CN111377986B - Method for purifying decitabine intermediate - Google Patents
Method for purifying decitabine intermediate Download PDFInfo
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- CN111377986B CN111377986B CN201811648512.3A CN201811648512A CN111377986B CN 111377986 B CN111377986 B CN 111377986B CN 201811648512 A CN201811648512 A CN 201811648512A CN 111377986 B CN111377986 B CN 111377986B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for purifying a decitabine intermediate; according to the method, the decitabine intermediate crude product is dissolved in a first solvent such as trichloromethane, and a second solvent such as methyl tert-butyl ether is added, so that impurities generated in the synthesis process can be effectively removed, and the proportion of beta-configuration products can be increased when the refined intermediate is subjected to glycosylation reaction.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a method for purifying a decitabine intermediate.
Background
Decitabine drug name: decitabine; registration name: decitabine; trade name: dacogen; the medicine is named as follows: 5-azacd, azadc; chemical name: 4-amino-1- (2-deoxy-beta-D-erythro-ribofuranose) -1,3,5-triazine-2 (1H) -ketone ] is an analogue of natural nucleoside 2' -deoxycytidine, and is developed and developed into a medicament by SuperGen company in the United states. The clinical phase III was completed in 2004, and the development right of global development, production, sale and development was assigned to MGI pharmaceutical company. The drugs approved by european EMEA and the us FDA for marketing at 2006, 4 months and 5 months, respectively, are effective drugs for the treatment of primary and secondary myelodysplastic syndromes (MDS).
There are several synthetic methods for decitabine, such as those described in patents EP2050757, EP2048151, US2010249394, CN101560232A, WO2012018235A2, CN101560232, WO2010129211, etc.
The currently common method is that 2-deoxy-D-ribose (III) is used as a starting material, reacts with a hydrochloric acid methanol solution to generate (IV), generates acylation reaction with Fmoc-Cl to generate (V), generates acetylation reaction with acetic anhydride in glacial acetic acid to generate (II), performs C-N condensation on the (II) and Hexamethyldisilazane (HDMS) converted 5-azacytosine (VI) to generate (VIII), and obtains I after deprotection. Such as the route disclosed in CN103739645A, CN103739636 a. The method has the advantages of easily available raw materials and mild reaction conditions, and can be well applied to industrial production. The reaction route is as follows:
CN102070679A also discloses that intermediate V is used as a raw material to synthesize intermediate II and further synthesizes decitabine with 5-azacytosine activator. The yield can reach 70-93%, the ratio of two isomers is alpha: β =1:1.
WO2009086687A1 discloses that intermediate V can also be used directly to perform glycosylation with 5-azacytosine activator. α to give intermediate VIII: beta is not less than 3:2.
CN103739645A, CN103739636A, CN102070679A did not purify intermediate II, which was an important intermediate for direct glycosidation, and its purity directly affected the subsequent reaction.
Therefore, the method for simply and quickly purifying the decitabine intermediate II is of great significance for improving the beta/alpha configuration ratio in the glycosylation reaction product.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides a method for purifying a decitabine intermediate. The purification method can effectively remove impurities and improve the purity of the decitabine intermediate.
In the actual production process, the inventor finds that the intermediate II is refined and then used for glycosylation reaction, so that the impurity amount of products of glycosylation reaction can be reduced, and the proportion of beta/alpha configuration products can be further improved; intermediate ii is shown below:
the intermediate II prepared from the intermediate V is catalyzed by acid mostly, and strong acid catalysis is easy to cause various side reactions. Resulting in a decrease in yield; the purity was poor.
A plurality of impurities are generated in the preparation process of the intermediate II, wherein 3 main impurities influencing the glycosylation reaction are generated in the intermediate II.
The three impurities are beneficial to the generation of alpha configuration products during the glycosylation reaction, particularly the impurity 3 (intermediate V), and the induction effect of the impurities on the alpha configuration products reduces the beta/alpha configuration ratio, so that the glycosylation reaction can not achieve the expected result.
In order to solve the above problems, the present invention provides the following technical solutions:
refluxing and dissolving the decitabine intermediate into a first solvent, cooling, dropwise adding a second solvent, separating out a solid, controlling the temperature, continuously stirring, filtering, removing a filter cake, and evaporating the filtrate under reduced pressure to obtain an intermediate;
the mass-volume ratio of the decitabine intermediate to the first solvent to the second solvent is 1:2-5:6-15 in g/ml/ml.
