A method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole

Abstract

The application belongs to the field of compound synthesis and particularly relates to a synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole. 2-methyl-3-butyn-2-ol is used as a starting material, reacts with p-toluenesulfonyl chloride under alkaline conditions to generate compound 1, the obtained compound 1 continues to react with acetoxyhydroxamic acid under alkaline conditions to generate compound 2, compound 2 generates compound 3 under acidic conditions, and compound 3 generates the target product 5,5-dimethyl-4,5-dihydroisoxazole under high-temperature conditions. The application provides a new synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole, the method is one-pot operation, simple operation, less types of solvents, less three wastes, and has high economic value and environmental protection value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of compound synthesis, and particularly relates to a synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole. BACKGROUND

[0002] 5,5-disubstituted-4,5-dihydroisoxazole is an important intermediate for medicines, pesticides and the like, among which pyroxasulfone as a herbicide with excellent herbicidal activity is well known. And 3-halogenated 5,5-dimethyl-4,5-dihydroisoxazole compound is an important intermediate for preparing pyroxasulfone herbicide.

[0003] The currently reported synthesis methods mainly include:

[0004] (1) Synlett 2008, No. 6, 827-830 and Chem. Eur. J. 2010, Vol. 16, 11325-11339 disclose a method for manufacturing 4,5-dihydroisoxazole derivatives using ketoxime. Since ketone is generated as a by-product, this method results in low atom utilization, poor productivity and operability, large environmental burden, uneconomicalness, and is not preferred in industry.

[0005] (2) The preparation method disclosed in W02011063842, 3-methyl-2-butenal and acetone oxime are used to prepare 5,5-dimethyl-4,5-dihydroisoxazole in the presence of acid-base catalyst; the preparation method disclosed in TW201945347A, 3-methyl-2-butenal and hydroxylamine aqueous solution are used to prepare 5,5-dimethyl-4,5-dihydroisoxazole compound in the presence of acid-base catalyst. 3-methyl-2-butenal is a raw material for preparing citral, which is prepared by high-temperature isomerization of 3-methyl-3-butenal catalyst, so the cost of the above preparation method is also high. SUMMARY

[0006] In view of the problems of high cost of raw materials, complex reaction steps, and generation of a large amount of waste in the prior art, the present application provides a new method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole. The method is one-pot operation, simple operation, less types of solvents, less waste generation, and has high economic value and environmental value.

[0007] The structure of 5,5-dimethyl-4,5-dihydroisoxazole synthesized by the present application is:

[0008] .

[0009] The technical scheme adopted by the present application to achieve the above-mentioned purposes is:

[0010] The application provides a synthesis method of 5,5-dimethyl-4,5-dihydroisoxazole, which comprises the following steps:

[0011] (A) under alkaline conditions, 2-methyl-3-butyne-2-ol is reacted with p-toluenesulfonyl chloride to generate compound 1;

[0012]

[0013] (B) under alkaline conditions, compound 1 is reacted with acetoxyhydroxamic acid to generate compound 2;

[0014]

[0015] (C) compound 2 is generated under acidic conditions to generate compound 3;

[0016]

[0017] (D) compound 3 is generated under high-temperature conditions to generate target product 5,5-dimethyl-4,5-dihydroisoxazole;

[0018]

[0019] Further, in step (A), the molar ratio of 2-methyl-3-butyne-2-ol to p-toluenesulfonyl chloride is 1:1.02-1.5, and the reaction temperature is -5-50 DEG C.

[0020] Further, according to the synthesis method of claim 2, in step (A), the alkaline conditions are realized by adding alkali; the alkali includes but is not limited to organic alkali and inorganic alkali, preferably, the alkali is triethylamine, sodium hydroxide or potassium hydroxide; the molar ratio of 2-methyl-3-butyne-2-ol to alkali is 1:2.1-3.6.

[0021] Further, in step (A), the reaction is carried out in two-phase solvents, and the solvents are water and organic solvents; the mass ratio of water to solvent is 1:2-10; the organic solvents include but are not limited to toluene, dimethylbenzene, n-heptane and n-octane.

[0022] Further, in step (B), the molar ratio of compound 1 to acetoxyhydroxamic acid is 1:1.02-1.5; and the reaction temperature is -5-50 DEG C.

[0023] Further, in step (C), the acidic conditions are realized by adding acid; the acid includes but is not limited to hydrochloric acid, sulfuric acid, acetic acid, formic acid or phosphoric acid.

