CN102367247A - Method for preparing high purity good stability strontium ranelate - Google Patents
Method for preparing high purity good stability strontium ranelate Download PDFInfo
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- CN102367247A CN102367247A CN2011102902891A CN201110290289A CN102367247A CN 102367247 A CN102367247 A CN 102367247A CN 2011102902891 A CN2011102902891 A CN 2011102902891A CN 201110290289 A CN201110290289 A CN 201110290289A CN 102367247 A CN102367247 A CN 102367247A
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- strontium ranelate
- strontium
- organic solvent
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- ranelate
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- DTOITDBQDACPAT-UHFFFAOYSA-N N#Cc1c(N(CC(O)=O)CC(O)=O)[s]cc1CC(O)=O Chemical compound N#Cc1c(N(CC(O)=O)CC(O)=O)[s]cc1CC(O)=O DTOITDBQDACPAT-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to high purity good stability strontium ranelate with the pH value of 8.5-10.0 and a preparation method thereof The method comprises the following steps: 1, adding a compound (II) 5-[bis(2-ethoxy-2-oxoethyl)amino]-4-cyan-3-(2-ethoxy-2-oxoethyl)-2-thiopheneethylformate to an organic solvent, adding an aqueous solution of an inorganic base to carry out a saponification reaction, carrying out liquid separation to remove the organic solvent, adjusting the pH to 9.5-12 by hydrochloric acid at -10-10DEG C, evaporating a water layer to dryness to remove the organic solvent, and adding an aqueous solution of strontium chloride to obtain crude products of strontium ranelate; and 2, adding the crude products to hot water, adjusting the pH to 9-13 by the hot water, carrying out hot filtration, washing with water, and drying to obtain strontium ranelate. According to the method of the invention, obtained strontium ranelate has a good yield and a good purity, single impurities (especially a decarboxylation impurity) and the product purity can be controlled to reach medicinal standards, and the stability of strontium ranelate is good.
Description
Technical field
The present invention relates to the high purity of suitable suitability for industrialized production and the pH value of good stability is Strontium Ranelate of 8.5～10.0 and preparation method thereof.
Background technology
Strontium Ranelate (strontium ranelate) is to be developed by Servier company; Go on the market in Ireland first on November 15th, 2004; December 1 the same year, this medical instrument had very valuable pharmacological effect in India's listing in 2005 in Britain's listing; Particularly aspect osteoporosis: it can promote bone forming, can also suppress bone simultaneously and heavily absorb.Make this compound be used to treat osteopathia.
The compound patent EP0415850 of Strontium Ranelate discloses some preparing methods of Strontium Ranelate.
This patent discloses three kinds of methods that prepare Strontium Ranelate with compound (II).
Method one: compound (II) is joined hydrolysis in the pure water blended sodium hydroxide solution; Water layer with hcl acidifying after; Handle to remove sodium ion with acidic resins again, residue earlier with behind the ether with THF or acetone recrystallization, then with strontium chloride salify in water.Can generate eight hydrates of Strontium Ranelate in this way, dry under dry gas stream, generate heptahydrate, decompression (10mmHg) 55 ℃ of following dryings obtain corresponding four hydrates, but the preparation method is complicated, and product purity is not high yet.
Method two: compound (II) is joined hydrolysis in the pure water blended sodium hydroxide solution, with all solvent evaporates to dryness, obtain the tetra-na salt solid after the hydrolysis; Again with the strontium chloride salify, but the easy moisture absorption of sodium salt, inconvenient operation; Yield is lower than 70%, and product purity is not high yet.
Method three: compound (II) is joined hydrolysis in the pure water blended strontium hydroxide solution, steam ethanol then, remaining 100 ℃ of heat filterings of the aqueous solution, washing obtains Strontium Ranelate eight hydrates.But Strontium Ranelate is dissolving hardly in common solvent, and the product that this method obtains almost can't be purified, and is difficult to realize suitability for industrialized production.
EP1403266 has improved method three among the EP0415850, with compound (II) back flow reaction in strontium hydroxide/water, refilter product.Product purity is not high yet.
US2009082578 has improved the technology of method two among the EP0415850; Compound (II) is under the organic solvent existence condition; With sodium hydroxide or potassium hydroxide aqueous solution saponification reaction at ambient temperature; Under the organic solvent existence condition, add strontium chloride aqueous solution crystallization again, cross and filter Strontium Ranelate.But in repeating the process of patent, find under organic solvent existence condition, have a spot of not exclusively saponified residually, can not in refining, remove; It is residual that other gained bullion contains more strontium hydroxide.
