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Compound and its use in the synthesis of brivaracetam intermediates and raw materials

A compound and reducing agent technology, applied in the fields of sulfonyl-substituted compounds and their synthesis, synthesis of brivaracetam intermediates and raw materials, can solve the problem of being unsuitable for large-scale industrial production, unable to be purified by crystallization or requiring column chromatography , purification and other issues

Active Publication Date: 2021-05-11
FUJIAN HAIXI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] This route requires ultra-low temperature reaction, which requires high equipment, and the multi-step intermediate is oily, which cannot be purified by crystallization or column chromatography
[0016] Based on the above known synthetic methods, most of the intermediates included have no UV absorption, and most of them are liquid, difficult to purify, difficult to detect and quality control, or the synthesis cost is high, or special equipment is required to complete the isomer column Chromatography for separation and purification is not suitable for large-scale industrial production

Method used

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  • Compound and its use in the synthesis of brivaracetam intermediates and raw materials
  • Compound and its use in the synthesis of brivaracetam intermediates and raw materials
  • Compound and its use in the synthesis of brivaracetam intermediates and raw materials

Examples

Experimental program
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Effect test

Embodiment 1

[0104] Embodiment 1 prepares compound II

[0105] Add compound I (5.1 mmol) and 30 mL methanol into a 100 mL three-neck flask with mechanical stirring function, and stir at room temperature. Add sodium methoxide (1.10 g, 20.4 mmol) in batches, raise the temperature to 35-40° C., and stir for 10 minutes. The temperature was lowered to 20-25°C, and R-epichlorohydrin (0.71 g, 0.97 mmol) was added, and the addition was completed in about 10 minutes. The internal temperature rose to 50-55°C and stirred for 4h. Add 5ml of water and 5ml of acetic acid mixed solvent, and stir for 15h. The reaction solution was extracted by adding 20 mL of water and 30 mL of dichloromethane, the aqueous phase was extracted with dichloromethane (30 ml*2), and the organic phases were combined. Wash twice with saturated sodium bicarbonate solution (15 mL*2), dry the organic phase with anhydrous sodium sulfate, remove most of the solvent under reduced pressure, ethanol crystallization or column chromato...

Embodiment 2

[0111] Embodiment 2 prepares compound III

[0112] Add tetrahydrofuran (10ml) and cuprous iodide (224mg, 1.18mmol) into a 100mL three-necked flask with mechanical stirring function, cool to -45°C-50°C, add ethylmagnesium chloride (2.1ml, 4.2mmol) dropwise, about 1h dropwise addition is complete. Afterwards, the temperature was raised to -5°C and stirring was continued for 1 h, then a solution of compound II (1.49 mmol) in tetrahydrofuran (5 ml) was added dropwise, and the temperature was maintained at -5 to -10°C, and the addition was completed in 45 min. After 15 min, saturated ammonium chloride aqueous solution (5 ml) was slowly added, followed by MTBE (5 ml), and stirred for 2.5 h. Stand to separate and separate, collect the organic phase, extract the aqueous phase with 10ml MTBE again, combine the organic phases, wash with water (10ml*2), wash with saturated brine (10ml), dry over anhydrous sodium sulfate, filter with suction, concentrate, add an appropriate volume mixed...

Embodiment 7III-3

[0126] The preparation of embodiment 7III-3

[0127] Add 100ml of tetrahydrofuran and cuprous cyanide (10.6g, 117.8mmol) into a 2.0L three-necked flask with mechanical stirring function, cool to -45°C-50°C, add ethylmagnesium bromide (185ml, 370.0mmol) dropwise, About 1h dropwise completed. Stirring was continued for 1 h, and a tetrahydrofuran solution of compound II-3 (42.2 g dissolved in 240 ml tetrahydrofuran) was added dropwise. The temperature was maintained at -45° C. to 50° C., and the addition was completed in about 1 h. Warm up to -15°C and stir for 2h, add saturated aqueous ammonium chloride solution (400ml), then add ethyl acetate (400ml), stir for 2h. Stand to separate layers, collect the organic phase, extract the water phase with 200ml ethyl acetate once more, combine the organic phases, wash with water (200ml*2), wash with saturated brine (200ml), dry over anhydrous sodium sulfate, filter with suction, concentrate, add Isopropanol was crystallized to obtain 23...

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Abstract

The application provides a compound of formula III, and also provides its use and synthesis method for synthesizing Brivaracetam (Brivracetam) intermediates and raw materials. The raw materials involved in the method described in the present application are cheap and easy to obtain, and (R)-4-propyl-dihydrofuran-2-ketone with high optical purity can be prepared, which avoids cumbersome separation and purification steps, reduces costs, and is more suitable for in industrial production.

Description

technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a class of sulfonyl-substituted compounds and their synthesis, as well as their use in the synthesis of Brivaracetam intermediates and raw materials. The information provided is intended only to aid the reader's understanding. Neither the information provided nor the references cited is an admission that it is prior art to the present invention. Each reference cited is incorporated herein in its entirety and may be used for any purpose. Background technique [0002] Brivaracetam belongs to the third generation of anti-epileptic drugs. It is a new type of high-affinity ligand for synaptophysin 2A (SV2A), and it also has a certain inhibitory effect on voltage-dependent sodium ion channels. . In 2016, buvaracetam was approved by the FDA for the treatment of epileptic seizures, and research results have shown that brivaracetam has a good effect on generaliz...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/33C07D307/93C07D207/27
CPCC07D307/93C07D307/33C07D405/12C07D207/27A61K31/4015C07B2200/07
Inventor 冯岩王如勇叶一章张风森龚轩王中红康心汕
Owner FUJIAN HAIXI PHARMA
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