Electrochemical oxidation of compounds having allylic c-h bonds to yield alpha,beta-unsaturated ketones

Abstract

The present invention relates to the electrochemical oxidation of allylic C- H bonds in specific compounds to obtain specific α,β unsaturated ketones in the presence of t-butyl hydroperoxide. This process is particularly suitable for the electrochemical oxidation of cholesterol, stigmasterol, campesterol, β-sitosterol, brassicasterol, 25-hydroxycholesterol, 24-hydroxycholesterol, lanosterol, pregnenolone, and the esters thereof.

Description

[0001] allylic C-H bonds in specific compounds to obtain specific a,p unsaturated ketones.

[0002] Background of the invention

[0003] Electrochemical processes have emerged as environment-friendly methods and sustainable technologies that offer a different solution to many environmental problems because they are versatile, efficient, cost-effective, easily automatable, and the electrons are a clean reagent (inexpensive and suitable reagent to drive the conversion), avoiding conventional chemical oxidizers or reducing agents

[0004] To oxidise allylic compound, the prior art discloses a variety of ways such as photochemical process or using strong oxidizing agents.

[0005] So far, only a few electrochemical or electrocatalytic processes for allylic C-H oxidation are known, wherein the conditions are not ideal and / or the yields are not good. An electrochemical mediator is needed, which makes the reaction mixture even more complex.

[0006] Particularly, N-hydroxyphthalimide and its derivatives, particularly tetra- chloro-N-hydroxyphthalimide, are known as mediator. However, the use of this compound class is highly controversial, leading to the fact that for example the use of tetrachloro-N-hydroxyphthalimide is banned in Europe. Therefore, any oxidation methods without using N-hydroxyphthalimide or derivatives are highly appreciated by the industry and market. Summary of the invention

[0007] Therefore, the problem to be solved by the present invention is to offer a method of producing specific a,p unsaturated ketones compound from the respective compounds having allylic C-H bonds which allows high yield.

[0008] Surprisingly, it has been found the process according to claim 1 offers a solution to this problem.

[0009] A key element of this process is the use of t-buty I hydroperoxide. This leads to the advantage, that said process can be performed in the absence of oxygen, hydrogen peroxide or any peroxide different from t-butyl hydroperoxide.

[0010] It has been particularly found that this process can be performed in the absence of any additional mediator, particularly in the absence of N-oxide derivatives or N-hydroxyphthalimide derivatives.

[0011] Furthermore, it has been found that said process can be performed in the absence of any transition metals salts.

[0012] Said process has an excellent yield and can be performed in such a way that it has big economical as well as ecological advantages and bears low risks of hazard and working safety.

[0013] Further aspects of the invention are subject of further independent claims. Particularly preferred embodiments are subject of dependent claims.

[0014] Detailed description of the invention

[0015] In a first aspect the present invention relates to a process for preparing a compound of the formula (I) by electrochemical oxidation of a compound of the formula (II)

[0016] in the presence of t-butyl hydroperoxide, characterized in that

[0017] R1represents either

[0018] OR or a Ci -io-alkyl group which optionally is olefinic or carries at least a carbonyl or hydroxyl group; and

[0019] R2represents H;

[0020] R3and R4, independently from each other, represent either H or a methyl group;

[0021] R7and R8, independently from each other, represent either H or a methyl group;

[0022] R represents hydrogen or R' which is a protecting group; and with the proviso that if R7= R8= methyl the double bond in formula (I) and

[0023] (II) is switched its position to the formula (I’) and (II’)

[0024] For sake of clarity, some terms used in the present document are defined as follows:

[0025] In the present document, a “Cx-y-alkyl” group is an alkyl group comprising x to y carbon atoms, i.e. , for example, a Ci-3-alkyl group is an alkyl group comprising 1 to 3 carbon atoms. The alkyl group can be linear or branched. For example -CH(CH3)-CH2-CH3 is considered as a C4-alkyl group.

[0026] In case identical labels for symbols or groups are present in several formulae, in the present document, the definition of said group or symbol made in the context of one specific formula applies also to other formulae which comprises the same said label.