The first solvent is one or a mixture of more than two of dichloromethane, trichloromethane, ethyl acetate and acetonitrile, and dichloromethane is preferred.
The second solvent is one or a mixture of more than two of toluene, n-hexane, methyl tert-butyl ether, xylene and petroleum ether, and preferably methyl tert-butyl ether.
The dropping time is 2-4 hours.
The temperature for dropping the second solvent is-10 ℃ to 10 ℃, preferably-5 ℃ to 5 ℃.
The stirring process time is 3-5 hours.
The temperature in the stirring process is-10 ℃ to 10 ℃, and preferably-5 ℃ to 5 ℃.
The preparation method of the decitabine intermediate II can be a scheme or route disclosed in the prior art.
In some embodiments of the invention, 2-deoxy-D-ribose is used as a starting material, and reacted with a solution of hydrochloric acid in methanol to form a C-1 methoxy protected compound of 2-deoxy-D-ribose, which is acylated with Fmc-Cl to form C-2 and C-5 Fmoc-protected compounds of 2-deoxy-D-ribose, and then acetylated with acetic anhydride in methylene chloride to form II.
The obtained decitabine intermediate II is subjected to glycosylation according to the methods in the patent or the literature, and the ratio of beta/alpha configuration products is determined by HPLC.
The scheme of the invention has the advantages that:
1. the refining method can remove three main impurities which affect the glycosylation reaction, and has the refining yield of more than 90 percent and the purity of more than 95 percent.
2. The invention can improve the proportion of beta configuration in the glycosylation reaction product.
3. The purification method provided by the invention is simple to operate and suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The detection method comprises the following steps: the purity of the intermediate II is determined by an HPLC method, and an HPLC normalization method comprises the following steps: column C18 (4.6 mm. Times.250mm, 5 μm); acetonitrile: water = 80; the detection wavelength is 220nm; the flow rate was 1.0ml/min, and the column temperature was 30 ℃.
Example 1 Synthesis of Decitabine intermediate II
Dissolving 44.2g of 2-deoxy-D-ribose in 440ml of methanol, cooling to 10-20 ℃, slowly dropwise adding 44ml of 1% methanol hydrochloride solution, stirring for reaction for 1h after dropwise adding, detecting by TLC (thin layer chromatography) (ethyl acetate) to complete the reaction, and evaporating to dryness under reduced pressure to obtain 51.7g of oily substance.
Dissolving the oily matter in 1000ml dichloromethane, cooling to-10-0 ℃, adding 82.7g pyridine, dropwise adding 189.5g Fmoc-Cl (dissolved in 200ml dichloromethane), stirring for reaction for 2h, detecting the reaction completion by TLC (developing agent: petroleum ether: ethyl acetate = 3:1), washing the reaction liquid with 1000ml 1N HCl solution, 1000ml saturated sodium bicarbonate water solution and 1000ml saturated saline solution respectively, adding 50g anhydrous sodium sulfate, drying for 3-4 h, and filtering to obtain filtrate for later use.
Cooling the filtrate to-10-0 ℃, adding 92g of acetic anhydride, slowly dropwise adding 5ml of concentrated sulfuric acid, stirring for reaction for 3h, detecting by TLC (developing agent: petroleum ether: ethyl acetate = 3:1) that the reaction is finished, adjusting the pH to 7-8 by using saturated sodium bicarbonate aqueous solution, separating out an organic phase, washing the organic phase by using 1000ml of saturated sodium chloride solution, decompressing and evaporating the organic phase to dryness to obtain 230.4g of a black oily intermediate II, wherein the purity is 97.78%, the impurity 1 is 0.60%, the impurity 2 is 0.51%, the impurity 3 is 0.90%, and the other single impurity is less than 0.1% by HPLC detection.
Example 2 purification of decitabine intermediate II
Taking 20g of the black oily intermediate II obtained in the example 1, adding 40ml of dichloromethane, heating until the mixture is refluxed and dissolved, cooling to-10 ℃, slowly dropwise adding 120ml of methyl tert-butyl ether, keeping the temperature and stirring for 3 hours after dropwise adding is finished, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a reddish brown oily substance with the yield of 91%. The purity is 99.65 percent through HPLC detection; 0.08% for impurity 1, 0.07% for impurity 2, and 0.1% for impurity 3.
Example 3 purification of decitabine intermediate II
And (3) taking 20g of the black oily intermediate II obtained in the example 1, adding 80ml of dichloromethane, heating until the mixture is refluxed and dissolved, cooling to-5 ℃, slowly dropwise adding 180ml of methyl tert-butyl ether, keeping the temperature and stirring for 3 hours after dropwise adding is finished, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a reddish brown oily substance with the yield of 96%. The purity is 99.86 percent through HPLC detection; 0.06% of impurity 1, 0.04% of impurity 2, and 0.03% of impurity 3.
Example 4 purification of Decitabine intermediate II
Taking 20g of the black oily intermediate II obtained in the example 1, adding 40ml of dichloromethane, heating until the mixture is refluxed and dissolved, cooling to-5 ℃, slowly dropwise adding 300ml of methyl tert-butyl ether, keeping the temperature and stirring for 3 hours after dropwise adding is finished, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a reddish brown oily substance with the yield of 97%. The purity is 99.52 percent through HPLC detection; 0.18% of impurity 1, 0.10% of impurity 2, 0.09% of impurity 3 and less than 0.1% of other single impurities.
Example 5 purification of Decitabine intermediate II
And (3) taking 20g of the black oily intermediate II obtained in the example 1, adding 80ml of trichloromethane, refluxing and dissolving, cooling to 5 ℃, slowly dropwise adding 180ml of methyl tert-butyl ether, keeping the temperature and stirring for 4 hours after dropwise adding for 2 hours, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a reddish brown oily substance with the yield of 93%. The purity is 99.74 percent through HPLC detection; 0.06% of impurity 1, 0.05% of impurity 2, and 0.03% of impurity 3.
Example 6 purification of Decitabine intermediate II
Taking 20g of the black oily intermediate II obtained in the example 1, adding 100ml of ethyl acetate, refluxing for dissolution, cooling to 5 ℃, slowly dropwise adding 300ml of petroleum ether, continuing to keep the temperature and stir for 5 hours after dropwise adding is completed for 2 hours, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a reddish brown oily substance, wherein the yield is 94%, and the purity is 99.65% through HPLC detection; 0.11% for impurity 1, 0.09% for impurity 2, and 0.06% for impurity 3.
Example 7 purification of decitabine intermediate II
And (2) taking 20g of the black oily intermediate II obtained in the example 1, adding 80ml of acetonitrile, refluxing and dissolving, cooling to 10 ℃, slowly dropwise adding 180ml of n-hexane for 4 hours, cooling to 0 ℃, keeping the temperature and stirring for 4 hours, filtering, and evaporating the filtrate under reduced pressure to obtain a reddish brown oily substance with the yield of 95%. The purity is 99.71% by HPLC detection; 0.10% of impurity 1, 0.09% of impurity 2, and 0.08% of impurity 3.
EXAMPLE 8 purification of Decitabine intermediate II
And (2) taking 20g of the black oily intermediate II obtained in the example 1, adding 80ml of dichloromethane, dissolving at a reflux temperature, cooling to-5 ℃, slowly dropwise adding 180ml of toluene, cooling to-5 ℃ after dropwise adding for 3 hours, continuously keeping the temperature and stirring for 4 hours, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a reddish brown oily substance with the yield of 95%. The purity is 99.58 percent through HPLC detection; 0.11% for impurity 1, 0.12% for impurity 2, and 0.09% for impurity 3.
Example 9 purification of Decitabine intermediate II
Taking 20g of the black oily substance in the example 1, adding 80ml of dichloromethane, dissolving at the reflux temperature, cooling to-5 ℃, slowly dropwise adding 340ml of methyl tert-butyl ether, after 4 hours of dropwise addition, heating to 10 ℃, continuing to keep the temperature and stir for 5 hours, filtering, and evaporating the filtrate under reduced pressure to dryness to obtain a reddish brown oily substance with the yield of 90%. The purity is 99.61% by HPLC detection; impurity 1 was 0.09, impurity 2 was 0.08, and impurity 3 was 0.12%.
EXAMPLE 10 silylation of 5-azacytosine
Weighing 15g of 5-azacytosine, adding 150ml of hexamethyldisilazane, heating to reflux, reacting for 5 hours under heat preservation, and concentrating the reaction solution under reduced pressure to obtain 34.3g of white solid.
