CN1304401C - Method for preparing Alendronic acid - Google Patents
Method for preparing Alendronic acid Download PDFInfo
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- CN1304401C CN1304401C CNB2004100991049A CN200410099104A CN1304401C CN 1304401 C CN1304401 C CN 1304401C CN B2004100991049 A CNB2004100991049 A CN B2004100991049A CN 200410099104 A CN200410099104 A CN 200410099104A CN 1304401 C CN1304401 C CN 1304401C
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- Prior art keywords
- jidingsuan
- alendronic acid
- acid
- phosphorus trichloride
- solvent
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- 238000000034 method Methods 0.000 title claims abstract 4
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 title claims description 41
- 229960004343 alendronic acid Drugs 0.000 title claims description 41
- 238000010992 reflux Methods 0.000 claims abstract description 44
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims abstract description 30
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 239000012442 inert solvent Substances 0.000 claims abstract description 12
- 238000009835 boiling Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 40
- 238000010438 heat treatment Methods 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 29
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- 235000015110 jellies Nutrition 0.000 claims description 24
- 239000008274 jelly Substances 0.000 claims description 24
- 238000013019 agitation Methods 0.000 claims description 20
- 238000001816 cooling Methods 0.000 claims description 20
- 239000012153 distilled water Substances 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 20
- 239000002244 precipitate Substances 0.000 claims description 20
- 239000003292 glue Substances 0.000 claims description 19
- 238000009413 insulation Methods 0.000 claims description 19
- 238000003756 stirring Methods 0.000 claims description 19
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 5
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229920006048 Arlen™ Polymers 0.000 abstract 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 abstract 2
- 238000012805 post-processing Methods 0.000 abstract 1
- 239000000843 powder Substances 0.000 description 18
- 208000001132 Osteoporosis Diseases 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 3
- 101100232929 Caenorhabditis elegans pat-4 gene Proteins 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 3
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000001177 diphosphate Substances 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940078581 Bone resorption inhibitor Drugs 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
Abstract
The present invention relates to an arlen phosphonic acid preparation method which comprises the following steps: gamma-aminobutanoic acid, phosphorus trichloride and phosphorous acid are taken as raw materials and react at refluxing temperature, under the existence of inert solvents with boiling point or initial boiling point between 50 and 90DEGC; arlen phosphonic acid as the product is obtained through post-processing; the refluxing temperature (reaction temperature) of the inert solvents is approximately equal to boiling point (or initial boiling point). The method can perfectly control reaction temperature, cause reaction to be capable of being stably carried out and greatly enhance the security of production, and the method has a good industrialization addition prospect.
Description
(1) technical field
The present invention relates to a kind of preparation method of Alendronic acid.
(2) background technology
Osteoporosis brings huge misery for countless gerontal patient and families thereof, and this has caused the concern of the whole society.As far back as the seventies, just the someone brings into use diphosphate to treat osteoporosis, and systematically be applied to clinical the eighties, becomes the medicine of the important protect against osteoporosis of a class gradually.Sodium alendronate (Alendronate sodium) is the medicine of the third generation diphosphate treatment osteoporosis of having gone on the market, is a kind of new and effective bone resorption inhibitor.The reaction formula of the precursor Alendronic acid of synthetic preparation sodium alendronate is as follows:
U.S. Pat 4 407 761 and US 4 621 077 make solvent with chlorobenzene, are raw material with gamma-aminobutyric acid, phosphorous acid, phosphorus trichloride, by reacting by heating, and hydrochloric acidolysis, refining Alendronic acid.Solvent chlorobenzene low price, raw materials cost is lower, but there is the serious safety problem of dashing material in this technology, easily the autoacceleration exothermic effects takes place and out of control when temperature of reaction surpasses 85 ℃, thus material is dashed in outburst; U.S. Pat 4 705 651 is a solvent with excessive phosphorus trichloride and phosphorous acid, by gamma-aminobutyric acid, phosphorous acid, phosphorus trichloride reaction, again through follow-up react Alendronic acid.Reactant as solvent is excessive greatly, and solvent is difficult to recycle, so cost is too high, is not suitable for suitability for industrialized production, and solvent can not be stablized control reaction temperature; U.S. Pat 4 922 007 is made solvent with methylsulphonic acid, also by gamma-aminobutyric acid, phosphorous acid, phosphorus trichloride reaction, again through follow-up react Alendronic acid.As solvent, reclaim by both uneconomical also being difficult for methanesulfonic at high price for this technology, and the purity that not only influences product also can be brought certain trouble to environment protection, and solvent can not be stablized control reaction temperature.In addition, amplifying under the situation of scale, these three kinds of operational paths all exist from heat release and dash material serious problems out of control, and this is that suitability for industrialized production never allows.