[0027] The term “independently from each other” in this document means, in the context of substituents, moieties, or groups, that identically designated substituents, moieties, or groups can occur simultaneously with a different meaning in the same molecule.

[0028] Any single dotted line in any formulae represents the bond by which said substituent is bound to the rest of a molecule.

[0029] In this document a “non-aqueous solvent” means that no water is included in the solvent on purpose. However, it might be possible that said solvent comprises traces of water (usually below 5 wt.-%, based on the total weight of the solvent). Preferably, a non-aqueous solvent comprises less than 1 % by weight, particularly less than 0.1 % by weight, based on the total weight of the solvent. and of the formula

[0030] The compound of the formula (I) is prepared by electrochemical oxidation of a compound of the formula (II) in the presence of t-butyl hydroperoxide.

[0031] R represents hydrogen or R' which is a protecting group.

[0032] A protecting group is a group which protects the hydroxylic group and the protecting group can be easily removed, i.e. by state-of-the-art methods, resulting to the respective compound with the free hydroxylic group again.

[0033] The protecting group R' is introduced by a chemical reaction of the compound of the respective formula having H as R with a protecting agent.

[0034] The protecting agents leading to the corresponding protecting groups are known to the person skilled in the art, as well as the chemical process and conditions for this reaction. If, for example, the protecting group forms with the rest of the molecule an ester, the suitable protecting agent is for example an acid, an anhydride, or an acyl halide.

[0035] The protecting group R' is particularly selected from the groups consisting of wherein R31represent independently from each other a Ci -15-alkyl or a fluorinated Ci-15-alkyl or a Ci-15-cycloalkyl or a C?-i5-aralkyl group;

[0036] R32represents a Ci-15-alkylene or a Ce-15-alkylene group; and wherein either

[0037] R33represents a Ci -15-alkyl group or an alkyleneoxyalkyl group or a polyoxyalkylene group;

[0038] R34represents hydrogen or a Ci-15-alkyl group; or

[0039] R33and R34represent together a Cs-7-alkylene group forming a 5 to 7 membered ring;

[0040] R35and R36and R37represent independently from each other a Ci-15-alkyl or a fluorinated Ci -15-alkyl or Ce-15-aryl group; and wherein Y1represents either hydrogen or a group of the formula and wherein the single dotted line represents the bond by which said substituent is bound to the rest of a molecule.

[0041] If R' is represented by , the respective compound is an ester of a carboxylic acid or dicarboxylic acid, which can be formed by the reaction of the respective protecting agent with the hydroxylic group.

[0042] If the compound of the respective formula is an ester of a carboxylic acid or dicarboxylic acid, it is preferred that R is an Ci-7-acyl, preferably acetyl, trifluoroacetyl, propionyl or benzoyl group, or a substituted benzoyl group.

[0043] Esters can be easily deprotected under the influence of an acid or a base. the respective compound is an acetal, which can be formed by the reaction of the respective protecting agent with the hydroxylic group (OH). In this case, the protecting agent may be for example, a respective aldehyde, alkyl halide, e.g. MeO(CH2)2OCH2CI, or an enol ether, e.g. 3,4-dihydro- 2H- pyran.

[0044] In this case, the substituent Ft' is preferably

[0045] In some instances, acetals are also called “ethers”, particularly in the cases mentioned above: methoxymethyl ether (MOM-ether), p-methoxyethoxy- methyl ether (MEM-ether) or tetrahydropyranyl ether (THP-ether).

[0046] Acetals can be easily deprotected under the influence of acids.

[0047] In another embodiment, the respective compound is an ester of phosphoric acid, pyrophosphoric acid, phosphorous acid, sulphuric acid or sulphurous acid.

[0048] Depending on the reaction conditions, the esterification is either complete or partial, leaving some residual acid groups of the respective acid non-esterified.

