CN102786489A - Preparation method of 5-methyl isoxazole-4-ethyl formate - Google Patents
Preparation method of 5-methyl isoxazole-4-ethyl formate Download PDFInfo
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Abstract
The invention relates to a preparation method of 5-methyl isoxazole-4-ethyl formate, characterized by using cheap and easily available ethyl acetoacetate and triethyl orthoformate as raw materials and condensing the raw materials to prepare 2-ethoxymethylene ethyl acetoacetate, then reacting 2-ethoxymethylene ethyl acetoacetate with an aqueous solution of hydroxylamine hydrochloride and inorganic base in an organic solvent to prepare 5-methyl isoxazole-4-ethyl formate, wherein the total yield of the two steps is higher than 78.0%, the content is higher than 99.0%, and the content of the isomer 3-methyl isoxazole-4-ethyl formate is less than 1.0%. The preparation method has the advantages of low production cost, low content of the isomer 3-methyl isoxazole-4-ethyl formate, simple process, and mild reaction conditions, and is suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of a kind of key intermediate 5-methyl-isoxazole-4-ethyl formate of leflunomide, belong to the medical chemistry field, can be used for preparing highly purified leflunomide.
Background technology
Leflunomide (I) is a kind of novel active immunomodulator of multiple physiological that has, and belongs to isoxazole derivant, and chemistry N-(4-trifluoromethylbenzene) by name-5-methyl-isoxazole-4-methane amide is mainly used in the treatment rheumatoid arthritis.Leflunomide can not only rheumatoid arthritis symptom, can also effectively suppress PD, and toxic side effect is low, be to be exclusively used in the clinical line medicine that the treatment rheumatoid arthritis can mitigate the disease.
5-methyl-isoxazole-4-ethyl formate is the essential raw material of synthetic leflunomide, and it gets leflunomide through hydrolysis, chlorination, acidylate three-step reaction, and route is shown in the following figure:
The synthetic anti-method of bibliographical information 5-methyl-isoxazole-4-ethyl formate mainly contains two kinds: (1) is by 2-ethoxymethyl methyl ethyl acetoacetate and free hydroxylamine or azanol inorganic salt prepared in reaction in alcoholic solvent; (2) by N, N-dimethylaminomethylene methyl aceto acetate and free hydroxylamine or azanol inorganic salt prepared in reaction in alcoholic solvent.Two kinds of maximum differences of method are raw materials used difference; Compare with the 2-ethoxymethyl methyl ethyl acetoacetate, N, the reactive behavior of N-dimethylaminomethylene methyl aceto acetate is stronger; But price is also expensive more, will certainly increase production cost as reaction raw materials.Therefore, system of selection (1) is synthetic practices thrift cost more through 5-methyl-isoxazole-4-ethyl formate, economic and practical.But also depositing significant disadvantages with the 2-ethoxymethyl methyl ethyl acetoacetate as reaction raw materials and free hydroxylamine or azanol inorganic salt reaction, introducing isomer impurities in the reaction process easily.Though the specific activity carbonyl of methylene radical wants high in the 2-ethoxymethyl methyl ethyl acetoacetate, the lone-pair electron on the azanol nitrogen still can nonselective and carbonyl or methylene radical generation nucleophilic addition.With its product of methylene radical addition be 5-methyl-isoxazole-4-ethyl formate, and with its product of carbonyl addition be that 3-methyl-isoxazole-4-ethyl formate is 5-methyl-4-isoxazole carboxylic acid ethyl ester isomer.3-methyl-isoxazole-4-ethyl formate is introduced related substance leflunomide-3-methyl isomery (II) through hydrolysis, chlorination, acidylate in final leflunomide product, reduced product purity, influences quality.
In the 3 steps reaction of above-mentioned synthetic leflunomide; The content of the isomer decision content of related substance 3-methyl isomer in the leflunomide product of knowing clearly in raw material 5-methyl-isoxazole-4-ethyl formate; And the purity of 5-methyl-isoxazole-4-ethyl formate is determined by the height of the regioselectivity of cyclization; There is clearly regulation in State Food and Drug Administration to the content of leflunomide-3-methyl isomer, and its content can not surpass 0.1%.