The condition of influence preparation Alendronic acid has: reaction solvent, the mol ratio of γ-An Jidingsuan, phosphorous acid, phosphorus trichloride, temperature of reaction and reaction times, wherein reaction solvent is the important factor that can reaction steadily be carried out, and other conditions then are the productive rates of influence reaction.
(3) summary of the invention
For overcome in the prior art temperature of reaction be difficult to control easy generation from heat release the deficiency towards the material problem, the invention provides a kind of preparation method who makes the Alendronic acid that the reaction safety and steady carries out.
The technical solution adopted for the present invention to solve the technical problems is: a kind of preparation method of Alendronic acid, it is characterized in that comprising the following steps: with γ-An Jidingsuan, phosphorus trichloride and phosphorous acid are raw material, in boiling point in the presence of the inert solvent between 50～90 ℃, reaction is 5 hours under reflux temperature, remove by filter solvent, get jelly, jelly is added an amount of distilled water make dissolving, continued reflux 0.5～1.5 hour, use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure after the cooling, under agitation is added drop-wise to concentrated solution in 40～60 ℃ of an amount of hot methanols, produce white precipitate, cold after-filtration separate the product Alendronic acid.
Wherein, γ-An Jidingsuan: phosphorus trichloride: the molar ratio of phosphorous acid is 1: 1.2～1.6: 1.2～1.6, be more preferably 1: 1.2: 1.2, the consumption of inert solvent is 0.5～20 times of quality to γ-An Jidingsuan, and preferably 3～10 times to the quality of γ-An Jidingsuan.
Preferably, described inert solvent is selected from one of following: hexanaphthene, benzene, normal hexane or its mixed solvent.Preferred, described inert solvent is a hexanaphthene.
More recommend the step of preparation Alendronic acid as follows: the γ-An Jidingsuan that with mol ratio is 1: 1.2, phosphorous acid joins 5 times in the hexanaphthene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing, insulation, treat that solution is translucent behind the glue, begin to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans, continued heated and stirred 3.5～4.5 hours, stop heating, be cooled to room temperature, remove by filter solvent, get jelly, jelly is added an amount of distilled water make the jelly dissolving, continued reflux 0.5～1.5 hour, use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in 40～60 ℃ of an amount of hot methanols, produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder.
The preparation method's of Alendronic acid of the present invention beneficial effect mainly shows: the temperature of reaction of inert solvent is that reflux temperature is substantially equal to boiling point, can control the temperature of reaction well, reaction can stably be carried out, improve the security of producing widely, had good industrial applications prospect.
(4) embodiment
Below in conjunction with the drawings and specific embodiments the present invention is further described.
Embodiment one
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 5 times in the hexanaphthene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans.Continued heated and stirred 4 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 58%.
Embodiment two
With mol ratio is that 1: 1.4 γ-An Jidingsuan, phosphorous acid joins 5 times in the benzene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans.Continued heated and stirred 3.5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 57.5%.
Embodiment three
With mol ratio is that 1: 1.3 γ-An Jidingsuan, phosphorous acid joins 5 times in the normal hexane of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans.Continued heated and stirred 8 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 57%.
