HK1104277B - Epimerisation of allylic alcohols - Google Patents

Description

Epimerization of allyl alcohol

Technical Field

The present invention relates to a novel epimerization process of compounds, such as compounds useful for the synthesis of vitamin D analogs, having a hydroxyl substituent on an asymmetric allylic carbon, such as at the 24 position. The invention further relates to the use of an intermediate produced using this method for the preparation of calcipotriol, i.e., { (5Z, 7E, 22E, 24S) -24-cyclopropyl-9, 10-secocholesteric-5, 7, 10(19), 22-tetraene-1 α -3 β -24-triol } or calcipotriol monohydrate.

Background

Calcipotriol (structure I) [ CAS 112965-21-6] showed strong activity in inhibiting undesirable proliferation of epidermal keratinocytes [ f.a.c.m.casteligins, m.j.gerritsen, i.m.j.j.van

Vlijmen-willlems, p.j.van Erp, p.c.m.van de Kerkhof; acta derm. venereol.79, 11, 1999 ]. The efficacy of calcipotriol and calcipotriol monohydrate (I-hydrate) in the treatment of psoriasis has been shown in a number of clinical trials [ d.m. ashcroft et al; brit.med.j.320, 963-67, 2000] and calcipotriol is currently used in a variety of commercially available pharmaceutical formulations.

In the preparation of calcipotriol, the specific stereochemistry of the hydroxyl group at C-24 is essential for the full expression of biological activity.

In the previously disclosed process for the preparation of calcipotriol I, the hydroxy-protected C-24 ketone of I is reduced to form a mixture of the C-24 epimers IIIa and IIIb, wherein R₁And R₂May be the same or different and represent hydrogen or a hydroxyl-protecting group, for example as described in WO87/00834&Calverley; tetrahedron, 43(20), 4609-19, 1987.

The undesired epimer IIIb is then removed, for example by chromatographic separation of the desired epimer IIIa, followed by photoisomerization and removal of the protecting group to give calcipotriol. Thus, losses are high and overall yields and process productivity are low.

WO03/106412 describes a process by which the undesired epimer IIIb can be converted to the C-24 ester of IIIb, which can then be epimerized by contacting the ester with an epimerisation-active solid. After hydrolysis of the mixture of C-24 esters of IIIa and IIIb, a mixture enriched in the desired epimer IIIa can be obtained and the enriched mixture can be recycled to the separation step. This epimerization process has the following disadvantages: it involves two additional chemical transformations, namely esterification and saponification of IIIb, making the process economically disadvantageous, especially on an industrial scale.

WO94/07853 discloses multivitamin D analogs having a hydroxyl substituent on the asymmetric allylic carbon at the 24-position, but does not disclose a method for epimerizing the alcohol. The particular C-24 epimer (Tisocalcate) described in WO94/07853 is currently in phase 2 clinical trials.

Summary of The Invention

Surprisingly, the present invention provides a novel process for epimerising an alcohol of a compound having a hydroxyl substituent at the asymmetric allylic carbon, such as a compound useful for the synthesis of vitamin D analogs, wherein the hydroxyl substituent is at the 24 position, in the presence of an acid and water. The vitamin D epimer obtainable by this process can be used as an intermediate in the synthesis of calcipotriol, for example. The new process employs inexpensive chemicals and is easy to operate on an industrial scale. Since the novel process allows recycling of the undesired C-24 hydroxy epimer of the calcipotriol precursor or derivative, while avoiding the additional esterification and saponification steps described in WO03/106412, the overall yield and process productivity can be improved.

In one aspect, the invention relates to a process for epimerising an epimer or epimeric mixture of compounds comprising side chains of the general formula A and/or B,

at the hydroxy group and R₃At the position of the attached carbon atom;

the process comprises contacting the epimer or mixture of epimers with an acid in the presence of water;

wherein R is₃Is alkyl, alkenyl, alkynyl or cycloalkyl, optionally substituted with one or more substituents selected from alkyl, alkoxycarbonyl, halogen, hydroxy, methoxy and ethoxy;

wherein the carbon marked with an asterisk is attached by a single bond to the C-17 carbon atom of the vitamin D analog fragment; or wherein the carbon marked with an asterisk is linked by a single bond to the fragment of the precursor for the synthesis of a vitamin D analogue in its C-17 analogous position.

In another aspect, the present invention relates to a method for preparing calcipotriol or calcipotriol monohydrate, comprising in one or more steps the above method.

In another aspect, the present invention relates to a method for producing calcipotriol or calcipotriol monohydrate, comprising the steps of:

(i) epimerising the vitamin D analogue of formula IIb with an acid in the presence of water,

wherein R is₁And R₂May be identical or different and represents hydrogen or a hydroxyl-protecting group, to give a mixture of compounds of the formulae IIa and IIb, in which R is₁And R₂As defined above;

(ii) optionally separating the compound of formula IIa from a mixture of compounds of formula IIa and IIb, wherein R₁And R₂As defined above;

(iii) when R is₁And/or R₂When not hydrogen, a hydroxy protecting group R of a compound of formula IIa₁And/or R₂Removing to produce calcipotriol; and

(iv) optionally crystallizing calcipotriol from a mixture of an organic solvent and water to form calcipotriol monohydrate.

In another aspect, the present invention relates to a method for producing calcipotriol or calcipotriol monohydrate, comprising the steps of:

(i) epimerising the vitamin D analogue of formula IIIb with an acid in the presence of water,

wherein R is₁And R₂May be the same or different and represents hydrogen or a hydroxyl protecting group,

to form a mixture of compounds of formulae IIIa and IIIb,

wherein R is₁And R₂As defined above;

(ii) optionally separating the compound of formula IIIa from the mixture of compounds of formulae IIIa and IIIb;

(iii) photoisomerization of the compound of formula IIIa to a compound of formula IIa,

wherein R is₁And R₂As defined above;

(iv) when R is₁And/or R₂When not hydrogen, a hydroxy protecting group R of a compound of formula IIa₁And/or R₂Removing to produce calcipotriol; and

(v) optionally crystallizing calcipotriol from a mixture of an organic solvent and water to form calcipotriol monohydrate;

wherein steps (iii) and (iv) may be performed in reverse order.

