CN106674019A - Cinacalcet hydrochloride active pharmaceutical ingredient and preparation method thereof - Google Patents

Cinacalcet hydrochloride active pharmaceutical ingredient and preparation method thereof Download PDF

Info

Publication number
CN106674019A
CN106674019A CN201611186354.5A CN201611186354A CN106674019A CN 106674019 A CN106674019 A CN 106674019A CN 201611186354 A CN201611186354 A CN 201611186354A CN 106674019 A CN106674019 A CN 106674019A
Authority
CN
China
Prior art keywords
cinacalcet hydrochloride
preparation
bulk drug
cinacalcet
naphthyls
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
Application number
CN201611186354.5A
Other languages
Chinese (zh)
Other versions
CN106674019B (en
Inventor
王宁
胡良明
沙伟
方文
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NANJING HENCER PHARMACY CO., LTD.
Nanjing Lifenergy R&D Co Ltd
Original Assignee
Nanjing Lifenergy R&D Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nanjing Lifenergy R&D Co Ltd filed Critical Nanjing Lifenergy R&D Co Ltd
Priority to CN201611186354.5A priority Critical patent/CN106674019B/en
Publication of CN106674019A publication Critical patent/CN106674019A/en
Application granted granted Critical
Publication of CN106674019B publication Critical patent/CN106674019B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/28—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with other reducing agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Abstract

The invention discloses a cinacalcet hydrochloride active pharmaceutical ingredient and a preparation method thereof. The active pharmaceutical ingredient comprises 0.005 to 0.05 percent of one or several kinds of materials from specific compounds of N-X-(R)-1-(1-naphthyl) ethylamine hydrochloride, wherein X is 1-butyl, 1-isobutyl and 2-butyl. The pharmaceutical ingredient has the advantages that the stability is high; under the conditions of the temperature being 30+/-2DEG C and the humidity being 65+/-5 percent, the impurity addition in the active pharmaceutical ingredient after 24 months does not exceed 0.06 percent.