Embodiment four
Is that 1: 1.3 γ-An Jidingsuan, phosphorous acid joins 0.5 times in the normal hexane of γ-An Jidingsuan weight with mol ratio with mol ratio, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans.Continued heated and stirred 5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (40 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 55.3%.
Embodiment five
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 20 times in the hexanaphthene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.5 equivalent γ-An Jidingsuans.Continued heated and stirred 3.5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1.5 hours.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 56.8%.
Embodiment six
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 3 times in the hexanaphthene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.4 equivalent γ-An Jidingsuans.Continued heated and stirred 4.5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 0.5 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (45 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 56.3%.
Embodiment seven
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 10 times in the benzene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans.Continued heated and stirred 4 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 57.8%.
Embodiment eight
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 2 times in the hexanaphthene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.4 equivalent γ-An Jidingsuans.Continued heated and stirred 4 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (60 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 56.6%.
Embodiment nine
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 15 times in the normal hexane of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.3 equivalent γ-An Jidingsuans.Continued heated and stirred 5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1.5 hours.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 56.9%.
Embodiment ten
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 5 times in the mixed solvent of the hexanaphthene of γ-An Jidingsuan weight and benzene, stir down, heating in water bath is to refluxing, insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans.Continued heated and stirred 4 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (55 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 57.2%.
Embodiment 11
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 7 times in the hexanaphthene and normal hexane mixed solvent of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing, insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.3 equivalent γ-An Jidingsuans.Continued heated and stirred 5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1.5 hours.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 56.6%.
Embodiment 12
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins in 12 times of hexanaphthenes to γ-An Jidingsuan weight, benzene and the normal hexane mixed solvent, stir down, heating in water bath is to refluxing, insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.4 equivalent γ-An Jidingsuans.Continued heated and stirred 5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 57.4%.
Embodiment 13
With mol ratio is that 1: 1.3 γ-An Jidingsuan, phosphorous acid joins in the mixed solvent of 7 times of normal hexanes to γ-An Jidingsuan weight, benzene, stir down, heating in water bath is to refluxing, insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.3 equivalent γ-An Jidingsuans.Continued heated and stirred 5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 57.1%.
Embodiment 14
With mol ratio is that 1: 1.4 γ-An Jidingsuan, phosphorous acid joins 5 times in the hexanaphthene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.4 equivalent γ-An Jidingsuans.Continued heated and stirred 3.5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1.5 hours.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 57.7%.
Embodiment 15
With mol ratio is that 1: 1.4 γ-An Jidingsuan, phosphorous acid joins 5 times in the sherwood oil of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.5 equivalent γ-An Jidingsuans.Continued heated and stirred 5 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 56.9%.
Embodiment 16
With mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins in 6 times of hexanaphthenes to γ-An Jidingsuan weight, the sherwood oil mixed solvent, stir down, heating in water bath is to refluxing, insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans.Continued heated and stirred 4 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 56.4%.
Embodiment 17
With mol ratio is that 1: 1.5 γ-An Jidingsuan, phosphorous acid joins in 5 times of hexanaphthenes to γ-An Jidingsuan weight, sherwood oil, the benzene mixed solvent, stir down, heating in water bath is to refluxing, insulation, treat that solution is translucent behind the glue, begins to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans.Continued heated and stirred 4 hours.Stop heating, be cooled to room temperature, remove by filter solvent; Add an amount of distilled water subsequently and make the jelly dissolving, continued reflux 1 hour.Use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure, after the cooling, under agitation concentrated solution is added drop-wise in an amount of hot methanol (50 ℃), produces white precipitate, cold after-filtration separate the Alendronic acid white crystalline powder, m.p.229 ℃, productive rate 57.3%.
