Method for synthesizing paricalcitol

A technology for paricalcitol and a synthesis method, which is applied in the directions of organic chemistry, bulk chemical production, etc., can solve problems such as being unsuitable for industrialized production of paricalcitol, difficult to identify and purify, and complex intermediates, etc. Structural identification and purification, easy large-scale preparation, simple operation effect

Inactive Publication Date: 2013-05-08
SHANGHAI PUYI CHEM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These synthetic methods all carry out structural modification on the mother nucleus of vitamin D2, and there are problems such as low yield, complicated intermediates, difficult identification and purification, etc.
Therefore above-mentioned these synthetic methods are all not suitable for the industrialized production of paricalcitol

Method used

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  • Method for synthesizing paricalcitol
  • Method for synthesizing paricalcitol
  • Method for synthesizing paricalcitol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] 1.1 Preparation of compound IIIa

[0026]

[0027] Under nitrogen protection, compound II (0.51 g) was dissolved in 4 ml of anhydrous tetrahydrofuran, the temperature was lowered to -65 ° C, 1 ml of bistrimethylsilylamide lithium (1M) was added dropwise to the above solution, and stirred for 10 Minutes, then dissolve compound Ia (0.3g) in 2 ml of tetrahydrofuran, add dropwise to the above reaction system, keep the internal temperature at -57°C for 3 hours, after the reaction, warm up to room temperature, add ethyl acetate and chloride Ammonium solution, the organic layer was separated, dried over sodium sulfate and evaporated to dryness, and purified by column chromatography to obtain 0.45 g of compound IIIa with a yield of 74%.

[0028] 1 H NMR (CCl 3 ,400MHz):δ=-0.04(s,6H),0.00(s,6H),0.60(s,3H),0.83(s,18H),0.95(m,6H),1.10(s,3H),1.14 (s,3H),1.21(m,3H),1.54(m,3H),1.67(m,2H),1.90(m,7H),2.15(m,4H),2.38(m,1H),3.34( s,3H),4.00(m,2H),4.68(s,2H),5.25(m,2H),6.03(d,J=12H...

Embodiment 2

[0066] 2.1 Preparation of compound IVa

[0067]

[0068] Compound IIIa (0.40 g) obtained in Example 1 and 7 ml of tetrahydrofuran were added at room temperature, and tetrabutylammonium fluoride trihydrate (0.73 g) was heated to 60° C. for 8 h. After the reaction was completed, ethyl acetate was added. It was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was purified by column chromatography to obtain 0.23 g of IVa with a yield of 88%.

[0069] 1 H NMR (CCl 3 ,400MHz): δ=0.65(s,3H),1.02(m,6H),1.13(s,3H),1.17(s,3H),1.25-1.54(m,3H),1.86-2.10(m,14H ),2.15-2.23(m,3H),3.37(s,3H),4.07(m,2H),4.72(s,2H),5.30(m,2H),6.13(d,J=11.2Hz,1H) ,6.47(d,J=11.2Hz,1H).

[0070] MS (EI): m / e=460.

[0071] 2.2 Preparation of compound IVa

[0072]

[0073]Compound IIIa (0.40 g) obtained in Example 1, 3 ml of tetrahydrofuran, and 5 ml of methanol were added at room temperature, and potassium fluoride (0.14 g) wa...

Embodiment 3

[0112] 3.1 Preparation of Compound V, i.e. Paricalcitol

[0113]

[0114] Compound IVa (0.20 g) prepared in Example 2 was dissolved in 3 ml of methanol, p-toluenesulfonic acid (83 mg) was added, and reacted at room temperature 25° C. for 8 h. After the reaction was completed, triethylamine was added to adjust the pH to 7~8, ethyl acetate was added to extract, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography to obtain compound V (0.14g, yield 75%) .

[0115] 1 H NMR (CCl 3,400MHz): δ=0.65(s,3H),1.01(m,6H),1.11(s,3H),1.14(s,3H),1.26-1.30(m,3H),1.60-2.15(m,17H ), 4.03-4.10(m, 2H), 5.28-5.40(m, 2H), 6.11(d, J=11.6Hz, 1H), 6.44(d, J=11.6Hz, 1H).

[0116] MS (EI): m / e=416.

[0117] 3.2 Preparation of Compound V, i.e. Paricalcitol

[0118]

[0119] Compound IVa (0.20 g) prepared in Example 2 was dissolved in 5 ml of methanol, concentrated hydrochloric acid (50 mg) was added, and reacted at room ...

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Abstract

The invention provides a new method for synthesizing paricalcitol, comprising the following steps of: a. reacting a compound II with alkali, then adding a compound I, carrying out a Julia reaction to generate a compound III; b. reacting the compound III with a fluorine-containing reagent to remove the protecting group so as to obtain a compound IV; c. removing the protecting group of the compound IV under acidic condition to obtain the product of paricalcitol. The method for synthesizing paricalcitol disclosed the invention has the advantages of low cost and high yield, and is simple in operation and easy in industrial production.

Description

technical field [0001] The invention relates to the technical field of compound preparation, in particular to the technical field of paricalcitol preparation. Background technique [0002] Paricalcitol is developed by Abbott to prevent and treat secondary hyperparathyroidism. The injection was launched in 1998, and the capsule formulation was launched in 2005. Paricalcitol has become the most widely used drug for the prevention and treatment of hyperparathyroidism in dialysis patients. [0003] Currently, there are several synthetic methods of paricalcitol reported, but all synthetic routes are obtained by structural modification on the mother nucleus of vitamin D2 using vitamin D2 as raw material. [0004] The literature (Drugs of the Future 1998, vol.23, p.602) summarizes the synthesis method of paricalcitol. In the method, 25-hydroxyvitamin D2 is used as a raw material through multi-step synthesis. The main problems of this route include the following aspects: (1) the ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C401/00
CPCY02P20/55
Inventor 罗宇王博
Owner SHANGHAI PUYI CHEM CO LTD
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