HK1098122B

HK1098122B - Stereoselective synthesis of vitamin d analogues

Info

Publication number: HK1098122B
Application number: HK07104320.6A
Authority: HK
Inventors: Thomas Peter Sabroe; Martin John Calverley
Original assignee: Leo Pharma A/S
Priority date: 2004-03-18
Filing date: 2005-03-10
Publication date: 2012-05-11

Description

Stereoselective synthesis of vitamin D analogs

Technical Field

The present invention relates to a process for the preparation of calcipotriol { (5Z, 7E, 22E, 24S) -24-cyclopropyl-9, 10-secocholesteric (secochola) -5, 7, 10(19), 22-tetraene-1 α -3 β -24-triol } or calcipotriol monohydrate by stereoselective reduction. The invention further provides novel intermediates and methods for synthesizing intermediates useful for preparing calcipotriol or calcipotriol monohydrate.

Background

Calcipotriol or calcipotriene (structure I) [ CAS 112965-21-6] showed strong activity in inhibiting undesirable epidermal keratinocyte proliferation [ f.a.c.m.casteligins, m.j.gerritsen, i.m.j.j.van Vlijmen-Willems, p.j.van Erp, p.c.m.van deKerkhof; acta derm. venereol.79, 11, 1999 ]. The efficacy of calcipotriol and calcipotriol (II) monohydrate in the treatment of psoriasis has been demonstrated in a number of clinical trials [ d.m.ashcroft et al, brit.med.j.320, 963-67, 2000] and calcipotriol is currently used in many commercial pharmaceutical formulations.

In the preparation of calcipotriol, the specific stereochemistry of the hydroxyl group at C-24 is essential for the complete expression of biological activity. In the current method, the desired stereochemistry is introduced by one of the following methods:

(i) non-diastereomeric stereoselective reduction of C-24 ketotrienes followed by chromatographic separation of the resulting diastereomeric mixture of C-24 hydroxy epimers (WO 87/00834 and M.J. Calverley, Tetrahedron, 43(20), 4609-19, 1987),

(ii) the enantiomerically pure side chain bearing the C-24 hydroxyl group was attached to the vitamin D backbone (M.J. Calverley, Synlett, 157-59, 1990),

(iii) one of the C-24 hydroxy epimers is subjected to selective enzymatic esterification followed by separation by chromatography (WO 03/060094).

The most widely used procedure for obtaining the desired epimer is the non-diastereomeric stereoselective reduction of the C-24 ketotriene followed by chromatographic separation of the epimer mixture (i). This reduction process yields predominantly the undesired C-24 epimeric alcohol (typically containing about 60% of the undesired 24-R epimer) and it is difficult to separate the desired S-epimer from the mixture by chromatography on a preparative scale.

The stereoselective synthesis of (ii) is also not suitable for scale-up due to its multiple steps and cost and due to the use of toxic intermediates.

The enzymatic esterification process (iii) has the disadvantage, in addition to the high cost of the enzymes used, that it introduces 1 to 2 additional reaction steps depending on the selectivity of the enzymes, which further increase the cost of the process.

The stereoselective reduction of C-24 ketones directly to the desired C-24 hydroxy epimer has been described for example in WO 98/24800 and by M.Ishiguro et al, J.C.S.chem.Comm.115-117, 1981 for cholesterol derivatives. Stereoselective reduction of the side chain triple bond analogs of calcipotriol with unprotected triene systems using S-alpine (alpine) borane is described in M.J.Calverly et al, bioorg.Med.chem.Lett., 1841-1844, 3(9), 1993.

One major technical problem in the synthesis of calcipotriol using stereoselective reduction methods stems from the fact that the unsaturated triene systems known to date for the synthesis of intermediates of calcipotriol are chemically unstable, e.g. unstable to Lewis (Lewis) acidic conditions, they are relatively easily oxidized and they are generally incompatible with the typical reduction reaction conditions used. This leads to a reduction in yield, impure product and a lengthy work-up procedure, especially for large-scale production.

It is an object of the present invention to provide an alternative method for the synthesis of calcipotriol which overcomes one or more of the various problems and disadvantages described above.

Disclosure of Invention

The present invention provides a novel process for the preparation of diastereoisomeric C-24 hydroxy epimers of calcipotriol derivatives using a novel synthetic route comprising a stereoselective reduction step. The present invention further provides new intermediates which are chemically more stable, wherein the unstable triene system is protected in the form of a sulphur dioxide adduct. By preparing the diastereomer-rich C-24 hydroxy epimer of the calcipotriol derivative, the yield and efficiency of subsequent separation of the desired C-24S-hydroxy epimer can be greatly improved.

It has been surprisingly found that compounds of the general structure III,

wherein X represents hydrogen OR OR₂，

And wherein R₁And R₂Which may be identical or different and represent hydrogen or a hydroxyl-protecting group, together with a reducing agent in an inert solvent or in the presence of a chiral auxiliary to give a mixture of compounds of the general structures IVa and IVb,

the mixture is rich in IVa, wherein X, R₁And R₂As defined above.

In a first aspect, the present invention relates to a process for preparing 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:

(a) reduction of a compound of the general structure III (wherein X represents OR) with a reducing agent in an inert solvent OR in the presence of a chiral auxiliary₂And 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 general structures IVa and IVb which is enriched in IVa, and in which X, R₁And R₂As defined above;

(b) reacting a mixture of compounds of general structures IVa and IVb enriched in IVa in the presence of a base to obtain a mixture of compounds of general structures Va and Vb enriched in Va

X, R therein₁And R₂As defined above;

(c) separating the compound of formula Va from a mixture of compounds of formula Va and Vb enriched with Va, wherein X, R₁And R₂As defined above;

(d) isomerizing a compound of general structure Va to a compound of general structure VIa,

x, R therein₁And R₂As defined above; and

(e) when R is₁And/or R₂When not hydrogen, removing the hydroxy protecting group R of the compound of general structure VIa₁And/or R₂To produce calcipotriol or calcipotriol monohydrate.

In another aspect, the present invention relates to a process for the preparation of calcipotriol or calcipotriol monohydrate comprising the above steps (a) - (b) and further comprising the steps of:

(f) a mixture of compounds of the general structures Va and Vb (wherein X, R) enriched with Va₁And R₂As defined in claim 2) to a mixture of VIa-enriched compounds of the general structures VIa and VIb,

x, R therein₁And R₂As defined above;

(g) separating the compound of general structure VIa from the mixture of VIa-enriched compounds of general structures VIa and VIb, wherein X, R₁And R₂As defined above;

(h) when R is₁And/or R₂When not hydrogen, removing the hydroxy protecting group R of the compound of general structure VIa₁And/or R₂To produce calcipotriol or calcipotriol monohydrate.

In yet another aspect, the present invention relates to a process for preparing 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:

(j) reducing a compound of general structure III (wherein X represents hydrogen, and wherein R represents hydrogen) with a reducing agent in an inert solvent or in the presence of a chiral auxiliary₁Representing hydrogen or a hydroxyl protecting group) to give a mixture of compounds of the general structures IVa and IVb enriched in IVa, in which X and R₁As defined above, the above-mentioned,

(k) reacting a mixture of compounds of general structures IVa and IVb enriched in IVa in the presence of a base to obtain a mixture of compounds of general structures Va and Vb enriched in Va, wherein X and R₁As defined above;

(l) Separating the compound of formula Va from a mixture of compounds of formula Va and Vb enriched with Va, wherein X and R₁As defined above;

(m) hydroxylating a compound of general structure Va (wherein X and R are₁As defined above) to give a compound of general structure Va, wherein X represents OR₂And R is₂Represents hydrogen, R₁As defined above;

(o) isomerizing a compound of general structure Va to a compound of general structure VIa, wherein X, R₁And R₂As defined above; and

(p) when R is₁When not hydrogen, removing the hydroxy protecting group R of the compound of general structure VIa₁To produce calcipotriol or calcipotriol monohydrate.

In yet another aspect, the present invention relates to a method of preparing calcipotriol or calcipotriol monohydrate comprising steps (j) to (l) of claim 4 and further comprising the steps of:

(q) protecting the C-24 hydroxyl group of a compound of the general structure Va with a hydroxyl protecting group, wherein X represents hydrogen, and wherein R represents hydrogen₁Represents hydrogen or a hydroxyl protecting group;

(R) Compounds of the general Structure Va (wherein X and R are₁As defined above) to give a C-24 hydroxy-protected compound of the general structure Va, wherein X represents OR₂And R is₂Represents hydrogen, R₁As defined above;

(s) removing the C-24 hydroxyl protecting group of the compound of general structure Va;

(t) isomerizing a compound of general structure Va to a compound of general structure VIa, wherein X, R₁And R₂As defined above; and

(u) when R is₁When not hydrogen, removing the hydroxy protecting group R of the compound of general structure VIa₁To produce calcipotriol or calcipotriol monohydrate.

In yet another aspect, the invention relates to a method of treating a cancer by reacting a compound of general structure VII or VIII

Wherein R is₁And R₂As defined above, the above-mentioned,

a process for the preparation of a compound of general structure III by reaction with sulphur dioxide,

wherein X represents hydrogen OR OR₂And wherein R is₁And R₂May be the same or different and represents hydrogen or a hydroxyl protecting group.

