SI21657A - Procedure for obtaining derivatives of vitamin d from monohalogenovinyl compounds - Google Patents

Abstract

A new procedure for obtaining derivatives of vitamin D with the formula: comprising a reaction of (C20)-monohalogenovinyl derivative with metallic or organo-metallic reagents and then with other activated reagents.

Description

Process for the production of vitamin D derivatives from monohalogenous vinyl compounds

DESCRIPTION

FIELD OF THE INVENTION

The present invention relates to a process for the production of vitamin D derivatives of general formula (I), comprising the reaction of (C20) -monohalogenovinyl compounds of general formula (II) with metal or organometallic reagents and then with other suitable reagents. The invention also relates to the use of compounds of general formula (II) for the preparation of vitamin D derivatives of general formula (I) that are useful or potentially useful in various therapeutic fields, such as e.g. in the treatment and / or prevention of metabolic bone diseases, diseases characterized by a change in cell differentiation and proliferation (dermatology and oncology), etc.

(II)

BACKGROUND OF THE INVENTION

The chemistry of steroids, both closed and open cyclic systems, is a complex chemistry due to the simultaneous occurrence of different functions and numerous chiral centers in molecules, with special interest in reactions and reagents that allow for higher selectivity and specificity in reaction products.

Vitamin D derivatives, such as tacalcitol, calcipotriol, floccalcitriol, 22-oxacalcitriol, secalciferol, etc., are steroidal compounds that are used or are being developed in various therapeutic fields, e.g. metabolic bone diseases, diseases characterized by changes in cell differentiation and proliferation (dermatology and oncology), etc.

Taking the chemical structure of vitamin D ₂ as a reference

Vitamin D _{2 is} derived from the aforementioned derivatives mainly from more or less thorough modifications of the C20 side chain and also from alternative modifications which are monohydroxylated or dihydroxylated with respect to C1 and C3 positions.

Important analogues originate from the fact that la, 25-dihydroxyvitamin D ₃ (calcitriol) is a metabolite of vitamin D ₃ with hormonal activity. In recent years, in addition to interest in 25-hydroxy analogues, hormonal activity has been modulated by translocation of 25 hydroxyl to positions 24 or 26 and by introducing a double bond between positions C22-C23 (vitamin D ₂ already has this double bond) or triple bonds at the same positions C22, thus creating interest in C22-C23 alkyne analogues.

In many cases, these unsaturated derivatives have been used as precursors of saturated derivatives because they are obtained by simple hydrogenation. With C22-C23 saturated derivatives also becoming important.

C24 hydroxylated vitamin D derivatives are very therapeutically interesting, especially because of the low tendency to cause hypercalcaemia that does not occur or is of low intensity on C25 hydroxylated derivatives. Examples of C24 derivatives are secalciferol used in the treatment of osteoporosis, tacalcitol and calcipotriol, both used as antipsoriatics.

TACALCITOL SECALCFEROL

Therefore, hydroxylation at different C20 side chain carbons, the formation of a C22-C23 double or triple bond as well as the corresponding saturated ones, is important in Vitamin D chemistry.

The formation of C22-C23 double bonds in vitamin D chemistry is derived from the C20 aldehyde (IV), which is usually obtained from aldehyde (III) (Carverley: Tetrahedron, Vol. 43, no. 20, 4609 (1987) and W087 / 00834-A Hesse: EP0078704), with a Wittig or Wittig-Homer reaction, an aldol reaction, or a Julia-Lythgoe olefmation reaction. Since stereochemistry is a double bond with the pharmacological activity of trans, other methods that give a cis or cis-trans mixture will be useful only if the next reaction is hydrogenation to give a saturated derivative.

The formation of the C22-C23 triple bonds is also derived from an aldehyde of formula (III) by a Wittig reaction with a polyhalogenated methane derivative (WO92 / 03414).

(IV)

(III)

One of the most serious flaws in these methodologies is the deprotection of an aldehyde of formula (III) into a compound of formula (IV), which is done in a weakly alkaline medium that results in a certain isomerization of C20 carbonyl (5% or more depending on conditions). Separation of the epimer is usually carried out after the introduction of the chain, but separation can be difficult in the case of industrial production.

On the other hand, the Wittig-Homei, aldol, and Julia-Lythgoe reactions, which are carried out in an alkaline medium, achieve an additional increase of the C20 epimer. Therefore, the methodology that allows the extension of the C20 side chain with minimal C20 epimer formation will be very interesting.

In a Wittig or Wittig-Homei reaction, a double bond is formed with a trans configuration if C24 is a carbonyl function or unsaturation, yielding conjugated eons or dienes, and usually a trans-cis mixture is formed when these functions are not present. However, these reactions can produce high returns {Tetrahedron, Vol. 43, n ° 20, 1987) or low yields (CA 2026671) for single C24 carbonyl compounds. With respect to Julia-Lythgoe olefination {Journal Organic Chemistry, 53, 3450 (1988)), the yield is usually low. Furthermore, this olefination is practically impracticable on an industrial scale due to the desulfurization of the sulfone intermediate with sodium amalgam. On the other hand, the deprotection of an aldehyde of formula (III) into a compound of formula (IV) must also be considered, a reaction which also yields moderate yields.

From the enons existing from the Wittig or aldol reaction, C24 alcohols are usually obtained by reduction or reaction with organometallic compounds. In the case of reduction, there is a partial reduction of the double bond, which results in a decrease in winnings. If NaBH ₄ / CeCl ₃ reagent is used, the saturated alcohols are reduced by up to 1%, and the S / R ratio of C24 epimemic alcohols is favorable for the R epimer, which is usually inactive. Higher S / R ratios are achieved using lithium and aluminum hydrides mixed with chiral or acrylic alcohols, but many by-products are formed (double bond reduction, OH substitution with H, etc.), resulting in overall gains. Chiral reagents, on the other hand, are usually very expensive, making them quite inappropriate on an industrial scale.

It is also possible to introduce a C22-C23 unsaturated chain with a single C24 epimer according to the methodology described in Sinlett, 157 (1990), in which the compound of formula (IV) is converted to selenoacetal, which reacts with chiral hydroxyaldehyde. However, this method mainly yields low-yield C23-C24 cis alkenes.

Reaction schemes mentioned

Vittig-Horner \ ^CH0 ₊ R

CH = CHR '(Ph ₃ ) P-CH'-R'

R '= CH ₂ R; COR; CH = CHR '

Vittig-Horner \ CHO base in CH = CH - COR '

Ύ + (MeOLP (O) -CH-COR ′ - I

R 2 2 _R

Aldol

CHO

OH

I \ CH-CH-COR '+ CH ₃ COR ^{ba? A} - "I ³ R acid CH = CH-COR

- * - T

R

Julia-Lvtghoe yHO R

base

Hg / Na

CH = CH-CH ₂ R '

The Julia-Lythgoe olefination reaction is often used to introduce a hydroxyl group in more distant positions (C25 or C26), and its major drawbacks are the moderate gains they achieve (J. Org. Chem. 58, 1496, 1993). Another method is still the Wittig reaction, but only with good gains in the formation of dienes conjugated with C26 carbonyl, which is then converted to hydroxyl by reaction with organometallic reagents (WO 91/00855). If at position 24-25 carbon is saturated then the yield is smaller and significant amounts of the cis isomer C22-C23 double bond can be obtained.

The extraction of alkenes from the corresponding C22-C23 alkyne by reduction of the triple bond has only been described to give a cis double bond (Bioorganic & Medical Chemistry Letters, vol. 3, 1841-1844 (1993)).

It should also be noted that Wittig's, Wittig-Homei's and Julia-Lythgoe's reagents are usually not commercially available and need to be synthesized, often at many stages, making the process more expensive (J. Org. Chem. 51, 4819, 1986; Chemical Reviews, 89, 863, 1989; Tetrahedron, 43, 20, 4609, 1987).

The preparation of C20 alkynes from the dihalogenovinyl derivatives of V-a (X = C1) and V-b (X = Br) by reaction with "-BuLi" has been described.

(Va): X = Cl (Vb): X = Br (V)

The resulting lithium acetylide is digested in situ with electrophiles or hydrolyzed with water to give the corresponding alkyne with the S configuration at C20 (Biorganic & Medicinal Chemistry Letters, Vol. 13, no. 9, 1841 (1993)), with the R configuration at C20 ( WO 92/03414).

The dihalogenated compounds of type (V) are prepared from deprotected aldehyde, in which case the inevitable C20 isomerization, which was mentioned in the discussion of C20 alkenes production, also occurs.

Another of the drawbacks of this methodology is the fact that the conversion of compound (V) to lithium acetylide must be done with very precise amounts of n-BuLi due to the fact that its excess is adiabated to the vitamin D skeleton.

By preparing C20 alkynes from iodine derivatives of formula (II), which is one aspect of the present invention, the former defects are solved by the fact that deprotection of the iodine derivative is carried out without racemization, which does not occur during the alkyne synthesis process.

On the other hand, the use of LDA or t-BuOK to produce alkyne allows the use of excess reagent without admixture to the vitamin D skeleton.

Alkines with a C24 oxo or hydroxyl group prepared by the present invention are already known (Bioorganic Medicinal Chemistry Letters, Vol. 13, No. 9 1841 (1993)), but are obtained from compounds (Va). However, the method provided by the present invention has not yet been described.

As a result, there is a need to find new ways to obtain Vitamin D derivatives hydroxylated at the C24, C25 or C26 side chain that combine high or exclusive stereoselectivity for the trans configuration of the double bond between C22 and C23, high yields with commercially available reagents, gives fewer by-products, which provide a more favorable delineation of the desired C24 R configurations and the corresponding C25 and C26 configurations.

SUMMARY OF THE INVENTION

The inventors of the present invention have found that the new compounds of formula (II) described in patent application no. 200302806, which is simultaneously in a process having a C20 mono-alloyl group as a side chain, provide a novel synthetic route capable of providing pharmacologically useful vitamin D derivatives with better yields and higher stereoselectivity, methodological simplicity and less by-products or impurities .

More specifically, the process as proposed by the present invention has the following advantages, among the most important, in particular for its industrial production:

- Stereochemistry of the C22-C23 trans bond is retained.

- Isomerism of new thyme alkynes (C24-C25) is also trans.

- No significant C20 racemization occurs at any stage.

- Chain formation reactions are usually carried out in high yields.

- In many cases, the reagents are commercially available and do not have to be converted to activated derivatives (such as the Wittig reaction in phosphorans or the Julia-Lythgoe reaction in sulfones).

- In the case of the preparation of C24 hydroxyl groups, the preparation of C24 S / R epimers is 1: 1, which is higher than the ratio resulting from the reduction of C24 carbonyl with NaBH ₄ / CeCl3 (1 / 1.5) when using procedures 3.1, 3.3 and 3.4 (see detailed description of the invention); however, this situation reaches 9/1 when using procedure 3.2 with propargyl alcohol prepared by reducing its ketone with Alpine-borane, 2.5 / 1 with Dip-chloride, with a minimum S / R of 1/1.

- In the case of C26 chiral alcohols, a single isomer is easily obtained from optically pure (often commercially available) allyl or propargyl alcohol (Procedures 5/01 and 6B / 2).

Therefore, there is an object of the present invention to use novel monohalogeninyl compounds of formula (II) as a starting material for the preparation of vitamin D derivatives of formula (I).

Further, the process for converting monohalogenovinyl compounds of formula (II) into vitamin D derivatives of formula (I) also forms part of the object of the present invention.

These alkenyl monohalo derivatives of formula (II) are susceptible to being used to prepare a large variety of organometallic compounds by substituting halogens with metals that are satisfactorily used to form new C-C bonds. It thus illustrates lithium or magnesium substitution and the subsequent reaction with carbonyl compounds to give a large number of allyl alcohols, a reaction which can also be carried out with Cr (Nozaki reaction); while palladium substitution allows the preparation of polyenes / polyins by reaction with alkenes or alkynes in accordance with Kumada, Negishi, Stille, Suzuki, Heck and Sonogashira reactions, and monoalkenes are obtained by reaction with other organo-vinyl compounds.

Removal of a halogen in a compound of formula (II) with e.g. LDA, or Z-BuOK / DMSO, allows the preparation of alkynes, and subsequent reaction with carbonyl compounds and epoxides allows a large number of hydroxyalkines to be obtained.

The following reactions of the obtained products make it possible, for example: to reduce the production of new alkenes from alkynes; preparation of hydroxylated derivatives of carbonyl compounds; and obtaining derivatives saturated with hydrogenation of the double-stranded chain.

DETAILED DESCRIPTION OF THE INVENTION

Vitamin D derivatives obtainable from compounds of formula (II) correspond to the general formula (I) <> (C _R = CR ₂ ) - (C ^ C) _n - (CR ₃ R ₄ ) _p -D

D (D where

A is chosen from the residues of the general formulas (Al), (A2) and (Α3):

CHR '·,

With (A1) (A2) (A3) where

Z and Z 'independently of one another are hydrogen; hydroxyl; or hydroxyl protected by a hydroxyl protecting group;

W is dienophil, preferably dienophil, selected from SO ₂ and a di-acid azo such as 4-phenyl-1,2,4-triazoline-3,5-dione; and phthalazine-1,4-dione; and they are

R'i, R ' ₂ and R' ₃ independently of one another are hydrogen; halogen; hydroxyl; hydroxyl protected by a hydroxyl protecting group; C _r C6 alkyl optionally substituted with halogen, hydroxyl, cyano or amino; C ₂ -C 6 alkenyl optionally substituted by halogen, hydroxyl, cyano or amino; di (Ci-C ₃₎ alkyl ether; or Ci-C ₅ alkyl amino;

R 1, R ₂ , R ₃ and R 1 are independently hydrogen; Ci-C ₈ alkyl; C ₃ -C 6 cycloalkyl; or C ₆ -C 14 aryl;

Hydrogen;

-CR ₅ R ₅ V where R ₅ and R 8 are independently from each other hydrogen; C _r C ₈ alkyl; C ₃ -C ₆ cycloalkyl; C6-C ₁₄ aryl; or -OR _{7 is a} group wherein R _{7 is} hydrogen; Ci-C ₈ alkyl; C ₃ -C ₆ cycloalkyl; or C ₆ -C 14 aryl; and Y is hydrogen; hydroxyl; hydroxyl protected by a hydroxyl protecting group; or -OR _{7 a} group wherein R _{7 has the} same meaning as above; or

-C (O) R ₅ , wherein R _{5 has the} same meaning as above;

m is an integer selected from 0, 1 and 2;

n is an integer selected from 0 and 1;

p is an integer selected from 0, 1, 2, 3, 4, 5 and 6;

with the proviso that at least one of m, n or p is 0 and the sum of m, n and p is equal to or greater than 1 (m + n + ”p> 1).

As used herein, the term hydroxyl protecting group includes any group capable of protecting a hydroxyl group. Examples of protecting groups for the hydroxyl group are described by Green TW et al. in Protective Groups in Organic Synthesis, 3 ^rd Edition (1999), Ed. John Wiley & Sons (ISBN 0-471-16019-9). Although virtually any hydroxyl protecting group may be used, in a particular embodiment, the hydroxyl protecting group is a silyl derivative, e.g. Z-butyldimethylsilyl (TBDMS), occasionally identified herein as STBDM or MDBTS, wherein the hydroxyl group is protected by silylether formation, or the hydroxyl protecting group is an acyl group derived from a carboxylic acid, e.g. acetyl group (Ac) [CH ₃ -C (O) -j, wherein the hydroxyl group is protected as a carboxylic acid ester, e.g. acetic acid esters.

The term C 1 -C ₆ alkyl refers to a residue derived from straight or branched alkane having 1 to 6 carbon atoms. Similarly, the term C 1 -C ₅ alkyl refers to a residue derived from a saturated straight or branched hydrocarbon having 1 to 5 carbon atoms, while the term C 1 -C ₈ alkyl refers to a residue derived from a saturated natural or branched hydrocarbon with 1 to 8 carbon atoms.

The term C ₂ -C ₆ alkenyl refers to a residue derived from straight or branched alkene having 2 to 6 carbon atoms.

The term C ₃ -C ₆ cycloalkyl refers to a residue derived from cycloalkanes of 3 to 6 carbon atoms.

The term Cg-C10 aryl refers to a residue derived from an aromatic hydrocarbon having 6 to 10 carbon atoms due to the loss of hydrogen in the carbon atom of the nucleus. Similarly, the term C1-Cm aryl refers to a residue derived from an aromatic hydrocarbon having 6 to 14 carbon atoms due to the loss of hydrogen in the carbon atom of the nucleus.

Vitamin D derivatives of formula (I) include different classes of compounds according to the existence (or not) of unsaturation (double and / or triple bonds) and / or the existence (or not) of optionally substituted methylenes in the side chain as well as existing functions in D.

One class of vitamin D derivatives of formula (I) includes those compounds of formula (I) in which m = 0, n = 0 and p ^ O (i.e., p is an integer selected from 1 and 6).

Another class of vitamin D derivatives of formula (I) includes those compounds of formula (I) in which m = 0, n ^ O (i.e. an integer between 1 and 3) and p = 0.

Another class of vitamin D derivatives of formula (I) includes those compounds of formula (I) in which m = 0, nAO (i.e., n is an integer between 1 and 3) and pAO (i.e., p is an integer selected from 1 and 6).

Another class of vitamin D derivatives of formula (I) includes those compounds of formula (I) in which mAO (i.e., m is 1 or 2), n = 0 and p = 0.

Another class of vitamin D derivatives of formula (I) includes those compounds of formula (I) in which mA is 0 (i.e., m = 1 or 2), nAO (i.e., an integer between 1 and 3) and p = 0.

Another class of vitamin D derivatives of formula (I) includes those compounds of formula (I) in which mAO (i.e., m = l or 2), n = 0, and pAO (i.e., p is an integer between 1 and 6).

Among the vitamin D derivatives of formula (I) obtainable by the process of the present invention are the following:

(S), 3 (R) -bis (/ tert-butyldimethylsilyloxy) -20 (S) - (ethynyl) -9,10-secopregna-5 (E), 15

7 (Ε), 10 (19) -triene (compound 1);

(S), 3 (R) -bis (/ tert-butyldimethylsilyloxy) -20 (S) - (ethynyl) -9,10-secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 2);

(S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) - (3 '-cyclopropyl-3' -oxopropin-1 yl) -9,10-secopreg-5 (E), - 7 ( E), 10 (19) -triene (compound 3); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) - (3'-cyclopropyl-3'-oxopropin-1'yl) -9,10-secopreg-5 (Z), - 7 (E), 10 (19) -triene (compound 4); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (S) - (3'-cyclopropyl-3 '- (R) hydroxypropin-1'-yl) -9,10-secopreg-5 (E), - 7 (E), 10 (19) -triene (compound 5 (R)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (S) - (3'-cyclopropyl-3 '- (S) hydroxypropin-1'-yl) -9,10-secopreg-5 (E), - 7 (E), 10 (19) -triene (compound 5 (S));

(S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) - (3 '-cyclopropyl-3' - (R) hydroxypropin-1 '-yl) -9,10-secopreg-5 (Z ), - 7 (E), 10 (19) -triene (compound 6 (R)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (S) - (3'-cyclopropyl-3 '- (S) hydroxypropin-1'-yl) -9,10-secopreg-5 (Z), - 7 (E), 10 (19) -triene (compound 6 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) - (4'-hydroxy-4'-methylpentin-1'-yl) 9.10-secopreg-5 (E), - 7 ( E), 10 (19) -triene (compound 7);

SO2 adduct 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4 '-hydroxy-4' methylpent-1 '-inyl) -9,10-secopreg-5,7 (E), 10 (19) -triene (compound 8);

(S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3 '-hydroxy-3' (R) -isopropylpropan-1'-yl) -9,10-secopreg-5 (E ), - 7 (E), 10 (19) -triene (compound 9 (R)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (3'-hydroxy-3 '(S) -isopropylpropanyl-yl) -9,10-secopregna-5 (E ), - 7 (E), 10 (19) -triene (compound 9 (S)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-hydroxy-4'-methylpentan-1'-yl) 9.10-secopreg-5 (E), 7 ( E), 10 (19) -triene (compound 10);

SO ₂ adduct 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-oxo-pentan-1'-yl)

9.10- secopreg-5.7 (E), 10 (19) -triene (compound 11);

1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-oxopentan-1'-yl) -9,10secopy-5 (E), 7 (E), 10 (19) -triene (compound 12);

(S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (butan-1'-yl) -9,10-secopregne16

5 (E), 7 (E), 10 (19) -triene (compound 13);

1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-methylpentan-1'-yl) -9,10secopy-5 (E), 7 (E), 10 ( 19) -triene (compound 14);

SO ₂ adduct 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '-hydroxyl-5' methylpentan-1 '-yl) -9,10-secopreg-5,7 (E), 10 (19) -triene (compound 15);

SO ₂ adduct 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-oxo-pent-1 '(E) enyl) -9,10-secopreg-5, 7 (E), 10 (19) -triene (compound 16);

1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (buten-1 '(E) -yl) -9,10-secopregne5 (E), 7 (E), 10 (19) -triene (compound 17);

1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-methylpenten-1'E) -yl) -9,10secoprene-5 (E), 7 (E). 10 (19) -triene (compound 18);

1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(R) -hydroxypropyl' (E) -enyl) -9,10-sec -5 (E), 7 (E), 10 (19) -triene (compound 19 (R));

(S), 3 (R) ~ bis (tert-butyldimethylsilyloxy) -20 (R) - (3 '-cyclopropyl-3' (S) -hydroxypropyl '(E) -enyl) -9,10-secopreg-5 ( E), 7 (E), 10 (19) -triene (compound 19 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-dimethyl-3 '(R) -hydroxypental' (E) -enyl) -9,10-secopregna-5 (E), 7 (E), 10 (19) -triene (compound 20 (R)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-dimethyl) -3 '(S) -hydroxypentar (E) -enyl) -9,10-secopregn- 5 (E), 7 (E), 10 (19) -triene (compound 20 (S)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(R) -hydroxypropyl' (E) -enyl) -9,10-secopregn- 5 (Z), 7 (E), 10 (19) -triene (compound 21 (R)); 1 (S), 3 (R) -bis ((erc. butyl dimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(S) -hydroxypropyl' (E) -enyl) -9,10-sec -pregna-5 (Z), 7 (E), 10 (19) -triene (compound 21 (S));

(S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3 '(R) -hydroxy-4'-methylpent-1' (E) enyl) -9,10-secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 22 (R));

(S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (3 '(S) -hydroxy-4'-methylpent-1' (E) enyl) -9,10-secopregn- 5 (Z), 7 (E), 10 (19) -triene (compound 22 (S)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-cyclohexyl-3 '(R) -hydroxypropyl' (E) -enyl) -9,10-secopregn- 5 (E), 7 (E), 10 (19) -triene (compound 23 (R)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-cyclohexyl-3 '(S) -hydroxypropyl-1' (E) -enyl) -9,10-secopregn -5 (E), 7 (E), 10 (19) -triene (compound 23 (S));

(S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (3 '(R) -hydroxy-4'-methylpent-1' (E) enyl) -9,10-secopregn- 5 (E), 7 (E), 10 (19) -triene (compound 24 (R)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3 '(S) -hydroxy-4'-methylpent-r (E) enyl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 24 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-cyclohexyl-3 '(R) -hydroxyprop (E) -enyl) -9,10-secopreg-5 ( Z), 7 (E), 10 (19) -triene (compound 25 (R)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-cyclohexyl-3 '(S) -hydroxypropyl' (E) -enyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (compound 25 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-dimethyl-3 '(R) -hydroxypent-r (E) enyl) -9,10-secopreg-5 ( Z), 7 (E), 10 (19) -triene (compound 26 (R)); 1 (S), 3 (R} -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-dimethyl-3 '(S) -hydroxypent-r (E) enyl) -9,10-secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 26 (S)); 20 (R) - (3'-cyclopropyl-3 '(R) -hydroxyprop-1' (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10-copreg-5 (Z), 7 (E), 10 (19) -triene (compound 27 (R));

20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-r (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10seco-5 (Z), 7 ( E), 10 (19) -triene (compound 27 (S));

20 (R) - (3'-cyclopropyl-3 '(R) -hydroxyprop-1' (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10-copreg-5 (E ), 7 (E), 10 (19) -triene (compound 28 (R));

20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-1' (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10sec-5-E (7) (E), 10 (19) -triene (compound 28 (S));

1 (S), 3 (R) -dihydroxy-20 (R) - (3 '(S) -hydroxy-4'-methylpent-r (E) -enyl) -9,10-secopregna-5 (E). 7 (E), 10 (19) -triene (compound 29 (R));

1 (S), 3 (R) -dihydroxy-20 (R) - (3 '(S) -hydroxy-4'-methylpent-r (E) -enyl) -9,10secopro-5 (E), 7 ( E), 10 (19) -triene (compound 29 (S));

(S), 3 (R) -dihydroxy-20 (R) - (3 '(S) -hydroxy-4' -methylpent-1 '(E) -enyl) -9,10-secopreg-5 (Z). 7 (E), 10 (19) -triene (compound 30 (R));

1 (S), 3 (R) -dihydroxy-20 (R) - (3 '(S) -hydroxy-4'-methylpent-1' (E) -enyl) -9,10secopy-5 (Z), 7 (E), 10 (19) -triene (compound 30 (S));

