CN106397442B - Purification method of regadenoson - Google Patents
Purification method of regadenoson Download PDFInfo
- Publication number
- CN106397442B CN106397442B CN201510459549.1A CN201510459549A CN106397442B CN 106397442 B CN106397442 B CN 106397442B CN 201510459549 A CN201510459549 A CN 201510459549A CN 106397442 B CN106397442 B CN 106397442B
- Authority
- CN
- China
- Prior art keywords
- regadenoson
- solvent
- polar organic
- organic solvent
- impurity
- 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.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a regadenosonThe method of purifying (1). The method comprises the following steps: under the action of alkaline water, mixing the crude product of the regadenoson containing the impurity A with a polar organic solvent, and crystallizing; wherein, the content of the impurity A in the crude product of the regadenoson is 0.1 to 1.0 percent. The purification method can efficiently remove the impurity A in the crude product of the regadenoson, the content of the impurity A in the obtained regadenoson product is below 0.10 percent, the lowest content is below 0.04 percent, and the HPLC purity of the regadenoson product is further improved, so that the HPLC purity of the finally obtained regadenoson product is above 99.80 percent; the product has good quality and completely meets the impurity limit standard of ICH Q3 a.
Description
Technical Field
The invention provides a purification method of regadenoson.
Background
Regadenoson, common english name Regadenoson, chemical name 1- (6-amino-9- β -D-ribofuranosyl-9H-purin-2-yl) -N-methyl-1H-pyrazole-4-carboxamide, formula C15H18N8O5And a molecular weight of 390.35 CAS registry number 875148-45-1, adenosine A, co-developed by CV Therapeutics and Astellas Pharma, USA2AReceptor agonists by activation of adenosine A2AThe receptor expands coronary artery blood vessels, increases coronary artery blood flow to assist in diagnosing coronary artery disease, is marketed in the united states 4 months 2008 for radionuclide myocardial perfusion imaging, and has the following structure:
patent CN102260311A reports that the synthesis method of regadenoson is: taking 2-chloroadenosine 2 as an initial raw material, preparing 2-hydrazino adenosine 3 by hydrazine hydrate substitution, then condensing and closing with 2-formyl 3-oxo ethyl propionate to obtain a compound 4, and hydrolyzing the compound 4 by methylamine aqueous solution to obtain the regadenoson 1, wherein the specific synthetic route is as follows:
the patent also discloses a purification method of the regadenoson, which comprises the following specific steps: dissolving the crude product of the regadenoson in dimethyl sulfoxide, adding pure water into the solution, filtering the slurry formed by the solution, washing a filter cake by water and ethanol in sequence, and finally drying to obtain the product of the regadenoson.
Patent CN101668768A discloses a preparation method and a purification method of regadenoson, wherein the synthetic route of the preparation method of the crude product is shown in the above reaction equation, and the patent also discloses a purification method of regadenoson, which specifically comprises the following steps: dissolving the crude product of the regadenoson in dimethyl sulfoxide to obtain a solution, maintaining the temperature at 78-88 ℃, adding the solution into pure water to form slurry, filtering the slurry, washing a filter cake by water and ethanol in sequence, and finally drying to obtain the regadenoson product.
However, the inventor of the present application repeated the above-mentioned methods for synthesizing and purifying CN102260311A and CN101668768A, and found that the crude regadenoson product contains an impurity with a content of > 0.1%, so that the final regadenoson product does not meet the impurity limit standard of ICH Q3a (note: the standard requires that the content of single impurity of the drug is less than 0.1%), and cannot meet the quality requirement of the drug. Therefore, there is a need in the art for a purification method of regadenoson to solve the above technical problems.
