CN104961715B - A kind of preparation method of Dapagliflozin - Google Patents
A kind of preparation method of Dapagliflozin Download PDFInfo
- Publication number
- CN104961715B CN104961715B CN201510404207.XA CN201510404207A CN104961715B CN 104961715 B CN104961715 B CN 104961715B CN 201510404207 A CN201510404207 A CN 201510404207A CN 104961715 B CN104961715 B CN 104961715B
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- dapagliflozin
- preparation
- present
- 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.)
- Active
Links
- 0 *C[C@](C1(CC1)CC12CC1)OC2=O Chemical compound *C[C@](C1(CC1)CC12CC1)OC2=O 0.000 description 2
- ZUNCHZBITMUSRD-UHFFFAOYSA-N CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1 Chemical compound CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1 ZUNCHZBITMUSRD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings 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
- C07D309/10—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation method of Dapagliflozin, instilled after compound 2 is mixed with phenetole in the present invention in the aluminum trichloride solution of suspension, the ortho isomer impurity of generation is less than 1%.Compound 4 is set first to be reacted with butyl lithium in the present invention, generate following formula: compound 5, then compound 5 is reacted with compound 1 again, avoid the generation of sulfonic acid esters genotoxicity impurity, so as to improve the utilization rate of raw material to a certain extent, the problem of post processing is cumbersome is avoided, and improves the purity and yield of product;Compound 6 is reduced using boron hydride and sulfuric acid in the present invention, reduction reaction and deprotection is carried out simultaneously, greatly reduces pollution;Raw material and reagent price of the present invention is relatively cheap, with low cost, and whole preparation process reaction condition is gentle, safety simple to operate, is easy to implement industrialized production.
Description
Technical field
The present invention relates to the synthesis technical field of compound, a kind of preparation method of Dapagliflozin is referred specifically to.
Background technology
Dapagliflozin (dapagliflozin, ForxigaTM) chemical name is (1S) -1,5- dehydrations -1-C- [chloro- 3- of 4-
[(4- ethoxyl phenenyls) methyl] phenyl]-D-Glucose alcohol, structural formula is
It is a kind of new antidiabetic medicine by Bristol Myers Squibb and Astrazeneca AB's joint development, is one
Plant the sodium-dependent glucose transport protein SGLT2 inhibitor expected in kidney.The mechanism of action of Dapagliflozin is to block grape
Sugar enters one in the reabsorption of kidney, so as to which glucose excessive in vivo be discharged via urine while reduction blood glucose is reached
Step mitigates the body weight of patient.
The synthetic route of current disclosed Dapagliflozin has following several:
Route 1:
Above-mentioned route is by document J.Med.Chem.2014,57,1236-1251and references cited in
Thereof reports that protection of the circuit to phenolic hydroxyl group is excessively cumbersome, and impurity is also easy to produce during demethoxylation, what reducing carbonyl was used
Method is dangerous, and the line size production difficulty is larger, is not easy to carry out industrialized production.
Route 2:
Above-mentioned route is announced by the B1 of patent EP 1506211, and triethyl group is used when the circuit reducing carbonyl and methoxyl group
Silane and boron trifluoride ether solution, pollution is big, operational hazards, largely result in production cost rise.
Route 3:
Patent WO 2013152476A etc. report above-mentioned circuit, the circuit using the chloro- 5- iodo-benzoic acids of 2- as initiation material,
Side chain and parent nucleus are connected by grignard reaction.The price of the chloro- 5- iodo-benzoic acids of 2- is the octuple of the chloro- 5- bromobenzoic acids of 2-, the line
Obviously 5- bromobenzoic acids more chloro- than 2- are the high of initiation material on road, and the line characteristics impure by-products A and accessory substance B can
It can be difficult to refine, cause the utilization rate of raw material low.
