CN1752086A - Improved method of preparing azhediping - Google Patents
Improved method of preparing azhediping Download PDFInfo
- Publication number
- CN1752086A CN1752086A CN 200510104895 CN200510104895A CN1752086A CN 1752086 A CN1752086 A CN 1752086A CN 200510104895 CN200510104895 CN 200510104895 CN 200510104895 A CN200510104895 A CN 200510104895A CN 1752086 A CN1752086 A CN 1752086A
- Authority
- CN
- China
- Prior art keywords
- solvent
- aqueous solution
- reaction
- acid
- compound
- 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.)
- Granted
Links
Landscapes
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An improved process for preparing Azhediping includes such steps as reaction between three raw compounds in solvent while stirring, filtering, water washing of filtrate, extracting in organic solvent, washing with alkali solution, drying, vacuum concentrating, crystallizing in methol, and recrystallizing. Its advantages are high output rate and high purity.
Description
Technical field
The present invention relates to a kind of synthetic method of dihydropyridine type calcium antagonists, more particularly, the present invention relates to a kind of method for preparing Azelnidipine.
Background technology
Azelnidipine, chemistry is called 3, the 5-pyridine dicarboxylic acid, 1,4-dihydropyridine-2-amino-6-methyl-4-(3-nitrophenyl)-, 3-(1-(diphenyl-methyl)-3-azetidinyl) 5-(1-methylethyl) ester, (±).It was the altogether calcium antagonist of new generation of (SANKYO) Co., Ltd. exploitation of Japan three, and the said firm has proposed the compound patent application in Europe in 1986, on September 8th, 1993 Granted publication, patent No. EP0266922.This product 2003 is in Japan's listing that goes through.
(SANKYO) Co., Ltd. is in China proposition Azelnidipine preparation method's patent application altogether for Japan three in 1987, and on August 19th, 1992, authorization was announced, and the patent No. is ZL87107150.
At present, relevant Azelnidipine preparation method's reference comprises: European patent EP 0266922; Chinese patent ZL87107150; Chem.Pharm.Bull.43 (5), 1995, P797-817; The clear 63-253082 of TOHKEMY; The flat 11-116570 of TOHKEMY; Drugs ofFuture Vol.15, No.7,1990P671-673.The Azelnidipine preparation method who provides in these documents all adopts compound (3-1) and compound (4) under strong basicity (as sodium methylate, sodium hydroxide, potassium hydroxide etc.) condition, is solvent with the Virahol, high temperature reflux reaction (shown in reaction formula 1).After having reacted, cooling is removed Virahol in (interior temperature) below 60 ℃ concentrating under reduced pressure, and residue stirs after using ethyl acetate and saturated NaCl water dissolution
Reaction formula 1:
Azelnidipine
Mix 30min, add saturated NaHCO again
3The aqueous solution stirs 15min, standing demix, with organic layer with saturated NaCl solution washing, anhydrous Na
2SO
4Drying and dehydrating filters, and filter cake washs in the filtrate with ethyl acetate, and concentrating under reduced pressure (interior temperature control is below 60 ℃) gets brown viscous liquid (HPLC97.7%, yield 95.7%), to wherein adding methyl alcohol, N
2Be warming up to backflow under the atmosphere, stir 1h, be cooled to 5～10 ℃, stir 1h, crystallization, suction filtration gets light yellow crystal (Azelnidipine methanol solvate thing) HPLC 99.8% with methanol wash, and the crystal that this is wet uses methyl alcohol at N
2Atmosphere is chilled to 60 ℃ after refluxing down and dissolving, and hot suction filtration is removed insolubles, solution is cooled to 5～10 ℃ stirs 1h down, separate out crystal, suction filtration, methanol wash, 30 ℃ of drying under reduced pressure get faint yellow Azelnidipine methylate crystal, mp80～90 ℃, yield 85.6%, HPLC 99.99%.This Azelnidipine methylate is suspended with 20 times of hexanaphthenes, when being warming up to interior warm 50 ℃, begin to remove under reduced pressure methyl alcohol and part hexanaphthene (50～60 ℃), when reaching 60 ℃, insulation is steamed once more and is removed the part hexanaphthene, vacuum tightness is 600～350mmHg, removes vacuum, in cooling crystallization below 30 ℃, suction filtration, the gained crystal washs with hexanaphthene, and is dry below 60 ℃, get faint yellow Azelnidipine crystal, yield 85.6%, HPLC 99.99%, methyl alcohol is 2ppm, mp121～123 ℃.
