CN104592039A - Method for preparing highly pure memantine hydrochloride - Google Patents
Method for preparing highly pure memantine hydrochloride Download PDFInfo
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- CN104592039A CN104592039A CN201310535562.1A CN201310535562A CN104592039A CN 104592039 A CN104592039 A CN 104592039A CN 201310535562 A CN201310535562 A CN 201310535562A CN 104592039 A CN104592039 A CN 104592039A
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Abstract
The invention discloses a method for preparing highly pure memantine hydrochloride. 1-Amino-3,5-dimethyladamantane (memantine) with the purity of 96% is adopted as an initial raw material, and the purity of the hydrochloride of the initial material cannot reach raw medicine standards, so the highly pure memantine hydrochloride can be obtained through a technological scheme. The technologic scheme is characterized in that the method comprises the following steps: dissolving memantine in a dichloromethane and ethanol mixed solution with a certain proportioning concentration, adding water, adjusting the pH value, extracting, adding dichloromethane, adding an alkali to adjust the pH value, and extracting; carrying out rotary reduced pressure evaporation on the above obtained organic phase to dryness in order to obtain a concentrate; dissolving the concentrate in a proper amount of acetonitrile, adding concentrated hydrochloric acid, and adjusting the pH value to 1-3 in order to obtain a large amount of a solid; carrying out pumping filtration, and leaching the obtained filter cake with cold acetonitrile; and re-crystallizing with 95% ethanol to obtain the highly pure memantine hydrochloride. In the preparation process, dichloromethane, ethanol, water, acetonitrile and other solvents are selected by post-treatmetn, so the method has the advantages of small toxicity, small pollution to environment, simple and feasible operation, and convenient industrial large-scale production. The purity of the memantine hydrochloride can reach 99.99%, and is higher than memantine hydrochloride prepared through traditional preparation methods.
Description
Technical field
The novel method of the preparation high-purity memantine hydrochloride that the present invention relates to, belongs to medicine, chemical technology field.
Background technology
Memantine is a kind of white solid, and its chemical name is amino-3, the 5-dimethyl memantine hydrochloride of 1-or amino-3,5-dimethyl three ring [3,3,1, the 1] decane hydrochloride of 1-.Its chemical structure is as follows:
Memantine is particularly centering to the diseases relevant to N-methyl-D-aspartate (NMDA) receptor antagonist such as severe Alzheimer's disease in treatment dementia good curative effect, thus in the market in future, has very large development prospect.
The patent preparing memantine delivered both at home and abroad is at present many, such as US3391142, US4122193, CN1400205, CN1335299 etc., but the patent being all prepared by relevant memantine.Up to the present, do not find the report to memantine purifying, memantine purity is commercially 96%, if directly do not reach the production standard of memantine hydrochloride raw material medicine with its hcl acidifying salify.
Summary of the invention
The present invention is directed to above-mentioned the deficiencies in the prior art, a kind of method preparing high-purity memantine hydrochloride is provided, finally can obtains the memantine of purity 99.99%.
The method preparing high-purity memantine hydrochloride of the present invention, with MEM (memantine) for starting raw material, dissolve through solvothermal successively, the acid adjustment that adds water extracts, and the alkali tune that adds methylene chloride extracts, concentrating under reduced pressure, after concentrated, then adds dissolution with solvents, hcl acidifying salify, suction filtration, 95% ethyl alcohol recrystallization, dries and obtains highly purified target product memantine solid, detect through GC, purity can reach 99.99%.
The method preparing high-purity memantine hydrochloride of the present invention, the starting raw material used is MEM, and its purity is 96%.
The above-mentioned method preparing high-purity memantine hydrochloride, described solvent is organic solvent, the mixed solvent of the preferred methylene dichloride of described organic solvent and ethanol.
The above-mentioned method preparing high-purity memantine hydrochloride, described memantine quality (g) is 1:10 with volume (ml) proportioning of mixed solvent, and the proportioning volume of methylene dichloride and ethanol is 10:1-10:0, is preferable over 10:1.
