CN107721941B - Preparation method of 3-amino-5-methyl isoxazole - Google Patents
Preparation method of 3-amino-5-methyl isoxazole Download PDFInfo
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- CN107721941B CN107721941B CN201710939463.8A CN201710939463A CN107721941B CN 107721941 B CN107721941 B CN 107721941B CN 201710939463 A CN201710939463 A CN 201710939463A CN 107721941 B CN107721941 B CN 107721941B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/14—Nitrogen atoms
Abstract
The invention discloses a preparation method of 3-amino-5-methyl isoxazole, which is completed by three steps and belongs to the technical field of organic chemistry. The method comprises the steps of firstly forming acetyl acetonitrile from easily obtained raw material ethyl acetate and acetonitrile in the presence of metal alkali, then reacting with p-toluenesulfonyl hydrazide to form hydrazone, and then performing ring closure reaction with hydroxylamine under an alkaline condition to obtain the 3-amino-5-methyl isoxazole. Raw materials are common in the reaction, so that chloroform or carbon tetrachloride in the traditional method is avoided, and the generation of similar isomers of the product is not detected in the reaction process.
Description
The technical field is as follows:
the invention relates to a preparation method of 3-amino-5-methyl isoxazole, belonging to the technical field of organic synthesis.
Background art:
3-Amino-5-Methylisoxazole, the english name 3-Amino-5-Methylisoxazole, white crystal, CAS: 1072-67-9. Dissolving in alcohol or ether, and volatilizing with water vapor. A pharmaceutical intermediate. Can be used for producing sulfonamides, especially anti-infective sulfamethoxazole. Sulfamethoxazole, a broad-spectrum antibiotic, belongs to the primary antibacterial class, and is used for urinary tract infection, respiratory tract infection, skin suppurative infection, tonsillitis; when the composition is used together with a synergist, the antibacterial effect of the composition is obviously enhanced and can be increased by several times to tens of times. The traditional Chinese medicine composition is clinically used for tonsillitis, acute bronchitis, lung infection, urinary tract infection, skin suppurative infection, bacillary dysentery, typhoid fever and the like.
The existing synthesis method of the compound mainly comprises the following steps:
firstly, chlorinating 5-methylisoxazole-3-formamide in a sodium hypochlorite aqueous solution to generate N-chloramide sodium, then heating and de-coupling under normal pressure or pressurization to generate 3-amino-5-methylisoxazole, and de-coupling under normal pressure at 104 ℃, wherein the yield is 83%; when the pressure is removed at 150 ℃, the yield is 95 percent. When trial production is carried out in China, normal pressure stripping is adopted, and the yield is only 67%. In the above process, chloroform is selected for extraction. Large chloroform consumption, low recovery rate and easy emulsification during layering.
Secondly, the 5-methyl-3-amino isoxazole is prepared by taking hydroxylamine hydrochloride and 2-methyl-2-acetonitrile-1, 3-dioxolane as raw materials. Dissolving hydroxylamine hydrochloride in ammonia water, adding 2-methyl-2-acetonitrile-1, 3-dioxolane, reacting for 6 hours at 60 ℃ to obtain 2-methyl-2-acetamidomethyl-1, 3-dioxolane, adding chloroform for dissolving, adding concentrated hydrochloric acid for refluxing, adjusting the pH value to be more than 13, extracting by using chloroform, and evaporating to dryness to obtain 5-methyl-3-aminoisoxazole.
Thirdly, reacting substituted acetyl acetonitrile with hydroxylamine hydrochloride under the alkalescent condition to obtain a mixture of amidoxime and a byproduct 5-amino-3-substituted isoxazole compound, then removing the byproduct by adopting a carbon tetrachloride extraction method, and carrying out cyclization reaction on the amidoxime under the action of weak acid to finally obtain the 5-substituted-3-amino-isoxazole compound.
In the above processes, chloroform or carbon tetrachloride, which are extremely toxic solvents, are inevitably used, and either strong oxidation conditions are required or separation of isomers is required, so that the amount of single impurities is strictly controlled in the pharmaceutical field, and particularly, isomers with very similar properties are adversely affected.
