Patent Application: US-31746702-A

Abstract:
a method of purifying 2 - methylene - 19 - nor - 20 - 1α - hydroxy - bis - homo - pregnacaciferol to obtain 2 - methylene - 19 - nor - 20 - 1α - hydroxy - bis - homo - pregnacalciferol in crystalline form . the method includes the steps of boiling a solvent such as acetone under inert atmosphere , dissolving a product containing 2 - methylene - 19 - nor - 20 - 1α - hydroxy - bis - homo - pregnacalciferol 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 2 - methylene - 19 - nor - 20 - 1α - hydroxy - bis - homo - pregnacalciferol crystals , and recovering the 2 - methylene - 19 - nor - 20 - 1α - hydroxy - bis - homo - pregnacalciferol crystals .

Description:
the present invention provides 2 - methylene - 19 - nor - 20 ( s )- 1α - hydroxy - bis - homo - pregnacalciferol ( 2mbp ) in crystalline form , a pharmacologically important compound , characterized by the formula shown below : the present invention also provides a valuable method of purification of 2mbp . the purification technique involves obtaining the 2mbp product in crystalline form by utilizing a crystallization procedure wherein the 2mbp material to be purified is dissolved using as the solvent a single solvent system comprised of acetone , ethyl acetate , isopropanol , chloroform , dichloromethane , or diethyl ether . the preferred solvent is acetone . thereafter , the solvent can be removed by evaporation , with or without vacuum , or other means as is well known . the technique can be used to purify a wide range of final products containing 2mbp 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 2mbp to be purified . the usefulness and advantages of the present crystallization procedures is shown in the following specific examples 1 and 2 . after crystallization , the precipitated material was observed under a microscope to confirm its crystalline form . additionally , x - ray diffraction analysis was performed . yields of crystallizations were high and the obtained crystals showed a relatively sharp melting point of 162 - 164 ° c . the described crystallization process of the synthetic 2mbp product represents a valuable purification method , which can remove not only some side products derived from the synthetic path , but , moreover , concomitant 1α - hydroxyvitamin d 4 . such impurity is the result of the contamination of natural ergosterol with its 22 , 23 - dihydro analog . ( a ) 2mbp product to be purified may be dissolved in boiling acetone ( 1 . 2 ml , aldrich ) under argon atmosphere , left at room temperature ( 68 ° f .) for a few hours ( 1 - 3 hrs ) and then in a refrigerator ( 35 - 45 ° f .) overnight ( 8 - 12 hrs ). the precipitated crystals should be filtered off , washed with a small volume of a cold ( 0 ° c .) acetone and dried . ( b ) these crystals of 2mbp may then be recrystallized with acetone ( 0 . 5 ml ) as described in example 1 ( a ). the precipitated crystals have a relatively sharp melting point of 162 - 164 ° c ., and were observed under a microscope to confirm their crystalline form . a colorless plate - shaped crystal of dimensions 0 . 40 × 0 . 25 × 0 . 03 mm was utilized for the structural analysis . intensity data were collected with a siemens histar area detector mounted on a platform goniometer using cu kα radiation ( λ = 1 . 54178 å ) focused with goebel optics . the crystal was mounted on a thin nylon fiber with vacuum grease and data were collected at ambient temperature , 293 ° k . the intensity data were measured as a series of ω oscillation frames each of 0 . 