CN105130998B - Ku Pannixi preparation method - Google Patents
Ku Pannixi preparation method Download PDFInfo
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract
Present invention is disclosed a kind of Ku Pannixi (Copanlisib；BAY80 6946) preparation method, it is initiation material by 2 amino of known compound 3 methoxyl group 4 (the base propoxyl group of 3 morpholine 4) cyanophenyl, through unit processes such as jeterocyclic chemistry, condensation and cyclization, halo amination and amidatioons, target compound Ku Pannixi is made.The preparation method raw material is easy to get, and concise in technology is economic and environment-friendly, is adapted to industrialized production.
Description
Technical field
It is more particularly to a kind of the invention belongs to organic synthetic route design and its bulk drug and intermediate preparing technical field
Preparation method available for the drug reservoir Pan Nixi for the treatment of leukaemia.
Background technology
Ku Pannixi (Copanlisib) is the novel oral phosphoinositide of one kind developed by Bayer Bitterfeld GmbH (Bayer) company
3 kinases (PI3K) inhibitor.Existing clinical research shows, the medicine be by blocking PI3K signal paths, suppress leukaemia and
Growth of cancer cells in Lymphoma body.In order to further prove the prospect of this medicine, Beyer Co., Ltd deploys again within 2015
Two clinic III phases are studied：By being used alone or treating a kind of rare NHL with Rituxan combinations
(NHL), and with exclusive use Rituxan effect contrasted.In addition, Beyer Co., Ltd's also program launched one on
A kind of clinical II phases of Copanlisib treatment diffusivity large B cell lymphoid tumors (pernicious NHL hypotypes) are studied.Because the medicine does not have also
There is the Chinese translation of standard, therefore its transliteration is herein " Ku Pannixi " by the applicant.
Ku Pannixi's (Copanlisib, I) is chemical entitled：2- amino-N- [2,3- dihydro -7- methoxyl groups -8- [3- (4-
Morpholinyl) propoxyl group] imidazo [1,2-C] quinazoline -5- bases] -5- pyrimidine carboxamides, its structural formula is：
The PCT Patent WO2008070150 of Yuan Yan companies discloses Ku Pannixi and the like preparation method, this article
Offer and refer to following five synthetic routes that may be used altogether.
Synthetic route one：
Synthetic route two：
Synthetic route three：
Synthetic route four：
Synthetic route five：
Above-mentioned five synthetic routes are analyzed, wherein preceding four routes are all by vanillic aldehyde (3- methoxyl group -4- hydroxy benzenes first
Aldehyde) it is primary raw material, protection and deprotection, nitrification, reduction, itrile group, cyclisation, bicyclicization and propylmorpholin through perhydroxyl radical
Link of side chain and aminopyrimidine side chain etc. reacts to realize Ku Pannixi preparation.Its difference is mainly manifested in above-mentioned each unit
The order of reaction is different, so that the number of times and method of the step of reaction, the selection of protection group and deprotection are different, also makes
Obtain reaction condition different with total recovery.But any bar synthetic route no matter is selected, it is anti-with deprotection that its course of reaction all refers to protection
Should, such as unconventional reagent of bromination nitrile also can be all used, adds that reactions steps are more, total recovery is low, thus is not conducive to its work
Industry metaplasia is produced.Article 5 synthetic route be then using a kind of compound containing quinazolinone structure as initiation material, by chlorination,
Substitution, cyclisation, deprotection reaction and the analog that Ku Pannixi is prepared with the reaction such as the condensation of side chain.From the reaction scheme
Design process, which can be seen that, two chlorine atoms on the quinazoline ring after chlorination, substitution reaction can be made to produce the competing of diverse location
The side reaction of striving property, quality and purifying process to product can bring adverse effect.
For existing defective workmanship, concise in technology is developed, the economic and environment-friendly and technology of preparing that has good quality, especially
Seek to can adapt to the technology of industrialized production, the economic and social benefit of the medicine, which is improved, has important reality to anticipate
Justice.
The content of the invention
Be easy to get it is an object of the invention to provide a kind of raw material, concise in technology, economic and environment-friendly and suitable industrialized production
Ku Pannixi (Copanlisib, I) preparation method.