[0049] It is most preferred that the protecting group Ft' is a benzoyl group or a C1-4- acyl group, particularly acetyl or trifluoroacetyl group, more particularly acetyl group. The molecules in which Ft' represents an acyl group, particularly an acetyl group, can be easily prepared from the corresponding unprotected molecule by esterification, and the unprotected hydroxylic compound can be obtained from the corresponding ester by ester hydrolysis.

[0050] Most preferably protecting group Ft' is an acetyl group or a benzoyl group, particularly an acetyl group.

[0051] The compound of the formula (I) and (II) have chirality centers. It is preferred that the compounds of the formula (I), resp. (II) have the following configurations given in formula (l-A) resp. (I l-A)

[0052] As mentioned above, in case R7= R8= methyl, the double bond in formula (I) and (II) is switched its position to the formula (I’) and (II’). In said case, it is preferred that the compounds of the formula (I’), resp. (II’) have the following configurations given in formula (I’-A) resp. (H’-A)

[0053] The groups R3and R4, independently from each other, represent either H or a methyl group. It is preferred that groups R3= R4= CH3.

[0054] R7and R8, independently from each other, represent either H or a methyl group. It is preferred that R7= R8, particularly preferred that R7= R8= CH3. R2represents either H.

[0055] R1represents either or a Ci -io-alkyl group which optionally is olefinic or carries at least a carbonyl or hydroxyl group.

[0056] In a first embodiment, R1represents OR, wherein R represents H or R' which is a protecting group.

[0057] In this embodiment the dotted line ( ) represents a single bond in the formulae (I) and (II).

[0058] Preferably, the compound of the formula (II) is either (I l-2a) or (I l-2b)

[0059] In a second, most preferred, embodiment, R1forms a Ci-io-alkyl group which optionally is olefinic or carries at least a carbonyl or hydroxyl group.

[0060] Preferably, R1is a substituent of the formula (III) wherein R5represents either H or CHs or CH2CH3 or OH and

[0061] R6represents either H or OH; and the bonds having dotted line ( ) in formula (III) represents either a single bond or a double bond; and wherein the single dotted line represents the bond by which said substituent is bound to the rest of a molecule.

[0062] Some of the carbon atoms in the substituent of the formula (III) are chiral. It is preferred that they have the following the following configurations given in formula (Ill-chiral)

[0063] It is preferred that only one of the bonds having dotted lines ( ) in formula (III) and (Ill-chiral) is a carbon-carbon double bond.

[0064] In case that (III) or (Ill-chiral) has a double carbon-carbon bond, it is preferred that it is in the E- configuration.

[0065] More specifically, the substituent of the formula (III) is selected from the group consisting of (lll-A),(ll l-B),(ll l-C),(l ll-D), (lll-E), (lll-F), (lll-G), (lll-H), (lll-l) and (lll-J)

[0066] It is preferred that the compound of the formula (II) of this embodiment is selected from the group consisting of cholesterol, stigmasterol, campesterol, 0- sitosterol, brassicasterol, 25-hydroxycholesterol, 24-hydroxycholesterol, lanosterol and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms, preferably selected from the group consisting of cholesterol, 25-hydroxychole- sterol, cholesteryl acetate, 25-hydroxycholesteryl acetate, cholesteryl acetate, 25- hydroxycholesteryl acetate, cholesteryl benzoate and 25-hydroxycholesteryl benzoate.

[0067] In a further embodiment, R1is a Ci- -alkyl group which carries at least a carbonyl group.

[0068] Preferably such a substituent of the formula , wherein R10is a Ci-w-alkyl group, preferably CH3.

[0069] It is particularly preferred that the compound of the formula (II) of this embodiment is pregnenolone or its esters with a carboxylic acid having 1 to 7 carbon atoms, particularly pregnenolone acetate.