Wherein, document (Takashi etc., Chem.Pharm.Bull.43 (5), 1995, P797-817) provide a kind of method (shown in reaction formula 2) for preparing compound (4), this preparation method be with compound (1) and compound (2) in Virahol, do under the catalyzer at acetic acid (or sulfuric acid) pyridinium salt, back flow reaction separates making again.
Reaction formula 2:
The preparation method who uses these documents to provide prepares this product, and we find that its operation is extremely loaded down with trivial details, and yield, quality are all very undesirable, and actual recovery only has about 15%, and the yield (85.6%) that provides with document differs greatly; The final product quality aspect, HPLC (area normalization method) content is about 95%, it is extremely difficult further to improve the quality, even can not obtain to meet the Azelnidipine finished product that pharmaceutical quality requires, and can reach finished product HPLC (area normalization method) content that document provides far away 99.99%.By reducing temperature of reaction, change post processing mode, as direct underpressure distillation being changed into underpressure distillation again after the extraction, though some improvement of yield and quality, meet the Azelnidipine finished product that pharmaceutical quality requires but still can not make, yield and quality still can not reach the data that document provides far away.
Open closely related group wait " antihypertensive drug nitrendipine synthetic " (" medicine industry ", 1984, disclose 3-nitrobenzaldehyde, methyl aceto acetate and beta-amino crotonic aldehyde in 15:41) and under the condition of dehydrated alcohol, backflow, react the generation nifedipine:
Reaction formula 3:
Because it is bigger to be used to prepare the compound 3-1 chemical group of Azelnidipine, chemical property alters a great deal compared to the β-An Jibadousuanzhi that is used for above-mentioned homologue preparation, the amine groups of guanidino group on the compound 3-1 on the β-An Jibadousuanzhi, its active group is more, and spatial obstacle increases, as encircle butylamine and phenylbenzene, therefore, can't expect this method is applied to prepare Azelnidipine.In addition, from reaction formula 1 and reaction formula 2 and they separately reaction conditions analyze, though find both all back flow reaction in Virahol, but the potential of hydrogen difference of both reaction systems, reaction formula 1 is to react under highly basic catalysis, reaction formula 2 then under neutrality or slightly acidic environment, is made catalyzer, back flow reaction with acetic acid pyridinium salt or pyridine sulfate salt.This contradiction will make the preparation Azelnidipine possibly can't find a suitable acid or alkali environment that reaction is carried out smoothly.
Summary of the invention
The purpose of this invention is to provide a kind of method for preparing Azelnidipine.
This method can obtain high yield, high purity, low cost and meet the Azelnidipine that pharmaceutical quality requires.
This can save equipment, manpower etc., shorten reaction time, reduce cost, and this is very important in suitability for industrialized production.
A kind of method of synthetic Azelnidipine, this method comprise compound (1), compound (2) and compound (3) reacted and prepare Azelnidipine,
Wherein, compound (1) is:
Compound (2) is:
Compound (3) is:
Here, A represents pharmaceutically acceptable acid or does not exist.Wherein said pharmaceutically acceptable acid is selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, formic acid.
Described reaction further comprise be reflected in the appropriate solvent carry out, temperature of reaction is at 0 to 60 ℃ and stirring reaction 1-20 hour, filter, the filtrate washing, organic solvent extraction or standing demix, organic layer soda lye wash, saturated common salt water washing, drying and dehydrating, concentrating under reduced pressure, methanol crystallization is changeed brilliant again.
The described reaction in appropriate solvent is meant at water, acetone, tetrahydrofuran (THF), methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, butyl alcohol-tert, ethyl acetate, benzene,toluene,xylene, chloroform, methylene dichloride, N, reacts in the mixed solvent of one or more of dinethylformamide, methyl-sulphoxide equal solvent.The preferred reaction solvent is one or more a mixed solvent of water, Virahol, ethyl acetate, chloroform, methylene dichloride equal solvent.Wherein, more preferably reaction solvent is one or more a mixed solvent of water, Virahol, ethyl acetate equal solvent.The mixed solvent of one or more that special preferred reaction solvent is Virahol, ethyl acetate equal solvent.Only reaction solvent is a Virahol.Described temperature of reaction is 0-50 ℃.Preferable reaction temperature is meant reaction between 0-40 ℃.More preferably temperature of reaction is 0-30 ℃.Most preferably the reaction times is 4-16 hour.
