CN104829591A - Preparation method of deuterated pimozide - Google Patents
Preparation method of deuterated pimozide Download PDFInfo
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- CN104829591A CN104829591A CN201510206526.XA CN201510206526A CN104829591A CN 104829591 A CN104829591 A CN 104829591A CN 201510206526 A CN201510206526 A CN 201510206526A CN 104829591 A CN104829591 A CN 104829591A
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- IVSMXLYLTMTDJL-UHFFFAOYSA-N Cc1ccc(C(CCCN)c(c(O)c(c(I)c2O)O)c2O)cc1 Chemical compound Cc1ccc(C(CCCN)c(c(O)c(c(I)c2O)O)c2O)cc1 IVSMXLYLTMTDJL-UHFFFAOYSA-N 0.000 description 1
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a preparation method of deuterated pimozide. The pimozide-d4 is synthesized from 4-bromopentafluorobenzene-d4 through eight steps. The provided preparation method has the advantages of reasonable technological design, simple operation, easy product separation and purification, easily-available raw materials, high yield, and high purity. The isotope abundance of the obtained target product is high. The prepared stable isotope-labeled pimozide-d4 can be well applied to clinical pharmacokinetics researches, so people can acknowledge the metabolism process and action mechanism of pimozide in human body more precisely and conveniently, and thus the deuterated pimozide has an important application value.
Description
Technical field
The invention belongs to the bulk drug preparing technical field of cold labeling, be specifically related to a kind of preparation method of deuterated pimozide.
Background technology
Pimozide (Pimozide) its medicine another name is for pimozide, and Opiram, Orap are in 1970 in Belgian Initial Public Offering, and it belongs to two fluorobenzene derivatives of droperidol, is clinically used for the treatment of schizophrenia, mania and tourette syndrome.This medicine has good anti-illusion, vain hope effect, and the patient making chronic retraction passive is active.There is more long-acting antipsycholic action.For acute and chronic schizophrenia, to illusion, vain hope, indifferent effective.Particularly applicable to chronic retraction venereal disease people.Compared with chlorpromazine, the side effects such as its calmness, step-down, cholinolytic are more weak.
The bulk drug of stable isotope mark is identical with common cold bulk drug in chemical property and biological property, just there is different nuclear physics character, it is commonly used to replace corresponding nonlabelled compound to detect and follow the trail of it in vivo or external position, quantity and transformation thereof etc., better studies metabolic process and the mechanism of action of bulk drug.The medicine of stable isotope mark can utilize its difference to common corresponding isotopic quality, and by mass spectrograph, gas chromatograph, the analytical instrument of quality such as nucleus magnetic resonance measure.Thus be applied to the research of Clinical pharmacokinetics aspect.
Pimozide-the d4 of cold labeling can well be applied to the research of Clinical pharmacokinetics aspect, thus more accurately and easily understand the metabolic process of pimozide in human body and mechanism of action, and not yet find report at present about the synthesis of the pimozide-d4 compound of cold labeling.
Summary of the invention
Goal of the invention: the object of this invention is to provide a kind of preparation method about pimozide-d4 compound.
Technical scheme: for realizing above object, the technical scheme that the present invention takes is:
A preparation method for deuterated pimozide, the method comprises the following steps:
(1) first get 4-bromofluorobenzene-d4 and be prepared into Grignard reagent, then with intermediate 2, at 20 DEG C ~ 80 DEG C, react 2 ~ 6 hours, obtained intermediate 3;
(2) get intermediate 3 and thionyl chloride, at 60 DEG C ~ 100 DEG C temperature, be obtained by reacting intermediate 4;
(3) get intermediate 4 under the palladium carbon effect of catalyzer 10%, hydrogenation obtains intermediate 5;
(4) get intermediate 6 and intermediate 7, in the basic conditions, at 60 DEG C ~ 100 DEG C temperature, under catalyst action, carry out substitution reaction generate intermediate 8;
(5) get intermediate 8, at palladium catalyst carbon, under the effect of Raney's nickel or ammonium formiate, reduction obtains intermediate 9;
(6) get intermediate 9, in the basic conditions, with become cyclization reagent room temperature under be obtained by reacting intermediate 10;
(7) intermediate 10 and trifluoroacetic acid, under room temperature, reaction prepares intermediate 11 in 1 ~ 2 hour;
(8) intermediate 11 is got and intermediate 5 is obtained by reacting intermediate 12.