Claims (6)
1. the preparation method of an Alendronic acid, it is characterized in that comprising the following steps: that with γ-An Jidingsuan, phosphorus trichloride and phosphorous acid be raw material, initial boiling point is in the presence of the inert solvent between 50～90 ℃, and reaction is 5 hours under reflux temperature, gets the product Alendronic acid through aftertreatment; Wherein: the molar ratio of described γ-An Jidingsuan, phosphorus trichloride, phosphorous acid is 1: 1.2～1.6: 1.2～1.6, and the consumption of described inert solvent is 0.5～20 times of quality of γ-An Jidingsuan;
Described aftertreatment is carried out according to the following step: remove by filter solvent, get jelly, jelly is added an amount of distilled water make dissolving, continued reflux 0.5～1.5 hour, use activated carbon decolorizing, filter clear colorless solution, concentrating under reduced pressure after the cooling, under agitation is added drop-wise to concentrated solution in 40～60 ℃ of an amount of hot methanols, produce white precipitate, cold after-filtration separate the product Alendronic acid.
2. the preparation method of Alendronic acid as claimed in claim 1, it is characterized in that: the mol ratio of described γ-An Jidingsuan, phosphorus trichloride, phosphorous acid is 1: 1.2: 1.2.
3. the preparation method of Alendronic acid as claimed in claim 1 is characterized in that: described inert solvent is selected from one of following: hexanaphthene, benzene, normal hexane, sherwood oil or its mixed solvent.
4. the preparation method of Alendronic acid as claimed in claim 3, it is characterized in that: described inert solvent is a hexanaphthene.
5. the preparation method of Alendronic acid as claimed in claim 1 is characterized in that: the consumption of described inert solvent is 3～10 times of quality of γ-An Jidingsuan.
6. the preparation method of Alendronic acid as claimed in claim 1, it is characterized in that described method prepares as follows: with mol ratio is that 1: 1.2 γ-An Jidingsuan, phosphorous acid joins 5 times in the hexanaphthene of γ-An Jidingsuan weight, stir down, heating in water bath is to refluxing, insulation, treat that solution is translucent behind the glue, begin to drip the phosphorus trichloride that is equivalent to 1.2 equivalent γ-An Jidingsuans, continued heated and stirred 3.5～4.5 hours, stop heating, be cooled to room temperature, get the product Alendronic acid through aftertreatment.
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| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100991049A CN1304401C (en) | 2004-12-28 | 2004-12-28 | Method for preparing Alendronic acid |
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| CNB2004100991049A CN1304401C (en) | 2004-12-28 | 2004-12-28 | Method for preparing Alendronic acid |
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| CN1660860A CN1660860A (en) | 2005-08-31 |
| CN1304401C true CN1304401C (en) | 2007-03-14 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4621077A (en) * | 1982-04-15 | 1986-11-04 | Istituto Gentili S.P.A. | Pharmacologically active biphosphonates, process for the preparation thereof and pharmaceutical compositions therefrom |
| US4705651A (en) * | 1984-10-29 | 1987-11-10 | Istituto Gentili S.P.A. | Process for the preparation of diphosphonic acids |
| US4922007A (en) * | 1989-06-09 | 1990-05-01 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
| EP0693285A2 (en) * | 1994-07-22 | 1996-01-24 | Eli Lilly And Company | Pharmaceutical compositions containing a bisphosphonate and an anti-resorptive agent for inhibiting bone loss |
-
2004
- 2004-12-28 CN CNB2004100991049A patent/CN1304401C/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4621077A (en) * | 1982-04-15 | 1986-11-04 | Istituto Gentili S.P.A. | Pharmacologically active biphosphonates, process for the preparation thereof and pharmaceutical compositions therefrom |
| US4705651A (en) * | 1984-10-29 | 1987-11-10 | Istituto Gentili S.P.A. | Process for the preparation of diphosphonic acids |
| US4922007A (en) * | 1989-06-09 | 1990-05-01 | Merck & Co., Inc. | Process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or salts thereof |
| EP0693285A2 (en) * | 1994-07-22 | 1996-01-24 | Eli Lilly And Company | Pharmaceutical compositions containing a bisphosphonate and an anti-resorptive agent for inhibiting bone loss |
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| CN1660860A (en) | 2005-08-31 |
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