1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '(R) -hydroxy-prop-r (E) -enyl) 18

9.10- secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 31 (R));

1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-r (E) -enyl) -9,10secopreg-5 (Z) , 7 (E), 10 (19) -triene (compound 31 (S));

(S), 3 (R) -bis (acetoxy) -20 (R) - (3 '-cyclopropyl-3' (R) -hydroxy-prop-1 '(E) -enyl) 9.10-secopreg-5 (E ), 7 (E), 10 (19) -triene (compound 32 (R));

(S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-1' (E) -enyl) -9,10seco-5 (E) , 7 (E), 10 (19) -triene (compound 32 (S));

SO ₂ adduct 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(R) hydroxyprop-1' (E) -enyl) -9,10 -Secogene-5.7 (E), 10 (19) -triene (compound 33 (R)); SO ₂ adduct 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(S) hydroxyprop-r (E) -enyl) -9,10- secopreg-5,7 (E), 10 (19) -triene (compound 33 (S)); SO ₂ adduct 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3 '(R) -hydroxy-4'-methylpent (E) -enyl), 9,10-secopreg-5,7 (E), 10 (19) -triene (compound 34 (R));

SO ₂ adduct 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (3 '(S) -hydroxy-4'-methylpent 1' (E) -enyl), 9,10-secopreg-na -5,7 (E), 10 (19) -triene (compound 34 (S));

SO ₂ adduct 1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '- (R) -hydroxyprop (r) (E) -enyl) -9,10-secoprogen -5,7 (E), 10 (19) -triene (compound 35 (R));

SO ₂ adduct 1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-1' (E) enyl) -9,10-sec -prena-5.7 (E), 10 (19) -triene (compound 35 (S));

(S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-phenyl-4'-oxobut-1 '(E) -enyl) 9.10-secopreg-5 (E). 7 ((E), 10 (19) -triene (compound 36);

1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-cyclopropyl-4'-oxobut-r (E) enyl) -9,10-secopreg-5 (E) , 7 (E), 10 (19) -triene (compound 37);

(S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-oxopent-1 '(E) -enyl) -9,10-secopregna-5 (E), 7 (( E), 10 (19) -triene (compound 38);

1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-hydroxy-4'-methylpent-r (E) enyl) -9,10-secopreg-5 (E) -7 (E), 10 (19) -triene (compound 39); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5'-hydroxy-5'-methylhex-3'-ynr (E) -enyl) -9,10-secopregn- 5.7 (E), 10 (19) -triene (compound 40); l (S), 3 (E) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxy-5'-methylhep-3'-in19 l' (E) -enyl) -9 , 10-secopreg-5.7 (E), 10 (19) -triene (compound 41 (R));

1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 ^, (S) -hydroxy-5'-methylhep-3'-yl '(E) -enyl) -9, 10-secopreg-5.7 (E), 10 (19) -triene (compound 41 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5 '-hydroxyhep-3' -in-1 '(E) enyl) -9,10- secopregna-5 (E), 7 (E), 10 (19) -triene (compound 42); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxyhex-3'-in-1' (E) enyl) -9,10-secopregn- 5.7 (E), 10 (19) -triene (compound 43 (R)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxyhex-3'-in-1' (E) enyl) -9,10-secopregn- 5.7 (E), 10 (19) -triene (compound 43 (S));

(S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5'-hydroxyhep-3 '-in-1' (E) enyl) -9,10- secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 44);

SO ₂ adduct 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5'-hydroxyhep 3'-in-1 '(E) -enyl) -9 , 10-secopreg-5,7 (E), 10 (19) -triene (compound 45);

(S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-oxo-pent-1 '(E), 3' (E) -dien-1 'yl) -9 , 10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 46); 1 (S) -3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-methoxycarbonylbutar (E), 3 '(E) -dien-1'-yl) -9,10-secopregn -5 (E), 7 (E), 10 (19) -triene (compound 47); 1 (S) -3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (5'-hydroxypent-r (E), 3 '(E) -dienyl-yl) -9,10- secopregna-5 (E), 7 (E), 10 (19) -triene (compound 48);

(S) -3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxyhexa-1' (E), 3 '(E) dien-1'-yl) -9 , 10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 49 (R));

(S) -3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxyhexa-1' (E), 3 '(E) dien-1'-yl) - 9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 49 (S)); l (S) -3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxyhepta-r (E), 3' (E) dien-r-yl) -9 , 10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 50 (R)); l (S) -3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxyhepta-r (E), 3' (E) dien-l'-yl) -9 , 10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 50 (S)); 1 (S), 3 (R) -bis - ((tert-butyldimethylsilyloxy) -20 (R) - (5'-hydroxy-5'-methylhexa-r (E), 3 '(E) -diene-1' -yl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 51); l (S), 3 (R) -bis - (N -butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxy-5'-methylhepta20 r (E), 3' (E) -diene- 1'-yl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 52 (R)); 1 (S), 3 (R) -bis - (/ ert.butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxy-5'-methylheptal' (E), 3 '(E) -diene- r-yl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 52 (S)); 1 (S), 3 (R) -bis - ((tert-butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5'-hydroxyheptar (E), 3 '(E) -dien-1'-yl ) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 53);

(S), 3 (R) -bis- (Zert-butyldimethylsilyloxy) -20 (R) - (5'-hydroxy-5'-methylhexa-1 '(E), 3' (E) -dien-r-yl ) -9,10-secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 54); and l (S), 3 (R) -bis - (N -butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5'-hydroxyheptar (E), 3 '(E) -diene-l'- yl) -9,10-secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 55).

Among the preferred vitamin D derivatives of formula (I) are those with a C24 hydroxyl group, e.g. secalciferol, calcipotriol, tacalcitol, etc., a C25 hydroxyl group, e.g. catitriol, etc., or a C26 hydroxyl group, e.g. EB-1089 etc.

More specifically, the preferred vitamin derivatives of formula (I) are those with unsaturation (eg trans double bond or triple bond) between C22-C23 carbons, followed by a chain which may be hydroxylated at positions 24, 25 or 26 and / or contain other unsaturation.

Vitamin D derivatives of formula (I) can be obtained from an alkenylmonohalo derivative of formula (II) (») wherein

But the same meaning as above; and is

X is a halogen atom selected from chlorine, bromine and iodine.

In a particular embodiment, a compound of formula (II) is used wherein A is selected from Al, A2 and A3 and X is selected from chlorine, bromine and iodine, preferably iodine.

In another particular embodiment, a compound of formula (II) is used wherein A is Al and W is SO 2.

In another particular embodiment, a compound of formula (II) is used wherein Z and Z 'are independently a hydroxyl group or a hydroxyl group protected by a hydroxyl protecting group, e.g. such as a silyl or acyl derivative, and R ' _b R' ₂ and R ' _{3 are} simultaneously hydrogen.

In another particular embodiment, a compound of formula (II) is used wherein A is selected from Al, A2 and A3; X is selected from chlorine, bromine and iodine, preferably iodine; Z and Z 'are, independently of one another, a hydroxyl group or a hydroxyl group protected by a hydroxyl protecting group, e.g. such as a silyl or acyl derivative, and R'i, R ' ₂ and R' _{3 are} simultaneously hydrogen.

In a specific embodiment, a compound of formula (II) is selected from the group consisting of compounds of formulas (IIA1), (IIA2) and (ΙΙΑ3):

Compounds IIA1

MDBTS

I (IIA1b)

Compounds of IIA2

(IIA2a)

(IIA2b) (IIA3a)

(IIA3b) where

STBDM or MDBTS tert.butyldimethylsilyl group; and Ac is an acetyl group.

The compound of formula (II) used is a compound in which C22-C23 has a double bond trans stereochemistry.

The compounds of formula (II) can be used to prepare compounds of formula (I) by processes comprising the pre-formation of a large variety of organo-wine compounds by substituting the halogen present in the compound of formula (II) with a metal, optionally complexed. These organometallic intermediates can be used satisfactorily to form new CC bonds in the synthesis of vitamin D derivatives of formula (I), preferably in the synthesis of those compounds of formula (I) by unsaturation (e.g., trans double bond or triple bond) between C22-C23 carbons, followed by a chain which may be hydroxylated at positions 24, 25 or 26 and / or contain other unsaturation. Unsaturated compounds, on the other hand, can be reduced to saturated compounds after preliminary protection of the triene system.

More specifically, the invention provides a process for the synthesis of a vitamin D derivative of a previously defined formula (I) from a compound of formula (II), comprising (i) reacting an alkenyl monohalo derivative of formula (II) with (A) a compound of formula

M (NR ₈ R ₉ ) where

M alkali metal and sta

Rg and R ₉ independently of one another hydrogen; C1-C6 alkyl; C _r C6 alkylsilyl; or C ₃ -C ₆ cycloalkyl, in a solvent to give the corresponding metal alkynylide, and then reacting the metal alkynylide with a compound selected from:

compounds of formula

R ₅ CON (CH ₃ ) OCH ₃ wherein R _{5 has the} same meaning as above and the compounds of formula

R _{5 is} CHO where R _{5 has the} same meaning as above;

to give a compound of formula (I) wherein m = 0, n = 1 and p = 0; or with (B) a metal alkoxide of formula

MOR10 where it is

M is an alkali metal and is

Rio C1-C8 alkyl;

in a solvent and then with a silyl agent and then with an alkyl lithium compound of formula

LiR ₁₀ where R _{10 has the} same meaning as above;

to give the corresponding lithium alkynylide; and then reacting lithium alkynylide with a compound selected from:

compounds of formula

R ₅ CON (CH ₃ ) OCH ₃ wherein R _{5 has the} same meaning as above and the compounds of formula

R _{5 is} CHO where R _{5 has the} same meaning as above;

to give a compound of formula (I) in which nr = 0, n = l and p = 0, or (C) a compound of formula

M (NR ₈ R ₉ ) wherein M, R _s and R _{9 have the} same meanings as above; in the first solvent and then with the epoxide of the formula

Ο

FL

R, where R ₅ and R 4 have the same meanings as above, in another solvent, to give a compound of formula (I) in which m = 0, n = 1 and p = 1; or with (D) a palladium or nickel complex in a solvent and an organometallic compound of formula (T) ₀ M '(CR ₃ R ₄ ) pCHR ₅ R ₆ where

M 'is selected from Li, Mg, Zn, Al, Zr, B and Sn;

T is halogen or C1-C5 alkyl;

o is 0 or 1, which is 0 when M 'is a monovalent metal; and p, R ₃ , R 4, R ₅ and R 1 have the same meanings as above; to obtain a compound of formula (I) wherein m = 1, n = 0 and p = 1-6; or with (E) a compound of formula

M (L ') q where

M is selected from alkali metal, alkaline earth metal, Zn, Cu and Ti; L'is halogen, C 1 -C 5 alkyl, triphenylphosphine, cyanide or sulfocyanide; and q is an integer selected from 0, 1,2, 3, 4, 5 and 6;

in a solvent to give the compound of formula (E) vM (L ') q where

E is a residue of the formula

where A has the same meaning as above;

v is an integer between 1 and the valence of the metal M; and they have

M, L 'and q have the same meanings as above, with the proviso that v + q represents the valence of M and / or the coordination number of M; and then reacting the compound with the compound of formula

RsCOK wherein R5 and R4 have the same meanings as above;

to give a compound of formula (I) wherein m = 1, n = 0 and p = O;

or with (F) a chromium compound in the presence of a nickel and / or palladium salt in a solvent and with a compound of the formula

R5COR6 where R ₅ and R ₍ have the same meanings as above;

to give a compound of formula (I) wherein m = 1, n = 0 and p = 0;

or with (G) a palladium compound in the presence of a base in the solvent and with a ketone of formula

CH ₃ COR ₅ wherein R _{5 has the} same meaning as above except hydrogen;

to give a compound of formula (I) wherein m = 1, n = 0 and p = 1;

or with (H) a palladium compound in the presence of a base and optionally complexed copper salt (I) in a solvent, optionally in the presence of a phase transfer catalyst, and with propargyl alcohol of the formula

CH = CC (OH) R ₅ Ri where R ₅ and R _{0 have the} same meaning as above;

to give a compound of formula (I) wherein m = 1, n = 1 and p = 0;

or with (I) a palladium compound in the presence of a base in the solvent, optionally in the presence of a phase transfer catalyst, and with a compound of the formula

R _r CH = CH-COR ₅ wherein R 1 and R _{5 have the} same meanings as above;

to give a compound of formula (I) wherein m = 2, m = 0 and p = 0;

or with (J) a palladium compound in the presence of a base and a silver salt in a solvent and with a compound of the formula

R 1 -CH-C (OH) R ₅ R ₆ where R _b R ₅ and R _{6 have the} same meanings as above; to give a compound of formula (I) wherein m = 2, n = 0 and p = 0;

and optionally (ii) converting a compound of formula (I) into another compound of formula (I).

In a particular embodiment, the alternative that follows is Alternative (A), wherein the compound of formula (II) is selected from a compound of formula (IIA2) and a compound of formula (IIA3);

a compound of formula M (NR ₈ R 9) is selected from the group consisting of lithium diisopropylamide, lithium dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide and sodium amide;

a solvent is an organic solvent selected from ether, hydrocarbon and mixtures thereof, preferably tetrahydrofuran (THF);

an amide of the formula R ₅ CON (CH ₃ ) OCH ₃ is selected from cyclopropanecarboxylic acid A, A-methoxymethylhydroxylamide, 2-methylpropanoic acid and N, N -methoxymethyl-hydroxylamide; and the compound of formula R ₅ CHO is selected from 2-methylpropanal and cyclopropanecarboxaldehyde.

In another particular embodiment, the alternative that follows is Alternative B, wherein the compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

a metal alkoxide of the formula MOR10 is selected from the group consisting of sodium t-butoxide, potassium Z-butoxide, sodium Z-pentoxide and lithium ethoxide;

a solvent is a polar aprotic organic solvent selected from DMSO, DMF, DMPU, HMPT and mixtures thereof;

a silyl agent is a compound of the formula ClSi (Rii) (Ri ₂ ) (Ri ₃ ) wherein Rh, R ₂ and R _{3 are} independently hydrogen; Ci-C ₈ alkyl; C ₃ -C ₆ cycloalkyl; or C ₆ -C ₁₄ aryl; preferably Z-butyldimethylsilyl chloride;

an alkyl lithium compound of the formula LiR ₁₀ is selected from the group consisting of 2-butyl lithium and ethyl lithium;

an amide of the formula R ₅ CON (CH ₃ ) OCH3 is selected from the N, N-methoxymethylhydroxylamide of 2-methylpropanoic acid and the cyclopropanecarboxylic acid N, N-methoxymethyl-hydroxylamide; and the compound of formula R5CHO is selected from 2-methylpropanal and cyclopropanecarboxaldehyde.

In another particular embodiment, the alternative that follows is Alternative (C) wherein the compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

a compound of formula M (NRgR9) is selected from the group consisting of lithium diisopropylamide, lithium dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide and sodium amide;

the first solvent is ether, preferably THF; epoxide is zzo-butylene oxide; and the second solvent is a polar aprotic organic solvent, preferably DMPU.

In another particular embodiment, the alternative that follows is Alternative (D) wherein the compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

a palladium or nickel complex is a compound selected from the group consisting of dichloro (1,1 '-bis (diphenylphosphino) ferrocene) palladium, tetrakis (triphenylphosphine) palladium and dichloro (1,1' -bis (diphenylphosphino) ferrocene) nickel;

a solvent is an aprotic organic solvent selected from the group consisting of benzene, toluene, tetrahydrofuran, hexane and mixtures thereof; and an organometallic compound of formula (T) ₀ M '(CR 3 R 4) _p CHR ₅ R 6 is selected from diethyl zinc and isobutyl magnesium bromide.

In another particular embodiment, the alternative that follows is Alternative (E), wherein the compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

a compound of formula M (L ') q is selected from lithium, sodium, potassium, N-butyllithium, sec-butyl lithium and Z-butyllithium;

a solvent is an organic solvent selected from ether, hydrocarbon and mixtures thereof, preferably ethyl ether; and a compound of formula R ₅ COR (, selected from 2-methylpropanal, cyclopropanecarboxaldehyde, Z-butanecarboxaldehyde and cyclohexanecarboxaldehyde.

In another particular embodiment, the following is an alternative (F), wherein the compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2, and a compound of formula IIA3;

the chromium derivative is selected from chromium halide, chromocene and dichromocene;

a nickel salt is selected from nickel halide and nickel acetylacetonate; palladium evo salt is selected from palladium eve halide and palladium eve acetylacetonate;

solvent is a polar aprotic organic solvent selected from DMSO, DMF, DMPU, HMPT, DME and mixtures thereof; and the compound of formula R ₅ COR ₆ is selected from 2-methylpropanal, cyclopropanecarboxaldehyde, t-butanecarboxaldehyde and cyclohexanecarboxaldehyde.

In another particular embodiment, the alternative that follows is Alternative (G) wherein the compound of formula (II) is selected from a compound of formula IIA2 and a compound of formula IIA3;

a palladium compound is an optionally complexed palladium salt or palladium complex selected from palladium eve acetate or chloride complexed with a phosphine ligand selected from 3 - / - butylphosphine, tricyclohexylphosphine, Ι, Γbis (di - / - butylphosphine) pherocene, phenoxyphenyl-phenoxyphenyl-phenoxyphenyl-phenoxyphenol - (di-butylphosphine) ethylferocene, triphenylphosphine, ditriphenylphosphine, tetrakis- (triphenylphosphine), and tris (dibenzylidenoacetone) dipaladia;

the base is selected from (i) a metal alkoxide of the formula Morio, where M is alkali metal and R _is an C _r C6 alkyl; (ii) an amine of the formula N (R ₁₄₎ (R ₁₅₎ (R ₁₆₎ where R 14, R 15 and R ₁₆ independently of one another hydrogen, C _r C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ - C _{1 O} aryl; (iii) heterocyclic bases having 6 atoms of which at least 1 is nitrogen, e.g. pyridine; and (iv) an inorganic base selected from alkali carbonate and alkali hydroxide, the base being preferably Z-butoxide sodium; the solvent is a polar organic solvent selected from THF, DMF, benzene, dioxane, acetonitrile and mixtures thereof; and a ketone of formula CH ₃ COR ₅ is selected from acetophenone, methylcyclopropylketone and propanone.

In another particular embodiment, the following is an alternative (H) wherein the compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2, and a compound of formula IIA3;

a palladium compound is an optionally complexed palladium salt or palladium complex selected from palladium eve acetate or chloride complexed with a phosphine ligand selected from 3-Z-butylphosphine, tricyclohexylphosphine, 1,1'bis (di-Z-butylphosphine) ferrocene, diphenylphosphine, diphenylphosphine -2- (di-Z-butylphosphine) ethylferocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine), and tris (dibenzylideneacetone) dipaladia;

the base is selected from (i) a metal alkoxide of the formula MOR ₁₀ , in which M is an alkali metal and _{R 1 is} C ₁ -C ₆ alkyl; (ii) an amine of the formula N (R _I4) (R ₅₎ (R ₁₆₎ where R _14, R ₁₅ and R _J6 are independently selected from hydrogen, Ci-C ₆ alkyl, C ₃ -C 6 cycloalkyl, C ^ -Cio aryl; (iii) heterocyclic bases having 6 atoms, of which at least 1 is nitrogen, e.g. pyridine; and (iv) an inorganic base selected from alkali carbonate and alkali hydroxide, the base being preferably Z-butoxide sodium;

the phase transfer catalyst is alkylammonium halide, preferably tetrabutylammonium chloride;

optionally complexed copper salt (I) is selected from CuBr, Cul, optionally complexed with a phosphine ligand, preferably triphenylphosphine;

the solvent is selected from a base and an aromatic hydrocarbon, preferably benzene or toluene; and propargyl alcohol is selected from 3-methyl-1-butin-3-ol, 3-methyl-1-pentin-3ol, 3-ethyl-1-pentin-3-ol, and 1-butin-3-ol.

In another particular embodiment, the alternative to be followed is alternative (I). wherein the compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2, and a compound of formula IIA3;

a palladium compound is an optionally complexed palladium salt or palladium complex selected from palladium acetate or chloride complexed with a phosphine ligand selected from 3 - / - butylphosphine, tricyclohexylphosphine, 1,1'bis (di-butylphosphine) ferrocene, diphenylphosphino-diphenylphosphine-diphenylphosphine 2- (di - / - butylphosphine) ethylferocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine), and tris (dibenzylideneacetone) dipaladia; preferably palladium acetate, optionally complexed with triphenylphosphine or 3-Z-butylphosphine;

the base is selected from (i) a metal alkoxide of formula MOR _10, where M is alkali metal and R ₁₀ is C _r C ₆ alkyl; (ii) an amine of the formula N (R ₄₎ (R ₅₎ (R _16), wherein Ri4, R ₅ and R ₁₆ independently of one another hydrogen, C _r C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C _{1 O} aryl; (iii) heterocyclic bases having 6 atoms, of which at least 1 is nitrogen, e.g. pyridine; and (iv) an inorganic base selected from alkali carbonate and alkali hydroxide, the base being preferably potassium carbonate;

the phase transfer catalyst is alkylammonium halide, preferably tetrabutylammonium chloride;

a solvent is a polar solvent selected from THF, DMF, dioxane, acetonitrile and mixtures thereof; and the compound of formula Rj-CTUCU-CORs is selected from methyl acrylate, ethyl acrylate, acrolein and vinylmethylketone.

In another particular embodiment, the following is an alternative (J) wherein the compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2, and a compound of formula IIA3;

the palladium compound is an optionally complex palladium salt or palladium complex selected from palladium acetate or chloride complexed with a phosphine ligand selected from 3-Z-butylphosphine, tricyclohexylphosphine, 1,1'bis (di-t-butylphosphine) ferrocene, diphenylphosphine, diphenylphosphine -2- (di-t-butylphosphine) ethylferocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine), and tris (dibenzylideneacetone idipaladium; preferably palladium acetate, optionally complexed with 3-tbutylphosphine;

the silver salt is selected from silver acetate, silver carbonate and silver nitrate;

the solvent is a polar solvent selected from THF, DMF, dioxane, acetonitrile and mixtures thereof, preferably THF; and a compound of formula R1-CH2C1H2R5SIL is selected from 1-buten-3-ol, 1penten-3-ol, 3-methyl-1-buten-3-ol, 3-methyl-1-penten-3-ol, and l-Propen-3-ol.

If desired, the compound of formula (I) thus obtained can be converted to another desired compound of formula (I) by (a) forming SO ₂ adducts of compounds of formula (I) in which A is A2 or A3 by treatment with SO ₂ in a solvent to give a compound of formula (I) wherein A is Al and W is SO ₂ ;

or (b) reducing a compound of formula (I) containing at least a triple bond (n> 1) and a hydroxyl group (Y = OH) with a triple bond reducing agent, optionally in the presence of a base, in a solvent, that a compound of formula (I) containing at least one double bond and one OH group (Y = OH) is obtained; or by (c) reducing a compound of formula (I) in which D is -C (O) R ₅ with a carbonyl reducing agent in a solvent to give a compound of formula (I) in which Y is OH ; or (d) hydrogenating a compound of formula (I) in which m> 1 or n> 1 or m and n are both> 1, after prior protection with SO ₂ containing groups A2 or A3, in the presence of a metal catalyst in a solvent; or (e) decomposing the adduct of a compound of formula (I) in which A is Al and W is SO ₂ by heating in a solvent, in the presence of a base, to give a compound of general formula (I) in which A is A2; or by (f) photochemical isomerization of a compound of formula (I) in which A is A2 to give a compound of formula (I) in which A is A3; or (g) deprotecting a compound of formula (I) in which Z and Z 'are simultaneously hydroxyl groups protected by hydroxyl protecting groups by reaction with a deprotecting agent to give a compound of formula (I) wherein Z and Z 'simultaneously hydroxyl group.

In a particular embodiment, alternative (a) is carried out, comprising the use of a solvent such as an aprotic organic solvent selected from ether, methylene chloride, benzene and mixtures thereof, preferably methylene chloride.

In another particular embodiment, the alternative (b) comprises the use of a triple bond reducing agent such as aluminum hydride selected from Redal, LiAlH ₄ , methyl-di-iso-butylaluminum and lithium hydride; a base such as a metal alkoxide selected from sodium methoxide, sodium ethoxide and potassium ributoxide; in a solvent selected from ether, an aromatic hydrocarbon and mixtures thereof, preferably THF.

In another particular embodiment, while implementing alternative (c), this involves the use of a carbonyl group reducing agent such as a metal hydride or alkyl metal selected from alkyl lithium, alkyl cere, and organomagnesium, e.g. LiAlH ₄ , NaBH ₄ , Redala, Alpine-borane, Dibala, DIP-chloride, Ca (BH ₄ ) ₂ , NaBH ₄ / CeCl ₃ , methyl lithium or ethyl lithium.

In another particular embodiment, while performing alternative (d), this involves the use of a metal catalyst selected from Pd, Pt and Rh, preferably Pt / C; and a solvent comprising a polar solvent selected from methanol, ethanol, ethyl acetate, DMF and mixtures thereof, optionally admixed with an apolamic solvent selected from benzene, toluene and mixtures thereof, preferably ethanol / benzene mixtures.