The purification of Strontium Ranelate is disclosed among the patent CN1995034: bullion is added acid for adjusting pH make it dissociate into thunder Buddhist nun acid; Add alkali then and be transferred to alkalescence, the method that forms Strontium Ranelate is again purified, though this method can be purified; But refining yield is low; The crude product refining yield has only 75%～85%, and the acid adjustment process is introduced decarboxylation impurity easily, suc as formula the carboxylic acid shown in (III) or its salt.
CN101747316 discloses a kind of preparation method of high purity Strontium Ranelate, and compound (II) is joined hydrolysis in water or the water/organic solvent blended sodium hydroxide solution, with transferring pH to 4～7 to add the strontium acetate salify then; Cross and filter Strontium Ranelate; Purity is higher, and single assorted less, but pH is than under the low condition in the actual industrial operation; Possibly cause decarboxylation impurity ([formula (III) or its salt]) to raise because the treatment time prolongs, and product stability is bad.
To sum up, existing Strontium Ranelate preparation method exists product purity not high, and perhaps purity is higher but single assorted control is bad; Perhaps purity is controlled all better but the insufficient situation of product stability with single mixing; The inventor has researched and developed a kind of industrialized compound method that is fit to above situation, and it can be so that yield and purity obtain Strontium Ranelate preferably; Not only can control single impurity (especially decarboxylation impurity) and product purity and reach medicinal standard, and the stability of product better.
Summary of the invention
The application contriver has researched and developed a kind of industrialized compound method that is fit to; It can be so that yield and purity obtain Strontium Ranelate preferably; Ability control single impurity (especially decarboxylation impurity) and product purity reach medicinal standard; And its stability in storage is also better, and product purity is very stable under various conditions such as hot and humid, accelerated tests.
Particularly, the invention provides the compound method of the Strontium Ranelate of a kind of preparation structural formula (I), comprise following steps:
1) compound (II) joins in the organic solvent; Wherein the volume of organic solvent consumption is 1-3 times (ml/g) of compound (II) quality; Saponification reaction 4～6h takes place down for 10～35 ℃ in temperature in the inorganic base aqueous solution that adds 4.5～5.5 times of amounts (ml/g) compounds (II).
2) separatory cools to-10～10 ℃ with salt acid for adjusting pH value to 9.5～12, and 10～30 ℃ of concentrating under reduced pressure of water layer add the strontium chloride aqueous solution, crystallization 5～15h after removing organic solvent.Cross and filter the Strontium Ranelate bullion.Preferably regulate pH to 10～11 with hydrochloric acid.
3) bullion Strontium Ranelate filter cake being joined pH is in 9～13 boiling water, 80～100 ℃ of making beating 10min～3h.Heat filtering, filter cake is used hot wash, and drying is prepared into Strontium Ranelate four water things, five water things, six water things, seven water things, eight water things.Wherein said pH value preferably is adjusted to 10～12.
Wherein the described organic solvent of step 1 can be selected from THF, acetone, and inorganic base aqueous solution can be selected from aqueous sodium hydroxide solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution.
Step 2 uses the strontium chloride mole dosage of the strontium chloride aqueous solution doubly to measure (mol/mol) as compound (II) 2-2.5.
Through the control of pH value in above each step, particularly process, make the present invention can obtain yield height and purity height, the product of good stability.
The pH of above method gained Strontium Ranelate (pH is low, and stability of sample is then not good) its steadiness between 8.5～10.0 sees the following form:
Wherein decarboxylation impurity is formula (III) compound or its salt
Hot and humid condition is: 60 ℃, and 75%RH, polyethylene bag+four layer composite film packaging
Acceleration environment is: 40 ℃, and 75%RH, polyethylene bag+four layer composite film packaging
Embodiment
Following embodiment is to specify the present invention, and unrestricted the present invention.
Embodiment 1
Get 5-[two (2-oxyethyl group-2-oxoethyl) amino]-4-cyanic acid-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate (20g, 0.044mol), THF 40ml stirs, and cools to the aqueous solution 90ml of 0 ℃ of dropping sodium 8.8g (0.22mol); 10～25 ℃ of reactions of temperature control 5h, separatory, 0～10 ℃ drips 3.5g concentrated hydrochloric acid adjusting pH is 11; Dry tetrahydrofuran is revolved in decompression; Add gac 2g stirring at normal temperature 1h, filter, stir the aqueous solution 80ml that adds six water strontium chloride 35g down; Room temperature crystallization 15h crosses and filters the Strontium Ranelate bullion.
Filter cake joins among the hot water 160ml, regulates pH to 11.0, is heated to 85 ℃ and keeps 1h, heat filtering.Hot water 20ml washing.
Dry the Strontium Ranelate finished product, yield 88%, HPLC:99.92%, maximum single assorted: 0.03%, pH=8.9.
Strontium Ranelate related substance HPLC analytical procedure:
Instrument: high performance liquid chromatograph is equipped with UV-detector
Chromatographic column: Waters Sunfire
TMC18 250 * 4.6mm 5 μ m
Mobile phase A: 0.5mL perchloric acid is dissolved in (the pH value is about 2.3) in the 1000mL water
Mobile phase B: acetonitrile
Diluent: 0.1mL ammoniacal liquor is in 1000mL water
Chromatographic column temperature: 30 ℃ are detected wavelength: 306nm
Flow velocity: 1.0mL/min working time: 40min
Sample size: 40 μ L
Gradient table:
| Time (min) | Mobile phase A (%V/V) | Mobile phase B (%V/V) |
| 0→13 | 91 | 9 |
| 13→20 | 91→65 | 9→35 |
| 20→25 | 65→15 | 35→85 |
| 25→34 | 15 | 85 |
| 34→35 | 15→91 | 85→9 |
| 35→40 | 91 | 9 |
Take by weighing 25mg strontium ranelate trial-product, the accurate title in the 50mL volumetric flask, is with the diluent dissolving and be diluted to scale, mixing.(strontium ranelate concentration: 0.5mg/mL)
Embodiment 2
Get 5-[two (2-oxyethyl group-2-oxoethyl) amino]-4-cyanic acid-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate (20g, 0.044mol), THF 40ml stirs, and cools to the aqueous solution 90ml of 0 ℃ of dropping sodium 8.8g (0.22mol); 10～25 ℃ of reactions of temperature control 5h, separatory, 0～10 ℃ drips 2.4g Glacial acetic acid min. 99.5 adjusting pH is 10; Dry tetrahydrofuran is revolved in decompression; Add gac 2g stirring at normal temperature 1h, filter, stir the aqueous solution 80ml that adds six water strontium chloride 35g down; Room temperature crystallization 15h crosses and filters the Strontium Ranelate bullion.
Filter cake joins among the hot water 160ml, regulates pH to 11, is heated to 85 ℃ and keeps 1.5h, heat filtering.Hot water 20ml washing.
Dry the Strontium Ranelate finished product, yield 91%, HPLC:99.97%, maximum single assorted: 0.02%, pH=8.5.
Embodiment 3
Get 5-[two (2-oxyethyl group-2-oxoethyl) amino]-4-cyanic acid-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate (20g, 0.044mol), THF 40ml stirs, and cools to 0 ℃ of aqueous solution 90ml that drips Pottasium Hydroxide 12.2g (0.22mol); 10～25 ℃ of reactions of temperature control 5h, separatory is regulated pH to 12 with hydrochloric acid; Dry tetrahydrofuran is revolved in decompression; Add gac 2g stirring at normal temperature 1h, filter, stir the aqueous solution 80ml that adds six water strontium chloride 35g down; Room temperature crystallization 15h crosses and filters the Strontium Ranelate bullion.
Filter cake joins among the hot water 160ml, regulates pH to 11.2, is heated to 85 ℃ and keeps 1.5h, heat filtering.Hot water 20ml washing.
Dry the Strontium Ranelate finished product, yield 85%, HPLC:99.82%, maximum single assorted: 0.04%, pH=9.2.
Embodiment 4
Get 5-[two (2-oxyethyl group-2-oxoethyl) amino]-4-cyanic acid-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate (20g; 0.044mol), acetone 30ml and NaOH (8g; 0.2mol) water 80ml solution, join in the reaction flask, stir; Control reaction temperature is reacted 5h at 10-30 ℃.Regulate pH to 9.5 with hydrochloric acid for-10～10 ℃ behind the separatory, the 35 ℃ of concentrating under reduced pressure 1h that filtrates remove organic solvent, add the 2g gac and stir 1h, filtration.
Stir and add six water strontium chlorides (25.8g, water 136ml solution 0.092mol) down.Room temperature crystallization 15h, filtering Strontium Ranelate bullion.
Filter cake joins among the hot water 160ml, regulates pH to 11.5, is heated to 95 ℃ and keeps 5min, heat filtering.Boiling water 20ml washing.
Dry the Strontium Ranelate finished product, yield 82%, HPLC:99.80%, maximum single assorted: 0.05%, pH=8.6.
Embodiment 5
Get 5-[two (2-oxyethyl group-2-oxoethyl) amino]-4-cyanic acid-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate (20g; 0.044mol), ethanol 40ml and LiOH (6.3g; 0.26mol) water 80ml solution, join in the reaction flask, stir; Control reaction temperature is reacted 6h at 10-30 ℃.Cool to-10～10 ℃ with hydrochloric acid adjusting pH to 11, the 35 ℃ of concentrating under reduced pressure of filtrating are removed ethanol, add the 2g gac and stir 1h, filter.
Stir and add six water strontium chlorides (30g, water 136ml solution 0.112mol) down.Room temperature crystallization 15h, filtering Strontium Ranelate bullion.
Filter cake joins among the hot water 160ml, regulates pH to 11.0, is heated to 90 ℃ and keeps 30min, heat filtering.Boiling water 20ml washing.
Dry the Strontium Ranelate finished product, yield 84%, HPLC:99.83%, maximum single assorted: 0.04%, pH=8.7.
Claims (6)
1. a stable Strontium Ranelate (5-[two (ethyloic) amino]-2-carboxyl-4-cyanic acid-3-thiophene acetic acid two strontiums), the pH value that it is characterized in that this Strontium Ranelate is 8.5～10.0.
2. method for preparing Strontium Ranelate as claimed in claim 1 is characterized in that may further comprise the steps:
(1) with compound (II) 5-[two (2-oxyethyl group-2-oxoethyl) amino]-4-cyanic acid-3-(2-oxyethyl group-2-oxoethyl)-2-thiophene ethyl formate, joins and carry out saponification reaction in organic solvent, the inorganic base aqueous solution.
(2) saponification finishes, and separatory is removed organic solvent, regulates PH to 9.5～12 with hydrochloric acid for-10～10 ℃, and water layer evaporate to dryness organic solvent adds the gac whip attachment, behind the elimination gac, adds the strontium chloride aqueous solution, obtains the Strontium Ranelate bullion;
(3) the Strontium Ranelate bullion with gained adds in the hydrothermal solution, regulates pH to 9～13 with hot water, heat filtering, and washing, drying obtains Strontium Ranelate.
3. according to the preparation method of claim 2, it is characterized in that regulating pH to 10～11 with hydrochloric acid in the step (2).
4. according to the preparation method of claim 2, it is characterized in that the quality of the gac that step (2) is used is 5%～20% of compound (II) quality.
5. according to the preparation method of claim 2, it is characterized in that step (2) adds that the whip attachment temperature is 15 ℃～35 ℃ behind the gac.
6. according to the preparation method of claim 2, it is characterized in that regulating pH to 10～12 with hot water in the step (3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110290289.1A CN102367247B (en) | 2011-09-20 | A kind of method of preparing high purity good stability strontium ranelate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110290289.1A CN102367247B (en) | 2011-09-20 | A kind of method of preparing high purity good stability strontium ranelate |
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| Publication Number | Publication Date |
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| CN102367247A true CN102367247A (en) | 2012-03-07 |
| CN102367247B CN102367247B (en) | 2016-12-14 |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1839827A (en) * | 2006-01-16 | 2006-10-04 | 重庆医药工业研究院有限责任公司 | Strontium ranelate chewing tablet and its preparation process |
| CN1995034A (en) * | 2006-01-04 | 2007-07-11 | 上海医药工业研究院 | Process for preparing strontium ranelate tetrahydrate |
| CN101397292A (en) * | 2007-09-26 | 2009-04-01 | 瑟维尔实验室 | Method for producing strontium ranelate and its hydrates |
| CN101775002A (en) * | 2009-12-23 | 2010-07-14 | 浙江华海药业股份有限公司 | Method for preparing strontium ranelate |
| CN101812048A (en) * | 2010-04-06 | 2010-08-25 | 浙江东亚药业有限公司 | Synthesis method of strontium ranelate and hydrate thereof |
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1995034A (en) * | 2006-01-04 | 2007-07-11 | 上海医药工业研究院 | Process for preparing strontium ranelate tetrahydrate |
| CN1839827A (en) * | 2006-01-16 | 2006-10-04 | 重庆医药工业研究院有限责任公司 | Strontium ranelate chewing tablet and its preparation process |
| CN101397292A (en) * | 2007-09-26 | 2009-04-01 | 瑟维尔实验室 | Method for producing strontium ranelate and its hydrates |
| CN101775002A (en) * | 2009-12-23 | 2010-07-14 | 浙江华海药业股份有限公司 | Method for preparing strontium ranelate |
| CN101812048A (en) * | 2010-04-06 | 2010-08-25 | 浙江东亚药业有限公司 | Synthesis method of strontium ranelate and hydrate thereof |
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