DD282230A5 - PROCESS FOR PREPARING (3S) -3,24,25-TRIHYDROXYCHOLESTA-5,7-DIENES - Google Patents

Abstract

The invention relates to a process for the preparation of * and their 26,27-dialkyl derivatives for the synthesis of 24,25-Dihydroxycholecalciferolen with long-lasting calcium transport effect without significant calcium mobilizing properties and immunoregulatory and antiproliferative effect by reaction of * or * with * or * or * to * and dearylsulfonation of these to target products. {* * 24,25-Dihydroxy-cholecalciferol; Calcium transport effect; * * Oxirane; 2- (alkyl-hydroxy-alkyl) oxirane; * * * Dearylsulfonation}

Description

in which R ¹ and R ² and R ^{4 have} the meanings mentioned, and the compounds of general formula Vl to (3S) -3,24,25-trihydroxy-cholesta-5,7-serve the general formula I dearylsulfoniert.

2. The method according to claim 1, characterized in that the reaction between the 22-arylsulfonyl-23,24-bisnorchola-5,7-serve the general formula II and the oxiranes of the general formula III or the sulfonic acid-2,3-dihydroxy 3-alkyl-alkyl esters of the general formula IV or the 1-halo-2,3-dihydroxy-3-alkyl-alkyl esters of the general formula V is carried out by the action of strong bases in inert solvents.

3. The method according to claim 1 and 2, characterized in that are used as strong bases alkali metal amides such as lithium diisopropylamide or Lithiumcyclohexylisopropylamid or metal alkyls such as n- or tert-butyllithium.

4. The method according to claim 1 to 3, characterized in that the inert solvent! aprotic or aliphatic or aromatic hydrocarbons, in particular benzene or toluene, or ethers, in particular diethyl ether, 1,2-dimethoxy-ethane and tetrahydrofuran, or mixtures thereof.

5. The method according to claim 1 to 4, characterized in that the reaction takes place in the temperature range between -80 and +30 ⁰ C.

6. The method according to claim 1, characterized in that the removal of the 22-arylsulfonyl from the (3S) -22-arylsulfonyl-3,24,25-trihydroxy-cholesta-5,7-serve the general formula Vl with amalgams of suitable metals as done with alkali metal amalgams, alkaline earth metal amalgams and aluminum amalgams.

7. Apparatus according to claim 1 and 6, characterized in that sodium amalgam is used with a content of 3 to 5% sodium.

8. The method of claim 1, 6 and 7, characterized in that the dearylsulfonierung in lower alcohols, preferably methanol, or optionally in admixture with suitable solvents such as ethers, in particular tetrahydrofuran, or esters, in particular ethyl acetate, is performed.

9. The method of claim 1 and 6 to 8, characterized in that the Dearylsulfonierung in the temperature range between -20 Uiid +50 ⁰ C, preferably between 0 and 25 ⁰ C, takes place.

Field of application of the invention

The invention relates to a process for the preparation of (3S) -3,24,25-trihydroxy-cholesta-5,7-compounds of general formula I.

which symbolizes the compounds having (24R) or (24S) configuration or else mixtures of both and in which R ¹ and R ² denote hydrogen or identical or different alkyl groups having 1 to 4 C atoms.

The compounds obtained according to the invention serve as intermediates for the synthesis of 24, 25-dihydroxy vitamin D ₃ derivatives having a long-lasting calcium transport effect without significant calcium mobilizing properties as well as immunoregulatory, antiproliferative and cell differentiation action, especially against leukemia cells.

Characteristic of the known state of the art

It is already known to represent compounds of the formula I in which R ¹ and R ^{2 are} hydrogen by reacting (3S) -3-alkoxy-22-arylsulfonyl-23,24-bis-norchola-5,7-diene or ( 3S) -22-arylsulfonyl-3-silyloxy-23,24-bisnorchola-5,7-serve with, for example, sulfonic acid-2,3-dihydroxy-3-methyl-butyl esters or 2- (1-hydroxy-1-methyl-en ' iyl) -oxirane in the presence of basic reagents, in particular of alkali metal amides or metal alkyls, (3S) -3-alkoxy-22-arylsulfonyl-24,25-dihydroxy- or (3S) -22-arylsulfonyl-24,25-dihydroxy-3- silyloxy-cholesta-5,7-dienes whose dearylsulfonation with sodium amalgam give (3S) -3-alkoxy-24,25-dihydroxy or (3S) -24,25-dihydroxy-3-silyloxy-cholesta-5,7 Clienes leads from which then by cleavage of the 3-hydroxy protective group in an acidic medium, the target compounds are obtained (EP-PS 0045524).

This method has several significant disadvantages.