Disclosure of Invention
The invention aims to solve the technical problem of providing a purification method of regadenoson, aiming at overcoming the defects that the regadenoson product obtained by the existing purification method of the regadenoson crude product with impurity A as the main impurity has high impurity A content and poor quality, the regadenoson product with impurity A content less than 0.1 percent and meeting the medicine quality requirement and the like. The purification method can efficiently remove the impurity A in the crude product of the regadenoson, the content of the impurity A in the obtained regadenoson product is below 0.10 percent, the lowest content is below 0.04 percent, the HPLC purity of the regadenoson product is further improved, and the HPLC purity of the finally obtained regadenoson product is above 99.80 percent; the product has good quality and completely meets the impurity limit standard of ICH Q3 a.
The inventors isolated, purified and structurally identified impurities in the regadenoson products obtained in the methods disclosed in the above-mentioned CN102260311A and CN101668768A patents, and confirmed that the structural formula of the impurities is as follows, and named as impurity a:
after the intensive research and analysis of the inventors, the cause of the impurity a is mainly: in both the above processes for the preparation of regadenoson, compound 4 undergoes a hydrolysis side reaction simultaneously with the aminolysis in aqueous methylamine solution, thus producing impurity a with properties very similar to those of the regadenoson product.
The inventor prepares crude regadenoson HPLC purity of 99.58% and impurity A content of 0.35% according to the two synthetic routes; repeating the two purification methods to obtain the product of the regadenoson, wherein the HPLC purity of the product of the regadenoson is 99.60 percent, and the content of the impurity A is 0.33 percent; it can be seen that the above two purification methods have difficulty in removing impurity a. Moreover, the main impurity in the regadenoson product prepared by the two synthesis methods is the impurity A, and the existence of the impurity A has great influence on the quality of the regadenoson product, so that the effective control and removal of the impurity are the key points for obtaining the regadenoson product meeting the quality requirement of medicines. In addition, the presence of this impurity may cause serious side reactions, and thus, there is a strong need in the art for a method for effectively removing impurity a from the product of regadenoson, in order to solve the above technical problems.
The invention mainly solves the technical problem through the following technical scheme.
The invention provides a purification method of regadenoson, which comprises the following steps: under the action of alkaline water, mixing the crude product of the regadenoson containing the impurity A with a polar organic solvent, and crystallizing; wherein, the content of the impurity A in the crude product of the regadenoson is 0.1 to 1.0 percent.
In the purification method, the HPLC purity of the crude regadenoson product is not particularly limited as long as the main impurity in the crude regadenoson product is impurity a, preferably the HPLC purity of the crude regadenoson product is 98.0% to 99.8%, more preferably 99.0% to 99.8%, and most preferably 99.5% to 99.7%. The content of the impurity A is preferably 0.1-0.5%.
The purification method is preferably any one of the following modes:
the first method is as follows: mixing the crude product of the regadenoson with a polar organic solvent, adding an alkaline aqueous solution at the temperature of 50-80 ℃ (preferably 65-80 ℃), and crystallizing;
the second method comprises the following steps: mixing the crude product of the regadenoson with a solvent at the temperature of 50-80 ℃ (preferably 65-80 ℃), and crystallizing; the solvent is a mixed solution of a polar organic solvent and an alkaline water solution.
In the present invention, the polar organic solvent preferably includes a protic polar organic solvent and/or an aprotic polar organic solvent. The protic polar organic solvent may be a protic polar organic solvent as is conventional in the art, preferably C1～C4The alcohol solvent of (1). Said C1～C4The alcoholic solvent of (a) is preferably one or more of methanol, ethanol, isopropanol and n-butanol, more preferably one or more of methanol, ethanol and isopropanol. When said C is1～C4When the alcohol solvent is n-butanol, it is generally necessary to use the alcohol solvent in combination with another protic polar organic solvent and/or the aprotic polar organic solvent of the present invention. The other protic polar organic solvent is preferably one or more of methanol, ethanol and isopropanol. The aprotic polar organic solvent may be an aprotic polar organic solvent which is conventional in the art, and preferably one or more of a ketone solvent, a sulfoxide solvent and an amide solvent. The ketone solvent is preferably acetone. The sulfoxide solvent is preferably dimethyl sulfoxide. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide.