In another particular embodiment, while implementing alternative (e), this comprises the use of a base selected from alkali carbonate and alkali bicarbonate, preferably sodium bicarbonate, and a polar solvent selected from methanol, ethanol, isopropanol, butanol, DMF and mixtures thereof, preferably DMF.

In another particular embodiment, photochemical isomerization of a compound of formula (I) in which A is A2 (alternative (f)) is carried out in a diffused daylight solvent and I ₂ optionally in the presence of an amine of formula N (Ri ₄ ) (Ri ₅₎ (Ri6), wherein R _14, R ₅ and R ₆ independently of one another hydrogen, C _r C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ Cio aryl; or by diffused light and I ₂ , optionally in the presence of a heterocyclic base of 6 atoms, of which at least 1 is nitrogen; or by phenyl diselenide and tungsten light or by ultraviolet light in the presence of an aromatic photosensitizer.

Photochemical isomerization with UV light is advantageous, the solvent is toluene and the photosensitizer is anthracene.

For the implementation of alternative (g), the nature of the hydroxyl protecting group must be taken into account; in an illustrative way:

when the hydroxyl protecting group is a silyl group, deprotection is carried out with a deprotecting agent selected from fluoride and alkoxide in a solvent, optionally in the presence of a phase transfer catalyst; and when the hydroxyl protecting group is an acyl group, deprotection with a deprotecting agent, such as a metal alkoxide or inorganic base, is carried out in a solvent, optionally in the presence of a phase transfer catalyst.

In a particular embodiment, the hydroxyl protecting group is a silyl group and the deprotecting agent is tetrabutylammonium fluoride in tetrahydrofuran or alternatively potassium tbutoxide in DMSO. In another particular embodiment, the hydroxyl protecting group is an acyl group and the deprotecting agent is sodium or potassium hydroxide and the solvent is ethanol.

The compound of formula (II) can be obtained by reaction of a compound of formula

wherein A has the same meaning as above with respect to a compound of formula (I), with a haloform selected from chloroform, bromoform and iodoform, in the presence of a salt or divalent chromium complex (Cr) in an organic solvent, as described in patent application no. 200302806, which is simultaneously pending.

Specific examples for the preparation of vitamin D derivatives of formula (I) from the compounds of formula (II) according to the process proposed by the present invention are described below, in accordance with the nomenclature of the procedures used in the examples and Tables 1 and 2. see, compounds of formula (II) are used to synthesize compounds of formula (I) by pre-forming a large variety of organometallic compounds by replacing the halogen (X) present in the compound of formula (II) with a metal with reagents generically named M (L) ) qin this description, where M is a metal, e.g. alkali metal (Li, Na, K, etc.), metal of the 6th group of the periodic system of elements (Cr, etc.), metal of the 10th group of the periodic system of elements (Ni, Pd, etc.), etc .; L is a ligand that forms covalent or complex ionic bonds, e.g. alkoxide, halide, alkylide, alkyl carboxylate, amide, phosphine derivative, etc .; and q is an integer between 0 and 6 and denotes a valence and / or coordination number of M.

Claims 1. The preparation of compounds of formula (I) in which m = 0, n = 1, p = 0 or 1 and Y = OH

Section A: p = 0

Procedure 1A / 1

These alkyne derivatives can be prepared according to the methodology described in Calverley (Bioorg. Med. Chem. Letter, 1993) or from the monohalogenalkenes (IIA2) and (IIA3) as described in the present invention by reaction with a compound of type M (L) qs formula M (NR ₈ R ₉ ), wherein M, R ₈ and R _{9 have the} same meanings as above as LDA, in THF, or with a compound of the formula MORio, wherein M and R _{0 have the} same meanings as above potassium tbutoxide (Z-BuOK) in DMSO. When the reaction is carried out with lithium diisopropylamide (LDA), the intermediate is obtained lithium salt (lithium alkynylide) (step 1a), while with Z-BuOK / DMSO we form desilylated alkyne (step 1b), which after being silylated with silyl by means, e.g. with a compound of the formula ClSi (Rn) (Ri ₂ ) (Ri ₃ ), where R _1b R 1 ₂ and R _{J 3 have the} same meanings as above, and treated with a LiR _10- type reagent where R 1 has the same meaning as above as n- BuLi also provided lithium alkynylide (step 2b). The resulting lithium alkinilid can be reacted with a suitable amide, Ν, Ν-metoksimetilhidroksilamina (level 2a), and the resulting propargyl ketone is reduced with reducing agents, such as DIP-chloride, R Li, NaBH _4, REDAL, Alpineboran, etc. (Level 3a); alternatively, the lithium salt can be reacted with an aldehyde (step 3b) of the formula R ₅ CHO, where R _{5 has the} same meaning as above.

Any other compound of formula M (NR ₈ Rq) may be used instead of LDA, e.g. lithium dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide, sodium amide, etc. The reaction is carried out in a solvent such as ether, hydrocarbon or a mixture of both, and at a temperature between -100 ° C and +50 ° C, preferably between -80 ° C and -70 ° C.

Similarly, another alkoxide of formula MOR _{! 0} may be used instead of Z-BuOK, e.g. sodium Z-butoxide, sodium Z-pentoxide, lithium ethoxide, etc., in a polar aprotic organic solvent such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), DMPU, HMPT, etc., with DMSO being the preferred solvent. The reaction is carried out at a temperature between -10 ° C and +120 ° C, preferably between 50 ° C and 60 ° C.

Step 2b), treatment with &quot; -BuLi (&quot; -buryl lithium) can also be carried out with another alkyl lithium of the formula LiR &apos;, e.g. ethyl lithium etc. to give the corresponding alkynylide.

Aldehydes 2-methylpropanal and cyclopropanecarboxaldehyde are among the preferred compounds of formula C ₅ CHO.

Cyclopropanecarboxylic acid Ν, Ν-methoxymethyl-hydroxylamide of 2-methylpropanoic acid and N, N-methoxymethylhydroxylamide are among the preferred amides of the formula

R ₅ CON (CH ₃ ) OCH ₃ .

The acetone obtained can be reduced by propargyl ketone reducing agents, such as NaBH ₄ , Alpine-borane, Dip-chloride, Redal etc., preferably Alpine-borane or Dip-chloride, if C-24 enriched alcohols are enriched (S / R ratio 9 / 1 for S-Alpine-borane according to Biorg Med Chem Chem Letter, 1993, S / R ratio 2.5 / 1 for (+) Dipchloride and 1/1 ratio when using aldehyde pathway (step 3b)).

Section B: p = 1

Procedure 1B / 1

This type of compound is obtained from a compound of formula (II), e.g. compounds of formula (IIA2a) or (IIA3a), by reaction of a compound of type M (L) qs formula MfNRgRp), wherein M, R ₈ and R ₉ are as defined above, and by the following reaction with an epoxide of formula

R

R 'where R ₅ and R 4 have the same meaning as above in the presence of a polar aprotic solvent according to the following scheme:

The same amides described by procedure 1A / 1 as LDA, lithium dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide, sodium amide, etc., preferably lithium derivatives, more preferably LDA, can be used as reagents of formula M (NR ₈ R ₉ ).

Epoxides are preferred zzo-butylene oxide.

The ether, hydrocarbon or mixture thereof is used as a solvent of step a), preferably TE1F.

A polar aprotic solvent, such as DMSO, DMPU, DMI, HMPT, TMU, etc., is added to the first solvent (step a)), preferably DMPU, as the solvent of step b) (second solvent).

The reaction is carried out at temperatures between -100 ° C and +50 ° C, preferably between -15 ° C and 5 ° C.

If the epoxy is chiral, a chiral alcohol is obtained which retains the optical purity of the epoxy.

2. Preparation of compounds of formula (I) in which m = l, n = 0, p = 0-6 and Y = H

Procedure 2/1

This type of compound is prepared by reaction of compounds of formula (IIA2) or (IIA3) with a palladium or nickel complex [reagent type M (L) q] in a solvent and with an organometallic compound of formula (T) _O M '(CR ₃ R4) _P CHR ₅ R <5, where T, M ', R ₃ , R 4, R ₅ , R 4, o and p have the same meanings as above, according to the equation:

Among the palladium or nickel complexes that may be used are phosphine derivatives such as dichloro (1, r-bis (diphenylphofmo) ferrocene) palladium, tetrakis (triphenylphosphine) palladium, dichloro (1,1 '-bis (diphenylphosphino) ferrocene) nickel etc .;

preferably tetrakis (triphenylphosphine) palladium.

Preferred are those in which M 'is Mg or Zn, and among them diethyl zinc and iso-butyl magnesium bromide.

The reaction is carried out in an aprotic solvent or mixtures thereof, preferably in benzene, toluene, THF and hexane, or mixtures thereof, at a temperature between 30 ° C and +60 ° C, preferably between 20 ° C and 30 ° C.

3. Preparation of compounds in which m = l, n = 0, p = 0 and ¥ = OH

Procedure 3/1

This type of compound can be prepared by the reaction of a monohalogenalkene of formula (II), e.g. Compounds of formula (IIA2a) or (IIA3a), with reagent type M (L) qs having the general formula M (L ') q, where M, L' and q have the same meanings as above with respect to alternative (E) of the preparation process compounds of general formula (I), and the following reaction with an aldehyde or with a ketone according to the formula:

The intermediate organometallic compound of formula (Via) can be prepared in various ways, for example:

a) by direct insertion of a metal, in particular alkali metal, alkaline earth metal or Zn, preferably lithium;

b) by reaction with an organometallic, in particular lithium derivative or magnesium derivative, e.g. n-BulI, .veLBuLi, Z-BuLi, CH ₃ BrMg, etc .;

c) by transmetallizing the compounds of section b) (especially when the metal is a transition metal), e.g. by transmetallizing the lithium derivative with Znl ₂ , CuBr, Cel _3, etc.

An intermediate organometallic compound of formula (Via) is advantageously obtained by reaction with an organometallic compound, preferably by reaction with / -BuLi.

The reaction is carried out in an organic solvent selected from ether, hydrocarbon and mixtures thereof, preferably ethyl ether, at a temperature between -100 ° C and +25 ° C, preferably between 70 ° C and -80 ° C.

Among the carbonyl compounds of formula R ₅ COI%, preferred aldehydes, e.g. 2methylpropanal, cyclopropanecarboxaldehyde, trimethylacetaldehyde or cyclohexanecarboxaldehyde.

When R ₅ and Rg are different from each other, the resulting alcohols are chiral at C-24, with S / R distances equal to 1 and greater than that obtained by reduction of the corresponding ketone with NaBH ₄ . This Sisome increase is achieved without the need to use chiral reagents or catalysts.

Procedure 3/2

These compounds can also be obtained by reduction of the corresponding alkynes (m = 0, n = l, p = 0) by suitable reducing agents, e.g. metal hydrides.

reduce the * »means

R,

OH '6

Alkines can be prepared according to the methodology described in Section A of Chapter 1: Preparation of Compounds of Formula (I) in which m-0, n = 1, p = 0 and Y = OH.

The triple bond can be reduced to give the corresponding rans-alkene, with metal hydrides, preferably aluminum hydride derivatives such as Redal, LiAlH ₄ , lithium and methyldiisobutylaluminium hydride, etc., optionally in the presence of a base, e.g. alkoxide, such as sodium methoxide, sodium ethoxide, potassium ributoxide, etc. The triple bond reduction is preferably carried out with Redalo or LiAlH ₄ and Cyl ₃ ONa.

This reaction is carried out in an organic solvent selected from ether, e.g. ethyl ether, dioxane, THF, etc., hydrocarbons, e.g. benzene, toluene, etc., and mixtures thereof, preferably THF, dioxane or mixtures thereof.

The reaction may be carried out at a temperature between 0 ° C and the boiling point of the solvent, preferably at a temperature between 60 ° C and 70 ° C.

When R ₅ and R 4 are different, the alcohols obtained are chiral, with the S / R ratio at C-24 being equal to that of the starting propargyl alcohol (which can reach 9/1 if the propargyl alcohol is prepared by reducing its corresponding ketone with ( S) -Alpineborane).

Procedure 3/3

Another way of preparing these compounds is to react a compound of formula (II), e.g. compounds of formula (IIA1), (IIA2) or (IIA3), with a carbonyl compound in the presence of a chromium compound [reagent M (L) q] and catalytic amounts of Ni or Pd salts according to the equation:

5 \

C = O

Among the preferred chromium compounds are those in which chromium is divalent chromium (Cr ⁺² ), e.g. CrCl2, chromocene, dichloro-chromocene, etc., preferably CrCl ₂ ; which can also be used in catalytic amounts and regenerated with Mn or using CrCl ₂ obtained by in situ reduction of CrCl ₃ with Mn or tetrakis (dimethylamino) ethylene.

Preferred Ni ²⁺ or Pd ²⁺ salts are selected from halides, preferably chlorides, and acetyl acetonate type organic salts.

This reaction is carried out in a polar aprotic organic solvent such as DMSO, DMF, DMPU, HMPT, DME, etc., preferably DMSO or DMF.

The reaction may be carried out at a temperature between -30 ° C and +70 ° C, preferably between 20 ° C and 30 ° C.

Preferred carbonyl compounds are aldehydes, including cyclopropanecarboxaldehyde and

2-methyl-propanaldehyde.

Preferred compounds of formula (II) are compounds of formula (IIA1).

As in procedure 3/1, if the alcohols obtained are chiral (R ₅ + R 4), the S / R isomers of the C-24 is 1/1.

Procedure 3/4

The preparation of these compounds can also be carried out by the one-pot procedure of aldehydes of formula (III) or (IV)

wherein Z, Z 'and W have the same meanings as above with respect to the compounds of formula (I), preferably of an aldehyde of formula (IV), by reaction with a haloform selected from chloroform, bromoform and iodoform, in the presence of a divalent chromium complex ( Cr ²⁺ ) or salts in an organic solvent without isolating the halogenated derivative according to the scheme:

Preferred starting aldehydes are SO ₂ adducts [compounds of formula (IV) wherein W is SO ₂ ].

The preferred haloform is iodoform (I3CH).

2 “b

In fact, any divalent chromium salt (Cr) can be used; however, in a particular embodiment, the divalent chromium salt is selected from Cl ₂ Cr, chromocene, dichlorochromocene or Cl ₃ Cr, reduced in situ by e.g. Mn (Mn / Et ₃ SiCl) or tetrakis (dimethylamino) ethylene, preferably Cl ₂ Cr. This salt can be used in catalytic amounts, regenerating it with Mn or Mn / Et ₃ SiCl.

The solvent of step a) is a polar aprotic organic solvent, preferably THF. The solvent of step b) is a polar aprotic organic solvent, preferably DMF or DMSO.

The first reaction step [step a)] can be carried out at a temperature between -80 ° C and +60 ° C, preferably between -5 ° C and +5 ° C. The second step [step b)] can be carried out at a temperature between -30 ° C and +60 ° C, preferably 20 ° C and 30 ° C.

Preferred carbonyl compounds are preferably 2-methylpropanal and cyclopropanecarboxaldehyde.

Even in this case, if R _{5 is} R ^, the S and R isomers are formed at C-24 at a 1: 1 ratio.

Procedure 3/5

Compounds obtained according to processes 3/3 and 3/4 protected in the form of SO ₂ adducts can be reversed into a triene system (decomposition of the adduct) by heating in a polar solvent such as ethanol, isopropanol, butanol, DMF, etc., in the presence bases such as alkali carbonate or bicarbonate. In a particular embodiment, the decomposition of the adduct is carried out at 80 ° C in DMF or EtOH and in the presence of NaHCO ₃ .

Procedure 3/6

Compounds with the / rans-triene system at C-5 obtained by procedures 3/1, 3/2 and 3/5 can be converted to their corresponding cis homolog at C-5 by photochemical isomerization with diffused daylight and I ₂ , after optionally in the presence of (i) an amine of formula N (R ₁₄ ) (Ris) (R ₁₆ ), wherein R _J4 , Ris and R _{16 have the} same meanings as above, or (ii) heterocyclic bases having 6 atoms, of which at least one nitrogen, e.g. pyridine; or by treatment with phenyl diselenide and tungsten light or by treatment with ultraviolet light in the presence of aromatic photosensitizers such as anthracene, acetylanthracene, phenazine, acridine, etc., in an apolamic organic solvent such as hexane, toluene, benzene, xylene, tbut, etc.

Procedure 3/7

Compounds prepared by the preceding processes (3/1 to 3/6) which were protected in hydroxides at positions 1 and 3 (Z = Z-hydroxyl protected by a hydroxyl protecting group) can be deprotected with fluorides or alkoxides when R a silyl radical, optionally in the presence of a phase transfer catalyst such as crown ether or tetraalkylammonium halide, at a temperature between 0 ° C and 65 ° C to give compounds of formula (I) in which Z = Z '= OH. Tetrabutylammonium fluoride is preferably used at a temperature between 0 ° C and 65 ° C.

Procedure 3/8

Compounds prepared according to the previous procedures 3/1 to 3/6, which were protected in hydroxides at positions 1 and 3 (Z = ZZ = hydroxyl protected by a hydroxyl protecting group) can be deprotected by treatment with alkoxides or inorganic bases, preferably sodium or potassium inorganic bases, where the hydroxyl protecting group is an acetyl group, optionally in the presence of a phase transfer catalyst such as crown ether or tetraalkylammonium halide, at a temperature between 0 ° C and 65 ° C to obtain compounds of formula (I) in which is Z = Z-OH. In a particular embodiment, deprotection in this case is performed with EtOH / NaOH or EtOH / KOH at a temperature between 0 ° C and 65 ° C.

This hydrolysis can also be carried out on the reaction crude product of process 3/5 without isolating the de-added products.

4. The preparation of compounds of formula (I) in which m = 1, n = 0, p = 1 and D = C (O) R _S, or

D = CRsRfiY, where Y = OH

Procedure 4/1

Compounds of formula (I) in which DC (O) is R ₅ can be obtained by reacting a compound of formula (II) as a compound of formula (ΙΙΑ2) or (IIA3) by condensation with a ketone in the presence of palladium compound [Pd (L) q], as a palladium complex or a complex palladium salt and a suitable ligand, such as e.g. phosphine type ligand according to the following scheme:

Among the palladium compounds that may be used are palladium acetate or palladium chloride, optionally complexed with 3-Zerc.butylphosphine, tricyclohexylphosphine, 1,1'bis (di-Zerc.butylphosphine) ferrocene (D - / - BPF), diphenylphosphine- 2- (diZere.butylphosphino) ethylferocene (PPF - / - Bu ₂ ), etc., and palladium complexes, such as tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ); preferably palladium acetate complexed with 3-Zerc.butylphosphine is used.

The reaction is carried out in the presence of a base selected from (i) a metal alkoxide of the formula MOR10 ⁱⁿ which M and R10 have the same meanings as above; (ii) an amine of formula N (R _{) 4} ) (R ₁₅ ) (R ₁₆ ), wherein R ₁₄ , R ₁₅ and R _{16 have the} same meanings as above; (iii) heterocyclic bases having 6 atoms, at least one of which is nitrogen; and (iv) inorganic bases selected from alkali carbonate and alkali hydroxide. The base is preferably sodium Z-butoxide.

The reaction is carried out in a polar organic solvent, such as THF, dioxane, benzene, DMF, acetonitrile, etc., preferably THF, at a temperature between -10 ° C and the boiling point of the solvent, preferably between 10 ° C and 30 ° C.

In the ketone of formula CH ₃ COR ₅ , R _{5 has the} same meaning as above. Acetophenone, methylcyclopropyl ketone and propanone are preferred among the ketones that can be used.

Procedure 4/2

Reduction of ketones obtained by process 4/1 with a suitable reducing agent such as alkyl metal or metal hydride gives a compound of formula (I) in which m = 1, n = 0, p = 1 and D = CR 5 R 6 Y, where Y = OH, according to the following scheme:

Examples of metal hydrides that may be used include LiAlH ₄ , NaBH ₄ , Redal, Alpine-borane, Dibal, DIP-chloride, Ca (BH ₄ ) ₂ , NaBH ₄ / CeCl ₃ , etc., preferably NaBH ₄ .

Among the alkyl metals that can be used are alkyl lithium, organomagnesium, alkyl ceria, etc., preferably alkyl lithium, wherein the alkyl moiety is a low molecular weight alkyl moiety, e.g. CRC ₆ alkyl radical.

The reaction is carried out in a solvent selected to be compatible with the reducing agent used, e.g. in the ether, hydrocarbon or mixture of such solvents, preferably THF.

The reaction may be carried out at a temperature between -100 ° C and +20 ° C, preferably between -60 ° C for reaction with alkyl lithium and between -20 ° C and 0 ° C for reaction with metal hydrides.

5. Preparation of compounds m = 1, n = 1, p = 0, Run Ra = alkyl and Y = OH

Procedure 5/1

It is possible to introduce hydroxylated alkynes from compounds of formula (II), e.g. of halogen derivatives (IIA1), (IIA2) or (IIA3), using the palladium compound [Pd (L) q], as a palladium complex or optionally complexed palladium salt, base, copper salt [Cu ⁺ ] and propargyl alcohol according to the following scheme :

CH = C — Ο _χ

Among the palladium compounds that may be used are palladium chloride or acetate, optionally complexed with tri-tert.butylphosphine, tricyclohexylphosphine, l, l'-bis (di / erc. Butylphosphinepherocene (D - / - BPF), diphenylphospho-2 - (diterc.butylphosphino) ethylferocene (PPF - / - Bu ₂ ), etc., and palladium complexes such as tris (dibenzylideneacetone) dipaladium (Pd ₂ (dba) ₃ ), PdCl ₂ ) PPh ₃ ) ₂ , tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ) etc. In a particular embodiment, the palladium compound is selected from PdCl ₂ , PdCl ₂ (PPh ₃ ) ₂ and Pd (PPh ₃ ) ₄ ), preferably Pd (PPh ₃ ) ₄ .

The reaction is carried out in the presence of a base selected from (i) a metal alkoxide of the formula Morio, in which M and _{R) 0} have the same meanings as above; (ii) an amine of the formula N (R ₁₄₎ (R ₅₎ (Ri6), wherein R _i4, Ri ₅ and R ₁₆ have the same meanings as above; (iii) heterocyclic bases having 6 atoms, at least one of which is nitrogen; and (iv) inorganic bases selected from alkali carbonate and alkali hydroxide. The base is preferably selected from triethylamine, pyridine, NaOH and CO ₃ K ₂ and more preferably concentrated sodium hydroxide.

The yield of the reaction can be increased by using a phase-transfer catalyst when the base is dissolved in water, such as quartemic ammonium halide, e.g. benzyltriethylammonium chloride.

Copper halide (I) optionally complexed with a suitable ligand, e.g. with a phosphine ligand such as BrCu, ICu, ICu.PPh ₃ etc., preferably ICu, can be used as a copper salt.

Only the base, if it is organic, or hydrocarbon, can be used as the reaction solvent. If the base is dissolved in water (inorganic), in this case hydrocarbons are aromatic hydrocarbons such as benzene, toluene, etc.

The reaction is carried out at a temperature between 0 ° C and the boiling point of the solvent, preferably at a reflux temperature for organic bases and at a temperature between 20 ° C and 30 ° C for aqueous inorganic bases.

As propargyl alcohols of the formula CHsC-C (OH) R ₅ R ₆ , wherein R ₅ and R ₍ , having the same meanings as above, are preferred 3-methyl-1-butin-3-ol, 3-methyl-1-pentin -3-ol, 3-ethyl-pentin-3-ol and 1-butin-3-ol.

If Rs ^ Rfi, the S / R isomer of 1: 1 at C-26 is obtained if it is derived from racemic propargyl alcohol.

If propargyl alcohol is optically pure on one of the 2 enantiomers, only S or only R is the final product.

6. Preparation of compounds of formula (I) in which m = 2, n = 0, p = 0.

SECTION A: R ₄ = H, alkyl, -OR ₇ and D = C (O) R 1

Procedure 6A / 1

This type of compound is prepared by reaction of a compound of formula (II), e.g. compounds of formula (IIA1), (IIA2) or (IIA3), with an alkene having a carbonyl function in the presence of a base, this reaction catalyzing the effect of the palladium compound [Pd (L) q], as a palladium complex or optionally complexed palladium salt , according to the following scheme:

Among the palladium compounds that can be used are palladium acetate, optionally complexed with a phosphine ligand, e.g. tri-n-butylphosphine, tri./erc.butylphosphine, triphenylphosphine, tricyclohexylphosphine, l, r-bis (di- / ert.butylphosphine) ferrocene (D-tBPF), diphenylphospho-2- (di-tert.butylphosphino) ethylferocene PPF -? - Bu2), etc., and palladium complexes such as tris (dibenzylideneacetone) dipaladium (Pd ₂ (dba) ₃ ); preferably palladium acetate complexed with tri-n-butylphosphine or triphenylphosphine is used.

The reaction is carried out in the presence of a base selected from (i) a metal alkoxide of the formula MOR10, wherein M and R10 _{have the} same meanings as above; (ii) an amine of formula N (Ri ₄ ) (Ri ₅ ) (R ₁₆ ) wherein R ₁₄ , Ri ₅ and R _{16 have the} same meanings as above; (iii) heterocyclic bases having 6 atoms, at least one of which is nitrogen; and (iv) inorganic bases selected from alkali carbonate and alkali hydroxide. The base is preferably sodium / -butoxide.