Preferably, the preparation method of above-described deuterated pimozide, 4-bromofluorobenzene-d4 and intermediate 2 mol ratio of step (1) they are 1:0.8 ~ 1:1.2; Be preferably 1:1; Temperature of reaction is 20 DEG C-80 DEG C, is preferably 40 DEG C; Reaction solvent is ether, toluene, tetrahydrofuran (THF), is preferably tetrahydrofuran (THF).
Preferably, the preparation method of above-described deuterated pimozide, step (2) anti-solvent-applied is toluene, benzene, methylene dichloride; Be preferably toluene; Temperature of reaction is 60 DEG C-100 DEG C, and be preferably 80 DEG C, the mol ratio that intermediate 3 and dichloro carry out sulfone is preferably 1:0.7.
Preferably, the preparation method of above-described deuterated pimozide, the reagent of step (3) hydrogenation is methyl alcohol, ethanol or Virahol; Be particularly preferably Virahol.
Preferably, the preparation method of above-described deuterated pimozide, the intermediate 6 described in step (4) and the mol ratio of intermediate 7 are 1:0.8 ~ 1:2, are particularly preferably 1:1; The alkali of reaction is triethylamine, salt of wormwood, and sodium carbonate, is particularly preferably sodium carbonate, and reacting the solvent used is DMF, acetonitrile, ethanol or Virahol, particularly preferably DMF (DMF); Described catalyzer is potassiumiodide or sodium iodide.
Preferably, the preparation method of above-described deuterated pimozide, the reaction solvent described in step (5) is methyl alcohol, ethanol, Virahol; Temperature of reaction is 60 ~ 80 DEG C, and the reaction times is 1 ~ 2 hour.
Preferably, the preparation method of above-described deuterated pimozide, the alkali that step (6) is reacted used is triethylamine, pyridine or Isopropylamine; Cyclization reagent is become to be triphosgene or carbon back diimidazole.
Preferably, the preparation method of above-described deuterated pimozide, step (7) intermediate 10 take methylene dichloride as solvent, at room temperature reacts prepare intermediate 11 in 1 hour with trifluoroacetic acid.
Preferably, the preparation method of above-described deuterated pimozide, is characterized in that, step (8) gets intermediate 11 and intermediate 5, makes alkali with salt of wormwood, refluxes and spends the night, be obtained by reacting intermediate 12 in glycerol formal.
Beneficial effect: the preparation method of deuterated pimozide provided by the invention has the following advantages:
The preparation method of deuterated pimozide provided by the invention, filters out best reactions steps by great many of experiments, concrete temperature of reaction, the concrete technology parameters such as time, whole technological design is reasonable, workable, can realize commercially producing, the yield of every single step reaction is all very high, and raw material is easy to get, easy purifying, purity is greater than 99%, total recovery is high, can reach more than 90%, and D abundance >99%.Pimozide-the d4 of the cold labeling that the present invention prepares can well be applied to the research of Clinical pharmacokinetics aspect, thus more accurately and easily understand the metabolic process of pimozide in human body and mechanism of action, there is important application prospect.
Accompanying drawing explanation
fig. 1for preparation technology's flow process of deuterated pimozide
figure.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but should understand scope of the present invention and be not limited in this, is also contained in the present invention the apparent change of those of ordinary skill in the art and modification.
Embodiment 1
as Fig. 1for preparation technology's flow process of deuterated pimozide
figure.
The preparation of intermediate 3: the magnesium powder getting 0.43 gram is suspended in 3ml tetrahydrofuran (THF), add the iodine of catalytic amount, mixture is warmed up to 60C, drip 3 grams of deuterated p-Fluoro bromo benzene (i.e. compound 1) solution in 7ml tetrahydrofuran (THF), drip about 10min, drip rear reaction to be warmed up to 70C and to react the Grignard reagent that 1.5 hours obtain deuterated p-Fluoro bromo benzene, then the Grignard reagent cool to room temperature will obtained, add the tetrahydrofuran solution of 2.75 grams of intermediates 2 wherein, 40 DEG C are reacted 1 hour, then reaction solution is dropped to room temperature, add saturated aqueous ammonium chloride, extract with ethyl, organic phase is washed with saturated sodium-chloride again, organic phase is dry, the concentrated crude product purified by silica gel column chromatography purification obtained is purified, developping agent is: volume ratio is the sherwood oil of 30:1: ethyl acetate, obtain 2.3 grams of target product intermediates 3, yield is 52%.
The preparation of intermediate 4: get 2.3 grams of intermediates 3 and be dissolved in toluene, add the thionyl chloride of 0.74 gram, the reaction solution obtained, 80 DEG C of reactions 4 hours, it is complete that raw material reaction observed by some plate, by solvent evaporate to dryness, the crude product purified by silica gel column chromatography obtained is purified, and developping agent is the sherwood oil of volume ratio 20:1: ethyl acetate; Obtain 2.2 grams of intermediates 4, yield is 89%.
The preparation of intermediate 5: get 2.2 grams of intermediates 4 and be dissolved in 15ml Virahol, add the palladium/carbon 150mg of 10%, hydrogenation reacts 24 hours under 4 normal atmosphere, it is complete that raw material reaction observed by some plate, catalyst filtration is fallen, filtrate portion evaporate to dryness obtains target product 2.1 grams of target product intermediates 5, yield 95%.
The preparation of intermediate 8: the o-fluoronitrobenzene (compound 6) getting 3.5 grams, the 4-amino piperidine (compound 7) of 5 grams of N-BOC protections, 3.9 grams of salt of wormwood, the potassiumiodide 40mg of catalytic amount, the mixture obtained in DMF, be heated to 80 DEG C of reactions 16 hours, obtain the orange solution of a clarification, it is complete that raw material reaction observed by some plate, reaction solution is down to room temperature, add water and ethyl acetate, isolate organic phase, anhydrous sodium sulfate drying, concentrated, the crude product purified by silica gel pillar obtained is purified, developping agent is the sherwood oil of volume ratio 10:1: ethyl acetate, obtain 7.6 grams of target product intermediates 8, yield 95%.
The preparation of intermediate 9: get 6.4 grams of intermediates 8 and be dissolved in 60ml methyl alcohol, add the ammonium formiate of 8.6 grams, the palladium/carbon of 640mg10%, reacting liquid temperature is elevated to 60C and reacts 1 hour, some board raw material reacts completely, reaction solution cool to room temperature, filter, filtrate evaporate to dryness, the residue obtained is dissolved in methylene dichloride again, washes with water, organic phase branches away with anhydrous sodium sulfate drying, concentrated, obtain 5.7 grams of target product intermediates 9, yield 98%.