In another aspect, the present invention relates to a method for producing calcipotriol or calcipotriol monohydrate, comprising the steps of:

(i) epimerising a vitamin D analogue of formula IVba and/or IVbb with an acid in the presence of water,

wherein R is₁And R₂May be the same or different and represents hydrogen or a hydroxyl protecting group,

to form a mixture of compounds of the formulae IVba and/or IVbb and IVaa and/or IVab,

wherein R is₁And R₂As defined above;

(ii) optionally isolating the compound of formula IVaa and/or IVab from the reaction mixture;

(iii) heating the compound of formula IVaa and/or IVab to above 60 ℃ in the presence of a base to produce a compound of formula IIIa,

wherein R is₁And R₂As defined above;

(iv) photoisomerization of the compound of formula IIIa to a compound of formula IIa,

wherein R is₁And R₂As defined above;

(v) when R is₁And/or R₂When not hydrogen, a hydroxy protecting group R of a compound of formula IIa₁And/or R₂Removing to produce calcipotriol; and

(vi) optionally, crystallizing calcipotriol from a mixture of an organic solvent and water to form calcipotriol monohydrate;

wherein steps (iv) and (v) may be performed in reverse order.

In another aspect, the present invention relates to the use of the above method for the preparation of calcipotriol or calcipotriol monohydrate.

In another aspect, the present invention relates to the use of the above method for the preparation of a pharmaceutical formulation or medicament, such as a cream, ointment or gel, containing calcipotriol or calcipotriol monohydrate.

In another aspect, the present invention relates to calcipotriol or calcipotriol monohydrate obtained by a process comprising the above-described process.

Detailed Description

Definition of

As used herein, "hydroxy protecting group" includes any group that forms a derivative that is stable to the intended reaction, wherein the hydroxy protecting group can be selectively removed by a reagent that does not interfere with the regeneration of the hydroxy group. The derivatives can be obtained by selective reaction of a hydroxyl protecting agent with a hydroxyl group. Silyl derivatives, such as tert-butyldimethylsilyl, which form silyl ethers are examples of hydroxyl protecting groups. Silyl chlorides, such as tert-butyldimethylsilyl chloride (TBSCl), trimethylsilyl chloride, triethylsilyl chloride, diphenylmethylsilyl chloride, triisopropylsilyl chloride, and tert-butyldiphenylsilyl chloride are examples of hydroxyl protecting agents. Hydrogen fluoride, for example aqueous HF or tetra-n-butylammonium fluoride in acetonitrile, are examples of reagents from which silyl groups can be removed. Other hydroxyl protecting groups include ethers, such as Tetrahydropyranyl (THP) ether, including alkoxyalkyl ethers (acetals), such as methoxymethyl (MOM) ether, or benzyl ether; or esters, such as chloroacetate, pivalate, acetate or benzoate. Non-limiting examples of hydroxyl Protecting Groups and methods of protection and removal, all included within the scope of the present application, may be found, for example, in "Protective Groups in organic synthesis", 3 rd edition, ed. t.w. Greene & p.g. m.wuts, eds, John Wiley 1999 and "Protective Groups", 1 st edition, p.j.kocienski, g. Thieme 2000, which are incorporated herein by reference.

In the present context, the term "alkyl" means a group obtained when one hydrogen atom is removed from a hydrocarbon. The alkyl group contains 1 to 20, preferably 1 to 12 (e.g. 1 to 7, e.g. 1 to 4) carbon atoms. The term includes the subclasses n-alkyl (n-alkyl), secondary alkyl and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertiary-butyl, pentyl, isopentyl, hexyl, isohexyl and tertiary-butyldimethyl.

The term "alkoxycarbonyl" means a group of the formula-C (O) -O-R 'wherein R' is an alkyl group as described above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, and the like.

The term "cycloalkyl" means a saturated cycloalkyl group containing 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, in particular 3 to 8 carbon atoms (e.g. 3 to 6), such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term "alkenyl" means a mono-, di-, tri-, tetra-or pentaunsaturated hydrocarbon radical containing from 2 to 10 carbon atoms, in particular from 2 to 6 carbon atoms (e.g. 2 to 4), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl.

The term "alkynyl" means a hydrocarbon group containing 1-5C-C triple bonds and 2-20 carbon atoms, the alkyl chain typically containing 2-10 carbon atoms, in particular 2-6 carbon atoms, for example 2-4 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl.

The term "halogen" means a substituent from main group 7 of the periodic table, preferably fluorine, chlorine and bromine.

"vitamin D analogues" as used herein includes vitamin D₂Or D₃Any derivative of (e.g. 1 alpha, 25-dihydroxyvitamin D)₂Or 1 alpha, 25-dihydroxyvitamin D₃Including derivatives in which one or more of the A, C or D rings have been modified or/and in which the side chain is linked to C-17, other than natural vitamin D₂Or D₃. Examples of Vitamin D analogues can be found, for example, in "Vitamin D", D.Feldman eds., Academic Press, San Diego, USA, 1997]And [ G. -D.Zhu et al, chem.Rev.1995, 95, 1877-1952]And the references cited therein, all of which are incorporated herein by reference, and include calcipotriol and its C-24 epimer and Tisocalcite [9, 10-secocholesteric-5, 7, 10(19), 22-tetraene-25-carboxylic acid, 1, 3, 24-trihydroxy-, 1-methylethyl ester, (1 α, 3 β, 5Z, 7E, 22E, 24R)]And the C-24 epimer thereof.

As used herein, "vitamin D analogue fragment" means the C-17 group of a vitamin D analogue as defined above, without the side chain normally attached at C-17.

As used herein, "precursor for the synthesis of a vitamin D analogue" means any molecule, e.g. starting material or intermediate, for the synthesis of a vitamin D derivative as defined above, wherein part of the precursor molecule or the whole molecule is optionally incorporated into the final vitamin D analogue after further chemical conversion. Examples include, but are not limited to, steroid ring systems such as ergosterol, cholesterol or 7-dehydrocholesterol, or steroid CD ring derivatives such as glendmann's ketone or glendmann's ketone derivatives. Examples of precursors for the synthesis of vitamin D analogues can be found in [ G. -D.Zhu et al, chem.Rev.1995, 95, 1877-1952] and the references cited therein, which are incorporated herein by reference. Examples of particular derivatives of the steroid CD ring that are particularly useful are the ring structures M and N illustrated below, where PG is hydrogen or a hydrogen protecting group as defined above, such as benzyl or benzoyl.

The C-17 analogous site of the precursor means the carbon atom of the precursor, which will correspond to the C-17 carbon atom in the final vitamin D analog.

As used herein, "fragment of a precursor for the synthesis of a vitamin D analogue" means a group of precursors for the synthesis of a vitamin D analogue as defined above. For example, a fragment of a precursor for the synthesis of a vitamin D analogue may be a fragment of the steroid ring system, which may be represented by the structure Q or R, wherein the C-17 analogous site in the sense of the present invention is indicated below.

