CN103804345A - Method for preparing high-purity strontium ranelate through centralized control of HPLC (High Performance Liquid Chromatography) method - Google Patents
Method for preparing high-purity strontium ranelate through centralized control of HPLC (High Performance Liquid Chromatography) method Download PDFInfo
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- 238000004128 high performance liquid chromatography Methods 0.000 title claims abstract description 56
- 238000000034 method Methods 0.000 title claims abstract description 51
- 229940079488 strontium ranelate Drugs 0.000 title claims abstract description 41
- XXUZFRDUEGQHOV-UHFFFAOYSA-J strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 title claims abstract 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 39
- 150000001875 compounds Chemical class 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 14
- 238000004821 distillation Methods 0.000 claims abstract description 12
- 229910001631 strontium chloride Inorganic materials 0.000 claims abstract description 9
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 claims abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000000047 product Substances 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000010792 warming Methods 0.000 claims description 15
- 239000008213 purified water Substances 0.000 claims description 13
- 239000012065 filter cake Substances 0.000 claims description 8
- 238000011010 flushing procedure Methods 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- 238000010009 beating Methods 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 150000003983 crown ethers Chemical class 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 3
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 238000012544 monitoring process Methods 0.000 claims description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 2
- 238000007127 saponification reaction Methods 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- 239000007788 liquid Substances 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 5
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 3
- 230000035484 reaction time Effects 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000001035 drying Methods 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- ZHEZAQJNZMLYBA-UHFFFAOYSA-J distrontium;5-[bis(carboxylatomethyl)amino]-3-(carboxylatomethyl)-4-cyanothiophene-2-carboxylate;octahydrate Chemical compound O.O.O.O.O.O.O.O.[Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N ZHEZAQJNZMLYBA-UHFFFAOYSA-J 0.000 description 25
- 238000002360 preparation method Methods 0.000 description 11
- 238000009835 boiling Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000006837 decompression Effects 0.000 description 4
- 239000002351 wastewater Substances 0.000 description 4
- 239000000356 contaminant Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- DJSXNILVACEBLP-UHFFFAOYSA-N ranelic acid Chemical compound OC(=O)CN(CC(O)=O)C=1SC(C(O)=O)=C(CC(O)=O)C=1C#N DJSXNILVACEBLP-UHFFFAOYSA-N 0.000 description 2
- 229950003464 ranelic acid Drugs 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 230000001009 osteoporotic effect Effects 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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
The present invention relates to a kind of preparation method of Strontium Ranelate, be specifically related to a kind of method with the standby high purity Strontium Ranelate of control in HPLC method of applicable suitability for industrialized production, belong to the synthetic field of medicine.
Background technology
Strontium Ranelate is by the development of (servier) company of France, and on November 15th, 2004 first at the osteoporotic medicine for the treatment of of Ireland listing, it has dual function to bone, suppresses bone resorption and promotes osteogenesis.Because the taking dose of Strontium Ranelate is larger, the control of its cost is had to realistic meaning.Two (carboxymethyl) amino of chemistry 5-[by name of Strontium Ranelate]-2-carboxyl-4-cyano group-3-thiophene acetic acid two strontiums, its chemical structural formula is:
At present, produce highly purified Strontium Ranelate and mainly realize through refining purification step, but because Strontium Ranelate is dissolved in general inorganic or organic solvent hardly, its recrystallization or purification difficult, can produce a large amount of waste liquids, product cost is higher.
In EP0415850, describe strontium ranelate salt, its preparation method and therepic use thereof, disclose three kinds of methods of preparing Strontium Ranelate and four hydrates, heptahydrate and eight hydrates.Its purification process has two kinds: the one, and Ranelic acid sodium is by ion exchange resin, then underpressure distillation obtains the method that adopts organic solvent and elutriation crystalline substance after Ranelic acid, and this purification process cycle is oversize and can produce a large amount of waste water, is not suitable for suitability for industrialized production; The 2nd, after reaction finishes, remove most water by decompression, then use a large amount of alcohol crystals, but in industry, subtracting steaming water is the operation that energy consumption is high, the time is long, in operating process, easily produce new impurity simultaneously, 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 repeatedly crystallization to purify in the method preparation process, produces a large amount of waste water and waste liquid, and the production cycle is long, energy consumption is high, productive rate is low.Chinese patent CN102367247A discloses a kind of method of preparing high purity good stability strontium ranelate, and the method product purity is high, but processing step is loaded down with trivial details, long reaction time, and subsequent process need to be refined purifying, produces a large amount of waste water and waste liquid, and yield is low.
