Synlett 2013; 24(19): 2606-2608
DOI: 10.1055/s-0033-1339867
letter
© Georg Thieme Verlag Stuttgart · New York

A Modified Synthesis of the Antiosteoporosis Drug Alfacalcidol via a Key Photochemical Transformation of 1α-5,6-trans-Vitamin D3

Junyuan Ding
Key Laboratory of Systems Bioengineering, Ministry of Education and Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. of China   Fax: +86(22)27403487   eMail: guoxh@tju.edu.cn
,
Xianghai Guo*
Key Laboratory of Systems Bioengineering, Ministry of Education and Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. of China   Fax: +86(22)27403487   eMail: guoxh@tju.edu.cn
,
Zhouliangzi Zeng
Key Laboratory of Systems Bioengineering, Ministry of Education and Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. of China   Fax: +86(22)27403487   eMail: guoxh@tju.edu.cn
,
Ningzhi Liu
Key Laboratory of Systems Bioengineering, Ministry of Education and Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, P. R. of China   Fax: +86(22)27403487   eMail: guoxh@tju.edu.cn
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Publikationsverlauf

Received: 28. Juli 2013

Accepted after revision; 28. August 2013

Publikationsdatum:
14. Oktober 2013 (online)


Abstract

Alfacalcidol (1α-hydroxyvitamin D3) is an important clinical drug for the treatment of osteoporosis. Its practical synthesis has been intensively pursued across academia. The difficulties of separating 5,6-cis and 5,6-trans isomers in the current process was avoided by photochemical transformation of the 5,6-trans isomer into the 5,6-cis isomer. Employing vitamin D3 as a starting material, alfacalcidol was obtained by a five-step reaction sequence of esterification, cyclization, oxidation, solvolysis ring-opening, and subsequent photochemical reaction. The overall yield has been greatly improved from 17% to 31%.

