Title:
Crystallization of 1alpha-Hydroxy-2-Methylene-18,19-Dinor-Homopregnacalciferol
Kind Code:
A1


Abstract:
A method of purifying 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol to obtain 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol in crystalline form using precipitation with hexane from ethyl acetate. A method of preparing 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals acceptable for X-ray experiment using precipitation with hexane from benzene by diffusive exchange of the solvents is also described.



Inventors:
Deluca, Hector F. (Deerfield, WI, US)
Barycki, Rafal (Madison, WI, US)
Thoden, James B. (Madison, WI, US)
Holden, Hazel M. (Fitchburg, WI, US)
Application Number:
13/632791
Publication Date:
04/11/2013
Filing Date:
10/01/2012
Assignee:
WISCONSIN ALUMNI RESEARCH FOUNDATION (Madison, WI, US)
Primary Class:
International Classes:
C07C401/00
View Patent Images:



Primary Examiner:
QAZI, SABIHA NAIM
Attorney, Agent or Firm:
Andrus Intellectual Property Law, LLP (100 East Wisconsin Avenue Suite 1100 Milwaukee WI 53202-4178)
Claims:
We claim:

1. 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol in crystalline form.

2. The crystalline form of 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol having molecular packing arrangement defined by space group P2 and unit cell dimensions a=4.8 Å, b=22.9 Å, c=36.1 Å, α=90°, β=90° and γ=90°.

3. A three dimensional structure for 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol as defined by the molecular packing arrangement set forth in claim 2.

4. A method of purifying 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol, comprising the steps of: (a) dissolving a product containing 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol to be purified in a solvent comprising ethyl acetate; (b) adding hexane to said solvent and dissolved product to form a mixture; (c) cooling said mixture containing said dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals; and (d) separating the 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals from the mixture.

5. The method of claim 4 wherein the step of separating comprises filtering the mixture and precipitate to obtain the crystals.

6. The method of claim 4 including a further step (d) comprising repeating steps (a) through (c) using the recovered crystals from step (c) as the product of step (a).

7. The method of claim 4 wherein a ratio of ethyl acetate and hexane is about 1:99, by volume.

8. A method of preparing 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals by diffusive exchange of solvents, comprising the steps of: (a) dissolving a product containing 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol in a first solvent comprising benzene; (b) providing a second solvent comprising hexane; (c) allowing said first solvent with dissolved product and said second solvent to diffuse together for a sufficient amount of time to form a precipitate of 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals; and (d) recovering the 1α-hydroxy-2-methyelene-18,19-dinor-homopregnacalciferol crystals.

9. The method of claim 8 wherein a ratio of benzene and hexane is about 13:87, by volume.

10. The method of claim 8 wherein the step of recovering comprises filtering to obtain the crystals.

11. The method of claim 8 wherein the step of allowing said first solvent with dissolved product and said second solvent to diffuse together takes place in a closed system purged with argon.

12. The method of claim 8 wherein the step of allowing said first solvent with dissolved product and said second solvent to diffuse together takes place at room temperature.

Description:

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-2-methylene-18,19-dinor-homopregnacalciferol (referred to herein as “051810”) 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 SeO2/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 SeO2/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 D4 is another undesirable contaminant found in 1α-hydroxyvitamin D compounds synthesized from vitamin D2 or from ergosterol. 1α-hydroxyvitamin D4 results from C-1 oxidation of vitamin D4, 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 D4. Thus, a purification technique that would eliminate or substantially reduce the amount of 1α-hydroxyvitamin D4 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-hydroxylation 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 051810 is required.

SUMMARY OF THE INVENTION

The present invention relates to a method of purifying 051810 by means of crystallization to obtain 051810 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 051810, 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 051810. However, it was found that a mixture of ethyl acetate and hexane, was most useful for the crystallization of 051810. In particular, it was determined that a mixture of about 1% ethyl acetate with about 99% hexane (by volume) performed well. The ethyl acetate/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.

Accordingly, there is obtained 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol in crystalline form. The crystalline form and three dimensional structure of 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol has a molecular packing arrangement defined by space group P2 and unit cell dimensions a=4.8 Å, b=22.9 Å, c=36.1 Å, α=90°, β=90° and γ=9°.

In one embodiment, there is described a method of purifying 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol, comprising the steps of:

(a) dissolving a product containing 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol to be purified in a solvent comprising ethyl acetate;

(b) adding hexane to said solvent and dissolved product to form a mixture;

(c) cooling said mixture containing said dissolved product below ambient temperature for a sufficient amount of time to form a precipitate of 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals; and

(d) separating the 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals from the mixture.

In another embodiment, there is described a method of preparing 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals by diffusive exchange of solvents, comprising the steps of:

(a) dissolving a product containing 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol in a first solvent comprising benzene;

(b) providing a second solvent comprising hexane;

(c) allowing said first solvent with dissolved product and said second solvent to diffuse together for a sufficient amount of time to form a precipitate of 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol crystals; and

(d) recovering the 1α-hydroxy-2-methyelene-18,19-dinor-homopregnacalciferol crystals.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the three dimensional structure of the first crystallographic asymmetric molecule for 051810 as defined by the atomic positional parameters discovered and set forth herein;

FIG. 2a is an illustration of the three dimensional structure of the second crystallographic asymmetric molecule for 051810 in the absence of the benzene molecule and as defined by the atomic positional parameters discovered and set forth herein;

FIG. 2b is an illustration of the three dimensional structure of the second asymmetric molecule for 051810 in the presence of the benzene molecule and as defined by the atomic positional parameters discovered and set forth herein; and

FIG. 3 is an illustration of a ball-and-stick representation of the entire asymmetric unit for 051810.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol (051810) in crystalline form, a pharmacologically important compound, characterized by the formula I shown below:

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The present invention also provides a valuable method of purification of 051810. The purification technique involves obtaining the 051810 product in crystalline form by utilizing a crystallization procedure wherein the 051810 material to be purified is dissolved using ethyl acetate as the solvent and further precipitation with hexane. Preferably a ratio of ethyl acetate and hexane is about 1:99 (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 051810 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 051810 to be purified.

The usefulness and advantages of the present crystallization procedure is shown in the following specific Example 1. 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 051810 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-2-methylene-18,19-dinor-homopregnacalciferol (051810)

Example 1

Crystallization from Ethyl Acetate/Hexane

1.25 g of prepurified (see U.S. Pat. No. 7,238,681) crude 1α-hydroxy-2-methylene-18,19-dinor-homopregnacalciferol was dissolved in ethyl acetate (3 ml) at room temperature and hexane (300 ml) was poured into the vigorously shaken solution. The mixture was kept in a refrigerator (at 4° C.) overnight and the resulted crystals were filtered off, washed with one portion (30 ml) of cooled (4° C.) hexane and dried under reduced pressure for 3 h giving 1.10 g of a pure product.

In order to obtain crystals acceptable for the X-ray experiment, 1α-Hydroxy-2-methylene-18,19-dinor-homopregnacalciferol (12 mg) was placed in an inner tube of a vessel and dissolved in 300 μl of benzene. To an outer tube of the vessel hexane (2 ml) was poured so that a benzene to hexane ratio of about 13:87, by volume, is obtained, and the whole system was carefully purged with argon, and then maintained as a closed system. The vessel was kept tightly closed for 4 days at room temperature. Crystals were grown employing diffusive exchange of the two solvents.