Patent CN200610165388.6 discloses a kind of method of the HPLC of employing method analyzing strontium ranelate raw material and preparation thereof, and the method can Accurate Determining strontium ranelate raw material and the content of preparation, the stability of indication Strontium Ranelate and preparation thereof, and accuracy is high.Patent CN102367247 discloses the application of HPLC aspect Strontium Ranelate finished product detection.But, HPLC is introduced to the preparation process of Strontium Ranelate, the quality product in Strontium Ranelate preparation process is monitored, have not been reported.
Summary of the invention
The object of the invention is to overcome defect of the prior art, provide a kind of technique simple, be easy to control, yield is high, the method with the standby high purity Strontium Ranelate of control in HPLC method that cost is low.
For solving the problems of the technologies described above, the present invention adopts following technical scheme to realize:
By a method of controlling standby high purity Strontium Ranelate in HPLC method, comprise the steps:
(1) prepare formula II compound: formula I compound, tetrahydrofuran (THF), Anhydrous potassium carbonate, ethyl bromoacetate are dropped in reactor and reacted under catalyst, be warming up to backflow, middle control detects, reaction finishes, after filtration, and underpressure distillation, the making beating of ethanol ice bath, filter, use alcohol flushing filter cake, dry and obtain formula II compound;
(Ⅰ)
(Ⅱ)
(2) prepare formula III compound: formula II compound is dissolved in to tetrahydrofuran solution, be added drop-wise to and in inorganic base aqueous solution, carry out saponification reaction, in HPLC, control, through underpressure distillation, filtration, hydrochloric acid regulates after pH value, add the strontium chloride aqueous solution, obtain formula III Strontium Ranelate crude product, the dry target finished product that obtains.
(Ⅲ)
The mol ratio 1.0:3.5-4.5:3-5 of formula I compound, Anhydrous potassium carbonate and ethyl bromoacetate in described step (1).
Catalyzer in described step (1) is Tetrabutyl amonium bromide, crown ether, KF/Al
2o
3, the mass ratio of raw material and catalyzer is 1:0.008-0.025.
The temperature of reaction of described step (1) is 50-90 ℃.
Ethanol low temperature making beating in described step (1), temperature is 0-10 ℃, the time is 3-5h.
Described step (2) is hydrolyzed and is first cooled to 20-30 ℃ in inorganic base aqueous solution, is then warming up to backflow, reaction end HPLC monitoring.
Described in described step (2), inorganic base aqueous solution is the sodium hydroxide solution of being prepared by purified water.
In the inorganic base aqueous solution of described step (2), the mass ratio of sodium hydroxide and purified water is 1:18-25.
Described step (2) dilute hydrochloric acid regulates PH to 8.5-9.
After described step (2) stirring at normal temperature crystallization 0.5-1h, be warming up to backflow.
Described HPLC: chromatographic column: octadecyl silane is weighting agent, moving phase: acetonitrile-water (75:25), PH3.0, flow velocity: 1.0ml/min, detects wavelength: 237nm, sampling volume: 10 μ l.
Beneficial effect of the present invention: HPLC is applied in the quality control of Strontium Ranelate preparation process, technical process and parameter are optimized, the product chemical purity obtaining is high and relatively stable, has reduced subsequent purification separating step, does not have a large amount of waste water and waste liquid to produce, its organic solvent is through processing recyclable applying mechanically, whole production technique is simple, easy handling, and the product yield of preparation is high, cost is low, is easy to suitability for industrialized production.Product purity is greater than 99.7%, single assorted <0.1%, and always assorted <0.5%, yield is 90-92%.
Accompanying drawing explanation
Fig. 1 is control figure in embodiment 1 the first step reaction end HPLC.
Fig. 2 is embodiment 1 formula II compound products HPLC purity detecting figure.
Fig. 3 is control figure in embodiment 1 second step reaction end HPLC.
Fig. 4 is the HPLC purity detecting figure of embodiment 1 finished product formula III compound.
Fig. 5 is control figure in embodiment 2 the first step reaction end HPLC.
Fig. 6 is embodiment 2 formula II compound products HPLC purity detecting figure.
Fig. 7 is control figure in embodiment 2 second step reaction end HPLC.
Fig. 8 is the HPLC purity detecting figure of embodiment 2 finished product formula III compounds.
