MXPA00011210A - Method for making hydroxy-25-ene-vitamin d compounds - Google Patents

Abstract

The present invention provides a method for preparing a novel class of vitamin D compounds in which the C-25 or equivalent position has a double bond. In addition, the side chain is optionally extended by one or two methylene or methyne groups. The compounds prepared by the method of the present invention are of value as prodrugs for active 1&agr;, 24-dihydroxylated vitamin D compounds.

Description

METHOD FOR THE PRODUCTION OF COMPOUNDS OF HYDROXY-25-ENO-VITAMIN D CROSS REFERENCE TO RELATED REQUESTS This application claims the benefit of the priority date under 35 U.S.C. §119 of the provisional patent application of the US. No. 60/087, 222 filed May 9, 1998. BACKGROUND OF THE INVENTION This invention relates generally to novel vitamin D compounds and in particular to vitamin D compounds at the C-5 position or equivalent having a double bond , and specifically to a method for the production of these compounds. For a long time it has been established that vitamin D has an important biological role in the metabolism of bones and minerals. For example, vitamin D plays a critical role in stimulating calcium absorption and regulating calcium metabolism. It is also known that it is not vitamin D itself, but metabolites generated from it in vivo, which are effective in regulating calcium metabolism. The discovery of active forms of vitamin D, in the 1970s (M.F. Holick et al 68 Proc. Na ti.Acid. Sci. USA, 803-80 (1971); G. Jones et al 14 Biochemistry (Biochemistry), 1250-1256 (1975)), and other active vitamin D analogues (M.F. Holick et al 180 Science (Science) 190-191 (1973), - H.Y. Lam and collaborators 186 Science (Science) 1038-10 0 (197)) caused great excitement and speculation regarding the usefulness of these compounds in the treatment of bone depletion disorders. Studies in animals that examine the effects of these active vitamin D compounds, particularly the 25-dihydroxyvitamin D3, the hormonally active form of vitamin D3, suggest that these agents would be useful in restoring calcium balance. An early clinical study indicated that oral administration of 0.5 μg / day of the 25-dihydroxyvitamin D3 to a group of post-menopausal women improved intestinal calcium absorption as well as calcium balance in women. Based on this, U.S. Pat. No. 4, 225, 596 ("Patent '596") describes and claims the use of the, 25-dihydroxyvitamin D3 to increase calcium absorption and retention, ie this compound is highly potent for stimulating the intestinal absorption of calcium as well as bone calcium resorption (ie, bone mobilization). The best indicator of the efficacy of vitamin D compounds, however, for prevention or treatment of bone depletion disorders, however, is the bone itself instead of calcium absorption or calcium balance. More recent clinical data indicate that, at the dosage ranges shown in the Patent '596, the, 25-dihydroxyvitamin D3 has at best, modest efficacy to avoid or restore the loss of bone mass or bone mineral content (SM Ott and CH Chesnut, 110 Ann. Int. Med. 267-27 (1989) JC Gallagher et al 113 Ann. Int. Med. 6 9-655 (1990); J. Aloia et al. 84 Amer. J. Med. 401-408 (1988)).

These clinical studies with the 25-dihydroxyvitamin D3, and others conducted with the hydroxyvitamin D3 (M. Shiraki et al 32 Endocrinol, Japan 305-315 (1985)), indicate that the ability of these two vitamin D3 compounds to restore the lost bone mass or the mineral content of bones, is related to the dose. These studies also indicate, however, that in the dose ranges required for these agents to be truly effective, toxicity in the form of hypercalcemia and hypercalciuria becomes a major problem. Specifically, attempts to increase the amount of 25-d? Hydroxyvitamin D3 over 0.5μg / day have frequently resulted in toxicity. At dose levels below 0.5 μg / day, no effects on bone mass or mineral content are observed. (See, G.F. Jensen et al 16 Clin Invest. 305-309 (1981)).

