CN107827762A - A kind of (2,3 dioleoyl propyl group) three changes ammonio methacrylate and its production and use - Google Patents
A kind of (2,3 dioleoyl propyl group) three changes ammonio methacrylate and its production and use Download PDFInfo
- Publication number
- CN107827762A CN107827762A CN201711121867.2A CN201711121867A CN107827762A CN 107827762 A CN107827762 A CN 107827762A CN 201711121867 A CN201711121867 A CN 201711121867A CN 107827762 A CN107827762 A CN 107827762A
- Authority
- CN
- China
- Prior art keywords
- preparation
- dioleoyls
- propyl group
- ammonio methacrylate
- methyl
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
Abstract
The invention discloses the preparation method that a kind of (2,3 dioleoyl propyl group) three changes ammonio methacrylate, prepare with the following method：First; the propane diols of 3 dimethylamino 1,2 and oleic acid or oleoyl chloride are reacted to obtain the amido propane of 1,2 dioleoyl 3 two; then react to obtain the change ammonio methacrylate of (2,3 dioleoyl propyl group) three with chloromethanes under 0.1 10 MPas.The method of the invention is adapted to pilot-scale production, and it is a kind of cationic-liposome phosphatide that (2, the 3 dioleoyl propyl group) three being prepared, which changes ammonio methacrylate, pharmaceutic adjuvant can be used as to be used for all kinds medicines such as parenteral solution, tablet, capsule.
Description
Technical field
The invention belongs to medical auxiliary materials field.Change ammonio methacrylate more particularly to a kind of (2,3- dioleoyls-propyl group) three
And preparation method and purposes.
Background technology
Phosphatide is the important component of biomembrane, and it is intrinsic not only to have a hydrophily but also have lipophilic parents' property and cause
Phosphatide spontaneous can form closure bilayer in aqueous medium, turn into biomembrane skeleton.Grown up using the property a kind of new
The liposome of type drug preparation technique one.Liposome is initially to be dispersed in water phosphatide by British scholar Bangham to pass through Electronic Speculum
Found during observation, liposome is used for pharmaceutical carrier by Britain Lai Men in 1971 et al..Hydrogenated soy phosphatidyl choline is with soybean phosphorus
Fat is raw material, extracts high purity lecithin, then develop by catalytic hydrogenation process.The product is in faint yellow or milky white toner
Shape.Due to using catalysis and hydrogenation technique, the unsaturated chain of unrighted acid in soybean lecithin molecular structure is set to disappear, so as to
Greatly improve chemical stability, dispersiveness, the emulsibility of lecithin.With decolouring, deodorization functions, it is more beneficial for storage and protects
Pipe, improves the effect in medicine, superior cosmetics, light industry.Particularly it is applicable and does intravenous injection fatty emulsifying agent and nutrition
Agent.It makees blood fat emulsifying agent, prevents artery sclerosis, and has easy to digest, easy the advantages of absorbing, be hardly remaining in internal organ.
The structure that (2,3- dioleoyls-propyl group) three changes ammonio methacrylate is as follows：
The content of the invention
At present it is not yet reported that (2,3- dioleoyls-propyl group) three change the preparation method of ammonio methacrylate, this hair in document
A kind of bright to be tested by substantial amounts of, the creative industrialization for providing (2,3- dioleoyls-propyl group) three and changing ammonio methacrylate
Preparation method, using 3- dimethylamino-1,2-propanediols as reaction raw materials, react to obtain the oil of 1,2- bis- with oleic acid or oleoyl chloride
Two amidos of acyl group -3--propane, then reacted with chloromethanes under certain temperature and pressure and obtain (2,3- dioleoyls-propyl group) three
Change ammonio methacrylate, can obtain (2,3- dioleoyls-propyl group) three of the purity more than 99% by crystallization purifying method changes methyl chloride
Change ammonium.Preparation method of the present invention is simple to operate, and purification step is simple, is adapted to industrialized production.
