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Optical activity di(heteto)aryl methanol and asymmetric synthesis method thereof

An optically active, aryl methanol technology, applied in asymmetric synthesis, organic chemistry methods, chemical instruments and methods, etc., to achieve the effects of low price, mild reaction conditions, and simple synthesis

Inactive Publication Date: 2017-06-13
CHINA THREE GORGES UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, there are few reports on the asymmetric transfer hydrogenation synthesis of optically active di(hetero)arylmethanols.

Method used

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  • Optical activity di(heteto)aryl methanol and asymmetric synthesis method thereof
  • Optical activity di(heteto)aryl methanol and asymmetric synthesis method thereof
  • Optical activity di(heteto)aryl methanol and asymmetric synthesis method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: Catalyst A-I catalyzes the asymmetric synthesis of (2-methylphenyl) (2-pyridyl) methanol

[0030] Add 0.01 mmol of catalysts numbered A-I to 10 ml of Schlenk test tubes, add 0.2 mmol (2-methylphenyl) (2-pyridyl) ketone, 2 mmol sodium formate, seal the test tube, and replace the gas with nitrogen for 3 times , add 1 mL DMSO / HO by syringe 2 O (1:1) mixed solvent, reacted at 50°C for 24 hours. After the reaction was completed, it was extracted 3 times with ethyl acetate, combined and concentrated to dryness, and analyzed by nuclear magnetic resonance 1 The reaction conversion was determined by HNMR, and the enantiomeric excess ee value of the product (2-methylphenyl)(2-pyridyl)methanol was determined by HPLC. The results are shown in Table 1. HPLC separation conditions: chiral column Daicel AD-H column, mobile phase: n-hexane / isopropanol=95:5 (volume ratio), flow rate: 1.0 ml / min, wavelength: 254 nm, column temperature: 30 degrees Celsius, t 1 = 13.70 m...

Embodiment 2

[0033] Example 2: Asymmetric synthesis of (2-methylphenyl)(2-pyridyl)methanol in different solvents

[0034] Add 0.01 mmol of catalyst A to a 10 ml Schlenk test tube, add 0.2 mmol (2-methylphenyl) (2-pyridyl) ketone, 2 mmol sodium formate, seal the test tube, replace the gas with nitrogen for 3 times, and add it with a syringe 1 ml of solvent was reacted at 50°C for 24 hours. After the reaction was completed, it was extracted 3 times with ethyl acetate, combined and concentrated to dryness, and analyzed by nuclear magnetic resonance 1 The reaction conversion was determined by H NMR, and the enantiomeric excess ee value of the product (2-methylphenyl)(2-pyridyl)methanol was determined by HPLC. The results are shown in Table 2.

[0035] Table 2 Catalyst A-I catalyzes the asymmetric synthesis of (2-methylphenyl) (2-pyridyl) methanol

[0036]

Embodiment 3

[0037] Embodiment 3: Taking formic acid / triethylamine as the asymmetric synthesis of hydrogen source (2-methylphenyl)(2-pyridyl)methanol

[0038] 0.01mmol catalyst A is added respectively in the Schlenk test tube of 10 milliliters, adds 0.2mmol (2-methylphenyl) (2-pyridyl) ketone, 1 milliliter of formic acid / triethylamine (molar ratio 1.1 / 1), Seal the test tube, replace the gas with nitrogen three times, and react at 50°C for 24 hours. After the reaction was completed, water was added, extracted 3 times with ethyl acetate, combined and concentrated to dryness, and analyzed by nuclear magnetic resonance 1 The reaction conversion rate was 63% as measured by HNMR, and the enantiomeric excess ee value of the product (2-methylphenyl)(2-pyridyl)methanol as determined by HPLC was 93%.

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Abstract

The invention relates to optical activity di(heteto)aryl methanol and an asymmetric synthesis method thereof. The method comprises the following steps: taking mono-sulfonyl chiral diamine and a complex of metals ruthenium, rhodium and iridium as catalysts, taking sodium formate or formic acid / triethylamine or isopropanol as a hydrogen source, carrying out an asymmetric transfer hydrogenation reaction of di(heteto)aryl ketone first, thereby obtaining the optical activity di(heteto)aryl methanol. The method is mild in reaction conditions, easy and convenient to operate, readily available in raw materials, wide in substrate application range and high in enantioselectivity and has important application prospects in the aspects of synthesis of antihistamine chiral drugs such as diphenhydramine, methyldiphenhydramine, carbinoxamine and bepotastine.

Description

technical field [0001] The invention belongs to the technical field of asymmetric catalysis, and in particular relates to a catalytic asymmetric synthesis method of an optically active di(hetero)aryl carbinol. Background technique [0002] Optically active di(hetero)arylmethanols are synthetic intermediates of many natural products, drugs, pesticides, bioactive substances, and chiral ligands. For example, antihistamines diphenhydramine, tolufenhydramine, carbinoxamine, bepotastine, etc. (Chem. Rev. 2006, 106, 2734-2793; Pharmacologist 1959, 1, 60-78). At present, the methods for synthesizing optically active di(hetero)arylmethanols can be divided into three categories: (1) Asymmetric 1,2-addition reaction of aromatic organometallic reagents and heteroaromatic aldehydes (J.Am.Chem.Soc. 2009,131,12483-12493); (2) biocatalyzed asymmetric reduction of di(hetero)aryl ketones (Org.Lett.2007,9,335–338); (3) chemically catalyzed bi(hetero)aryl Asymmetric reduction of methyl ketone...

Claims

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Application Information

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IPC IPC(8): C07D213/30C07D215/14C07D217/16C07D241/42C07C29/143C07C33/20C07B53/00
CPCC07D213/30C07B53/00C07B2200/07C07C29/143C07C217/10C07D215/14C07D217/18C07D241/42C07C33/24
Inventor 周海峰王百贵刘祈星陆国仁
Owner CHINA THREE GORGES UNIV
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