The conversion of the (3S) -3-alkoxy-22-arylsulfonyl and (3S) -22-arylsulfonyl-3-silyloxy-23,24-bisnorchola-5,7-dienes into (3S) -3,24,25- Trihydroxy-cholesta-5,7-dienes requires three reaction stages, of which especially the dearylsulfonierung and the elimination of the 3-hydroxy protective group difficulties.

For the dearylsulfonation of (3S) -3-alkoxy-22-arylsulfonyl-24,25-dihydroxy or (3S) -22-arylsulfonyl-24,25-dihydro:; y-3-silyloxy-cholesta-5,7- Serve after the said process with sodium amalgam is an addition of disodium hydrogen phosphate is indispensable, which leads to problems in the required large amount in the isolation of the desired compounds from the reaction mixture.

The release of the 3-hydroxy group in an acidic medium requires gentle conditions during very long reaction times and is nevertheless only feasible in moderate yields.

In addition, the (3S) -3-alkoxy-22-arylsulfonyl or (3S) -22-arylsulfonyl-3-silyloxy-23,24-bisnorchola-5,7-dienes used as starting compounds for the said process are only in lengthy synthesis of low overall yield based on the basic steroid ergosterol.

Object of the invention

It is an object of the invention, in order to avoid the abovementioned disadvantages, to develop a process according to which the preparation of (3S) -3,24,25-trihydroxy-cholesta-5,7-dienes of the general formula I is improved in a shortened process Yield is possible and with the effort for the synthesis can be significantly reduced.

Explanation of the essence of the invention

The object of the invention is the preparation of (3S) -3,24,25-trihydroxy-cholesta-5,7-serve the general formula I in a shortened two-stage process while avoiding the use of disodium hydrogen phosphate in the Dephenylsulfonier'jng and bypass a release of the 3-hydroxy group under acidic conditions more favorable.

The object is achieved in that in the 3-position substituted 22-arylsulfonyl-23,24-bisnorchola-5,7-dienes of the general formula II,

in the

R ^{3 is} hydrogen or acyl, in particular carbonic acid derivatives, ζ. Methoxycarbonyl and N-phenyl-carbamoyl, aliphatic

Acyl with 1 to 5 carbon atoms, z. Acetyl, trifluoroacetyl and pivaloyl, or aromatic acyl, ζ. B. benzoyl and naphthoyl, and R ⁴ aryl, in particular phenyl, substituted, preferably lower alkyl-substituted phenyl such as 4-methyl-phenyl biphenylyl

and naphthyl, mean, with oxiranes of general formula III,

• A

in which R 'and R ^{2 have} the meanings given,

or with sulfonic acid-2,3-dihydroxy-3-alkyl-alko esters of the general formula IV,

off

fc so /

in which R ¹ and R ^{2 have} the meanings mentioned and R ^{5 is} alkyl, ζ. Methyl to butyl and trifluoromethyl, or aryl, e.g. Phenyl, substituted phenyl, in particular 4-methylphenyl, biphenylyl and naphthyl, or with 1-halo-2,3-dihydroxy-3-alkylalkanes of the general formula V,

Ott

in which X is chlorine, bromine or iodine and R ¹ and R ^{2 have} the meanings given, to give (322-S) -arylsulfonyl-3,24,2G-trihydroxy-cholesta-5,7-dienes of general formula VI,

Vl

in which R ', R ² and R ^{4 have} the meanings mentioned,

reacted and the compounds of general formula Vl to (3S) -3,24,25-trihydroxy-cholesta-5,7-serve the general formula I dearylsulfoniert.

The oxiranes of the general formula III used for the reaction with 22-arylsulfonyl-23,24-bis-norchola-5,7-of the general formula II as side-chain building blocks or sulfonic acid-2,3-dihydroxy-3-alkyl-alkyl esters of the general formula IV or 1-halo-2,3-dihydroxy-3-alkyl-alkanes of the general formula V have (R) - or (S) -configuration. It is also possible to use mixtures of both stereoisomers.

The reagents between the 22-arylsulfonyl-23,24-bisnorchola-5,7-serve the general formula II and the oxiranes of the general formula III or the sulfonic acid-2,3-dihydroxy-3-alkyl-alkyl esters of the general formula IV or the 1-halo-2,3-dihydroxy-3-alkyl-alkanes of the general formula V is carried out by the action of strong bases in inert solvents. As strong bases are alkali metal amides, eg. For example, lithium diisopropylamide or lithium cyclohexyl isopropylamide, or metal alkyls, e.g. B n- or tert-butyllithium, suitable.

Examples of inert solvents are those aprotic as well as aliphatic or aromatic hydrocarbons, eg. Benzene or toluene, or ethers, e.g. Diethyl ether, 1,2-dimethoxy-ethane and tetrahydrofuran, or mixtures thereof.

The reaction is carried out in the temperature range between -80 and + 30'C.

