DD289540A5 - METHOD FOR PRODUCING STEROID C17-CYANHYDRIN SILILETHERS - Google Patents

Abstract

An improved process for the preparation of steroid C17 cyanohydrin silyl ethers is described, by which steroid C17 cyanohydrins are reacted with trimethylsilyl halides in the presence of organic bases in organic solvents to give the corresponding steroid C17 cyanohydrin silyl ethers and from the reaction mixture the excess of trimethylsilyl halides used in the excess be distilled off under vacuum. By this procedure, the formation of hexamethyldisiloxane is avoided in the work-up processes, as much facilitated by the isolation and purification of Silyletherderivates and a yield improvement is achieved. The separated from the reaction mixture by vacuum distillation mixture of trimethylsilyl halide / org. Solvent can be reused in the silylation process without further treatment. By this procedure, the technical implementation is made economically much more favorable, the reaction minimizes the formation of by-products and simplifies the isolation process.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of steroid C 17-cyanohydrin silyl ethers from steroid C 17-cyanohydrins. Steroid C 17-cyanohydrin silyl ethers are important intermediates for steroid syntheses, such. B. for Pregnanseitenkettenaufbau.

-2- 289 540 Characteristic of the known technical solutions

The preparation of silyl ethers is well known in the literature. It is preferably used as an easily introduced protective moiety for alcohols for a range of reactions (TW Greene, Protective Groups in Organic Synthesis, Wileyl Sciences, New York, 1981 / AE Pierce "Silylation of Organic Compounds", Piorce Chemical Co, Rockford III, 1968). , the following methods have mainly been used:

Reaction of alcohols with trimethylchlorosilane in the presence of pyridine, NH.sub.3, imidazole or triethylamine, toluene, tetrahydrofuran (THF) or dimethylformamide (DMF) being preferably used as solvent (RO Sauer, JACS 66, 1708 [1944], FA Henglein et al Ber. 92, 1638 [19591, EJ Corey et al., JACS 94, 6190 [1972]).

Reaction of alcohols with diethylaminotrimethylsilane in acetone, THF or DMF (K. Rühlmann et al J. Prakt Chem .. / 4/9, 315 [1959]; Chem. Ber. 94, 1876 [1961]; Synthesis 1971, 248).

- Reaction of alcohols with hexamethyldisilazane in org. Solvents, according to this variant, an addition of trimethylchlorosilane (up to 30%) is preferred (H. Vorbrüggen, Angew Chem 84.348 [1972]; H. Niederprüm et al., Liebigs Ann. Chem. 1973,20, G.Teichmüller and others DD -WP 74032).

According to the methods mentioned here, the conversion of alcohols into the corresponding silyl ethers is generally feasible, but they lead to tertiary alcohols, especially hindered tert. Alcohols are generally unsuccessful, or the complete implementation is possible only by using a very large excess of silylating agent and drastic reaction conditions (elevated temperature and long reaction times), which of course results in greater yield losses. Another major disadvantage of these known Silyletherdarstellungsmethoden is that in the work-up of the reaction mixtures, the z. T. used in large excess trimethylsilyl derivative is converted to hexamethyldisiloxane. Since hexamethyldisiloxane is a good solvent for silyl ethers, the complete separation of which is extremely difficult to realize, this, as a good solvent for silyl ethers, can prevent the complete crystallization of the silyl ethers represented and thus be the cause of yield reductions. It should also not be overlooked that Use of a large excess of silylating agent and its destruction in the work-up process significantly burdened the economics of such processes.

The preparation of a steroid C 17 cyanohydrin silyl ether was described by J. C. Gases et al. L. Nedelec (Tetrahedron Letters 22, 2005 [1971].) The authors translated 17β-cyano-3,3-ethylenedi'oxy-17β-hydroxy-5 (10), 9 (11) -estradiene in pyridine with trimethylchlorosilane The disadvantages of the known silylation processes already outlined in the general description also fully apply to this method of presentation.

Object of the invention

The aim of the invention is a novel process, according to which steroid C 17-cyanohydrin can be prepared in a technologically simple and economically favorable manner.

Explanation of the essence of the invention

The invention has for its object to provide a new improved process for the preparation of steroid C 17 cyanohydrinsilyl ethers, according to which these products can be prepared on an industrial scale in a technologically simple and economically favorable manner

According to the invention, this object is achieved in that tertiary steroid C 17-cyanhydride of the general formula I in which Ri = CH ₃ , C ₂ H ₆ and

R ₂ = CN, then R ₃ = OH and

R ₃ = CN, then R ₂ = OH and

R ₄ = H or OH,

and a double bond between the carbon atoms 9 and 11 may be contained, wherein the rings A and B of the steroid backbone have the substructures a, b, c, d, e and f, in which

