CN102079708A - Synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate - Google Patents
Synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate Download PDFInfo
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Abstract
The invention discloses a synthetic method of 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate, and the method comprises three synthetic routes, wherein in the three routes, 3-butyne-1-ol and 4-halo-alpha, alpha-dimethyl phenylacetate are used as raw materials and high-purity 4-(4-halobutyryl)-alpha, alpha-dimethyl phenylacetate is obtained through coupling reaction, halogenation reaction, and hydration reaction. The method has the advantages of cheap and easily available raw materials, low cost, and high operability; the method is suitable for industrial production; and the prepared products have high purity.
Description
Technical field
The present invention relates to the synthetic field of organic compound, be specifically related to a kind of 4-(4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester.
Background technology
4-(4-halogen butyryl radicals)-α, alpha-alpha-dimethyl phenyl acetic acid ester are the key intermediates of preparation antihistamine drug fexofenadine (Fexofenadine), and fexofenadine is a kind of novel specificity histamine H
1Receptor antagonist possesses no nervus centralis sedative effect and the low characteristic of cardiac toxic, can obviously improve patient's quality of life.
The chemistry of fexofenadine is called 4-{1-hydroxyl-4-[4-(hydroxy benzophenone base)-piperidino] butyl }-α; alpha-alpha-dimethyl phenyl acetic acid; has the structure shown in the structural formula 2; disclose α among U.S. Pat 4254129 and the US4254130; α-diphenyl-piperidine methyl alcohol (shown in the structural formula 3) 4-(4-halogen butyryl radicals)-α; the alpha-alpha-dimethyl phenyl acetic acid ester is (shown in the structural formula 1; R is an alkyl; X is a halogen) after the alkylation, again ketone carbonyl reduction, hydrolysis of ester group are made the method for fexofenadine.4-(4-halogen butyryl radicals)-α wherein, the alpha-alpha-dimethyl phenyl acetic acid ester is by α, alpha-alpha-dimethyl phenyl acetic acid ester and 4-halogen acyl halide generation friedel-crafts reaction obtain; Concrete preparation method is: in solvent dithiocarbonic anhydride, with aluminum chloride catalysis α, alpha-alpha-dimethyl phenyl acetic acid ethyl ester and 4-chlorobutanoylchloride generation friedel-crafts reaction can prepare 4-(4-halogen butyryl radicals)-α, alpha-alpha-dimethyl phenyl acetic acid ethyl ester (shown in the structural formula 4).Yet; U.S. Pat 6147216 waits other relevant patent and us found through experiments; the product that friedel-crafts reaction obtains is to be difficult to isolating 4-(4-halogen butyryl radicals)-α; alpha-alpha-dimethyl phenyl acetic acid ethyl ester (contraposition product) and 3-(4-halogen butyryl radicals)-α, the mixture of alpha-alpha-dimethyl phenyl acetic acid ethyl ester (metacompaund).
Proposed in the U.S. Pat 6242606 by Crystallization Separation 4-(4-halogen butyryl radicals)-α; the alpha-alpha-dimethyl phenyl acetic acid ester (comprises methyl esters; ethyl ester) and 3-(4-halogen butyryl radicals)-α; the method of the mixture of alpha-alpha-dimethyl phenyl acetic acid ester; but this crystallization method will carry out under-50 ℃ low temperature; and need secondary crystal, complex operation, yield also have only 14%.
Announced the higher relatively generation 4-of a kind of selectivity (4-halogen butyryl radicals)-α among the patent EP648759; the alpha-alpha-dimethyl phenyl acetic acid ester (comprises methyl esters; ethyl ester) method of contraposition product; in solvent dithiocarbonic anhydride; with aluminum chloride catalysis α; alpha-alpha-dimethyl phenylethyl alcohol acetic ester (shown in the structural formula 5) and 4-chlorobutanoylchloride generation friedel-crafts reaction can obtain metacompaund content at the contraposition acylate below 10%.Yet the metacompaund in that this friedel-crafts reaction stage produces remains the obstacle that obtains high purity end product fexofenadine.And complex separation process wastes time and energy, and wastes raw material, and increases cost.And the hydroxylic moiety in this reaction product also will pass through the hydrolysis deacetylate at last, just can be converted into final required carboxylic acid through peroxidation again, has increased reactions steps, has also increased cost.