Further examples of fragments for the synthesis of vitamin D analogue precursors are fragments of derivatives of the steroid CD ring, which may for example be represented by the structure E or P, wherein C-17 analogous sites in the sense of the present invention are indicated and wherein PG is as defined above.

As used herein, "isolating a compound" includes purifying and/or isolating the compound, e.g., to at least 90% purity, e.g., to at least 95% purity, e.g., 97% purity, 98% purity, or 99% purity. The term "isolating a compound" also includes increasing the concentration of the compound in a mixture of the compound, optionally including a solvent, such that the mixture is further enriched in a desired or preferred compound or isomer, e.g., an epimer, after the separation.

Detailed description of the preferred embodiments

In a preferred embodiment of the invention, the vitamin D analogue fragment is represented by fragment F, G, H, J, K or L,

wherein R is₁And/or R₂May be the same or different and represents hydrogen or a hydroxyl protecting group.

In a further preferred embodiment of the invention, R₁And R₂Represents alkylsilyl or hydrogen.

In a further preferred embodiment of the invention, R₁And R₂Represents tert-butyldimethylsilyl.

In a further preferred embodiment of the invention, R₃Is cyclopropyl or-C (CH)₃)₂-C(O)-O-CH(CH₃)₂。

In another preferred embodiment of the present invention, the configuration at the carbon atom C-20 of the side chain marked with an asterisk is (R) and the configuration at C-17 or a C-17-like site is the same as that at natural vitamin D₃The same as in (1).

In a further preferred embodiment of the invention, the epimer is compound IIIba or an epimeric mixture comprising compounds IIIaa and IIIba.

Other examples of specific molecules which are epimerised at C-24 by contacting the molecule with an acid in the presence of water are compounds XX, XXI, XXII, XXIII, XXIV or their corresponding C-24 epimers or mixtures of C-24 epimers, where R1 and R2 can be the same or different and represent hydrogen or a hydroxyl protecting group.

The compounds and intermediates of the present invention may contain asymmetrically substituted (chiral) carbon atoms and carbon-carbon double bonds, which may result in the presence of isomeric forms, such as enantiomers, diastereomers and geometric isomers. Diastereomers having an opposite configuration (R or S) at one of a plurality of tetrahedral stereocenters in a molecule having a plurality of stereocenters are referred to as epimers, e.g. the vitamin D analogs described herein. Thus, for example, the designation of C-24 as the epimeric center of a pair of enantiomers indicates that the configuration at the other stereosymmetric center of the pair of enantiomers is the same. The process of converting one of the epimer pairs to the other by changing stereochemistry at only one asymmetric center can be referred to as epimerization.

By the process of the invention, a first epimer (S or R), for example the 24S or 24R epimer of a vitamin D analogue, which alone or comprises an amount of a second epimer having the opposite configuration to the first epimer, for example the epimer of a vitamin D analogue having the opposite configuration to the first epimer at C-24, is converted into a mixture which is relatively enriched in the second epimer with respect to the starting mixture. I.e. the diastereomeric excess of the starting epimer or mixture of epimers decreases from its initial value. The present invention provides a process for preparing mixed epimers, such as mixed epimers of vitamin D analogs having a hydroxy substituent on an asymmetric allylic carbon atom (e.g., the carbon atom at the C-24 position of the vitamin D analog), starting from a single epimer or a mixture of epimers having an initial diastereomeric excess. The epimerization process of the present invention can be continuous or preferably batch-wise.

It is quite unexpected that the new epimerization process achieves the desired epimerization without significant formation of degradation products and thus without significant loss of yield. It is assumed that the epimerization process of the present invention proceeds by protonation with the oxygen atom of the hydroxyl group of the epimeric carbon atom. Passing through water, via SN₁Or SN₂The mechanism makes a nucleophilic attack on the carbon atom and the configuration on the carbon atom will be reversed. Under the reaction conditions of the present invention, it is expected that allyl alcohols containing the side chain of the compound to be epimerized will be significantDegradation, for example by intermolecular ether formation or by rearrangement of the intermediate carbocations formed by treatment with an acid. Furthermore, vitamin D analogues, in particular with an unprotected triene system, would not be expected to be resistant to the acidic conditions used in the method.

Any acid capable of protonating the oxygen atom of the hydroxyl group attached to the epimeric carbon atom may be a suitable acid to obtain epimerization. Such acids include phosphoric acid, organic acids such as p-toluenesulfonic acid, and inorganic acids such as sulfuric acid, hydrobromic acid, hydroiodide or hydrochloric acid. In a preferred embodiment of the invention, the acid is provided in the form of an aqueous solution of a salt of the acid, for example a salt of a polyvalent mineral acid, such as an aqueous solution of sodium bisulfate. It has the following advantages: the appropriate pH range is obtained without slowly adjusting the pH by titration and facilitates dose adjustment under production conditions. The pH in the contact/epimerization is preferably below 3.0, such as below 2.0, such as from 0 to 2.5, from 1.1 to 1.9, such as from 1.25, or from 1.2 to 1.7, or from 1.4 to 1.6.

Due to the attack involved in the epimerization mechanism of water, water is present at least in trace amounts, e.g. as residual water in organic solvents or preferably as co-solvent. Preferably a large molar excess of water, for example an aqueous mixture of the matrix and an organic solvent. The epimerization is preferably carried out in the absence of nucleophiles that would otherwise compete with water. Thus, preferred acids are those having a non-nucleophilic counterion and preferred solvents are non-nucleophilic solvents.

Suitable solvents are any solvents or mixtures of such solvents which are compatible with the reaction conditions employed, for example organic solvents. Non-limiting examples of solvents include hydrocarbons (e.g., toluene), ketones (e.g., acetone), esters (e.g., ethyl acetate), alcohols (e.g., methanol, ethanol, or 2-propanol), and ethers (e.g., t-butyl methyl ether, Tetrahydrofuran (THF), or dioxane). The solvent capable of dissolving the matrix is preferably a water-miscible solvent and mixtures of such solvents. Preferred contacting of the epimerized compounds is a homogeneous mixture, such as a solution comprising the compound to be epimerized, an organic solvent or mixture of organic solvents, water and one or more acids. In a preferred embodiment of the invention, the epimerization is carried out in a mixture of one or more water-miscible solvents and water, preferably in a mixture comprising water, acetone and tetrahydrofuran; water and acetone; or a mixture of water and tetrahydrofuran.

In another embodiment of the invention, the epimerization reaction may be carried out under phase transfer conditions using a mixture of water and a water-immiscible solvent (e.g., toluene or xylene) under acidic conditions in the presence of a suitable phase transfer catalyst.