The preparation of intermediate 10: the intermediate 9 getting 5.7 grams is dissolved in the methylene dichloride of 100ml, add the triethylamine of 4 grams, 1.4 grams of triphosgene/bis-(trichloromethyl) carbonic ethers, room temperature reaction half an hour, it is complete that raw material reaction observed by some plate, the hydrochloric acid of 1M is added in reaction solution, separate organic phase, aqueous phase uses dichloromethane extraction again, merge organic phase, with anhydrous sodium sulfate drying, filter, the concentrated crude product methylene dichloride/Diethyl ether recrystallization obtained is purified and is obtained 4 grams of target products 10, yield 63%
The preparation of intermediate 11: get 4 grams of intermediates 10 and be dissolved in 200ml methylene dichloride, add 40ml trifluoroacetic acid, room temperature reaction 1 hour, raw material reaction is complete, reaction solution concentrates, and the residue obtained is dissolved in methylene dichloride and in water, adjusts PH to 10 with ammoniacal liquor, separate organic phase, anhydrous sodium sulfate drying, filters, concentrated, crude product methylene dichloride/the Diethyl ether recrystallization obtained obtains 2g target product 11, yield 73%.
The preparation of intermediate 12: get 750mg intermediate 11,1.08 grams of intermediate 5,400mg sodium carbonate, 19mg potassiumiodide, 80 DEG C of reactions 16 hours, it is complete that raw material reaction observed by some plate, add 50ml water and 100ml ethyl acetate, separate organic phase, with anhydrous sodium sulfate drying, filter, evaporate to dryness, the crude product purified by silica gel pillar obtained is purified, the methylene dichloride of eluent to be volume ratio be 98:2: methyl alcohol, obtain 1.5 grams of target products 12, yield 93%, HPLC purity 99.22%.MS:464 [M-H
+], 466 [M+H
+].
1hNMR (300MHz, CDCl3) is as follows, and detecting isotopic abundance is 99.8%.
Its 1HNMR (300MHz, CDCl3) information is: δ 9.0 (1H1s, NH), 6.9-7.3 (7H, m, Ar), 4.2-4.4 (1H, m, CH), 3.9 (1H, t, CH, J=7.8MHz), 3.0 (2H, d, CH2, J=11.4MHz), 2.47 (2H, t, CH2, J=6MHz), 2.45 (2H, t, CH2, J=6MHz), 2.07 (2H1q, J=6MHz), 1.7-1.9 (2H, m), 1.47 (2H, m).
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. a preparation method for deuterated pimozide, is characterized in that, the method comprises the following steps:
Then and intermediate (1) first get 4-bromofluorobenzene-d4 and be prepared into Grignard reagent,
2, at 20 DEG C ~ 80 DEG C, react 2 ~ 6 hours, obtained intermediate
3;
(2) intermediate is got
3and thionyl chloride, at 60 DEG C ~ 100 DEG C temperature, be obtained by reacting intermediate
4;
(3) intermediate is got
4under the palladium carbon effect of catalyzer 10%, hydrogenation obtains intermediate
5;
(4) get intermediate 6 and intermediate 7, in the basic conditions, at 60 DEG C ~ 100 DEG C temperature, under catalyst action, carry out substitution reaction generate intermediate 8;
(5) intermediate is got
8,palladium catalyst carbon, under the effect of Raney's nickel or ammonium formiate, reduction obtains intermediate
9;
(6) intermediate is got
9,in the basic conditions, with under becoming cyclization reagent room temperature intermediate is obtained by reacting
10;
(7) intermediate is got
10and trifluoroacetic acid, under room temperature, reaction prepares intermediate 11 in 1 ~ 2 hour;
(8) intermediate is got
11and intermediate
5be obtained by reacting intermediate
12.
2. the preparation method of deuterated pimozide according to claim 1, is characterized in that, the reaction solvent of step (1) is ether, toluene or tetrahydrofuran (THF); 4-bromofluorobenzene-d4 and intermediate 2 mol ratio are 1:0.8 ~ 1:1.2.
3. the preparation method of deuterated pimozide according to claim 1, is characterized in that, step (2) anti-solvent-applied is toluene, benzene or methylene dichloride.
4. the preparation method of deuterated pimozide according to claim 1, is characterized in that, the reagent of step (3) hydrogenation is methyl alcohol, ethanol or Virahol.
5. the preparation method of deuterated pimozide according to claim 1, is characterized in that, the intermediate described in step (4)
6be 1:0.8 ~ 1:2 with the mol ratio of intermediate 7; The alkali of reaction is triethylamine, salt of wormwood, sodium carbonate, and reacting the solvent used is DMF, acetonitrile, ethanol or Virahol; Described catalyzer is potassiumiodide or sodium iodide.
6. the preparation method of deuterated pimozide according to claim 1, is characterized in that, the reaction solvent described in step (5) is methyl alcohol, ethanol, Virahol; Temperature of reaction is 60 ~ 80 DEG C, and the reaction times is 1 ~ 2 hour.
7. the preparation method of deuterated pimozide according to claim 1, is characterized in that, the alkali that step (6) is reacted used is triethylamine, pyridine or Isopropylamine; Cyclization reagent is become to be triphosgene or carbon back diimidazole.
8. the preparation method of deuterated pimozide according to claim 1, is characterized in that, step (7) intermediate
10take methylene dichloride as solvent, at room temperature react with trifluoroacetic acid and prepare intermediate 11 in 1 hour.
9. the preparation method of deuterated pimozide according to claim 1, is characterized in that, step (8) gets intermediate
11and intermediate
5, add salt of wormwood, reflux in glycerol formal and spend the night, be obtained by reacting intermediate 12.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979399A (en) * | 2019-12-02 | 2021-06-18 | 中国科学院福建物质结构研究所 | Method for alkyl-arylation of olefin compound and application |
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|---|---|---|---|---|
| US4352811A (en) * | 1981-11-12 | 1982-10-05 | Hoechst-Roussel Pharmaceuticals Inc. | 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles |
| WO2006135826A1 (en) * | 2005-06-10 | 2006-12-21 | Boehringer Ingelheim International Gmbh | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
| WO2008080601A2 (en) * | 2006-12-28 | 2008-07-10 | Institut Universitari De Ciència I Tecnologia | Process for the preparation of loperamide |
| WO2008157271A1 (en) * | 2007-06-14 | 2008-12-24 | Protia Llc | Deuterium-enriched escitalopram |
-
2015
- 2015-04-27 CN CN201510206526.XA patent/CN104829591B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4352811A (en) * | 1981-11-12 | 1982-10-05 | Hoechst-Roussel Pharmaceuticals Inc. | 3-(1-Substituted-4-piperidyl)-1,2-benzisoxazoles |
| WO2006135826A1 (en) * | 2005-06-10 | 2006-12-21 | Boehringer Ingelheim International Gmbh | Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof |
| WO2008080601A2 (en) * | 2006-12-28 | 2008-07-10 | Institut Universitari De Ciència I Tecnologia | Process for the preparation of loperamide |
| WO2008157271A1 (en) * | 2007-06-14 | 2008-12-24 | Protia Llc | Deuterium-enriched escitalopram |
Non-Patent Citations (3)
| Title |
|---|
| HIROYUKI OBASE, ET AL.: "Synthesis of (1-Substituted Piperidin-4-yl)-1H-benzimidazoles and (1-Substituted Piperidin-4-yl)-3,4-dihydroquinazolines as Possible Antihypertensive Agents", 《J.HETEROCYCLIC CHEM.》 * |
| MOHAMMED ABDUL RASHEED,ET AL.: "Concise and Simple Synthesis of M1 Allosteric Agonist TBPB", 《SYNTHETIC COMMUNICATIONS》 * |
| RICCARDO RONDANIN, ET AL.: "Inhibition of activated STAT5 in Bcr/Abl expressing leukemia cells with new pimozide derivatives", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112979399A (en) * | 2019-12-02 | 2021-06-18 | 中国科学院福建物质结构研究所 | Method for alkyl-arylation of olefin compound and application |
| CN112979399B (en) * | 2019-12-02 | 2022-07-19 | 中国科学院福建物质结构研究所 | Method for alkyl-arylation of olefin compound and application |
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