Fig. 9 is control figure in embodiment 3 the first step reaction end HPLC.
Figure 10 is embodiment 3 formula II compound products HPLC purity detecting figure.
Figure 11 is control figure in embodiment 3 second step reaction end HPLC.
Figure 12 is the HPLC purity detecting figure of embodiment 3 finished product formula III compounds.
Embodiment
For making the object, technical solutions and advantages of the present invention more cheer and bright, the present invention adopts following specific embodiment to elaborate to technical scheme of the present invention.
(1) in 500mL four-hole boiling flask, add formula I compound 25g, tetrahydrofuran (THF) 300mL, Anhydrous potassium carbonate 48g, ethyl bromoacetate 58g, crown ether 0.5g, be warming up to backflow, middle control detects (Fig. 1 is control figure in reaction end HPLC), reacts about 3h and finishes, filter, filtrate decompression distillation, adds 100mL ethanol ice bath making beating 3-4h, filter cake ice alcohol flushing after finishing.Put into 45 ℃ of baking ovens, dry, obtain formula II compound 36g, yield is 90%, and purity is that 99.84%, Fig. 2 is formula II compound H PLC purity detecting figure.
(2) in 500mL four-hole boiling flask, add formula II compound 25g, tetrahydrofuran (THF) 215mL, dissolves and is cooled to 5 ℃.9.7g sodium hydroxide is dissolved in 190mL purified water, is cooled to 10 ℃ and adds in four-hole boiling flask.Be warming up to backflow, middle control detection (Fig. 3 is control figure in reaction end HPLC) is reacted about 1-2h and is finished.Underpressure distillation, tune pH value is 8.5-9, adds the strontium chloride aqueous solution (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 alcohol flushing filter cake, put into 45 ℃ of baking ovens, dry, obtain formula III Strontium Ranelate finished product 30.5g, yield is 85%, and purity is 99.82%, single maximum contaminant: 0.06%, Fig. 4 is finished product HPLC purity detecting figure.
(1) in 1000mL four-hole boiling flask, add formula I compound 50g, tetrahydrofuran (THF) 600mL, salt of wormwood 96g, ethyl bromoacetate 118g, crown ether 1.0g, be warming up to backflow, in HPLC, control (Fig. 5 is control figure in reaction end HPLC), reacts about 3h and finishes, filter, filtrate decompression distillation, adds 200mL ethanol ice bath making beating 3-4h, filter cake ice alcohol flushing after finishing.Put into 45 ℃ of baking ovens, dry, obtain formula II compound 72g, yield is 90%, and purity is that 99.92%, Fig. 6 is the HPLC purity detecting figure of formula II compound.
(2) in 1000mL four-hole boiling flask, add formula II compound 50g, tetrahydrofuran (THF) 430mL, dissolves and is cooled to 10 ℃.19.4g sodium hydroxide is dissolved in 360mL purified water, is cooled to 10 ℃ and adds in four-hole boiling flask.Be warming up to backflow, middle control detects (Fig. 7 is control figure in reaction end HPLC) about 2-3h reaction and finishes.Underpressure distillation, tune pH value is 8.5-9, adds the strontium chloride aqueous solution (strontium chloride 76g, purified water 368.6mL) stirring at normal temperature crystallization 0.5-1h, after be warming up to backflow, filter, with purified water and alcohol flushing filter cake, put into 45 ℃ of baking ovens, dry, obtain formula III Strontium Ranelate finished product 63g, yield is 91.5%, and purity is 99.80%, single maximum contaminant: 0.06%, Fig. 8 is finished product HPLC purity detecting figure.
embodiment 3
(1) in 20L reactor, add formula I compound 1kg, tetrahydrofuran (THF) 12L, salt of wormwood 1.92kg, ethyl bromoacetate 2.3kg, crown ether 20g, is warming up to backflow, control (Fig. 9 is control figure in reaction end HPLC) in HPLC, reacting about 3-4h finishes, filter filtrate decompression distillation, 4L ethanol ice bath making beating 3-4h, filter, filter cake ice alcohol flushing, puts into 45 ℃ of baking ovens, dries, obtain formula II compound 1.25kg, yield is 91%, and purity is that 99.86%, Figure 10 is formula II compound H PLC purity detecting figure.