In yet another aspectThe invention relates to a process for the preparation of a mixture of compounds of the general structures IVa and IVb (where X stands for hydrogen OR OR) enriched in IVa in the presence of a base₂And wherein R is₁And R₂Which may be the same or different and represent hydrogen or a hydroxyl protecting group) to give a mixture of compounds of general structures Va and Vb enriched in Va (wherein X, R₁And R₂As defined above).

In yet another aspect, the invention relates to a method of making 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 any of the above methods.

In yet another aspect, the invention relates to compounds of general structure IIIa or IIIb, or mixtures thereof,

wherein X represents hydrogen OR OR₂，

And wherein R₁And R₂May be the same or different and represents hydrogen or a hydroxyl protecting group.

In yet another aspect, the present invention relates to compounds of the general structures IVaa, IVab, IVba, IVbb, IVb, or mixtures thereof,

wherein X represents hydrogen OR OR₂，

In a further aspect, the present invention relates to the use of compounds of general structures IIIa, IIb, iva, IVba, iva, IVbb as intermediates for the production of calcipotriol or calcipotriol monohydrate.

Definition of

As used herein, "hydroxyl protecting group" refers to any group that is capable of forming a derivative that is stable to the intended reaction, wherein the hydroxyl protecting group can be selectively removed by an agent that does not attack the regenerated hydroxyl group. The derivatives can be obtained by selective reaction of a hydroxyl protecting reagent with hydroxyl. Silyl derivatives, such as tert-butyldimethylsilyl, which form silyl ethers, are examples of hydroxyl protecting groups. Chlorosilanes, such as tert-butyldimethylchlorosilane (TBSCl), trimethylchlorosilane, triethylchlorosilane, diphenylmethylchlorosilane, triisopropylchlorosilane and tert-butyldiphenylchlorosilane are examples of the hydroxyl protecting agent. Hydrogen fluoride, for example aqueous HF in acetonitrile, or tetra (n-butylammonium) fluoride are examples of reagents that can remove silane groups. Other hydroxyl protecting groups include ethers (e.g., Tetrahydropyran (THP) ether), including alkoxyalkyl ethers (acetals) (e.g., methoxymethyl (MOM) ether) or esters (e.g., chloroacetate, pivalate, acetate, or benzoate). Non-limiting examples of all hydroxy Protecting Groups and methods of protection and deprotection included within the scope of the present application are found in "protective Groups in Organic Synthesis", 3 rd edition, ed.t.w.Greene and p.g.m.Wuts, eds John Wiley 1999, and "protective Groups", 1 st edition, p.j.Kocienski, g.Thieme 2000.

As used herein, "alkyl" refers to a straight or branched chain alkyl group, which may be cyclic or acyclic, having from one to twenty carbon atoms, preferably from one to seven carbon atoms. Methyl, ethyl, n-propyl, isopropyl, pentyl, hexyl and tert-butyldimethyl are non-limiting examples of alkyl groups.

As used herein, "reducing agent" refers to any agent that can reduce (including enantioselective or diastereoselective) the C-24 keto group of a compound of general structure III to give a compound of general structure IV. In one embodiment, the reducing agent may be reduced without the need for a chiral auxiliaryThe C-24 keto group of the compound of general structure III to give a mixture of compounds of general structure IV, wherein the mixture is enriched in the desired epimer IVa (preferably to give the 24-S isomer). In another embodiment, the reducing agent can reduce the C-24 keto group of the compound of general structure III in the presence of a chiral auxiliary to give a mixture of compounds of general structure IV, wherein the mixture is enriched in the desired epimer IVa (preferably to give the 24-S isomer). The reducing agent may be chiral or achiral. Examples of reducing agents include, but are not limited to, borane reducing agents, metal hydrides such as lithium aluminum hydride, sodium borohydride, or AlH₃(optionally in lanthanide salts (e.g., LaCl)₃、CeBr₃、CeCl₃) In the presence of) or NaBH₃(OAc)、Zn(BH₄)₂And Et₃SiH. Other reducing agents include, but are not limited to, hydrogen in the presence of a catalyst such as platinum or ruthenium, sodium in ethanol, isopropanol, and aluminum isopropoxide, and zinc powder in water or alcohol.

As used herein, "borane reducing agent" includes borane or any borane derivative, such as a complex of borane with an amine or ether. Non-limiting examples of borane reducing agents include N, N-diethylaniline-borane, borane-tetrahydrofuran, 9-borabicyclononane (9-BBN), or borane dimethylsulfide.

As used herein, "chiral auxiliary" refers to any chiral compound or optically active catalyst, e.g., a compound containing an asymmetrically substituted carbon atom or an axially chiral compound, or a mixture of chiral compounds and/or optically active catalysts, which can provide improved yields of compounds of general structure IVa relative to their epimeric yields (increased molar ratio IVa: IVb) during reduction of compounds of general structure III with said reducing agent. Thus, the chiral auxiliary is any compound that is capable of increasing stereoselectivity in the reduction of the compound of general structure III compared to IVa production or stereoselectivity in the absence or involvement of the chiral auxiliary. Non-limiting examples of chiral auxiliary agents include chiral 1, 2-aminoalcohols, such as chiral cis-1-amino-2-indanol derivatives, such as (1S, 2R) - (-) -cis-1-amino-2-indanol, or cis-1-amino-1, 2, 3, 4-tetrahydronaphthalen-2-ol, such as (1S, 2R) -cis-1-amino-1, 2, 3, 4-tetrahydronaphthalen-2-ol. Further examples are binaphthyl derivatives, such as (R) -acetic acid (R) -2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl-ruthenium, 2, 2 '-dihydroxy-1, 1' -binaphthyl derivatives. Other examples include, but are not limited to, (R) - (+) - α, α -diphenyl-2-pyrrolidinemethanol, (R) - (+) -2-amino-4-methyl-1, 1-diphenyl-1-pentanol, (R) - (-) -2-amino-3-methyl-1, 1-diphenyl-1-butanol, (R) - (+) -2-amino-1, 1, 3-triphenyl-1-propanol and (1R, 2S) - (-) -2-amino-1, 2-diphenylethanol.

"inert solvent" as used herein refers to any organic solvent or mixture of solvents that is compatible with the reducing agent under the reaction conditions used. The choice of the solvent depends on the particular reducing agent used. Non-limiting examples of inert solvents include hydrocarbons such as toluene and ethers such as t-butyl methyl ether or tetrahydrofuran.

By a mixture of compounds of general structure IVa and IVb enriched in IVa is meant a mixture optionally comprising other compounds or solvents, having a molar ratio IVa/IVb (diastereomer ratio) of 1 (50: 50) or more than 1, such that the mixture contains at least 50% of the compounds of general structure IVa (containing 50% or less of the compounds of general structure IVb).

By a mixture of compounds of general structure Va and Vb enriched in Va is meant a mixture optionally comprising other compounds or solvents, having a molar ratio (diastereomer ratio) of Va/Vb of 1 (50: 50) or greater than 1, such that the mixture contains at least 50% of compounds of general structure Va (containing 50% or less of compounds of general structure Vb).

By a VIa-enriched mixture of compounds of general structure VIa and VIb is meant a mixture optionally comprising other compounds or solvents, having a VIa/VIb molar ratio (diastereomer ratio) of 1 (50: 50) or more than 1, such that the mixture contains at least 50% of compounds of general structure VIa (containing 50% or less of compounds of general structure VIb).

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

Detailed description of the preferred embodiments

In the presently preferred embodiment of the invention X represents OR₂. In a presently preferred embodiment of the invention R₁And/or R₂Represents alkylsilyl, e.g. tert-butyldimethylsilyl, most preferably R₁And R₂The same is true.

In another embodiment of the invention R₁And R₂Represents hydrogen.

In a currently preferred embodiment of the invention the reducing agent is a borane reducing agent, such as N, N-diethylaniline-borane, borane-tetrahydrofuran or borane dimethylsulfide.

In a currently preferred embodiment of the invention, the reduction step is carried out with a chiral reducing agent or in the presence of a chiral auxiliary.

In a currently preferred embodiment of the invention, the chiral auxiliary is a chiral 1, 2-amino-alcohol, such as a chiral cis-1-amino-2-indanol derivative, such as (1S, 2R) - (-) -cis-1-amino-2-indanol.

In a currently preferred embodiment of the invention, the reduction step is carried out at a temperature of between 10 and 20 deg.C, in particular between 15 and 20 deg.C.

In another embodiment of the invention, the molar ratio of the mixture of compounds of general structure IVa and IVb enriched in IVa (diastereomer ratio IVa/IVb) is greater than 55: 45, such as 56: 44, such as 57: 43, such as 59: 41, such as 60: 40, such as 63: 37, such as 65: 35, such as 68: 32, such as 70: 30, such as 72: 28, such as 73: 27, such as 74: 26, such as 75: 25, such as 76: 24, such as 77: 23, such as 78: 22, such as 79: 21, such as 80: 20.