EXAMPLE 11 glycosylation of intermediate II
Taking 9g of the intermediate in example 5, dissolving in 30ml of trichloromethane, adding 4.49g of silanized 5-azacytosine, cooling to about 0 ℃, and dropwise adding SnCl 4 ·5H 2 O4.05 g, stirring and reacting for 5-7 h under the condition of heat preservation at minus 5-0 ℃, detecting by TLC after the reaction is finished, adjusting the pH to alkalescence by using a saturated sodium bicarbonate aqueous solution, separating out an organic phase, and evaporating to dryness under reduced pressure to obtain a dark red bubble solid. The beta/alpha ratio was 1.2 by HPLC. [ HPLC normalization method: column C18 (4.6 mm. Times.250mm, 5 μm); 0.05mol/L ammonium dihydrogen phosphate solution (pH =3.0 adjusted with phosphoric acid): acetonitrile = 20; the detection wavelength is 240nm; flow rate 1.0ml/min]。
EXAMPLE 12 glycosylation of intermediate II
Taking 10.6g of the black solid in example 1, dissolving the black solid in 30ml of trichloromethane, adding 4.49g of silanized 5-azacytosine, cooling to about 0 ℃, and dropwise adding SnCl 4 ·5H 2 O4.05 g, keeping the temperature of-5-0 ℃, stirring and reacting for 5-7 h, detecting by TLC after the reaction is finished, adjusting the pH to alkalescence by using a saturated sodium bicarbonate aqueous solution, separating an organic phase, and evaporating to dryness under reduced pressure to obtain a black oily solid. The beta/alpha ratio was 1.0 by HPLC. [ HPLC normalization method: column C18 (4.6 mm. Times.250mm, 5 μm); 0.05mol/L ammonium dihydrogen phosphate solution (pH =3.0 adjusted with phosphoric acid): acetonitrile = 20; the detection wavelength is 240nm; flow rate 1.0ml/min]。
Claims (1)
1. A method for purifying a decitabine intermediate, wherein the intermediate is shown as a formula II, is characterized by comprising the following steps: refluxing and dissolving the decitabine intermediate into a first solvent, cooling, dropwise adding a second solvent, separating out a solid, controlling the temperature, continuously stirring, filtering, removing a filter cake, and evaporating the filtrate under reduced pressure to obtain an intermediate;
wherein the decitabine intermediate, the first solvent and the second solvent have a mass-to-volume ratio of 1:2-5:6-15 in g/ml/ml;
the first solvent is one or a mixture of more than two of dichloromethane, trichloromethane, ethyl acetate and acetonitrile;
the second solvent is one or a mixture of more than two of methylbenzene, normal hexane, methyl tert-butyl ether, dimethylbenzene and petroleum ether;
the dripping time is 2 to 4 hours;
the temperature for dripping the second solvent is-10 ℃ to 10 ℃;
the stirring process time is 3-5 hours;
the temperature of the stirring process is-10 ℃ to 10 ℃.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948493A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Industrialized production method for high-purity decitabine |
| CN102070679A (en) * | 2010-12-24 | 2011-05-25 | 齐鲁制药有限公司 | 1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose and application |
| CN102212097A (en) * | 2011-04-12 | 2011-10-12 | 重庆泰濠制药有限公司 | Synthetic method of decitabine |
| CN102391338A (en) * | 2011-09-30 | 2012-03-28 | 重庆泰濠制药有限公司 | Method for purifying decitabine intermediate crude product |
| CN102827224A (en) * | 2011-06-16 | 2012-12-19 | 江苏豪森医药集团连云港宏创医药有限公司 | Decitabine synthesis and industrial production method |
| CN103739636A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Preparation method of decitabine intermediate |
| CN103739645A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Preparation method of decitabine |
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- 2018-12-30 CN CN201811648512.3A patent/CN111377986B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101948493A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Industrialized production method for high-purity decitabine |
| CN102070679A (en) * | 2010-12-24 | 2011-05-25 | 齐鲁制药有限公司 | 1-acetoxyl-2-deoxy-3, 5-di-O-fluorenylmethyloxycarbonyl acyl-D-ribofuranose and application |
| CN102212097A (en) * | 2011-04-12 | 2011-10-12 | 重庆泰濠制药有限公司 | Synthetic method of decitabine |
| CN102827224A (en) * | 2011-06-16 | 2012-12-19 | 江苏豪森医药集团连云港宏创医药有限公司 | Decitabine synthesis and industrial production method |
| CN102391338A (en) * | 2011-09-30 | 2012-03-28 | 重庆泰濠制药有限公司 | Method for purifying decitabine intermediate crude product |
| CN103739636A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Preparation method of decitabine intermediate |
| CN103739645A (en) * | 2014-01-09 | 2014-04-23 | 山东新时代药业有限公司 | Preparation method of decitabine |
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