CN103804345B - A kind of method for controlling standby high-purity strontium ranelate in use HPLC method - Google Patents
A kind of method for controlling standby high-purity strontium ranelate in use HPLC method Download PDFInfo
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- CN103804345B CN103804345B CN201310399682.3A CN201310399682A CN103804345B CN 103804345 B CN103804345 B CN 103804345B CN 201310399682 A CN201310399682 A CN 201310399682A CN 103804345 B CN103804345 B CN 103804345B
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a kind of method for controlling standby high-purity strontium ranelate in use HPLC method, belongs to pharmaceutical synthesis field, is made up of following step：（1）Formula (II) compound：Obtain reacting under catalyst in formula (I) compound, tetrahydrofuran, Anhydrous potassium carbonate, bromoacetate input reactor, HPLC monitors reaction end；（2）Formula (III) compound：The tetrahydrofuran solution for dissolving in formula (II) compound is added drop-wise in inorganic base aqueous solution carries out saponification, control in HPLC, through vacuum distillation, filtration, after hydrochloric acid adjusts pH value, the strontium chloride aqueous solution is added, Strontium Ranelate crude product is obtained, purity is more than 99.7%, single miscellaneous is less than 0.1%, always miscellaneous be less than 0.5%, be dried to obtain target finished product.Strontium Ranelate prepared by the present invention, control reaction in HPLC, determines optimum reacting time, reduces polishing purification step, and its process is simple, it is easy to control, product purity are high, and waste liquid is few, and energy consumption is low, and cost is relatively low, are suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of Strontium Ranelate, and in particular to a kind of suitable industrialized production uses HPLC methods
Middle control belongs to pharmaceutical synthesis field for the method for high-purity strontium ranelate.
Background technology
Strontium Ranelate is by France（servier）Company develops, on November 15th, 2004 first in Ireland listing
The osteoporotic medicine for the treatment of, it has double action to bone, that is, suppress bone information and promote bone uptake.Due to Strontium Ranelate
Taking dose larger, there is realistic meaning to the control of its cost.Chemical entitled 5- [double (carboxymethyl) ammonia of Strontium Ranelate
Base] two strontium of -2- carboxyl -4- cyano group -3- thiophene acetic acids, its chemical structural formula is：
At present, produce highly purified Strontium Ranelate mainly to realize through polishing purification step, but due to Strontium Ranelate almost
General inorganic or organic solvent is not dissolved in, which recrystallizes or purification difficult, can produce substantial amounts of waste liquid, and product cost is higher.
Strontium ranelate salt, its preparation method and its therapeutical uses are described in EP0415850, are disclosed three kinds and are prepared thunder Buddhist nun
Sour strontium and the method for four hydrates, heptahydrate and eight hydrates.Its purification process has two kinds：One is that ranelic acid sodium leads to
Spend ion exchange resin, then the method for adopting organic solvent and elutriation brilliant after vacuum distillation obtains ranelic acid, the purification process cycle
Oversize and substantial amounts of waste water can be produced, be not suitable for industrialized production；Two is after reaction terminates, and is removed by reducing pressure most
Water, then substantial amounts of alcohol crystal is used, but in the industry, it is high energy consumption, the operation of time length to subtract steaming water, while in operation
New impurity is easily produced, the yield of its product is low, and quality can not be guaranteed.
Chinese patent CN102321068A discloses a kind of preparation method of Strontium Ranelate, needs in the method preparation process
Repeatedly crystallization purification, produces a large amount of waste water and waste liquids, long the production cycle, high energy consumption, low yield.Chinese patent CN102367247A is public
A kind of method of preparing high purity good stability strontium ranelate is opened, the method product purity is high, but processing step is loaded down with trivial details, reaction
Time is long, and subsequent process needs polishing purification, produces a large amount of waste water and waste liquids, and yield is low.
Patent CN200610165388.6 discloses the side of a kind of employing HPLC methods analyzing strontium ranelate raw material and its preparation
Method, the method with Accurate Determining strontium ranelate raw material and its content of preparation, can indicate the stability of Strontium Ranelate and its preparation,
The degree of accuracy is high.Patent CN102367247 discloses applications of the HPLC in terms of Strontium Ranelate finished product detection.But, HPLC is drawn
Enter the preparation process of Strontium Ranelate, the product quality in Strontium Ranelate preparation process is monitored, is had not been reported.
