CN107759519A - A kind of celecoxib impurity B preparation method - Google Patents
A kind of celecoxib impurity B preparation method Download PDFInfo
- Publication number
- CN107759519A CN107759519A CN201710883849.1A CN201710883849A CN107759519A CN 107759519 A CN107759519 A CN 107759519A CN 201710883849 A CN201710883849 A CN 201710883849A CN 107759519 A CN107759519 A CN 107759519A
- Authority
- CN
- China
- Prior art keywords
- preparation
- alkanols
- impurity
- mixed solvent
- methanol
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
Abstract
The invention discloses a kind of celecoxib process contaminants B preparation method, the content of impurity B is increased to more than 25% by this method by the method for synthesis, then impurity B is purified into purity for more than 99% by the application of supercritical fluid chromatography isolation technics.
Description
Technical field
The present invention relates to pharmaceutical technology, specifically, is related to a kind of celecoxib process contaminants B preparation method.
This method not only increases celecoxib impurity B content, and improves the yield of purifying and the purity of product.
Background technology
Patent US5760068 describes the synthetic method of celecoxib, and 4,4,4- tri- fluoro- 1- (4- aminomethyl phenyls) butane-
1,3- diketone synthesizes celecoxib with 4- Hydrazinobenzenesulfonamides hydrochloride by addition, ring closure reaction；Course of reaction can produce one
Fixed by-product impurities B.In the step course of reaction, 1,3- dione compounds have two electrophilic sites, 4- Hydrazinobenzenesulfonamides
Hydrochloride has two nucleophilic sites.It is different according to site activity, higher site Nu1 and the E1 condensation of activity first, then Nu2 and
E2 cyclizations generate celecoxib, conversely, Nu1 and E2 condensations, Nu2 and E1 cyclizations then generate impurity B.The chemical entitled 4- of impurity B
[3- (4- aminomethyl phenyls) -5- (trifluoromethyl) pyrazol-1-yl] benzsulfamide.
At present, research finds that major impurity has 7 kinds in celecoxib bulk drug, and its structural formula is respectively：
Huang Ping etc. (" synthesis of the celecoxib about material ",《Chinese pharmaceutical chemistry magazine》, volume 22, the 6th phase, 2012
Year December, p503-506) compound D and compound B preparation method is reported, wherein compound B is by reclaiming plug come former times
The filtrate of cloth preparation process, then separate (mobile phase by liquid chromatogram：Acetonitrile-water, volume ratio 60:40, flow velocity：3ml/
Min) obtain, yield 3.0%；The method for reclaiming filtrate by recrystallizing in the method is enriched to impurity B in crude product
Content is 12.4%, and HPLC detections and main peak relative retention time are 1.11.Pass through the receipts of compound B made from this method
Rate is relatively low, and is purified using reversed phase chromatography separation, and the boiling point of the cut water of collection and the mixed solvent of acetonitrile is higher, follow-up place
Reason needs plenty of time even frozen dried, substantially increases production cost, is not suitable for production application.
The content of the invention
Inventor developed a kind of celecoxib impurity B preparation method, not only improves the content of impurity B in crude product
Crude product is isolated and purified to more than 30%, and by SFC methods so that obtained product is methanol solution, by simple
Be concentrated under reduced pressure and just can obtain product, simplify operation, reduce cost, and obtained product purity reaches more than 99%, with
The method of prior art report such as yellow duckweed contrasts improves 10 times by the yield of product.
It is an object of the invention to provide a kind of celecoxib impurity B preparation method.