In the present invention, the alkali in the aqueous alkali solution is preferably an inorganic alkali and/or an organic alkali. The inorganic base may be an inorganic base conventional in the art, preferably one or more of an alkali metal hydroxide, an alkaline earth metal hydroxide and an alkali metal carbonate, more preferably an alkali metal hydroxide and/or an alkali metal carbonate. The alkali metal hydroxide is preferably sodium hydroxide and/or potassium hydroxide. The alkaline earth metal hydroxide is preferably calcium hydroxide. The alkali metal carbonate is preferably sodium carbonate and/or potassium carbonate. The organic base may be any organic base conventional in the art, preferably C1～C6Of an alkylamine of (a). Said C1～C6The alkylamine of (a) is preferably one or more of methylamine, dimethylamine, diethylamine and triethylamine. The molar concentration of the aqueous alkali solution is preferably 0.01 to 1 mol/L.
In the first embodiment, the volume/mass ratio of the polar organic solvent to the crude regadenoson product is preferably 3 to 20mL/g, more preferably 6 to 10 mL/g. The ratio of the alkaline aqueous solution with the molar concentration of 0.01-1 mol/L to the volume mass of the regadenoson is preferably 3-20 mL/g, more preferably 3-15 mL/g. The addition is preferably dropwise. The dropping speed is preferably controlled to be between 50 and 80 ℃ (preferably 65 to 80 ℃), and is generally 1mL/min to 10 mL/min.
In the second embodiment, the solvent is a mixed solution of a polar organic solvent and an aqueous alkali solution, wherein the volume ratio of the polar organic solvent to the aqueous alkali solution is preferably 1:1 to 10:1, and more preferably 1:1 to 3: 1. The volume and mass ratio of the solvent to the crude product of the regadenoson is preferably 40mL/g to 80 mL/g.
In the first or second mode, the crystallization is preferably performed by stirring. The time for crystallization is preferably 1 to 3 hours. The temperature for crystallization is preferably room temperature (10-30 ℃).
In the first or second mode, after the crystallization, the method preferably further comprises the following steps: filtering the system after crystallization, and sequentially using water and C1～C4Washing the filter cake with the alcohol solvent, and drying to obtain the product of the regadenoson. Wherein, said C1～C4The alcoholic solvent of (b) is preferably methanol and/or ethanol. Said water or said C1～C4The alcohol solvent of (2) is preferably 5mL/g to 10mL/g in comparison with the crude product of regadenoson in terms of volume and mass. The drying method may be a method conventional in the art, and preferably vacuum drying. The temperature of the vacuum drying is preferably 45-55 ℃.
In the invention, the crude regadenoson product can be prepared according to a conventional preparation method of the crude regadenoson product in the field, preferably according to a method described in embodiments 2-4 of a patent CN102260311 or a patent CN101668768, and the HPLC purity of the crude regadenoson product is generally between 98% and 99.8%; the content of the impurity A is generally between 0.1 and 1.0 percent.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the purification method can efficiently remove the impurity A in the crude product of the regadenoson, the content of the impurity A in the obtained regadenoson product is below 0.10 percent, the lowest content is below 0.04 percent, the HPLC purity of the regadenoson product is further improved, and the HPLC purity of the finally obtained regadenoson product is above 99.80 percent; the product has good quality and completely meets the impurity limit standard of ICH Q3 a.
Drawings
FIG. 1 is an HPLC chromatogram of crude regadenoson of example 1.
FIG. 2 is HPLC chromatogram of purified regadenoson product of example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The crude product of regadenoson in the following examples is prepared by the method described in patent CN102260311 or patent CN101668768 examples 2-4, and the HPLC purity is 98-99.8%; the content of the impurity A is 0.1-1.0%.