It is an object of the present invention to provide the preparation side that a kind of (2,3- dioleoyls-propyl group) three changes ammonio methacrylate
Method, comprise the following steps：
(1) 3- dimethylamino -1,2- propane diols and oleic acid obtained under condensation reagent effect the amidos of 1,2- dioleoyls -3- two -
Propane, or, 3- dimethylamino-1,2-propanediols and oleoyl chloride and alkali reaction be prepared the amidos of 1,2- dioleoyls -3- two -
Propane；
Or
The reaction dissolvent of above-mentioned reaction is selected from tetrahydrofuran, 2- methyltetrahydrofurans, dichloromethane, chloroform, acetonitrile, 1,4-
One or more in dioxane, toluene, methyl tertiary butyl ether(MTBE), N,N-dimethylformamide, acetone 1-METHYLPYRROLIDONE.
The condensation reagent that above-mentioned reaction uses is selected from DCC-DMAP systems, HOBT-HATU systems or the miaow of N, N'- carbonyl two
Azoles.
The alkali that above-mentioned reaction uses is selected from sodium carbonate, sodium acid carbonate, potassium carbonate, saleratus, lithium hydroxide, hydroxide
Sodium, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, three second
Amine, diisopropyl ethyl amine, pyridine, N, N- lutidines, N- methyl piperidines, morpholine or one kind or several in N-methylmorpholine
Kind.
The reaction temperature of above-mentioned reaction is -30 DEG C to 50 DEG C, reaction time 1-10h, -20 DEG C of preferable reaction temperature -10 DEG C,
Reaction time 2-5h.
Two amidos of 1,2- dioleoyl -3--propane reacts to obtain the change methyl of (2,3- dioleoyls-propyl group) three with chloromethanes
Ammonium chloride；
The reaction dissolvent of above-mentioned reaction is selected from methanol, ethanol, isopropanol, water, tetrahydrofuran, 2- methyltetrahydrofurans, dichloromethane
Alkane, chloroform, acetonitrile, 1,4- dioxane, toluene, methyl tertiary butyl ether(MTBE), N,N-dimethylformamide, acetone N- methyl pyrroles
One or more in pyrrolidone.
The reaction temperature of above-mentioned reaction is -20 DEG C to 200 DEG C.The reaction pressure of above-mentioned reaction is 0.1-10 MPas.It is preferred that
Reaction pressure 1.5MPa, reacts 5-24h by 60 DEG C -90 DEG C.
Under normal temperature and pressure, chloromethanes is gaseous state, can make chloromethanes in liquid form by selecting control pressure and temperature
Reacted with 1,2- dioleoyl -3-, two amidos-propane, such as -30 DEG C~-25 DEG C, chloromethanes is liquid, selects normal pressure, when
When temperature is higher than -23.7 DEG C, by adjusting reacting kettle inner pressure, gaseous chloromethanes is converted into liquid and participate in reaction.
Preparation method of the present invention can further include purification step, using methanol, ethanol, isopropanol, water,
Tetrahydrofuran, 2- methyltetrahydrofurans, dichloromethane, chloroform, acetonitrile, 1,4- dioxane, toluene, methyl tertbutyl
One or more in ether, N,N-dimethylformamide, acetone, 1-METHYLPYRROLIDONE are to (2,3- dioleoyls-propyl group) three
Change ammonio methacrylate and carry out crystallization purifying.
Another object of the present invention is to provide a kind of hydrogenated soy phosphatidyl choline, it is characterised in that the method for the invention system
Standby purifying obtains, wherein the purity that (2,3- dioleoyls-propyl group) three change ammonio methacrylate is not less than 99%.
Another object of the present invention is to provide the purposes of above-mentioned hydrogenated soy phosphatidyl choline, it is used for medicine as medical auxiliary materials
Or the preparation of health products.
The product quality obtained in the present invention is stable, by degerming and vacuum drying, meets medical injection and excipient substance
Standard.
Brief description of the drawings
Fig. 1 is that (2,3- dioleoyls-propyl group) three is made using external standard method the inventive method to change ammonio methacrylate
HPLC schemes.
Embodiment
It will be helpful to understand the present invention by following embodiments, but should not be construed as limiting the invention.