Two μg / day of hydroxyvitamin D3 is found to be effective in increasing bone mass in patients exhibiting senile osteoporosis (O.H. Sorensen et al. 7 Clin. Endocr. 169-175 (1977)). Data from clinical studies in Japan, a population that has low 'calcium absorption, indicate that efficacy is found with hydroxyvitamin D3? when administered at 1 μg / day (M. Shi raki et al., 32 Endocrinol. Japan, 305-315 (1985); H. Orimo et al., 3 Bone and Mineral (Bone and Mineral) M-S (1987)). However, at 2 μg / day toxicity with hydroxyvitamin D3 occurs in approximately 67 percent of patients, and at 1 μg / day, this percentage is approximately 0 percent. In this way, the hydroxylated vitamin D3 compounds can produce blood calcium levels dangerously high due to their inherent calcéraica activity. Due to their toxicity, the 1-hydroxylated vitamin D3 compounds can only be administered in oral doses that are in the best of conditions, modestly beneficial to avoid or treat the loss of bones or mineral contents in bones. Undoubtedly, Aloia recommends that alternate administration routes be sought, which could avoid toxicity problems and allow higher dose levels to be achieved (J. Aloia et al., 8 Amer. J. Med. 01-08 (1988)). Despite reported toxicities of la-hydroxyvitamin D3, these two compounds remain the drugs of choice for many bone-depleting disease treatments. and calcium metabolism disorders, such as renal osteodystrophy, hypoparathyroidism, rickets and osteoporosis resistant to vitamin D. These two drugs also remain the only approved forms of la-hydroxylated vitamin D to treat or prevent hyperparathyroidism that occurs secondary to kidney disease of terminal stage although both drugs are not currently approved in all major pharmaceutical markets. More recently, in addition to the role of the vitamin D to regulate calcium homeostasis, other biological roles for vitamin D have come to light. Specific nuclear receptors for the, 25-dihydroxyvitamin D3 have been found in cells of various organs not involved in calcium homeostasis. For example, Miller et al., 52 Cancer Res. (1992) 515-520, have demonstrated specific, biologically active receptors for 5-dihydroxyvitamin D3 in the human prostate carcinoma cell line, LNCaP. It has also been reported that certain vitamin D compounds and analogues are potent inhibitors of malignant cell proliferation and inducers / stimulators of cell differentiation. For example, U.S. Pat. No., 391,802 issued to Suda et al., Describes that compounds of la-hydroxyvitamin D, specifically, 25-dihydroxyvitamin D3 and -hydroxyvitamin D3, possess potent anti-leukemic activity by virtue of inducing the differentiation of malignant cells (specifically leukemia cells) into non-malignant macrophages (monocytes), and are useful in the treatment of leukemia . Additionally, Skowronski et al., 136 Endocrinology (Endocrinology) 20-26 (1995), have reported anti-proliferative and differentiation actions of 25-dihydroxyvitamin D3 and other vitamin D3 analogues in prostate cancer cell lines. Still other roles for vitamin D have been suggested in the modulation of the immune response (see for example, US Patent No. 4,749,710 issued to Truitt et al; US Patent No. 5,559,107 to Gates et al; U.S. Patent No. 5,540,919, 5,518,725 and 5,562,910 issued to Daynes et al.) And the inflammatory response (see, for example, US Patent No. 5,589,471 issued to Hansen et al.) As well as the treatment of multiple sclerosis (see, U.S. Patent No. 5,716,946, issued to DeLuca et al.). However, despite its activity in various biological functions remains the fact that at the levels required in vivo for effective use, for example, as anti-leukemic agents, vitamin D compounds known "can induce markedly elevated and potentially dangerous blood calcium levels" by virtue of their inherent calcemic activity. That is, the clinical use of active vitamin D compounds such as 1,2-dihydroxyvitamin D and other vitamin D3 analogs is severely avoided or limited due to their equally high potency as agents that affect calcium metabolism, ie by the risk of hypercalcemia. Considering the diverse biological actions of vitamin D and its potential as a therapeutic agent, there is a need for compounds with higher specific activity and action selectivity, for example vitamin D compounds with anti-proliferative and differentiation effects but that have less calcemic activity the therapeutic amounts of the known compounds or vitamin D analogs. BRIEF COMPENDI OF THE INVENTION The present invention provides a method for preparing hydroxy-5-ene-vitamin D compounds. These compounds are considered valuable as pharmaceuticals because its vitamin D activity, but low toxicity, when compared to the known vitamin D compounds. Specifically, these compounds are hydroxy-25-ene-vitamin D such co or la-hydroxy-25-ene-vitamin D compounds and 24-hydroxy-25-ene compounds. - "8,1 .. -vitamin D. These compounds are conveniently prodrugs for 24-dihydroxylated vitamin D compounds since they are hydroxylated in vivo at the 2-position in the case of the -hydroxy-25-ene compounds -vitamin D and in the position the in the case of the compounds of la-hydroxy-25-ene-vitamin D to become the active forms of vitamin D. As prodrugs, these compounds in fact exceed the consideration of the first step ^ on the Vitamin, intestinal receptor binding, which resulted in intestinal calcium absorption, thus resulting in reduced or no hypercalcemia compared to similar dosing with known active vitamin D compounds such as, 25-d? hydrox? -v D3 The above and other advantages of the present invention are achieved in one aspect thereof, in a method for producing hydroxy-25-ene-vitamin D compounds. The 25-ene-vitamin- D are already hydroxylated or 24-hydroxylated in such a way that " When they are administered to a human or an animal, they become dihydrroxylated in vitamin D compounds, active 24-dihydroxylates. The method includes ~ reacting the vitamin D starting material appropriate for CO-S02 and- ^ pfqteg.eE-a-hydroxyl functionality at C-3 and / or C'-1 with t-butyldimethylsiloxychloride to produce an adduct of S02. Ozonolysis and reduction of the S02 adduct cuts the C-17 chain and produces a chain C-22 alcohol truncated lateral Extrusion of S02 and subsequent oxidation using the known Swern oxidation produces an aldehyde C-22. The side chain is reassembled by reaction of the C-22 aldehyde with an appropriate phenyl sulfone to result in a la-hydroxy-25-ene-vitamin D compound or a 25-ene-vitamin D compound, depending on the nature of the material. departure. If the 24-hydroxylated 25-ene-vitamin D compound is the desired final product, the 25-ene-vitamin D compound is incubated with human hepatoma cells and the 24-hydroxy metabolite is isolated and purified to result in the compound 24 (S) -25-ene-vitamin D. Specifically, the invention provides a method for producing hydroxy-25-ene-vitamin D compounds, comprising the steps of reacting a 2,3-dimethyl-3-buten phenyl sulfone With a C-22 hydroxyl aldehyde protected from a vitamin D, vitamin D is protected with hydroxyl in C-3 or C-3 and Cl. The 2,3-dimethyl-3-buten phenyl sulfone is prepared by methylation, isomerization and hydrolyzation of ethyl dimethylacrylate to result in a dimethyl-3-ene-butanoic acid; amidating dimethyl-3-ene-butanoic acid with oxazolidone to form oxazolidinones; separating the oxazolidinones to the desired isomer; oxidizing and reducing the desired isomer, to result in a methyl-3-ene-butanol; react with methane sulphonyl fluoride to form a mesylate; and replacing a phenyl sulfone group with the mesylate group, to result in 2,3-dimethyl-3-buten phenyl sulfone. The aldehyde C-22 hydroxyl -protected from vitamin D, is prepared by hydroxyl protection of the C-3 position of a vitamin D2 to result in a vitamin D2 hydroxyl protected at C-3; sulfonate vitamin D2 hydroxyl protected at C-3 to result in an adduct of S02; subjecting the adduct to an extrusion of S02 to result in the trans-hydroxyl vitamin D2 protected at C-3; hydroxylating the D2 trans-hydroxyl vitamin protected at C-3 at the D-1 position; hydroxyl protection of position C-1; form an adduct of S02; truncate side chain C-17 to form a C-22 alcohol; and subjecting the C-22 alcohol to S02 extrusion and Swern oxidation, to form the C-22 aldehyde. The method of the present invention further includes reduction, isomerization, deprotection and irradiation of the hydroxyl protected 25-ene-vitamin D, which is produced from the reaction of the phenyl sulfone and the C-22 aldehyde to result in a hydroxy -25-ene-vitamin D2. If the 25-ene-vitamin D2 compounds are desired, the protected C-22 hydroxyl aldehyde of vitamin D is prepared by protecting the hydroxyl at the C-3 position of vitamin D2 to result in a hydroxyl-protected vitamin D2 at C-3; sulfonate vitamin D2 hydroxyl protected at C-3 to result in an S02 adduct; truncate the side chain C-17 to form a C-22 alcohol; and subjecting the C-22 alcohol to S02 extrusion and Swern oxidation to form the C-22 aldehyde. The reaction of the C-22 aldehyde and the phenyl sulfone reaction produces a hydroxyl-protected 25-ene-vitamin D, which is reduced, isomerized and deprotected to result in a 25-ene-vitamin D2. If 24-hydroxy compounds are desired, 25-ene-vitamin D2 is further incubated with hepatoma cells to give 24-hydroxy-25-ene-vitamin D2. It is noted that the starting material for the method of the present invention is conveniently a vitamin D, a previtamin D, a cholesterol or an ergosterol. Other advantages and a more complete appreciation of the specific attributes of this invention will be achieved upon examination of the following drawings, detailed description of preferred embodiments and appended claims. It is expressly understood that the drawings are for the purpose of illustration and description only, and are not intended as a definition of the limits of the invention. BRIEF DESCRIPTION OF THE DRAWINGS The preferred exemplary embodiment of the present invention will now be described in conjunction with the accompanying drawings in which like designations refer to similar elements therethrough and where: Figure 1 is a reaction scheme for the preparation of phenyl sulfone to connect the appropriate side chain to vitamin D of Figure 2; Figures 2 A-2B are a reaction scheme for the preparation of la-hydroxy-25-ene-vitamin D2 according to the present invention; and Figure 3 is a reaction scheme for the preparation of 24-hydroxy-25-ene-vitamin D2 according to the present invention. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods for preparing a novel class of vitamin D compounds having highly advantageous biological activity. Specifically, the method of the present invention is more particularly adapted to produce hydroxy-5-ene-vitamin D compounds. Accordingly, the present invention is now described in detail with respect to these efforts; however, those skilled in the art will appreciate that this description of the invention is intended to be exemplary only and will not be seen as limiting its full scope. The method of the present invention is characterized by resulting in prodrugs of the 24-dihydroxy vitamin D compounds as hydroxylated in vivo at position 24 or at the position to become active forms of vitamin D. As prodrugs, these compounds, in effect, derive the consideration of the first step on the binding of intestinal vitamin D receptor that mediates the absorption of intestinal calcium, thus resulting in reduced or no hypercalcemia, in comparison with similar dosage with known active vitamin D compounds such as the, 25-dihydroxyvitamin D3. As used herein, the terms "calcemic activity" and "calcemic action" refer to the well-known ability of vitamin D compounds to elevate blood calcium levels by virtue of their intestinal calcium absorption stimulus (calcium transport). ) and bone calcium resorption (mobilization of bone). Also, as used herein, the term "lower" as a modifier for alkyl, alkenyl, fluoroalkyl, fluoroalkenyl or cycloalkyl, is intended to refer to a straight or branched, saturated and unsaturated hydrocarbon radical having 1 to 4 atoms of carbon. Specific examples of these hydrocarbon groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, ethenyl, propenyl, butenyl, isobutenyl, isopropenyl, formyl, acetyl, propionyl, butyryl or cyclopropyl. As used herein, the term "hydrocarbon portion" refers to a hydrocarbon radical of 1 to 4 carbon atoms straight, branched or cyclic, saturated or unsaturated, for example a lower alkyl, a lower alkenyl or a lower cycloalkyl. Also, the term "equivalent position" as used herein, for example at the C-24 position or equivalent, is intended to refer to a particular carbon in the C-17 secondary chain of a vitamin D compound, wherein said carbon would be carbon C-24 but for homologation of the secondary chain. The term "hydroxyl-protected" is meant to refer to an oxygen that binds to a protecting group, for example TBDMSCI, which remains inert unless it is specifically converted to a hydroxyl group. Structurally, the key feature of the compounds according to the present invention having the suitable biological attributes is that in their side chain C-17 they have double bond at the C-25 position or equivalent. In addition, the side chain optionally extends by insertion of one or more methylene (CH2-) or methine (CH =) units. In this manner, the vitamin D compounds of the present invention are conveniently represented by the general formula (I): D - Z (I) wherein D is a portion that is D1, D2 or D3 wherein D1 is a vitamin D, D2 is a previtamin D, and D3 is a cholesterol or ergosterol portion described below as formulas (II), (III) and (IV) ), respectively, and wherein Z represents a C-17 side chain which is a hydrocarbon group of 4 to 18 carbon atoms, saturated or unsaturated, substituted or unsubstituted, straight-chain, branched or cyclic, wherein the C-position Or the equivalent position has a double bond and wherein the C-24 position or equivalent is linked by a single CC bond with a lower alkyl, fluoroalkyl, lower alkenyl or fluoroalkenyl lower group and by a second bond to a hydrogen or group hydroxyl It is noted that the compounds of previtamin D are the thermal isomers of the corresponding vitamin D compounds, for example previtamin D3 is the thermal isomer of vitamin D3 and exists in thermal equilibrium therewith. Cholesterol compounds and are the well-known precursors in the biosynthesis of vitamin D compounds. Preferably, D'-Z is a vitamin D analog characterized by the general formula (II): wherein Z is as described above; And it is a methylene group, if the bond- to Y is a double bond or a methyl group "or hydrogen, if the bond to Y is a single bond, that is" when Y is hydrogen, the compound of the formula (II) it is a 19-nor compound; R is hydrogen or hydroxyl such that when R is hydrogen, Z is a secondary chain wherein the C-24 position or equivalent is hydroxylated; and when R is hydroxyl, the C-24 position or equivalent of the side chain Z is not hydroxylated; Y X is hydrogen, lower alkyl or lower fluoroalkyl.

