Synthesis method of cycloalkene-1-boronic acid pinacol ester

A technology of pinacol ester and synthesis method, which is applied in the field of organic chemical synthesis, can solve the problems of difficult purification, cumbersome operation, and high cost of raw materials, and achieve the effects of cheap and easy-to-obtain raw materials, reduced process difficulty, and simple operation

Inactive Publication Date: 2015-04-01
DALIAN NETCHEM CHIRAL TECH
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  • Abstract
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Problems solved by technology

[0005] However, this method has many defects: (1) The reaction requires ultra-low temperature, the industrial scale-up operation is cumbersome, and the refrigeration cost is increased; (2) The selectivity of the reaction is very poor, and there are many impurities , the yield is low and the purification is difficult during vacuum distillation; (3) 4eq butyllithium is used in the literature, and isopropoxy borate pinacol ester needs to be self-made, the cost of raw materials is high and there are safety hazards in operation; (4) The p-toluenesulfonyl hydrazide used in the literature forms an oxime with a ketone and then leaves, and its molecular weight is very large, and the atom utilization rate is low
[0008] The disadvantage of this method is: (1) Although 1-chlorocyclohexene (intermediate 1) is also prepared by itself, the purity requirement is too high, and its purity It directly affects the purity of the product, so the raw material needs to be rectified, and the product also needs to be obtained by rectification, and the operation is cumbersome; (2) This reaction uses a precious metal palladium catalyst, and the raw material is expensive

Method used

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  • Synthesis method of cycloalkene-1-boronic acid pinacol ester

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Experimental program
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Effect test

Embodiment 1

[0029] Taking the preparation of cyclohexene-1-boronic acid pinacol ester as an example, taking cyclohexanone as raw material, solvent A For n-heptane, solvent B is tetrahydrofuran, solvent C to ethyl acetate

[0030] The preparation of the first step raw material 1-chlorocyclohexene:

[0031] Add 320.3g (1.556 mol, 1.05eq) of phosphorus pentachloride and 801 g of n-heptane into a 2L four-necked flask equipped with a magnetic stirrer, a thermometer, a condenser tube and a tail gas lye absorption device, raise the temperature to 72°C, drop Add 150.2g (1.533mol, 1eq) cyclohexanone, drop it for about 2 hours, continue to react for half an hour, after cooling down to 0°C, add 0.51kg of 6mol / L sodium hydroxide solution dropwise, stir for 1 hour, and separate the upper layer The organic layer was washed once with 100 g of saturated sodium bicarbonate to obtain 757.1 g of 1-chlorocyclohexene solution, with an internal standard yield of 82.2%;

[0032] The preparation of the secon...

Embodiment 2

[0037] Taking the preparation of cyclopentene-1-boronic acid pinacol ester as an example, taking cyclopentanone as raw material, solvent A For n-hexane, solvent B is tetrahydrofuran, solvent C for toluene

[0038] The preparation of the first step raw material 1-chlorocyclopentene:

[0039] Add 374.2 (1.818 mol, 1.05) phosphorus pentachloride and 863 g of n-heptane to a 2L four-neck flask equipped with a magnetic stirrer, thermometer, condenser tube and tail gas alkali absorption device, raise the temperature to 70 ° C, and add dropwise 151.4 g (1.803mol, 1eq) cyclopentanone, drop it in about 2 hours, continue to react for half an hour, after cooling down to 0°C, add 0.69kg of 6mol / L sodium hydroxide solution dropwise, stir for one hour, and separate the upper organic layer , the organic layer was washed once with saturated sodium bicarbonate to obtain 799 g of n-hexane solution of 1-chlorocyclopentene, and the internal standard yield was 81.1%;

[0040]The preparation of ...

Embodiment 3

[0045] Take the preparation of 3,3,5,5-tetramethyl-cyclohexene-1-boronic acid pinacol ester as an example, with 3,3,5,5-tetramethylcyclohexanone as raw material, solvent A For n-heptane, solvent B is tetrahydrofuran, solvent C MTBE

[0046] Preparation of the first step raw material 3,3,5,5-tetramethyl-1-chlorocyclohexene:

[0047] Add 191.5 (0.930 mol, 1.05) phosphorus pentachloride and 663 g of n-heptane to a 2L four-necked flask equipped with a magnetic stirrer, thermometer, condenser tube and tail gas alkali absorption device, raise the temperature to 75 ° C, and drop 136.4 g (0.886mol, 1eq) 3,3,5,5-tetramethylcyclohexanone, after about 2 hours, continue to react for half an hour, after cooling down to 0°C, add dropwise 6mol / L sodium hydroxide solution 0.43 kg, stirred for one hour, separated the upper organic layer, and washed the organic layer once with saturated sodium bicarbonate to obtain 659 g of n-heptane solution of 3,3,5,5-tetramethyl-1-chlorocyclohexene, inter...

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Abstract

The invention discloses a synthesis method of cycloalkene-1-boronic acid pinacol ester. The synthesis method comprises three reaction steps of enabling cycloketone to react with phosphorus pentachloride to obtain 1-cycloolefin chloride, preparing cycloalkene-1-boronic acid through 1-cycloolefin chloride, lithium metal and a boronizing agent by the one-step method, and enabling cycloalkene-1-boronic acid to react with pinacol to obtain the final product. According to the method, the reaction is under mild conditions, 1-cycloolefin chloride can directly enter the next reaction without distilling and purifying, and intermediates and products obtained in each step do not need distilling, so that the operation is simple, and moreover, the raw materials are low in cost and easy to obtain, and as a result, mass production can be performed.

Description

technical field [0001] The invention relates to a synthesis method of cycloalkenyl-1-boronic acid pinacol ester, which belongs to the field of organic chemical synthesis. Background technique [0002] In modern drug synthesis, it is more and more common to introduce cycloalkenyl as a common structural unit, and it is often introduced as a substituent group to investigate the structure-activity relationship. In recent years, cycloalkenylboronic acid pinacol ester and corresponding It is more common for aromatic or heterocyclic halides to introduce cycloalkenyl groups through suzuki coupling reactions (references Billingsley, Kelcin; Barder Timthye. Angewandtechemle.International Edition; vol.46;nb:28;(2007);p 5359-5363) , its synthesis method has the following several kinds: [0003] Method 1: Reported in J.AM.CHEM.SOC.VOL.130.NO.2008.8481-8490 [0004] . [0005] However, this method has many defects: (1) The reaction requires ultra-low temperature, and the industrial ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/04
CPCC07F5/04
Inventor 安昌辉郑鹏
Owner DALIAN NETCHEM CHIRAL TECH
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