In embodiments of the invention, the invention provides a kind of celecoxib impurity B preparation method, including it is following
Step：
A, under nitrogen protection, using 4- methyl acetophenones, Trifluoroacetic Acid Ethyl Ester as raw material, passed through in the presence of highly basic
Claisen condensation reactions, obtain fluoro- 1- (4- aminomethyl phenyls) butane -1, the 3- diketone of compound 4,4,4- tri-, the compound 4,4,
Tri- fluoro- 1- of 4- (4- aminomethyl phenyls) butane -1,3- diketone synthesizes impurity B with 4- Hydrazinobenzenesulfonamide hydrochloride addition ring closure reactions
Crude product；
Here, the highly basic in the Claisen condensation reactions, the ethanol of methanol solution, caustic alcohol selected from sodium methoxide are molten
The t-butanol solution of liquid, the t-butanol solution of sodium tert-butoxide or potassium tert-butoxide；
Described Claisen condensation reactions are carried out in polar aprotic solvent or C1-C4 alkanols, the pole
Property non-protonic solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate or methyl tertiary butyl ether(MTBE)；The C1-C4 alkanols are selected from first
Alcohol, ethanol or isopropanol；
The post processing of described Claisen condensation reactions is that watery hydrochloric acid adjusts pH value, and pH value range is 5~8；
Described addition ring closure reaction is in C1-C4 alkanols or the progress of the in the mixed solvent of C1-C4 alkanols and purified water
, described C1-C4 alkanols are selected from absolute methanol, absolute ethyl alcohol, isopropanol；Or described mixed solvent is selected from without water beetle
The mixed solvent of alcohol, absolute ethyl alcohol or anhydrous isopropyl alcohol and pure water；Moreover, the volume ratio of C1-C4 alkanols and purified water is 1：
1、2：1、3：1、4：1 or 3：2；
B, impurity B crude product isolates and purifies, using supercritical fluid chromatography technology：
Using chiral chromatographic column, the chiral chromatographic column be selected from CHIRALPAK A.Y., CHIRALPAK I.C.,
CHIRALPAK O.J.、CHIRALPAK I.D.；
Mobile phase used is the mixture of supercritical carbon dioxide and C1-C4 alkanols, wherein the C1-C4 alkanols are first
Alcohol, ethanol or isopropanol.
In a preferred embodiment of the invention, a kind of celecoxib impurity B provided by the invention preparation method, its
In, the highly basic in the Claisen condensation reactions is the ethanol solution of 20 weight % caustic alcohols.
In a preferred embodiment of the invention, a kind of celecoxib impurity B provided by the invention preparation method, its
In, described Claisen condensation reactions are carried out in polar aprotic solvent, and the polar aprotic solvent is first
Base tertbutyl ether.
In a preferred embodiment of the invention, a kind of celecoxib impurity B provided by the invention preparation method, its
In, the post processing of described Claisen condensation reactions adjusts pH value to 7~8 for watery hydrochloric acid；
In a preferred embodiment of the invention, a kind of celecoxib impurity B provided by the invention preparation method, its
In, described addition ring closure reaction is carried out in the in the mixed solvent of C1-C4 alkanols and purified water, and described mixed solvent is
The mixed solvent of absolute ethyl alcohol and pure water；Moreover, the volume ratio of the absolute ethyl alcohol and the pure water is 4：1.
In a preferred embodiment of the invention, a kind of celecoxib impurity B provided by the invention preparation method, its
In, the chiral chromatographic column of the supercritical fluid chromatography technology is CHIRALPAK I.D..
In a preferred embodiment of the invention, a kind of celecoxib impurity B provided by the invention preparation method, its
In, the mobile phase of the supercritical fluid chromatography technology is supercritical carbon dioxide and the mixture of methanol.
Brief description of the drawings
What Fig. 1 was represented is the gained celecoxib impurity B of embodiment 2 HPLC content collection of illustrative plates, and abscissa represents to protect in accompanying drawing
The time (min) is stayed, ordinate represents absorption intensity (mAU).
What Fig. 2 was represented is the gained celecoxib impurity B of embodiment 4 HPLC content collection of illustrative plates, and abscissa represents to protect in accompanying drawing
The time (min) is stayed, ordinate represents absorption intensity (mAU).