In another embodiment of the invention, the epimerization reaction can be carried out using an acidic ion exchange resin as the acid, such as a strongly acidic cation resin.

In another embodiment of the invention, the epimerization reaction may be carried out in a two-phase mixture of water and a water-immiscible solvent.

It has been found that reaction/contact time and temperature can affect the formation of by-products and thus the purity of the epimer mixture obtained by the process described herein. Preferably, the contacting is carried out at a temperature of about 5 to 40 ℃ (e.g., 10 to 35 ℃, e.g., 15 to 30 ℃, e.g., 20 to 25 ℃). Preferred contact times are from about 1 to 8 hours, such as from 2 to 6 hours, such as from 3 to 4 hours, such as from 2 to 4 hours. The most preferred contact is by contacting the epimer mixture with an acid in the presence of water at 15-30 ℃ for about 2-4 hours.

In the sense of the present invention, an epimeric mixture of the compound to be epimerized may comprise any epimer of the epimeric ratio (R) to (S), including the epimers in pure form. The invention also includes all possible epimer ratios (R) to (S), even if not specifically indicated. In epimerization the epimer ratio will change until equilibrium is reached. Since epimer centers are usually adjacent to other chiral centers, the equilibrium can deviate from 50: 50, which is attributed to diastereoisomersStructure-body interactions. However, the epimerization is advantageously stopped before equilibrium is reached at a point which provides the best compromise in reaction time, yield of the desired epimer and amount of impurities formed in the epimerization (e.g. due to decomposition or degradation). In a presently preferred embodiment of the invention, the epimerization process is stopped when the epimeric mixture after epimerization contains C-24 epimers with an epimer ratio (S): (R) exceeding 29: 71 (e.g. exceeding 40: 60). Since too long a contact time in the epimerization may cause a yield loss, the pH of the reaction mixture is increased (by adding a base, for example NaHCO)₃、Na₂CO₃NaOH, KOH or K₂CO₃Until a neutral or basic pH value, for example to a pH of 7 to 10, for example to a pH of 7.5 to 9.0, for example to a pH of 8.0 to 8.5) is advantageous.

In a typical presently preferred process, the epimer mixture to be epimerized dissolved in an organic solvent or mixture thereof is concentrated and redissolved in a 1: 1 (v: v) mixture of acetone and tetrahydrofuran. Dissolving NaHSO in water₄Is added to the reaction mixture. After stirring the mixture at 20 ℃ for about 2-4 hours, the mixture was substantially neutralized with a base to stop the epimerization.

After epimerisation, the epimeric mixture can preferably be separated chromatographically into the pure epimers or into a mixture of the epimers enriched in one epimer. The separation, isolation and purification methods of the present invention include, but are not limited to, chromatography, such as adsorption chromatography (including column chromatography and Simulated Moving Bed (SMB)), crystallization, or distillation. The separation, isolation and purification methods can be used sequentially or in combination.

Column chromatography suitable for isolating vitamin D analogues of the invention or precursors for synthesizing vitamin D analogues of the invention is well known to those skilled in the art of pharmaceutical chemistry, organic chemistry or process chemistry. This technique employs a column packed with a stationary phase (e.g., silica, such as pretreated silica) onto which a sample to be separated is loaded. The sample is then eluted with a suitable eluent. The elution may be an isocratic elution or a so-called solvent procedure (gradient) elution, wherein the composition of the eluent is varied regularly (e.g. linearly) or irregularly (e.g. stepwise) over time. Pretreated silica gel (well known to those skilled in the art of chromatography) is a suitable stationary phase. Elution with 5% (v: v) ethyl acetate in hexane or heptane followed by pure ethyl acetate is only one example of an elution procedure that yields the desired separation. Other suitable eluents will be derived by the skilled person by routine development methods, for example by using mixtures of heptane and ethyl acetate of appropriate polarity.

For chromatography, any combination of stationary phase (packing) and eluent capable of redissolving the epimer mixture may be used. This combination can be readily determined by the skilled person by routine experimentation. An example of a preferred stationary phase is silica, such as treated silica.

The process of the invention is particularly useful for recycling undesired epimers in the production process of vitamin D derivatives, wherein the undesired epimers are usually discarded. The process comprises a plurality of epimerization and purification steps, i.e. the undesired epimers obtained by separating the mixture after epimerization can be epimerized again and then separated for another epimerization step, etc. Batches of epimers of different origin and chemical or diastereomeric purity are suitably collected prior to epimerisation.

Synthesis method

Epimers of compounds comprising side chains of formula a or B of the present invention can be synthesized by methods well known to those skilled in the art. For example, general synthetic methods can be found in, for example, [ "Vitamin D", D.Feldman eds., Academic Press, San Diego, USA, 1997] and [ G. -D.Zhu et al, chem.Rev.1995, 95, 1877-.

More specifically, the compound of formula IV can be synthesized, for example, by Diels-Alder reaction (Diels-Alder reaction) by treating the compound of formula IIIa or IIIb with sulfur dioxide. The sulphur dioxide used may be in liquid, gaseous or dissolved in a suitable solvent. Suitable solvents for the Diels-Alder reaction are all solvents compatible with the reaction conditions, such as alkanes (e.g., hexane or heptane), hydrocarbons (e.g., xylene, toluene), ethers (diethyl ether or methyl tert-butyl ether (MTBE), acetates (e.g., ethyl acetate or 2-propyl acetate), halogenated solvents (e.g., dichloromethane) or mixtures of the above solvents. Most, for example, 10 ℃ to 25 ℃, for example, 15 ℃ to 20 ℃. Preferably, an excess (mol/mol) of sulphur dioxide is used, for example a 5-100 mol excess, for example a 7-30 mol excess, for example a 10-15 mol excess. Any excess unreacted sulphur dioxide may be removed from the reaction mixture, for example by washing with an aqueous base, such as sodium hydroxide in water, or by distilling off sulphur dioxide, optionally together with the solvent, optionally under reduced pressure. The compounds of formula IV are usually obtained as mixtures of their epimers IVba and IVbb or IVaa and IVab.

Furthermore, the compounds of the general formula IV can be synthesized by enantioselective or diastereoselective reduction of their 24-keto-derivatives, for example with N, N-diethylaniline borane and optionally a chiral auxiliary (e.g. (1S, 2R) -cis-1-amino-2-indanol). The 24-keto-derivative can be prepared by a diels-alder reaction by working with a 24-keto-derivative derived from structure III obtainable as outlined in m.j. calverley, Tetrahedron, vol 43, No. 20, 1987 or WO 87/00834.