Another example of the compound Dx-Z is represented by the formula (HA) below: wherein X, Y, R and Z are as defined above. D2-Z is an analogue of previtamin D represented by the general formula (III): wherein Z, R and X are as described above and Y is hydrogen or a methyl group. D3-Z is an cholesterol or ergoesterol analog characterized by the general formula (IV): wherein Z, R and X are as described above and Y is hydrogen or a methyl group. Preferably, Z the side chain C-17, is represented by the general formula (VA): where n is an integer that is 1 or 2; R is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; R "and R5 independently are lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl, A is carbon, oxygen, sulfur or nitrogen, r is 1 and s is zero when A is nitrogen, r and s are 1 when A is carbon, r and s are zero when A is sulfur or oxygen, and R6 and R7 are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl. For example, Z includes a secondary chain where A is carbon and r and s are 1 and n is 1, and that is represented by the formula (VB): wherein R3, R6 and R1 independently are hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl, and R4 and R5 are lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl. Also, Z includes a secondary chain represented by the formula (VC): wherein a dotted line on the side chain represents an additional, optional C-C bond; q is zero or an integer that is 1 or 2; R3 is hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl; A is carbon, oxygen, sulfur or nitrogen; r is 1 and s is zero when A is nitrogen; r and s are zero when A is sulfur or oxygen; R6 and R7 are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl. As for the optional C-C links, if q = O, there may be a single, double or triple link between C-22 and C-23. As for the group which q refers to, this group is -CH2-. For example, Z includes a secondary chain where q is zero, A is carbon, and that is represented by the formula (VD): wherein R3, R6 and R7 independently are hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl, and lower fluoroalkenyl and R4 and R5 independently they are lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl.

