Abstract:
A method of purifying 1α-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3  to obtain 1α-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3  in crystalline form. The method includes the steps of preparing a solvent of either ethyl formate or a mixture of ethyl formate and hexane, dissolving a product containing 1α-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3  to be purified in the solvent, cooling the solvent and dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 1α-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3  crystals, and recovering the 1α-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3  crystals.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application claims the benefit of U.S. Provisional Application No. 61/529,007, filed Aug. 30, 2011, which is incorporated by reference herein in its entirety for any purpose. 
    
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
     This invention was made with government support under DK047814 awarded by the National Institutes of Health. The government has certain rights in the invention. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates to purification of organic compounds, and more particularly to the purification of 1α-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3  (referred to herein as “20DCM”) by preparing it in crystalline form. 
     Purification of organic compounds, especially those designated for pharmaceutical use, is of considerable importance for chemists synthesizing such compounds. Preparation of the compound usually requires many synthetic steps and, therefore, the final product can be contaminated not only with side-products derived from the last synthetic step of the procedure but also with compounds that were formed in previous steps. Even chromatographic purification, which is a very efficient but relatively time-consuming process, does not usually provide compounds which are sufficiently pure to be used as drugs. 
     Depending on the method used to synthesize 1α-hydroxyvitamin D compounds, different minor undesirable compounds can accompany the final product. Thus, for example, if direct C-1 hydroxylation of 5,6-trans geometric isomer of vitamin D is performed, followed by SeO 2 /NMO oxidation and photochemical irradiation [see Andrews et al.,  J. Org. Chem.  51, 1635 (1986); Calverley et al.,  Tetrahedron  43, 4609 (1987); Choudry et al,  J. Org. Chem.  58, 1496 (1993)], the final 1α-hydroxyvitamin D product can be contaminated with 1β-hydroxy- as well as 5,6-trans isomers. If the method consists of C-1 allylic oxidation of the 4-phenyl-1,2,4-triazoline-3,5-dione adduct of the previtamin D compound, followed by cycloreversion of the modified adduct under basic conditions [Nevinckx et al.,  Tetrahedron  47, 9419 (1991); Vanmaele et al,  Tetrahedron  41, 141 (1985) and 40, 1179 (1994); Vanmaele et al.,  Tetrahedron Lett.  23. 995 (1982)], one can expect that the desired 1α-hydroxyvitamin can be contaminated with the previtamin 5(10), 6,8-triene and 1β-hydroxy isomer. One of the most useful C-1 hydroxylation methods, of very broad scope and numerous applications, is the experimentally simple procedure elaborated by Paaren et al. [see  J. Org. Chem.  45, 3253 (1980) and  Proc. Natl. Acad. Sci U.S.A.  75, 2080 (1978)]. This method consists of allylic oxidation of 3,5-cyclovitamin D derivatives, readily obtained from the buffered solvolysis of vitamin D tosylates, with SeO 2 /t-BuOOH and subsequent acid-catalyzed cycloreversion to the desired 1α-hydroxy compounds. Taking into account this synthetic path it is reasonable to assume that the final product can be contaminated with 1α-hydroxy epimer, 5,6-trans isomer and the previtamin D form. 1α-hydroxyvitamin D 4  is another undesirable contaminant found in 1α-hydroxyvitamin D compounds synthesized from vitamin D 2  or from ergosterol. 1α-hydroxyvitamin D 4  results from C-1 oxidation of vitamin D 4 , which in turn is derived from contamination of the commercial ergosterol material. Typically, the final product may contain up to about 1.5% by weight 1α-hydroxyvitamin D 4 . Thus, a purification technique that would eliminate or substantially reduce the amount of 1α-hydroxyvitamin D 4  in the final product to less than about 0.1-0.2% would be highly desirable. 
     The vitamin D conjugated triene system is not only heat- and light-sensitive but it is also prone to oxidation, leading to the complex mixture of very polar compounds. Oxidation usually happens when a vitamin D compound has been stored for a prolonged time. Other types of processes that can lead to a partial decomposition of vitamin D compounds consist of some water-elimination reactions; their driving force is allylic (1α-) and homoallylic (3β-) position of the hydroxy groups. The presence of such above-mentioned oxidation and elimination products can be easily detected by thin-layer chromatography. 
     Usually, all 1α-hydroxylatation procedures require at least one chromatographic purification. However, even chromatographically purified 1α-hydroxyvitamin D compounds, although showing consistent spectroscopic data, suggesting homogeneity, do not meet the purity criteria required for therapeutic agents that can be orally, parenterally or transdermally administered. Therefore, it was evident that a suitable method of purification of the 1α-hydroxylated vitamin D compound 20DCM is required. 
     SUMMARY OF THE INVENTION 
     The present invention relates to a method of purifying 20DCM by means of crystallization to obtain 20DCM in crystalline form. The solvent plays a crucial role in the crystallization process, and is typically an individual liquid substance or a suitable mixture of different liquids. For crystallizing 20DCM, the most appropriate solvent and/or solvent system is characterized by the following factors:
         (1) low toxicity;   (2) low boiling point;   (3) significant dependence of solubility properties with regard to temperature (condition necessary for providing satisfactory crystallization yield); and   (4) relatively low cost.       

     Interestingly, hexane, so frequently used for crystallization purposes, was found less suitable as the sole solvent for crystallization of 20DCM. However, it was found that either ethyl formate, or a mixture of ethyl formate and hexane, was most useful for the crystallization of 20DCM. In particular, it was determined that a mixture of about 75% ethyl formate with about 25% hexane (by volume) performed well. The ethyl formate/hexane solvent mixture was also easy to remove by evaporation or other well known methods. In all cases the crystallization process occurred easily and efficiently; and the precipitated crystals were sufficiently large to assure their recovery by filtration or other means. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is an illustration of the three dimensional molecular structure for 20DCM as defined by the atomic positional parameters discovered and set forth herein; 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention provides 1α-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3  (20DCM) in crystalline form, a pharmacologically important compound, characterized by the formula I shown below: 
     
       
                 
         
             
             
         
      
     
     The present invention also provides a valuable method of purification of 20DCM. The purification technique involves obtaining the 20DCM product in crystalline form by utilizing a crystallization procedure wherein the 20DCM material to be purified is dissolved using as the solvent either ethyl formate as the sole solvent, or a mixture comprised of ethyl formate and hexane. Preferably the mixture comprises about 75% ethyl formate and about 25% hexane (by volume). Thereafter, the solvent can be removed by evaporation, with or without vacuum, or other means as is well known, or the resultant crystals may be filtered from the mother liquor. The technique can be used to purify a wide range of final products containing 20DCM obtained from any known synthesis thereof, and in varying concentrations, i.e. from microgram amounts to kilogram amounts. As is well known to those skilled in this art, the amount of solvent utilized should be minimized and/or adjusted according to the amount of 20DCM to be purified. 
     The usefulness and advantages of the present crystallization procedure is shown in the following specific Examples 1, 2 and 3. After crystallization, the precipitated material was observed under a microscope to confirm its crystalline form. Yields of crystals were relatively high and the obtained crystals showed a relatively sharp melting point of 140-145° C. 
     The described crystallization process of the synthetic 20DCM product represents a valuable purification method, which can remove most side products derived from the synthetic path. Such impurity is the result of the contamination of starting raw materials. The crystallization process occurred easily and efficiently; and the precipitated crystals were sufficiently large to assure their recovery by filtration, or other means. 
     Crystallization of 1α-hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3  (20DCM) 
     EXAMPLE 1 
     Crystallization from Ethyl Formate 
     1α-Hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3 , 20DCM (15 mg), was dissolved in boiling ethyl formate (0.35 mL) and left at room temperature for about 1 hour, then it was kept in a refrigerator for about 18 hours. The precipitated crystals were filtered off, washed with a small volume of a cold (0° C.) ethyl formate and dried to give 9 mg (60%) of crystalline material. 
     EXAMPLE 2 
     Crystallization from Ethyl Formate/Hexane 
     1α-Hydroxy-20-methyl-2-methylene-19,24,25,26,27-pentanorvitamin D 3 , 20DCM (15 mg), was dissolved in boiling ethyl formate (0.30 mL) and hexane (0.10 mL) was added. It was left at room temperature for about 1 hour, then it was kept in a refrigerator for about 18 hours. The precipitated crystals were filtered off, washed with a small volume of a cold (0° C.) ethyl formate/hexane (3:1) mixture and dried to give 10 mg (67%) of crystalline material. 
     EXAMPLE 3 
     Experimental 
     All crystal measurements were performed on a KM4CCD κ-axis diffractometer with graphite-monochromated MoK α  radiation. The crystal was positioned at 62 mm from the CCD camera. 2186 frames were measured at 0.5° intervals with a counting time of 12 sec. The data were corrected for Lorentz and polarization effects. Empirical correction for absorption was applied [1]  Data reduction and analysis were carried out with the Oxford Diffraction programs. [2]   
     The structure was solved by direct methods [3]  and refined using SHELXL. [4]  The refinement was based on F 2  for all reflections except those with very negative F 2 . Weighted R factors wR and all goodness-of-fit S values are based on F 2 . Conventional R factors are based on F with F set to zero for negative F 2 . The F o   2 &gt;2σ(F o   2 ) criterion was used only for calculating R factors and is not relevant to the choice of reflections for the refinement. The R factors based on F 2  are about twice as large as those based on F. All hydrogen atoms were located geometrically and their position and temperature factors were not refined. Scattering factors were taken from Tables 6.1.1.4 and 4.2.4.2 in Reference 5. 
     The three dimensional structure of 20DCM as defined by the following physical data and atomic positional parameters described and calculated herein is illustrated in  FIG. 1 . 
     
       
         
               
             
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 Crystal data and structure refinement for 20DCM. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 Identification code 
                 20dcm 
               
               
                   
                 Empirical formula 
                 C24H38O2 
               
               
                   
                 Formula weight 
                 358.54 
               
               
                   
                 Temperature 
                 100(2) K 
               
               
                   
                 Wavelength 
                 0.71073 A 
               
               
                   
                 Crystal system, space group 
                 Orthorhombic, P2(1)2(1)2(1) 
               
               
                   
                 Unit cell dimensions: 
               
               
                   
                 a = 6.6085(2) A 
                 alpha = 90 deg. 
               
               
                   
                 b = 15.8069(5) A 
                 beta = 90 deg. 
               
               
                   
                 c = 20.0641(7) A 
                 gamma = 90 deg. 
               
               
                   
                 Z, Calculated density 
                 4, 1.136 Mg/m{circumflex over ( )}3 
               
               
                   
                 Absorption coefficient 
                 0.070 mm{circumflex over ( )}−1 
               
               
                   
                 F(000) 
                 792 
               
               
                   
                 Crystal size 
                 0.70 × 0.40 × 0.35 mm 
               
               
                   
                 Theta range for data collection 
                 2.77 to 28.73 deg. 
               
               
                   
                 Limiting indices 
                 −8 &lt;= h &lt;= 8, −20 &lt;= k &lt;= 21, 
               
               
                   
                   
                 −26 &lt;= 1 &lt;= 26 
               
               
                   
                 Reflections collected/unique 
                 35848/3009 [R(int) = 0.0196] 
               
               
                   
                 Completeness to theta 
                 = 28.00 99.7% 
               
               
                   
                 Absorption correction 
                 Semi-empirical from equivalents 
               
               
                   
                 Max. and min. transmission 
                 0.98 and 0.96 
               
               
                   
                 Refinement method 
                 Full-matrix least-squares on F{circumflex over ( )}2 
               
               
                   
                 Data/restraints/parameters 
                 3009/13/261 
               
               
                   
                 Goodness-of-fit on F{circumflex over ( )}2 
                 1.084 
               
               
                   
                 Final R indices [I &gt; 2sigma(I)] 
                 R1 = 0.0412, wR2 = 0.1103 
               
               
                   
                 R indices (all data) 
                 R1 = 0.0479, wR2 = 0.1136 
               
               
                   
                 Largest diff. peak and hole 
                 0.217 and −0.256 e · A{circumflex over ( )}−3 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Atomic coordinates (×10 4 ) and equivalent isotropic displacement 
               
               
                 parameters (A 2  × 10 3 ) for 20DCM. U(eq) is defined as one third of the 
               
               
                 trace of the orthogonalized Uij tensor. 
               
             
          
           
               
                   
                 x 
                 y 
                 z 
                 U(eq) 
               
               
                   
                   
               
             
          
           
               
                   
                 O(1) 
                 8264(2) 
                 −1494(1) 
                 9984(1) 
                 30(1) 
               
               
                   
                 O(2) 
                 2152(2) 
                 −1902(1) 
                 10503(1) 
                 35(1) 
               
               
                   
                 C(1) 
                 6215(2) 
                 −1295(1) 
                 10144(1) 
                 26(1) 
               
               
                   
                 C(2) 
                 5551(3) 
                 −1666(1) 
                 10802(1) 
                 33(1) 
               
               
                   
                 C(2′) 
                 6749(3) 
                 −2110(2) 
                 11197(1) 
                 54(1) 
               
               
                   
                 C(3) 
                 3382(3) 
                 −1462(1) 
                 10976(1) 
                 34(1) 
               
               
                   
                 C(4) 
                 3028(3) 
                 −510(1) 
                 10959(1) 
                 39(1) 
               
               
                   
                 C(5) 
                 3801(3) 
                 −104(1) 
                 10329(1) 
                 33(1) 
               
               
                   
                 C(6) 
                 2600(3) 
                 403(1) 
                 9970(1) 
                 37(1) 
               
               
                   
                 C(7) 
                 3083(3) 
                 859(1) 
                 9363(1) 
                 36(1) 
               
               
                   
                 C(8) 
                 1807(3) 
                 1350(2) 
                 9016(1) 
                 40(1) 
               
               
                   
                 C(9) 
                 −379(3) 
                 1525(2) 
                 9198(1) 
                 58(1) 
               
               
                   
                 C(10) 
                 5961(3) 
                 −331(1) 
                 10158(1) 
                 30(1) 
               
               
                   
                 C(11) 
                 −833(4) 
                 2464(2) 
                 9220(1) 
                 67(1) 
               
               
                   
                 C(12) 
                 −225(4) 
                 2915(2) 
                 8572(1) 
                 58(1) 
               
               
                   
                 C(13) 
                 2015(3) 
                 2770(1) 
                 8411(1) 
                 38(1) 
               
               
                   
                 C(14) 
                 2368(3) 
                 1800(1) 
                 8383(1) 
                 37(1) 
               
               
                   
                 C(15) 
                 4498(3) 
                 1722(1) 
                 8100(1) 
                 37(1) 
               
               
                   
                 C(16) 
                 4621(3) 
                 2444(1) 
                 7585(1) 
                 34(1) 
               
               
                   
                 C(17) 
                 2724(3) 
                 3012(1) 
                 7691(1) 
                 36(1) 
               
               
                   
                 C(18) 
                 3346(4) 
                 3155(1) 
                 8960(1) 
                 45(1) 
               
               
                   
                 C(20) 
                 3039(4) 
                 3933(1) 
                 7453(1) 
                 49(1) 
               
               
                   
                 C(20′) 
                 4583(6) 
                 4425(2) 
                 7858(1) 
                 72(1) 
               
               
                   
                 C(21) 
                 3813(5) 
                 3899(2) 
                 6726(1) 
                 57(1) 
               
               
                   
                 C(22A) 
                 1282(8) 
                 4571(3) 
                 7457(3) 
                 53(1) 
               
               
                   
                 C(23A) 
                 −387(7) 
                 4296(3) 
                 6993(3) 
                 71(2) 
               
               
                   
                 C(22B) 
                  749(8) 
                 4221(5) 
                 7469(4) 
                 49(2) 
               
               
                   
                 C(23B) 
                  348(13) 
                 5097(5) 
                 7183(4) 
                 71(3) 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Bond lengths [Å] for 20DCM. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 O(1)—C(1) 
                 1.426(2) 
               
               
                   
                 O(1)—H(1O) 
                 0.8400 
               
               
                   
                 O(2)—C(3) 
                 1.430(2) 
               
               
                   
                 O(2)—H(2O) 
                 0.8400 
               
               
                   
                 C(1)—C(2) 
                 1.510(2) 
               
               
                   
                 C(1)—C(10) 
                 1.534(2) 
               
               
                   
                 C(1)—H(1) 
                 1.0000 
               
               
                   
                 C(2)—C(2′) 
                 1.321(3) 
               
               
                   
                 C(2)—C(3) 
                 1.510(3) 
               
               
                   
                 C(2′)—H(2′A) 
                 0.9500 
               
               
                   
                 C(2′)—H(2′B) 
                 0.9500 
               
               
                   
                 C(3)—C(4) 
                 1.524(3) 
               
               
                   
                 C(3)—H(3) 
                 1.0000 
               
               
                   
                 C(4)—C(5) 
                 1.507(3) 
               
               
                   
                 C(4)—H(4A) 
                 0.9900 
               
               
                   
                 C(4)—H(4B) 
                 0.9900 
               
               
                   
                 C(5)—C(6) 
                 1.338(3) 
               
               
                   
                 C(5)—C(10) 
                 1.512(3) 
               
               
                   
                 C(6)—C(7) 
                 1.452(3) 
               
               
                   
                 C(6)—H(6) 
                 0.9500 
               
               
                   
                 C(7)—C(8) 
                 1.340(3) 
               
               
                   
                 C(7)—H(7) 
                 0.9500 
               
               
                   
                 C(8)—C(14) 
                 1.503(3) 
               
               
                   
                 C(8)—C(9) 
                 1.516(3) 
               
               
                   
                 C(9)—C(11) 
                 1.515(4) 
               
               
                   
                 C(9)—H(9A) 
                 0.9900 
               
               
                   
                 C(9)—H(9B) 
                 0.9900 
               
               
                   
                 C(10)—H(10A) 
                 0.9900 
               
               
                   
                 C(10)—H(10B) 
                 0.9900 
               
               
                   
                 C(11)—C(12) 
                 1.535(4) 
               
               
                   
                 C(11)—H(11A) 
                 0.9900 
               
               
                   
                 C(11)—H(11B) 
                 0.9900 
               
               
                   
                 C(12)—C(13) 
                 1.533(3) 
               
               
                   
                 C(12)—H(12A) 
                 0.9900 
               
               
                   
                 C(12)—H(12B) 
                 0.9900 
               
               
                   
                 C(13)—C(18) 
                 1.535(3) 
               
               
                   
                 C(13)—C(14) 
                 1.552(3) 
               
               
                   
                 C(13)—C(17) 
                 1.565(3) 
               
               
                   
                 C(14)—C(15) 
                 1.523(3) 
               
               
                   
                 C(14)—H(14) 
                 1.0000 
               
               
                   
                 C(15)—C(16) 
                 1.541(3) 
               
               
                   
                 C(15)—H(15A) 
                 0.9900 
               
               
                   
                 C(15)—H(15B) 
                 0.9900 
               
               
                   
                 C(16)—C(17) 
                 1.556(3) 
               
               
                   
                 C(16)—H(16A) 
                 0.9900 
               
               
                   
                 C(16)—H(16B) 
                 0.9900 
               
               
                   
                 C(17)—C(20) 
                 1.547(3) 
               
               
                   
                 C(17)—H(17) 
                 1.0000 
               
               
                   
                 C(18)—H(18A) 
                 0.9800 
               
               
                   
                 C(18)—H(18B) 
                 0.9800 
               
               
                   
                 C(18)—H(18C) 
                 0.9800 
               
               
                   
                 C(20)—C(20′) 
                 1.518(4) 
               
               
                   
                 C(20)—C(22A) 
                 1.537(4) 
               
               
                   
                 C(20)—C(21) 
                 1.547(3) 
               
               
                   
                 C(20)—C(22B) 
                 1.580(5) 
               
               
                   
                 C(20′)—H(20D) 
                 0.9800 
               
               
                   
                 C(20′)—H(20E) 
                 0.9800 
               
               
                   
                 C(20′)—H(20F) 
                 0.9800 
               
               
                   
                 C(21)—H(21A) 
                 0.9800 
               
               
                   
                 C(21)—H(21B) 
                 0.9800 
               
               
                   
                 C(21)—H(21C) 
                 0.9800 
               
               
                   
                 C(22A)—C(23A) 
                 1.507(8) 
               
               
                   
                 C(22A)—H(22A) 
                 0.9900 
               
               
                   
                 C(22A)—H(22B) 
                 0.9900 
               
               
                   
                 C(23A)—H(23A) 
                 0.9800 
               
               
                   
                 C(23A)—H(23B) 
                 0.9800 
               
               
                   
                 C(23A)—H(23C) 
                 0.9800 
               
               
                   
                 C(22B)—C(23B) 
                 1.523(9) 
               
               
                   
                 C(22B)—H(22C) 
                 0.9900 
               
               
                   
                 C(22B)—H(22D) 
                 0.9900 
               
               
                   
                 C(23B)—H(23D) 
                 0.9800 
               
               
                   
                 C(23B)—H(23E) 
                 0.9800 
               
               
                   
                 C(23B)—H(23F) 
                 0.9800 
               
               
                   
                   
               
             
          
         
       
     
                                   TABLE 4               Bond angles [°] for 20DCM.                                    C(1)—O(1)—H(1O)   109.5           C(3)—O(2)—H(2O)   109.5           O(1)—C(1)—C(2)   112.81(14)           O(1)—C(1)—C(10)   109.03(14)           C(2)—C(1)—C(10)   109.76(15)           O(1)—C(1)—H(1)   108.4           C(2)—C(1)—H(1)   108.4           C(10)—C(1)—H(1)   108.4           C(2′)—C(2)—C(3)   122.96(18)           C(2′)—C(2)—C(1)   123.77(18)           C(3)—C(2)—C(1)   113.25(15)           C(2)—C(2′)—H(2′A)   120.0           C(2)—C(2′)—H(2′B)   120.0           H(2′A)—C(2′)—H(2′B)   120.0           O(2)—C(3)—C(2)   106.43(15)           O(2)—C(3)—C(4)   112.18(16)           C(2)—C(3)—C(4)   110.58(17)           O(2)—C(3)—H(3)   109.2           C(2)—C(3)—H(3)   109.2           C(4)—C(3)—H(3)   109.2           C(5)—C(4)—C(3)   112.82(16)           C(5)—C(4)—H(4A)   109.0           C(3)—C(4)—H(4A)   109.0           C(5)—C(4)—H(4B)   109.0           C(3)—C(4)—H(4B)   109.0           H(4A)—C(4)—H(4B)   107.8           C(6)—C(5)—C(4)   120.34(18)           C(6)—C(5)—C(10)   125.47(18)           C(4)—C(5)—C(10)   114.19(18)           C(5)—C(6)—C(7)   128.22(18)           C(5)—C(6)—H(6)   115.9           C(7)—C(6)—H(6)   115.9           C(8)—C(7)—C(6)   125.78(18)           C(8)—C(7)—H(7)   117.1           C(6)—C(7)—H(7)   117.1           C(7)—C(8)—C(14)   123.88(17)           C(7)—C(8)—C(9)   125.5(2)           C(14)—C(8)—C(9)   110.64(19)           C(11)—C(9)—C(8)   112.0(2)           C(11)—C(9)—H(9A)   109.2           C(8)—C(9)—H(9A)   109.2           C(11)—C(9)—H(9B)   109.2           C(8)—C(9)—H(9B)   109.2           H(9A)—C(9)—H(9B)   107.9           C(5)—C(10)—C(1)   110.07(15)           C(5)—C(10)—H(10A)   109.6           C(1)—C(10)—H(10A)   109.6           C(5)—C(10)—H(10B)   109.6           C(1)—C(10)—H(10B)   109.6           H(10A)—C(10)—H(10B)   108.2           C(9)—C(11)—C(12)   112.3(2)           C(9)—C(11)—H(11A)   109.1           C(12)—C(11)—H(11A)   109.1           C(9)—C(11)—H(11B)   109.1           C(12)—C(11)—H(11B)   109.1           H(11A)—C(11)—H(11B)   107.9           C(13)—C(12)—C(11)   111.20(18)           C(13)—C(12)—H(12A)   109.4           C(11)—C(12)—H(12A)   109.4           C(13)—C(12)—H(12B)   109.4           C(11)—C(12)—H(12B)   109.4           H(12A)—C(12)—H(12B)   108.0           C(12)—C(13)—C(18)   110.03(17)           C(12)—C(13)—C(14)   107.5(2)           C(18)—C(13)—C(14)   109.37(15)           C(12)—C(13)—C(17)   116.55(16)           C(18)—C(13)—C(17)   113.17(19)           C(14)—C(13)—C(17)   99.38(15)           C(8)—C(14)—C(15)   120.36(17)           C(8)—C(14)—C(13)   113.59(16)           C(15)—C(14)—C(13)   103.42(17)           C(8)—C(14)—H(14)   106.2           C(15)—C(14)—H(14)   106.2           C(13)—C(14)—H(14)   106.2           C(14)—C(15)—C(16)   103.82(16)           C(14)—C(15)—H(15A)   111.0           C(16)—C(15)—H(15A)   111.0           C(14)—C(15)—H(15B)   111.0           C(16)—C(15)—H(15B)   111.0           H(15A)—C(15)—H(15B)   109.0           C(15)—C(16)—C(17)   107.05(16)           C(15)—C(16)—H(16A)   110.3           C(17)—C(16)—H(16A)   110.3           C(15)—C(16)—H(16B)   110.3           C(17)—C(16)—H(16B)   110.3           H(16A)—C(16)—H(16B)   108.6           C(20)—C(17)—C(16)   113.09(18)           C(20)—C(17)—C(13)   123.75(16)           C(16)—C(17)—C(13)   103.07(15)           C(20)—C(17)—H(17)   105.1           C(16)—C(17)—H(17)   105.1           C(13)—C(17)—H(17)   105.1           C(13)—C(18)—H(18A)   109.5           C(13)—C(18)—H(18B)   109.5           H(18A)—C(18)—H(18B)   109.5           C(13)—C(18)—H(18C)   109.5           H(18A)—C(18)—H(18C)   109.5           H(18B)—C(18)—H(18C)   109.5           C(20′)—C(20)—C(22A)   99.7(3)           C(20′)—C(20)—C(17)   114.01(17)           C(22A)—C(20)—C(17)   120.9(3)           C(20′)—C(20)—C(21)   107.5(2)           C(22A)—C(20)—C(21)   106.1(3)           C(17)—C(20)—C(21)   107.65(17)           C(20′)—C(20)—C(22B)   119.1(4)           C(17)—C(20)—C(22B)   97.8(3)           C(21)—C(20)—C(22B)   110.2(3)           C(20)—C(20′)—H(20D)   109.5           C(20)—C(20′)—H(20E)   109.5           H(20D)—C(20′)—H(20E)   109.5           C(20)—C(20′)—H(20F)   109.5           H(20D)—C(20′)—H(20F)   109.5           H(20E)—C(20′)—H(20F)   109.5           C(20)—C(21)—H(21A)   109.5           C(20)—C(21)—H(21B)   109.5           H(21A)—C(21)—H(21B)   109.5           C(20)—C(21)—H(21C)   109.5           H(21A)—C(21)—H(21C)   109.5           H(21B)—C(21)—H(21C)   109.5           C(23A)—C(22A)—C(20)   111.1(4)           C(23A)—C(22A)—H(22A)   109.4           C(20)—C(22A)—H(22A)   109.4           C(23A)—C(22A)—H(22B)   109.4           C(20)—C(22A)—H(22B)   109.4           H(22A)—C(22A)—H(22B)   108.0           C(23B)—C(22B)—C(20)   114.9(6)           C(23B)—C(22B)—H(22C)   108.5           C(20)—C(22B)—H(22C)   108.5           C(23B)—C(22B)—H(22D)   108.5           C(20)—C(22B)—H(22D)   108.5           H(22C)—C(22B)—H(22D)   107.5           C(22B)—C(23B)—H(23D)   109.5           C(22B)—C(23B)—H(23E)   109.5           H(23D)—C(23B)—H(23E)   109.5           C(22B)—C(23B)—H(23F)   109.5           H(23D)—C(23B)—H(23F)   109.5           H(23E)—C(23B)—H(23F)   109.5                        
Symmetry transformations used to generate equivalent atoms:
 
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Anisotropic displacement parameters (Å 2  × 10 3 ) for 20DCM. 
               
               
                 The anisotropic displacement factor exponent takes the form: 
               
               
                 −2π 2 [h 2 a* 2 U 11  + . . . + 2hka*b*U 12 ] 
               
             
          
           
               
                   
                 U11 
                 U22 
                 U33 
                 U23 
                 U13 
                 U12 
               
               
                   
                   
               
             
          
           
               
                 O(1) 
                 17(1) 
                 39(1) 
                 35(1) 
                  7(1) 
                 −2(1) 
                  1(1) 
               
               
                 O(2) 
                 19(1) 
                 38(1) 
                 49(1) 
                  3(1) 
                 −5(1) 
                  1(1) 
               
               
                 C(1) 
                 16(1) 
                 36(1) 
                 25(1) 
                  5(1) 
                 −2(1) 
                 −2(1) 
               
               
                 C(2) 
                 23(1) 
                 47(1) 
                 28(1) 
                 11(1) 
                 −3(1) 
                 −7(1) 
               
               
                 C(2′) 
                 29(1) 
                 91(2) 
                 41(1) 
                 35(1) 
                 −4(1) 
                 −6(1) 
               
               
                 C(3) 
                 26(1) 
                 49(1) 
                 27(1) 
                  7(1) 
                  4(1) 
                 −6(1) 
               
               
                 C(4) 
                 37(1) 
                 49(1) 
                 32(1) 
                 −7(1) 
                 11(1) 
                 −7(1) 
               
               
                 C(5) 
                 30(1) 
                 35(1) 
                 34(1) 
                 −7(1) 
                  9(1) 
                 −5(1) 
               
               
                 C(6) 
                 27(1) 
                 43(1) 
                 42(1) 
                 −7(1) 
                 10(1) 
                  3(1) 
               
               
                 C(7) 
                 24(1) 
                 45(1) 
                 39(1) 
                 −5(1) 
                  9(1) 
                  5(1) 
               
               
                 C(8) 
                 24(1) 
                 59(1) 
                 36(1) 
                 −5(1) 
                  6(1) 
                  9(1) 
               
               
                 C(9) 
                 23(1) 
                 109(2)  
                 43(1) 
                  5(1) 
                  8(1) 
                 18(1) 
               
               
                 C(10) 
                 24(1) 
                 35(1) 
                 30(1) 
                  0(1) 
                  3(1) 
                 −4(1) 
               
               
                 C(11) 
                 35(1) 
                 124(3)  
                 43(1) 
                  7(1) 
                 10(1) 
                 47(2) 
               
               
                 C(12) 
                 37(1) 
                 102(2)  
                 36(1) 
                  1(1) 
                  1(1) 
                 43(1) 
               
               
                 C(13) 
                 31(1) 
                 60(1) 
                 23(1) 
                 −6(1) 
                 −4(1) 
                 26(1) 
               
               
                 C(14) 
                 22(1) 
                 58(1) 
                 30(1) 
                 −8(1) 
                  2(1) 
                 10(1) 
               
               
                 C(15) 
                 30(1) 
                 37(1) 
                 43(1) 
                 −6(1) 
                 10(1) 
                 10(1) 
               
               
                 C(16) 
                 29(1) 
                 42(1) 
                 30(1) 
                 −7(1) 
                  2(1) 
                  6(1) 
               
               
                 C(17) 
                 34(1) 
                 55(1) 
                 21(1) 
                 −10(1)  
                 −9(1) 
                 19(1) 
               
               
                 C(18) 
                 59(1) 
                 52(1) 
                 23(1) 
                 −7(1) 
                 −10(1)  
                 30(1) 
               
               
                 C(20) 
                 69(2) 
                 54(1) 
                 22(1) 
                 −5(1) 
                 −10(1)  
                 33(1) 
               
               
                 C(20′) 
                 135(3)  
                 43(1) 
                 37(1) 
                  3(1) 
                 −22(2)  
                  4(2) 
               
               
                 C(21) 
                 83(2) 
                 61(1) 
                 27(1) 
                 −1(1) 
                 −6(1) 
                 25(2) 
               
               
                 C(22A) 
                 71(3) 
                 32(2) 
                 54(2) 
                  3(2) 
                  1(2) 
                 26(2) 
               
               
                 C(23A) 
                 46(2) 
                 60(3) 
                 107(4)  
                 30(3) 
                 −18(3)  
                 13(2) 
               
               
                 C(22B) 
                 72(4) 
                 28(3) 
                 47(3) 
                  5(3) 
                  1(3) 
                 22(3) 
               
               
                 C(23B) 
                 70(5) 
                 54(4) 
                 88(5) 
                 33(4) 
                  9(4) 
                 20(4) 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Hydrogen coordinates (×10 4 ) and isotropic displacement parameters 
               
               
                 (Å 2  × 10 3 ) for 20DCM. 
               
             
          
           
               
                   
                 x 
                 y 
                 z 
                 U(eq) 
               
               
                   
                   
               
             
          
           
               
                   
                 H(1O) 
                 8320 
                 −1979 
                 9815 
                 45 
               
               
                   
                 H(2O) 
                 1091 
                 −1624 
                 10431 
                 53 
               
               
                   
                 H(1) 
                 5325 
                 −1529 
                 9785 
                 31 
               
               
                   
                 H(2′A) 
                 6255 
                 −2317 
                 11610 
                 64 
               
               
                   
                 H(2′B) 
                 8104 
                 −2223 
                 11066 
                 64 
               
               
                   
                 H(3) 
                 3079 
                 −1679 
                 11433 
                 41 
               
               
                   
                 H(4A) 
                 1559 
                 −398 
                 11000 
                 47 
               
               
                   
                 H(4B) 
                 3709 
                 −248 
                 11346 
                 47 
               
               
                   
                 H(6) 
                 1262 
                 474 
                 10134 
                 44 
               
               
                   
                 H(7) 
                 4422 
                 805 
                 9196 
                 43 
               
               
                   
                 H(9A) 
                 −1276 
                 1251 
                 8867 
                 70 
               
               
                   
                 H(9B) 
                 −672 
                 1274 
                 9640 
                 70 
               
               
                   
                 H(10A) 
                 6888 
                 −84 
                 10493 
                 35 
               
               
                   
                 H(10B) 
                 6316 
                 −92 
                 9717 
                 35 
               
               
                   
                 H(11A) 
                 −95 
                 2722 
                 9598 
                 80 
               
               
                   
                 H(11B) 
                 −2299 
                 2547 
                 9297 
                 80 
               
               
                   
                 H(12A) 
                 −1066 
                 2702 
                 8200 
                 70 
               
               
                   
                 H(12B) 
                 −482 
                 3530 
                 8618 
                 70 
               
               
                   
                 H(14) 
                 1435 
                 1579 
                 8031 
                 44 
               
               
                   
                 H(15A) 
                 4697 
                 1165 
                 7883 
                 44 
               
               
                   
                 H(15B) 
                 5528 
                 1795 
                 8453 
                 44 
               
               
                   
                 H(16A) 
                 4632 
                 2212 
                 7127 
                 40 
               
               
                   
                 H(16B) 
                 5872 
                 2778 
                 7653 
                 40 
               
               
                   
                 H(17) 
                 1668 
                 2773 
                 7388 
                 44 
               
               
                   
                 H(18A) 
                 3262 
                 2804 
                 9362 
                 67 
               
               
                   
                 H(18B) 
                 2873 
                 3728 
                 9062 
                 67 
               
               
                   
                 H(18C) 
                 4753 
                 3179 
                 8806 
                 67 
               
               
                   
                 H(20D) 
                 4016 
                 4558 
                 8297 
                 108 
               
               
                   
                 H(20E) 
                 4922 
                 4952 
                 7625 
                 108 
               
               
                   
                 H(20F) 
                 5809 
                 4083 
                 7913 
                 108 
               
               
                   
                 H(21A) 
                 5186 
                 3665 
                 6719 
                 86 
               
               
                   
                 H(21B) 
                 3829 
                 4472 
                 6538 
                 86 
               
               
                   
                 H(21C) 
                 2915 
                 3539 
                 6460 
                 86 
               
               
                   
                 H(22A) 
                 741 
                 4623 
                 7915 
                 63 
               
               
                   
                 H(22B) 
                 1788 
                 5133 
                 7318 
                 63 
               
               
                   
                 H(23A) 
                 −924 
                 3749 
                 7140 
                 107 
               
               
                   
                 H(23B) 
                 149 
                 4242 
                 6540 
                 107 
               
               
                   
                 H(23C) 
                 −1472 
                 4719 
                 6998 
                 107 
               
               
                   
                 H(22C) 
                 −64 
                 3804 
                 7216 
                 59 
               
               
                   
                 H(22D) 
                 274 
                 4210 
                 7937 
                 59 
               
               
                   
                 H(23D) 
                 595 
                 5091 
                 6701 
                 106 
               
               
                   
                 H(23E) 
                 1251 
                 5509 
                 7395 
                 106 
               
               
                   
                 H(23F) 
                 −1062 
                 5256 
                 7268 
                 106 
               
               
                   
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 Torsion angles [deg] for 20DCM. 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 O(1)—C(1)—C(2)—C(2′) 
                 1.5(3) 
               
               
                   
                 C(10)—C(1)—C(2)—C(2′) 
                 −120.3(2) 
               
               
                   
                 O(1)—C(1)—C(2)—C(3) 
                 −179.83(15) 
               
               
                   
                 C(10)—C(1)—C(2)—C(3) 
                 58.4(2) 
               
               
                   
                 C(2′)—C(2)—C(3)—O(2) 
                 −113.9(2) 
               
               
                   
                 C(1)—C(2)—C(3)—O(2) 
                 67.4(2) 
               
               
                   
                 C(2′)—C(2)—C(3)—C(4) 
                 124.0(2) 
               
               
                   
                 C(1)—C(2)—C(3)—C(4) 
                 −54.7(2) 
               
               
                   
                 O(2)—C(3)—C(4)—C(5) 
                 −69.2(2) 
               
               
                   
                 C(2)—C(3)—C(4)—C(5) 
                 49.5(2) 
               
               
                   
                 C(3)—C(4)—C(5)—C(6) 
                 128.9(2) 
               
               
                   
                 C(3)—C(4)—C(5)—C(10) 
                 −50.6(2) 
               
               
                   
                 C(4)—C(5)—C(6)—C(7) 
                 178.79(18) 
               
               
                   
                 C(10)—C(5)—C(6)—C(7) 
                 −1.8(3) 
               
               
                   
                 C(5)—C(6)—C(7)—C(8) 
                 178.8(2) 
               
               
                   
                 C(6)—C(7)—C(8)—C(14) 
                 −179.09(19) 
               
               
                   
                 C(6)—C(7)—C(8)—C(9) 
                 0.6(4) 
               
               
                   
                 C(7)—C(8)—C(9)—C(11) 
                 127.4(3) 
               
               
                   
                 C(14)—C(8)—C(9)—C(11) 
                 −52.9(3) 
               
               
                   
                 C(6)—C(5)—C(10)—C(1) 
                 −126.2(2) 
               
               
                   
                 C(4)—C(5)—C(10)—C(1) 
                 53.3(2) 
               
               
                   
                 O(1)—C(1)—C(10)—C(5) 
                 −179.82(14) 
               
               
                   
                 C(2)—C(1)—C(10)—C(5) 
                 −55.79(19) 
               
               
                   
                 C(8)—C(9)—C(11)—C(12) 
                 53.4(3) 
               
               
                   
                 C(9)—C(11)—C(12)—C(13) 
                 −56.1(3) 
               
               
                   
                 C(11)—C(12)—C(13)—C(18) 
                 −63.1(3) 
               
               
                   
                 C(11)—C(12)—C(13)—C(14) 
                 56.0(3) 
               
               
                   
                 C(11)—C(12)—C(13)—C(17) 
                 166.4(2) 
               
               
                   
                 C(7)—C(8)—C(14)—C(15) 
                 −0.5(3) 
               
               
                   
                 C(9)—C(8)—C(14)—C(15) 
                 179.8(2) 
               
               
                   
                 C(7)—C(8)—C(14)—C(13) 
                 −123.9(2) 
               
               
                   
                 C(9)—C(8)—C(14)—C(13) 
                 56.4(3) 
               
               
                   
                 C(12)—C(13)—C(14)—C(8) 
                 −57.8(2) 
               
               
                   
                 C(18)—C(13)—C(14)—C(8) 
                 61.7(2) 
               
               
                   
                 C(17)—C(13)—C(14)—C(8) 
                 −179.57(16) 
               
               
                   
                 C(12)—C(13)—C(14)—C(15) 
                 170.08(15) 
               
               
                   
                 C(18)—C(13)—C(14)—C(15) 
                 −70.5(2) 
               
               
                   
                 C(17)—C(13)—C(14)—C(15) 
                 48.27(18) 
               
               
                   
                 C(8)—C(14)—C(15)—C(16) 
                 −165.00(19) 
               
               
                   
                 C(13)—C(14)—C(15)—C(16) 
                 −36.93(18) 
               
               
                   
                 C(14)—C(15)—C(16)—C(17) 
                 10.8(2) 
               
               
                   
                 C(15)—C(16)—C(17)—C(20) 
                 154.93(16) 
               
               
                   
                 C(15)—C(16)—C(17)—C(13) 
                 19.0(2) 
               
               
                   
                 C(12)—C(13)—C(17)—C(20) 
                 74.9(3) 
               
               
                   
                 C(18)—C(13)—C(17)—C(20) 
                 −54.2(2) 
               
               
                   
                 C(14)—C(13)—C(17)—C(20) 
                 −170.08(19) 
               
               
                   
                 C(12)—C(13)—C(17)—C(16) 
                 −155.4(2) 
               
               
                   
                 C(18)—C(13)—C(17)—C(16) 
                 75.53(19) 
               
               
                   
                 C(14)—C(13)—C(17)—C(16) 
                 −40.34(18) 
               
               
                   
                 C(16)—C(17)—C(20)—C(20′) 
                 −66.7(3) 
               
               
                   
                 C(13)—C(17)—C(20)—C(20′) 
                 58.8(3) 
               
               
                   
                 C(16)—C(17)—C(20)—C(22A) 
                 174.4(3) 
               
               
                   
                 C(13)—C(17)—C(20)—C(22A) 
                 −60.1(4) 
               
               
                   
                 C(16)—C(17)—C(20)—C(21) 
                 52.4(2) 
               
               
                   
                 C(13)—C(17)—C(20)—C(21) 
                 177.91(19) 
               
               
                   
                 C(16)—C(17)—C(20)—C(22B) 
                 166.6(3) 
               
               
                   
                 C(13)—C(17)—C(20)—C(22B) 
                 −67.9(4) 
               
               
                   
                 C(20′)—C(20)—C(22A)—C(23A) 
                 171.3(4) 
               
               
                   
                 C(17)—C(20)—C(22A)—C(23A) 
                 −62.9(5) 
               
               
                   
                 C(21)—C(20)—C(22A)—C(23A) 
                 59.8(5) 
               
               
                   
                 C(22B)—C(20)—C(22A)—C(23A) 
                 −43.7(9) 
               
               
                   
                 C(20′)—C(20)—C(22B)—C(23B) 
                 63.7(7) 
               
               
                   
                 C(22A)—C(20)—C(22B)—C(23B) 
                 23.3(8) 
               
               
                   
                 C(17)—C(20)—C(22B)—C(23B) 
                 −173.2(6) 
               
               
                   
                 C(21)—C(20)—C(22B)—C(23B) 
                 −61.1(7) 
               
               
                   
                   
               
             
          
         
       
     
                                           TABLE 8                   Hydrogen bonds for 20DCM [A and deg.]            D-H . . . A   d(D-H)   d(H . . . A)   d(D . . . A)   &lt;(DHA)               O(1)—H(1O) . . . O(2)#1   0.84   2.03   2.8149(19)   154.8       O(2)—H(2O) . . . O(1)#2   0.84   2.08   2.8466(17)   150.9                    
Symmetry transformations used to generate equivalent atoms:
 
#1 x+1/2,−y−1/2,−z+2 #2 x−1,y,z
 
     REFERENCES 
     
         
         [1] CrysAlis RED, Oxford Diffraction Ltd.,Version 1.171.28cycle2 beta (release 25-10-2005 CrysAlis171.NET) (compiled Oct. 25, 2005, 08:50:05). Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. 
         [2] CrysAlis CCD, Oxford Diffraction Ltd., Version 1.171.28cycle2 beta; CrysAlis RED, Oxford Diffraction Ltd.,Version 1.171.28cycle2 beta 
         [3] G. M. Sheldrick, Acta Crystallogr. 1990, A46, 467-473. 
         [4] G. M. Sheldrick, SHELXL93.  Program for the Refinement of Crystal Structures. , Univ. of Göttingen, Germany. 
         [5]  International Tables for Crystallography , Ed. A. J. C. Wilson, Kluwer:Dordrecht, 1992, Vol.C. 
       
    
     EXAMPLE 4 
     Synthesis of 20DCM 
     The preparation of 20DCM having the basic structure I can be accomplished by a common general method, i.e. the condensation of a bicyclic Windaus-Grundmann type ketone II with the allylic phosphine oxide III to the corresponding 2-methylene-19-nor-vitamin D analog IV followed by deprotection at C-1 and C-3 in the latter compound IV to obtain compound I, i.e. 20DCM. 
     
       
                 
         
             
             
         
      
     
     In phosphine oxide III, Y 1  and Y 2  are preferably hydroxy-protecting groups such as silyl protecting groups. The t-butyldimethylsilyl (TMDMS) group is an example of a particularly useful hydroxy-protecting group. The process described above represents an application of the convergent synthesis concept, which has been applied effectively to the preparation of numerous vitamin D compounds (see Lythgoe et al.,  J. Chem. Soc. Perkin Trans. I,  590 (1978); Lythgoe,  Chem. Soc. Rev.  9, 449 (1983); Toh et al.,  J. Org. Chem.  48, 1414 (1983); Baggiolini et al.,  J. Org. Chem.  51, 3098 (1986); Sardina et al.,  J. Org. Chem.  51, 1264 (1986);  J. Org. Chem.  51, 1269 (1986); DeLuca et al., U.S. Pat. No. 5,086,191; DeLuca et al., U.S. Pat. No. 5,536,713; and DeLuca et al, U.S. Pat. No. 5,843,928 all of which are hereby incorporated by reference in their entirety and for all purposes as if fully set forth herein. 
     Phosphine oxide III is a convenient reagent that can be used to prepare a large number of 19-nor-vitamin D compounds and is prepared according to the procedures described by Sicinski et al.,  J. Med. Chem.,  41, 4662 (1998), DeLuca et al., U.S. Pat. No. 5,843,928; Perlman et al.,  Tetrahedron Lett.  32, 7663 (1991); and DeLuca et al., U.S. Pat. No. 5,086,191 which are hereby incorporated by reference in their entirety as if fully set forth herein. 
     The overall process of the synthesis of compound I is illustrated and described more completely in U.S. Pat. No. 5,843,928 entitled “2-Alkylidene-19-Nor-Vitamin D Compounds” and in application Ser. No. 12/343,602 filed Dec. 24, 2008, entitled “2-Methylene-20-Methyl-19,24,25,26,27-Pentanor-Vitamin D Analogs” published as U.S. Publication No. US 2009/0170822 the specifications of which are specifically incorporated herein by reference.