CN106699635B - A method of preparing Delamanid intermediate - Google Patents
A method of preparing Delamanid intermediate Download PDFInfo
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- CN106699635B CN106699635B CN201510768673.6A CN201510768673A CN106699635B CN 106699635 B CN106699635 B CN 106699635B CN 201510768673 A CN201510768673 A CN 201510768673A CN 106699635 B CN106699635 B CN 106699635B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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Abstract
The present invention provides a kind of method for preparing high-purity delamanid intermediate, the intermediate is 4- [4- (trifluoromethoxy) phenoxy group] piperidines, hydrogen chloride is dissolved in ethyl acetate by this method in removing Boc group step, it is purified using the dissolution sex differernce of product and impurity in ethyl acetate, it avoids using cumbersome column chromatographic purification methods, the final product of higher yields and purity can also be obtained simultaneously, reduces production cost, be suitble to industrialization large-scale production.
Description
Technical field
The present invention relates to the preparation methods of a kind of nitro glyoxalidine and the intermediate of oxazole derivatives, are specifically
The preparation method of Delamanid intermediate.
Background technique
Delamanid is used for Drug resistant pulmonary tubeculosis disease by the nitro glyoxalidine and oxazole derivatives of big tomb pharmaceutical development
The treatment of adult patient, Delamanid are a kind of fungicide with novel binding mode, can inhibit the synthesis of mycolic acid.
The medicine has very high bactericidal activity, including resistance to line antituberculotic in vitro experiment, to a variety of different MTB bacterial strains
The bacterial strain of (such as isoniazid, rifampin).The chemical name of Delamanid are as follows: (2R) -2- methyl -6- nitro -2- [(4- { 4- [4-
(trifluoromethoxy) phenoxy group] piperidin-1-yl } phenoxy group) methyl] -2,3- glyoxalidine simultaneously [2,1-b] oxazole, structural formula is such as
Under:
。
4- [4- (trifluoromethoxy) phenoxy group] piperidines is the important intermediate for synthesizing Delamanid, patent
CN102725269 discloses the method for preparing Delamanid using the important intermediate, and specific synthetic route is as follows:
。
It is less to the research of Delamanid intermediate 4- [4- (trifluoromethoxy) phenoxy group] piperidines in the prior art, specially
The preparation method of the intermediate is disclosed in sharp CN102234287, will to trifluoro-methoxy-phenol, N-Boc-4- hydroxy piperidine,
Triphenylphosphine is dissolved in dry THF, the cooling lower dropwise addition DIAD(diisopropyl azodiformate of ice bath), drop, which finishes, to be stirred at room temperature
Night, rotation remove THF, and residue is extracted with petroleum ether, and extract is directly dissolved in TFA, and rotation removes TFA, and sodium hydroxide solution tune pH is added
To 10 or more, ethyl acetate extracts concentrated column chromatography.It is disclosed in patent CN1360577 and is added to diethyl azodiformate
In the THF mixed liquor of N-Boc-4- piperidine alcohols, 4- trifluoro-methoxy-phenol and triphenyl phasphine, concentrated column chromatography is reacted, is contained
The Boc- amine of impurity, adds the dioxane solution reaction of hydrogen chloride, and concentrated reaction mixture is diluted with ether, obtained white
The aqueous solution of sodium bicarbonate is added in color solid, with extracted by ether, washs dry 4- [4- (trifluoromethoxy) phenoxy group] piperidines.
Trifluoro-methoxy-phenol reacts under conditions of triphenylphosphine and DIAD with N-Boc-4- hydroxy piperidine, can generate big
Measure impurity, and be not easy to remove, directly affect Delamanid intermediate 4- [4- (trifluoromethoxy) phenoxy group] piperidines purity and
Yield all removes the impurity generated using the method for column chromatography in above-mentioned patent, although can be by impurity and target using column chromatography
Product separates, but this method is cumbersome, and stake tomography devices are needed in industrial production, time-consuming special in operation
It is long, and cost also greatly improves, therefore, column chromatographic purification methods are not suitable for large-scale industrial production.
In conclusion needing one kind that can obtain high-purity 4- [4- (trifluoromethoxy) phenoxy group] piperidines, and post-process
Simple and easy preparation and purification method is suitble to industrialization large-scale production to reduce production cost.
Summary of the invention
The present invention provides a kind of high-purity Delamanid intermediate 4- [4- (trifluoromethoxy) phenoxy group] piperidines of preparing
Method, this method are used as removal reagent using Hydrochloride/ethyl acetate in removing Boc group step, utilize ethyl acetate
The dissolution properties of compound III are purified, and then obtain the 4- [4- (trifluoromethoxy) phenoxy group] of higher yields and purity
Piperidines, this method avoid chromatographing this cumbersome purification process using column, reduce production cost, are suitble to industrialization extensive
Production.
The specific method provided by the invention for preparing Delamanid intermediate 4- [4- (trifluoromethoxy) phenoxy group] piperidines
Are as follows:
(1) chemical compounds I with to trifluoro-methoxy-phenol three replace phosphines and azo active ester effect under, obtain compound ii
Crude product;
(2) compound ii crude product is added in the ethyl acetate solution of hydrogen chloride, and acetic acid second is added in precipitation compounds III
It is beaten in ester, obtains compound III fine work;
(3) alkaline aqueous solution is added in compound III fine work, obtains compounds Ⅳ.
Always with more or less complete raw material of by-product and unreacted in chemical reaction process, therefore, reaction
Post-processing step it is very crucial, whether this is related to can isolate pure and high yield whole produce from reaction mixture
Product.Same reaction isolates and purifies used step, solvent, method difference, will result directly in its yield and purity is also different.
The product and shirtsleeve operation step of high-purity are always to purify post-processing problem to be solved.
It can generate a large amount of impurity in the reaction process of above-mentioned steps (1), and the generation of a large amount of impurity and impurity and product
Difficult separation characteristic, be that the post-processing of entire reaction route increases difficulty, have in the prior art using cumbersome, no
It is purified conducive to the column chromatography of industrialized production.By being ground to reaction step each in reaction route in the present invention
Study carefully, seeks to find and a kind of simple and easy go deimpurity method.Inventor has found dissolution of the compound III in ethyl acetate
Very little is spent, and the other impurities that step (1) reaction generates can be dissolved in ethyl acetate, inventor utilizes compound III and impurity
Deliquescent difference, compound ii is added in the ethyl acetate of hydrogen chloride and is reacted in ethyl acetate, removes Boc protecting group
The compound III that group obtains is precipitated insoluble in ethyl acetate, and the impurity in back reaction is dissolved in ethyl acetate and stays in solution
In.Compound III recycles ethyl acetate to carry out mashing purification process, further increases its purity and obtains compound III fine work.Change
III fine work of object is closed under the action of alkaline solution except de-chlorine hydride can obtain the compounds Ⅳ of high-purity, is not introduced in reaction new
Impurity, without purifying again.
In above-mentioned reaction, when the concentration of hydrogen chloride ethyl acetate is 1-3mol/L, the purification effect of compound III is obtained more
It is good.
Chemical compounds I and the work that phosphine and azo active ester are replaced three to trifluoro-methoxy-phenol in above-mentioned reaction step (1)
Mitsunobu reaction is carried out under, three used in reaction replace phosphine and azo active ester can known reaction examination for this field
Agent, three replace phosphine to be selected from triphenylphosphine, trimethyl-phosphine, triethyl phosphine, tripropyl phosphine, tributylphosphine, trimethoxy phosphine, three ethoxies
Base phosphine, tricyclohexyl phosphine etc..Azo active ester is selected from diisopropyl azodiformate, diethyl azodiformate, azo diformazan
Sour di tert butyl carbonate, two piperidines of azoformic acid, N, N, N', N'- tetramethyl azodicarbonamide etc..
It removes under the conditions of the hydrogen chloride in compound III is known in the art and carries out in above-mentioned reaction step (3), including
Use sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, the alkaline solution of saleratus etc..
Specific embodiment
Embodiment 1
Under nitrogen protection into reaction kettle be added tetrahydrofuran (17.5L), N-Boc-4- hydroxy piperidine (7.04kg,
35.0mol), to trifluoro-methoxy-phenol (6.86kg, 38.5mol), triphenylphosphine (10.10kg, 38.5mol), stirring and dissolving
After be cooled to 0 DEG C, be added dropwise diisopropyl azodiformate (7.78kg, 38.5mol), maintain temperature of reaction system during being added dropwise
Lower than 10 DEG C.Cryostat is removed after being added dropwise, and obtains compound ii after reacting at room temperature 12h, normal heptane is added into reaction system
(52.5L) is filtered after 8h is stirred at room temperature, and is directly used in after filtrate concentration and is reacted in next step.
Crude product obtained by upper step is cooled to 0 DEG C, be added 2mol/L Hydrochloride/ethyl acetate (35.0L,
70.0mol), the compound as white solid III of precipitation is filtered after stirring 5h.Compound III is beaten twice with ethyl acetate (15.0L)
Obtain compound III fine work, purity 97.5%.
Compound III fine work is dissolved in water (8.0L), is added dropwise 25% sodium hydrate aqueous solution (4.58kg, 28.6mol), is added dropwise
After precipitation compounds IV and continue to stir 1h, filtering, solid washs with water (3 × 8.0L), dry compounds Ⅳ
(6.74kg, 25.8mol), yield 73.7%, purity 99.6%.
Embodiment 2
Under nitrogen protection into reaction kettle be added tetrahydrofuran (16.6L), N-Boc-4- hydroxy piperidine (7.04kg,
35.0mol), to trifluoro-methoxy-phenol (6.86kg, 38.5mol), triethyl phosphine (4.55kg, 38.5mol), after stirring and dissolving
It is cooled to 0 DEG C, is added dropwise tert-butyl azodicarboxylate (8.87kg, 38.5mol), maintains temperature of reaction system low during being added dropwise
In 10 DEG C.Cryostat is removed after being added dropwise, and obtains compound ii after reacting at room temperature 10h, normal heptane is added into reaction system
(48.5L) is filtered after 9h is stirred at room temperature, and is directly used in after filtrate concentration and is reacted in next step.
Crude product obtained by upper step is cooled to 0 DEG C, be added 1.5mol/L Hydrochloride/ethyl acetate (44.0L,
66.0mol), the compound as white solid III of precipitation is filtered after stirring 5h.Compound III is beaten twice with ethyl acetate (20.0L)
Obtain compound III fine work, purity 97.7%.
Compound III fine work is dissolved in water (8.0L), is added dropwise 20% potassium hydroxide aqueous solution (7.74kg, 27.6mol), is added dropwise
After precipitation compounds IV and continue to stir 1h, filtering, solid washs with water (3 × 8.0L), dry compounds Ⅳ
(6.58kg, 25.2mol), yield 72.0%, purity 99.4%.
Embodiment 3
Under nitrogen protection into reaction kettle be added tetrahydrofuran (15.0L), N-Boc-4- hydroxy piperidine (6.04kg,
30.0mol), to trifluoro-methoxy-phenol (6.23kg, 35.0mol), trimethyl-phosphine (2.73kg, 35.0mol), after stirring and dissolving
It is cooled to 0 DEG C, is added dropwise diisopropyl azodiformate (6.10kg, 35.0mol), maintains temperature of reaction system low during being added dropwise
In 10 DEG C.Cryostat is removed after being added dropwise, and obtains compound ii after reacting at room temperature 12h, normal heptane is added into reaction system
(45.0L) is filtered after 8h is stirred at room temperature, and is directly used in after filtrate concentration and is reacted in next step.
Crude product obtained by upper step is cooled to 0 DEG C, be added 2.5mol/L Hydrochloride/ethyl acetate (24.0L,
60.0mol), the compound as white solid III of precipitation is filtered after stirring 5h.Compound III is beaten twice with ethyl acetate (15.0L)
Obtain compound III fine work, purity 97.0%.
Compound III fine work is dissolved in water (8.0L), is added dropwise 30% wet chemical (13.2kg, 28.65mol), is added dropwise
After precipitation compounds IV and continue to stir 1h, filtering, solid washs with water (3 × 8.0L), dry compounds Ⅳ
(5.67kg, 21.7mol), yield 72.3%, purity 99.3%.
Embodiment 4
Under nitrogen protection into reaction kettle be added Isosorbide-5-Nitrae-dioxane (17.0L), N-Boc-4- hydroxy piperidine (7.04kg,
35.0mol), to trifluoro-methoxy-phenol (6.86kg, 38.5mol), tributylphosphine (10.10kg, 38.5mol), stirring and dissolving
After be cooled to 0 DEG C, be added dropwise two piperidines of azoformic acid (9.71kg, 38.5mol), maintain temperature of reaction system low during being added dropwise
In 10 DEG C.Cryostat is removed after being added dropwise, and obtains compound ii after reacting at room temperature 12h, normal heptane is added into reaction system
(55L) is filtered after 8h is stirred at room temperature, and is directly used in after filtrate concentration and is reacted in next step.
Crude product obtained by upper step is cooled to 0 DEG C, be added 1mol/L Hydrochloride/ethyl acetate (60.0L,
60.0mol), the compound as white solid III of precipitation is filtered after stirring 6h.Compound III is beaten twice with ethyl acetate (18.0L)
Obtain compound III fine work, purity 96.9%.
Compound III fine work is dissolved in water (8.0L), is added dropwise 20% aqueous sodium carbonate (15.10kg, 28.5mol), is added dropwise
After precipitation compounds IV and continue to stir 1h, filtering, solid washs with water (3 × 8.0L), dry compounds Ⅳ
(6.56kg, 25.1mol), yield 71.7%, purity 99.4%.
Embodiment 5
Under nitrogen protection into reaction kettle be added (17.5L), N-Boc-4- hydroxy piperidine (7.04kg, 35.0mol), to three
Fluorine methoxyl group phenol (6.86kg, 38.5mol), triethoxy phosphine (7.01kg, 38.5mol) are cooled to 0 DEG C after stirring and dissolving,
N, N, N' is added dropwise, N'- tetramethyl azodicarbonamide (6.63kg, 38.5mol) maintains temperature of reaction system low during being added dropwise
In 10 DEG C.Cryostat is removed after being added dropwise, and obtains compound ii after reacting at room temperature 12h, normal heptane is added into reaction system
(50.0L) is filtered after 8h is stirred at room temperature, and is directly used in after filtrate concentration and is reacted in next step.
Crude product obtained by upper step is cooled to 0 DEG C, be added 3mol/L Hydrochloride/ethyl acetate (25.0L,
75.0mol), the compound as white solid III of precipitation is filtered after stirring 5h.Compound III is beaten twice with ethyl acetate (20.0L)
Obtain compound III fine work, purity 97.4%.
Compound III fine work is dissolved in water (4.0L), is added dropwise 7% sodium bicarbonate aqueous solution (33.6kg, 28.0mol), is added dropwise
After precipitation compounds IV and continue to stir 1h, filtering, solid washs with water (3 × 8.0L), dry compounds Ⅳ
(6.52kg, 24.95mol), yield 71.3%, purity 99.1%.
Embodiment 6
Under nitrogen protection into reaction kettle be added tetrahydrofuran (25L), N-Boc-4- hydroxy piperidine (8.05kg,
40.0mol), to trifluoro-methoxy-phenol (7.66kg, 43.0mol), tricyclohexyl phosphine (12.06g, 43.0mol), stirring and dissolving
After be cooled to 0 DEG C, be added dropwise diisopropyl azodiformate (8.70kg, 43.0mol), maintain temperature of reaction system during being added dropwise
Lower than 10 DEG C.Cryostat is removed after being added dropwise, and obtains compound ii after reacting at room temperature 12h, normal heptane is added into reaction system
(55L) is filtered after 10h is stirred at room temperature, and is directly used in after filtrate concentration and is reacted in next step.
Crude product obtained by upper step is cooled to 0 DEG C, be added 3.5mol/L Hydrochloride/ethyl acetate (20.0L,
70.0mol), the compound as white solid III of precipitation is filtered after stirring 5h.Compound III is beaten twice with ethyl acetate (15.0L)
Obtain compound III fine work, purity 96.0%.
Compound III fine work is dissolved in water (8.0L), is added dropwise 30% potassium bicarbonate aqueous solution (10.01kg, 30.0mol), drop
Precipitation compounds IV and continue to stir 1h after adding, filtering, solid washs with water (3 × 8.0L), dry compounds Ⅳ
(7.54kg, 28.86mol), yield 72.2%, purity 98.5%.
Comparative example 1
Under nitrogen protection into reaction kettle be added tetrahydrofuran (17.5L), N-Boc-4- hydroxy piperidine (7.04kg,
35.0mol), to trifluoro-methoxy-phenol (6.86kg, 38.5mol), triphenylphosphine (10.10kg, 38.5mol), stirring and dissolving
After be cooled to 0 DEG C, be added dropwise diisopropyl azodiformate (7.78kg, 38.5mol), maintain temperature of reaction system during being added dropwise
Lower than 10 DEG C.Cryostat is removed after being added dropwise, and obtains compound ii after reacting at room temperature 12h, normal heptane is added into reaction system
(52.5L) is filtered after 8h is stirred at room temperature, and is directly used in after filtrate concentration and is reacted in next step.
Crude product obtained by upper step is cooled to 0 DEG C, is added hydrochloric acid (70.0mol), after stirring 5h, concentrated reaction mixture,
It is diluted with ether, obtains compound as white solid III, purity 70.2%.
Compound III is dissolved in water (8.0L), is added dropwise 25% sodium hydrate aqueous solution (4.26kg, 26.6mol), is added dropwise
Precipitation compounds IV and continuing to stir 1h afterwards, filtering, solid washs with water (3 × 8.0L), dry compounds Ⅳ (6.86kg,
26.25mol), yield 75.0%, purity 72.6%.
Comparative example 2
Under nitrogen protection into reaction kettle be added tetrahydrofuran (17.5L), N-Boc-4- hydroxy piperidine (7.04kg,
35.0mol), to trifluoro-methoxy-phenol (6.86kg, 38.5mol), triphenylphosphine (10.10kg, 38.5mol), stirring and dissolving
After be cooled to 0 DEG C, be added dropwise diisopropyl azodiformate (7.78kg, 38.5mol), maintain temperature of reaction system during being added dropwise
Lower than 10 DEG C.Cryostat is removed after being added dropwise, and obtains compound ii after reacting at room temperature 12h, normal heptane is added into reaction system
(52.5L) is filtered after 8h is stirred at room temperature, and is directly used in after filtrate concentration and is reacted in next step.
Crude product obtained by upper step is cooled to 0 DEG C, be added 2mol/L hydrogen chloride dioxane solution (35.0L,
70.0mol), after stirring 5h, concentrated reaction mixture is diluted with ether, obtains compound as white solid III, purity 69.5%.
Compound III is dissolved in water (8.0L), is added dropwise 25% sodium hydrate aqueous solution (4.26kg, 26.6mol), is added dropwise
Precipitation compounds IV and continuing to stir 1h afterwards, filtering, solid washs with water (3 × 8.0L), dry compounds Ⅳ (6.81kg,
26.07mol), yield 74.5%, purity 71.9%.
According to above-described embodiment, the yield of compound III purity and target product Delamanid midbody compound IV
Table is summarized as follows with purity:
As known from the above, the solvent of hydrogen chloride solution is different, yield to compound III purity and compounds Ⅳ and pure
Degree influences significantly, and the present invention uses Hydrochloride/ethyl acetate, then carries out purifying mashing with ethyl acetate, can use chemical combination
The dissolution sex differernce of object III and impurity in ethyl acetate, is purified and is obtained higher purity, to it to obtain high yield
Preparation with the compounds Ⅳ of purity lays the foundation.Comparative example 1 and comparative example 2 are respectively with hydrochloric acid and hydrogen chloride
Dioxane solution, and compound III and impurity can be dissolved in simultaneously in water and dioxane, and precipitation cannot be separated with impurity, be reached
Less than the effect of purifying.
Claims (4)
1. a kind of method for preparing Delamanid midbody compound IV, which comprises the steps of:
(1) chemical compounds I with to trifluoro-methoxy-phenol three replace phosphines and azo active ester effect under, it is thick to obtain compound ii
Product;
(2) compound ii crude product is added in the ethyl acetate solution of hydrogen chloride, and precipitation compounds III are added in ethyl acetate
Mashing, obtains compound III fine work;
(3) alkaline aqueous solution is added in compound III fine work, obtains compounds Ⅳ;
Wherein, azo active ester is selected from diisopropyl azodiformate, diethyl azodiformate, the tertiary fourth of azoformic acid two
Ester, two piperidines of azoformic acid, N, N, N', N'- tetramethyl azodicarbonamide.
2. the method according to claim 1, wherein the concentration of hydrogen chloride ethyl acetate is 1- in step (2)
3mol/L。
3. the method according to claim 1, wherein three substitution phosphines are selected from triphenylphosphine, trimethyl in step (1)
Phosphine, triethyl phosphine, tripropyl phosphine, tributylphosphine, trimethoxy phosphine, triethoxy phosphine, tricyclohexyl phosphine.
4. the method according to claim 1, wherein the alkali in step (3) is sodium hydroxide, potassium hydroxide, carbon
Sour sodium, potassium carbonate, sodium bicarbonate, saleratus.
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1360577A (en) * | 1999-05-12 | 2002-07-24 | G.D.瑟尔公司 | Hydroxamic acid derivs. as matrix metalloprotease inhibitors |
WO2004091549A2 (en) * | 2003-03-25 | 2004-10-28 | Pharmacia Corporation | Process for making alpha-substituted hydroxamic acids |
CN100478325C (en) * | 2004-03-25 | 2009-04-15 | 大塚制药株式会社 | Preparation method for aminophenol compound |
CN102234287A (en) * | 2010-04-26 | 2011-11-09 | 上海阳帆医药科技有限公司 | Nitro imidazole compound, its preparation method and application |
CN104520292A (en) * | 2012-05-30 | 2015-04-15 | 武田药品工业株式会社 | Sulfonyl piperidine derivatives and use for treating prokineticin mediated diseases |
-
2015
- 2015-11-12 CN CN201510768673.6A patent/CN106699635B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1360577A (en) * | 1999-05-12 | 2002-07-24 | G.D.瑟尔公司 | Hydroxamic acid derivs. as matrix metalloprotease inhibitors |
WO2004091549A2 (en) * | 2003-03-25 | 2004-10-28 | Pharmacia Corporation | Process for making alpha-substituted hydroxamic acids |
CN100478325C (en) * | 2004-03-25 | 2009-04-15 | 大塚制药株式会社 | Preparation method for aminophenol compound |
CN102234287A (en) * | 2010-04-26 | 2011-11-09 | 上海阳帆医药科技有限公司 | Nitro imidazole compound, its preparation method and application |
CN104520292A (en) * | 2012-05-30 | 2015-04-15 | 武田药品工业株式会社 | Sulfonyl piperidine derivatives and use for treating prokineticin mediated diseases |
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Address after: 101113 Beijing Guangyuan Tongzhou District Industrial Development Zone in Tongzhou Street No. 8 Applicant after: Beijing Fuyuan Pharmaceutical Co., Ltd. Address before: 101113 Beijing Guangyuan Tongzhou District Industrial Development Zone in Tongzhou Street No. 8 Applicant before: Beijing Winsunny Pharmaceutical Co., Ltd. |
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