Preparation method of chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound

A technology of dibutyl ketone and diphenyl, which is applied in the field of preparation of chiral 1,4-diphenyl-2-hydroxy-1,4-dibutanone compounds, can solve the enantioselective selection of substrate applicability Sex needs to be further improved and other issues

Pending Publication Date: 2021-06-18
UNIV OF SCI & TECH OF CHINA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Despite the above breakthroughs in the aldol reaction, the asymmetric Mukaiyamaaldol reaction of biscarbonyl compounds still needs to be researched and developed, and the applicability of the substrate and the enantioselectivity of the reaction need to be further improved.

Method used

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  • Preparation method of chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound
  • Preparation method of chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound
  • Preparation method of chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound

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[0095]Therefore, the present invention also provides a simple and environmentally friendly preparation method of 1,4-diphenyl-2-hydroxyl-1,4-dibutanone compounds, the method comprising: using the chiral Metal complexes or chiral metal complexes prepared according to the present invention are mixed with enol silyl ethers and phenylglyoxal monohydrate or substituted phenylglyoxal monohydrate to obtain 1,4-di Phenyl-2-hydroxyl-1,4-dibutanone compounds, the R of the enol silyl ether 1 It is a phenyl or furan structure, the substituent R in the substituted phenylglyoxal monohydrate 2 One or more selected from hydrogen atom, halogen, methyl, methoxy, nitro and trifluoromethyl, the substituent R 2 In the ortho, meta or para position of the benzene ring.

[0096]

[0097] The chiral metal complex described in the present invention can participate in the reaction at a concentration of 0.5-5mmol / L; the temperature of the Mukaiyama aldol reaction is -10-25°C; the time of the Mukaiya...

Embodiment 1

[0115] Preparation of proline-derived chiral ligands, taking L-proline with a protecting group to prepare chiral ligand L2 as an example;

[0116] The synthetic route is as follows:

[0117]

[0118] Add solvent tetrahydrofuran (20 mL) into a three-necked flask filled with nitrogen atmosphere, add magnesium strips (0.36 g, 15 mmol) and p-methylbromobenzene (1.3 g, 7.5 mmol), and heat with a hair dryer until the reaction is initiated. The remaining p-methylbromobenzene (1.3 g, 7.5 mmol) was added dropwise over 20 min. After the dropwise addition, continue to heat to 70°C and reflux for 2h. A tetrahydrofuran solution (20 mL) of benzyl-protected L-proline A (3.3 g, 15 mmol) was added dropwise to the reaction system, and continued to reflux at 70° C. for 7 h. The completion of the reaction was monitored by thin layer chromatography and quenched with saturated aqueous ammonium chloride. Extract with ethyl acetate, back extract with saturated brine. After drying over anhydrou...

Embodiment 2

[0122] Preparation of proline-derived chiral ligands, taking L-proline with a protecting group to prepare chiral ligand L3 as an example;

[0123] The synthetic route is as follows:

[0124]

[0125] Add solvent tetrahydrofuran (20 mL) into a three-necked flask filled with nitrogen atmosphere, add magnesium strips (0.36 g, 15 mmol) and p-methoxybromobenzene (1.4 g, 7.5 mmol), and heat with a blower until the reaction is initiated. The remaining p-methoxybromobenzene (1.4 g, 7.5 mmol) was added dropwise over 20 min. After the dropwise addition, continue to heat to 70°C and reflux for 2h. A tetrahydrofuran solution (20 mL) of benzyl-protected L-proline A (3.3 g, 15 mmol) was added dropwise to the reaction system, and continued to reflux at 70° C. for 7 h. The completion of the reaction was monitored by thin layer chromatography and quenched with saturated aqueous ammonium chloride. Extract with ethyl acetate, back extract with saturated brine. After drying over anhydrous ...

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Abstract

The invention provides a preparation method of a chiral 1, 4-diphenyl-2-hydroxyl-1, 4-dibutanone compound. The method comprises the following steps: in the presence of a chiral metal compound, mixing silyl enol ether and phenylacetaldehyde monohydrate or substituted phenylacetaldehyde monohydrate in a solvent and performing action to obtain the chiral 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound, wherein the reaction equation is as shown in the formula 1; R1 of silyl enol ether is of a phenyl or furan structure, a substituent R2 in substituted phenyl glyoxal monohydrate is selected from one or more of hydrogen atoms, halogen, methyl, methoxyl, nitryl and trifluoromethyl, and the substituent is at the ortho-position, meta-position or para-position of a benzene ring. The chiral metal compound can efficiently and highly enantioselectively catalyze the asymmetric Mukaiyama aldol reaction of the phenylacetaldehyde monohydrate compound, a new method for synthesizing the 1, 4-diphenyl-2-hydroxy-1, 4-dibutanone compound is provided, the problem that conditions are harsh in the original reaction is solved, and the chiral metal compound is more environmentally friendly.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a preparation method of chiral 1,4-diphenyl-2-hydroxyl-1,4-dibutanone compounds. Background technique [0002] Asymmetric catalytic reaction is the key method to prepare chiral substances, and asymmetric Mukaiyama aldol reaction is an important method to construct C-C bond, which has key applications in the synthesis and preparation of biomedicine and natural products. [0003] Since the discovery of the Aldol reaction, it has important applications in the construction of various important carbon skeletons, and the research on the Aldol reaction is still in-depth. In 2016, Ikemoto et al. chose glyoxylate as an electrophile to participate in the asymmetric aldol reaction, and the product structure is the key skeleton of anti-AIDS drugs (Org. Process Res. Dev., 2016, 20, 1615.). In 2020, Da's group used enzymes to catalyze the aldol reaction of glyoxylate and aldehydes to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/08C07F1/08C07F3/06C07F15/02C07D307/46C07C45/68C07C49/83C07C49/84C07C201/12C07C205/45B01J31/22C07B53/00
CPCB01J31/2217B01J2231/342B01J2531/16B01J2531/26B01J2531/842C07B53/00C07B2200/07C07C45/68C07C201/12C07D207/08C07D307/46C07F1/005C07F3/003C07F15/025C07C49/83C07C49/84C07C205/45
Inventor 汪志勇戚鸣李金东
Owner UNIV OF SCI & TECH OF CHINA
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