[0024] Further, in step (C), the pH value of the reaction is 0-6, preferably 3-4; and the reaction temperature is -5-50 DEG C.

[0025] Further, in step (D), the reaction solvent is the organic solvent after separation in step (C); the reaction temperature is 90-150°C, preferably the reflux temperature of the solvent used.

[0026] Compared with the prior art, the method provided by the present application has the advantages that: compared with the prior art, the synthesis method provided by the present application only needs one-pot operation, is simple to operate, uses less types of solvents, produces less waste, and has high economic value and environmental protection value. DETAILED DESCRIPTION

[0027] The present application is further described below in conjunction with specific examples. The following description is only exemplary and does not limit the scope of protection. Other embodiments obtained by those skilled in the art without creative labor on the basis of the inventive concept of the present application are also within the scope of protection.

[0028] In the following examples, the raw materials used are commercially available products, unless otherwise specified.

[0029] In the following examples, the concentrations are mass percentages, unless otherwise specified.

[0030] In the following examples, the yield = actual mass of product x purity / theoretical mass of product.

[0031] Example 1

[0032] Take 50g of water and 100g of toluene into a reaction bottle, add 8.58g (0.1mol) of 2-methyl-3-butyne-2-ol and 25.55g (0.25mol) of triethylamine, cool to 0°C, then add 21.18g (0.11mol) of p-toluenesulfonyl chloride dropwise, react for 2h, then detect 2-methyl-3-butyne-2-ol by HPLC, which is <0.5% (HPLC area %), and the purity of compound 1 is >99% (HPLC area %).

[0033] After the reaction, acetyloxime acid 8.34 g (0.11 mol) was continuously added dropwise, and the reaction was maintained at 0°C for 2.5 h. HPLC detection showed that the purity of compound 1 was <0.5% (HPLC area %), and the purity of compound 2 was >97% (HPLC area %). After the reaction of compound 1 was completed, 36% hydrochloric acid was added dropwise to maintain the pH value of the reaction system at 3, and the temperature was raised to 25°C for continuous reaction for 2 h. HPLC detection showed that the purity of compound 2 was <0.5% (HPLC area %), and the purity of compound 3 was >98% (HPLC area %). After the reaction of compound 2 was completed, the toluene layer was obtained by liquid separation, and the toluene layer was heated to 110°C for reflux reaction for 4 h. HPLC detection showed that the purity of compound 3 was <0.5% (HPLC area %). After the reaction of compound 3 was completed, desolventization was performed. After desolventization, 5,5-dimethyl-4,5-dihydroisoxazole oil 9.16 g was obtained, with a purity of 96.7%, and a total yield of 89.4%.

[0034] Example 2

[0035] Water 50 g and xylene 150 g were put into a reaction bottle, 2-methyl-3-butyn-2-ol 8.58 g (0.1 mol) and sodium hydroxide 13.33 g (0.32 mol) were added, and the temperature was lowered to -5°C. Then, p-toluenesulfonyl chloride 26.96 g (0.14 mol) was added dropwise. After the dropwise addition was completed, the temperature was raised to 25°C, and the reaction was maintained for 0.5 h. HPLC detection showed that the purity of 2-methyl-3-butyn-2-ol was <0.5% (HPLC area %), and the purity of compound 1 was >99% (HPLC area %).

[0036] After the reaction, acetyloxime acid 9.86 g (0.13 mol) was continuously added dropwise, and the reaction was maintained at 25°C for 1 h. HPLC detection showed that the purity of compound 1 was <0.5% (HPLC area %), and the purity of compound 2 was >98% (HPLC area %). After the reaction of compound 1 was completed, sulfuric acid was added dropwise to maintain the pH value of the reaction system at 3.5, and the reaction was continuously maintained for 2 h. HPLC detection showed that the purity of compound 2 was <0.5% (HPLC area %), and the purity of compound 3 was >98% (HPLC area %). After the reaction of compound 2 was completed, the toluene layer was obtained by liquid separation, and the toluene layer was heated to 140°C for reflux reaction for 2 h. HPLC detection showed that the purity of compound 3 was <0.5% (HPLC area %). After the reaction of compound 3 was completed, desolventization was performed. After desolventization, 5,5-dimethyl-4,5-dihydroisoxazole oil 9.22 g was obtained, with a purity of 97.5%, and a total yield of 90.7%.

