Preparation method of 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-yloxy)benzonitrile

A technology of methyl tetrahydrofuran and boric acid ester, which is applied in the fields of compounds containing group 3/13 elements of the periodic table, chemical instruments and methods, organic chemistry, etc., can solve complex process, high price of pinacol borate, Problems such as high raw material cost and production cost, to achieve the effect of benefiting protection, obvious production cost advantage, and obvious raw material cost advantage

Active Publication Date: 2018-03-06
2Y CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route also adopts the strategy of protection and deprotection, and the process is complicated
The price of palladium catalyst and pinacol diborate is very high, resulting in high raw material cost and production cost

Method used

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  • Preparation method of 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-yloxy)benzonitrile
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  • Preparation method of 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-yloxy)benzonitrile

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Experimental program
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Effect test

Embodiment 1

[0032] Synthesis of 4-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzocyanide (Compound I)

[0033]

[0034] Compound II was prepared by reference WO2007095638 method.

[0035] In a three-necked flask, add compound II (1.9g), tetrahydrofuran (57mL), triisopropyl borate (1.53g) and cool to below -78°C, add butyllithium (6.25mL, concentration 2.5M) dropwise, dropwise The reaction was completed for more than 30 minutes, and 1N hydrochloric acid (57 mL) was added to quench the reaction after the reaction was completed, stirred for more than 30 minutes, and allowed to stand to separate layers. The organic phase was concentrated under reduced pressure until the solvent was evaporated, and methanol (20 mL) and concentrated hydrochloric acid (0.5 mL) were added to the obtained oil, and stirred at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure to obtain about 1.8 g of the target compound I. 1 H-NMR (CDCl 3 ), δ7.79...

Embodiment 2

[0037] Synthesis of 4-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzocyanide (Compound I)

[0038]

[0039] In a three-necked flask, add compound II (20g), tetrahydrofuran (600mL), trimethyl borate (14g) and cool to below -78°C, add butyllithium (64mL, concentration 2.5M) dropwise, and dropwise react for 30 minutes Above, after the reaction was completed, 1N hydrochloric acid (600 mL) was added to quench the reaction, stirred for more than 30 minutes, and stood to separate layers. The organic phase was concentrated to dryness under reduced pressure, and methanol (200 mL) and concentrated hydrochloric acid (5 mL) were added to the obtained oil, and stirred at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure to obtain about 17 g of the target compound I. 1 H-NMR (CDCl 3 ), δ7.79(1H,m),7.64(2H,m),7.04(4H,m),5.20(2H,s),MS:252[M+H] + .

Embodiment 3

[0041]Synthesis of 4-(1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)benzocyanide (Compound I)

[0042]

[0043] In a three-necked flask, add compound II (2g), methyltetrahydrofuran (60mL), trimethyl borate (1.4g) and cool to below -78°C, add butyllithium (6mL, concentration 2.5M) dropwise, dropwise React for more than 30 minutes. After the reaction, add 1N hydrochloric acid (60 mL) to quench the reaction, stir for more than 30 minutes, and let stand to separate layers. The organic phase was concentrated to dryness under reduced pressure, and methanol (20 mL) and concentrated hydrochloric acid (0.5 mL) were added to the obtained oil, and stirred at room temperature overnight. After the reaction was completed, it was concentrated under reduced pressure to obtain about 1.6 g of the target compound I. 1 H-NMR (CDCl 3 ), δ7.79(1H,m),7.64(2H,m),7.04(4H,m),5.20(2H,s),MS:252[M+H] + .

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Abstract

The invention discloses a preparation method of an anti-inflammatory drug boron-containing small molecule 4-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-yloxy)benzonitrile (compound I). The preparation method comprises that a compound II is used as a starting material and reacts with borate in an organic solvent in the presence of a strong alkali to generate a boric acid intermediate, and a ringclosure reaction is continuously performed without separation to prepare the compound I through a one-pot method. According to the present invention, the compound I is prepared through the one-pot method, such that the cumbersome steps of protection and deprotection are avoided, and the method has advantages of simple operation, environmental friendliness and obvious cost advantage, and is suitable for industrial large-scale production. The formulas I and II are defined in the specification.

Description

technical field [0001] The invention relates to an anti-inflammatory drug containing boron small molecule 4-(1-hydroxyl-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy) The preparation method of benzene cyanide. Background technique [0002] Irregular inflammation is a major factor in a wide range of human diseases. People with degenerative disorders often exhibit excessive levels of pro-inflammatory modulators in their blood. One such class of pro-inflammatory modulators are cytokines. Non-limiting examples of common medical problems directly caused by inflammatory cytokines include: arthritis, where inflammatory cytokines can cause damage in the synovium and destroy articular cartilage and bone; kidney failure, where inflammatory cytokines restrict circulation and damage nephrons; including: lupus, in which inflammatory cytokines exacerbate immune complex deposition and damage; asthma, in which inflammatory cytokines obstruct the airways; pseudosoriasis, in which inflammatory ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F5/04
CPCC07F5/04
Inventor 王元刘传军唐文生何训贵
Owner 2Y CHEM
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