The preparation of two amidos of 1,2- dioleoyl-3- of embodiment 1-propane
Method 1：3- dimethylamino -1,2- propane diols 500g, 1600g diisopropylethylamine and 15L tetrahydrofurans are added into reaction
In kettle, subzero 5 DEG C are cooled to, it is nitrogen to replace gas in axe, and oleoyl chloride 2800g tetrahydrofuran solution is slowly added dropwise, and is kept
Reactor temperature is not higher than 10 DEG C, is then slowly increased to room temperature, continues to react 2-3 hours, is concentrated under reduced pressure, adds second
Acetoacetic ester and cold water, liquid separation, organic phase saturated common salt water washing, liquid separation, organic phase, filtering are dried with anhydrous magnesium sulfate.Have
Machine is mutually concentrated and dried and obtains 1,2- dioleoyl -3-, two amidos-propane 2580g, yield 95% at reduced pressure conditions.
Method 2：By oleic acid (751g, 251mmol, 3.0 equivalent), DCC (3.0 equivalent), DMAP (2.1 equivalent) and 1L chloroforms
Add in reaction bulb, be cooled to 5-10 DEG C, it is nitrogen to replace gas in axe, and 3- dimethylamino-1,2-propanediols are slowly added dropwise
The chloroformic solution of (100g, 84mmol), keep reactor temperature to be not higher than 10 DEG C, be then slowly increased to room temperature, continue to react
12-20 hours, concentrate under reduced pressure, crude product is purified with silica gel chromatography, obtains 1,2- dioleoyl -3-, two amidos-propane
468g, yield 86%.
1H NMR(300MHz,d6DMSO) δ=5.53 (m, 4H), 4.57 (m, 1H), 2.11-2.76 (m, 14H), 2.83
(s,6H),1.21-1.36(m,40H),0.89(m,6H)；MS(m/z)[M+H]+calcd for C41H78NO4+648.6,
found 648.5。
Embodiment 2 (2,3- dioleoyls-propyl group) three changes the preparation of ammonio methacrylate
The influence of reaction temperature, pressure, solvent to product is investigated with reference to table 1.By two amidos of 1,2- dioleoyl -3--propane and
Reaction dissolvent is added in autoclave, and it is nitrogen to replace gas in axe, is then chloromethanes by nitrogen displacement, slowly boosts to
1.5 MPas, pressure is kept, is slowly ramped to design temperature, and reacts 5-24 hours at this temperature and pressure, is down to room temperature,
Blowdown pressure, reaction solution is gone in normal-pressure reaction kettle, be slowly added into recrystallisation solvent, now had white solid precipitation, continue
Stirred under normal temperature 2-5 hours, filtering, solid is washed with recrystallisation solvent, and solid is dried at reduced pressure conditions, obtains (2,3- bis- oil
Acyl group-propyl group) three change ammonio methacrylates, calculate feed stock conversion.
The influence of the different temperatures of table 1 and pressure to feed stock conversion
| Two amidos of 1,2- dioleoyl -3--propane | Reaction dissolvent | Temperature DEG C | Pressure | Conversion ratio | |
| 1 | 50g | Tetrahydrofuran | 50 | 1.5 MPa | 26.3% |
| 2 | 50g | Tetrahydrofuran | 60 | 1.5 MPa | 53.5% |
| 3 | 50g | Tetrahydrofuran | 70 | 1.5 MPa | 87.2% |
| 4 | 50g | Tetrahydrofuran | 85 | 1.5 MPa | 95.3% |
| 5 | 50g | Tetrahydrofuran | 90 | 1.5 MPa | 95.2% |
As a result show, under 1.5 MPas, when being increased to 85 DEG C with reaction temperature, the conversion ratio of raw material reaches highest.Selection
It is prepared by the reaction condition.The influence of reaction dissolvent and purification solvent to product yield and purity is investigated with reference to the condition of table 3.