The invention content is as follows:
in order to overcome the defects, the invention aims to provide a preparation method of 3-amino-5-methyl isoxazole, which is completed by three steps. The method comprises the steps of firstly forming acetyl acetonitrile from easily obtained raw material ethyl acetate and acetonitrile in the presence of metal alkali, then reacting with p-toluenesulfonyl hydrazide to form hydrazone, and then performing ring closure reaction with hydroxylamine under an alkaline condition to obtain the 3-amino-5-methyl isoxazole.
A preparation method of 3-amino-5-methyl isoxazole is obtained by three steps of reactions, and adopts the technical scheme that:
in the first step, acetonitrile reacts in metal alkali to generate negative ions, and then the negative ions react with ethyl acetate or methyl acetate to obtain the acetyl acetonitrile.
And secondly, adding the acetyl acetonitrile into an alcohol solvent and the p-toluenesulfonyl hydrazide, and performing reflux reaction to obtain corresponding hydrazone.
And step three, adding hydroxylamine hydrochloride into potassium carbonate for dissociation, then adding the hydrazone obtained in the step, heating and ring closing for reaction to obtain the 3-amino-5-methyl isoxazole.
The reaction route is as follows:
further, in the first step, the metal base is NaH, n-BuLi or LDA, and the amount of the metal base added is 1.1 to 1.4 equivalents based on acetonitrile and is 1 equivalent based on ethyl acetate or methyl acetate.
Further, in the second step, the alcoholic solvent is selected from methanol or ethanol. The equivalent ratio of the acetyl acetonitrile to the p-toluenesulfonyl hydrazide is 1: 0.95-1, and the hydrazone obtained after the reaction is a white crystalline solid.
Further, in the third step, potassium carbonate is added in an amount of 2.2 to 4 equivalents based on hydroxylamine hydrochloride. After the dissociation is finished, ethylene glycol dimethyl ether, diethoxymethane, tetrahydrofuran, 2-methyltetrahydrofuran or toluene is added for ring closing reaction.
Further, the optimal reaction temperature of the third step of the ring closing reaction is 65-90 ℃, namely, the solvent is slightly refluxed to be carried out under the reflux condition, when the temperature is reduced to be below 40 ℃, the reaction can be completed within 3 days, and the reaction does not occur at room temperature. Toluene is used as a solvent, and the reaction can be completed within 1 hour under the reflux condition. In view of the ease of extraction and separation, the reaction solvent is preferably diethoxymethane or 2-methyltetrahydrofuran.
The invention has the beneficial effects that:
(1) the raw materials in the reaction are common, the price is low, and the purchase, the transportation and the use are convenient.
(2) In the reaction process, hydrazine is utilized to generate positive ions under an alkaline condition, so that the attack of hydroxyl is facilitated to achieve rapid ring closing;
(3) diethoxymethane and 2-methyltetrahydrofuran are adopted to replace chloroform or carbon tetrachloride in the traditional method, so that labor protection is reduced.
(4) No formation of analogous isomers of the product was detected during the reaction by HPLC-MS.
Detailed Description
Example 1
First, sodium hydride (12.0g, 0.3mol, 60%) was added to a solution of 120mL tetrahydrofuran in acetonitrile (10.3g, 0.25mol), followed by ethyl acetate (26.4g, 0.3mol), heated under reflux for 4 hours, cooled to room temperature, quenched with ice water, adjusted to pH 5-6 with 2N HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate for the organic layer, and concentrated to give 18.9g of acetonitrile, 96% GC purity, 91% yield.
And secondly, dissolving the product of the acetyl acetonitrile (18.9g and 0.23mol) obtained in the previous step in 600mL of methanol in a 1L reaction bottle, adding p-toluenesulfonyl hydrazide (40.2g and 0.22mol), heating and refluxing for 2 hours, cooling and crystallizing, and filtering to obtain white crystalline solid hydrazone 50.3g with the HPLC purity of 99 percent and the yield of 88 percent.
Thirdly, adding hydroxylamine hydrochloride (16.7g, 0.24mol), potassium carbonate (99.5g, 0.72mol) and 40mL of water into a 500mL reaction bottle, stirring at room temperature for 0.5 hour, adding tetrahydrofuran (360mL) and hydrazone (50.3g, 0.20mol) obtained in the previous step, heating to 65 ℃, keeping the temperature for 2 hours, cooling, dropwise adding concentrated hydrochloric acid to adjust the pH value to 1, stirring for 1 hour, layering, discarding an organic layer, dissolving a water layer with 20% sodium hydroxide to adjust the pH value to 10-12, precipitating a large amount of precipitate, filtering, and drying to obtain light yellow crystal 3-amino-5-methylisoxazole 15.5g, wherein the HPLC purity is 98.8%, and the yield is 79%.