The removal of the 22-arylsulfonyl from (3S) -22-arylsulfonyl-3,24,25-trihydroxy-cholesta-5,7-serve the general formula VI is carried out with amalgams of suitable metals, for. B. with Alkalimet.illamalgamen, Erdalkalimetal'amalgamen and Aluminiumamalgamen. Preferably, sodium amalgam is used at a level of from 3 to 5% sodium. The dearylsulfonierung is in lower alcohols, preferably in methanol, optionally mixed with suitable solvents such as ethers, eg. For example, tetrahydrofuran, or esters, for. As ethyl acetate, performed. The reaction temperature is in the range between -20 and + 5O ⁰ C, preferably between 0 and +25 "C.

The surprising finding that compounds of the general formula VI alone can be desulfonated using amalgams without the addition of sodium dihydrogen phosphate, means significant improvements in this process step, in the saving of Nätriumdihydrogenphosphat and especially in the significantly better isolation of the reaction product, associated with higher yields , lie.

The work-up of the reaction mixtures is carried out in the usual manner. The purification of the (3S) -3,24,25-trihydroxy-cholesta-5,7-dienes of the general formula I is carried out in a known manner by recrystallization or chromatography. The comparison of the known method to a synthesis step shortened representation of the target products according to general formula I is achieved by the use of 22-arylsulfonyl-23,24-bisnorchola-5,7-serve with free (3S) -hydroxy group or in that the acylated (3S) -hydroxy group in the presence of said strong bases reaction with said side-chain building blocks to (3S) -22-arylsulfonyl-3,24,25-trihydroxy-cholesta-5,7-serve the general formula VI in more simultaneously Reaction at the same time leads to the 3-acyl cleavage with release of the (3S) -hydroxy group under nichtaciden and thus gentle conditions.

The inventive method also has the decisive advantage that the starting compounds of the general formula II are obtained in contrast to those of the known method in a simple manner at low yields (DD-PS 247008).

embodiment

example 1

To dissolve 993 mg (2 mmol) of 3β-acetoxy-22-phenylsulfonyl-23,24-bisnorchola-5,7-diene and 1,097 mg (4 mmol) of (R) -p-toluenesulfonic acid 2,3-dihydroxy-3- Methyl-butyl ester in 32 ml of tetrahydrofuran are added dropwise under argon and stirring at -30 ° C 16ml (16mmol) of a n-butyllithium Imolaren solution in hexane. It is stirred for 1.5 h, mixed with 14 ml of ammonium chloride solution and extracted with ethyl acetate. The extract is dried over magnesium sulfate. It is chromatographed on silica gel 60 with hexane-ethyl acetate mixtures of the composition 10: 1 to 1: 2.

There are obtained 871 mg (78.2%) of (24R) -3β, 24,25-trihydroxy-22-phenylsulfonyl-cholesta-5,7-diene. White solid.

F.172bis200 ° C (dec.).

¹ H-NMR (δ, CDCL ₃ ): 0.57 ppm (s, 3H, 18-CH ₃ ), 0.90 ppm (d, J = 5Hz, 3H, 21-CH ₃ ), 1.04 ppm (s, 3H , 19-CH _3), 1.11 ppm (d, J = 6Hz, 6H, 26-CH _3, 27-CH _3), 3,55pprn (m, 1H, 3a-H), 5,28ppm (d, J = 6Hz, 1H, olefin proton), 5.49ppm (d, J = 6Hz, 1H, olefin proton) 7.3 to 8.0ppm (m, 5H, aromatic protons).

MS (m / e): 556 (M, 80%), 523 (70%), 497 (50%), 356 (90%), 323 (50%), 293 (50%), 143 (80%) , 59 (100%), C ₃₃ H ₄₈ O ₅ S (556.8)

C71.19 H8.69 S5.76

gef. C71.32 H8.61 S5.65

Example 2

To a solution of 455 mg (1 mmol) of 3β-hydroxy-22-phenylsulfonyl-23,24-bisnorchola-5,7-diene and 506 mg (5 mmol) of diisopropylamine in 30 ml of tetrahydrofuran under argon and stirring at -3O ⁰ C 5ml (5mmol ) of a n-butyllithimolare solution in hexane. It is stirred for 30 min at the same temperature. Subsequently, 204 mg (2 mmol) of (S) -2- (1-hydroxy-1-methyl-ethy ') - oxirane in 2 ml tetrahydrofuran registered. The mixture is stirred for 2 h and worked up as described in Example 1.

There are obtained 421 mg (75.6%) of (24S) -3β, 24,25-trihydroxy-22-phenylsulfonyl-cholesta-5,7-diene.