HPLC conditions：
With C18 chromatographic columns, example Phenomenex, Gemini, 5u C18 110A,：With methanol-acetic acid salt buffer (pH=4.5)
=9:1 is mobile phase A, chloroform-methanol-acetate buffer (PH=4.5)=30:20:1 is Mobile phase B；40 DEG C of column temperature；Press
Table 2 carries out gradient elution；EISD Agilent A380,40 DEG C of temperature, nitrogen flow rate are 1.5L per minute.
Table 2
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 85 | 15 |
| 30 | 0 | 100 |
| 30.1 | 85 | 15 |
| 40 | 85 | 15 |
The influence of the differential responses solvent of table 3 and purification solvent to product yield and purity
| DOTAP | Reaction dissolvent | Recrystallisation solvent | Yield % | Purity | |
| 1 | 10.0g | Tetrahydrofuran | Methyl tertiary butyl ether(MTBE) | 89% | 99% |
| 2 | 10.0g | Tetrahydrofuran | Acetone | 91% | 96.5% |
| 3 | 10.0g | Chloroform | Methyl tertiary butyl ether(MTBE) | 73% | 99% |
| 4 | 10.0g | Dichloromethane | Methyl tertiary butyl ether(MTBE) | 87% | 98.3% |
| 5 | 10.0g | Chloroform | Acetone | 83% | 97.9% |
| 6 | 10.0g | Dichloromethane | Acetone | 92% | 97.3% |
As a result show that more excellent product purity can be reached using methyl tertiary butyl ether(MTBE) as recrystallisation solvent.The condition is selected to prepare
(2,3- dioleoyls-propyl group) three changes ammonio methacrylate.
1,2- dioleoyl -3-, two amidos-propane 2200g and 13.2L tetrahydrofuran is added in autoclave, displacement
Gas is nitrogen in axe, is then chloromethanes by nitrogen displacement, slowly boosts to 1.5 MPas, keeps pressure, is slowly ramped to 85
DEG C, and 5-24 hours are reacted at this temperature and pressure, room temperature is down to, blowdown pressure, reaction solution is gone in normal-pressure reaction kettle,
Methyl tertiary butyl ether(MTBE) 10L is slowly added into, now there is white solid precipitation, continues to stir at normal temperatures 2-5 hours, filtering, solid
Washed with methyl tertiary butyl ether(MTBE), solid is dried at reduced pressure conditions, is obtained (2,3- dioleoyls-propyl group) three and is changed ammonio methacrylate
2107g, yield 89%, the HPLC purity of external standard method product is used as 99.1%, as a result as shown in Figure 1.
1H NMR(300MHz,d6DMSO) δ=5.62 (m, 4H), 4.63 (m, 1H), 2.14-2.72 (m, 14H), 3.62
(s,9H),1.19-1.32(m,40H),0.91(m,6H)；MS(m/z)[M+H]+calcd for C41H78NO4+648.6,
found 648.5。white solid。
Claims (10)
- (1. 2,3- dioleoyls-propyl group) three change the preparation method of ammonio methacrylate, it is characterised in that comprise the following steps：(1) 3- dimethylamino -1,2- propane diols and oleic acid obtained under condensation reagent effect the amidos of 1,2- dioleoyls -3- two - Propane, or, 3- dimethylamino-1,2-propanediols and oleoyl chloride and alkali reaction be prepared the amidos of 1,2- dioleoyls -3- two - Propane,(2) two amidos of 1,2- dioleoyls -3--propane reacts to obtain the change methyl of (2,3- dioleoyls-propyl group) three with chloromethanes Ammonium chloride,
- 2. preparation method as claimed in claim 1, it is characterised in that step (1) reaction dissolvent is tetrahydrofuran, 2- methyl four Hydrogen furans, dichloromethane, chloroform, acetonitrile, 1,4- dioxane, toluene, methyl tertiary butyl ether(MTBE), N, N- dimethyl formyls One or more in amine, acetone 1-METHYLPYRROLIDONE.
- 3. preparation method as claimed in claim 1, it is characterised in that the condensation reagent used in step (1) is selected from DCC-DMAP System, HOBT-HATU systems or N, N'- carbonyl dimidazoles.