Description

A kind of cinacalcet hydrochloride bulk drug and preparation method thereof
Technical field：
The invention belongs to pharmaceutical technology field, and in particular to a kind of cinacalcet hydrochloride bulk drug and preparation method thereof.
Background technology：
Cinacalcet hydrochloride, is the Sensipar researched and developed by NPS companies of the U.S., is listed in the U.S. first within 2004, is also me State ratifies the first oral medicine of the SHPT for maintenance dialysis patient.Cinacalcet hydrochloride can swash Calcium acceptor in parathyroid gland living, so that the secretion of parathormone is reduced, and the behavior can be by strengthening acceptor in blood The sensitiveness of calcium level, reduces the level of parathormone, calcium, phosphorus and calcium/phosphorus compounded thing.
Cinacalcet hydrochloride, chemical name：N- ((1R) -1- (1- naphthyls) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1- Amine hydrochlorate, molecular formula C22H22F3N.HCl, No. CAS：364782-34-3, structural formula is as follows：
Patent US6211244 prepares cinacalcet hydrochloride using reductive amination process, with m-trifluoromethyl benzenepropanal and R-1- (1- naphthyls) ethamine be raw material, through titanium tetraisopropylate catalyst into schiff bases, then through sodium cyanoborohydride reduction, hydrochloric acid into Salt is obtained.The reduction impurity content contained in products obtained therefrom is higher, and the stability of product declines very fast during keeping sample.
CN101180261, CN20120170026, US20110172455 disclose a kind of alkylation process prepare hydrochloric acid west that The method of jam：Reacted with R-1- (1- naphthyls) ethamine after mesyl chloride is activated with trifluoromethyl phenylpropanol, into salt gained. But the patent is pointed out, R-1- (1- naphthyls) ethamine is similar to cinacalcet hydrochloride property, is alkaline matter.Placed in product Cheng Zhong, R-1- (1- naphthyls) ethamine and cinacalcet hydrochloride are also easy to produce oxidation impurities, are also easily generated with m-trifluoromethyl phenylpropanol Di impurity etc., these oxidation impurities and reduction impurity are easily degraded during long-term setting-out with cinacalcet hydrochloride Reaction, causes impurity content elevation amplitude larger.
International monopoly WO2006125026 is reported by compound I (X represents leaving group) and R-1- (1- naphthyls) second The method that amine reaction prepares cinacalcet, reaction dissolvent is done with acetonitrile, the back flow reaction in alkaline environment, obtains product Xi Naka Plug, then with hydrochloric acid into salt.
There is the impurity that multiple is difficult to refined removing in the method products obtained therefrom, be extremely difficult to the requirement of ICH guides.These are miscellaneous Matter may chemically react in cinacalcet hydrochloride bulk drug with cinacalcet hydrochloride, generate other impurities, cause miscellaneous Matter content is raised, and influences its stability.
The group and its structure contained in itself from cinacalcet hydrochloride, it is alkaline matter.Introduced in preparation process Reduction impurity, oxidation impurities etc. can and cinacalcet hydrochloride reaction generation degradation impurity, impurity content is too high in causing product, Stability declines.
In summary, in the prior art, there is cinacalcet hydrochloride to some extent in long-time stability setting-out process In, there are the phenomenons such as degradation impurity content is raised, stability declines.Therefore, if can suppress long-term by certain technological means The generation of degradation impurity during setting-out, then be a kind of new breakthrough.
The content of the invention：
It is an object of the invention to provide a kind of cinacalcet hydrochloride bulk drug containing specific compound and preparation method thereof, Described preparation method cinacalcet hydrochloride good stability.
The purpose of the present invention is achieved through the following technical solutions：
A kind of cinacalcet hydrochloride bulk drug, wherein containing 0.005~0.05% following spy described in one or more Determine compound N-X- (R) -1- (1- naphthyls) ethylamine hydrochloride, wherein X can be 1- butyl, 1- isobutyl groups or 2- butyl,
A kind of preparation method of cinacalcet hydrochloride bulk drug of the present invention, comprises the following steps：
A) 3- (trifluoromethyl) benzenpropanal, R-1- (1- naphthyls) ethamine, mixing aprotic solvent are added in reaction vessel, instead Answer 0.5h；
B) add acetic acid and sodium triacetoxy borohydride reacts 0.5~3h, reaction solution is extracted with aqueous slkali, concentration；
C) cinacalcet base organic phase through hydrochloric acid into after salt cinacalcet hydrochloride crude product；
D) crude product it is purified, dry after cinacalcet hydrochloride highly finished product.
A) it is water to mix aprotic solvent described in step a kind of, another or several aprotic solvent be selected from acetone, Acetonitrile, dimethyl sulfoxide, tetrahydrofuran, water are 1 with aprotic solvent weight ratio:5~20；And it is another or several non-proton Contain one or more in hutanal, isobutylaldehyde, the butanone that content is 10~90ppm in solvent.
Another preferred tetrahydrofuran of aprotic solvent；In tetrahydrofuran it is a kind of in hutanal, isobutylaldehyde, butanone or Several contents is more preferably 20~60ppm.
A) in step preferably：3- (trifluoromethyl) benzenpropanal is 1 weight portion, R-1- (1- naphthyls) ethamine is 0.8~1.1 weight Amount part, mixing aprotic solvent are 8~20 weight portions.
B) in step preferably：Acetic acid is 1~2 weight portion, sodium triacetoxy borohydride is 1.5~3 weight portions, reaction temperature Spend is 10~50 DEG C.
B) in step, further preferred 20~30 DEG C of the reaction temperature of solution.
A kind of preparation method of described cinacalcet hydrochloride bulk drug, by the hydrochloric acid west of 2000~12000 weight portions that It is obtained after N-X- (R) -1- (1- naphthyls) ethylamine hydrochloride of jam and 1 weight portion is well mixed.
Beneficial effect：Present inventors have unexpectedly found that, in cinacalcet hydrochloride jam bulk drug, there is specific compound N-X- (R) during -1- (1- naphthyls) ethylamine hydrochloride, the stability of cinacalcet hydrochloride bulk drug is significantly improved.This is probably specialization Compound hinders reducing impurity or oxidative impurities and is reacted with cinacalcet hydrochloride, and then improves its stability.This hair The cinacalcet hydrochloride bulk drug good stability of bright offer, it is former after 24 months under the conditions of 30 ± 2 DEG C of temperature, humidity 65 ± 5% Impurity incrementss are no more than 0.06% in material medicine.
Specific embodiment
