CN102367247B - A kind of method of preparing high purity good stability strontium ranelate - Google Patents
A kind of method of preparing high purity good stability strontium ranelate Download PDFInfo
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- CN102367247B CN102367247B CN201110290289.1A CN201110290289A CN102367247B CN 102367247 B CN102367247 B CN 102367247B CN 201110290289 A CN201110290289 A CN 201110290289A CN 102367247 B CN102367247 B CN 102367247B
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- strontium ranelate
- strontium
- organic solvent
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- aqueous solution
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- 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 description 45
- 229940079488 strontium ranelate Drugs 0.000 title claims abstract description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000007864 aqueous solution Substances 0.000 claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 14
- AHBGXTDRMVNFER-UHFFFAOYSA-L Strontium chloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 239000000243 solution Substances 0.000 claims abstract description 10
- 229940013553 strontium chloride Drugs 0.000 claims abstract description 10
- 229910001631 strontium chloride Inorganic materials 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
- 238000007127 saponification reaction Methods 0.000 claims abstract description 5
- 238000005406 washing Methods 0.000 claims abstract description 5
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000011780 sodium chloride Substances 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- CIOAGBVUUVVLOB-UHFFFAOYSA-N strontium Chemical compound [Sr] CIOAGBVUUVVLOB-UHFFFAOYSA-N 0.000 claims description 4
- 229910052712 strontium Inorganic materials 0.000 claims description 4
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 20
- 239000012535 impurity Substances 0.000 abstract description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 6
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 6
- LAPGMTOHOQPDGI-UHFFFAOYSA-N 4-amino-2,5-difluorobenzonitrile Chemical group NC1=CC(F)=C(C#N)C=C1F LAPGMTOHOQPDGI-UHFFFAOYSA-N 0.000 abstract 1
- HGAPCFNXSLPISY-UHFFFAOYSA-N S1C=CC=C1.C(=O)OCC Chemical class S1C=CC=C1.C(=O)OCC HGAPCFNXSLPISY-UHFFFAOYSA-N 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 4
- UUCCCPNEFXQJEL-UHFFFAOYSA-L Strontium hydroxide Chemical compound [OH-].[OH-].[Sr+2] UUCCCPNEFXQJEL-UHFFFAOYSA-L 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 210000000988 Bone and Bones Anatomy 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229960000583 Acetic Acid Drugs 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001866 strontium hydroxide Inorganic materials 0.000 description 1
- RXSHXLOMRZJCLB-UHFFFAOYSA-L strontium;diacetate Chemical compound [Sr+2].CC([O-])=O.CC([O-])=O RXSHXLOMRZJCLB-UHFFFAOYSA-L 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Abstract
Strontium Ranelate that pH value is 8.5～10.0 that the present invention relates to a kind of high-purity and good stability and preparation method thereof.The method is by compound (II) 5 [double (2 ethyoxyl 2 oxoethyl) amino] 4 cyano group 3 (2 ethyoxyl 2 oxoethyl) 2 thiophene ethyl formates, join and organic solvent, inorganic base aqueous solution carry out saponification, separatory removes organic solvent afterwards, 10～10 DEG C regulate PH to 9.5～12 with hydrochloric acid, water layer is evaporated organic solvent, add strontium chloride aqueous solution, obtain Strontium Ranelate crude product；Crude product is added in hydrothermal solution, regulate pH to 9～13, heat filtering, washing with hot water, be dried to obtain Strontium Ranelate.The present invention can obtain Strontium Ranelate with preferable yield and purity, not only can control single impurity (especially decarboxylation impurity) and product purity reaches medicinal standard, and the stability of product is preferable.
Description
Technical field
The present invention relates to be suitable for high-purity and the Strontium Ranelate that pH value is 8.5～10.0 of good stability of industrialized production
And preparation method thereof.
Background technology
Strontium Ranelate (strontium ranelate) is to be developed by Servier company, on November 15th, 2004 first
Listing in Ireland, the same year, December listed in Britain on the 1st, within 2005, listed in India, and this medical instrument has the most valuable pharmacology
Effect, particularly in terms of osteoporosis: it can promoting bone growing, simultaneously bone can also be suppressed heavily to absorb.Make this compound
For treating osteopathia.
Compound patent EP0415850 of Strontium Ranelate discloses some preparation methoies of Strontium Ranelate.
Which disclose three kinds of methods preparing Strontium Ranelate with compound (II).