[0070] It is preferred that the compound of the formula (II) is selected from the group consisting of cholesterol, stigmasterol, campesterol, 0-sitosterol, brassicasterol, 25-hydroxycholesterol, 24-hydroxycholesterol, lanosterol, pregnenolone, and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms; preferably selected from the group consisting of cholesterol acetate, stigmasterol acetate, campesterol acetate, 0-sitosterol acetate, brassicasterol acetate, 25- hydroxycholesterol acetate, 24-hydroxycholesterol acetate, pregnenolone acetate,; cholesterol benzoate, stigmasterol benzoate, campesterol benzoate, 0- sitosterol benzoate, brassicasterol benzoate, 25-hydroxycholesterol benzoate, 24- hydroxycholesterol benzoate, and pregnenolone benzoate.

[0071] Figure 1 shows the structures of cholesterol, stigmasterol, campesterol, 0- sitosterol, brassicasterol, 25-hydroxycholesterol, 24-hydroxycholesterol, lanosterol and pregnenolone.

[0072] It is particularly preferred that the compound of the formula (II) is selected from the group consisting of pregnenolone and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms; preferably selected from the group consisting of pregnenolone, pregnenolone acetate and pregnenolone benzoate.

[0073] In one embodiment, it is particularly preferred, that the compound of the formula (II) is selected from the group consisting of cholesterol, pregnenolone, and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms; preferably selected from the group consisting of cholesterol, pregnenolone, cholesteryl acetate and pregnenolone acetate, more preferably selected from the group consisting of cholesterol, cholesteryl acetate, and pregnenolone acetate.

[0074] It is even more preferred that the compound of the formula (II) is selected from the group consisting of cholesterol, stigmasterol, campesterol, 0-sitosterol, brassicasterol, 25-hydroxycholesterol, 24-hydroxycholesterol, lanosterol and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms; preferably selected from the group consisting of cholesterol, 25-hydroxycholesterol, cholesteryl acetate, 25-hydroxycholesteryl acetate, cholesteryl acetate, 25- hydroxycholesteryl acetate, cholesteryl benzoate and 25-hydroxycholesteryl benzoate.

[0075] It is even more preferred that the compound of the formula (II) is selected from the group consisting of cholesterol, stigmasterol, campesterol, 0-sitosterol, brassicasterol, 25-hydroxycholesterol, 24-hydroxycholesterol and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms. Most preferably, the compound of the formula (II) is selected from the group consisting of cholesterol, 25-hydroxycholesterol and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms; preferably selected from the group consisting of cholesterol, 25-hydroxycholesterol, cholesteryl acetate, 25- hydroxycholesteryl acetate, cholesteryl benzoate and 25-hydroxycholesteryl benzoate, preferably cholesterol or 25-hydroxycholesterol.

[0076] It is evident to person skilled in the art that the respective oxidation product of the above preferred compounds (II) is the respective a,p unsaturated ketone of the formula (I). The configuration at the chirality centers remains unchanged by the electrochemical oxidation reaction.

[0077] The compound of the formula (I) is prepared from the compound of the formula (II) as described above in the presence of t-butyl hydroperoxide (by electrochemical oxidization. t-Butyl hydroperoxide ( (CHs)3C-OOH ) is commercially available in large volumes and several suppliers.

[0078] Electrochemical reaction

[0079] The process of the present invention to oxidise the compound of formula (II) has great advantages such as

[0080] Electricity as a safe and cost-effective oxidizing agent

[0081] Simplified method for electrochemical allylic oxidation

[0082] Reaction conditions suitable for industry-relevant scaling of the approaches

[0083] Dual functionality of oxygen source and mediator

[0084] Avoidance of brittle, unwieldy electrode material

[0085] Avoidance of potentially explosive conductive salts

[0086] Elimination of cost-intensive catalytic converter systems

[0087] As known by the person skilled in the art, an electrochemical oxidization requires electrodes, i.e. an anode and a cathode. In the present invention, the material of the anode and the cathode is not critical and can be any suitable materials known in the art, such as steel, glassy carbon and platinum.

[0088] Preferably, the material of the electrode is steel, glassy carbon and / or platinum.

[0089] The form and size (which also means the surface area) of the electrodes in the present invention are also not critical. They may be in any size and in any form, such as in a form of a wire, a rod, a cell, a mesh, a grid, a sponge, or any other design suitable for the electrochemical reactor (cell) used in the process of the present invention.

