DD247008A1 - PROCESS FOR PREPARING ARYL-3BETA-HYDROXY-23,24-BISNORCHOLA-5,7-DIEN-22-YL-SULPHON DERIVATIVES - Google Patents

Abstract

The invention relates to a process for preparing aryl-3b-hydroxy-23,24-bisnorchola-5,7-dien-22-yl-sulfone derivatives, which are intermediates for the synthesis of side-chain-modified steriodes, by ozonolysis of phthalazine-1, 4-dione adducts of 3b-OH-protected steroid-5,7,22-trienes, reduction of the 22,23-ozonides to protected 23,24-bis-norchola-5,7-dien-22-ols, conversion into 22- Halogen and 22-sulphonyloxy compounds, reaction with sulfinates to give protected 22-arylsulfonyl compounds and liberation of the 5,7-diene system to the target product of the general formula I, in which R 1 is alkyl, acyl and silyl and R 2 is aryl. Formula I

Description

Field of application of the invention

The invention relates to a process for the preparation of aryl-3jS-hydroxy-23,24-bisnorchola-5,7-dien-22-yl-solfone derivatives of general formula I,

in the

R ^{1 is} hydrogen, alkyls having 1 to 5 C atoms, alkoxy-substituted alkyls, for. For example, methoxymethyl and methoxyethoxymethyl, cyclic ether residues, z. As tetrahydropyranyl, acyl, especially carbonic acid derivatives, for. As methyl carbonate and N-phenyl carbamate, aliphatic acyl having 1 to 5 carbon atoms, for. Acetyl, trichloroacetyl and pivaloyl, aromatic acyls, e.g. Benzoyl and naphthoyl, as well as silyl radicals, e.g. Trimethylsilyl and tert-butyldimethylsilyl, and

R ^{2 is} aryl, in particular phenyl, 4-methyl-phenyl and naphthyl,

mean the intermediates for the synthesis of side chain-modified steroids, in particular of provitamin D derivatives,

are. , *

Characteristic of the known technical solutions

It is already known that compounds of the general formula I in which R ^{1 is} tetrahydropyranyl, / 3-IVethoxyethoxymethyl, methoxymethyl and tert-butyldimethylsilyl and R ^{2 is} phenyl, alkyl- or phenyl-substituted phenyl, are obtained by ozonolysis of the 22,23-double bond of OH- protected 5a, 8a (3,5-dioxo-4-phenyl-1,2,4-triazolidin-1,2-ylene) -3/3-hydroxy-24-methyl-cholesta-6,22-diene. Reduction of the ozonide to the protected 22-alcohol, removal of the diene protecting to give 3/3-OH-protected 3 / 3,22-dihydroxy-23,24-bis-norchola-5,7-diene, esterification to a 22-sulfonic acid ester, conversion to a 22-halo derivative and reaction of this with arylsulfinate represent (EP-PS 0045524)

 This process has a number of significant disadvantages.

In the ozonolysis of OH-protected 5a, 8a (3,5-dioxo-4-phenyl-1,2,4-triazolidin-1,2-ylene) -3β-hydroxy-24-methyl-cholesta-6,22 -dia and reduction of the ozonide is only a yield of 30% to achieve. Thus, the majority of the valuable starting compound obtained from ergosterol is lost in side reactions.

The immediate subsequent removal of the diene protecting group brings further decisive disadvantages. Steroids with 5,7-Dienstruktur are extremely air- 'and photosensitive, so that their handling during many stages of reaction under Lichtschutz und.iriertgas means a considerable technical and economic effort. While 5,7-protected compounds have a yellow color in the above-mentioned manner and do not require any special detection in the case of required purification operations, in particular chromatographic ones, the derived products with free 5,7-diene grouping are colorless, requiring specially selected detection methods are. Because of the photosensitivity of the 5,7-dienes, continuous detection methods based on UV absorption in particular are not applicable.

A considerable effort to eliminate light and oxygen is especially necessary to avoid the risk of formation and accumulation of highly severable highly toxic by-products, which increases significantly over a variety of reaction stages in the reaction of 5,7-dienes.