[0037] Example 3

[0038] Take water 40 g and n-heptane 160 g into the reaction bottle, add 2-methyl-3-butyn-2-ol 8.58 g (0.1 mol) and potassium hydroxide 18.70 g (0.30 mol), cool to 10 ℃, then add p-toluenesulfonyl chloride 23.11 g (0.12 mol) dropwise, after the dropwise addition is completed, warm to 35 ℃, and react for 0.5 h. HPLC detection shows that 2-methyl-3-butyn-2-ol is less than 0.5% (HPLC area%) and the purity of compound 1 is greater than 99% (HPLC area%).

[0039] After the reaction is completed, continue to add acetoxyhydroxamic acid 10.62 g (0.14 mol), and warm to 35 ℃. After reacting for 1 h, HPLC detection shows that compound 1 is less than 0.5% (HPLC area%) and the purity of compound 2 is greater than 97% (HPLC area%). After the reaction of compound 1 is completed, add acetic acid to maintain the pH value of the reaction system at 4, and continue to react for 1 h. HPLC detection shows that compound 2 is less than 0.5% (HPLC area%) and the purity of compound 3 is greater than 96% (HPLC area%). After the reaction of compound 2 is completed, perform liquid separation treatment. The obtained n-heptane layer is warmed to 98 ℃ and refluxed for 8 h. HPLC detection shows that compound 3 is less than 0.5% (HPLC area%). After the reaction of compound 3 is completed, perform desolubilization. After desolubilization, 5,5-dimethyl-4,5-dihydroisoxazole oily substance 9.59 g is obtained, with a purity of 91.2% and a total yield of 88.2%.

[0040] Example 4

[0041] Take water 150 g and toluene 500 g into the reaction bottle, add 2-methyl-3-butyn-2-ol 34.33 g (0.4 mol) and potassium hydroxide 47.61 g (0.84 mol), cool to -5 ℃, then add p-toluenesulfonyl chloride 78.75 g (0.408 mol) dropwise, after the dropwise addition is completed, warm to 35 ℃, and react for 0.5 h. HPLC detection shows that 2-methyl-3-butyn-2-ol is less than 0.5% (HPLC area%) and the purity of compound 1 is greater than 99% (HPLC area%).

[0042] After the reaction is completed, acetyloxime acid 30.94 g (0.408 mol) is continuously added dropwise, and the temperature is lowered to 20°C for reaction for 2 h. HPLC detection shows that the purity of compound 1 is <0.5% (HPLC area %), and the purity of compound 2 is >99% (HPLC area %). After the reaction of compound 1 is completed, 36% hydrochloric acid is added dropwise to adjust the pH value of the reaction system to 1. After the addition of the hydrochloric acid is completed, the reaction is continuously carried out for 1 h. HPLC detection shows that the purity of compound 2 is <0.5% (HPLC area %), and the purity of compound 3 is >98% (HPLC area %). After the reaction of compound 2 is completed, liquid separation is carried out. The obtained toluene layer is warmed to 110°C and refluxed for 4 h. HPLC detection shows that the purity of compound 3 is <0.5% (HPLC area %). After the reaction of compound 3 is completed, desolubilization is carried out. After desolubilization, 36.94 g of oil is obtained, with a purity of 97.8%, and the total yield is 91.1%.

[0043] Example 5

[0044] Water 50 g and n-octane 200 g are put into a reaction bottle, 2-methyl-3-butyne-2-ol 8.58 g (0.1 mol) and sodium hydroxide 10.42 g (0.25 mol) are added, and p-toluenesulfonyl chloride 21.18 g (0.11 mol) is added dropwise at 25°C. After the dropwise addition is completed, the temperature is raised to 50°C, and the reaction is carried out for 0.5 h. HPLC detection shows that the purity of 2-methyl-3-butyne-2-ol is <0.5% (HPLC area %), and the purity of compound 1 is >99% (HPLC area %).