25 °; these were comprised of 5 scans ( 500 images each , 40 sec ./ image ) at detector 2θ of − 85 ° and 2 scans ( 500 images each , 20 sec ./ image ) at detector 2θ of − 40 °. the detector was operated in 512 × 512 mode and was positioned 6 . 0 cm from the sample . coverage of unique data was 95 . 4 % complete to 58 . 88 degrees in θ . the first 50 frames were repeated at the end of data collection and showed essentially no decay of the crystal diffraction during the data collection . a total of 6917 data was measured in the range 4 . 38 & lt ; θ58 . 88 °. the data were merged and scaled to form a set of 2697 independent data with r ( int )= 0 . 0562 using saint ( bruker - axs , inc .). 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 f 2 using shelxl - 97 ( g . m . sheldrick , 1994 ; shelxtl version 5 reference manual , bruker - axs , inc .). hydrogen atom positions were intially located in fourier difference maps , but refined by a riding model with idealized geometries . non - hydrogen atoms were refined with anisotropic displacement parameters . a total of 229 parameters were refined against 0 restraints and 2697 data to give wr ( f 2 )= 0 . 1369 and s = 1 . 088 for weights of w = i /[ s 2 ( f 2 )+( 0 . 0824 p ) 2 ], where p =[ f o 2 + 2f c 2 ]/ 3 . the final r ( f ) was 0 . 0544 for the 2697 observed , [ f & gt ; 2s ( f )], data . the final difference map had maxima and minima of 0 . 126 and − 0 . 153 e / å 3 , respectively . the three dimensional structure of 2mbp as defined by the following physical data and atomic positional parameters described and calculated herein is illustrated in fig1 . [ 0023 ] table 2 atomic coordinates (× 10 4 ) and equivalent isotropic displacement parameters ( å 2 × 10 3 ) for 2 - mbisp . u ( eq ) is defined as one third of the trace of the orthogonalized uij tensor . x y z u ( eq ) o ( 1 ) 1842 ( 3 ) 3525 ( 1 ) 5011 ( 1 ) 62 ( 1 ) o ( 3 ) 7954 ( 4 ) 3113 ( 1 ) 4476 ( 2 ) 78 ( 1 ) c ( 1 ) 3883 ( 5 ) 3729 ( 2 ) 4852 ( 2 ) 50 ( 1 ) c ( 2 ) 4569 ( 5 ) 3359 ( 2 ) 4201 ( 2 ) 58 ( 1 ) c ( 3 ) 6698 ( 5 ) 3569 ( 2 ) 4030 ( 2 ) 61 ( 1 ) c ( 4 ) 7074 ( 6 ) 4537 ( 2 ) 4057 ( 2 ) 59 ( 1 ) c ( 5 ) 6301 ( 5 ) 4937 ( 2 ) 4686 ( 2 ) 48 ( 1 ) c ( 6 ) 7497 ( 5 ) 5433 ( 2 ) 5059 ( 2 ) 52 ( 1 ) c ( 7 ) 7012 ( 5 ) 5872 ( 2 ) 5673 ( 2 ) 53 ( 1 ) c ( 8 ) 8248 ( 5 ) 6371 ( 2 ) 6020 ( 2 ) 50 ( 1 ) c ( 9 ) 10390 ( 5 ) 6589 ( 2 ) 5828 ( 2 ) 65 ( 1 ) c ( 10 ) 4161 ( 5 ) 4704 ( 2 ) 4851 ( 2 ) 51 ( 1 ) c ( 11 ) 10739 ( 6 ) 7562 ( 2 ) 5809 ( 2 ) 70 ( 1 ) c ( 12 ) 10108 ( 6 ) 8006 ( 2 ) 6452 ( 2 ) 61 ( 1 ) c ( 13 ) 7933 ( 5 ) 7806 ( 2 ) 6640 ( 1 ) 47 ( 1 ) c ( 14 ) 7696 ( 5 ) 6814 ( 2 ) 6661 ( 2 ) 50 ( 1 ) c ( 15 ) 5663 ( 6 ) 6668 ( 2 ) 6982 ( 2 ) 62 ( 1 ) c ( 16 ) 5453 ( 5 ) 7416 ( 2 ) 7474 ( 2 ) 59 ( 1 ) c ( 17 ) 7251 ( 5 ) 8038 ( 2 ) 7353 ( 2 ) 51 ( 1 ) c ( 18 ) 6466 ( 6 ) 8205 ( 2 ) 6135 ( 2 ) 64 ( 1 ) c ( 19 ) 3405 ( 7 ) 2898 ( 3 ) 3811 ( 2 ) 97 ( 2 ) c ( 20 ) 6703 ( 6 ) 8967 ( 2 ) 7542 ( 2 ) 65 ( 1 ) c ( 21 ) 6012 ( 8 ) 9017 ( 3 ) 8269 ( 2 ) 92 ( 2 ) c ( 22 ) 8368 ( 7 ) 9636 ( 2 ) 7418 ( 2 ) 89 ( 1 ) c ( 23 ) 10284 ( 9 ) 9512 ( 3 ) 7809 ( 3 ) 116 ( 2 ) [ 0024 ] table 3 bond lengths [ å ] and angles [°] for 2 - mbisp . o ( 1 )- c ( 1 ) 1 . 426 ( 4 ) o ( 3 )- c ( 3 ) 1 . 416 ( 4 ) c ( 1 )- c ( 2 ) 1 . 505 ( 5 ) c ( 1 )- c ( 10 ) 1 . 524 ( 4 ) c ( 2 )- c ( 19 ) 1 . 314 ( 5 ) c ( 2 )- c ( 3 ) 1 . 490 ( 5 ) c ( 3 )- c ( 4 ) 1 . 522 ( 4 ) c ( 4 )- c ( 5 ) 1 . 504 ( 5 ) c ( 5 )- c ( 6 ) 1 . 335 ( 4 ) c ( 5 )- c ( 10 ) 1 . 502 ( 5 ) c ( 6 )- c ( 7 ) 1 . 452 ( 4 ) c ( 7 )- c ( 8 ) 1 . 327 ( 4 ) c ( 8 )- c ( 9 ) 1 . 511 ( 5 ) c ( 8 )- c ( 14 ) 1 . 