Route 4:
Lemaire et al. (Organic Letters, 2012, vol.14,1480-1483) is reported by 2,3,4,6-O-
Four pivaloyl group-ALPHA-D- bromos glucopyranoses are initiation material, and the route that key intermediate is made is coupled by a step,
The route grinds route relative to original and shortens step, but 2,3,4,6-O- tetra- pivaloyl group-ALPHA-D- bromo glucopyranoses
Price is compared with glucolactone price height, and the zincon and lithium reagent large usage quantity used, requirement are higher, cause production cost pole
Height, industrialization production difficulty is larger.
Route 5:
The price of 1,6- dehydrations-β-D-Glucose is generally 200RMB/250mg in the circuit, and production cost is too high, no work
Industry productive value.
Therefore, for the preparation method of current Dapagliflozin, further improved is awaited.
The content of the invention
The technical problem to be solved by the invention for the present situation of prior art is to provide a kind of high income, cost are low
The preparation method of Dapagliflozin, this method processing step is simple, use raw material cheap and easily-available, industrialization is easy to implement, whole
Unharmful substance is produced in individual preparation process, environmentally safe, and reaction condition is gentle, safe operation.
The present invention solve the technical scheme that is used of above-mentioned technical problem for:A kind of preparation method of Dapagliflozin, it is special
Levy and be to comprise the following steps:
(1) using halogenated hydrocarbons as solvent, the halogenated hydrocarbons is added in reactor, alchlor is added, phenetole is then added dropwise
With the mixed liquor of following formula: compound 2,1~4h is reacted after completion of dropping, following formula: compound 3 is generated;
(2) silane reagent is added dropwise into step (1) reactor after completion of the reaction, the silane reagent and the compound 3
Reduction reaction is carried out, is quenched after completion of the reaction below 35 DEG C, then layering washing, by organic phase condensing crystallizing, suction filtration
Following formula: compound 4 is obtained after drying;
(3) compound 4 described in is first reacted with butyl lithium, generates following formula: compound 5, then the compound 5 and compound 1
Carry out coupling reaction, reaction finish be quenched after obtain following formula: compound 6;
(4) compound 6 first with metallic boron hydrides and sulfuric acid reaction, then carry out the silicon substrate reaction of removing trimethyl,
Following compounds 7 are generated, the compound 7 is described Dapagliflozin
Preferably, the halogenated hydrocarbons described in step (1) is dichloromethane or 1,1,2,2- tetrachloroethanes.
Preferably, the reaction temperature in step (1) is -10~5 DEG C.
Preferably, the silane reagent described in step (2) is selected from tri isopropyl silane, triethyl silicane or the silicon of tetramethyl two
Oxygen alkane.
Preferably, the silane reagent described in step (2) is 1,1,3,3- tetramethyl disiloxane.
Preferably, it is aqueous acetic acid or ammonium chloride solution that the reagent that process uses is quenched described in step (3).
Preferably, the metallic boron hydrides described in step (4) is times in lithium borohydride, zinc borohydride, sodium borohydride
Meaning is a kind of.
As an improvement, the compound 4 described in step (3) is first reacted with butyl lithium, following formula: compound 5 is generated, then should
Compound 5 carries out coupling reaction with compound 1.
Compared with prior art, the advantage of the invention is that:
In the aluminum trichloride solution that suspension is instilled after compound 2 is mixed with phenetole in the present invention, if being directly added into benzene
Ether can then generate ortho isomer impurity about 7%, and use above-mentioned feed postition, it is ensured that the life of ortho isomer impurity
It is less than 1% into amount, so as to improve the purity of product.
Compound 4 is first reacted with butyl lithium in the present invention, generate following formula: compound 5, then compound 5 again with compound
1 is reacted, it is to avoid the generation of sulfonic acid esters genotoxicity impurity, so as to improve the utilization of raw material to a certain extent
Rate, it is to avoid the problem of post processing is cumbersome, and improve the purity and yield of product;
Compound 6 is reduced using boron hydride and sulfuric acid in the present invention, makes reduction reaction and deprotection while entering
OK, pollution is greatly reduced;
Raw material and reagent price of the present invention is relatively cheap, with low cost, and whole preparation process reaction condition
Gently, safety simple to operate, is easy to implement industrialized production.