R ₅ = H or CH ₃ R _{6 is} omitted in the presence of a double bond Δ ⁵ (10) R ₆ = H or Ac

R ₇ = CH ₃ or (CH ₂ )

R ₈ = CH ₃ or C ₂ H ₅ , with a silylating agent in the presence of organic bases and organic solvents at reaction temperatures of

- 1O ⁰ C to + 8O ⁰ C in the tertiary Steroidcyanhydrinsilylether the general formula II, in the

R, = CH ₃ , C ₂ H ₆ and

R ₂ = CN, then R ₃ = OSi (CH ₃ ) ₃ or

R ₃ = CN, then R ₂ = OSi (CH ₃ ) ₃ and

R ₄ = H or OSi (CH ₃ I ₃

and a double bond between the carbon atoms 9 and 11 may be contained, wherein the rings A and B of the steroid skeleton and the substituents R ₆ to R _{8 have} the same meanings as in formula I, and then that in this Reaction in excess silylating agent separated with the addition of organic solvents by distillation and the tertiary steroid C 17-cyanohydrin silyl ether derivatives after treatment with aqueous alkali solutions and NaH ₂ PO ₄ solutions are isolated.

According to the present process are used as silylating trimethylsilyl halides such as trimethylchlorosilane and trimethylbromosilane in amounts of from 1.2 mol to 3.7 mol / mol of steroid in the presence of 1.02 mol to 1.25 mol of organic base / mole of trimethylsilyl halide and the reaction in selected organic solvents at reaction temperatures of from -1O ⁰ C to +80 ⁰ C, preferably at 25 ° C. to 45 ° C. The organic bases used for this process are preferably trialkylamines such. For example, trimethylamine, triethylamine, tributylamine or cyclic

unsaturated amines such as pyridine, collidine and the like a. The organic solvents selected for this process are aromatic hydrocarbons such as benzene, toluene and the like, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, cyclic hydrocarbons such as cyclohexane, ethers such as. For example, diethyl ether, tetrahydrofuran, etc., esters, such as. B.

Ethyl acetate, butyl acetate and the like. and ketones, such as. Acetone, methyl ethyl ketone u, a. and mixtures of the listed solvents.

Compared to the known and hitherto mainly used method of reaction with trimethylchlorosilane in pyridine and reaction times of 16 to 24 hours for hindered tertiary steroid C 17 alcohols are according to the present silylation only up to 2 or max. 4 hours reaction time required, which also the side reactions and thus the formation of by-products can be significantly limited. This is of particular importance for the reaction of steroid C 17-cyanohydrins which have an acetal or Ketalgruppierung in the 3-position of the steroid skeleton and under the known conditions of the reaction with trimethylchlorosilane in pyridine in the case required long reaction times of 16 to 24 Hours of partial division subject. According to the new procedure, this cleavage of the acetals and ketals can not be completely suppressed, but it is max. only up to 2%.

Another essential feature of the present silylation process is that the excess securing agent contained in the reaction mixture is separated from the reaction mixture by vacuum distillation after completion of the reaction and the volume of the reaction mixture is kept constant by addition of organic solvents. In this case, it is quite possible to proceed in such a way that even a solvent which interferes with the work-up is largely distilled off with it.

By separating off the excess silylating agent, the formation of hexamethyldisiloxane is avoided in the work-up of the reaction mixtures, whereby the isolation and purification of the steroid cyanohydrin silyl ether is substantially promoted. The resulting in the separation process mixtures of trimethylsilyl halide / org. Solvents can be reused in the silylation process without further work-up, which substantially improves the economics of the silylation process.

The examples given below are intended to explain the process according to the invention in more detail without restricting it in any way.

embodiments

example 1

NSS-carbonitrile ^ a ^-trimethylsilyloxy -androsten-S-on

2.5 g (0.008 mol) of 17β-carbonitrile-17α-hydroxy-4-androsten-3-one are dissolved in 7.5 ml of chloroform and 2.7 ml of pyridine and admixed with 3.3 ml (0.026 mol) of trimethylchlorosilane. The mixture is heated to temperatures of 40 to 45 ° C for up to 3 hours, optionally left for a further 3 hours at room temperature and then treated with 25 ml of NaHCC ₃ solution. The organic phase is separated, the aqueous phase repeatedly extracted with chloroform, the combined phases 2 χ with water and washed 3x with NaH ₂ PO ₄ -Lös'jng (5- to 10%), largely concentrated on a rotary evaporator, repeatedly with hexane mixed, pulled dry on a vacuum and then taken up in hexane and crystallized. The crystals are filtered off with suction, washed with a small amount of solvent and then dried.

Yield: 2.8 g = 93.4% of theory

Mp: 167 ° C [a] g ⁰ '+ 95 ° (c = 1, CHCl ₃ )

Example 2

na-carbonitrile ^ ^ ß-trimethylsilyloxy -androsten-S-on

According to Example 1, 3.7 g of 17a-carbonitrile-17ß-hydroxy-4-androsten-3-one using butyl acetate: as solvent and triethylamine as org. Base implemented.