[0090] Preferably, the electrode is in the form of a wire, a rod, a cell, a mesh, a grid, a sponge, or any other design suitable for the electrochemical reactor (cell).

[0091] As known by the person skilled in the art, an electrochemical oxidization is performed in a cell.

[0092] The cell, also known as voltaic cells or galvanic cells, used in the process according to the present invention can be any one of those known by a person skilled in the art. Usually and preferably, it is a two-compartments electrochemical flow-cell.

[0093] The process according to the present invention is carried out preferably in at least one solvent.

[0094] It is preferred that the electrochemical reaction is performed in water or a non-aqueous solvent or mixture thereof, preferably in a non-aqueous organic solvent, particularly selected from the group consisting of alkylene carbonates, dialkylcarbonates, polyethylene glycol, N-methyl-2-pyrrolidone, N-butylpyrrolidone (NBP), alcohols, esters, ketones, particularly acetone and 2-butanone; acetic acid, sulpholane, dimethylsulphoxide (DMSO), tetrahydrofuran (THF), 2-methyl-tetra- hydrofuran (MeTHF), dimethylformamide (DMF), hexa-methylphosphoramide, acetonitrile (MeCN), dichloromethane (DCM), dimethoxyethane (DME) and hexafluoro-2-propanol, and mixtures thereof.

[0095] Particularly preferred is acetonitrile (=MeCN) and 2-butanone (=methyl ethyl ketone = MEK). Most preferred is 2-butanone. The electrochemical oxidation is preferably performed in the presence of a supporting electrolyte, which may be added to in the form of a salt and / or in form of an acid. Any commonly known and commonly used supporting electrolyte can be used. Examples of the suitable supporting electrolytes include but are not limited to HCI, H2SO4, Na2SO4, NaCI, NaHSO4, alkyl- or arylsulfonic acids (such as methanesulfonic acid and p-toluenesulfonic acid), phosphoric acid, phosphates, and tetraalkylammonium salts (such as tetrabutylammonium acetate (NBu4OAc), tetrabutylammonium tetrafluoroborate and tetrabutylammonium hexafluorophosphate). Preferably, the supporting electrolyte used in the present invention is an acid such as HCI, H2SO4, phosphoric acid or mixture thereof.

[0096] It is preferred that the supporting electrolyte is selected from the group consisting of HCI, H2SO4, Na2SO4, NaCI, NaHSO4, alkyl- or arylsulfonic acids (such as methanesulfonic acid and p-toluenesulfonic acid), phosphoric acid, phosphates, and tetraalkylammonium salts (such as tetrabutylammonium acetate (NBu4OAc), tetrabutylammonium tetrafluoroborate and tetrabutylammonium hexafluorophosphate), most preferably from the group consisting of HCI, H2SO4 and phosphoric acid.

[0097] It is preferred to add some salts as supporting electrolytes. Such supporting electrolytes are particularly selected from the water soluble alkali salts, particularly of sodium and lithium.

[0098] It is preferred that the supporting electrolyte is selected from the group of water soluble alkali salts of tetrafluoroborate and perchlorate, particularly lithium perchlorate and sodium tetrafluoroborate.

[0099] Due to the process hazards, it is preferred that the supporting electrolyte is not a perchlorate salt.

[0100] It has been, furthermore, found that said process is preferably performed in the presence of an alkali salt of tetrafluoroborate, particularly of sodium tetrafluoroborate. These salts can advantageously support the electrochemical oxidation by its function as supporting electrolyte

[0101] These salts of high commercial availability, favorable in view of ecological and working hazards and of costs As mentioned below, it is believed that t- butyl hydroperoxide has also a mediator function in the electrochemical oxidation process.

[0102] It is a particular advantage that the above process can be performed without an additional mediator, i.e. without any mediator which is not that t- butyl hydroperoxide.

