CN101279905B - Preparation of ethynyl benzoic acid - Google Patents
Preparation of ethynyl benzoic acid Download PDFInfo
- Publication number
- CN101279905B CN101279905B CN2008100369256A CN200810036925A CN101279905B CN 101279905 B CN101279905 B CN 101279905B CN 2008100369256 A CN2008100369256 A CN 2008100369256A CN 200810036925 A CN200810036925 A CN 200810036925A CN 101279905 B CN101279905 B CN 101279905B
- Authority
- CN
- China
- Prior art keywords
- reaction
- carboxyl
- dibromobenzene
- propionic acid
- acid
- 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.)
- Expired - Fee Related
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention pertains to the technical field of medial intermediate compound synthesis, in particular to method to prepare 4-acetylenyl phenylformic acid. The method takes 4-carboxyl-2 and 3-dibromobenzene monoprop as materials to synthesize 4-acetylenyl phenylformic acid in N,N-methyl formamide through <one-cauldron> method. The 4-acetylenyl phenylformic acid synthesized with the method contains carboxyl and terminal alkynyl, and is a valuable synthesized <building block> used in organic chemistry and is of great prospect to be applied in biomedicine, medicine field, etc, particularly in replacing phenylacetylene which is recently widely used in the synthesis of aromatic heterocycle, such as triazole. The method is simple in operation and low in cost and is easy to apply in industrial production.
Description
Technical field
The invention belongs to the pharmaceutical intermediate synthesis technical field, be specifically related to the benzoic preparation method of a kind of 4-ethynyl.
Background technology
Present method synthetic 4-acetylenylbenzene formic acid, owing to contain two kinds of important function groups of acidic group and terminal alkynyl simultaneously, thereby crucial application prospect is arranged in fields such as organic chemistry, macromolecular material, biomedicine, medicine and pesticide intermediates.Containing acidic group and terminal alkynyl in this compounds, all is extremely valuable synthetic " building blocks " in synthesizing.Substitutedphenylethynyl particularly, it is the important electron industrial chemicals, at aspects such as liquid crystal novel material, special catalyst, electrode materials and chemiluminescent materials, demonstrated remarkable good characteristic, it is synthetic to be widely used in aromaticity heterocyclic such as triazole in recent years again, is one of focus of paying close attention to of Organometallic Chemistry, pharmaceutical chemistry and biochemical research person.
[1，2]
Based on carboxyl and terminal alkynyl peculiar property separately and the benzoic potential value of 4-ethynyl that contains two kinds of functional groups simultaneously, the research of this compound being carried out synthetic method has great importance.
The existing synthetic method of substitutedphenylethynyl mainly contains three kinds: (1) is raw material with the halohydrocarbon, use organic alkali dehydrohalogenations such as n-Butyl Lithium, sodium amide or tert.-butoxy potassium, or use alkali metal hydroxide (sodium hydroxide or the potassium hydroxide) dehydrohalogenation that at high temperature (is higher than 200 ℃).The shortcoming of this method is that organic bases is relatively more difficult in preparation and operating aspect, and mineral alkali then needs harsh temperature of reaction; (2) be raw material with the iodo-benzoic acid acid esters, use contains ethynyl reagent such as the ethynyl trimethyl silicane connects ethynyl under metal catalytic, and this method involves great expense, and the strict operational condition of metal catalysed reaction needs, has limited its large-scale production; (3) be raw material with aldehyde, Corey-Fuchs is arranged, Witting-Horner-Emmons, the whole bag of tricks that Gilbert-Seyferth etc. propose.These class methods all need to use phosphorus reagent, owing to need discharge a large amount of waste water when the toxicity of phosphorus reagent and preparation, have also limited the application in scale operation of present method
[3-6]
Reference:
1.Vani?P.Mocharla，Benoit?Colasson，Lac?V.Lee，Stefanie?
K.Barry?Sharpless，Chi-HueyWong，and?Hartmuth?C.Kolb，Angew.Chem.Int.Ed.2005，44，116-120.
2.Jinyi?Wang，Guodong?Sui，Vani?P.Mocharla，Rachel?J.Lin，Michael?E.Phelps，Hartmuth?C.Kolb?and?Hsian-Rong?Tseng，Angew.Chem.Int.Ed.2006，45，5276-5281.
3.E.J.Corey，P.L.Fuchs，Tetrahedron?Lett.，1972，13，3769.
4.E.J.Corey，K.Achiwa?andJ.A.Katzenellenbogen，J.Am.Chem.Soc.，1969，91，4318.
5.J.C.Gilbert，U.Weerasooriya，J.Org.Chem.，1982，47，1837.
6.a)S.Müller，B.Liepold，G.J.Roth，H.J.Bestman.Synlett.，1996，521.b)G.J.Roth，B.Liepold，S.G.Müller，H.J.Bestman.Synthesis，2004，59.