Content of the invention
It is an object of the invention to overcoming defect of the prior art, there is provided a kind of process is simple, it is easy to control, yield
Height, the method for controlling standby high-purity strontium ranelate in the use HPLC method of low cost.
For solving above-mentioned technical problem, the present invention adopts the following technical scheme that realization：
A kind of method for controlling standby high-purity strontium ranelate in use HPLC method, comprises the steps：
（1）Formula (II) compound：By formula (I) compound, tetrahydrofuran, Anhydrous potassium carbonate, bromoacetate input
React under catalyst in reactor, be warming up to backflow, middle control detects that reaction terminates, through filtering, vacuum distillation, ethanol
Ice bath is beaten, and filters, and uses alcohol flushing filter cake, dries and obtains formula (II) compound；
(Ⅰ)
(Ⅱ)
（2）Formula (III) compound：Formula (II) compound is dissolved in tetrahydrofuran solution, inorganic base aqueous solution is added drop-wise to
In carry out saponification, control in HPLC, through vacuum distillation, filtration, after hydrochloric acid adjusts pH value, add the strontium chloride aqueous solution, obtain
Formula (III) Strontium Ranelate crude product, is dried to obtain target finished product.
(Ⅲ)
The mol ratio 1.0 of step (1) Chinese style (I) compound, Anhydrous potassium carbonate and bromoacetate:3.5-4.5:3-
5.
Catalyst in step (1) is TBAB, crown ether, KF/Al2O3, the mass ratio of raw material and catalyst
For 1:0.008-0.025.
The reaction temperature of step (1) is 50-90 DEG C.
Ethanol low temperature beating in step (1), temperature is 0-10 DEG C, and the time is 3-5h.
Step (2) hydrolyze in inorganic base aqueous solution and are first cooled to 20-30 DEG C, then heat to flow back, and reaction is eventually
Point HPLC is monitored.
Described in step (2), inorganic base aqueous solution is the sodium hydroxide solution that is prepared by purified water.
In the inorganic base aqueous solution of step (2), the mass ratio of NaOH and purified water is 1:18-25.
Step (2) watery hydrochloric acid adjusts PH to 8.5-9.
Backflow is warming up to after step (2) stirring at normal temperature crystallization 0.5-1h.
The HPLC:Chromatographic column:Octadecyl silane is filler, mobile phase:Acetonitrile-water (75:25),
PH3.0, flow velocity:1.0ml/min, Detection wavelength:237nm, sampling volume:10μl.
Beneficial effects of the present invention：By in the quality control of HPLC application to Strontium Ranelate preparation process, technique is optimized
Flow process and parameter, the product chemical purity for obtaining are high and relatively stable, reduce subsequent purification separating step, without a large amount of waste water
Waste liquid is produced, its organic solvent through process recyclable apply mechanically, whole simple production process, it is easy to operate, the finished product of preparation are received
Rate is high, low cost, it is easy to industrialized production.Product purity is more than 99.7%, and list is miscellaneous<0.1%, always miscellaneous<0.5%, yield is 90-
92%.
Description of the drawings
Fig. 1 is control figure in 1 first step reaction end HPLC of embodiment.
Fig. 2 is embodiment 1 formula (II) compound products HPLC purity detecting figures.
Fig. 3 is control figure in 1 second step reaction end HPLC of embodiment.
HPLC purity detecting figures of the Fig. 4 for 1 finished product formula (III) compound of embodiment.
Fig. 5 is control figure in 2 first step reaction end HPLC of embodiment.
Fig. 6 is embodiment 2 formula (II) compound products HPLC purity detecting figures.
Fig. 7 is control figure in 2 second step reaction end HPLC of embodiment.
HPLC purity detecting figures of the Fig. 8 for 2 finished product formula (III) compound of embodiment.
Fig. 9 is control figure in 3 first step reaction end HPLC of embodiment.
Figure 10 is embodiment 3 formula (II) compound products HPLC purity detecting figures.
Figure 11 is control figure in 3 second step reaction end HPLC of embodiment.
HPLC purity detecting figures of the Figure 12 for 3 finished product formula (III) compound of embodiment.
Specific embodiment
For making the object, technical solutions and advantages of the present invention of greater clarity, the present invention adopts specific examples below
Technical scheme is elaborated.