Brief description of the drawings
Fig. 1 is the ESI-MS spectrograms of compound 4 in the embodiment of the present invention 1;
Fig. 2 is the HPLC spectrograms of product prepared by the embodiment of the present invention 1.
Embodiment
The present invention is described in further detail below in conjunction with accompanying drawing embodiment.
Embodiment 1:
The preparation method of Dapagliflozin comprises the following steps in the present embodiment:
(1) dichloromethane 500mL is added into reaction bulb, -10 DEG C are cooled under maintaining nitrogen purge state, and to reaction bulb
Middle addition 80g AlCl3, less than 0 DEG C adds 0.5moL compounds 2 and 0.5moL phenetoles and 100mL dichloromethanes into reaction bulb
The mixed solution of alkane, drop finishes complete to TLC detection reactions after insulation reaction at 0~5 DEG C;
Less than (2) 5 DEG C instill the tetramethyl disiloxanes of 106g 1,1,3,3- into the reaction bulb of step (1), at room temperature instead
It should react complete to TLC detection compounds 3;Reaction is quenched in less than the 5 DEG C hydrochloric acid 250mL that 1moL/L is added dropwise into reaction bulb, quiet
Organic layer, then stratification are washed after putting layering, organic layer is evaporated and obtains grease, ethanol knot is added into gained grease
Crystalline substance, filtration drying obtains off-white powder 65g, and the off-white powder is compound 4, and yield is 80%;As shown in figure 1, ESI-
MS(m/z):326[M+H]+, the stronger quasi-molecular ions in positive ion mass spectrum figure at m/z326 corresponds to [M+H] of sample+Ion,
It can thus be appreciated that the molecular weight of sample is 325, it may be determined that molecular weight analyte is consistent with the molecular weight of compound 4;
(3) 70mL THF, 145mL toluene, 16.3g compounds 4 are mixed, -50 DEG C are cooled under maintaining nitrogen purge state,
And 2.5M butyl lithium 50mL is added dropwise, drop finishes after insulation reaction 30min at -37 DEG C, obtains compound 5;
0.06moL compounds 1, toluene 100mL are mixed, -50 DEG C are cooled under maintaining nitrogen purge state, and be added dropwise above-mentioned
The solution of compound 5 finished is reacted, drop finishes complete to TLC detection reactions after insulation reaction at -45 DEG C;
Maintain the temperature in the range of -30~-20 DEG C, 1M acetum 100mL are added dropwise into above-mentioned reaction system, drip
30min is incubated after finishing, 20 DEG C of insulation reactions are to slowly warm up to complete to TLC detection reactions;
Control temperature to add ethyl acetate 150mL into above-mentioned reaction system below 5 DEG C, unsaturated carbonate hydrogen is then added dropwise
Sodium adjusts PH to 7.5~8, adds water 200mL, layering, and organic layer is washed 2 times with 10% saline solution 200mL, less than 40 DEG C decompressions
It is evaporated, obtains grease, the grease is compound 6;
(4) above-claimed cpd 6 is added in 100mL tetrahydrofurans, is cooled to -10 DEG C, kept for less than 0 DEG C and put into batches
4.7g NaBH4, finish 30~60min of insulated and stirred;Then the dense sulphur of 30mL is slowly added dropwise in the range of keeping temperature -10~0 DEG C
Acid, completion of dropping reacts 1h after insulated and stirred at -5~5 DEG C, and room temperature is then slowly increased under the state that is kept stirring for until anti-
Should be complete;
Keeping temperature is no more than at 20 DEG C, and reaction solution is poured slowly into 150mL frozen water, then in guarantor at 20~25 DEG C
Warm 30~60min of stirring reaction is simultaneously filtered, and after filter cake is washed with 50mL in input 500mL reaction bulb, is added into the reaction bulb
Enter be slowly added dropwise at 200mL water, 10~20 DEG C 5% sodium bicarbonate solution regulation PH to 6.5~7.5, at 20~25 DEG C protect
Warm stirring reaction 30min, filtering, filter cake is washed with 50mL water, 50mL normal heptanes successively;Finally by filter cake in drum at 45~50 DEG C
Dry 10~15h is air-dried, product dry weight 12.3g is obtained, the product is Dapagliflozin, and yield is 60%.As shown in Fig. 2 chromatogram
Purity is more than 95%.
