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A kind of preparation method of 3,3-dimethylbenzo[c][1,2]oxaborolan-1(3h)-alcohol

A technology of oxaborane and dimethylbenzene, which is applied in the field of intermediate synthesis, can solve problems such as low molar yield, difficult synthesis, and difficult availability of raw materials, and achieve the effect of increasing yield

Inactive Publication Date: 2020-12-15
被忽略疾病药物研发组织
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] This synthetic route, because raw material terminal has alkenyl group, synthetic difficulty, raw material is not easy to obtain, and molar yield is low, and bibliographical report only has 55%

Method used

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  • A kind of preparation method of 3,3-dimethylbenzo[c][1,2]oxaborolan-1(3h)-alcohol
  • A kind of preparation method of 3,3-dimethylbenzo[c][1,2]oxaborolan-1(3h)-alcohol
  • A kind of preparation method of 3,3-dimethylbenzo[c][1,2]oxaborolan-1(3h)-alcohol

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Embodiment 1

[0058] A kind of preparation method of 3,3-dimethylbenzo[C][1,2]oxaborolan-1(3H)-alcohol comprises the steps:

[0059] (1) At 5°C, add n-butyllithium (2.5mol) dropwise to n-heptane at a rate of 4mL / min, and then add 2-phenyl-2-propanol dropwise at a rate of 12mL / min ( 1mol), then warming up to 50°C to carry out the lithiation of the ortho-position carbon atom; the mixing mass ratio of the 2-phenyl-2-propanol and n-heptane is 1:8;

[0060] (2) At 5°C, add 1.8mol of triisopropyl borate to the reaction product of step (1);

[0061] (3) at 5 DEG C, add 0.2mol of silver carbonate to the product of step (2) for decomposition reaction, after acidification (6mol / L hydrochloric acid) hydrolysis under pH value 3~4 conditions, the product of acidification hydrolysis The aqueous phase is extracted with a solvent. After combining the organic phases, the organic phase is extracted with a 1mol / L aqueous sodium hydroxide solution. The organic phase is recovered 2-phenyl-2-propanol, and the a...

Embodiment 2

[0083] A kind of preparation method of 3,3-dimethylbenzo[C][1,2]oxaborolan-1(3H)-alcohol comprises the steps:

[0084] (1) At 0°C, add n-butyllithium (3mol) dropwise to n-heptane at a rate of 5mL / min, and then add 2-phenyl-2-propanol (1mol) dropwise at a rate of 15mL / min ), then warming up to 60°C to carry out the lithiation of the ortho-position carbon atom; the mixing mass ratio of the 2-phenyl-2-propanol and n-heptane is 1:10;

[0085] (2) at 0 DEG C, add 2mol triisopropyl borate to the reaction product of step (1);

[0086] (3) under the condition of 0 DEG C, add 0.5mol silver carbonate to the product of step (2) and carry out the decomposition reaction, after the acidification (8mol / L hydrochloric acid) hydrolysis under the condition of pH value 3~4, the product of the acidification hydrolysis The aqueous phase is extracted with a solvent. After combining the organic phases, the organic phase is extracted with a 1mol / L aqueous sodium hydroxide solution. The organic phase...

Embodiment 3

[0093] A kind of preparation method of 3,3-dimethylbenzo[C][1,2]oxaborolan-1(3H)-alcohol comprises the steps:

[0094] (1) At 10°C, add n-butyllithium (2mol) dropwise at a rate of 3mL / min to n-heptane, and then add 2-phenyl-2-propanol (1mol) dropwise at a rate of 15mL / min ), and then warming up to 40°C to carry out the lithiation of the ortho-position carbon atom; the mixing mass ratio of the 2-phenyl-2-propanol and n-heptane is 1:6;

[0095] (2) under the condition of 10 DEG C, add 1.2mol triisopropyl borate to the reaction product of step (1);

[0096] (3) At 10°C, add 0.05 mol of silver carbonate to the product of step (2) for decomposition reaction, acid (6 mol / L hydrochloric acid) hydrolysis under the pH value of 3 to 4, and then acidify and hydrolyze the product The aqueous phase is extracted with a solvent, and after the organic phases are combined, the organic phase is extracted with a 1mol / L aqueous sodium hydroxide solution. The organic phase is recovered 2-phenyl-2...

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Abstract

The invention relates to a preparation method of 3,3-dimethylbenz[C][1,2]oxa-pentaborane-1(3H)-alcohol. The preparation method comprises the following steps: mixing 2-phenyl-2-propyl alcohol and n-butyllithium in n-heptane under the condition of 0-10 DEG C, implementing hydroxyl lithiation, then raising the temperature to 40-60 DEG C to conduct lithiation on an ortho carbon atom; borating; addingsilver carbonate to have a decomposition reaction, extracting and washing an aqueous phase with alkali after acidifying hydrolysis, obtaining a sodium salt dispersing phase of the 3,3-dimethylbenz[C][1,2]oxa-pentaborane-1(3H)-alcohol; acidifying, extracting with a solvent, conducting vacuum concentration to obtain the 3,3-dimethylbenz[C][1,2]oxa-pentaborane-1(3H)-alcohol. The invention provides the method for preparing the 3,3-dimethylbenz[C][1,2]oxa-pentaborane-1(3H)-alcohol by using 2-phenyl-2-propyl alcohol as the raw material, the method chooses the proper lithiation temperature (0-10 DEGC) to obtain a target product, but the problem of the byproduct is serious at the same time, the proper post-processing method is chosen, the byproduct is reacted to become a target object after beingacidified, and therefore, the yield and the purity of the target object are increased.

Description

technical field [0001] The invention belongs to the field of intermediate synthesis, and in particular relates to a preparation method of 3,3-dimethylbenzo[C][1,2]oxaborolan-1(3H)-alcohol. Background technique [0002] Mavatrep is an orally bioavailable TRPV1 antagonist with high affinity for hTRPV1 channels, inhibits the binding of TRPV1 agonists to [3H]-Resiniferatoxin (Ki=6.5nM), and acts on the enzymatic activity of CYP subtypes 3A4, 1A2 and 2D6 less effective. The chemical structure of the Mavatrep is as follows: [0003] [0004] 3,3-Dimethylbenzo[C][1,2]oxaborolan-1(3H)-ol is an important raw material for the synthesis of Mavatrep. The chemical structure of the 3,3-dimethylbenzo[c][1,2]oxaborolan-1(3H)-alcohol is as follows: [0005] [0006] 3,3-Dimethylbenzo[C][1,2]oxaborolan-1(3H)-ol. [0007] The chemical reaction formula for preparing Mavatrep from 3,3-dimethylbenzo[c][1,2]oxaborolan-1(3H)-alcohol is as follows: [0008] [0009] In the prior art, t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F5/02
CPCC07F5/025
Inventor 戴尔芬 弗朗索瓦兹 莫妮卡 劳内 劳内·加拉夫迈克尔特里维廉威廉姆斯尤维斯拉梅什尚德拉潘地亚莱哈古普塔
Owner 被忽略疾病药物研发组织