The specific conditions for HPLC testing of crude and product regadenoson in the following examples are as follows:
adopting a Thermo UltiMate 3000 high performance liquid chromatograph; chromatography column Waters X-bridge C18 column (4.6 mm. times.150 mm, 3.5 μm); mobile phase 20mmol/L potassium dihydrogen phosphate solution (pH 6.8) (a), acetonitrile (B); gradient elution (0 → 5min, a 95%; 5 → 20min, a 95% → 85%; 20 → 30min, a 85% → 40%; 30 → 38min, a 40%; 38 → 38.1min, a 40% → 95%; 38.1 → 45min, a 95%); the detection wavelength is 245 nm; the flow rate is 1.0 ml/min; column temperature 25 deg.C
Example 1
Taking 1g of a crude product of the regadenoson (the HPLC purity is 99.58 percent, and the content of the impurity A is 0.35 percent), adding 6mL of LDMSO to dissolve the crude product, heating the crude product to about 80 ℃, dropwise adding 9mL of a sodium hydroxide aqueous solution with the concentration of 0.1mol/L, gradually separating out a white solid in the dropwise adding process, naturally cooling the crude product to room temperature after the dropwise adding is finished, stirring the solution for 2 hours, filtering the solution, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 50 ℃ to obtain 0.97g of the regadeno. HPLC results showed 99.89% regadenoson and 0.05% impurity a.
Example 2
Taking 1g of a crude product of the regadenoson (the HPLC purity is 98.0%, the content of the impurity A is 1.0%), adding 20mL of LDMSO to dissolve the crude product, heating the crude product to about 70 ℃, dropwise adding 3mL of a 0.5mol/L potassium carbonate aqueous solution, gradually separating out a solid in the dropwise adding process, naturally cooling the crude product to room temperature after the dropwise adding is finished, stirring the crude product for 3 hours, filtering the solution, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 55 ℃ to obtain 0.85g of the regadenoson product. The HPLC results showed that the content of regadenoson was 99.87% and the content of impurity a was 0.03%.
Example 3
Taking 1g of a crude product of the regadenoson (the HPLC purity is 99.50 percent, the content of the impurity A is 0.45 percent), adding 10mL of DMMF to dissolve the crude product, heating the crude product to about 70 ℃, dropwise adding 6mL of a sodium carbonate aqueous solution with the concentration of 0.1mol/L, gradually separating out a solid in the dropwise adding process, naturally cooling the crude product to room temperature after the dropwise adding is finished, stirring the solution for 2 hours, filtering the solution, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 50 ℃ to obtain 0.95g of the regadeno. HPLC results showed that the content of regadenoson was 99.89% and the content of impurity a was 0.04%.
Example 4
2g of crude regadenoson (with HPLC purity of 99.58 percent and impurity A content of 0.35 percent) is taken, 80mL of 0.01mol/L potassium hydroxide aqueous solution/methanol mixed solvent (with volume ratio of 10/1) is added, the mixture is heated to about 75 ℃, the solid is completely dissolved, then the mixture is naturally cooled to room temperature, the mixture is stirred for 1h, the filtration is carried out, 10mL of pure water and 10mL of ethanol are sequentially used for washing a filter cake, and the vacuum drying at 50 ℃ is carried out to obtain 1.86g of the regadenoson product. The HPLC results showed a content of 99.88% for regadenoson and 0.05% for impurity a.
Example 5
2g of a crude product of the regadenoson (the HPLC purity is 98.0%, the content of the impurity A is 1.0%) is taken, 80mL (the volume ratio is 1/1) of a dimethylamine aqueous solution/n-butanol mixed solvent of 1mol/L is added, the mixture is heated to about 50 ℃, the solid is completely dissolved, then the mixture is naturally cooled to room temperature, the mixture is stirred for 2 hours, the filtration is carried out, 10mL of pure water and 10mL of ethanol are used for washing a filter cake, and the vacuum drying is carried out at 45 ℃ to obtain 1.81g of the regadenoson product. The HPLC results showed that the content of regadenoson was 99.82% and the content of impurity a was 0.09%.