511 ( 4 ) c ( 9 )- c ( 11 ) 1 . 527 ( 5 ) c ( 11 )- c ( 12 ) 1 . 530 ( 5 ) c ( 12 )- c ( 13 ) 1 . 523 ( 5 ) c ( 13 )- c ( 18 ) 1 . 539 ( 5 ) c ( 13 )- c ( 14 ) 1 . 548 ( 4 ) c ( 13 )- c ( 17 ) 1 . 553 ( 4 ) c ( 14 )- c ( 15 ) 1 . 513 ( 5 ) c ( 15 )- c ( 16 ) 1 . 534 ( 5 ) c ( 16 )- c ( 17 ) 1 . 553 ( 5 ) c ( 17 )- c ( 20 ) 1 . 535 ( 5 ) c ( 20 )- c ( 22 ) 1 . 536 ( 6 ) c ( 20 )- c ( 21 ) 1 . 540 ( 5 ) c ( 22 )- c ( 23 ) 1 . 508 ( 7 ) o ( 1 )- c ( 1 )- c ( 2 ) 113 . 5 ( 2 ) o ( 1 )- c ( 1 )- c ( 10 ) 109 . 6 ( 2 ) c ( 2 )- c ( 1 )- c ( 10 ) 109 . 9 ( 3 ) c ( 19 )- c ( 2 )- c ( 3 ) 122 . 5 ( 3 ) c ( 19 )- c ( 2 )- c ( 1 ) 123 . 6 ( 3 ) c ( 3 )- c ( 2 )- c ( 1 ) 113 . 9 ( 3 ) o ( 3 )- c ( 3 )- c ( 2 ) 107 . 5 ( 3 ) o ( 3 )- c ( 3 )- c ( 4 ) 111 . 9 ( 3 ) c ( 2 )- c ( 3 )- c ( 4 ) 111 . 3 ( 3 ) c ( 5 )- c ( 4 )- c ( 3 ) 112 . 5 ( 3 ) c ( 6 )- c ( 5 )- c ( 10 ) 125 . 1 ( 3 ) c ( 6 )- c ( 5 )- c ( 4 ) 120 . 7 ( 3 ) c ( 10 )- c ( 5 )- c ( 4 ) 114 . 2 ( 3 ) c ( 5 )- c ( 6 )- c ( 7 ) 128 . 3 ( 3 ) c ( 8 )- c ( 7 )- c ( 6 ) 126 . 0 ( 3 ) c ( 7 )- c ( 8 )- c ( 9 ) 125 . 1 ( 3 ) c ( 7 )- c ( 8 )- c ( 14 ) 124 . 6 ( 3 ) c ( 9 )- c ( 8 )- c ( 14 ) 110 . 3 ( 3 ) c ( 8 )- c ( 9 )- c ( 11 ) 111 . 7 ( 3 ) c ( 5 )- c ( 10 )- c ( 1 ) 110 . 8 ( 2 ) c ( 9 )- c ( 11 )- c ( 12 ) 112 . 5 ( 3 ) c ( 13 )- c ( 12 )- c ( 11 ) 112 . 2 ( 3 ) c ( 12 )- c ( 13 )- c ( 18 ) 110 . 6 ( 3 ) c ( 12 )- c ( 13 )- c ( 14 ) 107 . 8 ( 3 ) c ( 18 )- c ( 13 )- c ( 14 ) 110 . 8 ( 3 ) c ( 12 )- c ( 13 )- c ( 17 ) 117 . 3 ( 3 ) c ( 18 )- c ( 13 )- c ( 17 ) 109 . 7 ( 3 ) c ( 14 )- c ( 13 )- c ( 17 ) 100 . 1 ( 2 ) c ( 15 )- c ( 14 )- c ( 8 ) 121 . 0 ( 3 ) c ( 15 )- c ( 14 )- c ( 13 ) 104 . 6 ( 3 ) c ( 8 )- c ( 14 )- c ( 13 ) 113 . 8 ( 2 ) c ( 14 )- c ( 15 )- c ( 16 ) 104 . 2 ( 3 ) c ( 15 )- c ( 16 )- c ( 17 ) 107 . 4 ( 3 ) c ( 20 )- c ( 17 )- c ( 16 ) 111 . 3 ( 3 ) c ( 20 )- c ( 17 )- c ( 13 ) 121 . 2 ( 3 ) c ( 16 )- c ( 17 )- c ( 13 ) 103 . 0 ( 2 ) c ( 22 )- c ( 20 )- c ( 17 ) 115 . 0 ( 3 ) c ( 22 )- c ( 20 )- c ( 21 ) 1 . 09 . 6 ( 3 ) c ( 17 )- c ( 20 )- c ( 21 ) 110 . 8 ( 3 ) c ( 23 )- c ( 22 )- c ( 20 ) 115 . 7 ( 4 ) [ 0025 ] table 4 anisotropic displacement parameters ( å 2 × 10 3 ) for 2 - mbisp . the anisotropic displacement factor exponent takes the form : − 2π 2 [ h 2 a * 2 u11 + . . . + 2 h k a * b * u12 ] u11 u22 u33 u23 u13 u12 o ( 1 ) 36 ( 1 ) 59 ( 1 ) 92 ( 2 ) − 7 ( 1 ) − 3 ( 1 ) − 5 ( 1 ) o ( 3 ) 42 ( 1 ) 48 ( 1 ) 145 ( 2 ) 3 ( 1 ) − 17 ( 2 ) 2 ( 1 ) c ( 1 ) 34 ( 2 ) 45 ( 2 ) 70 ( 2 ) − 5 ( 2 ) − 11 ( 2 ) − 1 ( 1 ) c ( 2 ) 39 ( 2 ) 51 ( 2 ) 83 ( 2 ) − 21 ( 2 ) − 14 ( 2 ) 6 ( 1 ) c ( 3 ) 55 ( 2 ) 52 ( 2 ) 75 ( 2 ) − 19 ( 2 ) − 7 ( 2 ) 8 ( 2 ) c ( 4 ) 60 ( 2 ) 56 ( 2 ) 61 ( 2 ) − 2 ( 2 ) 2 ( 2 ) 0 ( 2 ) c ( 5 ) 52 ( 2 ) 34 ( 1 ) 58 ( 2 ) 3 ( 1 ) − 5 ( 2 ) 1 ( 1 ) c ( 6 ) 51 ( 2 ) 45 ( 2 ) 61 ( 2 ) 2 ( 1 ) 5 ( 2 ) − 9 ( 2 ) c ( 7 ) 56 ( 2 ) 42 ( 2 ) 62 ( 2 ) 2 ( 1 ) 6 ( 2 ) − 8 ( 2 ) c ( 8 ) 47 ( 2 ) 44 ( 2 ) 58 ( 2 ) 3 ( 1 ) − 1 ( 2 ) − 10 ( 2 ) c ( 9 ) 48 ( 2 ) 75 ( 2 ) 73 ( 2 ) − 15 ( 2 ) 3 ( 2 ) − 12 ( 2 ) c ( 10 ) 44 ( 2 ) 41 ( 2 ) 66 ( 2 ) − 11 ( 1 ) − 6 ( 2 ) 4 ( 1 ) c ( 11 ) 59 ( 2 ) 78 ( 2 ) 72 ( 2 ) − 12 ( 2 ) 11 ( 2 ) − 32 ( 2 ) c ( 12 ) 59 ( 2 ) 61 ( 2 ) 63 ( 2 ) − 5 ( 2 ) 1 ( 2 ) − 22 ( 2 ) c ( 13 ) 43 ( 2 ) 51 ( 2 ) 47 ( 2 ) 5 ( 1 ) − 6 ( 2 ) − 7 ( 2 ) c ( 14 ) 45 ( 2 ) 52 ( 2 ) 53 ( 2 ) 4 ( 1 ) − 4 ( 2 ) − 8 ( 2 ) c ( 15 ) 53 ( 2 ) 64 ( 2 ) 69 ( 2 ) 1 ( 2 ) 9 ( 2 ) − 19 ( 2 ) c ( 16 ) 48 ( 2 ) 71 ( 2 ) 58 ( 2 ) 3 ( 2 ) 4 ( 2 ) 0 ( 2 ) c ( 17 ) 49 ( 2 ) 53 ( 2 ) 50 ( 2 ) 1 ( 1 ) − 7 ( 2 ) − 1 ( 2 ) c ( 18 ) 71 ( 3 ) 66 ( 2 ) 57 ( 2 ) 10 ( 2 ) − 11 ( 2 ) − 5 ( 2 ) c ( 19 ) 53 ( 3 ) 122 ( 4 ) 117 ( 3 ) − 68 ( 3 ) − 9 ( 3 ) − 8 ( 2 ) c ( 20 ) 73 ( 3 ) 59 ( 2 ) 64 ( 2 ) − 5 ( 2 ) − 2 ( 2 ) 8 ( 2 ) c ( 21 ) 117 ( 4 ) 82 ( 3 ) 76 ( 2 ) − 16 ( 2 ) 20 ( 3 ) 9 ( 3 ) c ( 22 ) 104 ( 4 ) 63 ( 2 ) 99 ( 3 ) − 12 ( 2 ) 18 ( 3 ) − 6 ( 2 ) c ( 23 ) 107 ( 4 ) 101 ( 4 ) 140 ( 5 ) − 39 ( 3 ) − 4 ( 4 ) − 25 ( 3 ) [ 0026 ] table 5 hydrogen coordinates (× 10 4 ) and isotropic displacement parameters ( å 2 × 10 3 ) for 2 - mbisp . x y z u ( eq ) h ( 1o ) 2030 2820 5188 75 h ( 3o ) 9248 3381 4573 94 h ( 1 ) 4744 3489 5201 60 h ( 3 ) 6972 3366 3580 73 h ( 4a ) 8510 4644 4021 71 h ( 4b ) 6418 4808 3682 71 h ( 6 ) 8807 5506 4904 63 h ( 7 ) 5716 5796 5840 64 h ( 9a ) 10678 6347 5395 78 h ( 9b ) 11311 6330 6144 78 h ( 10a ) 3261 4960 4528 61 h ( 10b ) 3817 4933 5284 61 h ( 11a ) 9979 7806 5444 84 h ( 11b ) 12157 7673 5728 84 h ( 12a ) 10992 7820 6807 74 h ( 12b ) 10264 8624 6403 74 h ( 14 ) 8690 6614 6986 60 h ( 15a ) 5627 6117 7210 74 h ( 15b ) 4592 6682 6655 74 h ( 16a ) 5482 7201 7925 71 h ( 16b ) 4186 7714 7405 71 h ( 17 ) 8337 7857 7652 61 h ( 18a ) 6780 8804 6077 97 h ( 18b ) 5109 8148 6295 97 h ( 18c ) 6593 7911 5719 97 h ( 19a ) 3904 2689 3412 117 h ( 19b ) 2083 2780 3935 117 h ( 20 ) 5547 9133 7268 78 h ( 21a ) 7037 8779 8551 138 h ( 21b ) 4785 8697 8323 138 h ( 21c ) 5783 9609 8388 138 h ( 22a ) 8703 9627 6950 106 h ( 22b ) 7832 10203 7518 106 h ( 23a ) 9974 9502 8273 174 h ( 23b ) 11194 9978 7717 174 h ( 23c ) 10902 8976 7684 174 [ 0027 ] table 6 torsion angles [°] for 2 - mbisp . o ( 1 )- c ( 1 )- c ( 2 )- c ( 19 ) 0 . 5 ( 5 ) c ( 10 )- c ( 1 )- c ( 2 )- c ( 19 ) − 122 . 6 ( 4 ) o ( 1 )- c ( 1 )- c ( 2 )- c ( 3 ) 179 . 9 ( 3 ) c ( 10 )- c ( 1 )- c ( 2 )- c ( 3 ) 56 . 8 ( 3 ) c ( 19 )- c ( 2 )- c ( 3 )- o ( 3 ) − 111 . 3 ( 4 ) c ( 1 )- c ( 2 )- c ( 3 )- o ( 3 ) 69 . 2 ( 3 ) c ( 19 )- c ( 2 )- c ( 3 )- c ( 4 ) 125 . 8 ( 4 ) c ( 1 )- c ( 2 )- c ( 3 )- c ( 4 ) − 53 . 7 ( 4 ) o ( 3 )- c ( 3 )- c ( 4 )- c ( 5 ) − 71 . 4 ( 4 ) c ( 2 )- c ( 3 )- c ( 4 )- c ( 5 ) 48 . 9 ( 4 ) c ( 3 )- c ( 4 )- c ( 5 )- c ( 6 ) 128 . 0 ( 3 ) c ( 3 )- c ( 4 )- c ( 5 )- c ( 10 ) − 50 . 1 ( 4 ) c ( 10 )- c ( 5 )- c ( 6 )- c ( 7 ) − 2 . 4 ( 5 ) c ( 4 )- c ( 5 )- c ( 6 )- c ( 7 ) 179 . 7 ( 3 ) c ( 5 )- c ( 6 )- c ( 7 )- c ( 8 ) − 178 . 8 ( 3 ) c ( 6 )- c ( 7 )- c ( 8 )- c ( 9 ) 1 . 4 ( 5 ) c ( 6 )- c ( 7 )- c ( 8 )- c ( 14 ) − 179 . 6 ( 3 ) c ( 7 )- c ( 8 )- c ( 9 )- c ( 11 ) 125 . 7 ( 3 ) c ( 14 )- c ( 8 )- c ( 9 )- c ( 11 ) − 53 . 4 ( 4 ) c ( 6 )- c ( 5 )- c ( 10 )- c ( 1 ) − 125 . 0 ( 3 ) c ( 4 )- c ( 5 )- c ( 10 )- c ( 1 ) 53 . 1 ( 3 ) o ( 1 )- c ( 1 )- c ( 10 )- c ( 5 ) 179 . 9 ( 2 ) c ( 2 )- c ( 1 )- c ( 10 )- c ( 5 ) − 54 . 7 ( 3 ) c ( 8 )- c ( 9 )- c ( 11 )- c ( 12 ) 53 . 0 ( 4 ) c ( 9 )- c ( 11 )- c ( 12 )- − 54 . 6 ( 4 ) c ( 11 )- c ( 12 )- c ( 13 )- c ( 18 ) − 66 . 8 ( 4 ) c ( 13 ) c ( 11 )- c ( 12 )- c ( 13 )- 54 . 5 ( 4 ) c ( 11 )- c ( 12 )- c ( 13 )- c ( 17 ) 166 . 4 ( 3 ) c ( 14 ) c ( 7 )- c ( 8 )- c ( 14 )- c ( 15 ) 3 . 9 ( 5 ) c ( 9 )- c ( 8 )- c ( 14 )- c ( 15 ) − 177 . 0 ( 3 ) c ( 7 )- c ( 8 )- c ( 14 )- c ( 13 ) − 122 . 0 ( 3 ) c ( 9 )- c ( 8 )- c ( 14 )- c ( 13 ) 57 . 2 ( 4 ) c ( 12 )- c ( 13 )- c ( 14 )- 168 . 8 ( 3 ) c ( 18 )- c ( 13 )- c ( 14 )- c ( 15 ) − 70 . 1 ( 3 ) c ( 15 ) c ( 17 )- c ( 13 )- c ( 14 )- 45 . 6 ( 3 ) c ( 12 )- c ( 13 )- c ( 14 )- c ( 8 ) − 57 . 1 ( 3 ) c ( 15 ) c ( 18 )- c ( 13 )- c ( 14 )- 64 . 1 ( 4 ) c ( 17 )- c ( 13 )- c ( 14 )- c ( 8 ) 179 . 7 ( 3 ) c ( 8 ) c ( 8 )- c ( 14 )- c ( 15 )- − 163 . 1 ( 3 ) c ( 13 )- c ( 14 )- c ( 15 )- c ( 16 ) − 33 . 1 ( 3 ) c ( 16 ) c ( 14 )- c ( 15 )- c ( 16 )- 7 . 