- 4. preparation method as claimed in claim 1, it is characterised in that the alkali used in step (1) is selected from sodium carbonate, bicarbonate Sodium, potassium carbonate, saleratus, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, methanol Sodium, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropyl ethyl amine, pyridine, N, N- lutidines, N- methyl One or more in piperidines, morpholine or N-methylmorpholine.
- 5. preparation method as claimed in claim 1, it is characterised in that step (1) reaction temperature is -30 DEG C to 80 DEG C.
- 6. preparation method as claimed in claim 1, it is characterised in that step (2) reaction dissolvent be methanol, ethanol, isopropanol, Water, tetrahydrofuran, 2- methyltetrahydrofurans, dichloromethane, chloroform, acetonitrile, 1,4- dioxane, toluene, methyl- tert fourth One or more in base ether, N,N-dimethylformamide, acetone 1-METHYLPYRROLIDONE.
- 7. preparation method as claimed in claim 1, it is characterised in that the reaction temperature of step (2) is -20 DEG C to 200 DEG C, instead It is 0.1-10 MPas to answer pressure.
- 8. preparation method as claimed in claim 1, it is characterised in that also including further purification step, use methanol, second Alcohol, isopropanol, water, tetrahydrofuran, 2- methyltetrahydrofurans, dichloromethane, chloroform, acetonitrile, 1,4- dioxane, first One or more in benzene, methyl tertiary butyl ether(MTBE), N,N-dimethylformamide, acetone 1-METHYLPYRROLIDONE are crystallized.
- 9. a kind of (2,3- dioleoyls-propyl group) three change ammonio methacrylate, it is characterised in that wherein (2,3- dioleoyls-propyl group) Three purity for changing ammonio methacrylate are not less than 99%.
- 10. (2,3- dioleoyls-propyl group) three as claimed in claim 9 change the purposes of ammonio methacrylate, it is characterised in that make It is used for the preparation of medicine or health products for medical auxiliary materials.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711121867.2A CN107827762B (en) | 2017-11-14 | 2017-11-14 | (2, 3-dioleoyl-propyl) trimethyl ammonium chloride and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711121867.2A CN107827762B (en) | 2017-11-14 | 2017-11-14 | (2, 3-dioleoyl-propyl) trimethyl ammonium chloride and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107827762A true CN107827762A (en) | 2018-03-23 |
| CN107827762B CN107827762B (en) | 2020-10-02 |
Family
ID=61654372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711121867.2A Active CN107827762B (en) | 2017-11-14 | 2017-11-14 | (2, 3-dioleoyl-propyl) trimethyl ammonium chloride and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107827762B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264618A (en) * | 1990-04-19 | 1993-11-23 | Vical, Inc. | Cationic lipids for intracellular delivery of biologically active molecules |
| US5595756A (en) * | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
| WO2012024233A2 (en) * | 2010-08-14 | 2012-02-23 | The Regents Of The University Of California | Zwitterionic lipids |
| CN103547560A (en) * | 2011-05-20 | 2014-01-29 | 默克专利股份有限公司 | Stable crystal modifications of DOTAP chloride |
| CN104922141A (en) * | 2015-05-28 | 2015-09-23 | 厦门成坤生物技术有限公司 | siRNA composition for treating viral hepatitis B |
| CN107001238A (en) * | 2014-12-08 | 2017-08-01 | 日油株式会社 | The manufacture method of cation lipid |
-
2017
- 2017-11-14 CN CN201711121867.2A patent/CN107827762B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5264618A (en) * | 1990-04-19 | 1993-11-23 | Vical, Inc. | Cationic lipids for intracellular delivery of biologically active molecules |
| US5595756A (en) * | 1993-12-22 | 1997-01-21 | Inex Pharmaceuticals Corporation | Liposomal compositions for enhanced retention of bioactive agents |
| WO2012024233A2 (en) * | 2010-08-14 | 2012-02-23 | The Regents Of The University Of California | Zwitterionic lipids |