Example 2
First, sodium hydride (14g, 0.35mol, 60%) was added to a solution of 120mL tetrahydrofuran in acetonitrile (10.3g, 0.25mol), followed by methyl acetate (25.9g, 0.35mol), heated under reflux for 4 hours, cooled to room temperature, quenched with ice water, adjusted to pH 5-6 with 2N HCl, extracted with ethyl acetate, dried over anhydrous sodium sulfate in the organic layer, and concentrated to give 19.1g of acetonitrile, 96% GC purity, 92% yield.
And secondly, dissolving the product of the acetyl acetonitrile (19.1g and 0.23mol) obtained in the previous step in 600mL of ethanol in a 1L reaction bottle, adding p-toluenesulfonyl hydrazide (42.8g and 0.23mol), heating and refluxing for 2 hours, cooling and crystallizing, and filtering to obtain 52.0g of white crystalline solid hydrazone, wherein the HPLC purity is 99% and the yield is 90%.
Thirdly, adding hydroxylamine hydrochloride (17.3g, 0.25mol), potassium carbonate (75.4g, 0.55mol) and 40mL of water into a 500mL reaction bottle, stirring at room temperature for 0.5 hour, adding 2-methyltetrahydrofuran (360mL) and hydrazone (0.21mol) obtained in the previous step, heating to 80 ℃, preserving heat for 2 hours, cooling, dropwise adding concentrated hydrochloric acid to adjust the pH value to 1, stirring for 1 hour, layering, removing an organic layer, dissolving a water layer by using 20% sodium hydroxide to adjust the pH value to 10-12, precipitating a large amount of precipitate, filtering, and drying to obtain light yellow crystal 3-amino-5-methylisoxazole 15.8g, wherein the HPLC purity is 98.8%, and the yield is 78%.
Example 3
Firstly, in a 500mL reaction flask, a tetrahydrofuran (140mL) solution system of diisopropylamine (35.4g, 0.35mol) is cooled to below-30 ℃, N-butyl lithium N-hexane solution (140mL, 0.35mol, 2.5M) is dropwise added under the protection of nitrogen, after the dropwise addition is completed, the reaction is stirred at room temperature for 30 minutes, the reaction temperature is reduced to below-78 ℃, ethyl acetate (30.8g, 0.35mol) acetonitrile (10.3g, 0.25mol) solution is dropwise added, after the dropwise addition is completed, the reaction is stirred at room temperature for 2 hours, after the reaction is completed, 2N HCl is quenched and the pH value is adjusted to 5-6, ethyl acetate is extracted, an organic layer is dried by anhydrous sodium sulfate, and then the solvent is concentrated to obtain colorless oily acetyl acetonitrile 18.1g, the GC purity is 98%, and the yield is 87%.
And secondly, dissolving 18.1g of the product of the acetoacetonitrile obtained in the previous step in 600mL of methanol in a 1L reaction bottle, adding p-toluenesulfonyl hydrazide (40.5g and 0.22mol), heating and refluxing for 2 hours, cooling and crystallizing, and filtering to obtain 48.1g of white crystalline solid hydrazone, wherein the HPLC purity is 99% and the yield is 88%.
Thirdly, adding hydroxylamine hydrochloride (16.0g, 0.23mol), potassium carbonate (127.1g, 0.92mol) and 40mL of water into a 500mL reaction bottle, stirring at room temperature for 0.5 hour, adding diethoxymethane (360mL) and hydrazone (48.1g, 0.19mol) obtained in the previous step, heating to 85 ℃, keeping the temperature for 2 hours, cooling, dropwise adding concentrated hydrochloric acid to adjust the pH value to 1, stirring for 1 hour, layering, discarding an organic layer, adjusting the pH value of a water layer to 10-12 by using 20% sodium hydroxide, precipitating a large amount of precipitates, filtering, and drying to obtain light yellow crystals, namely 15.0g of 3-amino-5-methylisoxazole, wherein the HPLC purity is 98.7%, and the yield is 80%.
