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Preparation method and intermediate of deuterated calcitriol

A technology of calcitriol and compounds, which is applied in the field of preparation of deuterated calcitriol, can solve problems such as harsh reaction conditions, use of special reagents, complex separation and purification, etc.

Active Publication Date: 2020-03-17
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] The technical problem to be solved by the present invention is to overcome many defects in the existing preparation method of deuterated calcitriol, such as expensive and difficult to obtain starting materials, use of harsh reaction conditions, use of special reagents, complicated separation and purification, etc. , and provide a preparation method of deuterated calcitriol, and its intermediate

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  • Preparation method and intermediate of deuterated calcitriol
  • Preparation method and intermediate of deuterated calcitriol
  • Preparation method and intermediate of deuterated calcitriol

Examples

Experimental program
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Embodiment 1

[0095] (1α,3β,5E,7E)-26,27-Hexadeuterio-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-9,10-open Preparation of Cyclocholesta-5,7,10(19)-trien-25-ol (DG-3)

[0096] Under an argon atmosphere, DG-2 (3.2g, 4.85mmol) was dissolved in anhydrous tetrahydrofuran (16ml), and deuteromethylmagnesium iodide (CD 3 MgI) in 1.0mol / L ether solution (19.4ml, 19.4mmol). After dropping, the reaction mixture was raised to room temperature and stirred for 3 h. The resulting reaction mixture was cooled to 0 °C and carefully quenched with saturated aqueous ammonium chloride. Ethyl acetate was added for extraction. The organic extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and dry in vacuo to obtain DG-3 (quantitative yield). The obtained DG-3 does not contain DG-2 and can be directly put into the next reaction without purification. 1 H NMR (400MHz, CDCl 3 )δ: 6.46(d, J=11.5Hz, 1H), 5.83(d, J=11.5Hz, 1H), ...

Embodiment 2

[0098] (1α,3β,5E,7E)-26,27-Hexadeuterio-1,3-bis[[(1,1-dimethylethyl)dimethylsilyl]oxy]-9,10-open Preparation of Cyclocholesta-5,7,10(19)-trien-25-ol (DG-3)

[0099] Mix magnesium scraps (1.33g, 54.7mmol) with anhydrous ether (6ml), add deuteromethyl iodide (6.33g, 43.66mmol) in anhydrous ether (26ml) dropwise at 0-5°C in an argon atmosphere solution. Dropping finishes, reflux reaction 30min, on-the-spot preparation deuterium methylmagnesium iodide (CD 3 MgI). Then, a solution of DG-2 (3.2 g, 4.85 mmol) in anhydrous tetrahydrofuran (16 ml) was added dropwise to the above reactant at 0-5°C. Stir at 0°C for 30 min, then at room temperature for 1 h. With cooling, the reaction was quenched by the careful addition of saturated aqueous ammonium chloride. Ethyl acetate was added for extraction. The organic extract was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Concentrate under reduced pressure and dry in vacuo to obtain DG-3 (quantit...

Embodiment 3

[0101] Preparation of (1α,3β,5E,7E)-9,10-cyclocholesta-5,7,10(19)-triene-1,3,25-triol (DG-4)

[0102] Under an argon atmosphere, DG-3 (according to quantitative yield, 4.85mmol) obtained in Example 2 was dissolved in anhydrous tetrahydrofuran (36ml), and a 1.0mol / L tetrahydrofuran solution of tetrabutylammonium fluoride (TBAF) was added (64ml, 64mmol), stirred at room temperature for 8h. The resulting reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue for extraction. The organic extract was washed with half-saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave a solid residue. The obtained crude product was purified by flash silica gel preparative chromatography (eluted with ethyl acetate / petroleum ether (volume ratio 50:50)) to obtain white solid DG-4 (1.64 g, yield 80%). 1 H NMR (400MHz, CDCl 3 )δ: 6.58(d, J=11.5Hz, 1H), 5.89(d, J=11.5Hz, 1H), 5.13(d, J=1.4Hz,...

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Abstract

The invention discloses a preparation method and an intermediate of deuterated calcitriol. The preparation method of deuterated calcitriol represented by formula DG-1 comprises the following steps: (1) carrying out a hydroxyl protecting group removal reaction shown in the description on a compound represented by formula II in an organic solvent 1 under the action of a deprotective agent to obtaina compound represented by formula DG-4; and (2) carrying out a photoisomerization reaction shown in the description on the compound of the formula DG-4 obtained in step (1) in an organic solvent 2 inthe presence of light irradiation and a photosensitizer to obtain the deuterated calcitriol of the formula DG-1, wherein R1 is a hydroxyl protecting group. The deuterated calcitriol preparation methodadopting the intermediate has the advantages of easily available initial raw materials, short synthesis route, simplicity in operation, and high yield.

Description

technical field [0001] The invention relates to a preparation method of deuterated calcitriol and an intermediate thereof. Background technique [0002] Calcitriol, a vitamin D drug, is clinically used to treat osteoporosis, secondary hyperparathyroidism and other diseases. 26,26,26,27,27,27-hexadeuterio-1α,25-dihydroxyvitamin D 3 It is a calcitriol labeled with stable isotope deuterium, CAS accession number is 78782-99-7, other names include (1α,3β,5Z,7E)-9,10-cyclocholesterol-5,7, 10(19)-triene-26,26,26,27,27,27-hexadeuterio-1,3,25-triol, Ro 21-5535 / 2, etc., hereinafter referred to as deuteriocalcitriol. Its chemical structural formula is shown in formula DG-1. [0003] [0004] Vitamin D compounds labeled with stable heavy isotope deuterium can be used to determine vitamin D compounds in biological samples such as blood and tissue. Specifically, deuterated vitamin D compounds can be used as internal standards for mass spectrometry and LC-MS. For example, YuanC et ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C401/00C07B59/00
CPCC07C401/00C07B59/001C07C2601/14C07C2602/24C07B2200/05Y02P20/55
Inventor 张庆文齐丽春张德杰
Owner SHANGHAI INST OF PHARMA IND CO LTD
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