Example 3

3β-Benzoyloxy-22-phenylsulfonyl-23,24-bisnorchola-5,7-diene and (R) -trifluoromethanesulfonic acid-2,3-dihydroxy-3-methyl-butyl ester (24R) are obtained in the manner described in Example 1. 3β, 24,25, -trihydroxy-22-phenylsulfonyl-cholesta-5,7-diene in a yield of 80.5% of theory. Th. Received.

Example 4

In the manner described in Example 1, from 3β-acetoxy-22-phenylsulfonyl-23,24-bisnorchola-5,7-diene and (R, S) -1-bromo-3-methyl-butane-2,3-diol using sec-butyllithium in cyclohexane (24 R, S) -3β, 24,25-trihydroxy-22-phenylsulfonylcholesta-5,7-diene in a yield of 65.7% of theory receive.

Example 5

Under argon, 1.05 ml of mercury are added to 1.05 g of sodium. After cooling, 24 ml of tetrahydrofuran, 15 ml of methanol and 557 mg (1 mmol) of (24R) -3β, 24,25-trihydroxy-22-phenylsulfonyl-cholesta-5,7-diene are added. It is stirred for 2 h at room temperature, separated from the remaining amalgam, mixed with 10 ml of ammonium chloride solution and concentrated to Trorkne. The residue is taken up in water, filtered off with suction, washed with water and dried.

There are obtained 380 mg (91.2%) of (24R) -3β, 24,25-trihydroxy-cholesta-5,7-diene. White solid.

F.214bis217 ° C (dec.).

¹ H-NMR (δ, CDCl ₃ ): 0.64 ppm (s, 3H, 18-CH ₃ , 0.93 ppm (s, 3H, 19-CH ₃ ), 0.97 ppm (d, J = 7Hz, 3H, 21-CH ₃ ), 1.14ppm (s, 6H, 26 -CH ₃ ), 27-CH ₃ ), 3.63ppm (m, 1H, 3a-H), 5.36ppm (d, J = 6Hz, 1 H, olefin proton), 5.53 ppm (d, J = 6Hz, 1H, olefin proton).

MS (m / e): 416 (M, 60%), 383 (100%), 357 (70%), 143 (60%), 59 (60%).

C ₂₇ H ₄₄ O ₃ (416.6) calc. C 77.84 H 10.65 C 77.76 H 10.78

Example 6

In the manner described in Example 1, 3-β-acetoxy-22-phenylsulfonyl-23,24-bisnorchola-5,7-diene and (R) -p-toluenesulfonic acid-2,3-dihydroxy-3-propyl-hoxyl ester ( 24R) -26,27-diethyl-3β, 24,25-trihydroxy-22-phenyl-sulfonyl-cholesta-5,7-diene in a yield of 50.9% d. Th. Received.

Example 7

In the manner described in Example 5, (24 R) -3β, 24,25-trihydroxy-22-phenylsulfonyl-26,27-dipropyl-cholesta-5,7-diene (24 R) -3β, 24,25 -Trihydroxy-26,27-dipropyl-cholesta-5,7-diene in a yield of 68.6% d. Th. Received.

Claims (1)

claims: 1. A process for the preparation of (3S) -3,24,25-trihydroxy-cholesta-5,7-compounds of general formula I, which symbolizes the compounds having the (24R) or (24S) configuration or else mixtures of both, and in which R ¹ and R ² denote hydrogen or the same or different alkyl groups having 1 to 4 C atoms, characterized in that 3-substituted-22-arylsulphonyl-23, 24-bis-chloro-5,7-dienes of general formula II, in the R ^{3 is} hydrogen of acyl, in particular carbonic acid derivatives, for. B. methoxycarbonyl and N-phenylcarbamoyl, aliphatic acyl having 1 to 5 carbon atoms, ζ. Acetyl, trifluoroacetyl and pivaloyl, or aromatic acyl, eg benzoyl and naphthoyl, and
R ^{4 is} aryl, in particular phenyl, substituted, preferably lower alkyl-substituted phenyl, such as 4-methylphenyl, biphenylyl and naphthyl, with oxiranes of the general formula III O, in which R ¹ and R ^{2 have} the meanings given, or with sulfonic acid-2,3-dihydroxy-3-alkylalkyl esters of the general formula IV, (M IV in which R ¹ and R ^{2 have} the meanings mentioned and R ^{5 is} alkyl, for example methyl to butyl and trifluoromethyl, or aryl, ζ. As phenyl, substituted phenyl, especially 4-methylphenyl, biphenylyl and naphthyl, or with 1-halo-2,3-dihydroxy-3-alkyl-alkanes of the general formula V OH in which X is chlorine, bromine or iodine and R ¹ and R ^{2 have} the meanings mentioned, wherein the compounds of the general formulas III, IV and V can be present in the (R) or (S) -configuration or as mixtures of both (3S) -22-arylsulfonyl-3,24,25-trihydroxy-cholesta-5,7-serve the general formula Vl, Vl