The reaction is carried out in a polar organic solvent, such as THF, dioxane, benzene, DMF, acetonitrile, etc., preferably THF, at a temperature between -10 ° C and the boiling point of the solvent, preferably between 10 ° C and 30 ° C.

The reaction is carried out in the presence of a base selected from (i) a metal alkoxide of the formula MOR ₁₀ , wherein M and R _{10 have the} same meanings as above; (ii) an amine of formula N (Ri ₄ ) (Ri ₅ (Ri ₆ ) wherein R ₁₄ , Ri ₅ and Ri _{6 have the} same meanings as above; (iii) heterocyclic bases with 6 atoms of which at least one is nitrogen; and (iv) inorganic bases selected from alkali carbonate and alkali hydroxide The base is preferably selected from triethylamine, Na ₂ CO3, K ₂ CO3, Cs ₂ CO3, KOH, etc., more preferably K ₂ CO ₃ . use a phase transfer catalyst such as quartemic ammonium halide, eg tetrabutylammonium chloride.

A polar solvent such as water, DMF, dioxane, THF, acetonitrile or mixtures thereof, preferably a THF / DMF mixture, can be used as the reaction solvent.

The reaction may be carried out at a temperature between -10 ° C and the boiling point of the solvent, preferably between 20 ° C and 30 ° C.

Among the α, β unsaturated carbonyl compounds that may be used are methyl or ethyl acrylate, vinylmethyl ketone and acrolein.

SECTION B; R <1> and R <4> alkyl and Y = OH

Procedure 6B / 1

These compounds can be obtained from the compounds of the preceding Section 6A / 1, converting the carbonyl function to alcohol by reduction with a suitable reducing agent, such as an organometallic metal compound of the type of alkyl metal or metal hydride, according to the following scheme:

Among the alkyl metals that can be used are alkyl lithium, organomagnesium, alkyl ceria, etc., preferably alkyl lithium, wherein the alkyl moiety is a low molecular weight alkyl moiety, e.g. Ci-C ₆ alkyl radical.

Examples of metal hydrides that may be used include LiAlH ₄ , NaBH ₄ , Redal, Alpine-borane, Dibal, DIP-chloride, Ca (BH ₄ ) ₂ , NaBH ₄ / CeCI _3, etc., preferably NaBH ₄ / CeCl ₃ .

The reaction is carried out in a solvent selected to be compatible with the reducing agent used. In a particular embodiment, the solvent comprises one or more polar organic solvents, e.g. THF or THF / MeOH for reduction with NaBH ₄ / CeCl ₃ .

The reaction may be carried out at a temperature between -100 ° C and +35 ° C, preferably between -60 ° C and -70 ° C for reactions with alkyl lithium and between -15 ° C and +25 ° C for reactions with metal hydrides.

Procedure 6B / 2

These compounds may also be obtained by reaction of a compound of formula (II), e.g. compounds of formula (IIA1), (IIA2) and (IIA3), with an alkene having a hydroxyl function at as formula R 1 CH = C (OH) R ₅ R 6, where R _b R ₅ and R (, have the same meanings as above; in an alkaline medium in the presence of silver salts, the reaction being catalyzed by the effect of the palladium compound [Pd (L) q], as a palladium complex or an optionally complex palladium salt, according to the following scheme:

Among the palladium compounds that may be used are palladium acetate or chloride, optionally complexed with tri - / e rc.butyl phosphine, tricyclohexylphosphine, l, l * - bis (difert.butylphospho myferocene (DZ-BPF), diphenylphosphino-2- ( diferc.butylphospho) ethylferocene (PPF - / - Bu2), etc., and palladium complexes such as tris (dibenzylideneacetone) dipaladium (Pd ₂ (dba) ₃ ); preferably, palladium acetate (PdAc ₂ ) complexed with phosphine, such as triphenylphosphine or tri-rerc.butylphosphine.

The reaction is carried out in the presence of a base selected from (i) a metal alkoxide of formula MOR 5, wherein M and R _{10 have the} same meanings as above; (ii) an amine of formula (N (Ri ₄ ) (R ₁₅ ) (R ₁₆ ) wherein R ₁₄ , R ₁₅ and R _{16 have the} same meanings as above; (iii) heterocyclic bases with 6 atoms of which at least one nitrogen; and (iv) inorganic bases selected from alkali carbonate and alkali hydroxide The base is preferably selected from K ₂ CO ₃ , Cs ₂ CO ₃ and Et ₃ N, more preferably Cs ₂ CO ₃ .

An organic salt such as silver acetate, etc., or an inorganic salt, e.g. silver carbonate or nitrate; the silver salt used is preferably silver carbonate.

The reaction is carried out in a polar organic solvent such as CH ₃ CN, DMF, THF, dioxane or mixtures thereof, preferably THF.

The reaction may be carried out at a temperature between 0 ° C and the reflux temperature of the solvent, preferably between 60 ° C and 70 ° C.

In a particular embodiment, a compound of formula R 1 -CH = C (OH) R ₅ R ₅ 'wherein R _b R ₅ and R _{(1 have the} same meanings as above) is selected from l-propen-3-ol, l-butyl-3- ol, 1-penten-3ol, 3-methyl-1-buten-3-ol, and 3-methyl-1-penten-3-ol.

When R ₅ and R 4 are different from each other, chiral allyl alcohols are obtained, with the S / R isomers being equal to that of the starting alcohol (if racemic, 1 will be).

Procedure 6B / 3

These compounds can also be obtained by reducing the triple bond of the compounds prepared according to the 5/1 process with a suitable reducing agent according to the following scheme.

The triple bond can be reduced to give the corresponding trans alkene, with metal hydrides, preferably aluminum hydrides such as Redal, LiAlH ₄ , methyl disobutylaluminum and lithium hydride, optionally in the presence of a base, such as a metal alkoxide, e.g. sodium methoxide, sodium ethoxide, potassium Z-butoxide, etc .; preferably with Redal or LiAlH ₄ / MeONa.

The reaction is carried out in an organic solvent selected from ether, e.g. ethyl ether, dioxane, THF, etc., a hydrocarbon such as an aromatic hydrocarbon, e.g. benzene, toluene, xylene, etc., or mixtures thereof, preferably THF, dioxane or mixtures thereof.

The reaction is carried out at a temperature between -10 ° C and the reflux temperature of the solvent, preferably between 60 ° C and 70 ° C.

When R ₅ and R 4 are different from each other, chiral allyl alcohols are obtained with an S / R isomer ratio equal to that of the parental propargyl alcohol.

7. The preparation of compounds of formula (I) in which m = 0, n = 0, p> 2

These compounds can be prepared from the compounds of interest to us in the previous reduction sections, e.g. by catalytic hydrogenation with 5% platinum on the carbon support after preliminary protection of the triene system, if unprotected, and its subsequent deprotection. The triene system can be protected by any suitable conventional method, e.g. by forming SO ₂ adducts by reaction with liquid SO ₂ in an aprotic organic solvent such as ether, methylene chloride, benzene, etc.

In a particular embodiment, the reduction is carried out with H ₂ and the transition metal, such as Pd, Pt, Rh, etc., preferably 5% Pt on the carbon carrier; in polar solvents such as methanol, ethanol, ethyl acetate, etc., or in mixtures of polar solvents with apolymer solvents such as benzene, toluene, etc.

By carefully selecting the reducing agent, partial reductions can be made, e.g. of alkynes to alkenes (cis) or, if there is more than one double bond, only one of them can be reduced.

Saturated compounds with carbonyl function can be converted to the corresponding alcohols by reaction with alkyl metals (preferably alkyl lithium) or metal hydrides according to the methodology described in the previous sections.

When the reduction is complete, SO _{2 is} removed by conventional methods, e.g. by heating in a polar solvent such as ethanol, isopropanol, butanol, DMF, etc., in the presence of a base such as alkali carbonate or bicarbonate. In a special embodiment, the removal of SO ₂ is carried out at a temperature of 80 ° C in DMF or EtOH and in the presence of a base, preferably NaHCO ₃ .

As mentioned above, the compounds of formula (I) thus obtained can be converted, if desired, to other compounds of formula (I). Therefore, in a particular embodiment, the processes described in sections 3/5, 3/6, 3/7 and 3/8 can be applied, if desired or considered necessary, to the compounds obtained by the procedures described in the previous sections.

The following examples illustrate the invention and should not be construed as limiting.

In cases:

Nuclear magnetic resonance spectra (NMR, δ) were performed at 300 and 200 MHz in CDC1 ₃ solution using TMS or CHCI3 internal standard. The coupling constants J are given in Hertz (s = singlet, d = doublet, t = triplet, dd = double doublet, AB = AB system, m = multiplet, and bb = wide band or sum of multiple signals).

Infrared spectra (IR) were performed with KBr pellets and only the most intense or characteristic frequencies are given in cm ^-1 .

High-performance liquid chromatography (HPLC) was performed with a normal phase column: Hypersil, 5 μπι and 4.6x100 mm and as eluents of a mixture of hexane and dichloroethane or ethyl acetate depending on the type of compound to be eluted and analyzed.

Preparative high performance liquid chromatography was carried out in a 10x250 mm Microporasil column or in 40 x 100 mm silica gel PrePac Waters.

Thin layer chromatography (TLC) was performed with Merck 60F254 silica gel plates.

Flash preparative chromatography was performed with silica gel 60A and 35-70 pm and at a pressure of 0.75-1.0 bar.

Photochemical reactions with ultraviolet light were performed with a TQ 500 Z2 Heraeus lamp.

The solutions were dried on anhydrous sodium sulfate containing 5% anhydrous Na ₂ SO ₄ and 5% anhydrous K ₂ CO ₃ ; they were filtered and concentrated on a rotary blade.

BTEAC stands for: benzyltributylammonium chloride.

DMAP stands for: dimethylaminopyridine.

DMI means: 1,3-dimethyl imidazolidinone.

DMPU stands for: Ν, Ν'-dimethylpropylene urea.

EBM stands for: t-butylmethyl ether.

HMPT stands for: hexamethylphosphorotriamide.

LDA means: lithium diisopropylamide.

TBAC stands for: tetramethylammonium chloride.

TBDMS stands for: Zert.butyldimethylsilyl.

TMU stands for: tetramethylurea.

All reactions were carried out under a nitrogen atmosphere and it was necessary to completely exclude the presence of O ₂ and H ₂ O in reactions in which Cr ²⁺ intervenes; and it is even necessary to weigh the reagent under a nitrogen atmosphere.

The reaction in which divalent chromium (Cr ²⁺ ) intervenes was always carried out with the highest possible absence of light to prevent cisltrans isomerization.

Examples of Preparation of Vitamin D Derivatives of Formula (I)

Vitamin D derivatives of formula (I) obtained by the process of the present invention are shown in Tables 1 and 2.

Table 1

Examples of derivatives of formula (I) in which D = CR ₅ R 6Y (CR 2 CR ₅ -C ₄ O-f C 4 R 4 -D (1a))

A '

The derivative A Z and T, ' m N P r ₅ Rč Y Process 1 < ^5E > / trans OSMD BT 0 1 0 - - 1A / 1 2 ; ά · Cis OSMD BT 0 1 0 - - - 1A / 1 5 (SE) / ^hc in JL OSMD BT 0 1 0 cyclopro- pil H OH 1A / 1 6 (NW) / , ώ: OSMD BT 0 1 0 cyclopro- Pil H OH 1A / 1

7 Z ΖΙ '' \ ^ Ν _Ζ · OSMD ΒΤ 0 1 1 methyl methyl OH 1B / 1 8 X OSMD ΒΤ 0 1 1 methyl methyl OH 7/1 9 (SE) / Ύχ OSMD ΒΤ 0 0 2 Η isopropyl OH 7/2 in 7/3 10 «X Λ OSMD ΒΤ 0 0 3 methyl methyl OH 7/3 13 ^(5Ε) ('Χλ OSMD ΒΤ 0 0 3 Η H H 7 / 1.7 / 2 and 7/3 14 (5Ε) / ^η JL ^! ο _ζ ι '' \ Ζ> ζ · OSMD ΒΤ 0 0 3 methyl methyl H 7/1 in 7/2 and 7/3 15 OSMD ΒΤ 0 0 3 methyl methyl OH 7/2

17 H C JI ; uj OSMD BT 1 0 1 H H H 2/1 18 ^<5 Y ^{, c} u OSMD BT 1 0 1 methyl methyl H 2/1 19 ^(5E> / OSMD BT 1 0 0 cyclo- propyl H OH 3 / 1.3 / 2, 3/5 20 (SE) / 'XX OSMD BT 1 0 0 i-butyl H OH 3/1 21 ^(5Z > (xx OSMD BT 1 0 0 cyclo- propyl H OH 3 / 1,3 / 2 and 3/6 22 (OT) f , cr '' ^^ 'Ζ · OSMD BT 1 0 0 iso- propyl H OH 3/1 in 3/6

23 (SE) / nA OSMD BT 1 0 0 cyclo- hexyl H OH 3/1 xS _z - (SE) / / ^H 2 ^c yA A Zl '' \ x J> Z- iso- 3/1 in 24 OSMD 1 0 0 propyl H OH 3/5 BT ^ ^CH 2 _Ζ Ά ^ k cyclo- 3/1 in 25 OSMD 1 0 0 hexyl H OH 3/6 BT (OT) A A ^ ^CH 2 Zl '' \ x L 3/1 in 26 OSMD 1 0 0 Z-butyl H OH 3/6 BT A ^ ^CH 2 _With l '' \ X k cyclo- 3/3, 3/7 27 OH 1 0 0 propyl H OH and 3/8

28 'Λ OH 1 0 0 cyclo- propyl H OH 3/4, 3/7 and 3/8 29 Ύ Η ^C v kk o _Z | i'k ^ k _z . OH 1 0 0 iso- propyl H OH 3/4 in 3/7 30 (OT) ζ , cr OH 1 0 0 iso- propyl H OH 3/3 in 3/7 31 (SZ) f a Zl''k ^ xN, _z . OAc 1 0 0 cyclo- propyl H OH 3/3 in 3/6 32 (SE) / HC, Jk o _Z K '<X ^ S _Z · OAc 1 0 0 cyclo- propyl H OH 3/4 in 3/5

33 ii OSMD BT 1 0 0 cyclo- propyl H OH 3/3 in 3/4 34 OSMD BT 1 0 0 isopropyl H OH 3/3 in 3/4 35 δΟρ-ηΧ ' _ζ ιΆχΑ _ζ · OAc 1 0 0 cyclo- propyl H OH 3/3 in 3/4 39 (SE) / ΎΧ OSMD BT 1 0 1 methyl methyl OH 4/2

40 ^<5 Ύ Ό OSMD ΒΤ 1 1 0 methyl methyl OH 5/1 41 <5Ε> / Η C JL in _Ζ | Ι '^^> _Ζ · OSMD ΒΤ 1 1 0 methyl ethyl OH 5/1 42 (5Ε) ζ Υι Ζΐ ' ^{, ς} Χζ ^> Ζ- OSMD ΒΤ 1 1 0 ethyl ethyl OH 5/1 43 (5Ε) Ζ OSMD ΒΤ 1 1 0 Η methyl OH 5/1

44 (5Ζ) / JL ^ CH q ' OSMD BT 1 1 0 ethyl ethyl OH 5/1 45 / J. OSMD BT 1 1 0 ethyl ethyl OH 5/1 48 (SE) / HC JL ^! o OSMD BT 2 0 0 H H OH 6B / 2 49 (SE) / ⁱⁿ OSMD BT 2 0 0 H methyl OH 6B / 2 in 6B / 3

50 Z OSMD ΒΤ 2 0 0 Η ethyl OH 6B / 2 51 (5Ε) / Ύχ OSMD ΒΤ 2 0 0 methyl methyl OH 6B / 1, 6B / 2 and 6B / 3 52 <5Ε) / XX OSMD ΒΤ 2 0 0 methyl ethyl OH 6B / 2 in 6B / 3 53 (SE) / Η C UL _ζ ιι ^ι1 \ Ζ> ζ · OSMD ΒΤ 2 0 0 ethyl ethyl OH 6B / 1 in 6B / 3

54 <5Z> ( OSMD BT 2 0 0 methyl methyl OH 6B / 2 X r -y ^CH 2 Z'C χΧ _Ζ · 55 OSMD 2 0 0 ethyl ethyl OH 6B / 3 BT

In all cases, R ₃ = R4 = Hzap ^ 0

Table 2

Examples of derivatives of formula (I) in which D = C (O) R ₅ ^ _in (CR = CR ₂ ) - (C _S C) - (CR ₃ R ₄ ) -D

J ( ^Ib )

K

The derivative A Z and Z ' m N P r ₅ D Process 3 ^<5 Y Ό OSMD BT 0 1 0 cyclo- propyl C (O) R ₅ 1A / 1

4 , 6? OSMD BT 0 1 0 cyclo- propyl C (O) R ₅ 1A / 1 11 OSMD BT 0 0 3 methyl C (O) R ₅ 7/2 12 (5E) / A OSMD BT 0 0 3 methyl C (O) R ₅ 7/3 16 X; OSMD BT 1 0 1 methyl C (O) R ₅ 7/1 36 “Ό OSMD BT 1 0 1 phenyl C (O) R ₅ 4/1

37 (SE) / Ό OSMD BT 1 0 1 cyclo- propyl C (O) R ₅ 4/1 38 (SE) With H C X XX OSMD BT 1 0 1 methyl C (O) R ₅ 4/1 46 (SE) With ^H 'U ζΐ'-Νχ ^ ζ- OSMD BT 2 0 0 methyl C (O) R ₅ 6A / 1 47 (SE) Z h k JL XX OSMD BT 2 0 0 och ₃ C (O) R ₅ 6A / 1

Claims 1. The preparation of compounds of formula (I) in which M = 0, n = 1, p = 0 or 1 and Y = OH SECTION A; p = 0

Procedure 1A / 1: Compounds (1), (2), (3), (4), (5) and (6)

Step la: Compound (1) ml of 1.5 M LDA was added dropwise to a solution of 2.30 g of the iodine derivative (IIA2a) in 25 ml of anhydrous THF and cooled for 1 hour at -70 ° C to ensure that the temperature did not go above - 65 ° C. After the addition is complete, stir for 5 minutes and add 5 ml of water. Allow the temperature to rise to 0 ° C and distribute the mixture between 200 ml EBM and 150 ml NH ₄ C1. The organic phase was separated and washed twice with 100 ml of brine each. The crude product was purified by flash chromatography eluting with hexane / Cl ₂ CH ₂ 10: 1 and 4: 1. The fractions containing the product were collected and concentrated to give 1.63 g of a white solid (87% yield).

Level Ib: Compound (1)

A solution of 1.4 g of the iodine derivative (IIA2a) in 10 ml of EBM and 30 ml of DMSO was heated at 55-60 ° C and 2.24 g of potassium / ether.butoxide was added in small portions. When the reaction is complete (usually 60-90 minutes), 100 ml of EBM is added, washed with NH4Cl solution and 3 times with 100 ml of brine each time, dried and placed in a rotary evaporator. The crude product was purified by flash chromatography eluting with 1: 1 hexane / ether and EBM. Product containing fractions were collected, concentrated and pre-silylated with tetrabutylsilyl chloride / imidazole to give 636 mg of white solid (93% yield).

Compound (1) 'HNMR

0.06 (s, 12H (CH ₃ -Si)), 0.57 (s, 3H (C-18)), 0.87 and 0.90 (2 s, 18H ((CH ₃ ) ₃ C)) , 1.24 (d, J: 7 Hz, 3H (C-21)), 2.03 (d, J: 116 Hz, 1H (C-23)), 4.22 (m, 1H (C-3) )), 4.53 (m, 1H (Cl)), 4.97 (d, J: 9Hz, 2H (C-19)), 5.83 (d, J: 11Hz, 1H (C-7)) , 6.455 (d, J: 11.2 Hz, 1H (C-6)) ppm

IR (KBr)

3313 and 2106 (C = CH), 1255, 1084, 837 and 724 (TBDMS groups), 1170 (CO), 908 (= CH ₂ ) cm ' ¹

Compound (2)

Alkin (2) is obtained from the iodine derivative (IIA3).

NMR (CDC1 ₃₎

0.06 (s, 12H (CH ₃ -Si)), 0.56 (2, 3H (C-18)), 0.88 (s, 18H ((CH ₃ ) ₃ C), 1.20 (d , J = 6.6 Hz, 3H (C-21)), 2.02 (d, J = 2.4 Hz, 1H (C-23)), 4.19 (m, 1H (C-3)) , 4.38 (m, 1H (C1)), 4.86 (d, J = 2.6 Hz, 1H (C-19)), 5.48 (s, 1H (C-19)), 5. 28 (d, J = 11.2 Hz, 1H (C7)), 6.30 (d, J = 11.8 Hz) ppm.

IR (KBr)

3320 and 2112 (C = CH), 1255,1084, 837 and 724 (TBDMS groups), 908 (= CH ₂ ) cm ' ¹

Step la + step 2a: Dissolve compounds (3) and (4) g (20 mmol) of compound IIA2 in 100 ml of anhydrous THF and in an N ₂ atmosphere. Cool to -78 ° C and add 1.5 M LDA in cyclohexane until more than 90% of the iodine derivative is converted to alkyne, with cannulae and dropwise, maintaining the temperature below -70 ° C.

Stirred for 1 hour at this temperature and then increased to +5 ° C. Add the same volume of LDA, stir for 15 minutes at this temperature and cool again to -40 ° C. Then 3.2 g of cyclopropanecarboxamide N, N-dimethylhydroxylamine are added dropwise 10 minutes. Stirred for 1 hour at this temperature and for 1 hour at 0 ° C.

Finally, it was partitioned between dilute bicarbonate and hexane and the organic phase was dried and purified by medium pressure flash chromatography eluting with increasing AcOEt mixtures in hexane from 0.5% to 3%. In this way 9.8 g (74%) of propargyl ketone (3) (white crystals) and 2.4 g of alkyne (1) are obtained (recuperating 20.2%).

The ketone (4) from alkyne IIA3a is also obtained.

Compound 3

NMR (CDC1 ₃₎

0.065 (s, 12H (CH ₃ -Si)), 0.58 (s, 3H (C-18), 0.86 and 0.90 (2s, 18 H, (CH _{3) 3} C)), 1.00 and

1.21 (2 m, 4H (C ₂₆ + C ₂₇ ), 1.28 (d, J = 6.8 Hz, 3H (C-21)), 2.63 (m, 1H, (C-25) ), 4.23 (m, 1H (C-3)), 4.54 (m, 1H (Cl), 4.95 and 4.99 (2s, 2H (C-19)), 5.84 (d , J = 11.8 Hz, 1H (C-7)), 6.45 (d, / = 11.8 Hz, 1H (C-6)) ppm.

IR (KBr)

2220 (C = C), 1255, 1084, 837 and 724 (TBDMS groups), 1664 (C = O), 1120 (CO), 908 (C = CH ₂ ) cm ¹ Compound (4)

NMR (CDC1 ₃₎

0.06 (s, 12H (CH ₃ -Si)), 0.58 (s, 3H (C-18), 0.86 and 0.90 (2s, 18 H (CH ₃ ) ₃ C)), 1 , 00 in

1.20 (2 m, 4H (C ₂₆ + C ₂₇ ), 1.27 (d, J = 6.8 Hz, 3H (C-21)), 2.63 (m, 1H, (C-25) ), 4.20 (m, 1H (C-3)), 4.39 (m, 1H (cl), 5.18 and 5.32 (2s, 2H (C-19)), 5.02 (d , J = 11.8 Hz, 1H (C-7)), 6.24 (d, 7 = 11.8 Hz, 1H (C-6)) ppm.

IR (KBr)

2220 (C = C), 1255, 1084 (bb includes C-0 stretch), 837 and 724 (TBDMS groups), 1664 (C = O), 1120 (CO), 908 (C = CH ₂ ) cm ' ¹ .

Level 3a: Compound (5) and (6)

5.792 g (18.1 mmol) of (+) - DIP-chloride weighed in an N ₂ atmosphere was placed in a flask with an N ₂ atmosphere and cooled to -40 ° C. Subsequently, 3.1 mg (4.86 mmol) of propargyl ketone (3) is added in 15 ml of anhydrous ether and then 1.82 g (2 ml, 18.1 mmol) of N-methylmorpholine and the reaction temperature is adjusted to -15 ° C.

Samples were taken every hour and analyzed by HPLC, considered complete after 6 hours (ketone <15%).

Add 5 ml of acetaldehyde to 5 ml of hexane and stir for 30 minutes at -10 ° C. Then 200 ml of hexane and 200 ml of t-butylmethyl ether are added and washed twice with 200 ml of brine each. The organic phase was stirred for 20 minutes with 10 ml of 6N NaOH and finally extracted with 100 ml of 3N NaOH. The organic phase was again washed with dilute bicarbonate, dried on anhydrous MgSO ₄ and concentrated until 8.6 g of oil was obtained.

The oil was purified by medium pressure flash chromatography eluting with increasing hexane / i-butylmethyl ether mixtures from 3% to 15%. 2.34 g of propargyl alcohols (5) are thus obtained (S / R = 2.46; clear oils; yield 75.4%) and 180 mg of ketone recovered (5.8% recovery).

The corresponding R / S alcohols (6) are obtained from propargyl ketone (4).