Example 6
0.8g of crude regadenoson (HPLC purity 99.80%, impurity A content 0.16%) is taken, 64mL (volume ratio of 1/10) of 1mol/L triethylamine water solution/acetone mixed solvent is added, the mixture is heated to about 68 ℃ to completely dissolve the solid, then the solid is naturally cooled to room temperature, the mixture is stirred for 1h, filtered, 8mL of pure water and 8mL of ethanol are used for washing a filter cake, and vacuum drying is carried out at 50 ℃ to obtain 0.65g of the regadenoson product. The HPLC results showed that the content of regadenoson was 99.91% and the content of impurity a was 0.06%.
Example 7
Taking 1g of a crude product of the regadenoson (the HPLC purity is 98.0%, the content of the impurity A is 1.0%), adding 3mL of N, N-dimethylacetamide, heating to about 68 ℃, dropwise adding 15mL of a calcium hydroxide aqueous solution with the concentration of 0.01mol/L, gradually separating out a solid in the dropwise adding process, naturally cooling to room temperature after dropwise adding, stirring for 3h, filtering, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 50 ℃ to obtain 0.85g of the regadenoson product. The HPLC results showed that the content of regadenoson was 99.87% and the content of impurity a was 0.04%.
Fig. 1 and table 1 show HPLC spectra of crude regadenoson prepared by the method described in example 2 of patent CN102260311A, and information on retention time, peak height, peak area, relative area, etc. Wherein 1, 2 and 3 correspond to the information of retention time, peak height, peak area, relative area and the like of each component in the regadenoson product. 1 represents impurity a, 2 represents regadenoson, and 3 represents other impurities.
Fig. 2 and table 2 show information on retention time, peak height, peak area, relative area, etc. of the HPLC chromatogram of the regadenoson product obtained in example 1. Wherein, 1, 2 and 3 correspond to the information of retention time, peak height, peak area, relative area and the like of each component in the regadenoson product. 1 represents impurity a, 2 represents regadenoson, and 3 represents other impurities.
TABLE 1
TABLE 2
Comparative example 1
Taking 1g of a crude product of the regadenoson (the HPLC purity is 99.58 percent, and the content of the impurity A is 0.35 percent), adding 6mL of LDMSO to dissolve the crude product, heating the crude product to about 80 ℃, dropwise adding 9mL of pure water, gradually separating out a white solid in the dropwise adding process, naturally cooling the crude product to room temperature after the dropwise adding is finished, stirring the crude product for 2 hours, filtering the solution, washing a filter cake by using 10mL of pure water and 10mL of ethanol in sequence, and performing vacuum drying at 50 ℃ to obtain 0.97g of the regadenoson. The HPLC results showed that the regadenoson content was 99.62% and the impurity a content was 0.33%.
Claims (8)
1. A purification method of regadenoson, characterized in that it comprises the following steps: under the action of alkaline water, mixing the crude product of the regadenoson containing the impurity A with a polar organic solvent, and crystallizing; wherein, the content of the impurity A in the crude product of the regadenoson is 0.1 to 1.0 percent; the molar concentration of the alkaline water solution is 0.01-1 mol/L; the HPLC purity of the crude product of the regadenoson is 98.0 to 99.8 percent;
the purification method is any one of the following modes:
the first method is as follows: mixing the crude product of the regadenoson with a polar organic solvent, adding an alkaline aqueous solution at the temperature of 50-80 ℃, and crystallizing;
the second method comprises the following steps: mixing the crude product of the regadenoson with a solvent at the temperature of 50-80 ℃, and crystallizing; the solvent is a mixed solution of a polar organic solvent and an aqueous alkali solution;
the polar organic solvent comprises a protic polar organic solvent and/or an aprotic polar organic solvent; the alkali in the alkali aqueous solution is inorganic alkali and/or organic alkali;
the protic polar organic solvent is C1～C4The alcohol solvent of (1); the aprotic polar organic solvent is one or more of a ketone solvent, a sulfoxide solvent and an amide solvent; the inorganic alkali is one or more of alkali metal hydroxide, alkaline earth metal hydroxide and alkali metal carbonate; the organic base is C1～C6An alkylamine of (a);
in the first mode, the volume mass of the polar organic solvent and the crude product of the regadenoson is 3-20 mL/g; the volume-mass ratio of the alkaline aqueous solution with the molar concentration of 0.01-1 mol/L to the regadenoson is 3-20 mL/g;
in the second mode, the solvent is a mixed solution of a polar organic solvent and an aqueous alkali solution, wherein the volume ratio of the polar organic solvent to the aqueous alkali solution is 1: 1-10: 1; the volume-mass ratio of the solvent to the crude product of the regadenoson is 40 mL/g-80 mL/g;
2. the purification process according to claim 1, wherein the crude regadenoson has an impurity a content of 0.1% to 0.5%.
