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A kind of preparation method and application of 2r/2s-trifluoromethylmorpholine and its hydrochloride

A technology of hydrochloride and triethylamine, which is applied in the field of synthesis of pharmaceutical intermediates, can solve problems such as unsuitable for large-scale preparation, difficult separation and purification in ordinary organic synthesis laboratories, and high equipment requirements

Active Publication Date: 2020-07-03
PHARMABLOCK SCIENCES (NANJING) INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The fourth step of this route needs to use Chiralcel OJ 20μm chiral column is used for SFC chiral resolution, and two products with absolute configuration are separated. Simple column chromatography or recrystallization separation cannot obtain the intermediate product with the required absolute configuration. This condition requires very high equipment , it is difficult to achieve separation and purification in ordinary organic synthesis laboratories, and it is not suitable for large-scale preparation

Method used

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  • A kind of preparation method and application of 2r/2s-trifluoromethylmorpholine and its hydrochloride
  • A kind of preparation method and application of 2r/2s-trifluoromethylmorpholine and its hydrochloride
  • A kind of preparation method and application of 2r/2s-trifluoromethylmorpholine and its hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036]

[0037] Preparation of compound IV:

[0038] Under a nitrogen atmosphere, compound III (648.3g, 5.35mol, 1.0e.q.) was added to a 5L four-necked flask, stirred at room temperature for 10min, compound II (600.0g, 5.35mol, 1.0e.q.) was added dropwise, and the temperature was controlled at 10-15°C. After dripping, reacting at room temperature for 1 hour, a large amount of solids precipitated, standing for 12 hours, nuclear magnetic detection of raw materials reacted, adding n-hexane under stirring to make a slurry, filtering, and drying the filter cake to obtain 920.9g of compound IV as a white solid, yield: 73.8%. 1 H-NMR (400MHz, CDCl 3 ): 7.46 to 7.26 (m, 5H), 3.99 to 3.76 (m, 2H), 2.91 to 2.70 (m, 2H), 1.43 to 1.41 (d, 3H).

[0039] Preparation of compound V-1:

[0040] Under nitrogen atmosphere, add compound IV (920.0g, 3.94mol, 1.0eq) into a 20L four-neck flask, add DCM 7500mL, add TEA (398.65g, 3.94mol, 1.0eq) at room temperature while stirring, and control the temperature...

Embodiment 2

[0046]

[0047] Preparation of compound IV:

[0048] Under nitrogen atmosphere, compound III (108.0g, 0.89mol, 1.0e.q.) was added to a 1L four-neck flask, stirred at room temperature for 10min, compound II (119.8g, 1.07mol, 1.2e.q.) was added dropwise, and the temperature was controlled at 25-35°C. After dripping, the reaction was stirred at room temperature for 1.5 hours, a large amount of solids precipitated, and the reaction was allowed to stand for 12 hours. After the reaction of the raw materials was detected by nuclear magnetic field, the reaction was completed by adding n-hexane while stirring, filtered, and the filter cake was dried to obtain 180.4g of compound IV as a white solid. Yield: 86.9 %. 1 H-NMR (400MHz, CDCl 3 ): 7.46 to 7.26 (m, 5H), 3.99 to 3.76 (m, 2H), 2.91 to 2.70 (m, 2H), 1.43 to 1.41 (d, 3H).

[0049] Preparation of compound V-1:

[0050] Under nitrogen atmosphere, add compound IV (100g, 0.429mol, 1.0eq) into a 2L four-neck flask, add 500mL DCM, add triethyl...

Embodiment 3

[0058]

[0059] Preparation of compound IV:

[0060] Under a nitrogen atmosphere, compound III (300.1g, 2.48mol, 1.0e.q.) was added to a 5L four-neck flask, stirred for 10min, compound II (554.8g, 4.95mol, 2.0e.q.) was added dropwise, and the temperature was controlled at 10°C. After dripping, the reaction was stirred at 40°C for 5 hours, a large amount of solids precipitated, and the reaction was allowed to stand for 16 hours. After the reaction of the raw materials was detected by nuclear magnetic field, the reaction was completed by adding n-hexane under stirring, filtered, and the filter cake was dried to obtain 484.7g of compound IV as a white solid. Yield: 83.8 %. 1 H-NMR (400MHz, CDCl 3 ): 7.46 to 7.26 (m, 5H), 3.99 to 3.76 (m, 2H), 2.91 to 2.70 (m, 2H), 1.43 to 1.41 (d, 3H).

[0061] Preparation of compound V-2:

[0062] Under nitrogen atmosphere, add compound IV (400g, 1.72mol, 1.0eq) into a 10L four-neck flask, add 4L of DCM, add triethylamine (520.6g, 5.15mol, 3.0eq) at r...

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Abstract

The invention discloses a preparation method and an application of 2R / 2S-trifluoromethyl morpholine and hydrochloride thereof. The preparation method includes the steps: taking 1, 1, 1-trifluoro-2, 3-epoxypropane (compound II) as a raw material and performing reaction with (S)-(-)-alpha-methylbenzylamine (compound III) to generate a compound IV; performing condensation reaction on the compound IVand acyl halide to generate a compound V; performing ring closure on the compound V under alkaline conditions and performing column chromatography isolation to obtain two diastereomeric isomer compounds VI and VI'; selectively reducing carbonyl of the compounds VI and VI' to obtain compounds VII and VII'; finally, deaminizing protecting groups to prepare the 2R / 2S-trifluoromethyl morpholine and the hydrochloride (compound I and compound I').

Description

Technical field [0001] The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method and application of 2R / 2S-trifluoromethylmorpholine and its hydrochloride. Background technique [0002] Morpholine molecular building blocks are an important class of six-membered nitrogen and oxygen heterocyclic compounds. With their unique structure, they play an important role in drug research and development. Drugs containing morpholine fragments approved by the US FDA are currently on the market. There are as many as 19 kinds. The introduction of trifluoromethyl into the morpholine fragment can significantly improve the physical, chemical and pharmacological properties of the drug. Chiral-2-trifluoromethylmorpholine and its hydrochloride are a kind of morpholine molecular building block compounds, which is an important intermediate in pharmaceutical synthesis, and can be used to prepare pyrazolopyrimidine compounds as AMPA receptor m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D265/30
CPCC07B2200/07C07D265/30Y02P20/55
Inventor 李继龙祁磊
Owner PHARMABLOCK SCIENCES (NANJING) INC