Yield: 4.05 g = 91% of theory

Mp .: 173 ⁰ C [AJG ° "+ 44 ° (c = 1, CHCI ₃

Example 3

-estrene-17.beta.-carbonitrile 3,3-dimethoxy-17a-trimethylsilyloxy-5 (10)

According to Example 1, 10 g of 17β-carbonitrile-3,3-dimethoxy-17α-hydroxy-5610-styrene are dissolved in 28 ml of tetrahydrofuran / chloroform with the addition of 12 ml of collidine, and 12 ml of trimethylchlorosilane are added with stirring. Reaction and working up are carried out as described in Example 1.

Yield: 11.28 g = 93.6% of theory

Example 4

17 (J-bis- (trimethylsilyloxy) -5-androsten-17a-carbonitrile 3ß,

According to Example 1, 6 g of l7a-carbonitrile-3β, 17β-dihydroxy-5-androstene are dissolved in 20 ml of tetrahydrofuran / chloroform / trimethylamine and mixed with stirring with a mixture of 10 ml of trimethylchlorosilane / 10 ml of chloroform. The reaction mixture is stirred for 3 hours at 45 ⁰ C, allowed to stand for 2 hours at room temperature and then worked up as described in Example 1.

Yield: 7.76 g = 87.3% of theory.

Mp .: 157 ⁰ C | ala ° "-90 ° (c = 1, CHCI ₃₎

Example 5

17β-carbonitrile-3,3-ethylenedioxy-17a-trimefiylsilyloxy-5,9 (11) -androstadiene 20.0g 17β-carbonitrile-3,3-ethylenedioxy-17α-hydroxy-5,9 (11) - androstadiene are dissolved in a mixture of 80 ml of chloroform and triethylamine and treated with stirring over 10 minutes with a mixture of 28.4 ml of trimethylchlorosilane and 20 ml of chloroform, wherein the temperature of the reaction mixture can rise to 45 ⁰ C. The reaction mixture

-4- 289 54Ü

is stirred for 2 to 4 hours at this temperature, then distilled off under vacuum, the excess trimethylchlorosilane and kept constant the volume of the reaction solution by the addition of chloroform. The chloroform solution obtained as the distillation residue is treated with 200 ml of cold NaHCO ₃ solution, the CHCl ₃ solution is separated off and the NaHCO ₃ solution is back-extracted ₃ times with chloroform. The chloroform extracts are combined, washed 2 / with water, 3x with NaH ₂ PO ₄ solution, dried over Na ₂ SO ₄ and then concentrated to dryness in vacuo. The distillation residue is concentrated several times under vacuum with the addition of toluene to dryness and then recrystallized from toluene / hexane. Yield: 22.6 g = 94% of theory

M.p .: 105 to 110 ⁰ C, [a] g ^0>: -11 ° (c = 1, CHCI ₃₎

Example 6

NSS-carbonitrile ^ a ^-trimethylsilyloxy-.gUD androstadien-S-on

6.3 g of 17β-carbonitrile-17α-hydroxy-4,9 (11) -androstadien-3-one are dissolved in a mixture of 25 ml of dichloroethane / pyridine and 8 ml of trimethylchlorosilane are added with stirring. Reaction and working up are carried out as described in Example 5.

Yield: 7.55 g = 96% of theory

Mp .: 190 ⁰ C [a] ° g "+ 65 ° (c = 1, CHCI ₃₎

Example 7

17a-carbonitrile-17-trimethylsilyloxy-4,9 (11) -androstadien-3-one

According to Example 5, 5.8 g of 17a-carbonitrile-17β-hydroxy-4,9 (11) -androstadien-3-one are dissolved in 34 ml of trichloroethane / triethylamine and admixed with 7.25 ml of trimethylchlorosilane. Reaction procedure and workup are as described.

Yield: 6.57 g = 91% of theory

Mp: 168 "C; [a] g ° 'i6.4 ° (c = 1, CHCl ₃ )

Example 8

na-carbonitrile NSS trimethy'cjyloxy-IAandrostadien-S-on

3.3 g of 17a-carbonitrile-17β-hydroxy-1,4-androstadien-3-one are reacted in a mixture of dichloroethane / tributylamine with 5 ml of trimethylchlorosilane according to Example 5 and worked up.

Yield: 3.74 g = 92.5% of theory.