Embodiment 2:
The preparation method of Dapagliflozin comprises the following steps in the present embodiment:
(1) added into reaction bulb and be cooled to -10 DEG C under 1,1,2,2- tetrachloroethanes 500mL, maintaining nitrogen purge state, and
80g AlCl are added into reaction bulb3, less than 0 DEG C added into reaction bulb 0.5moL compounds 2 and 0.5moL phenetoles with
The mixed solution of 100mL dichloromethane, drop finishes complete to TLC detection reactions after insulation reaction at -10~0 DEG C;
Less than (2) 5 DEG C instill 158g tri isopropyl silanes into the reaction bulb of step (1), react at room temperature to TLC detections
Compound 3 reacts complete;Washing after reaction, stratification is quenched in less than the 5 DEG C hydrochloric acid 250mL that 1moL/L is added dropwise into reaction bulb
Organic layer, then stratification, are evaporated organic layer and obtain grease, and alcohol crystal is added into gained grease, and filtration drying is obtained
Off-white powder 65g, the off-white powder is compound 4, and yield is 80%;
(3) 70mL tetrahydrofurans, 145mL toluene, 16.3g compounds 4 are mixed, be cooled under maintaining nitrogen purge state-
50 DEG C, and 2.5M butyl lithium 60mL is added dropwise, drop finishes after insulation reaction 30min at -37 DEG C, obtains compound 5;
0.06moL compounds 1, toluene 100mL are mixed, -50 DEG C are cooled under maintaining nitrogen purge state, and be added dropwise above-mentioned
The solution of compound 5 finished is reacted, drop finishes complete to TLC detection reactions after insulation reaction at -45 DEG C;
Maintain the temperature in the range of -30~-20 DEG C, 2M ammonium chloride solution 100mL are added dropwise into above-mentioned reaction system, be added dropwise
30min is incubated after finishing, 20 DEG C of insulation reactions are to slowly warm up to complete to TLC detection reactions;
Control temperature to add ethyl acetate 150mL into above-mentioned reaction system below 5 DEG C, unsaturated carbonate hydrogen is then added dropwise
Sodium adjusts PH to 7.5~8, adds water 200mL, layering, and organic layer is washed 2 times with 10% saline solution 200mL, less than 40 DEG C decompressions
It is evaporated, obtains grease, the grease is compound 6;
(4) above-claimed cpd 6 is added in 100mL tetrahydrofurans, is cooled to -10 DEG C, kept for less than 0 DEG C and put into batches
4.5g lithium borohydride, finishes 30~60min of insulated and stirred;Then 30mL is slowly added dropwise in the range of keeping temperature -10~0 DEG C dense
Sulfuric acid, completion of dropping after at -5~5 DEG C insulated and stirred react 1h, be then slowly increased under the state that is kept stirring for room temperature until
Reaction is complete;
Keeping temperature is no more than at 20 DEG C, and reaction solution is poured slowly into 150mL frozen water, then in guarantor at 20~25 DEG C
Warm 30~60min of stirring reaction is simultaneously filtered, and after filter cake is washed with 50mL in input 500mL reaction bulb, is added into the reaction bulb
Enter be slowly added dropwise at 200mL water, 10~20 DEG C 5% sodium bicarbonate solution regulation PH to 6.5~7.5, at 20~25 DEG C protect
Warm stirring reaction 30min, filtering, filter cake is washed with 50mL water, 50mL normal heptanes successively;Finally by filter cake in drum at 45~50 DEG C
Dry 10~15h is air-dried, product dry weight 11.9g is obtained, the product is Dapagliflozin, and yield is 58%.