Example 4
Firstly, in a 500mL reaction flask, a tetrahydrofuran (100mL) solution system of diisopropylamine (27.8g, 0.28mol) is cooled to below-30 ℃, an N-hexane solution of N-butyllithium (110mL, 0.28mol, 2.5M) is dropwise added under the protection of nitrogen, after the dropwise addition is completed, the reaction is stirred at room temperature for 30 minutes, the reaction is cooled to below-78 ℃, an acetonitrile (10.3g, 0.25mol) solution of methyl acetate (20.4g, 0.28mol) is dropwise added, after the dropwise addition is completed, the reaction is stirred at room temperature for 2 hours, after the reaction is completed, 2N HCl is quenched and the pH value is adjusted to 5-6, ethyl acetate is extracted, an organic layer is dried by anhydrous sodium sulfate, and then the solvent is concentrated to obtain 17.7g of colorless oily acetonitrile, the GC purity is 98%, and the yield is 85%.
And secondly, dissolving the product of the acetyl acetonitrile (17.7g and 0.21mol) obtained in the previous step in 600mL of ethanol in a 1L reaction bottle, adding p-toluenesulfonyl hydrazide (39.6g and 0.21mol), heating and refluxing for 2 hours, cooling and crystallizing, and filtering to obtain white crystalline solid hydrazone (48.1 g), wherein the HPLC purity is 99 percent, and the yield is 90 percent.
Thirdly, adding hydroxylamine hydrochloride (16.0g, 0.23mol), potassium carbonate (95.2g, 0.69mol) and 40mL of water into a 500mL reaction bottle, stirring at room temperature for 0.5 hour, adding ethylene glycol dimethyl ether (360mL) and hydrazone (48.1g, 0.19mol) obtained in the previous step, heating to 80 ℃, keeping the temperature for 2 hours, cooling, dropwise adding concentrated hydrochloric acid to adjust the pH value to be 1, stirring for 1 hour, layering, discarding an organic layer, dissolving a water layer by using 20% sodium hydroxide to adjust the pH value to be 10-12, precipitating a large amount of precipitates, filtering, and drying to obtain a light yellow crystal, namely 14.6g of 3-amino-5-methylisoxazole, wherein the HPLC purity is 98.8%, and the yield is 78%.
Example 5
Firstly, in a 500mL reaction bottle, a tetrahydrofuran (50mL) solution system of acetonitrile (10.3g, 0.25mol) is cooled to-78 ℃, N-butyl lithium N-hexane solution (140mL, 0.35mol, 2.5M) is dripped under the protection of nitrogen, after dripping is finished, the mixture is kept and stirred for 30 minutes under the condition of heat preservation, ethyl acetate (30.8g, 0.35mol) tetrahydrofuran (60mL) solution is dripped at-78 ℃, after dripping is finished, the mixture is stirred at room temperature for 2 hours, after the reaction is finished, 2N HCl is quenched and adjusted to pH value to 5-6, ethyl acetate is extracted, after an organic layer is dried by anhydrous sodium sulfate, the solvent is concentrated to obtain colorless oily acetyl acetonitrile 17.6g, the GC purity is 98%, and the yield is 85%.
And secondly, dissolving the product of the acetyl acetonitrile (17.6g and 0.21mol) obtained in the previous step in 600mL of ethanol in a 1L reaction bottle, adding p-toluenesulfonyl hydrazide (37.6g and 0.20mol), heating and refluxing for 2 hours, cooling and crystallizing, and filtering to obtain white crystalline solid hydrazone (48.0 g), wherein the HPLC purity is 99% and the yield is 90%.
Thirdly, adding hydroxylamine hydrochloride (15.9g, 0.23mol), potassium carbonate (95.0g, 0.69mol) and 40mL of water into a 500mL reaction bottle, stirring for 0.5 hour at room temperature, adding toluene (360mL) and hydrazone (48.0g, 0.19mol) obtained in the previous step, heating to 90 ℃, preserving heat for 2 hours, cooling, dropwise adding concentrated hydrochloric acid to adjust the pH value to 1, stirring for 1 hour, layering, discarding an organic layer, dissolving a water layer with 20% sodium hydroxide to adjust the pH value to 10-12, precipitating a large amount of precipitate, filtering, and drying to obtain light yellow crystal 3-amino-5-methylisoxazole 15.0g, wherein the HPLC purity is 98.9%, and the yield is 80%.
