CH628907A5 - Process for the preparation of 24,25-dihydroxycholesterol derivatives - Google Patents

Description

628 907

2nd

1. A process for the preparation of a compound of the formula in which R9 is lower alkanoyloxy and R10 is hydroxy or lower alkanoyloxy or R9 and R10 are hydroxy, characterized in that a compound of the formula ^

wherein R, hydroxy, lower-alkoxy, phenyl-lower-alkoxy, never- The invention relates to a process for the preparation of new der-alkanoyloxy or benzoyloxy, treated with an acid in a stereochemical medium known from 45 24,25-dihydroxycholesterol derivatives. at C atom 24, which is used for the stereospecific synthesis of

2. The method according to claim 1, characterized in that 24R, 25- and 24S, 25-dihydroxycholecalciferol can be used. Ri is lower alkoxy, especially methoxy. The term "alkyl group" used below

3. The method according spoke 1, characterized in that refers to straight-chain or branched hydrocarbon-the absolute configuration of the 24-hydroxy group Rist. 5 ° rest with 20C atoms. Examples of alkyl groups are

4. The method according to claim 1, characterized in that methyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl, octal, is the absolute configuration of the 24-hydroxy group S. Examples of alkoxy groups are methoxy, ethoxy, isopropyl

5. The method according to claim 1, characterized in that poxy and tert-butoxy. Examples of phenylalkoxy groups are the acid a strong acid, especially sulfuric acid or benzyloxy, 2-phenylethoxy and 4-phenylbutoxy. Examples of an organic sulfonic acid if R9 and R10 are hydroxy, 55 alkanoyloxy groups are formyloxy, acetoxy, butyryloxy and and an acid of formula R9 is H, especially acetic acid, if hexanoyloxy. The term "lower" refers to groups R) and Rm are lower alkanoyloxy. with 1 to 2 carbon atoms.

6. The method according to claim 1, characterized in that in the formulas a solid line () to the medium denotes a compound R9 H, in particular acetic acid, a substituent on the steroid ring β-orientation (ie above, if R9 is lower alkanoyloxy and Rt0 hydroxy is, and 60 half of the molecular level), a broken line (...,) and the medium the compound R9H and (Rg) 20, in particular binding to a substituent in the a-position (ie below the

Acetic acid and acetic anhydride contains, if R9 and R, n lower molecular level) and a wavy line () a substituent

Are alkanoyloxy. in a or ß position. The formulas show the connections in

7. The method according to claim 1, characterized in that an absolute stereochemical configuration. Since the temperature is 25 to 100 ° C., in particular 60 to 80 ° C., if R | () 65 starting materials are derived from the naturally occurring stigmasterol hydroxy, and in particular 40 to 80 ° C., if R, n are derived, these substances exist in the single alkanoyloxy shown here, is. absolute configuration. The method according to the invention is nevertheless intended to be based on the synthesis of steroids

628 907

unnatural and racemic series, d. H. the enantiomers of the compounds and mixtures shown here are used in the formulas. The synthesis can therefore be carried out using unnatural or racemic starting compounds in order to produce unnatural or racemic products. Optically active compounds can then be obtained by cleaving racemates using techniques known per se in steroid chemistry.

The stereospecific synthesis of 24R, 25- and 24S, 25-dihydroxycholesterol and its alkanoyl-5 derivatives according to the invention consists of a retro-i rearrangement of compounds of the formula

OH

wherein Ri is hydroxy, lower alakoxy, phenyl-lower alkoxy, never-the alkanoyloxy or benzoyjoxy, in cholesterols of the formula w, ï

C_H3 ^ ™ CH3

II

wherein R (j is lower alkanoyloxy and R10 is hydroxy or lower alkanoyloxy or R9 and R10 are hydroxy.