3. The purification process according to claim 1, wherein the crude regadenoson has an HPLC purity of 99.0% to 99.8%.
4. The purification process according to claim 3, wherein the crude regadenoson has an HPLC purity of 99.5% to 99.7%.
5. The purification method according to claim 1, wherein in the first or second mode, the crystallization is performed by stirring; the crystallization time is 1-3 h; and/or the temperature of crystallization is 10-30 ℃.
6. The purification method of claim 1, wherein C is1～C4The alcohol solvent is one or more of methanol, ethanol, isopropanol and n-butanol; when said C is1～C4When the alcohol solvent is n-butyl alcohol, the n-butyl alcohol is mixed with other protonic polar organic solvent and/or the aprotic polar organic solvent for use; the other protonic polar organic solvent is one or more of methanol, ethanol and isopropanol; the ketone solvent is acetone; the sulfoxide solvent is dimethyl sulfoxide; the amide solvent is N, N-dimethylformamide and/or N, N-dimethylacetamide; the alkali metal hydroxide is sodium hydroxide and/or potassium hydroxide; the alkaline earth metal hydroxide is calcium hydroxide; the carbonate of the alkali metal is sodium carbonate and/or potassium carbonate; and/or, said C1～C6The alkylamine of (a) is one or more of methylamine, dimethylamine, diethylamine and triethylamine.
7. The purification method of claim 1, wherein in the first mode, the adding mode is dropwise; and/or the dropping speed is controlled to be 50-80 ℃ in the reaction system.
8. The purification method according to claim 1, wherein in the first or second mode, after the crystallization is completed, the method further comprises the following steps: filtering the system after crystallization, and sequentially using water and C1～C4Washing the filter cake with the alcohol solvent, and drying to obtain the product of the regadenoson.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510459549.1A CN106397442B (en) | 2015-07-28 | 2015-07-28 | Purification method of regadenoson |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510459549.1A CN106397442B (en) | 2015-07-28 | 2015-07-28 | Purification method of regadenoson |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106397442A CN106397442A (en) | 2017-02-15 |
| CN106397442B true CN106397442B (en) | 2020-03-27 |
Family
ID=58008882
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510459549.1A Active CN106397442B (en) | 2015-07-28 | 2015-07-28 | Purification method of regadenoson |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106397442B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110117305B (en) * | 2018-02-06 | 2023-06-02 | 上海键合医药科技有限公司 | Method for purifying regadenoson and novel crystal form thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000078779A2 (en) * | 1999-06-22 | 2000-12-28 | Cv Therapeutics, Inc. | N-pyrazole a2a receptor agonists |
| WO2007092372A1 (en) * | 2006-02-03 | 2007-08-16 | Cv Therapeutics, Inc. | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| WO2008143667A1 (en) * | 2007-05-17 | 2008-11-27 | Cv Therapeutics, Inc. | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| CN104744540A (en) * | 2013-12-26 | 2015-07-01 | 上海紫源制药有限公司 | Preparation method for regadenoson |
-
2015
- 2015-07-28 CN CN201510459549.1A patent/CN106397442B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000078779A2 (en) * | 1999-06-22 | 2000-12-28 | Cv Therapeutics, Inc. | N-pyrazole a2a receptor agonists |