Method one: being joined by compound (II) in the sodium hydroxide solution of alcohol water mixing and hydrolyze, water layer hydrochloric acid is acidified
After, then with acidic resins process remove sodium ion, residue first with after ether with oxolane or acetone recrystallization, then with chlorination
Strontium becomes salt in water.Eight hydrates of Strontium Ranelate can be generated in this way, be dried under dry gas stream, generate seven aquations
Compound, is dried to obtain corresponding four hydrates at decompression (10mmHg) 55 DEG C, but preparation method is more complicated, and product purity is the most not
High.
Method two: compound (II) is joined in the sodium hydroxide solution of alcohol water mixing and hydrolyze, by all molten after hydrolysis
Agent is evaporated, and obtains tetrasodium salt solid, then becomes salt with strontium chloride, but the easy moisture absorption of sodium salt, inconvenient operation, and yield is less than
70%, product purity is the highest.
Method three: compound (II) is joined in the strontium hydroxide solution of alcohol water mixing and hydrolyze, then steam ethanol, surplus
100 DEG C of heat filterings of lower aqueous solution, washing, obtain Strontium Ranelate eight hydrate.But Strontium Ranelate in common solvent almost
Insoluble, the product that this method obtains almost cannot purify, it is difficult to realizes industrialized production.
EP1403266 improves method three in EP0415850, by compound (II) back flow reaction in Strontium hydrate ./water,
Refilter to obtain product.Product purity is the highest.
US2009082578 improves the technique of method two in EP0415850, and compound (II) exists bar at organic solvent
Under part, and sodium hydroxide or potassium hydroxide aqueous solution saponification at ambient temperature, then under organic solvent existence condition, add
Enter strontium chloride aqueous solution crystallize, filter to obtain Strontium Ranelate.But find during repeating patent, when organic solvent existence condition
Under, there is a small amount of incomplete saponified residual, it is impossible to remove in refined；It is residual that another gained crude product contains more Strontium hydrate.
Stay.
Patent CN1995034 discloses the purification of Strontium Ranelate: crude product is added acid for adjusting pH and makes it dissociate into thunder Buddhist nun acid,
It is subsequently adding alkali and is transferred to alkalescence, then the method forming Strontium Ranelate purifies, although the method can purify, but refined receipts
Rate is low, and crude product refining yield only has 75%～85%, and acid adjustment process is readily incorporated decarboxylation impurity, the carboxylic acid as shown in formula (III)
Or its salt.
CN101747316 discloses the preparation method of a kind of high-purity strontium ranelate, compound (II) is joined water or
The sodium hydroxide solution of water/organic solvent mixing hydrolyzes, becomes salt with adjusting pH to 4～7 to be subsequently adding strontium acetate, filter get Lei Ni
Acid strontium, purity is higher, and single miscellaneous less, but under the conditions of pH is relatively low in actual industrialization operates, is likely to be due to the process time
Extending causes decarboxylation impurity ([formula (III) or its salt]) to raise, and product stability is bad.
To sum up, it is the highest to there is product purity in existing Strontium Ranelate preparation method, or purity is higher but single miscellaneous control not
Good, or purity and single miscellaneous control all preferably but the not enough situation of product stability, the present inventor, for case above, have developed
A kind of applicable industrialized synthetic method, it can obtain Strontium Ranelate with preferable yield and purity, not only can control single
Impurity (especially decarboxylation impurity) and product purity reach medicinal standard, and the stability of product is preferable.
Summary of the invention
Present inventor have developed a kind of applicable industrialized synthetic method, and it can obtain with preferable yield and purity
Obtain Strontium Ranelate, single impurity (especially decarboxylation impurity) can be controlled and product purity reaches medicinal standard, and it stores steady
Qualitative also preferable, under the conditions of hot and humid, Acceleration study etc. is various, product purity is the most stable.
Specifically, the invention provides the synthetic method of a kind of Strontium Ranelate preparing structure formula (I), comprise following step
Rapid:
1) compound (II) joins in organic solvent, and wherein the volumetric usage of organic solvent is compound (II) quality
1-3 times (ml/g), adds the inorganic base aqueous solution of 4.5～5.5 times amount (ml/g) compounds (II), issues temperature 10～35 DEG C
Raw saponification 4～6h.
2) separatory, cools to-10～10 DEG C and removes with salt acid for adjusting pH value to 9.5～12, water layer 10～30 DEG C of concentrating under reduced pressure
Strontium chloride aqueous solution, crystallize 5～15h is added after removing organic solvent.Filter to obtain Strontium Ranelate crude product.Preferably arrive with salt acid for adjusting pH
10～11.
3) crude product Strontium Ranelate filter cake joining pH is in 9～13 boiling water, 80～100 DEG C of making beating 10min～3h.Hot mistake
Filter, filter cake hot wash, it is dried and is prepared into Strontium Ranelate four water thing, five water things, six water things, seven water things, eight water things.Wherein institute
State pH value and be preferably adjusted to 10～12.