Compound (5)

NMR (CDC1 ₃₎

0.06 (s, 12H (CH ₃ -Si)), 0.38-0.6 (m, 4H (C-CH ₂ )), 0.56 (s, 3H (C-18)), 0. 86 and 0.90 (2s, 18H (CH _{3) 3} C)), 1.22 (t, 7 = 7 Hz, IH (C-CH)), 1.24 (d, J = 7 Hz, 3H ( C-21)), 4.22 (m, 1H (C-3)), 4.29 (m, 1H (C-24)), 4.53 (m, 1H (C-1)), 4. 95 and 4.99 (2s, 2H (C-19)),

5.83 (d, 7 = 11.6 Hz, 1H (C-7)), 6.45 (d, 7 = 11.6 Hz (C-6)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 965 {trans CH = CH), 897 (C = CH ₂ ) cm ^-1 .

Compound (6)

NMR (CDC1 ₃₎

0.06 (s, 12H (CH ₃ -Si)), 0.38-0.6 (m, 4H (C-CH ₂ )), 0.55 (s, 3H (C-18)), 0. 88 (s, 18H (CH ₃ ) ₃ C)), 1.19 (t, 7 = 6.8 Hz, 3H (C-21)), 1.23 (sc, 1H (C-CH)), 4 , 19 (m, 1H (C-3)), 4.27 (m, 1H (C-24)), 4.38 (m, 1H (Cl)), 5.18 and 5.32 (2s, 2H) (C-19)), 5.02 (d, 7 = 11.4)

Hz, 1H (C-7)), 6.24 (d, 7 = 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 1084 (bb includes C-0 stretch), 837 and 729 (TBDMS group), 989 {trans CH = CH), 908 (C = Ch ₂ ) cm ' ¹ .

SECTION B: p = l

Procedure 1B / 1: Compound (7)

1.5 M LDA in cyclohexane was added to 350 mg (0.5 mmol) of iodine derivative (IIA2a) solution in 10 ml of anhydrous THF until more than 90% of the starting product was converted to alkyne. The same volume of LDA was then added to give the lithium salt, stirred for 60 minutes, cooled to -40 ° C, and 5 ml of DMPU and 360 mg (443 pl, 5 mmol) of isobutylene oxide were added. Allow room temperature to increase and stir for 12 hours.

The crude product was partitioned into hexane and brine and the organic phase was washed with water and sodium sulfite, dried over Na ₂ SO ₄ and concentrated.

The crude product was purified by flash chromatography eluting with hexane / AcOEt mixtures (10: 1, 7: 1 and 4: 1) to give 119 mg of (7) (34%) and 153 mg of alkyne (1) ( 54%).

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)) , 1.19 (d, J = 6.9 Hz, 3H (C-21)), 1.26 (s, 6H (C-26 + C-27)), 2.31 (d, J = 2. 4, 2H (C-24)),

4.20 (m, 1H (C-3)), 4.52 (m, 1H (C-1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.81 ( d, 7 = 11.4 Hz, 1H (C-7)), 6.43 (d, J = 11.4 Hz, 1H (C-6)) ppm.

IR (KBr):

3645-3770 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 906 (= CH ₂ )

2. Preparation of compounds of formula (I) in which m = 1, n = 0 and Y = H

Procedure 2/1: Compounds (17) and (18)

Compound (17)

350 mg (0.5 mmol) of the iodine derivative (IIA2a) and 50 mg (0.04 mmol) of tetrakis triphenylphosphine palladium were added to a 10 ml compartment closure vial. A nitrogen atmosphere is formed and then 2 ml of anhydrous THF, 2 ml of anhydrous C ₆ H ₆ and 2 ml (2 mmol) of IM diethyl zinc in hexane are added with a syringe. The mixture was stirred at room temperature for 4 hours until the starting product disappeared (HPLC // 4% heptane / dichloroethane, iodine derivative <1%).

Divide between 50 ml of hexane and 50 ml of brine and filter through celite. The organic phase was washed with brine, dried on anhydrous Na ₂ SO4 and filtered through 50 g of flash silica gel, eluting with 2% hexane / ethyl acetate (AcOEt) until eluting the entire major product. The latter was purified by high resolution chromatography eluting with 0.1% hexane / AcOEt to give 269 mg of white crystals (90% yield).

NMR (CDC1 ₃₎

0.04 (sa, 12H (CH ₃ -Si), 0.53 (2, 3H (C-18)), 0.85 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 0 , 93 (t, J = 7.2 Hz, 3H (C-25)), 0.99 (d, / = 6.6 Hz, 3H (C-21)), 1.95 (m, 2H, ( C-24)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.19 and 5.24 (dd, J = 15 and 15.3 Hz, 1H (C-22)), 5.32 and 5.37 (dt, J = 6 Hz 15.3 HZ, 1H (C- 23)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 6.45 (d, 11.1 Hz, 1H (C-8)) ppm

IR (KBr)

1255, 1084, 837 and 724 (TBDMS groups), 1117 (C-0), 968 (CH = CH trans}, 895 (= CH ₂ ) cm ' ¹

Compound (18)

700 mg (1 mmol) of the iodine derivative (IIA2a) and 100 mg (0.085 mmol) of tetrakis triphenylphosphine palladium and 2 ml of anhydrous benzene were added to a 10 ml vial with a compartment closure and stirred until complete dissolution.

640 mg (2 mmol) of anhydrous zinc iodide and 3 ml of anhydrous tetrahydro furan were placed in a 25 ml flask. Cool with ice and add 1 ml (2 mmol) of 2M isobutyl magnesium bromide in ethyl ether to form a white precipitate. The mixture was stirred for 30 minutes at room temperature and then the contents of the vial were added with a syringe.

The mixture was stirred at room temperature for 4 hours until the starting product disappeared (HPLC / 4% heptane / dichloroethane, iodine derivative <1%).

Divide between 50 ml of hexane and 50 ml of brine and filter through celite. The organic phase was washed with brine, dried on anhydrous Na ₂ SO4 and filtered through 50 g of flash silica gel, eluting with 2% hexane / AcOEt to elute the entire major product. This was purified by high resolution chromatography eluting with 0.1% hexane / AcOEt to give 544 mg of white crystals (87% yield) ·

NMR (CDC1 ₃₎

0.04 (sa, 12H (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 0.85 (2d, J = 6.6 Hz, 6H (C-26 + C-27)), 1.00 (d, J = 6.6 Hz, 3H (C-21)), 1.82 ( m, 2H (C24)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)) ), 5.17 in

5.22 (dd, J = 15.3 Hz, 1H (C-22)), 5.26 and 5.31 (dt, J = 6.9 Hz and 15 Hz, 1H (C-23)), 5 , 80 (d, 7 = 11.4 Hz, 1H (C-7)), 6.44 (d, J = 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

1255, 1084, 837 and 724 (TBDMS groups, 1117 (CO), 968 (CH = CH trans), 895 (= CH ₂ ) cm ' ¹

3. Preparation of compounds of formula (I) in which m = l, n = 0, p = 0 and Y = OH

Procedure 3/1: Compounds (19), (20), (21), (22), (23), (24), (25) and (26) ml 1.7 M (5.1 mM) Z- butyl lithium is added dropwise to a solution of 3.48 g (5 mM) of the corresponding iodine derivatives (IIA2a) or (IIA3a) in 40 ml of anhydrous ether and cooled to -78 ° C, ensuring that the temperature does not rise above -70 ° C. The reaction was monitored by HPLC and 0.3 ml of Z-butyl lithium was added until the starting material disappeared. Maintained at -78 ° C for 10 minutes and then 6.25 mmol of the corresponding aldehyde was added dropwise. After 1 hour, 5 ml of concentrated NH ₄ C1 solution was added, the temperature was raised to 0 - +5 ° C, brine was added and the organic phase was separated, which was washed with sodium sulfite solution, dried and concentrated.

The crude product was purified by flash chromatography eluting with hexane / AcOEt mixtures from 12: 1 to 4: 1.

Yield: 85-92% in R / S isomers (1: 1) of the mixture.

Compound 19

NMR (CDC1 ₃₎

0.065 (s, 12H (CH ₃ -Si)), 0.15-0.65 (m, 4H (c-CH ₂ )), 0.57 (s, 3H (C-18)), 0.87 and 0.90 (2s, 18H ((CH _{3) 3)),} 0.95 (m, IH (c-CH)), 1.05 (d, J: 6.8 Hz, 3H (c-21)) , 3.47 (m, 1H (C-24)),

4.21 (m, 1H (C-3)), 4.55 (m, 1H (Cl)), 4.96 (m, 2H (C-19)), 5.49 (m, 2H (C- 22 / C-23), 5.82 (d, J: 11.2 Hz, 1H (C-7)), 6.47 (d, J: 11.2 Hz, 1H (C-6)).

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups) 1117 (C-0 elongation), 976 (trans CH = CH) and 905 (= CH ₂ ) cm ^-1 .

Compound 20

NMR (CDC1 ₃₎

0.065 (s, 12H (CH ₃ -Si)), 0.57 (s, 3H (C-l8), 0.87 and 0.90 (2s, 27H, (CH _{3) 3} C)), 1.05 (d, J:

6.8 Hz, 3H (C-21)), 3.67 (m, 1H (C-24)), 4.21 (m, 1H (C-3)), 4.54 (m, 1H, ( Cl)), 4.96 (m, 2H (C-19)), 5.45 (m, 2H (C-22 / C-23)), 5.82 (d, J: 11.2 Hz, 1H (C-7)), 6.45 (d, J: 11.2 Hz, 1H (C-6)).

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups) 1117 (C-0 elongation), 976 (trans CH = CH) and 905 (= CH ₂ ) cm ^-1 .

Compound 21

NMR (CDC1 ₃₎

0.061 (s, 12H (CH ₃ -Si)), 0.13-0.60 (m, 4H (c-CH ₂ )), 0.55 (s, 3H, (C-18)), 0.88 and 0.90 (2s, 18H ((CH ₃ ) ₃ C)), 0.8-0.94 (m, 1H (c-CH)), 1.05 (d, J: 6.8 Hz, 3H) (C-21)), 3.46 (m, 1H (C24)), 4.19 (m, 1H (C-3), 4.38 (m, 1H (Cl)), 4.87 (m. 1H (C-19)), 5.18 (m, 1H (C-19)),

5.49 (m, 2H (C-22 / C-23)), 6.01 (d, J: 11.4 Hz, 1H (C-7)), 6.24 (d, J: 11.4 Hz, 1H (C-7)) ppm.

IR (KBr)

3650-3125 (OH), 1255, 1084, 837 and 724 (TBDMS groups; also a wide band including C-0 stretch centered at 1084), 975 (trans CH = CH) and 909 (= CH ₂ ) cm ' ¹ .

Compound 22

NMR (CDC1 ₃₎

0.061 (s, 12H (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.87 (d, J: 7.0 Hz, 6H (C-26 / C-27) ), 0,880,90 (2s, 18H ((CH _{3) 3} C)), 1.05 (d, J: 6.8 Hz, 3H (C-21)), 3.63 (m, IH (C 24)), 4.20 (m, 1H (C-3)), 4.36 (m, 1H (Cl)), 4.86 (m, 1H (C-19)), 5.17 (m. 1H (C-19), 5.45 (m, 2H (C22 / C-23)), 6.00 (d, J: 11.4 Hz, 1H (C-7)), 6.24 (d , J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3125 (OH), 1255, 1084, 837 and 724 (TBDMS groups; also a wide band including C-0 stretch centered at 1084), 975 (trans CH = CH) and 909 (= CH ₂ ) cm ' ¹ .

Compound 23

NMR (CDC1 ₃₎

0.066 (s, 12H (CH ₃ -Si)), 0.56 (s, 3H (C-18)), 0.87 and 0.90 (2s, 18H ((CH ₃ ) ₃ C)), 1. 05 (d, J:

6.8 Hz, 3H (C-21)), 3.74 (m, 1H (C-24)), 4.21 (m, 1H (C-3)), 4.55 (m, 1H (Cl )), 4.96 (m, 2H (C-19)), 5.42 (m, 2H (C-22 / C-23)), 5.81 (d, J: 11.2 Hz, 1H ( C-7)), 6.45 (d, J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups) 1117 (C-0 elongation), 976 (trans CH = CH) and 905 (= CH ₂ ) cm ^-1 .

Compound 24

NMR (CDC1 ₃₎

0.066 (s, 12H (CH ₃ -Si)), 0.56 (s, 3H (C-18)), 0.87 (d, J: 7.0 Hz, 6H (C-26 / C-27) ), 0,880,90 (2s, 18H ((CH _{3) 3} C)), 1.05 (d, J: 6.8 Hz, 3H (C-21)), 3.69 (m, IH (C 24)), 4.21 (m, 1H (C-3)), 4.55 (m, 1H (Cl)), 4.96 (m, 2H (C-19)), 5.49 (m, 2H (C-22 / C-23), 5.81 (d, J:

11.2 Hz, 1H (C-7)), 6.47 (d, J: 11.2 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups) 1117 (CO stretch), 976 (trans CH = CH) and 905 (= CH ₂ ) cm ¹ .

Compound 25

NMR (CDC1 ₃₎

0.066 (s, 12H (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.88 (s, 18H ((CH ₃ ) ₃ C)), 1.04 (d. J: 6.8 Hz, 3H (C-21)), 3.76 (m, 1H (C-24)), 4.19 (m, 1H (C-3)), 4.36 (m, 1H (Cl)), 4.86 (m, 1H (C19)), 5.17 (m, 1H (C-21)), 5.42 (m, 2H (C-19)), 6.01 and 6 , 23 (2d, J: 11.4 Hz, 2H (C-6 / C7)) ppm.

IR (KBr)

3650-3125 (OH), 1255, 1084, 837 and 724 (TBDMS groups; also a wide band including CO stretch centered at 1084), 975 {trans CH = CH) and 909 (= CH ₂ ) cm ' ¹ are observed .

Compound 26

NMR (CDC1 ₃₎

0.066 (s, 12H (CH ₃ -Si)), 0.56 (s, 3H (C-18)), 0.88 and 0.90 (2s, 27H ((CH ₃ ) ₃ C)), 1. 04 (d, J:

6.8 Hz, 3H (C-21)), 3.65 (m, 1H, (C-24)), 4.21 (m, 1H (C-3)), 4.35 (m, 1H ( Cl)), 4.86 (m, 1H (C-19)), 5.16 (m, 1H (C-19)), 5.45 (m, 2H (C-22 / C-23)), 5.99 (d, J: 11.4 Hz, 1H (C-7)), 6.24 (d, J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3650-3125 (OH), 1255, 1084, 837 and 724 (TBDMS groups; also a wide band including CO stretch centered at 1084), 975 {trans CH = CH) and 909 (= CH ₂ ) cm ' ¹ are observed .

Procedure 3/2: Compounds (19) and (21)

2.55 g (4 mmol) of propargyl alcohol (5) and 25 ml of anhydrous tetrahydrofuran are placed in a cylinder and heated to a bath temperature of 70 ° C. 2.1 g (6.8 mmol) of 65% Reduction in toluene or a suspension of 432 mg (8 mmol) of sodium methoxide in 8 ml of 1 M lithium aluminum hydride in tetrahydrofuran are added dropwise. Addition is carried out in 15 minutes and analyzed every 15 minutes. The reaction is considered complete when the amount of saturated alcohol exceeds 1.5%. Transfer to a mixture of hexane / tbutylmethyl ether (300/150 ml) and 350 ml of 0.1 N sulfuric acid. The organic phase was separated and washed with brine and sodium carbonate, dried and concentrated to give 2.8 g of an oily crude product. This was purified by high resolution chromatography eluting with 10% hexane / AcOEt to give 0.32 g of starting propargyl alcohol (recovering 12.5%), 0.61 g of allyl alcohol (19) (R isomer) (yield 23 , 8%) and 1.51 g of allyl alcohol (19) (S isomer) (59% yield).

The corresponding alcohols (21) are similarly obtained from alcohols (6).

Procedure 3/3: Compounds (33), (34) and (35)

A mixture of 1 mmol of the corresponding aldehyde and 0.5 mmol of iodine derivative (IIAla) or iodine derivative (IIAlb) diluted in some DMF (from 0.5 to 1 ml, if the reagents are insoluble in DMF, dilute them into some anhydrous THF), placed in a flask containing 308 mg of CrCl ₂ (2.5 mmol), 0.3 mg of NiCl ₂ and 10 ml of anhydrous DMF, ensuring that the temperature does not exceed 25 ° C. The reaction is occasionally monitored by HPLC, and when the reaction is no longer advanced, brine is added and extracted with hexane. The upper phase is washed twice with sodium sulfite solution, dried and concentrated.

The crude product obtained is purified by flash chromatography eluting with hexane / AcOEt mixtures. The starting iodine derivative can be recovered from the most apolame fraction by preparative chromatography.

Compound (33)

NMR (CDC1 ₃₎

0.02, 0.04 and 0.05 (3 s, 12 H (CH ₃ -Si)), 0.16, -0.65 (m, 4H (C-CH ₂ )), 0.68 and 0 , 58 (minor isomer) (s, 3H (C-18)), 0.87 and 0.90 (2s, 18H (CH ₃ ) ₃ C)), 0.95 (m, 1H (CCH)), 1 , 09 (d, J = 6.8 Hz, 3H (C-21)), 3.47 (m, 1H (C-24)), 3.75 (qAB, J = 16 Hz, 2H (C-19) ), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (Cl)), 4.66 and 4.70 (minor isomer) (qAB, J - 10.2 Hz, 2H) (C-6 + C-7)), 5.49 (m, 2H (C-22 + C-23)) ppm.

IR (KBr)

3650-3100 (OH), 1255, 837 and 724 (TBDMS groups), 1317, 1095 (bb includes C-0 and SiO stretches), and 873 (SO ₂ ), 989 {trans CfUCH jcrri ¹ .

Compound (34)

NMR (CDC1 ₃₎

0.02, 0.04 and 0.05 (3 s, 12 H (CH ₃ -Si)), 0.68 and 0.58 (smaller isomer) (S, 3H (C-18)), 0.87 (d, J = 7Hz, 6H (C-26 / C-27), 0.87 and 0.90 (2s, 18H (CH ₃ ) ₃ C)), 1.05 (d, 7 = 6.8 Hz) , 3H (C-21)), 3.69 (m, 1H (C-24)), 3.76 (qAB, 7 = 16 Hz, 2H (C-19), 4.16 (m, 1H (C -3)), 4.34 (m, 1H (Cl)), 4.66 and 4.70 (smaller isomer) (qAB, 7 = 10.2 Hz, 2H (C-6 + C-7)), 5.49 (m, 2H (C-22 + C-23)) ppm.

IR (KBr)

3700-3100 (OH), 1305 and 1055 (SO ₂ ), 1113 (C-0) and 987 {trans CH = CH) cm ^-1 .

Compound (35)

NMR (CDC1 ₃₎

0.16, -0.62 (m, 4H (C-CH ₂ )), 0.67 and 0.56 (minor isomer) (s, 3H (C-18)), 0.95 (m, 1H ( C-CH)), 1.05 (d, 7 = 6.8 Hz, 3H (C-21)), 2.06 and 2.08 (2s, 2x3H (COOCH ₃ )), 3.47 (m, 1H (C-24), 3.75 (qAB, 7 = 16 Hz, 2H (C-19), 4.69 (m, 2H (C-6 + C-7)), 5.48 (m. 3H (Cl, C-22 and C-23)) ppm.

IR (KBr)

3600-3100 (OH), 1738 (CO), 1317 and 1037 (SO ₂ ), 1236 (C-0) and 989 {trans CH = CH) cm ' ¹ .

Procedure 3/4: Compounds (33) and (34)

In this process, recoveries are made of the corresponding aldehydes of formula (IV) without isolating the corresponding intermediates of formula (II).

mmol of the corresponding VII-Al aldehyde and 4 mmol of I ₃ CH in 15 ml of anhydrous THF were added dropwise to a flask of 2.46 CrCl ₂ (20 mM) and 15 ml of anhydrous THF with strict exclusion of oxygen and humidity while maintaining the temperature at 0 ° C. After all the aldehyde has reacted (2-3 hours), the solvent is removed under vacuum and at 0 ° C.

ml of DMF containing 4 mmol of the corresponding aldehyde and 2 mg of NiCl ₂ were added to the resulting chocolate-colored mass and stirred at 25 ° C until the reaction progressed (HPLC control).

After the reaction is complete, proceed as described in procedure 3/3.

Procedure 3/5: Compounds (19), (24) and (32)

A mixture of 2 mmol SO ₂ adducts (33, 34 and 35), 1.5 g NaHCO ₃ and 150 ml DMF was heated at 80 ° C and under N ₂ atmosphere until the starting product disappeared (2-3 hours). 15 ml of water and 150 ml of hexane were added and the above phase was washed with water, dried and concentrated to give compounds (19), (24) and (32) (90% yield).

Procedure 3/6. Compounds (21), (22), (25), (26) and (31)

A mixture of 10 mmol trans derivative (19, 20, 23, 24 and 32), 1 g of anthracene and 800 ml of toluene is irradiated with a UV lamp (Heraeus TQ 150 Z ₂ ) for about 1 hour (until the amount of trans compound is less than 5%).

When the reaction is complete, it is filtered, concentrated under vacuum and the crude product is purified by preparative chromatography eluting with 10% to 2% hexane / AcOEt and isolating both R and S isomers (1: 1 preparation in a yield of 85% to 93% ) of compounds (21), (22), (25), (26) and (31).

Procedure 3/7. Compounds (27), (28), (29) and (30) mmol of the silylated compound (19, 21, 22 or 24, R, S isomers or mixtures thereof) were dissolved in 70 ml of 1 M tetrabutylammonium fluoride (70 mmol) and heated 50 minutes at 60-65 ° C.

After the reaction is complete, partition between 500 ml AcOEt and water and dilute the organic phase with 300 ml CI2CH2, dry over Na ₂ SO ₄ and directly purify by flash chromatography eluting with AcOEt. The crude product thus obtained is crystallized from methyl formate to give 70% of the corresponding compounds (27), (28), (29) or (30).

Procedure 3/8

3/8 a. Compound (28)

Procedure 3/5 was applied to 2 mmol of compound (35) using absolute EtOH but not DMF. When the reaction is complete, 2 g (50 mmol) of NaOH powder are added, 15 ml of water are added and stirred at room temperature until the acetates are gone.

After the reaction is complete, ethyl acetate and sufficient water are added to form 2 phases. The upper phase was dried over Na ₂ SO ₄ , concentrated and purified by preparative chromatography eluting with AcOEt to give compound (28) in 85% yield (R / S isomer mixture).

3/8 b. Compound (27) and (28) ml of 96 ° alcohol and 1.32 g KOH were added to 1 mol of compounds (31) or (32). Stirred at room temperature until the acetates have disappeared. The corresponding compounds (28) and (27) are thus obtained in 95% yield (R / S isomer mixture).

Compound (27)

NMR (CDCI3 + 5% CD3OD)

0.15-0.60 (m, 4H (c-CH ₂ )), 0.56 (s, 3H (C-18)), 0.92-1.04 (m, 1H (c-CH)) , 1.05 (d, J: 6.6 Hz, 3H (C-21)), 3.43 (m, 1H (C-24)), 4.20 (m, 1H (C-3)), 4.40 (m, 1H (Cl)), 4.99 (m, 1H (C-19)), 5.32 (m, 1H (C-19)), 5.46 (m, 2H (C- 22 / C-23), 6.02 (d, J: 11.4 Hz, 1H (C-7)),

6.37 (d, J: 11.4 Hz, 1H (C-6)) ppm.

IR (KBr)

3600-3150 (OH), 1062 and 1029 (CO stretch), 975 {trans CH = CH) and 910 (= CH ₂ ) cm ' ¹ .

Compound 28

NMR (CDCl ₃ + 5% CD ₃ OD)

0.15-0.61 (m, 4H (c-CH ₂ )), 0.58 (s, 3H (C-18)), 0.87-1.08 (m, 1H (c-CH)) , 1.06 (d, J: 6.6 Hz, 3H (C-21)), 3.41 (m, 1H (C-24)), 4.20 (m, 1H (C-3)), 4.48 (m, 1H (Cl)), 4.97 (m, 1H (C-19)), 5.12 (m, 1H (C-19)), 5.47 (m, 2H (C- 22 / C-23), 5.89 (d, J: 11.2 Hz, 1H (C-7)), 6.57 (d, J: 11.2 Hz, 1H (C-6)) ppm .

IR (KBr)

3600-3150 (OH), 1055 and 1029 (CO stretch), 975 {trans CH = CH) and 906 (= CH ₂ ) cm '.

Compound 29

NMR (CDCl ₃ + 5% CD ₃ OD)

0.56 (s, 3H (C-18), 0.87 (d, J: 7.0 Hz, 6H (C-26-C-27)), 1.06 (d, J: 6.6 Hz) , 3H (C-21)), 1.75 (m, 1H (C-25)), 3.71 (m, 1H (C-24)), 4.20 (m, 1H (C-3)) , 4.48 (m, 1H (Cl)), 4.97 (m, 1H (C-19)), 5.12 (m, 1H (C-19)), 5.47 (m, 2H (C -22 / C-23), 5.89 (d, J: 11.2 Hz, 1H (C-7)), 6.57 (d, J: 11.2 Hz, 1H (C-6)) ppm.