Claims (7)
1. a kind of preparation method of Dapagliflozin, it is characterised in that comprise the following steps:
(1) using halogenated hydrocarbons as solvent, the halogenated hydrocarbons is added in reactor, alchlor is added, phenetole is then added dropwise with
1~4h is reacted after the mixed liquor of formula compound 2, completion of dropping, following formula: compound 3 is generated;
(2) silane reagent is added dropwise into step (1) reactor after completion of the reaction, the silane reagent is carried out with the compound 3
Reduction reaction, is quenched below 35 DEG C after completion of the reaction, then layering washing, and by organic phase condensing crystallizing, suction filtration dries
After obtain following formula: compound 4;
(3) compound 4 described in is first reacted with butyl lithium, generates following formula: compound 5, then the compound 5 is carried out with compound 1
Coupling reaction, reaction finish be quenched after obtain following formula: compound 6;
(4) compound 6 first with metallic boron hydrides and sulfuric acid reaction, then carry out the silicon substrate reaction of removing trimethyl, generation
Following compounds 7, the compound 7 is described Dapagliflozin
2. the preparation method of Dapagliflozin according to claim 1, it is characterised in that:Halogenated hydrocarbons described in step (1)
For dichloromethane or 1,1,2,2- tetrachloroethanes.
3. the preparation method of Dapagliflozin according to claim 1, it is characterised in that:Reaction temperature in step (1) for-
10~5 DEG C.
4. the preparation method of Dapagliflozin according to claim 1, it is characterised in that:Silane examination described in step (2)
Agent is selected from tri isopropyl silane, triethyl silicane or tetramethyl disiloxane.
5. the preparation method of Dapagliflozin according to claim 4, it is characterised in that:Silane examination described in step (2)
Agent is 1,1,3,3- tetramethyl disiloxanes.
6. the preparation method of Dapagliflozin according to claim 1, it is characterised in that:Process is quenched described in (3) in step
The reagent used is aqueous acetic acid or ammonium chloride solution.
7. the preparation method of Dapagliflozin according to claim 1, it is characterised in that:Metal boron described in step (4)
Hydride is any one in lithium borohydride, zinc borohydride, sodium borohydride.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510404207.XA CN104961715B (en) | 2015-07-10 | 2015-07-10 | A kind of preparation method of Dapagliflozin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510404207.XA CN104961715B (en) | 2015-07-10 | 2015-07-10 | A kind of preparation method of Dapagliflozin |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104961715A CN104961715A (en) | 2015-10-07 |
CN104961715B true CN104961715B (en) | 2017-08-22 |
Family
ID=54215839
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510404207.XA Active CN104961715B (en) | 2015-07-10 | 2015-07-10 | A kind of preparation method of Dapagliflozin |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104961715B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105294624B (en) * | 2015-11-16 | 2018-01-12 | 山东罗欣药业集团股份有限公司 | A kind of preparation method of Dapagliflozin |
CN107304194A (en) * | 2016-04-20 | 2017-10-31 | 扬子江药业集团上海海尼药业有限公司 | The method for preparing Dapagliflozin |
CN107200683A (en) * | 2017-07-31 | 2017-09-26 | 青岛辰达生物科技有限公司 | A kind of preparation method for being used to treat type II diabetes Dapagliflozin intermediate |