In another embodiment of the invention, the molar ratio of the mixture of compounds Va and Vb of the general structure enriched in Va (diastereomer ratio Va/Vb) is greater than 55: 45, such as 56: 44, such as 57: 43, such as 59: 41, such as 60: 40, such as 63: 37, such as 65: 35, such as 68: 32, such as 70: 30, such as 72: 28, such as 73: 27, such as 74: 26, such as 75: 25, such as 76: 24, such as 77: 23, such as 78: 22, such as 79: 21, such as 80: 20.

In another embodiment of the invention the molar ratio of the mixture of VIa-enriched compounds of general structure VIa and VIb (diastereomer ratio VIa/VIb) is greater than 55: 45, such as 56: 44, such as 57: 43, such as 59: 41, such as 60: 40, such as 63: 37, such as 65: 35, such as 68: 32, such as 70: 30, such as 72: 28, such as 73: 27, such as 74: 26, such as 75: 25, such as 76: 24, such as 77: 23, such as 78: 22, such as 79: 21, such as 80: 20.

In one embodiment of the invention, the compound of general structure Va is isolated, for example by chromatography, from a mixture of compounds of general structure Va and Vb enriched in Va, wherein X, R₁And R₂As defined above in step (c).

In another embodiment of the invention, the compound of general structure VIa is separated chromatographically from a VIa-enriched mixture of compounds of general structure VIa and VIb, wherein X, R₁And R₂As defined above in step (g).

Synthesis method

For example, compounds of general structure III can be synthesized by treating compounds of general structure VII or VIII with sulfur dioxide via a Diels-Alder reaction. The sulphur dioxide used may be liquid, gaseous or dissolved in a suitable solvent. Suitable solvents for the Diels-Alder reaction are all solvents which are compatible with the reaction conditions, for example alkanes such as hexane or heptane, hydrocarbons such as xylene, toluene, ethers such as diethyl ether or methyl tert-butyl ether (MTBE) ether, acetates such as ethyl acetate or 2-propyl acetate, halogenated solvents such as dichloromethane, or mixtures of the stated solvents. In a preferred embodiment, the solvent is toluene. In another preferred embodiment, the solvent is a mixture of a water-immiscible solvent and water, for example a mixture of toluene and water. The reaction can also be carried out in pure sulfur dioxide without solvent. Suitable reaction temperatures for the reaction process are from-50 ℃ to 60 ℃, such as from-30 ℃ to 50 ℃, for example from-15 ℃ to 40 ℃, such as from-5 ℃ to 30 ℃, for example from 0 ℃ to 35 ℃, such as from 5 ℃ to 30 ℃, most preferably from 10 ℃ to 25 ℃, such as from 15 ℃ to 20 ℃. In one embodiment, the sulphur dioxide is used in excess (molar ratio), for example in an amount of from 5 to 100 moles, for example in an amount of from 7 to 30 moles, for example in an amount of from 10 to 15 moles. Any excess unreacted sulphur dioxide may be removed from the reaction mixture, for example by washing with an aqueous base (e.g. aqueous sodium hydroxide) or by distilling off sulphur dioxide (optionally with solvent, optionally under reduced pressure). The compounds of general structure III are generally obtained as a mixture of their epimers IIIa and IIIb.

The molar ratio IIIa/IIIb of the epimeric mixture obtained in the Diels-Alder reaction depends on the group X, R₁And R₂And the reaction conditions used. The present invention includes mixtures of all possible compositions (molar ratio IIIa/IIIb), for example 1: 99, for example 2: 98, for example 3: 97, for example 4: 96, for example 5: 95, for example 10: 90, for example 85: 15, for example 80: 20, for example 75: 25, for example 30: 70, for example 35: 65, for example 40: 60, for example 45: 55, for example 50: 50, for example 55: 45, for example 60: 40, for example 65: 35, for example 70: 30, for example 75: 25, such as 80: 20, such as 85: 10, such as 90: 10, such as 95: 5, such as 96: 4, such as 97: 3, such as 98: 2, such as 99: 1,

formula III includes mixtures of all possible compositions (molar ratios IIIa/IIIb) as described above. In one embodiment of the invention, compounds IIIa and IIIb are used in the form of a mixture, as shown in formula III in the reduction step below. The mixture of IIIa and IIIb can optionally be purified or separated, for example by chromatography or crystallization. In another embodiment, compound IIIa is used in the reduction step below. In yet another embodiment, compound IIIb is used in the following reduction step.

For example, compounds of general structure VII may be synthesized according to methods such as those disclosed in M.J. Calverley, Tetrahedron, Vol.43, No. 20, pp.4609-4619, 1987 or in WO 87/00834 and references cited therein. For example, compound VII (wherein X is OR) described in the reference₂And R is₁And R₂All t-butyldimethylsilyl groups) can be deprotected with aqueous hydrofluoric acid in acetonitrile to obtain a compound in which X is OR₂And R is₁Or R₂Mixtures of compounds which are hydrogen, OR to obtain compounds in which X is OR₂And R is₁And R₂All are hydrogen compounds. As described herein, the mixture of compounds can be isolated, for example, by chromatography or crystallization. By reacting a compound of the general structure VII (wherein R is₁And/or R₂Hydrogen) with suitable protecting agents, new radicals R being introduced₁And/or R₂. Depending on the stoichiometry of the protecting reagent used and the reaction conditions, mixtures of unprotected, mono-protected and di-protected compounds are obtained. Then any intermediate of the mixture (where X is OR)₂And R is₁Or R₂One being hydrogen) can be isolated by chromatography and reacted with a suitable protecting agent different from the protecting agent used for the first time to give compounds in which X is OR₂And R is₁Is different from R₂A compound of general structure VII.

For example, compounds of general structure VII, wherein X is hydrogen and R is a general synthetic method, can be prepared starting from compounds 7a and/or 7b as described in m.j.calverley, Tetrahedron, volume 43, phase 20, page 4610, 1987 and following similar procedures and general synthetic methods as described above and in the references cited above₁Is hydrogen or a hydroxyl protecting group.

The reduction process of the present invention can be carried out, for example, by reacting a prochiral ketone of the general structure III with a chiral borane reducing agent or with a borane reducing agent in the presence of a chiral auxiliary. This process leads to an enantioselective/diastereoselective reduction of the prochiral ketone, so that the formation of one of the two possible epimers IVa or IVb predominates over the corresponding epimer. The degree of enantioselectivity/diastereoselectivity depends on the reducing agent, the chiral auxiliary and the reaction conditions used.

The reduction of the compound of general structure III is typically carried out at a temperature interval between-80 ℃ and 70 ℃, such as-40 ℃ to 60 ℃, such as-15 ℃ to 50 ℃, such as-5 ℃ to 40 ℃, for example 0 ℃ to 5 ℃ or 5 ℃ to 35 ℃. In one embodiment, the temperature interval is between 10 ℃ and 30 ℃, such as 15 ℃ to 25 ℃, for example 15 ℃ to 20 ℃. The optimum temperature depends on the particular reaction conditions and reagents used. In one embodiment of the invention, the reaction mixture is cooled to 0-10 ℃ immediately after the reaction is complete to avoid the formation of by-products. If N, N-diethylaniline is used as the reducing agent, the N, N-diethylaniline formed can be easily removed from the reaction mixture by extraction with aqueous hydrochloric acid. The extraction is preferably carried out with one molar equivalent of 1M hydrochloric acid with respect to the extracted base.

For example, a reducing agent, optionally dissolved in or mixed with an inert solvent, is added to a compound of general structure III, optionally dissolved in or mixed with an inert solvent, under an inert atmosphere such as nitrogen. Alternatively, the compound of general structure III, optionally dissolved in or mixed with an inert solvent, may be added to a reducing agent, optionally dissolved in or mixed with an inert solvent (in reverse order).

In one embodiment of the invention, the reducing agent is used in an equimolar or molar excess amount to the compound of general structure III. In one embodiment of the invention, the molar ratio of reducing agent/compound of general structure III is from 1.0 to 5.0. In a presently preferred embodiment, the molar ratio of reducing agent/compound of general structure III is from 1.8 to 3.0, such as from 2.3 to 2.9, such as from 2.5 to 2.7.

The chiral auxiliary agent may react with the reducing agent in situ prior to the reduction reaction to form the chiral reducing agent, or the chiral auxiliary agent may act, for example, as a ligand in a complex formed with the reducing agent to give the chiral reducing agent. The invention comprises the use of said chiral reducing agent or chiral ligand-reducing agent complex, which is prepared and isolated, respectively, prior to reduction of the compound of general structure III.

Thus, the term "reducing agent in the presence of a chiral auxiliary" includes any chiral reducing agent. For example, the chiral auxiliary may be reacted in situ with the borane reducing agent to form the chiral borane reducing agent prior to the reduction reaction, or the chiral auxiliary may act as a chiral ligand in the borane complex. Examples of such chiral borane reducing agents are chiral oxaborolidines or oxaborolidines, such as chiral oxazaborolidine reagents derived from (1R, 2S) -cis-1-amino-2-indanol, (1S, 2R) -cis-1-amino-2-indanol, (S) -prolinol, (R) -prolinol or B- (3-pinyl) -9-borabicyclo [3.3.2] nonane (alpine-borane), or for example 5, 5-diphenyl-2-methyl-3, 4-oxopropylene-1, 3, 2-oxazaborolidine, (S) -2-methyl-CBS-oxazaborolidine, (R) -2-methyl-CBS-oxazaborolidine. The present invention thus includes the use of such chiral reducing agents (e.g., chiral borane reducing agents) or chiral ligand-reducing agent complexes (e.g., chiral ligand-borane complexes) prepared and isolated prior to reduction of the compound of general structure III.

Another example of a complex of a chiral ligand with a reducing agent is LiAlH₄And 2, 2 '-dihydroxy-1, 1' -binaphthyl.

The molar ratio of reducing agent/chiral auxiliary is generally in the range of from 0.1 to 20.0, such as from 0.4 to 10.0, such as from 0.3 to 5.0, such as from 0.5 to 4.5, such as from 1.0 to 4.0, such as from 1.9 to 3.1, such as from 2.1 to 2.9, such as from 2.3 to 2.7, such as 10.8, 5.4, 2.6, 2.5 or 1.6.

The chiral auxiliary may be present in catalytic amounts, for example in a substoichiometric or equimolar or molar excess relative to the compound of the general structure III or the reducing agent. For example, the ratio chiral auxiliary/compound III may be from 0.25 to 2.5, such as from 0.5 to 2.0, such as from 0.8 to 1.3, such as from 0.9 to 1.2, such as from 1.0 to 1.1.

The selectivity of the chiral auxiliary to a particular enantiomer will determine the stereoselective positioning of the C-24 hydroxyl group in the compounds of general structure IV. Preference is given to chiral auxiliaries which predominantly give the S-configuration in the C-24 position.

The borane catalyzed reactions are reviewed by Deloux and Srebnik [ chem.Rev.93, 763, 1993 ]. Examples of effective catalysts based on chirally modified boranes can be found, for example, in [ a.hirao, j.chem.soc.chem.commun.315, 1981, e.j.corey, j.am.chem.soc.109, 7925, 1987 ].

Examples of the synthesis and/or use of, for example, 1, 2-and 1, 3-aminoalcohols in stereoselective reductions using boranes are found, for example, in [ E.Didier et al, Tetrahedron 47, 4941-4958, 1991, C.H.Senayake et al, Tetrahedron Letters, 36(42), 7615-18, 1995, EP0698028, EP 0640089, EP 0305180, WO 93/23408, WO 94/26751 ]. The Synthesis and/or use of chiral cis-1-amino-2-indanol derivatives in borane reduction reactions is for example found in [ C.H. Senana yake, Aldrich Acta, 31(1), 1-15, 1998, A.K. Ghosh et al, Synthesis, 937-.

The process for the preparation of calcipotriol 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 invention includes all such modifications.

The process for the preparation of calcipotriol as described herein further comprises the hydroxy protecting group R of the compounds or intermediates therein₁And/or R₂(wherein R is₁And/or R₂Not hydrogen) are removed at any stage of the reaction sequence. Wherein R is₁And/or R₂Compounds or intermediates that are hydrogen may be protected at any stage of the reaction sequence with protecting reagents, including protecting reagents that produce protecting groups different from those that are removed early in the reaction sequence.

The compounds and intermediates of the present invention may contain asymmetrically substituted (chiral) carbon atoms and carbon-carbon double bonds leading to isomeric forms, such as enantiomers, diastereomers and geometric isomers.

Epimers refer to diastereomers having the opposite configuration (R or S) only at one of the tetrahedral stereocenters of a molecule (e.g., a vitamin D analog to which the present invention relates) having multiple stereocenters that produce stereogenic centers.

Thus, designating, for example, C-24 as the epimeric center of a pair of enantiomers means that the configuration at the other stereosymmetric center of the pair of enantiomers is the same.

The present invention relates to all isomeric forms, e.g., epimers, whether in pure form or as mixtures thereof.

Specifying a particular conformation or configuration in the molecular formula or name of a compound or intermediate of the invention indicates that the particular conformation or configuration is a preferred embodiment of the invention. Specifying a particular conformation or configuration in the molecular formula or name of a compound or intermediate of the present invention also includes any other isomer (in pure form or in the form of a mixture thereof) than specifically specified as another embodiment of the present invention.

The absence of a particular conformation or configuration in the molecular formula or name of the compounds or intermediates of the invention indicates that a mixture of these particular conformations or configurations is a preferred embodiment of the invention. For example, the compound of formula III is a mixture of epimers of formulae IIIa and IIIb.

Where no particular conformation or configuration is specified in the molecular formula or name or number of a compound or intermediate of the invention, any particular isomer (although not specifically designated in pure form) will be included as a further embodiment of the invention.

For example, compounds of formula IVa include the following two epimers IVaa and IVab.

The meaning of the compounds of the formula III therefore includes the epimers IIIa and IIIb.

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

The separation, resolution 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, resolution and purification methods can be used sequentially or in combination.

Column chromatography suitable for isolating vitamin D analogues of the invention is well known to those skilled in the art of pharmaceutical chemistry. This technique uses a column filled with a stationary phase (e.g., silica, such as pretreated silica) on which the sample to be separated is loaded. The sample is then eluted with a suitable eluent. The elution may be an isocratic (isocratic) elution or a so-called solvent-programmed (gradient) elution, wherein the composition of the eluent is varied regularly (e.g. linearly) or irregularly (e.g. stepwise over time). Pretreated silica gels well known to those skilled in the art of chromatography are suitable stationary phases. An example of an elution procedure to achieve the desired separation is elution with 5% (v/v) ethyl acetate in hexane or heptane followed by elution with pure ethyl acetate. Other suitable eluents may be derived by the skilled person by routine development, for example, mixtures of heptane and ethyl acetate with appropriate polarity may be used.

For the chromatography step, any combination of stationary phase (packing) and eluent capable of resolving a mixture of C-24 epimers can be used. Such combinations can be readily determined by the skilled person by routine experimentation. An example of a preferred stationary phase is silica, such as treated silica.

A mixture of compounds of general structures IVa and IVb enriched in IVa in the presence of a base produces a mixture of compounds of general structures Va and Vb enriched in Va (wherein X, R₁And R₂As defined above) can be carried out in all solvents compatible with the reaction conditions, for example alkanes such as hexane or heptane, hydrocarbons such as xylene, toluene, ethers such as diethyl ether or methyl tert-butyl ether (MTBE), acetates such as ethyl acetate or 2-propyl acetate, halogenated solvents such as dichloromethane, water or mixtures of said solvents.

Such reverse Diels-Alder reaction methods 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.

For reversing Dielsuitable bases in the s-Alder reaction include, but are not limited to, NaHCO₃、KHCO₃、Na₂CO₃Or K₂CO₃. In one embodiment of the invention, the base is NaHCO₃The aqueous solution and/or the retro Diels-Alder reaction is carried out at above 60 ℃, such as above 70 ℃, such as between 70 ℃ and 120 ℃, such as between 74 ℃ and 79 ℃, such as between 72 ℃ and 78 ℃.

In one embodiment of the invention, the temperature range for extraction and phase separation during the post-reaction treatment after completion of the retro Diels-Alder reaction is between about 30 ℃ and 40 ℃.

The compounds of the general structure VIII can be obtained by isomerization of the compounds of the general structure VII.

Methods for isomerizing compounds of formula Va and/or Vb to VIa and/or VIb, or VII to VIII, are well known to those skilled in the art of vitamin D synthesis. The reaction conditions can be found, for example, in M.J. Calverley, Tetrahedron, Vol.43, No. 20, p.4609-4619, 1987 or WO 87/00834 and the references cited therein. In a preferred embodiment of the invention, the isomerization is a photoisomerization, for example with Ultraviolet (UV) light in the presence of a triplet sensitizer (e.g. anthracene or 9-acetyl anthracene).

For example, under the conditions developed by Hesse, e.g. with SeO₂And N-methylmorpholine N-oxide in refluxing methanol and/or dichloromethane [ d.r.andrews et al, j.org.chem., 1986, 51, 1637]OR hydroxylating a compound of formula III, IV, V, VI OR VII wherein X ═ hydrogen by selenite mediated allylic hydroxylation as described in M.J. Calverley, Tetrahedron, Vol.43, No. 20, pp.4609-4619, 1987 OR WO 87/00834, with a suitable hydroxylating agent to give a compound of formula III, IV, V, VI OR VII wherein X ═ hydroxy (X ═ OR)₂And R is₂H) of formula III, IV, V, VI or VII. The hydroxyl groups of the starting materials may be modified by a method such as that described aboveThe process is protected with a suitable protecting group such as defined above, for example to avoid undesired oxidation of the hydroxyl group.

Hydrated calcipotriol can be obtained by crystallizing calcipotriol from an aqueous solvent, for example, by the method described in WO 94/15912.

Examples

Summary:

unless otherwise noted, all chemicals were from commercial sources. All melting points are uncorrected. Unless otherwise stated, for¹H Nuclear Magnetic Resonance (NMR) Spectroscopy (300MHz) and¹³for C NMR (75.6MHz), the chemical shift value (δ) (in ppm) of the deuterated chloroform solution is relative to tetramethylsilane (δ ═ 0.00) or chloroform (δ ═ 7.26) or deuterated chloroform (for the internal standard, for¹³C NMR δ 76.81) standard. Unless a range is given, the value of a defined (doublet (d), triplet (t), quartet (q)) or undefined (m) multiplet is the value near the midpoint. All organic solvents used belong to the technical class. Chromatography is performed on silica gel, optionally using flash chromatography techniques. Silica gel coated TLC plates from Merck KGaA. The silica used for chromatography is preferably from Merck KGaA Germany: LiChroprepSi60(15-25 μm). Unless otherwise noted, ethyl acetate, dichloromethane, hexane, n-hexane, heptane or an appropriate mixture of ethyl acetate, dichloromethane, methanol and petroleum ether (40-60), hexane or heptane is used as eluent. All reactions may conveniently be carried out under an inert atmosphere, for example under a nitrogen atmosphere.

A compound of the general structure III

Example 1:

III：X＝OR₂，R₁、R₂tert-butyldimethylsilyl radical

1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna (secopregna) -5(E), 7(E), 10(19) -triene SO₂Adducts

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, p.20, p.4609-4619, 1987) (20.0g) was dissolved in toluene (210ml) at 20 ℃ and water (40ml) and SO were added with stirring₂(20 ml). After the reaction has been completed (usually after 2-2.5 hours) as judged by HPLC { column LiChrosorb Si 605 μm from Merck, 250X 4mm, flow rate of 2ml/min, detection and mass detection at 270nm, hexane/ethyl acetate 9: 1 (volume ratio) }, a mixture of sodium hydroxide (27.7%, 60ml) and water (80ml) is added at 10-18 ℃ until the reaction mixture has a pH of 6. The toluene phase is separated and the solvent is removed under vacuum without heating (preferably below 30 ℃) to give the two epimeric SO as a solid mixture₂Adducts IIIa and IIIb, detected by TLC, contain predominantly IIIa. Two epimeric SO' s₂The adducts IIIa and IIIb can be separated by chromatography. The crystalline state IIIa can be obtained by triturating the solid mixture with methanol.¹H NMR(CDCl₃)IIIa/X＝OR₂，R₁、R₂T-butyldimethylsilyl group is 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.

Preparation example 1:

VII：X＝OR₂，R₁、R₂hydrogen ═ hydrogen

1(S), 3(R) -dihydroxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene

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 obtained according to the method described in M.J. Calverley, Tetrahedron, Vol.43, No. 20, p.4614-4619, 1987 was dissolved in acetonitrile. Aqueous hydrofluoric acid (40%) was added and the mixture was stirred at room temperature for about 1 hour. The progress of the reaction can be conveniently checked by TLC using ethyl acetate as eluent. Ethyl acetate was added to the reaction mixture and the mixture was washed with aqueous sodium hydroxide solution. The organic phase is MgSO₄Dried and concentrated. The crystals formed (white needles) were filtered off, washed with ethyl acetate and dried in vacuo to give the title compound VII (X ═ OR)₂，R₁、R₂Hydrogen).¹H NMR(CDCl₃)VII/X＝OR₂，R₁、R₂Hydrogen is 6.77(dd, 1H), 6.57(d, 1H), 6.15(d, 1H), 5.88(dd, 1H), 5.13(dd, 1H), 4.98(s, 1H), 4.50(m, 1H), 4.23(m, 1H), 2.86(m, 2H), 2.29(m, 2H), 2.14-1.20(m, 16H), 1.14(d, 3H), 1.08(m, 2H), 0.89(m, 2H), 0.61(s, 3H) ppm.

Example 2

III：X＝OR₂，R₁、R₂Hydrogen ═ hydrogen

1(S), 3(R) -dihydroxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂-an adduct.

The procedure was the same as in example 1, except that the starting material was 1(S), 3(R) -dihydroxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene prepared in preparation example 1.¹H NMR(CDCl₃)III/X＝OR₂，R₁、R₂Hydrogen δ 6.80(dd, 1H), 6.15(d, 1H), 4.75(m, 2H), 4.5-3.9(m,4H)、3.70(d，1H)、2.60(m，1H)、2.5-0.8(m，25H)、0.68(s，3H)ppm；¹³C NMR(CDCl₃)III/X＝OR₂，R₁、R₂hydrogen δ 201.0, 152.1, 151.0, 133.7, 129.2, 128.3, 108.8, 67.3, 65.1, 63.6, 56.1, 55.9, 55.5, 46.5, 40.1, 39.9, 33.9, 29.8, 27.4, 23.9, 22.1, 19.5, 18.9, 12.2, 11.2 ppm.

Preparation example 2:

VII：X＝OR₂，R₁hydrogen, R₂Tert-butyldimethylsilyl radical

1(S) -tert-butyldimethylsilyl-3 (R) -hydroxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene.

The same deprotection conditions as used in preparation 1 were used to deprotect 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 moiety to give a mixture of unreacted starting material, two partially deprotected intermediates and the compound of preparation 1. Purification by chromatography gave the pure title compound.

Discovery¹H NMR was consistent with the structure.¹H NMR(CDCl₃)VII/X＝OR₂，R₁Hydrogen, R₂T-butyldimethylsilyl group δ is 6.75(dd, 1H), 6.50(d, 1H), 6.14(d, 1H), 5.84(d, 1H), 5.00(s, 1H), 4.92(s, 1H), 4.47(t, 1H), 4.22(m, 1H), 2.85(dd, 1H), 2.62(dd, 1H), 2.43(dd, 1H), 2.29(m, 1H), 2.15-1.15(m, 15H), 1.11(d, 3H), 1.06(m, 2H), 0.87(s, 9H), 0.86(m, 2H), 0.59(s, 3H), 0.06(s, 3H), 0.04(s, 3H) ppm.

Example 3:

III：X＝OR₂，R₁hydrogen, R₂Tert-butyldimethylsilyl radical

1(S) -tert-butylDimethylsilyl-3 (R) -hydroxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂An adduct.

The procedure was as in example 1 except that the starting material was 1(S) -tert-butyldimethylsilyl-3 (R) -hydroxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene prepared in preparation example 2.¹³C NMR(CDCl₃)III/X＝OR₂，R₁Hydrogen, R₂T-butyldimethylsilyl δ of 200.3, 151.5, 150.4, 132.0, 129.5, 128.0, 108.5, 66.8, 65.5, 63.8, 56.1, 55.9, 55.2, 46.2, 39.8, 33.6, 29.5, 27.2, 25.4, 23.7, 21.8, 19.2, 18.5, 17.7, 11.8, 10.7, -4.7, -5.2 ppm;¹H NMR(CDCl₃)IIIb/X＝OR₂，R₁hydrogen, R₂T-butyldimethylsilyl δ is 6.75(dd, 1H), 6.14(d, 1H), 4.80(d, 1H), 4.65(d, 1H), 4.43(m, 1H), 4.25(m, 1H), 3.92(d, 1H), 3.63(dd, 1H), 2.60(d, 1H), 2.5-1.2(m, 18H), 1.12(d, 3H), 1.06(m, 2H), 0.88(s, 9H), 0.87(m, 2H), 0.59(s, 3H), 0.09(s, 3H), 0.07(s, 3H) ppm.

Preparation example 3:

VII：X＝OR₂，R₁＝COCMe₃，R₂tert-butyldimethylsilyl radical

1(S) -tert-butyldimethylsilyl-3 (R) -pivaloyloxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene.

1(S) -tert-butyldimethylsilyl-3 (R) -hydroxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene from preparation 2 was reacted with trimethylacetyl chloride in the presence of triethylamine in dichloromethane.

The resulting crude product can be purified by chromatography to give the pure title compound.

Preparation example 4:

VII：X＝OR₂，R₁＝COCMe₃，R₂hydrogen ═ hydrogen

1(S) -hydroxy-3 (R) -trimethylacetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene.

1(S) -tert-butyldimethylsilyl-3 (R) -pivaloyloxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene was deprotected using the same deprotection conditions as used in preparation example 1. The resulting crude product can be purified by chromatography to give the pure title compound.

Example 4:

III：X＝OR₂，R₁＝COCMe₃，R₂hydrogen ═ hydrogen

1(S) -hydroxy-3 (R) -trimethylacetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂An adduct.

The procedure was as in example 1 except that the starting material was 1(S) -hydroxy-3 (R) -trimethylacetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene prepared in preparation example 4.¹³C NMR(CDCl₃)IIIa/X＝OR₂，R₁＝COCMe₃，R₂Hydrogen δ is 200.4, 177.6, 151.6, 150.9, 132.8, 129.3, 128.1, 108.8, 66.9, 66.3, 64.6, 55.8, 55.5, 55.3, 46.3, 39.9, 38.5, 36.3, 30.2, 29.6, 27.2, 26.9, 23.7, 21.8, 19.3, 18.6, 11.9, 10.8 ppm.

Example 5:

III：X＝OR₂，R₁＝COCMe₃，R₂tert-butyldimethylsilyl radical

1(S) -tert-butyldimethylsilyl-3 (R) -pivaloyloxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂An adduct.

The procedure is as in example 1, except that the starting material is, for example, 1(S) -tert-butyldimethylsilyl-3 (R) -trimethylacetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene, which is obtainable from preparation example 3.

Preparation example 5:

VII：X＝OR₂，R₁＝COMe，R₂hydrogen ═ hydrogen

1(S) -hydroxy-3 (R) -acetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene.

1(S), 3(R) -dihydroxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (VII: X ═ OR) from preparation example 1 was added₂，R₁、R₂Hydrogen) is reacted with one equivalent of acetyl chloride in the presence of triethylamine. The mixture of products can be purified by silica chromatography to give the pure title compound.

Example 6:

III：X＝OR₂，R₁＝COMe，R₂hydrogen ═ hydrogen

1(S) -hydroxy-3 (R) -acetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂An adduct.

The procedure was as in example 1, except that the starting material was 1(S) -hydroxy-3 (R) -acetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene (VII: X ═ OR) prepared in preparation example 5₂，R₁＝COMe，R₂Hydrogen).¹³C NMR(CDCl₃)IIIa/X＝OR₂，R₁＝COMe，R₂Hydrogen δ is 200.5, 170.3, 151.6, 150.9, 132.8, 129.2, 128.1, 108.3, 66.8, 66.4, 64.6, 55.9, 55.7, 55.3, 46.3, 39.9, 36.4, 30.4, 29.6, 27.2, 23.7, 21.8, 21.0, 19.3, 18.6, 11.9, 10.8.

Example 7:

III：X＝OR₂，R₁＝COMe，R₂tert-butyldimethylsilyl radical

1(S) -tert-butyldimethylsilyl-3 (R) -acetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂An adduct.

The procedure is as in example 1 except that the starting material is 1(S) -tert-butyldimethylsilyl-3 (R) -acetoxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene.¹H NMR(CDCl₃)IIIa/X＝OR₂，R₁＝COMe，R₂T-butyldimethylsilyl group δ was 6.75(dd, 1H), 6.16(d, 1H), 5.20(m, 1H), 4.71(s, 2H), 4.33(s, 1H), 3.95(d, 1H), 3.60(d, 1H), 2.61(m, 1H), 2.31(m, 2H), 2.15-1.2(m, 15H), 2.03(s, 3H), 1.11(d, 3H), 1.07(m, 2H), 0.89(m, 2H), 0.88(s, 9H), 0.68(s, 3H), 0.08(s, 3H), 0.07(s, 3H) ppm.

Example 8:

III: x is hydrogen, R₁Tert-butyldimethylsilyl radical

3(R) -tert-butyldimethylsilyloxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂An adduct.

Starting materials VII, X ═ hydrogen, R₁Tert-butyldimethylsilyl (prepared according to the method described in M.J. Calverley, Tetrahedron, Vol.43, No. 20, p.4609-4619, 1987) (38.5g)Dissolved in toluene (550ml) at 20 ℃ and then water (105ml) and SO were added with stirring₂(53 ml). After the reaction has been completed (usually after 2-2.5 hours) as judged by HPLC { column LiChrosorb Si 605 μm from Merck, 250X 4mm, flow rate of 2ml/min, detection and mass detection at 270nm, hexane/ethyl acetate 9: 1 (volume ratio) }, a mixture of sodium hydroxide (27.7%, 150ml) and water (480ml) is added at 10-18 ℃ until the pH of the reaction mixture is 6. The toluene phase is separated and the solvent is removed under vacuum without heating (preferably below 30 ℃) to give the two epimeric SO as a solid mixture₂Adducts IIIa and IIIb (X ═ hydrogen, R)₁Tert-butyldimethylsilyl group), which contains mainly IIIa, as detected by TLC. Two epimeric SO' s₂The adduct may be separated by chromatography. The crystalline state IIIa can be obtained by triturating the solid mixture with methanol.¹³CNMR(CDCl₃) (III: x is hydrogen, R₁Tert-butyldimethylsilyl, mixture of isomers IIIa and IIIb): 200.3, 151.6, 151.4, 149.8, 149.2, 130.5, 130.1, 128.3, 128.1, 126.6, 126.3, 110.5, 110.0, 67.4, 66.7, 66.6, 66.3, 58.0, 57.9, 55.8, 55.6, 55.3, 55.2, 46.3, 45.5, 39.9, 39.7, 34.4, 34.1, 33.9, 31.4, 30.8, 30.5, 29.6, 29.1, 27.3, 27.1, 26.7, 25.6, 25.1, 24.4, 24.1, 23.6, 23.2, 22.4, 21.9, 19.4, 19.3, 18.6, 18.4, 17.9, 13.9, 12.2, 11.9, -10.5, 0.

A compound of general structure IV

Example 9:

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) -triene₂Adduct compounds

(IVa：X＝OR₂，R₁、R₂T-butyldimethylsilyl), and

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 SO₂Adduct compounds

(IVb：X＝OR₂，R₁、R₂T-butyldimethylsilyl group).

(1S, 2R) - (-) -cis-1-amino-2-indanol (5.0g) was mixed with MTBE (160ml) under nitrogen at 15-25 ℃ and N, N-diethylaniline-borane (16.0ml) was added at that temperature. The mixture was stirred until no further hydrogen evolution was observed. SO of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene obtained in example 1 was added₂Mixtures of adducts (III: X ═ OR)₂，R₁、R₂Tert-butyldimethylsilyl) was dissolved in toluene (160ml) and MTBE (80 ml). The solution is added dropwise to the borane-containing mixture at 15-25 ℃. After complete addition the mixture was stirred for about 30-60 minutes and then saturated NaHCO was used₃The reaction was terminated with an aqueous solution (110ml) at 10-15 ℃. The organic phase was separated off and washed with 1M hydrochloric acid (100ml) at 0-10 ℃ and then with saturated NaHCO₃Aqueous solution (100ml) was washed. The organic phase was checked by HPLC analysis of an aliquot after the reverse Diels-Alder reaction and analyzed according to the method described in example 10, with SO containing 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 in a molar ratio of 72-78: 22-28 (IVa: IVb)₂Adduct (IVa: X ═ OR)₂，R₁、R₂Tert-butyldimethylsilyl group) 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) -triene₂Adduct (IVb: X ═ OR)₂，R₁、R₂T-butyldimethylsilyl group). Compound iva was isolated by silica chromatography.¹³C NMR(CDCl₃)IVa/X＝OR₂，R₁、R₂Is tert-butyl diMethylsilyl δ 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, -5.2 ppm.

Example 10:

3(R) -tert-butyldimethylsilyloxy-20 (R) - (3 ' -cyclopropyl-3 ' (S) -hydroxypropan-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂Adduct compounds

(IVa: X ═ hydrogen, R)₁T-butyldimethylsilyl), and

3(R) -tert-butyldimethylsilyloxy-20 (R) - (3 ' -cyclopropyl-3 ' (R) -hydroxypropan-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂Adduct compounds

(IVb: X ═ hydrogen, R)₁T-butyldimethylsilyl group).

(1S, 2R) - (-) -cis-1-amino-2-indanol (1.22g, 1.08 eq.) was mixed with MTBE (36ml) under nitrogen at 15-25 deg.C, then N, N-diethylaniline-borane (3.6ml, 2.7 eq.) was added at this temperature. The mixture was stirred until no further hydrogen evolution was observed. SO of 3(R) -tert-butyldimethylsilyloxy-20 (R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene obtained in example 8₂Mixtures of adducts (III: X ═ hydrogen, R₁Tert-butyldimethylsilyl) (4.32g) was dissolved in a mixture of MTBE (18ml) and toluene (36ml) at room temperature and then added dropwise to the borane-containing mixture over 15 minutes at 15-25 ℃. After the addition was complete, the mixture was stirred for about 60 minutes and then saturated NaHCO₃The reaction was terminated with an aqueous solution (25 ml). The organic phase was separated and washed with 1M hydrochloric acid (25ml) at 0-10 ℃ and then with saturated NaHCO at 10-20 ℃₃Aqueous solution (25ml) was washed. The organic phase contains 3(R) -tert-butyldimethylsilyloxy-20 (R) - (3 '-cyclopropyl-3 (S)'-hydroxypropan-1' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene SO₂Adduct (IVa: X ═ hydrogen, R)₁Tert-butyldimethylsilyl) and 3(R) -tert-butyldimethylsilyloxy-20 (R) - (3 ' -cyclopropyl-3 (R) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene₂Adduct (IVb: X ═ hydrogen, R)₁T-butyldimethylsilyl group).

A compound of the general structure V

Example 11:

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

(Va：X＝OR₂，R₁、R₂T-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

(Vb：X＝OR₂，R₁、R₂Tertbutyl dimethylsilyl radical)

The compound from example 9 containing IVa (X ═ OR)₂，R₁、R₂T-butyldimethylsilyl) and IVb (X ═ OR)₂，R₁、R₂T-butyldimethylsilyl) SO₂Organic phase of adduct and saturated NaHCO₃The aqueous solution (110ml) was stirred vigorously and then heated (bath temperature about 90 ℃ C.) to distill off MTBE. The reverse Diels-Alder reaction can conveniently be monitored by HPLC { column LiChrosorb Si60 from Merck, 250X 4mm, flow rate of 1ml/min, detection at 270nm, hexane/ethyl acetate 9: 1.5 (volume ratio) }. After completion of the reaction (typically 2-2.5 hours), the reaction mixture is cooled to 30-40 ℃ and the organic phase is separated off, washed with saturated NaHCO₃Aqueous solution (110ml) and water (100 ml). The solvent was removed in vacuo and the resulting oil (29g) was dissolved inHexane (200 ml). The organic mixture was cooled to about-15 deg.C, filtered through a short piece of silica, and the residue was washed with hexane (about 100 ml). The hexane phase was washed with a mixture of methanol and water (1: 2) and the organic solvent was removed in vacuo. By HPLC { column LiChrosorb Si 605 μm from Merck, 250X 4mm, flow rate of 1ml/min, detection at 270nm, n-heptane/2-propanol 100: 0.25 (volume ratio): RT Va about 14.3 min, Vb: 11.9 minutes; or hexane/ethyl acetate 90: 15 (volume ratio): RT Va about 7.6 min, Vb: 6.4 min } 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 (Va: X ═ OR) in a molar ratio of 72-78: 22-28 (Va: Vb)₂，R₁、R₂Tert-butyldimethylsilyl group) 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 (Vb: x is OR₂，R₁、R₂T-butyldimethylsilyl) which oil is purified by chromatography as described previously in m.j. calverley, Tetrahedron, vol 43, phase 20, p 4609-4619, 1987 OR in WO 87/00834 to yield after crystallization from a mixture of hexane and methanol and a small amount of triethylamine (by slow evaporation of hexane and subsequent cooling to-15 ℃) 10.9g (98.9% HPLC purity) of Va/X ═ OR₂，R₁、R₂Tert-butyldimethylsilyl radical, which is in full accordance with the information described in Tetrahedron, volume 43, phase 20, page 4617, 1987 for compound 22 by m.j.¹³C NMR(CDCl₃)Va/X＝OR₂，R₁、R₂T-butyldimethylsilyl δ 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, 23.3, 22.0, 20.3, 18.0, 17.9, 17.4, 12.1, 2.9, 1.6, -5.0, -5.1, Vb/X OR₂，R₁、 R₂Tert-butyldimethylsilyl group, δ 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。

Example 12:

3(R) -tert-butyldimethylsilyloxy-20 (R) - (3 ' -cyclopropyl-3 (S) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene

(Va: X ═ hydrogen, R₁T-butyldimethylsilyl), and

3(R) -tert-butyldimethylsilyloxy-20 (R) - (3 ' -cyclopropyl-3 (R) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene

(Vb: X ═ hydrogen, R₁Tertbutyl dimethylsilyl radical)

Containing IVa from example 10 (X ═ hydrogen, R)₁Tert-butyldimethylsilyl) and IVb (X ═ hydrogen, R₁T-butyldimethylsilyl) SO₂Organic solution of adduct with saturated NaHCO₃The aqueous solution (25ml) was stirred vigorously and then heated (bath temperature about 90 ℃ C.) to distill off MTBE. The reverse Diels-Alder reaction can conveniently be monitored by HPLC { column LiChrosorb Si60 from Merck, 250X 4mm, flow rate of 1ml/min, detection at 270nm, hexane/ethyl acetate 9: 1.5 (volume ratio) }. After completion of the reaction (about 2 hours), the reaction mixture was cooled to 15-25 ℃ and the organic phase was separated and washed with water (25 ml). By HPLC { column LiChrosorb Si 605 μm from Merck, 250X 4mm, flow rate of 1ml/min, detection at 270nm, hexane/ethyl acetate 90: 15 (volume ratio): RT Vb: about 6.1 min, RT Va: about 7.4 minutes } assay containing Va: Vb (X ═ hydrogen, R) in a molar ratio of (75: 25)₁Tert-butyldimethylsilyl group).¹H NMR(CDCl₃) Va/X ═ hydrogen, R₁T-butyldimethylsilyl group δ 6.45(d, 1H), 5.84(d, 1H), 5.46(m, 2H), 4.92(s, 1H), 4.63(s, 1H), 3.84(m, 1H), and,3.42(m, 1H), 2.85(d, 1H), 2.64(d, 1H), 2.45(m, 1H), 2.32-1.18(m, 17H), 1.04(d, 3H), 0.98(m, 1H), 0.87(s, 9H), 0.56(s, 3H), 0.51(m, 2H), 0.32(m, 1H), 0.22(m, 1H), 0.05(s, 3H), 0.04(s, 3H); Vb/X ═ hydrogen, R₁T-butyldimethylsilyl δ is 6.45(d, 1H), 5.83(d, 1H), 5.47(m, 2H), 4.90(s, 1H), 4.62(s, 1H), 3.83(m, 1H), 3.45(m, 1H), 2.83(d, 1H), 2.62(d, 1H), 2.44(m, 1H), 2.24(m, 1H), 2.18-1.17(m, 16H), 1.03(d, 3H), 0.96(m, 1H), 0.86(s, 9H), 0.55(s, 3H), 0.50(m, 2H), 0.30(m, 1H), 0.20(m, 1H), 0.05(s, 3H), 0.04(s, 3H).

A compound of the general structure VI

Example 13:

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

(X＝OR₂，VIa：R₁，R₂T-butyldimethylsilyl group).

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 (Va: X ═ OR) obtained in example 11 was subjected to a high-pressure UV lamp at 20 ℃ as described previously in M.J. Calverley, Tetrahedron, Vol.43, No. 20, pp.4609-4619, 1987 OR in WO 87/00834, except that 9-acetyl anthracene was used instead of anthracene₂，R₁、R₂T-butyldimethylsilyl group) in toluene to give 1(S), 3(R) -bis (t-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 (S) ' -hydroxyprop-1 ' (E) -enyl) -9, 10-secopregna-5 (Z), 7(E), 10(19) -triene (VIa: x is OR₂，R₁、R₂T-butyldimethylsilyl) which is in full accordance with the information described for compound 28 in Tetrahedron, volume 43, phase 20, page 4618, 1987, by m.j.

Calcipotriol

Example 14:

1(S), 3(R) -dihydroxy-20 (R) - (3 ' -cyclopropyl-3 (S) ' -hydroxypropan-1 ' (E) -enyl) -9, 10-secopregna-5 (Z), 7(E), 10(19) -triene

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 (VIa: X ═ OR) obtained in example 13 was reacted at 60 ℃ with tetrabutylammonium fluoride in tetrahydrofuran as described previously in M.J. Calverley, Tetrahedron, Vol.43, No. 20, pp.4609-4619, 1987 OR in WO 87/00834₂，R₁、R₂Tert-butyldimethylsilyl) and then chromatographed. Crystallization from ethyl acetate/hexane containing a few drops of triethylamine gave calcipotriol in full agreement with the data described in m.j. calverley in Tetrahedron, volume 43, phase 20, page 4618, 1987 for compound 4.

Calcipotriol monohydrate

Example 15:

the calcipotriol prepared in example 14 was crystallized in ethyl acetate/water as described in WO 94/15912 to give calcipotriol monohydrate, which is fully in accordance with the characteristic data described in said patent.

Diastereoselective reduction under various reducing conditions

Example 16:

chiral auxiliary (equivalent)	Reducing agent (equivalent)	Temperature (. degree.C.)	Solvent(s)	Ratio Va: Vb (%)
					(1S, 2R) - (-) -cis-1-amino-2-indanol (1.1 equiv)	DEANB (2.7 equivalent)	15-20	MTBE/toluene	72∶28
(1S, 2R) - (-) -cis-1-amino-2-indanol (1.1 equiv)	DEANB (2.7 equivalent)	20-25	MTBE/toluene	72∶28
					(1S, 2R) - (-) -cis-1-amino-2-indanol (1.1 equiv)	DEANB (2.7 equivalent)	10-15	MTBE/toluene	70∶30
(1S, 2R) - (-) -cis-1-amino-2-indanol (0.5 equiv)	DEANB (2.7 equivalent)	15-20	MTBE/toluene	72∶28

(1S, 2R) - (-) -cis-1-amino-2-indanol (0.25 equiv)	DEANB (2.7 equivalent)	15-20	MTBE/toluene	56∶44
					(1S, 2R) - (-) -cis-1-amino-2-indanol (1.1 equiv)	DEANB (1.8 equivalent)	15-20	MTBE/toluene	59∶41
(1S, 2R) - (-) -cis-1-amino-2-indanol (1.1 equiv)	BH₃THF (2.7 equivalents)	15-20	MTBE/toluene	75∶25
					(1S, 2R) - (-) -cis-1-amino-2-indanol(1.1 equivalent)	BH₃.SMe₂(2.7 eq)	15-20	MTBE/toluene	73∶27
(1S, 2R) - (-) -cis-1-amino-2-indanol (1.1 equiv)	DEANB (2.7 equivalent)	15-20	THF	63∶37
					(R) - (+) - α, α -Diphenyl-2-pyrrolidinemethanol (1 equivalent)	DEANB (2.7 equivalent)	15-20	MTBE/toluene	68∶32
(R) - (+) -2-amino-4-methyl-1, 1-diphenyl-1-pentanol (0.5 eq)	DEANB (2.7 equivalent)	15-20	MTBE/toluene	72∶28
					(R) - (-) -2-amino-3-methyl-1, 1-diphenyl-1-butanol (0.5 eq)	DEANB (2.7 equivalent)	15-20	MTBE/toluene	76∶24
(R) - (+) -2-amino-1, 1, 3-triphenyl-1-propanol (0.5 eq)	DEANB (2.7 equivalent)	15-20	MTBE/toluene	74∶26

(1R, 2S) - (-) -2-amino-1, 2-diphenylethanol (0.5 eq)

DEANB (2.7 equivalent)

15-20

MTBE/toluene

57∶43

Table 1:

diastereoselective reduction of X ═ OR in the process according to a method analogous to example 9₂And R is₁And R₂Compounds of general structure III of tert-butyldimethylsilyl (SO of 1(S), 3(R) -bis (tert-butyldimethylsilyloxy) -20(R) - (3 ' -cyclopropyl-3 ' -oxoprop-1 ' (E) -enyl) -9, 10-secopregna-5 (E), 7(E), 10(19) -triene from example 1₂A mixture of adducts) and then chelating extruded (cheletropic extrusion) sulfur dioxide according to a method similar to example 11 to give structure Va: x is OR₂，R₁、R₂T-butyldimethylsilyl group and Vb: x is OR₂，R₁、R₂Tert-butyldimethylsilyl compound (equivalent to molar equivalent with respect to III; MTBE ═ tert-butylmethyl ether; DEANB ═ N, N-diethylaniline borane).

Claims

1. A process for reducing a compound of general structure III with a chiral reducing agent in an inert solvent or with a reducing agent in the presence of a chiral auxiliary:

wherein X represents hydrogen OR OR₂，

And wherein R₁And R₂Identical or different and represents hydrogen or a hydroxyl-protecting group,

to obtain a mixture of compounds of the general structures IVa and IVb,

the mixture is enriched in IVa, wherein X, R₁And R₂As defined above.

2. A process for preparing 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:

(a) reducing a compound of the general formula structure III with a chiral reducing agent in an inert solvent or with a reducing agent in the presence of a chiral auxiliary,

wherein X represents OR₂，

And wherein R₁And R₂Identical or different and represent hydrogen or a hydroxyl-protecting group,

to give a mixture of compounds of the general structures IVa and IVb,

it is rich in IVa, wherein X, R₁And R₂As defined in the claims;

(b) reacting a mixture of compounds of general structures IVa and IVb enriched in IVa in the presence of a base to give a mixture of compounds of general structures Va and Vb enriched in Va,

x, R therein₁And R₂As defined in the claims;

(c) separating the compound of formula Va from a mixture of compounds of formula Va and Vb enriched with Va, wherein X, R₁And R₂As defined in the claims;

x, R therein₁And R₂As defined in the claims; and

3. A method of preparing calcipotriol or calcipotriol monohydrate comprising steps (a) - (b) of claim 2 and further comprising the steps of:

(f) mixing Va-enriched compounds of the general structures Va and Vb, wherein X, R₁And R₂As defined in claim 2, to a mixture of VIa-enriched compounds of the general structures VIa and VIb,

x, R therein₁And R₂As defined in claim 2;

(g) separating the compound of general structure VIa from the mixture of VIa-enriched compounds of general structures VIa and VIb, wherein X, R₁And R₂As defined in claim 2;

4. A process for preparing 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:

(j) reduction of compounds of the general structure III with chiral reducing agents in inert solvents or with reducing agents in the presence of chiral auxiliary agents

Wherein X represents hydrogen, and X represents hydrogen,

and wherein R₁Represents hydrogen or a hydroxyl-protecting group,

to obtain a mixture of compounds of the general structures IVa and IVb enriched in IVa,

wherein X and R₁As defined in the claims;

(k) reacting a mixture of compounds of general structures IVa and IVb enriched in IVa in the presence of a base to give a mixture of compounds of general structures Va and Vb enriched in Va,

wherein X and R₁As defined in the claims;

(l) Separating the compound of formula Va from a mixture of compounds of formula Va and Vb enriched with Va, wherein X and R₁As defined in the claims;

(m) hydroxylating a compound of general structure Va, wherein X and R are₁As defined in the claims, to give compounds of general structure Va, in which X represents OR₂And R is₂Represents hydrogen, R₁As defined in the claims;

(o) isomerizing the compound of general structure Va obtained in step (m) to a compound of general structure VIa,

wherein X represents OR₂And R is₂Represents hydrogen, R₁As defined in the claims; and

5. A method of preparing calcipotriol or calcipotriol monohydrate comprising steps (j) - (l) of claim 4 and further comprising the steps of:

(q) protecting the C-24 hydroxyl group of the compound of general structure Va with a hydroxyl protecting group,

wherein X represents hydrogen, and wherein R₁Represents hydrogen or a hydroxyl protecting group;

(R) hydroxylating a C-24 hydroxy-protected compound of general structure Va, wherein X represents H and R₁As defined in the claims to give a compound of general structure Va with protected C-24 hydroxy group, wherein X represents OR₂And R is₂Represents hydrogen, R₁As defined in the claims;

(s) removing the C-24 hydroxy protecting group of the compound of general structure Va obtained in step (r);

(t) isomerizing the compound of general structure Va obtained in step(s) to a compound of general structure VIa,

6. A process as claimed in any one of claims 1 to 5, wherein the reduction step is carried out with a reducing agent in the presence of a chiral auxiliary.

7. A process according to claim 6, wherein the reducing agent is N, N-diethylaniline-borane, borane-tetrahydrofuran or borane dimethylsulfide.

8. A process as claimed in any one of claims 1 to 5, wherein the chiral auxiliary is a chiral 1, 2-amino alcohol.

9. A process as claimed in any one of claims 1 to 5, wherein the chiral auxiliary is (1S, 2R) - (-) -cis-1-amino-2-indanol.

10. A process according to any one of claims 1 to 5 wherein the inert solvent is toluene, tert-butyl methyl ether, tetrahydrofuran or mixtures thereof.

11. The process of any one of claims 1-5, wherein the mixture of compounds of general structures IVa and 1Vb obtained by reduction of the compound of general structure III has a molar ratio IVa: IVb of at least 56: 44.

12. A process according to any one of claims 1 to 5 wherein the reduction step is carried out at a temperature of between 10 and 20 ℃.

13. A process for the preparation of a compound of the general structure III,

wherein X represents hydrogen OR OR₂And wherein R is₁And R₂Identical or different and represents hydrogen or a hydroxyl-protecting group, which process comprises reacting a compound of the general structure VII or VIII with sulfur dioxide,

wherein X represents hydrogen OR OR₂And wherein R is₁And R₂As defined in the claims.

14. The method of any one of claims 1 and 13, wherein the compound of general structure III is an epimer of general structure IIIa

Wherein X represents hydrogen OR OR₂And wherein R is₁And R₂Identical or different and represent hydrogen or a hydroxyl-protecting group.

15. The method of any one of claims 2 and 3, wherein the compound of general structure III is an epimer of general structure IIIa

Wherein X represents OR₂And wherein R is₁And R₂Identical or different and represent hydrogen or a hydroxyl-protecting group.

16. The method of any one of claims 4 and 5, wherein the compound of general structure III is an epimer of general structure IIIa

Wherein X represents hydrogen, and R₁Represents hydrogen or a hydroxyl protecting group.

17. The method of any one of claims 1 and 13, wherein the compound of general structure III

The compound is an epimer with a general structure IIIb

18. The method of any one of claims 2 and 3, wherein the compound of general structure III is an epimer of general structure IIIb

19. The method of any one of claims 4 and 5, wherein the compound of general structure III is an epimer of general structure IIIb

20. A process for reacting a mixture of compounds of the general structures IVa and IVb enriched in IVa in the presence of a base,

wherein X represents hydrogen OR OR₂And wherein R is₁And R₂Identical or different and represent hydrogen or a hydroxyl-protecting group,

to obtain a mixture of compounds of the general structures Va and Vb enriched with Va,

x, R therein₁And R₂As defined in the claims.

21. The method of any one of claims 1, 13 OR 20, wherein X represents OR₂。

22. The method of any one of claims 1-3, 13, or 20, wherein R₁And/or R₂Represents an alkylsilyl group.

23. The method of claim 22, wherein R₁And/or R₂Represents a tert-butyldimethylsilyl group.

24. A compound of general structure IIIa or IIIb, or mixtures thereof,

wherein X represents hydrogen OR OR₂，

And wherein R₁And R₂Identical or different and represent hydrogen or a hydroxyl-protecting group.

25. A compound of the general structures IVaa, IVab, IVba, IVbb, or mixtures thereof,

wherein X represents hydrogen OR OR₂，

26. A compound according to claim 24 OR 25, wherein X represents OR₂。

27. The compound of claim 24 or 25, wherein R₁And R₂Represents an alkylsilyl group.

28. The compound of claim 27, wherein R₁And R₂Represents a tert-butyldimethylsilyl group.

29. The compound of claim 24 or 25, wherein R₁And R₂Represents hydrogen.

30. Use of a compound according to any one of claims 24 to 29 as an intermediate in the preparation of calcipotriol or calcipotriol monohydrate.