What Fig. 3 was represented is the gained celecoxib impurity B of embodiment 5 HPLC content collection of illustrative plates, and abscissa represents to protect in accompanying drawing
The time (min) is stayed, ordinate represents absorption intensity (mAU).
What Fig. 4 was represented is that the gained celecoxib impurity B of embodiment 2 prepares result collection of illustrative plates using chiral chromatographic column O.J..
What Fig. 5 was represented is that the gained celecoxib impurity B of embodiment 2 prepares result collection of illustrative plates using chiral chromatographic column I.C..
What Fig. 6 was represented is that the gained celecoxib impurity B of embodiment 6 prepares result collection of illustrative plates using chiral chromatographic column I.D., attached
Abscissa represents retention time (min) in figure, and ordinate represents absorption intensity (μ V).
What Fig. 7 was represented is the gained celecoxib impurity B of embodiment 6 content collection of illustrative plates, when abscissa represents to retain in accompanying drawing
Between (min), ordinate represent absorption intensity (μ V).
Embodiment
The following examples be in order to be described in detail the present invention embodiment, rather than in order to the present invention protect
Any restrictions of scope.
HPLC instruments：Efficient liquid phase Agilent 1260, DAD detector；Condition：With reference to USP36 version celecoxib raw materials
The relevant material detection method of medicine.
Embodiment 1：The synthesis of 4,4,4- tri- fluoro- 1- (4- aminomethyl phenyls) butane -1,3- diketone
Under nitrogen protection, it is separately added into the ethanol solution of methyl tertiary butyl ether(MTBE) (3.0L) and 20 weight % caustic alcohols
(3.55kg, 10.43mol), displacement nitrogen 3 times.Control temperature to be no more than 25 ± 5 DEG C, mechanical agitation, trifluoro is added portionwise successively
Ethyl acetate (3) (1.27kg, 8.94mol) and melilotal (4) (1.0kg, 7.45mol).Under nitrogen protection, control is anti-
It is 25 ± 5 DEG C to answer temperature, mechanical agitation 24h.TLC is detected to raw material reaction of disappearance and is finished (solvent：Petrol ether/ethyl acetate,
1/1) volume ratio is.
Stopping reaction, it is 7.0~8.0 that 5 weight % hydrochloric acid solutions (6.5L) regulation PH is added in reaction solution, stands 15min,
Layering, collects organic phase, and aqueous phase is extracted with ethyl acetate (2.0L)；Merge organic phase, eaten successively with pure water (8L) and saturation
Salt solution (5.0L) is washed, and organic phase is dried with anhydrous sodium sulfate (1.0kg), is filtered, and filter cake is eluted with a small amount of ethyl acetate, filtrate
It is concentrated under reduced pressure into 45 DEG C dry, obtains the brownish red crude oil of compound 1.Yield 99.8%, HPLC detection purity is 98.4%.
Embodiment 2：Celecoxib impurity B preparation
Absolute ethyl alcohol (19.2L), pure water (4.8L) and fluoro- 1- (the 4- methylbenzenes of 4,4,4- tri- are separately added into reactor
Base) butane -1,3- diketone (1.6kg, 6.84mol), dissolving is complete, addition 4- Hydrazinobenzenesulfonamides hydrochloride (1.61kg,
7.18mol), mechanical agitation, backflow is warming up to, reacts 20h, HPLC detection compounds 1 disappear, and stop heating.Reactant mixture
Cooling, crystallization, when temperature reaches 20 DEG C, keeping temperature stirs 3h.Centrifugation, filter cake a small amount of mixed solvent (absolute ethyl alcohol/water：
1/1) elute, collect solid wet product, wet product obtains crude product in 45 DEG C of forced air drying 16h, and HPLC detects the content of impurity B in crude product
For 32.8% (accompanying drawing 1).
