CN104497048A - Preparation method of minodronic acid - Google Patents
Preparation method of minodronic acid Download PDFInfo
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Abstract
The invention discloses a preparation method of minodronic acid. The preparation method comprises the following steps: performing acetal hydrolysis on a compound I to obtain a compound II, performing closed-loop treatment and hydrolysis on the compound II and 2-aminopyridine to obtain a compound III, and finally, performing phosphorylation on the compound III to obtain a compound IV. By adopting the preparation method disclosed by the invention, highly toxic chemical reagents including sodium cyanide or bromine and the like are avoided, the reaction conditions are mild and controllable, the reaction steps are relatively short, the yield is relatively high, and the cost is relatively low, so that the preparation method is suitable for industrial production.
Description
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of preparation method of minodronic acid.
Background technology
Minodronic acid (Minodronate), chemistry 1-hydroxyl-2-{ imidazo [1 by name, 2-a] pyridin-3-yl } ethylidene-1,1-two banks, it is the new type heterocycle bis-phosphonic acids compounds developed by Japanese Yamanouchi company, be used for the treatment of the hypercalcemia caused by osteoporosis and malignant tumour, its suppression bone resorption activity is 2 times, 10 times and 100 times of incadronate disodium, alendronate sodium and Pamidronate Disodium respectively.This product has remarkable benefit in spinal fracture incidence, and in stomach side effect, have very large minimizing, oneself is defined as the novel drugs of effective osteoporosis now simultaneously, prevention fracture.The development of this medicine undoubtedly will for clinical disease patient provide a kind of safer, effectively, medicine easily, good Social benefit and economic benefit will be produced after listing.
The each method of system of minodronic acid has report respectively in EP0354806 (publication date: 1990-02-14), its chemistry 1-hydroxyl-2-{ imidazo [1,2-a] pyridin-3-yl by name } ethylidene-1,1-two banks, structural formula is as follows:
EP0354806 (publication date: 1990-02-14)
The each method of the disclosed system of EP0354806 (publication date: 1990-02-14):
The each method of the disclosed system of EP0354806 (publication date: 1990-02-14) does not provide raw material sources, and yield is lower.
The each method of the disclosed system of document Bioorganic & Medicinal Chemistry Letters 9 (1999) 97-102 is as follows:
PA is starting raw material, through closed loop, aldehyde radical, aldehyde radical reduces, chlorination, cyaniding, cyan-hydrolysis, phosphorylation obtain minodronic acid, and the method is totally 7 step reactions, and synthetic route is longer, lower the obtaining of yield employs violent in toxicity sodium cyanide, operational hazards, the side reaction simultaneously generated is more, the more difficult purifying of product.Use sulfur oxychloride chlorination in synthetic route, larger infringement is caused to conversion unit.And employ phosphorus oxychloride highly toxic product, amplify phosphorus oxychloride aftertreatment when producing and there is energy accumulation, be not suitable for industrial production.
Disclosed in patent, route is as follows:
With 2-imidazo [1,2-a] pyridine is starting raw material, through closed loop, amination, cyaniding, cyan-hydrolysis, phosphorylation obtain minodronic acid, the method is totally 6 step reactions, and synthetic route is longer, and starting raw material is not easy to obtain, and employ violent in toxicity sodium cyanide, operational hazards, the side reaction simultaneously generated is more, the more difficult purifying of product.2-(imidazo [1,2-a] pyridin-3-yl) acetic acid good water solubility in addition, sodium cyanide reaction is carried out in aqueous, is difficult to obtain 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.
Consider the Social benefit and economic benefit that minodronic acid is good and reaction yield, industrialized condition and environmental protection policy, the present invention develop a kind of can safely and hold the preparation method of manageable compound IV.
Summary of the invention
The object of Japanese invention is difficult to the shortcoming of accomplishing scale production for existing method; by on the basis of great many of experiments, provide a kind of and effectively can avoid using that hypertoxic chemical reagent, reaction conditions are gentle, controllability is strong, reactions steps compared with short, yield compared with high, cost compared with low, environmental pollution is little, be applicable to the method preparing minodronic acid of suitability for industrialized production.
Object of the present invention can be reached by following measures:
A kind of preparation formula (IV) compound 1-hydroxyl-2-{ imidazo [1,2-a] pyridin-3-yl } ethylidene-1, the method of 1-two banks: first Compound I is become Compound II per through acetal hydro, again by Compound II per and PA closed loop, be hydrolyzed and obtain compound III, the last phosphoric acid again of compound III changes into compound IV, and its reaction scheme is as follows:
The reaction system acetone/water of Compound I and Compound II per, temperature are 40-50 DEG C.