Embodiment 1
（1）Formula (I) compound 25g, tetrahydrofuran 300mL, Anhydrous potassium carbonate 48g, bromine is added in 500mL four-hole boiling flasks
Ethyl acetate 58g, crown ether 0.5g, are warming up to backflow, middle control detection（Fig. 1 is control figure in reaction end HPLC）, reaction about 3h knots
Beam, filters, and filtrate decompression is distilled, and adds 100mL ethanol ice bath beating 3-4h, filter cake ice alcohol flushing after terminating.It is put into 45 DEG C
Baking oven, dries, obtains formula (II) compound 36g, and yield is 90%, and purity is that 99.84%, Fig. 2 is pure for formula (II) compound HPLC
Degree detection figure.
（2）In 500mL four-hole boiling flasks, add formula (II) compound 25g, tetrahydrofuran 215mL, dissolving to be cooled to 5 DEG C.
9.7g NaOH is dissolved in 190mL purified waters, 10 DEG C is cooled to and is added in four-hole boiling flask.It is warming up to backflow, middle control detection
（Fig. 3 is control figure in reaction end HPLC）Reaction about 1-2h terminates.Vacuum distillation, tune pH value are 8.5-9, add strontium chloride water-soluble
Liquid (strontium chloride 38g, purified water 100mL) stirring at normal temperature crystallization 0.5-1h, after be warming up to backflow, filter, with purified water and second
Alcohol rinses filter cake, is put into 45 DEG C of baking ovens, dries, obtains formula (III) Strontium Ranelate finished product 30.5g, and yield is 85%, and purity is
99.82%, single maximum contaminant：0.06%, Fig. 4 are finished product HPLC purity detecting figures.
Embodiment 2
（1）Formula (I) compound 50g, tetrahydrofuran 600mL, potassium carbonate 96g, bromine second is added in 1000mL four-hole boiling flasks
Acetoacetic ester 118g, crown ether 1.0g, are warming up to backflow, and in HPLC, (Fig. 5 is control figure in reaction end HPLC for control）, reaction about 3h knots
Beam, filters, and filtrate decompression is distilled, and adds 200mL ethanol ice bath beating 3-4h, filter cake ice alcohol flushing after terminating.It is put into 45 DEG C
Baking oven, dries, obtains formula (II) compound 72g, and yield is 90%, and purity is the HPLC that 99.92%, Fig. 6 is formula (II) compound
Purity detecting figure.
（2）In 1000mL four-hole boiling flasks, add formula (II) compound 50g, tetrahydrofuran 430mL, dissolving to be cooled to 10
℃.19.4g NaOH is dissolved in 360mL purified waters, 10 DEG C is cooled to and is added in four-hole boiling flask.It is warming up to backflow, middle control
Detection（Fig. 7 is control figure in reaction end HPLC）About 2-3h reactions terminate.Vacuum distillation, tune pH value are 8.5-9, add strontium chloride
The aqueous solution (strontium chloride 76g, purified water 368.6mL) stirring at normal temperature crystallization 0.5-1h, after be warming up to backflow, filter, use purified water
And alcohol flushing filter cake, 45 DEG C of baking ovens being put into, is dried, is obtained formula (III) Strontium Ranelate finished product 63g, yield is 91.5%, purity
For 99.80%, single maximum contaminant：0.06%, Fig. 8 are finished product HPLC purity detecting figures.
Embodiment 3
（1）In 20L reactors, formula (I) compound 1kg, tetrahydrofuran 12L, potassium carbonate 1.92kg, bromoacetic acid second is added
Ester 2.3kg, crown ether 20g, are warming up to backflow, control in HPLC（Fig. 9 is control figure in reaction end HPLC）, react about 3-4h and terminate,
Filter, filtrate decompression is distilled, 4L ethanol ice bath is beaten 3-4h, filter, filter cake ice alcohol flushing is put into 45 DEG C of baking ovens, dry,
Formula (II) compound 1.25kg is obtained, yield is 91%, it is formula (II) compound HPLC purity detectings that purity is 99.86%, Figure 10
Figure.