Preferably, Z is also a secondary chain represented by the formula (VE): where n is an integer that is 1 or 2; R3 is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; R 4 and R 5 independently are lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; A is carbon, oxygen, sulfur or nitrogen; r is 1 and s is zero when A is nitrogen; r and s are 1 when A is carbon; r and s are zero when A is sulfur or oxygen; and R6 and R7 independently are hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl. For example, Z includes a secondary chain when n is 1, A is carbon, r and s are 1 and R3, R4, R5, Rd and R7 are as described above and represented by the formula (VF): Also, Z includes a side chain represented by the formula (VG): wherein a dotted line on the side chain represents an additional, optional C-C bond; q is zero or an integer that is 1 or 2; R3 is hydrogen, lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; R4 and R7 independently are lower alkyl, lower fluoroalkyl, lower alkenyl or lower fluoroalkenyl; A is carbon, oxygen, sulfur or nitrogen; r is 1 and s is zero when A is nitrogen; r and s are 1 when A is carbon; r and s are zero when A is sulfur or oxygen; R9 and R10 are independently hydrogen, lower alkyl, lower alkenyl, lower fluoroalkyl or lower fluoroalkenyl. As for the optional links, for example, when q = 0, there may be a double bond between C-22 and C-23. For example, Z includes a secondary chain where q is zero, A is carbon, r and s are 1, R3, R4, R5, R6 and R7 are as described above and represented by the formula (VH): R4 .OH R3 (VH) Rd R? Preferred among the compounds of the formula (I) are the hydroxylated or 2-hydroxylated compounds which are prodrugs for the 24-dihydroxylated vitamin D. Examples of the compounds of the formula (I) are: la-hydroxy-25-ene-vitamin D2 la-hydroxy-25-oxo-vitamin D2 24-hydroxy-25-ene-vitamin D2 24-hydroxy-25-oxo- vitamin D2 Preferred among the compounds of the formula (III) are the 1-hydroxy-pre-vitamin D compounds which are prodrugs and isomers for vitamin D, 24-dihydroxylates. Examples of the compounds of the formula (III) are: la-hydroxy-25-ene-previtamine D2 la-hydroxy-25-oxo-previtamine D2 2-hydroxy-25-ene-previtamine D2 24-hydroxy-25-oxo-previtamine D2 Preferred among the compounds of the formula (IV) are the lahydroxylated precursor compounds of vitamin D compounds, ie la-hydroxylated cholesterol or ergosterol compounds, which are also prodrugs for vitamin D, 24-dihydroxylated. Examples of the compounds of the formula (IV) are: la-hydroxy-24-methyl-25-ene-cholesterol la-hydroxy-24-methyl-25-oxo-cholesterol 24-hydroxy-25-ene-cholesterol 24 -hydroxy -25-ene-ergosterol 24-hydroxy-25-oxo-cholesterol 24-hydroxy-25-oxo-ergosterol Those compounds of the present invention having chiral centers, for example on the C-17 chain at C-20 or C- 24, it is understood that both are diastereomers, (for example R and S) and their mixture are within the scope of the present invention. In the following description of the method of the invention, process steps are taken at temperature environment (RT = Room Temperature) and atmospheric pressure unless otherwise specified. The compounds of the formula (I) can be prepared by the exemplary reaction process illustrated in Figure 1. The synthesis is characterized by coupling the appropriate unit and separately synthesizing the side chain to the desired preformed vitamin D core, which contains a displaceable group in C-2. The required side chain is prepared as a phenyl sulfone derivative. Specifically, the method of the present invention for preparing the la-hydroxylated compounds, involves using vitamin D as starting material, hydroxylating the carbon-1 position and protecting it and then forming the la-hydroxy-5-ene-vitamin D. To prepare the 24-hydroxy compounds, the starting material is also vitamin D and a 25-ene-vitamin D compound is formed, which is then hydroxylated at the position 24 for example by biological generation. Reference is now made to Figures 2A-2B which is an exemplary reaction scheme for the synthesis of la-hydroxy-5-ene-vitamin D2. The hydroxyl functionality in the C-3 position of vitamin D2 (11), is protected with t-butyldimethylsilyloxychloride (TBDMSC1) in the presence of imidazole, to form the protected product C-3 (1), which is then reacted with S02 , resulting in adduct intermediary (13). The adduct (13) is then subjected to extrusion of S02 (sodium bicarbonate (NaHC03) / ethanol (EtOH)) to result in trans-isomer (14) of (12) The trans-isomer (14) is hydroxylated (NMO / Se02) at position C-1 to result (15). The hydroxyl functionality in C-1 is then protected (TBDMSC1) and reacted with S02 to form the adduct (17). Ozonolysis and reduction produce a C-22 alcohol (19) (see Manchand et al, 60 J. Org. Chem. (1995) 6574, incorporated herein by reference). Extrusion of S02 (NaHC03; EtOH) and subsequent oxidation using the known Swern oxidation ((C0C1) 2; DMSO) produces aldehyde C-22 (20). The side chain is introduced by reaction of aldehyde (20) with the appropriate phenyl sulfone (10), followed by reduction, deprotection and appropriate isomerization to result in the compound (1) la-hydroxy-25-ene-vitamin D2.