Compound II per and PA ring-closure reaction, reaction solvent is methyl alcohol, ethanol or both mix polar solvent; Wherein preferred alcohol is reaction solvent.Catalysts selects one or more in the strong acid such as hydrochloric acid, sulfuric acid and p-methyl benzenesulfonic acid for catalyzer; Wherein preferably p-methyl benzenesulfonic acid is catalyzer.The mass ratio of catalysts and Compound I is 1:8-12, is preferably 1:9-11.Compound II per is 1-3 times of the quality of PA, is preferably 1.5-2.5 doubly.The ring-closure reaction temperature of Compound II per and PA is 60-70 DEG C.
Compound II per hydrolysis reaction carries out in the basic conditions, and described alkali is selected from one or both mixed bases in potassium hydroxide and the medium inorganic strong alkali of sodium hydroxide.Compound II per hydrolysising reacting temperature is 40-50 DEG C.
In compound III phosphorylation reaction, reaction solvent is selected from one or more in toluene, dimethylbenzene, chlorobenzene and bromobenzene; One or both mixed solvents in preferred chlorobenzene or toluene are reaction solvent.Compound III phosphorylation reaction reagent be selected from phosphorous acid, phosphorus trichloride one or both; The mass ratio of compound VI and phosphorylation reaction reagent is 1:2-6, is preferably 1:3-5; Phosphorylation reaction temperature is 80-90 DEG C.
Synthetic route of the present invention is shown below:
Beneficial effect of the present invention is further illustrated below by way of contrast optimization:
One, synthetic route one contrasts
The synthesis road that document Bioorganic & Medicinal Chemistry Letters 9 (1999) 97-102 reports
Line is as follows:
With 2 ?aminopyridine for starting raw material, a water minodronic acid is obtained through closed loop, aldehyde radical, aldehyde radical reduction, chlorination, cyaniding, cyan-hydrolysis, phosphorylation, the method is totally 7 step reactions, synthetic route is longer, yield is lower, employs violent in toxicity sodium cyanide, operational hazards, the side reaction simultaneously generated is more, the more difficult purifying of product.Sulfur oxychloride chlorination in synthetic route, causes larger infringement to conversion unit.And employ phosphorus oxychloride highly toxic product, amplify phosphorus oxychloride aftertreatment when producing and there is energy accumulation, be not suitable for industrial production.
In the present invention, synthetic route advantage is as follows: reactions steps is 3 steps, and route is shorter; Avoid using violent in toxicity sodium cyanide; Sulfur oxychloride is not suitable for enterprises production and application, and ingenious the avoiding of the present invention uses sulfur oxychloride; Through process optimization, the phosphorus oxychloride that toxicity is very large is replaced by phosphorus trichloride.
Two, synthetic route two contrasts
Chinese Journal of Pharmaceuticals 35 (4), disclosed in 2004,193-194, route is as follows:
With 2-imidazo [1,2-a] pyridine is starting raw material, through closed loop, amination, cyaniding, cyan-hydrolysis, phosphorylation obtain minodronic acid, the method is totally 6 step reactions, and synthetic route is longer, and starting raw material is not easy to obtain, and employ violent in toxicity sodium cyanide, operational hazards, the side reaction simultaneously generated is more, the more difficult purifying of product.2-(imidazo [1,2-a] pyridin-3-yl) acetic acid good water solubility in addition, sodium cyanide reaction is carried out in aqueous, is difficult to obtain 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.
In the present invention, synthetic route advantage is as follows: reactions steps is 3 steps, and route is shorter; Starting raw material in document is difficult to obtain, and should not be appointed as raw materials for production, the present invention selected be easy to get, cheap starting material
In a word, present invention, avoiding use that hypertoxic chemical reagent, reaction conditions are gentle, controllability strong, reactions steps compared with short, yield compared with high, cost compared with low, environmental pollution is little, be applicable to suitability for industrialized production.
Embodiment:
By the specific embodiments of following examples form, foregoing of the present invention is described in detail further, to those skilled in the art, this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following instance.
Embodiment 1
1, the preparation of 4-oxo butenoic acid ethyl
25.2g (E)-4,4-dimethoxys-2-butylene acetoacetic ester, 40mL acetone, 20mL purified water and 2.14g p-methyl benzenesulfonic acid is added in 250ml there-necked flask; Stir, be heated to 40-50 DEG C, insulation reaction 1-1.5h, concentration of reaction solution, add acetone 30mL, be heated to 50 ~ 60 DEG C, continue stirring 1 ~ 2h, GC monitors, and meets inner quality standard, stopped reaction.Concentration of reaction solution, obtains yellow oily liquid.