50 The compounds of formula II can be in those of the formulas

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where Rg is hydroxy or lower alkanoyloxy and the absolute configuration at the C atom is 24 R,

where Rg and R10 deliver lower alkanoyloxy with 1 to 8 carbon atoms. In this case a strong acid is not necessary

represent and the absolute configuration at the C atom is 24 S, 40 since the alkane carboxylic acid is sufficiently strong to be used as solvent

split up. source to serve. To promote solvolysis, one sets

The process according to the invention is thereby preferably sodium acetate. The reaction can be increased. that the i-cholesteryl diols with an acid in a temperature between about 40 ° C and the boiling point of the reac-

treated solvolytic medium. tion mixture, preferably at 60 ° C.

For example, for the preparation of 24R- and 24S, 25-45. If a 3,24-di (lower alkanoyloxy) derivative is produced

Dihydroxycholesterol of the compound of formulas IIa and IIb, len wants, d. H. a compound of the formula Ile or Ild, in which R9 is hydroxy, the compounds of the formula I are carried out with the reaction in a solvent medium which comprises that of a strong acid in an aqueous medium which is a mixed-lower alkane carboxylic acid and a lower Alkane carboxylic acid

bares Cosoivens contains, solvolysed. Suitable strong acids contain hydride, which corresponds to the purpose to be introduced in the 3- and 24-position mineral acids, such as hydrochloric acid, bromine, alkanoyloxy group. For example, one uses seric acid and sulfuric acid; organic sulfonic acid such as glacial acetic acid and acetic anhydride as the solvent and adds sodium acetate

Benzenesulfonic acid and p-toluenesulfonic acid. Sulfuric acid is preferred to promote solvolysis at 24R, 25- or 24S, 25-. Suitable miscible cosolvents can be ether-dihydroxycholesteryl-3,24-diacetate. Increased Reak

cal solvents such as tetrahydrofuran, dioxane and ketone tion temperatures, between 40 ° C and the boiling point of such as acetone and methyl ethyl ketone. Essential solvents can also be applied to the solvents, especially dioxane, are particularly preferred. retro-i rearrangement. A solvolysis reaction

Although the retro-i steroid rearrangement without further ado over temperature of 60 ° C. is particularly preferred. •

over a wide temperature range, it is preferable to use 24R, 25- and 24S, 25-dihydroxycholesterol and alkanoylderi-the reaction at temperatures from about 25 ° C to the boiling point thereof are useful as intermediates for the preparation point of the reaction medium. A temperature of 80 ° C is best for most 60 C-24 stereoisomers of the biologically important vitamin solvent systems. D. ^ - Metabolites, namely 24R, 25-dihydroxycholecalciferol and

If you want to make a 3-lower alkanoyloxy derivative, the unnatural 24S stereoisomer. This conversion d. H. a compound of the formula IIa or IIb, in which R <j can be reduced in a manner known per se by introducing an À7-

Alkanoyloxv, the retro-i rearrangement is carried out in a double bond (generally by halogenation-dehy-

Solvent system containing an alkane carboxylic acid, 65 drohalogenation) followed by photolysis of the diene, thermal that of the 3-position desired alkanoyloxy group isomerization of the previtamin and hydrolysis of the aikanoyloxy

speaks. For example, glacial acetic acid is used as solvent groups that can be achieved (J. Redel, et al., And H.-Y. Lam, et al.,

tel, um24R, 25-or24S, 25-dihydroxycholesteryl-3-acetate-L.C.).

628 907

The preparation of the starting compounds of the formula I is described in German Offenlegungsschrift 2,645,527.

The following examples illustrate the process according to the invention.

Example 1 5

A. Preparation of the starting material a) A mixture of 5 g of 6β-methoxy-25- (2-tetrahydr'opyranyl-oxy) -3a, 5-cyclo-5cx-cholest-23-in, 0.01 g of p-toluenesulfonic acid mono- nohydrate and 250 ml of methanol were stirred at 0 ° C. for 1 hour, then 1 g of potassium carbonate was added and the mixture was stirred at 0 ° C. After half an hour the solvent was evaporated under reduced pressure, 200 ml of water was added and the mixture was extracted twice with 100 ml of ethyl acetate. The combined organic layers were washed with 15 100 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-6β-methoxy-3cc, 5-cyclo-5a-cholest-23-in were obtained. 20 [a] g = + 49.7 ° C (c = 0.99 in CHC13).

b) A mixture of 1.2 g of 25-hydroxyx-6β-methoxy-3a, 5-cyclo-5a-cholest-23-in, 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 ° C., 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 ° C for 1 hour, the solids were collected, triturated with methylene chloride and filtered. The combined filtrates were evaporated and the residue dissolved in methylene chloride and a silica gel column filtered. After evaporation of the solvent and recrystallization from hexane, 0.9 g (81%) of 25-hydroxy-6β-methoxy-3a, 5-cyclo-5a-cho-lest-23 (E) -en, melting point 126-127 ° C. .