[0103] The concentration of the supporting electrolyte in the reaction medium is preferably up to 5 mol / L (M), more preferably from 0.01 M to 4 M, even more preferably from 0.01 M to 3 M, the most preferably from 0.01 M to 1 .5 M.

[0104] The compound t-butyl hydroperoxide is commercially available from different sources.

[0105] The compound t- butyl hydroperoxide has a function as an oxygen source. Furthermore, it is believed that t- butyl hydroperoxide has also a mediator function in the electrochemical oxidation process.

[0106] Preferably, t- butyl hydroperoxide is included in the reaction medium in an amount of from 0.1 vol.-% to 20 vol.-%, preferably from 0.5 vol.-% to 15.0 vol.-%, more preferably from 1 .0 vol.-% to 10 vol.-%, such as 1 vol.-%, 2 vol.-%, 3 vol.-%,

[0107] 3.5 vol.-%, 4 vol.-%, 4.5 vol.-%, 5 vol.-%, 5.5 vol.-%, 6 vol.-%, 6.5 vol.-%, 7 vol.-%,

[0108] 7.5 vol.-%, 8 vol.-%, 8.5 vol.-%, 9 vol.-%, 9.5 vol.-% and 10 vol.-%.

[0109] In one preferable embodiment, t-butyl hydroperoxide is included in the reaction medium in an amount of from 1 .0 vol.-% to 10 vol.-%, preferably from 2.0 vol.-% to 7.5 vol.-%, more preferably from 4.0 vol.-% to 6.0 vol.-% such as 4.0 vol.-%, 4.5 vol.-% and 5.0 vol.-%.

[0110] Preferably, the molar ratio of t-buty I hydroperoxide I compound of the formula (II) is preferably in the range of 1 :1 to 10:1 , more preferably 1.1 :1 to 8:1 , even more preferably 1 .5:1 to 5:1 . It is most preferred that of molar ratio of t-butyl hydroperoxide / compound of formula (II) is 2.5:1 to 4.5:1 .

[0111] Optionally, another additional oxygen source (in combination with t-butyl hydroperoxide) could be used, but it is not needed.

[0112] Particularly preferred the process is performed in the absence of oxygen, hydrogen peroxide or any peroxide different from t-buty I hydroperoxide, parti- cularly in the absence of hydrogen peroxide or any peroxide different from t-butyl hydroperoxide.

[0113] The compound of the formula (II) may be added into the reaction medium preferably in an amount of from 0.1 mmol / L (mM) to 100 mM, preferably from 0.2 mM to 75 mM, more preferably from 0.2 mM to 50 mM.

[0114] For this electrochemical oxidation process, the transferred charge (Q) for the electrochemical oxidation is preferably 10 Faraday (F) or less. A suitable range is particularly 1 -15 F, preferred is 1.5-10 F; more preferred is 1.5-9 F; most preferred is 1 .5-8 F such as 2, 3, 4, 5, 6, 7 and 8 F.

[0115] For this electrochemical oxidation process, the current density ( / ) used in the electrochemical oxidation may be preferably from 0.1 mA / cm2to 100 mA / cm2, preferably from 0.3 mA / cm2to 50 mA / cm2, preferably from 0.5 mA / cm2to 20 mA / cm2.

[0116] The described electrochemical oxidation can be carried out in Galvano- static or potentiostatic mode. Depending on the cell, the electrochemical oxidation according to the present invention can be carried out batch-wise, semi-batch-wise, or in a continuous way, preferably in a continuous way.

[0117] Therefore, in one embodiment, the electrochemical oxidation is preferably carried out in galvanostatic mode.

[0118] In another embodiment, the electrochemical oxidation is preferably carried out in potentiostatic mode

[0119] In another embodiment, the electrochemical oxidation is preferably carried out carried out batch-wise.

[0120] In another embodiment, the electrochemical oxidation is preferably carried out carried out batch-wise.

[0121] In another embodiment, the electrochemical oxidation is preferably carried out carried out semi-batch-wise.

