CN101955498A - Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof - Google Patents
Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof Download PDFInfo
- Publication number
- CN101955498A CN101955498A CN 201010220849 CN201010220849A CN101955498A CN 101955498 A CN101955498 A CN 101955498A CN 201010220849 CN201010220849 CN 201010220849 CN 201010220849 A CN201010220849 A CN 201010220849A CN 101955498 A CN101955498 A CN 101955498A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- alkyl
- perhaps
- compounds
- 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
Abstract
The invention relates to a preparation of organic compounds, in particular to a preparation method of a common side chain of a series of 25-hydroxyitamin D2 medicines. The structure of the compounds is represented in the formula 1. The compounds have wide application and are more stable than the traditional compounds with the same application, so that the compounds are convenient to storage and use. The method for synthesizing the target compounds (1) has high yield, short synthesis route and easily purified products.
Description
Technical field
The present invention relates to a kind of preparation method of organic compound, is the preparation method about the common side chain of a series of 25-hydroxy-vitamin D 2 class medicines exactly, and its structure is as shown in the formula shown in 1.
Formula 1
Wherein, R be hydrogen atom or-SiR
3R
4R
5Perhaps-R
3Perhaps-R
6OR
4Perhaps-C (=O) R
3, R here
1, R
2, R
3, R
4, R
5, R
6Be the amino of alkyl or-oxyl or amino or alkyl replacement, they can be identical, also can be different.
Background technology
Formula 2
Formula 3
A series of 25-hydroxy-vitamin Ds 2 class medicines as shown in Equation 2 all have a common side chain, and these medicines can be synthesized through the process shown in the formula 3 by compound 1.These medicines comprise 25-hydroxy-vitamin D 2,1a, and 25-dihydroxyvitamin D 2, Zemplar, or the like.These medicines all are the conditioning agents of calcium phosphorus running balance in animal and human's body
1,2Their activity in cell recognition have also been found in nearest research
3,4,5Therefore, various types of novel vitamin D analogues have caused investigator's extensive interest, the for example analogue of the derivative of vitamins D side chain, different hydroxyl models, the analogue of different steric configurations, Deng, all be widely used in polytype active testing, a plurality of known these compounds have all been showed good active in external body, shown effect good in multiple disease treatment and potential using value, as the rickets of the dysplasia of treatment sclerotin, anti-vitamins D
6, osteoporosis
7, vitamin D deficiency such as psoriasis
8For example, Zemplar is the medicine of prevention and treatment secondary hyperparathyroidism (SHPT), it demonstrates prevention and treatment curative effect to accepting III before dialysis and the transplantation and IV phase chronic renal disease (CKD) patient's SHPT, has become the most widely used SHPT of dialysis patients and has prevented and medicine.
The existing compound that is used to construct above-mentioned 25-hydroxy-vitamin D 2 medicine series side chains mainly contains as shown in Equation 4 two kinds, i.e. the sulfone 4 of patent (US4847012, US5260290 etc.) report and the Yelide salt 5 of other bibliographical informations.Wherein, compound 4 is when a series of similar medicines that are used for compound 2 synthetic, and yield is very low.Compound 5 not only be used for medicine when synthetic yield low, and the synthetic and purifying of compound 5 itself are difficult to, its building-up process also causes some limitations for protecting group R functional group.
Formula 4
Summary of the invention
The invention provides and a kind ofly new can overcome above-mentioned insufficient compound, its structure is compound 1 as shown in Equation 1, and the present invention also provides the synthetic method of this compound.Compound as shown in Equation 1 provided by the present invention
1Hafner，V.；Rutsch，C.；Ding，R.；Heinrich，T.；Diedrichs，L.；Schmidt-Gayk，H.；Walter-Sack，I.；Bommer，J.；Mikus，G.Int.J.Clin.Pharm.Therap.2008，46(3)，131-135.
2Nakane，Masaki；Ma，Junli；Rose，Andrew?E.；Osinski，Mark?A.；Wu-Wong，J.Ruth.J.Steroid?Biochem.Mol.Biology?2007，103(1)，84-89
3Coyne，D.W.；Grieff，M.；Ahya，S.N.；Giles，K.；Norwood，K.；Slatopolsky，E.Am.J.Kidney?Diseases?2002，40(6)，1283-1288
4Slatopolsky，E.；Cozzolino，M.；Finch，J.L.Kidney?International?2002，62(4)，1277-1284.
5Rown，A.J.；Finch，J.；Slatopolsky，E.J.Lab.Clin.Med.2002，139(5)，279-284.
6Puschett?J.B.；Genel?M.；Rastegar?A.；Anast?C.；DeLuca?H.F.；Friedman?A.Clin.pharm.Thera.1975，17(2)，202-11.
7Balint，E.；Marshall，C.F.；Sprague，S.M.Am.J.Kidney?Diseases?2000，36(4)，789-796.
8Petkovich, P.M.; Helvig, C.F.; Melnick, J.Z.PCT Int.Appl.2009, bibliographical information is not seen in synthesizing of 61pp.WO2009124210.1 as yet.
The present invention is a starting raw material with (R)-2-methyl-3-hydroxy methyl propionate (being compound 5), by method as shown in Equation 5, and preparation compound 1: at first, compound 5 and methylmetal reagents reaction are obtained compound 6.Optionally the primary alconol in the compound 6 is carried out halo or the sulphonyl esterification can obtain compound 7, protect the tertiary alcohol in 7 to obtain compound 8 then, the metallic compound reaction with compound 8 and diaryl phosphine obtains target compound again.Here the methylmetal reagents with compound 5 reactions can be lithium methide, methylmagnesium-halide, methyl zinc.Compound 6 is converted into compound 7 can obtain halogenide 7 by the direct exchange of alcohol and halogen; also alcohol and sulfonylation agent reaction can be obtained sulphonate 7, the primary alconol acyl in the compound 6 can also be protected with alkylsulfonyl and carry out halo with metal halide again and obtain halogenide 7.Three grades of hydroxyls of protection compound 7 can be used silicon ether, acyl group, alkyl, alkoxyalkyl, tetrahydropyrans, tetrahydrofuran (THF).
Formula 4
Wherein, R ' is an alkyl, and X is halogen or sulfonyloxy R " SO
2O-, R here " be alkyl.R be hydrogen atom or-SiR
3R
4R
5Perhaps-R
3Perhaps-R
6OR
4Perhaps-C (=O) R
3, R here
1, R
2, R
3, R
4, R
5, R
6Be the amino of alkyl or-oxyl or amino or alkyl replacement, they can be identical, also can be different.
The present invention has the following advantages: 1.The invention provides the compound of the new Synthetic 2 5-HEC medicine series side chain of a class, this use of a compound is extensive, and more stable than the compound of existing same purposes, is convenient to preserve and use; 2.The method yield height of synthesising target compound 1 provided by the invention, route is brief, and product is easy to purifying.
Embodiment
Below provide specific embodiments of the invention, to show possible implementation process.
Embodiment one: compound 1a, its molecular structure is as follows, R1=R2=OCH2CH3 wherein, R=CH2OCH3.
Its synthetic route is as follows:
(11.8g 100mmol) is dissolved in the ether, under the zero degrees celsius to get (R)-3-hydroxy-2-methyl methyl propionate, in the argon atmospher to wherein splash into MeMgBr (3M, 100mL, 300mmol), after dripping off, continue to stir 6 hours, to wherein slowly splashing into 1M hydrochloric acid cancellation reaction, ethyl acetate extraction (300mL is each) three times, merge organic phase, anhydrous magnesium sulfate drying, filtering and concentrating obtain colorless oil 11 (10.7g), yield 90%.
1H?NMR(300MHz，δ，ppm)0.81(3H，d，J＝6.9Hz)，1.14(3H，s)，1.22(3H，s)，1.77(1H，m)，3.58(1H，b)，3.66(2H，m)，3.84(1H，b).
13C?NMR(75MHz，δ，ppm)12.9，23.9，29.6，43.9，66.1，74.5.ESI-HRMS(m/z)[M
+]118.0，100.0，85.0，59.0.