[a] g + 46.0 ° C (c = 0.98 in CHC13).

25th

30th

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c) A mixture of 0.321 g of 25-hydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholest-23-in, 6 ml of methanol and 0.05 g of Lindlar catalyst (made from palladium on calcium carbonate, with diacetate 40 and quinoline according to "Organic Syntheses", Coll., Vol. V, John Wiley and Sons, New York, NY, 1973, pp. 880-883), the mixture 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 45 evaporation of the solvent to dryness, gave 0.31 g (99%) of 25-hydroxy-6β-methoxy-3a, 5-cyclo-5a-cholest-23 (Z) -en,

[a] g + 37.4 ° C (c = 1.24 in chloroform).

d) A mixture of 0.13 g of 25-hydroxy-6β-methoxy-3a, 5-50 cyclo-5a-cholest-23 (E) -en, 0.001 g of vanadylacetoacetate and 3 ml of toluene was cooled to -78 ° C and added dropwise with 0.06 g of a mixture of 90% tert-butyl hydroperoxide and 10% tert-butyl alcohol in 3 ml toluene. The solution was then stirred at -78 ° C for 2 hours and then allowed to warm up slowly to 55-20 ° C. The solution was then stirred at -20 ° C for 6 hours, 50 ml of methylene chloride was added 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 60 filtrate was concentrated under reduced pressure. Chromatography of the residue on silica gel yielded 0.088 g (81%) 23R, 24S-epoxy-25-hydroxy-6ß-methoxy-3a, 5-cyclo-5a-choestane. Melting point 112-113 ° C. [a] g + 52.9 ° C (c = 1.06 in chloro form). 65

e) A mixture of 0.03 g of 25-hydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholest-23 (Z) -en, 0.103 g of vanadylacetoacetate and 3 ml of toluene was cooled to -78 ° C and with 3 ml of 90% tert-butyl hydroperoxide and 10% tert-butyl alcohol in toluene are added dropwise. Thereafter, the solution was stirred at -78 ° C for 2 hours and slowly stirred to -20 ° C, 50 ml of methylene chloride was added, and washed successively with 25 ml of saturated aqueous sodium bisulfite solution and 25 ml of water. The organic phase was dried, filtered and concentrated. Chromatography of the residue on silica gel provided 0.083 g (77%) of 23R, 24R-epoxy-25-hydroxy-6β-methoxy-3a, 5-cyclo-5a-cholestan.

f) A mixture of 0.046 g of 23R, 24S-epoxy-25-hydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholestan, 0.038 g of lithium aluminum hydride and 2 ml of tetrahydrofuran was stirred for 1 hour at 0 ° C and 1 hour at 25 ° C stirred, then cooled to 0 ° C and diluted with 4 ml of ether. Then 0.08 ml of water and 0.06 ml of 10% sodium hydroxide solution were added in succession and the mixture was stirred at 25 ° C. for 1 hour. It was then filtered and the filtrate evaporated. The residue was triturated with 3 times 10 ml of methylene chloride, filtered and the combined filtrates are 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-6ß-methoxy-3a, 5-cyclo-5cx-cholestane from the melting point

167-168 ° C, [a] g + 39.0 ° C (c = 0.88 in chloroform).

