CN100453522C - Preparation of 4-[4-(1-oxethylacyl-1-ethyl methyl benzene)]-4-ketobutyric acid - Google Patents
Preparation of 4-[4-(1-oxethylacyl-1-ethyl methyl benzene)]-4-ketobutyric acid Download PDFInfo
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- CN100453522C CN100453522C CNB2005100377174A CN200510037717A CN100453522C CN 100453522 C CN100453522 C CN 100453522C CN B2005100377174 A CNB2005100377174 A CN B2005100377174A CN 200510037717 A CN200510037717 A CN 200510037717A CN 100453522 C CN100453522 C CN 100453522C
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Abstract
The present invention relates to a preparation method for 4-[4-(1-oxethylacyl-1-ethyl methyl benzene)]-4-ketobutyric acid, which is characterized in that 1 mol of alpha, alpha-dimethylphenylacetic acid, 2.5 to 3 mol of ethanol and 250 to 300 ml of toluene are boiled for separating water under the catalysis of toluene-4-sulfoacid in order to generate alpha, alpha-dimethylphenylacetic acid ethyl ester; a Fridel-Crafts acyl reaction is carried out to 1 mol of alpha, alpha-dimethylphenylacetic acid, 1 to 1.2 mol of succinic anhydride and 350 to 450 ml of methylene chloride at the temperature of-20 DEG C to-10 DEG C in order to generate mixed acid; per gram of the mixed acid is dissolved in 1.2 to 1.5 ml of crystallized solvents to form a mixed acid solution which can be slowly cooled to obtain crystals at the temperature of-5 DEG C to-25 DEG C. the present invention has the advantages of simple steps, high yield and low cost; 3-[4-(1-oxethylacy-1-ethyl methyl benzene)]-4-ketobutyric acid as a byproduct in the mixed acid has low content and is easy to remove.
Description
Technical field:
The invention belongs to the organic compound preparation field, particularly the 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene) of the important synthetic intermediate of antihistamine drug fexofenadine hydrochloride (Fexofenadine Hydrochloride)]-preparation method of 4-ketobutyric acid.
Background technology:
Fexofenadine is the active metabolite of Triludan at human body, has good antihistamine H1 receptor acting, it is is at first researched and developed by your pharmaceutical factory (Hoechest Marion Roussel) of German Ruse, (it is called Telfast at local commodity such as Australia, France, Germany and Hong Kong to ratify listing by FDA in 1996, at Indonesian commodity Telfast BD by name, at the commodity of U.S. Allegra by name).U.S. Pat 2003/0105329 adopts 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-the 4-ketobutyric acid is the intermediate preparation fexofenadine; 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene) wherein]-preparation of 4-ketobutyric acid is earlier with α; alpha-alpha-dimethyl phenyl acetic acid ethyl ester and succinyl oxide carry out friedel-crafts acylation reaction; obtain 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid and 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-mixture of 4-ketobutyric acid; behind the phenylethylamine salify; carry out crystallization again and split mixture; the phenylethylamine salt acidifying that then fractionation is obtained obtains pure 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-the 4-ketobutyric acid.This method is because friedel-crafts acylation reaction temperature wherein is too high; generate the by product 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene) in the nitration mixture]-4-ketobutyric acid too high levels and be difficult to remove; need to be removed through above-mentioned three-step reaction; thereby route is long; be not easy operation; the production cost height is unfavorable for suitability for industrialized production.
Summary of the invention:
The invention provides a kind of with α; alpha-alpha-dimethyl phenyl acetic acid is feedstock production 4-[4-(a 1-oxyethyl group acyl group-1-ethyl methyl benzene)]-simple preparation method of 4-ketobutyric acid, and solve the by product 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene) that produces in its preparation process]-problem that the 4-ketobutyric acid is difficult to remove.
4-[4-of the present invention (1-oxyethyl group acyl group-1-ethyl methyl benzene)]-preparation method of 4-ketobutyric acid, press earlier α, alpha-alpha-dimethyl phenyl acetic acid: ethanol: toluene=1 mole: 2.5～3 moles: 250～300 milliliters, under toluene-4-sulfonic acid catalysis, azeotropic divided water 8～12 hours, generate α, the alpha-alpha-dimethyl phenyl acetic acid ethyl ester; It is characterized in that: press α again, alpha-alpha-dimethyl phenyl acetic acid ethyl ester: succinyl oxide: methylene dichloride=1 mole: 1～1.2 mole: 350～450 milliliters, under-20 ℃～-10 ℃, carry out friedel-crafts acylation reaction, generate 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid and 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-regional isomer intermixture of 4-ketobutyric acid is a nitration mixture; Be dissolved in the used solvent of 1.2～1.5 milliliters of crystallizations by every gram nitration mixture and form mixed acid solution, slowly be cooled to-5 ℃～-25 ℃ crystallizations, promptly obtain 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-the 4-ketobutyric acid.
The consumption of described catalyzer toluene-4-sulfonic acid is generally 1%～2% of reaction system gross weight.
The used solvent of described crystallization comprises: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, acetone or ethyl acetate, or ethanol and sherwood oil volume ratio be 1: 1～2.5 mixed solvent, or ethyl acetate and sherwood oil volume ratio are 1: 1～3.5 mixed solvent.
Said process can be expressed as with reaction formula:
Compared with prior art, the present invention is owing to adopt methylene dichloride to make the solvent low-temp reaction in Fu-Ke reaction, reaction mixture viscosity is little, 4-[4-in the gained nitration mixture (1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid and 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-ratio of 4-ketobutyric acid is 8: 2, by product 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-content of 4-ketobutyric acid is less, is easier to be removed through recrystallization; And prior art adopts dithiocarbonic anhydride to make the solvent of Fu-Ke reaction; reaction mixture viscosity is big; the temperature of reaction height that requires; make 4-[4-in the nitration mixture that obtains (1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid and 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-ratio of 4-ketobutyric acid reaches 6: 4; shared ratio height in the product; by product 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-the 4-ketobutyric acid is difficult to remove by recrystallization method, is difficult to realize industrialization.
In purification step, the present invention adopts nitration mixture crystallization in solvent (as ethanol, ethyl acetate), can directly obtain 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-the 4-ketobutyric acid, productive rate reaches 40%～45%, and step is simple, and production cost is low; And prior art is that nitration mixture and phenylethylamine salify, crystallization are split, dissociate into sour three-step reaction and just obtain pure 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-the 4-ketobutyric acid, step is many, and complicated operation is unfavorable for suitability for industrialized production.
Description of drawings:
Fig. 1 is the gas chromatography-mass spectrum figure of intermediate product nitration mixture of the present invention;
Fig. 2 is product 4-[4-of the present invention (a 1-oxyethyl group acyl group-1-ethyl methyl benzene)]-the gas chromatography-mass spectrum figure of 4-ketobutyric acid.
Embodiment:
Embodiment 1:4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-preparation of 4-ketobutyric acid
With 164g α, alpha-alpha-dimethyl phenyl acetic acid, 80ml dehydrated alcohol, the 8g toluene-4-sulfonic acid joins at the bottom of the garden of 500ml in the flask, adds toluene 250ml, 100 ℃ of following azeotropic band water reactions 12 hours, steam toluene and excess ethyl alcohol, debris adds the 200ml ethyl acetate, washes with 100ml 5% sodium hydroxide solution, use 100ml * 2 washings again, anhydrous sodium sulfate drying, decompression steams ethyl acetate, gets α, alpha-alpha-dimethyl phenyl acetic acid ethyl ester 185.4g, productive rate are 96.3%.
In three-necked bottle, add Succinic anhydried 34.5 grams, anhydrous methylene chloride 400ml, cooling, when interior temperature reaches below-15 ℃, divide 3 batches slowly to add the aluminum trichloride (anhydrous) that total amount is 200 grams, and warm in making below-10 ℃, finish, slowly rise to room temperature, stirred 2 hours, cryosel is bathed cooling, when interior temperature reaches below-15 ℃, slowly drips 60 gram α, the alpha-alpha-dimethyl phenyl acetic acid ethyl ester, drip and finish, slowly rise to room temperature, stirring is spent the night.Stop to stir, slowly pour in the 600 gram frozen water, divide and get organic layer, water layer (100ml * 2) ethyl acetate extraction, reclaim organic layer and get residuum, with the acetic acid ethyl dissolution of aqueous layer extracted, (100ml * 2) washing gets organic layer, reclaim solvent and get the oily residuum, with the neutralization of 10% sodium carbonate solution, transferring to pH is about 8, with (100ml * 2) ethyl acetate extraction water layer.It is 2-3 that water layer transfers to pH with 15% hydrochloric acid, divides and gets organic layer, and water layer merges organic layer with (100ml * 1) ethyl acetate extraction, (100ml * 2) washing, and with anhydrous sodium sulfate drying, decompression steams solvent and gets oily product 85 grams, and productive rate is 93.2%.
Oily product to gained carries out the gas chromatography-mass spectrum detection, obtains gas chromatography-mass spectrum figure as shown in Figure 1.As seen from Figure 1, the 4-[4-in the nitration mixture (1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid (gas-chromatography 17.98 is told the peak): 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid (gas-chromatography 18.84 is told the peak)=7.2: 2.8.
Above-mentioned oily product 50g nitration mixture is joined in the 100ml flask, and add 30ml ethanol and 30ml sherwood oil, it is dissolved fully in 50 ℃, under agitation slowly cool to room temperature, be transferred to-10 ℃ but standing over night of refrigerator and cooled then.Solid collected by filtration, and wash with the 5ml sherwood oil, the 23.4g white solid, productive rate is 46.8%.
The gained white solid is carried out gas chromatography-mass spectrum detect, the gas chromatography-mass spectrum figure that obtains nitration mixture as shown in Figure 2.As seen from Figure 2: 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-appearance time of 4-ketobutyric acid is at 18,95 minutes, its content＞99%.
Embodiment 2:(3) 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid nitration mixture crystallization purifying
The oily nitration mixture 50g of gained among the embodiment 1 is joined in the 100ml flask, and add 30ml ethyl acetate and 30ml sherwood oil, it is dissolved fully in 40 ℃, under agitation slowly cool to room temperature, be transferred to-10 ℃ but standing over night of refrigerator and cooled then.Solid collected by filtration, and wash with the 5ml sherwood oil, the 24.2g white solid.
Gas chromatography-mass spectrum detects: 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid content＞99%, productive rate is 48.4%.
Embodiment 3:(3) 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid nitration mixture crystallization purifying
The oily nitration mixture 50g that gets gained among the embodiment 1 joins in the 100ml flask, and adds the 50ml ethyl acetate, it is dissolved fully in 50 ℃, under agitation slowly cools to room temperature, is transferred to-15 ℃ but standing over night of refrigerator and cooled then.Solid collected by filtration, and wash with the 5ml sherwood oil, the 22.5g white solid.
Gas chromatography-mass spectrum detects: 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid content＞98%, productive rate is 49%.
Claims (1)
1, a kind of 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-preparation method of 4-ketobutyric acid, press earlier α, alpha-alpha-dimethyl phenyl acetic acid: ethanol: toluene=1 mole: 2.5～3 moles: 250～300 milliliters, under toluene-4-sulfonic acid catalysis, azeotropic divided water 8～12 hours, generate α, the alpha-alpha-dimethyl phenyl acetic acid ethyl ester; It is characterized in that: press α again, alpha-alpha-dimethyl phenyl acetic acid ethyl ester: succinyl oxide: methylene dichloride=1 mole: 1～1.2 mole: 350～450 milliliters, under-20 ℃～-10 ℃, carry out friedel-crafts acylation reaction, generate 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-4-ketobutyric acid and 3-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-regional isomer intermixture of 4-ketobutyric acid is a nitration mixture; Be dissolved in 1.2～1.5 milliliters of recrystallisation solvents by every gram nitration mixture and form mixed acid solution, slowly be cooled to-5 ℃～-25 ℃ crystallizations, promptly obtain 4-[4-(1-oxyethyl group acyl group-1-ethyl methyl benzene)]-the 4-ketobutyric acid; Described recrystallisation solvent comprises: methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, acetone or ethyl acetate, or ethanol and sherwood oil volume ratio be 1: 1～2.5 mixed solvent, or ethyl acetate and sherwood oil volume ratio are 1: 1～3.5 mixed solvent.
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| CN1516689A (en) * | 2001-06-15 | 2004-07-28 | ������ҽҩ�¹�����˾ | Process for production of piperidine derivative fexofenadine |
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