Pay spark [Chinese Journal of Pharmaceuticals, 2000,31 (12): 533-534], Wang Bin [chemical reagent; 2001; 23 (1): 38], Xu Jun [Chinese Journal of Pharmaceuticals, 2002,33 (4): 158-159], Zhou Jinpei [China Medicine University's journal; 2000,31 (5): 330-331] all adopt following path of preparing 5-methyl-isoxazole-4-ethyl formate.With triethyl orthoformate and methyl aceto acetate is that raw material and diacetyl oxide reacting by heating prepare the 2-ethoxymethyl methyl ethyl acetoacetate; Preparation gained 2-ethoxymethyl methyl ethyl acetoacetate reacts with oxammonium hydrochloride under the reflux condition in methyl alcohol or alcohol solvent.The advantage of this route is that the ring-closure reaction time is short; Shortcoming is condensation reaction yield low (55～82%), long reaction time, and diacetyl oxide drips in the reaction that has, and has reduced production efficiency; The ring-closure reaction condition is harsh, yield low (61.3～75%), and the content of isomer in the designated products not, and low yield maybe too high to cause the raw material oxammonium hydrochloride to decompose relevant with temperature of reaction.
Patent US4284786, US4892963, WO03042193 and Su Guodong [print during chemical industry; 2011; 25 (4): 1 1-14], Wang Shaojie [Chinese pharmaceutical chemistry magazine, 2000,10 (3): 199-200] all adopts following path of preparing 5-methyl-isoxazole-4-ethyl formate.The preparation method of 2-ethoxymethyl methyl ethyl acetoacetate is mutually identical; With triethyl orthoformate and methyl aceto acetate is raw material reacting by heating preparation in the diacetyl oxide solvent, and the reactant aqueous solution of preparation gained 2-ethoxymethyl methyl ethyl acetoacetate and azanol inorganic salt and mineral alkali is with preparation 5-methyl-isoxazole-4-ethyl formate.Patent US4284786, the disclosed compound method of US4892963 are under room temperature condition, the ethanolic soln of 2-ethoxymethyl methyl ethyl acetoacetate to be dropped in the aqueous solution of oxammonium hydrochloride and sodium hydroxide of equimolar amount to react; This method shortcoming is that long reaction time needs 30h, and content of isomer is high in the product; The compound method that Su Guodong proposes and patent US4284786, the disclosed compound method of US4892963 are similar; Difference is to drip reversed in order, and temperature of reaction changes 0～10 ℃ of following low-temp reaction into by room temperature, and reaction yield is high; Time is short only to need a 4h, but the content of isomer in the designated products not; The disclosed compound method of patent WO03042193 is under-5 ℃, hydroxylamine sulfate solution to be dropped in the aqueous ethanolic solution of sodium acetate and 2-ethoxymethyl methyl ethyl acetoacetate to react; Keeping temperature of reaction during dropping is 0 ℃, is added dropwise to complete the back and places 0 ℃ of reaction down, and yield is 85%; The content of isomer is 2.5%; There is significant disadvantages in this method, and reaction yield is general, and content of isomer is higher in the product; The compound method that Wang Shaojie proposes is similar with patent WO03042193 disclosed method; Sodium acetate that alkalescence is more weak and oxammonium hydrochloride are made into the ethanolic soln reaction of the aqueous solution and 2-ethoxymethyl methyl ethyl acetoacetate; Yield is 85%, but does not point out the content of isomer in the product.
Patent WO2007086076 discloses the preparation method of other a kind of 5-methyl-isoxazole-4-ethyl formate, and synthetic route is shown in the following figure.With triethyl orthoformate and methyl aceto acetate is raw material reacting by heating in the diacetyl oxide solvent, and the low-boiling by-products that generation is removed in reaction simultaneously prepares the 2-ethoxymethyl methyl ethyl acetoacetate, and by product is mainly ETHYLE ACETATE, and the reaction times is short, and yield is higher.The aqueous solution with 50% aqueous solutions of free hydroxylamine replacement oxammonium hydrochloride or oxammonium sulfate and alkali reacts with the 2-ethoxymethyl methyl ethyl acetoacetate in methanol solvate, and yield is 79%, and product gas purity is greater than 98%, and wherein the content of isomer is less than 0.5%.The advantage of this method is that the regioselectivity of reaction is high, and content of isomer is low; Shortcoming is that reaction yield is low.
Summary of the invention
The present invention is intended to overcome the deficiency that exists in the existing synthetic technology; Provide that a kind of production cost is low, technology is simple, reaction conditions is gentle, content of isomer is low, be fit to the preparation method of the 5-methyl-isoxazole-4-ethyl formate of suitability for industrialized production, for the preparation leflunomide provides high-quality reaction raw materials.
The present invention implements through following synthetic route and method:
The present invention is a feedstock production 2-ethoxymethyl methyl ethyl acetoacetate (III) with triethyl orthoformate and methyl aceto acetate; III in organic solvent with the reactant aqueous solution of oxammonium hydrochloride and mineral alkali, high regioselectivity be prepared into 5-methyl-isoxazole-4-ethyl formate (IV).
Synthetic route is shown in the following figure:
Detailed preparation method of the present invention explains as follows:
The preparation method of a kind of 5-methyl-isoxazole-4-ethyl formate, step is following:
(1) triethyl orthoformate and methyl aceto acetate reacting by heating in the diacetyl oxide solvent prepares 2-ethoxymethyl methyl ethyl acetoacetate (III);
(2) oxammonium hydrochloride and mineral alkali are used water dissolution, regulator solution pH processes aqueous hydroxylamine;
(3) step (1) preparation gained compound III is used organic solvent dissolution; React with the aqueous hydroxylamine of step (2) preparation;
(4) after reaction was accomplished, solution left standstill was divided into two-layer, and the upper strata is an organic phase, and lower floor is a water.Tell organic phase, water is used organic solvent extraction, merges organic phase, organic phase water and saturated common salt water washing, anhydrous sodium sulfate drying, concentrated thick liquid 5-methyl-isoxazole-4-ethyl formate (IV).
In the above-mentioned steps (1), used reactant feed mol ratio is a methyl aceto acetate: triethyl orthoformate: diacetyl oxide=1: 1.0～2.0: 1.0～3.0.The temperature of reaction is 95 ℃～145 ℃, and the by-product acetic acid ethyl ester that is lower than 100 ℃ of boiling points is removed in reaction distillation simultaneously, and underpressure distillation was purified after reaction was accomplished.
In the above-mentioned steps (2), oxammonium hydrochloride with water dissolution after with mineral alkali regulator solution pH value, make reacting liquid pH value 8.0～14.0.Used mineral alkali can be selected Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, potassium acetate.
In the above-mentioned steps (3), used reactant feed mol ratio is the 2-ethoxymethyl methyl ethyl acetoacetate: oxammonium hydrochloride=1: 0.5～2.0.
In the above-mentioned steps (3), used organic solvent can be selected methyl alcohol, ethanol, Virahol, THF, acetone, N, a kind of or its mixing in the dinethylformamide.
In the above-mentioned steps (3), the temperature of reaction is 15 ℃～75 ℃.
In the above-mentioned steps (4), aftertreatment extracts the optional ETHYLE ACETATE of used organic solvent, methylene dichloride, ether.Measure water layer pH during the water washing organic phase, show neutral to water layer, organic phase with the saturated common salt water washing once.
The present invention is a feedstock production 2-ethoxymethyl methyl ethyl acetoacetate with triethyl orthoformate and methyl aceto acetate, has reduced production cost.The present invention finds that pH and the temperature of reaction of azanol reaction liquid is bigger to the influence that reaction generates isomer; Control reaction temperature is 15 ℃～75 ℃ during reaction; Regulate synthesizing isoxazole ring in the organic solvent that oxammonium hydrochloride aqueous solution pH to 8.0～14.0 drop to the 2-ethoxymethyl methyl ethyl acetoacetate with mineral alkali, be prepared into 5-methyl-isoxazole-4-ethyl formate.This method regioselectivity is high; The content of isomer low (less than 1.0%) in the HPLC testing product, and reaction conditions is gentle, and yield is high; Production cost is low; Can reduce the content of the 3-methyl isomer in the finished product leflunomide, reduce recrystallization number of times in the synthesis technique, for the suitability for industrialized production of leflunomide provides high-quality reaction raw materials.
