CN106336401B - A kind of refining methd of avanaphil - Google Patents
A kind of refining methd of avanaphil Download PDFInfo
- Publication number
- CN106336401B CN106336401B CN201510415287.9A CN201510415287A CN106336401B CN 106336401 B CN106336401 B CN 106336401B CN 201510415287 A CN201510415287 A CN 201510415287A CN 106336401 B CN106336401 B CN 106336401B
- Authority
- CN
- China
- Prior art keywords
- avanaphil
- ethyl acetate
- solvent
- refining methd
- volume ratio
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
The invention discloses a kind of refining methds of avanaphil.Using avanaphil bulk pharmaceutical chemicals made from this method, granularity partial size≤30 μm, so that in the drying process, organic solvent is readily volatilized to be come out, and its dissolvent residual is lower.It is comprised the concrete steps that: avanaphil crude product being added in organic solvent, is heated to flowing back, after solid is completely dissolved, standing is cooled to 40 DEG C~20 DEG C, and stirring is cooled to 10 DEG C~-10 DEG C later, keeps the temperature 1~3 hour, filters, and filter cake is vacuum dried to obtain the final product;Organic solvent is the combination of two kinds of solvents, and one is intensive polar solvent, and another is middle polarity or nonpolar solvent.
Description
Technical field
The present invention relates to a kind of refining methds, and in particular to a kind of refining methd of avanaphil.Belong to medical science neck
Domain.
Background technique
Avanaphil (Avanafil) is to authorize U.S. Wei Fusi drugmaker by Japanese Tanabe Mitsubishi Pharmaceutical Co
The drug for being used to treat male erectile dysfunction of exploitation.Avanaphil is a kind of to take orally quick-acting highly selective di-phosphate esters
Enzyme -5 (PDE-5) inhibitor, can inhibit the metabolism of cyclic guanosine monophosphate in vivo, be added so that the diastole of smooth muscle be made to act on
By force, the blood flow of penis increases, and then helps to erect.Its chemical structural formula is as follows:
Chinese patent application CN103819460A discloses a kind of avanaphil process for refining, and this method includes following step
It is rapid:
1) avanaphil crude product is added in the reaction kettle containing methylene chloride, it is extremely clear is stirred at reflux (38 DEG C~40 DEG C)
Clear solution, the hydrochloric acid solution that concentration is 1-5% is added into the solution, and stirring and dissolving makes the pH value range of solution in 0.5-2.0
Between, liquid separation takes hydrochloric acid solution layer;2) mixed solution (two that methylene chloride and ethyl acetate form is added to hydrochloric acid solution layer
Chloromethanes: ethyl acetate=5:1), the sodium carbonate liquor that concentration is 5-10% is added into the solution for stirring, and stirring makes solution
PH value range between 6.0-7.0, liquid separation takes methylene chloride and ethyl acetate mixture layer;3) to methylene chloride, acetic acid
Ethyl ester mixed solution layer is added active carbon and sodium carbonate mixture (active carbon: sodium carbonate=1:9) and stirs, and is cooled to -5-0
DEG C, the reaction mass to filtrate is repeatedly filtered with diatomite (Hyflo) bed and is clarified, and is washed with glacial acetic acid ethyl ester, vacuum (>=
Methylene chloride and ethyl acetate 500mmHg) are evaporated off completely, draws off wet product, is done under the conditions of vacuum (>=650mmHg), 55-65 DEG C
Dry 15 hours, dry product was drawn off to get avanaphil highly finished product.99.9% or more avanaphil of purity can be made in this method, still,
Applicant is in practice, it has been found that its granularity of avanaphil made from the method is larger, its partial size granularity >=90 μm, is doing after measured
It is not easy to go out in organic reagent methylene chloride, ethyl acetate during dry, in avanaphil raw material finished product obtained, is easy
Methylene chloride, ethyl acetate content are exceeded.In addition, avanaphil crude product is dissolved in methylene chloride, (acetic acid is added through the molten alkali analysis of acid
Ethyl ester) method carry out purification need to extract repeatedly, technique is cumbersome, though removal impurity effect it is obvious, need to operate repeatedly, and
It refers to be repeatedly filtered with diatomite (Hyflo) bed, is unfavorable for the realization of industrialized production.Also, it has been found that with should
The bulk pharmaceutical chemicals that method prepares, are made that tablet its result of extraction is bad, and dissolution rate much grinds medicine not as good as original.
Chinese patent application CN 104003981A discloses the refining methd of avanaphil, and specific as follows: crude product is pure
Change: filtering the white solid removed in crude product, ethyl acetate (60mL) dilute reaction solution is then added into system, then uses and steam
Distilled water (30mL × 2) washes organic layer, after collected organic layer, is concentrated into 30mL, is washed with water (30mL × 3), and organic layer is with anhydrous
Na2SO4It is dry, white solid is obtained after vacuum rotary steam, then finally obtains white powder crystal, yield with recrystallizing methanol
75%, 162 DEG C of fusing point.In this method, avanaphil is recrystallized using methanol, and applicant is in practice, it has been found that single use
Its granularity of the avanaphil that methanol is recrystallized to give is also bigger, avanaphil raw material its granularity generally yielded >=110 μ
M, it is also difficult to remove organic solvent ethyl acetate and methanol during drying.Also, it has been found that with party's legal system
The standby bulk pharmaceutical chemicals come out, are made that tablet its result of extraction is bad, and dissolution rate also much grinds medicine not as good as original.
Summary of the invention
The purpose of the present invention is to overcome above-mentioned the deficiencies in the prior art, provide a kind of refining methd of avanaphil.It adopts
The avanaphil bulk pharmaceutical chemicals made from this method, granularity partial size≤30 μm, so that in the drying process, organic solvent is easy to wave
It issues, dissolvent residual is lower.
To achieve the above object, the present invention adopts the following technical solutions:
A kind of refining methd of avanaphil, comprises the concrete steps that: avanaphil crude product being added in organic solvent, is heated
To reflux, after solid is completely dissolved, standing is cooled to 40 DEG C~20 DEG C, and stirring later is cooled to 10 DEG C~-10 DEG C, heat preservation 1~3
Hour, it filters, filter cake is vacuum dried to obtain the final product;
The organic solvent is the combination of two kinds of solvents, and one is intensive polar solvent, and another is middle polarity or nonpolarity
Solvent, the volume ratio of the two are 1:2~5;The intensive polar solvent is dimethyl sulfoxide, N,N-dimethylformamide, without water beetle
Any one of alcohol, dehydrated alcohol or isopropanol, the middle polarity or nonpolar solvent are ethyl acetate, butyl acetate or different
Any one of propyl ether.
The mass volume ratio of avanaphil crude product and organic solvent is 1g:6~21mL.
The group of described two solvents is combined into dehydrated alcohol and ethyl acetate, and the volume ratio of the two is 1:2.
The group of described two solvents is combined into anhydrous methanol and isopropyl ether, and the volume ratio of the two is 1:2.
The group of described two solvents is combined into dimethyl sulfoxide and ethyl acetate, and the volume ratio of the two is 1:5.
Soaking time is 2 hours after stirring cooling.
Vacuum drying temperature is 40 DEG C~80 DEG C.
Its mechanism is as follows:
First, containing alcoholic extract hydroxyl group in avanaphil molecule, and molecular weight is bigger than normal, structure is complicated is easily generated with intensive polar solvent
Hydrogen bond and form solvate, cause dissolvent residual can not be removed by external force (vacuum drying), present invention combination Ah cutting down that
Non- design feature, adds a kind of middle polarity or nonpolar solvent is recrystallized, and destroys intensive polar solvent and alcoholic extract hydroxyl group shape
At hydrogen bond.
In addition, controlling stirring in Crystallization Process, so that highly finished product granularity is smaller, avoid precipitating crystal packet bigger than normal and easy
Solvent is pressed from both sides, causes dissolvent residual exceeded.The present invention carries out verification experimental verification by above-mentioned mechanism, and products obtained therefrom, which has reached medicinal, to be wanted
It asks.
Beneficial effects of the present invention:
(1) refining methd of avanaphil provided by the invention, easy to operate, stably and controllable, gained avanaphil raw material
The purity and yield of medicine are higher, have preferable economic benefit, are convenient for industrialized production.
(2) dissolvent residual of bulk pharmaceutical chemicals is an important factor for influencing its tablet safety, using avanaphil of the invention
Refining methd prepare avanaphil bulk pharmaceutical chemicals, dissolvent residual is lower, and products obtained therefrom meets in Chinese Pharmacopoeia to dissolvent residual
Standard requirements.
(3) avanaphil raw material its partial size obtained using refining methd of the invention ≤30 μm, using this raw material
Medicine is made into preparation, and it is similar that result of extraction to original grinds tablet.
Detailed description of the invention
Fig. 1 be reference preparation in pH6.8 buffer solution, partial size d (0.9)=64.9 μm and partial size d (0.9)≤30 μm it is molten
Curve out;
Fig. 2 is the dissolution curve of reference preparation in water, partial size d (0.9)=64.9 μm and partial size d (0.9)≤30 μm;
Fig. 3 is reference preparation, partial size d (0.9)≤30 μm of dissolution curve in pH4.0 buffer solution;
Fig. 4 is reference preparation, partial size d (0.9)≤30 μm of dissolution curve in pH1.2 buffer solution.
Specific embodiment
The present invention will be further elaborated with reference to the accompanying drawings and examples, it should which explanation, following the description is only
It is not to be defined to its content to explain the present invention.
This application involves avanaphil crude product according to the method system of embodiment 1 in Chinese patent application CN1374953A
It is standby to obtain.
Embodiment 1
At room temperature, by the avanaphil crude product of 20g purity 98.5% (HPLC measurement) be added to 280mL ethyl acetate and
The in the mixed solvent of 140mL dehydrated alcohol is heated to flowing back after mixing evenly, and after solid is completely dissolved, standing is naturally cooling to
After 40 DEG C, stirring is opened, after ice bath is cooled to 10 DEG C.Filter cake, vacuum (- 0.09Mpa) 40-50 are collected in heat preservation 1 hour, filtering
DEG C dry 8 hours avanaphil 16g, purity 99.91% (HPLC measurement).Yield: 80%.
Dissolvent residual: ethyl acetate, 0.08%, ethyl alcohol 0.10% (GC measurement), partial size :≤30 μm.
Embodiment 2
At room temperature, the avanaphil crude product of 50g purity 98.5% (HPLC measurement) is added to 300mL methanol and 600mL
The in the mixed solvent of isopropyl ether is heated to flowing back after mixing evenly, and after solid is completely dissolved, standing is naturally cooling to 30 DEG C, opens
Stirring is opened, after ice bath is cooled to 0 DEG C, keeps the temperature 3 hours, filter cake, the drying 8 hours of 40-50 DEG C of vacuum (- 0.09Mpa) are collected in filtering
Obtain avanaphil 41g, purity 99.90% (HPLC measurement).Yield: 82%.
Dissolvent residual: isopropyl ether is not detected, methanol 0.13% (GC measurement), partial size :≤30 μm.
Embodiment 3
At room temperature, by the avanaphil crude product of 100g purity 98.5% (HPLC measurement) be added to 100mL dimethyl sulfoxide,
The in the mixed solvent of 500mL ethyl acetate under stirring, is heated to flowing back, and after solid is completely dissolved, is naturally cooling to 20 DEG C, opens
Stirring is opened, ice bath slow cooling keeps the temperature 2 hours to -10 DEG C, and filter cake, 75-80 DEG C of drying of vacuum (- 0.09Mpa) are collected in filtering
Obtain avanaphil 83.5g, purity 99.93% (HPLC measurement) within 12 hours.Yield: 83.5%.
Dissolvent residual: dimethyl sulfoxide 0.15%, ethyl acetate 0.19% (GC measurement), partial size :≤30 μm.
Comparative example 1
At room temperature, by the avanaphil crude product of 10g purity 98.5% (HPLC measurement) be added to 140mL ethyl acetate and
The in the mixed solvent of 70mL dehydrated alcohol is heated to flowing back after mixing evenly, and after solid is completely dissolved, standing is naturally cooling to
After 50 DEG C, stirring is opened, after ice bath is cooled to 10 DEG C, keeps the temperature 1 hour, filter cake, vacuum (- 0.09Mpa) 40-50 are collected in filtering
DEG C dry 8 hours avanaphil 8.2g, purity 99.50% (HPLC measurement).Yield: 82%.
Dissolvent residual: ethyl acetate, 0.05%, ethyl alcohol 0.12% (GC measurement), partial size :≤30 μm.
The comparative example is stirred cooling the difference from embodiment 1 is that standing and being cooled to 50 DEG C, and other conditions are similar,
The purity of products obtained therefrom is obviously lower than embodiment 1.
Comparative example 2
At room temperature, the avanaphil crude product of 50g purity 98.5% (HPLC measurement) is added to 50mL dimethyl sulfoxide
The in the mixed solvent of 300mL ethyl acetate under stirring, is heated to flowing back, and after solid is completely dissolved, is naturally cooling to 20 DEG C, opens
Stirring is opened, ice bath slow cooling keeps the temperature 2 hours to -10 DEG C, and filter cake, 75-80 DEG C of drying of vacuum (- 0.09Mpa) are collected in filtering
Obtain avanaphil 41g, purity 99.40% (HPLC measurement) within 12 hours.Yield: 82%.
Dissolvent residual: dimethyl sulfoxide 0.35%, ethyl acetate 0.30% (GC measurement), partial size :≤30 μm.
The comparative example is that intensive polar solvent and middle polarity/nonpolar solvent proportion are different from the difference of embodiment 3,
Other conditions are similar, and after increasing middle polarity/nonpolar solvent additional amount, the purity of products obtained therefrom is obviously lower than embodiment 3, and
And the residual quantity of dimethyl sulfoxide and ethyl acetate is also obviously got higher.
Comparative example 3 (using the method for CN103819460A)
Avanaphil crude product 10g is added in the methylene chloride containing 200mL, it is extremely clear to be stirred at reflux (38 DEG C~40 DEG C)
The hydrochloric acid solution that concentration is 1% is added into the solution for clear solution, and stirring and dissolving makes the pH=2.0 of solution, and liquid separation takes hydrochloric acid
Solution layer, to hydrochloric acid solution layer be added 200mL methylene chloride and ethyl acetate mixed solution (methylene chloride: ethyl acetate=
5:1), it stirs, the sodium carbonate liquor that concentration is 9% is added into the solution, stirring makes the pH=6.5 of solution, liquid separation takes two
Chloromethanes and ethyl acetate mixture layer;5g active carbon is added to ethyl acetate methylene chloride mixed solution layer and sodium carbonate is mixed
It closes object (active carbon: sodium carbonate=1:9) and stirs, be cooled to -5-0 DEG C, with diatomite (Hyflo) bed, repeatedly filter the reaction
Material to filtrate is clarified, and is washed with glacial acetic acid ethyl ester, and methylene chloride and ethyl acetate is evaporated off in vacuum (>=500mmHg) completely
Mixed solution obtains wet product, 15 hours dry under the conditions of vacuum (>=650mmHg), 55-65 DEG C, obtains avanaphil product 8.1g.
Yield is 81%, purity 99.88%, dissolvent residual: methylene chloride 0.25%, ethyl acetate 0.65% (GC measurement).Partial size >=
90μm。
Comparative example 4 (using the method for CN 104003981A)
At room temperature, the avanaphil crude product of 10g purity 98.0% (HPLC measurement) is added to the methanol containing 40mL
In reaction flask, reflux 30 minutes is warming up under stirring, solid has that part is undissolved, adds methanol 20mL under this condition, solid is complete
Fully dissolved is cooled to 5 DEG C, keeps the temperature crystallization 1 hour, and filtering, filter cake is dried in vacuo 50 DEG C of (- 0.095Mpa) drying 12 hours and obtains
7.6g, yield 76%, purity 99.82%.Methanol solvate residual: 0.57% (GC measurement), partial size >=110 μm.
The common residual solvent in part and its limit are shown in Table 1 in 2010 editions one middle regulation drug of Chinese Pharmacopoeia.
The common residual solvent in part and its limit in drug are provided in 1 Chinese Pharmacopoeia of table 2010 editions one
Solvent title | Limit/% | Solvent title | Limit/% |
Dimethyl sulfoxide | 0.5 | Ethyl alcohol | 0.5 |
N,N-dimethylformamide | 0.088 | Isopropanol | 0.5 |
Ethyl acetate | 0.5 | Isopropyl ether | 0.5 |
Butyl acetate | 0.5 | Methylene chloride | 0.06 |
Methanol | 0.3 |
Contrast table 1, it is known that the avanaphil that the refining methd of avanaphil of the invention is refining to obtain, dissolvent residual are complete
Portion is qualified.And avanaphil prepared by comparative example 3 and comparative example 4, methylene chloride and methanol residual are exceeded.
Avanaphil is low-solubility drug, and the granularity of avanaphil bulk pharmaceutical chemicals is to influence the key factor of drug-eluting,
In order to investigate influence of the bulk pharmaceutical chemicals partial size to dissolution, two will be carried out after bulk pharmaceutical chemicals mixed in equal amounts made from comparative example 3 and comparative example 4
Secondary crushing is 64.9 μm through detection partial size d (0.9), the raw material for optionally taking the embodiment of the present invention to obtain (partial size d (0.9)≤30 μ
M), it is prepared into avanaphil piece sample by same prescription and preparation method, carries out dissolution curve measurement (dissolution measuring method respectively
Consult drug registered standard guideline), former triturate is reference preparation, the results are shown in Table 2~5.
Dissolution curve similitude comparing result (100mg specification) in 2. pH6.8 buffer solution of table
Dissolution curve similitude comparing result (100mg specification) in 3. water of table
Dissolution curve similitude comparing result (100mg specification) in 4. pH4.0 buffer solution of table
Dissolution curve similitude comparing result (100mg specification) in 5. pH1.2 hydrochloric acid of table
Note: " * " former triturate and own product dissolution rate in 15 minutes are all larger than 85%, it is possible to determine that are similar.
By dissolution correlation result it is found that this product 100mg specification piece is four when bulk pharmaceutical chemicals partial size (0.9)≤30 μm d
Dissolution curve is similar to former triturate dissolution curve in kind dissolution medium, it was demonstrated that makes partial size≤30 μm of avanaphil bulk pharmaceutical chemicals
Standby tablet and former triturate relatively compared with, dissolution rate is similar.
Above-mentioned, although the foregoing specific embodiments of the present invention is described with reference to the accompanying drawings, not protects model to the present invention
The limitation enclosed, based on the technical solutions of the present invention, those skilled in the art are not needed to make the creative labor and can be done
Various modifications or changes out are still within protection scope of the present invention.
Claims (6)
1. a kind of refining methd of avanaphil, which is characterized in that comprise the concrete steps that: avanaphil crude product being added to organic molten
It in agent, is heated to flowing back, after solid is completely dissolved, standing is cooled to 40 DEG C~20 DEG C, and stirring is cooled to 10 DEG C~-10 later
DEG C, it keeps the temperature 1~3 hour, filters, filter cake is vacuum dried to obtain the final product;
The organic solvent be two kinds of solvents combination, one is intensive polar solvent, it is another be middle polarity or nonpolar solvent,
The volume ratio of the two is 1:2~5;The intensive polar solvent is dimethyl sulfoxide, N,N-dimethylformamide, anhydrous methanol, nothing
Any one of water-ethanol or isopropanol, the middle polarity or nonpolar solvent are ethyl acetate, butyl acetate or isopropyl ether
Any one of;The mass volume ratio of avanaphil crude product and organic solvent is 1g:6~21mL.
2. a kind of refining methd of avanaphil according to claim 1, which is characterized in that the combination of described two solvents
For dehydrated alcohol and ethyl acetate, the volume ratio of the two is 1:2.
3. a kind of refining methd of avanaphil according to claim 1, which is characterized in that the combination of described two solvents
For anhydrous methanol and isopropyl ether, the volume ratio of the two is 1:2.
4. a kind of refining methd of avanaphil according to claim 1, which is characterized in that the combination of described two solvents
For dimethyl sulfoxide and ethyl acetate, the volume ratio of the two is 1:5.
5. a kind of refining methd of avanaphil according to claim 1, which is characterized in that soaking time after stirring cooling
It is 2 hours.
6. a kind of refining methd of avanaphil according to claim 1, which is characterized in that vacuum drying temperature is 40
DEG C~80 DEG C.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510415287.9A CN106336401B (en) | 2015-07-15 | 2015-07-15 | A kind of refining methd of avanaphil |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510415287.9A CN106336401B (en) | 2015-07-15 | 2015-07-15 | A kind of refining methd of avanaphil |
Publications (2)
Publication Number | Publication Date |
---|---|
CN106336401A CN106336401A (en) | 2017-01-18 |
CN106336401B true CN106336401B (en) | 2019-05-28 |
Family
ID=57826728
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510415287.9A Active CN106336401B (en) | 2015-07-15 | 2015-07-15 | A kind of refining methd of avanaphil |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN106336401B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108690000A (en) * | 2018-06-29 | 2018-10-23 | 苏州中联化学制药有限公司 | A kind of process for purification of avanaphil |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103819460A (en) * | 2014-03-18 | 2014-05-28 | 南京正科制药有限公司 | Technology for refining avanafil |
CN104003981A (en) * | 2014-05-28 | 2014-08-27 | 河北康泰药业有限公司 | Synthesis method of avanafil |
WO2014174529A2 (en) * | 2013-04-23 | 2014-10-30 | Hetero Research Foundation | Polymorphs of avanafil |
CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
CN104628707A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Amorphous form of avanafil, preparation method of, application and medicine composition of amorphous form of avanafil |
-
2015
- 2015-07-15 CN CN201510415287.9A patent/CN106336401B/en active Active
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014174529A2 (en) * | 2013-04-23 | 2014-10-30 | Hetero Research Foundation | Polymorphs of avanafil |
CN104628708A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Avanaphil crystal form as well as preparation method, application and pharmaceutical composition thereof |
CN104628707A (en) * | 2013-11-13 | 2015-05-20 | 北大方正集团有限公司 | Amorphous form of avanafil, preparation method of, application and medicine composition of amorphous form of avanafil |
CN103819460A (en) * | 2014-03-18 | 2014-05-28 | 南京正科制药有限公司 | Technology for refining avanafil |
CN104003981A (en) * | 2014-05-28 | 2014-08-27 | 河北康泰药业有限公司 | Synthesis method of avanafil |
Non-Patent Citations (1)
Title |
---|
阿伐那非的合成研究进展;田红潮等;《山东化工》;20150508;第44卷(第9期);58-61页 |
Also Published As
Publication number | Publication date |
---|---|
CN106336401A (en) | 2017-01-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105968093B (en) | The preparation method of amber love song Ge Lieting | |
CN104861029A (en) | Preparation method of ammonium 18alpha,beta-H-glycyrrhetate and hydrate thereof | |
CN106478600B (en) | A kind of refining methd of Lansoprazole | |
CA3076282A1 (en) | Tricyclic oxepane derivative from limax, methods of isolation, and uses thereof | |
CN105085373A (en) | Purification method for Apremilast products | |
JP2007099680A (en) | Method for producing epalrestat | |
CN105566322A (en) | Preparation method of moxifloxacin impurity G compound | |
CN102020635B (en) | Preparation method of hydrochloride Fasudil hemihydrate | |
CN104326990B (en) | A kind of method of cytosine fluorination synthesis 5-flurocytosine | |
CN106336401B (en) | A kind of refining methd of avanaphil | |
CN104387421B (en) | Adefovir ester monohydrate and preparation method thereof | |
CN108558759A (en) | The method that one kettle way prepares celecoxib | |
CN104193766A (en) | Method for preparing cefetamet acid | |
CN104530006B (en) | The preparation method of Lansoprazole | |
CN106336411B (en) | The preparation technology and purposes of CDK4/6 inhibitor Pa Boxini high-purity raw medicines | |
CN108250183A (en) | A kind of preparation method of the Topiroxostat of high-purity | |
CN104844604B (en) | A kind of preparation method of allopurinol sodium | |
CN108440324B (en) | Ornithine aspartate and crystallization method thereof | |
CN104098524B (en) | 1-meta-methoxy benzoyl-3-phenyl-Isosorbide-5-Nitrae-dihydro-1,2,4,5-tetrazine and Synthesis and applications | |
CN107814769B (en) | Purification method of bosutinib | |
CN105585564A (en) | Purifying method of emtricitabine | |
CN110862429A (en) | Preparation method of sodium aescinate | |
CN109060473A (en) | A kind of preparation method of ambroxol hydrochloride impurity reference substance | |
CN111450051B (en) | Preparation method of ketotifen fumarate oral solution | |
CN104224797A (en) | Application of oleanane type pentacyclic triterpene ester derivative for preparing anti-aging medicine |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
TR01 | Transfer of patent right |
Effective date of registration: 20230921 Address after: The first, second, and fourth floors of the quality inspection building at 2350 Kaifeng Road, Jinan City, Shandong Province, 250101 Patentee after: Shandong Chengchuang Blue Sea Pharmaceutical Technology Co.,Ltd. Address before: 250101 2350 development road, hi tech Development Zone, Ji'nan, Shandong Patentee before: SHANDONG CHENGCHUANG PHARMACEUTICAL R&D Co.,Ltd. |
|
TR01 | Transfer of patent right |