4 ( 4 ) c ( 15 )- c ( 16 )- c ( 17 )- c ( 20 ) 151 . 9 ( 3 ) c ( 17 ) c ( 15 )- c ( 16 )- c ( 17 )- 20 . 6 ( 3 ) c ( 12 )- c ( 13 )- c ( 17 )- c ( 20 ) 79 . 2 ( 4 ) c ( 13 ) c ( 18 )- c ( 13 )- c ( 17 )- − 48 . 2 ( 4 ) c ( 14 )- c ( 13 )- c ( 17 )- c ( 20 ) − 164 . 7 ( 3 ) c ( 20 ) c ( 12 )- c ( 13 )- c ( 17 )- − 155 . 7 ( 3 ) c ( 18 )- c ( 13 )- c ( 17 )- c ( 16 ) 76 . 9 ( 3 ) c ( 16 ) c ( 14 )- c ( 13 )- c ( 17 )- − 39 . 5 ( 3 ) c ( 16 )- c ( 17 )- c ( 20 )- c ( 22 ) − 178 . 0 ( 3 ) c ( 16 ) c ( 13 )- c ( 17 )- c ( 20 )- − 56 . 8 ( 5 ) c ( 16 )- c ( 17 )- c ( 20 )- c ( 21 ) 56 . 9 ( 4 ) c ( 22 ) c ( 13 )- c ( 17 )- c ( 20 )- 178 . 1 ( 3 ) c ( 17 )- c ( 20 )- c ( 22 )- c ( 23 ) − 62 . 9 ( 5 ) c ( 21 ) c ( 21 )- c ( 20 )- c ( 22 )- 62 . 8 ( 5 ) c ( 23 ) [ 0028 ] table 7 observed and calculated structure factors for 2 - mbisp . h k l 10fo 10fc 10s h k l 10fo 10fc 10s h k l 10fo 10fc 10s h k l 10fo 10fc 10s h k l 10fo 10fc 10s 4 0 0 51 50 3 1 15 0 43 53 3 0 6 1 298 328 8 − 4 14 1 38 35 5 1 5 2 153 145 7 6 0 0 48 54 4 2 15 0 82 87 2 1 6 1 326 324 4 − 3 14 1 54 53 3 2 5 2 175 176 2 1 1 0 108 125 1 3 15 0 53 49 3 2 6 1 62 70 2 − 2 14 1 95 101 3 3 5 2 156 167 5 2 1 0 813 823 10 0 16 0 28 24 8 3 6 1 76 73 2 − 1 14 1 78 78 2 4 5 2 194 188 2 4 1 0 448 435 4 1 16 0 25 18 5 4 6 1 68 62 1 0 14 1 73 68 1 5 5 2 99 96 2 5 1 0 62 62 1 2 16 0 17 12 8 5 6 1 125 129 2 1 14 1 78 79 1 6 5 2 84 79 3 6 1 0 65 72 2 1 17 0 54 37 10 6 6 1 89 91 2 2 14 1 97 101 2 7 5 2 70 47 4 0 2 0 650 820 8 1 0 1 304 297 5 − 5 7 1 152 158 5 3 14 1 44 53 5 − 6 6 2 65 66 3 1 2 0 510 519 6 2 0 1 86 79 1 − 4 7 1 168 165 1 4 14 1 44 34 5 − 5 6 2 60 66 2 2 2 0 88 88 2 4 0 1 115 107 1 − 3 7 1 138 136 2 − 3 15 1 33 5 5 − 4 6 2 74 77 1 4 2 0 217 213 2 5 0 1 111 115 2 − 2 7 1 101 94 2 − 2 15 1 46 46 6 − 3 6 2 130 128 3 5 2 0 120 117 1 6 0 1 36 28 4 − 1 7 1 219 219 3 − 1 15 1 25 30 6 − 2 6 2 150 159 2 6 2 0 36 42 5 − 6 1 1 56 55 3 0 7 1 223 236 2 0 15 1 38 30 2 − 1 6 2 233 248 3 7 2 0 37 49 7 − 5 1 1 107 120 2 1 7 1 213 220 3 1 15 1 38 30 5 0 6 2 529 545 4 1 3 0 352 375 3 − 4 1 1 162 152 4 2 7 1 91 93 2 2 15 1 34 46 6 1 6 2 238 248 11 2 3 0 39 35 3 − 2 1 1 338 350 3 3 7 1 136 137 1 3 15 1 27 4 5 2 6 2 152 158 2 3 3 0 58 55 2 − 1 1 1 1141 1205 14 4 7 1 174 165 1 − 2 16 1 24 27 7 3 6 2 131 128 1 4 3 0 84 80 1 1 1 1 1134 1206 11 5 7 1 160 158 2 − 1 16 1 27 13 6 4 6 2 77 77 2 5 3 0 43 42 8 4 1 1 163 152 1 6 7 1 33 17 24 0 16 1 18 4 17 5 6 2 61 66 2 6 3 0 54 51 5 5 1 1 109 120 2 − 6 8 1 61 46 10 1 16 1 33 13 8 6 6 2 69 66 3 7 3 0 34 7 7 6 1 1 56 55 11 − 5 8 1 65 60 11 2 16 1 20 28 6 − 6 7 2 39 49 13 0 4 0 114 118 2 7 1 1 19 16 18 − 4 8 1 52 51 2 0 17 1 24 32 5 − 5 7 2 96 98 3 1 4 0 17 3 3 − 7 2 1 38 15 7 − 3 8 1 150 145 1 1 17 1 17 3 17 − 4 7 2 65 63 2 2 4 0 88 82 1 − 6 2 1 41 44 4 − 2 8 1 86 88 1 0 0 2 393 405 5 − 3 7 2 99 90 2 4 4 0 87 87 1 − 5 2 1 28 16 5 − 1 8 1 68 69 5 1 0 2 332 336 8 − 2 7 2 141 157 2 5 4 0 19 15 18 − 4 2 1 256 252 5 0 8 1 378 391 3 2 0 2 412 409 8 − 1 7 2 442 439 5 6 4 0 99 104 5 − 3 2 1 108 98 2 1 8 1 69 68 2 4 0 2 137 137 3 0 7 2 252 268 2 7 4 0 66 56 4 − 2 2 1 98 100 2 2 8 1 89 87 2 − 6 1 2 34 44 5 1 7 2 447 439 14 1 5 0 17 4 7 − 1 2 1 465 481 4 3 8 1 152 145 1 − 5 1 2 114 119 4 2 7 2 146 157 2 2 5 0 72 64 1 0 2 1 15 2 3 4 8 1 54 51 6 − 4 1 2 52 49 2 3 7 2 98 89 1 3 5 0 108 106 6 1 2 1 478 482 4 5 8 1 67 59 4 − 2 1 2 174 178 1 4 7 2 69 63 2 4 5 0 86 82 1 2 2 1 93 99 2 6 8 1 46 46 4 − 1 1 2 599 599 5 5 7 2 102 97 2 5 5 0 34 29 3 4 2 1 257 252 2 − 6 9 1 37 28 12 0 1 2 166 164 2 6 7 2 51 48 4 6 5 0 29 22 6 5 2 1 17 16 8 − 5 9 1 84 71 3 2 1 2 178 178 2 − 6 8 2 20 16 13 7 5 0 57 41 6 6 2 