Description of drawings
Fig. 1 is the liquid chromatogram of 5-methyl-isoxazole-4-ethyl formate and isomer mixture thereof.
Among the figure: 1 3-methyl-isoxazole-4-ethyl formate; 2 5-methyl-isoxazole-4-ethyl formate;
Fig. 2 is the high-efficient liquid phase chromatogram of 5-methyl-isoxazole-4-ethyl formate.
Among the figure: the A solvent methanol; B 5-methyl-isoxazole-4-ethyl formate.
Embodiment
Further explain the present invention with embodiment below, but protection scope of the present invention is not limited to these embodiment.
The preparation of embodiment 1:2-ethoxymethyl methyl ethyl acetoacetate (III)
, the 1000ml four-hole bottle of rectifying volumn adds methyl aceto acetate 133.1g (1.02mol), triethyl orthoformate 184.6g (1.24mol), second aceticanhydride 256.2g (2.01mol) in being housed; Heated and stirred is warming up to 115-125 ℃, fractionates out the by product of lower boiling (≤100 ℃) in the reaction process simultaneously.TLC detects (ETHYLE ACETATE: sherwood oil=1: 2 is a developping agent) no raw material stopped reaction behind the reaction 2h; 10 ℃/0.69kPa of 106-1 cut is collected in underpressure distillation; Get weak yellow liquid 2-ethoxymethyl methyl ethyl acetoacetate 156g; Yield is 84.7%, 2-ethoxymethyl methyl ethyl acetoacetate content 99.10% (gas chromatographic detection).
The preparation of embodiment 2:2-ethoxymethyl methyl ethyl acetoacetate (III)
, the 2000ml four-hole bottle of rectifying volumn adds methyl aceto acetate 260.5g (2.00mol), triethyl orthoformate 362.6g (2.44mol), second aceticanhydride 521.1g (4.09mol) in being housed; Heated and stirred is warming up to 113-121 ℃, fractionates out lower boiling (≤100 ℃) by product in the reaction process simultaneously.TLC detects (ETHYLE ACETATE: sherwood oil=1: 2 is a developping agent) no raw material stopped reaction behind the reaction 2h; 106-108 ℃/0.67kPa cut is collected in underpressure distillation; Get weak yellow liquid 2-ethoxymethyl methyl ethyl acetoacetate 309.5g; Yield is 83.1%, 2-ethoxymethyl methyl ethyl acetoacetate content 99.2% (gas chromatographic detection).
The preparation oxammonium hydrochloride 2.52g (0.036mol) of embodiment 3:5-methyl-isoxazole-4-ethyl formate (IV), 9ml water slowly add sodium hydrate regulator solution pH to 12.1 in 5 ℃ of stirring and dissolving under stirring.Preparation 2-ethoxymethyl methyl ethyl acetoacetate 6.14g (0.033mol) mixes the 7ml ethanol solution; Drip the oxammonium hydrochloride of above-mentioned preparation and the aqueous solution of sodium hydroxide in room temperature; In 25 ℃ of following insulated and stirred reaction 4h (TLC follows the tracks of reaction process, ETHYLE ACETATE: sherwood oil=1: 4 is a developping agent).Reaction finishes, and reaction solution is divided into two-layer, tells upper organic phase solution; Lower floor's aqueous phase solution with dichloromethane extraction (2 * 50ml), merge organic phase.(4 * 50ml) is apparent neutral to water layer with water washing for organic phase; (1 * 50ml), anhydrous sodium sulfate drying removes by filter the sodium sulfate solid to use the saturated common salt water washing again; Filtrating revolve steam yellow transparent liquid 5-methyl-isoxazole-4-ethyl formate 4.73g; Yield 92.5%, content 99.2%, isomer 3-methyl-isoxazole-4-ethyl formate content is 0.10%.
1H?NMR(400?MHz，CDCl
3)δ8.47(s，1H，ring?H)，4.33(q，J＝7.1?Hz，2H，
CH
2CH
3)，2.70(s，3H，ring?CH
3)，1.37(t，J＝7.1?Hz，3H，CH
2 CH
3).