CN111039784A (en) * | 2019-12-18 | 2020-04-21 | 厦门云凡医药科技有限公司 | Preparation method of bilastine intermediate |
CN111099975A (en) * | 2019-12-23 | 2020-05-05 | 河北合佳医药科技集团股份有限公司 | Preparation method of 5-bromo-2-chloro-4' -ethoxy benzophenone |
CN115785045A (en) * | 2022-11-25 | 2023-03-14 | 湖北省宏源药业科技股份有限公司 | Photocatalytic Endapagliflozin precursor and synthetic method thereof |
CN117658784A (en) * | 2023-12-30 | 2024-03-08 | 山东诚汇双达药业有限公司 | Preparation method of dapagliflozin intermediate |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101628905A (en) * | 2002-05-20 | 2010-01-20 | 百时美施贵宝公司 | C-aryl glucoside SGLT2 inhibitors and method |
CN104059041A (en) * | 2013-03-20 | 2014-09-24 | 爱康药业有限公司 | Preparation method of antidiabetic dapagliflozin intermediate |
-
2015
- 2015-07-10 CN CN201510404207.XA patent/CN104961715B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101628905A (en) * | 2002-05-20 | 2010-01-20 | 百时美施贵宝公司 | C-aryl glucoside SGLT2 inhibitors and method |
CN104059041A (en) * | 2013-03-20 | 2014-09-24 | 爱康药业有限公司 | Preparation method of antidiabetic dapagliflozin intermediate |
Non-Patent Citations (2)
Title |
---|
达格列净合成路线图解;张帅阳等;《中国医药工业杂志》;20141231;第45卷(第12期);1192-1195 * |
达格列净的合成工艺改进;任建国等;《中国药物化学杂志》;20141031;第24卷(第5期);375-379 * |
Also Published As
Publication number | Publication date |
---|---|
CN104961715A (en) | 2015-10-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104961715B (en) | A kind of preparation method of Dapagliflozin | |
CN104496952B (en) | Synthesis method of dapagliflozin | |
CN105481915A (en) | Preparation method of SGLT-2 inhibitor compound | |
CN107556302A (en) | It is a kind of to prepare the net methods of Yi Palie | |
CN103073519A (en) | Method for preparing dextro-pramipexole hydrochloride | |
CN107602651A (en) | A kind of preparation method of dehydroepiandros-sterone intermediate and dehydroepiandros-sterone | |
CN105254569B (en) | Ornidazole injection impurity 1(3 Chloroallyls)The preparation method of the nitroimidazole of 2 methyl 5 | |
CN110590587A (en) | Synthetic method of 3-chloro-L-alanine methyl ester hydrochloride | |
CN102442972B (en) | Industrial preparation method for pramipexole and its dihydrochloride monohydrate | |
CN108610316B (en) | Preparation method of dapagliflozin | |
Xu et al. | Open-cage fullerene with a stopper acts as a molecular vial for a single water molecule | |
CN101787038B (en) | Preparation method of cefquinome sulfate | |
CN106831826B (en) | A kind of method that eldisine is prepared from catharanthus roseus | |
CN107739390A (en) | A kind of synthetic method of astaxanthin intermediate | |
CN109305981B (en) | Synthesis method of 2-hydroxynaphthalene-1-boric acid | |
CN101974021B (en) | Method for synthesizing cefuroxime acid | |
CN108840895B (en) | Preparation method of etonogestrel and desogestrel intermediate | |
CN104774166A (en) | Synthetic method for disulfide diisopropyl xanthate | |
CN104817482A (en) | 2-substituted pyrrolidine compound, preparation method and application thereof in preparation of vildagliptin | |
CN109369768A (en) | The preparation method of Dexamethasone Intermediate | |
CN115490701B (en) | Method for synthesizing cantharidin | |
CN112979688B (en) | Preparation method of 2-fluoro-4-trifluoromethylphenylboronic acid | |
CN103848879A (en) | Method for preparing progesterone by taking 1,4-androstenedione as raw material | |
CN110396119A (en) | The preparation method of canagliflozin intermediate | |
CN113698374B (en) | Monoiodoamiodarone and preparation method and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |