CN1304401C - Method for preparing Alendronic acid - Google Patents
Method for preparing Alendronic acid Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- acid
- alendronic acid
- alendronic
- phosphorus trichloride
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
一种阿伦膦酸的制备方法，包括下列步骤：以γ-氨基丁酸、三氯化磷和亚磷酸为原料，沸点或初沸点在50～90℃之间的惰性溶剂存在下，在回流温度下反应，经后处理得产物阿伦膦酸。惰性溶剂的回流温度(反应温度)大致等于沸点(或初沸点)，可以很好地控制反应的温度，使反应能够稳定地进行，大大地提高了生产的安全性，具有很好的工业化应用前景。A preparation method for alendronic acid, comprising the following steps: using gamma-aminobutyric acid, phosphorus trichloride and phosphorous acid as raw materials, in the presence of an inert solvent with a boiling point or an initial boiling point between 50 and 90°C, under reflux Reaction at high temperature, the product alendronic acid is obtained after post-treatment. The reflux temperature (reaction temperature) of the inert solvent is roughly equal to the boiling point (or initial boiling point), which can well control the reaction temperature, so that the reaction can be carried out stably, greatly improving the safety of production, and has a good industrial application 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)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100991049A CN1304401C (en) | 2004-12-28 | 2004-12-28 | Method for preparing Alendronic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100991049A CN1304401C (en) | 2004-12-28 | 2004-12-28 | Method for preparing Alendronic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1660860A CN1660860A (en) | 2005-08-31 |
| CN1304401C true CN1304401C (en) | 2007-03-14 |
Family
ID=35010443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100991049A Expired - Fee Related CN1304401C (en) | 2004-12-28 | 2004-12-28 | Method for preparing Alendronic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1304401C (en) |
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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1660860A (en) | 2005-08-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4742212B2 (en) | Process for producing silsesquioxane derivative and silsesquioxane derivative | |
| CA2533173A1 (en) | Method for the production of cyclic phosphonic acid anhydrides | |
| KR20100101010A (en) | Hydrosilylation reactions activated through radiation | |
| JP4961361B2 (en) | Method for producing phosphorus-based oxazine | |
| CN101857540B (en) | Method for producing adipic acid, hexamethylenediamine hydrochloride and polyhexamethylene (di)guanidine chloride from nylon-66 through depolymerization | |
| CN1304401C (en) | Method for preparing Alendronic acid | |
| JP7447084B2 (en) | Method for producing bisphenol phosphate hydroxyaluminum salt nucleating agent | |
| CN1163617A (en) | Process for producing N-phosphonomethylglycine | |
| CN1834092A (en) | Prepn. of pramipexole | |
| CN101054391A (en) | Chiral (1-phenylethylamino)methyl phosphonic acid and preparation method thereof | |
| CN1916005A (en) | Method for preparing Phosphonomethyl iminodiacetic acid (PMIDA) through hydrolysis of imino diacetonitrile | |
| CN114907400B (en) | Preparation process of BDP intermediate | |
| CN1096296A (en) | The method for preparing folic acid | |
| CN1911941B (en) | Preparation method of 2,10-dihydro-9-oxo-10-phospho hetero phenanthrene | |
| WO2011050534A1 (en) | N-substituted acrylamides, preparation method and use thereof | |
| CN117285568A (en) | Catalytic preparation method of hexachlorocyclotriphosphazene | |
| CN116693813A (en) | Modified alumina reinforced PDCPD composite material and preparation method thereof | |
| CN1259359C (en) | Synthetic method of benzoxazole polymer | |
| CN116199719A (en) | A bio-based high-efficiency flame retardant containing biphenyl structure and phosphorus | |
| CN106977725A (en) | A kind of preparation method of polysiloxane-modified polyacrylate resin | |
| CN1752001A (en) | The preparation method of sodium thiophosphate | |
| CN1733691A (en) | Industrial synthesis method of 3,5-di tertiary butyl-4-hydroxyl phenyl methyl propionate | |
| CN1944444A (en) | Synthetic method for N-phosphonyl methyl imino diacetic acid | |
| CN1200072C (en) | Preparation method of antioxidant trinonylphengl phosphite | |
| CN1676516A (en) | Novel method for industrially preparing trichloropyridine sodium alcoholate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20070314 Termination date: 20100128 |