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Method for preparing paricalcitol

A paricalcitol and chemical reaction technology, applied in the field of 1-α-hydroxy-19-de-methylene vitamin D2 for the treatment of osteoporosis, can solve the uneconomical and complicated operation of paricalcitol , many steps and other problems, to achieve the effect of increasing yield, simplifying process flow and reducing manufacturing cost

Inactive Publication Date: 2012-03-28
SOUTHWEST JIAOTONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second method has many steps, chiral resolution is performed many times, and the yield is extremely low, which is very uneconomical for the synthesis of Paricalcitol
The first method has relatively fewer steps, but still uses highly toxic and expensive osmium tetroxide as an alkene dihydroxylation reagent, or uses rare 25-hydroxyvitamin D 2 As a raw material, or use ozone to break the 22, 23 double bond, and then introduce the 25 hydroxyl side chain, there are still too many steps in production, the operation is complicated, the yield is low, and the total yield is only about 0.1%.

Method used

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  • Method for preparing paricalcitol
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  • Method for preparing paricalcitol

Examples

Experimental program
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Effect test

Embodiment 1

[0034] 1-Hydroxy-19-norvitamin D 2 Preparation of (viii)

[0035] a) 10-oxo-3,5-cyclovitamin D 2 Synthesis of (iv)

[0036] 3,5-cyclovitamin D 2 The synthesis of (iii) adopts the method such as DeLuca (US4195027) vitamin D 2 Converted to 3,5-cyclized vitamin D 2 (iii), add 3.88g, 9.46mmol) 3,5 cyclic vitamin D in the reaction flask 2 , dissolved in 300ml ethanol, cooled to -20°C, and then potassium permanganate solution (KMnO 4 3.33g, H 2 O 100ml), about 20 minutes. Stir at this temperature for 1 h, and then stir for 15 min in a water bath at 40 °C. After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain light yellow oily mixture 4 (3.67 g). The crude product was dissolved in 300 ml of ethanol, 100 ml of saturated sodium periodate was added, and stirred at room temperature for 2.5 h. The reaction solution was extracted with ethyl acetate (2×200ml) and washed with saturated sodium chloride solution (1×200ml). The organic layer was ...

Embodiment 2

[0042] a) 10-oxo-3,5-cyclovitamin D 2 Synthesis of (iv)

[0043] 3,5-cyclovitamin D 2 The synthesis of (iii) adopts the method such as DeLuca (US4195027) vitamin D 2 Converted to 3,5-cyclized vitamin D 2 (iii), 3,5-cycling VD 2 5 g, dissolved in 150 ml of ethanol, placed in a low-temperature bath at -20°C, and added dropwise with 3% KMnO 4(3% aqueous solution) 320 milliliters, dropwise, continue to react for 2 hours, timed TLC detection, 3 hours, raw material consumption is complete, 40 ℃ stirs 15 minutes, solidifies manganese dioxide, diatomaceous earth filter, concentrates to remove alcohol, adds ethyl acetate 100 ml of ester, extracted twice, concentrated to dryness, dissolved the crude product in 300 ml of ethanol, added 100 ml of saturated sodium periodate, and stirred at room temperature for 2.5 h. The reaction solution was extracted with ethyl acetate (2×200ml) and washed with saturated sodium chloride solution (1×200ml). The organic layer was dehydrated with anhy...

Embodiment 3

[0049] 100ml culture medium in a 500m shaker flask, 1.5% glucose, 1.5% soybean cake powder, 0.5% corn steep liquor, 0.5% NaCl, 0.2% CaCO 3 , pH 7.0. The medium was sterilized at 121°C for 20 minutes. Insert 2 ml of spore suspension of strain CGMCC 5098, rotate at 27°C at 240rpm, culture for 4 days, 50mg of 1-hydroxy-19-norvitamin D 2 (viii) and 10 mg of β-cyclodextrin and 10 mg of Tween-80 were dissolved in 2 mL of ethanol, and the mixture was added to the culture medium, continued to cultivate for 3 days, filtered, and the filtrate was extracted with 2×50 mL of ethyl acetate, and the extract Concentrate and separate with a silica gel column [column chromatography silica gel, ethyl acetate:petroleum ether (1:2)] to obtain 31 mg of the 25-hydroxylation product Paricalcitol with a yield of 60%. 1 H NMR (400MHz, CD 3 OD) δ6.21(d, 1H, J=11Hz, H6), 5.88(d, 1H, J=11Hz, H7), 5.35(dd, 1H, J=8 and 15Hz, H23), 5.27(dd, 1H , J=8 and 15Hz, H22), 4.04(m, 1H, H1), 3.98(m, 1H, H3), 2.84(...

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Abstract

The invention discloses a method for preparing drug paricalcitol for treating osteoporosis, which comprises the following steps of: taking vitamin D2 as raw materials and obtaining a target object through the steps of chemical reaction and biological reaction; omitting the use of an expensive toxic dihydroxylation reagent and bond-breaking dihydroxylation adopting cheap effective reagent oxide potassium permanganate solution into ketone; isomerizing into olefin under an alkaline reagent, carrying out hydroboration reaction by applying a borohydride reagent 9-BBN, borane and other reagents; introducing 1-hydroxyl, ring-opening to obtain 19-demethyl vitamin D2, taking pseudonocardiaautotrophica SEJTUQL-3701021 (Autotrophic false Nocardia CGMCC 5098) as hydroxylation bacteria, carrying out 25-direct hydroxylation by using a biotransformation method and obtaining the paricalcitol through extraction and separation. Through a chemical-biological transformation combination method, the reaction steps of the paricalcitol are shortened from known 27 to 9, so that the total yield is improved, and the process route is shortened. The invention provides a new process route for solving the industrial preparation of the paricalcitol.

Description

technical field [0001] The invention relates to chemical and biopharmaceuticals, especially 1-alpha-hydroxyl-19-demethylene vitamin D for treating osteoporosis 2 technology field. Background technique [0002] Paricalcitol is a new type of active vitamin drug developed by Abbott in 1998. Its trade name is Zemplar, which has been approved by the FDA and is clinically used for the prevention and treatment of animals with secondary hyperparathyroidism. Experimental and clinical studies have shown that paricalcitol has relatively selective pharmacological effects, can safely and effectively inhibit the secretion of parathyroid hormone and hyperplasia of parathyroid glands, and rarely cause hypercalcemia and hyperphosphatemia, and can replace calcitriol (calcitriol) for uremia is especially suitable for the treatment of secondary hyperparathyroidism in long-term hemodialysis patients. [0003] 1-alpha-Hydroxy-19-demethylene vitamin D 2 (1α-19-nor-VD 2 ), that is, the known sy...

Claims

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Application Information

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IPC IPC(8): C12P7/02C12R1/01
Inventor 陆群冯海婷文鹏孙博万阳周傲群
Owner SOUTHWEST JIAOTONG UNIV
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