Wherein the organic solvent described in step 1 is selected from oxolane, acetone, and inorganic base aqueous solution is selected from sodium hydroxide
Aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution.
Step 2 uses the strontium chloride mole dosage of strontium chloride aqueous solution to be compound (II) 2-2.5 times amount (mol/mol).
By above each step, particularly during the control of pH value so that the present invention is obtained in that yield is high and purity
Height, the product of good stability.
The pH of above method gained Strontium Ranelate between 8.5～10.0 (stability of the relatively low sample of pH is the best) it is steady
Qualitative situation see table:
Wherein decarboxylation impurity i.e. formula (III) compound or its salt
Hot and humid condition is: 60 DEG C, 75%RH ,+four layers of composite film packaging of Polythene Bag
Acceleration environment is: 40 DEG C, 75%RH ,+four layers of composite film packaging of Polythene Bag
Detailed description of the invention
Below example is to describe the present invention, and the unrestricted present invention in detail.
Embodiment 1
Take 5-[double (2-ethyoxyl-2-oxoethyl) amino]-4-cyano group-3-(2-ethyoxyl-2-oxoethyl)-2-thiophene
Fen Ethyl formate (20g, 0.044mol), oxolane 40ml stir, and cool to 0 DEG C of dropping sodium hydroxide 8.8g (0.22mol)
Aqueous solution 90ml, temperature control 10～25 DEG C reaction 5h, separatory, 0～10 DEG C dropping 3.5g concentrated hydrochloric acid regulation pH be 11, decompression is spin-dried for
Oxolane, adds activated carbon 2g stirring at normal temperature 1h, filters, the lower aqueous solution 80ml adding six water strontium chloride 35g of stirring, room temperature
Crystallize 15h, filters to obtain Strontium Ranelate crude product.
Filter cake joins in hot water 160ml, regulates pH to 11.0, is heated to 85 DEG C and keeps 1h, heat filtering.Hot water 20ml washes
Wash.
Drying to obtain Strontium Ranelate finished product, yield 88%, HPLC:99.92%, maximum list is miscellaneous: 0.03%, pH=8.9.
Strontium Ranelate have related substance HPLC analyze method:
Instrument: high performance liquid chromatograph is equipped with UV-detector
Chromatographic column: Waters SunfireTM C18 250×4.6mm 5μm
Mobile phase A: 0.5mL perchloric acid is dissolved in (pH value is about 2.3) in 1000mL water
Mobile phase B: acetonitrile
Diluent: in 0.1mL ammonia to 1000mL water
Chromatographic column temperature: 30 DEG C of detection wavelength: 306nm
Flow velocity: 1.0mL/min runs 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 |
Weigh 25mg strontium ranelate test sample, accurately weighed in 50mL volumetric flask, dissolve with diluent and be diluted to carve
Degree, mixing.(strontium ranelate concentration: 0.5mg/mL)
Embodiment 2
Take 5-[double (2-ethyoxyl-2-oxoethyl) amino]-4-cyano group-3-(2-ethyoxyl-2-oxoethyl)-2-thiophene
Fen Ethyl formate (20g, 0.044mol), oxolane 40ml stir, and cool to 0 DEG C of dropping sodium hydroxide 8.8g (0.22mol)
Aqueous solution 90ml, temperature control 10～25 DEG C reaction 5h, separatory, 0～10 DEG C dropping 2.4g glacial acetic acid regulation pH be 10, decompression is spin-dried for
Oxolane, adds activated carbon 2g stirring at normal temperature 1h, filters, the lower aqueous solution 80ml adding six water strontium chloride 35g of stirring, room temperature
Crystallize 15h, filters to obtain Strontium Ranelate crude product.
Filter cake joins in hot water 160ml, regulates pH to 11, is heated to 85 DEG C and keeps 1.5h, heat filtering.Hot water 20ml washes
Wash.
Drying to obtain Strontium Ranelate finished product, yield 91%, HPLC:99.97%, maximum list is miscellaneous: 0.02%, pH=8.5.
Embodiment 3
Take 5-[double (2-ethyoxyl-2-oxoethyl) amino]-4-cyano group-3-(2-ethyoxyl-2-oxoethyl)-2-thiophene
Fen Ethyl formate (20g, 0.044mol), oxolane 40ml stir, and cool to 0 DEG C of dropping potassium hydroxide 12.2g (0.22mol)
Aqueous solution 90ml, temperature control 10～25 DEG C of reaction 5h, separatory, with salt acid for adjusting pH to 12, decompression is spin-dried for oxolane, adds and lives
Property charcoal 2g stirring at normal temperature 1h, filter, lower aqueous solution 80ml, the room temperature crystallize 15h adding six water strontium chloride 35g of stirring, filter
Strontium Ranelate crude product.
