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A kind of method of controlling and preparing high-purity strontium ranelate by hplc method

A high-purity strontium ranelate technology, applied in the field of strontium ranelate preparation, can solve the problems of cumbersome process steps, long reaction time, and low product yield, optimize the process flow and parameters, and reduce purification and separation steps , Ease of industrial production

Active Publication Date: 2017-03-15
JINGHUA PHARMA GRP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are two purification methods: one is sodium ranelate through ion exchange resin, and then decompression distillation to obtain ranelic acid, and then use organic solvent and water crystallization method, the purification method cycle is too long and will produce a large amount of waste water, It is not suitable for industrialized production; the second is that after the reaction is completed, most of the water is removed by decompression, and then crystallized with a large amount of ethanol, but in industry, reducing steamed water is an operation with high energy consumption and long time. It is easy to produce new impurities, the yield of the product is low, and the quality cannot be guaranteed
[0006] Chinese patent CN102321068A discloses a method for preparing strontium ranelate, which requires multiple crystallization and purification during the preparation process, resulting in a large amount of waste water and waste liquid, long production cycle, high energy consumption, and low yield
Chinese patent CN102367247A discloses a high-purity method for preparing stable strontium ranelate. This method has high product purity, but the process steps are cumbersome, the reaction time is long, and the follow-up process requires refining and purification, resulting in a large amount of waste water and waste liquid, and the yield is low.
But, HPLC is introduced into the preparation process of strontium ranelate, and the product quality in the preparation process of strontium ranelate is monitored, and there is no report yet

Method used

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  • A kind of method of controlling and preparing high-purity strontium ranelate by hplc method
  • A kind of method of controlling and preparing high-purity strontium ranelate by hplc method
  • A kind of method of controlling and preparing high-purity strontium ranelate by hplc method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (1) Add 25g of the compound of formula (I), 300mL of tetrahydrofuran, 48g of anhydrous potassium carbonate, 58g of ethyl bromoacetate, and 0.5g of crown ether into a 500mL four-neck flask, raise the temperature to reflux, and detect in the central control ( figure 1 HPLC control chart for the reaction end point), the reaction was completed in about 3 hours, filtered, and the filtrate was distilled under reduced pressure. After the end, 100 mL of ethanol was added to the ice bath for beating for 3-4 hours, and the filter cake was washed with ice ethanol. Put into 45 ℃ oven, dry, obtain formula (II) compound 36g, yield is 90%, and purity is 99.84%, figure 2 It is the HPLC purity detection chart of the compound of formula (II).

[0045] (2) Add 25g of the compound of formula (II) and 215mL of tetrahydrofuran into a 500mL four-neck flask, dissolve and cool down to 5°C. Dissolve 9.7g of sodium hydroxide in 190mL of purified water, cool to 10°C and add to a four-necked flas...

Embodiment 2

[0047] (1) Add 50g of the compound of formula (I), 600mL of tetrahydrofuran, 96g of potassium carbonate, 118g of ethyl bromoacetate, and 1.0g of crown ether into a 1000mL four-neck flask, heat up to reflux, and control in HPLC ( Figure 5 HPLC control chart for the reaction end point), the reaction was completed in about 3 hours, filtered, and the filtrate was distilled under reduced pressure. After the end, 200 mL of ethanol was added to the ice bath for beating for 3-4 hours, and the filter cake was washed with ice ethanol. Put into 45 ℃ oven, dry, obtain formula (II) compound 72g, yield is 90%, and purity is 99.92%, Figure 6 It is the HPLC purity detection chart of the compound of formula (II).

[0048] (2) Add 50g of the compound of formula (II) and 430mL of tetrahydrofuran into a 1000mL four-neck flask, dissolve and cool down to 10°C. Dissolve 19.4g of sodium hydroxide in 360mL of purified water, cool to 10°C and add to a four-necked flask. Heat up to reflux, central c...

Embodiment 3

[0050] (1) In a 20L reaction kettle, add 1kg of compound of formula (I), 12L of tetrahydrofuran, 1.92kg of potassium carbonate, 2.3kg of ethyl bromoacetate, 20g of crown ether, heat up to reflux, and control in HPLC ( Figure 9 is the reaction end point HPLC control chart), the reaction is about 3-4h, filter, the filtrate is distilled under reduced pressure, 4L ethanol ice bath beating for 3-4h, filter, the filter cake is rinsed with ice ethanol, put in an oven at 45°C, and dry. Obtain formula (II) compound 1.25kg, yield is 91%, and purity is 99.86%, Figure 10 It is the HPLC purity detection chart of the compound of formula (II).

[0051] (2) Add 2kg of compound of formula (II) and 17.2L of tetrahydrofuran to a 50L reaction axe, dissolve and cool down to 5°C, dissolve 0.78kg of sodium hydroxide in 14L of purified water, cool to 5-10°C and add to the reaction kettle . Raise the temperature to reflux, react for about 3.5-4h and take a sample in the control ( Figure 11 is th...

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Abstract

The invention discloses a method for preparing high-purity strontium ranelate through centralized control of the HPLC (High Performance Liquid Chromatography) method, and belongs to the field of pharmaceutical synthesis. The method comprises the following steps: (1) preparing a compound as shown in formula (II), namely, feeding a compound as shown in formula (I), tetrahydrofuran, anhydrous potassium carbonate and ethyl bromoacetate to a reaction kettle, and performing catalytic reaction through a catalyst, wherein the reaction endpoint is monitored through the HPLC; and (2) preparing a compound as shown in formula (III), namely, dropping a tetrahydrofuran solution in which the compound as shown in formula (II) is dissolved to inorganic aqueous alkali to saponify under the centralized control of the HPLC; performing reduced pressure distillation and filtering; regulating the pH (Power of Hydrogen) with hydrochloric acid; then adding a strontium chloride aqueous solution to obtain crude strontium ranelate which is characterized in that the purity is more than 99.7%, the single impurity is less than 0.1%, and the total impurity is less than 0.5%; and finally drying to obtain the targeted strontium ranelate. The strontium ranelate prepared by the method has the advantages that by means of the HPLC based centralized control, the optimal reaction time is determined and the refining and purifying steps are reduced; in addition, the method is simple in process, easy to control, high in product purity, less in waste liquid, low in energy consumption, relatively low in cost, and applicable to industrial production.

Description

technical field [0001] The invention relates to a method for preparing strontium ranelate, in particular to a method for preparing high-purity strontium ranelate by means of an HPLC method suitable for industrial production, and belongs to the field of drug synthesis. Background technique [0002] Strontium ranelate was developed by a French (servier) company and first launched in Ireland on November 15, 2004, as a drug for the treatment of osteoporosis. It has dual effects on bone, that is, inhibits bone resorption and promotes bone growth. Since the dosage of strontium ranelate is relatively large, it is of practical significance to control its cost. The chemical name of strontium ranelate is distrontium 5-[bis(carboxymethyl)amino]-2-carboxy-4-cyano-3-thiophene acetate, and its chemical structure is: [0003] [0004] At present, the production of high-purity strontium ranelate is mainly realized through refining and purification steps, but since strontium ranelate is ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/38
CPCC07D333/38
Inventor 朱春林滕飞顾建波李淑芬周莉莉
Owner JINGHUA PHARMA GRP