CN103554031B - Preparation method of azilsartan intermediate - Google Patents
Preparation method of azilsartan intermediate Download PDFInfo
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- CN103554031B CN103554031B CN201310535874.2A CN201310535874A CN103554031B CN 103554031 B CN103554031 B CN 103554031B CN 201310535874 A CN201310535874 A CN 201310535874A CN 103554031 B CN103554031 B CN 103554031B
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- 239000005485 Azilsartan Substances 0.000 title claims abstract description 17
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960002731 azilsartan Drugs 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 8
- 239000012065 filter cake Substances 0.000 claims description 7
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 7
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 238000007605 air drying Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 3
- 238000007710 freezing Methods 0.000 claims description 3
- 230000008014 freezing Effects 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 abstract description 17
- 238000000034 method Methods 0.000 abstract description 15
- 239000012535 impurity Substances 0.000 abstract description 12
- 239000002253 acid Substances 0.000 abstract description 6
- 239000003513 alkali Substances 0.000 abstract description 6
- 239000012043 crude product Substances 0.000 abstract description 5
- 239000013078 crystal Substances 0.000 abstract 1
- KXPVENIYRMNDKU-UHFFFAOYSA-N ethanol;hydroxylamine Chemical compound ON.CCO KXPVENIYRMNDKU-UHFFFAOYSA-N 0.000 abstract 1
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 238000010992 reflux Methods 0.000 abstract 1
- 230000001105 regulatory effect Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 150000003536 tetrazoles Chemical group 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical group CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 2
- 229960000932 candesartan Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- PCJFEVUKVKQSSL-UHFFFAOYSA-N 2h-1,2,4-oxadiazol-5-one Chemical group O=C1N=CNO1 PCJFEVUKVKQSSL-UHFFFAOYSA-N 0.000 description 1
- DVODSSZMOBIHGO-UHFFFAOYSA-N CCOC(c1c2[n](Cc(cc3)ccc3-c(cccc3)c3/C(/N)=N/O)c(OCC)nc2ccc1)=O Chemical compound CCOC(c1c2[n](Cc(cc3)ccc3-c(cccc3)c3/C(/N)=N/O)c(OCC)nc2ccc1)=O DVODSSZMOBIHGO-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- -1 carboxylate methyl ester Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical group C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of an azilsartan intermediate. The method comprises the following reaction steps of (1) adding a compound (I) to a hydroxylamine ethanol solution to undergo reflux reaction, thus obtaining a crude product; (2) dissolving the crude product with acid liquor, regulating the pH value with an alkali, and precipitating a crystal, thus obtaining the azilsartan intermediate. By adopting the preparation method, amide impurities generated in the prior art are greatly reduced and are stabilized between 10% and 20%, and the yield and the efficiency are increased.
Description
Technical field
The present invention relates to the preparation of medical compounds, particularly a kind of preparation method of Angiotensin Ⅱ receptor antagonist Azilsartan intermediate.
Background technology
Azilsartan (Azilsartan) is the Angiotensin Ⅱ receptor antagonist researched and developed by Japanese Takede Chemical Industries Ltd, can oral potent depressor.The chemical name of Azilsartan: 2-oxyethyl group-1-{ [2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-base) biphenyl-4-base] methyl }-1H-benzoglyoxaline-7-carboxylic acid, molecular formula: C
25h
20n
4o
5, molecular weight: 456.45, structural formula:
In its structure 4,5-dihydro-5-oxo-1,2,4-oxadiazole rings is the bioisostere of tetrazole ring in Candesartan structure, the deficiency of tetrazole ring in synthesis and metabolism can be overcome, compound containing tetrazole ring and have higher bioavailability compared with tetrazole ring when having the dangerous ， oxadiazole rings of blast oral for the preparation of their triazo-compound.
The starting raw material that Azilsartan use prepared by major part document is compound VI
Also document is had to use chemical compounds I
Compound I is also the starting material of preparation Candesartan, both difference be the former 7 upper be carboxylate methyl ester, and the latter is carboxylic acid, ethyl ester.Prepare Azilsartan intermediate as shown in formula II by chemical compounds I and adopt azanol reaction.
Chinese Journal of Pharmaceuticals 2010,41 (12), 881-883 and document CN201010245420.8 in hydroxylamine solution all use 50% aqueous hydroxylamine.
Journal of Medicinal Chemistry, in 1996, Vol.39, No.26,5228-5235 and EP0520423A2, hydroxylamine solution is self-control, and above reaction, through verification experimental verification, produces a kind of side reaction in reaction, namely generates amide compound III impurity,
Its growing amount is more than 20%
This compound has higher toxicity, and its existence has a negative impact to quality product.
For the generation of control above-claimed cpd III, the present invention, through research, finds to adopt anhydrous hydroxylamine solution, then passes through the adjustment of reaction process pH, and during this step is reacted, the growing amount of amide impurities controls about 10%.
Method that the present invention adopts, simple to operate, solvent is friendly, and yield is higher, avoids the use of expensive reagent 50% aqueous hydroxylamine simultaneously, has greatly saved cost, is applicable to suitability for industrialized production.
Summary of the invention
The present invention is directed to deficiency of the prior art, provide a kind of synthetic method of new Azilsartan intermediate Compound II per.
The invention provides a kind of method for the preparation of Azilsartan intermediate, it is characterized in that: reactions steps is as follows:
Step 1, by compound (I), adds back flow reaction in azanol ethanolic soln, obtains crude product;
Step 2, crude product acid fluid dissolves, uses alkali adjust ph, and crystallization obtains Azilsartan intermediate (II)
Wherein, described azanol ethanolic soln, by hydroxylammonium salt, solid alkali, ethanol mixed preparing forms, and step 1 also can add acid binding agent and participate in reaction.
Method of the present invention, is characterized in that, in step 1, hydroxylammonium salt is selected from vitriol, hydrochloride, and described solid alkali is selected from sodium hydroxide, sodium ethylate, and described acid binding agent is selected from sodium bicarbonate, triethylamine.
Method of the present invention, preferably, described hydroxylammonium salt is oxammonium hydrochloride, and described solid alkali is sodium ethylate, and described acid binding agent is triethylamine, and described azanol ethanolic soln is anhydrous azanol ethanolic soln.
Method of the present invention, wherein, the mol ratio of oxammonium hydrochloride and sodium ethylate is 1:0.7.Compound (I) is 1:1 with the mol ratio of triethylamine.Compound (I) is 1:10 with the mol ratio of sodium ethylate;
Method of the present invention, adds azanol ethanolic soln feed way for once to add, drip or to add in batches.Preferred hydroxylamine solution feed way preferably adds in batches, adds in three batches, within every 8 hours, feeds in raw material once.
Method of the present invention, acid solution described in step 2 is ethanol solution hydrochloride, and described alkali is sodium hydroxide solution.Wherein said ethanol solution hydrochloride, be that use hydrochloric acid and ethanol are formulated, concentration of hydrochloric acid is 0.5N, wherein said sodium hydroxide solution, naoh concentration 1N, and recrystallization temperature is-5 ~ 10 DEG C.
Preferably, preparation method of the present invention is as follows:
Step 1, gets compound (I), divides and adds the azanol ethanolic soln made for 1-3 time, be warming up to 60-100 DEG C, back flow reaction 10-30h.Freezing and filtering, obtains crude product.
Step 2, the hydrochloric acid of thick product 0.5-1N and dissolve with ethanol, filter, and the sodium hydroxide solution dripping 0.5-1N adjusts pH to 7-9, separates out precipitation, drips and finishes, and stirs 0.5-1h, filters, filter cake washing with alcohol, dry, obtains product.
The most preferred preparation method of the present invention is shown in embodiment.
The present invention compared to the prior art advantage is:
Hydroxylamine solution is made by oneself, avoids the use of expensive reagent 50% hydroxylamine solution, greatly reduces cost;
Greatly reduce the generation of amide impurities, improve the yield of target product;
Cost is low, and solvent is friendly, is suitable for suitability for industrialized production
Below by way of experimental data, further illustrate beneficial effect of the present invention.
The thick product adopting the method for existing CN201010245420.8 document to obtain detects through HPLC, and wherein the content of amide compound III impurity is 17%.
The thick product adopting the method for existing EP0520423A2 document to obtain detects through HPLC, and wherein the content of amide compound III impurity is 40.5%.
The thick product adopting the method for embodiment of the present invention 1-2 to obtain detects through HPLC, and wherein the content of amide compound III impurity is 12%, 7%.
The invention provides a kind of method of applicable suitability for industrialized production high-purity azilsartan intermediate, the method is compared with the method for synthesizing Azilsartan intermediate in existing document, advantage is that hydroxylamine solution is made by oneself, azanol reaction produces amide impurities Absorbable organic halogens and controls about 10%, particularly embodiment 2, only has 7%, improves yield simultaneously, greatly reduce cost, be applicable to suitability for industrialized production.
Embodiment
Embodiment below in conjunction with embodiment is described in further detail the present invention, but does not therefore limit the present invention among described scope of embodiments.
Embodiment 1
Oxammonium hydrochloride 23.4g, adds ethanol 60ml, and stir and be cooled to 0 DEG C, 0-10 DEG C slowly adds sodium ethylate 15.3g, pH value of solution about 7, and filter, solution adds triethylamine 1g, and obtained azanol ethanolic soln is for subsequent use.
Add raw material 4g as shown in formula I, in three batches interval 8h, add the ethanolic soln of the azanol made, be warming up to 80 DEG C, back flow reaction 24h.Freezing and filtering, obtains thick product 3.9g.HPLC detects (product: acid amides: raw material=86%:12%:0%).
Thick product 3g, dissolves with 0.5N hydrochloric acid soln (concentrated hydrochloric acid 1.2g, purified water 24ml) and ethanol 12ml, filter, ice bath drips 1N sodium hydroxide solution 7.2ml and adjusts filtrate pH8, and now solution has a large amount of solid to separate out, and drips and finishes, 0 DEG C is stirred 0.5h, filter, a small amount of cold washing with alcohol of filter cake, 40 DEG C of forced air dryings are to constant weight, obtain product 2.4g as shown in formula II, weight yield about 78%.HPLC detects purity 98.2%.
Embodiment 2
Dropped in 50L reactor by oxammonium hydrochloride 8167g, add ethanol 35L, stir and be cooled to 0 DEG C, 0-10 DEG C slowly adds sodium ethylate 5594g, pH value of solution about 7, filters, and obtained azanol ethanolic soln is for subsequent use.
To join in 50L reactor by raw material 3500g as shown in formula I, interval 8h in three batches, and add triethylamine 832.4g azanol alcohol mixed solution, be warming up to 80 DEG C, back flow reaction 24h.HPLC detects (product: acid amides: raw material=91%:7%:0.3%).
Reaction solution is cooled to 0 DEG C, and filter, filter cake 0.5N hydrochloric acid soln 28L and ethanol 14L dissolves, filter, 0-10 DEG C drips 1N sodium hydroxide solution 4.83L and adjusts filtrate pH7-8, and now solution has a large amount of solid to separate out, and drips and finishes, 0 DEG C is stirred 0.5h, filter, a small amount of cold washing with alcohol of filter cake, 40 DEG C of forced air dryings are to constant weight, obtain intermediate 2866.2g as shown in formula II, weight yield about 82%.HPLC detects purity 95.2%
Comparative example 1
Oxammonium hydrochloride 12.2g, DMF100ml, heat 25 DEG C, 25-30 DEG C slowly adds sodium bicarbonate 20.4g, heats up 45 DEG C, adds raw material 4g as shown in formula VI, put into 85 DEG C of oil baths, reaction 24h.The 100ml that adds water stirs, and filter, 40 DEG C of forced air dryings, to constant weight, obtain thick product 3.7g.HPLC detects (product: acid amides: raw material=55%:40.5%:2.5%).
Thick product 3g, dissolve with 0.5N hydrochloric acid soln (concentrated hydrochloric acid 1.2g, purified water 24ml) and ethanol 12ml, filter, ice bath drips 1N sodium hydroxide solution 7.1ml and adjusts filtrate pH8, now solution has a large amount of solid to separate out, and drips and finishes, and 0 DEG C is stirred 0.5h, filter, the a small amount of cold washing with alcohol of filter cake, obtains product 1.8g, weight yield about 55%.HPLC detects purity 97.1%
Comparative example 2
Add raw material 4g as shown in formula VI, 50% aqueous hydroxylamine 6.8g, triethylamine 1g, ethanol 40ml, heat 90 DEG C, back flow reaction 24h.Cooling, filter, 40 DEG C of forced air dryings, to constant weight, obtain thick product 3.2g.HPLC detects (product: acid amides: raw material=68%:17%:1.6%).
Thick product 3g, dissolve with 0.5N hydrochloric acid soln (concentrated hydrochloric acid 1.2g, purified water 24ml) and ethanol 12ml, filter, ice bath drips 1N sodium hydroxide solution 7.1ml and adjusts filtrate pH8, now solution has a large amount of solid to separate out, and drips and finishes, and 0 DEG C is stirred 0.5h, filter, the a small amount of cold washing with alcohol of filter cake, obtains product 2.4g, weight yield about 64%.HPLC detects purity 98.6%
In above example,
Product is: Azilsartan intermediate (II)
Acid amides is: impurity compound (III)
Raw material is: formula I compound
In the present invention, 50% aqueous hydroxylamine unit price is approximately 5000 yuan/kg, and homemade hydroxylamine solution cost only 100 yuan/kg, greatly reduces cost.
The ratio of product and acid amides from thick product, can find out the occurrence degree of side reaction and the content of by product, visible after comprehensive enforcement comparative example data: to be both the other technologies using self-control hydroxylamine solution, to produce amide impurities higher than the present invention; The amide impurities content that the amide impurities produced when using 50% hydroxylamine solution to prepare target product and present invention process use self-control hydroxylamine solution to produce is compared also higher, and hydroxylamine solution cost is much higher than the self-control azanol that the present invention uses.Visible the present invention is better than prior art.
Claims (1)
1. a preparation method for Azilsartan intermediate compound (II), is characterized in that: reactions steps is as follows:
Oxammonium hydrochloride 23.4g, adds ethanol 60ml, and stir and be cooled to 0 DEG C, 0-10 DEG C slowly adds sodium ethylate 15.3g, pH value of solution about 7, and filter, solution adds triethylamine 1g, and obtained azanol ethanolic soln is for subsequent use;
Add compound (I)
4g, in three batches interval 8h, add the ethanolic soln of the azanol made, and is warming up to 80 DEG C, back flow reaction 24h; Freezing and filtering, obtains thick product 3.9g;
Thick product 3g, use concentrated hydrochloric acid 1.2g, the 0.5N hydrochloric acid soln that purified water 24ml is made into and ethanol 12ml dissolve, and filter, ice bath drips 1N sodium hydroxide solution 7.2ml and adjusts filtrate pH8, now solution has a large amount of solid to separate out, and drips and finishes, and 0 DEG C is stirred 0.5h, filter, the a small amount of cold washing with alcohol of filter cake, 40 DEG C of forced air dryings, to constant weight, obtain compound (II) 2.4g.
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| CN103880756B (en) * | 2014-03-26 | 2016-06-01 | 四川奥邦药业有限公司 | The preparation method of a kind of Azilsartan intermediate |
| JP6676487B2 (en) * | 2016-07-05 | 2020-04-08 | 株式会社トクヤマ | Method for producing amidoxime compound as intermediate of azilsartan, and method for producing azilsartan |
| CN109415327A (en) * | 2016-07-05 | 2019-03-01 | 株式会社德山 | Azilsartan intermediate, Azilsartan and their manufacturing method |
| CN106478515B (en) * | 2016-10-13 | 2018-11-23 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Azilsartan intermediate |
| CN108640911B (en) * | 2018-04-03 | 2020-03-27 | 科兴生物制药股份有限公司 | Preparation method of azilsartan |
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| CN102731491B (en) * | 2012-07-04 | 2015-03-18 | 北京科莱博医药开发有限责任公司 | Preparation method of azilsartan intermediate |
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Effective date of registration: 20160325 Address after: 518000 Guangdong city of Shenzhen province Nanshan District Guangdong streets Kexing Science Park B building 4 unit 18 floor area D Patentee after: Shenzhen Measuring Technology Co., Ltd. Address before: 518057 No. 13, science and technology road, Nanshan District Science Park, Guangdong, Shenzhen Patentee before: Shenzhen Kexing Biotech Co., Ltd. |
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Address after: 518000 Guangdong city of Shenzhen province Nanshan District Guangdong streets Kexing Science Park B building 4 unit 18 floor area D Patentee after: Shenzhen Xiang Xiang Biotechnology Co., Ltd. Address before: Guangdong city of Shenzhen province Nanshan District Guangdong streets Kexing Science Park B building 4 unit 18 floor area D Patentee before: Shenzhen Measuring Technology Co., Ltd. |
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Effective date of registration: 20180905 Address after: 518000 18, B4 unit, Kexing Science Park, 15 Keyuan Road, Nanshan District, Shenzhen, Guangdong. Patentee after: Shenzhen Kexing Pharmaceutical Co., Ltd. Address before: Guangdong city of Shenzhen province Nanshan District Guangdong streets Kexing Science Park B building 4 unit 18 floor area D Patentee before: Shenzhen Xiang Xiang Biotechnology Co., Ltd. |
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Address after: 518000 b1601, Chuangyi technology building, No.1 Keji Road, Maling community, Yuehai street, Nanshan District, Shenzhen City, Guangdong Province Patentee after: SHENZHEN KEXING PHARMACEUTICAL Co.,Ltd. Address before: 518000 18, B4 unit, Kexing Science Park, 15 Keyuan Road, Nanshan District, Shenzhen, Guangdong. Patentee before: SHENZHEN KEXING PHARMACEUTICAL Co.,Ltd. |