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Synthetic method of 5-methyl-3, 4-diphenyl isoxazole

A technology of diphenylisoxazole and a synthesis method, applied in the field of medicine, can solve problems such as difficulty in obtaining raw materials, and achieve the effects of increased reaction continuity and convenient operation

Active Publication Date: 2021-02-26
CHEMVON BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the above synthesis method, the raw materials are not easy to obtain, or the indium catalyst is used to synthesize the raw materials

Method used

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  • Synthetic method of 5-methyl-3, 4-diphenyl isoxazole
  • Synthetic method of 5-methyl-3, 4-diphenyl isoxazole
  • Synthetic method of 5-methyl-3, 4-diphenyl isoxazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] The first step: Synthesis of 1,3-diphenylpropane-1,3-diketone monoxime

[0028]

[0029] Under the protection of nitrogen, 112g (0.5mol, 1eq) of raw material I was added to 1000mL of 25% methanol aqueous solution, and the temperature was controlled at 25-32°C. 68.8g (0.495mol, 0.99) of hydroxylammonium hydrochloride was added in batches, and sodium acetate was added dropwise. The aqueous solution adjusts Ph=5.7. After the addition, react at 25°C for 24 hours, let it stand still, take the supernatant raw material ≤ 2%, concentrate under reduced pressure at 35-45°C, distill off methanol, cool down to 20-25°C, and filter , the filter cake was rinsed with water, and dried in vacuum at 35-45°C to obtain 112 g of 1,3-diphenylpropane-1,3-diketone monoxime, with a chemical purity of 96.1% and a yield of 93.6% as determined by HPLC. 1 HNMR (400MHz, DMSO-d6): δ=7.86(m,2H), 7.67-7.45(m,3H), 7.37-7.30(m,5H), 6.43(s,1H), 3.98(m,2H).

[0030]

[0031] Under nitrogen protection...

Embodiment 2

[0033] The second step: the synthesis of (3-methyl-3-phenyl-oxirane)-phenyl ketone oxime.

[0034]

[0035] Under the protection of nitrogen, dissolve 112g of intermediate II in 500g of tetrahydrofuran, cool down to -15°C, add dropwise (2M / L) methylmagnesium chloride tetrahydrofuran solution 665.2mL, after the dropwise addition, slowly raise the temperature to 5°C, and react for 1 hour. Add saturated ammonium chloride aqueous solution to quench, let stand to separate layers, extract the organic phase with 500mL of dichloromethane, combine the organic phases, add 102g of trifluoroacetic acid, heat up to 45°C and react for 5h, then sample LC intermediate 4≥87% , concentrated under reduced pressure to the remaining 1 volume, cooled to 10-25 ° C, added 300 g of n-heptane to make a slurry, filtered, and dried to obtain the intermediate (3-methyl-3-phenyl-oxirane)-phenylmethanol Ketoxime 100.4g, HPLC detection chemical purity 97.3%. Yield 85.2%, 1 HNMR (400MHz, DMSO-d6): δ=7.60...

Embodiment 3

[0039] The third step: the synthesis of 5-methyl-3,4-diphenylisoxazole.

[0040]

[0041] Under the protection of nitrogen, 4100g (0.395mol, 1eq) of the intermediate was dissolved in 700mL of dichloromethane, cooled to 0°C, and 511.9g (1.659mol, 4.2eq) of 46% boron trifluoride etherate was added dropwise, slowly Raise the temperature to 20°C and react for 2h. Sampling LC detection of raw materials <1%, the reaction solution cooled to 0-10 ° C, the reaction solution was added to 1N hydrochloric acid 500mL water quenched, static layering, the aqueous phase was extracted with 500mL of dichloromethane, the organic phase was combined, the organic phase Concentrate under reduced pressure to the remaining 3 volumes, then add 109 g of trifluoroacetic acid, raise the temperature to 40-45 ° C for 6 hours, take a sample for LC detection of intermediate 5 ≤ 1%, concentrate under reduced pressure to the remaining 2 volumes, add n-heptane to precipitate, filter get crude. The crude pro...

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Abstract

The invention discloses a synthetic method of 5-methyl-3, 4-diphenyl isoxazole, and belongs to the technical field of synthesis of medical intermediates. Dibenzoylmethane is used as a raw material andreacts with hydroxylamine to generate ketoxime, then the ketoxime and a methyl Grignard reagent are used for conducting addition on carbonyl, epoxidation is conducted to obtain (3-methyl-3-phenyl-oxirane)-phenyl ketoxime, and finally 5-methyl-3, 4-diphenyl isoxazole is obtained through Lewis catalytic cyclization, dehydration and rearrangement. By adopting the process route, the initial raw materials are easy to obtain, the cost is low, industrial operation is facilitated, and a basis is provided for large-scale application of downstream medicines.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to the synthesis of various novel anticancer drug intermediates 5-methyl-3,4-diphenylisoxazole. [0002] technical background [0003] 5-Methyl-3,4-diphenylisoxazole, CAS: 37928-17-9, its structural formula is as follows: [0004] [0005] Isoxazole compounds have very good biological activity, and have broad application value in the application of material chemistry in the field of agriculture and medicine. Isoxazoles are widely used as drug backbones in biopharmaceuticals, such as protein kinase inhibitors, non-steroidal anti-inflammatory drugs, etc. Among them, 5-methyl-3,4-diphenylisoxazole is an important intermediate of the analgesic drug Parecoxib Sodium, benefiting from its wide range of analgesic applications and small side effects, it can even replace or reduce the dosage of morphine , its demand is increasing. [0006] Wherein [Journal ofHeterocyclic Chemistry, 198...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/08
CPCC07D261/08
Inventor 薛峰刘洪强
Owner CHEMVON BIOTECH CO LTD
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