The preparation of embodiment 4:5-methyl-isoxazole-4-ethyl formate (IV)
Sodium hydroxide 4.00g (0.100mol), 22ml water slowly add oxammonium hydrochloride regulator solution pH to 13.0 in 10 ℃ of stirring and dissolving under stirring, shared oxammonium hydrochloride 6.3g (0.091mol), and solution is transferred in the constant pressure funnel.Preparation 2-ethoxymethyl methyl ethyl acetoacetate 15.35g (0.082mol) mixes the 17ml ethanol solution; Slowly drip the oxammonium hydrochloride of above-mentioned preparation and the aqueous solution of sodium hydroxide in 17 ℃; About 1h dropwises; In 30 ℃ of following insulated and stirred reaction 4h (TLC follows the tracks of reaction process, ETHYLE ACETATE: sherwood oil=1: 4 is a developping agent).Reaction finishes, and reaction solution is divided into two-layer, tells upper organic phase solution; Lower floor's aqueous phase solution with ethyl acetate extraction (2 * 125ml), merge organic phase.(4 * 125ml) is apparent neutral to water layer with water washing for organic phase; (1 * 125ml), anhydrous sodium sulfate drying removes by filter the sodium sulfate solid to use the saturated common salt water washing again; Filtrating revolve steam yellow transparent liquid 5-methyl-isoxazole-4-ethyl formate 11.94g; Yield 93.3%, content 99.20%, isomer 3-methyl-isoxazole-4-ethyl formate content is 0.35%.
1H?NMR(400?MHz，CDCl
3)δ8.47(s，1H，ring?H)，4.33(q，J＝7.1?Hz，2H，
CH
2CH
3)，2.70(s，3H，ring?CH
3)，1.37(t，J＝7.1?Hz，3H，CH
2 CH
3).
The preparation of embodiment 5:5-methyl-isoxazole-4-ethyl formate (IV)
Oxammonium hydrochloride 1.26g (0.018mol), 15ml water dissolve in stirring at room, stir slowly to add manganese hydrogen sodium regulating solution pH to 8.50 down.Preparation 2-ethoxymethyl methyl ethyl acetoacetate 3.07g (0.017mol) mixes the 5ml ethanol solution; Drip the oxammonium hydrochloride of above-mentioned preparation and the aqueous solution of sodium hydrogencarbonate in room temperature; Dropwise in 70 ℃ of following insulated and stirred reaction 3h (TLC follows the tracks of reaction process, ETHYLE ACETATE: sherwood oil=1: 4 is a developping agent).Reaction finishes, and reaction solution is divided into two-layer, tells upper organic phase solution; Lower floor's aqueous phase solution with dichloromethane extraction (2 * 25ml), merge organic phase.(4 * 25ml) is apparent neutral to water layer with water washing for organic phase; (1 * 30ml), anhydrous sodium sulfate drying removes by filter the sodium sulfate solid to use the saturated common salt water washing again; Filtrating revolve steam yellow transparent liquid 5-methyl-isoxazole-4-ethyl formate 2.30g; Yield 89.8%, content 99.1%, isomer 3-methyl-isoxazole-4-ethyl formate content is 0.53%.
1H?NMR(400?MHz，CDCl
3)δ8.47(s，1H，ring?H)，4.33(q，J＝7.1?Hz，2H，
CH
2CH
3)，2.70(s，3H，ring?CH
3)，1.37(t，J＝7.1?Hz，3H，CH
2 CH
3).
The embodiment 6:5-methyl-isoxazole-preparation oxammonium hydrochloride 1.00g (0.014mol) of 4-ethyl formate (IV), 10ml water dissolve in stirring at room, stir slowly to add sodium carbonate regulating solution pH to 10.70 down.Preparation 2-ethoxymethyl methyl ethyl acetoacetate 3.07g (0.017mol) mixes the 5ml ethanol solution; Drip the oxammonium hydrochloride of above-mentioned preparation and the aqueous solution of yellow soda ash in room temperature; Dropwise in 50 ℃ of following insulated and stirred reaction 5h (TLC follows the tracks of reaction process, ETHYLE ACETATE: sherwood oil=1: 4 is a developping agent).Reaction finishes, and reaction solution is divided into two-layer, tells upper organic phase solution;
Lower floor's aqueous phase solution with ethyl acetate extraction (2 * 25ml), merge organic phase.(4 * 25ml) is apparent neutral to water layer with water washing for organic phase; (1 * 30ml), anhydrous sodium sulfate drying removes by filter the sodium sulfate solid to use the saturated common salt water washing again; Filtrating revolve steam yellow transparent liquid 5-methyl-isoxazole-4-ethyl formate 2.25g; Yield 87.9%, content 99.1%, the content of isomer 3-methyl-isoxazole-4-ethyl formate is 0.65%.