The compounds of the formula (III) can generally be prepared by the processes of Figures 1 and 2, wherein the prestaitamin starting materials can be prepared by exemplary reaction processes given for example in US Pat. No. 5, 52,191 issued to Pauli et al., The US patent. No. 5,035,783 issued to Coethals et al., The US patent. No. 4,388,243, all of which here they are incorporated by reference. The 19-nor compounds of the formula (1) can in general also be prepared by exemplary reaction processes given here, the starting material for which it can be prepared by the exemplary process given in US Pat. No. 5,710, 94, incorporated herein by reference. The process given in Figure 1 is also convenient for the preparation of compounds of the formula (IV), wherein the cholesterol and ergosterol starting materials are commercially available. To form the appropriate phenyl sulfone (10), reference is now made to Figure 1, which illustrates a reaction scheme. Ethyl dimethylacrylate (2) is subjected to methylation and double bond isomerization at the C-3 position. The ether group is converted to an alcohol group to form an acid (4). The acid (4) is converted to the isomers of oxazolidinone (5) and separated to produce the desired isomer (6). Oxazolidinone (6) is converted to a butanoic-3-ene acid (7). The carbonyl group of this acid (7) is removed to result in alcohol (8). The alcohol (8) is reacted to replace the alcohol group to result in a mesylate (9). The mesylate (9) is then converted to a phenyl sulfone group to result in R- (2,3-dimethyl-3-buten-l-yl) phenyl sulfone (10). Certain of the compounds described herein and methods for producing them are described in Calverley, Tetrahedron 5L (1987) 1609; Manchand et al., J. Org. Chem. £ 0 (1995) 657; alba and collaborators, J \ Org. Chem. 53 (1988) 1046; Smith III et al., J. Am. Chem. Soc. 103 (1981) 1996, all of which are incorporated herein by reference. The compounds of the formula (II) wherein the side chain is represented by the formulas (IIC) or (HE) can be prepared by the exemplary reaction processes illustrated in Figure 3. Specifically, a method for preparing 24-hydroxy-25 -neuro-vitamin D2 involves the use of vitamin D2, as a starting material, eliminating the hydroxylation and protection stages C-1 of the process of Figure 2A, and forming the 25-ene-vitamin D2, followed by incubation of the 25- eno-vitamin D2 with for example cultured human hepatoma cells, HEP3B or HEPG3, to result in the metabolite 24 (S) -hydroxy-25-ene-vitamin D2 which is then isolated, purified by high pressure liquid chromatography. As seen in Figure 3, and similarly to Figures 2A-2B, vitamin D2 (11) is reacted with S02 and the functionality of hydroxyl in C-3 is protected with t-butyldimethylsilyloxychloride resulting in the adduct intermediate. (24) Ozonolysis and reduction produces alcohol C ^ 2 (5). Extrusion of OS2 and subsequent Oxidation using the known Swern oxidation results in the aldehyde (26). The side chain is introduced by reaction of aldehyde (9) with the appropriate phenyl sulfone reagent to result in the compound 25-ene-vitamin D2 (27) with appropriate reduction, isomerization and deprotection. The 25-ene-vitamin D2 is then incubated with human hepatoma cells to result in 24-hydroxy-25-ene-vitamin D2 (28) which is extracted and purified in the 24 (S) -hydroxy diaesteromer. The present invention is further explained by the following examples which are not to be construed as limiting the scope of the present invention. * H NMR spectra were recorded on a Varian VXR-300 machine. Chemical shifts are denoted in units d (ppm) with respect to TMS. For HPLC analysis, a platinum column of EPS C18 150 x 4.6 mm, is used with liquid phase of CH3CN - 0.1% COOH 70:30, with a detection wavelength of 265 nm, a flow of 1 mL / min and a temperature of 22 ° C. Melting points were determined on an apparatus to determine Metttler FP-2 melting points equipped with a 'Mettier FP-21 microscope. Example 1: Synthesis of la-hydroxy-25-ene-vitamin D Preparation of R- (2,3-Dimethyl-3-buten-l-yl) phenyl sulfone (10) To a solution of 110 mL of diisopropylamine in 750 mL of tetramethylfurane (THF) is added 315 mL of n-butyllithium 2.5 N (n-BuLi) at a temperature between -25 ° C and -10 ° C. The mixture is cooled to -70 ° C and 150 mL of HMPA are added dropwise and the mixture is stirred for an additional hour at this temperature. After the dropwise addition of 100 g ethyl dimethyl acrylate (2) in 100 mL of THF, the mixture is stirred for 2 hours at 70 ° C followed by the addition of 60 mL of methyl iodide (Mel), maintaining a lower temperature at -50 ° C. The reaction mixture is allowed to reach room temperature RT overnight and neutralized or quenched by the addition of 400 mL of saturated NH 4 Cl solution. The layers were separated and the aqueous phase extracted with ether-hexane 1: 1 (400 mL and 300 mL). The combined organic layers were washed with 0.5 N HCl, saturated NaHCO 3 solution, brine and dried (Na 2 SO 4). The evaporation of the solvents produces 113 g of the crude product (3) as an oil. NMR (CDC13): d: 1.2 (m, 6H); 1.65 (s, 3H), 3.15 (q, 1H); 4.05 (q, 2H); 4.75 (s, 2H). The oil (3) is stirred in 800 mL of EtOH-water 1: 1 with 52 g KOH for 4 days at RT. After the mixture had been concentrated, it was washed with ether (2 x 100 mL), acidified and extracted with ether-hexane 1: 1 (x 300 mL). The combined organic layers were washed with brine, dried, (Na2SO4), and the solvents were evaporated to give result 74 g of the acid compound (4). NMR (CDC13): d: 1.3 (d, 3H); 1.8 (s, 3H); 3.2 (q, 1H); 4.9 (s, 2H); 11 (broad, s, 1H). A solution of 71.5 g of compound (4) and 175 triethylamine (NET3) in 1.25 L of THF was mechanically stirred and cooled to -40 ° C. To the solution, 83 g of pivaloylchloride were added dropwise. The resulting white suspension is stirred for 1.5 hours while the temperature reached -8 ° C and was cooled again to -50 ° C, followed by the addition of 29.5 G LiCl and 102.2 g of S (+) phenyl oxazolidone. The mixture was allowed to reach RT overnight, vacuum in 1 L of water, and extracted with ethyl acetate (EtOAC) (2 x 0.5 L). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. Bulb-to-bulb ventilation yielded 136 g (75% relative to ethyldimethylacrylate) of oxazolidinone products (5) as a thick yellow oil. NMR (CDC13): d: 1.2 (d, 3H), 1.65 and 1.8 (2s, 3H); 4.2 (dd, 1H); 4.35 (m, 1H); 4.45,: 75, 4.8, 4.85 (4s, 2H); 4.65 (m, 1H); 5.45 (m, 1H); 7.3 (m, 5H). The oxazolidinones (5) are chromatographed using 8.6 kg of silica and CH2C12 as eluent. Collection of the appropriate fraction (R £ = 0.5) yielded 581 g of the desired isomer (6). NMR (CDC13): d: 1.2 (d, 3H); 1.8 (s, 3H); 4.2 (dd, 1H); 4.4 (q, 1H); 4.65 (q, 1H); 4.8 (s, 1H); 4.85 (s, 1H); 5.4 (dd, 1H); 7.3 (m, 5H). 3% C 61.6 G of the oxazolidinone (6) in 1 L of THF was cooled to 0 ° C and 21 g of LiOH.H20 in 300 mL were added per drops followed by 95 mL of 30% H202. The mixture was allowed to slowly reach RT overnight and was again cooled to 0 ° C. Na 2 SO 2 (105 g) is added, followed by 200 mL of water and 100 mL of ether to achieve phase separation. The aqueous phase is washed with hexane, acidified and extracted with ether (3 x 250 mL, 150 mL). The ether layers were dried (Na2SO4) and the solvent was evaporated, resulting in 23 g of the acid (7). A solution of this acid in 100 mL of THF is added dropwise to a mixture of 8.2 g of LiAlH4 in 150 mL of THF with cooling. After the mixture reached RT, it was refluxed for 1 hour, cooled to 0 ° C and neutralized with a solution of Na 2 SO 4 per drop. The resulting solid was filtered and washed with THF. The combined THF layers containing the alcohol (8) were cooled to 0 ° C, followed by the introduction of 4 mL of NEt3 and 0 mL of methane sulphonylchloride per drops. The mixture was left at RT overnight, vacuum in 300 mL of water and extracted with EtOAc (2 x 300 mL). The combined organic layers were washed with brine, dried and evaporated. Bulb to bulb distillation produces 4.9 g of a mesylate (9) as a colorless oil (11% relative to oxazolidinone). NMR (CDC13): d: 1.1 (d, 3H); 1.7 (s, 3H); 2.55 (m, 1H); 2.95 (s, 3H); 4.1 (m, 1H); 4.75 (s, 1H); .85 (s, 1H).

A solution of 4.9 g (9), 5.8 g of sodium benzensulfinate (PhS02Na) and 4.1 g Nal in 50 mL of dimethylfuran (DMF) is stirred at 50 ° C for 4 days. The mixture is drained in 100 mL of ice-water and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried and evaporated. Bulb-to-bulb distillation produced 5.6 g (90%) of the product R- (2,3-methyl-3-buten-1-yl) phenyl sulfone (10) as a colorless oil. NMR (CDC13): d: 1152 (d, 3H); 1.6 (s, 3H); 2.7 (m, 1H); 3 (dd, 1H); 3.2 (dd, 1H); 5.65 (s, 2H); 7.5 (m, 3H); 7.85 (d, 2H). Preparation of 1 (S), 3 (R) -Bis- (t-butyldimethylsulfoxy) -20 (S) -formyl-9 10-secopregna-5 (E), 10 (19) -thiene (20) 57.5 g ( 145 mmoles) of vitamin D2 (11) and 16.1 g of imidazole in 500 mL of CH2C12 are cooled to -5 ° C. To this mixture 28.9 g of TBDMSC1 are added in portions. The temperature was allowed to reach RT and left at this temperature for 5 hours. The reaction was verified by thin layer chromatography (TLC) (silica CH2C12), empty in water and the layers separated. The aqueous phase is extracted with CH2C12 and the combined organic layers are washed with water and brine. Drying (Na2SO4) and evaporation yield the protected compound C-3 (12), as a yellow oil. NMR (CDC13): d: 0 (s, 6H); 0.5 (s, 3H), 0.9 (m, 18H); 1 (d. 3H); 1.1 - 24 (m, 20H); 2.75 (d, 1H); 3.75 (m, 1H); 4.7 (s, 1 HOUR); 4.95 (s, 1H); 5.15 (m, 2H); 5.95 (d, 1H); 6.1 (d, 1H).

The oil (12) is dissolved in 100 mL of ether and added to 100 mL of S02 at -50 ° C. The mixture is refluxed for 2 hours at -10 ° C and the S02 is evaporated under an argon atmosphere, resulting in the protected adduct compound (13) as an off-white solid. NMR (CDC13): d: 0 (s, 6H); 0.6, 0.65 (2s, 3H); 0.9 (m, 18H); 1 (d, 1H); 1 (d, 3H); l.l-2.2 (m, 20H); 2.5 (m, 1H); 3.6 (broad s, 2H); 3.95 (m, 1H); 4.4-4.75 (m, 2H); 5.15 (m, 2H). The whitish residual solid (13) is dissolved in 675 mL of 96% ethanol; 75 g of NaHCO 3 is added and the mixture is refluxed until LC (silica, CH 2 C 12) exhibits disappearance of the starting material (4 hours). The reaction is cooled to 0 ° C, hexane (700 mL) and EtOAc (700 mL) are added, and the mixture is filtered over Celite ™. Evaporation produces 73 g of the trans compound (14) as a yellow oil. NMR (CDC13): d: 0 (s, 6H); 0.5 (s, 3H); 0. 9 (m, 18H); 1 (d, 3H); 1.1-2.3 (m, 18H); 2.5 (m, 1H); 2.65 (dd, 1H); 2.85 (dd, 1H); 3.85 (m, 1H); 4.65 (s, 1H); 4.95 (s, 1H); 5.2 (m, 2H); 5.85 (d, 1H); 6.5 (d, 1H). The oil (14) is dissolved in 600 mL of CH2C12.