1 41 44 6 − 4 9 1 105 103 1 4 1 2 50 49 2 − 5 8 2 53 52 4 0 6 0 645 708 8 7 2 1 17 14 16 − 3 9 1 156 151 1 5 1 2 119 118 2 − 4 8 2 118 118 1 1 6 0 360 437 50 − 7 3 1 41 49 6 − 2 9 1 54 46 1 6 1 2 47 44 3 − 3 8 2 92 90 4 2 6 0 101 96 21 − 6 3 1 52 50 4 − 1 9 1 194 201 8 7 1 2 59 55 5 − 2 8 2 40 37 2 3 6 0 36 39 3 − 5 3 1 171 175 1 0 9 1 227 233 2 − 7 2 2 39 34 6 − 1 8 2 325 343 4 4 6 0 19 17 4 − 4 3 1 239 231 3 1 9 1 190 201 7 − 6 2 2 106 111 2 0 8 2 165 186 2 5 6 0 80 76 5 − 3 3 1 457 454 6 2 9 1 50 46 3 − 5 2 2 211 211 3 1 8 2 312 344 4 6 6 0 48 44 4 − 2 3 1 306 308 4 3 9 1 157 151 1 − 4 2 2 74 77 1 2 8 2 38 37 1 1 7 0 31 28 3 − 1 3 1 375 403 4 4 9 1 114 103 1 − 3 2 2 385 373 5 3 8 2 92 91 1 2 7 0 110 128 25 0 3 1 358 411 19 5 9 1 74 71 5 − 2 2 2 96 91 1 4 8 2 118 118 3 3 7 0 72 70 1 1 3 1 394 402 3 6 9 1 36 28 6 − 1 2 2 614 632 19 5 8 2 54 52 4 4 7 0 79 78 2 2 3 1 304 307 4 − 5 10 1 54 57 4 0 2 2 371 373 7 6 8 2 32 16 15 5 7 0 171 167 2 3 3 1 472 455 6 − 4 10 1 107 110 3 1 2 2 623 632 8 − 6 9 2 76 71 5 6 7 0 49 48 4 4 3 1 240 231 2 − 3 10 1 168 166 1 2 2 2 105 92 2 − 5 9 2 42 36 6 0 8 0 134 137 2 5 3 1 169 176 3 − 2 10 1 79 79 3 4 2 2 80 78 1 − 4 9 2 170 164 2 1 8 0 226 226 8 6 3 1 44 50 5 − 1 10 1 139 149 2 5 2 2 211 211 6 − 3 9 2 83 82 1 2 8 0 211 196 3 7 3 1 54 49 5 0 10 1 127 138 1 6 2 2 116 111 3 − 2 9 2 44 39 2 3 8 0 66 64 1 − 7 4 1 46 41 5 1 10 1 145 148 1 7 2 2 34 35 7 − 1 9 2 77 79 1 4 8 0 315 302 2 − 6 4 1 81 84 2 2 10 1 74 79 1 − 7 3 2 69 71 4 0 9 2 84 93 3 5 8 0 67 63 3 − 5 4 1 34 26 20 3 10 1 168 165 1 − 6 3 2 75 81 4 1 9 2 80 79 2 6 8 0 38 28 6 − 4 4 1 171 165 1 4 10 1 107 110 2 − 5 3 2 112 104 1 2 9 2 40 38 1 1 9 0 247 260 7 − 3 4 1 189 193 3 5 10 1 62 57 4 − 4 3 2 147 144 3 3 9 2 85 82 1 2 9 0 243 244 2 − 2 4 1 199 199 3 − 5 11 1 22 6 13 − 3 3 2 190 177 3 4 9 2 172 164 4 3 9 0 193 186 2 − 1 4 1 346 367 4 − 4 11 1 77 79 2 − 2 3 2 105 107 2 5 9 2 25 36 9 4 9 0 405 398 3 0 4 1 450 520 19 − 3 11 1 51 50 1 − 1 3 2 395 396 14 6 9 2 77 71 6 5 9 0 8 2 8 1 4 1 356 368 13 − 2 11 1 70 71 1 0 3 2 252 272 12 − 5 10 2 29 11 11 6 9 0 81 75 7 2 4 1 195 200 2 − 1 11 1 92 93 2 1 3 2 391 396 5 − 4 10 2 100 99 4 0 10 0 119 124 2 3 4 1 182 194 3 0 11 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1 6 15 116 121 2 − 1 5 16 41 41 2 − 3 5 17 43 36 4 − 3 7 18 25 17 10 1 9 14 60 59 2 2 6 15 70 73 2 0 5 16 84 88 1 − 2 5 17 42 39 4 − 2 7 18 45 38 3 0 9 14 34 28 3 3 6 15 33 39 8 1 5 16 44 40 2 − 1 5 17 113 109 1 − 1 7 18 30 17 5 1 9 14 57 59 2 4 6 15 17 36 16 2 5 16 78 79 2 0 5 17 70 68 2 0 7 18 42 45 15 2 9 14 69 66 2 − 4 7 15 43 39 5 3 5 16 25 9 8 1 5 17 113 109 2 1 7 18 31 17 19 4 9 14 16 27 16 − 3 7 15 33 31 12 4 5 16 26 38 10 2 5 17 36 39 4 2 7 18 36 38 3 3 10 14 39 37 4 − 2 7 15 83 78 2 − 4 6 16 45 23 10 3 5 17 31 36 4 − 2 8 18 52 51 3 2 10 14 37 37 4 − 1 7 15 38 29 5 − 3 6 16 63 66 2 4 5 17 38 49 6 − 1 8 18 61 61 3 1 10 14 46 43 2 0 7 15 54 45 3 − 2 6 16 17 14 17 − 3 6 17 45 7 5 0 8 18 55 65 3 0 10 14 72 75 2 1 7 15 44 29 8 − 1 6 16 64 64 1 − 2 6 17 26 17 6 1 8 18 55 61 9 1 10 14 45 43 5 2 7 15 79 78 2 0 6 16 77 80 1 − 1 6 17 56 54 2 2 8 18 47 51 3 2 10 14 33 37 4 3 7 15 6 31 5 1 6 16 69 64 2 0 6 17 65 56 3 − 1 9 18 39 41 5 3 10 14 43 37 6 4 7 15 36 39 7 2 6 16 21 14 7 1 6 17 60 53 3 0 9 18 16 12 13 3 11 14 27 19 9 − 4 8 15 35 32 6 3 6 16 68 66 5 2 6 17 23 17 22 1 9 18 42 41 6 2 11 14 54 48 3 − 3 8 15 48 53 6 4 6 16 9 23 9 3 6 17 18 7 18 1 0 19 15 6 15 1 11 14 51 53 3 − 2 8 15 28 37 5 − 4 7 16 28 3 7 − 3 7 17 57 58 3 2 0 19 29 24 9 0 11 14 78 75 2 − 1 8 15 47 42 4 − 3 7 16 50 41 3 − 2 7 17 96 98 2 3 0 19 37 25 20 1 11 14 53 53 4 0 8 15 120 122 2 − 2 7 16 74 76 2 − 1 7 17 58 62 4 − 3 1 19 63 66 2 2 11 14 50 48 4 1 8 15 49 42 2 − 1 7 16 96 97 2 0 7 17 97 96 5 − 2 1 19 48 54 3 2 12 14 32 30 4 2 8 15 40 37 20 0 7 16 67 69 3 1 7 17 58 61 3 − 1 1 19 53 52 4 1 12 14 69 71 2 3 8 15 58 53 5 1 7 16 98 97 2 2 7 17 92 98 3 0 1 19 17 8 12 0 12 14 22 4 8 − 3 9 15 73 79 2 2 7 16 73 76 5 3 7 17 64 58 4 1 1 19 54 52 3 1 12 14 70 71 4 − 2 9 15 37 39 5 3 7 16 25 41 13 − 3 8 17 50 51 3 2 1 19 52 54 5 2 12 14 34 30 10 − 1 9 15 55 53 6 4 7 16 4 3 4 − 2 8 17 78 82 2 3 1 19 59 66 2 1 13 14 33 39 5 0 9 15 36 27 4 − 3 8 16 62 61 2 − 1 8 17 31 32 8 − 3 2 19 36 50 4 0 13 14 28 28 8 1 9 15 59 53 3 − 2 8 16 33 24 4 0 8 17 31 12 11 − 2 2 19 48 34 3 1 13 14 15 39 14 2 9 15 41 39 7 − 1 8 16 75 73 6 1 8 17 18 32 18 − 1 2 19 34 29 4 1 0 15 309 302 3 3 9 15 63 79 9 0 8 16 48 51 4 2 8 17 83 82 6 0 2 19 29 12 7 2 0 15 63 62 1 − 3 10 15 45 45 4 1 8 16 72 73 2 3 8 17 41 51 6 1 2 19 19 29 10 3 0 15 21 13 19 − 2 10 15 21 22 7 2 8 16 28 24 5 − 2 9 17 49 54 3 2 2 19 34 34 6 4 0 15 37 38 5 − 1 10 15 59 48 3 3 8 16 62 62 4 − 1 9 17 44 37 4 3 2 19 42 50 8 5 1 15 48 57 5 0 10 15 17 15 12 − 3 9 16 23 28 8 0 9 17 35 1 9 − 3 3 19 29 14 6 4 1 15 52 57 3 1 10 15 46 48 3 − 2 9 16 43 47 3 1 9 17 36 37 4 − 2 3 19 35 24 4 3 1 15 138 130 3 2 10 15 24 22 7 − 1 9 16 48 39 3 2 9 17 55 54 2 − 1 3 19 45 39 3 2 1 15 161 151 2 3 10 15 32 44 6 0 9 16 30 42 5 − 1 10 17 27 21 4 0 3 19 35 33 7 1 1 15 102 95 1 − 2 11 15 39 38 3 1 9 16 42 39 3 0 10 17 22 2 10 1 3 19 30 39 5 0 1 15 93 90 1 − 1 11 15 33 20 4 2 9 16 40 47 3 1 10 17 18 21 12 2 3 19 41 24 4 1 1 15 101 95 2 0 11 15 22 21 8 3 9 16 26 28 12 0 0 18 27 7 6 − 3 4 19 24 19 10 2 4 19 53 54 2 2 7 19 13 15 12 0 2 20 34 10 13 2 5 20 21 25 6 2 2 21 36 32 16 1 4 19 33 31 3 − 1 8 19 57 58 3 1 2 20 27 41 7 − 2 6 20 30 18 8 − 2 3 21 39 37 6 0 4 19 50 51 4 0 8 19 43 41 4 2 2 20 71 71 3 − 1 6 20 28 26 5 − 1 3 21 37 17 6 1 4 19 20 31 10 1 8 19 54 58 13 3 2 20 46 47 6 0 6 20 20 5 11 1 3 21 25 17 7 2 4 19 46 54 5 0 0 20 41 45 5 − 3 3 20 58 58 3 1 6 20 33 26 6 2 3 21 33 37 11 2 5 19 38 27 7 1 0 20 131 131 3 − 2 3 20 39 37 4 0 7 20 21 2 15 − 1 4 21 14 19 14 1 5 19 20 10 9 2 0 20 46 36 4 − 1 3 20 31 33 4 1 7 20 13 7 12 0 4 21 41 29 5 0 5 19 19 18 11 3 0 20 30 9 7 0 3 20 29 20 9 1 0 21 45 43 4 0 5 21 29 15 14 2 5 19 33 28 10 − 3 1 20 38 13 8 1 3 20 41 33 4 2 0 21 33 28 7 1 5 21 10 14 9 2 6 19 29 29 6 − 2 1 20 63 65 4 2 3 20 36 37 3 − 2 1 21 61 69 6 0 0 22 24 49 4 1 6 19 19 20 18 − 1 1 20 34 37 5 − 2 4 20 40 34 3 − 1 1 21 50 51 6 1 0 22 44 35 5 0 6 19 29 12 6 0 1 20 38 43 3 − 1 4 20 53 47 4 0 1 21 21 19 6 − 1 1 22 39 31 6 1 6 19 31 20 5 1 1 20 32 37 6 0 4 20 31 30 4 1 1 21 61 51 3 0 1 22 27 13 6 2 6 19 22 29 8 2 1 20 65 65 6 1 4 20 57 47 9 2 1 21 55 69 4 1 1 22 21 31 20 2 7 19 34 15 10 3 1 20 34 13 9 2 4 20 26 34 5 − 2 2 21 27 32 7 0 2 22 35 37 6 1 7 19 16 23 15 − 3 2 20 46 47 10 − 2 5 20 30 25 8 − 1 2 21 44 47 3 0 7 19 27 20 15 − 2 2 20 72 71 2 − 1 5 20 27 20 6 0 2 21 28 24 5 1 7 19 32 23 5 − 1 2 20 40 41 3 0 5 20 18 18 17 1 2 21 45 47 5 the preparation of 2mbp 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 . 2mbp . in the structures ii , iii , and iv groups y 1 and y 2 are hydroxy - protecting groups , it being also understood that any functionalities that might be sensitive , or that interfere with the condensation reaction , be suitably protected as is well - known in the art . the process shown above represents an application of the convergent synthesis concept , which has been applied effectively for the preparation of vitamin d compounds [ e . g . lythgoe et al ., j . chem . soc . perkin trans . 