g) A mixture of 0.072 g of 23R, 24R-epoxy-25-hydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholestane, 0.1 g of lithium aluminum hydride and 4 ml of tetrahydrofuran were at 1 ° C and 1 hour at Stirred at 25 ° C. The reaction mixture was diluted with 8 ml ether and cooled to 0 ° C. Then 0.2 ml of water and 0.16 ml of 10% aqueous sodium hydroxide solution were added in succession and the mixture was stirred at 25 ° C. for 1 hour. The mixture was then filtered, the filtrate evaporated and the residue triturated with 3 times 10 ml of methylene chloride and filtered. The combined filtrates were evaporated to dryness. Recrystallization from ethyl acetate gave 0.062 g (86%) of 24R, 25-dihydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholestane, melting point 142-143 ° C, [ci] d + 62.5 ° C (c = 0.96 in chloroform).

B. Procedure

A solution of 0.108 g24S, 25-dihydroxy-6β-methoxy-3a, 5-cyclo-5a-cholestane, 1 ml of 0.1N aqueous sulfuric acid and 4 ml of dioxane were stirred at 80 ° C. for 4 hours. The reaction mixture was then mixed with 50 ml of water and extracted with 3 times 50 ml of methylene chloride. The combined organic extracts were washed in 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 with a melting point of 196-198 ° C [a] o -46.0 ° C (c = 0.99 in methanol).

Example 2

A mixture of 0.2 g of 24S, 25-dihydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholestan and 1M sodium acetate in 3 ml of acetic acid was heated to 60 ° C 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-dihydroxy-cholesteryl-3-acetate was obtained. The recrystallized pure product melts at 157-158 ° C, [a] g -58.3 ° C (c = 1.03 in chloroform).

Example 3

A mixture of 0.02 g of 24S, 25-dihydroxy-6ß-methoxy-3a, 5-cyclo-5a-cholestan, 0.024 g of acetic anhydride and 1 ml of 1M sodium

ozs V «7 6

Acetate in acetic acid was stirred at 60 ° C for 24 hours. After adding 25 ml of methylene chloride, the solution was washed with 25 ml of water and 25 ml of saturated aqueous sodium bicarbonate solution and dried. Evaporation of the solvent and recrystallization gave 0.018 g (78%) 24S, 25-5 dihydroxycholesteryl-3,24-diacetate, melting point 173-174 ° C, [a] g -40.9 ° C (c = 0.99 in chloroform).

10th

Example 4

A solution of 0.194 g24R, 25-dihydroxy-6β-methoxy-3a, 5-cyclo-5ß-cholestane, 2 ml of 0, IN sulfuric acid and 6 ml of dioxane 15 were stirred at 80 ° C. for 4 hours. After adding 50 water, the solution was extracted with 3 times 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 20 0.15 g (79%) of 24R, 25-dihydroxycholesterol with a melting point of 200-202 ° C, ["B -11.6 ° C (c = 0.93 in methanol).

Example 5

A solution of 0.2 g of 24S, 25-dihydroxy-6β-methoxy-3a, 5-cyclo-5a-cholestan and 3 ml of 1M sodium acetate in acetic acid was heated to 60 ° C. for 24 hours. After adding 25 ml of methylene chloride, the solution was washed with 25 ml of water and 25 ml of saturated aqueous sodium bicarbonate solution, dried and evaporated. Recrystallization of the residue gave 0.187 g (88%) of 24R, 25-dihydroxycholesteryl-3-acetate with a melting point of 164-165 ° C, [a] g-31.2 ° C (c = 0.95 in chloroform).

Example 6

A mixture of 0.03 g of 24R, 25-dihydroxy-6ß-methoxy-3a, 5-cyclo-5ß-cholestane, 0.02 g of acetic anhydride and 1 ml of 1M sodium acetate in acetic acid was stirred at 60 ° C for 24 hours. After adding 25 ml of water to the reaction mixture, the solution was extracted with 3 times 25 ml of methylene chloride. The combined organic layers were washed in 3 times 25 ml of saturated aqueous sodium carbonate solution, dried and evaporated. Recrystallization of the residue provided 0.03 g (85%) of 24R, 25-dihydroxycholesteryl-3,24-diacetate, melting point 122-123 ° C, [a] g - 36.8 ° C (c = 1.1 in chloroform.

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