Summary of the invention
The object of the invention is to provide a kind of 4-ethynyl benzoic preparation method.
The final product that the present invention obtains is a 4-acetylenylbenzene formic acid (III), and intermediate product is that cis-4-carboxyl bromobenzene second is rare, and its synthetic route is as follows:
Concrete steps are as follows:
(1) become alkene reaction:
In container, add 4-carboxyl-2 respectively, 3-dibromobenzene propionic acid (Compound I), N, N`-dimethyl formamide (DMF) and triethylamine (Et
3N), mix, microwave reaction 45-90 second under 200-350W, TLC shows that reaction finishes; Wherein: 4-carboxyl-2,3-dibromobenzene propionic acid and N, the mol ratio of N`-dimethyl formamide is 1: 100-1: 150,4-carboxyl-2, the mol ratio of 3-dibromobenzene propionic acid and triethylamine is 1: 2-1: 5,
(2) become alkyne reaction:
Add sodium ethylate (NaOEt) in the system of step (1) gained, 80-140 ℃ of condition lower magnetic force stirring reaction 3-12 hour, TLC showed that reaction finishes; 4-carboxyl-2, the mol ratio of 3-dibromobenzene propionic acid and sodium ethylate are 1: 2-1: 5;
(3) extract:
Step (2) gained system is returned to room temperature, and being acidified to the pH value with the cryosel acid of 0.1mol/L is 2-5, suction filtration, and filter cake washs with frozen water, through Vanadium Pentoxide in FLAKES vacuum-drying, obtains white powder, is 4-acetylenylbenzene first carboxylic (compound III).
The present invention is with 4-carboxyl-2 cheap and easy to get, and 3-dibromobenzene propionic acid is a raw material, and with N, dinethylformamide is a solvent, becomes alkene with triethylamine decarboxylation under microwave action, and system is directly synthesized 4-acetylenylbenzene formic acid with the sodium ethylate effect again.This synthetic route obtains the final objective thing by one pot of two step reaction, has reduced the purification step of intermediate compound, has reduced the usage quantity of organic solvent.This synthetic route has that raw material is easy to get, the advantages such as effect of easy and simple to handle, easily-controlled reaction conditions, tool environmental emission reduction, is convenient to suitability for industrialized production.
Method of the present invention is not appeared in the newspapers as yet.
Embodiment
Followingly further specify the present invention, but can not limit content of the present invention by embodiment.
Embodiment 1:
(1) becomes alkene
Add 1.760g (5mmol) 4-carboxyl-2 in the round-bottomed flask of 100mL, 3-dibromobenzene propionic acid (Compound I) adds N, and N`-dimethyl formamide (DMF) 40mL adds 1.4mL (10mmol) triethylamine (Et
3N), microwave reaction is 50 seconds under 350W, and TLC (ethyl acetate/normal hexane/acetate=10/5/1 is a developping agent) demonstration reaction is finished.
(2) become alkynes
Add sodium ethylate 0.68g (10mmol) in the system that the first step reaction finishes, 80 ℃ of lower magnetic force stirring reactions 12 hours, TLC (ethyl acetate/normal hexane/ethanol=10/40/1 be a developping agent) showed to react and finishes.
(3) product extracts
Treat that the second step reaction system returns to that the cryosel acid with 0.1mol/L is acidified to pH=2 after the room temperature, suction filtration, filter cake divides three washings with the 45mL frozen water, gets white powder 0.673g again after Vanadium Pentoxide in FLAKES vacuum-drying, be the basic formic acid of acetylene (compound III), yield 93%.
Characterization data is as follows:
White?solid；m.p.209.3-210.5℃.
1H?NMR(400MHz，DMSO-d6)：δ＝4.44(1H，s)，7.58(2H，d，J＝8.22Hz)，7.96(2H，d，J＝8.22Hz)，13.16(1H，s).
Embodiment 2:
(1) becomes alkene
Add 1.760g (5mmol) 4-carboxyl-2 in the round-bottomed flask of 100mL, 3-dibromobenzene propionic acid (Compound I) adds N, and N`-dimethyl formamide (DMF) 50mL adds 2.1mL (15mmol) triethylamine (Et
3N), microwave reaction is 50 seconds under 300W, and TLC (ethyl acetate/normal hexane/acetate=10/5/1 is a developping agent) demonstration reaction is finished.
(2) become alkynes
Add sodium ethylate 0.748g (11mmol) in the system that the first step reaction finishes, 80 ℃ of lower magnetic force stirring reactions 10 hours, TLC (ethyl acetate/normal hexane/ethanol=10/40/1 be a developping agent) showed to react and finishes.
(3) product extracts
After treating second the step, reaction system returning to room temperature, be acidified to pH=3, suction filtration with the cryosel acid of 0.1mol/L, filter cake divides three washings with the 45mL frozen water, get white powder 0.695g through Vanadium Pentoxide in FLAKES vacuum-drying again, be the basic formic acid of acetylene (compound III), yield 96%.
Embodiment 3:
(1) becomes alkene
Add 1.760g (5mmol) 4-carboxyl-2 in the round-bottomed flask of 100mL, 3-dibromobenzene propionic acid (Compound I) adds N, and N`-dimethyl formamide (DMF) 60mL adds 1.4mL (10mmol) triethylamine (Et
3N), microwave reaction is 80 seconds under 250W, and TLC (ethyl acetate/normal hexane/acetate=10/5/1 is a developping agent) demonstration reaction is finished.
(2) become alkynes
Add sodium ethylate 1.020g (15mmol) in the system that the first step reaction finishes, 80 ℃ of lower magnetic force stirring reactions 7 hours, TLC (ethyl acetate/normal hexane/ethanol=10/40/1 be a developping agent) showed to react and finishes.
(3) product extracts
After treating second the step, reaction system returning to room temperature, be acidified to pH=4, suction filtration with the cryosel acid of 0.1mol/L, filter cake divides three washings with the 45mL frozen water, after Vanadium Pentoxide in FLAKES vacuum-drying, get white powder 0.70g again, be the basic formic acid of acetylene (compound III), yield 97%.
Embodiment 4:
(1) becomes alkene
Add 1.760g (5mmol) 4-carboxyl-2 in the round-bottomed flask of 100mL, 3-dibromobenzene propionic acid (Compound I) adds N, and N`-dimethyl formamide (DMF) 60mL adds 2.8mL (20mmol) triethylamine (Et
3N), microwave reaction is 90 seconds under 200W, and TLC (ethyl acetate/normal hexane/acetate=10/5/1 is a developping agent) demonstration reaction is finished.
(2) become alkynes
Add sodium ethylate 1.380g (20mmol) in the system that the first step reaction finishes, 120 ℃ of lower magnetic force stirring reactions 6 hours, TLC (ethyl acetate/normal hexane/ethanol=10/40/1 be a developping agent) showed to react and finishes.
(3) product extracts
After treating second the step, reaction system returning to room temperature, be acidified to pH=4, suction filtration with the cryosel acid of 0.1mol/L, filter is sick to divide three washings with the 45mL frozen water, get white powder 0.696g through Vanadium Pentoxide in FLAKES vacuum-drying again, be the basic formic acid of acetylene (compound III), yield 96%.
Embodiment 5:
(1) becomes alkene
Add 1.760g (5mmol) 4-carboxyl-2 in the round-bottomed flask of 100mL, 3-dibromobenzene propionic acid (Compound I) adds N, and N`-dimethyl formamide (DMF) 60mL adds 1.4mL (10mmol) triethylamine (Et
3N), microwave reaction is 90 seconds under 200W, and TLC (ethyl acetate/normal hexane/acetate=10/5/1 is a developping agent) demonstration reaction is finished.
(2) become alkynes
Add sodium ethylate 1.020g (15mmol) in the system that the first step reaction finishes, reflux condition lower magnetic force stirring reaction 3 hours, TLC (ethyl acetate/normal hexane/ethanol=10/40/1 be a developping agent) showed to react and finishes.
(3) product extracts
After treating second the step, reaction system returning to room temperature, be acidified to pH=5, suction filtration with the cryosel acid of 0.1mol/L, filter cake divides three washings with the 45mL frozen water, get white powder 0.682g through Vanadium Pentoxide in FLAKES vacuum-drying again, be the basic formic acid of acetylene (compound III), yield 94%.
Claims (1)
1. benzoic preparation method of 4-ethynyl is characterized in that gained 4-acetylenylbenzene formic acid structural formula is as follows:
Synthetic route is as follows:
Concrete steps are as follows:
(1) become alkene reaction:
In container, add 4-carboxyl-2 respectively, 3-dibromobenzene propionic acid, N, N`-dimethyl formamide and triethylamine mix, and microwave reaction 45-90 second under 200-350W, TLC shows that reaction finishes; Wherein: 4-carboxyl-2,3-dibromobenzene propionic acid and N, the mol ratio of N`-dimethyl formamide is 1: 100-1: 150,4-carboxyl-2, the mol ratio of 3-dibromobenzene propionic acid and triethylamine is 1: 2-1: 5,
(2) become alkyne reaction:
Add sodium ethylate in the system of step (1) gained, 80-140 ℃ of condition lower magnetic force stirring reaction 3-12 hour, TLC showed that reaction finishes; 4-carboxyl-2, the mol ratio of 3-dibromobenzene propionic acid and sodium ethylate are 1: 2-1: 5;
(3) extract:
Step (2) gained system is returned to room temperature, and being acidified to the pH value with the cryosel acid of 0.1mol/L is 2-5, suction filtration, and filter cake washs with frozen water, through Vanadium Pentoxide in FLAKES vacuum-drying, obtains white powder, is 4-acetylenylbenzene first carboxylic.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100369256A CN101279905B (en) | 2008-04-30 | 2008-04-30 | Preparation of ethynyl benzoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100369256A CN101279905B (en) | 2008-04-30 | 2008-04-30 | Preparation of ethynyl benzoic acid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101279905A CN101279905A (en) | 2008-10-08 |
| CN101279905B true CN101279905B (en) | 2011-06-22 |
Family
ID=40012602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100369256A Expired - Fee Related CN101279905B (en) | 2008-04-30 | 2008-04-30 | Preparation of ethynyl benzoic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101279905B (en) |
-
2008
- 2008-04-30 CN CN2008100369256A patent/CN101279905B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN101279905A (en) | 2008-10-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Li et al. | A highly efficient three-component coupling of aldehyde, terminal alkyne, and amine via C–H activation catalyzed by reusable immobilized copper in organic–inorganic hybrid materials under solvent-free reaction conditions | |
| Chen et al. | Silica supported palladium-phosphine complex: recyclable catalyst for Suzuki–Miyaura cross-coupling reactions at ambient temperature | |
| Tu et al. | A robust hydrophilic pyridine-bridged bis-benzimidazolylidene palladium pincer complex: Synthesis and its catalytic application towards Suzuki–Miyaura couplings in aqueous solvents | |
| Chen et al. | Acetonitrile-dependent oxyphosphorylation: A mild one-pot synthesis of β-ketophosphonates from alkenyl acids or alkenes | |
| Liu et al. | FeCl3 as Lewis acid catalyzed one-pot three-component aza-Friedel–Crafts reactions of indoles, aldehydes, and tertiary aromatic amines | |
| Zeng et al. | In (OTf) 3/acid co-catalyzed hydration of 1-haloalkynes to α-halomethyl ketones | |
| Patil et al. | CES as an efficient natural catalyst for synthesis of Schiff bases under solvent-free conditions: an innovative green approach | |
| Santos-Filho et al. | Environmentally friendly homocoupling reaction of functionalized potassium aryl trifluoroborates salts in aqueous media | |
| CN102249879B (en) | 1,2-diketone derivant and preparation method thereof | |
| CN108558949B (en) | Method for catalytically synthesizing benzo-phospha-cyclopentadiene by using Pd nanoparticles | |
| Gholinejad et al. | One-pot odorless thia-Michael reaction by copper ferrite nanoparticle-catalyzed reaction of elemental sulfur, aryl halides and electron-deficient alkenes | |
| Adib et al. | Reaction between anthranilic acids, salicylaldehydes and isocyanides in water: an efficient synthesis of 2-{[2-(alkylimino)-1-benzofuran-3-yliden] amino} benzoic acids | |
| CN109096150A (en) | A kind of nonmetal catalyzed method for preparing beta-amino ketones of photoinduction | |
| Wang et al. | An ionic liquid catalyzed probase method for one-pot synthesis of α, β-unsaturated esters from esters and aldehydes under mild conditions | |
| Yadav et al. | FeCl3-catalyzed alkylation of indoles with 1, 3-dicarbonyl compounds: an expedient synthesis of 3-substituted indoles | |
| Davoodnia et al. | A Modified and Green Procedure for the Synthesis of β‐Amido Ketones Using a Br? nsted‐Acidic Ionic Liquid as Novel and Reusable Catalyst | |
| Zhou et al. | Air Oxidative Radical Oxysulfurization of Alkynes Leading to α-Thioaldehydes | |
| CN101279905B (en) | Preparation of ethynyl benzoic acid | |
| Li et al. | The unprecedented C-alkylation and tandem C-/O-alkylation of phenanthrolinium salts with cyclic 1, 3-dicarbonyl compounds | |
| Huang et al. | Preparation of resin-bound alkynyl iodonium salts and their application in organic synthesis as alkynyl transfer reagents | |
| CN101245040B (en) | Process for producing 4-ethynyl benzene sulfonamide (I) | |
| Durka et al. | Formation of dilithiated bis-(1H-pyrazol-1-yl) alkanes and their application in the synthesis of diboronic acids | |
| CN105272918B (en) | Halogenation -1- alkyl -3- vinyl -2,4,5- triarylimidazoles and preparation method and purposes | |
| Reddy et al. | An efficient synthesis of 2-aryl-1, 4-diketones via hydroacylation of enones | |
| Liu et al. | Polymer-supported tertiaryphosphine (JJ–TPP) as a green and recyclable organocatalyst for α-addition of carbon nucleophiles to α, β-unsaturated compounds |
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 | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110622 Termination date: 20140430 |