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Cyclopropane derivatives, and preparation method and application thereof

An alkyl and reaction technology, applied in the field of cyclopropane derivatives and their preparation, can solve the problem of low stereoselectivity, no high stereoselectivity type synthesis of optically pure sulfoximine-substituted cyclopropane compounds, poor substrate universality, etc. question

Inactive Publication Date: 2014-10-29
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the above method for synthesizing sulfoximine to replace cyclopropane is cumbersome, has poor substrate universality, and low stereoselectivity.
In particular, there is no report on the synthesis of optically pure sulfoximine-substituted cyclopropane compounds with high stereoselectivity

Method used

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  • Cyclopropane derivatives, and preparation method and application thereof
  • Cyclopropane derivatives, and preparation method and application thereof
  • Cyclopropane derivatives, and preparation method and application thereof

Examples

Experimental program
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preparation example Construction

[0119] The preparation method of the compound of formula I provided by the invention comprises steps:

[0120] (a3) reacting the compound of formula b with an oxidation reagent to obtain the compound of formula II;

[0121]

[0122] (b) reacting a compound of formula III with a compound of formula II in an organic solvent and in the presence of a base to form the compound of formula I,

[0123]

[0124] In various forms, R 1 , R 2 , Ra, Rb, R 4 is defined as above;

[0125] In another preferred embodiment, in the step (b), the compound of formula III and the compound of formula II are reacted at -78°C to 60°C (preferably, -78°C to 25°C) for 0.5-72 hours (preferably 0.5-5 hours), to obtain the compound of formula I.

[0126] In another preference, in the step (b), the organic solvent is selected from: tetrahydrofuran THF, toluene PhCH 3 , dichloromethane CH 2 Cl 2 , Hexamethyl triamine phosphate HMPA, ethylene glycol dimethyl ether DME, ether Et 2 O, dimethylfo...

Embodiment 1

[0219] Example 1 (1S, 2S, 3S)-2-phenyl-3-fluoro-N-methoxy-N-methyl-cyclopropylcarbonamide (1S, 2S, 3S)-2-phenyl-3- Preparation of fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide

[0220]

[0221] N 2 Under protection, [(R)-N-p-toluenesulfonyl] monofluoromethylphenyl sulfoximine (196mg, 0.6mmol), nitrogen-methyl-nitrogen-methoxy Cinnamamide (76mg, 0.4mmol) and 4mL of dry THF were cooled to -78°C, and LHMDS (lithium hexamethylsilylamide 0.52mmol) was slowly added dropwise, stirred for 20min, the cooling bath was removed, and the temperature was naturally raised to room temperature at 25 Stir at ℃ for 3 h, add 2 mL of water to quench the reaction, extract with anhydrous ether (15 mL×3), combine the organic phases, wash with saturated brine (5 mL), and dry over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product (80 mg, yield 90%) was obtained by flash column chromatography (5:1).

[0222] colorless liquid. Op...

Embodiment 2

[0224] Example 2 (1S, 2S, 3S)-2-(3-chlorophenyl)-3-fluoro-N-methoxy-N-methyl-cyclopropylcarbonamide (1S, 2S, 3S)-2 - Preparation of (3-chlorophenyl)-3-fluoro-N-methoxy-N-methyl-cyclopropanecarboxamide

[0225] N 2 Under protection, [(R)-N-p-toluenesulfonyl] monofluoromethylphenyl sulfoximine (196mg, 0.6mmol) was added to a 25mL Schlenk reaction tube, (90mg, 0.4mmol) and 4mL dry THF, cooled to -78°C, slowly added LHMDS (0.52mmol) dropwise, stirred for 20min, removed the cooling bath, naturally raised to room temperature 25°C and stirred for 3h, added 5mL of water to quench the reaction, Extract with anhydrous ether (15 mL×3), combine the organic phases, wash with saturated brine (5 mL), and dry over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation under reduced pressure, and the product was obtained by flash column chromatography (5:1) (91 mg, yield 88%).

[0226] White solid. Melting point. 51–52°C. [α] D 28 =+110.0°(c=1.0,CH 2 Cl 2 ). The ena...

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Abstract

The invention discloses a kind of cyclopropane derivatives, and a preparation method and application thereof. Concretely, the cyclopropane derivatives have the structural formula X3 shown in the specification. In the formula, Ra, R1, R2, Rb and R4 are defined in the specification. The invention also provides a simple effective method for preparing the cyclopropane derivatives, raw material toxicity is low, and the obtained products are high in purity. The method is capable of preparing racemic compounds, and also is capable of preparing non-racemic compounds. The cyclopropane derivatives are further applicable to synthesize other cyclopropane derivatives.

Description

technical field [0001] The invention relates to cyclopropane compounds, in particular to a cyclopropane derivative and its preparation method and application. Background technique [0002] Due to its special bonding, the cyclopropane structure is an important structural unit of many bioactive molecules. Many marketed drug molecules have a cyclopropane structure, such as Odanacatib (cathepsin K inhibitor), Singulair (anti-asthma drug) and Ciprofloxacin (broad-spectrum antibiotic) (H.W.Liu, C.T.Walsh, Biochemistry of the CyclopropylGroup.In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; Wiley: New York, 1987, p959; J. Salaün, Top. Curr. Chem. 2000, 207, 1. et al.). [0003] Sulfoximine compounds are a very important class of biologically active substances. For example, MSO is a selective acceptor of gamma-glutamylcysteine ​​synthetase, which has a catalytic effect on the rate-determining step of biosynthetic glutathione (Griffith, O.W.; Meister, A.J.Biol.Chem.19...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/57C07C231/14C07D333/24C07C49/84C07C45/68C07C381/10
Inventor 胡金波沈晓
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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