The above-mentioned method preparing high-purity memantine hydrochloride, in the described acid adjustment that adds water, volume (ml) proportioning of memantine quality (g) and purified water is between 1:2-1:10, wherein 1:6.25 is optimum, and acid used is mineral acid or the organic acids such as hydrochloric acid, sulfuric acid, nitric acid, regulates pH=1-3.
The above-mentioned method preparing high-purity memantine hydrochloride, describedly add methylene chloride in alkali tune process, volume (ml) proportioning of diamantane quality (g) and methylene dichloride is between 1:2-1:10, wherein 1:5 is optimum, described alkali is the mineral alkalis such as sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood, adjusts PH=7-8.
The above-mentioned method preparing high-purity memantine hydrochloride, after concentrated, solvent used is water, acetonitrile, ethanol, acetone, tetrahydrofuran (THF), ethyl acetate or ethyl acetate-ethyl ether, preferred acetonitrile.
The above-mentioned method preparing high-purity memantine hydrochloride, in hcl acidifying salification process, concentration of hydrochloric acid is 36%-37%, and diamantane and hydrogenchloride mol ratio are 1:1-1:5, and wherein 1:1.3 reaction is best.
The above-mentioned method preparing high-purity memantine hydrochloride, in recrystallization, memantine quality (g) is 1:1-1:15 with volume (ml) proportioning of 95% ethanol, and wherein 1:7.5 is best.
The invention also discloses a kind of preferred method preparing high-purity memantine hydrochloride, concrete steps are as follows:
1) with MEM (memantine) for starting raw material, dissolve through solvothermal, heating for dissolving temperature is 25-30 DEG C, and the acid adjustment that adds water extracts, and divides to fall organic phase to retain aqueous phase, repeat 2-3 time, aqueous phase adds methylene dichloride again, adds alkali and regulates pH=7-8, divide to fall aqueous phase to retain organic phase, repeat 2-3 time, TLC detects the basic disappearance of assorted point, after extraction, organic phase decompression rotary evaporation concentrates, and temperature is arranged on 35-40 DEG C;
2) after system concentrates, then add dissolution with solvents, hcl acidifying salify, concentrated hydrochloric acid slowly drips under the low temperature agitation condition of 10 ± 2 DEG C, regulates pH=1-3, obtains a large amount of white solid suction filtration;
3), after hcl acidifying obtains a large amount of white solid, decompress filter, the cold acetonitrile drip washing of filter cake, 95% ethyl alcohol recrystallization, the solid after recrystallization is placed in 60 DEG C-70 DEG C baking oven vacuum-dryings, final highly purified memantine.
Of the present invention take MEM as raw material, through a series of purifying salify obtain high-purity memantine hydrochloride based on chemical equation as follows:
By the method preparing memantine of the present invention, purity reaches as high as 99.99%, and compared with prior art, and methylene dichloride, ethanol, water, acetonitrile equal solvent are selected in whole process, and toxicity is less, and environmental pollution is little; And operation is simple, be convenient to industrial scale and produce.
Embodiment
Embodiment 1:
Prepare the method for high-purity memantine hydrochloride, preferred embodiment is, adds the 1-amino-3 of 80 grams in the there-necked flask of 2 liters, 5-dimethyladamantane, adds the mixing solutions (methylene dichloride 727ml, ethanol 73ml) of 800ml methylene dichloride and the ethanol configured, 25-30 DEG C of heated and stirred, dissolves.Add the purified water of 500ml again, salt adding acid for adjusting pH=1-3, divide to fall organic phase to retain aqueous phase, repeat 2-3 time.Aqueous phase adds 400ml methylene dichloride again, and hydro-oxidation sodium regulates pH=7-8, divides to fall aqueous phase to retain organic phase, repeats 2-3 time, and TLC detects assorted point and substantially disappears.Organic phase rotates evaporated under reduced pressure and obtains enriched material at 35-40 DEG C, and the acetonitrile that enriched material adds 600ml dissolves, and adds 58.6g concentrated hydrochloric acid (36%), regulates pH=1-3, obtains a large amount of white solid.Decompress filter, the acetonitrile drip washing that filter cake 100ml is cold. finally use 95% ethyl alcohol recrystallization of 600ml, suction filtration obtains white solid, is placed in 60 DEG C-70 DEG C baking oven vacuum-dryings, obtains highly purified memantine 88g.Purity is 99.99% after testing, and yield can reach 92%.