A colorless rod-shaped crystal of dimensions 0.73×0.08×0.02 mm was selected for structural analysis. Intensity data were collected using a Bruker AXS Platinum 135 CCD detector controlled with the PROTEUM software suite (Bruker AXS Inc., Madison, Wis.). The x-ray source was CuKα radiation (1.54178 Å) from a Rigaku RU200 x-ray generator equipped with Montel optics, operated at 50 kV and 90 mA. The x-ray data were processed with SAINT version 7.06 Å (Bruker AXS Inc.) and internally scaled with SADABS version 2005/1 (Bruker AXS Inc.). The sample was mounted on a glass fiber using vacuum grease and cooled to 100 K. The intensity data were measured as a series of phi and omega oscillation frames each of 10 for 60-120 sec/frame. The detector was operated in 1024×1024 mode and was positioned 5.0 cm from the sample. Cell parameters were determined from a non-linear least squares fit of 9999 peaks in the range of 3.0<theta<50.80. The data were merged to form a set of 4693 independent data with R(int)=0.0884.

The orthorhombic space group P2(1)2(1)2(1) was determined by systematic absences and statistical tests and verified by subsequent refinement. The structure was solved by direct methods and refined by full-matrix least-squares methods on F2, (a) G. M. Sheldrick (1994), SHELXTL Version 5 Reference Manual, Bruker AXS Inc.; (b) International Tables for Crystallography, Vol. C, Kluwer: Boston (1995). The asymmetric unit is comprised of two molecules of 051810 and a benzene molecule. Molecule “A” is shown in FIG. 1, with thermal ellipsoids drawn at the 40% probability level. Based on lattice packing, the benzene molecule could not be present at full occupancy, and refinement of its occupancy led to a value of approximately 0.5. The presence of the benzene molecule lead to a disorder in a portion of molecule “B”. Refinement of the occupancies of the two disordered configurations independently of the occupancy of the benzene converged also at a value of about 0.5 for each. FIG. 2a shows molecule B in its configuration in the absence of the benzene molecule, and FIG. 2b shows its configuration in the presence of the benzene molecule; both figures are drawn with thermal ellipsoids at the 40% probability level. FIG. 3 shows a ball-and-stick representation of the entire asymmetric unit, with the hollow bonds showing the conformation in the presence of the benzene molecule. Hydrogen atom positions were refined by a riding model with idealized geometry. Non-hydrogen atoms were refined with anisotropic displacement parameters. The benzene molecule was refined with idealized geometry. A total of 559 parameters were refined against 26 restraints and 4693 data to give wR2=0.2524 and S=0.951 for weights of w=1/[s2(F2)+(0.1719P)2], where P=[Fo2+2Fc2]/3. The final R(F) was 0.0910 for the 6781 observed data. The largest shift/s.u. was 0.001 in the final refinement cycle and the final difference map had maxima and minima of 0.366 and −0.305 e/Å3, respectively. The absolute structure was determined by refinement of the Flack parameter, H. D. Flack, Acta Cryst. A, vol. 39, 876-881 (1983).

The three dimensional structure of 051810 as defined by the following physical data and atomic positional parameters described and calculated herein is illustrated in FIGS. 1, 2a, 2b and 3.

TABLE 1
Crystal data and structure refinement for 051810.
Identification Code051810
Empirical formulaC45 H67 O4
Formula weight671.99
Temperature100(1) K
Wavelength1.54178 Å
Crystal systemOrthorhombic
Space groupP2(1)2(1)2(1)
Unit cell dimensionsa = 4.8020(10) Å α = 90°
b = 22.940(5) Å β = 90°
c = 36.124(7) Å γ = 90°
Volume3979.3(14) Å3
Z4
Density (calculated)1.122 Mg/m3
Absorption coefficient0.533 mm−1
F(000)1476
Crystal0.73 × 0.08 × 0.02 mm
Theta range for data collection2.28 to 54.17°
Limiting indices−4 < h < 4, −24 < k < 23, −37 < 1 < 37
Reflections collected12592
Independent reflections4693 [R(int) = 0.0884]
Completeness to Theta = 54.17°98.2%
Refinement methodFull-matrix least-squares on F2
Data/restraints/parameters4693/26/559
Goodness-of-fit on F20.951
Final R indices [I > 2σ(I)]R1 = 0.0910, wR2 = 0.2214
R indices (all data)R1 = 0.1268, wR2 = 0.2524
Extinction coefficient0.0124(12)
Largest diff. peak and hole0.366 and −0.305 e/A3
Melting Point140-145° C.

TABLE 2
Atomic coordinates (× 104) and equivalent isotropic
displacement parameters (Å × 103] for 051810. U(eq) is defined
as one third of the trace of the orthogonalized Uij tensor.
XyzU(eq)
O(1A) −322(12) 7615(2)6913(2) 59(2)
O(3A)−2739(11) 9404(2)7179(1) 51(1)
C(10A) −165(18) 8424(3)6486(2) 47(2)
C(1A) −994(17) 8232(3)6868(2) 46(2)
C(3A)   148(16) 9249(3)7108(2) 49(2)
C(14A)−7331(19) 8940(3)5377(2) 48(2)
C(4A)   864(18) 9437(3)6719(2) 49(2)
C(13A)−6378(17) 9119(3)4990(2) 42(2)
C(7A)−4130(18) 9025(3)5916(2) 50(2)
C(17A)−7691(17) 8673(3)4726(2) 47(2)
C(2A)   472(16) 8595(3)7156(2) 47(2)
C(15A)−7129(18) 8276(3)5360(2) 49(2)
C(8A)−5795(16) 9274(3)5667(2) 43(2)
C(9A)−6387(19) 9924(3)5624(2) 52(2)
C(12A)−7120(18) 9770(3)4931(2) 46(2)
C(5A) −649(16) 9072(3)6439(2) 43(2)
C(16A)−8423(18) 8158(3)4986(2) 50(2)
C(21A)−4792(18) 9008(3)4177(2) 48(2)
C(20A)−5793(17) 8486(3)4408(2) 45(2)
C(11A)−5708(19)10137(3)5234(2) 51(2)
C(6A)−2416(17) 9326(3)6193(2) 47(2)
C(22A)−7262(18) 8050(3)4144(2) 55(2)
C(2A′)  1940(20) 8381(4)7432(2) 76(3)
O(3B)−3150(11)10326(2)7677(1) 48(1)
O(1B)−4693(10)12069(2)8071(1) 40(1)
C(1B)−4362(16)11592(3)7816(2) 39(2)
C(2B)−6068(16)11074(3)7930(2) 40(2)
C(10B)−5147(19)11778(3)7423(2) 49(2)
C(3B)−5950(17)10575(3)7667(2) 46(2)
C(4B)−6576(18)10759(3)7270(2) 48(2)
C(6B)−3204(17)11254(3)6861(2) 51(2)
C(5B)−4833(17)11275(3)7155(2) 44(2)
C(7B)−1376(17)11745(4)6734(2) 58(2)
C(2B)−7707(19)11071(3)8221(2) 56(2)
C(8B)   259(18)11713(5)6435(3) 75(3)
C(12B)  2040(50)12137(10)5703(5)105(13)
C(9B)   720(60)11337(11)6171(5) 65(7)
C(14B)  1730(40)12297(7)6369(5) 66(5)
C(13B)  1580(50)12609(9)5997(5) 86(8)
C(11B)   420(50)11584(11)5782(5) 96(11)
C(15B)  1870(60)12851(8)6602(7)111(14)
C(17B)  3160(40)13190(9)5995(8)109(12)
C(16B)  3350(40)13356(9)6404(7)101(9)
C(20B)  2050(50)13662(10)5735(7)151(15)
C(22B)  3890(50)14206(10)5741(8)185(18)
C(21B)  1610(120) 13442(14)5339(8)230(30)
C(12′)  1350(40)11726(7)5609(6) 45(6)
C(9′)   160(70)11067(10)6145(6) 46(8)
C(14′)  2290(40)12120(8)6246(4) 45(8)
C(13′)  1240(50)12265(7)5860(4) 36(6)
C(11′) −560(50)11251(8)5752(5) 39(6)
C(15′)  2350(40)12687(8)6459(5) 33(5)
C(17′)  2980(40)12809(6)5789(4) 38(5)
C(16′)  3750(40)13067(7)6167(4) 35(6)
C(20′)  1650(50)13270(7)5543(5) 72(8)
C(22′)  3670(70)13750(10)5428(8) 78(9)
C(21′)   80(60)13041(10)5206(6) 76(9)
C(1)  1350(20)14678(5)6378(3) 67(5)
C(2)  1060(20)14340(5)6695(4) 64(5)
C(3)  3410(30)14137(4)6879(2) 69(5)
C(4)  6050(20)14270(4)6746(3) 58(5)
C(5)  6340(20)14608(4)6429(3) 62(5)
C(6)  3990(30)14811(4)6245(3) 74(6)