Above-mentioned gained colorless oil is dissolved in methylene dichloride (100mL) and the pyridine (10mL), to wherein adding 4-(N, the N-dimethyl amido) pyridine (1g) and Tosyl chloride (20g, 105mmol), stirred overnight at room temperature, after treating that raw material disappears, reaction solution is slowly poured in the frozen water solution (200mL) of NaHCO3 (15g) into stirring at room 30 minutes, separatory, water dichloromethane extraction (200mL) three times, merge organic phase and wash with 1M hydrochloric acid (20mL), anhydrous sodium sulfate drying is after the filtering and concentrating, purification by silica gel column chromatography obtains colorless oil compound 12 (20g), yield 82%.
1H?NMR(300MHz，δ，ppm)0.93(3H，d，J＝6.9Hz)，1.09(3H，s)，1.16(3H，s)，1.83(1H，m)，2.42(3H，s)，3.89(1H，dd，J＝7.5，9.6Hz)，4.22(1H，dd，J＝4.5，9.6Hz)，7.32(2H，d，J＝7.5Hz)，7.76(2H，d，J＝7.5Hz).
13C?NMR(75MHz，δ，ppm)12.6，21.6，26.0，28.5，43.4，71.9，72.6，127.8，129.8，132.9，144.7.
With above-mentioned p-toluenesulfonic esters (19.0g, 70mmol) be dissolved among the exsiccant CH3CN (50mL), to wherein add anhydrous Na I (11g, 73mmol), after the reflux 5 hours, concentrate and remove CH3CN, add ether (100mL) and filter, with ether (200mL) washing leaching cake, merging filtrate washs (50mL) with sodium thiosulfate solution, organic phase is crossed the elimination siccative through anhydrous magnesium sulfate drying, is directly used in next step after concentrating.
Get above-mentioned iodide 13 (16g 70mmol) is dissolved among the dry CH2Cl2 (300mL), ice-water bath cooling down, to wherein add diisopropyl ethyl amine (10g, 100mmol) and methoxyl methyl chlorine (7g, 85mmol).Behind the room temperature reaction 12 hours, add washing, water extracts with CH2Cl2.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains colorless oil 14 (13.6g) with purification by silica gel column chromatography, two step total recoverys 71%.
1H?NMR(300MHz，δ，ppm)1.08(3H，d，J＝5.7Hz)，1.12(3H，s)，1.23(3H，s)，1.97(1H，m)，2.85(1H，dd，J＝9.3，11.1Hz)，3.35(3H，s)，3.68(1H，dd，J＝1.8，9.3Hz)，4.67(2H，m).
13C?NMR(75MHz，δ，ppm)。
Get above-mentioned gained and look for oily matter 14 (11g) to mix with triethyl-phosphite (20g), reflux is after 5 hours, the triethyl-phosphite that pressure reducing and steaming is excessive, and resistates obtains colorless oil 1a (9g), yield 79% with the silica gel column chromatography fast purifying.
Embodiment two: 1b's is synthetic.R1=R2=OMe wherein, R=THP, molecular structure is as follows:
Its synthetic route is as follows:
(11.8g 100mmol) is dissolved in the ether, under the zero degrees celsius to get (R)-3-hydroxy-2-methyl ethyl propionate, in the argon atmospher to wherein splash into MeLi (1M, 300mL, 300mmol), after dripping off, continue to stir 6 hours, to wherein slowly splashing into 1M hydrochloric acid cancellation reaction, ethyl acetate extraction (300mL is each) three times, merge organic phase, anhydrous magnesium sulfate drying, filtering and concentrating obtain colorless oil 11 (10.1g), yield 85%.
Above-mentioned gained colorless oil is dissolved in methylene dichloride (100mL) and the triethylamine (10mL), cryosel is bathed cooling down to wherein adding methylsulfonyl chloride (11.4g, 100mmol), after continuation is stirred and was treated that raw material disappeared in 2 hours, add the shrend reaction of going out, separatory, water is with dichloromethane extraction (200mL) three times, anhydrous sodium sulfate drying is directly used in next step after the filtering and concentrating.
Above-mentioned methanesulfonates 16 is dissolved among the exsiccant CH3CN (100mL), to wherein add anhydrous Na I (15g, 100mmol), reflux is after 5 hours, concentrate and remove CH3CN, add ether (100mL) and filter, with ether (200mL) washing leaching cake, merging filtrate washs (50mL) with sodium thiosulfate solution, organic phase is through anhydrous magnesium sulfate drying, cross the elimination siccative, concentrate, two step yields 60% after the silica gel column chromatography purifying obtains iodide 13 (13.7g).
1H?NMR(300MHz，δ，ppm)1.08(3H，d，J＝6.3Hz)，1.14(3H，s)，1.23(3H，s)，1.85(1H，m)，2.89(1H，dd，J＝9.3，11.1Hz)，3.65(1H，dd，J＝1.5，9.3Hz).
13C?NMR(75MHz，δ，ppm)11.1，16.0，25.1，28.5，47.6，73.1.
Get above-mentioned iodide 13 (11.4g 50mmol) is dissolved among the dry CH2Cl2 (100mL), ice-water bath cooling down, to wherein adding tosic acid (0.5g), then slowly to wherein splash into dihydropyrane (5g, 60mmol).Behind the room temperature reaction 12 hours, add washing, water extracts with CH2Cl2.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains colorless oil 17 (13g), yield 82% with purification by silica gel column chromatography.
Get above-mentioned gained and look for oily matter 17 (9.4g) to mix with trimethyl phosphite (20g), reflux is after 5 hours, the trimethyl phosphite that pressure reducing and steaming is excessive, and resistates obtains colorless oil 1a (7.9g), yield 81% with the silica gel column chromatography fast purifying.
Embodiment three: 1c's is synthetic.R1=R2=Ph wherein, R=Bz, its molecular structure is as shown below:
Its synthetic route is as follows:
(13.6g 50mmo1) is dissolved among the dry CH2C12 (100mL), under the ice-water bath cooling, to wherein adding pyridine (10g) and 4-(N, N-dimethyl amido) pyridine, then slowly to wherein splashing into Benzoyl chloride (10g) to get above-mentioned p-toluenesulfonic esters 12.Behind the room temperature reaction 12 hours, add washing, water extracts with CH2Cl2.Merge organic phase, use anhydrous sodium sulfate drying, after the filtering and concentrating, resistates obtains product 18 (13g), yield 78% with purification by silica gel column chromatography.
Above-mentioned methanesulfonates 18 (11.3g) is dissolved among the exsiccant CH3CN (100mL), to wherein adding anhydrous Na I (5g), after the reflux 5 hours, concentrate and remove CH3CN, add ether (100mL) and filter, with ether (200mL) washing leaching cake, merging filtrate is crossed the elimination siccative with sodium thiosulfate solution washing (50mL), organic phase through anhydrous magnesium sulfate drying, concentrate after the silica gel column chromatography purifying obtains iodide 19 (7g), yield 70%.
Phenylbenzene phosphatization hydrogen (3.72g) is dissolved among the anhydrous THF, after being cooled to subzero 78 degrees centigrade under the argon atmospher, to the hexane solution (2.8M that wherein slowly splashes into butyllithium, 7ml), stirring reaction is after 30 minutes, to the THF solution that wherein adds iodide 19 (4.5g), continue to stir 2 hours, to wherein adding the shrend reaction of going out, then to wherein add hydrogen peroxide (30%, 3ml), continue to stir and heat up naturally, after 5 minutes, separatory, water ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, resistates obtains target compound 1c with purification by silica gel column chromatography, yield 75% behind the filtration evaporate to dryness.