The technical scheme invented is further described in conjunction with specific embodiment.
Comparative example 1：
Tetrahydrofuran 65g, purified water 6g, R-1- (1- naphthyls) ethamine 4g and 3- (trifluoromethyl) benzene are added in there-necked flask Propionic aldehyde 4.3g, nitrogen protection, 25 DEG C of stirring 30min.Add sodium triacetoxy borohydride 8g, glacial acetic acid 6g, 25 DEG C of stirrings 2h.The sodium carbonate liquor of 80g 10% is added, stirring stands 20min, and point liquid is concentrated under reduced pressure.Concentrate adds 2M hydrochloric acid 18g Into salt, 45g normal heptane dissolveds are added, stirred, centrifugation, 70 DEG C of drying under reduced pressure 8h obtain crude product.Crude product is again with 7 times of isopropyls of amount Alcohol is recrystallized, products obtained therefrom total recovery 55.63%, highly finished product purity 99.840%.
Embodiment 1：
Tetrahydrofuran (hutanal 20.9ppm) 34.2g, purified water 3.2g, R-1- (1- naphthyls) second are added in there-necked flask Amine 3.5g and 3- (trifluoromethyl) benzenpropanal 4.3g, nitrogen protection, 29 DEG C of stirring 30min.Add triacetoxy boron hydride Sodium 6.8g, glacial acetic acid 4.6g, 29 DEG C of stirring 2h.The sodium carbonate liquor of 80g 10% is added, stirring stands 20min, and point liquid subtracts Pressure concentration.Concentrate adds 2M hydrochloric acid 18g into salt, adds 45g normal heptane dissolveds, stirs, centrifugation, 70 DEG C of drying under reduced pressure 8h, Obtain crude product.Crude product again with 7 times amount recrystallisation from isopropanol, products obtained therefrom total recovery 57.68%, highly finished product purity 99.892%, Specific compound total content 0.007%.
Embodiment 2：
Tetrahydrofuran (hutanal 57.8ppm) 77.6g, purified water 7.2g, R-1- (1- naphthyls) second are added in there-necked flask Amine 4.5g and 3- (trifluoromethyl) benzenpropanal 4.3g, nitrogen protection, 22 DEG C of stirring 30min.Add triacetoxy boron hydride Sodium 12.3g, glacial acetic acid 8.2g, 22 DEG C of stirring 2h.The sodium carbonate liquor of 80g 10% is added, stirring stands 20min, and point liquid subtracts Pressure concentration.Concentrate adds 2M hydrochloric acid 18g into salt, adds 45g normal heptane dissolveds, stirs, centrifugation, 70 DEG C of drying under reduced pressure 8h, Obtain crude product.Crude product again with 7 times amount recrystallisation from isopropanol, products obtained therefrom total recovery 59.31%, highly finished product purity 99.905%, Specific compound total content 0.044%.
Embodiment 3：
Tetrahydrofuran (hutanal 30.6ppm) 65g, purified water 6g, R-1- (1- naphthyls) ethamine 4g are added in there-necked flask With 3- (trifluoromethyl) benzenpropanal 4.3g, nitrogen protection, 25 DEG C of stirring 30min.Add sodium triacetoxy borohydride 8g, ice Acetic acid 6g, 25 DEG C of stirring 2h.The sodium carbonate liquor of 80g 10% is added, stirring stands 20min, and point liquid is concentrated under reduced pressure.Concentration Liquid adds 2M hydrochloric acid 18g into salt, adds 45g normal heptane dissolveds, stirs, and centrifugation, 70 DEG C of drying under reduced pressure 8h obtain crude product.Crude product Again with 7 times of recrystallisation from isopropanol of amount, products obtained therefrom total recovery 61.08%, highly finished product purity 99.912%, specific compound is total Content 0.029%.
Embodiment 4：
Tetrahydrofuran (isobutylaldehyde 28.1ppm) 65g, purified water 6g, R-1- (1- naphthyls) ethamine 4g are added in there-necked flask With 3- (trifluoromethyl) benzenpropanal 4.3g, nitrogen protection, 25 DEG C of stirring 30min.Add sodium triacetoxy borohydride 8g, ice Acetic acid 6g, 25 DEG C of stirring 2h.The sodium carbonate liquor of 80g 10% is added, stirring stands 20min, and point liquid is concentrated under reduced pressure.Concentration Liquid adds 2M hydrochloric acid 18g into salt, adds 45g normal heptane dissolveds, stirs, and centrifugation, 70 DEG C of drying under reduced pressure 8h obtain crude product.Crude product Again with 7 times of recrystallisation from isopropanol of amount, products obtained therefrom total recovery 62.54%, highly finished product purity 99.932%, specific compound is total Content 0.025%.
Embodiment 5：
In there-necked flask add tetrahydrofuran (butanone 35.6ppm) 65g, purified water 6g, R-1- (1- naphthyls) ethamine 4g and 3- (trifluoromethyl) benzenpropanal 4.3g, nitrogen protection, 25 DEG C of stirring 30min.Add sodium triacetoxy borohydride 8g, ice vinegar Sour 6g, 25 DEG C of stirring 2h.The sodium carbonate liquor of 80g 10% is added, stirring stands 20min, and point liquid is concentrated under reduced pressure.Concentrate Add 2M hydrochloric acid 18g into salt, add 45g normal heptane dissolveds, stir, centrifugation, 70 DEG C of drying under reduced pressure 8h obtain crude product.Crude product is again With 7 times amount recrystallisation from isopropanol, products obtained therefrom total recovery 60.60%, highly finished product purity 99.879%, specific compound always contains Amount 0.031%.
Embodiment 6：
The cinacalcet hydrochloride highly finished product 5.01g that purity is 99.90% is taken, N- (1- butyl)-(R) -1- (1- naphthalenes are added Base) ethylamine hydrochloride 0.450mg, it is well mixed, highly finished product purity 99.891%, specific compound total content 0.009% can be obtained.
Embodiment 7：
The cinacalcet hydrochloride highly finished product 5.00g that purity is 99.90% is taken, N- (1- butyl)-(R) -1- (1- naphthalenes are added Base) ethylamine hydrochloride 1.501mg, it is well mixed, highly finished product purity 99.870%, specific compound total content 0.030% can be obtained.
Embodiment 8：
The cinacalcet hydrochloride highly finished product 5.00g that purity is 99.90% is taken, N- (1- butyl)-(R) -1- (1- naphthalenes are added Base) ethylamine hydrochloride 2.251mg, it is well mixed, highly finished product purity 99.855%, specific compound total content 0.045% can be obtained.
Embodiment 9：
The cinacalcet hydrochloride highly finished product 5.00g that purity is 99.90% is taken, N- (1- isobutyl groups)-(R) -1- (1- naphthalenes are added Base) ethylamine hydrochloride 1.601mg, it is well mixed, highly finished product purity 99.868%, specific compound total content 0.032% can be obtained.
Embodiment 10：
The cinacalcet hydrochloride highly finished product 5.00g that purity is 99.90% is taken, N- (2- butyl)-(R) -1- (1- naphthalenes are added Base) ethylamine hydrochloride 1.400mg, it is well mixed, highly finished product purity 99.872%, specific compound total content 0.028% can be obtained.
Embodiment 11：
Comparative example 1 and embodiment 2~10 are carried out into setting-out (setting-out condition：30 ± 2 DEG C of temperature, humidity 65 ± 5%), 24 Sampled after month, as a result detect as follows：
Unless otherwise specified, " % " in the present invention refers both to weight/mass percentage composition.