[0122] In another embodiment, the electrochemical oxidation is preferably carried out carried out in a continuous way. The electrochemical oxidation is preferably carried out at a temperature range of from 10 °C to 75 °C, preferably from 15 °C to 60 °C, more preferably at ambient temperature (23°C).

[0123] The electrochemical oxidation is preferably carried out at ambient pressure (1013 hPa).

[0124] It has been found that said process is preferably performed in the presence of a base, particularly in the presence of an organic base, most preferably in the presence of pyridine.

[0125] It is preferred that the molar ratio of pyridine / compound of formula (II) is in the range of 1 :1 to 10:1 , more preferably 1 .1 :1 to 8:1 , even more preferably 1 .5:1 to 5:1 . It is most preferred that of molar ratio of pyridine / compound of formula (II) is 2.5:1 to 3.5:1 .

[0126] Particularly advantageous is, that the above process can be performed in the absence of any N-oxide derivatives, such as TEMPO ((2,2,6,6-tetramethyl- piperidin-1 -yl)oxyl) or N-hydroxyphthalimide derivatives. These compounds have significant hazard properties and particularly the use of N-hydroxyphthalimide derivatives is highly controversial and, leading to the fact that for example the use of tetrachloro-N-hydroxyphthalimide is banned in Europe.

[0127] It has been, furthermore, observed that the above process can be performed in the absence of any transition metals salts. This is very advantageous as transition metals, particularly soluble transition metals are difficult to recycle from the reaction mixture and / or are disadvantageous in view of ecological point of view.

[0128] The big advantage that the electrochemical oxidation can be performed as described above, particularly in the absence of a variety of substances, which are typically required to be present for electrochemical oxidations, is significant as only a low number of ingredients need to be mixed, and the different ingredients of a less complex mixture can be can separated more easily from a reaction mixture after that the reaction has occurred, particularly when the reaction has such high conversion, yield and selectivity as enabled by the present process.

[0129] This reaction is particularly interesting for the industrial production of the compounds (I) from the compound of the formula (II) as described above in great details. As pointed above, a key element of this process is the use of t-buty I hydroperoxide for the above process.

[0130] Hence, in a further aspect, the present invention relates the use of t-buty I hydroperoxide in the electrochemical oxidation of a compound of the formula (II).

[0131] The compound of the formula (II), its preferred embodiments as well the details of said use, particularly the conditions and presence resp. absence of further ingredients are disclosed above in great detail for the process for preparing a compound of the formula (I).

[0132] Examples

[0133] The present invention is further illustrated by the following experiments.

[0134] General Example

[0135] The undivided Teflon cells used for electrolysis were purchased from IKA (IKA-Werke GmbH & Co. KG, Staufen, Germany). The dimensions of the electrodes are 7 cm x 1 cm x 0.3 cm.

[0136] In an undivided 7 mL Teflon pot cell, the 2-butanone (5 mL) is presented and then sodium tetrafluoroborate or lithium perchlorate, t-butyl hydroperoxide, pyridine and a compound of formula (II) are dissolved (further details see table 1 ). The cell is equipped with vitreous carbon electrodes at a distance of 0.5 cm. The immersion area of the electrodes is 1 .8 cm2. Stirring rate is 400 rpm. After the cell is fixed in a stainless steel block, galvanostatic electrolysis is performed with a current density as given in table 1 at 25 °C.

[0137] 1NaBF4= sodium tetrafluoroborate; LPC=lithium perchlorate=LiCIO4

[0138] 2Py=pyridine3©HP=t-butyl hydroperoxide

[0139] 4Q = transferred charge5j = current density

[0140] After completion of the reaction, the reaction was processed with a saturated, aqueous NaCI solution and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and removed under reduced pressure. Subsequently, the corresponding ketone of the formula (I) was obtained after column chromatographic purification. The yield is given in table 1 .