For achieving the above object, present invention employs following main technical schemes：A kind of preparation of Ku Pannixi (I)
Method,
Its preparation process includes：2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyls (II) are tried with cyclisation
Agent chloro-carbonic acid isocyanates, chlorosulfonic acid isocyanate, benzoyl isocyanate or urea generation heterocyclization generation 4- amino-
7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 (1H) -one (III)；4- amino -7- (3- morpholine -4- the third oxygen of base
Base) -8- methoxyquinazoline hydrochlorides -2 (1H) -one (III) with 2- ethylene halohydrins give birth to by the generation condensation and cyclization reaction under acid binding agent effect
Into 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5 (6H) -one (IV)；7-
Methoxyl group -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5 (6H) -one (IV) through halo and
Aminating reaction generates 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- amine
(V)；7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- amine (V) and 2- ammonia
Yl pyrimidines -5- formic acid occurs amidation process under condensing agent and the effect of alkali accelerator and Ku Pannixi (I) is made.
Halogen in wherein described 2- ethylene halohydrins is fluorine, chlorine, bromine or iodine.
In addition, the present invention also proposes following attached technical scheme：
The cyclization reagent of the heterocyclization is chloro-carbonic acid isocyanates, chlorosulfonic acid isocyanate, benzoyl isocyanic acid
Ester or urea, preferably benzoic acid isocyanates.
The solvent of the heterocyclization be dichloromethane, chloroform, 1,2- dichloroethanes, acetonitrile, toluene, tetrahydrofuran,
Dimethyl carbonate or dioxane, preferably dioxane or tetrahydrofuran.
The temperature of the heterocyclization is 0-120 DEG C, preferably 20-90 DEG C.
Raw material 4- amino -7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 of the condensation and cyclization reaction
The molar ratio of (1H) -one (III) and 2- ethylene halohydrins is 1: 1.0-2.0, preferably 1: 1.0-1.5.
Halogen in the raw material 2- ethylene halohydrins of the condensation and cyclization reaction is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
The acid binding agent of the condensation and cyclization reaction is triethylamine, pyridine, N- methylmorpholines, diisopropylethylamine, 4- bis-
Methylamino pyridine, potassium carbonate, lithium carbonate, cesium carbonate or potassium tert-butoxide, preferably cesium carbonate or potassium tert-butoxide.
The solvent of the condensation and cyclization reaction is tetrahydrofuran, dioxane, 1,2- dichloroethanes, acetonitrile, toluene, carbonic acid
Dimethyl ester, N, N- dimethyl formyl or dimethyl sulfoxide, preferably DMF or dimethyl sulfoxide.
The temperature of the condensation and cyclization reaction is 25-150 DEG C, preferably 80-90 DEG C.
The halogenating agent of the halogenating reaction is phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, POCl3, tribromo oxygen phosphorus, two
Chlorine sulfoxide, oxalyl chloride or phosgene, preferably POCl3.
The temperature of the halogenating reaction is 50-150 DEG C, preferably 90-105 DEG C.
The aminating agent of the aminating reaction is ammoniacal liquor or ammonia.
The temperature of the aminating reaction is 50-150 DEG C, preferably 90-105 DEG C.
The condensing agent of the amidation process be N, N ,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N,
N '-DIC (DIC), 1- hydroxyls-BTA (HOBt), O- BTAs-N, N, N ', N '-tetramethyl
Base urea tetrafluoro boric acid ester (TBTU), O- (7- azos BTA)-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HATU),
BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or (dimethylamino of BTA -1- bases epoxide three
Base) phosphorus hexafluorophosphate (BOP), preferably BTA-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (HBTU) or benzene
And (dimethylamino) the phosphorus hexafluorophosphate (BOP) of triazole -1- bases epoxide three.
The alkali accelerator of the amidation process is triethylamine (TEA), pyridine, 2,6- lutidines, 4- dimethylaminos
Pyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DlEA), 1,5- diazabicylos
[4.3.0]-nonyl- 5- alkene (DBN), -7- alkene (DBU) of 1,8- diazabicyclos [5.4.0]-ten one or Isosorbide-5-Nitrae-diazabicylo
[2.2.2] octane (DABCO), -7- alkene (DBU) of preferably 1,8- diazabicyclos [5.4.0]-ten one or 1,5- diazabicylo
[4.3.0]-nonyl- 5- alkene (DBN) or Isosorbide-5-Nitrae-diazabicylo [2.2.2] octane (DABCO).
The solvent of the amidation process is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butyl acetate, diformazan Asia
Sulfone, DMF or acetonitrile, preferably acetonitrile.
The temperature of the amidation process is 0-120 DEG C, preferably 50-60 DEG C.
Compared to prior art, Ku Pannixi (I) involved in the present invention preparation method is easy to get, technique with raw material
Succinct and economic and environment-friendly the features such as, so beneficial to the industrialized production of the bulk drug, promote the development of its economic technology.
Embodiment
Technical solution of the present invention is further non-limitingly described in detail below in conjunction with several preferred embodiments.Wherein
The system of raw material 2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyls (II) and side chain 2- aminopyrimidine -5- formic acid
Standby is on June 12nd, 2008 and entitled " Preparation of substituted2,3- referring to publication date
Dihydroimidazo [1,2-c] quinazoline derivatives for treating hyper-proliferative
Disorders and diseases associated with angiogenesis " WO2008070150 pairs of international monopoly
The preparation method of identical compound.
Embodiment one：
In blanket of nitrogen, 2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyl is added in dry reaction bottle
(II) (5.82g, 20mmol) and dioxane 50mL, add benzoyl isocyanate (3.23g, 22mmol) room temperature and stir at room temperature
Mix 20 hours, TLC detection reactions are completed.Stand, filtering, filter cake is washed with n-hexane and ethyl acetate (4: 1) mixed solvent, very
Empty dry off-white powder 4- amino -7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 (1H) -one (III)
4.55g, yield 68.1%；Mass spectrum (EI)：m/z 335(M+H).Embodiment two：
In blanket of nitrogen, 2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyl is added in dry reaction bottle
(II) (5.82g, 20mmol) and tetrahydrofuran 50mL, are added dropwise the four of chlorosulfonic acid isocyanate (3.25g, 23mmol) at 0-5 DEG C
Hydrogen furans 15mL solution.Drop finishes, and is warmed to room temperature, stirring reaction 6-8 hours, and TLC detection reactions are completed.Adjusted with 5% sodium hydroxide
PH is saved to neutrality, dichloromethane is extracted three times.Merge organic phase, water, saturated common salt water washing are used with this.It is concentrated under reduced pressure, it is remaining
Thing is washed with n-hexane and ethyl acetate (4: 1) mixed solvent, is dried in vacuo to obtain off-white powder 4- amino -7- (3- morpholines -4-
Base propoxyl group) -8- methoxyquinazoline hydrochlorides -2 (1H) -one (III) 5.10g, yield 76.3%；Mass spectrum (EI)：m/z 335(M+H).
Embodiment three：
In blanket of nitrogen, 4- amino -7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 are added in reaction bulb
(1H) -one (III) (3.3g, 10mmol), ethylene chlorhydrin (0.97g, 12mmol), potassium tert-butoxide (1.68g, 15mmol) and N, N-
Dimethylformamide 25mL, is warming up to 80-90 DEG C, stirring reaction 4-6 hours.Room temperature is down to, reaction solution is inclined to weight percent
Than in the sodium hydroxide solution for 5%, being heated to 60 DEG C, 2 hours are incubated, room temperature is cooled to, there is solid precipitation, filtered, washing,
N-hexane wash, be dried in vacuo faint yellow solid 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine is simultaneously
[1,2-c] quinazoline -5 (6H) -one (IV) 2.12g, yield 58.9%；Mass spectrum (EI)：m/z 361(M+H).
Example IV：
In blanket of nitrogen, 4- amino -7- (3- morpholine -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 are added in reaction bulb
(6H) -one (III) (3.3g, 10mmol), ethylene bromohyrin (1.50g, 12mmol), cesium carbonate (3.57g, 11mmol) and and diformazan
Sulfoxide 35mL, is warming up to 80-90 DEG C, stirring reaction 4-6 hours.Room temperature is down to, it is 5% that reaction solution, which is inclined to percentage by weight,
In sodium hydroxide solution, 60 DEG C are heated to, 2 hours is incubated, is cooled to room temperature, there is solid precipitation, is filtered, washing, n-hexane is washed
Wash, be dried in vacuo to obtain faint yellow solid 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinoline
Oxazoline -5 (6H) -one (IV) 2.30g, yield 63.9%；Mass spectrum (EI)：m/z 361(M+H).
Embodiment five：
In blanket of nitrogen, -2,3- glyoxalidine is simultaneously by addition 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) in reaction bulb
[1,2-c] quinazoline -5 (6H) -one (IV) (1.8g, 5mmol), POCl3 10mL and N, N- dimethyl formyl 1mL, are warming up to
90-105 DEG C, stirring reaction 4-5 hours, TLC detection consumption of raw materialss are completed.Room temperature is down to, reaction solution is inclined into frozen water 50mL,
There is solid precipitation.Filtering.Filter cake is washed with water 2 times, and gained wet product adds the ammoniacal liquor of percentage by weight 30% without processing
20mL, is placed in seal pipe, is warming up to 100 DEG C, reacts 12-16 hours.Room temperature is down to, is filtered, filter cake is washed with water.Vacuum is done
It is dry to obtain faint yellow solid 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5-
Amine (V) 1.32g, yield 73.5%；Mass spectrum (EI)：m/z 360(M+H)；Hydrogen is composed1H NMR(DMSO-d6) δ 1.88 (m, 2H),
2.36 (m, 4H), 2.44 (m, 2H), 3.56 (m, 4H), 3.70 (s, 3H), 3.89 (m, 4H), 4.04 (t, 2H), 6.74 (m, 3H),
7.43 (m, 1H).
Embodiment six：
In blanket of nitrogen, -2,3- glyoxalidine is simultaneously by addition 7- methoxyl groups -8- (3- morpholine -4- bases propoxyl group) in reaction bulb
[1,2-c] quinazoline -5- amine (V) (0.36g, 1mmol), 2- aminopyrimidine -5- formic acid (0.15g, 1.1mmol) and acetonitrile
25mL, adds (dimethylamino) the phosphorus hexafluorophosphate (0.49g, 1.1mmol) of condensing agent BTA -1- bases epoxide three
With base catalyst 1,5- diazabicylos [4.3.0]-nonyl- 5- alkene (0.50g, 4mmol) are reacted at room temperature 12 hours.It is warming up to again
50-60 DEG C, stirring reaction 6-8 hours, TLC detection reactions are completed.Decompression steams solvent, is down to room temperature, adds ethyl acetate, has
Solid is separated out.Filtering, filter cake is washed with cold methanol, is dried in vacuo to obtain off-white powder Ku Pannixi (I) 0.27g, yield
56.3%；EI-MS m/z：481[M+H]+,1H NMR(CDCl3) δ 2.05 (m, 2H), 2.48 (m, 4H), 2.56 (m, 2H), 3.72
(t, 4H), 4.02 (s, 3H), 4.16 (m, 7H), 5.36 (s, 2H), 6.84 (d, 1H), 7.08 (d, 1H), 9.10 (s, 2H).
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, ripe its object is to allow
Present disclosure can be understood and implement according to this by knowing the personage of technique, and the protection model of the present invention can not be limited with this
Enclose.Any equivalent change or modification in accordance with the spirit of the invention, should all be included within the scope of the present invention.
Claims (10)
1. a kind of Ku Pannixi preparation method,
Its preparation process includes：2- amino -3- methoxyl groups -4- (3- morpholine -4- bases propoxyl group) cyanophenyls and cyclization reagent chloro-carbonic acid
Heterocyclization generation 4- amino -7- (3- occur for isocyanates, chlorosulfonic acid isocyanate, benzoyl isocyanate or urea
Quinoline -4- bases propoxyl group) -8- methoxyquinazoline hydrochlorides -2 (1H) -one；4- amino -7- (3- morpholine -4- bases the propoxyl group) -8- first
With 2- ethylene halohydrins condensation and cyclization reaction generation 7- methoxyl groups -8- occurs under acid binding agent effect for (1H) -one of epoxide quinazoline -2
(3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5 (6H) -one；7- methoxyl groups -8- (the 3-
Quinoline -4- bases propoxyl group) simultaneously [1,2-c] quinazoline -5 (6H) -one generates 7- methoxies to -2,3- glyoxalidine through halo aminating reaction
Base -8- (3- morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- amine；7- methoxyl groups -8- (the 3-
Morpholine -4- bases propoxyl group) -2,3- glyoxalidine simultaneously [1,2-c] quinazoline -5- amine and 2- aminopyrimidine -5- formic acid in condensing agent
Ku Pannixi is made with the lower generation amidation process of alkali accelerator effect；Halogen in wherein described 2- ethylene halohydrins is fluorine, chlorine,
Bromine or iodine.
2. Ku Pannixi as claimed in claim 1 preparation method, the solvent of the heterocyclization is dichloromethane, chloroform,
1,2- dichloroethanes, acetonitrile, toluene, tetrahydrofuran, dimethyl carbonate or dioxane；The temperature of the heterocyclization is 0-
120℃。
3. Ku Pannixi as claimed in claim 1 preparation method, the condensation and cyclization reaction raw materials 4- amino -7- (3- morpholines -
4- bases propoxyl group) molar ratio of (1H) -one of -8- methoxyquinazoline hydrochlorides -2 and 2- ethylene halohydrins is 1:1.0-2.0.
4. Ku Pannixi as claimed in claim 1 preparation method, the acid binding agent of the condensation and cyclization reaction is triethylamine, pyrrole
Pyridine, N- methylmorpholines, diisopropylethylamine, DMAP, potassium carbonate, lithium carbonate, cesium carbonate or potassium tert-butoxide.
5. Ku Pannixi as claimed in claim 1 preparation method, the solvent of the condensation and cyclization reaction is tetrahydrofuran, dioxy
Six rings, 1,2- dichloroethanes, acetonitrile, toluene, dimethyl carbonate, N,N-dimethylformamide or dimethyl sulfoxide；The condensed ring
The temperature for changing reaction is 25-150 DEG C.
6. Ku Pannixi as claimed in claim 1 preparation method, the halogenating agent of the halo aminating reaction is phosphorus trichloride, three
Phosphonium bromide, phosphorus pentachloride, POCl3, tribromo oxygen phosphorus, thionyl chloride, oxalyl chloride or phosgene；The halo aminating reaction
Aminating agent is ammoniacal liquor or ammonia.
7. Ku Pannixi as claimed in claim 1 preparation method, the temperature of the halo aminating reaction is 50-150 DEG C.
8. Ku Pannixi as claimed in claim 1 preparation method, the condensing agent of the amidation process is N, N ,-dicyclohexyl
Carbodiimide, carbonyl dimidazoles, N, N '-DIC, 1- hydroxyl-BTA, O- BTA-N, N,
N', N'- tetramethylurea tetrafluoro boric acid ester, O- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester, benzene
And triazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester or (dimethylamino) phosphorus of BTA -1- bases epoxide three
Hexafluorophosphate.
9. Ku Pannixi as claimed in claim 1 preparation method, the alkali accelerator of the amidation process is triethylamine, pyrrole
Pyridine, 2,6- lutidines, DMAP, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5- phenodiazines
Miscellaneous two ring [4.3.0]-nonyl- 5- the alkene, -7- alkene of 1,8- diazabicyclos [5.4.0]-ten one or 1,4- diazabicylos [2.2.2]
Octane.
10. Ku Pannixi as claimed in claim 1 preparation method, the solvent of the amidation process is toluene, dimethylbenzene, second
Acetoacetic ester, isopropyl acetate, butyl acetate, dimethyl sulfoxide, N,N-dimethylformamide or acetonitrile；The temperature of the amidation process
Spend for 0-120 DEG C.
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| KR1020187011225A KR102104957B1 (en) | 2015-09-25 | 2016-07-01 | Manufacturing method of copanriship |
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| SG10202007262PA (en) * | 2016-02-01 | 2020-09-29 | Bayer Pharma AG | Copanlisib biomarkers |
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| JP2003252875A (en) * | 2002-03-04 | 2003-09-10 | Lotte Co Ltd | Novel purine derivative |
| SI1549652T1 (en) * | 2002-09-30 | 2009-04-30 | Bayer Healthcare Ag | Fused azole-pyrimidine derivatives |
| AR064106A1 (en) * | 2006-12-05 | 2009-03-11 | Bayer Schering Pharma Ag | DERIVATIVES OF 2,3-DIHYDROIMIDAZO [1,2-C] SUBSTITUTED QUINAZOLINE USEFUL FOR THE TREATMENT OF HYPER-PROLIFERATIVE DISEASES ASSOCIATED WITH ANGIOGENESIS |
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| EP3018131A1 (en) * | 2014-11-07 | 2016-05-11 | Bayer Pharma Aktiengesellschaft | Synthesis of copanlisib and its dihydrochloride salt |
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Effective date of registration: 20200714 Address after: Hu Suzhou high tech Zone of Jiangsu province 215151 City Road No. 21 Tang Guan District Patentee after: SUZHOU LIXIN PHARMACEUTICAL Co.,Ltd. Address before: 215151 No. 21 West Tong Road, hi tech Development Zone, Jiangsu, Suzhou Co-patentee before: Xu Xuenong Patentee before: SUZHOU LIXIN PHARMACEUTICAL Co.,Ltd. |