1H?NMR(400?MHz，CDCl
3)δ8.47(s，1H，ring?H)，4.33(q，J＝7.1?Hz，2H，
CH
2CH
3)，2.70(s，3H，ring?CH
3)，1.37(t，J＝7.1?Hz，3H，CH
2 CH
3).
The preparation of embodiment 7:5-methyl-isoxazole-4-ethyl formate (IV)
Oxammonium hydrochloride 1.74g (0.025mol), 8ml water slowly add Lithium Hydroxide MonoHydrate regulator solution pH to 13.8 in 15 ℃ of stirring and dissolving under stirring.Preparation 2-ethoxymethyl methyl ethyl acetoacetate 3.07g (0.017mol) mixes the 6ml ethanol solution; Drip the oxammonium hydrochloride of above-mentioned preparation and the aqueous solution of Lithium Hydroxide MonoHydrate in room temperature; Dropwise in 40 ℃ of following insulated and stirred reaction 4h (TLC follows the tracks of reaction process, ETHYLE ACETATE: sherwood oil=1: 4 is a developping agent).Reaction finishes, and reaction solution is divided into two-layer, tells upper organic phase solution; Lower floor's aqueous phase solution with dichloromethane extraction (2 * 20ml), merge organic phase.(4 * 20ml) is apparent neutral to water layer with water washing for organic phase; (1 * 20ml), anhydrous sodium sulfate drying removes by filter the sodium sulfate solid to use the saturated common salt water washing again; Filtrating revolve steam yellow transparent liquid 5-methyl-isoxazole-4-ethyl formate 2.42g; Yield 93.8%, content 99.3%, the content of isomer 3-methyl-isoxazole-4-ethyl formate is 0.27%.
1H?NMR(400?MHz，CDCl
3)δ8.47(s，1H，ring?H)，4.33(q，J＝7.1?Hz，2H，
CH
2CH
3)，2.70(s，3H，ring?CH
3)，1.37(t，J＝7.1?Hz，3H，CH
2 CH
3)。
Claims (9)
1. the preparation method of 5-methyl-isoxazole-4-ethyl formate; With triethyl orthoformate and methyl aceto acetate is that the raw material condensation reaction prepares the 2-ethoxymethyl methyl ethyl acetoacetate; Then the 2-ethoxymethyl methyl ethyl acetoacetate in organic solvent with the reactant aqueous solution of oxammonium hydrochloride and mineral alkali, it is characterized in that may further comprise the steps:
(1) condensation reaction in the diacetyl oxide solvent of triethyl orthoformate and methyl aceto acetate prepares the 2-ethoxymethyl methyl ethyl acetoacetate;
(2) oxammonium hydrochloride and mineral alkali are used water dissolution, regulator solution pH processes aqueous hydroxylamine;
(3) step ⑴ is prepared gained 2-ethoxymethyl methyl ethyl acetoacetate and use organic solvent dissolution; React with the aqueous hydroxylamine of step ⑵ preparation;
(4) after reaction was accomplished, solution left standstill was divided into two-layer, and the upper strata is an organic phase, and lower floor is a water; Organic phase and the water told are used organic solvent extraction, merge organic phase, organic phase water and saturated common salt water washing, anhydrous sodium sulfate drying, concentrated thick liquid 5-methyl-isoxazole-4-ethyl formate.
2. according to the preparation method of the said 5-methyl-isoxazole of claim 1-4-ethyl formate, it is characterized in that used reactant feed mol ratio is a methyl aceto acetate in the above-mentioned steps (1): triethyl orthoformate: diacetyl oxide=1:1.0～2.0:1.0～3.0.