| CN103547560A (en) * | 2011-05-20 | 2014-01-29 | 默克专利股份有限公司 | Stable crystal modifications of DOTAP chloride |
| CN107001238A (en) * | 2014-12-08 | 2017-08-01 | 日油株式会社 | The manufacture method of cation lipid |
| CN104922141A (en) * | 2015-05-28 | 2015-09-23 | 厦门成坤生物技术有限公司 | siRNA composition for treating viral hepatitis B |
Non-Patent Citations (3)
| Title |
|---|
| FRANCIS C. SZOKA, JR.等: "Inverse-Phosphocholine Lipids: A Remix of a Common Phospholipid", 《J. AM. CHEM. SOC.》 * |
| FRANCIS C. SZOKA等: "Synthesis and characterization of novel zwitterionic lipids with pH-responsive biophysical properties", 《CHEM. COMMUN.》 * |
| YOUNG-BAE SEU等: "Synthesis of NBD-Labeled DOTAP Analog to Track Intracellular Delivery of Liposome", 《J. MICROBIOL. BIOTECHNOL.》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107827762B (en) | 2020-10-02 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105175401A (en) | Preparation method of brexpiprazole | |
| CN110330524A (en) | Bis- palmityl-SN- glycerol -3- phosphatidyl ethanolamine of 1,2- and preparation method thereof | |
| CN103374050B (en) | One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid | |
| CN107827762A (en) | A kind of (2,3 dioleoyl propyl group) three changes ammonio methacrylate and its production and use | |
| CN107033210B (en) | A kind of preparation method of fulvestrant and its intermediate | |
| EP2669293A1 (en) | Preparation method of rocuronium | |
| CN111978281A (en) | Method for preparing cyclohexanone/chromene pyrone compound and application of cyclohexanone/chromene pyrone compound | |
| CN105523957B (en) | The method that one kettle way prepares scheme for lacosamide | |
| CN114437043B (en) | Preparation method of anti-new crown drug Nirmatrelvir | |
| CN110305142A (en) | A kind of Stereoselective synthesizing process of 6 beta-hydroxy morphine derivatives | |
| CN103145636A (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| CN103374049B (en) | One prepares 5,6, the method for 4 '-trihydroxyflavone-7-0-D-glucuronic acid | |
| CN101215281A (en) | Isoflavone sulfonate derivatives and synthetic method thereof | |
| CN105646284B (en) | A kind of synthetic method of scheme for lacosamide | |
| CN104529958A (en) | Preparation method of Ramelteon | |
| CN112745309B (en) | Chromone 3-position nitric oxide donor derivative and preparation method and application thereof | |
| CN103864638A (en) | Benzoic acid compound, and preparation method and application thereof | |
| CN103044467A (en) | Method for preparing intermediate used for synthesizing bortezomib | |
| CN112745310B (en) | Chromone 2-piperazine linked furazan derivative and preparation method and application thereof | |
| CN102731437A (en) | Preparation method of 4-piperazine-3-trifluoromethylaniline hydrochloride | |
| EP2586774A1 (en) | Method for preparation of ranolazine | |
| CN111574524B (en) | 2- (tert-butoxycarbonyl) -7-oxyylidene-2, 6-diazaspiro [3.4] octane-5-carboxylic acid preparation method | |
| CN101812099B (en) | Flavonoids compound and synthesis method and application thereof | |
| CN112679484B (en) | Preparation method of chiral intermediate and chiral isomer of neuraminidase inhibitor | |
| CN107400065A (en) | Application of the asymmetric conjugated reaction reaction in the synthesis of Yi Gelieting intermediates |
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 | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zong Xi Inventor after: Yu Wenyuan Inventor after: Wang Dongdong Inventor after: Hu Haiyan Inventor after: Ji Min Inventor after: Zhang Ying Inventor before: Ji Min Inventor before: Hu Haiyan Inventor before: Liu Haidong Inventor before: Zong Xi Inventor before: Li Rui Inventor before: Wan Guangpeng Inventor before: Wang Dongdong Inventor before: Yang Su Inventor before: Yu Wenyuan Inventor before: Zhang Ying |