For example, compounds of the general formula I, IIa, IIb, IIIa or IIIb can be synthesized according to the methods disclosed, for example, in M.J. Calverley, Tetrahedron, Vol.43, No. 20, p.4609-4619, 1987 or in WO 87/00834.

For example, compound IIIa (wherein R is₁And R₂Is tert-butyldimethylsilyl) can be deprotected in aqueous hydrofluoric acid in acetonitrile or tetrabutylammonium fluoride in THF to form a compound in which R is₁Or R₂Mixtures of compounds which are hydrogen, or to form compounds in which R is₁And R₂A compound which is hydrogen. Mixtures of such compounds may be isolated, for example, by chromatography or crystallized as generally described herein. By the compounds of the formula IIIa (wherein R₁And/or R₂Hydrogen) with suitable protecting agents, new radicals R being introduced₁And/or R₂. Depending on the stoichiometry of the protecting agent used and the reaction conditions, mixtures of unprotected, mono-protected and di-protected compounds are obtained. Then, any intermediate of the mixture (wherein R is₁Or R₂One being hydrogen) can be isolated by chromatography and reacted with a suitable protecting agent different from the first protecting agent used to give a compound of the formula IIIa (in which R is₁Is different from R₂). Suitably, R may be varied in the same way for other derivatives of the invention, e.g. for compounds of the general formulae I, IIa, IIb, IIIb, IV₁And R₂。

The method of producing calcipotriol as described herein may be modified in the order of the reaction steps by omitting one or more reaction steps or by introducing additional purification or reaction steps at any stage of the reaction sequence. The present invention includes all such modifications.

The methods of producing calcipotriol as described herein further include all variations, compounds or intermediates thereof (wherein R is₁And/or R₂Not hydrogen) hydroxy-protecting groups R₁And/or R₂At any stage of the reaction sequenceIs removed. Wherein R is₁And/or R₂The compound or intermediate that is hydrogen may be protected with a protecting agent at any stage of the reaction sequence, including protecting agents that generate other protecting groups different from those protecting groups previously removed in the reaction sequence.

The present invention relates to all isomeric forms, in pure form or in mixtures thereof. For the specification of a particular conformation or configuration in the formula of the present invention or in the name of the compound or intermediate of the present invention, it should be specified that the particular conformation or configuration is a preferred embodiment of the present invention. For a description of a particular conformation or configuration in the formula of the invention or in the name of a compound or intermediate of the invention, any other isomer other than the particular description (in pure form or as a mixture thereof) shall be included as a further embodiment of the invention.

For the description of a non-specific conformation or configuration in the formula of the present invention or in the name of the compound or intermediate of the present invention, it should be noted that the specific conformation or mixture of conformations is a preferred embodiment of the present invention, and although not specifically stated, it should include all specific conformations or configurations as embodiments. For example, the compounds of the formula IVa are preferably epimeric mixtures of the formulae IVaa and IVab. The meaning of the compounds of the general formula IVa includes the pure epimers IVa and IVa b as further embodiments of the invention.

For the specification of a non-specific conformation or configuration in the formula of the invention or in the name or number of the compound or intermediate of the invention, any particular isomer should be included in pure form, although not explicitly specified, for example as a further embodiment of the invention.

Pure stereoisomeric forms of the compounds and intermediates of the present invention may be obtained by applying methods well known in the art, e.g. by chromatography or crystallization or by stereoselective synthesis.

The reverse Diels-Alder reaction of a mixture of compounds of formula IV to give a compound of formula III in the presence of a base can be carried out in all solvents compatible with the reaction conditionsSuch as an alkane (e.g., hexane or heptane), a hydrocarbon (e.g., xylene, toluene), an ether (e.g., diethyl ether or methyl tert-butyl ether (MTBE)), an acetate (e.g., ethyl acetate or 2-propyl acetate), a halogenated solvent (e.g., dichloromethane), water, or a mixture of the above solvents. Methods for such reverse Diels-Alder reactions are well known to those skilled in the art of vitamin D synthesis (see, e.g., M.J. Calverley, Tetrahedron, Vol.43, No. 20, pp.4609-4619, 1987 or WO 87/00834). Preferred solvents are toluene, tert-butyl methyl ether, water or mixtures thereof. Suitable bases for use in the reverse Diels-Alder reaction include, but are not limited to NaHCO₃、KHCO₃、Na₂CO₃Or K₂CO₃. In a preferred embodiment of the invention, the base is NaHCO₃The aqueous solution and/or the retro diels-alder reaction is carried out at above 70 ℃, for example between 70 ℃ and 120 ℃, most preferably between 74 ℃ and 79 ℃.

The isomerization of vitamin D derivatives and in particular the isomerization of compounds of the general formula IIIa and/or IIIb to IIa and/or IIb is well known to the person skilled in the art of vitamin D synthesis. The reaction conditions can be found, for example, in M.J. Calverley, Tetrahedron, volume 43, stage 20, pages 4609-4619, 1987 or WO87/00834 and the references cited therein. In a preferred embodiment of the invention, the epimerization is a photoaepimerization, which is preferably carried out with UV light in the presence of a triplet sensitizer (e.g. anthracene) or more preferably in the presence of 9-acetyl anthracene.

Methods for crystallizing, for example, vitamin D derivatives, in particular calcipotriol or calcipotriol monohydrate can be found, for example, in [ M.J. Calverley, Tetrahedron, Vol.43, No. 20, p.4609-4619, 1987, WO 94/15912; WO2004/046097] and comprises crystallization from a mixture of ethyl acetate and hexane of appropriate polarity.

The compounds prepared by the epimerization process of the present invention can be formulated with pharmaceutically acceptable adjuvants or excipients into pharmaceutical preparations or medicaments, such as creams, ointments or gels.

Examples

General purpose:

all chemicals were commercially available unless otherwise noted. All melting points are uncorrected. Unless otherwise stated, reference is made to deuterated chloroform solution versus internal tetramethylsilane (δ ═ 0.00) or chloroform (δ ═ 7.26) or deuterated chloroform (δ ═ 7.26)¹³δ 76.81 for C NMR) standard¹H Nuclear Magnetic Resonance (NMR) Spectroscopy (300MHz) and¹³chemical shift value (. delta.) (in ppm) by C NMR (75.6 MHz). Unless a range is quoted, values are given for the defined (doublet (d), triplet (t), quartet (q)) or undefined multiplet (m) at the approximate midpoint. Chromatography is performed on silica gel, optionally using flash technology. Silica gel coated TLC plates were purchased from Merck KGaA. Preferably, the silica used for chromatography is purchased from merckkkgaa Germany:si60(15-25 μm). Unless otherwise stated, ethyl acetate, dichloromethane, or a suitable mixture of ethyl acetate, dichloromethane, methanol and petroleum ether (40-60) or heptane is used as eluent.

The preparation method comprises the following steps:

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 '-cyclopropyl-3' -oxopropan) -1' (E) -alkenyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO ₂ Adducts

20(R), 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20- (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (prepared according to the method described in M.J. Calverley, Tetrahedron, Vol.43, No. 20, p.4609-4, p.4619, 1987) (20.0g) was dissolved in toluene (210mL) at 20 ℃ and then water (40 mL) was added with stirringmL) and SO₂(20 mL). When the reaction is judged to be complete by HPLC { column LiChrosorb Si605 μm 250X 4mm, from Merck, 2mL/min flow rate, detection and mass detection at 270nm, hexane/ethyl acetate 9: 1 (v: v) }, usually after 2-2.5 hours, a mixture of sodium hydroxide (27.7%, 60mL) and water (80mL) is added at 10-18 ℃ until the pH of the reaction mixture is 6. The toluene phase is separated and the solvent is removed in vacuo without heating (preferably below 30 ℃) to give the two epimers SO₂-an adduct as a solid mixture. Separation of two epimers SO by chromatography₂-adduct and additionally obtaining a crystalline sample in the main form by grinding the solid mixture with methanol:¹H NMR(CDCl₃)＝6.73(dd，1H)，6.14(d，1H)，4.69(d，1H)，4.62(d，1H)，4.35(s，1H)，4.17(m，1H)，3.92(d，1H)，3.58(d，1H)，2.61(m，1H)，2.29(m，1H)，2.2-1.2(m，16H)，1.11(d，3H)，1.05(m，2H)，0.90(m，2H)，0.87(s，9H)，0.85(s，9H)，0.68(s，3H)，0.06(s，3H)，0.05(s，3H)，0.04(s，3H)，0.02(s，3H)ppm。

the preparation method 2 comprises the following steps:

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 '-cyclopropyl-3' (S) -hydroxy SO of prop-1' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene ₂ Adducts (IVa: R) ₁ 、 R ₂ T-butyldimethylsilyl) and

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 '-cyclopropyl-3' (R) -hydroxy SO of prop-1' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene ₂ Adducts (IVb: R) ₁ 、 R ₂ Tertbutyldimethylsilyl group)

(1S, 2R) - (-) -cis-1-amino-2-indanol (5.0g) was mixed with MTBE (160mL) at 15-25 ℃ under a nitrogen atmosphere, followed by addition of N, N-diethylaniline-borane (16.0mL) at that temperature. The mixture was stirred until no more hydrogen evolution was observed. SO of 1(S), 3(R) -di (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene obtained in preparation method 1₂The mixture of adducts was dissolved in toluene (160mL) and MTBE (80 mL). This solution was added dropwise to the mixture at 15-25 ℃. After the addition was complete, the mixture was stirred for about 30 minutes and then saturated NaHCO at 10-15 deg.C₃The aqueous solution quenched the reaction. The organic phase was separated and washed with 1M hydrochloric acid (100mL) at 0-10 deg.C, then saturated NaHCO₃Aqueous (100mL) wash. Examination of the organic phase by HPLC analysis of aliquots after the reverse Diels-Alder reaction and analysis according to the method described in example 2 checked that the SO of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 (S) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene was contained in the organic phase₂Adducts (IVa: R)₁、R₂Tert-butyldimethylsilyl) and SO of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' (R) -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene₂Adducts (IVb: R)₁、R₂T-butyldimethylsilyl) in a molar ratio of 78: 22 (IVa: IVb). Compound iva was isolated by silica gel chromatography.¹³C-NMR(CDCl₃)IVa/R₁、R₂T-butyldimethylsilyl δ of 150.6, 137.6, 132.3, 129.3, 128.8, 109.0, 76.9, 67.3, 65.8, 64.5, 56.2, 56.1, 55.9, 46.0, 40.5, 40.0, 39.6, 34.1, 29.6, 27.4, 25.6, 25.5, 23.8, 21.8, 20.3, 17.8, 17.7, 17.4, 11.8, 2.8, 1.7, -4.7, -5.0, -5.0, -5.2 ppm.

The preparation method 3 comprises the following steps:

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 '-cyclopropyl-3 (S)' -hydroxy Prop-1' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIa: r ₁ 、R ₂ Is tert-butyl di Methylsilyl) and

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 '-cyclopropyl-3' (R) -hydroxy Prop-1' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIb: r ₁ 、R ₂ Is tert-butyl di Methylsilyl group)

Adding IVa (R) -containing compound obtained by preparation method 2₁、R₂Tert-butyldimethylsilyl) and IVb (R)₁、R₂T-butyldimethylsilyl) SO₂Organic phase of adduct and saturated NaHCO₃The aqueous solution (110mL) was stirred vigorously and then heated (bath temperature about 90 ℃ C.), wherein MTBE was distilled off. The reverse Diels-Alder reaction can be conveniently examined by HPLC { column LiChrosorb Si 60250X 4mm, available from Merck, flow rate 1mL/min, detection at 270nm, hexane/ethyl acetate 9: 1.5 (v: v) }. After completion, typically over 2-2.5 hours, the reaction mixture is cooled to 15-25 ℃ and the organic phase is separated, washed with saturated NaHCO₃Aqueous solution (110mL) and water (100 mL). The solvent was removed in vacuo and the resulting oil (29g) was dissolved in hexane (200 mL). The organic mixture was cooled to about-15 ℃, filtered through a short column of silica, and the residue was washed with hexane (about 100 mL). The hexane was removed in vacuo and the residue was purified by HPLC { column LiChrosorbSi 605 μm 250X 4mm, from Merck, flow rate 1mL/min, detection at 270nm, positiveHexane/2-propanol 100: 0.25 (v: v): retention time IIIa about 14.3 minutes, IIIb: 11.9 min } check that the residual oil contained 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 (S) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIa: R)₁、R₂Tert-butyldimethylsilyl) and 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' (R) -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIb: r₁、R₂T-butyldimethylsilyl) in a molar ratio of 78: 22 (IIIa: IIIb) was purified by chromatography as described previously in M.J. Calverley, Tetrahedron, Vol.43, No. 20, p.4609-4619, 1987 or WO87/00834, crystallization from a mixture of dioxane and methanol (and a small amount of triethylamine) to give 10.9g (98.9% HPLC purity) of IIIa (R87/00834)₁、R₂Tert-butyldimethylsilyl), was completely compatible with the data for compound 22 in m.j.calverley, Tetrahedron, volume 43, phase 20, page 4617, 1987.¹³C NMR(CDCl₃)IIIa(R₁、R₂T-butyldimethylsilyl) ═ 153.4, 142.9, 137.9, 135.2, 128.7, 121.5, 116.3, 106.4, 77.1, 70.0, 67.0, 56.2, 55.8, 45.7, 43.7, 40.2, 39.8, 36.3, 28.7, 27.5, 25.6, 25.6, 23.3, 22.0, 20.3, 18.0, 17.9, 17.4, 12.1, 2.9, 1.6, -5.0, -5.0, -5.1; IIIb (R)₁、R₂T-butyldimethylsilyl group) 153.5, 142.9, 137.6, 135.3, 128.7, 121.5, 116.3, 106.4, 76.8, 70.0, 67.0, 56.2, 56.0, 45.7, 43.8, 40.2, 39.7, 36.4, 28.7, 27.6, 25.7, 25.6, 23.3, 22.0, 20.3, 18.0, 17.9, 17.3, 12.1, 2.8, 1.6, -5.0, -5.1, -5.1 ppm.