Embodiment four: 1d's is synthetic.R1=R3=Ph wherein, R=SiEt3, its molecular structure is as shown below:
Its synthetic route is as follows:
Iodohydrin 13 (2.72g) is dissolved in the methylene dichloride (20ml), under the room temperature to wherein adding triethylamine (3ml) and chlorotriethyl silane (5g), stirred overnight at room temperature, in reaction solution, add the shrend reaction of going out, separatory, water dichloromethane extraction, merge organic phase, use anhydrous sodium sulfate drying, resistates obtains silicon ether 20 (3g), yield 80% with purification by silica gel column chromatography behind the filtration evaporate to dryness.
Phenylbenzene phosphatization hydrogen (3.72g) is dissolved among the anhydrous THF, after being cooled to subzero 78 degrees centigrade under the argon atmospher, to the hexane solution (2.8M that wherein slowly splashes into butyllithium, 7ml), stirring reaction is after 30 minutes, to the THF solution that wherein adds iodide 20 (4.5g), continue to stir 2 hours, add the shrend reaction of going out, then to wherein add hydrogen peroxide (30%, 3ml), continue to stir and heat up naturally, after 5 minutes, separatory, water ethyl acetate extraction, merge organic phase, use anhydrous sodium sulfate drying, resistates obtains target compound 1d with purification by silica gel column chromatography, yield 85% behind the filtration evaporate to dryness.
Claims (8)
1. compound 1 as shown in Equation 1:
Formula 1
Wherein, R be hydrogen atom or-SiR
3R
4R
5Perhaps-R
3Perhaps-R
6OR
4Perhaps-C (=O) R
3, R here
1, R
2, R
3, R
4, R
5, R
6Be the amino of alkyl or-oxyl or amino or alkyl replacement, they can be identical, also can be different.
2. in the compound 1 according to claim 1, R is alkyl or alkoxyalkyl or silica-based.
3. in the compound 1 according to claim 1, R
1And R
2Be respectively aryl or alkoxyl group or alkyl.
4. the preparation method of compound 1 according to claim 1, this preparation method are through as shown in Equation 2 process:
Wherein, R ' is an alkyl, and X is halogen or sulfonyloxy R " SO
2O-, R here " be alkyl.R be hydrogen atom or-SiR
3R
4R
5Perhaps-R
3Perhaps-R
6OR
4Perhaps-C (=O) R
3, R here
1, R
2, R
3, R
4, R
5, R
6Be the amino of alkyl or-oxyl or amino or alkyl replacement, they can be identical, also can be different.
5. among the preparation method of compound 1 according to claim 4, compound 2 obtains compound 3 with the methylmetal reagents reaction.
6. among the preparation method of compound 1 according to claim 4, compound 3 by the sulfonic acid esterification after and then obtain compound 4 with the metal halide reactant salt.
7. among the preparation method of compound 1 according to claim 4, compound 3 directly reacts with halogen and obtains compound 4;
8. among the preparation method of compound 1 according to claim 4, compound 3 obtains compound 4 by the sulfonic acid esterification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102208491A CN101955498B (en) | 2010-07-06 | 2010-07-06 | Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102208491A CN101955498B (en) | 2010-07-06 | 2010-07-06 | Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101955498A true CN101955498A (en) | 2011-01-26 |
| CN101955498B CN101955498B (en) | 2012-06-27 |
Family
ID=43483114
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102208491A Active CN101955498B (en) | 2010-07-06 | 2010-07-06 | Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101955498B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351901A (en) * | 2011-08-15 | 2012-02-15 | 上海皓元化学科技有限公司 | 25-hydroxy vitamin D2 series medicament side chain and its preparation method |
| CN102643302A (en) * | 2012-04-06 | 2012-08-22 | 上海皓元化学科技有限公司 | Preparation method of synthetic intermediate of 25-hydroxyvitamin D2and 1α, 25-dihydroxyvitamin D2 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4847012A (en) * | 1988-04-29 | 1989-07-11 | Wisconsin Alumni Research Foundation | Vitamin D related compounds and processes for their preparation |
| US5260290A (en) * | 1990-02-14 | 1993-11-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