Example 6
Firstly, in a 500mL reaction bottle, a tetrahydrofuran (50mL) solution system of acetonitrile (10.3g, 0.25mol) is cooled to-78 ℃, N-butyl lithium N-hexane solution (110mL, 0.28mol, 2.5M) is dripped under the protection of nitrogen, after dripping is finished, the mixture is kept at the temperature and stirred for 30 minutes, methyl acetate (20.4g, 0.28mol) tetrahydrofuran (40mL) solution is dripped at-78 ℃, after dripping is finished, the mixture is stirred at room temperature for 2 hours, after the reaction is finished, 2N HCl is quenched and adjusted to pH value to 5-6, ethyl acetate is extracted, after an organic layer is dried by anhydrous sodium sulfate, the solvent is concentrated to obtain 17.4g of the acetoacetonitrile, the GC purity is 97%, and the yield is 84%.
And secondly, dissolving the product of the acetyl acetonitrile (17.4g and 0.21mol) obtained in the previous step in 600mL of methanol in a 1L reaction bottle, adding p-toluenesulfonyl hydrazide (37.2g and 0.20mol), heating and refluxing for 2 hours, cooling and crystallizing, and filtering to obtain white crystalline solid hydrazone 46.4g, wherein the HPLC purity is 99 percent, and the yield is 88 percent.
Thirdly, adding hydroxylamine hydrochloride (15.4g, 0.22mol) into a 500mL reaction bottle, adding potassium carbonate (76.0g, 0.55mol) and 40mL water, stirring at room temperature for 0.5 hour, adding 2-methyltetrahydrofuran (360mL) and hydrazone (46.4g, 0.18mol) obtained in the previous step, heating to 80 ℃, preserving the temperature for 2 hours, cooling, dropwise adding concentrated hydrochloric acid to adjust the pH value to 1, stirring for 1 hour, layering, removing an organic layer, dissolving a water layer by using 20% sodium hydroxide to adjust the pH value to 10-12, precipitating a large amount of precipitates, filtering, and drying to obtain a light yellow crystal 3-amino-5-methylisoxazole 14.1g, wherein the HPLC purity is 98.7%, and the yield is 78%.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. A preparation method of 3-amino-5-methyl isoxazole is characterized by comprising the following steps: generating acetyl acetonitrile by ethyl acetate and acetonitrile in the presence of metal base, then reacting with p-toluenesulfonyl hydrazide to form hydrazone, and then performing ring closing reaction with hydroxylamine hydrochloride under an alkaline condition to obtain 3-amino-5-methyl isoxazole; wherein, the metal alkali is NaH, n-BuLi or LDA.
2. A process for the preparation of 3-amino-5-methylisoxazole according to claim 1 which comprises the steps of: firstly, reacting acetonitrile in metal base to generate negative ions, and then reacting the negative ions with ethyl acetate to obtain the acetoacetonitrile; secondly, adding acetyl acetonitrile into an alcohol solvent and p-toluenesulfonyl hydrazide, and performing reflux reaction to obtain corresponding hydrazone; and thirdly, adding hydroxylamine hydrochloride into potassium carbonate for dissociation, then adding the hydrazone obtained in the previous step, and heating for ring closing reaction to obtain the 3-amino-5-methyl isoxazole.
3. A process for the preparation of 3-amino-5-methylisoxazole according to claim 1 or 2 characterised in that: the amount of the metal base added is 1.1 to 1.4 equivalents based on acetonitrile and 1 equivalent based on ethyl acetate.
4. The process for producing 3-amino-5-methylisoxazole according to claim 2 wherein: in the second step, the alcoholic solvent is selected from methanol or ethanol.
5. A process for the preparation of 3-amino-5-methylisoxazole according to claim 1 or 2 characterised in that: the molar ratio of the acetoacetonitrile to the p-toluenesulfonyl hydrazide is 1: 0.95-1.
6. The process for producing 3-amino-5-methylisoxazole according to claim 2 wherein: the addition amount of the potassium carbonate is 2.2 to 4 equivalents of hydroxylamine hydrochloride.
7. The process for producing 3-amino-5-methylisoxazole according to claim 2 wherein: in the third step, the reaction solvent is selected from ethylene glycol dimethyl ether, diethoxymethane, tetrahydrofuran or 2-methyltetrahydrofuran.
8. The process for producing 3-amino-5-methylisoxazole according to claim 2 wherein: in the third step, the reaction temperature is 65-90 ℃.
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