CN103664754B - Prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] method of ethyl ketone - Google Patents
Prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] method of ethyl ketone Download PDFInfo
- Publication number
- CN103664754B CN103664754B CN201310553620.3A CN201310553620A CN103664754B CN 103664754 B CN103664754 B CN 103664754B CN 201310553620 A CN201310553620 A CN 201310553620A CN 103664754 B CN103664754 B CN 103664754B
- Authority
- CN
- China
- Prior art keywords
- formula
- picoline
- isoxazole
- ketone
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 *N1OCCC1 Chemical compound *N1OCCC1 0.000 description 1
- LKRPQZOVEFZODS-UHFFFAOYSA-N CN1OCCC1 Chemical compound CN1OCCC1 LKRPQZOVEFZODS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
Abstract
The present invention relates to one and prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] new method of ethyl ketone, the method is to comprise that the RMgBr of formula (II) and isoxazole alkane-2-base of formula (III)-(6-picoline-3-yl)-ketone reacts 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl of the formula of making (I) between-20 DEG C to 0 DEG C] ethyl ketone product. Compared with prior art, the present invention has advantages such as having reduced the explosive danger of reaction system.
Description
Technical field
The present invention relates to the preparation method of the intermediate of Etoricoxib, especially relate to a kind of Etoricoxib of preparingIntermediate 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] new method of ethyl ketone.
Background technology
1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] ethyl ketone (I) is synthetic high selectivity Cycloxygenase-2 (COX-2) inhibitor---a kind of important intermediate of Etoricoxib (Etoricoxib). Its performance is more traditionalNSAIDs (NSAIDs) increases, and is used by Chinese food Drug Administration (sFDA) approvalIn the sings and symptoms for the treatment of osteoarthritis acute stage and chronic phase, and treatment acute gouty arthritis.
The synthetic method of compound (I) has description more in patent and document, its Patent WO01/07410A1With US2003/0088107A1, synthetic route () is described:
Wherein 2-(4-(methyl mercapto) phenyl) acetonitrile and the condensation under alkali condition of 6-methylnicotinic acid ethyl ester, thenUnder acid condition, hydrolysis and decarboxylation, obtain compound (I).
Patent WO2006/080256A1 has described synthetic route (two):
Wherein 2-(4-(methyl mercapto) phenyl) ethyl acetate and the condensation under alkali condition of 6-methylnicotinic acid ethyl ester,Under acid condition, obtain again compound (I).
Patent WO99/15503A2 has described synthetic route (three):
Wherein RMgBr reacts with acid amides and obtains compound (I). Amide reagent wherein contains N, O-diformazanBase azanol fragment, in course of reaction, this fragment can come off, the N of generation, O-dimethyl hydroxylamine has very strongExcitant, can produce spread effect to eyes, respiratory tract and skin, if heating can be decomposed generation carbon monoxide,Carbon dioxide, the dangerous gas of the tools such as oxynitrides, causes reaction system explosive.
EP2497767A1 and US2012/0232281A1 have described synthetic route (four) in addition:
And patent WO2012/066570A2 has described synthetic route (five):
Summary of the invention
Object of the present invention is exactly to provide one to prepare 1-(6-in order to overcome the defect that above-mentioned prior art existsPicoline-3-yl)-2-[4-methyl mercapto-phenyl] new method of ethyl ketone.
Object of the present invention can be achieved through the following technical solutions: one is prepared 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] new method of ethyl ketone, it is characterized in that, the method is to comprise the RMgBr of formula (II)And isoxazole alkane-2-base of formula (III)-(6-picoline-3-yl)-ketone reacts the formula of making at-20 DEG C between 0 DEG C1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl of (I)] ethyl ketone product;
The structural formula of described RMgBr is:
Wherein X is selected from chlorine atom, bromine atoms, fluorine atom or iodine atom;
The molecular formula of described isoxazole alkane-2-base-(6-picoline-3-yl)-ketone is:
Described 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] molecular formula of ethyl ketone is:
The method of above-mentioned preparation formula (I) compound is specially: under nitrogen protection, by isoxazole alkane-2-base-(6-Picoline-3-yl)-ketone (III) is dissolved in solvent, and gained solution a is cooled to-20 DEG C. By RMgBr(II) be dissolved in the solution b that is made into 2mol/L in solvent, slowly join in cooling solution a. Reaction temperatureDegree is controlled between-20 DEG C to-10 DEG C, stirs after 1 hour, adds successively acetic acid, water. Water is removed in separation,Organic phase hcl as extraction agent solution, then use sodium hydrate aqueous solution regulator solution pH to 12, filter, wash with waterFilter cake is dried 24 hours between 50 DEG C to 55 DEG C, obtains formula (I) compound of yellow solid.
Isoxazole alkane-2-base-(the 6-picoline-3-yl) of the RMgBr of described formula (II) and formula (III)-The mol ratio of ketone is between 1:1 to 2:1.
Isoxazole alkane-2-base-(the 6-picoline-3-yl) of the RMgBr of described formula (II) and formula (III)-Ketone reacts in solvent, and described solvent is selected from toluene, benzene, ether, oxolane, 2-ethyoxyl fourThe mixing of one or both solvents of hydrogen furans.
Isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of described formula (III) is the chemical combination of a new constructionThing, makes by the following method: will comprise the isoxazole salt of formula (IV) and the 6-methylnicotinic acid first of formula (V)Ester reacts and makes under the existence of alkali condition;
The molecular formula of described isoxazole salt is:
Wherein Y is selected from hydrochloric acid, sulfuric acid, phosphoric acid and p-methyl benzenesulfonic acid;
The molecular formula of described 6-methylnicotinic acid methyl esters is:
The method of above-mentioned preparation formula (III) compound is specially: under nitrogen protection, by 6-methylnicotinic acid methyl esters (V)Add in solvent with isoxazole salt (IV), gained solution c is cooled to-20 DEG C. Alkaline solution is slowly joinedIn cooling solution c. Reaction temperature is controlled between-20 DEG C to-10 DEG C, stirs after 0.5 hour, adds acetic acidSolution, separates and removes water, and vapourisation under reduced pressure organic solvent obtains formula (III) compound of yellow liquid.
The mol ratio of the isoxazole salt of described formula (IV) and the 6-methylnicotinic acid methyl esters of formula (V) is at 1.5:1Between 1:1.
Isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of described formula (III) makes by the following method:To comprise that the isoxazole salt of formula (IV) and the 6-methyl nicotinoyl chlorine of formula (VI) react under the existence of alkali conditionMake;
The molecular formula of described isoxazole salt is:
Wherein Y is selected from hydrochloric acid, sulfuric acid, phosphoric acid and p-methyl benzenesulfonic acid;
The molecular formula of described 6-methyl nicotinoyl chlorine is:
The method of above-mentioned preparation formula (III) compound is specially: alkaline solution is cooled to 15 DEG C. Isoxazole salt (IV)Add and in cooling alkaline solution, obtain solution d. By 6-methyl nicotinoyl chlorine (VI) evenly suspended dispersed at solventIn, then join in the solution d of 15-25 DEG C. Mixed solution stirs 0.5 hour, separates and removes water, hasMachine is used anhydrous sodium sulfate drying after washing with water mutually. Vapourisation under reduced pressure organic solvent, obtains the formula (III) of yellow liquidCompound.
The mol ratio of the isoxazole salt of described formula (IV) and the 6-methyl nicotinoyl chlorine of formula (VI) at 1.5:1 extremelyBetween 1:1.
Described alkali condition for to react under organic base and inorganic base condition.
Described organic base is selected from NaOH, potassium hydroxide, sodium carbonate or potash; Described inorganic base is selected fromTriethylamine, 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene (DBU), HMDS lithium salts(LHMDS), lithium diisopropylamine (LDA) or isopropylmagnesium chloride (i-PrMgCl).
In the preparation process of isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of described formula (III), adoptSolvent is selected from the mixing of a kind of or any two kinds of solvents of toluene, benzene, ether, oxolane or carrene.
The present invention has synthesized a kind of isoxazole alkane-2-base-(6-picoline-3-yl) of compound formula (III) of new construction-ketone, and taking isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of formula (III) as raw material and RMgBr anti-Should produce 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl with formula of the present invention (1) structure] ethyl ketone productProduct. Patent of the present invention is compared to patent WO99/15503A2 and has significant advantage, owing to having increased acid amidesAzanol length in reagent, and carried out close ring process obtain isoxazole alkyl fragment, this fragment is compared to speciallyThe N of profit WO99/15503A2, O-dimethyl hydroxylamine fragment, has advantages of more stable, stable significantlyAzanol reagent, avoids it to be heated and easily decomposes and produce gas, has reduced the explosive danger of reaction system.
Detailed description of the invention
Further illustrate the present invention by the following example, but do not limit the invention.
Embodiment 1
Synthesizing of isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of formula (III)
Synthetic route:
Under nitrogen protection, the 6-methylnicotinic acid methyl esters (V) of 150g and the isoxazole hydrochloride (IV) of 120gAdd in 500ml toluene, solution is cooled to-20 DEG C. By the oxolane of the isopropylmagnesium chloride of 2.2mol/LSolution slowly joins in cooling solution. Reaction temperature is controlled between-20 DEG C to-10 DEG C, stirs 0.5 hourAfter, add the acetum of 500ml20%, separate and remove water, vapourisation under reduced pressure organic solvent, obtains HuangFormula (III) compound (152g, 80%) of look liquid.1HNMR(300MHz,CDCl3)δ2.36(t,2H,J＝7.8Hz),2.59(s,3H),3.94(m,4H),7.19(d,1H,J＝8.1Hz),8.01(dd,1H,J＝7.8Hz,1.2Hz),8.94(s,1H)。
1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl of formula (I)] ethyl ketone synthetic
Synthetic route:
Under nitrogen protection, by molten isoxazole alkane-2-base of 191g-(6-picoline-3-yl)-ketone (III)Solution, in the toluene of 350ml, is cooled to solution-20 DEG C. By 4-(methyl mercapto) benzylmagnesium chloride (II)Tetrahydrofuran solution solution (1L, 2mol/L) slowly joins in cooling solution. Reaction temperature is controlled at-20 DEG CBetween-10 DEG C, stir after 1 hour, add successively 300ml50% acetic acid, 300ml water. Water is removed in separation,The hcl as extraction agent solution of the 150ml of organic phase use 2N 3 times, then use 20% sodium hydrate aqueous solution regulator solutionPH to 12, filters, and with the water washing filter cake of 200ml, between 50 DEG C to 55 DEG C, is dried 24 hours, obtainsFormula (I) compound (155g, 60%) of yellow solid.1HNMR(300MHz,CDCl3)δ2.48(s,3H),2.65(s,3H),4.24(s,3H),7.26(m,5H),8.17(m,1H),9.13(s,1H)。
Embodiment 2
Synthesizing of isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of formula (III)
Synthetic route:
The sodium carbonate of 230g adds in 600ml water, is cooled to 15 DEG C. The isoxazole hydrochloride (IV) of 120g addsEnter wherein. Even the 6-methyl nicotinoyl chlorine (VI) of 155g suspended dispersed, in carrene, is then addedIn the aqueous sodium carbonate of 15-25 DEG C. Mixed solution stirs 0.5 hour, separates and removes water, and organic phase is usedAfter washing, use anhydrous sodium sulfate drying. Vapourisation under reduced pressure organic solvent, the formula (III) that obtains yellow liquid is changedCompound (123g, 65%).
1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl of formula (I)] ethyl ketone synthetic
Synthetic route:
Under nitrogen protection, by molten isoxazole alkane-2-base of 191g-(6-picoline-3-yl)-ketone (III)Solution, in the toluene of 350ml, is cooled to solution-20 DEG C. By 4-(methyl mercapto) benzylmagnesium chloride (II)Tetrahydrofuran solution solution (1L, 2mol/L) slowly joins in cooling solution. Reaction temperature is controlled at-20 DEG CBetween-10 DEG C, stir after 1 hour, add successively 300ml50% acetic acid, 300ml water. Water is removed in separation,The hcl as extraction agent solution of the 150ml of organic phase use 2N 3 times, then use 20% sodium hydrate aqueous solution regulator solutionPH to 12, filters, and with the water washing filter cake of 200ml, between 50 DEG C to 55 DEG C, is dried 24 hours, obtainsFormula (I) compound (155g, 60%) of yellow solid.1HNMR(300MHz,CDCl3)δ2.48(s,3H),2.65(s,3H),4.24(s,3H),7.26(m,5H),8.17(m,1H),9.13(s,1H)。
Embodiment 3
One is prepared 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] new method of ethyl ketone, will comprise formula (II)RMgBr and isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of formula (III) be-10 DEG C to 0 DEG C itBetween in solvent toluene in molar ratio 1:1 react and make product;
The structural formula of described RMgBr is:
Wherein X is chlorine atom;
Described isoxazole alkane-2-base-(6-picoline-3-yl)-ketone: be to comprise the isoxazole of formula (IV)The 6-methylnicotinic acid methyl esters of salt and formula (V) in molar ratio 1.5:1 under the existence of NaOH in solvent tolueneMiddle reaction makes.
The molecular formula of described isoxazole salt is:
Wherein Y is hydrochloric acid.
Embodiment 4
One is prepared 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] new method of ethyl ketone, will comprise formula (II)RMgBr and isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of formula (III) be-10 DEG C to 0 DEG C itBetween in solvent ether in molar ratio 2:1 react and make product;
The structural formula of described RMgBr is:
Wherein X is bromine atoms;
Described isoxazole alkane-2-base-(6-picoline-3-yl)-ketone: be to comprise the isoxazole of formula (IV)The 6-methyl nicotinoyl chlorine of salt and (VI) in molar ratio 1:1 at HMDS lithium salts (LHMDS)What under existence, in solvent ether, reaction made.
The molecular formula of described isoxazole salt is:
Wherein Y is sulfuric acid.
Claims (5)
1. prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] method of ethyl ketone, its feature existsIn, the method be by isoxazole alkane-2-base of the RMgBr of formula (II) and formula (III)-(6-picoline-3-yl)-Ketone between-20 DEG C to 0 DEG C, react make 1-(6-picoline-3-yl)-2-[4-methyl mercapto of formula (I)-Phenyl] ethyl ketone product;
The structural formula of described RMgBr is:
Wherein X is selected from chlorine atom, bromine atoms, fluorine atom or iodine atom;
The molecular formula of described isoxazole alkane-2-base-(6-picoline-3-yl)-ketone is:
Described 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] molecular formula of ethyl ketone is:
Isoxazole alkane-2-base-(6-picoline-3-yl)-ketone of described formula (III) makes by the following method:6-methylnicotinic acid methyl esters system of reacting under the existence of alkali condition by the isoxazole salt of formula (IV) with formula (V);
The molecular formula of described isoxazole salt is:
Wherein Y is selected from hydrochloric acid, sulfuric acid, phosphoric acid and p-methyl benzenesulfonic acid;
The molecular formula of described 6-methylnicotinic acid methyl esters is:
Isoxazole alkane-2-base-(the 6-picoline-3-yl) of the RMgBr of described formula (II) and formula (III)-The mol ratio of ketone is between 1:1 to 2:1;
Isoxazole alkane-2-base-(the 6-picoline-3-yl) of the RMgBr of described formula (II) and formula (III)-Ketone reacts in solvent, and described solvent is selected from toluene, benzene, ether, oxolane, 2-ethyoxyl fourThe mixing of one or both solvents of hydrogen furans;
The mol ratio of the isoxazole salt of described formula (IV) and the 6-methylnicotinic acid methyl esters of formula (V) is at 1.5:1Between 1:1;
Or, described formula (III) isoxazole alkane-2-base-(6-picoline-3-yl)-ketone by the following methodMake: the 6-methyl nicotinoyl chlorine of the isoxazole salt of formula (IV) and formula (VI) is anti-under the existence of alkali conditionShould make;
The molecular formula of described isoxazole salt is:
Wherein Y is selected from hydrochloric acid, sulfuric acid, phosphoric acid and p-methyl benzenesulfonic acid;
The molecular formula of described 6-methyl nicotinoyl chlorine is:
2. one according to claim 1 is prepared 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl]The method of ethyl ketone, is characterized in that, the isoxazole salt of described formula (IV) and the 6-methyl nicotinoyl of formula (VI)The mol ratio of chlorine is between 1.5:1 to 1:1.
3. one according to claim 1 is prepared 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl]The method of ethyl ketone, is characterized in that, described alkali condition for to react under organic base and inorganic base condition.
4. one according to claim 3 is prepared 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl]The method of ethyl ketone, is characterized in that, described inorganic base is selected from NaOH, potassium hydroxide, sodium carbonate or carbonic acidPotassium; Described organic base is selected from triethylamine, 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene, hexamethyl two silicon nitrogenAlkane lithium salts, lithium diisopropylamine or isopropylmagnesium chloride.
5. one according to claim 1 is prepared 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl]The method of ethyl ketone, is characterized in that, isoxazole alkane-2-base-(6-picoline-3-yl)-first of described formula (III)The solvent adopting in the preparation process of ketone is selected from a kind of of toluene, benzene, ether, oxolane or carrene or appointsThe mixing of two kinds of solvents of meaning.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310553620.3A CN103664754B (en) | 2013-11-08 | 2013-11-08 | Prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] method of ethyl ketone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310553620.3A CN103664754B (en) | 2013-11-08 | 2013-11-08 | Prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] method of ethyl ketone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103664754A CN103664754A (en) | 2014-03-26 |
| CN103664754B true CN103664754B (en) | 2016-05-25 |
Family
ID=50303634
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310553620.3A Active CN103664754B (en) | 2013-11-08 | 2013-11-08 | Prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] method of ethyl ketone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103664754B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3278666A1 (en) * | 2016-08-04 | 2018-02-07 | Bayer CropScience Aktiengesellschaft | Aqueous capsule suspension concentrates based on 2-(2,4-dichlorobenzyl)-4,4-dimethyl-1,2-oxazolidin-3-one |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731374A (en) * | 2011-03-09 | 2012-10-17 | 意大利合成制造有限公司 | Improved process for preparing 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate of etoricoxib |
| WO2013065064A1 (en) * | 2011-10-31 | 2013-05-10 | Sequent Scientific Limited | A process for preparation of l-(6-methylpyridin-3-yl)-2-[4-(meth.ylsulfonyi)phenyl]ethanone field of invention |
| WO2013104546A1 (en) * | 2012-01-13 | 2013-07-18 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Process for the synthesis of etoricoxib |
-
2013
- 2013-11-08 CN CN201310553620.3A patent/CN103664754B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102731374A (en) * | 2011-03-09 | 2012-10-17 | 意大利合成制造有限公司 | Improved process for preparing 1-(6-methylpyridin-3-yl)-2-[4-(methylsulfonyl)phenyl]ethanone, an intermediate of etoricoxib |
| WO2013065064A1 (en) * | 2011-10-31 | 2013-05-10 | Sequent Scientific Limited | A process for preparation of l-(6-methylpyridin-3-yl)-2-[4-(meth.ylsulfonyi)phenyl]ethanone field of invention |
| WO2013104546A1 (en) * | 2012-01-13 | 2013-07-18 | Alfred E. Tiefenbacher (Gmbh & Co. Kg) | Process for the synthesis of etoricoxib |
Non-Patent Citations (3)
| Title |
|---|
| A new general method for preparation of N-methoxy-N-methylamides application in direct conversion of an ester to a ketone;J. Michael Williams等;《Tetrahedron Letters》;19951231;第36卷(第31期);第5464页第1段 * |
| A Practical Synthesis of a COX-2-Specific Inhibitor;Ian. W. Davies等;《J. Org. Chem》;20000919;第65卷(第25期);第8420页左栏倒数第1段、右栏第1段、第8417页右栏流程图、第8416页右栏流程图、左栏倒数第1段 * |
| COX-2抑制剂Etoricoxib中间体的合成;黄银华;《浙江大学硕士学位论文》;20061231;第3-7页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103664754A (en) | 2014-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW201625542A (en) | Process for the preparation of 4-alkoxy-3-hydroxypicolinic acids | |
| CN102964313A (en) | Synthetic method of febuxostat | |
| CN105566215B (en) | A kind of Rui Gefeini preparation method | |
| CN103664754B (en) | Prepare 1-(6-picoline-3-yl)-2-[4-methyl mercapto-phenyl] method of ethyl ketone | |
| CN103833560A (en) | Preparation method of (S)-5-chloro-alpha-cyclopropinyl-2-amino-alpha-trifluoromethyl phenylcarbinol | |
| CN106632014A (en) | Preparation of 2-amino-5-chloropyridine | |
| CN103772278A (en) | Important tetrahydroisoquinoline derivative midbody and synthesis method thereof | |
| TWI621609B (en) | Process for preparing 4-haloalkyl-3-mercapto-substituted 2-hydroxybenzoic acid derivatives | |
| CN103664824A (en) | Preparation method of thiadiazole carboxamide compounds | |
| JP6719648B2 (en) | A simple method for preparing avibactam intermediates | |
| CN106588921B (en) | A kind of synthetic method of the methyl formate of 7 azaindole 3 | |
| CN109134395A (en) | The synthetic method of Parecoxib Sodium Isomeric impurities | |
| CN104230743B (en) | Method for preparing 4-benzyl-1-phenethyl piperazine-2,6-diketone | |
| CN105566260A (en) | Furosemide preparation method | |
| CN105777581A (en) | Cis-1-cyano-4-methoxycyclohexyl-2-(2, 5-dimethylphenyl)acetamide, preparation method and application thereof | |
| CN104829588B (en) | A kind of Preparation Method And Their Intermediate of benzo [b] thiophene | |
| JP5750199B1 (en) | Method for producing pyridine-3-sulfonyl chloride | |
| CN112939893B (en) | Synthesis method of 4- (4-aminophenyl) -3-morpholinone | |
| CN103086962A (en) | Synthetic method for 5-chlorine-2,4-dyhydroxyl pyridine | |
| CN101481349A (en) | Preparation of alkyl pyridine-2-sulfonic acid amide | |
| CN103864786A (en) | Method for synthesizing 6-fluoroimidazo-[1,2-a]-pyridine-3-formic acid | |
| CN105130886A (en) | Preparation method for 4-fluoro-3-methyl-methyl pyridine-2-carboxylate | |
| CN105384725B (en) | A kind of preparation method and applications of azimsulfuron key intermediate | |
| CN104151232A (en) | Method for preparing etocoxib | |
| CN103833530A (en) | Preparation method of organic intermediate 3-phenoxyl-1, 2-propylene glycol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190805 Address after: 200240 Dongchuan Road, Shanghai, No. 800, No. Co-patentee after: Shanghai Pharmaceutical Technology Co., Ltd. Patentee after: Shanghai Jiao Tong University Address before: 200240 Dongchuan Road, Shanghai, No. 800, No. Co-patentee before: Shanghai Jinse Medical Technology Development Co., Ltd. Patentee before: Shanghai Jiao Tong University |
|
| TR01 | Transfer of patent right |