Mp .: 136 ⁰ C [ctjg ⁰ '-4 ° (c = 1, CHCI ₃₎

Example 9

17β-carbonitrile-17c-trimethylsilylox \ -1,4-androstadien-3-one

5.0 g of 17β-carbonitrile-17α-hydroxy-1,4-androstadien-3-one are dissolved in a mixture of 15 ml of methylene chloride / toluene / 4.4 ml of pyridine and then admixed with 6.5 ml of trimethylchlorosilane. The reaction mixture is stirred at 4O ⁰ C for 4 hours to 45 ⁰ C, then distilled off the excess trimethylchlorosilane under vacuum and the distillation residue and cold NaHCO ₃ solution. The org. Phase is separated, the NaHCOj solution nachextraiert several times, the org. Phases then combined, washed with water and NaH ₂ PO ₄ solution and then concentrated under vacuum. The resulting distillation residue is added to complete removal of pyridine several times with toluene and a few drops of water and concentrated in vacuo to dryness.

Yield: 5.66 g = 92% of theory.

Mp .: 162 ⁰ C IaJg ⁰ '+ 52 ° (c = 1, CHCI ₃₎

Example 10

^ Ss-carbonitrile S, S-ethylenc'ioxy-na-trimethylsilyloxy-ö-androstene

Dissolved 25g ^ ß-carbonitrile-SS-ethylenedioxy ^ a-hydroxy-androstensten in a mixture of 100ml chloroform / pyridine and reacted at 4O ⁰ C to 45 ⁰ C with 32ml trimethylchlorosilane according to Example 9 and worked up.

Yield: 28.6 g = 95.4% c.Th.

Mp .: 145 ⁰ C to 1f 0 ° C [a] g ⁰ '-30.5 ° (c = 1, CHCI ₃₎

Example 11

17-carbonitrile 3.beta.-acetoxy-17a-trimethylsilyloxy-5-androstene

4.5 g of 17β-carbonitrile-3β-ace'oxy-17α-hydroxy-5-androstene are added in a mixture of 22.5 ml of chloroform / triethylamine with the addition of 2.1 g of trimethylsilyl bromide at room temperature in a reaction time of 0.5 hours corresponding steroid C 17-cyanhydrinsily lether reacted. Workup and isolation are carried out as described in Example 9.

Yield: 5.34 g = 97% of theory.

Claims (6)

1. A process for the preparation of tertiary steroid-C IT cyanohydrin silyl ethers, characterized in that tertiary steroid C 17-cyanohydrins of the general formula I in which Ri = CH ₃ , C ₂ H ₆ and R ₂ = CN, then isc R ₃ = OH or R ₃ = CN, then R ₂ = OH and R ₄ = H or OH, and one Double bond between the carbon atoms 9 and 11 may be included, wherein the rings A and B of the steroid backbone have the substructures a, b, c, d, e and f and in which R ₅ = H or CH ₃ R ₅ deleted if present a double bond Δ ^{5 | 10)} R ₆ = H or Ac R ₇ = CH ₃ or - (CH ₂ ) - R ₈ = CH ₃ or C ₂ H ₆ mean, with a securing agent in the presence of organic bases and organic solvents at reaction temperatures of -10 ⁰ C to +80 ⁰ C in the tertiary steroid C 17-cyanohydrin silyl ether of the general formula II, in the R ₁ = CH ₃ , C ₂ H ₅ and R ₂ = CN, then R ₃ = OSi (CH ₃ ) ₃ or R ₃ = CN, then R ₂ = OSi (CH ₃ J ₃ and R ₄ = H or OSi (CH ₃ J ₃ and a double bond can be contained between the carbon atoms 9 and 11, the rings A and B of the steroid backbone and the substituents R ₅ to R ₈ having the same meanings as in formula I, and then that in this reaction Silylating agents used in excess are separated by distillation with the addition of organic solvents, and the tertiary steroid C 17-cyanohydrin silyl ether derivatives are isolated after treatment with aqueous alkali solutions and NaH ₂ PO ₄ solutions. 2. The method according to claim 1, characterized in that are used as silylating trimethylsilyl halides, such as trimethylchlorosilane and trimethylbromosilane. 3. Process according to Claims 1 and 2, characterized in that the organic solvents used are aromatic hydrocarbons ₍ such as, for example, benzene, toluene, etc.), halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, cyclic hydrocarbons such as cyclohexane, ethers, such as, for example, diethyl ether , tetrahydrofuran, among others esters such as _t ζ., ethyl acetate, butyl acetate or mixtures thereof can be used. 4. The method according to claims 1 to 3, characterized in that as organic bases trialkyl amines _(such. As trimethylamine, triethylamine, tributylamine, among others, cyclic, unsaturated amines _t Wiez., Pyridine, collidine are used, among other things. 5. Process according to claims 1 to 4, characterized in that the reaction is preferably carried out at 25 ⁰ C to 45 ° C and the excess silylating agent is preferably distilled off under vacuum. 6. Process according to claims 1 to 5, characterized in that the distilled off from the reaction mixture silylating agent or mixture of silylating / org. Solvent is used again for silylation reaction.