3. according to the preparation method of claim 1 or 2 said 5-methyl-isoxazole-4-ethyl formates, it is characterized in that in the step (1) that methyl aceto acetate and triethyl orthoformate temperature of reaction in the diacetyl oxide solvent is 95 ℃～145 ℃; The by product that is lower than 100 ℃ of boiling points is removed in reaction distillation simultaneously, and underpressure distillation was purified after reaction was accomplished.
4. according to the preparation method of the said 5-methyl-isoxazole of claim 1-4-ethyl formate, it is characterized in that reacting liquid pH value is 8.0～14.0 in the above-mentioned steps (2).
5. according to the preparation method of the said 5-methyl-isoxazole of claim 4-4-ethyl formate, it is characterized in that used mineral alkali is Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, potassium acetate.
6. according to the preparation method of the said 5-methyl-isoxazole of claim 1-4-ethyl formate, used reactant feed mol ratio is 2-ethoxymethyl methyl ethyl acetoacetate: oxammonium hydrochloride=1:0.5～2.0 in the above-mentioned steps (3).
7. according to the preparation method of the said 5-methyl-isoxazole of claim 1-4-ethyl formate; It is characterized in that used organic solvent is methyl alcohol, ethanol, Virahol, THF, acetone, N in the above-mentioned steps (3), a kind of or its mixing in the dinethylformamide.
8. according to the preparation method of the said 5-methyl-isoxazole of claim 1-4-ethyl formate, it is characterized in that in the step (3), the temperature of reaction is 15 ℃～75 ℃.
9. according to the preparation method of the said 5-methyl-isoxazole of claim 1-4-ethyl formate, it is characterized in that in the step (4), it is ETHYLE ACETATE, methylene dichloride, ether that aftertreatment extracts used organic solvent; Measure water layer pH during the water washing organic phase, show neutral to water layer, organic phase with the saturated common salt water washing once.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104744256A (en) * | 2013-12-27 | 2015-07-01 | 北京乐威泰克医药技术有限公司 | Methods for preparing 2-(alkoxylalkylene)-3-oxocarboxylate and pyrimidine compound and application of iron used as catalyst |
| CN110669022A (en) * | 2019-10-31 | 2020-01-10 | 常州沃腾化工科技有限公司 | Micro-channel continuous preparation method of 5-methyl isoxazole-4-formic acid |
| CN113024437A (en) * | 2021-03-19 | 2021-06-25 | 苏州百灵威超精细材料有限公司 | Preparation method of 4', 6-diamidino-2-phenylindole dihydrochloride |
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| 沈敬山等: "来氟米特的合成", 《中国医药工业杂志》 * |
| 苏国栋等: "来氟米特合成工艺的改进", 《化工时刊》 * |
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| CN104744256A (en) * | 2013-12-27 | 2015-07-01 | 北京乐威泰克医药技术有限公司 | Methods for preparing 2-(alkoxylalkylene)-3-oxocarboxylate and pyrimidine compound and application of iron used as catalyst |
| WO2015096786A1 (en) * | 2013-12-27 | 2015-07-02 | 北京乐威泰克医药技术有限公司 | Method for preparing 2-alkoxyalkylene-3-oxo-carboxylate ester, method for preparing pyrimidine compound and use of fe as catalyst |
| CN104744256B (en) * | 2013-12-27 | 2017-01-04 | 北京乐威泰克医药技术有限公司 | Prepare 2-(alkoxyalkylene)-3-oxo carboxylic acid ester, the method for pyrimidine compound and the ferrum purposes as catalyst |
| CN110669022A (en) * | 2019-10-31 | 2020-01-10 | 常州沃腾化工科技有限公司 | Micro-channel continuous preparation method of 5-methyl isoxazole-4-formic acid |
| CN110669022B (en) * | 2019-10-31 | 2022-03-11 | 常州沃腾化工科技有限公司 | Micro-channel continuous preparation method of 5-methyl isoxazole-4-formic acid |
| CN113024437A (en) * | 2021-03-19 | 2021-06-25 | 苏州百灵威超精细材料有限公司 | Preparation method of 4', 6-diamidino-2-phenylindole dihydrochloride |
| CN113024437B (en) * | 2021-03-19 | 2022-05-06 | 苏州百灵威超精细材料有限公司 | Preparation method of 4', 6-diamidino-2-phenylindole dihydrochloride |
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