[0045] After the reaction is completed, acetyloxime acid 8.34 g (0.11 mol) is continuously added dropwise, and the temperature is raised to 50°C for reaction for 0.5 h. HPLC detection shows that the purity of compound 1 is <0.5% (HPLC area %), and the purity of compound 2 is >96% (HPLC area %). After the reaction of compound 1 is completed, formic acid is added dropwise to maintain the pH value of the reaction system at 2. The reaction is continuously carried out for 1 h. HPLC detection shows that the purity of compound 2 is <0.5% (HPLC area %), and the purity of compound 3 is >98% (HPLC area %). After the reaction of compound 2 is completed, liquid separation is carried out. The obtained n-octane layer is warmed to 127°C and refluxed for 4 h. HPLC detection shows that the purity of compound 3 is <0.5% (HPLC area %). After the reaction of compound 3 is completed, desolubilization is carried out. After desolubilization, 5,5-dimethyl-4,5-dihydroisoxazole oil 9.42 g is obtained, with a purity of 93.3%, and the total yield is 88.7%.

[0046] Comparative Example 1

[0047] Toluene 150 g was put into a reaction bottle, 2-methyl-3-butyn-2-ol 8.58 g (0.1 mol) and sodium hydroxide 13.33 g (0.32 mol) were added, and then p-toluenesulfonyl chloride 26.96 g (0.14 mol) was added dropwise at 5°C. After the dropwise addition was completed, the temperature was raised to 25°C, and the reaction was carried out for 6 h. HPLC detection showed that 2-methyl-3-butyn-2-ol was less than 0.5% (HPLC area%), and the purity of compound 1 was greater than 97% (HPLC area%).

[0048] After the reaction was completed, acetyloxime acid 9.86 g (0.13 mol) was continuously added dropwise. After the reaction was carried out at 25°C for 24 h, HPLC detection showed that compound 1 was still greater than 70% (HPLC area%), and the reaction was stopped.

[0049] Comparative Example 2

[0050] Water 150 g was put into a reaction bottle, 2-methyl-3-butyn-2-ol 8.58 g (0.1 mol) and sodium hydroxide 13.33 g (0.32 mol) were added, and then p-toluenesulfonyl chloride 26.96 g (0.14 mol) was added dropwise at 5°C. After the dropwise addition was completed, the temperature was raised to 25°C, and the reaction was carried out for 24 h. HPLC detection showed that 2-methyl-3-butyn-2-ol was greater than 30% (HPLC area%), and HPLC detection showed that compound 1 was less than 5% (HPLC area%), and the reaction was stopped.

Claims

1. A method for the synthesis of 5,5-dimethyl-4,5-dihydroisoxazole, characterized in that, The method comprises the following steps: (A) reacting 2-methyl-3-butyne-2-ol with p-toluenesulfonyl chloride under alkaline condition to obtain compound 1; ； (B) reacting compound 1 with acetoxyhydroxamic acid under alkaline condition to obtain compound 2; ； (C) reacting compound 2 under acidic condition to obtain compound 3; ； (D) reacting compound 3 under the condition of 90-150 ℃ to obtain the target product 5,5-dimethyl-4,5-dihydroisoxazole. ； In step (A), the reaction is carried out in a two-phase solvent, which is water and an organic solvent.

2. The method of synthesis of claim 1, wherein, In step (A), the molar ratio of 2-methyl-3-butyne-2-ol to p-toluenesulfonyl chloride is 1:1.02-1.5, and the reaction temperature is -5-50 ℃.

3. The method of synthesis of claim 2, wherein, In step (A), the alkaline condition is realized by adding a base; the base is an organic base or an inorganic base; the molar ratio of 2-methyl-3-butyne-2-ol to the base is 1:2.1-3.

6.

4. The method of synthesis of claim 3, wherein, The base is triethylamine, sodium hydroxide or potassium hydroxide.

5. The method of synthesis of claim 1, wherein, In step (A), the mass ratio of water to the organic solvent is 1:2-10; the organic solvent is toluene, xylene, n-heptane or n-octane.

6. The method of synthesis of claim 1, wherein, In step (B), the molar ratio of compound 1 to acetoxyhydroxamic acid is 1:1.02-1.

5.

7. The method of synthesis according to claim 1 or 6, wherein, In step (B), the reaction temperature is -5-50 ℃.

8. The method of synthesis of claim 1, wherein, In step (C), the acidic condition is realized by adding an acid; the acid is hydrochloric acid, sulfuric acid, acetic acid, formic acid or phosphoric acid.

9. The method of synthesis of claim 8, wherein, In step (C), the pH value of the reaction is 0-6, and the reaction temperature is -5-50 ℃.

10. The method of synthesis of claim 9, wherein, In step (C), the pH value is 3-4.

11. The method of synthesis of claim 1, wherein, In step (D), the solvent of the reaction is the organic solvent after separation in step (C).

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