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Synthesizing method of 4-iodo-methylisoxazole-5-formaldehyde

A technique for synthesizing methylisoxazole and its synthesis method, which is applied in the field of synthesis of 4-iodo-3-methylisoxazole-5-carbaldehyde, can solve the problems of high raw material cost, low yield, long route, etc., and achieve The effect of simple operation, short reaction route and low cost of raw materials

Active Publication Date: 2018-07-27
成都道合尔医药技术有限公司
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  • Abstract
  • Description
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Problems solved by technology

[0011] Overall, there is no literature report on the synthesis of 4-iodo-3-methylisoxazole-5-carbaldehyde
And using related analogues such as 4-iodo-3-methylisoxazole-5-carboxylic acid and 4-iodo-3-methylisoxazole-5-methanol as starting materials to convert 4-iodo-3-methylisoxazole The route of oxazole-5-carbaldehyde generally has problems such as high raw material cost, low yield or long route

Method used

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  • Synthesizing method of 4-iodo-methylisoxazole-5-formaldehyde
  • Synthesizing method of 4-iodo-methylisoxazole-5-formaldehyde
  • Synthesizing method of 4-iodo-methylisoxazole-5-formaldehyde

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: Preparation of 5-(diethoxymethyl)-3-methyl-4,5-dihydroisoxazol-5-ol:

[0031]

[0032] Add 500 g (6.84 mol, 1.8 eq) of acetone oxime into 10 L of tetrahydrofuran and lower the temperature to 0-10°C. 6.84L (17.1mol, 4.5eq) of 2.5M n-butyllithium was added dropwise, and the internal temperature was controlled at 0-20°C. After the addition was complete, the mixture was stirred at -5-0°C for 0.5 hours. 670g (3.80mol, 1.0eq) of ethyl 2,2-diethoxyacetate was added dropwise, and the internal temperature was controlled at -5-0°C. After dropping, stir at 0-15°C for 3 hours. Add 15 L of 20% citric acid aqueous solution dropwise, adjust the pH=2, and control the inner temperature to less than 15°C. Stand still to separate the liquids, extract the aqueous phase with 3.0Lx2 ethyl acetate, combine the organic phases, and wash with 3L saturated brine. The organic phase was concentrated to dryness under reduced pressure, and was directly used in the next reaction to o...

Embodiment 2

[0034] Embodiment 2: the preparation of 5-(diethoxymethyl)-3-methylisoxazole:

[0035]

[0036] Add 300 g (1.48 mol, 1.0 eq) of 5-(diethoxymethyl)-3-methyl-4,5-dihydroisoxazol-5-ol 2 into 3 L of dichloroethane, and react The liquid drops to 0-10°C. Add 497g (3.85mol, 2.6eq) of diisopropylethylamine. 212g (1.85mol, 1.25eq) of methanesulfonyl chloride was added dropwise, and the internal temperature was controlled at 0-15°C. After dropping, react at 25°C for 12h. Add 1L of water, adjust the pH to 5-6 with 20% citric acid, and let stand to separate the liquid. The organic phase was washed with 1 L of saturated brine. The organic phase was concentrated to dryness under reduced pressure to obtain a crude product, which was distilled under reduced pressure to obtain 222 g of 5-(diethoxymethyl)-3-methylisoxazole 3 with a yield of 81%.

[0037] h 1 NMR (400 MHz, CDCl3): 6.21 (s, 1H), 5.63 (s, 1H), 3.66 (q, 4H), 2.33 (s, 3H), 1.27 (t, 6H).

Embodiment 3

[0038] Embodiment 3: Preparation of 4-iodo-3-methylisoxazole-5-carbaldehyde:

[0039]

[0040] Add 5-(diethoxymethyl)-3-methylisoxazole 3 300g (1.62mol, 1.0eq) into acetonitrile 1.5L, add iodobutadieneamine imine 656g (2.92mol, 1.8eq ). 0.5 L of trifluoroacetic acid was added dropwise, and the temperature was raised to 65-75° C. to react for 12 hours. Concentrate under reduced pressure until no liquid flows out obviously, and cool down to room temperature. 1 L of 5% sodium carbonate solution was added, and the aqueous phase was extracted with 900 mL x 2 of ethyl acetate. The organic phases were combined and washed successively with 500 mL of 5% hydrosulfite solution and 500 mL of saturated brine. The organic phase was concentrated to dryness under reduced pressure to obtain a crude product, and the silica gel pad was shortened, rinsed with ethyl acetate / petroleum ether=1 / 7, and the filtrate was concentrated to dryness to obtain 4(4-iodo-3-methylisoxazole-5-carbaldehyde ...

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Abstract

The invention belongs to the technical field of organic synthesis and provides a synthesizing method of 4-iodo-methylisoxazole-5-formaldehyde. The synthesizing method of the 4-iodo-methylisoxazole-5-formaldehyde comprises (1) condensation reaction including condensing the raw material of acetone oxime with 2, 2-ethyl diethoxyacetate to obtain 5-(diethoxymethyl)-3-methyl-4, 5-dihydroisoxazole-5-alcohol, (2) acylation reaction including aromatizing the 5-(diethoxymethyl)-3-methyl-4, 5-dihydroisoxazole-5-alcohol through methylsulfonyl chloride to obtain 5-(diethoxymethyl)-3-methylisoxazole, (3) iodination reaction including iodinating the 5-(diethoxymethyl)-3-methylisoxazole in acetonitrile through iodosuccinimide to obtain the 4-iodo-methylisoxazole-5-formaldehyde. The preparation method ofthe 4-iodo-methylisoxazole-5-formaldehyde is short in reaction path, low in costs of raw materials, simple in operation and applicable large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a synthesis method of 4-iodo-3-methylisoxazole-5-carbaldehyde. Background technique [0002] Isoxazole is a very important compound with high biological activity and pharmacological and physiological activity. Many clinical experiments have shown that isoxazole derivatives have good effects in antibacterial and anti-inflammatory, anti-tumor, lowering blood sugar, and treating certain immune diseases. Certain isoxazole derivatives also exhibit the efficacy of inhibiting weeds and soil bacteria, and are used in the fields of pesticides and insecticides. In addition, isoxazole compounds are also an important class of organic synthesis building blocks, which are widely used in the field of organic synthesis. [0003] [0004] In the series of isoxazole derivatives, 4-iodo-3-methylisoxazole-5-carbaldehyde is a new compound capable of reacting with amines through diffe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/10
CPCC07D261/10
Inventor 宁兆伦魏庚辉黄湘川
Owner 成都道合尔医药技术有限公司
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