Claims

Claims1 . A process for preparing a compound of the formula (I) by electrochemical oxidation of a compound of the formula (II)in the presence of t-butyl hydroperoxide, characterized in thatR1represents eitherOR or a Ci -10-alkyl group which optionally is olefinic or carries at least a carbonyl or hydroxyl group; andR2represents H;R3and R4, independently from each other, represent either H or a methyl group;R7and R8, independently from each other, represent either H or a methyl group;R represents hydrogen or R' which is a protecting group;with the proviso that if R7= R8= methyl the double bond in formula (I) and (II) is switched its position to the formula (I’) and (II’)2. The process according to claim 1 characterized in that R2= H.

3. The process according to claim 1 or 2 characterized in that R1a substituent of the formula (III)wherein R5represents either H or CHs or CH2CH3 or OH andR6represents either H or OH; and the bond having dotted line () in figure (III) represents either a single bond or a double bond; and wherein the single dotted line represents the bond by which said substituent is bound to the rest of a molecule.

4. The process of claim 3 characterized in that the substituent of the formula (III) is selected from the group consisting of (lll-A),(lll-B),(lll-C),(lll-D), (lll-E),5. The process according to any of the preceding claims, characterized in that R3=R4=CH3.

6. The process according to any of preceding claims characterized in that R represents R' which is an acyl group, particularly an acetyl group or a benzoyl group.

7. The process according to any of preceding claims characterized in that the process is performed in the presence of a base, particularly in the presence of an organic base, most preferably in the presence of pyridine.

8. The process according to any of preceding claims characterized in that the process is performed in the presence of an alkali salt of tetrafluoroborate, particularly of sodium tetrafluoroborate.

9. The process according to any of preceding claims characterized in that the process is performed in the absence of any additional mediator, particular in the absence of any N-oxide derivatives or N-hydroxyphthalimide derivatives.

10. The process according to any of preceding claims characterized in that the process is performed in the absence of any transition metals salts.11 . The process according to any of preceding claims characterized in that the process is performed in the absence of hydrogen peroxide or any peroxide different from t-butyl hydroperoxide.

12. The process according to any of preceding claims characterized in that the process is performed in water or a non-aqueous solvent or mixture thereof, preferably in a non-aqueous organic solvent, particularly selected from the group consisting of alkylene carbonates, dialkylcarbonates, polyethylene glycol, N-methyl-2-pyrrolidone, N-butylpyrrolidone (NBP), alcohols, esters, ketones, particularly acetone and 2-butanone; acetic acid, sulpholane, dimethylsulphoxide (DMSO), tetrahydrofuran (THF), 2-methyl-tetrahydro- furan (MeTHF), dimethylformamide (DMF), hexa-methylphosphoramide, acetonitrile (MeCN), dichloromethane (DCM), dimethoxyethane (DME) and hexafluoro-2-propanol, and mixtures thereof.

13. The process according to any of preceding claims characterized in that the compound of the formula (II) is selected from the group consisting of pregnenolone, and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms; preferably selected from the group consisting of pregnenolone, pregnenolone acetate and pregnenolone benzoate.

14. The process according to any of preceding claims characterized in that the compound of the formula (II) is selected from the group consisting of cholesterol, stigmasterol, campesterol, -sitosterol, brassicasterol, 25- hydroxycholesterol, 24-hydroxycholesterol, lanosterol and the esters thereof with a carboxylic acid having 1 to 7 carbon atoms; preferably selected from the group consisting cholesterol, 25- hydroxycholesterol, cholesteryl acetate, 25-hydroxycholesteryl acetate, cholesteryl benzoate and 25-hydroxycholesteryl benzoate, more preferably cholesterol or 25-hydroxycholesterol.

15. Use of t-butyl hydroperoxide in the electrochemical oxidation of a compound of the formula (II)characterized in that R1represents eitherOR or a Ci -io-alkyl group which optionally is olefinic or carries at least a carbonyl or hydroxyl group; andR2represents H;R3and R4, independently from each other, represent either H or a methyl group; R7and R8, independently from each other, represent either H or a methyl group;R represents hydrogen or R' which is a protecting group with the proviso that if R7= R8= methyl the double bond in formula (I) and(II) is switched its position to the formula (I’) and (II’)

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