1 , 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 ]. hydrindanones of the general structure ii are known , or can be prepared by known methods . for the preparation of the required phosphine oxides of general structure iii , a synthetic route has been developed starting from a methyl quinicate derivative which is easily obtained from commercial ( 1r , 3r , 4s , 5r )-(−)- quinic acid as described by perlman et al ., tetrahedron lett . 32 , 7663 ( 1991 ) and deluca et al ., u . s . pat . no . 5 , 086 , 191 . 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 . 09 / 878 , 438 filed jun . 11 , 2001 entitled “ 1α - hydroxy - 2 - methylene - 19 - nor - homopregnacalciferol and its uses ” the specifications of which are specifically incorporated herein by reference . as used in the description and in the claims , the term “ hydroxy - protecting group ” signifies any group commonly used for the temporary protection of hydroxy functions , such as for example , alkoxycarbonyl , acyl , alkylsilyl or alkylarylsilyl groups ( hereinafter referred to simply as “ silyl ” groups ), and alkoxyalkyl groups . alkoxycarbonyl protecting groups are alkyl - o - co - groupings such as methoxycarbonyl , ethoxycarbonyl , propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , isobutoxycarbonyl , tert - butoxycarbonyl , benzyloxycarbonyl or allyloxycarbonyl . the term “ acyl ” signifies an alkanoyl group of 1 to 6 carbons , in all of its isomeric forms , or a carboxyalkanoyl group of 1 to 6 carbons , such as an oxalyl , malonyl , succinyl , glutaryl group , or an aromatic acyl group such as benzoyl , or a halo , nitro or alkyl substituted benzoyl group . the word “ alkyl ” as used in the description of the claims , denotes a straight - chain or branched alkyl radical of 1 to 10 carbons , in all its isomeric forms . alkoxyalkyl protecting groups are groupings such as methoxymethyl , ethoxymethyl , methoxyethoxymethyl , or tetrahydrofuranyl and tetrahydropyranyl . preferred silyl - protecting groups are trimethylsilyl , triethylsilyl , t - butyldimethylsilyl , dibutylmethylsilyl , diphenylmethylsilyl , phenyldimethylsilyl , diphenyl - t - butylsilyl and analogous alkylated silyl radicals . the term “ aryl ” specifies a phenyl -, or an alkyl -, nitro - or halo - substituted phenyl group . a “ protected hydroxy ” group is a hydroxy group derivatised or protected by any of the above groups commonly used for the temporary or permanent protection of hydroxy functions , e . g . the silyl , alkoxyalkyl , acyl or alkoxycarbonyl groups , as previously defined . the terms “ hydroxyalkyl ”, “ deuteroalkyl ”, “ aminoalkyl ”, “ halogenalkyl ”, “ alkoxyalkyl ”, “ aryloxyalkyl ”, and “ fluoroalkyl ” refer to an alkyl radical substituted by one or more hydroxy , deuterium , amino , halogen , alkoxy , aryloxy , or fluoro group respectively . a “ halogen ” group includes any of the five elements fluorine , chlorine , bromine , iodine and astatine that form a part of group viia of the periodic table . referring now to schemes i - iii , there are illustrated three different methods of synthesizing 2mbp starting with vitamin d 2 . the first five steps are identical ( shown in scheme i ) for each synthesis to obtain the protected 20 ( s )- aldehyde . thereafter , in schemes i and ii the aldehyde is converted to a protected 20 ( s )- alcohol which in turn has its side chain converted to bis - homo in two different ways ( scheme i versus scheme ii ). in contrast , scheme iii illustrates a direct conversion of the protected 20 ( s )- aldehyde to the bis - homo side chain .