The preparation method 4 comprises the following steps:

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 '-cyclopropyl-3 (S)' -hydroxy Prop-1' (E) -enyl) -9, 10-secopregna-5 (Z), 7(E), 10(19) -triene (IIa)：R ₁ 、R ₂ Tert-butyl dimethyl Silyl radical)

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 (S) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIa: R) obtained in preparation method 3 was treated at 20 ℃ with a high-pressure UV lamp as described previously in M.J. Calverley, Tetrahedron, Vol.43, No. 20, pp.4609-4619, 1987 or WO87/00834₁、R₂Photoisomerization in toluene (with the exception of 9-acetylanthracene instead of anthracene) yielded, after chromatography, 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 (S) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (Z), 7(E), 10(19) -triene (IIa: r₁、R₂Tert-butyldimethylsilyl), the data comply with the data for compound 28 in m.j.calverley, Tetrahedron, volume 43, phase 20, page 4618, 1987.

Example 1:MC898/MC901

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' (R) -hydroxypropan-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIb: R)₁、R₂Tert-butyldimethylsilyl) (10mg), THF (1mL) and aqueous sulfuric acid (0.4mL, pH 1.7) were mixed in a test tube. After standing overnight at room temperature, HPLC analysis (normal phase silica 20cm analytical column, 4mL/min, AcOEt/n-hexane 4/96 (v: v)) indicated the presence of about 40% of the starting epimer and about 45% of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 (S) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIa: R)₁、R₂Tert-butyldimethylsilyl) along with about 12% of two major and less polar impurities of unknown structure.

Example 2:

containing about 95% of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' (R) -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIb: R)₁、R₂Tert-butyldimethylsilyl) and < 5% of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 (S) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIa: r₁、R₂Tert-butyldimethylsilyl) was dissolved in a mixture of acetone (58L) and THF (58.5L). A solution of sodium bisulfate (0.3kg) in water (20L) (pH 1.58) was added with stirring while maintaining an internal temperature of 20-25 ℃. After 220 minutes, saturated NaHCO₃Solution (6L) was added to the reaction mixture. The organic solvent was largely removed in vacuo and the residue redissolved in ethyl acetate (100L). The organic solution was then washed with brine (2L of saturated NaCl solution in 180L of water). The ethyl acetate was then removed in vacuo, the residue redissolved in hexane and the epimer mixture was separated by column chromatography on silica gel (by HPLC { column LiChrosorb Si605 μm 250X 4mm, from Merck, flow rate of 1mL/min, detection at 270nm, n-hexane/2-propanol 100: 0.25 (v: v): retention time IIIa about 14.3 minutes, IIIb: 11.9 minutes) } it was checked that it contained IIIa and IIIb with an epimer ratio of 67: 33 (R)₁、R₂T-butyldimethylsilyl)) to yield pure IIIa and IIIb (R)₁、R₂T-butyldimethylsilyl).

Example 3:

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' (R) -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIb: R) is added under stirring₁、R₂Tert-butyldimethylsilyl group) (150g), ethyl acetate (1.2L), acetone (1.2L) and aqueous sulfuric acid (121mL, pH 1.25) were mixed. Stirring at 27 deg.CAfter about 35 minutes, HPLC analysis indicated that the epimer mixture contained IIIa and IIIb (R) in an epimer ratio of 53: 47₁、R₂T-butyldimethylsilyl).

Example 4:

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' (R) -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIb: R) is added under stirring₁、R₂Tert-butyldimethylsilyl group) (10g), tetrahydrofuran (10mL), acetone (10mL) and phosphoric acid (1mL, pH 1.48) were mixed. After stirring for about 1140 minutes at 20 deg.C, HPLC analysis indicated that the epimer mixture contained IIIa and IIIb in an epimer ratio of 39: 61 (R)₁、R₂T-butyldimethylsilyl).

Example 5:

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' (R) -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (IIIb: R) is added under stirring₁、R₂Tert-butyldimethylsilyl group) (10g), tetrahydrofuran (10mL), acetone (10mL) and phosphoric acid (2mL, pH 1.01) were mixed. After stirring for about 360 minutes at 30 deg.C, HPLC analysis indicated that the epimer mixture contained IIIa and IIIb (R) in an epimer ratio of 38: 62₁、R₂T-butyldimethylsilyl).

Claims (22)

1. A process for epimerising an epimer or epimeric mixture of a compound comprising a side chain of the general formula A and/or B,

at the hydroxy group and R₃The site of the attached carbon atom occurs;

the process is carried out by contacting the epimer or epimer mixture in the presence of water with an acid selected from phosphoric acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid, hydroiodide or hydrochloric acid or provided in the form of an aqueous sodium bisulfate solution;

wherein R is₃Is cyclopropyl;

wherein the carbon marked with an asterisk is attached by a single bond to the C-17 carbon atom of the vitamin D analog fragment;

or wherein the carbon marked with an asterisk is linked by a single bond to a fragment of a precursor for the synthesis of a vitamin D analogue at its C-17 analogous site;

wherein the fragment of the precursor for the synthesis of the vitamin D analogue is a fragment of the steroid ring system or a fragment of the steroid CD ring system;

wherein the fragment of the steroid ring system is represented by the structure Q or R

Wherein a fragment of the steroid CD ring system is represented by structure E or P

Wherein PG represents hydrogen or a hydroxy protecting group;

wherein the vitamin D analog fragment is represented by any one of fragment F, G, H, J, K or L,

wherein R is₁And/or R₂May be the same or different and represents hydrogen or a hydroxyl protecting group.