Filter cake joins in hot water 160ml, regulates pH to 11.2, is heated to 85 DEG C and keeps 1.5h, heat filtering.Hot water 20ml
Washing.
Drying to obtain Strontium Ranelate finished product, yield 85%, HPLC:99.82%, maximum list is miscellaneous: 0.04%, pH=9.2.
Embodiment 4
Take 5-[double (2-ethyoxyl-2-oxoethyl) amino]-4-cyano group-3-(2-ethyoxyl-2-oxoethyl)-2-thiophene
Fen Ethyl formate (20g, 0.044mol), the water 80ml solution of acetone 30ml and NaOH (8g, 0.2mol), join reaction bulb
In, stirring, control reaction temperature, at 10-30 DEG C, reacts 5h.After separatory-10～10 DEG C with salt acid for adjusting pH to 9.5, filtrate 35
DEG C concentrating under reduced pressure 1h removes organic solvent, adds 2g activated carbon stirring 1h, filters.
The lower water 136ml solution adding six water strontium chlorides (25.8g, 0.092mol) of stirring.Room temperature crystallize 15h, filtration
Strontium Ranelate crude product.
Filter cake joins in hot water 160ml, regulates pH to 11.5, is heated to 95 DEG C and keeps 5min, heat filtering.Boiling water 20ml
Washing.
Drying to obtain Strontium Ranelate finished product, yield 82%, HPLC:99.80%, maximum list is miscellaneous: 0.05%, pH=8.6.
Embodiment 5
Take 5-[double (2-ethyoxyl-2-oxoethyl) amino]-4-cyano group-3-(2-ethyoxyl-2-oxoethyl)-2-thiophene
Fen Ethyl formate (20g, 0.044mol), the water 80ml solution of ethanol 40ml and LiOH (6.3g, 0.26mol), join reaction
In Ping, stirring, control reaction temperature, at 10-30 DEG C, reacts 6h.Cool to-10～10 DEG C with salt acid for adjusting pH to 11, filtrate 35
DEG C concentrating under reduced pressure removes ethanol, adds 2g activated carbon stirring 1h, filters.
The lower water 136ml solution adding six water strontium chlorides (30g, 0.112mol) of stirring.Room temperature crystallize 15h, the thunder of filtration
Buddhist nun's acid strontium crude product.
Filter cake joins in hot water 160ml, regulates pH to 11.0, is heated to 90 DEG C and keeps 30min, heat filtering.Boiling water
20ml washs.
Drying to obtain Strontium Ranelate finished product, yield 84%, HPLC:99.83%, maximum list is miscellaneous: 0.04%, pH=8.7.
Claims (6)
1. a stable Strontium Ranelate (5-[double (carboxymethyl) amino]-2-carboxyl-4-cyano group-3-thiophene acetic acid two strontium), its
The pH value being characterised by this Strontium Ranelate is 8.5～10.0
。
2. the method preparing Strontium Ranelate as claimed in claim 1, it is characterised in that comprise the following steps: (1) generalization
Compound (II) 5-[double (2-ethyoxyl-2-oxoethyl) amino]-4-cyano group-3-(2-ethyoxyl-2-oxoethyl)-2-thiophene
Ethyl formate, joins and carries out saponification in organic solvent, inorganic base aqueous solution；
(2) saponification is complete, and separatory removes organic solvent ,-10～10 DEG C with salt acid for adjusting pH to 9.5～12, water layer is evaporated organic
Solvent, adds activated carbon stirring and adsorbing, after filtering off activated carbon, adds strontium chloride aqueous solution, obtains Strontium Ranelate crude product；
(3) the Strontium Ranelate crude product of gained is added in hydrothermal solution, regulate pH to 9～13, heat filtering, washing with hot water, do
Dry obtain Strontium Ranelate.
Preparation method the most according to claim 2, it is characterised in that with salt acid for adjusting pH to 10～11 in step (2).
Preparation method the most according to claim 2, it is characterised in that the quality of the activated carbon that step (2) uses is compound (II)
The 5%～20% of quality.
Preparation method the most according to claim 2, it is characterised in that after step (2) addition activated carbon, stirring and adsorbing temperature is 15 DEG C
～35 DEG C.
Preparation method the most according to claim 2, it is characterised in that regulate pH to 10～12 with hot water in step (3).
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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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| 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 CN102367247A (en) | 2012-03-07 |
| CN102367247B true 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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