Embodiment 3：Celecoxib impurity B preparation
Fluoro- 1- (4- aminomethyl phenyls) butane -1, the 3- diketone of 10g 4,4,4- tri- is taken, adds ethanol (120mL) dissolving completely,
It is 7~8 to survey its pH value, then adds pure water (30mL) and 4- Hydrazinobenzenesulfonamides hydrochloride (10.2g, 46.0mmol), stirs
Mix, heat up, after the 20h that flows back, sampling HPLC checked for impurities B contents reach 26.1%, stop reaction, are concentrated under reduced pressure into dry.
Embodiment 4：Celecoxib impurity B preparation
Fluoro- 1- (4- aminomethyl phenyls) butane -1, the 3- diketone of 10g compounds 4,4,4- tri- is taken, ethyl acetate is added and has dissolved
Entirely, it is 7~8 to survey its pH value, and it is 1~2 to add 5% salt acid for adjusting pH, liquid separation, collects organic phase, is dried, and is concentrated to give after being acidified
Compound 1, then add absolute ethyl alcohol (120mL), pure water (30mL) and 4- Hydrazinobenzenesulfonamides hydrochloride (10.2g,
46.0mmol), stir, heating, after the 20h that flows back, sampling, HPLC checked for impurities B contents reach 2.43%, stop reaction, cooling
Crystallization, reported according to Huang Ping etc., solid recrystallizing methanol, crude product is obtained after mother liquor concentrations, and HPLC checked for impurities B content is
12.39% (accompanying drawing 2).
Embodiment 5：Celecoxib impurity B preparation
Absolute ethyl alcohol (120mL), pure water (30mL), fluoro- 1- (the 4- methylbenzenes of 4,4,4- tri- are separately added into reaction bulb
Base) butane -1,3- diketone (10.0g, 43mmol), triethylamine (4.62g, 46mmol) and 4- Hydrazinobenzenesulfonamide hydrochlorides
(10.2g, 46mmol), mechanical agitation, heating, flow back 20h, sampling, and HPLC checked for impurities B contents reach 1.38% (accompanying drawing 3),
Stop reaction, cooling, be concentrated under reduced pressure into dry.
Embodiment 6：Celecoxib impurity B preparation
The crude product 30.06g obtained in embodiment 2 is weighed, the separation of impurity B is carried out using SFC methods, actual conditions is chromatogram
Post：Chiral PAK I.D.；Chromatographic column specification:0.46cm×15cm L；Mobile phase:MeOH/CO2=20/80 (V/V)；Ripple
It is long:UV 254nm；Flow velocity:2.0ml/min；Temperature:25℃；The methanol solution of impurity B is obtained, through the 4- [3- (4- that are concentrated under reduced pressure to obtain
Aminomethyl phenyl) -5- (trifluoromethyl) pyrazol-1-yl] benzsulfamide (impurity B) 9.7g, yield 32.3%, purity is
99.57% (accompanying drawing 7).ESI-MS m/z：382.08[M+H]+。1H-NMR(500MHz,DMSO)δ：8.04 (dd, J=6.5Hz,
1.5Hz, 2H), 7.85 (d, J=8.5Hz, 2H), 7.83 (d, J=8.5Hz, 2H), 7.75 (s, 1H), 7.60 (s, 2H), 7.29
(d, J=8.0Hz, 2H), 2.35 (s, 3H).13C-NMR(500MHz,DMSO)δ：152.13,145.30,141.38,138.98,
133.26,129.98,128.65,127.46,126.68,126.06,120.07,107.99,21.35.