(2) in the reaction ax of 50L, add formula II compound 2kg, tetrahydrofuran (THF) 17.2L, dissolves and is cooled to 5 ℃, and 0.78kg sodium hydroxide is dissolved in 14L purified water, is chilled to 5-10 ℃ and joins in reactor.Be warming up to backflow, react control (Figure 11 is control figure in reaction end HPLC) in about 3.5-4h sampling, after underpressure distillation, pH value is adjusted to 8.5-9, add the strontium chloride aqueous solution (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 alcohol flushing filter cake, put into 45 ℃ of oven dryings, obtain formula III Strontium Ranelate finished product 2.7kg, yield is 90%, purity is 99.86%, and single maximum contaminant: 0.06%, Figure 12 is finished product HPLC purity detecting figure.
Above-described embodiment is only in order to illustrate technical scheme of the present invention; but not design of the present invention and protection domain are limited; those of ordinary skill in the art modifies or is equal to replacement technical scheme of the present invention; and not departing from aim and the scope of technical scheme, it all should be encompassed in claim scope of the present invention.
Claims (11)
1. by a method of controlling standby high purity Strontium Ranelate in HPLC method, it is characterized in that: comprise the steps:
(1) prepare formula II compound: formula I compound, tetrahydrofuran (THF), Anhydrous potassium carbonate, ethyl bromoacetate are dropped in reactor and reacted under catalyst, be warming up to backflow, middle control detects, reaction finishes, after filtration, and underpressure distillation, the making beating of ethanol ice bath, filter, use alcohol flushing filter cake, dry and obtain formula II compound;
(Ⅰ)
(Ⅱ)
(2) prepare formula III compound: formula II compound is dissolved in to tetrahydrofuran solution, be added drop-wise to and in inorganic base aqueous solution, carry out saponification reaction, in HPLC, control, through underpressure distillation, filtration, hydrochloric acid regulates after pH value, add the strontium chloride aqueous solution, obtain formula III Strontium Ranelate crude product, the dry target finished product that obtains.
(Ⅲ)
2. a kind of method with controlling standby high purity Strontium Ranelate in HPLC method according to claim 1, is characterized in that: the mol ratio 1.0:3.5-4.5:3-5 of formula I compound, Anhydrous potassium carbonate and ethyl bromoacetate in described step (1).
3. a kind of method with controlling standby high purity Strontium Ranelate in HPLC method according to claim 1, is characterized in that: the catalyzer in described step (1) is Tetrabutyl amonium bromide, crown ether, KF/Al
2o
3, the mass ratio of raw material and catalyzer is 1:0.008-0.025.
4. a kind of method with controlling standby high purity Strontium Ranelate in HPLC method according to claim 1, is characterized in that: the temperature of reaction of described step (1) is 50-90 ℃.
5. a kind of method with controlling standby high purity Strontium Ranelate in HPLC method according to claim 1, is characterized in that: ethanol low temperature making beating in described step (1), and temperature is 0-10 ℃, the time is 3-5h.
6. a kind of method with controlling standby high purity Strontium Ranelate in HPLC method according to claim 1, it is characterized in that: described step (2) is hydrolyzed and is first cooled to 20-30 ℃ in inorganic base aqueous solution, then be warming up to backflow, reaction end HPLC monitoring.
7. according to a kind of method with controlling standby high purity Strontium Ranelate in HPLC method described in claim 1 or 6, it is characterized in that: described in described step (2), inorganic base aqueous solution is the sodium hydroxide solution of being prepared by purified water.
8. a kind of method with controlling standby high purity Strontium Ranelate in HPLC method according to claim 7, is characterized in that: in the inorganic base aqueous solution of described step (2), the mass ratio of sodium hydroxide and purified water is 1:18-25.
9. a kind of method with controlling standby high purity Strontium Ranelate in HPLC method according to claim 1, is characterized in that: described step (2) dilute hydrochloric acid regulates PH to 8.5-9.
10. a kind of method with controlling standby high purity Strontium Ranelate in HPLC method according to claim 1, is characterized in that: after described step (2) stirring at normal temperature crystallization 0.5-1h, be warming up to backflow.
11. a kind of methods with controlling standby high purity Strontium Ranelate in HPLC method according to claim 1, it is characterized in that: described HPLC: chromatographic column: octadecyl silane is weighting agent, moving phase: acetonitrile-water (75:25), PH3.0, flow velocity: 1.0ml/min, detect wavelength: 237nm, sampling volume: 10 μ l.
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| CN (1) | CN103804345B (en) |
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| 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 |
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