| WO2007092372A1 (en) * | 2006-02-03 | 2007-08-16 | Cv Therapeutics, Inc. | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| CN102260311A (en) * | 2006-02-03 | 2011-11-30 | 吉利德帕洛阿尔托股份有限公司 | Process for preparing an A2A-adenosine receptor agonist and its polymorphs |
| WO2008143667A1 (en) * | 2007-05-17 | 2008-11-27 | Cv Therapeutics, Inc. | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| CN101668768B (en) * | 2007-05-17 | 2012-08-29 | 吉利德帕洛阿尔托股份有限公司 | Process for preparing an a2a-adenosine receptor agonist and its polymorphs |
| CN104744540A (en) * | 2013-12-26 | 2015-07-01 | 上海紫源制药有限公司 | Preparation method for regadenoson |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106397442A (en) | 2017-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JPH02167286A (en) | Salt of clavulanic acid, and production and use | |
| CN106478747B (en) | The industrial manufacturing process of gemcitabine key intermediate sulfonation sugar | |
| CN110283122B (en) | Preparation method of high-purity Lunvatinib and salt thereof | |
| CN106397442B (en) | Purification method of regadenoson | |
| TWI712611B (en) | The manufacturing method of pantoxin and its novel manufacturing intermediate | |
| CN101209990A (en) | Resolution method for 3-piperidine formic acid ester | |
| CN112694445A (en) | Purification method of oxalaggrin sodium intermediate | |
| CN1454212A (en) | Intermediates in cephalosporing production | |
| KR100375957B1 (en) | D4t polymorphic form i process | |
| MXPA96001957A (en) | Process for the obtaining of the 2 ', 3'-dideshidro-3'-desoxitimidina polimorfica, form | |
| US20080207896A1 (en) | Process For the Manufacture of Mirtazapine | |
| CN109836424B (en) | Method for preparing caffeine by methylation of environment-friendly theophylline sodium salt | |
| CN113004279B (en) | Method for controlling water content of PARP inhibitor-containing sesquihydrate product | |
| CN104418855A (en) | Improved method for preparing paliperidone and intermediates of paliperidone | |
| KR20180105450A (en) | A Method of preparing Fimarsartan choline salt and hydrate thereof | |
| JP4603274B2 (en) | Process for producing 2'-deoxy-5-trifluoromethyluridine | |
| CN103937866B (en) | A kind of preparation method of the ampicillin of improvement | |
| WO2010126138A1 (en) | Novel crystal forms of tricyclic benzopyran compound and processes for producing same | |
| CN105753732A (en) | Crystal form of AHU377 as well as preparation method and application thereof | |
| CN112500441A (en) | Preparation process of high-purity glycosyl phosphate | |
| US5451671A (en) | Method of purifying 2',3'-dideoxynucleosides | |
| JP2001525843A (en) | Method for producing deoxyuridine derivative | |
| JP3123238B2 (en) | Purification method of nucleoside derivative | |
| CN105985296B (en) | It is a kind of can be with the process for refining of industrialized lesinurad intermediates 1- naphthalene triazolinthiones | |
| CN106478618A (en) | The preparation method of emtricitabine halogen acid salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: 232000 No.16 Chaoyang East Road, Huainan Economic and Technological Development Zone, Anhui Province Patentee after: CHINA NATIONAL MEDICINES GUORUI PHARMACEUTICAL Co.,Ltd. Patentee after: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY Address before: 232001 No.28, Guoqing West Road, Huainan City, Anhui Province Patentee before: CHINA NATIONAL MEDICINES GUORUI PHARMACEUTICAL Co.,Ltd. Patentee before: SHANGHAI INSTITUTE OF PHARMACEUTICAL INDUSTRY |