of 25-hydroxy-6β-methoxy-3a, 5-cyclo-5a-cholest-23-yne, 1.65 g of lithium aluminum hydride and 50 ml of tetrahydrofuran was heated to reflux with stirring for 48 hours. The reaction mixture was then cooled to 0 °, 100 ml of ether, 3.3 ml of water and finally 2.6 ml of 10% sodium hydroxide solution were added dropwise with stirring. The mixture was stirred at 0 ° for 1 hour, the solids were collected, triturated with methylene chloride and filtered. The combined filtrates were evaporated and the residue was dissolved in methylene chloride and a silica gel column was filtered. After evaporation of the solvent and recrystallization from hexane, 0.9 g (81%) of 25-hydroxy-6/3-methoxy-3cc, S-cyclo-Sct-cholest-23 (E) -en, melting point 126-127 ° _/

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- JK) -

[α] ρ ⁵ + 46.0 ° (c = 0.98 in CHCl ₃ ).

Example 3

A mixture of 0.321 g of 25-hydroxy-6/3-methoxy-3cc, 5-cyclo-5a-cholest-23-yne, 6 ml of methanol and 0.05 g of Lindlar catalyst (made from palladium on calcium carbonate, lead jiacetate and quinoline according to " Organic Syntheses ", Coll., Vol. V, John Wiley and Sons, New York, NY, 1973, pp. 880-883) was stirred under a hydrogen atmosphere until gas absorption ceased, which was the case after 24 hours. The reaction mixture was filtered through diatomaceous earth and, after evaporation of the solvent to dryness, gave 0.31 g (99%) of 25-hydroxy-63-methoxy-3a, S-cyclo-Sa-cholest-23 (Z) -en, [a] ^ ⁵ + 37.4 ° (c = 1.24 in chloroform).

Example 4

A mixture of 0.13 g of 25-hydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholest-23 (E) -en, 0.001 g of vanadyl acetoacetate and 3 ml of toluene was cooled to -78 ° and added dropwise with 0, 06 g of a mixture of 90% tert-butyl hydroperoxide and 10% tert-butyl alcohol in 3 ml of toluene were added. The solution was then stirred at -78 ° for 2 hours and then allowed to warm slowly to -20 °. The solution was then stirred for 6 hours at -20 °, mixed with 50 ml of methylene chloride and washed successively with 25 ml of saturated aqueous sodium bisulfite solution and 25 ml of water. The organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. Chromatography of the residue on silica gel gave 0.088 g (81%) of '23R, 24S-epoxy-25-hydroxy-6β-methoxy-3a, 5-cyclo-5a-cholestane, melting point 112-113 °. [a] ^ ⁵ + 52.9 ° (c = 1.06 in chloroform).

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Example 5

0.104 g of 25-hydroxy-6β-methoxy-3cc, 5-cyclo-5acholest-23 (E) -ene in 1 ml of tetrahydrofuran were added to 1 ml of a 1 molar borane solution in tetrahydrofuran. The mixture was stirred at 0 ° for 1 hour and at 25 ° overnight. The reaction mixture was then cooled again to 0 °, and 0.1 g of ice was added in order to decompose excess borane. Then 0.3 ml of 3N aqueous sodium hydroxide solution and 0.3 ml of 30% aqueous hydrogen peroxide were added successively to the reaction mixture. The mixture was stirred for 1 hour, then 25 ml of water were added and the mixture was extracted 3 times with 25 ml of methylene chloride. The combined organic extracts were washed with 25 ml of water, dried, filtered and evaporated. The residue was dissolved in 4 ml of tetrahydrofuran and cooled to 0 °. Thereafter, 1 ml of 0.1N aqueous sulfuric acid was added dropwise: and the mixture was stirred at 0 ° for 2 hours. Then 25 ml of water were added and the solution was extracted 3 times with 25 ml of methylene chloride. The combined organic extracts were washed twice with 25 ml of saturated aqueous sodium bicarbonate solution, dried and filtered. After evaporation of the solvent under reduced pressure, recrystallization from benzene gave 0.06 g (55%) of 24S, 25-dihydro-6β-methoxy-3a, S-cyclo-sacholestane of melting point 167-168 °, [cc] ^ ⁵ + 38.2 ° (c = 0.9 in chloroform).

Example 6

A mixture of 0.03 g of 25-hydroxy-6/3-methoxy-3a, 5-cyclo-5a-cholest-23 (Z) -ene, 0.103 g of vanadyl acetoacetate and 3 ml of toluene were cooled to -78 ° and treated with 3 ml of 90% tert-butyl hydroperoxide and 10% t-butyl alcohol in toluene dropwise offset. The solution was then stirred at -78 ° for 2 hours and allowed to warm slowly to -20 °. The solution was then stirred for 6 hours at -2 0 °, treated with 50 ml of methylene chloride and successively with 2 5 ml of saturated

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aqueous sodium bisulfite solution and 2 5 ml of water. The organic phase was dried, filtered and concentrated. Chromatography of the residue on silica gel gave 0.083 g (77%) 23R, 24R-epoxy-25-hydroxy-6β-methoxy-3a, 5-cyclo-5a-cholestane.

Example 7

To 1 ml of a 1 molar solution of borane in tetrahydrofuran, 0.104 g of 25-hydroxy-6β-methoxy-3a, 5-cyclo-5cc-cholest-23 (Z) -en added to 1 ml of tetrahydrofuran. The mixture was left at 0 ° for 1 hour and at 25 ° overnight

stirred, then cooled again to 0 °
with

and / 0.1 g ice added to destroy excess borane. Then 0.3 ml of 3N sodium hydroxide solution and 0.3 ml of 30% hydrogen peroxide were added one after the other. The mixture was stirred for 1 hour, then 25 ml of water were added and the mixture was extracted 3 times with 25 ml of methylene chloride. The combined organic extracts were washed with 25 ml of water, dried, filtered and evaporated. The residue was dissolved in 4 ml of tetrahydrofuran and the solution was cooled to 0 °. After 1 ml of 0.1N sulfuric acid had been added dropwise, the mixture was stirred at 0 ° for 2 hours, combined with 25 ml of water and extracted 3 times with 25 ml of methylene chloride. The combined organic extracts were washed twice with 25 ml of saturated aqueous sodium bicarbonate solution, dried and filtered. After evaporation of the solvent under reduced pressure and recrystallization from ethyl acetate, 0.057 g (52%) of 24R, 25-dihydroxy-6β-methoxy-3cc, S-cyclo-Scc-cholestane with a melting point of 142-143 °, [a] ^ ⁵ + 62.1 ° (c = 1.14 in chloroform).

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Example 8

A mixture of 0.046 g of 23R, 24S-epoxy-25-hydroxy-6j3-methoxy-3a, 5-cyclo-5a-cholestane, 0.038 g of lithium aluminum hydride and 2 ml of tetrahydrofuran was 1 hour at 0 ° and Stirred for 1 hour at 25 °, then cooled to 0 ° and diluted with 4 ml of ether. After that, 0.08 ml of water were added one after the other and 0.06 ml of 10% sodium hydroxide solution were added and the mixture was stirred at 25 ° for 1 hour. Then it was filtered and that Evaporated filtrate. The residue was triturated 3 times with 10 ml of methylene chloride, filtered and the combined filtrates were evaporated to dryness. Purification of the residue by preparative thin-layer chromatography on silica gel (1: 1 Benzene-ethyl acetate) yielded 0.022 g (47%) of 24S, 25-dihydroxy-6β-methoxy-3a, S-cyclo-Scc-cholestane with a melting point of 167-168 °, [cc] Ο + 39.0 ° (c = 0.88 in chloroform).

Example 9

A mixture of 0.072 g of 23R, 24R-epoxy-25-hydroxy-6/3-methoxy-3a, 5-cyclo-5a-cholestane, .0.1 g lithium aluminum hydride and 4 ml tetrahydrofuran was 1 hour at 0 ° and Stirred at 25 ° for 1 hour. The reaction mixture was with 8 ml of ether diluted and cooled to 0 °. Then 0.2 ml of water and 0.16 ml of 10% were successively. watery Sodium hydroxide solution was added and the mixture was stirred at 25 ° for 1 hour. The mixture was then filtered, the filtrate evaporated and the residue with 3 times 10 ml of methylene chloride ground and filtered. The combined filtrates were evaporated to dryness. Recrystallization from ethyl acetate provided 0.062 g (86%) 24R, 25-dihydroxy-6β-methoxy-3cc, 5-cyclo-5a-cholestane from melting point 142-14 3 °, + 62.5 ° (c = 0.96 in chloroform).

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Example 10

A solution of 0.108 g of 24S, 25-dihydroxy-6j3-methoxy-3α, 5-cyclo-5α-cholestane, 1 ml of O, IN aqueous sulfuric acid and 4 ml of dioxane were stirred at 80 ° for 4 hours. The reaction mixture was then treated with 50 ml of water and extracted 3 times with 50 ml of methylene chloride. The combined organic extracts were washed / 50 ml of saturated aqueous sodium bicarbonate solution, dried and filtered. Recrystallization of the evaporation residue from methanol gave 0.085 g (81%) of 24S, 25-dihydroxycholesterol of melting point 196-198 °, [a] ^ ⁵ -46.0 ° (c = 0.99 in methanol).

Example 11

A mixture of 0.2 g of 24S, 25-dihydroxy-6β-methoxy-3a, 5-cyclo-5a-cholestane and 1M sodium acetate in 3 ml of acetic acid was heated to 60 ° for 32 hours. After adding 50 ml of methylene chloride, the solution was washed with 25 ml of water and 25 ml of saturated aqueous sodium bicarbonate solution and dried. After evaporation of the solvent, 0.21 g (99%) of 24S, 25-dihydroxycholesteryl-3-acetate were obtained. The recrystallized pure product melts at 157-158 °, [a] p ⁵ -58.3 ° (c = 1.03 in chloroform).

Example 12

A mixture of 0.02 g of 24S, 25-dihydroxy-6ß-methoxy-3oc, 5-cyclo-5a-cholestane, 0.024 g of acetic anhydride and 1 ml of 1M sodium acetate in acetic acid were stirred at 60 ° for 24 hours. After adding 25 ml of methylene chloride, the solution was mixed with 25 ml of water and 25 ml of saturated aqueous sodium bicarbonate solution washed and dried. Evaporation of the solvent and recrystallization gave 0.018 g (78%) of 24S, 25-dihydroxycholesteryl-3,24-diacetate, Melting point 173-174 °, [α] "-40.9 ° (c = 0.99 in chloroform).

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Example 13

A solution of 0.194 g of 24R, 25-dihydroxy-6β-methoxy-3a, 5-cyclo-5a-cholestane, 2 ml of 0.1N sulfuric acid and 6 ml of dioxane was stirred at 80 ° for 4 hours. After adding 50 ml of water, the solution was extracted 3 times with 50 ml of methylene chloride. The combined organic extracts were washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried and filtered. Recrystallization of the evaporation residue gave 0.15 g (79%) of 24R, 25-dihydroxycholesterol with a melting point of 200-202 °, [a] ^ ⁵ -11.6 ° (c = 0.93 in methanol).

Example 14

A solution of 0.2 g of 24S, 25-dihydroxy-6/3-methoxy-3a, 5-cyclo-5a-cholestane and 3 ml of IM sodium acetate in acetic acid was heated to 60 ° for 24 hours. After adding 25 ml of methylene chloride became the solution with 25 ml of water and 25 ml of saturated aqueous sodium bicarbonate solution washed, dried and evaporated. Recrystallization of the residue gave 0.187 g (88%) of 24R, 25-dihydroxycholesteryl-3-acetate melting point 164-165 °, [α] -31.2 ° (c = 0.95 in chloroform).

Example 15

A mixture of 0.03 g of 24R, 25-dihydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholestane, 0.02 g of acetic anhydride and 1 ml of 1M sodium acetate in acetic acid were stirred at 60 ° for 24 hours. After adding 25 ml of water to the reaction mixture, the solution was extracted 3 times with 25 ml of methylene chloride. The unite

with

The th organic layers were washed 3 times with 25 ml of saturated aqueous sodium bicarbonate solution, dried and evaporated. Recrystallization of the residue afforded 0.03 g (85%) 24R, 25-Dihydroxycholesteryl-3,24-diacetate of melting point 122-123 °, [a] ^ ⁵ -36.8 ° (c = 1.1 in chloroform).

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Example 16

To a solution of 1.49 g of methoxy-SajS-cyclo-Sacholest-24-en a solution of 1 g of osmium tetroxide in 10 ml of pyridine was added to 20 ml of pyridine. The mixture was 20 hours stirred at 25 ° in the dark. A solution of 1.66 g of sodium bisulfite in 25 ml of water was then added and the mixture was stirred at 40 ° for 3 hours. The reacfctonsgearaisch was then diluted raitiOOml water and with 3 times 100 ml of ethyl acetate extracted. The combined organic extracts were with 2 times 100 ml of 10% aqueous sulfuric acid, Washed twice 100 ml of saturated aqueous sodium bicarbonate solution and saturated sodium chloride solution. The organic layer was dried and evaporated. 1.4 g (87%) of a 1: 1 mixture of the diols were obtained.

The reaction product was analyzed using a Waters Associate Chromatography Model 202 at an 8 feet / 3/8 inch Porasil Α column separated using a mixture of n-heptane ethyl ether.

In a second experiment, which was carried out under the same reaction conditions, the 1: 1 diol mixture was dissolved in hot benzene and seeded with 24S, 25-dihydroxy-6j3-methoxy-3a, 5-cyclo-5acholestane which had previously been prepared. 0.6 g (37%) of pure 24S isomer with a melting point of 167-168 °, [a] ^ ⁵ + 39.0 ° (c = 1.04 in chloroform) were obtained.

The benzene filtrate was evaporated and the residue was dissolved in hot methyl acetate and inoculated with otherwise prepared 24R, 25-dihydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholestane. 0.54 g (33%) of pure 24R isomer with a melting point of 142-143 °, [α]? ⁵ + 63.2 ° (c = 1.11 in chloroform).

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- 7ΤΓ -

Example 17

To a solution of 0.05 g of 24R, 25-dihydroxy-6j3-methoxy-3a, 5-cyclo-5a-cholestane in 0.5 ml of dry pyridine, 0.05 ml of methylsulfonyl chloride were added at 0 °. The reaction mixture was stirred for 1/2 hour at 0 °, then 0.1 g of ice was added to destroy excess methanesulfonyl chloride. After brief stirring, the solution became 10% strength twice with 10 ml Sulfuric acid and 10 ml of saturated aqueous sodium bicarbonate solution twice. The organic layer was washed dried and evaporated to give 0.059 g of 100% 25-hydroxy-6β-methoxy-24R-methylsulfonyloxy-3a, 5-cyclo-5a ~

25th

cholestane, [α] + 44.7 ° (c = 1.03 in chloroform).

Example 18

In analogy to the procedure of Example 17 was

25-Hydroxy-6ß-methoxy-24S-methylsulfonyloxy-3a, 5-cyclo-5a-

25 cholestane obtained in 100% yield. [a] _D + 39.5 ° (c = 0.8 in chloroform).

Example 19

A solution was added dropwise at 0 ° to a suspension of 0.024 g of sodium hydride in 1 ml of tetrahydrofuran of 0.059 g of 25-hydroxy-6β-methoxy-24R-methylsulfonyloxy-3a, 5-cyclo-5a-cholestane in 0.5 ml of tetrahydrofuran with stirring given. After half an hour, the reaction mixture was diluted with 10 ml of water and the solution with 3 times 10 ml Extracted methylene chloride. The combined organic extracts were washed with 2 times 10 ml of water and dried and evaporated to dryness, recrystallization of the residue from methyl ethyl ketone yielded 0.041 g (91%) 24S, 25-epoxy-6ß-

cyclo-sa-cholestane with a melting point of 100-102 °, + 42.2 ° (c = 0.97 in chloroform).

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Example 20

In analogy to the process of Example 19, 25-hydroxy-6/3-methoxy-24S-methylsulfonyloxy-3a, 5-cyclo-5cc-cholestane da, s 24R, 25-epoxy-3a, 5-cyclo-5a-cholestane was obtained obtained in 93% yield. Melting point 126-127 °, [a] ^ ⁵ + 58.0 ° (c = 1.08 in chloroform).

Example 21

A solution of 0.2 g of 24S, 25-epoxy-6/3-methoxy-3a, 5-cyclo-5a-cholestane, 8 ml of tetrahydrofuran and 2 ml of 1N sulfuric acid was stirred at 0 ° for 3 hours. The reaction mixture was then diluted with 25 ml of water and extracted 3 times with 25 ml of methylene chloride. The combined organic phases were washed with 25 ml of saturated sodium bicarbonate solution, dried and evaporated. Recrystallization of the residue from benzene gave 0.153 g (73%) 24S, 25-dihydroxy-6β-methoxy-3a, 5-cyclo-5cc-cholestane, melting point 167-168 °, [σ] ^ ⁵ + 38.7 ° (c = 0.96 in chloroform).

Example 22

A solution of 0.104 g of 24R, 25-epoxy-6/3-methoxy-3a, 5-cyclo-5a-cholestane, 8 ml of tetrahydrofuran and 2 ml of 1N sulfuric acid was stirred at 0 ° for 4 hours. After adding 25 ml of water, the solution was extracted 3 times with 25 ml of methylene chloride and the organic phases were washed with 25 ml of saturated aqueous sodium bicarbonate solution, dried and evaporated. Recrystallization of the residue from ethyl acetate gave 0.09 g (83%) 24R, 25-dihydroxy-6β-methoxy-3a, 5-cyclo-5cc-cholestane with a melting point of 142-143 ° [a] ^ ⁵ + 63.0 ° ( c = 1.08 in chloroform)

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Example 23

A mixture of 5 g öß

24-ene, 75 ml of methylene chloride and 6 g of sodium bicarbonate were admixed with 2.81 g of m-chloroperbenzoic acid (85% pure) at 0 ° with stirring. The reaction mixture was stirred at 0 ° for one hour and at room temperature for 16 hours. The mixture was then diluted with 75 ml of water and extracted 3 times with 75 ml of ethyl acetate. The extracts were washed with 75 ml of 10% sodium hydroxide solution, water and sodium chloride solution, dried and evaporated. 4.88 g (94%) of a 55:45 mixture of the 24R and 24S isomers were obtained, which was determined by high pressure liquid chromatography according to the method described in Example 1. Fractional crystallization of the mixture from acetone yielded 2.3 g of 24R, 25-epoxy-6j3-methoxy-3a, 5-cyclo-5cc-cholestane with a melting point of 126-127 °. ^ ⁵ + 58.1 ° (c = 1.1.0 in chloroform).

Recrystallization of the residue obtained from methyl ketone by evaporation of the mother liquors yielded 1.8 g of 24S, 25-epoxy-eß-methoxy-SoCiS-cyclo-socholestane with a melting point of 100-102 °, [cc] ^ ⁵ + 42.6 ° ( c = 1.03 in chloroform).

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Claims (1)

Claims Process for the preparation of a compound of the formula OH CH ₃ in which R-, hydroxy, lower-alkoxy, phenyl-lower alkoxy, lower-alkanoyloxy or benzoyloxy, characterized in that one a compound of the formula 709816/1157 -JfL ~ where R, has the above meaning, with a lower alkyl or aryl lower alkyl hydroperoxide in the presence of a compound of the formula R- HC CH ₂ CH ₂ H! wherein R-, and R _{0 are} hydrogen or lower / ο Are alkyl, in an inert solvent at reduced temperature to give a compound of the formula CH ₃ in the R, which has the above meaning, reacts, and the compound of formula IV with a complex metal hydride in an inert solvent treated at reduced temperature; or a compound of the formula II with a borane of the formula 70981S / 1157 Βί— ¹ H in which R ₅ and R _g independently of one another represent hydrogen, alkyl or cycloalkyl or together lower-alkylene, in an inert organic solvent at reduced temperature to give a compound of the formula ^R 5 ^R 6 -CH ₃ , where R ^, Rj- and R, have the above meaning to have, reacts, and the compound of formula VI with an oxidizing agent in an inert organic solvent treated; or a compound of the formula 709816 / 11S7 .CH ₃ VII where R-, has the above meaning, with osmium tetroxide in an inert organic solvent converts to an osmic acid ester and treats the osmic acid ester with water in the presence of a reducing agent. 2 ■ '. Method according to claim 1, characterized in that that R 1 is lower alkoxy. 3. The method according to claim 1, characterized in that R _{1 is} methoxy. 4th Method according to claim 1, characterized in that that the configuration of the 23,24 double bond in the compound of the formula II cis, i.e. Z / is. 5. Method according to claim 1, characterized in that that the configuration of the 23,24 double bond in the compound of formula II trans, i.e. Efist. 6th Method according to claim 1, characterized in that " that the lower-alkyl hydroperoxide is a lower-tert-alkyl peroxide is. 7th Method according to Claim 6, characterized in that " that the lower-tert ..- Alkylhydroperoxxd tert-butyl hydroperoxide is. 709816/1157 8 .. 'Method according to claim 6, characterized in that that the aryl lower alkyl hydroperoxide is cumy hydroperoxide. 9 '. Method according to claim 1, characterized in that that R-, and R _{0 are} hydrogen.
/ ο 10. Method according to claim 1, characterized in that that the inert organic solvent in the reaction of a compound of formula II is an aromatic solvent is. 11 '. Process according to claim 10 /, characterized in that the aromatic solvent is toluene. 12 ". A method according to claim 1, characterized in that the temperature is reduced in the reaction of a compound of formula II with the compound of formula III from about -100 ° to about 0 ⁰ C. 13 '. Method according to claim 12, characterized in that the reduced temperature is approximately -78 ° to approximately -20 ⁰ C .. 14th Method according to claim 1, characterized in that that the complex metal hydride is an alkali metal aluminum hydride. 15 ··. Method according to claim 14, characterized in that that the alkali metal aluminum hydride is lithium aluminum hydride is. · 16. Method according to claim 1, characterized in that that the inert organic solvent in the reaction of a compound of the formula IV is an essential solvent is. 709818/1157 17 ,; Method according to Claim 3 6, characterized in that that the ethereal solvent is tetrahydrofuran. 1β. The method of claim 1, characterized in that the reduced temperature in the reaction of a compound of formula IV about -25 ° to about +25 ⁰ C. T9. Method according to Claim 18, characterized in that the reduced temperature is approximately 0 ^° C. 20th Method according to claim 1, characterized in that that the inert organic solvent in step c) is a heteroaromatic, ethereal or aromatic solvent is. 21!. Method according to claim 20, characterized in that that the heteroaromatic solvent is pyridine. 22 ■ ·. A method according to claim 1, characterized in that the temperature in step c) is about 0 ° to about 50 ⁰ C. 23, The method of claim 22, characterized labeled in ze ichitet that the temperature is about 20 ° to about 40 ⁰ C. 24 _m The method of claim 1, characterized in that the reducing agent in step c) an alkali metal sulfite or bisulfite. 25th Process according to Claim 2, characterized in that the alkali metal bisulfite is sodium bisulfite. 26th Process according to claim 1, characterized in that Rj and Rg are hydrogen alkyl or cycloalkyl. 709816/1157 27.. Process according to Claim 26 /, characterized in that Rj. And R _{fi are} hydrogen. 28. The method according to claim 1, characterized in that that the inert organic solvent in the reaction of a compound of the formula II with a borane of the formula V is an essential solvent. '29. The method of claim 28; characterized, that the ethereal solvent is tetrahydrofuran. , 30- Method according to claim 1, characterized in that the reduced -Temperature in the implementation of a \ compound of formula II with a borane of the formula V to about 40 ⁰ C beträgt.- about -25 ° -3ΤΊ method according to claim 30, characterized in, that the reduced temperature is about 0 ° to about 25 ° C amounts to. 32V method according to claim 1, characterized in that the oxidizing agent in the conversion of a compound of formula VI is oxygen. 33. The method according to claim 1, characterized in that the oxidizing agent in the conversion of a compound of Formula VI is aqueous alkaline hydrogen peroxide at reduced temperature. 34. The method of claim 33, characterized in that the alkali is an alkali metal hydroxide. 35. Method according to claim 34, characterized in that that the alkali metal hydroxide is sodium hydroxide. 709816/1157 - Hrf - 36 *. Method according to Claim 35, characterized in that that the hydrogen peroxide is about 10 to about 50%. 37. Method according to Claim 36, characterized in that that the hydrogen peroxide is 30%. 38. Method according to claim 34, characterized in that that the reduced temperature is around -25 to +50 C. 39. The method according to claim 38, characterized in that the reduced temperature is approximately 0 to approximately 30 ^° C. 40t./ A compound of the formula wherein R, hydroxy, lower-alkoxy, phenyl-lower-alkoxy, lower-alkanoyloxy or Is benzoyloxy. 41 '!. A compound according to claim 40 · .V wherein R is lower-alkoxy and the absolute configuration of the 24-hydroxy group is R or S. 42 .. The compound according to claim 41 'in which R, methoxy and the absolute configuration of the 24-hydroxy group is R. 43?. The compound of Claim 41 wherein R is methoxy and the absolute configuration of the 24-hydroxy group is S. 44;. A connection ^ dex. Rormalg η -CH ₃ wherein R, hydroxy, lower-alkoxy, phenyl-lower-alkoxy, lower alkanoyloxy or benzoyloxy. 45 ". A compound according to claim 44 /, in which R, lower-alkoxy is. 4 <? ' ^: . A compound according to claim 45, in which R- is methoxy. 47, A compound according to claim 44 ^l, in which the configuration of the 23, 2 4-Doppe lbindung ice, ie · Z is. A connection according to claim 44, -ixn the configuration the 23,24 double bond is trans, i.e. E. 49v. A compound of the formula CH ₃ IV 6/1157 wherein R, hydroxy, lower-alkoxy, - phenyl-lower-alkoxy, lower alkanoyloxy or benzoyloxy. 50 ,. A compound according to claim '49, in which R-, lower-alkoxy and the absolute configuration of the epoxy group is 23R, 24S or 23R, 24R. 5t ^'f \ The! Compound according to claim 49 ,, wherein R, is methoxy and the absolute configuration of the epoxy group 23R is 24S. 52 ... The compound according to claim "49, in which R, methoxy and the absolute configuration of the epoxy group is 23R, 24R. 709816/1 157