2. The method of claim 1, wherein the configuration at the carbon atom C-20 of the side chain marked with an asterisk is (R) and wherein the configuration at C-17 or a C-17-like site is identical to that at natureVitamin D₃The same as in (1).

3. The process according to claim 1, wherein the epimer of the compound of the structure IIIba or the epimer mixture comprising the compounds IIIaa and IIIba is epimerized by contacting the epimer or epimer mixture with an acid selected from phosphoric acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid, hydroiodide or hydrochloric acid, or provided in the form of aqueous sodium hydrogensulfate solution, in the presence of water,

4. a process according to any one of claims 1 to 3, wherein the acid is sulphuric acid.

5. A process according to any one of claims 1 to 3, wherein the acid is provided as an aqueous solution of sodium bisulphate.

6. The method of any one of claims 1 to 3, wherein the contacting is performed at a pH below 3.0.

7. The method of claim 6, wherein the contacting is performed at a pH between 1.2 and 1.7.

8. The process of any one of claims 1 to 3, wherein the contacting is carried out at a temperature of 15-30 ℃.

9. The method of any one of claims 1 to 3, wherein the contacting is performed for 2 to 4 hours.

10. A process according to any one of claims 1 to 3, wherein the contacting is carried out in a mixture of one or more water miscible solvents and water.

11. The process of claim 10, wherein the contacting is carried out in a mixture comprising water, acetone, and tetrahydrofuran.

12. The process of any one of claims 1 to 3, wherein the epimeric mixture is separated by chromatography after epimerization.

13. A process for the preparation of calcipotriol or calcipotriol monohydrate comprising in one or more steps the process of any one of claims 1 to 12.

14. A method for producing calcipotriol { (5Z, 7E, 22E, 24S) -24-cyclopropyl-9, 10-secocholesteric-5, 7, 10(19), 22-tetraen-1 α -3 β -24-triol } or calcipotriol monohydrate, comprising the steps of:

(i) epimerising the vitamin D analogues of formula IIb with an acid selected from phosphoric acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid, hydroiodide or hydrochloric acid, or provided as aqueous sodium bisulfate, in the presence of water,

wherein R is₁And R₂May be identical or different and represents hydrogen or a hydroxyl-protecting group, to give a mixture of compounds of the formulae IIa and IIb, in which R is₁And R₂As defined above;

(ii) optionally separating the compound of formula IIa from a mixture of compounds of formula IIa and IIb, wherein R₁And R₂As hereinbefore describedDefining;

(iii) when R is₁And/or R₂When not hydrogen, a hydroxy protecting group R of a compound of formula IIa₁And/or R₂Removing to produce calcipotriol; and

(iv) optionally crystallizing calcipotriol from a mixture of an organic solvent and water to form calcipotriol monohydrate.

15. A method for producing calcipotriol { (5Z, 7E, 22E, 24S) -24-cyclopropyl-9, 10-secocholesteric-5, 7, 10(19), 22-tetraen-1 α -3 β -24-triol } or calcipotriol monohydrate, comprising the steps of:

(i) epimerising the vitamin D analogue of formula IIIb with an acid selected from phosphoric acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid, hydroiodide or hydrochloric acid, or provided as aqueous sodium bisulfate, in the presence of water,

wherein R is₁And R₂Which may be identical or different and represent hydrogen or a hydroxyl protecting group, to give a mixture of compounds of the formulae IIIa and IIIb,

wherein R is₁And R₂As defined above;

(ii) optionally separating the compound of formula IIIa from the mixture of compounds of formulae IIIa and IIIb;

(iii) photoisomerization of the compound of formula IIIa to a compound of formula IIa,

wherein R is₁And R₂As defined above;

(iv) when R is₁And/or R₂When not hydrogen, a hydroxy protecting group R of a compound of formula IIa₁And/or R₂Removing to produce calcipotriol; and

(v) optionally crystallizing calcipotriol from a mixture of an organic solvent and water to form calcipotriol monohydrate;

wherein steps (iii) and (iv) may be performed in reverse order.

16. A method for producing calcipotriol { (5Z, 7E, 22E, 24S) -24-cyclopropyl-9, 10-secocholesteric-5, 7, 10(19), 22-tetraen-1 α -3 β -24-triol } or calcipotriol monohydrate, comprising the steps of:

(i) epimerising the vitamin D analogues of formula IVba and/or IVbb with an acid selected from phosphoric acid, p-toluenesulfonic acid, sulfuric acid, hydrobromic acid, hydroiodide or hydrochloric acid, or provided as aqueous sodium bisulfate, in the presence of water,

wherein R is₁And R₂May be the same or different and represents hydrogen or a hydroxyl protecting group,

to form a mixture of compounds of the formulae IVba and/or IVbb and IVaa and/or IVab,

wherein R is₁And R₂As defined above;

(ii) optionally isolating the compound of formula IVaa and/or IVab from the reaction mixture;

(iii) heating the compound of formula IVaa and/or IVab to above 60 ℃ in the presence of a base to produce a compound of formula IIIa,

wherein R is₁And R₂As defined above;

(iv) photoisomerization of the compound of formula IIIa to a compound of formula IIa,

wherein R is₁And R₂As defined above;

(v) when R is₁And/or R₂When not hydrogen, a hydroxy protecting group R of a compound of formula IIa₁And/or R₂Removing to produce calcipotriol; and

(vi) optionally, crystallizing calcipotriol from a mixture of an organic solvent and water to form calcipotriol monohydrate;

wherein steps (iv) and (v) may be performed in reverse order.

17. The method of claim 1, 14, 15 or 16, wherein R₁And R₂Represents alkylsilyl or hydrogen.

18. The method of claim 17, wherein R₁And R₂Represents tert-butyldimethylsilyl.

19. The process of claim 1, wherein an epimer of a compound of structure IIIba or an epimer mixture comprising compounds IIIaa and IIIba is epimerized,

the process is carried out by contacting the epimer or epimer mixture with an acid in the presence of water at a temperature of 15-30 ℃ and a pH of less than 3.0 for 2-4 hours, wherein the acid is provided as an aqueous solution of sodium bisulfate.

20. Use of the method of any one of claims 1 to 19 in the preparation of calcipotriol or calcipotriol monohydrate.

21. A method of preparing a pharmaceutical formulation or medicament containing calcipotriol or calcipotriol monohydrate comprising the method of any one of claims 1 to 19.

22. The method of claim 21, wherein the pharmaceutical formulation or medicament is a cream, ointment, or gel.