CN103086875A - Synthetic method of felbinac non-steroidal anti-inflammatory agent - Google Patents
Synthetic method of felbinac non-steroidal anti-inflammatory agent Download PDFInfo
- Publication number
- CN103086875A CN103086875A CN2013100386604A CN201310038660A CN103086875A CN 103086875 A CN103086875 A CN 103086875A CN 2013100386604 A CN2013100386604 A CN 2013100386604A CN 201310038660 A CN201310038660 A CN 201310038660A CN 103086875 A CN103086875 A CN 103086875A
- Authority
- CN
- China
- Prior art keywords
- synthetic method
- felbinac
- preferred
- ethylene glycol
- base catalysis
- 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.)
- Pending
Links
- QRZAKQDHEVVFRX-UHFFFAOYSA-N biphenyl-4-ylacetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 229960000192 felbinac Drugs 0.000 title claims abstract description 29
- 238000010189 synthetic method Methods 0.000 title claims abstract description 17
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 title claims abstract description 9
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 title abstract description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 37
- HSZCNGTZJWZAMF-UHFFFAOYSA-N 2-(4-phenylphenyl)acetonitrile Chemical compound C1=CC(CC#N)=CC=C1C1=CC=CC=C1 HSZCNGTZJWZAMF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000001953 recrystallisation Methods 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 230000007062 hydrolysis Effects 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 239000012046 mixed solvent Substances 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 10
- 238000005815 base catalysis Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- WWLVEMOKDAVHDW-UHFFFAOYSA-N C(CO)O.[Na].[Na] Chemical compound C(CO)O.[Na].[Na] WWLVEMOKDAVHDW-UHFFFAOYSA-N 0.000 claims description 3
- -1 hydrated barta Chemical compound 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 230000004044 response Effects 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 2
- 238000007171 acid catalysis Methods 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000006210 lotion Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical group [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 208000000112 Myalgia Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 238000001026 1H--1H correlation spectroscopy Methods 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010034464 Periarthritis Diseases 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 208000004760 Tenosynovitis Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 102000011759 adducin Human genes 0.000 description 1
- 108010076723 adducin Proteins 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- GWZCCUDJHOGOSO-UHFFFAOYSA-N diphenic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1C(O)=O GWZCCUDJHOGOSO-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 229940040145 liniment Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthetic method of a felbinac non-steroidal anti-inflammatory agent. The synthetic method is characterized by comprising the following steps of: regarding biphenyl acetonitrile as a starting raw material; and carrying out alkaline catalytic hydrolysis, acidification and recrystallization in a mixed solvent of ethylene glycol and water to obtain a target product. The synthetic method of the felbinac non-steroidal anti-inflammatory agent can avoid the problem of acid catalysis, hydrolysis, decarboxylation and allosterism of the biphenyl acetonitrile efficiently, and obviously improve purity and yield coefficient of the felbinac.
Description
Technical field
The invention belongs to the chemical pharmaceutical field, relate to the preparation method of organic drug, be specially a kind of synthetic method of non-steroid anti-inflammatory agent felbinac.
Background technology
Felbinac is NSAID (non-steroidal anti-inflammatory drug), has potent anti-inflammatory analgesic action, treatment of arthritis and myalgia is had the characteristics such as quick-acting, efficient and safety, is applicable to after arthritis deformans, scapulohumeral periarthritis, tenosynovitis, myalgia, wound the symptoms such as swelling.Felbinac ointment (trade(brand)name " Napagel ") goes on the market in Japan in September, 1986, and at present felbinac liniment (trade(brand)name " Fan Kexin ") and gelifying agent (trade(brand)name " Tong Er its ") go on the market in China.(CN 100439314 for document, CN101143815) the synthetic route great majority of report felbinac are that the biphenyl acetonitrile is through the aqueous sulfuric acid catalytic hydrolysis, but the reaction mechanism of this synthetic route is carbonium ion nucleophilic addition(Adn) process, easily decarboxylation generates the by product diphenic acid, and the biphenyl acetonitrile is slightly soluble in water, the principal product felbinac is water-soluble under acidic conditions also to be reduced greatly, substrate and product all can not be dissolved in reaction solution, cause the acidic catalyst hydrolysis to occur with solid-liquid two-phase form all the time, reacted product repeatedly all is being difficult to separating-purifying after recrystallization, yield is low.
The objective of the invention is for above-mentioned shortcoming, provide a kind of technique simple, easy to operate, the novel synthesis of the felbinac that product purity and yield are high.
Summary of the invention
The present invention synthesizes felbinac, is take the biphenyl acetonitrile as starting raw material, in the mixed solvent of ethylene glycol and water, obtains felbinac after base catalysis hydrolysis, acidifying, recrystallization.Reaction scheme is as follows:
The synthetic method of non-steroid anti-inflammatory agent felbinac of the present invention, that the biphenyl acetonitrile is dissolved in certain density aqueous glycol solution, add alkaline matter, be heated to certain temperature, reaction is cooling after certain hour splashes into acid, after question response liquid becomes acidity, filter the solid of separating out, obtain the high felbinac of purity after recrystallization.
In the mixed solvent of the above ethylene glycol and water, the volumetric concentration of ethylene glycol is 80%-95%, preferred 85%-90%.
The above alkaline matter is wherein any one of potassium hydroxide, sodium hydroxide, hydrated barta, sodium methylate, sodium ethylate, ethylene glycol disodium, preferred potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate.
The mol ratio of above-described alkaline matter and biphenyl acetonitrile is 2: 1-8: 1.
Above-described base catalysis hydrolysising reacting temperature is 120 ℃-160 ℃, preferred 140 ℃-150 ℃.
Above-described base catalysis hydrolysis time is 2h-8h, preferred 4h-6h.
The above acid is hydrochloric acid, and concentration is 1mol/L – 4mol/L, preferred 1mol/L – 2mol/L.
Above-described acidizing degree is pH3.5-4.0.
The invention has the beneficial effects as follows: adopt the mixed solvent of polyvalent alcohol and water, temperature of reaction improves, and the reaction times shortens, product is easy to purifying, and after recrystallization, the finished product yield still can reach 90% left and right, and purity reaches more than 99.8%, single assorted less than less than 0.1%, technique is applicable to industrial production.
Embodiment
In order to make those skilled in the art better understand technical scheme of the present invention, below in conjunction with embodiment, technical scheme of the present invention is described in further detail.
Embodiment 1:
Add biphenyl acetonitrile (20.9g, 0.1mol) in reaction flask, add 80% aqueous glycol solution 200mL, add potassium hydroxide (28g, 0.5mol) under stirring, be heated to 120 ℃, reaction 8h.Reaction is finished, and naturally cools to room temperature, and the hydrochloric acid of the cooling lower dropping 4mol/L of ice-water bath is to reaction solution pH3.5, in-20 ℃ of standing 12h, the solid that filtration is separated out, distilled water wash to the pH of washing lotion greater than 5.0, the butanone recrystallization, get felbinac white plates crystallization 20.6g, fusing point 163-164 ℃, to measure through HPLC, purity is more than 99.8%, single assorted less than 0.1%, yield 90.3%.
Embodiment 2:
Add biphenyl acetonitrile (20.9g, 0.1mol) in reaction flask, add 95% aqueous glycol solution 200mL, add sodium hydroxide (32g, 0.8mol) under stirring, be heated to 150 ℃, reaction 6.5h.Reaction is finished, and naturally cools to room temperature, and the hydrochloric acid of the cooling lower dropping 2mol/L of ice-water bath is to reaction solution pH3.5, in-20 ℃ of standing 12h, the solid that filtration is separated out, distilled water wash to the pH of washing lotion greater than 5.0, the butanone recrystallization, get felbinac white plates crystallization 22.3g, fusing point 163-165 ℃, to measure through HPLC, purity is more than 99.8%, single assorted less than 0.1%, yield 97.7%.
Embodiment 3:
Add biphenyl acetonitrile (20.9g, 0.1mol) in reaction flask, add 90% aqueous glycol solution 200mL, add sodium methylate (21.6g, 0.4mol) under stirring, be heated to 140 ℃, reaction 4h.Reaction is finished, and naturally cools to room temperature, and the hydrochloric acid of the cooling lower dropping 1mol/L of ice-water bath is to reaction solution pH3.5, in-20 ℃ of standing 12h, the solid that filtration is separated out, distilled water wash to the pH of washing lotion greater than 5.0, the butanone recrystallization, get felbinac white plates crystallization 21.9g, fusing point 163-164 ℃, to measure through HPLC, purity is more than 99.8%, single assorted less than 0.1%, yield 96.2%.
Embodiment 4:
Add biphenyl acetonitrile (20.9g, 0.1mol) in reaction flask, add 85% aqueous glycol solution 200mL, add sodium ethylate (34g, 0.5mol) under stirring, be heated to 130 ℃, reaction 5h.Reaction is finished, naturally cool to room temperature, the hydrochloric acid of the cooling lower dropping 1mol/L of ice-water bath filters the solid of separating out to reaction solution pH3.5, distilled water wash to the pH of washing lotion greater than 5.0, butanone recrystallization recrystallization gets felbinac white plates crystallization 21.7g, fusing point 163-164 ℃, measure through HPLC, purity is more than 99.8%, and is single assorted less than 0.1%, yield 95.6%.
Embodiment 5:
Add biphenyl acetonitrile (20.9g, 0.1mol) in reaction flask, add 80% aqueous glycol solution 300mL, add hydrated barta (42.8g, 0.25mol) under stirring, be heated to 120 ℃, reaction 7h.Reaction is finished, and naturally cools to room temperature, and the hydrochloric acid of the cooling lower dropping 4mol/L of ice-water bath is to reaction solution pH3.5, in-20 ℃ of standing 12h, the solid that filtration is separated out, distilled water wash to the pH of washing lotion greater than 5.0, the butanone recrystallization, get felbinac white plates crystallization 21.2g, fusing point 163-164 ℃, to measure through HPLC, purity is more than 99.8%, single assorted less than 0.1%, yield 94%.
Embodiment 6:
Add biphenyl acetonitrile (20.9g, 0.1mol) in reaction flask, add 80% aqueous glycol solution 100mL, add ethylene glycol disodium (21.2g, 0.2mol) under stirring, be heated to 120 ℃, reaction 4h.Reaction is finished, and naturally cools to room temperature, and the hydrochloric acid of the cooling lower dropping 1mol/L of ice-water bath is to reaction solution pH3.5, in-20 ℃ of standing 12h, the solid that filtration is separated out, distilled water wash to the pH of washing lotion greater than 5.0, the butanone recrystallization, get felbinac white plates crystallization 22.1g, fusing point 163-164 ℃, to measure through HPLC, purity is more than 99.8%, single assorted less than 0.1%, yield 97%.
Get appropriate felbinac sample, the ultimate analysis measured value: C:79.19 H:5.72 theoretical value: C:79.22 H:5.70; Measure
1H-NMR one dimension spectrum, heavy water exchange spectrum and
1H-
1H Correlated Spectroscopy (COSY) spectrum, determination data sees Table 1; In DMSO-d6
13C-NMR determination data (ppm) sees Table 2; Compose each absorption peak ownership at IR and see Table 3.
The hydrogen spectrum data (ppm) of table 1 felbinac sample in DMSO-d6
*After the heavy water exchange, the peak disappears.
Table 2 felbinac sample is in DMSO-d6
13C-NMR data (ppm)
The IR of table 3 felbinac sample composes each absorption peak ownership
With reference to above-described embodiment; the detailed description that the felbinac synthetic method is carried out is illustrative rather than determinate; can list several embodiment according to institute's limited range, therefore in the variation and the modification that do not break away under general plotting of the present invention, within protection scope of the present invention should be belonged to.
Claims (9)
1. the synthetic method of a non-steroid anti-inflammatory agent felbinac, is characterized in that take the biphenyl acetonitrile as starting raw material, in the mixed solvent of ethylene glycol and water, obtains target product after base catalysis hydrolysis, acidifying, recrystallization.
2. synthetic method according to claim 1, it is characterized in that: the biphenyl acetonitrile is dissolved in certain density aqueous glycol solution, add alkaline matter, be heated to certain temperature, reaction is cooling after certain hour splashes into acid, after question response liquid becomes acidity, filter the solid of separating out, obtain felbinac after recrystallization.
3. synthetic method according to claim 2 is characterized in that the volumetric concentration of ethylene glycol in the mixed solvent of described ethylene glycol and water is 80%-95%, preferred 85%-90%.
4. synthetic method according to claim 2, it is characterized in that described base catalysis hydrolysis alkaline matter used is wherein any one of potassium hydroxide, sodium hydroxide, hydrated barta, sodium methylate, sodium ethylate, ethylene glycol disodium, preferred potassium hydroxide, sodium hydroxide, sodium methylate, sodium ethylate.
5. synthetic method according to claim 2, is characterized in that described base catalysis is hydrolyzed alkaline matter used and the mol ratio of biphenyl acetonitrile is 4: 1-8: 1.
6. synthetic method according to claim 2, is characterized in that described base catalysis hydrolysising reacting temperature is 120 ℃-160 ℃, preferred 140 ℃-150 ℃.
7. synthetic method according to claim 2, is characterized in that described base catalysis hydrolysis time is 2h-8h, preferred 4h-6h.
8. synthetic method according to claim 2, is characterized in that described acidifying acid used is hydrochloric acid, and concentration is 1mol/L – 8mol/L, preferred 2mol/L – 4mol/L.
9. synthetic method according to claim 2, is characterized in that described acidizing degree is pH3.5-4.0.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100386604A CN103086875A (en) | 2013-02-01 | 2013-02-01 | Synthetic method of felbinac non-steroidal anti-inflammatory agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100386604A CN103086875A (en) | 2013-02-01 | 2013-02-01 | Synthetic method of felbinac non-steroidal anti-inflammatory agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103086875A true CN103086875A (en) | 2013-05-08 |
Family
ID=48200067
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013100386604A Pending CN103086875A (en) | 2013-02-01 | 2013-02-01 | Synthetic method of felbinac non-steroidal anti-inflammatory agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103086875A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1201661A1 (en) * | 1999-07-15 | 2002-05-02 | Sumitomo Pharmaceuticals Company, Limited | Heteroaromatic ring compounds |
| CN1807390A (en) * | 2006-01-27 | 2006-07-26 | 浙江大学 | Non-steroid anti-inflammatory agent felbinac preparation method |
| CN101143815A (en) * | 2007-07-09 | 2008-03-19 | 武汉工程大学 | The preparation method of felbinac |
| CN102010317A (en) * | 2010-11-02 | 2011-04-13 | 中国科学技术大学 | Method for synthesizing felbinac and derivatives thereof |
-
2013
- 2013-02-01 CN CN2013100386604A patent/CN103086875A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1201661A1 (en) * | 1999-07-15 | 2002-05-02 | Sumitomo Pharmaceuticals Company, Limited | Heteroaromatic ring compounds |
| CN1807390A (en) * | 2006-01-27 | 2006-07-26 | 浙江大学 | Non-steroid anti-inflammatory agent felbinac preparation method |
| CN101143815A (en) * | 2007-07-09 | 2008-03-19 | 武汉工程大学 | The preparation method of felbinac |
| CN102010317A (en) * | 2010-11-02 | 2011-04-13 | 中国科学技术大学 | Method for synthesizing felbinac and derivatives thereof |
Non-Patent Citations (3)
| Title |
|---|
| ANTONIO FACCHETTI，ANDREW STREITWIESER: "Ion Pair Acidities and Aggregation of Some Amide and Oxazoline Enolates in THF", 《J.ORG.CHEM.》 * |
| 伍晓春: "非甾体抗炎药联苯乙酸的简便合成方法", 《华西药学杂志》 * |
| 张田林 等: "4-联苯乙酸的新法合成", 《中国医药工业杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103664561B (en) | The preparation method of a kind of metconazole and intermediate thereof | |
| CN102516122A (en) | Environment friendly method for preparing DMF (Dimethyl Formamide) solution of 2-hydroxy-benzonitril, DMF solution of 2-hydroxy-benzonitril and application thereof | |
| CN106279104B (en) | A kind of process modification method preparing amber love song Ge Lieting | |
| CN105330598A (en) | Preparing method for pirfenidone | |
| CN103242177A (en) | Preparation method of 2,5-diaminophenethyl alcohol sulfate | |
| CN107118215B (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate | |
| CN100999483B (en) | Preparation process of p-nitro phenyl hydrazine hydrochloride | |
| CN104402890A (en) | Preparation method of penoxsulam | |
| CN102942532A (en) | Preparation method of 1,4,7,10-tetraazadodecane | |
| CN109988108A (en) | A kind of rich preparation method for Buddhist nun of card | |
| CN103086875A (en) | Synthetic method of felbinac non-steroidal anti-inflammatory agent | |
| CN103739417B (en) | A kind of method synthesizing aromatic primary amine in recirculated water phase system | |
| CN102516182B (en) | Preparation method for 4-amino-6-alkoxyl pyrimidine compounds | |
| CN102675148B (en) | The preparation method of p-hydroxybenzonitrile | |
| CN102382100B (en) | Preparation method of imatinib | |
| CN104628626A (en) | Preparation method of 2,2,6,6-tetramethyl-4-piperidinol | |
| CN103193666A (en) | Preparation method of 2-amino-3-chlorobenzoic methyl ester | |
| CN104910113B (en) | A kind of preparation method of hydroxyphthalic anhydride | |
| CN105859559A (en) | Production method of 3-ethoxy-4-nitrophenol | |
| CN106748770A (en) | A kind of simple and convenient process for preparing of felbinac | |
| WO2015012271A1 (en) | Method for producing heterocyclic compound | |
| CN111747975A (en) | Preparation method of bedaquiline racemate and intermediate thereof | |
| CN103553978A (en) | Sulfamide benzylation method | |
| CN103910689B (en) | The preparation method of 7-methoxyl group-6-(3-morpholine-4-base propoxy-) quinazoline-4 (3H)-one | |
| CN103193615A (en) | Novel synthesizing method of 5-chloro valeryl chloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C05 | Deemed withdrawal (patent law before 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130508 |