CN102002009B - Preparation method of 5-methyl isoxazole-4-formyl chloride - Google Patents
Preparation method of 5-methyl isoxazole-4-formyl chloride Download PDFInfo
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- CN102002009B CN102002009B CN2010105095762A CN201010509576A CN102002009B CN 102002009 B CN102002009 B CN 102002009B CN 2010105095762 A CN2010105095762 A CN 2010105095762A CN 201010509576 A CN201010509576 A CN 201010509576A CN 102002009 B CN102002009 B CN 102002009B
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Abstract
The invention relates to a preparation method of 5-methyl isoxazole-4-formyl chloride. The 5-methyl isoxazole-4-formyl chloride is obtained by reacting 5-methyl isoxazole-4-formic acid which serves as an initiative raw material with chloro-reagent diphosgene or triphosgene under the action of an organic amine catalyst. The preparation method has a simple process, safe and reliable production, high reaction yield and low production cost, does not produce three wastes basically and is very suitable for industrial production; and a product has high purity and a small number of impurities. The 5-methyl isoxazole-4-formyl chloride prepared by the method is taken as an intermediate for preparing high-purity leflunomide.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to the preparation method of a kind of key intermediate 5-methyl isoxzzole-4-formyl chloride of leflunomide, and the method for preparing high-purity leflunomide.
Background of invention
Leflunomide; Compound name is N-(4-trifluoromethyl)-5-methyl isoxzzole-4-methane amide, and structural formula is a kind of immunomodulator with antiproliferative activity suc as formula shown in the I; Be used to treat rheumatoid arthritis, help to improve similar rheumatism symptoms such as arthralgia.
There are many pieces of documents all to disclose in the prior art and utilize 5-methyl isoxzzole-4-formic acid and thionyl chloride reaction; Obtain midbody 5-methyl isoxzzole-4-formyl chloride through the fractionation purifying, this midbody is through reacting the method that obtains leflunomide with p-trifluoromethylaniline.Such as disclosing among the WO03042193A1 5-methyl isoxzzole-4-formic acid is mixed with the thionyl chloride that heavily steams, add dry toluene, react in nitrogen protection condition refluxed.Reaction with the brown solution that obtains fractionation under 85-90 ℃ of temperature, obtains the faint yellow oily thing of about 8-10ml after accomplishing.Under the nitrogen protection condition, the faint yellow oily thing that obtains is mixed with p-trifluoromethylaniline, with the dry toluene dilution, be cooled to 0-4 ℃, in system, drip triethylamine, after being added dropwise to complete, room temperature reaction spends the night.With the solid filtering that produces, toluene wash filter cake.Mother liquor washs with 6MHCl, organic phase with anhydrous sodium sulfate drying after, the distillation remove toluene, obtain faint yellow solid; Using and can getting content behind the toluene recrystallization is 99.8% leflunomide.Its reaction scheme is shown in the following figure:
In WO0160363A1, disclose the compound method with above-mentioned similar 5-methyl isoxzzole-4-formyl chloride, but in the leflunomide synthesis step, reaction system changes water react into by organic phase, reduces cost, and simplifies the operation.
The method of prior art has all adopted sulfur oxychloride to prepare key intermediate 5-methyl isoxzzole-4-formyl chloride as chlorinating agent.Sulfur oxychloride is classical, also more complete as the reaction of chlorinating agent; But sulfur oxychloride is comparatively serious to corrosion on Equipment, contains a large amount of asphyxiant sulfurous gas in the industrial tail gas, belongs to one of gas of the strict control of national environmental protection, three wastes difficult treatment.And the transportation of sulfur oxychloride and use receive strict control, and be very high to the conversion unit sealing requirements, invest also bigger, the production operation poor stability.
Summary of the invention
The present invention is directed to the deficiency that exists in the prior art; Provide that a kind of technology is simple, production safety is reliable, reaction yield is high, production cost is low, do not have the preparation method that the three wastes produce, are suitable for the 5-methyl isoxzzole-4-formyl chloride of suitability for industrialized production basically, and be used to prepare the method for high-purity leflunomide with the 5-methyl isoxzzole-4-formyl chloride of this method preparation.
