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Novel process for synthesizing cyclopropylboronic acid

A cyclopropylboronic acid and a new process technology are applied in the field of synthesis of organic compounds and achieve the effects of mild process conditions, easy operation, good process stability and simple synthesis steps.

Active Publication Date: 2009-05-27
大连双硼医药化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These unfavorable reaction characteristics limit the large-scale industrial synthesis of cyclopropylboronic acid, so it is very necessary to find a synthetic process that can avoid cryogenic temperature, high product purity, and suitable for industrial production

Method used

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  • Novel process for synthesizing cyclopropylboronic acid
  • Novel process for synthesizing cyclopropylboronic acid

Examples

Experimental program
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Effect test

Embodiment 1

[0026] a) Synthesis of cyclopropyllithium: under the protection of argon, add metal lithium nails (1.1 moles), 500 ml of anhydrous tert-butyl methyl ether to a 1-liter reaction flask equipped with a condenser tube and a constant pressure addition funnel, and store at room temperature Stir for 20 minutes. Maintain the temperature at 30-40°C, start to slowly add cyclopropyl bromide (0.5 mol) dropwise, and after 4-6 hours, add cyclohexane with 1% mass of cyclopropyl bromide as internal standard analysis, keep warm and continue the reaction 3-5 hours. When the internal standard analysis of cyclopropyl bromide is less than 1%, stop the reaction. The tert-butyl methyl ether solution of cyclopropyllithium was obtained, which was directly used in the next step of synthesis under the protection of argon.

[0027] b) Synthesis of cyclopropylboronic acid: a 1-liter reaction flask under the protection of argon was cooled to about -10°C, 175 ml of cyclohexane was added, and the compound ...

Embodiment 2

[0029] a) Synthesis of cyclopropyllithium: under the protection of argon, add metal lithium nails (2.5 moles) and 500 ml of diethyl ether to a 1-liter reaction flask equipped with a condenser tube and a constant pressure addition funnel, and stir at room temperature for 20 minutes. Maintain the temperature at 0-10°C, start to slowly add cyclopropyl bromide (0.5 mol) dropwise, and after 2-3 hours, add cyclohexane with 1% mass of cyclopropyl bromide as internal standard analysis, keep warm and continue the reaction 1-2 hours. When the internal standard analysis of cyclopropyl bromide is less than 1%, stop the reaction. The diethyl ether solution of cyclopropyllithium was obtained, which was directly used in the next step of synthesis under the protection of argon.

[0030] b) Synthesis of cyclopropyl boronic acid: Cool a 1-liter reaction flask under the protection of argon to about -10°C, add 150 ml of toluene, compound BrB(NMe 2 ) 2 (0.67 mol), stirred for 30 minutes. Start...

Embodiment 3

[0032]a) Synthesis of cyclopropyllithium: under the protection of argon, add metal lithium nails (2.2 moles) and 500 ml of tetrahydrofuran to a 1-liter reaction flask equipped with a condenser tube and a constant pressure addition funnel, and stir at room temperature for 20 minutes. Keep the temperature at 20-30°C, start to slowly add cyclopropyl bromide (0.5 mol) dropwise, and after 2-5 hours, add cyclohexane with 1% mass of cyclopropyl bromide as internal standard analysis, keep warm and continue the reaction 3-5 hours. When the internal standard analysis of cyclopropyl bromide is less than 1%, stop the reaction. The tetrahydrofuran solution of cyclopropyllithium was obtained, which was directly used in the next step of synthesis under the protection of argon.

[0033] b) Synthesis of cyclopropyl boronic acid: 1 liter reaction flask under the protection of argon, cooled to about -10 ℃, add 160 ml of benzene, compound IB(NMe 2 ) 2 (0.50 mol), stirred for 30 minutes. Start...

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Abstract

The invention relates to a method for synthesizing an organic compound, in particular to a novel process for synthesizing cyclopropyl-boronic acid. The method comprises the following steps: a) synthesis of cyclopropyl-lithium, in which, cyclopropyl-bromine as a raw material reacts with metal lithium in an absolute ether solvent at a temperature of between 0 and 40 DEG C to obtain the cyclopropyl-lithium; and b) synthesis of the cyclopropyl-boronic acid, in which, the cyclopropyl-lithium of the step a) is transferred to an XB(NR)2 solution at a temperature of between minus 10 and 40 DEG C to be thermally preserved and stirred for 2 to 10 hours, wherein in the formula, X is halogen, R is alkyl; then, water is added into the solution to quench excess XB(NR2)2; acid is added into the solution to adjust the pH value to be between 2 and 3; a cyclopropyl-boronic acid crude product is obtained after liquid separation and drying treatment; and the cyclopropyl-boronic acid is obtained through pulping treatment by an alkane solvent. The method can be operated simply and conveniently, does not require ultralow temperature in the whole technological process, has good technological stability, and is easy for realizing industrialized production, thereby effectively improving the market competitiveness of the cyclopropyl-boronic acid.

Description

1. Technical field [0001] The invention relates to a method for synthesizing organic compounds. 2. Background technology: [0002] In pharmaceutically active molecules, cyclopropyl is more and more common as a common structural unit, and is often introduced as a substituent to investigate structure-activity relationships. In the synthesis of drugs, the introduction of non-substituted cyclopropyl groups on heterocycles and aromatic rings usually requires diazomethaneation of the corresponding vinyl compounds [references: Turner, W.R.; Suto, M.J.Tetrahedron Lett.1993, 34, 281. ] or Suzuki coupling [References: For recent reviews, see: (a) Suzuki, A.J.Organomet.Chem.1999, 576,147. (b) Chemler, S.R.; Trauner, D.; Danishefsky, S.J.Angew.Chem., Int .Ed.2001, 40, 4544.] etc. In recent years, palladium-catalyzed Suzuki couplings of cyclopropylboronic acids and the corresponding chloro- or trifluorosulfonic acid compounds have become a commonly used method for the introduction of c...

Claims

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Application Information

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IPC IPC(8): C07F5/02
Inventor 郎丰睿
Owner 大连双硼医药化工有限公司
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