A kind of separation 4-(4-halogen butyryl radicals)-α has been proposed in the U.S. Pat 5578610; the alpha-alpha-dimethyl phenyl acetic acid ester (comprises methyl esters; ethyl ester) and the method for metacompaund; with 4-(4-halogen butyryl radicals)-α; the mixture of alpha-alpha-dimethyl phenyl acetic acid ethyl ester and metacompaund becomes sour with hydrolysis of ester group under strong alkaline condition; be converted into the mixture of isomers of the compound shown in the structural formula 6; with the mixture of isomers and the alkaloid cinchovatin reaction salify of the compound shown in the structural formula 6, obtain purer contraposition product by the crystalline method more then.This method yield is very low, and separation costs is higher.
Introduced the method for methyl esters of the mixture of isomers of the compound shown in a kind of purification structure formula 6 in the U.S. Pat 20100016599, the mixture that will contain 90% (quality percentage composition) contraposition product and 6.5% (quality percentage composition) metacompaund is in normal hexane,-20 ℃ of following crystallizations obtain purity and are 98.9% contraposition product.
Provide another to obtain the method for the compound contraposition product shown in the higher degree structural formula 6 in the U.S. Pat 6147216, the mix products of distillation friedel-crafts reaction under high vacuum, with crystallization under the product low temperature that obtains, obtain the contraposition product of the compound shown in the structural formula 6 again.This method complex operation, yield is low, is not suitable for industrial production.
In the U.S. Pat 6903232, be isomer mixture crystallization in hexanaphthene of the compound shown in 80: 20 the structural formula 6 with contraposition and metacompaund mass ratio, obtained purer contraposition product.
The product that above-mentioned existing method obtains is 4-(4-halogen butyryl radicals)-α; alpha-alpha-dimethyl phenyl acetic acid ethyl ester and 3-(4-halogen butyryl radicals)-α; the mixture of alpha-alpha-dimethyl phenyl acetic acid ethyl ester; need obtain contraposition product 4-(4-halogen butyryl radicals)-α by purge process; the alpha-alpha-dimethyl phenyl acetic acid ethyl ester; have complex operation, productive rate is lower, defectives such as cost height.
Structural formula 2 structural formulas 3
Structural formula 4 structural formulas 5
Structural formula 6 structural formulas 1
Summary of the invention
The invention provides the 4-that a kind of cost is low, technological process is simple and product purity is high (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester.
A kind of 4-(4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester, comprise three synthetic routes, article three, route is all with the pure and mild 4-halo-α of 3-butine-1-, the alpha-alpha-dimethyl phenyl acetic acid ester is a starting raw material, by linked reaction, halogenating reaction and hydration reaction, obtain high purity 4-(4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester; Article three, route is as follows respectively:
Route one may further comprise the steps:
(1) with the 3-butine shown in the structural formula 7-1-alcohol and halogenating agent through halogenating reaction, obtain the 4-halo-ethyl acetylene shown in the structural formula 8;
(2) the 4-halo-α shown in the structural formula 9, the 4-halo-ethyl acetylene shown in alpha-alpha-dimethyl phenyl acetic acid ester and the structural formula 8 obtain the 4-shown in the structural formula 10 (4-halo-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through linked reaction;
(3) 4-shown in the structural formula 10 (4-halo-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid ester obtain the 4-shown in the structural formula 1 (4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through hydration reaction;
Reaction process is as follows:
Perhaps, route two may further comprise the steps:
(1) with the 3-butine shown in the structural formula 7-1-alcohol and the 4-halo-α shown in the structural formula 9, the alpha-alpha-dimethyl phenyl acetic acid ester obtains the 4-shown in the structural formula 11 (4-hydroxyl-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through linked reaction;
(2) 4-shown in the structural formula 11 (4-hydroxyl-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid ester and halogenating agent obtain the 4-shown in the structural formula 10 (4-halo-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through halogenating reaction;
