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CC BY 4.0 · Pharmaceutical Fronts 2024; 06(02): e183-e191
DOI: 10.1055/s-0044-1787068
Original Article

Integrated Synthesis of Calcitriol and 26,27-Hexadeutero Calcitriol

Fei Tang
1   State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Feng Cui
1   State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Gang Yu
1   State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Lichun Qi
1   State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
,
Qingwen Zhang
1   State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai, People's Republic of China
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Abstract

Calcitriol (1α,25-dihydroxyvitamin D3, 1), a classical vitamin D drug, is indicated primarily in the treatment of patients with postmenopausal osteoporosis and renal osteodystrophy. In this study, a practical synthesis of calcitriol (1), from readily available commercial vitamin D2 (5) via hub intermediate 18, has been accomplished in 9% overall yield. This semi-synthetic process embedded four prominent elements of vitamin D chemistry: (1) cheletropic sulfur dioxide (SO2) adduction for the isomerization of the characteristic triene from (5Z,7E) to (5E,7E), or for the protection of the triene for selective ozonolysis of the side chain, and cheletropic extrusion of SO2 from the adduct in ethanolic sodium bicarbonate to retrieve the triene; (2) direct, regio- and stereoselective 1α-hydroxylation of 3β-TBS-protected (5E)-calciferol intermediate 19 using selenium dioxide in the presence of N-methylmorpholine N-oxide as a re-oxidant in a hot mixture of methylene chloride and methanol; (3) nickel(0)-mediated conjugate addition of the 22-iodide 23 to electron-deficient ethyl acrylate followed by Grignard reaction with methylmagnesium bromide to construct the calcitriol side chain; and (4) triplet-sensitized photoisomerization of 26 to access the bioactive (5Z,7E)-triene in calcitriol (1). The high-performance liquid chromatography purities of batches of the synthesized calcitriol (1) were consistently more than 99.9%, with related substances listed in the USP 2023 and EP 11.0 well controlled. This robust process proved amenable to pilot scale-up and industrial production. 26,27-Hexadeutero calcitriol (4), a deuterium-labeled calcitriol derivative, is useful as the internal standard in the bioanalysis for the quantification of calcitriol in serum. 4 was efficiently synthesized in an integrated manner from hub intermediate 18 in 48% yield.

Keywords

calcitriol - deuterium-labeled calcitriol - vitamin D - practical synthesis - related substances


Publication History

Received: 29 February 2024

Accepted: 26 April 2024

Article published online:
28 May 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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  • References