The contrast of celecoxib impurity B separation
Claims (8)
1. a kind of celecoxib impurity B preparation method, comprises the following steps：
A, under nitrogen protection, using 4- methyl acetophenones, Trifluoroacetic Acid Ethyl Ester as raw material, contracted in the presence of highly basic through Claisen
Reaction is closed, obtains fluoro- 1- (4- aminomethyl phenyls) butane -1, the 3- diketone of compound 4,4,4- tri-, 4,4,4- tri- fluoro- 1- of the compound
(4- aminomethyl phenyls) butane -1,3- diketone synthesizes impurity B crude product with 4- Hydrazinobenzenesulfonamide hydrochloride addition ring closure reactions；
Here, the highly basic in the Claisen condensation reactions, the ethanol solution of methanol solution, caustic alcohol selected from sodium methoxide, uncle
The t-butanol solution of sodium butoxide or the t-butanol solution of potassium tert-butoxide；
Described Claisen condensation reactions are carried out in polar aprotic solvent or C1-C4 alkanols, and the polarity is non-
Protonic solvent is selected from tetrahydrofuran, acetonitrile, ethyl acetate or methyl tertiary butyl ether(MTBE)；The C1-C4 alkanols are selected from methanol, second
Alcohol or isopropanol；
The post processing of described Claisen condensation reactions is that watery hydrochloric acid adjusts pH value, and pH value range includes 5~8；Described addition
Ring closure reaction is carried out in C1-C4 alkanols or the in the mixed solvent of C1-C4 alkanols and purified water, described C1-C4 alkanols
Selected from absolute methanol, absolute ethyl alcohol, isopropanol；Or described mixed solvent is selected from absolute methanol, absolute ethyl alcohol or anhydrous
The mixed solvent of isopropanol and pure water；Moreover, the volume ratio of C1-C4 alkanols and purified water is 1：1、2：1、3：1、4：1 or 3：
2；
B, impurity B crude product isolates and purifies, using supercritical fluid chromatography technology：
Using chiral chromatographic column, the chiral chromatographic column is selected from CHIRALPAK A.Y., CHIRALPAK I.C., CHIRALPAK
O.J.、CHIRALPAK I.D.；
Mobile phase used is the mixture of supercritical carbon dioxide and C1-C4 alkanols, wherein the C1-C4 alkanols are methanol, second
Alcohol or isopropanol.
2. preparation method as claimed in claim 1, wherein, the highly basic in the Claisen condensation reactions is 20 weight % second
The ethanol solution of sodium alkoxide.
3. preparation method as claimed in claim 1, wherein, described Claisen condensation reactions are molten in polar aprotic
Carried out in agent, the polar aprotic solvent is methyl tertiary butyl ether(MTBE).
4. preparation method as claimed in claim 1, wherein, the post processing of described Claisen condensation reactions is adjusted for watery hydrochloric acid
PH value is saved to 7~8.
5. preparation method as claimed in claim 1, wherein, described addition ring closure reaction is in C1-C4 alkanols and purified water
In the mixed solvent carry out, described mixed solvent is absolute ethyl alcohol and the mixed solvent of pure water.
6. preparation method as claimed in claim 5, wherein, the volume ratio of the absolute ethyl alcohol and the pure water is 4：1.