Claims (8)

1. a kind of cinacalcet hydrochloride bulk drug, it is characterised in that contain 0.005~0.05% in cinacalcet hydrochloride bulk drug Following specific compound N-X- (R) -1- (1- naphthyls) ethylamine hydrochloride described in one or more, wherein X can for 1- butyl, 1- isobutyl groups or 2- butyl,
2. a kind of preparation method of the cinacalcet hydrochloride bulk drug described in claim 1, comprises the following steps：
A) 3- (trifluoromethyl) benzenpropanal, R-1- (1- naphthyls) ethamine, mixing aprotic solvent, reaction are added in reaction vessel 0.5h；
B) add acetic acid and sodium triacetoxy borohydride reacts 0.5~3h, reaction solution is extracted with aqueous slkali, concentration；
C) cinacalcet base organic phase through hydrochloric acid into after salt cinacalcet hydrochloride crude product；
D) crude product it is purified, dry after cinacalcet hydrochloride highly finished product.
Characterized in that,
A) it is water to mix aprotic solvent described in step a kind of, another or several aprotic solvent be selected from acetone, acetonitrile, Dimethyl sulfoxide, tetrahydrofuran, water are 1 with aprotic solvent weight ratio:5~20；And another or several aprotic solvent In contain one or more in hutanal, isobutylaldehyde, the butanone that content is 10~90ppm.
3. the preparation method of cinacalcet hydrochloride bulk drug according to claim 2, it is characterised in that another non- Proton solvent is selected from tetrahydrofuran.
4. the preparation method of cinacalcet hydrochloride bulk drug according to claim 2, it is characterised in that in tetrahydrofuran just The content of one or more is 20~60ppm in butyraldehyde, isobutylaldehyde, butanone.
5. the preparation method of cinacalcet hydrochloride bulk drug according to claim 2, it is characterised in that a) in step, 3- It is 8 that (trifluoromethyl) benzenpropanal is 1 weight portion, R-1- (1- naphthyls) ethamine is 0.8~1.1 weight portion, mix aprotic solvent ~20 weight portions.
6. the preparation method of cinacalcet hydrochloride bulk drug according to claim 2, it is characterised in that b) in step, acetic acid For 1~2 weight portion, sodium triacetoxy borohydride are 1.5~3 weight portions, reaction temperature is 10~50 DEG C.
7. the preparation method of cinacalcet hydrochloride bulk drug according to claim 6, it is characterised in that molten b) in step The reaction temperature of liquid is 20~30 DEG C.
8. the preparation method of the cinacalcet hydrochloride bulk drug described in a kind of claim 1, it is characterised in that by 2000~ Made after N-X- (R) -1- (1- naphthyls) ethylamine hydrochloride of the cinacalcet hydrochloride of 12000 weight portions and 1 weight portion is well mixed .
CN201611186354.5A 2016-12-20 2016-12-20 A kind of cinacalcet hydrochloride bulk pharmaceutical chemicals and preparation method thereof Active CN106674019B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201611186354.5A CN106674019B (en) 2016-12-20 2016-12-20 A kind of cinacalcet hydrochloride bulk pharmaceutical chemicals and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201611186354.5A CN106674019B (en) 2016-12-20 2016-12-20 A kind of cinacalcet hydrochloride bulk pharmaceutical chemicals and preparation method thereof

Publications (2)

Publication Number Publication Date
CN106674019A true CN106674019A (en) 2017-05-17
CN106674019B CN106674019B (en) 2018-10-19

Family

ID=58869973

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201611186354.5A Active CN106674019B (en) 2016-12-20 2016-12-20 A kind of cinacalcet hydrochloride bulk pharmaceutical chemicals and preparation method thereof

Country Status (1)

Country Link
CN (1) CN106674019B (en)

Also Published As

Publication number Publication date
CN106674019B (en) 2018-10-19

Similar Documents

Publication Publication Date Title
EA025326B1 (en) Use of highly pure safinamide and ralfinamide for treatment of diseases and diseased states in conditions that do not suppress activity of cyp450 system cytochromes and do not manifest blocking properties in respect of herg channel
CN1015707B (en) Amide derivatives
CN1237106A (en) Stable medicinal compositions containing 4,5-epoxymorphinane derivatives
CN101607955A (en) A kind of preparation method of low-residue lipoic acid
CN104857517A (en) Enzalutamide soft capsule and preparation method thereof
EP4101449A1 (en) Application of nitazoxanide and active form thereof, tizoxanide, in treatment of sars-cov-2 infection
CN1041933C (en) Diamine salts of clavulanic acid
CN107629099A (en) A kind of preparation technology of Suo Feibuwei intermediates
CN106588847A (en) Dihydrocoumarin derivatives as well as preparation method and application thereof
CN106674019B (en) A kind of cinacalcet hydrochloride bulk pharmaceutical chemicals and preparation method thereof
CN1183721A (en) Pharmaceutical composition contg. tiagabine hydrochloride and process for its preparation
WO2005092096A1 (en) Single tank process for preparing tannate liquid and semi-solid dosage forms
CN106619502A (en) Levetiracetam oral solution and preparation method thereof
KR20170029141A (en) Method for the preparation of high purity Bazedoxifene Acetate
CN1036562A (en) To propanamine derivatives or improve one's methods relevant with propanamine derivatives
EP0135510B1 (en) New medicaments pertaining to the family of halogenobenzophenone-oxime derivative
CA2615926A1 (en) 3-[2-(dimethylamino)methyl-(cyclohex-1-yl)]-phenol maleate and the crystalline forms thereof
CN111072505A (en) Preparation method of venlafaxine impurity
CN1957933A (en) Application of theanine in preparing medication of curing sequela of apoplexy or convalescent period of apoplexy
CN116327697A (en) Norepinephrine bitartrate injection and preparation process thereof
CN105001102B (en) The method that chiral separation prepares single configuration fluoxetine
US20220409553A1 (en) Compositions comprising Quinone and/or Quinol and methods of preparations and use thereof
CN103705933A (en) Oxcarbazepine medicinal composition and preparation method thereof
JP4404710B2 (en) Method for producing sterol 5-en-3-one and method for analysis
CN86105229A (en) To eyes beta blocker selectively

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
TA01 Transfer of patent application right

Effective date of registration: 20180906

Address after: 210029 E building, Bai Jing Yu pharmaceutical factory, 1 Hui Zhong Road, Xingang Economic Development Zone, Nanjing, Jiangsu.

Applicant after: Nanjing Lifenergy R&D Co., Ltd.

Applicant after: NANJING HENCER PHARMACY CO., LTD.

Address before: 210029 E building, Bai Jing Yu pharmaceutical factory, 1 Hui Zhong Road, Xingang Economic Development Zone, Nanjing, Jiangsu.

Applicant before: Nanjing Lifenergy R&D Co., Ltd.

TA01 Transfer of patent application right
GR01 Patent grant
GR01 Patent grant