CN103183604B - The preparation method of Vedaprofen - Google Patents

The preparation method of Vedaprofen Download PDF

Info

Publication number
CN103183604B
CN103183604B CN201110448572.2A CN201110448572A CN103183604B CN 103183604 B CN103183604 B CN 103183604B CN 201110448572 A CN201110448572 A CN 201110448572A CN 103183604 B CN103183604 B CN 103183604B
Authority
CN
China
Prior art keywords
compound
acid
reaction
mol ratio
catalyzer
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
Application number
CN201110448572.2A
Other languages
Chinese (zh)
Other versions
CN103183604A (en
Inventor
王元
徐颖超
梅会群
何训贵
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
2Y-CHEM LTD
Original Assignee
2Y-CHEM LTD
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 2Y-CHEM LTD filed Critical 2Y-CHEM LTD
Priority to CN201110448572.2A priority Critical patent/CN103183604B/en
Publication of CN103183604A publication Critical patent/CN103183604A/en
Application granted granted Critical
Publication of CN103183604B publication Critical patent/CN103183604B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to the preparation method of Vedaprofen.Method provided by the invention only has four-step reaction, and desired raw material is all convenient source, and the method easy handling, and institute all can adopt in steps " one kettle way " carry out, be convenient to suitability for industrialized production.

Description

The preparation method of Vedaprofen
Technical field
The present invention relates to a kind of preparation method of Vedaprofen.
Background technology
Vedaprofen (vedaprofen) shown in following structural formula 1 is the general nomenclature of drug of compound 2-(4-cyclohexyl naphthyl) propionic acid.
Vedaprofen belongs to 2-arylpropionic acid compounds, is a kind of for antipyretic, analgesic NSAID, is mainly used in gout, internal secretion and metabolism class disease.This compound has a chiral centre, therefore has S (+) and R (-) a pair enantiomer.Modern pharmacology research proves, the S (+) of Vedaprofen and R (-) configuration are to prostaglandin(PG) (PGF 2 α) restraining effect on be identical, therefore these two kinds of configurations are all Eus.The racemic mixture of Vedaprofen has been developed to as horse class and Canidae class veterinary drug, has been licensed for the treatment of dog and horse at present America and Europe.Therefore, synthesis Vedaprofen, without the need to asymmetric synthesis or chiral separation, obtains raceme.
By literature search, principal synthetic routes and the method for its document or patent report have the following two kinds:
Such as, US Patent No. 4218473 discloses a kind of preparation method of Vedaprofen, and reaction formula is as follows:
(can reference literature Journal of the American Chemical Society with 1-cyclohexyl naphthalene, 2004,126 (12), 3686-3687 prepares and obtains) be starting raw material, first carrying out chloromethylation with formaldehyde, concentrated hydrochloric acid obtains 1-chloromethyl-4-cyclohexyl naphthalene; The chloromethylation intermediate sodium cyanide obtained is cyanalation, then is hydrolyzed cyano group and obtains intermediate 4-cyclohexyl-1-naphthylacetic acid; The sour intermediate methanol esterification obtained becomes corresponding methyl esters, then methylates in α position with methyl iodide, obtains 2-(4-cyclohexyl naphthyl) methyl propionate; This methyl esters is hydrolyzed by alkaline condition and obtains Vedaprofen with hcl acidifying.
This route need use the hypertoxic tubing products such as sodium cyanide and methyl iodide, the human health or safety of great threat operator during scale operation.In addition, this method route is longer, and step is more, and containing 6 step reactions, production cost is higher.
According to document [Journal of medicinal chemistry, 2007,50 (12), 2787-2798 and Tetrahedron, 1995,51 (46), 12583-12590], also can obtain a kind of preparation method of Vedaprofen, reaction formula is as follows:
With 1-cyclohexyl naphthalene for starting raw material, first carry out chlorine acetylation with Acetyl Chloride 98Min. and obtain 1-ethanoyl-4-cyclohexyl naphthalene; The aceted intermediate obtained becomes the cyano group of alcohol, hydroxy chloride and sodium cyanide to replace through sodium borohydride reduction, obtains 2-(4-cyclohexyl naphthyl) the third cyanogen; This third cyanogen intermediate obtains Vedaprofen by hydrolysis.
The shortcoming of this route remains need with hypertoxic tubing products such as sodium cyanides, and reactivity hazard is high, operation easier is large, but also needs 5 steps reactions.
Summary of the invention
For the problems referred to above, the object of this invention is to provide the new preparation process that one prepares compound 2-(4-cyclohexyl naphthyl) propionic acid.The method only has four-step reaction, and step is shorter, and desired raw material is all convenient source, avoids the use of highly toxic product sodium cyanide or potassium cyanide.And this route can adopt in steps " one kettle way " carry out, and constant product quality, be convenient to suitability for industrialized production.Therefore, this technique easy handling, is convenient to suitability for industrialized production.
In order to achieve the above object, the present invention realizes by the following technical solutions.
The preparation method of Vedaprofen of the present invention, comprises the following steps:
A) 1-cyclohexyl naphthalene (i.e. compound 2) and the propionating reagent of 2-halo carry out Fu Zhongsun, and obtain compound 3, its reaction formula is as follows:
B) compound 3 dibasic alcohol carries out ketalization protection, obtains compound 4, and its reaction formula is as follows:
C) compound 4 carries out aryl tropic rearrangement under Louis acid catalysis, obtains compound 5, and its reaction formula is as follows:
D) compound 5 is through hydrolysis, and obtain Vedaprofen (i.e. compound 1), its reaction formula is as follows:
Wherein, X is fluorine, chlorine, bromine or iodine,
Each R is hydrogen, methyl or ethyl independently,
N is 0,1 or 2;
Preferably,
X is chlorine or bromine,
Each R is hydrogen or methyl independently,
N is 0 or 1.
Be described in more detail below preparation method of the present invention:
In described steps A) in:
The propionating reagent of described 2-halo can be 2-chlorpromazine chloride, 2-chloropropionic acid acid anhydride, 2-bromo propionyl chloro or 2 bromopropionic acid acid anhydride etc.; The mol ratio of the propionating reagent of general 2-halo and compound 2 is 1.5: 1 ~ 1: 1, and preferably 1.1: 1.
Reaction uses Lewis acid as catalyzer, and described Lewis acid can be and is selected from AlCl 3, ZnCl 2, BF 3and TiCl 4in one or more, and Lewis acid is 2: 1 ~ 1: 1 with the mol ratio of compound 2, and preferably 1.2: 1.Its reaction mechanism is: Lewis acid is combined with acyl chlorides or acid anhydrides, and the carbonyl positive ion of formation can be combined the structure forming C-C by the carbanion on aromatic ring.
The solvent that this reaction uses can be methylene dichloride, chloroform, 1,2-ethylene dichloride or chlorobenzene etc.
This temperature range of reacting suitable is-78 DEG C ~ 30 DEG C, and preferably-10 DEG C ~ 0 DEG C.
After having reacted, adopt quencher cancellation reaction, then extract with organic solvent, then carry out concentrating under reduced pressure to extracting the organic phase obtained, obtained compound 3 crude product, compound 3 crude product can be directly used in next step reaction without the need to purifying.Wherein, described quencher can be selected from water, hydrochloric acid, sulfuric acid, formic acid, acetic acid, propionic acid, butyric acid, oxalic acid and citric acid one or more; The organic solvent that extraction uses is ethyl acetate, toluene, methylene dichloride or methyl tertiary butyl ether etc.
At described step B) in:
Carry out ketalization protection with dibasic alcohol to the carbonyl on compound 3, described dibasic alcohol can be ethylene glycol, 1,3 propylene glycol, neopentyl glycol etc.; The mol ratio of general dibasic alcohol reagent and compound 3 is 3: 1 ~ 1: 1, and preferably 1.5: 1.
Ketal reaction catalyzer used be selected from sulfuric acid, acetic acid, tosic acid, methylsulfonic acid, citric acid one or more; And the mol ratio of general acid catalyst and compound 3 is 0: 1 ~ 1: 1, and preferably 0.1: 1.
The solvent that this reaction uses can be benzene,toluene,xylene or chlorobenzene etc.Need in reaction process, by water trap or other de-watering apparatus or dehydration reagent, the moisture that reaction generates is separated removing in time.
After this reaction completes, reaction solution adopts water to be that quencher carrys out cancellation reaction; Concentrating under reduced pressure after organic phase washed with water and brine It, obtains compound 4 crude product, and the crude product of compound 4 can be directly used in next step reaction without the need to purifying.
At described step C) in:
The catalyzer of the aryl tropic rearrangement reaction use of compound 4 is for being selected from ZnO, ZnCl 2with Zn (OAc) 2in one or more, and the mol ratio of catalyzer and compound 4 is 0: 1 ~ 3: 1, and preferably 0.2: 1.Its reaction mechanism is: under the catalysis of zincon, and aryl migrates on the halogen atom place carbon at ortho position from ketal carbon, and halogen atom is combined with zincon and leaves away simultaneously, forms the ester group structure of compound 5.
The solvent that this reaction uses can be toluene, dimethylbenzene or chlorobenzene etc.
This temperature range of reacting suitable is 80 DEG C ~ 160 DEG C, and preferably 110 DEG C ~ 130 DEG C.
After this reaction completes, adopt quencher cancellation reaction, concentrating under reduced pressure after reaction organic phase washed with water and brine It, obtained compound 5 crude product, compound 5 crude product can be directly used in next step reaction without the need to purifying.Wherein, quencher can be selected from hydrochloric acid, sulfuric acid, formic acid, acetic acid and citric acid one or more.
At described step D) in:
The hydrolysis of compound 5, can in the basic conditions, also can be in acid condition.Hydrolysis of compound 5 alkali used can be KOH, NaOH, LiOH, K 2cO 3, Cs 2cO 3or Na 2cO 3deng; The mol ratio of general alkali and compound 5 is 5: 1 ~ 1: 1, and preferably 3: 1.Hydrolysis of compound 5 acid used can be sulfuric acid, hydrochloric acid or tosic acid etc.
Preparation method of the present invention, amount to four steps, synthetic route is short; Desired raw material is all convenient source, avoids the prussiate using severe toxicity.In this route, often step is popular response, and aftertreatment is simple, easy to operate; And after reaction terminates, the thick product that reaction solution obtains through aftertreatment can be directly used in next step reaction without the need to purifying, achieves whole piece route " one kettle way " and carries out, be convenient to suitability for industrialized production.
Embodiment
Following examples illustrate technical scheme of the present invention, the features and advantages of the present invention further, but the present invention is not limited to the following examples.
1. the synthesis of compound 3
Embodiment 1
The synthesis of 1-(2-chlorine propionyl)-4 cyclohexyl naphthalenes
At N 2under protection, in 500ml there-necked flask, add AlCl 3(22.8g, 0.17mol) and methylene dichloride (250mL) are also cooled to-10 DEG C ~ 0 DEG C.Under stirring, be added dropwise to methylene dichloride (50mL) solution of 2-chlorpromazine chloride (19.8g, 0.157mol) and 1-cyclohexyl naphthalene (2,30.0g, 0.143mol) mixture, and keep temperature of reaction all the time at-10 DEG C ~ 0 DEG C.After adding, continue to keep 2 hours until react completely at-10 DEG C ~ 0 DEG C.Reaction solution is poured into cancellation reaction in 300mL dilute hydrochloric acid (2N), stir layering and isolate organic layer, after organic layer 200mL water and 200mL saturated aqueous common salt are washed respectively, removing solvent under reduced pressure, obtain thick product, brown oil.Crude yield: quantitatively.
Crude product can be directly used in next step reaction without the need to purifying.
MS(ESI，m/z)：[M+] +301.2。
1H-NMR(400MHz，CDCl 3)：δ8.52(m，1H)；8.03(d，1H，J＝8.8Hz)；7.65～7.92(m，2H)；7.42～7.60(m，2H)；5.42(m，1H)；2.70(m，1H)；1.84-2.05(m，4H)；1.80(d，3H，J＝3.6Hz)；1.78(m，1H)；1.29-1.59(m，4H)；1.31(m，1H)。
Embodiment 2
At N 2under protection, in 500ml there-necked flask, add TiCl 4(32.2g, 0.17mol) and chlorobenzene (250mL) are also cooled to-10 DEG C ~ 0 DEG C.Under stirring, dropwise add chlorobenzene (50mL) solution of 2 bromopropionic acid acid anhydride (45.2g, 0.157mol) and 1-cyclohexyl naphthalene (30.0g, 0.143mol) mixture, and keep temperature of reaction all the time at-10 DEG C ~ 0 DEG C.After adding, continue to keep 2 hours until react completely at 10 DEG C ~ 0 DEG C.Reaction solution is poured into cancellation reaction in 300mL aqueous citric acid solution (2N), stir layering and isolate organic layer, organic layer, with after 200mL water and the water washing of 200mL saturated common salt, removes solvent under reduced pressure, obtains thick product, brown oil.Crude yield: quantitatively.
Crude product can be directly used in next step reaction without the need to purifying.
2. the synthesis of compound 4
Embodiment 3
The synthesis of 2-(1-chloroethyl)-2-(4-cyclohexyl naphthyl)-5,5-dimethyl-1,3-dioxanes
N 2under gas shielded, in 500ml there-necked flask, under normal temperature, add 1-(2-chlorine propionyl)-4 cyclohexyl naphthalene (3,42.9g, 0.143mol) and toluene (430mL).Under stirring, in reaction solution, add neopentyl glycol (22.3g, 0.214mol) and tosic acid (2.7g, 0.014mol).Finish, reaction flask assembles water trap, be then heated to reflux and keep backflow 20 hours until react completely.Cooling reaction solution is to room temperature, and add 200mL shrend and to go out reaction, stirring and segregation goes out organic phase.Organic phases washed with water twice (200mL × 2), saturated aqueous common salt (200mL) are washed once, remove solvent under reduced pressure, obtain thick product, brown oil.Crude yield: quantitatively.
Crude product can be directly used in next step reaction without the need to purifying.
MS(ESI，m/z)：[M+] +387.2。
1H-NMR(400MHz，CDCl 3)：δ7.81～7.88(m，2H)；7.38～7.51(m，3H)；7.16(m，1H)；4.14(m，1H)；3.52(m，4H)；2.70(m，1H)；1.81～1.98(m，4H)；1.46-1.59(m，4H)；1.25～1.44(m，7H)。
Embodiment 4
N 2under gas shielded, in 500ml there-necked flask, under normal temperature, add 1-(2-chlorine propionyl)-4 cyclohexyl naphthalene (3,42.9g, 0.143mol) and dimethylbenzene (430mL).Under stirring, in reaction solution, add ethylene glycol (13.3g, 0.214mol) and the vitriol oil (1.4g, 0.014mol).Finish, reaction flask assembles water trap, be then heated to reflux and keep backflow 20 hours until react completely.Cooling reaction solution is to room temperature, and add 200mL shrend and to go out reaction, stirring and segregation goes out organic phase.Organic phases washed with water twice (200mL × 2), saturated aqueous common salt (200mL) are washed once, then remove solvent under reduced pressure, obtain thick product, brown oil.Crude yield: quantitatively.
Crude product can be directly used in next step reaction without the need to purifying.
MS(ESI，m/z)：[M+] +345.1。
3. the synthesis of compound 5
Embodiment 5
The synthesis of chloro-2, the 2-dimethyl propyl 2-of 3-(4-cyclohexyl naphthyl) propionic ester
At N 2under protection; 2-(1-chloroethyl)-2-(4-cyclohexyl naphthyl)-5 is added in 500mL reaction flask; 5-dimethyl-1; 3-dioxane (4; 55.2g; 0.143mol), zinc oxide (2.4g, 0.029mol) and toluene (200mL).Reaction solution is heated to 110 DEG C ~ 130 DEG C and remains on this temperature stir more than 16 hours until react completely.Cooling reaction solution is to room temperature, and add 100mL dilute sulphuric acid (2N) cancellation reaction, stirring and segregation goes out organic phase.Organic phases washed with water twice (150mL × 2), saturated aqueous common salt (150mL) are washed once, then remove solvent under reduced pressure, obtain thick product, brown oil.Crude yield: 90%.
Crude product can be directly used in next step reaction without the need to purifying.
MS(ESI，m/z)：[M+] +387.2。
1H-NMR(400MHz，CDCl 3)：δ7.60～7.80(m，4H)；7.40(m，2H)；3.89(m，3H)；3.12(m，2H)；2.65(m，1H)；1.90-1.98(m，4H)；1.87(m，1H)；1.77(d，3H，J＝7.2Hz)；1.25-1.51(m，4H)；1.26(m，1H)；0.81(m，6H)。
Embodiment 6
At N 2under protection; 2-(1-chloroethyl)-2-(4-cyclohexyl naphthyl)-5 is added in 500mL reaction flask; 5-dimethyl-1; 3-dioxane (55.2g; 0.143mol), zinc oxide (2.4g; 0.029mol), zinc chloride (3.9g, 0.029mol) and dimethylbenzene (200mL).Reaction solution is heated to 110 DEG C ~ 130 DEG C and remains on this temperature stir more than 4 hours until react completely.Cooling reaction solution is to room temperature, and add 100mL dilute hydrochloric acid (2N) cancellation reaction, stirring and segregation goes out organic phase.Organic phases washed with water twice (150mL × 2), saturated aqueous common salt (150mL) are washed once, then remove solvent under reduced pressure, obtain thick product, brown oil.Crude yield: 90%.
Crude product can be directly used in next step reaction without the need to purifying.
Embodiment 7
At N 2under protection; 2-(1-chloroethyl)-2-(4-cyclohexyl naphthyl)-5 is added in 500mL reaction flask; 5-dimethyl-1; 3-dioxane (55.2g; 0.143mol), zinc acetate (5.4g, 0.029mol) and dimethylbenzene (200mL).Reaction solution is heated to 110 DEG C ~ 130 DEG C and remains on this temperature stir more than 6 hours until react completely.Cooling reaction solution is to room temperature, and add 100mL dilute hydrochloric acid (2N) cancellation reaction, stirring and segregation goes out organic phase.Organic phases washed with water twice (150mL × 2), saturated aqueous common salt (150mL) are washed once, then remove solvent under reduced pressure, obtain thick product, brown oil.Crude yield: 85%.
4. compound 1[Vedaprofen] synthesis
Embodiment 8
To in 500mL tri-mouthfuls of reaction flasks under room temperature, add chloro-2, the 2-dimethyl propyl 2-of 3-(4-cyclohexyl naphthyl) propionic ester (5,50.0g, 0.13mol), tetrahydrofuran (THF) (150mL) and methyl alcohol (150mL); Stir 5 minutes to solid molten clear after, in reaction solution, add 52mL aqueous sodium hydroxide solution (23%).The reaction mixture obtained is heated to 60 DEG C ~ 70 DEG C reactions 2 hours, until react completely.Reaction solution is cooled to room temperature, removes organic solvent under reduced pressure, the brown suspension 100mL water dilution obtained, then adds 200mL extraction into ethyl acetate.Separate organic layer, organic phase at room temperature stirs 1 hour, then is cooled to 0 DEG C ~ 10 DEG C stirrings 1 hour.Filter, filter cake ethyl acetate washing (40mL × 2) obtains the sodium salt that white solid is Vedaprofen.The white solid obtained is dropped in 100mL dilute hydrochloric acid (2N), stir after 30 minutes and filter, filter cake washes twice (40mL × 2) with water and obtains white solid, and this solid is dry under 50 DEG C of vacuum conditions obtains white solid, i.e. Vedaprofen in about 16 hours.Yield: ~ 30%, purity 99.7%.
MS(ESI，m/z)：[M+] +283.4。
1H-NMR(400MHz，DMSO-d 6)：δ7.73(d，2H，J＝8.0Hz)；7.65(d，2H，J＝17.6Hz)；6.84(dd，2H，J 1＝8.0Hz，J 2＝18.8Hz)；3.69(m，1H)；2.64(m，1H)；1.80-1.90(m，4H)；1.73(m，1H)；1.35-1.55(m，4H)；1.38(d，3H，J＝7.2Hz)；1.27(m，1H)。
Embodiment 9
To in 500mL tri-mouthfuls of reaction flasks under room temperature, add chloro-2, the 2-dimethyl propyl 2-of 3-(4-cyclohexyl naphthyl) propionic ester (50.0g, 0.13mol), acetone (300mL); Stir 5 minutes to solid molten clear after, in reaction solution, add 150mL wet chemical (30%).The reaction mixture obtained is heated to 60 DEG C ~ 70 DEG C reactions 2 hours, until react completely.Reaction solution is cooled to room temperature, removes organic solvent under reduced pressure, the brown suspension 100mL water dilution obtained, then adds the extraction of 200mL methyl tertiary butyl ether.Separate organic layer, organic phase at room temperature stirs 1 hour, then is cooled to 0 DEG C ~ 10 DEG C stirrings 1 hour.Filter, filter cake methyl tertiary butyl ether washing (40mL × 2) obtains the sodium salt that white solid is Vedaprofen.The white solid obtained is dropped in 100mL dilute hydrochloric acid (2N), stir after 30 minutes and filter, filter cake washes twice (40mL × 2) with water and obtains white solid, and this solid is dry under 50 DEG C of vacuum conditions obtains white solid, i.e. Vedaprofen in about 16 hours.Yield: ~ 30%, purity 99.7%.
More than describe and illustrate ultimate principle of the present invention, principal character and advantage.It should be appreciated by those skilled in the art; the present invention is not restricted to the described embodiments; the embodiment described in above-described embodiment and specification sheets is just for illustration of principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims.

Claims (4)

1. synthesize a method for Vedaprofen, comprise the following steps:
A) compound 2 and the propionating reagent of 2-halo carry out Fu Zhongsun, and obtain compound 3, its reaction formula is as follows:
Wherein, the propionating reagent of described 2-halo is 2-chlorpromazine chloride, 2-chloropropionic acid acid anhydride, 2-bromo propionyl chloro or 2 bromopropionic acid acid anhydride; The mol ratio of the propionating reagent of described 2-halo and compound 2 is 1.1:1;
Fu Zhongsun uses Lewis acid as catalyzer, and described Lewis acid is for being selected from AlCl 3, ZnCl 2, BF 3, TiCl 4in one or more, and Lewis acid is 1.2:1 with the mol ratio of compound 2;
The solvent that reaction uses is methylene dichloride;
After having reacted, adopt hydrochloric acid reaction;
B) compound 3 dibasic alcohol carries out ketalization protection, obtains compound 4, and its reaction formula is as follows:
Wherein, described dibasic alcohol is ethylene glycol, 1,3 propylene glycol or neopentyl glycol; The mol ratio of described dibasic alcohol and compound 3 is 1.5:1;
The solvent that this reaction uses is toluene;
C) compound 4 carries out aryl tropic rearrangement under Louis acid catalysis, obtains compound 5, and its reaction formula is as follows:
Wherein, the catalyzer of rearrangement reaction employing is for being selected from ZnO, ZnCl 2with Zn (OAc) 2in one or more;
The solvent used is toluene;
Range of reaction temperature is 110 DEG C ~ 130 DEG C;
D) compound 5 is through hydrolysis, and obtain Vedaprofen 1, its reaction formula is as follows:
Wherein, X is fluorine, chlorine, bromine or iodine,
Each R is hydrogen, methyl or ethyl independently,
N is 0,1 or 2.
2. method according to claim 1, wherein, in described steps A) in, range of reaction temperature is-10 DEG C ~ 0 DEG C.
3. method according to claim 1, wherein, at described step B) in, the catalyzer that described ketal reaction uses be selected from sulfuric acid, acetic acid, tosic acid, methylsulfonic acid, citric acid one or more; The mol ratio of described catalyzer and compound 3 is 0:1 ~ 1:1.
4. method according to claim 1, wherein, at described step C) in, the mol ratio of described catalyzer and compound 4 is 0:1 ~ 3:1.
CN201110448572.2A 2011-12-28 2011-12-28 The preparation method of Vedaprofen Active CN103183604B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201110448572.2A CN103183604B (en) 2011-12-28 2011-12-28 The preparation method of Vedaprofen

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201110448572.2A CN103183604B (en) 2011-12-28 2011-12-28 The preparation method of Vedaprofen

Publications (2)

Publication Number Publication Date
CN103183604A CN103183604A (en) 2013-07-03
CN103183604B true CN103183604B (en) 2015-07-29

Family

ID=48675084

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201110448572.2A Active CN103183604B (en) 2011-12-28 2011-12-28 The preparation method of Vedaprofen

Country Status (1)

Country Link
CN (1) CN103183604B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104710309A (en) * 2015-02-05 2015-06-17 浙江普洛医药科技有限公司 Synthetic methods of loxoprofen sodium and intermediate thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4218473A (en) * 1977-10-03 1980-08-19 Centre Europeen De Recherches Mauvernay Derivatives of 4-cyclohexyl-1-naphthalene-acetic acid and their use as drugs
US4623736A (en) * 1982-07-09 1986-11-18 The Upjohn Company Arylalkanoic acid process improvement
CN1082022A (en) * 1992-08-14 1994-02-16 山东新华制药厂 Molecular transposition prepares the technology of Ibuprofen BP/EP under the catalysis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4218473A (en) * 1977-10-03 1980-08-19 Centre Europeen De Recherches Mauvernay Derivatives of 4-cyclohexyl-1-naphthalene-acetic acid and their use as drugs
US4623736A (en) * 1982-07-09 1986-11-18 The Upjohn Company Arylalkanoic acid process improvement
CN1082022A (en) * 1992-08-14 1994-02-16 山东新华制药厂 Molecular transposition prepares the technology of Ibuprofen BP/EP under the catalysis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Zinc Salt Catalyzed Rearrangement of Acetals of Optically Active Aryl 1-Chloroethyl Ketones: Synthesis of Optically Active 2-Arylpropionic Acids and Esters;Oreste Piccolo等;《J.Org.Chem.》;19871231;第52卷;第10-14页 *

Also Published As

Publication number Publication date
CN103183604A (en) 2013-07-03

Similar Documents

Publication Publication Date Title
CN101830821B (en) Chemical synthesis method of N-alcoxyloxalyl alanine ester
CN102627573A (en) Synthesis method for 5-aminolevulinic acid hydrochloride
JP5873484B2 (en) Dronedarone and method for producing the salt thereof
CN102395591B (en) Method for preparing prasugrel
CN113603568A (en) Preparation method of cannabidiol
CN101575269A (en) Preparation method of aromatic methyl ether compound
WO2001060774A1 (en) Synthesis of resveratrol
CN108409602B (en) Method for preparing α -aryl nitrile compound
CN103183604B (en) The preparation method of Vedaprofen
CN104844593A (en) Synthetic method for Apixaban drug intermediate
CN106146457B (en) 5-chloro-2-acyl chloride thiophene intermediate and preparation method thereof
CN104402849B (en) The new preparation process of Ta Simeiqiong intermediate
CN103450130A (en) Toluylene compound and preparation method thereof
CN102617460A (en) Compounding method of midbody required in compounding of montelukast sodium
JP6695908B2 (en) Method for producing benzamide compound
CN110183380B (en) Synthesis method and application of 4-hydroxy-1, 8-naphthalimide derivative
CN111018928B (en) Synthetic method and application of gastrodin hemihydrate
CN110183371B (en) Preparation process of zafirlukast intermediate
CN103804187B (en) Synthesis method of diethylstilbestrol compound pigeon pea ketonic acid A
CN103073525A (en) Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide
CN108727323B (en) Method for catalytically synthesizing trifluoromethyl substituted homoisoflavone compound by using N-heterocyclic carbene
CN112624921A (en) Synthesis method and application of 1-hydroxymethyl cyclopropyl acetic acid
CN106749156B (en) Process for preparing benzo [1,3-d ] dioxoles and intermediates thereof
CN101148402A (en) Process for preparing 2-bromofluorenone
CN101723841B (en) Preparation method of 2-amino-5-alkoxy propiophenone

Legal Events

Date Code Title Description
C06 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