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(S)-Alpha, Alpha-fluorine-containing diaryl-2-pyrrolidine methanol derivative as well as preparation and applications thereof

A technology of pyrrolidine methanol and derivatives, which is applied in the preparation of organic compounds, carboxylic acid ester preparation, catalyst activation/preparation, etc., and can solve problems such as harsh reaction conditions, expensive catalysts, and environmental pollution

Active Publication Date: 2012-11-14
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, asymmetric synthesis plays a very important role, and the key in the asymmetric synthesis process lies in chiral catalysts. So far, the research on chiral transition metal catalysts has been the most in-depth, especially in industrial applications. The most extensive and successful, but chiral transition metal catalysts also have some significant disadvantages, such as expensive catalysts, harsh reaction conditions, environmental pollution, and difficult recovery of catalysts, etc.

Method used

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  • (S)-Alpha, Alpha-fluorine-containing diaryl-2-pyrrolidine methanol derivative as well as preparation and applications thereof
  • (S)-Alpha, Alpha-fluorine-containing diaryl-2-pyrrolidine methanol derivative as well as preparation and applications thereof
  • (S)-Alpha, Alpha-fluorine-containing diaryl-2-pyrrolidine methanol derivative as well as preparation and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Synthesis of Optically Pure (S)-α,α-bis(3,4,5-fluorobenzene)-trimethylsilyl ether 2-pyrrolidine catalyst

[0053] 1. Synthesis of L-proline methyl ester (b)

[0054]

[0055] Add 40mmol (46g) of L-proline (a) and 30mL of methanol to the reaction flask, cool in an ice bath, slowly add 100mmol (118g) of thionyl chloride dropwise while stirring, after dropping, heat and reflux for 6 hours, reduce The solvent was distilled off under pressure to obtain a light yellow oily liquid, which was the crude product (b) of L-proline methyl ester, which was directly used in the next reaction.

[0056] 2. Synthesis of (S)-N-benzyl-2-pyrrolidinecarboxylic acid methyl ester (c)

[0057]

[0058] The crude product (b) from the previous step was dissolved in 40 mL of methanol, 78 mmol (82.6 g) of sodium carbonate was added, 46 mmol (58 g) of benzyl chloride was added dropwise under reflux, and reflux was continued for 4 hours after the dropwise addition. After the reaction was comp...

Embodiment 2

[0072] Other operations are the same as in Example 1, except that in step 4, the protic solvent is changed to isopropanol, and the reaction conditions are as follows.

[0073] Preparation of (S)-α,α-(3,4,5-trifluoro)diphenyl-2-pyrrolidinemethanol (e)

[0074] Take 10 mmol of compound (d) from the previous step, add 0.45 g of 10 wt% palladium carbon, 20 mL of isopropanol, and stir at room temperature under the protection of hydrogen. After reacting for 2 hours, the palladium carbon was removed by filtration, and the solvent was evaporated under reduced pressure to obtain the pure product (S)-α, α-(3,4,5-trifluoro)diphenyl-2-pyrrolidinemethanol (e) 9.3 mmol, the yield is 93%.

Embodiment 3

[0076] Other operations are the same as in Example 1, except that in step 4, the protic solvent is changed to ethanol, and the reaction conditions are as follows.

[0077] (S)--α, α-(3,4,5-trifluoro)diphenyl-2-pyrrolidinemethanol (e) preparation

[0078] Take 10 mmol of compound (d) in the previous step, add 0.45 g of 10 wt% palladium carbon, 40 mL of ethanol, and stir at room temperature under the protection of hydrogen. After reacting for 4 hours, the palladium carbon was removed by filtration, and the solvent was evaporated under reduced pressure to obtain the pure product (S)-α, α-(3,4,5-trifluoro)diphenyl-2-pyrrolidinemethanol (e) 9.6 The mmol yield was 96%.

[0079] Subsequent operations and reaction conditions were the same as in Example 1 to obtain (S)-α,α-bis(3,4,5-fluorobenzene)-trimethylsilyl ether-2-pyrrolidine with a total yield of 38.1%.

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Abstract

The invention relates to a novel chiral catalyst of an (S)-Alpha, Alpha-fluorine-containing diaryl-2-pyrrolidine methanol derivative and provides a preparation method and applications in an asymmetric reaction thereof. The preparation method comprises the following steps: adopting amino protected N-substitute-2 pyrrolidine methyl formate to react with a grignard reagent, then removing the protecting group; and then reacting with alkyl chlorosilane to prepare the (S)-Alpha, Alpha-fluorine-containing diaryl-2-pyrrolidine methanol derivative. The invention has the following beneficial effects: compared with other chiral catalysts of aryl pyrrolidine methanol derivative, the chiral catalyst of the fluorine-containing aryl pyrrolidine methanol derivative not only enhances the activity on N andimproves catalysis, but also simultaneously increases substrates and hydrogen bonds of catalysts as well as stereoselective reaction of the substrates, and broadens the application scope of the substrates.

Description

(1) Technical field [0001] The invention relates to a novel (S)-α,α-difluorine-containing aryl-2-pyrrolidine methanol derivative chiral catalyst, a preparation method thereof, and an application in an asymmetric reaction. (2) Technical background [0002] Chirality is one of the essential properties of life. Biomacromolecules necessary for life activities, such as proteins, polysaccharides, nucleic acids, and enzymes, are almost all chiral, and these macromolecules often have important physiological functions in the body. Most of the drugs currently used are small organic molecules composed of less than 50 atoms, a large part of which is chiral, and their pharmacological effects are realized through strict chiral matching and molecular recognition with macromolecules in the body. The vast majority of drugs are composed of chiral molecules, and two chiral molecules may have significantly different biological activities. Therefore, asymmetric synthesis plays a very important...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18C07D207/08C07B53/00B01J31/02B01J37/00C07C67/347C07C69/738C07C69/716C07D311/74C07D407/04C07D311/94
CPCY02P20/55
Inventor 俞传明郑飞苏为科钟为慧叶海伟
Owner ZHEJIANG UNIV OF TECH
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