After addition of 36.3 g of NMO, the solution is dried over Na 2 SO 4, filtered and heated to reflux. To this solution, a solution of 16.2 g Se02 in 375 mL of hot MeOH was add within 5 minutes. The heating is continued for 70 minutes, the mixture is cooled and emptied in 700 mL of water. The phases were separated and the aqueous phase was extracted with CH2C12 (3 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and filtered through silica. Evaporation produced 73 g of yellow oil which was chromatographed using 800 g of silica, 5 L of 2.5% EtOAc in hexane and 2 L of 75% EtOAc in hexane. The last 2 L were collected and evaporated to yield 55.6 g of the protected compound C-1 (15) as a yellow oil. NMR (CDC13): d: 0 (s, 6H); 0.5 (s, 3H); 0.9 (m, 16H); 1 (d, 3H); 1.1-2.0 (m, 18H); 2.35 (d, 1H); 2.5 (d, 1H); 2.8 (d, 1H); 4.15 (m, 1H); 4.9 (m, 1H); 5.05 (s, 1H), 5.8 (d, 1H); 6.45 (d, 1H). 55.6 G of (15) are dissolved in 700 mL of CH2C12, 11. 8 g of imidazole were added and on cooling to -5 ° C, 21.3 g of TBDMSC1 were added. The mixture was reached RT overnight and emptied into 500 mL of water. The layers were separated, the aqueous phase was extracted with CH2C12 and the combined organic layers washed with water and brine. Drying (Na2SO4) and evaporation of the solvent yield 56.6 g of a solid. This solid is dissolved in 250 mL of hot EtOAc, and 300 mL of warm MeOH are added. Crystallization occurred in 10 minutes and the mixture was cooled to 0 ° C. The solid is isolated and washed with a mixture of MeOH and EtOAc. This produces 9.8 g (325 relative to (11)) of a-isomer (16) as a white crystalline solid. NMR (CDC13): d: 0 (s, 12H); 0.5 (s, 3H); 0.9 (m, 27H); 1 (d, 3H); ll-2. "0 (m, 16H), 2.25 ~ (d-, 1H), 2.5 (dd, 1H), 2.8 (d, 1H), 4.15 (m, 1H), 4.5 (m, 1H), 4.9 (s, 1H), 4.95 (s, 1H), 5.15 (m, H), - 5.8 (d, 1H), 6.4 (d, 1H) The compound (16) (9g) is dissolved in a mixture of 30 mL of S02 and 30 mL of CH2C12 and reflux for 1 hour The solvents were evaporated and 10 g of adduct product (17) are obtained as a white solid NMR (CDC13): d: 0 (s, 12H); 0.5 ( s, 3H), 0.9 (m, 27H), 1 (d, 3H), 1.1-2.2 (m, 18H), 2.55 (m, 1H), 3.6 (d, 1H), 3.9 (d, 1H), 4.15 (m, 1H), 4.35 (m, 1H), 4.6-4.8 (m, 2H), 5.15 (m, 2H) Ozonolysis of these 10 g of solid (17) is carried out at -65 ° C in 100 mL of CH2C12 and 50 mL of MeOH, and verify by TLC (silica, CH2C12) Subsequently, 2 g of NaBH4 are added, the reaction mixture is allowed to reach 10 ° C and empty in 150 mL of acetate buffer pH 4.3 (11 g of potassium acetate (KOAc)) The mixture is extracted with hexane (2 x 60 mL), the organic layers are washed with brine and dried (Na 2 SO 4). evaporation generated the crude product of the alcohol adduct (18) as a yellow oil which was dissolved in 150 mL of EtOH (96%). Upon addition of 12 g of NaHCO 3, the mixture was refluxed in an argon atmosphere until TLC (silica, CH 2 C 12) exhibited the absence of starting material (2 hours). After cooling, 200 mL of hexane and 100 mL of EtOAc are added, followed by Na 2 SO 4 and Celite Mβ. The mixture is filtered over Celite "R and the solvents are evaporated to yield 11 g of a yellow solidifying oil Column chromatography (silica, CH2C12) provides 5.2 g (64%) of the trans-isomer of the alcohol compound (19). (CDC13): d: 0 (s, 12H), 0.5 (s, 3H), 0.85 (s, 9H), 0.9 (s, 9H), 1 (d, 3H), 1.1-2 (, 14H), 2.55 (d, 1H), 2.5 (dd, 1H), 2.85 (d, 1H), 3.35 (m, 1H), 3.6 (m, 1H), 4.2 (m, 1H), 4.5 (m, 1H), 4.9 ( s, 1H), 4.95 (s, 1H), 5.8 (d, 1H), 6.4 (d, 1H) To a solution of 0.124 mL of oxaloylchloride in 30 mL of CH2C12 at -70 ° C, a solution of 0.26 mL (DMSO) in 10 mL CH2C12 for a period of 15 minutes keeping the temperature below -65 ° C and keeping at -60 ° C for 10 minutes The mixture is cooled again to -70 ° C and 710 mg of alcohol (19) in 30 mL of CH2C12, are added in 10 minutes keeping the temperature below -60 ° C. After 20 minutes at temperature between -60 ° C and 50 ° C, the turbid mixture is cooled again iar at -70 ° C and 0.88 mL of NEt3 are added immediately. The temperature is allowed to reach RT and the clear solution is emptied into 50 mL of water. The phases were separated, the water layer was extracted with CH2C12 (50 mL), the combined organic layers were washed with brine and dried (Na2SO4). After removal of the solvent, the residue is purified by column chromatography (silica, CH2C12) resulting in 630 mg (89%) of 1 (S), 3 (R) -bis- (t-utyldimethylsilyloxy) -20 (S) -form? -9, 10-secopregna-5 (E), 7 (El, 10 (19) triene- (20) "_ as - a white crystalline solid NMR (CDC13): d: 0 (s, 12H); 0.5 (s) , 3H), 0.85 (s, 9H), 0.9 (S, 9H), 1.1 (d, 3H), __ 1.2_-2.4 (m, 15H), 2.5 (dd, 1H), 2.85 (d ^ _ IH); 4.2 Cm, 1H), 4.5 (m, 1H), 4.9 (s, 1H), 4.95 (s, 1H), 5.8 (d, 1H), 6.4 (d, 1H), 9.55 (d, 1H). m / z (M +) Preparation of la-hydroxy-25-ene-vitamin D2 (1) A solution of 1.36 g of phenyl sulfone (10) in 40 mL THF is cooled to -70 ° C, 2.4 mL of n- BuLi 2.5 M is added and the mixture is stirred at the same temperature for 1 hour 850 mg of aldehyde (20) in 10 mL of THF is added dropwise and stirred for 15 minutes at -70 ° C. Subsequently, 10 mL of Saturated NH4C1 solution is added and the temperature is allowed to reach RT.The layers were separated and the aqueous phase was extracted with EtOAc (2 × 50 mL) The combined organic phases were washed with the crude product (21) as a mixture of diaesteromer with complex NMR data. MS m / z 797 (M +). Sodium (1.5 g) is dissolved in 130 g of Hg; 40 mL of THF are added and the mixture is cooled to -20 ° C. After the addition of 4 mL of MeOH - and -30 g of KH2P04, the Kidroxy-sulfone mixture. in 15 ml.de THF »it is added. The reaction Continue for 6 hours (verified by TLC (silica CH2C12)) at -10 ° C to -5 ° C before the water is added. The liquid phase is decanted, the residual Hg is washed with water (exothermic) and EtOAc and the layers are separated. The organic layers were washed with brine, dried (Na 2 SO 4) and evaporated. Column chromatography (silica, CH2C12) yields 440 mg (46%) of (22) as a white crystalline solid. NMR (CDC13): d: 0 (s, 12H); 0.5 (s, 3H); 0.85 (s, 9H); 0.9 (s, 9H); 0.95_ (d, _3H); 1.5 (d, 3H); 1.2-2 (m, 18H); 2.25 (d, 1H); 2.5 (dd, 1H); 2.7 (m, 1H); 2.85 (d, 1H); 4.2 (m, 1H), 4.5 (m ^ 1H); 4.65 (, 2H) ~, "4.9 (s, 1H), 4795 (s, 1H) r 5_.25 (m, 2H), 5: 8 (dT lH), 6.4 (d, 1H) MS m / z 639 (M +) A mixture of 140 mg of (22) in 35 mL of toluene, with 5 drops of NEt3 and 5 mg of 9 = acet? Lantracene is irradiated for 4 hours under a constant stream of argon. This produces 140 mg of the cis (23) NMR compound (CDC13): d: 0 (s7 12H); 0.5 (s, 3H); 0.85 (s, 9H); 0.9 (s, 9H); 0.95 (d, 3H); 1.05 (d, 3H); 1.2-2 (m, 18H); 2.2 (m, 1H); 2.45 (dd, 1H); 2.8 (m, 2H) -; .2 (.,? H); 4.35 (m, 1H), 4.7 (m, 2H); 4.85 (m, 1H); 5.15 (m, 1H); 5.25 (?, 21H); 6 (d, 1H); 6.25 (d, 1H). A mixture of 280 mg of TBAF and 140 mg of (23) in mL of THF is stirred at 45 ° C for 4 hours (checked by TLC (silica, CH22C12) .The mixture is emptied into 50 mL of NaHCO3 solution saturated and extracted with EtOAc. The organic layer is washed with water, brine and dried. Evaporation of solvent chromatography (silica, (EtOAc-hexane 2: 1)) affords 70 mg of product as a white solid. The compound contains approximately 10% of the trans compound.