Described reaction after-filtration, filtrate water is washed, and used water is acidity, neutrality or the alkaline aqueous solution of pH value for 0-14.When filtrate was handled with acidic aqueous solution, its used acidic aqueous solution was the dilute acid solution of preparations such as mineral acid or organic acid such as sulfuric acid, hydrochloric acid, Hydrogen bromide, hydrofluoric acid, phosphoric acid, acetate, formic acid, preferably with the dilute acid solution of acetate preparation.When filtrate is handled with alkaline aqueous solution, its used alkaline aqueous solution is the weakly alkaline aqueous solution that is mixed with mineral alkali or organic bases, as the weak alkaline aqueous solution that alkaline matters such as sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, pyridine, 4-Dimethylamino pyridine (DMAP), 2-amino-4-picoline, diisopropylethylamine, dihydroxy ethyl ethamine, three oxyethylamine are mixed with, the weak alkaline aqueous solution that preferred mineral alkali is mixed with.
After described filtrate is handled with acidic aqueous solution, the organic solvent that is used to extract can be the solvent that Azelnidipine and inorganic acid salt thereof or organic acid salt are had good solubility, as one or more mixed solvent of organic acid acetic kind solvents such as second (first) acetoacetic ester, second (first) propyl propionate, second (first) acid butyl ester, second (first) isopropyl propionate, the sour special butyl ester of second (first) and chloroform, methylene dichloride equal solvent.Preferred extract one or more the mixed solvent that solvent is ethyl acetate, chloroform, methylene dichloride equal solvent.More preferably extracting solvent is ethyl acetate.
When described reaction solvent was water-insoluble solvent, as ethyl acetate, chloroform, methylene dichloride equal solvent, filtrate was answered standing demix after handling with acidic aqueous solution.The alkali aqueous solution of washing organic layer is the weak alkaline aqueous solution that is mixed with by mineral alkali or organic bases, as the weak alkaline aqueous solution that alkaline matters such as sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, pyridine, 4-Dimethylamino pyridine (DMAP), 2-amino-4-picoline, diisopropylethylamine, dihydroxy ethyl ethamine, three oxyethylamine are mixed with, the weak alkaline aqueous solution that preferred mineral alkali is mixed with.The weak alkaline aqueous solution that preferred yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus and ammoniacal liquor are mixed with.The weak alkaline aqueous solution that preferred sodium bicarbonate, saleratus are mixed with.
Method of the present invention can be that compound (1), (2) and (3) are suspended in the Virahol, stirring at room stoichiometric number hour filters, and adds aqueous acid in the filtrate, stir, after ethyl acetate extraction, organic layer is used the saturated common salt water washing again with the solution washing of alkali, anhydrous sodium sulfate drying, the precipitation that reduces pressure below 60 ℃ adds the methylate that methyl alcohol is made Azelnidipine, changes the brilliant Azelnidipine finished product that pharmaceutically needs that makes with hexanaphthene again.
Use the inventive method to prepare Azelnidipine, simple to operate, yield is high, finished product purity height, with low cost.The method that the inventive method provides compared to document has following characteristics: 1) use room temperature reaction under subacidity or the neutral environment, avoided the generation of a large amount of side reactions that pyroreaction is brought under alkaline environment, help the raising of yield and purity, reduced energy consumption.2) react filtration, added acidic aqueous solution in the filtrate, ethyl acetate extraction, the saturated common salt water washing is used in soda lye wash again, anhydrous sodium sulfate drying, precipitation reduces pressure below 60 ℃.This post processing mode has destroyed the potential of hydrogen of reaction system and the filtering raw material of failing to have reacted, the generation of the by product that the intact back of reaction of having avoided literature method in pyroprocess directly causes because of the existence of the alkali that is used as catalyzer and the raw material of failing to have reacted during underpressure distillation, this has just simplified operation, has improved purity and yield.3) compare with existing preparation technology, reduced single step reaction, thereby reduced corresponding production equipment and personnel's configuration, shortened the production cycle, lowered energy consumption and cost.
On the basis of foregoing,,, can also make modification, replacement or the change of various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
Embodiment
By the embodiment of following examples form, foregoing of the present invention is described in further detail.For a person skilled in the art, this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example; All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
In the 5000ml there-necked flask, add Virahol 2800ml successively, and compound (1) 94g (0.62mol), compound (2) 84ml (88.8g, 0.62mol) and compound (3) free alkali 1 88.6g (0.59mol), stirring at room reaction about 12 hours.Suction filtration among the acetic acid water 7000ml with filtrate adding 5%, stirs, and uses ethyl acetate extraction, the saturated NaHCO of acetic acid ethyl fluid
3Water washing to water layer shows alkalescence, the saturated sodium-chloride water washing once, clear water washs once, anhydrous sodium sulfate drying, ethyl acetate is reclaimed in underpressure distillation, adds about 1000ml methyl alcohol, stirring heating (65 ℃) 1 hour in raffinate, stir cooling crystallization, suction filtration, methanol wash, 30 ℃ of drying under reduced pressure get Azelnidipine methylate 286g (pale yellow crystals), yield 79.1%, HPLC (area normalization method) content 99.527%, 286g joins in the 5720ml hexanaphthene with the Azelnidipine methylate, when being heated with stirring to interior warm 50 ℃, methyl alcohol and hexanaphthene are removed in underpressure distillation, when interior temperature is 60 ℃, be incubated 1 hour, underpressure distillation once more, when remaining the 700ml hexanaphthene approximately, stir cooling crystallization (more than 30 ℃), suction filtration, hexanaphthene washing, drying under reduced pressure below 60 ℃ gets Azelnidipine 262g (pale yellow crystals), yield 76.6%.[M+1]: 583, mp 117.8-126.1 ℃ (WRS-1A numeral fusing point instrument, not calibrated)
Extract solvent and use trichloromethane or methylene dichloride instead, also obtain Azelnidipine yield preferably, yield is respectively 73.1% and 80.7%.。
Embodiment 2
In the 5000ml there-necked flask, add ethyl acetate 2000ml successively, and compound (1) 94g (0.62mol), compound (2) 84ml (88.8g, 0.62mol) and compound (3-1) 224g (0.59mol), stirring at room reaction about 16 hours.Suction filtration adds 5%NaHCO with filtrate
3Among the water 3000ml, stir, standing demix, acetic acid ethyl fluid is used the saturated sodium-chloride water washing once, and clear water washs once, anhydrous sodium sulfate drying, ethyl acetate is reclaimed in underpressure distillation, adds about 1000ml methyl alcohol, stirring heating (65 ℃) 1 hour in raffinate, stir cooling crystallization, suction filtration, methanol wash, 30 ℃ of drying under reduced pressure get Azelnidipine methylate 264g (pale yellow crystals), yield 73%, HPLC (area normalization method) content 99.364%, 264g joins in the 5280ml hexanaphthene with the Azelnidipine methylate, when being heated with stirring to interior warm 50 ℃, methyl alcohol and hexanaphthene are removed in underpressure distillation, when interior temperature is 60 ℃, be incubated 1 hour, underpressure distillation once more, when remaining the 700ml hexanaphthene approximately, stir cooling crystallization (more than 30 ℃), suction filtration, hexanaphthene washing, drying under reduced pressure below 60 ℃ gets Azelnidipine 241g (pale yellow crystals), yield 70.46%.Mp 118.3-125.7 ℃ (WRS-1A numeral fusing point instrument, not calibrated)
Reaction solvent is used trichloromethane or methylene dichloride instead, obtains similar test-results, and yield is respectively 68.3% and 75.3%.。
Embodiment 3
The preparation scheme that provides according to present embodiment 1, carry out below 0 ℃ respectively, 0-10 ℃, 10-20 ℃, 20-30 ℃, 40 ℃, 50 ℃, 60 ℃ stirring reactions, obtain the yield of Azelnidipine 38.6%, 75.4%, 83.7%, 78.9%, 54.2%, 32.6%, 14.9% respectively.
Embodiment 4
The preparation scheme that provides according to embodiment 2, carry out below 0 ℃ respectively, 0-10 ℃, 10-20 ℃, 20-30 ℃, 40 ℃, 50 ℃, 60 ℃ stirring reactions, obtain the yield of Azelnidipine 33.4%, 70.8%, 78.2%, 74.5%, 49.8%, 28.9%, 11.2% respectively.
Claims (25)
1. the method for a synthetic Azelnidipine is characterized in that this method comprises compound (1), compound (2) reacted with compound (3) and prepares Azelnidipine,
Wherein, compound (1) is:
Compound (2) is:
Compound (3) is:
Here, A represents pharmaceutically acceptable acid or does not exist.
2. method according to claim 1, wherein said pharmaceutically acceptable acid are selected from hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, acetate, reach formic acid.
3. method according to claim 1, wherein said reaction further comprise be reflected in the appropriate solvent carry out, 0 to 60 ℃ of temperature of reaction and stirring reaction 1～20 hour.
4. method according to claim 1, wherein said reaction further comprises described compound in appropriate solvent, and in 0 to 60 ℃ of following stirring reaction 1～20 hour filters, washing filtrate, with organic solvent extraction or standing demix, organic layer washs with alkali aqueous solution, the saturated common salt water washing, drying and dehydrating, concentrating under reduced pressure, methanol crystallization is changeed brilliant again.
5. according to the described method of the arbitrary claim of claim 1 to 4, wherein said solvent is selected from water, acetone, tetrahydrofuran (THF), methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, butyl alcohol-tert, ethyl acetate, benzene,toluene,xylene, chloroform, methylene dichloride, N, dinethylformamide, and methyl-sulphoxide in one or more mixed solvent.
6. method according to claim 5, wherein said solvent be selected from water, Virahol, ethyl acetate, chloroform, and methylene dichloride in one or more mixed solvent.
7. method according to claim 6, wherein said solvent be selected from water, Virahol, and ethyl acetate in one or more mixed solvent.
8. method according to claim 7, wherein said solvent be selected from Virahol, and ethyl acetate in one or both mixed solvent.
9. method according to claim 8, wherein said solvent are Virahol.
10. according to the described method of the arbitrary claim of claim 3 to 4, wherein said temperature of reaction is 0 to 50 ℃.
11. method according to claim 10, wherein said temperature of reaction are 0 to 40 ℃.
12. method according to claim 11, wherein said temperature of reaction are 0 to 30 ℃.
13. according to the described method of the arbitrary claim of claim 3 to 4, the wherein said reaction times is 4～16 hours.
14. method according to claim 4, the pH value of wherein said washing water is 0～14.
15. according to claim 4 or 14 described methods, wherein said washing water is meant with acidic aqueous solution to be washed, described acidic aqueous solution is selected from the dilute acid solution of sulfuric acid, hydrochloric acid, Hydrogen bromide, hydrofluoric acid, phosphoric acid, acetate, formic acid preparation.
16. method according to claim 15, wherein said dilute acid solution is mixed with acetate.
17. according to claim 4 or 14 described methods, wherein said washing water is meant with alkaline aqueous solution to be washed, and described alkaline aqueous solution is selected from the weak base aqueous solution of sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus, triethylamine, pyridine, 4-Dimethylamino pyridine, 2-amino-4-picoline, diisopropylethylamine, dihydroxy ethyl ethamine, three oxyethylamine preparation.
18. method according to claim 17, wherein said alkaline aqueous solution is mixed with sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus.
19. method according to claim 4, the organic solvent of wherein said extraction usefulness is for being selected from second (first) acetoacetic ester, second (first) propyl propionate, second (first) acid butyl ester, second (first) isopropyl propionate, and the organosilane ester of the sour special butyl ester of second (first), and be selected from chloroform, and the halohydrocarbon of methylene dichloride in a kind of or more than one mixed solvent.
20. method according to claim 19, wherein said extraction organic solvent be ethyl acetate, chloroform, and methylene dichloride in a kind of or more than one mixed solvent.
21. method according to claim 20, wherein said extraction organic solvent is an ethyl acetate.
22. method according to claim 4, wherein, when the solvent of described reaction is water-insoluble solvent, after filtrate is washed with acidic aqueous solution, standing demix.
23. method according to claim 4, wherein, the alkali aqueous solution of described washing organic layer is the weak alkaline aqueous solution of mineral alkali or organic bases preparation; Described mineral alkali is selected from sodium hydroxide, potassium hydroxide, ammoniacal liquor, yellow soda ash, salt of wormwood, sodium bicarbonate, reaches saleratus; Described organic bases is selected from triethylamine, pyridine, 4-Dimethylamino pyridine, 2-amino-4-picoline, diisopropylethylamine, dihydroxy ethyl ethamine, reaches three oxyethylamine.
24. method according to claim 23, wherein, the alkali aqueous solution of described washing organic layer is to be selected from the weak alkaline aqueous solution that yellow soda ash, salt of wormwood, sodium bicarbonate, saleratus and ammoniacal liquor are mixed with.
25. method according to claim 24, wherein, the alkali aqueous solution of described washing organic layer is to be selected from the weak alkaline aqueous solution that sodium bicarbonate and saleratus are mixed with.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101048954A CN100352818C (en) | 2005-09-23 | 2005-09-23 | Improved method of preparing azhediping |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005101048954A CN100352818C (en) | 2005-09-23 | 2005-09-23 | Improved method of preparing azhediping |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1752086A true CN1752086A (en) | 2006-03-29 |
| CN100352818C CN100352818C (en) | 2007-12-05 |
Family
ID=36679100
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005101048954A Active CN100352818C (en) | 2005-09-23 | 2005-09-23 | Improved method of preparing azhediping |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100352818C (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2011006379A (en) * | 2009-05-26 | 2011-01-13 | Tokuyama Corp | Method for recrystallizing {2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid-3-[1-(diphenylmethyl)azetidin-3-yl]ester-5-isopropyl ester}(azelnidipine), isopropyl alcohol adduct of azelnidipine, and method for producing azelnidipine |
| JP2012020970A (en) * | 2010-07-15 | 2012-02-02 | Tokuyama Corp | Method for producing {3-(1-diphenylmethylazetidin-3-yl)ester-5-isopropyl ester 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate} |
| CN102382104A (en) * | 2011-11-21 | 2012-03-21 | 山东新华制药股份有限公司 | Preparation method of alpha-crystal Azalnidipine |
| CN102491902A (en) * | 2011-11-30 | 2012-06-13 | 青岛黄海制药有限责任公司 | Preparation method of isopropyl 2-(3-nitrobenzylidene)acetoacetate |
| CN101486705B (en) * | 2009-03-05 | 2012-08-08 | 青岛黄海制药有限责任公司 | Preparation of Azelnidipine alpha crystal form |
| CN101863879B (en) * | 2009-04-16 | 2012-12-19 | 四川科伦药物研究有限公司 | Preparation method of alpha crystal azelnidipine |
| CN103319458A (en) * | 2012-03-20 | 2013-09-25 | 北京晶润宏达医药科技有限公司 | Novel gamma-polymorph of Azelnidipine and applications thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4772596A (en) * | 1986-10-09 | 1988-09-20 | Sankyo Company Limited | Dihydropyridine derivatives, their preparation and their use |
| JP3491506B2 (en) * | 1997-10-14 | 2004-01-26 | 宇部興産株式会社 | Method for producing dihydropyridine derivative |
| RU2294328C2 (en) * | 2002-12-24 | 2007-02-27 | Санкио Компани, Лимитед | Optically active derivatives of dihydropyridine, their using and therapeutic agent based on thereof |
-
2005
- 2005-09-23 CN CNB2005101048954A patent/CN100352818C/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101486705B (en) * | 2009-03-05 | 2012-08-08 | 青岛黄海制药有限责任公司 | Preparation of Azelnidipine alpha crystal form |
| CN101863879B (en) * | 2009-04-16 | 2012-12-19 | 四川科伦药物研究有限公司 | Preparation method of alpha crystal azelnidipine |