IR (KBr)

3600-3150 (OH), 1062 and 1029 (CO stretch), 975 {trans CH = CH) and 910 (= CH ₂ ) cm ' ¹ .

Compound 30

NMR (CDCl ₃ + 5% CD ₃ OD)

0.56 (s, 3H (C-18)), 0.87 (d, J: 7.0 Hz, 6H (C-26-C-27)), 1.05 (d, J: 6.6 Hz, 3H (C-21)), 1.75 (m, 1H (C-25)), 3.63 (m, 1H (C-24)), 4.20 (m, 1H (C-3)) ), 4.40 (m, 1H (Cl)), 4.99 (m, 1H (C-19)), 5.32 (m, 1H (C-19)), 5.46 (m, 2H ( C-22 / C-23), 6.02 (d, J: 11.4 Hz, 1H (C-7)), 6.37 (d, J: 11.4 Hz, 1H (C-6) ) ppm.

IR (KBr)

3600-3150 (OH), 1062 and 1029 (C-0 elongation), 975 (trans CH = CH) and 910 (= CH ₂ ) cm ^-1 .

Compound 31

NMR (CDC1 ₃₎

0.22-0.58 (m, 4H (c-CH ₂ )), 0.53 (s, 3H (C-18)), 0.90-1.10 (m, 1H (c-CH)) , 1.03 (d, J: 6.6 Hz, 3H (C-21)), 2.03 and 2.05 (2s, 6H (CH ₃ CO)), 3.40 (m, 1H (C- 24)), 5.03 (m, 1H (C19)), 5.18 (m, 1H (C-3)), 5.31 (m, 1H (C-19)), 5.46 (sc. 3H (C-22 / C-23 + Cl)), 5.91 (d, J:

11.4 Hz, 1H (C-7)), 6.35 (d, J: 11.4 Hz, 1H (C-6)) ppm.

Compound 32

NMR (CDC1 ₃₎

0.21-0.58 (m, 4H (c-CH ₂ )), 0.55 (s, 3H (Cl 8)), 0.90-1.09 (m, 1H (C-CH)), 1.04 (d, J: 6.6 Hz, 3H (C-21)), 2.03 and 2.05 (2s, 6H (CH ₃ CO)), 3.40 (m, 1H (C-24)). )), 5.01 (m, 1H (C19)), 5.15 (m, 1H (C-19)), 5.18 (m, 1H (C-3)), 5.50 (sc, 3H) (C-22 / C-23 + Cl)), 5.82 (d, J:

11.6 Hz, 1H (C-7)), 6.46 (d, J: 11.6 Hz, 1H (C-6)) ppm.

4. Preparation of compounds of formula (I) in which m = 1, n = 0, p = 1-6

Procedure 4/1: Compounds (36), (37) and (38)

350 mg (0.5 mmol) of the iodine derivative (IIA2a), 15 mg (0.07 mmol) of Ac ₂ Pd and 528 mg (5.5 mmol) of Z-BuONa were added to a 5 ml vial. Close and add 3 ml of THF, 20 μΐ Z-Bu ₃ P (about 0.1 mol) and 580 μΐ (5 mmol) acetophenone with the syringe.

It was stirred for 1 hour at room temperature and partitioned between hexane and brine, and the organic phase was extracted 3 times with brine, dried and purified by flash chromatography eluting with 8: 1 hexane / AcOEt to give 275 mg of white crystals of compound (36) ( yield 80%).

Substitution of acetophenone with 5 mmol of cyclopropyl ketone or 5 mmol of propanone yields the compounds (37) and. (38) with a gain of 58% or. 37%.

Compound (36)

NMR (CDC1 ₃₎

0.07 (s, 12H (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.87 and 0.91 (2s, 18H ((CH ₃ ) ₃ C)), 1.04 (d, 7 = 6 Hz, 3H (C-21)), 3.67 (d, J = 6.3 Hz, 2H (C-24)), 4.22 (m, 1H (C- 3)), 4.54 (m, 1H (Cl)), 4.95 and 4.99 (2s, 2H (C-19)), 5.42 and 5.45 (dd, 7 = 15.3 Hz) , 1H (C-22)),

5.56 and 5.61 (dt, 7 = 6.6 Hz and 15.3 Hz, 1H (C-23)), 5.80 (d, J = 11.7 Hz, 1H (C-7)) , 6.46 (d, 7- 11.4 Hz, 1H (C-6)), 7.4-7.6 (sc, 3H (C-28 + C-29 - C-30)), 7, 98 (d, 7 =

7.5 Hz, 2H (C-27 + C-31)) ppm.

IR (KBr)

1255, 1084, 837, 724 (TBDMS groups), 1695 (C = O), 1120 (CO), 970 (trans CH = CH), 895 (= CH ₂ ) cm ' ¹

Compound (37)

NMR (CDC1 ₃₎

0.04 (s, 12H (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H (CH _{3) 3} C)), 0 , 75-0.9 and 0.95-1.05 (sC, 4H (C-27 and C-28)), 1.95 (sC, 1H (C-26)), 3.18 (d, 7 - 5.7 Hz, 2H (C-24)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.38 and 5.41 (dd, 7- 15.3 and 15 Hz, 1H (C-23)), 5.45 and 5.52 (dt, 7 = 15.3 and 6.3 Hz, 1H (C23)), 5.80 (d, 7 = 11.1 Hz, 1H (C-7)), 6.44 (d, 7 = 12 Hz, 1H (C-6) ppm IR (KBr):

1255,1084, 837 and 724 (TBDMS groups), 1705 (C = O), 1120 (CO), 970 (CH = CH), 902 (= CH ₂ ) cm ^-1 .

Compound (38)

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH3-S1)), 0.53 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 1.02 (d, J = 7.2 Hz, 3H (C-21)), 2.12 (s, 3H (COCH ₃ )), 3.05 (d, J = 5.7, 2H (C- 24)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5. 39 (sc, 2H (C-22 + C-23)), 5.80 (d, J = 11.4 Hz, 1H (C-7), 6.44 (d, J- 11.7 Hz, 1H (C-6)) ppm.

IR (KBr):

1716 (C-0), 1255, 1084, 837, and 724 (TBDMS groups), 1118 (CO), 968 (trans CH-CH), 885 (= CH ₂ ) cm ^-1 .

Procedure 4/2: Compound 39

It is obtained by the same procedure as described in procedure 6B / 1.

Yield: 83% from ketone (7).

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)) ,

1.02 (d, J = 6.6 Hz, 3H (C-21)), 1.21 (s, 6H (C-26 + C-27)), 2.12 (sc, 2H (C-24)) )), 4.20 (m, 1H (C-3)), 4.52 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.37 (sc, 2H (C-22 + C-23)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 6.44 (d, J = 12 Hz, 1H (C -6)) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1117 (CO), 966 (trans CH = CH), 902 (= CH ₂ ) cm ^-1 .

5. Preparation of compounds of formula (I) in which m = 1, n = 1, p = 0, Rs and Ra = alkyl and Y OH

Procedure 5/1; Compounds (40), (41), (42), (43), (44) and (45)

Compound (40) mg (0.078 mmol) of couponodide, 15 mg (0.066 mmol) of benzyltriethylammonium chloride and 100 mg (0.086 mmol) of tetrakis triphenylphosphine palladium were placed in a flask with an N ₂ atmosphere.

1.050 g (1.5 mmol) of the iodine derivative (IIA2a), 151 mg (175 μΐ, 1.8 mmol) of 3-methyl-lbutin-3-ol and 4.5 ml of benzene were added to the vial with a compartment. When all is dissolved, transfer to a flask with a syringe and then 4.5 ml of deaerated 5.5 N NaOH are quickly added. The mixture was stirred at room temperature and in the absence of light for 3 hours for 30 minutes, controlling the reaction by TLC (5% hexane / AcOEt) until the starting product actually disappeared. The reaction mixture was decanted and the organic phase was diluted with 100 ml of pentane, and this solution was filtered with 50 g of flash silica gel, eluting with 5% and 20% hexane / AcOEt until the major product was no longer visible.

The fractions containing the main product were combined and placed in a rotary evaporator to give 836 mg of white crystals (85%).

NMR (CDCl3)

0.04 (sa, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)) , 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.51 (s, 6H (C-27 + C-28)), 4.20 (m, 1H (C- 3)), 4.51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.39 (d, J = 15.9 Hz (C-23) )), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 5.95 and 5.98 (dd, J = 15.6, 15.9, 1H (C-22)). ), 6.43 (d, 7 = 11.1 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 2221 (C = C), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 960 (trans CH = CH), 895 (= CH ₂ ) cm ^-1 .

Compound (41)

Prepared according to the previous methodology from 3-methyl-1-pentin-3-ol. Flash chromatography eluent: 12: 1 hexane / AcOEt and 8: 1 hexane / AcOEt.

92% yield of white crystals.

NMR (CDC1 ₃₎

0.04 (sa, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)) , 1.02 (t, J = 7.5 Hz, 1H (C-29)), 1.03 (d, J = 7.2 Hz, 3H (C-21)), 1.46 (s, 3H (C-27)), 1.67 (m, 2H (C-28)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.40 (d, J = 15.9 Hz, 1H (C-23)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 5.95 and 5.98 (dd, 7 = 15.9, 1H (C-22)), 6.43 (d, J = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 2220 (C = C), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 960 {trans CH = CH), 897 (= CH ₂ ) cm ^-1 .

Compound (42)

Prepared according to the previous methodology from 3-methyl-1-pentin-3-ol. Flash chromatography eluent: 12: 1 hexane / AcOEt.

86% yield of white crystals.

NMR (CDC1 ₃₎

0.04 (sa, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)) , 1.01 (t, J = 7.5 Hz, 6H (C ₂₈ + C ₃₀ )), 1.03 (d, 7 = 6.6 Hz, 3H (C-21)), 1.65 and 1 , 66 (2q / =

7.2 and 7.5 Hz, 4H (C-27 + C-29)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)), 4.92 and

4.97 (2s, 2H (C-19)), 5.41 (d, J = 15.9 Hz, 1H (C-23)), 5.80 (d, 7 = 11.7 Hz, 1H ( C7)), 5.96 and 5.98 (dd, 7 = 15.6 and 15.9, 1H (C-22)), 6.43 (d, J = 11.4 Hz, 1H (C-6) ) ppm.

IR (KBr):

3600-3100 (OH), 2220 (C = C), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 960 {trans CH = CH), 897 (= CH ₂ ) cm ^-1 .

Compound (43)

Prepared according to the previous methodology from l-butin-3-ol. Flash chromatography eluent: 8: 1 hexane / AcOEt and 6: 1 hexane / AcOEt.

87% yield of white crystals.

NMR (CDC1 ₃₎

0.04 (sa, 12H, (CH3-S1)), 0.53 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)), 1.03 (d, J = 6.6 Hz, 3H (C-21)), 1.45 d, 7 = 6.6 Hz, 3H (C-27)), 4.20 (m, 1H (C -3)), 4.51 (m, 1H (Cl)), 4.61 (m, 1H (C-26)), 4.92 and 4.97 (2s, 2H (C-19)), 5 , 41 (d, 7 = 15.9 Hz, 1H (C-23)), 5.80 (d, 7 = 11.7 Hz, 1H (C-7)), 5.98 and 6.01 (dd , 7 = 15.6 and 15.9, 1H (C-22)), 6.43 (d, 7 = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 2221 (C = C), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 960 {trans CH = CH), 895 (= CH ₂ ) cm ' ¹ .

Compound (44)

Prepared according to the previous methodology from 3-ethyl-1-pentin-3-ol and from the cis iodine derivative (IIA3). Flash chromatography eluent: 6: 1 hexane / AcOEt.

83% yield of a foamy solid.

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.52 (s, 3H (C-18)), 0.85 (s, 18H ((CH ₃ ) ₃ C)), 1.02 (d, 7 = 6.6 Hz, 3H (C-21)), 1.51 (s, 6H (C-27 + C-28)), 4.17 (m, 1H (C-3)), 4.35 (m, 1H (Cl)),

4.83 (d, 7 = 2.1 Hz, 1H (C-19)), 5.16 (m, 1H (C-19)), 5.39 (d, 7 = 15.9 Hz, 1H ( C23), 5.95 and 5.98 (dd, 7 = 15.9, 15.6 Hz, 1H (C-22)), 5.98 (d, 7 = 11.7 Hz, 1H (C-). 7)),

6.21 (d, 7 = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3200 (OH), 2221 (C = C), 1255, 1084 (bb includes C-0 stretch), 837 and 724 (TBDMS groups), 989 {trans CH = CH), 908 (CH ₂ ) cm ' ¹ .

Compound (45)

Prepared according to the previous methodology from 3-ethyl-1-pentin-3-ol and SO ₂ adduct iodine derivative (IIAla). Flash chromatography eluent: 6: 1 hexane / AcOEt and 4: 1 hexane / AcOEt.

85% cream foam yield.

NMR (CDC1 ₃₎

0.02, 0.04, 0.05 (3s, 12H (CH ₃ -Si)), 0.64 and 0.55 (smaller isomer) (s, 3H (C-18)), 0.85 and 0 , 86 (2s, 18H ((CH ₃ ) ₃ C)), 1.01 (t, 7 = 7.5 Hz, 6H (C ₂₈ + C ₃₀ ), 1.03 / d, 7 = 6.6 Hz , 3H (C-21), 1.65 and 1.66 (2q, 7 = 7.2 and 7.5 Hz, 4H (C-27 + C-29)), 3.75 (qAB, 7 = 16 Hz, 2H (C-19)), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (Cl)), 4.65 and 4.73 (smaller isomer) (qAB. 7 = 9.6 Hz, 2H (C-6 + C ₇ )), 5.41 (d, 7 = 15.9 Hz, 1H (C-23)), 5.94 and 5.97 (dd, 7 = 15.9 Hz (C-22) ppm

IR (KBr)

3600-3200 (OH), 2221 (C = C), 1255, 1084, 837 and 724 (TBDMS groups), 1317, 1095 and 877 (SO ₂ ), 968 {trans CH = CH) cm ¹

6. Preparation of compounds of formula (I) in which m = 2, n = 0, p = 0.

SECTION A

Process 6A / 1: Compound (46) and (47)

Compound (46)

1400 mg (2 mmol) of the iodine derivative (IIA2a), 690 mg (5 mmol) of anhydrous potassium carbonate, 10 mg of palladium acetate (0.04 mmol) and 600 mg (2 mmol) of tetrabutylammonium chloride are added to the flask and allowed to flow nitrogen. 1400 mg (1.64 ml, 20 mmol) of vinylmethylketone and 2 ml of anhydrous tetrahydrofuran are added. It was stirred for 5 minutes, 10 ml of dimethylformamide was added and stirred at room temperature for 4-5 hours, until the starting product was actually determined by TLC (10: 1 hexane / AcOEt).

The crude product was partitioned between 100 ml of hexane and 100 ml of brine and filtered through celite. The organic phase is washed twice with brine and dried on anhydrous Na ₂ SO ₄ . Filter through 50 g of flash silica gel, eluting with 4: 1 hexane / AcOEt until elution of the title product. This was purified by medium pressure chromatography eluting with hexane / ethyl acetate from 5% to 30% to give 1.1 g of white crystals (86%).

NMR (CDC1 ₃₎

0.04 (sa, 12H (CH ₃ -Si)), 0.55 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 1.07 (d, 7 = 6.6 Hz, 3H (C-21)), 2.24 (s, 3H (COCH ₃ )), 4.20 (m, 1H (C-3)), 4. 51 (m, 1H (Cl)), 4.93 and 4.97 (2s, 2H (C-19)), 5.80 (d, J = 11.4 Hz, 1H (C-7)), 6 , 02 and 6.04 (dd, J = 15 Hz, 1H (C-22)), 6.04 (d, 7- 15.3 Hz, 1H (C-25)), 6.11 and 6.14 (dd, 7 = 15 Hz, 1H (C-23)), 6.43 (d, 7- 11.4 Hz, 1H (C-6)), 7.05 and 7.08 (dd, 7 = 15 , 6 and 15.9, 1H (C24)) ppm.

IR (KBr);

1255, 1084, 837, 724 (TBDMS groups), 1670 (C = O), 1636 (C = C), 1117 (CO), 1000 (trans (CH = CH) ₂ ), 906 (= CH ₂ ) cm ' ¹ .

Compound (47)

1400 mg (2 mmol) of the iodine derivative (IIA2a), 690 mg (5 mmol) of anhydrous potassium carbonate, 10 mg of palladium eva acetate (0.04 mmol) and 600 mg (2 mmol) of tetrabutylammonium chloride were placed in a flask, that nitrogen flows through it.

Then 1720 mg (1.8 ml, 20 mmol) of methyl acrylate and 2 ml of anhydrous tetrahydrofuran are added. It was stirred for 5 minutes and finally 10 ml of dimethylformamide was added and stirred at room temperature for 4-5 hours until the starting product was no longer visible by TLC (10: 1 hexane / ethyl acetate).

The crude product was partitioned between 100 ml of hexane and 100 ml of brine and filtered through celite. The organic phase was separated and washed twice with brine and finally dried on anhydrous Na ₂ SO ₄ .

The organic phase was filtered through 50 g of flash silica gel eluting with 10% hexane / AcOEt to elute the title product.

This was purified by medium pressure chromatography eluting with 5% hexane / ethyl acetate to give 1.25 g of white crystals (95%).

NMR (CDC1 ₃₎

0.04 (sa, 12H (CH ₃ -Si)), 0.54 (s, 3H, (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)) , 1.06 (d, J = 6.6 Hz, 3H (C-21)), 3.72 (s, 3H (OCH ₃ )), 4.20 (m, 1H (C-3)), 4 , 51 (m, 1H (C1)), 4.92 and 4.97 (2s, 2H (C-19)), 5.77 (d, J = 15 Hz, 1H (C-25)), 5. 80 (d, J = 11.4 Hz, 1H (C-7)), 5.96 and 5.99 (dd, J-15 Hz (C-22)), 6.09 and 6.12 (dd, J-15 Hz (C-23)), 6.43 (d, J-11.1 Hz (C-6)), 7.21 and 7.25 (dd, J = 15.3 HZ (C-24) )) ppm

IR (KBr):

1255, 1084, 837, 724 (TBDMS groups), 1727 (C = O), 1644 (CC), 1138 (CO), 1000 (trans (CH = CH) ₂ ), 906 (= CH ₂ ) cm ¹

SECTION 6B

Procedure 6B / 1: Compounds (51) and (53)

Compound (51)

400 μΐ IM methyl lithium (0.4 mmol) was added to a solution of 205 mg (0.32 mmol) (46) in 10 ml THF cooled at -70 ° C, controlling the reaction by HPLC (2.6% heptane / AcOEt). Every 100 μΐ added is analyzed, noting that no more alcohol (42% ketone / 56% alcohol) is formed after 400 μΐ due to ketone enolization.

The crude reaction product was partitioned between hexane and brine, and the organic phase was washed with dilute sodium bicarbonate, dried and concentrated.

The crude product was purified by flash chromatography eluting with 10% hexane / AcOEt to give 85 mg (40%) of the alcohol compound (51) and 33 mg of the starting ketone.

Similarly, 65 mg of alcohol (20% yield) (53) was obtained from 327 mg (0.05 mmol) of (47) and 1.25 ml of 0.5M ethyl lithium, recovering 200 mg of the starting ester. NMR (CDC1 ₃₎

0.04 (sa, 12H (CH ₃ -Si)), 0.54 (s, 3H, (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)) , 1.03 (d, 7- 6.6 Hz, 3H (C-21)), 1.32 (s, 6H (C-27 + C-28)), 4.20 (m, 1H (C- 3)), 4.51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.53 and 5.56 (dd, J = 15 Hz, 1H) (C-22)), 5.69 (d, 7- 15.6 Hz, 1H (C-25)), 5.80 (d, 7 = 11 Hz, 1H (C-7)), 5.92 and 5.95 (dd, 7 = 15.3 and 15 Hz, 1H (C-23)), 6.12 and 6.16 (dd, 7- 15.3 and 15.6 Hz, 1H (C-24) )), 6.44 (d, 7 =

11.4 Hz, 1H (C-6)) ppm

IR (KBr):

3600-3100 (OH), 1255, 1084, 837, 724 (TBDMS groups), 1117 (C = O), 989 {trans (CH = CH) ₂ ), 906 (= CH ₂ ) cm ¹

Compound (53)

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)) , 0.84 (t, J - 7.5 Hz, 6H (C ₂₈ + C ₃₀ )) 1.03 (d, 7 = 6.6 Hz, 3H (C-21)), 1.53 (q / = 7.5 Hz, 4H (C-27 + C-29)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)), 4.92 and 4, 97 (2s, 2H (C-19)),

5.50 (d, 7- 15.3 Hz, 1H (C-25)), 5.51 and 5.54 (dd, 7- 15 Hz, 1H (C-22)), 5.87 (d. 7 =

11.4 IH (C-7)), 5.94 and 5.97 (dd, 7 = 15 Hz, IH (C-23)), 6.12 and 6.15 (dd, 7 = 15 and 15, 3 Hz, 1H, (C-24)), 6.44 (d, 7- 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3200 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 989 {trans (CH = CH) ₂ ), 897 (= CH ₂ ) cm ^-1 .

Method 6B / 2: Compounds (48), (49), (50), (51), (52) and (54) mmol of the corresponding iodine derivative, 4.50 mg of palladium acetate (0.2 mmol), 652 mg ( 2 mmol) of cesium carbonate, 275 mg (1 mmol) of silver carbonate are placed in a flask under an N ₂ atmosphere. A compartment was placed and 5 ml of anhydrous tetrahydrofuran, 50 μΐ (about 0.2 mmol) of tri-Zerc.butylphosphine and finally 10 mmol of the corresponding allyl alcohol were added with the syringe.

Heat for 4 hours at reflux and 12 hours at room temperature.

The crude product obtained was partitioned between 100 ml of pentane and 100 ml of brine and the organic phase was purified by medium pressure flash chromatography eluting with 8: 1, 6: 1 and 4: 1 hexane / AcOEt.

Thus the following compounds were obtained:

Compound Rs R « Profit Stereochemistry 48 H H 46 5E 49 H ch ₃ 42 5E 50 H c ₂ h ₅ 72 5E 51 ch ₃ ch ₃ 73 5E 52 ch ₃ c ₂ h ₅ 90.5 5E 54 ch ₃ ch ₃ 72 5Z

Compound (48)

This is prepared from an iodine derivative (IIA2a) and allyl alcohol (l-propen-3-ol). 46% yield. Clear oil.

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)) , 1.03 (d, J = 6.6 Hz, 3H (C-21)), 4.14 (d, J = 5.7 Hz, 2H (C-26)), 4.20 (m, 1H (C-3)), 4.52 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.55 and 5.57 (dd, J = 15 Hz, 1H (C-22)), 5.68 and 5.73 (dt, / = 6 and 15.3 Hz, 1H (C-25)), 5.87 (d, 7- 11.4 Hz, 1H (C-7)), 5.95 and 5.99 (dd, 7 = 15 Hz, 1 H (C-23)), 6.16 and 6.19 (dd, 7 = 15.3 and 15 Hz , 1H, (C-24)), 6.44 (d, 7 = 11.4 Hz, 1H (C-6) ppm.

IR (KBr);

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 985 (trans (CH = CH) ₂ ), 895 (= CH ₂ ) cm ^-1 .

Compound (49)

It is prepared from the iodine derivative (IIA2a) and l-buten-3-ol.

42% yield. Clear oil.

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)) , 1.03 (d, 7 = 6.6 Hz, 3H (C-21)), 1.26 (d, 7 = 6.6 Hz, 3H (C-27)), 4.20 (m, 1H (C-3)), 4.31 (m, 1H (C-26)), 4.52 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)) , 5.53 and 5.56 (dd, J = 15 Hz, 1H (C-22)), 5.58 and 5.61 (dd, 7 = 15 Hz, 1H (C-25)), 5.80 (d, 7 = 11 Hz, 1H (C-7)), 5.23 and 5.95 (dd, 7 = 15.3 and 15 Hz, 1 H (C-23)), 6.11 and 6, 14 (dd, 7 = 15.3 and 15 Hz, 1H, (C-24)), 6.43 (d, 7 = 11.1 Hz, 1H (C-6) ppm.

IR (KBr):

3650-3100 (OH), 1255, 1084, 837, and 724 (TBDMS groups), 1120 (CO), 989 (trans (CH = CH) ₂ ), 895 (= CH ₂ ) cm ^-1 .

Compound (50)

It is prepared from an iodine derivative (IIA2a) and l-penten-3-ol.

72% profit. Clear oil.

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)) , 0.89 (t, J = 7.2 Hz, 3H (C-28)), 1.03 (d, 7 = 6.6 Hz, 3H (C-21)), 1.52 (sc, 2H (C-27)), 4.01 and 4.03 (dt, 7 = 6 and 6.6 Hz, 1H (C-25)), 4.20 (m, 1H (C-3)), 4, 51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.53, 5.54, 5.55 and 5.56 (2dd, 7 = 15 Hz) , 2H (C-22 + C-25)), 5.80 (d, 7 = 11 Hz, 1H (C-7)), 5.93 and 5.96 (dd, 7 = 14.7 Hz, 1 H (C-23), 6.12 and 6.15

100 (dd, J = 15 and 15.6 Hz, 1H, (C-24)), 6.44 (d, J = 11.4 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 989 (trans (CH = CH) ₂ ), 895 (= CH ₂ ) cm ^-1 .

Compound (51)

It is prepared from an iodine derivative (IIA2a) and 3-methyl-1-butene-3-ol.

73% yield. Clear oil.

Compound (52)

It is prepared from an iodine derivative (IIA2a) and 3-methyl-1-penten-3-ol.

90.5% yield. Clear oil.

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.54 (s, 3H (C-18)), 0.84 and 0, 88 (2s, 18H ((CH ₃ ) ₃ C)) , 0.86 (t, J = 7.5 Hz, 3H (C-29)), 1.03 (d, 7 = 6.6 Hz, 3H (C-21)), 1.26 (s, 3H (C-27)), 1.55 (q / = 7.5 Hz, 2H (C-28)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl )), 4.92 and 4.97 (2s, 2H (C-19)), 5.52 and 5.55 (dd, 7 = 14.7 and 15 Hz, 1H (C-22)), 5, 60 (d, 7 = 15.3 Hz, 1H (C-25)), 5.80 (d, 7 = 11.4 Hz, 1H (C-7)), 5.93 and 5.96 (dd, 7 = 15 Hz, 1 H (C-23)), 6.12 and 6.16 (dd, 7 = 15.3 Hz, 1H, (C-24)), 6.44 (d, 7 = 11. 7 Hz, 1H (C-6) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1120 (CO), 989 (trans (CH = CH) ₂ ), 895 (= CH ₂ ) cm ^-1 .

Compound (54)

It is prepared from an iodine derivative (IIA3a) and 3-methyl-1-butene-3-ol.

72% profit. Clear oil.

NMR (CDC1 ₃₎

101

0.04 (s, 12H, (CH ₃ -Si)), 0.53 (s, 3H (C-18)), 0.85 (s, 18H ((CH ₃ ) ₃ C)), 1.02 (d, 7-6.6 Hz, 3H (C-21)), 1.31 (s, 6H (C-27 + C-28)), 4.17 (m, 1H (C-3)), 4.35 (m, 1H (Cl)),

4.83 (d, 7-2.7 Hz, 1H (C-19)), 5.15 (m, 1H (C-19)), 5.52 and 5.55 (dd, 7 = 15.3) and 15 Hz, 1H (C-22)), 5.68 (d, 7- 15.6 Hz, 1H (C-25)), 5.91 and 5.94 (dd, 7 = 15 Hz, 1H ( C23)), 6.00 (d, 7- 11.7 Hz, 1H, (C-27)), 6.12 and 6.15 (dd, 7 = 15.3 Hz, 1H (C-24)) , 6.21 (d, 7 = 11.1 Hz, 1H (C-6)) ppm.

IR (KBr):

3600-3100 (OH), 1255, 1084 (bb includes C-0 stretch), 837 and 724 (TBDMS groups), 989 (trans (CH = CH) ₂ ), 908 (= CH ₂ ) cm ^-1 .

Procedure 6B / 3: Compound (49), (51), (52), (53) and (55)

A suspension of 432 mg (8 mmol) of sodium methoxide in 8 ml of IM lithium aluminum hydride in tetrahydrofuran was heated at a bath temperature of 70 ° C and then 2.72 g (4 mmol) of alkeno-propargyl alcohol (40) was added in 25 ml of anhydrous tetrahydrofuran. Addition is carried out in 5 minutes.

The reaction is considered complete when the amount of saturated alcohol exceeds 1.5% or less than 3% of the starting product remains (5-7 minutes).

Then it was transferred to a mixture of hexane / Z-butylmethyl ether (300/150 ml) and 350 ml of 20 N NaOH. The organic phase was separated and washed with brine and sodium carbonate, dried and concentrated to give 2.8 g of an oily crude product.

This was purified by flash chromatography eluting with 10% hexane / AcOEt to give 2.48 g of a clear oil (compound 51) (yield 91%).

The alkynes in question are obtained by the same procedure from alkynes (41), (42) and (43): compound (49): clear oil, yield 91%.

Compound (52): clear oil, yield 92%.

102

Compound (53): clear oil, 95% yield. Compound (55): clear oil, yield 92%.

NMR and IR spectra are consistent with the structure.

7. The preparation of compounds of formula (I) in which m = 0, n = 0, p> 2

Triene systems must be protected from hydrogenation processes because they cannot be directly hydrogenated.

Procedure 7/1

Triene systems must be protected from hydrogenation processes because they cannot be directly hydrogenated.

Preparation of unsaturated SOs? adduct intermediates: Compounds (8) and (16) mmol of the corresponding compound to be hydrogenated - obtained by any of the preceding procedures - were added to 20 ml of liquid SO ₂ in 4 ml of Cl 2 CH ₂ and kept at -10 ° C for 1 hour. SO ₂ and C1 ₂ CH _{2 are} distilled off and the corresponding intermediates are isolated as foams.

Compound (8)

This is obtained from compound (7)

NMR (CDC1 ₃₎

0.02, 0.04 and 0.05 (3s, 12 H (CH ₃ -Si)), 0.64 and 0.56 (smaller isomer) (s, 3H (C-18)), 0.85 and 0.86 (2s, 18H (CH _{3) 3} C)), 1.19 (d, 7, 7 Hz, 3H (C-21)), 1.26 (s, 6H (C-26 + C-27 )), 2.31 (d, 7- 2.4 Hz, 2H (C-24)), 3.74 (qAB, J = 16 Hz, 2H (C-19), 4.16 (m, 1H ( C-3)), 4.34 (m, 1H (Cl)), 4.66 and 4.70 (smaller isomer) (qAB, 7 = 10.2 Hz, 2H

103 (C-6 + C-7)), 5.49 (m, 2H (C-22 + C-23)) ppm.

IR (KBr)

3645-3050 (OH), 1255, 837 and 724 (TBDMS groups), 1317, 1095 (bb includes C-0 and SiO extensions) and 873 (SO ₂ ) cm ^-1 .

Compound (16)

It is obtained from compound (38).

NMR (CDC1 ₃₎

0.02, 0.04 and 0.05 (3s, 12H, (CH ₃ -Si)), 0.64 (s, 3H (C-18)), 0.85 and 0.86 (2s, 18H ( (CH ₃ ) ₃ C)), 1.02 (d, 7- 6.9 Hz, 3H (C-21)), 2.12 (s, 3H (CH ₃ CO)), 3.04 (d. 7 = 5.7 Hz, 2H (COCH ₂ )), 3.75 (qAB, 7 = 16 Hz, 2H (C-19)), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (Cl)), 4.65 (qAB, J = 9.6 Hz, 2H (C-6 + C-7)), 5.40 (sc, 2H (C-22 + C-23) ppm IR (KBr):

1716 (C = O), 1255, 1076, 837 and 724 (TBDMS groups), 1317, 1095 and 873 (SO ₂ ), 968 (trans CH = CH) cm ^-1 .

Procedure 7/2

Preparation of unsaturated SOs? of adduct intermediates: compounds (11) and (15)

450 mg of 5% Pt / C, 300 mg of sodium bicarbonate and 30 ml of 1: 1 benzene: ethanol were added to the adduct intermediates obtained from the previous section or obtained by any of the methods described above and stirred under an atmosphere of H ₂ (1 to 1, 5 bar) 24 hours.

The products can be isolated by filtration on celite and then concentrated by solvent distillation.

Compound (11)

104

This is obtained from compound (16).

NMR (CDC1 ₃₎

0.02, 0.04 and 0.05 (3s, 12H, (CH ₃ -Si)), 0.62 and 0.53 (smaller isomer) (s, 3H (C-18)), 0.85 and 0.86 (2s, 18H ((CH ₃ ) ₃ C)), 0.89 (d, J = 6.7 Hz, 3H (C-21)), 2.11 (s, 3H (CH ₃ CO)) ), 2.36 (sc, 2H (CH ₂ CO)), 3.75 (qAB, J = 16 Hz, 2H (C-19)), 4.16 (m, 1H (C-3)), 4 , 34 (m, 1H (Cl)), 4.65 (qAB, 7 = 9.6 Hz, 2H (C ₆ -C ₇ )), 4.73 (qAB, 7 = 10.2 Hz, 2H (C ₆ + C ₇ )) (smaller isomer)

IR (KBr):

1720 (CO), 1255.1076, 837 and 724 (TBDMS groups), 1317.1095 and 873 (SO ₂ ) cm ^-1 .

Compound (15)

It is obtained from compound (8).

NMR (CDC1 ₃₎

0.02, 0.04 and 0.05 (3s, 12H (CH ₃ -Si), 0.62 and 0.53 (smaller isomer) (s, 3H (C-18), 0.85 and 0.86 (2s, 18 H (CH ₃ ) ₃ C), 0.89 (d, 7- 6.8 Hz, 3H (C-21)), 1.20 (s, 6H (C-26 + C27)), 3.75 (qAB, 7- 16 Hz, 2 H (C-19)), 4.16 (m, 1H (C-3)), 4.34 (m, 1H (Cl)), 4.65 in 4.72 (minor isomer) (qAB, 7-10 Hz, 2H (C ₆ + C ₇ )) ppm.

IR (KBr)

3600-3100 (OH), 1255.1076, 837 and 724 (TBDMS groups), 1317.1095 and 870 (SO ₂ ) cm ^-1 .

Procedure 7/3

Preparation of saturated compounds: Hydrogenated compounds (9), (10), (12), (13) and (14)

1.5 g of sodium bicarbonate and 30 ml of dimethylformamide are added to the products isolated in the previous step or directly to the solution obtained after hydrogenation and concentration and heated at 80 ° C for 3 hours until the starting product disappears. When the reaction is complete, 30 ml of hexane and 0.5 ml of water are added and the upper phase is washed with water, filtered through celite and dried on anhydrous Na ₂ SO ₄ . Finally, it was concentrated to give the desired compound (yield:> 90%).

105

Compound (9)

This is obtained from compound (34).

NMR (CDC1 ₃₎

0.065 (s, 18 H (CH ₃ -Si)), 0.52 (s, 3H (C-18), 0.86 (s, 9H (CH ₃ ) ₃ C)), 0.87 (d, J = 7.0 Hz, 6H (C-26 / C-27)), 0.90 (sc, 12H ((CH ₃ ) ₃ C + C-21)), 4.20 (m, 1H (C-3) )), 4.55 (m, 1H (C-0)), 4.92 and 4.97 (2s, 2H (C-19), 5.81 (d, J = 11.5 Hz, 1H (C) -7)), 6.47 (d, J =

11.5 Hz, 1H (C-6)) ppm.

IR (KBr)

3600-3100 (OH), 1255, 1084, 837 and 724 (TBDMS groups), 1117 (C-0) and 898 (= CH ₂ )

Compound (10)

This is obtained from compound (15).

This compound can also be prepared by hydrogenation (8) or by reaction of MeLi on (12) according to the procedure 6B7 / 2.

NMR (CDC1 ₃₎

0.04 (s, 12H, (CH ₃ -Si)), 0.52 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)) , 0.90 (d, J = 7.2 Hz, 3H (C-21)), 1.21 (s, 6H (C-26 + C-27)), 4.20 (m, 1H (C- 3)), 4.52 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H (C-19)), 5.80 (d, J = 11.4 Hz, 1H (C) -7)), 6.44 (d, J = 12 Hz, 1H (C-6)) ppm.

IR (KBr):

3600-3100 (OH), 1255.1084, 837 and 724 (TBDMS groups), 1118 (CO), 899 (= CH ₂ ) cm ^-1 .

Compound (12)

This is obtained from compound (11) NMR (CDC1 ₃ )

106

0.04 (s, 12H, (CH ₃ -Si)), 0.52 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)) ,

0.90 (d, J = 6.7 Hz, 3H (C-21)), 2.12 (s, 3H (COCH ₃ )), 2.36 (2, 3H (CH ₃ CO)), 2. 36 (sc, 2H (CH ₂ CO)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)), 4.92 and 4.97 (2s, 2H ( C19)), 5.80 (d, 7 = 11.4 Hz, 1H (C-7), 6.44 (d, 7 = 11.7 Hz, 1H (C-6)) ppm.

IR (KBr);

1720 (C = O), 1255, 1084, 837, and 724 (TBDMS groups), 1118 (CO), 895 (= CH ₂ )

Compound (13)

This is obtained from compound (17).

NMR (CDC1 ₃₎

0.04 and 0.05 (2s, 12H (CH ₃ -Si)), 0.52 (s, 2H (C-18)), 0.83 to 0.91 (sc, 6H (C-21 + C25 )), 0.84 and 0.88 (2s, 18H (CH _{3) 3} C)), 4.20 (m, IH (C-3)), 4.51 (m, IH (Cl)), 4 , 92 in

4.97 (2s, 2H (C-19)), 5.80 (d, 7 = 11.4 Hz, 1H (C-7)), 6.44 (d, 7 = 11.4 Hz, 1H ( C-6)) ppm

IR (KBr):

1255,1084, 837 and 724 (TBDMS groups) 1117 (CO), 895 (= CH ₂ ) cm ¹

Compound (14)

This is obtained from compound (18).

NMR (CD Cl ₃ )

0.04 (sa, 12H (CH ₃ -Si)), 0.52 (s, 3H (C-18)), 0.84 and 0.88 (2s, 18H ((CH ₃ ) ₃ C)), 0.85 (2d, 7 = 6.6 Hz, 6H (C-26 + C-27)), 4.20 (m, 1H (C-3)), 4.51 (m, 1H (Cl)) , 4.92 in

4.97 (2s, 2H (C-19)), 5.80 (d, 7 = 11.7 Hz, 1H (C-7)), 6.44 (d, 7 = 11.4 Hz, 1H ( C-6)) ppm

IR (KBr)

1255, 1084, 837 and 724 (TBDMS groups), 1117 (CO), 895 (= CH ₂ ) cm ' ¹

Claims (33)

Patent claims 1. A process for preparing a vitamin D derivative of general formula _(I), N (CR = CR ₂₎ - (C ^ C) - (CR ₃ R ₄₎ -D J | (I) where A is chosen from the residues of the general formulas (Al), (A2) and (Α3): where they are Z and Z 'independently of one another are hydrogen; hydroxyl; or hydroxyl protected by a hydroxyl protecting group; W is dienophile; and they are R'i, R ' ₂ and R' ₃ independently of one another are hydrogen; halogen; hydroxyl; hydroxyl protected by a hydroxyl protecting group; C _r C ₆ alkyl optionally substituted with halogen, hydroxyl, cyano or amino; C ₂ -Cg alkenyl optionally substituted by halogen, hydroxyl, cyano or amino; di (Ci-C ₃₎ alkyl ether; or Ci-C ₅ alkyl amino; R 1, R ₂ , R ₃ and R 1 are independently hydrogen; C1-C8 alkyl; C ₃ -C ₆ cycloalkyl; or C ₆ -C ₁₄ aryl; Hydrogen; 108 -CR ₅ R 6Y where R ₅ and R 8 are independently hydrogen; C _r C ₈ alkyl; C ₃ -C ₆ cycloalkyl; C6-C14 aryl; or -OR _{7 is a} group wherein R _{7 is} hydrogen; C _r C ₈ alkyl; C ₃ -C ₆ cycloalkyl; or C6-C14 aryl; and Y is hydrogen; hydroxyl; hydroxyl protected by a hydroxyl protecting group; or -OR _{7 a} group wherein R _{7 has the} same meaning as above; or -C (O) R ₅ , wherein R _{5 has the} same meaning as above; m is an integer selected from 0, 1 and 2; n is an integer selected from 0 and 1; p is an integer selected from 0, 1,2, 3, 4, 5 and 6; with the proviso that at least one of m, n or p is 0 and the sum of m, n and p is equal to or greater than 1 (m + n + p> 1) comprising (i) the reaction of an alkenyl monohalo derivative of formula (II) wherein there is But the same meaning as above; and is X is a halogen atom selected from chlorine, bromine and iodine; with (A) a compound of formula M (NR ₈ R ₉ ) where M alkali metal and sta 109 R ₈ and R _{9 are} independently hydrogen; C1-C6 alkyl; C _r C ₆ alkylsilyl; or C ₃ -C ₆ cycloalkyl, in a solvent to give the corresponding metal alkynylide, and then reacting the metal alkynylide with a compound selected from: compounds of formula R ₅ CON (CH ₃ ) OCH ₃ wherein R _{5 has the} same meaning as above and the compounds of formula R5CHO wherein R ₅ has the same meaning as above; to give a compound of formula (I) wherein m = 0, n = 1 and p = 0; or with (B) a metal alkoxide of formula MUST be where it is M is an alkali metal and is R10 C1-C6 alkyl; in a solvent and then with a silyl agent and then with an alkyl lithium compound of formula LiRio where Ri _{0 has the} same meaning as above; to give the corresponding lithium alkynylide; and then reacting lithium alkynylide with a compound selected from: 110 compounds of formula R ₅ CON (CH ₃ ) OCH ₃ wherein R _{5 has the} same meaning as above and the compounds of formula R _{5 is} CHO where R _{5 has the} same meaning as above; to give a compound of formula (I) in which m = 0, n = l and p = 0, or (C) a compound of formula M (NR ₈ R ₉ ) wherein M, R ₈ and R _{9 have the} same meanings as above; in the first solvent and then with the epoxide of the formula FL R 'where R ₅ and R _{(l have the} same meanings as above in another solvent to give a compound of formula (I) in which m = 0, n = l and p = l; or with (D) a palladium or nickel complex in a solvent and an organometallic compound of formula (T) ₀ M '(CR ₃ R ₄ ) pCHR ₅ R ₆ 111 where M 'is selected from Li, Mg, Zn, Al, Zr, B and Sn; T is halogen or C1-C5 alkyl; o is 0 or 1, which is 0 when M 'is a monovalent metal; and p, R ₃ , R 4, R 5 and 1% have the same meanings as above; to give a compound of formula (I) wherein m = 1, n = 0 and p = 1-6; or with (E) a compound of formula M (L) q where M is selected from alkali metal, earth alkali metal, Zn, Cu and Ti; L 'is halogen, C _r C ₅ alkyl, triphenylphosphine, cyanide or sulfocianid; and q is an integer selected from 0, 1,2, 3, 4, 5 and 6; in a solvent to give the compound of formula (E) vM (L) q where E is a residue of the formula CH = CH where A has the same meaning as above; v is an integer between 1 and the valence of the metal M; and M, L 'and q have the same meanings as above, 112 with the proviso that v + q represents the valence of M and / or the coordination number of M; and then reacting the compound with the compound of formula RsCOR ^ where R ₅ and R ₍ have the same meanings as above; to give a compound of formula (I) wherein m = 1, n = 0 and p = 0; or with (F) a chromium compound in the presence of a nickel and / or palladium salt in a solvent and with a compound of the formula RsCORe wherein R ₅ and R _{f) have the} same meanings as above; to give a compound of formula (I) wherein m = 1, n = 0 and p = 0; or with (G) a palladium compound in the presence of a base in the solvent and with a ketone of formula CH ₃ COR ₅ wherein R _{5 has the} same meaning as above except hydrogen; to give a compound of formula (I) wherein m = 1, n = O and p = 1; or with (H) a palladium compound in the presence of a base and optionally complexed copper salt (I) in a solvent, optionally in the presence of a phase transfer catalyst, and with propargyl alcohol of the formula CH = CC (OH) R ₅ R ₆ where R ₅ and R ₅ have the same meaning as above; 113 to give a compound of formula (I) wherein m = 1, n = 1 and p-0; or with (I) a palladium compound in the presence of a base in the solvent, optionally in the presence of a phase transfer catalyst, and with a compound of the formula R 1 -CH = CH-COR ₅ wherein R 1 and R _{5 have the} same meanings as above; to give a compound of formula (I) wherein m = 2, n-0 and p = 0; or with (J) a palladium compound in the presence of a base and a silver salt in a solvent and with a compound of the formula RrCH-CCOHjRsR ^ wherein R _b R ₅ and R _{are the same meanings as above; to give a compound of formula (I) wherein m = 2, n = 0 and p = 0; and optionally (ii) converting a compound of formula (I) into another compound of formula (I). The process of claim 1, wherein in the compound of formula (II) X is an iodine atom. The process of claim 1, wherein in the compound of formula (II) W is SO ₂ . The process of claim 1, wherein in the compound of formula (II), Z and Z 'are, independently of one another, a hydroxyl group or a hydroxyl group protected by a hydroxyl protecting group, and R' _b R ' ₂ and R' _{3 are} simultaneously hydrogen . The process of claim 4, wherein the hydroxyl protecting group is selected from the silyl ether group and the carboxyl ester group. 114 The method of claim 1, wherein the compound of formula (II) is X atom j oda; A is selected from Al, A2 and A3; Z and Z 'are at the same time a hydroxyl group protected by a hydroxyl protecting group, wherein the protecting group is a silyl ether group or an ester derivative of acetate; and they are R'i, R'2 and R ' ₃ simultaneously hydrogen. The method of claim 1, wherein the compound of formula (II) is selected from the group consisting of compounds of formulas ΙΙΑ1, IIA2 and IIA3: Compounds IIA1 Compounds of IIA2 115 Compounds of IIA3 H C <3 ' H (IIA3a) (IIA3b) MDBTSOl ^^^^ OSTBDM I I AcO ¹ '' ^ <^ OAc where STBDM or MDBTS tert.butyldimethylsilyl group; and is Ac acetyl group. The method of any one of claims 1 to 7, wherein C22-C23 has a double bond in the compound of general formula (II) trans stereochemistry. A process according to any one of claims 1 to 7, wherein the compound of formula (I) thus obtained is a compound of formula (I) having a C24, C25 or C26 hydroxyl group. The method of claim 1, alternative (A), wherein the compound of formula (II) is selected from the compound of formula (IIA2) and the compound of formula (IIA3) according to claim 7; a compound of formula M (NR ₈ R ₉ ) is selected from the group consisting of lithium diisopropylamide, lithium dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide and sodium amide; a solvent is an organic solvent selected from ether, hydrocarbon and mixtures thereof, preferably tetrahydrofuran (THF); The 116 amide of formula R ₅ CON (CH ₃ ) OCH ₃ is selected from the cyclopropanecarboxylic acid ΛζΑ-methoxymethylhydroxylamide of 2-methylpropanoic acid and the α / N-methoxymethyl-hydroxylamide; and the compound of formula R ₅ CHO is selected from 2-methylpropanal and cyclopropanecarboxaldehyde. The process of claim 1, alternative (B), wherein the compound of formula (II) is selected from the compound of formula IIA2 and the compound of formula IIA3 according to claim 7; a metal alkoxide of the formula MOR10 is selected from the group consisting of sodium t-butoxide, potassium but-butoxide, sodium Z-pentoxide and lithium ethoxide; a solvent is a polar aprotic organic solvent selected from DMSO, DMF, DMPU, HMPT and mixtures thereof; silyl agent is a compound of formula CLSI (R) (R ₂₎ (R ₃₎ where R _lb R _L2 and R ₃ independently of one another hydrogen; Ci-C ₈ alkyl; C ₃ -C ₆ cycloalkyl; or C ₆ -C 14 aryl; preferably r-butyl dimers 1 and 1 and 1 chloride; an alkyl lithium compound of formula LiR ₁₀ is selected from the group consisting of z-butyl lithium and ethyl lithium; an amide of the formula R ₅ CON (CH ₃ ) OCH ₃ is selected from 2-methylpropanoic acid ilneα-methoxymethylhydroxylamide and cyclopropanecarboxylic acid Y, A-methoxymethyl-hydroxylamide; and the compound of formula R ₅ CHO is selected from 2-methylpropanal and cyclopropanecarboxaldehyde. The method of claim 1, alternative (C), wherein the compound of formula (II) is selected from the compound of formula IIA2 and the compound of formula IIA3 according to claim 7; 117 a compound of formula M (NR ₈ R ₉ ) is selected from the group consisting of lithium diisopropylamide, lithium dicyclohexylamide, lithium amide, sodium bis (trimethylsilyl) amide and sodium amide; the first solvent is ether, preferably THF; epoxide is e / iso-butyl oxide; and another is a polar aprotic organic solvent, preferably DMPU. The method of claim 1, alternative (D), wherein the compound of formula (II) is selected from the compound of formula IIA2 and the compound of formula IIA3 according to claim 7; a palladium or nickel complex is a compound selected from the group consisting of dichloro (1,1'-bis (diphenylphosphino) ferrocene) palladium, tetrakis (triphenylphosphine) palladium and dichloro (1,1 '-bis (diphenylphosphino) ferrocene) nickel; a solvent is an aprotic organic solvent selected from the group consisting of benzene, toluene, tetrahydrofuran, hexane and mixtures thereof; and an organometallic compound of formula (T) ₀ M '(CR ₃ R ₄ ) pCHR ₅ R ₆ is selected from diethyl zinc and isobutyl magnesium bromide. The method of claim 1, alternative (E), wherein the compound of formula (II) is selected from the compound of formula IIA2 and the compound of formula IIA3 according to claim 7; a compound of formula M (L) q is selected from lithium, sodium, potassium, butyl lithium, with ¢ 7: .- butyl lithium and / -butyl lithium a; a solvent is an organic solvent selected from ether, hydrocarbon and mixtures thereof, preferably ethyl ether; and the compound of formula R ₅ COR ₅ is selected from 2-methylpropanal, cyclopropanecarboxaldehyde, N-butanecarboxaldehyde and cyclohexanecarboxaldehyde. The method of claim 1, alternative (F), wherein 118 a compound of formula (II) is selected from a compound of formula IIA1, a compound of formula IIA2, and a compound of formula IIA3 according to claim 7; the chromium derivative is selected from chromium halide, chromocene and dichromocene; a nickel salt is selected from nickel halide and nickel acetylacetonate; palladium evo salt is selected from palladium halide and palladium acetylacetonate; solvent is a polar aprotic organic solvent selected from DMSO, DMF, DMPU, HMPT, DME and mixtures thereof; and the compound of formula R5COR6 is selected from 2-methylpropanal, cyclopropanecarboxaldehyde, Z-butanecarboxaldehyde and cyclohexanecarboxaldehyde. The method of claim 1, alternative (G), wherein the compound of formula (II) is selected from the compound of formula IIA2 and the compound of formula IIA3 according to claim 7; the palladium compound is an optionally complex palladium salt or palladium complex selected from palladium acetate or chloride complexed with a phosphine ligand selected from 3 - / - butylphosphine, tricyclohexylphosphine, 1,1'bis (di-Z-butylphosphine) ferrocene, diphenylphosphine 2- (di-Z-butylphosphine) ethylferocene, triphenylphosphine, ditriphenylphosphine, tetrakis- (triphenylphosphine), and tris (dibenzylidenoacetone) dipaladia; the base is selected from (i) a metal alkoxide of formula MOR ₁₀ , wherein M is an alkali metal and R _{10 is} C 1 -C ₆ alkyl; (ii) an amine of the formula N (Ri4) (R ₅₎ (R ₆₎ wherein R 14, R ₅ and R ₆ independently of one another hydrogen, C _r C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ - C ₁ aryl; (iii) heterocyclic bases having 6 atoms of which at least 1 is nitrogen; and (iv) an inorganic base selected from alkali carbonate and alkali hydroxide, the base being preferably Z-butoxide sodium; the solvent is a polar organic solvent selected from THF, DMF, benzene, dioxane, acetonitrile and mixtures thereof; and a ketone of formula CH ₃ COR ₅ is selected from acetophenone, methylcyclopropylketone and propanone. 119 The method of claim 1, alternative (H), wherein the compound of formula (II) is selected from the compound of formula IIA1, the compound of formula IIA2, and the compound of formula IIA3 according to claim 7; a palladium compound is an optionally complex palladium salt or palladium complex selected from palladium acetate or chloride complexed with a phosphine ligand selected from 3-Z-butylphosphine, tricyclohexylphosphine, 1,1'bis (di-Z-butylphosphine) ferrocene, diphenylphosphine-diphenylphosphine 2- (di-Z-butylphosphine) ethylferocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine), and tris (dibenzylideneacetone) dipaladia; the base is selected from (i) a metal alkoxide of the formula Morio, in which M is an alkali metal and R ₀ C _r C6 alkyl; (ii) an amine of formula N (R ₁₄ ) (Ri ₅ ) (Ri ₆ ), wherein R ₁₄ , R 1 and R 16 are independently hydrogen, C 1 -C ₆ alkyl, C ₃ -C 6 cycloalkyl, C ₆ -C 10 aryl ; (iii) heterocyclic bases having 6 atoms of which at least 1 is nitrogen; and (iv) an inorganic base selected from alkali carbonate and alkali hydroxide, the base being preferably Z-butoxide sodium; the phase transfer catalyst is alkylammonium halide, preferably tetrabutylammonium chloride; optionally the complexed copper salt (I) is selected from CuBr, Cul, optionally complexed with a phosphine ligand, preferably triphenylphosphine; the solvent is selected from a base and an aromatic hydrocarbon, preferably benzene or toluene; and propargyl alcohol is selected from 3-methyl-1-butin-3-ol, 3-methyl-1-pentin-3ol, 3-ethyl-1-pentin-3-ol, and 1-butin-3-ol. The method of claim 1, alternative (I), wherein the compound of formula (II) is selected from the compound of formula IIA1, the compound of formula IIA2, and the compound of formula IIA3 according to claim 7; a palladium compound is an optionally complexed palladium salt or palladium complex selected from palladium acetate or chloride complexed with 120 phosphine ligand selected from 3 -? - butylphosphine, tricyclohexylphosphine, 1,1'bis (di - / - butylphosphine) ferrocene, diphenylphosphino-2- (di - / - butylphosphine) ethylferocene, triphenylphosphine, ditriphenylphosphine, tetrakis (tetrakis), tetrakis (tetrakis) and tris (dibenzylideneacetone) dipaladia; preferably palladium acetate, optionally complexed with triphenylphosphine or 3 - [- butylphosphine]; the base is selected from (i) a metal alkoxide of formula MOR 5, wherein M is an alkali metal and R _{1 is} C 1 -C ₆ alkyl; (ii) an amine of formula N (Ri ₄ ) (Ri ₅ ) (Ri ₆ ) wherein R _{J 4} , R 15 and R _{16 are} independently hydrogen, C 1 -C ₆ alkyl, C ₃ -C 8 cycloalkyl, C ₆ -Cio aryl; (iii) heterocyclic bases having 6 atoms, of which at least 1 is nitrogen, e.g. pyridine; and (iv) an inorganic base selected from alkali carbonate and alkali hydroxide, the base being preferably potassium carbonate; the phase transfer catalyst is alkylammonium halide, preferably tetrabutylammonium chloride; a solvent is a polar solvent selected from THF, DMF, dioxane, acetonitrile and mixtures thereof; and a compound of the formula R-CH = CH-COR ₅ is selected from methyl acrylate, ethyl acrylate, acrolein and vinilmetilketona. The method of claim 1, alternative (J), wherein the compound of formula (II) is selected from the compound of formula IIA1, the compound of formula IIA2, and the compound of formula IIA3 according to claim 7; a palladium compound is an optionally complex palladium salt or palladium complex selected from palladium acetate or chloride complexed with a phosphine ligand selected from 3 - / - butylphosphine, tricyclohexylphosphine, 1,1 * bis (di - / - butylphosphine) ferrocene, diphenylphosphino- 2- (di - / - butylphosphine) ethylferocene, triphenylphosphine, ditriphenylphosphine, tetrakis (triphenylphosphine), and tris (dibenzylideneacetone) dipaladia; preferably palladium acetate, optionally complexed with 3-tbutylphosphine; the silver salt is selected from silver acetate, silver carbonate and silver nitrate; 121 is a polar solvent selected from THF, DMF, dioxane, acetonitrile and mixtures thereof, preferably THF; and a compound of formula R 1 -CH = C (OH) R ₅ R ₄ is selected from 1-buten-3-ol, 1penten-3-ol, 3-methyl-1-buten-3-ol, 3-methyl-1- penten-3-ols and l-propen-3-ols. A method according to claim 1, which comprises converting a compound of formula (I) into another compound of formula (I) by (a) forming SO ₂ adducts of compounds of formula (I) in which A is A2 or A3 by treatment with SO ₂ in a solvent to give a compound of formula (I) wherein A is Al and W is SO ₂ ; or (b) reducing a compound of formula (I) containing at least a triple bond (n> 1) and a hydroxyl group (Y = OH) with a triple bond reducing agent, optionally in the presence of a base, in a solvent, that a compound of formula (I) containing at least one double bond and one OH group (Y-OH) is obtained; or by (c) reducing a compound of formula (I) in which D is -C (O) R ₅ with a carbonyl reducing agent in a solvent to give a compound of formula (I) in which Y is OH ; or (d) hydrogenating a compound of formula (I) in which m> 1 or n> 1 or m and n are both> 1, after prior protection with SO ₂ containing groups A2 or A3, in the presence of a metal catalyst in a solvent; or (e) decomposing the adduct of a compound of formula (I) in which A is Al and W is SO ₂ by heating in a solvent, in the presence of a base, to give a compound of general formula (I) in which A is A2; or by (f) photochemical isomerization of a compound of formula (I) in which A is A2 to give a compound of formula (I) in which A is A3; or (g) deprotecting a compound of formula (I) in which Z and Z 'are simultaneously hydroxyl groups protected by hydroxyl protecting groups by reaction with a deprotecting agent to give a compound of formula (I) wherein Z and Z 'simultaneously hydroxyl group. 122 The process of claim 20, alternative (a), wherein the solvent is an aprotic organic solvent selected from ether, methylene chloride, benzene and mixtures thereof, preferably methylene chloride. The method of claim 20, alternative (b), wherein the triple bond reducing agent is an aluminum hydride derivative selected from Redal, LiAlH ₄ , methyl di-isobutylaluminum and lithium hydride; the base is a metal alkoxide selected from sodium methoxide, sodium ethoxide and potassium t-butoxide; and the solvent is selected from ether, an aromatic hydrocarbon and mixtures thereof, preferably THF. The method of claim 20, alternative (c), wherein the carbonyl group reducing agent is a metal hydride or alkyl metal selected from alkyl lithium, alkyl cere, and organomagnesium. The method of claim 23, wherein the carbonyl group reducing agent is selected from L1AIH4, NaBH ₄ , Redal, Alpine-borane, Dibal, DIP-chloride, Ca (BH ₄ ) ₂ , NaBH ₄ / CeCl ₃ , methyl lithium and ethyl lithium . The process of claim 20, alternative (d), wherein the metal catalyst is selected from Pd, Pt and Rh, preferably Pt / C, and the solvent comprises a polar solvent selected from methanol, ethanol, ethyl acetate, DMF and mixtures thereof, as desired mixed with an apollo solvent selected from benzene, toluene and mixtures thereof, preferably an ethanol / benzene mixture. The process of claim 20, alternative (e), wherein the base is selected from alkali carbonate and alkali bicarbonate, preferably sodium bicarbonate, and the solvent is a polar solvent selected from methanol, ethanol, isopropanol, butanol, DMF and mixtures thereof, preferably DMF. 123 27. The process of claim 20, alternative (f), wherein the photochemical isomerization of a compound of formula (I), wherein A is A2,)) is carried out in a diffused daylight solvent and I ₂ , optionally in the presence of an amine of formula N ( R ₁₄₎ (R ₅₎ (R ₆₎ where R _4, R ₅ and R _J6 independently of one another hydrogen, C _r C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₀ aryl; or by diffused light and I ₂ , optionally in the presence of a heterocyclic base of 6 atoms, of which at least 1 is nitrogen; or by phenyl diselenide and tungsten light or by ultraviolet light in the presence of an aromatic photosensitizer. The method of claim 27, wherein the photochemical isomerization is carried out with UV light, the solvent is toluene and the photosensitizer is anthracene. The process of claim 20, alternative (g), wherein the hydroxyl protecting group is a silyl group and the deprotecting agent is selected from fluoride and alkoxide, in a solvent, optionally in the presence of a phase-transfer catalyst; or the hydroxyl protecting group is an acyl group and the deprotecting agent is an alkoxide or inorganic base, in a solvent, optionally in the presence of a phase-transfer catalyst. The method of claim 29, wherein the hydroxyl protecting group is a silyl group and the deprotecting agent is tetrabutylammonium fluoride in tetrahydrofuran or alternatively potassium i-butoxide in DMSO; or the hydroxyl protecting group is an acyl group and the deprotecting agent is sodium or potassium hydroxide and the solvent is ethanol. 124 The method of claim 1, wherein the compound of formula (II) is obtained by reacting a compound of formula where A has the same meaning as above with respect to a compound of formula (I), with a haloform selected from chloroform, bromoform and iodoform, in the presence of salt or divalent chromium complex (Cr) in an organic solvent. The method of claim 1, wherein the compound of formula (I) thus obtained is selected from the following: 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (S) - (ethynyl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene ( compound 1); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) - (ethynyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (compound 2); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) - (3 '-cyclopropyl-3' -oxopropin-1 yl) -9,10-secopreg-5 (E), - 7 (E), 10 (19) -triene (compound 3); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (S) - (3 '-cyclopropyl-3' -oxopropin-1 yl) -9,10-secopreg-5 (Z), - 7 (E), 10 (19) -triene (compound 4); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (S) - (3 '-cyclopropyl-3' - (R) hydroxypropin-1'-yl) -9,10-secopreg-5 (E), - 7 (E), 10 (19) -triene (compound 5 (R)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (S) - (3'-cyclopropyl-3 '- (S) hydroxypropin-1'-yl) -9,10-secopreg-5 (E), - 7 (E), 10 (19) -triene (compound 5 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) - (3'-cyclopropyl-3 '- (R) hydroxypropin-1'-yl) -9,10-secopreg-5 ( Z), - 7 (E), 10 (19) -triene (compound 6 (R)); 125 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (S) - (3 '-cyclopropyl-3' - (S) hydroxypropin-r-yl) -9,10-secopreg-5 (Z ), - 7 (E), 10 (19) -triene (compound 6 (S)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (S) - (4'-hydroxy-4'-methylpentin-r-yl) 9.10-secopreg-5 (E), - 7 ( E), 10 (19) -triene (compound 7); SO ₂ adduct 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4 '-hydroxy-4' methylpent-1 '-inyl) -9,10-secopreg-5, 7 (E), 10 (19) -triene (compound 8); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (3'-hydroxy-3 '(R) -isopropylpropan-1'-yl) -9,10-secopregna-5 (E), - 7 (E), 10 (19) -triene (compound 9 (R)); 1 (S), 3 (R) -bis (Zert. Butyldimethylsilyloxy) -20 (R) - (3 '-hydroxy-3' (S) -isopropylpropanyl-yl) -9,10-secopreg-5 (E) , -7 (E), 10 (19) -triene (compound 9 (S)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-hydroxy-4'-methylpentan-1'-yl) 9.10-secopreg-5 (E), 7 ( E), 10 (19) -triene (compound 10); SO ₂ adduct 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-oxo-pentan-1'-yl) 9.10- secopreg-5.7 (E), 10 (19) -triene (compound 11); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4 ^, -oxopentan-1'-yl) -9,10sextra-5 (E), 7 (E), 10 (19) -triene (compound 12); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (butan-1'-yl) -9,10-secopregna5 (E), 7 (E), 10 (19) - triene (compound 13); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-methylpentan-1'-yl) -9,10secopy-5 (E), 7 (E), 10 ( 19) -triene (compound 14); SO ₂ adduct 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5'-hydroxyl-5 'methylpentan-1' -yl) -9,10-secopreg-5,7 (E), 10 (19) -triene (compound 15); SO ₂ adduct 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-oxo-pent-1 '(E) enyl) -9,10-secopreg-5,7 (E), 10 (19) -triene (compound 16); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (buten-1 '(E) -yl) -9,10-secoprene 5 (E), 7 (E), 10 (19) -triene (compound 17); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-methylpenten-1'E) -yl) -9,10secoprene-5 (E), 7 (E). 10 (19) -triene (compound 18); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (3 '-cyclopropyl-3' (R) -hydroxypropyl '(E) -enyl) -9,10-sec -5 (E), 7 (E), 10 (19) -triene (compound 19 (R)); 126 l (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop (1' (E) -enyl) -9,10-secopregn -5 (E), 7 (E), 10 (19) -triene (compound 19 (S)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (4'-dimethyl-3 '(R) -hydroxypental' (E) -enyl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 20 (R)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (4'-dimethyl) -3 '(S) -hydroxypental' (E) -enyl) -9,10-secopregn- 5 (E), 7 (E), 10 (19) -triene (compound 20 (S)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(R) -hydroxyprop (1' (E) -enyl) -9,10-secopregn- 5 (Z), 7 (E), 10 (19) -triene (compound 21 (R)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3 '-cyclopropyl-3' (S) -hydroxyprop (1 '(E) -enyl) -9,10-sec- pregna-5 (Z), 7 (E), 10 (19) -triene (compound 21 (S)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3 '(R) -hydroxy-4'-methylpent-1' (E) enyl) -9,10-secopregn- 5 (Z), 7 (E), 10 (19) -triene (compound 22 (R)); 1 (S), 3 (R} -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3 '(S) -hydroxy-4'-methylpent-r (E) enyl) -9,10-secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 22 (S)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (4'-cyclohexyl -3 '(R) -hydroxyprop' (E) -enyl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 23 (R)); l (S) , 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (4'-cyclohexyl-3 '(S) -hydroxyprop (E) -enyl) -9,10-secopregna-5 (E), 7 (E), 10 (19) -triene (compound 23 (S)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3 '(R) -hydroxy-4'-methylpent-1' (E) enyl) -9,10-secopregn- 5 (E), 7 (E), 10 (19) -triene (compound 24 (R)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3 '(S) -hydroxy-4'-methylpent-r (E) enyl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 24 (S)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (4'-cyclohexyl-3 '(R) -hydroxypropyl' (E) -enyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (compound 25 (R)); 1 (S), 3 (R) -bis (Zert. Butyldimethylsilyloxy) -20 (R) - (4'-cyclohexyl-3 '(S) -hydroxypropyl' (E) -enyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (compound 25 (S)); 1 (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (4'-dimethyl-3 '(R) -hydroxypent-1' (E) enyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (compound 26 (R)); l (S), 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (4'-dimethyl-3 '(S) -hydroxypent-r (E) · enyl) -9,10-secopregna-5 (Z), 7 (E), 10 (19) -triene (compound 26 (S)); 127 20 (R) - (3 '-cyclopropyl-3' (R) -hydroxyprop-1 '(E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10-secopreg-5 (Z) , 7 (E), 10 (19) -triene (compound 27 (R)); 20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-1' (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 27 (S)); 20 (R) - (3'-cyclopropyl-3 '(R) -hydroxyprop-1' (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10-secopregna-5 (E) , 7 (E), 10 (19) -triene (compound 28 (R)); 20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-r (E) -enyl) -1 (S), 3 (R) -dihydroxy-9,10sec-5 (E), 7 ( E), 10 (19) -triene (compound 28 (S)); 1 (S), 3 (R) -Dihydroxy-20 (R) - (3 '(S) -hydroxy-4'-methylpent-1' (E) -enyl) -9,10-secopregna-5 (E) , 7 (E), 10 (19) -triene (compound 29 (R)); 1 (S), 3 (R) -Dihydroxy-20 (R) - (3 '(S) -hydroxy-4'-methylpent-1' (E) -enyl) -9,10sec-5-E (7) (E), 10 (19) -triene (compound 29 (S)); 1 (S), 3 (R) -Dihydroxy-20 (R) - (3 '(S) -hydroxy-4' -methylpent-1 '(E) -enyl) -9,10-secopregna-5 (Z) , 7 (E), 10 (19) -triene (compound 30 (R)); 1 (S), 3 (R) -dihydroxy-20 (R) - (3 '(S) -hydroxy-4' -methylpent-1 '(E) -enyl) -9,10secopro-5 (Z), 7 (E), 10 (19) -triene (compound 30 (S)); 1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3 '-cyclopropyl-3' (R) -hydroxy-prop-1 '(E) -enyl) 9.10-secopreg-5 ( Z), 7 (E), 10 (19) -triene (compound 31 (R)); 1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-1' (E) -enyl) -9,10secopreg-5 (Z ), 7 (E), 10 (19) -triene (compound 31 (S)); 1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '(R) -hydroxy-prop-r (E) -enyl) 9.10-secopreg-5 (E ), 7 (E), 10 (19) -triene (compound 32 (R)); 1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-1' (E) -enyl) -9,10secopreg-5 (E ), 7 (E), 10 (19) -triene (compound 32 (S)); SO ₂ adduct 1 (g), 3 (R) -bis (tert-butyldimethylsilyloxy) -200R) - (3'-cyclopropyl-3'3) hydroxyprop-r (E) -enyl) -9,10-secopregna-5 , 7 (E), 10 (19) -triene (compound 33 (R)); SO ₂ adduct 1 (S), 3 (R) -bis (z'ert-butyldimethylsilyloxy) -20 (R) - (3'-cyclopropyl-3 '(S) hydroxyprop-1' (E) -enyl) -9 , 10-secopreg-5,7 (E), 10 (19) -triene (compound 33 (S)); SO ₂ adduct 3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (3 '(R) -hydroxy-4'-methylpent (E) -enyl), 9,10-secopreg-5,7 (E), 10 (19) -triene (compound 34 (R)); 128 S0 ₂ adduct 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (3 '(S) -hydroxy-4'-methylpent 1' (E) -enyl), 9,10-secopreg -5,7 (E), 10 (19) -triene (compound 34 (S)); SO ₂ adduct 1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '- (R) -hydroxyprop (1' (E) -enyl) -9,10- secopreg-5,7 (E), 10 (19) -triene (compound 35 (R)); SO ₂ adduct 1 (S), 3 (R) -bis (acetoxy) -20 (R) - (3'-cyclopropyl-3 '(S) -hydroxyprop-r (E) enyl) -9,10-sec- pregna-5,7 (E), 10 (19) -triene (compound 35 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-phenyl-4'-oxobut-1 '(E) -enyl) 9,10-secopreg-5 (E ), 7 ((E), 10 (19) -triene (compound 36); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-cyclopropyl-4'-oxobut-r (E) enyl) -9,10-secopreg-5 (E) , 7 (E), 10 (19) -triene (compound 37); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-oxopent-1 '(E) -enyl) -9,10-secopregna-5 (E), 7 ((E), 10 (19) -triene (compound 38); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-hydroxy-4'-methylpent-1 '(E) enyl) -9,10-secopreg-5 (E ) -7 (E), 10 (19) -triene (compound 39); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 ^, -hydroxy-5 ^, -methylhex-3'-ynr (E) -enyl) -9,10-secopregn- 5.7 (E), 10 (19) -triene (compound 40); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxy-5'-methylhep-3'-yl' (E) -enyl) -9 , 10-secopreg-5.7 (E), 10 (19) -triene (compound 41 (R)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxy-5'-methylhep-3'-inr (E) -enyl) -9 , 10-secopreg-5.7 (E), 10 (19) -triene (compound 41 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5 '-hydroxyhep-3' -in-1 '(E) enyl) -9,10- secopregna-5 (E), 7 (E), 10 (19) -triene (compound 42); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxyhex-3' -in-1 '(E) enyl) -9,10-secopregn- 5.7 (E), 10 (19) -triene (compound 43 (R)); 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxyhex-3' -in-1 '(E) enyl) -9,10-secopreg -5,7 (E), 10 (19) -triene (compound 43 (S)); 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5'-hydroxyhep-3 '-in-1' (E) enyl) -9,10- secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 44); SO ₂ adduct 1 (S), 3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5 '-hydroxyhep 3'-in-1' (E) -enyl) -9 , 10-secopreg-5,7 (E), 10 (19) -triene (compound 45); 129 1 (S), 3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (4'-oxo-pent-1 '(E), 3' (E) -dien-1 yl) -9 , 10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 46); 1 (S) -3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (4'-methoxycarbonylbutar (E), 3 '(E) -dien-1'-yl) -9,10-secopregn -5 (E), 7 (E), 10 (19) -triene (compound 47); 1 (S) -3 (R) -bis (Zert-butyldimethylsilyloxy) -20 (R) - (5'-hydroxypent-1 '(E), 3' (E) -dienyl-yl) -9,10- secopregna-5 (E), 7 (E), 10 (19) -triene (compound 48); 1 (S) -3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxyhexa-1' (E), 3 '(E) dien-r-yl) - 9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 49 (R)); 1 (S) -3 (R) -bis ((tert-butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxyhexa-1' (E), 3 '(E) dien-1'-yl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 49 (S)); l (S) -3 (R) -bis (tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxyhepta-r (E), 3' (E) dien-l'-yl) -9 , 10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 50 (R)); 1 (S) -3 (R) -bis (Zert. Butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxyhepta-1' (E), 3 '(E) dien-1'-yl) - 9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 50 (S)); 1 (S), 3 (R) -bis - (/ ert.butyldimethylsilyloxy) -20 (R) - (5'-hydroxy-5'-methylhexa-r (E), 3 '(E) -diene-1' -yl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 51); 1 (S), 3 (R) -bis- (tert-butyldimethylsilyloxy) -20 (R) - (5 '(R) -hydroxy-5'-methylheptar (E), 3' (E) -diene-1 ' -yl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 52 (R)); 1 (S), 3 (R) -bis- (tert-butyldimethylsilyloxy) -20 (R) - (5 '(S) -hydroxy-5'-methylheptar (E), 3' (E) -diene-1 ' -yl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 52 (S)); 1 (S), 3 (R) -bis- (tert-butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5'-hydroxyheptar (E), 3 '(E) -dien-1'-yl) -9,10-secopreg-5 (E), 7 (E), 10 (19) -triene (compound 53); 1 (S), 3 (R) -bis- (tert-butyldimethylsilyloxy) -20 (R) - (5'-hydroxy-5'-methylhexa-r (E), 3 '(E) -diene-1'- yl) -9,10-secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 54); and l (S), 3 (R) -bis - (N -butyldimethylsilyloxy) -20 (R) - (5'-ethyl-5'-hydroxyheptar (E), 3 '(E) -diene-l'- yl) -9,10-secopreg-5 (Z), 7 (E), 10 (19) -triene (compound 55). Use of a compound of formula (II) as defined in claim 1 for the preparation of a vitamin D derivative of formula (I) as defined in claim 1.