Supporting Information

 
  • References and Notes

    • 1a Kubodera N, Muromachi N, Chuo K. Molecules 2009; 14: 3869
    • 1b Higuchi Y, Sato K, Nanjo M, Isogai T, Takeda S, Kumaki K, Nishii Y. Vitamins 1994; 68: 87
    • 1c Nishii Y. J. Bone Miner. Metab. 2002; 20: 57
    • 1d Shiraishi A, Higashi S, Ohkawa H, Kubodera N, Hirasawa T, Ezawa I, Ilera K, Ogata E. Calcif. Tissue Int. 1999; 10: 339
    • 2a Plum LA, Deluca HF. Nat. Rev. 2010; 9: 941
    • 2b Holick MF. J. Cell. Biochem. 2003; 88: 296
  • 3 Kubodera N, Muromachi N, Chou K. Heterocycles 2010; 80: 83
    • 4a Nemoto H, Kimura T, Kurobe H, Fukumoto K, Kametani T. Chem. Lett. 1985; 1131
    • 4b Hirsch AL. In Vitamin D . Vol. 1. Feldman D, Pike JW, Adams JS. Elsevier; Oxford: 2011: 73-93
    • 4c Zhu GD, Okamura WH. Chem. Rev. 1995; 95: 1877
    • 5a Yamada S, Suzuki T, Takayama H, Miyamoto K, Matsunaga I, Nawata Y. J. Org. Chem. 1983; 48: 3483
    • 5b Paaren HE, Deluca HF, Schnoes HK. J. Org. Chem. 1980; 45: 3253
    • 5c Marshall JA, Grote J, Sheater B. J. Org. Chem. 1986; 51: 1635
    • 5d Singleton DA, Hang C. J. Org. Chem. 2000; 65: 7554
    • 6a Chen YS, Ren L, Zhai CY. Chin. J. New Drugs 2005; 14: 1441
    • 6b Sheves M, Mazur Y. J. Chem. Soc., Chem. Commun. 1977; 21
    • 7a Calverley MJ. Tetrahedron 1987; 43: 4609
    • 7b Chen YS, Zhai CY, Ren L. Chin. J. New Drugs 2005; 14: 69
  • 8 DeLuca HF, Schnoes HK, Lee SH, Phelps ME. US 4,554,106, 1985 ; Chem. Abstr. 1986, 105, 60827
  • 9 Wang MG, Ren L, Sun GY, Chen YS, Liu XX. CN 101,607,931, 2009 ; Chem. Abstr. 2009, 152, 144887
  • 10 Ng CS, Wei CP. US 20,090,318,722, 2009 ; Chem. Abstr. 2009, 152, 75277
  • 11 Synthesis of Vitamin D3 Tosylate (2) Vitamin D3 (1, 1.00 g, 2.6 mmol), 4-dimethylaminopyridine (1.00 g, 8.2 mmol), and dry pyridine (1.55 mL), contained in a 25 mL round-bottom flask, was kept cool in an ice bath. A solution of freshly recrystallized p-toluenesulfonyl chloride (0.87 g, 4.6 mmol) in CH2Cl2 (8.5 mL) was added to it several times. The solution system was stirred and reacted until its color deepened to glassy yellow. It was kept airtight under argon protection and being stirred at r.t. away from light. After 6.5 h, the solution turned light red and colorless transparent needle crystals were formed at the bottom of the flask. The mixture was transferred into a 100 mL beaker and sat. NaHCO3 (20 mL) was added in several times with stirring. Then the organic layer was washed with 3% HCl (3 × 30 mL), sat. NaHCO3 (1 × 20 mL), and sat. NaCl (1 × 20 mL), dried over MgSO4, and concentrated to 1.40 g of a white crystalline solid 2 in vacuo.
    • 12a Edwards HM. III, Majetich G. WO 2,011,002,756, 2011 ; Chem. Abstr. 2011, 154, 109857
    • 12b Ruan YM, Hu WX, Lu JQ. Chin. J. Synth. Chem. 2002; 10: 56
  • 13 Synthesis of 3,5-Cyclovitamin D3 (3) To a stirring solution of anhydrous MeOH (150 mL) was added finely divided NaHCO3 (2.00 g, 23.8 mmol) and vitamin D3 tosylate (2, 3.50 g, 6.50 mmol). The mixture was heated to 63 °C under Argon protection for 2.3 h, cooled to r.t. and concentrated in vacuo. The residue was diluted with distilled H2O (70 mL) and was extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with sat. brine (1 × 150 mL), dried over MgSO4, and concentrated to a transparent yellowish oil in vacuo. Silica gel column chromatography in PE–EtOAc (19:1) yielded 2.01 g of colorless 3,5-cyclo-vitamin D3 (3), which could be used for the next reaction without further purification.
  • 14 General Procedure for 1α-Hydroxyvitamin D3 5a and 5b lα-hydroxy-3,5-cyclo-vitamin D3 (4, 2.62 g, 6.3 mmol) was dissolved in DMSO (28.1 mL) and glacial acetic acid (22.4 mL). The mixture was heated to 50 °C under argon protection for 1 h and was then quenched by pouring the mixture over ice. The aqueous suspension was extracted with EtOAc (3 × 50 mL). The combined organic extracts were then washed with sat. NaHCO3 (3 × 100 mL) and sat. NaCl (3 × 100 mL), dried over MgSO4, and concentrated in vacuo. Silica gel column chromatography in PE–EtOAc (4:6) afforded 2.20 g (87% yield) of a yellowish crystalline solid, which contained 5,6-cis-1α-hydroxyvitamin D3 (5a) and 5,6-trans-1α-hydroxyvitamin D3 (5b).
  • 15 Mawhand PS, Yiannikouros GP, Belica PS, Madan P. J. Org. Chem. 1995; 60: 6574
  • 16 Phototransformation of 5,6-trans-1α-Hydroxyvitamin D3 (5b) to 5,6-cis-1α-Hydroxyvitamin D3 (5a) A solution of of the crystalline solid (0.5 g, 1.2 mmol) from the last step in anhydrous MeOH (80 mL) containing anthracene (18.0 mg, 0.1 mmol) was thoroughly degassed. A medium-pressure 500 W ultraviolet lamp was placed such that the outside of the water-cooled jacket was 15 cm from the reaction vessel. Ice water was passed in the jacket of the quartz tube to keep the reaction cool. The mixture was irradiated for 4.0 h under argon protection at r.t., until all of 5a was converted into 5b and then concentrated in vacuo. The residue was eluted by PE–EtOAc (4:6) to separate 5a, and further recrystallization from EtOAc and cyclohexane afforded 0.37 g (75% yield) of a white crystalline solid (5a) Analytcal Data IR (KBr): 3406, 1643, 1629, 1059, 909 cm–1. 1H NMR (500MHz, CDCl3): δ = 0.55 (3 H, s, 18-CH3), 0.87 (6 H, dd, J 1 = 2.3 Hz, J 2 = 6.6 Hz, 26-CH3, 27-CH3), 0.92 (3 H, d, J = 6.5 Hz, 21-CH3), 2.32 (1 H, dd, J 1 = 6.6 Hz, J 2 = 13.4 Hz, H-4β), 2.60 (1 H, dd, J 1 = 3.3 Hz, J 2 = 13.4 Hz, H-4α), 2.83 (1 H, dd, J 1 = 3.8 Hz, J 2 = 11.8 Hz, H-14), 4.24 (1 H, m, H-3α), 4.44 (1 H, dd, J 1 = 4.3 Hz, J 2 = 7.8 Hz, H-1β), 5.01 (1 H, s, H-19E), 5.33 (1 H, t, J = 1.5 Hz, H-19Z), 6.02 (1 H, d, J = 11.3 Hz, H-7), 6.39 (1 H, d, J = 11.3 Hz, H-6).