| JP2011006379A (en) * | 2009-05-26 | 2011-01-13 | Tokuyama Corp | Method for recrystallizing {2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid-3-[1-(diphenylmethyl)azetidin-3-yl]ester-5-isopropyl ester}(azelnidipine), isopropyl alcohol adduct of azelnidipine, and method for producing azelnidipine |
| JP2012020970A (en) * | 2010-07-15 | 2012-02-02 | Tokuyama Corp | Method for producing {3-(1-diphenylmethylazetidin-3-yl)ester-5-isopropyl ester 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate} |
| CN102382104A (en) * | 2011-11-21 | 2012-03-21 | 山东新华制药股份有限公司 | Preparation method of alpha-crystal Azalnidipine |
| CN102491902A (en) * | 2011-11-30 | 2012-06-13 | 青岛黄海制药有限责任公司 | Preparation method of isopropyl 2-(3-nitrobenzylidene)acetoacetate |
| CN103319458A (en) * | 2012-03-20 | 2013-09-25 | 北京晶润宏达医药科技有限公司 | Novel gamma-polymorph of Azelnidipine and applications thereof |
| CN103319458B (en) * | 2012-03-20 | 2015-11-25 | 北京晶润宏达医药科技有限公司 | Azelnidipine γ crystal-form substances and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100352818C (en) | 2007-12-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1752086A (en) | Improved method of preparing azhediping | |
| US7528254B2 (en) | Process for preparing montelukast and salts thereof | |
| JP4890466B2 (en) | Process for the synthesis of azetidinone | |
| CN114014874B (en) | Preparation method of Mabalo Sha Wei intermediate | |
| CN111269461A (en) | Phosphaphenanthrene silane grafted and modified graphene and preparation method thereof | |
| CN105669652B (en) | A kind of preparation method of improved benzene sulphur bepotastine | |
| CN1203059C (en) | Novel processes for preparing torsemide intermediate | |
| CN110655517A (en) | Preparation method of doriravir open-loop impurities and impurities thereof | |
| CN113354574A (en) | Synthetic method of sodium picosulfate | |
| JP2008505189A (en) | Aztreonam manufacturing method | |
| CN105440054B (en) | A kind of technique preparing cefathiamidine | |
| CN1293670A (en) | Chemical process for production of sulphinyl derivatives by oxidation of the corresponding co-derivatives with perborates | |
| CN1226295C (en) | Synthesis of Important intermediate for mosapride citrate | |
| CN1094492C (en) | Process for preparing 'Xidinafei' medicine | |
| CN111072633A (en) | Preparation method of esomeprazole magnesium trihydrate | |
| CN111116556B (en) | Preparation method of (R) -2- [ (4-chlorphenyl) (4-piperidinyloxy) methyl ] pyridine | |
| US20080207896A1 (en) | Process For the Manufacture of Mirtazapine | |
| CN1285829A (en) | Method for producing doxazodin mesylate in crystal modification designated as form A and intermediate product for producing the same | |
| CN101712687B (en) | Method for preparing intermediate of cefetamet pivoxil hydrochloride | |
| CN112920186A (en) | Preparation method of tofacitinib impurity | |
| WO2011117876A1 (en) | An improved process for the preparation of amlodipine free base and acid addition salts thereof | |
| CN102459243A (en) | Process for the preparation of olmesartan medoxomil | |
| CN113200918B (en) | Preparation method of cimetidine | |
| CN1067056C (en) | Method of prep. for 6-aryloxymethyl-1-hydroxy-4-methyl-2-pyridones | |
| US4837317A (en) | Process for the preparation of 6-[D(-)alpha-(4-ethyl-2,3-dioxopiperazin-1-ylcarbonylamino)-alpha-phenylacetamido]-penicillanic acid and intermediates useful in this process |
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 | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Sichuan Xinyuan Pharmaceutical Co., Ltd. Assignor: Sichuan Kelun Pharmaceutical Co., Ltd. Contract fulfillment period: 2009.8.1 to 2019.7.31 contract change Contract record no.: 2009510000136 Denomination of invention: Improved method of preparing azhediping Granted publication date: 20071205 License type: Exclusive license Record date: 20091030 |
|
| LIC | Patent licence contract for exploitation submitted for record |
Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.8.1 TO 2019.7.31; CHANGE OF CONTRACT Name of requester: SICHUAN XINYUAN PHARMACY CO., LTD. Effective date: 20091030 |