（2）In the reaction ax of 50L, add formula (II) compound 2kg, tetrahydrofuran 17.2L, dissolving to be cooled to 5 DEG C, will
0.78kg NaOH is dissolved in 14L purified waters, is cooled to 5-10 DEG C and is added in reactor.Backflow is warming up to, about 3.5- is reacted
Control in 4h samplings（Figure 11 is control figure in reaction end HPLC）, after vacuum distillation, pH value is adjusted to 8.5-9, adds strontium chloride water-soluble
Liquid (strontium chloride 3.04kg, purified water 8L) stirring at normal temperature crystallization 0.5-1h, after be warming up to backflow, filter, with purified water and second
Alcohol rinses filter cake, is put into 45 DEG C of oven dryings, obtains formula (III) Strontium Ranelate finished product 2.7kg, and yield is 90%, and purity is 99.86%,
Single maximum contaminant：0.06%, Figure 12 are finished product HPLC purity detecting figures.
Above-described embodiment is only in order to illustrating technical scheme, rather than the design to the present invention and protection domain are carried out
Limit, one of ordinary skill in the art modifies to technical scheme or equivalent, without deviating from technology
The objective and scope of scheme, which all should be covered in scope of the presently claimed invention.
Claims (1)
1. a kind of method for controlling standby high-purity strontium ranelate in use HPLC method, it is characterised in that：Comprise the steps：
（1）Formula (II) compound：By formula (I) compound, tetrahydrofuran, Anhydrous potassium carbonate, bromoacetate input reaction
React under catalyst in kettle, be warming up to backflow, middle control detects that reaction terminates, through filtering, vacuum distillation, ethanol ice bath
Beating, filters, and uses alcohol flushing filter cake, dries and obtains formula (II) compound；
(Ⅰ)
(Ⅱ)
（2）Formula (III) compound：Formula (II) compound is dissolved in tetrahydrofuran solution, is added drop-wise in inorganic base aqueous solution
Row saponification, controls in HPLC, through vacuum distillation, filtration, after salt acid for adjusting pH value, adds the strontium chloride aqueous solution, obtains formula
(III) Strontium Ranelate crude product, is dried to obtain target finished product；
(Ⅲ)
The mol ratio 1.0 of step (1) Chinese style (I) compound, Anhydrous potassium carbonate and bromoacetate:3.5-4.5:3-5；
Catalyst in step (1) is 1 for the mass ratio of crown ether, raw material and catalyst:0.008-0.025；
The reaction temperature of step (1) is 50-90 DEG C；
Ethanol low temperature beating in step (1), temperature is 0-10 DEG C, and the time is 3-5h；
Step (2) hydrolyze in inorganic base aqueous solution and are first cooled to 20-30 DEG C, then heat to flow back, reaction end
HPLC is monitored；
Described in step (2), inorganic base aqueous solution is the sodium hydroxide solution that is prepared by purified water；
In the inorganic base aqueous solution of step (2), the mass ratio of NaOH and purified water is 1:18-25；
Step (2) watery hydrochloric acid adjusts pH to 8.5-9；
Backflow is warming up to after step (2) stirring at normal temperature crystallization 0.5-1h；
The HPLC:Chromatographic column:Octadecyl silane is filler, mobile phase:Acetonitrile-water (75:25), pH3.0, stream
Speed:1.0mL/min, Detection wavelength:237nm, sampling volume:10μL.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5128367A (en) * | 1989-09-01 | 1992-07-07 | Adir Et Compagnie | Divalent metal salts of 2-[N-N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid |
| CN101747316A (en) * | 2008-12-12 | 2010-06-23 | 重庆医药工业研究院有限责任公司 | High-purity strontium ranelate and preparation method thereof |
| CN102241663A (en) * | 2010-05-10 | 2011-11-16 | 山东方明药业股份有限公司 | Preparation method of strontium ranelate octohydrate |
| CN102321068A (en) * | 2011-08-01 | 2012-01-18 | 山东铂源化学有限公司 | Method for preparing strontium ranelate |
-
2013
- 2013-09-06 CN CN201310399682.3A patent/CN103804345B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5128367A (en) * | 1989-09-01 | 1992-07-07 | Adir Et Compagnie | Divalent metal salts of 2-[N-N-di(carboxymethyl)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid |
| CN101747316A (en) * | 2008-12-12 | 2010-06-23 | 重庆医药工业研究院有限责任公司 | High-purity strontium ranelate and preparation method thereof |
| CN102241663A (en) * | 2010-05-10 | 2011-11-16 | 山东方明药业股份有限公司 | Preparation method of strontium ranelate octohydrate |
| CN102321068A (en) * | 2011-08-01 | 2012-01-18 | 山东铂源化学有限公司 | Method for preparing strontium ranelate |
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