Take 1.05g sodium bicarbonate, be configured to saturated solution by 12mL purified water, for subsequent use.In above-mentioned yellow liquid, add 30mL ethyl acetate, be cooled to 5 ~ 15 DEG C, slowly add pre-assigned saturated sodium bicarbonate solution, stir 10 ~ 15min, leave standstill 10 ~ 15min, layering, separates organic layer (upper strata); Aqueous phase 30mL ethyl acetate is extracted once, separates organic layer, merges organic phase; Organic phase 30mL purifies washing once, and leave standstill separatory, organic phase concentrates, and obtains 17g yellow liquid 4-oxo butenoic acid ethyl 16.6g, yield: 95%.
2, the preparation of 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid
In 250mL there-necked flask, add 56mL ethanol and 8.0g2-aminopyridine, stirring, heating for dissolving; Temperature is increased to 65-70 DEG C, and drip 4-oxo butenoic acid ethyl, about about 30min drips off, after dripping off, and insulation reaction 2-3h, in above-mentioned reaction solution, add 3.75g sodium hydroxide, temperature remains on 40-50 DEG C, reaction about 3h, stopped reaction; Be cooled to 10 ~ 15 DEG C, drip about 8.7g concentrated hydrochloric acid, adjustment pH is 4-7, and at 10 ~ 15 DEG C, stir 3 ~ 5h, suction filtration, obtain 19.6g2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, vacuum-drying, obtains 16.1g, yield: 77%.
3,1-hydroxyl-2-{ imidazo [1,2-a] pyridin-3-yl } preparation of ethylidene-1,1-two banks
In 250mL there-necked flask, add 72mL toluene, 32g phosphorous acid and 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, when stirring is warming up to 80 DEG C, drip 62g phosphorus trichloride, drip off, maintain the temperature at 90-110 DEG C of reaction 6-8h, stopped reaction, be cooled to room temperature, pour out reaction solution, then add 96g concentrated hydrochloric acid and be diluted to about 6mol/L, stir, be warming up to 40-50 DEG C of reaction 6 ~ 8h, filtered while hot, with 20mL6mol/L hydrochloric acid filter wash cake, filtrate concentrate, with 150mL*2 purify water-band acid.The mother liquor concentrated is down to 10 ~ 15 DEG C, regulates pH ≈ 4, stirring and crystallizing 2 ~ 6h with 20% sodium hydroxide solution; Suction filtration, with about 20mL purified water filter wash cake, and drains as far as possible, obtains crude product minodronic acid 15.4g, yield: 52%.
Embodiment 2
1, the preparation of 4-oxo butenoic acid ethyl
50.4g (E)-4,4-dimethoxys-2-butylene acetoacetic ester, 80mL acetone, 40mL purified water and 4.28g p-methyl benzenesulfonic acid is added in 500ml there-necked flask; Stir, be heated to 40-50 DEG C, insulation reaction 1-1.5h, concentration of reaction solution, add acetone 30mL, be heated to 50 ~ 60 DEG C, continue stirring 1 ~ 2h, GC monitors, and meets inner quality standard, stopped reaction.Concentration of reaction solution, obtains yellow oily liquid.
Take 2.1g sodium bicarbonate, be configured to saturated solution by 24mL purified water, for subsequent use.In above-mentioned yellow liquid, add 60mL ethyl acetate, be cooled to 5 ~ 15 DEG C, slowly add pre-assigned saturated sodium bicarbonate solution, stir 10 ~ 15min, leave standstill 10 ~ 15min, layering, separates organic layer (upper strata); Aqueous phase 60mL ethyl acetate is extracted once, separates organic layer, merges organic phase; Organic phase 30mL purifies washing once, and leave standstill separatory, organic phase concentrates, and obtains 33g yellow liquid 4-oxo butenoic acid ethyl, yield: 94%.
2, the preparation of 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid
In 500mL there-necked flask, add 112mL ethanol and 16g2-aminopyridine, stirring, heating for dissolving; Temperature is increased to 65-70 DEG C, and drip 4-oxo butenoic acid ethyl, about about 30min drips off, after dripping off, and insulation reaction 2-3h, in above-mentioned reaction solution, add 7.5g sodium hydroxide, temperature remains on 40-50 DEG C, reaction about 3h, stopped reaction; Be cooled to 10 ~ 15 DEG C, drip about 17.4g concentrated hydrochloric acid, adjustment pH is 4-7, and at 10 ~ 15 DEG C, stir 3 ~ 5h, suction filtration, obtain 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, vacuum-drying, obtains 32g, yield: 76%.
3,1-hydroxyl-2-{ imidazo [1,2-a] pyridin-3-yl } preparation of ethylidene-1,1-two banks
In 500mL there-necked flask, add 144mL toluene, 64g phosphorous acid and 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, when stirring is warming up to 80 DEG C, drip 124g phosphorus trichloride, drip off, maintain the temperature at 90-110 DEG C of reaction 6-8h, stopped reaction, be cooled to room temperature, pour out reaction solution, then add 192g concentrated hydrochloric acid and be diluted to about 6mol/L, stir, be warming up to 40-50 DEG C of reaction 6 ~ 8h, filtered while hot, with 40mL6mol/L hydrochloric acid filter wash cake, filtrate concentrate, with 300mL*2 purify water-band acid.The mother liquor concentrated is down to 10 ~ 15 DEG C, regulates pH ≈ 4, stirring and crystallizing 2 ~ 6h with 20% sodium hydroxide solution; Suction filtration, with about 40mL purified water filter wash cake, and drains as far as possible, obtains crude product minodronic acid 30g, yield: 51%.
The process for purification of crude product minodronic acid is: by crude product minodronic acid, adds in the hexanaphthene of the 1:1 of 5 times of weight and the mixing solutions of acetone, adds the gac of 1% weight, reflux 2 hours, cool rearmounted 4 degree of refrigerators 10 hours crystallizations, obtain white crystals after filtration, yield: 95%
Wherein, process for purification be through screening obtain, screening process is as follows:
The content of impurity in each sample after the process of thick product different solvents
| Solvent | Impurity (%) |
| Ethanol | 0.80 |
| Methylene dichloride | 0.73 |
| Ethyl acetate | 0.61 |
| Hexanaphthene | 0.57 |
| Acetone | 0.51 |
| Acetone and hexanaphthene (1:1) | 0.33 |
| Acetone and hexanaphthene (2:1) | 0.49 |
| Acetone and hexanaphthene (4:1) | 0.60 |
| Acetone and hexanaphthene (1:2) | 0.57 |
| Acetone and hexanaphthene (1:4) | 0.56 |
| Acetone and hexanaphthene (1:5) | 0.60 |
To the present invention and prior art carry out refining after product carry out HPLC analysis, purity and foreign matter content % as follows:
| The method of prior art | The embodiment of the present invention | |
| Minodronic acid | 99.43 | 99.57 |
| Impurity 1 | 0.14 | 0.08 |
| Impurity 2 | 0.21 | 0.09 |
As requested, total impurities content should be less than 1%, and the content of wherein each related impurities all should be less than
0.1%, process for purification of the present invention, only needs to refine once can reach this requirement.
Claims (9)
1. the preparation method of formula (IV) compound minodronic acid, it is characterized in that, first Compound I is become Compound II per through acetal hydro, again by Compound II per and PA closed loop, be hydrolyzed and obtain compound III, the last phosphoric acid again of compound III changes into compound IV, and its reaction scheme is as follows:
2. method according to claim 1, is characterized in that, the reaction system acetone/water of Compound I and Compound II per, temperature are 40-50 DEG C.
3. method according to claim 1, is characterized in that, Compound II per and PA ring-closure reaction, reaction solvent is methyl alcohol, ethanol or both mix polar solvent.
4. method according to claim 1, is characterized in that, Compound II per and PA ring-closure reaction temperature are 60-70 DEG C.
5. method according to claim 1, is characterized in that, Compound II per hydrolysis reaction carries out in the basic conditions, described alkali be selected from potassium hydroxide and sodium hydroxide one or both.
6. method according to claim 1, is characterized in that, Compound II per hydrolysising reacting temperature is 40-50 DEG C.
7. method according to claim 1, is characterized in that, in compound III phosphorylation reaction, reaction solvent is selected from one or more in toluene, dimethylbenzene, chlorobenzene and bromobenzene.
8. method according to claim 1, is characterized in that, compound III phosphorylation reaction reagent be selected from phosphorous acid, phosphorus trichloride one or both; Phosphorylation reaction temperature is 80-90 DEG C.
9. method according to claim 1, is characterized in that, step is as follows:
1), the preparation of 4-oxo butenoic acid ethyl
25.2g (E)-4,4-dimethoxys-2-butylene acetoacetic ester, 40mL acetone, 20mL purified water and 2.14g p-methyl benzenesulfonic acid is added in 250ml there-necked flask; Stir, be heated to 40-50 DEG C, insulation reaction 1-1.5h, concentration of reaction solution, add acetone 30mL, be heated to 50 ~ 60 DEG C, continue stirring 1 ~ 2h, GC monitors, and meets inner quality standard, stopped reaction.Concentration of reaction solution, obtains yellow oily liquid;
Take 1.05g sodium bicarbonate, be configured to saturated solution by 12mL purified water, for subsequent use.In above-mentioned yellow liquid, add 30mL ethyl acetate, be cooled to 5 ~ 15 DEG C, slowly add pre-assigned saturated sodium bicarbonate solution, stir 10 ~ 15min, leave standstill 10 ~ 15min, layering, separates organic layer (upper strata); Aqueous phase 30mL ethyl acetate is extracted once, separates organic layer, merges organic phase; Organic phase 30mL purifies washing once, and leave standstill separatory, organic phase concentrates, and obtains 17g yellow liquid 4-oxo butenoic acid ethyl 16.6g,
2), the preparation of 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid
In 250mL there-necked flask, add 56mL ethanol and 8.0g2-aminopyridine, stirring, heating for dissolving; Temperature is increased to 65-70 DEG C, and drip 4-oxo butenoic acid ethyl, about about 30min drips off, after dripping off, and insulation reaction 2-3h, in above-mentioned reaction solution, add 3.75g sodium hydroxide, temperature remains on 40-50 DEG C, reaction about 3h, stopped reaction; Be cooled to 10 ~ 15 DEG C, drip about 8.7g concentrated hydrochloric acid, adjustment pH is 4-7, and at 10 ~ 15 DEG C, stir 3 ~ 5h, suction filtration, obtain 19.6g2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, vacuum-drying, obtains 16.1g dry product,
3), 1-hydroxyl-2-{ imidazo [1,2-a] pyridin-3-yl } preparation of ethylidene-1,1-two banks
In 250mL there-necked flask, add 72mL toluene, 32g phosphorous acid and 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, when stirring is warming up to 80 DEG C, drip 62g phosphorus trichloride, drip off, maintain the temperature at 90-110 DEG C of reaction 6-8h, stopped reaction, be cooled to room temperature, pour out reaction solution, then add 96g concentrated hydrochloric acid and be diluted to about 6mol/L, stir, be warming up to 40-50 DEG C of reaction 6 ~ 8h, filtered while hot, with 20mL6mol/L hydrochloric acid filter wash cake, filtrate concentrate, with 150mL*2 purify water-band acid.The mother liquor concentrated is down to 10 ~ 15 DEG C, regulates pH ≈ 4, stirring and crystallizing 2 ~ 6h with 20% sodium hydroxide solution; Suction filtration, with about 20mL purified water filter wash cake, and drains as far as possible, obtains crude product minodronic acid 15.4g,
The process for purification of crude product minodronic acid is: by crude product minodronic acid, adds in the hexanaphthene of the 1:1 of 5 times of weight and the mixing solutions of acetone, adds the gac of 1% weight, reflux 2 hours, cool rearmounted 4 degree of refrigerators 10 hours crystallizations, obtain white crystals after filtration, to obtain final product.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104693241A (en) * | 2015-03-02 | 2015-06-10 | 北京万全德众医药生物技术有限公司 | Method for synthetizing minodronic acid intermediate and preparing minodronic acid by virtue of one-pot process |
| CN105467027A (en) * | 2015-11-18 | 2016-04-06 | 北京万全德众医药生物技术有限公司 | A method of separating and measuring compounds related to a minodronic acid intermediate through gas chromatography |
| CN106831873A (en) * | 2017-01-17 | 2017-06-13 | 成都归合科技有限公司 | A kind of technique for preparing high-purity minodronic acid |
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| WO2014091386A2 (en) * | 2012-12-13 | 2014-06-19 | Alembic Pharmaceuticals Limited | An improved process for preparation of minodronic acid |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104693241A (en) * | 2015-03-02 | 2015-06-10 | 北京万全德众医药生物技术有限公司 | Method for synthetizing minodronic acid intermediate and preparing minodronic acid by virtue of one-pot process |
| CN105467027A (en) * | 2015-11-18 | 2016-04-06 | 北京万全德众医药生物技术有限公司 | A method of separating and measuring compounds related to a minodronic acid intermediate through gas chromatography |
| CN105467027B (en) * | 2015-11-18 | 2021-09-21 | 北京万全德众医药生物技术有限公司 | Method for separating and measuring minodronate intermediate related substances by gas chromatography |
| CN106831873A (en) * | 2017-01-17 | 2017-06-13 | 成都归合科技有限公司 | A kind of technique for preparing high-purity minodronic acid |
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