Object of the invention

It is an object of the invention to provide a process according to which the preparation of aryl-3/3-hydroxy-23,24-bisnorchola-5,7-dien-22-yl-sulfone derivatives of general formula I with significantly improved Yield in the ozonization of 5,7-protected 5,7,22-Steroidtrien is possible and the disadvantages of the known method can be reduced.

Explanation of the essence of the invention

The object of the invention is the preparation of aryl-3/3-hydroxy-23,24-bisnorchola-5,7-dien-22-yl-sulfone derivatives of the general formula I with improved yield by increasing the selectivity of the ozone attack 5,7,22-Steroidtrien on the basis of a suitable diene protection to make cheaper, to minimize the complexity of the process thereby and to increase its safety by the number of reaction steps to be performed with free 5,7-dienegroup is reduced

 The object is achieved in that for the protection of the 5,7-diene system in compounds of general formula II,

in which R ^{1 has} the abovementioned meaning and R ³ denotes alkyl having 1 to 10 C atoms, according to the invention as the dienophile phthalazine-1,4-dione of the formula III,

III

which is optionally substituted, the cycloadduct of general formula IV,

IV

in which R ¹ and R ^{3 have} the abovementioned meanings, ozonized and the 22,23-ozonide optionally in stages to the protected 22-alcohol of the general formula V, '

in which R ^{1 has} the abovementioned meaning and R ^{4 is} hydroxyl, reduced, the compound of general formula V, in which R ^{4 is} hydroxyl, is converted into a compound of general formula V, in which R ^{4 is} halogen or sulphonyloxy and such a halogeno or sulphonyloxy compound is reacted with a sulfinic acid salt to give a sulfone of the general formula V in which R ^{4 is} SO ₂ R ² , where R ^{2 has} the meaning given above, and subsequently a steroiddiene of the general formula I by removal the diene protecting group is obtained.

The production of the aza-Diels-Alder cycloadducts from 5,7-diensterols of the general formula II and phthalazine-1,4-dione of the formula III is effected in that readily accessible from phthalic anhydride and hydrazine 2,3-dihydro-phthalazine-1 4-dione with the 5,7-diensterol in inert solvent, e.g. Dichloromethane, in the presence of an oxidizing agent to form phthalazine-1,4-dione, e.g. B. lead tetraacetate, is reacted.

The ozonization of a cycioadduct of the general formula IV is expedient by introducing an ozone-containing gas stream into the solution of the compound of the general formula IV in an inert solvent, for example hexane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, methanol and ethanol, or in mixtures of such solvents. optionally with the addition of pyridine, at temperatures below -2O ⁰ C made. The ozonides are converted by reducing agents, preferably by incorporation of complex hydrides, in particular sodium borohydride, into the reaction mixture of the preceding ozonization in protected 22-alcohol of the general formula V in which R ^{4 is} hydroxyl. Furthermore, the reduction of such ozonides with dimethyl sulfide, zinc dust or hexamethyltriaminophosphine is initially possible to the 22-aldehyde of the same structure and subsequent further reduction to the 22-alcohol. For the conversion of the protected 22-alcohol into compounds of the general formula V, in which R ^{4 is} halogen or sulphonyloxy, there are a number of possibilities.

Thus, the recovery of compounds of general formula V, in which R ^{4 is} chlorine, z. B. by reaction of 22-alcohol with chloromethylenedimethylammonium chloride in dimethylformamide for 2 hours at ⁰ ° C. Similarly, the 22-bromo derivative is accessible using bromomethylendimethylammonium bromide. Compounds of general formula V, in which R ^{4 is} iodine, are accessible, for example, by exchange of bromine in compounds of general formula V, in which R ^{4 is} bromine, to iodine by reaction with sodium iodide in acetone.

Compounds of the general formula V, in which R ^{4 is} sulphonyloxy, are protected on the action of sulfonic acid halides, for example benzene sulfochloride, 4-methylbenzenesulfobromide or trifluoromethanesulfonyl chloride

22-alcohol, expediently in the presence of inorganic or organic bases, in particular pyridine or triethylamine;

receive. They are also representable in the reaction of compounds of general formula V in which R ^{4 is} halide, with sulfonic acid salts.

On the other hand, by nucleophilic displacement of the sulfonyloxy group of compounds of general formula V with halide, z. As bromide or iodide, in dimethylformamide, compounds of general formula V in which R ^{4 is} halogen to obtain.

By reaction of compounds of general formula V in which R ^{4 is} halogen or sulphonyloxy, with sulfinic acid salts in, for example, dimethylformamide, tetrahydrofuran or alcohols, optionally in the presence of phase transfer catalysts, eg. B. tetrabutylammonium bromide, compounds of general formula V are obtained in which R ^{4 is} the radical SO ₂ R ² , wherein R ^{2 is} aryl, in particular phenyl, 4-methyl-phenyl and naphthyl.

The removal of the diene protecting group from compounds of the general formula V in which R ^{4 is} SO ₂ R ^{2 to give} aryl-3j 8 -hydroxy-23,24-bis-chloro-5,7-dien-22-yl-sulfone derivatives of general formula I is possible by means of a number of methods. It can by reaction with complex hydrides, eg. As lithium aluminum hydride, in tetrahydrofuran, by heating with potassium carbonate in dimethyl sulfoxide, alcoholic potassium hydroxide or high-boiling organic bases, for. B.

2,4,6-trimethyl-pyridine, as well as electrochemically.

The process of the invention once significantly higher yields than achieved by the known method; on the other storable intermediates of the synthesis side chain modified steroids are obtained, which are durable without special measures for the exclusion of air and light without time limit.

By cleavage of the diene protective 22-sulfonyl-5,7-diensteroids are available in a reaction step, which are universal building blocks for the preparation of derivatives derivatized in the side chain, especially of provitamins D, are.

It is particularly surprising that the removal of the diene protection, in particular according to the preferred methodology of

Reaction with complex hydrides, to obtain the 22-sulfonyl group can be made. " '

Embodiments ·

example 1

Phenyl-3 / 3- (tetrahydropyran-2-yloxy) -23.24-bisnorchola-5,7-dien-22-yl sulfone

a) 5, a, 8Q :-( 1,4-dioxo-phthalazin-2,3-ylene) -22-hydroxy-3i3- (tetrahydropyran-2-yloxy) -23,24-bis-noro-6-ene

To the solution of 5.13 g (8 mmol) of 5a, 8a (i; 4-dioxo-phthalazin-2,3-ylene) -24-methyl-3 / 3- (tetrahydropyran-2-yloxy) -cholesta-6, 22-diene in 400 ml of dichloromethane and 4 ml of pyridine is introduced with stirring at -65 ⁰ C an ozone-oxygen mixture until the starting compound is almost implemented. After 15 minutes, 1.82 g (48 mmol) of sodium borohydride are introduced. Subsequently, 150ml of methanol are added dropwise at such a rate that the temperature does not exceed ⁰ -5o C. In the course of 3 h allowed to come to room temperature. The mixture is stirred for 2 h at room temperature, the solvent removed in vacuo, the residue taken up in ethyl acetate, the solution washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue is chromatographed on silica gel with an ethyl acetate-hexane mixture. Yellow solid

Melting range: 130 to 175 ⁰ C

Yield: 3.29 g (71.6%); C ₃₅ H ₄₆ N ₂ O ₅ (574.8).

b) 4-Methyl-benzenesulfonic acid / 5a, 8a (1,4-dioxo-phthalazin-2,3-ylene) -3 / S- (tetrahydropyran-2-yloxy) -23,24-bis-n-chloro-6-ene -22-yl ester /

To dissolve 968 mg (1.68 mmol) of 5a, 8a- (1,4-dioxo-phthalazin-2,3-ylene) -22-hydroxy-3 / S- (tetrahydropyran-2-yloxy) -23,24-bis-chlorol -6-ene in 8.5 ml of dry pyridine are added with stirring and cooling at ^{0 0} C 2.58 g (13.5 mmol) of 4-methylbenzenesulfonyl chloride. It is stirred for 4 h in the cold, stored overnight at 5 ° C in the refrigerator and added to 80 g of ice. The precipitate is filtered off with suction, washed with water and, after drying, chromatographed on silica gel with an ethyl acetate-hexane mixture. Yellow solid

Melting range: 107 to 120 ° C; Yield: 1.03 g (83.8%); C ₄₂ H ₅₂ N ₂ O ₇ S (728.9).

c) 5a, 8a (1,4-dioxo-phthalazin-2,3-ylene) -3 / 3-tetrahydropyran-2-yl-oxy) -23,24-bis-n-chloro-6-en-22-ylphenyl sulfone

The mixture of 729 mg of 4-methyl-benzenesulfonic acid / 5a, 8a (1,4-dioxo-phthalazin-2,3-ylene) -3β- (tetrahydropyran-2-yloxy) -23,24-bis-n-chloro-6-ene 22-yl ester, 260 mg lithium bromide monohydrate, 170 mg lithium carbonate and 19.5 ml dimethylformamide. is stirred for 2.5 h at 78 to 82 ° C. After addition of 578 mg of sodium benzenesulfinate was heated at 8O ⁰ C for a further 3 h. It is taken up in 200 ml of ethyl acetate, the extract washed five times with 20 ml of saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated and the residue chromatographed on silica gel with an ethyl acetate-hexane mixture. Yellow solid

Melting range: 100 to 115 ^° C .; Yield: 356 mg (50.9%); C ₄ H 1 H ₅₀ N ₂ O ₆ S (698.9).

d) Phenyl-3 (8- (tetrahydropyran-2-yloxy) -23,24-bis-chloro-5,7-dien-22-yl-sulfone

In the stirred under inert gas suspension of 0.5 g (13 mmol) of lithium aluminum hydride in 10 ml of dry tetrahydrofuran, the solution of 150 mg (0.21 SmmoDöa ^ a-dADioxo-phthalazin ^ S-ylenl-SyS-ltetrahydropyran ^ -yloxy ^ S ^ -bisnorchol-e-en-22-yl-phenyl-sulfone in 12 ml of tetrahydrofuran is added dropwise over 15 min, followed by stirring for 30 min at 75 ° C. After cooling, 5 ml of 20% sodium hydroxide solution are added dropwise stirred, filtered from the precipitate, this with 15 ml

Washed tetrahydrofuran, the solvent evaporated and the residue chromatographed on silica gel with an ethyl acetate-hexane mixture. White solid. · Melting range: 165 to 175 ° C;

Yield: 70 mg (60.3%); -

C ₃₃ H ₄₆ O ₄ S (538.8).

Example 2

3) 8-Hydroxy-23,24-bisnorchola-5,7-dien-22-yl-phenyl sulfone

a) 3β-Benzoyloxy-5a, 8a: (1,4-dioxo-phthalazin-2,3-ylene) -22-hydroxy-23,24-bisnorcho! -6-ene

In the manner described in Example 1 a), 2.5 g of 3, S-benzoyl-oxy-5a, 8a- (1,4-dioxo-phthalazin-2,3-ylene) -24-methyl-.

ozonated cholesta-6,22-diene. The ozonide is reduced as described there with sodium borohydride. After working up and chromatography, the compound is obtained as a yellow solid.

Melting range: 168-173 ⁰ C;

Yield: 1.96 g (87.2%);

C ₃₇ H ₄₂ N ₂ O ₅ (594.8). '' _λ

b) 4-Methyl-benzenesulfonic acid / 3/3-benzoyloxy-5a, 8a- (1,4-dioxo-phthalazin-2,3-ylene) -23,24-bis-n-chloro-6-en-22-yl ester / In 948 mg of 3j3-benzoyloxy-5a, 8a- (1,4-dioxo-phthalazin-2,3-ylene) -23,24-bis-norchol-6-en-22-ol with 5 are obtained as described in Example 1 b) , 35g tosyl chloride reacted. It is, as described in Example 1 b), worked up and purified by column chromatography. Yellow solid.

Melting range: 132 to 141 ⁰ C;

Yield: 961 mg (80.5%); ,

C ₄₄ N ₄₈ N ₂ O ₇ S (748.9).

c) 3,3-Benzoyloxy-5a, 8a - (1,4-dioxo-phthalazin-2,3-ylene) -23,24-bisnorchol-6-en-22-ylphenyl-sulfone

In the manner described in Example 1 c), 1.72 g of 4-methyl-benzenesulfonic acid / 3j3-benzoyloxy-5o:, 8a! - (1,4-dioxophthalazin-2,3-ylene) -23,24-bisnorchol-6 are obtained -ben-22-ylester / with 784mg lithium bromide monohydrate and 514mg lithium carbonates 60ml dimethylformamide and subsequently reacted with 3.12 g of sodium benzene sulfinate. It is, as described in Example 1c), worked up and purified by column chromatography. Yellow solid. Melting range: 206 to 209 ° C; ',

Yield: 1.29 g (78.0%); C ₄₃ H ₄₆ N ₂ O ₆ S (718.9).

d) 3,3-Hydroxy-23,24-bis-chloro-5,7-dien-22-ylphenyl-sulfone

The solution of 100 mg (0.139 mmol) of 3/8-benzoyloxy-5a, 8a (1,4-dioxo-phthalazin-2,3-ylene) -23,24-bis-norchol-6-en-22-yl-phenylsulfone in 10 g of 5% potassium hydroxide solution in propanol is heated under argon at 95 ⁰ C for 2 h at reflux. The solvent is removed in vacuo and the residue taken up in 40 ml of water. It is extracted with 50 ml of dichloromethane, the dichloromethane solution washed with 15 ml of saturated sodium chloride solution, dried over magnesium sulfate, the solvent evaporated and the residue purified by column chromatography on silica gel 60 eluting with dichloromethane. Pale yellowish crystals

Melting range: 200 to 210 ° C; Yield: 47.7 mg (75.5%); C ₂₈ H ₃₈ O ₃ S (454.6).

Claims (1)

Invention claim: Process for the preparation of aryl-3β-hydroxy-23,24-bis-chloro-5,7-dien-22-yl-sulfone derivatives of general formula I, in the · R ^{1 is} hydrogen, alkyls having 1 to 5 C atoms, alkoxy-substituted alkyls, for. For example, methoxymethyl and methoxyethoxymethyl, cyclic ether residues, z. As tetrahydropyranyl, acyl, especially carbonic acid derivatives, for. For example, methyl carbonate and N-phenyl carbamate, aliphatic acyl having 1 to 5 carbon atoms, for. Acetyl, trichloroacetyl and pivaloyl, aromatic acyls, e.g. Benzoyl and naphthoyl, as well as silyl radicals, e.g. B. trimethylsilyl and tert-butyldimethylsilyl and R ² aryl, especially phenyl, 4-methyl-phenyi and naphthyl,. ^l mean, from steroids the general formula Il _ in which R ^{1 is} as defined above, and R ^{3 is} alkyl having 1 to 10 C atoms, characterized in that from the steroids of the general formula II and phthalazine-1,4-dione of the formula III III Aza-Diels-Alder adducts of general formula IV, IV in which R ¹ and R ^{3 have} the abovementioned meanings, these compounds of the general formula IV are ozonized, the formed 22,23-ozonides to protected 22-alcohols of the general formula V, in which R ^{1 has} the abovementioned meaning and R ^{4 is} hydroxyl, reduced, protected 22-alcohols of the general formula V in compounds of general formula V, in which R ⁴ halide, such as chlorine, bromine and iodine, or sulfonyloxy means transferred and those halogen or sulfohyloxy compounds having a sulfinic acid salt to give a sulfone of the general formula V, in which R ^{4 is} the radical SO ₂ R ² , where R ^{2 has} the abovementioned meaning, and subsequently the phthalazine-1,4-dione radical with regeneration of the 5,7-diene system and recovery of a sulfone derivative of the general
Formula I, in which R ¹ and R ^{2 have} the meanings mentioned above, is removed.