7. preparation method as claimed in claim 1, wherein, the chiral chromatographic column of the supercritical fluid chromatography technology is
CHIRALPAK I.D.。
8. preparation method as claimed in claim 1, wherein, the mobile phase of the supercritical fluid chromatography technology is overcritical two
The mixture of carbonoxide and methanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710883849.1A CN107759519B (en) | 2017-09-26 | 2017-09-26 | Preparation method of celecoxib impurity B |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710883849.1A CN107759519B (en) | 2017-09-26 | 2017-09-26 | Preparation method of celecoxib impurity B |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107759519A true CN107759519A (en) | 2018-03-06 |
| CN107759519B CN107759519B (en) | 2021-02-09 |
Family
ID=61267602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710883849.1A Active CN107759519B (en) | 2017-09-26 | 2017-09-26 | Preparation method of celecoxib impurity B |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107759519B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981805A (en) * | 2019-11-21 | 2020-04-10 | 武汉光谷亚太医药研究院有限公司 | Preparation method of celecoxib genotoxic impurity |
| CN111499576A (en) * | 2020-05-30 | 2020-08-07 | 迪嘉药业集团有限公司 | Preparation method of celecoxib impurity |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617474A (en) * | 2012-03-19 | 2012-08-01 | 苏州四同医药科技有限公司 | Preparation method for celecoxib isomer |
| CN103242233A (en) * | 2012-02-08 | 2013-08-14 | 黄华 | Novel method for preparing celecoxib |
-
2017
- 2017-09-26 CN CN201710883849.1A patent/CN107759519B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103242233A (en) * | 2012-02-08 | 2013-08-14 | 黄华 | Novel method for preparing celecoxib |
| CN102617474A (en) * | 2012-03-19 | 2012-08-01 | 苏州四同医药科技有限公司 | Preparation method for celecoxib isomer |
Non-Patent Citations (1)
| Title |
|---|
| 黄萍: "第一部分:芒果苷及其苷元的结构修饰和黄瞟昤氧化酶抑制活性的研究；第二部分:塞来昔布有关物质的合成", 《中国医学科学院&北京协和医学院硕士学位论文》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110981805A (en) * | 2019-11-21 | 2020-04-10 | 武汉光谷亚太医药研究院有限公司 | Preparation method of celecoxib genotoxic impurity |
| CN111499576A (en) * | 2020-05-30 | 2020-08-07 | 迪嘉药业集团有限公司 | Preparation method of celecoxib impurity |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107759519B (en) | 2021-02-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105418460B (en) | Intermediate of pimavanserin and similar compound thereof, and preparation method thereof, and method for preparing pimavanserin and similar compound thereof | |
| CN104447600B (en) | A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application | |
| CN104250232A (en) | Preparation method of parecoxib sodium | |
| CN105440020B (en) | 1,2,3- triazole class compounds with anti-tumor activity and preparation method thereof | |
| CN105524044A (en) | Trelagliptin impurity and its composition | |
| CN107759519A (en) | A kind of celecoxib impurity B preparation method | |
| CN104892614B (en) | A kind of synthetic method of 6H iso-indoles simultaneously ketone derivatives of [2,1 α] indoles 6 | |
| Cole et al. | Reagent-free continuous thermal tert-butyl ester deprotection | |
| EP1845091A1 (en) | Process for producing muscarine receptor antagonist and intermediate therefor | |
| CN105669651A (en) | Preparation technique of dabigatran methanesulfonate | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN105367508B (en) | A kind of preparation method of Parecoxib Sodium synthesis technique impurity | |
| CN106883192B (en) | The synthetic method of the benzoic acid derivative of nitrogenous class heterocyclic antineoplastic pharmaceutical actives oxazolyl modification | |
| CN105859640A (en) | Method for catalytically preparing quinazolinone amino carbamate derivative through copper | |
| CN106045914A (en) | Method for synthesizing tri-substituted imidazole compounds | |
| CN101914174A (en) | Linear polystyrene-supported (4S)-oxazolidine-2-benzimine as well as preparation method and application thereof | |
| CN112321514B (en) | Chiral barbituric acid compound and preparation method thereof | |
| CN105272918B (en) | Halogenation -1- alkyl -3- vinyl -2,4,5- triarylimidazoles and preparation method and purposes | |
| CN107556260B (en) | A kind of etoxazole preparation method | |
| CN104496737B (en) | A kind of method of synthesis α amine formyl ethyl fluoroacetate compounds | |
| CN103387574A (en) | Synthetic method of epiberberine | |
| CN112624966B (en) | Synthetic method of 2-aminomethyl-4-methyl-5-pyridine carboxylic acid | |
| CN106588841B (en) | The method for synthesizing 2,3- dihydro -1- benzofuran -4- formaldehyde | |
| CN107698547A (en) | A kind of preparation method of pyran derivate | |
| CN107501070A (en) | The process for purification and its intermediate of a kind of Teprenone |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |