CN1995034A - Process for preparing strontium ranelate tetrahydrate - Google Patents
Process for preparing strontium ranelate tetrahydrate Download PDFInfo
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- CN1995034A CN1995034A CN 200610023106 CN200610023106A CN1995034A CN 1995034 A CN1995034 A CN 1995034A CN 200610023106 CN200610023106 CN 200610023106 CN 200610023106 A CN200610023106 A CN 200610023106A CN 1995034 A CN1995034 A CN 1995034A
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- acid
- strontium ranelate
- aqueous solution
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Abstract
The invention discloses a making method of ranimycin strontium tetrahydrate, which comprises the following steps: adopting rough product of ranimycin strontium tetrahydrate with content over 80% as formula (I) as raw material; suspending in the water; adjusting pH value under indoor temperature or heating condition through acid until dissolving completely; obtaining the supernatant; washing through organic solvent; filtering; adjusting pH value through alkaline to neutral alkali-bias; stirring; filtering; drying to obtain the product with stable property.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to the preparation method of Strontium Ranelate tetrahydrate.
Background technology
Strontium Ranelate can be used for reducing the risk of new vertebral fracture of menelipsis after date osteoporosis women (have at the baseline place or do not have fragility fractures) and hip fracture.This medicine can suppress bone resorption also can promote bone forming (promoting that bone forming is the approach of the most worthy of treatment osteoporosis), to reducing risk of bone fracture, strengthening bone strength and bone density and have sure curative effect (to compare with placebo and can reduce by 41%～49% spinal fracture risk, and can make the vertebrae mineral density increase by 6.8%), this medicine better tolerance.
Synthetic and purposes to Strontium Ranelate in patent documentation EP0415850 is described, but chemical purity is not seen explanation, and actual result according to the preparation of synthetic method described in the document, the product purity that obtains generally can not surpass 95%.And in concrete the application, purity less than 99% and content be inappropriate less than 98% compound as active ingredients in pharmaceuticals, in view of Strontium Ranelate all is difficult to dissolving (it is all insoluble at water, alcohol, ester, ketone, nitrile, aromatic hydrocarbon, haloalkane, DMF, DMSO etc.) and the easy moisture absorption of Strontium Ranelate crude product and weathering in all kinds solvent, the unsettled relatively fact, be necessary when producing strontium ranelate, further to improve its purity and content, and improve its stability.External commercially available at present Strontium Ranelate preparation (inferring that from auxiliary material shown in the specification sheets auxiliary material is not moisture substantially) is done thermogravimetric analysis, detect its moisture situation and Strontium Ranelate in theory four parts of crystal water conform to, therefore infer that Strontium Ranelate tends to the existence form of four parts of crystal water in the preparation that reality is used.The preliminarily stabilised of medicine (influence factor test illumination, high temperature, high humidity and accelerated test) and the data of long-term stable experiment examination show that also the character of Strontium Ranelate tetrahydrate is more stable relatively.
Summary of the invention
The object of the present invention is to provide a kind of preparation method of Strontium Ranelate tetrahydrate, to obtain chemical purity greater than 99%, content is greater than 98.5%, and the metastable Strontium Ranelate tetrahydrate of chemical property, satisfies its needs as the active constituents of medicine purposes.
Method of the present invention comprises the steps:
Is raw material with content greater than compound crude product shown in 80% the formula (I), it is suspended in water, add acid for adjusting pH to acid, treat to dissolve fully the formation homogeneous phase solution, the clear liquid that obtains organic solvent washing after-filtration, filtrate is regulated pH to alkalescence with alkali, stirs, obtain chemical purity behind the filtration drying greater than 99%, content is greater than 98.5% Strontium Ranelate tetrahydrate.
When regulating the pH value, pH 〉=7.0 of alkalescence are regulated in regulating and controlling tart pH≤3.0
Described acid, optional from sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, acetate, the propionic acid and the aqueous solution thereof or mixing acid.
Described alkali can be selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, ammoniacal liquor, methylamine and the aqueous solution thereof or mixed base.
Compound with general formula I can adopt the EP0415850 disclosed method to be prepared.
The invention has the advantages that described method is simple to operate, do not need specific installation, resultant product chemical purity height; And the stability of Strontium Ranelate tetrahydrate is higher relatively, and therefore method provided by the invention is fit to suitability for industrialized production very much.The product that obtains with this method satisfies direct each side requirements such as purity, content and stability as active constituents of medicine.
Embodiment
The present invention is further elaborated below in conjunction with embodiment, but these embodiment do not constitute any restriction to the present invention.The testing tool that relates to use among the embodiment is: AM-400 nuclear magnetic resonance analyser, Bio-Red FTS-185 infrared test instrument, PerkinElmer Thermal Analysis thermal gravimetric analyzer.)
Embodiment 1
With Strontium Ranelate tetrahydrate (30.0g, 43.6mmol, content 85%), deionized water 100ml pours reaction flask into, 25 ℃ of stirring suspensions, drip the 6N sulphuric acid soln and regulate pH=1.0, solid dissolves fully, the clear liquid that the obtains inferior washing of ethyl acetate (30ml * 3), layering, water layer filters, be added dropwise to 6N sodium hydroxide solution adjusting pH=9.0 in filtrate, stirring at room 3h filters, solid washs with acetone (30ml * 2), drying under reduced pressure obtains Strontium Ranelate tetrahydrate 19.1g, (yield: 75%, purity: 99.2%, content: 98.9%).
Embodiment 2
With Strontium Ranelate tetrahydrate (30.0g, 42.1mmol, content 82%), deionized water 100ml pours reaction flask into, is heated to 40～50 ℃ and drips 6N hydrochloric acid soln adjusting pH=2.0, and solid dissolves fully, the clear liquid that the obtains inferior washing of ethyl acetate (30ml * 3), layering, water layer filters, and is added dropwise to 10% ammonia soln adjusting pH=10.0 in filtrate, stirring at room 5h, filter, solid washs with acetone (30ml * 2), drying under reduced pressure, obtain Strontium Ranelate tetrahydrate 19.7g, (yield: 80%, purity: 99.4%, content: 99.2%).
Embodiment 3
With Strontium Ranelate tetrahydrate (30.0g, 44.6mmol, content 87%), deionized water 100ml pours reaction flask into, is heated to 40～50 ℃ and drips 6N hydrochloric acid soln adjusting pH=3.0, and solid dissolves fully, the clear liquid that the obtains inferior washing of ethyl acetate (30ml * 3), layering, water layer filters, and is added dropwise to saturated sodium carbonate solution adjusting pH=8.0 in filtrate, stirring at room 4h, filter, solid washs with acetone (30ml * 2), drying under reduced pressure, obtain Strontium Ranelate tetrahydrate 20.1g, (yield: 77%, purity: 99.4%, content: 99.1%).
Embodiment 4
With Strontium Ranelate tetrahydrate (30.0g, 43.6mmol, content 85%), deionized water 100ml pours reaction flask into, is heated to 60～70 ℃ and drips 6N sulphuric acid soln adjusting pH=1.5, and solid dissolves fully, the clear liquid that the obtains inferior washing of ethyl acetate (30ml * 3), layering, water layer filters, and is added dropwise to aqueous methylamine solution adjusting pH=9.5 in filtrate, stirring at room 3h, filter, solid washs with acetone (30ml * 2), drying under reduced pressure, obtain Strontium Ranelate tetrahydrate 19.4g, (yield: 76%, purity: 99.3%, content: 99.2%).
Embodiment 5
With Strontium Ranelate tetrahydrate (30.0g, 44.6mmol, content 87%), deionized water 100ml pours reaction flask into, is heated to 40～50 ℃ and drips phosphoric acid solution adjusting pH=2.0, and solid dissolves fully, the clear liquid that the obtains inferior washing of ethyl acetate (30ml * 3), layering, water layer filters, and is added dropwise to 6N sodium hydroxide solution adjusting pH=9.0 in filtrate, stirring at room 3h, filter, solid washs with acetone (30ml * 2), drying under reduced pressure, obtain Strontium Ranelate tetrahydrate 19.1g, (yield: 75%, purity: 99.2%, content: 99.3%).
Embodiment 6
With Strontium Ranelate tetrahydrate (30.0g, 48.7mmol, content 95%), deionized water 100ml pours reaction flask into, is heated to 65～70 ℃ of Dropwise 5 0% acetic acid solutions and regulates pH=1.0, and solid dissolves fully, the clear liquid that the obtains inferior washing of ethyl acetate (30ml * 3), layering, water layer filters, and is added dropwise to 50% sodium hydroxide solution adjusting pH=8.0 in filtrate, stirring at room 5h, filter, solid washs with acetone (30ml * 2), drying under reduced pressure, obtain Strontium Ranelate tetrahydrate 22.5g, (yield: 79%, purity: 99.2%, content: 99.0%).
HNMR (solvent: D2O+HCl, in be designated as TMS)
4.109(s，2H)
4.561(s，4H)
IR (pellet technique scanning 400-4000cm-1)
3434.00cm-1
2210.87cm-1
2192.75cm-1
1572.81cm-1
1516.56cm-1
1387.34cm-1
TGA (10 ℃/min of heat-up rate, 30 ℃-450 ℃ of temperature ranges)
Delta?Y＝13.0864％
Claims (6)
1. the preparation method of a Strontium Ranelate tetrahydrate, it is characterized in that, comprise the steps: with crude product to be that raw material forms suspension with Strontium Ranelate shown in the formula (I), add acid or its aqueous solution and regulate pH and it is dissolved fully to acidity, regulate pH with mineral alkali or its aqueous solution then and separate out solid phase prod.
2. method according to claim 1, it is characterized in that comprising the steps: that with the crude product with Strontium Ranelate shown in the formula (I) be raw material, it is suspended in water, room temperature or heating drip acid down or its aqueous solution is adjusted to acidity, treat to dissolve fully the formation homogeneous phase, the clear liquid that obtains organic solvent washing after-filtration, filtrate is adjusted to middle meta-alkalescence with alkali or its aqueous solution again, stir, obtain the Strontium Ranelate tetrahydrate behind the filtration drying.
3. method according to claim 1 and 2 is characterized in that, pH 〉=7.0 of alkalescence are regulated in the pH of adjustment of acidity≤3.0.
4. method according to claim 1 and 2 is characterized in that described acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, acetate, the propionic acid and the aqueous solution thereof or mixing acid.
5. method according to claim 1 and 2 is characterized in that described alkali is selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, ammoniacal liquor, methylamine and the aqueous solution thereof or mixed base.
6. method according to claim 1 is characterized in that, temperature of reaction is not higher than 70 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610023106A CN100591677C (en) | 2006-01-04 | 2006-01-04 | Process for preparing strontium ranelate tetrahydrate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610023106A CN100591677C (en) | 2006-01-04 | 2006-01-04 | Process for preparing strontium ranelate tetrahydrate |
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| Publication Number | Publication Date |
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| CN1995034A true CN1995034A (en) | 2007-07-11 |
| CN100591677C CN100591677C (en) | 2010-02-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200610023106A Expired - Fee Related CN100591677C (en) | 2006-01-04 | 2006-01-04 | Process for preparing strontium ranelate tetrahydrate |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011107454A1 (en) | 2010-03-05 | 2011-09-09 | Chemelectiva Srl | Process for the preparation of a polymorph of strontium ranelate |
| CN102367247A (en) * | 2011-09-20 | 2012-03-07 | 浙江华海药业股份有限公司 | Method for preparing high purity good stability strontium ranelate |
| CN102367247B (en) * | 2011-09-20 | 2016-12-14 | 浙江华海药业股份有限公司 | A kind of method of preparing high purity good stability strontium ranelate |
-
2006
- 2006-01-04 CN CN200610023106A patent/CN100591677C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011107454A1 (en) | 2010-03-05 | 2011-09-09 | Chemelectiva Srl | Process for the preparation of a polymorph of strontium ranelate |
| CN102367247A (en) * | 2011-09-20 | 2012-03-07 | 浙江华海药业股份有限公司 | Method for preparing high purity good stability strontium ranelate |
| CN102367247B (en) * | 2011-09-20 | 2016-12-14 | 浙江华海药业股份有限公司 | A kind of method of preparing high purity good stability strontium ranelate |
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| Publication number | Publication date |
|---|---|
| CN100591677C (en) | 2010-02-24 |
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