A method for synthesizing pyrazole-4-boronic acid pinacol ester

A technology for synthesizing pyrazoles and alcohol borates, applied in chemical instruments and methods, compounds containing elements of group 3/13 of the periodic table, organic chemistry, etc., can solve the problem of increased reaction cycle, increased drying steps, and intermediates Stability and other issues, to achieve the effect of improved yield and product purity, simple operation of the process as a whole, and mild reaction conditions

Active Publication Date: 2018-02-06
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The above-mentioned synthesis method has disadvantages such as expensive catalyst, unstable intermediate (such as trimethylsilyl protection), and too complicated post-reaction treatment. It is inevitable to increase the drying step when scaling up, and the reaction cycle is greatly increased

Method used

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  • A method for synthesizing pyrazole-4-boronic acid pinacol ester
  • A method for synthesizing pyrazole-4-boronic acid pinacol ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025]

[0026] In the reaction kettle, add 4-bromopyrazole (1.47kg, 10mol) and 6kg of tetrahydrofuran, stir to dissolve, heat to 30-40°C, slowly add di-tert-butyl dicarbonate (2.18kg, 10mol), dropwise The temperature rises slightly, and the temperature is controlled not to exceed 45°C. After the dropwise addition was completed, the mixture was stirred for 1-2 hours, and TLC confirmed that the reaction was complete. The reaction solution was distilled under reduced pressure until it stopped flowing, and 1.2kg of n-heptane was added to cool down to 0°C for beating, filtered, and dried to obtain 2.01kg of N-BOC-4-bromopyrazole, with a yield of 92%, HPLC: 98.3 %.

[0027] In the reaction kettle, add 4.5kg of tetrahydrofuran and 1-BOC-4-bromopyrazole (2.01kg, 9.2mol), stir for 0.5 hours, cool down to -20°C, and add 3.2mol of Bu3MgLi dropwise at -10°C to 0°C [Preparation Method: Add 1.0eq n-butylmagnesium chloride dropwise to 2.0 equivalent n-butyllithium at -10°C~0°C], TLC to...

Embodiment 2

[0029]

[0030] In the reaction kettle, add 4-iodopyrazole (1.94kg, 10mol) and 5kg of tetrahydrofuran, stir to dissolve, heat to 20-30°C, slowly add di-tert-butyl dicarbonate (2.18kg, 10mol), dropwise The temperature rises slightly, and the temperature is controlled not to exceed 35°C. After the dropwise addition was completed, the mixture was stirred for 1-2 hours, and TLC confirmed that the reaction was complete. The reaction solution was distilled under reduced pressure until it stopped flowing, and 1.2kg of n-heptane was added to cool down to 0°C for beating, filtered, and dried to obtain 2.65kg of N-BOC-4-iodopyrazole, with a yield of 90%, HPLC: 97.4 %.

[0031] In the reaction kettle, add 4.5kg of 2-methyltetrahydrofuran and 1-BOC-4-iodopyrazole (2.65kg, 9.0mol), stir for 0.5 hours, cool down to -20°C, keep -10°C to 0°C and add dropwise 2.95 mol Bu3MgLi [preparation method: add 1.0eq isopropylmagnesium chloride dropwise to 2.0 equivalents of n-butyllithium at -10°C ...

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Abstract

The invention discloses a synthesis method of pyrazol-4-boronic acid pinacol ester. The method consists of: reacting 4-halogenopyrazole with BOC2O to obtain N-BOC-4-halogenopyrazole, then carrying out reaction with alkyl magnesium lithium, adding aminopinacol borate, conducting acid quenching deprotection, then carrying out rotary evaporation filtering to obtain a solid, and adding organic alkali to conduct dissociation so as to obtain a product. The synthesis method has the advantages of simple operation, good reproducibility and high product purity, and is suitable for large-scale production.

Description

technical field [0001] The invention relates to a method for synthesizing pyrazole-4-boronic acid pinacol ester, which belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] Ruxolitinib (Ruxolitinib, also known as Ruxolitinib) is a kinase inhibitor, approved by the European Union in August 2012, for the treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, true erythrocytes Patients with posthypertensive myelofibrosis and postessential thrombocythemia myelofibrosis. As a key intermediate for the synthesis of the bulk drug: pyrazole-4-boronic acid pinacol ester is not fully studied on the scale-up synthesis process. There are three main methods for the synthesis of this compound: [0003] The first one: using pyrazole and pinacol borane in the presence of a metal iridium catalyst, the tetrahydrofuran solvent reflux reaction is directly positioned at the 4-position to generate pyrazole-4-boronic acid ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
CPCC07F5/02
Inventor 冷延国桂迁申海兵
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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