- Large-Scale Synthesis of Eldecalcitol
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Industrial-scale synthesis of eldecalcitol is described. AA highly diastereoselective epoxidation of p-methoxybenzyl (PMB) protected dienol at room temperature provides the key epoxide intermediate with a secondary hydroxyl group, which is alkylated with a triflate to set up all of the subunits at the C-1, C-2, and C-3 positions of the A-ring fragment. Selective protecting group manipulation followed by palladium-catalyzed cyclization then provides the A-ring synthon. The C/D-ring fragment is obtained by (1) direct C-H hydroxylation of Grundman's ketone using in situ prepared trifluoropropanone dioxirane and (2) protection. Finally, the coupling of the A-ring with the C/D-ring fragment, global deprotection, and recrystallization provide the highly crystalline eldecalcitol.
- Moon, Hyung Wook,Lee, Seung Jong,Park, Seong Hu,Jung, Se Gyo,Jung, In A.,Seol, Chang Hun,Kim, Seung Woo,Lee, Seon Mi,Gangganna, Bogonda,Park, Seokhwi,Lee, Kee-Young,Oh, Chang-Young,Song, Juyoung,Jung, Jaehun,Heo, Ji Soo,Lee, Kang Hee,Kim, Hae Sol,Lee, Won Taek,Baek, Areum,Shin, Hyunik
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- PROCESS AND INTERMEDIATES FOR THE PREPARATION OF ELDECALCITOL
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The invention relates to new intermediates in the synthesis of Eldecalcitol and to processes for the preparation of said intermediates and of Eldecalcitol.
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- NOVEL CRYSTAL FORM OF VITAMIN D3 DERIVATIVE AND METHOD FOR PRODUCING THE SAME
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PROBLEM TO BE SOLVED: To provide a novel crystal form of a vitamin D3 derivative and a method of producing the same. SOLUTION: The present invention provides a production method including crystallizing 1α,25-dihydroxy-2β-(3-hydroxypropoxy) vitamin D3 (compound (1)), known a vitamin D3 derivative, by quenching from a hydrous organic solvent, and further heating it, to obtain C crystals of the compound (1), and a crystalline form obtained as a result of it. SELECTED DRAWING: Figure 5 COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0037
(2018/04/12)
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- Structural revisions of the reported A-ring phosphine oxide synthon for ED-71 (Eldecalcitol) and a new synthesis
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In a reported procedure for the synthesis of the ED-71 A-ring phosphine oxide, we discovered that unusual TBS transfer occurred from the 1α-position to the sterically more constrained 2β-position, and the subsequent Michael addition of ethyl acrylate predominated at the 1α-position. The X-ray analysis of a key intermediate confirmed our observations. We made a structural revision of the reported A-ring phosphine oxide synthon and ED-71. In addition, we provided the first stereoselective synthetic approach to ED-71 A-ring phosphine oxide applying the stereochemistry of d-mannitol.
- Zhao, Guo-Dong,Liu, Zhao-Peng
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p. 8033 - 8040
(2015/12/31)
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- Two convergent approaches to the synthesis of 1,25-dihydroxy 2-(3-hydroxypropoxy)vitamin D3 (ED-71) by the lythgoe and thf trost coupling reactions
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Two convergent syntheses of 1,25-dihydroxy-2-(3-hydroxypropoxy)vitamin D3 (ED-71) by the Lythgoe coupling reaction between the A-ring phosphine oxide and the C/D-ring ketone and the Trost coupling reaction between the A-ring ene-yne and the C/D-ring bromomethylene are described.
- Maeyama, Junji,Hiyamizu, Hiroko,Takahashi, Keisuke,Ishihara, Jun,Hatakeyama, Susumi,Kubodera, Noboru
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p. 295 - 307
(2008/04/18)
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- Design and efficient synthesis of 2α-(ω-hydroxyalkoxy)- 1α,25-dihydroxyvitamin D3 analogues, including 2-epi-ED-71 and their 20-epimers with HL-60 cell differentiation activity
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A concise and efficient synthetic approach to 2α-(ω- hydroxyalkoxy)-1α,25-dihydroxyvitamin D3 (4a-c), including 2-epi-ED-71, was developed starting from D-glucose as a chiral template for the construction of the 2α-modified A-ring precursors (11a-c). It was found that the best ligand for the bovine thymus vitamin D receptor (VDR) in this series is 4b, which has 1.8 times greater binding affinity for the bovine thymus VDR than that of the natural hormone 1. Interestingly, potency in the induction of HL-60 cell differentiation for 4a-c was almost the same or weaker than that of 1 despite the strong binding affinity for the VDR. Next, we were interested in the "double modification" of 1 based on 4a-c with C20-epimerization, affording 2α-(ω-hydroxyalkoxy)-20-epi-1α, 25-dihydroxyvitamin D3 (20-epi-4a-c). All three 2α-substituted 20-epi analogues of 1 (20-epi-4a-c) exhibited stronger binding affinities for the VDR, and their conformations in the ligand binding domain of VDR were analyzed by molecular modeling. Double-modified analogues of 20-epi-4a-c showed marked HL-60 cell differentiation activity, and 20-epi-4a possesses an activity 58-fold higher than that of the natural hormone 1.
- Saito, Nozomi,Suhara, Yoshitomo,Kurihara, Masaaki,Fujishima, Toshie,Honzawa, Shinobu,Takayanagi, Hitoshi,Kozono, Toshiro,Matsumoto, Masahiko,Ohmori, Masayuki,Miyata, Naoki,Takayama, Hiroaki,Kittaka, Atsushi
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p. 7463 - 7471
(2007/10/03)
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- Parallel synthesis of a vitamin D3 library in the solid-phase
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A highly efficient synthesis of the vitamin D3 system on solid support is described. Two synthetic strategies for the solid-phase synthesis of vitamin D3 were developed. One is for 11-hydroxy analogues, and the other is for most other synthetic analogues. In the latter strategy, the sulfonate-linked CD-ring 58 was initially immobilized on PS-DES resin to give solid-supported CD-ring 63 (Scheme 10). Similarly, solid-supported CD-ring 63 was prepared by attachment of the CD-ring 10 to the chlorosulfonate resin 64. The vitamin D3 system was synthesized by Horner-Wadsworth-Emmons reaction of the A-ring phosphine oxide to a solid-supported CD-ring, followed by simultaneous introduction of the side chain and cleavage from resin with a Cu1-catalyzed Grignard reagent. Parallel synthesis of the vitamin D3 analogues was accomplished by a split and pool methodology utilizing radio frequency encoded combinatorial chemistry, and a manual parallel synthesizer for side chain diversification and deprotection. Additionally, we demonstrated the synthesis of various A-rings in a similar protocol for efficient preparation of building blocks.
- Hijikuro,Doi,Takahashi
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p. 3716 - 3722
(2007/10/03)
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- Convergent synthesis of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 (ED-71)
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A convergent and versatile synthesis of the potent vitamin D analog, 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D3 [1] (ED-71) is described.
- Hatakeyama, Susumi,Ikeda, Tatsuhiko,Maeyama, Junji,Esumi, Tomoyuki,Iwabuchi, Yoshiharu,Irie, Hiroshi,Kawase, Akira,Kubodera, Noboru
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p. 2871 - 2874
(2007/10/03)
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