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Preparation method of cyclopropylboronic acid

A technology of cyclopropylboronic acid and cyclopropylboronic acid ester, which is applied in the field of preparation of cyclopropylboronic acid, can solve the problems of affecting product purity, inconvenient use, and low reaction temperature, so as to facilitate industrial production, reduce production costs, The effect of mild reaction temperature

Active Publication Date: 2012-10-31
HEILONGJIANG GREEN HEALTH BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] In method (1), the reaction temperature is too low, and there will be a certain amount of boric acid after the post-treatment is completed, thereby affecting the purity of the product
At the same time, the direct use of cyclopropyl Grignard reagent will increase the cost
[0016] In method (2), metal lithium is generally stored in liquid paraffin, which is easy to react with various inorganic reagents and organic reagents, and is also easy to react with nitrogen to form lithium nitride (Li 3 N) Crystal, inconvenient to use in large production and relatively expensive
[0017] In document (3), butyllithium is used. Butyllithium has extremely strong reducibility, and it is easy to generate heat and burn when it encounters water and oxidants. It is inconvenient to store and transport, and the price is expensive.
The reaction to generate cyclopropyl lithium and cyclopropyl borate needs to be carried out at an ultra-low temperature of -80 ~ -50 ° C, which is inconvenient to operate in chemical production

Method used

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  • Preparation method of cyclopropylboronic acid
  • Preparation method of cyclopropylboronic acid
  • Preparation method of cyclopropylboronic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0044] (1) Synthesis of cyclopropyl Grignard reagent:

[0045] In a 10L four-neck flask, add 500ml of anhydrous tetrahydrofuran, 144g (6mol) of magnesium chips, and 50g of cyclopropyl bromide, add a little iodine to initiate, mechanically stir, control the temperature at 40°C, and dropwise add the remaining 555g of cyclopropyl bromide ( A total of 5mol) of THF solution 2.5L. After the dropwise addition, the stirring reaction was continued for half an hour to obtain a tetrahydrofuran solution containing the reaction product cyclopropylmagnesium bromide.

[0046] (2) Synthesis of cyclopropyl borate:

[0047] In a 10L four-neck flask, add 2L of anhydrous tetrahydrofuran, add 675g (6.5mol) of trimethyl borate, cool down to -40°C, add cyclopropylmagnesium bromide tetrahydrofuran solution dropwise, and control the temperature at -35°C~- 45°C, after the dropwise addition, continue to stir for 1h.

[0048] (3) Synthesis of cyclopropylboronic acid sodium salt:

[0049] Add dropwise...

Embodiment 2

[0054] (1) Synthesis of cyclopropyl Grignard reagent:

[0055] In a 10L four-neck flask, add 500ml of anhydrous methyl tert-butyl ether, 180g (7.5mol) of magnesium chips, and 50g of cyclopropyl bromide, add a little iodine to trigger, stir mechanically, control the temperature at 50°C, and add the remaining Cyclopropyl bromide 555g (total 5mol) in anhydrous methyl tert-butyl ether solution 2.5L. After the dropwise addition, the stirring reaction was continued for half an hour to obtain an anhydrous methyl tert-butyl ether solution containing the reaction product cyclopropylmagnesium bromide.

[0056] (2) Synthesis of cyclopropyl borate:

[0057] In a 10L four-neck flask, add 3L of anhydrous methyl tert-butyl ether, add 1095g (7.5) mol of triethyl borate, cool down to -60°C, add cyclopropylmagnesium bromide anhydrous methyl tert-butyl dropwise Base ether solution, control the temperature at -60°C, after the dropwise addition, continue to stir for 1h.

[0058] (3) Synthesis o...

Embodiment 3

[0064] (1) Synthesis of cyclopropyl Grignard reagent:

[0065] In a 10L four-neck flask, add 200ml of anhydrous dipropyl ether, 132g (1.1mol) of magnesium chips, and 50g of cyclopropyl bromide, add a little iodine to initiate, stir mechanically, control the temperature at 40°C, and add the remaining cyclopropyl bromide dropwise. Bromine 555g (total 5mol) in anhydrous dipropyl ether solution 2.5L. After the dropwise addition, the stirring reaction was continued for half an hour to obtain an anhydrous dipropyl ether solution containing the reaction product cyclopropylmagnesium bromide.

[0066] (2) Synthesis of cyclopropyl borate:

[0067] In a 10L four-necked bottle, add 4L of anhydrous dipropyl ether, add 520g (5mol) of trimethyl borate, cool down to -35°C, add dropwise anhydrous dipropyl ether solution of cyclopropylmagnesium bromide, and control the temperature at -30°C~-40°C, after the dropwise addition, continue to stir for 1h.

[0068] (3) Synthesis of cyclopropylboron...

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Abstract

The invention discloses a preparation method of cyclopropylboronic acid. The preparation method includes: step one, obtaining an ether solution containing cyclopropylmagnesium bromide through the Grignard reaction; step two, adding dropwisely the cyclopropylmagnesium-bromide-containing ether solution obtained in the step one into an ether solvent of boric acid ester for reaction to generate a mixed suspension solution of cyclopropylboronic acid ester; step three, adding the mixed suspension solution of the cyclopropylboronic acid ester obtained in the step two into an opening container, adjusting the pH to 10-12 with an alkali liquor to generate cyclopropyl borate through reaction, and performing solid-liquid separation; step four, adding the solid obtained in the step three into the ester solvent, adjusting the pH to 1-5 with acid to obtain cyclopropylboronic acid; and step five, performing separation and purification to obtain the finished product of cyclopropylboronic acid. The cyclopropylboronic acid prepared by the method is high in purity and yield and low in cost, and production safety is improved.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of cyclopropylboronic acid. Background technique [0002] Cyclopropyl groups are often used for the structural design of new drugs. Among the current methods for introducing cyclopropyl groups, Suzuki coupling reaction is an ideal method for introducing cyclopropyl groups. The Suzuki coupling reaction is a cross-coupling reaction of aryl or alkenyl boronic acid or boronic acid ester with chlorine, bromine, iodoarenes or alkenes under the catalysis of zero-valent palladium complex. This reaction is widely used in organic synthesis, has strong substrate adaptability and functional group tolerance, and is often used in the synthesis of derivatives of polyenes, styrene and biphenyl, and thus applied in the synthesis of many natural products and organic materials . One of the starting materials for the Suzuki coupling reaction is a boronic acid compound. Cycl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/02
Inventor 王勇王建余贵菊程雪娇焦晓军
Owner HEILONGJIANG GREEN HEALTH BIOTECH
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