TABLE 3
Bond lengths [Å] for 051810.
O(1A)—C(1A)1.460(8)
O(1A)—H(1AA)0.8200
O(3A)—C(3A)1.454(9)
O(3A)—H(3AA)0.8200
C(10A)—C(1A)1.502(9)
C(10A)—C(5A)1.513(10)
C(10A)—H(10A)0.9700
C(10A)—H(10B)0.9700
C(1A)—C(2A)1.508(11)
C(1A)—H(1AB)0.9800
C(3A)—C(4A)1.507(10)
C(3A)—C(2A)1.518(10)
C(3A)—H(3AB)0.9800
C(14A)—C(8A)1.492(10)
C(14A)—C(13A)1.527(10)
C(14A)—C(15A)1.529(9)
C(14A)—H(14A)0.9800
C(4A)—C(5A)1.501(10)
C(4A)—H(4AA)0.9700
C(4A)—H(4AB)0.9700
C(13A)—C(17A)1.534(10)
C(13A)—C(12A)1.550(9)
C(13A)—H(13A)0.9800
C(7A)—C(8A)1.332(10)
C(7A)—C(6A)1.469(10)
C(7A)—H(7AA)0.9300
C(17A)—C(20A)1.529(10)
C(17A)—C(16A)1.548(10)
C(17A)—H(17A)0.9800
C(2A)—C(2A′)1.314(11)
C(15A)—C(16A)1.511(10)
C(15A)—H(15A)0.9700
C(15A)—H(15B)0.9700
C(8A)—C(9A)1.526(10)
C(9A)—C(11A)1.528(9)
C(9A)—H(9AA)0.9700
C(9A)—H(9AB)0.9700
C(12A)—C(11A)1.538(10)
C(12A)—H(12A)0.9700
C(12A)—H(12B)0.9700
C(5A)—C(6A)1.359(10)
C(16A)—H(16A)0.9700
C(16A)—H(16B)0.9700
C(21A)—C(20A)1.536(10)
C(21A)—H(21A)0.9600
C(21A)—H(21B)0.9600
C(21A)—H(21C)0.9600
C(20A)—C(22A)1.552(10)
C(20A)—H(20A)0.9800
C(11A)—H(11A)0.9700
C(11A)—H(118)0.9700
C(6A)—H(6AA)0.9300
C(22A)—H(22A)0.9600
C(22A)—H(22B) 0.9600
C(22A)—H(22C)0.9600
C(2A′)—H(1A′)0.9300
C(2A′)—H(2A′)0.9300
O(3B)—C(3B)1.461(10)
O(3B)—H(3BA)0.8200
O(1B)—C(1B)1.439(8)
O(1B)—H(1BA)0.8200
C(1B)—C(2B)1.501(10)
C(1B)—C(10B)1.532(9)
C(1B)—H(1BB)0.9800
C(2B)—C(2B′) 1.313(10)
C(2B)—C(3B)1.488(10)
C(10B)—C(5B)1.514(9)
C(10B)—H(10C)0.9700
C(10B)—H(10D)0.9700
C(3B)—C(4B)1.526(7)
C(3B)—H(3BB)0.9800
C(4B)—C(5B)1.506(10)
C(4B)—H(4BA)0.9700
C(4B)—H(4BB)0.9700
C(6B)—C(5B)1.321(10)
C(6B)—C(7B)1.499(8)
C(6B)—H(6BA)0.9300
C(7B)—C(8B)1.338(12)
C(7B)—H(7BA)0.9300
C(2B′)—H(1B′)0.9300
C(2B′)—H(2B′)0.9300
C(8B)—C(9B)1.50(2)
C(8B)—C(14′)1.514(10)
C(8B)—C(14B)1.534(10)
C(8B)—C(9′)1.52(2)
C(12B)—C(11B)1.516(10)
C(12B)—C(13B)1.534(10)
C(12B)—H(12C)0.9700
C(12B)—H(12D)0.9700
C(9B)—C(11B)1.522(10)
C(9B)—H(9BA)0.9700
C(9B)—H(9BB)0.9700
C(14B)—C(15B)1.527(10)
C(14B)—C(13B) 1.524(10)
C(14B)—H(14B)0.9800
C(13B)—C(17B) 1.532(10)
C(13B)—H(13B) 0.9800
C(11B)—H(11C)0.9700
C(11B)—H(11D)0.9700
C(15B)—C(16B)1.535(10)
C(15B)—H(15C)0.9700
C(15B)—H(15D)0.9700
C(17B)—C(16B)1.528(10)
C(17B)—C(20B)1.528(10)
C(17B)—H(17B) 0.9800
C(16B)—H(16C) 0.9700
C(16B)—H(16D)0.9700
C(20B)—C(22B)1.528(10)
C(20B)—C(21B)1.532(11)
C(20B)—H(20B)0.9800
C(22B)—H(22D)0.9600
C(22B)—H(22E) 0.9600
C(22B)—H(22F) 0.9600
C(21B)—H(21D) 0.9600
C(21B)—H(21E) 0.9600
C(21B)—H(21F) 0.9600
C(12′)—C(11′) 1.513(10)
C(12′)—C(13′) 1.534(10)
C(12′)—H(12E)0.9700
C(12′)—H(12F) 0.9700
C(9′)—C(11′)1.519(10)
C(9′)—H(9BC)0.9700
C(9′)—H(9BD)0.9700
C(14′)—C(15′) 1.512(10)
C(14′)—C(13′) 1.517(10)
C(14′)—H(14′) 0.9800
C(13′)—C(17′)1.523(10)
C(13′)—H(13′)0.9800
C(11′)—H(11E)0.9700
C(11′)—H(11F) 0.9700
C(15′)—C(16′) 1.524(10)
C(15′)—H(15E)0.9700
C(15′)—H(15F) 0.9700
C(17′)—C(20′) 1.523(10)
C(17′)—C(16′) 1.533(10)
C(17′)—H(17′)0.9800
C(16′)—H(16E)0.9700
C(16′)—H(16F) 0.9700
C(20′)—C(21′) 1.525(10)
C(20′)—C(22′) 1.528(10)
C(20′)—H(20C) 0.9800
C(22′)—H(22G) 0.9600
C(22′)—H(22H) 0.9600
C(22′)—H(22I) 0.9600
C(21′)—H(21G) 0.9600
C(21′)—H(21H) 0.9600
C(21′)—H(21I)0.9600
C(1)—C(2)1.3900
C(1)—C(6)1.3900
C(1)—H(1A)0.9300
C(2)—C(3)1.3900
C(2)—H(2A)0.9300
C(3)—C(4)1.3900
C(3)—H(3A)0.9300
C(4)—C(5)1.3900
C(4)—H(4A)0.9300
C(5)—C(6)1.3900
C(5)—H(5A)0.9300
C(6)—H6A)0.9300