Recrystallization from methylformate gave 15 mg (17%) of the pure hydroxy-25-ene-vitamin D2 (1). P.f. 134.6-138.4 ° C; NMR (CDC13): d: 0.5 (s, 3H); 0.95 (d, 3H); 1.05 (d, 3H); 1.05 (d, 3H); 1.2-2 (m, 185H); 2.25 (m, 1H); 2.55 (d, 1H); 2.65 (m, 1H); 2.8 (d, 1H); 4.2 (m, 1H); 4.4 (m, 1H); 4.65 (m, 2H), 4.95 (s, 1H); 5.2 (m, 2H); 5.3 (s, 1H); 6.0 (d, 1H); 6.35 (d, 1H). MS m / z 393 (M * -18) 413 (M *). To a solution of 320 mg of (2) in THF, 400 mg of TBAF are added. The mixture is stirred at RT overnight, 3 hours at 55 ° C and left in 75 mL of saturated NaHCO 3 solution. The mixture is extracted with EtOAc (2 x 50 mL) and the organic layers are washed with brine, dried and the solvents are evaporated. Column chromatography (silica (EtOAc-hexane: 1)) gave a white solid which is dissolved in 40 mL of toluene, and after addition of 6 drops of NEt3 and 5 mg of 9-acetylanthracene it is irradiated for 1.5 hours. Evaporation of the solvents followed by chromatography (silica (EtOAc-hexane 2: 1)) gave 65 mg (31%) of the hydroxy-25-ene-vitamin D2 (1), with a purity of 96.7% (HPLC). UV:? "Al. 265 nm.

Example 2: Synthesis of 24-hydroxy-25-ene-vitamin D2 The synthesis of 24-hydroxy-25-ene-vitamin D2 follows the same steps as -e- and -the- Example 1 above, except that the steps of hydroxylation at C-1 are removed and no protective group is added to the carbon-1 position. The product 25-ene-vitamin D2 is then incubated with human hepatoma cells to result in the 24-hydroxylated product which is extracted and purified by known methods. In summary, the present invention provides a method for preparing a novel class of vitamin D compounds wherein the C-25 position or equivalent has a double bond. In addition, the side chain is optionally extended by one or two methylene or methine groups. The compounds prepared by the method of the present invention are of value as prodrugs for 24-dihydroxylated vitamin D compounds. While the present invention has now been described and exemplified with some specificity, those skilled in the art will appreciate that various modifications, including variations, additions and omissions, can be made in what has been described. Accordingly, it is intended that these modifications also be encompassed by the present invention and that the scope of the present invention be limited only by the interpretation more that can be legally granted to the appended claims.

Claims (9)

1. CLAIMS 1. A method for producing 25-ene-vitamin D compounds, characterized in that it comprises the steps of reacting a 2,3-dimethyl-3-buten phenyl sulfone with a hydroxyl-protected C-22 aldehyde of a vitamin D, the vitamin D is hydroxyl-protected at C-3 or at C-3 and C-1.
2. 2. The method according to claim 1, characterized in that 2,3-dimethyl-3-buten phenyl sulfone is prepared by: methylating, isomerizing, and hydrolyzing ethyl dimethyl acrylate to result in a dimethyl-3-ene-butanoic acid amidate. dimethyl-3-ene-butanoic acid with oxazolidone to form oxazolidinones; separating the oxazolidinones to the desired isomer; oxidizing and reducing the desired isomer to result in a methyl-3-ene-butanol; reacting methyl-3-ene-butane with methanesulfonyl chloride to form a mesylate; and replacing a -phenyl sulfone group with the. group -mesylate to result in 2, 3-dimethyl-3-buten-phenyl sulfone.
3. 3. The method according to claim 1, characterized in that the C-22 hydroxyl protected aldehyde of vitamin D, is prepared by: protecting hydroxyl at the C-3 position of vitamin D2 to result in vitamin D2 hydroxyl protected in C-3; sulfonate vitamin D2 hydroxyl protected at C-3, to result in an adduct of S02; submit the adduct to extrusion of S02 to result in trans-hydroxylated vitamin D2 at C-3; hydrolyze trans-hydroxylated vitamin D2 at C-3 at position C-1; hydroxyl protection at position C-1; form an adduct of S02; truncate side chain C-17 to form a C-22 alcohol; and subjecting the C-22 alcohol to S02 extrusion and Swern oxidation to form the C-22 aldehyde.
4. The method according to claim 1, characterized in that the phenyl sulfone-aldehyde C-22 reaction produces a hydroxyl-protected 25-ene-vitamin D; and further comprising reducing, isomerizing, deprotecting and irradiating the hydroxyl-protected 25-ene-vitamin D to result in a 25-ene-vitamin D2.
5. The method according to claim 1, characterized in that the hydroxyl-protected C-22 aldehyde of vitamin D is prepared by: hydroxyl protection at the C-3 position of vitamin D2. to result in hydroxy-protected vitamin D2 at C-3; sulfonate hydroxy-protected vitamin D2 C-3 to result in an S02 adduct; truncating the side chain C-17 of the adduct to form a C-22 alcohol; subject C-22 alcohol to S02 extrusion and Swern oxidation to form C-22 aldehyde.
6. 6. The method according to claim 1, characterized in that the reaction of phenyl sulfone - aldehyde C-22 produces a hydroxy-protected 25-ene-vitamin D and further comprises: reducing, isomerizing and deprotecting the hydroxyl-protected 25-ene-vitamin D to result in a 25-ene-vitamin D2.
7. 7. The method of compliance with the claim 6, characterized in that it further comprises incubating 25-ene-vitamin D2 with hepatoma cells, to result in 24 (S) -hydroxy-25-ene-vitamin D2.
8. 8. The method according to claim 1, characterized in that vitamin D is a previtamin D.
9. 9. The method according to claim 1, characterized in that vitamin D is a cholesterol or an ergosterol.