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Preparation method of (R)-phenyl (pyridine-2-base) methanol derivative

A technology of derivatives and pyridine, which is applied in the field of preparation of phenylcarbinol derivatives, can solve the problems of unsatisfactory industrial production, single catalytic system, and poor substrate universality, and achieve great implementation value and social and economic benefits, three-dimensional Good selectivity and easy operation

Active Publication Date: 2019-05-21
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although considerable progress has been made in the preparation of (R)-phenyl(pyridin-2-yl)methanol derivatives by asymmetric hydrogenation techniques, several important issues remain unresolved: 1) The conversion number (TON) is too low to Meet the requirements of industrial production
2) The catalytic system is single, limited to bisphosphine ligands and ruthenium or rhodium metal salts
3) The universality of the substrate is poor, and the ee value is higher only when the pyridine ring does not contain any substituents

Method used

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  • Preparation method of (R)-phenyl (pyridine-2-base) methanol derivative
  • Preparation method of (R)-phenyl (pyridine-2-base) methanol derivative
  • Preparation method of (R)-phenyl (pyridine-2-base) methanol derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Preparation of (R)-phenyl(pyridin-2-yl)methanol

[0029] 1) The chiral ligand I-1 (16.6mg, 0.025mmol), metal complex [Ir(COD)Cl] 2 (8.0 mg, 0.012 mmol) was added to a reaction flask, methanol (1.5 mL) was added under argon atmosphere, and the reaction was stirred at 25° C. for 0.5 h to prepare a catalyst.

[0030] 2) Add phenyl(pyridin-2-yl)methanone (44.0g, 0.24mol) into the autoclave, add the catalyst prepared in step 1), potassium tert-butoxide (1.34g, 12mmol), methanol (100mL) , Charge H 2 (3.0MPa), react at 40℃ for 12h. After the reaction is over, the reaction solution is concentrated under reduced pressure to recover the organic solvent, then an appropriate amount of water is added, extracted with ethyl acetate, the organic phase is dried and desolventized to obtain (R)-phenyl (Pyridin-2-yl)methanol (42.6g, 0.23mol), yield: 96%, purity 97%, ee value 94%.

Embodiment 2

[0031] Example 2: Preparation of (R)-phenyl(pyridin-2-yl)methanol

[0032] 1) The chiral ligand I-1 (16.6mg, 0.025mmol), metal complex [Ir(COD)Cl] 2 (8.0 mg, 0.012 mmol) was added to a reaction flask, methanol (1.5 mL) was added under argon atmosphere, and the reaction was stirred at 25° C. for 0.5 h to prepare a catalyst.

[0033] 2) Add phenyl(pyridin-2-yl)methanone (44.0g, 0.24mol) into the autoclave, add the catalyst prepared in step 1), lithium tert-butoxide (0.96g, 12mmol), methanol (100mL) , Charge H 2 (3.0MPa), react at 40℃ for 12h. After the reaction is over, the reaction solution is concentrated under reduced pressure to recover the organic solvent, then an appropriate amount of water is added, extracted with ethyl acetate, the organic phase is dried and desolventized to obtain (R)-phenyl (Pyridin-2-yl)methanol (43.1g, 0.23mol), yield: 97%, purity 97%, ee value 99%.

Embodiment 3

[0034] Example 3: Preparation of (R)-phenyl(pyridin-2-yl)methanol

[0035] 1) The chiral ligand I-1 (16.6mg, 0.025mmol), metal complex [Ir(COD)Cl] 2 (8.0 mg, 0.012 mmol) was added to a reaction flask, methanol (1.5 mL) was added under argon atmosphere, and the reaction was stirred at 25° C. for 0.5 h to prepare a catalyst.

[0036] 2) Add phenyl(pyridin-2-yl)methanone (44.0g, 0.24mol) into the autoclave, add the catalyst prepared in step 1), sodium carbonate (1.3g, 12mmol), methanol (100mL), and charge Enter H 2 (3.0MPa), react at 40℃ for 12h. After the reaction is over, the reaction solution is concentrated under reduced pressure to recover the organic solvent, then an appropriate amount of water is added, extracted with ethyl acetate, the organic phase is dried and desolventized to obtain (R)-phenyl (Pyridin-2-yl)methanol (40.9g, 0.22mol), yield: 92%, purity 98%, ee value 95%.

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Abstract

The invention discloses a preparation method of a (R)-phenyl (pyridine-2-base) methanol derivative. The process comprises the following steps: - adding metal M complex and chiral ligand L * to solventA for 0.5-6 hours in argon atmosphere and at 10-40 DEG C to prepare catalyst [M] / L *. The metal M in the metal M complex is any one of Ru, Rh, Ir or Pd, adding phenyl (pyridine-2-base) methyl ketonederivative, the prepared catalyst [M] / L *, solvent B into a autoclave to perform an unsymmetrical hydrogenation reaction at 0-100 DEG C and hydrogen pressure of 0.1-10.0 MPa for 2-24 hours. After the reaction, the reaction solution is reduced pressure, concentrated and recovered solvent B, adding water, extracting by ethyl acetate, and separating into organic phase and water phase. The organic phase is dried and dissolved to obtain phenyl (pyridine-2-base) methanol derivative. According to the preparation method of the (R)-phenyl (pyridine-2-base) methanol derivative, in the asymmetric hydrogenation on phenyl (pyridine-2-base) methanol derivative, the yield is high, and (R)-phenyl (pyridine-2-base) methanol derivative is produced with high enantioselectivity and an e value above 99%.

Description

Technical field [0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of (R)-phenyl (pyridin-2-yl) methanol derivatives. Background technique [0002] (R)-Phenyl(pyridin-2-yl)methanol is an important type of skeleton containing chiral alcohols, which is widely used in the synthesis of various natural products, drugs, agrochemicals, and biologically active compounds. For example, the drug (R, S)-mefloquine can effectively kill intra-erythrocyte schizonts, especially for mature trophozoites and schizonts, and is mainly used to treat chloroquine-resistant or multi-drug resistant Falciparum malaria. [0003] The asymmetric synthesis methods of (R)-phenyl(pyridin-2-yl) methanol derivatives can be divided into three categories: (1) asymmetric addition of aryl organometallic reagents and heteroaromatic aldehydes; (2) biological Catalytic technology; (3) Asymmetric catalytic hydrogenation. Among them, from the perspect...

Claims

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Application Information

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IPC IPC(8): C07D213/30C07D213/61C07F17/02B01J31/24
Inventor 钟为慧凌飞年三飞陈佳琛
Owner ZHEJIANG UNIV OF TECH
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