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A method for synthesizing 3,6-dihydro-2h-pyr(thia)pyran-4-boronate

A technology of boric acid ester and thiopyran, which is applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of high cost and affecting production efficiency, and achieve the effect of low cost, mild conditions and easy availability of raw materials

Active Publication Date: 2017-04-26
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In the above method, the reaction requires ultra-low temperature, a large excess of metal copper salt is used, and the cost is relatively high. Unfavorable factors such as noble metal palladium catalyzed coupling, column chromatography purification, etc., these directly affect the scale-up production efficiency.

Method used

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  • A method for synthesizing 3,6-dihydro-2h-pyr(thia)pyran-4-boronate
  • A method for synthesizing 3,6-dihydro-2h-pyr(thia)pyran-4-boronate
  • A method for synthesizing 3,6-dihydro-2h-pyr(thia)pyran-4-boronate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Synthesis of 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester:

[0019]

[0020] Step 1: After mixing tetrahydropyran-4-one (10.0 g, 0.1 mol), p-toluenesulfonyl hydrazide (18.6 g, 0.1 mol) and 120 ml of ethanol, heat under reflux for reaction, and evaporate the solvent to dryness after the reaction is completed. Add pyridine (11.9 g, 0.15 mol) and 150 ml of dichloromethane directly, then add dropwise a solution of NBS (26.7 g, 0.15 mol) dissolved in 40 ml of dichloromethane, after the reaction is complete, add 10% hydrochloric acid to adjust the pH =2-3, separate the organic layer, evaporate the solvent to dryness under normal pressure, add 20 ml of sulfolane, and distill under reduced pressure to obtain 11.9 g of light yellow liquid: 3,6-dihydro-2H-pyran-4-bromo, GC: 98.2%, yield 73%;

[0021] Step 2: Add metal magnesium (1.9 g, 78 mmol) and 10 ml of tetrahydrofuran, add 2-3 drops of methyl iodide to trigger and start to drop 11.9 g of 3,6-dihydro-2H-pyran-4-bromo...

Embodiment 2

[0023] Synthesis of 3,6-dihydro-2H-pyran-4-boronic acid neopentyl glycol ester:

[0024]

[0025] Step 1: After mixing tetrahydropyran-4-one (10.0 g, 0.1 mol), p-toluenesulfonyl hydrazide (18.6 g, 0.1 mol) and 120 ml of ethanol, heat under reflux for reaction, and evaporate the solvent to dryness after the reaction is completed. Add DBU (22.8 g, 0.15 mol) and 150 ml of dichloromethane directly, then add dropwise a solution of NBS (26.7 g, 0.15 mol) dissolved in 40 ml of dichloromethane, after the reaction is complete, add 10% hydrochloric acid to adjust the pH =4-5, separate the organic layer, evaporate the solvent to dryness under normal pressure, add 20 ml of sulfolane, and distill under reduced pressure to obtain 12.2 g of light yellow liquid: 3,6-dihydro-2H-pyran-4-bromo, GC: 98.4%, yield 75%;

[0026] Step 2: Add metal magnesium (1.9 g, 78 mmol) and 10 ml of tetrahydrofuran, add 2-3 drops of methyl iodide to trigger and start to drop 12.2 g of 3,6-dihydro-2H-pyran-4-b...

Embodiment 3

[0028] Synthesis of 3,6-dihydro-2H-thiopyran-4-boronic acid pinacol ester:

[0029]

[0030] Step 1: After mixing tetrahydrothiopyran-4-one (10.0 g, 0.1 mol), p-toluenesulfonyl hydrazide (18.6 g, 0.1 mol) and 120 ml of ethanol, heat under reflux for reaction, and evaporate the solvent to dryness after the reaction is completed. Add pyridine (17.2 g, 0.22 mol) and 150 ml of dichloromethane directly, then add dropwise a solution of NBS (35.6 g, 0.20 mol) dissolved in 40 ml of dichloromethane, after the reaction is complete, add 10% hydrochloric acid to adjust the pH =2-3, separate the organic layer, evaporate the solvent to dryness under normal pressure, add 20 ml of sulfolane, and distill under reduced pressure to obtain 13.8 g of light yellow liquid: 3,6-dihydro-2H-thiopyran-4-bromo, GC: 98.7%, yield 77%;

[0031] Step 2: Add metal magnesium (2.2 g, 92 mmol) and 10 ml of tetrahydrofuran, add 2-3 drops of methyl iodide to trigger and start to drop 13.8 g of 3,6-dihydro-2H-p...

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Abstract

The invention discloses a method for synthesizing 3, 6-dihydro-2H-pyrazine (thiazine) furan-4-boric acid ester. According to the method, tetrahydropyrazole (thiazine) furan-4-ketone serves as the raw material, generates hydrazone with p-toluenesulfonhydrazide, then reacts with NBS / organic alkali to generate alkenyl bromide and next forms Grignard reagent with magnesium metal, after the Grignard reagent is formed, boron reagent is added for a reaction, and the 3, 6-dihydro-2H-pyrazine (thiazine) furan-4-boric acid ester is obtained. By means of the method, ultralow temperature, column chromatography and palladium catalyzed coupling in a literature method are avoided, raw materials are easy to obtain, cost is low, conditions are mild, and the method has potential industrial application and amplification prospect.

Description

technical field [0001] The invention relates to a method for synthesizing 3,6-dihydro-2H-pyr(thiopyran-4-boronate), which belongs to the field of synthesis of pharmaceutical intermediates. Background technique [0002] Cycloalkenyl structures widely exist in newly developed or marketed drugs, for example: 3,6-dihydro-2H-pyr(thiopyran-4-boronate), as a general synthetic intermediate, can be synthesized after Suzuki coupling It is used in the synthesis of natural products and anti-cancer and anti-HIV drugs. [0003] The synthesis of 3,6-dihydro-2H-pyr(thiopyr)-4-boronate is currently mainly: from tetrahydropyr(thio)pyr-4-one under strong alkali conditions, ultra-low temperature and PhNTf 2 The reaction produces alkenyl trifluorosulfonate, or reacts with hydrazine hydrate to form a hydrazone, followed by bromination in the CuBr2 / Et3N / MeOH system, the alkenyl bromide is obtained after DBU elimination, and then the product is obtained after Suzuki coupling under metal palladium ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/04
CPCC07F5/04
Inventor 冷延国田利国桂迁
Owner CANGZHOU PURUI DONGFANG SCI & TECH
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