-
2010
- 2010-07-06 CN CN2010102208491A patent/CN101955498B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4847012A (en) * | 1988-04-29 | 1989-07-11 | Wisconsin Alumni Research Foundation | Vitamin D related compounds and processes for their preparation |
| US5260290A (en) * | 1990-02-14 | 1993-11-09 | Wisconsin Alumni Research Foundation | Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives |
Non-Patent Citations (1)
| Title |
|---|
| 20111215 李宗韦 , 1 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102351901A (en) * | 2011-08-15 | 2012-02-15 | 上海皓元化学科技有限公司 | 25-hydroxy vitamin D2 series medicament side chain and its preparation method |
| WO2013023327A1 (en) * | 2011-08-15 | 2013-02-21 | 上海皓元化学科技有限公司 | Side chain of 25-hydroxyvitamin d2 series drug and preparation method thereof |
| CN102643302A (en) * | 2012-04-06 | 2012-08-22 | 上海皓元化学科技有限公司 | Preparation method of synthetic intermediate of 25-hydroxyvitamin D2and 1α, 25-dihydroxyvitamin D2 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101955498B (en) | 2012-06-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2007245194B2 (en) | Process for preparation of HIV protease inhibitors | |
| CN101193880B (en) | Exo- and diastereo- selective syntheses of himbacine analogs | |
| CN103476784A (en) | Method for producing oligonucleotide | |
| EP1916251A1 (en) | Erianin salts, their preparation methods and pharmaceutical compositions containing the same | |
| CN101307084A (en) | Synthetic process of decitabine | |
| CN100475832C (en) | Novel highly-solid selectively synthesizing gemcitabine process and intermediate | |
| CN105777544B (en) | A kind of preparation method of S- (+)-flurbiprofen axetil | |
| CN102351901A (en) | 25-hydroxy vitamin D2 series medicament side chain and its preparation method | |
| CN112645861A (en) | Method for separating carboprost 15-position isomer | |
| CN101955498B (en) | Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof | |
| CN104496871B (en) | A kind of preparation method of Tacalcitol | |
| CN109824725B (en) | Preparation method of 4-phosphate-2H-chromene derivative | |
| CN107033210A (en) | A kind of preparation method of fulvestrant and its intermediate | |
| CN104557891B (en) | Quercetin derivative and its preparation method and application | |
| CN102796134B (en) | Preparation method for Maxacalcitol intermediate | |
| CN102675415B (en) | Method for preparing bortezomib | |
| JPS6230791A (en) | Purification of l-ascorbic acid 2-phosphate | |
| CN102395559B (en) | Prepare the method for N-carbalkoxy Terleu | |
| CN106674281B (en) | A kind of Rosuvastatin midbody compound, preparation method and its usage | |
| CN107868105A (en) | A kind of preparation method of Suo Feibuwei key intermediates | |
| CN101143879A (en) | Sulfur-containing ring-free nucleosides phosphonate analogue and preparation method thereof | |
| CN103980172A (en) | 1alpha,25-dihydroxy vitamin D2 preparation method | |
| CN105541910A (en) | Diethyl p-toluenesulfonyloxy methylphosphonate synthesis method | |
| CN104829588A (en) | Preparation method and intermediate of benzo[b]thiophene | |
| CN102250127B (en) | Tetrahydro carboline derivative modified with two amino acids and preparation method and application thereof |
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 | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 201203 Shanghai city Pudong New Area Cailun Road No. 2 No. 601 720 Patentee after: Shanghai Hao Yuan pharmaceutical Limited by Share Ltd Address before: 201203 Shanghai city Pudong New Area Cailun Road No. 2 No. 601 720 Patentee before: Shanghai Haoyuan Chemical Technology Co., Ltd. |
|
| CP02 | Change in the address of a patent holder |
Address after: Room 501, No.2 Lane 720, Cailun Road, China (Shanghai) pilot Free Trade Zone, Pudong New Area, Shanghai, 201203 Patentee after: SHANGHAI HAOYUAN CHEMEXPRESS Co.,Ltd. Address before: 201203 Shanghai city Pudong New Area Cailun Road No. 2 No. 601 720 Patentee before: SHANGHAI HAOYUAN CHEMEXPRESS Co.,Ltd. |
|
| CP02 | Change in the address of a patent holder |