(3) 4-shown in the structural formula 10 (4-halo-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid ester obtain the 4-shown in the structural formula 1 (4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through hydration reaction;
Reaction process is as follows:
Perhaps, route three may further comprise the steps:
(1) with the 3-butine shown in the structural formula 7-1-alcohol and the 4-halo-α shown in the structural formula 9, the alpha-alpha-dimethyl phenyl acetic acid ester obtains the 4-shown in the structural formula 11 (4-hydroxyl-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through linked reaction;
(2) 4-shown in the structural formula 11 (4-hydroxyl-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester obtains the 4-shown in the structural formula 12 (4-maloyl group)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through hydration reaction;
(3) 4-shown in the structural formula 12 (4-maloyl group)-α, alpha-alpha-dimethyl phenyl acetic acid ester and halogenating agent obtain the 4-shown in the structural formula 1 (4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through halogenating reaction;
Reaction process is as follows:
Wherein, X is a halogen, is preferably Cl, Br or I; Y is a halogen, is preferably Cl, Br or I; X and Y can be the same or different; R is an alkyl, is preferably the alkyl of 1 to 6 carbon atom, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, straight chain pentyl, side chain pentyl or hexyl etc.
In order to reach better invention effect, preferably:
The temperature of reaction of described halogenating reaction is-30 ℃ to 30 ℃.
The temperature of reaction of described linked reaction is 0 ℃ to 100 ℃, and more preferably 50 ℃ to 100 ℃, optimum temps is 80 ℃.
The temperature of reaction of described hydration reaction is 0 ℃ to 100 ℃, more preferably 40 ℃.
The restriction that the reaction times of described halogenating reaction, linked reaction and hydration reaction is not strict, pass through timing sampling, (TLC) carries out trace analysis with tlc, all reacts when wherein a kind of raw material or plurality of raw materials to finish, and the terminal point that is considered as reacting gets final product.Through overtesting, to carry out fully in order to make reaction, the reaction times of described halogenating reaction was generally 0 to 30 hour; The reaction times of described linked reaction was generally 0 to 30 hour; The reaction times of described hydration reaction was generally 0 to 50 hour, was preferably 3 hours.
To the not strict restriction of the consumption between each raw material, generally get final product than being that mol ratio 1: 1 or part material are excessive in each step reaction of the present invention by the chemical reaction equation metering.
Described halogenating agent is selected the halogenating agent of hydroxyl in the energy halogenation alkynol for use, as chlorinating agent, brominated reagent or iodo reagent, and preferred thionyl chloride (SOCl
2), benzene sulphur jealous woman acyl chlorides (C
6H
5SOCl) etc. one or more in.
In order further to improve reaction efficiency, described halogenating reaction preferably carries out under pyridine catalysis.
In order further to improve reaction efficiency, described linked reaction is preferably carried out in the exsiccant protection of inert gas; Do not have the protection of rare gas element, alkynyl is oxidized easily.Described rare gas element is selected a kind of in the rare gas elementes commonly used such as argon gas, nitrogen for use.
In order further to improve reaction efficiency, described linked reaction is carried out in the presence of coupling catalyst; Described coupling catalyst is selected for use and is applicable to end-group alkyne and halogenated aromatic compound link coupled catalyzer, preferred tertiary amine organic compound, triphenyl phosphorus, cuprous halide and other coupling catalyst.
Described tertiary amine organic compound is preferably triethylamine.
Described cuprous halide is selected one or more in cuprous chloride, cuprous bromide, the cuprous iodide etc. for use, preferred cuprous iodide.
Described other coupling catalyst is selected one or more in cupric cyanide (CuCN), trivalent iron salt, palladium salt, nickel salt, cobalt salt, the aluminium salt etc. for use, preferred palladium salt.
Described trivalent iron salt is selected iron trichloride (FeCl for use
3), ferric bromide (FeBr
3), ferric acetyl acetonade (Fe (acac)
3) in one or more; Described palladium salt is triphenyl phosphorus base palladium chloride ((Ph
3P)
2PdCl
2), tetraphenylphosphonium base palladium ((Ph
3P)
4Pd), tertiary butyl phosphorus base palladium chloride ((t-But
3P)
2PdCl
2), palladium chloride (PdCl
2) in one or more.Preferred PdCl
2
The step of described linked reaction specifically comprises: with the 4-halo-α shown in the structural formula 9, the alpha-alpha-dimethyl phenyl acetic acid ester mixes with tertiary amine organic compound, triphenyl phosphorus and cuprous halide, be warming up to 50 ℃ to 100 ℃, preferred 80 ℃, add other coupling catalyst again, be incubated and be cooled to 65 ℃ to 75 ℃ after 0 to 10 hour, preferred insulation 30 minutes, drip 4-halo-ethyl acetylene or 3-butine-1-alcohol then continuously, the dropping time is 1 to 10 hour, the preferred dropping time is 2.5 hours to 3-5 hour, and after dripping, reaction finishes substantially.
Described hydration reaction is preferably carried out in the presence of solvent and catalyzer; Described solvent is selected the solvent that is fit to the acetylene bond hydration, one or both in optional water, the alcoholic solvent for use; In the alcohol of preferred 1 to 6 carbon atom of described alcoholic solvent one or more, as in methyl alcohol, ethanol, the Virahol etc. one or more, one or both effects in water, the methyl alcohol are preferable.
Described catalyzer is selected one or more in mercuric oxide compound, water-soluble mercuric salt, water-soluble palladium salt, water-soluble golden salt, the water-soluble platinum salt etc. for use.
The preferred red precipitate of described mercuric oxide compound; In the preferred mercury chloride of described water-soluble mercuric salt, mercuric bromide, red mercury iodide, Mercury bisulfate, the Mercury pernitrate one or more.
Compared with prior art, the present invention has following advantage:
The product of the product of the product of halogenating reaction, linked reaction and hydration reaction all only needs as extraction, washing, drying etc., just can obtain highly purified contraposition product through simple aftertreatment in the inventive method, need not crystallization or complicated isomer separation process.
The inventive method is raw materials used cheap and easy to get, and cost is low, and is simple to operate, is suitable for suitability for industrialized production, the product purity height that makes.
The resulting product of the inventive method does not contain metacompaund 3-(4-halogen the butyryl radicals)-α that is difficult to remove substantially, and alpha-alpha-dimethyl phenyl acetic acid ester impurity can obtain highly purified 4-(4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester.
Embodiment
Embodiment 1
1) 4-chloro-ethyl acetylene is synthetic:
The 100ml round-bottomed flask, (5.4g, 77.04mmol), 4 of pyridines stir several minutes, add SOCl with constant pressure funnel to add 3-butine-1-alcohol in the ice-water bath
2(9.2g, 77.04mmol dripped about 15 minutes) add the water-bath of recession deicing, stir 30 minutes.Then, be warming up to 70 ℃ times and heated up in a steamer 3.5 hours, stopped reaction to the 150ml frozen water, is used dichloromethane extraction 3 times with the reaction solution impouring, and the 50ml methylene dichloride/each (note does 3 * 50ml), and organic layer is with NaHCO
3(2 * 100ml) wash saturated solution, and (2 * 100ml) wash with water.Then use anhydrous Na
2SO
4Dry organic layer steams methylene dichloride and collects cut between 70 ℃ to 84 ℃, obtains the 2.9g colourless liquid, i.e. 4-chloro-ethyl acetylene.Repetitive operation once or increase each material quantity makes 5.8g4-chloro-ethyl acetylene altogether.
2) 4-(4-chloro-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters synthetic
Under nitrogen protection; in the 100ml there-necked flask, add earlier 4-bromo-α; the alpha-alpha-dimethyl phenyl acetic acid methyl esters (12.8g, 49.7mmol) and triethylamine (10.06g, 99.4mmol); add triphenyl phosphorus (0.156g again; 0.6mmol) and cuprous iodide (0.038g 0.3mmol), is warming up to 80 ℃ and adds palladium chloride (0.009g; 0.05 mmol), under this temperature, kept 30 minutes.Then be cooled to 70 ℃ to 73 ℃, (4g 49.7mmol), drips off about 3 hours, and after dripping, reaction finishes substantially slowly to add 4-chloro-ethyl acetylene continuously with syringe pump.Add the 100ml ethyl acetate, filter, filtrate boils off solvent and gets product palm fibre xanchromatic liquid 12.5g, i.e. 4-(4-chloro-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters.
3) 4-(4-chlorobutyryl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters synthetic
Get step reaction product 4-(4-chloro-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid methyl esters (1g 3.8mmol) is dissolved in the methyl alcohol of 10ml, under in 40 ℃ of oil baths, stirring, add by HgO (28mg, 0.129mmol) and H
2SO
4The aqueous solution (vitriol oil 0.21ml, 3.86mmol; Water 1.2ml) HgSO that makes
4Solution.After about three hours, the TLC detection reaction is finished substantially.Reaction solution is poured in the 150ml distilled water, stirred.This moment occurs a large amount of white flosss, add NaHCO
3Be neutralized to neutrality, with ethyl acetate (3 * 50ml) aqueous layer extracted.Merge organic layer, drying concentrates, and obtains colourless liquid 0.88g behind the silicagel column excessively.
The nuclear magnetic resonance data of product colourless liquid is in the step 3):
1H-NMR (CDCl
3): δ 1.61 (6H, s, 2 * Me); 2.20-2.25 (2H, quintet, J=6.7Hz, ClCH
2CH
2); 3.17 (2H, t, J=6.9Hz, CH
2CO); 3.68 (2H, t, J=5.9Hz, ClCH
2); 3.67 (3H, s, CO
2Me); 7.44 (2H, d, J=8.6Hz, Ar); 7.95 (J=8.6Hz Ar), shows to make 4-(4-chlorobutyryl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters for 2H, d.
The product colourless liquid is handled the optical purity test of organic matter in the step 3), does not find metacompaund 3-(4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester.
Embodiment 2
1) 4-(4-hydroxyl-1-alkynyl)-α, the preparation of alpha-alpha-dimethyl phenyl acetic acid methyl esters
Under nitrogen protection; in the 100ml there-necked flask, add earlier 4-bromo-α; the alpha-alpha-dimethyl phenyl acetic acid methyl esters (12.8g, 49.7mmol) and triethylamine (10.06g, 99.4mmol); add triphenyl phosphorus (0.156g again; 0.6mmol) and cuprous iodide (0.038g 0.3mmol), is warming up to 80 ℃ and adds palladium chloride (0.009g; 0.05mmol), under this temperature, kept 30 minutes.Then be cooled to 70 ℃ to 73 ℃, (3.48g, 49.7mmol), after dripping about 3 hours, reaction finishes substantially slowly to add 3-butine-1-alcohol with syringe pump.Add the 100ml ethyl acetate, filter, filtrate boils off solvent and gets pale brown look liquid 11.2g, i.e. 4-(4-hydroxyl-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters.
2) 4-(4-chloro-1-alkynyl)-α, the preparation of alpha-alpha-dimethyl phenyl acetic acid methyl esters
With 4-(4-hydroxyl-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters (1g, 4.06mmol) add in the round-bottomed flask, the methylene dichloride of pouring 10ml into makes its dissolving, places mixture of ice and water to stir reaction system, add thionyl chloride (0.35ml, 4.87mmol), this moment, solution became red-brown, splashed into several pyridines then, produce a large amount of white cigarettes, solution becomes light yellow.Wait for (about 15 minutes) after the white cigarette completely dissolve, remove ice-water bath, continue to stir, make reaction system return to room temperature, be placed in 70 ℃ the oil bath reflux then.After one and a half hours, reaction is finished substantially.Add the distilled water cancellation of 50ml earlier, add NaHCO then
3Be neutralized to neutrality, (3 * 50ml) aqueous layer extracted merge organic layer, and drying concentrates, and obtains brown liquid 1.0g, i.e. 4-(4-chloro-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters with ethyl acetate.
3) 4-(4-chlorobutyryl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters synthetic
4-(4-chloro-1-alkynyl)-α that the last step was obtained, the alpha-alpha-dimethyl phenyl acetic acid methyl esters (1g 3.8mmol) is dissolved in the methyl alcohol of 10ml, under in 40 ℃ of oil baths, stirring, add by HgO (28mg, 0.129mmol) and H
2SO
4The aqueous solution (vitriol oil 0.21ml, 3.86mmol; Water 1.2ml) HgSO that makes
4Solution.After about three hours, reaction is finished substantially.Reaction solution is poured in the 150ml distilled water, stirred.This moment occurs a large amount of white flosss, add NaHCO
3Be neutralized to neutrality, (3 * 50ml) aqueous layer extracted are till water layer is intimate colourless with ethyl acetate.Merge organic layer, drying concentrates, and obtains colourless liquid 0.81g behind column chromatography.
The nuclear magnetic resonance data of product colourless liquid is in the step 3):
1H-NMR (CDCl
3): δ 1.61 (6H, s, 2 * Me); 2.20-2.25 (2H, quintet, J=6.7Hz, ClCH
2CH
2); 3.17 (2H, t, J=6.9Hz, CH
2CO); 3.68 (2H, t, J=5.9Hz, ClCH
2); 3.67 (3H, s, CO
2Me); 7.44 (2H, d, J=8.6Hz, Ar); 7.95 (J=8.6Hz Ar), shows to make 4-(4-chlorobutyryl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters for 2H, d.
The product colourless liquid is handled the optical purity test of organic matter in the step 3), does not find metacompaund 3-(4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester.
Embodiment 3
1) 4-(4-hydroxyl-1-alkynyl)-α, the preparation of alpha-alpha-dimethyl phenyl acetic acid methyl esters
Under nitrogen protection; add 4-bromo-α in the 100ml there-necked flask; the alpha-alpha-dimethyl phenyl acetic acid methyl esters (12.8g, 49.7mmol) and triethylamine (10.06g, 99.4mmol); add triphenyl phosphorus (0.156g again; 0.6mmol) and cuprous iodide (0.038g 0.3mmol), is warming up to 80 ℃ and adds palladium chloride (0.009g; 0.05mmol), under this temperature, kept 30 minutes.Then be cooled to 70 ℃ to 73 ℃, (3.48g, 49.7mmol), after dripping about 3 hours, reaction finishes substantially slowly to add 3-butine-1-alcohol with syringe.Add the 100ml ethyl acetate, filter, filtrate boils off solvent and gets pale brown look liquid 11.2g, i.e. 4-(4-hydroxyl-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters.
2) 4-(4-maloyl group)-α, the preparation of alpha-alpha-dimethyl phenyl acetic acid methyl esters
With 4-(4-hydroxyl-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid methyl esters (1g 3.86mmol) is dissolved in the 50ml methyl alcohol, under in 40 ℃ of oil baths, stirring, add by HgO (28mg, 0.129mmol) and the H of 1.26ml
2SO
4Solution (vitriol oil 0.21ml, 3.86mmol; Water 1.1ml) HgSO that makes
4Solution.After about three hours, reaction is finished substantially.Reaction solution is poured in the 150ml distilled water, stirred, this moment occurs a large amount of white flosss, add NaHCO
3Be neutralized to neutrality, (3 * 50ml) aqueous layer extracted are till water layer is intimate colourless with ethyl acetate.Merge organic layer, drying concentrates, and obtains henna liquid 0.71g, i.e. 4-(4-maloyl group)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters.Repetitive operation once or increase each material quantity makes 1.42g4-(4-maloyl group)-α, the alpha-alpha-dimethyl phenyl acetic acid methyl esters altogether.
