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Method for preparing paricalcitol

A technology of paricalcitol and chemical reaction, which is applied in the field of 1-α-hydroxy-19-desmethylene vitamin D2, a drug for treating osteoporosis, can solve the problem that paricalcitol is uneconomical and has many steps. , complex operation and other problems, to achieve the effect of improving yield, simplifying process flow, and high yield

Inactive Publication Date: 2013-12-18
SOUTHWEST JIAOTONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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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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Experimental program
Comparison scheme
Effect test

Embodiment 1

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

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

[0036] 3,5-cyclovitamin D 2 (Ⅲ) was synthesized using the method of DeLuca et al. (US4195027) to synthesize vitamin D 2 Converted to 3,5-cyclized vitamin D 2 (Ⅲ), add 3.88g, 9.46mmol) 3,5-cyclovitamin D in the reaction flask 2 , dissolved in 300ml ethanol, cooled to -20°C, and then dropwise added potassium permanganate solution (KMnO 4 3.33g, H 2 O100ml), 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 (3.67g). The crude product was dissolved in 300ml of ethanol, 100ml of saturated sodium periodate was added, and stirred at room temperature for 2.5h. The reaction solution was extracted with ethyl acetate (2×200ml) and washed with saturated sodium chloride solution (1×200ml). The organic lay...

Embodiment 2

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

[0043] 3,5-cyclovitamin D 2 (Ⅲ) was synthesized using the method of DeLuca et al. (US4195027) to synthesize vitamin D 2 Converted to 3,5-cyclized vitamin D 2 (iii), 3,5-cyclized 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 ml, after dripping, continue to react for 2 hours, timed TLC detection, after 3 hours, the raw materials are consumed, stir at 40°C for 15 minutes, solidify manganese dioxide, filter with diatomaceous earth, concentrate to remove alcohol, add 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 dehydra...

Embodiment 3

[0049] 100ml of culture medium in a 500m shaker bottle, 1.5% glucose, 1.5% soybean cake powder, 0.5% corn steep liquor, 0.5% NaCl, 0.2% CaCO 3 , pH7.0. The medium was sterilized at 121°C for 20 minutes. Insert 2 ml of spore suspension of strain CGMCC5098, rotate at 27°C, rotate at 240rpm, cultivate for 4 days, 50mg 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 ethyl acetate 2×50 mL, 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 hydroxylated product Paricalcitol at position 25, 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=8and15Hz,H23),5.27(dd,1H,J =8and15Hz,H22),4.04(m,1H,H1),3.98(m,1H,H3),2.84(brd,1H,J=11...

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Abstract

The invention discloses a method for preparing a medicine paricalcitol treating osteoporosis. According to the method, vitamin D2 is taken as a raw material, and a target object is obtained through steps of chemical reaction and biological reaction. Expensive toxic double hydroxylation reagent is not used, and the double-hydroxylation broken bond of a cheap and effective oxidized reagent potassium permanganate solution is adopted for preparing ketone. The method comprises the following steps of preparing olefin in an alkaline reagent through isomerism; carrying out hydroboration through a hydroboration reagent 9-BBN and borane; introducing 1-OH, thereby obtaining 19-demethylation vitamin D2 through ring opening; and by taking Pseudonocardia autotrophica SWJTUQL-3721021 (autotrophy Pseudonocardia CGMCC 5098) as hydroxylation bacterium, carrying out direct hydroxylation on 25-OH through a biological conversion method, thereby obtaining the paricalcitol through extraction and separation. According to the method, 27 public known reaction steps are reduced to 9 reaction steps through combining the chemical conversion and biological conversion, so that the total recovery is improved, the process route is shortened, and the method provides a new process route for 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 to prevent and treat 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 synthesis of pari...

Claims

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Application Information

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IPC IPC(8): C12P7/02C07C401/00C12R1/01
Inventor 陆群冯海婷文鹏孙博万阳周傲群
Owner SOUTHWEST JIAOTONG UNIV
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