Embodiment 2:
Prepare the method for high-purity memantine hydrochloride, can decline to some extent if the mixed solvent methylene dichloride and ethanol that dissolve diamantane are changed to single solvent purity of alcohol, productive rate also can reduce greatly.In the there-necked flask of 2 liters, such as add the MEM of 80 grams, add ethanol 800m, 75 DEG C of heated and stirred, dissolve.Add the purified water of 500ml again, salt adding acid for adjusting pH=1-3, divide to fall organic phase to retain aqueous phase, repeat 2-3 time.Aqueous phase adds 400ml methylene dichloride again, and hydro-oxidation sodium regulates pH=7-8, divides to fall aqueous phase to retain organic phase, repeats 2-3 time, and TLC detects assorted point and substantially disappears.Organic phase rotates evaporated under reduced pressure and obtains enriched material at 35-40 DEG C, and the acetonitrile that enriched material adds 600ml dissolves, and adds 58.6g concentrated hydrochloric acid (36%), regulates pH=1-3, obtains a large amount of white solid.Decompress filter, the acetonitrile drip washing that filter cake 100ml is cold. finally use 95% ethyl alcohol recrystallization of 600ml, suction filtration obtains white solid, is placed in 60 DEG C-65 DEG C baking oven vacuum-dryings, the memantine 71g obtained.Purity is 99.0% after testing, and yield only has 80%.
Embodiment 3:
Prepare the method for high-purity memantine hydrochloride, in concentrated dissolution process again, through the contrast of a series of solvent as water, acetonitrile, ethanol, acetone, tetrahydrofuran (THF), ethyl acetate, ethyl acetate-ethyl ether etc., select acetonitrile best.
In the concentrated dissolution process again of table 1, different solvents and temperature are on the impact of productive rate
Other conditions are all identical with embodiment 1, under original constant condition of having ready conditions most as can be seen from Table 1, be not easy to dissolve with aqueous concentrate, ethanol, ethyl acetate and acetone are too soluble, capital causes productive rate lower, and the ethyl acetate-ethyl ether mixed solvent easy firing of patent report explodes before, cause accident, be not suitable for industrialization scale operation.
Prepare the method for high-purity memantine hydrochloride, in hcl acidifying process, the mol ratio of MEM and hydrogenchloride is 1:1.3, if be greater than the incomplete productive rate of this proportioning memantine salify lower than 92%, be less than this proportioning and salt excessive acid purity will reduce.
Embodiment 4: during for the mol ratio of MEM and hydrogenchloride for 1:1
In the there-necked flask of 2 liters, add the MEM of 80 grams, add the mixing solutions (methylene dichloride 727ml, ethanol 73ml) of 800ml methylene dichloride and the ethanol configured, 25-30 DEG C of heated and stirred, dissolve.Add the purified water of 500ml again, salt adding acid for adjusting pH=1-3, divide to fall organic phase to retain aqueous phase, repeat 2-3 time.Aqueous phase adds 400ml methylene dichloride again, and hydro-oxidation sodium regulates pH=7-8, divides to fall aqueous phase to retain organic phase, repeats 2-3 time, and TLC detects assorted point and substantially disappears.Organic phase rotates evaporated under reduced pressure and obtains enriched material at 35-40 DEG C, and the acetonitrile that enriched material adds 600ml dissolves, and adds 45g concentrated hydrochloric acid (36%), regulates pH=1-3, obtains a large amount of white solid.Decompress filter, the acetonitrile drip washing that filter cake 100ml is cold. finally use 95% ethyl alcohol recrystallization of 600ml, suction filtration obtains white solid, is placed in 60 DEG C-70 DEG C baking oven vacuum-dryings, obtains highly purified memantine 60g.Purity is 99.97% after testing, and yield can reach 67%.
Example 5: for the mol ratio of MEM and hydrogenchloride for 1:1.5
In the there-necked flask of 2 liters, add the MEM of 80 grams, add the mixing solutions (methylene dichloride 727ml, ethanol 73ml) of 800ml methylene dichloride and the ethanol configured, 25-30 DEG C of heated and stirred, dissolve.Add the purified water of 500ml again, salt adding acid for adjusting pH=1-3, divide to fall organic phase to retain aqueous phase, repeat 2-3 time.Aqueous phase adds 400ml methylene dichloride again, and hydro-oxidation sodium regulates pH=7-8, divides to fall aqueous phase to retain organic phase, repeats 2-3 time, and TLC detects assorted point and substantially disappears.Organic phase rotates evaporated under reduced pressure and obtains enriched material at 35-40 DEG C, and the acetonitrile that enriched material adds 600ml dissolves, and adds 68g concentrated hydrochloric acid (36%), regulates pH=1-3, obtains a large amount of white solid.Decompress filter, the acetonitrile drip washing that filter cake 100ml is cold. finally use 95% ethyl alcohol recrystallization of 600ml, suction filtration obtains white solid, is placed in 60 DEG C-70 DEG C baking oven vacuum-dryings, obtains highly purified memantine 60g.Purity is 98% after testing, and yield reaches 93%.
Embodiment 6:
The novel method of preparation high-purity memantine hydrochloride, memantine, after hcl acidifying salify, need can reach highly purified memantine with 95% appropriate ethyl alcohol recrystallization, otherwise purity is not high.
In the there-necked flask of 2 liters, add the MEM of 80 grams, add the mixing solutions (methylene dichloride 727ml, ethanol 73ml) of 800ml methylene dichloride and the ethanol configured, 25-30 DEG C of heated and stirred, dissolve.Add the purified water of 500ml again, add sulfuric acid and regulate pH=1-3, divide to fall organic phase to retain aqueous phase, repeat 2-3 time.Aqueous phase adds 400ml methylene dichloride again, adds sodium carbonate and regulates pH=7-8, divides to fall aqueous phase to retain organic phase, repeats 2-3 time, and TLC detects assorted point and substantially disappears.Organic phase rotates evaporated under reduced pressure and obtains enriched material at 35-40 DEG C, and the acetonitrile that enriched material adds 600ml dissolves, and adds 58.6g concentrated hydrochloric acid (36%), regulates pH=1-3, obtains a large amount of white solid.Decompress filter, the acetonitrile drip washing that filter cake 100ml is cold. obtain white solid, be placed in 60 DEG C-70 DEG C baking oven vacuum-dryings, obtain memantine 89g.Purity is 99.0% after testing.
Claims (10)
1. prepare the method for high-purity memantine hydrochloride, it is characterized in that: take MEM as starting raw material, dissolve through solvothermal successively, the acid adjustment that adds water extracts, and the alkali tune that adds methylene chloride extracts, concentrating under reduced pressure, after concentrated, add dissolution with solvents again, hcl acidifying salify, suction filtration, 95% ethyl alcohol recrystallization, dries and obtains highly purified target product memantine solid.
2. the method preparing high-purity memantine hydrochloride according to claim 1, is characterized in that: the purity of described MEM is 96%.
3. the method preparing high-purity memantine hydrochloride according to claim 1, it is characterized in that: during described solvothermal dissolves, solvent for use is the mixed solvent of methylene dichloride and ethanol, and described memantine quality (g) is 1:10 with volume (ml) proportioning of mixed solvent.
4. the method preparing high-purity memantine hydrochloride according to claim 3, is characterized in that: described methylene dichloride and proportion of ethanol scope are 10:1-10:0.
5. the method preparing high-purity memantine hydrochloride according to claim 1, it is characterized in that: described in diamantane quality (g) in acid adjustment that adds water be 1:2-1:10 with volume (ml) proportioning of purified water, acid used is mineral acid or organic acid, regulate pH=1-3, described mineral acid is hydrochloric acid, sulfuric acid or nitric acid.
6. the method preparing high-purity memantine hydrochloride according to claim 1, it is characterized in that: described in add methylene chloride in alkali tune, diamantane quality (g) is 1:2-1:10 with volume (ml) proportioning of methylene dichloride, described alkali is sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood, adjusts PH=7-8.
7. the method preparing high-purity memantine hydrochloride according to claim 1, is characterized in that: after concentrated, solvent used is acetonitrile.
8. the method preparing high-purity memantine hydrochloride according to claim 1, it is characterized in that: in hcl acidifying salification process, concentration of hydrochloric acid is 36%-37%, diamantane and hydrogenchloride mol ratio are 1:1-1:5, preferred 1:1.3.
9. the method preparing high-purity memantine hydrochloride according to claim 1, is characterized in that: in recrystallization, and memantine quality (g) is 1:1-1:15 with volume (ml) proportioning of 95% ethanol, preferred 1:7.5.
10. the method preparing high-purity memantine hydrochloride according to any one of claim 1-9, is characterized in that, comprise the steps:
With MEM (memantine) for starting raw material, dissolve through solvothermal, heating for dissolving temperature is 25-30 DEG C, and the acid adjustment that adds water extracts, and divides to fall organic phase to retain aqueous phase, repeat 2-3 time, aqueous phase adds methylene dichloride again, adds alkali and regulates pH=7-8, divide to fall aqueous phase to retain organic phase, repeat 2-3 time, TLC detects the basic disappearance of assorted point, after extraction, organic phase decompression rotary evaporation concentrates, and temperature is arranged on 35-40 DEG C;
After system is concentrated, then add dissolution with solvents, hcl acidifying salify, concentrated hydrochloric acid slowly drips under the low temperature agitation condition of 10 ± 2 DEG C, regulates pH=1-3, obtains a large amount of white solid suction filtration;
After hcl acidifying obtains a large amount of white solid, decompress filter, the cold acetonitrile drip washing of filter cake, 95% ethyl alcohol recrystallization, the solid after recrystallization is placed in 60 DEG C-70 DEG C baking oven vacuum-dryings, final highly purified memantine.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240668C (en) * | 2003-09-10 | 2006-02-08 | 上海医药工业研究院 | Method for preparing memantine hydrochloride |
| WO2010067252A1 (en) * | 2008-12-12 | 2010-06-17 | Alembic Limited | An improved process for the preparation of 1-bromo-3,5-dimethyl adamantane |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1240668C (en) * | 2003-09-10 | 2006-02-08 | 上海医药工业研究院 | Method for preparing memantine hydrochloride |
| WO2010067252A1 (en) * | 2008-12-12 | 2010-06-17 | Alembic Limited | An improved process for the preparation of 1-bromo-3,5-dimethyl adamantane |
Non-Patent Citations (2)
| Title |
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| 任会学等: "1-乙酰氨基-3 , 5-二甲基金刚烷的水解反应研究", 《精细化工中间体》 * |
| 黄正义等: "盐酸美金刚胺的合成工艺改进", 《安徽医药》 * |
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Address after: 221004 No. 6 Yangshan Road, Xuzhou Economic Development Zone, Jiangsu Province Co-patentee after: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee after: JIANGSU WANBANG BIOPHARMACEUTICAL GROUP CO.,LTD. Address before: 221004 No. 6 Yangshan Road, Xuzhou Economic Development Zone, Jiangsu Province Co-patentee before: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee before: Jiangsu Wan Bang Biochemical Medicine Co.,Ltd. Address after: 221004 No. 6 Yangshan Road, Xuzhou Economic Development Zone, Jiangsu Province Co-patentee after: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee after: Jiangsu Wan Bang Biochemical Medicine Co.,Ltd. Address before: 221004 No. 6 Yangshan Road, Xuzhou Economic Development Zone, Jiangsu Province Co-patentee before: SHANGHAI FOSUN PHARMACEUTICAL(GROUP)CO., Ltd. Patentee before: JIANGSU WANBANG BIOPHARMACEUTICALS Co.,Ltd. |
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