Technical scheme of the present invention is following:
The present invention is a starting raw material with 5-methyl isoxzzole-4-formic acid, reacts under the effect of organic amine catalyzer with chlorinating agent, makes 5-methyl isoxzzole-4-formyl chloride (midbody), and wherein, said chlorinating agent is trichloromethylchloroformate or TRIPHOSGENE 99.5.
This midbody 5-methyl isoxzzole-4-formyl chloride and p-trifluoromethylaniline reacted in aqueous phase system obtain the leflunomide bullion, the extraordinarily thick article of fluorine rice obtain highly purified leflunomide with the mixed solvent recrystallization of ethanol and water-insoluble organic solvent in the future.Reaction scheme is following:
The term explanation:
Trichloromethylchloroformate, the chemical name superpalite;
TRIPHOSGENE 99.5, chemical name two (trichloromethyl) carbonic ether.
More detailed preparation method explains as follows:
The preparation method of a kind of 5-methyl isoxzzole-4-formyl chloride, step is following:
(1) chlorinating agent dissolves with organic solvent I, processes chlorinating agent solution, and said chlorinating agent is trichloromethylchloroformate or TRIPHOSGENE 99.5;
(2) 5-methyl isoxzzole-4-formic acid is joined in the organic solvent II, and add the organic amine catalyzer, jolting, solid all dissolves clear, and the chlorinating agent solution that makes with step (1) mixes, in 0～60 ℃ of stirring reaction 1-20h;
(3) after reaction was accomplished, suction filtration was removed insolubles, revolves the steaming mother liquor, obtains oily matter 5-methyl isoxzzole-4-formyl chloride.
The 5-methyl isoxzzole-4-formyl chloride of method for preparing of the present invention continues following steps as the high-purity leflunomide of intermediate preparation:
(4) p-trifluoromethylaniline is dissolved in aqueous phase system, the 5-methyl isoxzzole-4-formyl chloride that obtains with step (3) is in 10～50 ℃ of insulation reaction 0.5～5h.After reaction finished, suction filtration used the ethanol making beating of volume by volume concentration as 40-55% with the filter cake that obtains, and suction filtration obtains pressed powder.Room temperature vacuum-drying obtains the leflunomide bullion;
(5) the leflunomide bullion that step (4) is obtained is with ethanol/water-insoluble organic solvent=(1～3): the mixed solvent recrystallization of 1 volume ratio, behind the ice bath crystallization, suction filtration obtains white crystalline powder, i.e. the pure article of leflunomide.
In the aforesaid method, the preferred TRIPHOSGENE 99.5 of chlorinating agent.
In the aforesaid method, the reactant molar ratio is 5-methyl isoxzzole-4-formic acid: TRIPHOSGENE 99.5: organic amine=1: 0.4～3: 0.5～1; Preferred molar ratio 5-methyl isoxzzole-4-formic acid: TRIPHOSGENE 99.5: organic amine=1: (0.4～0.8): (0.8～1).As chlorinating agent, its charging capacity is 1.5 times of TRIPHOSGENE 99.5 with trichloromethylchloroformate, and other raw material dosages are constant.
In the aforesaid method, described organic amine catalyzer is selected from: triethylamine, pyridine, N-methylmorpholine, N, dinethylformamide or 4-Dimethylamino pyridine; Preferred pyridine or triethylamine.The dosage of organic amine is a catalytic amount.
Organic solvent I described in the above-mentioned steps (1) is selected from benzene, toluene, normal hexane, hexanaphthene, Di Iso Propyl Ether, THF, ETHYLE ACETATE, methylene dichloride, 1, one of 4-dioxane or combination.Wherein, one of in preferred toluene, ETHYLE ACETATE, the methylene dichloride or combination.The consumption of organic solvent I is a meltage.
Organic solvent II described in the above-mentioned steps (2) is selected from benzene, toluene, normal hexane, hexanaphthene, Di Iso Propyl Ether, THF, ETHYLE ACETATE, methylene dichloride, 1, one of 4-dioxane or combination.Wherein, one of in preferred toluene, ETHYLE ACETATE, the methylene dichloride or combination.
The consumption of the organic solvent II described in the above-mentioned steps (2) is doubly (volume mass ratio, a unit: the milliliter Bick) of 5-methyl isoxzzole-4-formic acid 2-10; Wherein preferred, the consumption of organic solvent II is 5-7 times of (volume mass ratio, a unit: the milliliter Bick) of 5-methyl isoxzzole-4-formic acid.
Preferably, the organic solvent II described in organic solvent I described in the above-mentioned steps (1) and the step (2) is with a kind of solvent.
Preferably, react on 15～50 ℃ of stirring reaction 5-15h in the above-mentioned steps (2); Further preferred, react on 20～35 ℃ of stirring reaction 10-15h in the step (2).
Can also add siccative in the feed liquid that reaction is accomplished in the above-mentioned steps (3) and handle, and then carry out suction filtration.Said siccative is selected from: anhydrous magnesium sulfate, SODIUM SULPHATE ANHYDROUS 99PCT, Calcium Chloride Powder Anhydrous, Anhydrous potassium carbonate, Carbon Dioxide magnesium, molecular sieve etc.Wherein, preferred siccative is anhydrous magnesium sulfate or SODIUM SULPHATE ANHYDROUS 99PCT.
Aqueous phase system is selected from described in the above-mentioned steps (4): sodium bicarbonate aqueous solution, aqueous sodium carbonate, potassium bicarbonate aqueous solution or wet chemical; Wherein preferred sodium bicarbonate aqueous solution.
Preferably, reaction conditions is in 20～40 ℃ of insulation reaction 1～3h in the above-mentioned steps (4).
Water-insoluble organic solvent is selected from described in the above-mentioned steps (5): normal hexane, hexanaphthene, toluene, chlorobenzene, ETHYLE ACETATE; Preferred hexanaphthene.
At present, phosgene is used less in actually operating because toxicity is bigger.The method that trichloromethylchloroformate and TRIPHOSGENE 99.5 prepare acyl chlorides is used less in the prior art, and method is prematurity still; And, since in reaction trichloromethylchloroformate and TRIPHOSGENE 99.5 at first under nucleophilic reagents such as carbon, nitrogen, oxygen gentle reaction decomposes be that phosgene participates in reacting, react complicacy, thereby by product is many; Carbonylation, chlorination, chlorine formylation reaction, cyclization condensation and some polyreaction can take place such as TRIPHOSGENE 99.5.Because of the complicacy of its reaction, the application in actual production of trichloromethylchloroformate and TRIPHOSGENE 99.5 is also less.The unexpected discovery of the present invention has replaced the halogenating agent of traditional sulfur oxychloride as the acyl chlorides preparation with trichloromethylchloroformate or TRIPHOSGENE 99.5; The product purity that obtains is high, impurity is few; And on this improved basis, the compound method of having invented corresponding highly purified leflunomide.Its beneficial effect is embodied in: operational path is advanced, and processing condition are reasonable, got rid of the use of with serious pollution sulfur oxychloride; Eliminated fundamentally that the traditional technology potential safety hazard is big, the three wastes are difficult to problems such as processing; Safety simple to operate, reaction yield is high, and production cost is low; Basically do not have the three wastes and produce, have bigger implementary value and economic results in society.
The reaction mechanism that trichloromethylchloroformate and TRIPHOSGENE 99.5 are decomposed into phosgene is following: trichloromethylchloroformate of a part and TRIPHOSGENE 99.5 can produce two molecules and termolecular phosgene respectively.
The present invention compares with traditional technology, has production safety, and equipment corrosion is little, and is easy to operate, is convenient to metering, and reaction time is short, and raw material is easy to get, and reaction yield is high, and the three wastes are few and be easy to handle advantages such as good product quality.And byproduct hydrogen chloride absorbs through double tower and can prepare 30% technical hydrochloric acid, is one and is adapted to industrialized method.
Embodiment
Through following examples the present invention is done to further describe, but protection scope of the present invention is not limited thereto.
The preparation of embodiment 1,5-methyl isoxzzole-4-formyl chloride
Add 17.5g (0.06mol) TRIPHOSGENE 99.5 in the 250ml three-necked bottle,, connect drying installation and acid gas absorption device with the dissolving of 45ml methylene dichloride; 15g (0.12mol) 5-methyl isoxzzole-4-formic acid is joined in the 75ml methylene dichloride; And add 4.7g (0.06mol) pyridine, and jolting, solid all dissolves clear; Join in the TRIPHOSGENE 99.5 solution 30 ℃ of stirring reaction 15h.After reaction is accomplished, in reaction system, add an amount of anhydrous magnesium sulfate, stir, suction filtration revolves the steaming mother liquor and obtains pale brown look oily matter 17.5g, yield 100%.
1HNMR(CDCl3)：δ(ppm)2.73(3H，s，CH3)，8.56(1H，s，CH＝N)
The preparation of embodiment 2,5-methyl isoxzzole-4-formyl chloride
Add 17.5g (0.06mol) TRIPHOSGENE 99.5 in the 250ml three-necked bottle,, connect drying installation and acid gas absorption device, the ice bath cooling with the dissolving of 45ml toluene.15g (0.12mol) 5-methyl isoxzzole-4-formic acid is joined in the 150ml toluene, and add 4.7g (0.06mol) pyridine, jolting, solid all dissolves clear.Under condition of ice bath, 5-methyl isoxzzole-4-formic acid solution is splashed in the TRIPHOSGENE 99.5 solution, after dropwising, ice bath stirring reaction 20h.After reaction is accomplished, in reaction system, add an amount of Anhydrous potassium carbonate, stir, suction filtration revolves the steaming mother liquor and obtains pale brown look oily matter 13.0g, yield: 74.2%.
1HNMR(CDCl3)：δ(ppm)2.73(3H，s，CH3)，8.56(1H，s，CH＝N)。
The preparation of embodiment 3,5-methyl isoxzzole-4-formyl chloride
Add 17.5g (0.06mol) TRIPHOSGENE 99.5 in the 250ml three-necked bottle,, connect drying installation and acid gas absorption device with the dissolving of 45ml toluene; 15g (0.12mol) 5-methyl isoxzzole-4-formic acid is joined in the 150ml toluene, and add 2.3g (0.12mol) pyridine, jolting; Solid all dissolves clear; Splash in the TRIPHOSGENE 99.5 solution, after dropwising, 60 ℃ of reaction 5h.After reaction is accomplished, in reaction system, add an amount of anhydrous magnesium sulfate, stir, suction filtration revolves the steaming mother liquor and obtains pale brown look oily matter 15.5g, yield: 88.7%.
1HNMR(CDCl3)：δ(ppm)2.73(3H，s，CH3)，8.56(1H，s，CH＝N)。
The preparation of embodiment 4,5-methyl isoxzzole-4-formyl chloride
Add 28.5g (0.096mol) TRIPHOSGENE 99.5 in the 250ml three-necked bottle,, connect drying installation and acid gas absorption device with the dissolving of 45ml toluene; 15g (0.12mol) 5-methyl isoxzzole-4-formic acid is joined in the 150ml toluene, and add 2.3g (0.12mol) pyridine, jolting; Solid all dissolves clear; Splash in the TRIPHOSGENE 99.5 solution, after dropwising, 40 ℃ of reaction 10h.After reaction is accomplished, in reaction system, add an amount of SODIUM SULPHATE ANHYDROUS 99PCT, stir, suction filtration revolves the steaming mother liquor and obtains pale brown look oily matter 16.7g, yield: 95.5%.
1HNMR(CDCl3)：δ(ppm)2.73(3H，s，CH3)，8.56(1H，s，CH＝N)。
The preparation of embodiment 5,5-methyl isoxzzole-4-formyl chloride
Add 15g (0.12mol) 5-methyl isoxzzole-4-formic acid in the 250ml three-necked bottle and add, add 150ml toluene, be heated to 60 ℃, solid all dissolves clear.Connect drying installation and acid gas absorption device.With 14.3g (0.072mol) trichloromethylchloroformate, dissolve with 45ml toluene.Under 60 ℃, trichloromethylchloroformate is splashed in 5-methyl isoxzzole-4-formic acid solution solution, after dropwising, insulated and stirred 5h.After reaction is accomplished, revolve to steam and remove toluene, 80-92 ℃ cut is collected in fractionation, obtains faint yellow oily thing 13.8g, yield: 79.0%.
1HNMR(CDCl3)：δ(ppm)2.73(3H，s，CH3)，8.56(1H，s，CH＝N)。
The preparation of embodiment 6, leflunomide
Add 10.0g (0.12mol) sodium hydrogencarbonate in the 250ml three-necked bottle, add 100ml water and 19.3g (0.12mol) p-trifluoromethylaniline, be warming up to 40 ℃, solid all dissolves clear.5-methyl isoxzzole-4-formyl chloride 17.5g (by 17.2g (0.12mol)) that the last step was obtained is added drop-wise in the reaction system.Separate out a large amount of solids in the dropping process, be added dropwise to complete back insulation reaction 1h.After reaction finished, suction filtration was pulled an oar the filter cake that obtains with 40% ethanol, and suction filtration obtains the off-white color pressed powder.Room temperature vacuum-drying obtains leflunomide bullion 22.5g, yield: 69.4%.In the future the extraordinarily thick article of fluorine rice are with the mixed solvent recrystallization of 50ml ethanol/cyclohexane=3: 1, behind the ice bath crystallization, suction filtration obtain white crystalline powder 19.2g (fusing point: 166.2-166.8 ℃, literature value: 166.5 ℃.HPLC analyzes content 99.9%.
IR(KBr)σ3332，1692，1607，1541，1322cm
-1。
1HNMR(CDCl3)：δ(ppm)2.77(3H，s，CH3)，7.61(2H，d，A?rH)，7.70(2H，d，A?rH)，8.48(1H，s，A?rNH)。
The preparation of embodiment 7, leflunomide
Add 9.2g (0.11mol) sodium hydrogencarbonate in the 250ml three-necked bottle, add 100ml water and 17.7g (0.11mol) p-trifluoromethylaniline, be warming up to 50 ℃, solid all dissolves clear.5-methyl isoxzzole-4-formyl chloride 16.5g (0.11mol) is added drop-wise in the reaction system.Separate out a large amount of solids in the dropping process, be added dropwise to complete back insulation reaction 5h.After reaction finished, suction filtration was pulled an oar the filter cake that obtains with 40% ethanol, and suction filtration obtains the off-white color pressed powder.Room temperature vacuum-drying obtains leflunomide bullion 21.4g, yield: 72.0%.In the future the extraordinarily thick article of fluorine rice are with the mixed solvent recrystallization of 50ml ethanol/ETHYLE ACETATE=1: 1, behind the ice bath crystallization, suction filtration obtain white crystalline powder 16.1g (fusing point: 166.2-166.8 ℃, literature value: 166.5 ℃.HPLC analyzes content 99.9%.
IR(KBr)σ3332，1692，1607，1541，1322cm
-1。
1HNMR(CDCl3)：δ(ppm)2.77(3H，s，CH3)，7.61(2H，d，A?rH)，7.70(2H，d，A?rH)，8.48(1H，s，A?rNH)。
The preparation of embodiment 8, leflunomide
Add 10.0g (0.10mol) saleratus in the 250ml three-necked bottle, add 100ml water and 17.7g (0.10mol) p-trifluoromethylaniline, be warming up to 40 ℃, solid all dissolves clear.5-methyl isoxzzole-4-formyl chloride 15.5g (0.10mol) is added drop-wise in the reaction system.Separate out a large amount of solids in the dropping process, be added dropwise to complete back insulation reaction 5h.After reaction finished, suction filtration was pulled an oar the filter cake that obtains with 40% ethanol, and suction filtration obtains the off-white color pressed powder.Room temperature vacuum-drying obtains leflunomide bullion 18.5g, yield: 68.5%.In the future the extraordinarily thick article of fluorine rice are with the mixed solvent recrystallization of 100ml ethanol/cyclohexane=1: 1, behind the ice bath crystallization, suction filtration obtain white crystalline powder 15.7g (fusing point: 166.2-166.8 ℃, literature value: 166.5 ℃.HPLC analyzes content 99.9%.
IR(KBr)σ3332，1692，1607，1541，1322cm
-1。
1HNMR(CDCl3)：δ(ppm)2.77(3H，s，CH3)，7.61(2H，d，A?rH)，7.70(2H，d，A?rH)，8.48(1H，s，A?rNH)。
Said literature value comes from US4284786 among the above embodiment.
Claims (4)
1. the preparation method of a leflunomide is a starting raw material with 5-methyl isoxzzole-4-formic acid, reacts under the effect of organic amine catalyzer with chlorinating agent to make 5-methyl isoxzzole-4-formyl chloride, and 5-methyl isoxzzole-4-formyl chloride is used to prepare leflunomide; Said chlorinating agent is a TRIPHOSGENE 99.5, and step is following:
(1) chlorinating agent dissolves with organic solvent I, processes chlorinating agent solution;
(2) 5-methyl isoxzzole-4-formic acid is joined in the organic solvent II, and add the organic amine catalyzer, jolting, solid all dissolves clear, and the chlorinating agent solution that makes with step (1) mixes, in 20-35 ℃ of stirring reaction 10-15h;
(3) after reaction was accomplished, suction filtration was removed insolubles, revolves the steaming mother liquor, obtains oily matter 5-methyl isoxzzole-4-formyl chloride;
Said organic amine catalyzer is pyridine or triethylamine, and said reaction molar ratio is 5-methyl isoxzzole-4-formic acid: TRIPHOSGENE 99.5: organic amine=1: (0.4-0.8): (0.8-1); Said organic solvent I or organic solvent II are one of in toluene, ETHYLE ACETATE, the methylene dichloride or combination; The consumption of said organic solvent II be 5-methyl isoxzzole-4-formic acid 5-7 doubly, volume mass doubly, unit: milliliter Bick;
(4) p-trifluoromethylaniline is dissolved in aqueous phase system, splash into 5-methyl isoxzzole-4-formyl chloride that step (3) obtains, separate out a large amount of solids in the dropping process, be added dropwise to complete the back in 10～40 ℃ of insulation reaction 1～3h; After reaction finished, suction filtration used the ethanol making beating of volume by volume concentration as 40-55% with the filter cake that obtains, and suction filtration obtains pressed powder; Room temperature vacuum-drying obtains the leflunomide bullion;
(5) the leflunomide bullion that above-mentioned steps (4) is obtained is with ethanol/water-insoluble organic solvent=(1～3): the mixed solvent recrystallization of 1 volume ratio, behind the ice bath crystallization, suction filtration obtains white crystalline powder, i.e. the pure article of leflunomide.
2. the preparation method of leflunomide as claimed in claim 1, it is characterized in that: described chlorinating agent is a TRIPHOSGENE 99.5.
3. the preparation method of leflunomide as claimed in claim 1 is characterized in that: also add siccative in the feed liquid that reaction is accomplished in the step (3) and handle, and then carry out suction filtration; Said siccative is selected from: anhydrous magnesium sulfate, SODIUM SULPHATE ANHYDROUS 99PCT, Calcium Chloride Powder Anhydrous, Anhydrous potassium carbonate, Carbon Dioxide magnesium or molecular sieve.
4. the preparation method of leflunomide as claimed in claim 3, it is characterized in that: said siccative is anhydrous magnesium sulfate or SODIUM SULPHATE ANHYDROUS 99PCT.
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| WO2001060363A1 (en) * | 2000-02-15 | 2001-08-23 | Teva Pharmaceutical Industries Ltd. | A method for synthesizing leflunomide |
| CN101016272A (en) * | 2007-02-14 | 2007-08-15 | 浙江工业大学 | Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride |
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| WO2001060363A1 (en) * | 2000-02-15 | 2001-08-23 | Teva Pharmaceutical Industries Ltd. | A method for synthesizing leflunomide |
| CN101016272A (en) * | 2007-02-14 | 2007-08-15 | 浙江工业大学 | Synthetic method for 3-(2'-chloro-6'-fluorophenyl)-5-methyl-4-isooxazole formyl chloride |
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