3) 4-(4-chlorobutyryl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters synthetic
Get 4-(4-maloyl group)-α; alpha-alpha-dimethyl phenyl acetic acid methyl esters (1g; 3.8mmol) add in the round-bottomed flask; the methylene dichloride of pouring 10ml into makes its dissolving, places mixture of ice and water to stir reaction system, adds thionyl chloride (0.32ml; 4.54mmol); this moment, solution became red-brown, splashed into several pyridines then, produced a large amount of white cigarettes; reaction soln is pale brown look; wait for (about 15 minutes) after the white cigarette completely dissolve, remove ice-water bath, continue to stir; make reaction system return to room temperature; place 70 ℃ oil bath then, reflux, reaction soln becomes blackish green.Heat after one and a half hours, reaction is finished substantially.Add the cancellation of 50ml distilled water earlier, add NaHCO then
3Be neutralized to neutrality, (3 * 50ml) aqueous layer extracted repeatedly merge organic layer, and drying concentrates, and obtains colourless liquid 0.96g behind the column chromatography with ethyl acetate.
The nuclear magnetic resonance data of product colourless liquid is in the step 3):
1H-NMR (CDCl
3): δ 1.61 (6H, s, 2 * Me); 2.20-2.25 (2H, quintet, J=6.7Hz, ClCH
2CH
2); 3.17 (2H, t, J=6.9Hz, CH
2CO); 3.68 (2H, t, J=5.9Hz, ClCH
2); 3.67 (3H, s, CO
2Me); 7.44 (2H, d, J=8.6Hz, Ar); 7.95 (J=8.6Hz Ar), shows to make 4-(4-chlorobutyryl)-α, alpha-alpha-dimethyl phenyl acetic acid methyl esters for 2H, d.
The product colourless liquid is handled the optical purity test of organic matter in the step 3), does not find metacompaund 3-(4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester.
Claims (10)
1. a 4-(4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, may further comprise the steps:
(1) with 3-butine-1-alcohol and halogenating agent through halogenating reaction, obtain the 4-halo-ethyl acetylene shown in the structural formula 8;
(2) the 4-halo-α shown in the structural formula 9, the 4-halo-ethyl acetylene shown in alpha-alpha-dimethyl phenyl acetic acid ester and the structural formula 8 obtain the 4-shown in the structural formula 10 (4-halo-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through linked reaction;
(3) 4-shown in the structural formula 10 (4-halo-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid ester obtain the 4-shown in the structural formula 1 (4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through hydration reaction;
Perhaps, may further comprise the steps:
(1) with 3-butine-1-alcohol and the 4-halo-α shown in the structural formula 9, the alpha-alpha-dimethyl phenyl acetic acid ester obtains the 4-shown in the structural formula 11 (4-hydroxyl-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through linked reaction;
(2) 4-shown in the structural formula 11 (4-hydroxyl-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid ester and halogenating agent obtain the 4-shown in the structural formula 10 (4-halo-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through halogenating reaction;
(3) 4-shown in the structural formula 10 (4-halo-1-alkynyl)-α, alpha-alpha-dimethyl phenyl acetic acid ester obtain the 4-shown in the structural formula 1 (4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through hydration reaction;
Perhaps, may further comprise the steps:
(1) with 3-butine-1-alcohol and the 4-halo-α shown in the structural formula 9, the alpha-alpha-dimethyl phenyl acetic acid ester obtains the 4-shown in the structural formula 11 (4-hydroxyl-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through linked reaction;
(2) 4-shown in the structural formula 11 (4-hydroxyl-1-alkynyl)-α, the alpha-alpha-dimethyl phenyl acetic acid ester obtains the 4-shown in the structural formula 12 (4-maloyl group)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through hydration reaction;
(3) 4-shown in the structural formula 12 (4-maloyl group)-α, alpha-alpha-dimethyl phenyl acetic acid ester and halogenating agent obtain the 4-shown in the structural formula 1 (4-halogen butyryl radicals)-α, the alpha-alpha-dimethyl phenyl acetic acid ester through halogenating reaction;
Wherein, X is a halogen; Y is a halogen; R is an alkyl.
2. 4-according to claim 1 (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, described X is Cl, Br or I; Described Y is Cl, Br or I; Described R is the alkyl of 1 to 6 carbon atom.
3. 4-according to claim 1 (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, the temperature of reaction of described halogenating reaction is-30 ℃ to 30 ℃;
The temperature of reaction of described linked reaction is 0 ℃ to 100 ℃;
The temperature of reaction of described hydration reaction is 0 ℃ to 100 ℃.
4. 4-according to claim 1 (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, described halogenating agent is one or both in thionyl chloride, the benzene sulphur jealous woman acyl chlorides.
5. 4-according to claim 1 and 2 (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, described halogenating reaction carries out under pyridine catalysis.
6. 4-according to claim 1 and 2 (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, described linked reaction is carried out in the exsiccant protection of inert gas.
7. 4-according to claim 1 and 2 (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, described linked reaction is carried out in the presence of coupling catalyst; Described coupling catalyst is tertiary amine organic compound, triphenyl phosphorus, cuprous halide and other coupling catalyst;
Described other coupling catalyst is one or more in cuprous cyanide, trivalent iron salt, palladium salt, nickel salt, cobalt salt, the aluminium salt.
8. 4-according to claim 7 (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, described tertiary amine organic compound is a triethylamine; Described cuprous halide is one or more in cuprous chloride, cuprous bromide, the cuprous iodide; Described trivalent iron salt is one or more in iron trichloride, ferric bromide, the ferric acetyl acetonade; Described palladium salt is one or more in triphenyl phosphorus base palladium chloride, tetraphenylphosphonium base palladium, tertiary butyl phosphorus base palladium chloride, the palladium chloride.
9. 4-according to claim 7 (4-halogen butyryl radicals)-α; the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester; it is characterized in that; the step of described linked reaction comprises: with the 4-halo-α shown in the structural formula 9; the alpha-alpha-dimethyl phenyl acetic acid ester mixes with tertiary amine organic compound, triphenyl phosphorus and cuprous halide; be warming up to 50 ℃ to 100 ℃; add other coupling catalyst again; be incubated and be cooled to 65 ℃ to 75 ℃ after 0 to 10 hour; drip 4-halo-ethyl acetylene or 3-butine-1-alcohol then continuously, the dropping time is 1 to 10 hour.
10. 4-according to claim 1 (4-halogen butyryl radicals)-α, the synthetic method of alpha-alpha-dimethyl phenyl acetic acid ester is characterized in that, described hydration reaction is carried out in the presence of solvent and catalyzer; Described solvent is one or both in the alcohol of water, 1 to 6 carbon atom; Described catalyzer is one or more in mercuric oxide compound, water-soluble mercuric salt, water-soluble palladium salt, water-soluble golden salt, the water-soluble platinum salt.
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| EP1260505A1 (en) * | 2001-05-17 | 2002-11-27 | Dinamite Dipharma S.p.A. | A process for the preparation of 4-[1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl]-alpha, alpha-dimethylbenzeneacetic acid |
| US20100228034A1 (en) * | 2009-03-04 | 2010-09-09 | Dipharma Francis S.R.I. | Process for the preparation of keto intermediates |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1260505A1 (en) * | 2001-05-17 | 2002-11-27 | Dinamite Dipharma S.p.A. | A process for the preparation of 4-[1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl]-alpha, alpha-dimethylbenzeneacetic acid |
| US20100228034A1 (en) * | 2009-03-04 | 2010-09-09 | Dipharma Francis S.R.I. | Process for the preparation of keto intermediates |
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| STEPHEN H. KAWAI ET AL.: "A Facile Synthesis of an Oxidation Product of Terfenadine", 《J. ORG. CHEM.》 * |
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| CN102659667A (en) * | 2012-04-20 | 2012-09-12 | 浙江启明药业有限公司 | Synthetic method of fexofenadine intermediate |
| CN102659667B (en) * | 2012-04-20 | 2013-08-14 | 浙江启明药业有限公司 | Synthetic method of fexofenadine intermediate |
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