TABLE 4
Bond angles [°] for 051810.
C(1A)—O(1A)—H(1AA)109.5
C(3A)—O(3A)—H(3AA)109.5
C(1A)—C(10A)—C(5A)110.6(6)
C(1A)—C(10A)—H(10A)109.7
C(5A)—C(10A)—H(10A)109.6
C(1A)—C(10A)—H(10B)109.4
C(5A)—C(10A)—H(10B)109.4
H(10A)—C(10A)—H(10B)108.1
O(1A)—C(1A)—C(10A)109.1(6)
O(1A)—C(1A)—C(2A)110.9(6)
C(10A)—C(1A)—C(2A)110.4(6)
O(1A)—C(1A)—H(1AB)108.8
C(10A)—C(1A)—H(1AB)108.8
C(2A)—C(1A)—H(1AB)108.8
O(3A)—C(3A)—C(4A)108.2(6)
O(3A)—C(3A)—C(2A)108.6(6)
C(4A)—C(3A)—C(2A)111.5(6)
O(3A)—C(3A)—H(3AB)109.5
C(4A)—C(3A)—H(3AB)109.5
C(2A)—C(3A)—H(3AB)109.5
C(8A)—C(14A)—C(13A)110.9(7)
C(8A)—C(14A)—C(15A)120.6(7)
C(13A)—C(14A)—C(15A)102.2(6)
C(8A)—C(14A)—H(14A)107.5
C(13A)—C(14A)—H(14A)107.5
C(15A)—C(14A)—H(14A)107.6
C(5A)—C(4A)—C(3A)111.0(6)
C(5A)—C(4A)—H(4AA)109.4
C(3A)—C(4A)—H(4AA)109.4
C(5A)—C(4A)—H(4AB)109.4
C(3A)—C(4A)—H(4AB)109.5
H(4AA)—C(4A)—H(4AB)108.0
C(14A)—C(13A)—C(17A)105.5(6)
C(14A)—C(13A)—C(12A)108.4(6)
C(17A)—C(13A)—C(12A)117.6(6)
C(14A)—C(13A)—H(13A)108.4
C(17A)—C(13A)—H(13A)108.3
C(12A)—C(13A)—H(13A)108.4
C(8A)—C(7A)—C(6A)126.6(7)
C(8A)—C(7A)—H(7AA)116.8
C(6A)—C(7A)—H(7AA)116.6
C(20A)—C(17A)—C(13A)114.2(7)
C(20A)—C(17A)—C(16A)112.1(6)
C(13A)—C(17A)—C(16A)103.1(5)
C(20A)—C(17A)—H(17A) 109.1
C(13A)—C(17A)—H(17A) 109.1
C(16A)—C(17A)—H(17A) 109.1
C(2A′)—C(2A)—C(1A)124.4(7)
C(2A′)—C(2A)—C(3A)120.9(8)
C(1A)—C(2A)—C(3A)114.7(6)
C(16A)—C(15A)—C(14A)100.9(6)
C(16A)—C(15A)—H(15A) 111.6
C(14A)—C(15A)—H(15A) 111.6
C(16A)—C(15A)—H(15B) 111.6
C(14A)—C(15A)—H(15B)111.5
H(15A)—C(15A)—H(15B) 109.4
C(7A)—C(8A)—C(14A)123.4(6)
C(7A)—C(8A)—C(9A)126.8(7)
C(14A)—C(8A)—C(9A)109.8(6)
C(11A)—C(9A)—C(8A)111.5(6)
C(11A)—C(9A)—H(9AA)109.3
C(8A)—C(9A)—H(9AA)109.4
C(11A)—C(9A)—H(9AB)109.3
C(8A)—C(9A)—H(9AB)109.4
H(9AA)—C(9A)—H(9AB)108.0
C(11A)—C(12A)—C(13A) 109.2(6)
C(11A)—C(12A)—H(12A)109.8
C(13A)—C(12A)—H(12A) 109.8
C(11A)—C(12A)—H(12B) 109.9
C(13A)—C(12A)—H(12B) 109.8
H(12A)—C(12A)—H(12B)108.3
C(6A)—C(5A)—C(4A)120.2(6)
C(6A)—C(5A)—C(10A)126.2(7)
C(4A)—C(5A)—C(10A)113.4(6)
C(15A)—C(16A)—C(17A) 108.1(6)
C(15A)—C(16A)—H(16A)110.1
C(17A)—C(16A)—H(16A) 110.1
C(15A)—C(16A)—H(16B) 110.0
C(17A)—C(16A)—H(16B) 110.1
H(16A)—C(16A)—H(16B) 108.4
C(20A)—C(21A)—H(21A) 109.6
C(20A)—C(21A)—H(21B) 109.4
H(21A)—C(21A)—H(21B) 109.5
C(20A)—C(21A)—H(21C) 109.4
H(21A)—C(21A)—H(21C) 109.5
H(21B)—C(21A)—H(21C) 109.5
C(17A)—C(20A)—C(21A) 112.2(6)
C(17A)—C(20A)—C(22A) 111.9(7)
C(21A)—C(20A)—C(22A) 108.1(6)
C(17A)—C(20A)—H(20A) 108.2
C(21A)—C(20A)—H(20A) 108.2
C(22A)—C(20A)—H(20A) 108.2
C(9A)—C(11A)—C(12A) 112.8(7)
C(9A)—C(11A)—H(11A) 109.0
C(12A)—C(11A)—H(11A)109.0
C(9A)—C(11A)—H(11B) 109.1
C(12A)—C(11A)—H(11B)109.0
H(11A)—C(11A)—H(11B)107.8
C(5A)—C(6A)—C(7A)126.5(7)
C(5A)—C(6A)—H(6AA)116.8
C(7A)—C(6A)—H(6AA)116.7
C(20A)—C(22A)—H(22A)109.4
C(20A)—C(22A)—H(22B)109.5
H(22A)—C(22A)—H(22B)109.5
C(20A)—C(22A)—H(22C)109.5
H(22A)—C(22A)—H(22C)109.5
H(22B)—C(22A)—H(22C)109.5
C(2A)—C(2A′)—H(1A′)120.0
C(2A)—C(2A′)—H(2A′) 120.0
H(1A′)—C(2A′)—H(2A′)120.0
C(3B)—O(3B)—H(3BA)109.4
C(1B)—O(1B)—H(1BA)109.4
O(1B)—C(1B)—C(2B)111.5(5)
O(1B)—C(1B)—C(10B)110.7(5)
C(2B)—C(1B)—C(10B)110.0(6)
O(1B)—C(1B)—H(1BB)108.2
C(2B)—C(1B)—H(1BB)108.2
C(10B)—C(1B)—H(1BB)108.2
C(2B′)—C(2B)—C(3B)122.1(7)
C(2B′)—C(2B)—C(1B)123.4(7)
C(3B)—C(2B)—C(1B)114.4(6)
C(5B)—C(10B)—C(1B) 110.8(6)
C(5B)—C(10B)—H(10C) 109.6
C(1B)—C(10B)—H(10C) 109.5
C(5B)—C(10B)—H(10D) 109.4
C(1B)—C(10B)—H(10D)109.5
H(10C)—C(10B)—H(10D)108.1
O(3B)—C(3B)—C(2B)108.7(6)
O(3B)—C(3B)—C(4B)108.2(6)
C(2B)—C(3B)—C(4B)112.4(6)
O(3B)—C(3B)—H(3BB)109.1
C(2B)—C(3B)—H(3BB)109.2
C(4B)—C(3B)—H(3BB)109.2
C(5B)—C(4B)—C(3B)111.5(6)
C(5B)—C(4B)—H(4BA)109.3
C(3B)—C(4B)—H(4BA)109.2
C(5B)—C(4B)—H(4BB)109.4
C(3B)—C(4B)—H(4BB)109.4
H(4BA)—C(4B)—H(4BB)108.0
C(5B)—C(6B)—C(7B)124.5(7)
C(5B)—C(6B)—H(6BA)117.8
C(7B)—C(6B)—H(6BA)117.7
C(6B)—C(5B)—C(4B)121.5(6)
C(6B)—C(5B)—C(10B)126.9(7)
C(4B)—C(5B)—C(10B)111.6(6)
C(8B)—C(7B)—C(6B)123.3(8)
C(8B)—C(7B)—H(7BA)118.3
C(6B)—C(7B)—H(7BA)118.4
C(2B)—C(2B′)—H(1B′)120.1
C(2B)—C(2B′)—H(2B′)119.9
H(1B′)—C(2B′)—H(2B′)120.0
C(9B)—C(8B)—C(7B)136.7(13)
C(9B)—C(8B)—C(14′) 88.1(14)
C(7B)—C(8B)—C(14′)135.1(12)
C(9B)—C(8B)—C(14B)112.6(15)
C(7B)—C(8B)—C(14B)110.4(11)
C(14′)—C(8B)—C(14B) 24.9(8)
C(9B)—C(8B)—C(9′) 16.9(16)
C(7B)—C(8B)—C(9′)119.8(12)
C(14′)—C(8B)—C(9′)105.0(13)
C(14B)—C(8B)—C(9′)129.4(13)
C(11B)—C(12B)—C(13B)112.7(18)
C(11B)—C(12B)—H(12C)108.9
C(13B)—C(12B)—H(12C)108.6
C(11B)—C(12B)—H(12D)109.3
C(13B)—C(12B)—H(12D)109.5
H(12C)—C(12B)—H(12D)107.8
C(8B)—C(9B)—C(11B)114.4(19)
C(8B)—C(9B)—H(9BA)109.1
C(11B)—C(9B)—H(9BA)108.4
C(8B)—C(9B)—H(9BB)108.6
C(11B)—C(9B)—H(9BB)108.6
H(9BA)—C(9B)—H(9BB)107.6
C(15B)—C(14B)—C(13B) 95.5(15)
C(15B)—C(14B)—C(8B)131.5(13)
C(13B)—C(14B)—C(8B)121.8(14)
C(15B)—C(14B)—H(14B)100.6
C(13B)—C(14B)—H(14B)101.3
C(8B)—C(14B)—H(14B)101.0
C(14B)—C(13B)—C(17B)113.0(14)
C(14B)—C(13B)—C(12B)105.8(15)
C(17B)—C(13B)—C(12B)122.6(18)
C(14B)—C(13B)—H(13B)104.3
C(17B)—C(13B)—H(13B)104.4
C(12B)—C(13B)—H(13B)105.0
C(12B)—C(11B)—C(9B)115.9(19)
C(12B)—C(11B)—H(11C)108.0
C(9B)—C(11B)—H(11C)108.5
C(12B)—C(11B)—H(11D)108.5
C(9B)—C(11B)—H(11D)108.3
H(11)—C(11B)—H(11D) 107.4
C(14B)—C(15B)—C(16B)113.1(17)
C(14B)—C(15B)—H(15C)109.4
C(16B)—C(15B)—H(15C) 109.8
C(14B)—C(15B)—H(15D) 107.9
C(16B)—C(15B)—H(15D) 108.7
H(15C)—C(15B)—H(15D) 107.6
C(16B)—C(17B)—C(20B) 115.9(19)
C(16B)—C(17B)—C(13B) 104.0(16)
C(20B)—C(17B)—C(13B) 116.6(16)
C(16B)—C(17B)—H(17B)106.2
C(20B)—C(17B)—H(17B) 106.6
C(13B)—C(17B)—H(17B) 106.7
C(17B)—C(16B)—C(15B) 103.5(18)
C(17B)—C(16B)—H(16C) 111.1
C(15B)—C(16B)—H(16C) 110.8
C(17B)—C(16B)—H(16D) 111.7
C(15B)—C(16B)—H(16D) 110.5
H(16C)—C(16B)—H(16D) 109.2
C(22B)—C(20B)—C(17B) 111.7(17)
C(22B)—C(20B)—C(21B) 111(2)
C(17B)—C(20B)—C(21B)113(2)
C(22B)—C(20B)—H(20B) 107.2
C(17B)—C(20B)—H(20B) 107.2
C(21B)—C(20B)—H(20B) 106.3
C(20B)—C(22B)—H(22D)109.5
C(20B)—C(22B)—H(22E)109.5
H(22D)—C(22B)—H(22E)109.5
C(20B)—C(22B)—H(22F)109.3
H(22D)—C(22B)—H(22F)109.5
H(22E)—C(22B)—H(22F) 109.5
C(20B)—C(21B)—H(21D)110.2
C(20B)—C(21B)—H(21E) 109.4
H(21D)—C(21B)—H(21E) 109.5
C(20B)—C(21B)—H(21F)108.8
H(21D)—C(21B)—H(21F) 109.5
H(21E)—C(21B)—H(21F) 109.5
C(11′)—C(12′)—C(13′)111.0(13)
C(11′)—C(12′)—H(12E)109.4
C(13′)—C(12′)—H(12E) 109.7
C(11′)—C(12′)—H(12F) 109.8
C(13′)—C(12′)—H(12F) 108.9
H(12E)—C(12′)—H(12F)108.0
C(11′)—C(9′)—C(8B)108.5(15)
C(11′)—C(9′)—H(9BC)110.2
C(8B)—C(9′)—H(9BC)109.7
C(11′)—C(9′)—H(9BD)109.9
C(8B)—C(9′)—H(9BD)110.3
H(9BC)—C(9′)—H(9BD)108.3
C(8B)—C(14′)—C(15′)108.3(13)
C(8B)—C(14′)—C(13′)109.7(13)
C(15′)—C(14′)—C(13′) 106.5(15)
C(8B)—C(14′)—H(14′)111.1
C(15′)—C(14′)—H(14′)110.6
C(13′)—C(14′)—H(14′) 110.5
C(14′)—C(13′)—C(17′) 98.8(11)
C(14′)—C(13′)—C(12′) 110.8(17)
C(17′)—C(13′)—C(12′)122.8(15)
C(14′)—C(13′)—H(13′)107.9
C(17′)—C(13′)—H(13′) 107.7
C(12′)—C(13′)—H(13′) 107.8
C(12′)—C(11′)—C(9′)112.5(18)
C(12′)—C(11′)—H(11E) 108.6
C(9′)—C(11′)—H(11E)108.7
C(12′)—C(11′)—H(11F) 109.6
C(9′)—C(11′)—H(11F)109.5
H(11E)—C(11′)—H(11F)107.9
C(14′)—C(15′)—C(16′) 98.5(12)
C(14′)—C(15′)—H(15E)112.0
C(16′)—C(15′)—H(15E)112.7
C(14′)—C(15′)—H(15F)111.7
C(16′)—C(15′)—H(15F) 111.9
H(15E)—C(15′)—H(15F) 109.7
C(20′)—C(17′)—C(13′) 115.8(13)
C(20′)—C(17′)—C(16′) 110.6(13)
C(13′)—C(17′)—C(16′) 107.3(13)
C(20′)—C(17′)—H(17′) 107.9
C(13′)—C(17′)—H(17′) 107.4
C(16′)—C(17′)—H(17′) 107.5
C(15′)—C(16′)—C(17′) 106.8(14)
C(15′)—C(16′)—H(16E) 109.9
C(17′)—C(16′)—H(16E) 110.7
C(15′)—C(16′)—H(16F) 110.1
C(17′)—C(16′)—H(16F) 110.8
H(16E)—C(16′)—H(16F)108.6
C(17′)—C(20′)—C(21′) 115.7(14)
C(17′)—C(20′)—C(22′) 112.9(18)
C(21′)—C(20′)—C(22′) 110(2)
C(17′)—C(20′)—H(20C)105.6
C(21′)—C(20′)—H(20C) 105.5
C(22′)—C(20′)—H(20C)105.8
C(20′)—C(22′)—H(22G)109.6
C(20′)—C(22′)—H(22H) 109.7
H(22G)—C(22′)—H(22H)109.5
C(20′)—C(22′)—H(22I)109.1
H(22G)—C(22′)—H(22I)109.5
H(22H)—C(22′)—H(22I)109.5
C(20′)—C(21′)—H(21G)109.3
C(20′)—C(21′)—H(21H)109.7
H(21G)—C(21′)—H(21H)109.5
C(20′)—C(21′)—H(21I)109.5
H(21G)—C(21′)—H(21I)109.5
H(21H)—C(21′)—H(21I)109.5
C(2)—C(1)—C(6)120.0
C(2)—C(1)—H(1A)120.0
C(6)—C(1)—H(1A)120.0
C(1)—C(2)—C(3)120.0
C(1)—C(2)—H(2A)120.0
C(3)—C(2)—H(2A)120.0
C(2)—C(3)—C(4)120.0
C(2)—C(3)—H(3A)120.0
C(4)—C(3)—H(3A)120.0
C(5)—C(4)—C(3)120.0
C(5)—C(4)—H(4A)120.0
C(3)—C(4)—H(4A)120.0
C(4)—C(5)—C(6)120.00(5)
C(4)—C(5)—H(5A)120.0
C(6)—C(5)—H(5A)120.0
C(5)—C(6)—C(1)120.0
C(5)—C(6)—H(6A)120.0
C(1)—C(6)—H(6A)120.0

TABLE 5
Anisotropic displacement parameters [Å2 × 103] for 051810.
The anisotropic displacement factor exponent takes the form:
−2π2 [h2a*2U11 + . . . + 2hka*b*U12]
U11U22U33U23U13U12
O(1A)50 (4)34 (3)93 (4)21 (3)2 (3)9 (3)
O(3A)41 (4)48 (3)64 (3)−2 (3)7 (3)6 (3)
C (10A)53 (6)33 (4)54 (5)−5 (3)−2 (4)−4 (4)
C (1A)35 (5)27 (4)76 (5)12 (4)3 (4)5 (3)
C (3A)37 (5)36 (4)75 (5)−2 (4)−6 (4)4 (4)
C (14A)53 (6)36 (4)56 (5)3 (4)0 (4)6 (4)
C (4A)50 (6)36 (4)61 (5)7 (4)0 (4)−6 (4)
C (13A)42 (5)35 (4)50 (4)8 (3)4 (4)9 (4)
C (7A)60 (6)35 (4)55 (5)−8 (4)13 (4)−9 (4)
C (17A)42 (5)45 (4)52 (5)7 (4)−3 (4)3 (4)
C (2A)41 (5)50 (5)50 (4)12 (4)8 (4)4 (4)
C (15A)52 (6)39 (4)58 (5)8 (4)6 (4)0 (4)
C (8A)44 (5)35 (4)50 (5)8 (4)4 (4)6 (4)
C (9A)53 (6)47 (5)56 (5)2 (4)10 (4)1 (4)
C (12A)54 (6)36 (4)46 (4)6 (3)2 (4)9 (4)
C (5A)36 (5)39 (4)55 (4)0 (4)4 (4)1 (4)
C (16A)43(5)44 (5)62 (5)4 (4)−3 (4)2 (4)
C (21A)48 (6)43 (4)53 (4)1 (4)2 (4)10 (4)
C (20A)39 (5)38 (4)57 (5)1 (4)−1 (4)4 (4)
C (11A)59 (6)40 (4)53 (5)4 (4)3 (4)5 (4)
C (6A)50(5)33 (4)60 (5)2 (4)8 (4)−3 (4)
C (22A)59 (6)47 (5)59 (5)0 (4)−12 (4)−1 (4)
C (2A′)77(8)78 (6)74 (6)−4 (5)−5 (5)33 (6)
O (3B)49 (4)34 (3)60 (3)−1 (2)−3 (3)4 (2)
O (1B)48 (3)31 (3)41 (3)−5(2)−3 (2)4 (2)
C (1B)44 (5)28 (4)45 (4)−2 (3)−1 (3)−4 (3)
C (2B)37 (5)42 (4)41 (4)−3 (3)0 (3)−4 (3)
C (10B)54 (6)38 (4)56 (5)−3 (4)3 (4)−3 (4)
C (3B)49 (5)32 (4)57 (5)−6 (4)0 (4)−3 (4)
C (4B)49 (5)39 (4)55 (5)−10 (4)3 (4)−2 (4)
C (6B)49 (6)55 (5)48 (5)−6 (4)−4 (4)10 (4)
C (5B)45 (5)36 (4)51 (4)−10 (3)−3 (4)10 (4)
C (7B)38 (5)79 (6)57 (5)15 (4)1 (4)12 (5)
C(2B′)59 (6)42 (5)66 (5)−1 (4)1 (5)4 (4)
C (8B)33 (6)124 (9)68 (6)37 (7)6 (5)28 (6)
C (12B)83 (18)190 (30)43 (14)64 (16)31 (12)80 (20)
C (9B)43 (13)100 (20)48 (13)5 (13)−7 (9)8 (16)
C (14B)16 (11)118 (13)63 (11)38 (10)26 (8)27 (10)
C (13B)74(16)109 (19)74 (15)40 (15)38 (13)44 (15)
C(11B)32(16)170 (40)89 (19)40 (20)22 (12)20 (17)
C (15B)44 (14)140 (30)150 (30)110 (20)30 (20)20(20)
C (17B)9 (12)87 (19)230(30)70 (20)−3 (15)13 (11)
C (16B)50 (13)84 (15)170(20)66 (17)0 (13)−1 (11)
C (20B)110 (20)140(30)200 (30)120 (30)70 (20)90 (20)
C (22B)120 (20)140 (20)300 (40)140(30)130 (30)51 (19)
C (21B)410 (90)170 (50)120(30)100(40)100 (50)100 (50)
C(12′)44 (15)10 (9)82 (17)−11 (11)3 (11)0 (9)
C(9′ )38 (17)23 (13)77 (17)−8 (11)−5 (11)−1 (10)
C (14′)18(16)64(14)53(16)17 (12)35 (12)35 (12)
C (13′)50 (16)34 (14)26 (13)−8 (9)2 (11)0 (12)
C (11′)34 (14)42 (12)41 (11)−8 (9)0 (9)−22(9)
C(15′)15 (13)44 (9)39 (10)12 (7)5 (7)−3 (8)
C(17′) 44(13)13 (11)56 (12)2 (9)−7 (10)−4 (9)
C(16′)37 (14)14 (10)56 (13)−22(10)−7 (11)12 (9)
C(20′)130 (20)48 (17)42(14)−7 (13)−1 (15)−9 (16)
C(22′)160 (30)31 (13)46 (14)5 (11)35 (15)−24 (14)
C(21′)120 (20)49 (15)56 (14)18 (11)−35 (14)9 (14)
C(1)55 (14)51 (11)95(14)−8 (10)2 (10)11 (9)
C(2)62 (14)50 (10)80 (13)−31(10)15 (10)9 (10)
C(3)83 (16)53 (10)71 (12)−10 (9)12 (12)−1 (11)
C(4)63 (13)36 (9)74 (12)−12 (8)3 (9)4 (9)
C(5)91 (15)30 (9)67 (12)7 (8)7 (11)3 (9)
C(6)87 (17)49 (11)85 (13)−1 (10)7 (13)11 (11)

TABLE 6
Hydrogen coordinates (× 104) and isotropic
displacement parameters (Å2 × 103) for 051810.
xyzU(eq)
H(1AA)−7727508712188
H(3AA)−31659304738976
H(10A)−12478212630456
H(10B)17878337644556
H(1AB)−30088283689655
H(3AB)13589452728459
H(14A)−93079042539958
H(4AA)3639843668659
H(4AB)28559400668159
H(13A)−43499078497751
H(7AA)−40448620591460
H(17A)−94148836462456
H(15A)−52108145536959
H(15B)−81778093555759
H(9AA)−83369998567762
H(9AB)−528110140580262
H(12A)−64879896468955
H(12B)−91239821494355
H(16A)−104288123501060
H(16B)−77047797488460
H(21A)−38509281433472
H(21B)−63649194406372
H(21C)−35358874398872
H(20A)−41558293451453
H(11A)−370710126519861
H(11B)−630410539520961
H(6AA)−25539730620157
H(22A)−59817928395582
H(22B)−88418235403182
H(22C)−78707716428282
H(1A′)212379797458114
H(2A′)278986307600114
H(3BA)−277710226788972
H(1BA)−424811964828060
H(1BB)−239711477781647
H(10C)−705911915742059
H(10D)−395812098734659
H(3BB)−729810278774455
H(4BA)−620810435710557
H(4BB)−853210859724957
H(6BA)−319010912672361
H(7BA)−137912089687069
H(1B′)−884110751826884
H(2B′)−773311389838184
H(12C)1489122885463126
H(12D)4012120455691126
H(9BA)−56311014619978
H(9BB)259411184619978
H(14B)368712175637279
H(13B)−381127195970103
H(11C)1004112885606115
H(11D)−1538116615737155
H(15C)2846127676831134
H(15D)−5129726664134
H(17B)5058131045913131
H(16C)2418137246451121
H(16D)5278133876482121
H(20B)220137785830181
H(22D)3864143865502277
H(22E)5760140975804277
H(22F)3189144755922277
H(21D)−117135935245349
H(21E)1547130245339349
H(21F)3116135725186349
H(12E)78511834536054
H(12F)324111581559854
H(9BC)196310874614855
H(9BD)−122310796623755
H(14′)415011946623554
H(13′)−70812386588244
H(11E)−42710915559047
H(11F)−246411390574647
H(15E)344912658668339
H(15F)49012824651939
H(17′)471612684566945
H(16E)575313064620142
H(16F)309413466618542
H(20C)24013461569787
H(22G)2711140365282118
H(22H)5163135845286118
H(22I)4425139335646118
H(21G)−707133625071114
H(21H)−1382127845285114
H(21I)1345128325048114
H(1A)−21914814625581
H(2A)−70614251678477
H(3A)321313911709183
H(4A)761914134686969
H(5A)810514697634075
H(6A)418615037603289

TABLE 7
Observed and calculated
structure factors for 051810.
hkl10Fo10Fc10s
200423716
40013811 015
11043745011
21036232216
31025221824
0202712828
12042643714
22027725613
32035225029
42015815527
13017715810
23040036625
33050244119
43010811541
0402471182786
14036439910
24033733622
34026223210
4401219137
15076867
250798529
35011710112
45017522227
06029630914
16058967620
260864629
36019919914
1701111306
270991227
37016413210
08083392365
18027233526
280758641
38015815623
19030030518
29029327714
39030630216
010025918439
110025921011
210077543
3100978321
111034835913
2110861131
311023622517
411028830323
012058552737
112028323412
212034432115
3120883725
412016915621
113038937
21309712422
313016818818
413088440
014010510419
114016416111
21401239311
31408913927
41400501
1150836030
215024822710
315028327315
0160772625
1160402440
2160633923
3160629361
117050850
2170584657
317011414314
018010010025
118012212227
2180654429
3180672137
1190678234
2190867715
319044943
020018819919
12000421
30133632528
4010251
−31120115425
−2111161148
−111114396230
0111341573
111111596154
2111251149
31121215423
41115914116
−32144143024
−22143639919
−1211871148456
0211421553
12118191485117
22143240028
32145343134
4211178436
−3319510119
−23135635523
−13186184026
0311901144247
13185783930
23135835423
33113910015
431897257
−44114615730
−34129428411
−24133436420
−14141546411
04196190326
14141546410
24130836422
34129228312
44115415628
−35121816221
−25125121116
−15162167326
0511431206
15162467316
25121421219
35119316311
451973253
−36128624611
−26117917425
−16118720212
06147852614
1611702026
26117217518
36128424615
−37112211311
−27139936917
−17131737310
0711851707
1713133729
27136836928
37112811217
47114610024
−3811169114
−2811049313
−18119622311
0811157714
18119422213
2811079212
3811359112
4811016236
−3911149117
−29112211516
−19152256922
09155661016
19151357022
29112611611
391799230
−41011327827
−310119519419
−210126224810
−110137540014
010169069021
211132230023
3111632549
−412119420521
−312123227522
−212128425814
−112152252618
012168069430
112150952523
21212602689
312128527514
412119820520
−4131807945
−2131919113
−113116414611
013136533938
113115214710
2131699217
313129233316
4131807919
−414113212326
−3141569555
−214124722811
−1141837916
014132431111
1141657930
21412612279
3141779431
414111612314
−3151117211
−215116416710
−115111910213
0151625423
11518810319
215116616710
31510721
−316110612420
−2161989514
−1161795929
016140140
1161875925
2161889417
316111112418
−3171857125
−217127224710
−117116215215
0171761818
117115915315
217128024810
3171857118
−3181968016
−21811038313
−118114711815
018123621810
118111911824
2181668322
3181468046
−3191757721
−219111512411
−119110312019
019117517911
11917512028
219111812411
3191497748
−220121520911
−1201645432
0201698427
12010541
220120720914
−22110241
−1211779721
021115518011
1211839719
2211422542
−1221729522
022113015515
1221649554
22210551
−123112013312
−31226320323
−21231529610
−112108693428
01275267117
112104093433
21233829614
31224120326
41214711513
−4220441
−32229728926
−22267962820
02284895
22266362743
32229928925
422234423
−33217615817
−23255453024
−13240344712
0322072085
13240044611
23248153037
3321531587
432625062
−34230024111
−24221821911
−14263968717
0421221545
14265168615
24220021918
34231024112
4421139140
−35234630112
−252566124
−15276178725
05239343612
15274478720
2520611
35234430114
4521108242
−36217512310
−26224524512
−16219419718
06271776421
1621841997
26225224618
36215412312
462711671
−37220417211
−27223323619
−17214413616
07213313711
1721231356
27222423620
37220117210
4721412125
−482972138
−38221519610
−28221119712
−18219417115
08256174324
18216317112
28221719619
38220319710
4821102232
−49216015024
−39218318112
−29224821712
−19214611018
09235235113
19213611115
29224321713
39218518013
49217215021
−4102935339
−310213710214
−2102977216
−1102777617
010295093428
211235633716
311220617615
−4122929842
−312220019618
−21221781579
−112229425515
012228624228
112227525515
21221671579
312221619631
41221109816
−413216116522
−313220921718
−2132674028
−113213616732
013245743721
113217316712
2132604020
313222121720
413216616411
−414210611434
−314217019214
−21421188817
−114219715823
0142665726
114217115811
2142818916
314216519218
414211811414
−3152928621
−21522011839
−11521229613
015216515
11521259713
215219718213
3152718741
−316216117529
−21621179912
−116215714814
0162647121
116215214815
216210810014
316216517514
−3172858725
−2172523736
−1172918625
017236539610
1172878626
2172533735
3172808720
−3182464745
−218212814612
−11821617348
018215312616
1182747335
218215614513
3182514650
−319220920
−219215714918
−119214316714
01921096820
119211916716
219216014917
319255941
−2202989613
−12020921
0202711942
1202459345
22021049628
−221211211619
−12120311
0212642931
12120311
221212711617
−2222934738
−1222506743
022217115311
1222406740
220015414315
1210544841
221013811030
02201279619
122046346
2220041
1230564755
1012732779
20127725712
−21388376631
0132372985
11326881939125
21388176754
313557655
4138611273
−42319318513
−32315818230
−22370966124
−12371872018
02386178521
12368871921
22368266045
32318918223
42316318530
−433307330
−33327022217
−23343144721
−13382485329
033122212
13384585422
23336944830
33326122316
4330721
−44316721928
−34342740517
−24328526511
−14365569522
04374572820
14364369417
24325526621
34343040616
44319721924
−4539314053
−35329625219
−253655416
−15362368616
05336038311
15362068516
2530551
35328825213
4538814064
−4631057832
−36332833412
−26344343920
−16330636215
06335040711
1633083628
26344944028
36333133413
4630781
−47314411224
−37314312515
−27328325017
−17332239811
0730131
1733153979
27326925121
37313612512
−4831119532
−38321919111
−28328425914
−18316917416
083566716
1831561749
28329325921
38320719110
4831389525
−49315712924
−393837632
−2931179513
−19344245615
093616916
19344045717
2931109431
3931097718
49316112923
−4103775964
−310319518714
−21032442118
−110320117710
110137540114
210126424710
310119719313
−4111355135
−3111502550
−211132829917
−111124223911
011112810410
111124724010
−311315613016
−21131311248
−111335335714
011330833012
111336835513
211313012418
311317213019
411312311815
−41231082328
−3123857227
−212323221310
−112324721111
012341643619
112323221217
212326121310
31231057221
4123502450
−4133784053
−31336910328
−213311412911
−113336235414
013322920114
113335735211
21331451289
313311310418
4133674032
−4143284627
−314316520015
−214333530021
−11432241909
01430201
114321419010
214332630115
314316019928
4143694626
−31539211521
−21531931719
−115330728513
0153605425
115331128513
215319817110
31539011629
−31630301
−21631158412
−116319418513
0163614938
116318018516
2163898419
31630301
−317310810445
−2173957915
−11731218520
01732231849
11731038521
2173877916
31738810419
−318315816919
−2183797318
−118319613519
01830171
118314513521
2183547354
318317817011
−3193276326
−2193915225
−119318015220
0193862420
119315415314
2193805227
3193786321
−2203745517
−120310210217
02031086931
12038310219
2203745474
−2213775027
−121310111521
021333435712
12138611619
2213945121
−1223919720
02311008917
12319313321
0241732865
00273064822
10269665218
20254548223
30214312129
40215810414
−41212011517
00460960521
1041364114959
20425825118
3041246336
404852572
−41415514214
−31418317726
−21433031211
−1141251111736
0141481645
1141211111637
21430931123
3141861777
41414714230
−424916521
−324245524
−22450249717
−1241553134344
02491286624
1241484134347
22444049734
324335533
4240651
−43417515914
−33419718127
−2341471257
−13458060924
0341479123040
13456960815
23411712520
33420118110
43414016034
−444254925
−34424722414
−24428230713
−14456659119
0442492697
14455159115
24426430721
34426122411
444594859
−4541319313
−35419216712
−25428526313
−1541291368
0541651697
1541401375
25425526222
35420016811
454779377
−4641288933
−36421117911
−26456055337
−16419521119
06461660718
1641962106
26457855335
36417717912
464698968
−474818828
−3741841539
−27420518011
−17431137719
0741791767
1743183768
27417718122
37417315244
−484713271
−38411610617
−284835818
−18425823921
08414513810
18425923811
284645863
3848210523
4840321
−494617060
−39411811117
−29414110012
−19425923716
09469268621
1102877714
2102707135
310211210319
−41121188330
−311220017615
−211235133711
−111227625411
011222318012
111225825311
−210419619310
−110424122511
01041812029
110424722410
21041921948
3104837527
4104786819
−41141078432
−311414516616
−21141291289
−111463962122
011436637814
111463362128
211412712910
311416916714
4114768426
−412412612925
−312415717413
−21241741629
−112424726711
01240151
112425926720
21241771629
312415017517
412413712915
−413412614829
−3134666432
−21342312289
−113420418611
013418314213
11342021858
21342572287
3134646543
413417114814
−4144809754
−31441008517
−214419020110
−114427726110
01440251
114428626217
21441872009
3144698434
4144769722
−3154665544
−215436535512
−115417014319
01541631418
115414514212
215437435613
3154365536
−31641049717
−21642222029
−116419218815
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Example 2

Synthesis of 051810

The preparation of 051810 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. 051810.

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In phosphine oxide III, Y1 and Y2 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. Che., 41, 4662 (1998), DeLuca et al., U.S. Pat. No. 5,843,928; Perlman et al., Tetrahedron Let. 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 U.S. Pat. No. 7,238,681, entitled “2-Methylene-18,19-Dinor-1α-Hydroxy-Homopregnacalciferol and Its Uses” the specifications of which are specifically incorporated herein by reference.