  • 1 Suda T. Discovery of 1α,25-dihydroxyvitamin D3 and its impact on basic and clinical medicine. Bitamin 1995; 69 (01) 1-14
    Google Scholar
  • 2 Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry 1971; 10 (14) 2799-2804
    CrossrefPubMedGoogle Scholar
  • 3 Lawson DE, Fraser DR, Kodicek E, Morris HR, Williams DH. Identification of 1,25-dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism. Nature 1971; 230 (5291) 228-230
    CrossrefPubMedGoogle Scholar
  • 4 Roche Hexagon. Labels for NDA 021068 (ROCALTROL (CALCITRIOL)),. Accessed January 15, 2024 at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process(ApplNo=021068
    Google Scholar
  • 5 Xie C, Sun Q, Dong Y. et al. Calcitriol-loaded multifunctional nanospheres with superlubricity for advanced osteoarthritis treatment. ACS Nano 2023; 17 (13) 12842-12861
    CrossrefPubMedGoogle Scholar
  • 6 Stathi D, Fountoulakis N, Panagiotou A. et al. Impact of treatment with active vitamin D calcitriol on bone turnover markers in people with type 2 diabetes and stage 3 chronic kidney disease. Bone 2023; 166: 116581
    CrossrefPubMedGoogle Scholar
  • 7 Segovia-Mendoza M, García-Quiroz J, Díaz L, García-Becerra R. Combinations of calcitriol with anticancer treatments for breast cancer: an update. Int J Mol Sci 2021; 22 (23) 12741
    CrossrefPubMedGoogle Scholar
  • 8 Tajalli-Nezhad S, Mohammadi S, Atlasi MA. et al. Calcitriol modulate post-ischemic TLR signaling pathway in ischemic stroke patients. J Neuroimmunol 2023; 375: 578013
    CrossrefPubMedGoogle Scholar
  • 9 Hua R, Liu B, He W. et al. Calcitriol reverses age-related hypertension via downregulating renal AP1/AT1R pathway through regulating mitochondrial function. Clin Exp Hypertens 2023; 45 (01) 2277653
    CrossrefPubMedGoogle Scholar
  • 10 Robat-Jazi B, Oraei M, Bitarafan S. et al. Immunoregulatory effect of calcitriol on experimental autoimmune encephalomyelitis (EAE) mice. Iran J Allergy Asthma Immunol 2023; 22 (05) 452-467
    PubMedGoogle Scholar
  • 11 Sutedja EK, Amarassaphira D, Goenawan H. et al. Calcitriol inhibits proliferation and potentially induces apoptosis in B16–F10 cells. Med Sci Monit Basic Res 2022; 28: e935139
    CrossrefPubMedGoogle Scholar
  • 12 Cass WA, Peters LE. Calcitriol protects against reductions in striatal serotonin in rats treated with neurotoxic doses of methamphetamine. Neurochem Int 2023; 169: 105590
    CrossrefPubMedGoogle Scholar
  • 13 Wang Y, Huang M, Xu W, Li F, Ma C, Tang X. Calcitriol-enhanced autophagy in gingival epithelium attenuates periodontal inflammation in rats with type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2023; 13: 1051374
    CrossrefPubMedGoogle Scholar
  • 14 Yuan C, Kosewick J, He X, Kozak M, Wang S. Sensitive measurement of serum 1α,25-dihydroxyvitamin D by liquid chromatography/tandem mass spectrometry after removing interference with immunoaffinity extraction. Rapid Commun Mass Spectrom 2011; 25 (09) 1241-1249
    CrossrefPubMedGoogle Scholar
  • 15 Zhu GD, Okamura WH. Synthesis of vitamin D (calciferol). Chem Rev 1995; 95 (06) 1877-1952
    CrossrefGoogle Scholar
  • 16 Bendik I, Holler U, Marty M, Schutz J, Labler L. Discovery of 1α,25-dihydroxyvitamin D3 and its impact on basic and clinical medicine. In: Elvers B. ed. Ullmann's Encyclopedia of Industrial Chemistry. Weinheim:: Wiley-VCH;; 2019: 1-15
    Google Scholar
  • 17 Kametani T, Furuyama H. Synthesis of vitamin D3 and related compounds. Med Res Rev 1987; 7 (02) 147-171
    CrossrefPubMedGoogle Scholar
  • 18 Van Arnum SD, Moffet H, Carpenter BK. Process control limits from a laboratory study on the Ni(0)-mediated coupling of ethyl acrylate with a C-22 steroidal iodide: a case study on the role of experimental design in highly developed processes. Org Process Res Dev 2004; 8 (05) 769-776
    CrossrefGoogle Scholar
  • 19 Uskokovic MR, Narwid TA, Iacobelli JA, Baggiolini E. Process for the preparation of 1α,25-dihydroxycholecalciferol. U.S. Patent 3993675A. November, 1976
    PubMedGoogle Scholar
  • 20 Andrews DR, Barton DHR, Hesse RH, Pechet MM. Synthesis of 25-hydroxy- and 1α,25-dihydroxy vitamin D3 from vitamin D2 (calciferol). J Org Chem 1986; 51 (25) 4819-4828
    CrossrefGoogle Scholar
  • 21 Calverley MJ. Synthesis of MC 903, a biologically active vitamin D metabolite analogue. Tetrahedron 1987; 43 (20) 4609-4619
    CrossrefGoogle Scholar
  • 22 Choudhry SC, Belica PS, Coffen DL. et al. Synthesis of a biologically active vitamin-D2 metabolite. J Org Chem 1993; 58 (06) 1496-1500
    CrossrefGoogle Scholar
  • 23 Manchand PS, Yiannikouros GP, Belica PS, Madan P. Nickel-mediated conjugate addition. Elaboration of calcitriol from ergocalciferol. J Org Chem 1995; 60 (20) 6574-6581
    CrossrefGoogle Scholar
  • 24 Andrews DR, Barton DHR, Cheng KP. et al. A direct, regio- and stereoselective 1α-hydroxylation of (5E)-calciferol derivatives. J Org Chem 1986; 51 (09) 1635-1637
    CrossrefGoogle Scholar
  • 25 Gómez-Reino C, Vitale C, Maestro M, Mouriño A. Pd-catalyzed carbocyclization-Negishi cross-coupling cascade: a novel approach to 1α,25-dihydroxyvitamin D3 and analogues. Org Lett 2005; 7 (26) 5885-5887
    CrossrefPubMedGoogle Scholar
  • 26 Kang DJ, Im JH, Kang JH, Kim KH. Whole cell bioconversion of vitamin D3 to calcitriol using Pseudonocardia sp. KCTC 1029BP. Bioprocess Biosyst Eng 2015; 38 (07) 1281-1290
    CrossrefPubMedGoogle Scholar
  • 27 Abbas AM, Elkhatib WF, Aboulwafa MM, Hassouna NA, Aboshanab KM. Bioconversion of vitamin D3 into calcitriol by Actinomyces hyovaginalis isolate CCASU- A11-2. AMB Express 2023; 13 (01) 73
    CrossrefPubMedGoogle Scholar
  • 28 Sestelo JP, Mascarenas JL, Castedo L, Mourino A. Ultrasonically induced conjugate addition of iodides to electron-deficient olefins and its application to the synthesis of side-chain analogs of the hormone lα,25-dihydroxyvitamin D3 . J Org Chem 1993; 58 (01) 118-123
    CrossrefGoogle Scholar
  • 29 De Luca HF, Schnoes HK, Napoli JL, Fivizzani MA. Isotopically labeled vitamin D derivatives and processes for preparing same. U.S. Patent 4269777A. May, 1981
    PubMedGoogle Scholar
  • 30 Zhang Q, Qi L, Zhang D. Preparing method of deuterated calcitriol, and intermediate thereof [in Chinese]. CN Patent 110885304B. April, 2022
    PubMedGoogle Scholar