Unlock instant, AI-driven research and patent intelligence for your innovation.

Synthetic method of difluoromethyl substituted oxane-2-one

A synthesis method and technology of difluoromethyl, applied in the direction of organic chemistry, etc., can solve the problems of unstable volatility of compound 2, difficult to control, and long reaction period, and achieve the increase of atom economy, convenient monitoring of central control, shortening Synthesis Cycle Effects

Active Publication Date: 2019-01-25
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD
View PDF9 Cites 1 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The inventors found that compound 2 is unstable and highly volatile, and can only be stored stably for 4-5 days under the condition of -20°C filled with argon; and the purity of compound 2 has a great influence on the fluorination reaction. The inventors found that when the compound 2 When the purity is less than 80%, the preparation of compound 3 by NMR monitoring of the fluorination reaction is very messy, and the yield of compound 3 obtained after purification is less than 30%. larger
Compound 3 cannot be detected by thin-layer chromatography and liquid chromatography, which makes the fluorination reaction difficult to control
In addition, when preparing compound 7 from compound 6, it is necessary to use highly dangerous sodium azide, and the introduced azide group needs to be hydrogenated and reduced to the amino group using an expensive palladium catalyst.
In summary, the existing methods for preparing 4,4-(difluoromethyl)oxazolidin-2-one have high risk of reaction, long reaction cycle, difficult central control, difficult storage, high cost, and atom economy Poor performance and other problems, not suitable for industrial production

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthetic method of difluoromethyl substituted oxane-2-one
  • Synthetic method of difluoromethyl substituted oxane-2-one
  • Synthetic method of difluoromethyl substituted oxane-2-one

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0022] Raw material preparation

[0023] 1. Preparation of (S)-2-oxo-3-trityloxazolidine-4-carbaldehyde

[0024] The preparation of step (1), N-trityl-L-serine methyl ester

[0025] Disperse L-serine methyl ester hydrochloride (300g, 1.93mol) in dichloromethane (2.5L), add triethylamine (391g, 3.86mol), control the internal temperature between 0 and 10°C, and add three Dichloromethane solution (1.5L) of phenylchloromethane (541g, 1.93mol) was added dropwise and then raised to room temperature to react overnight. Slowly pour the reaction solution into saturated brine (2L), stir and separate the layers, separate the organic phase, add DCM (2×1L) to the aqueous phase for extraction, combine the organic phases and wash with saturated sodium chloride (2L). Dry over sodium sulfate, concentrate, and suck to dryness to obtain white solid N-trityl-L-serine methyl ester (590 g, yield 84.5%).

[0026] Step (2), the preparation of (S)-2-oxo-3-trityl oxazolidine-4-carboxylic acid methyl...

Embodiment 1

[0036] Step (1): Preparation of (S)-4-(difluoromethyl)-3-trityloxazolidin-2-one

[0037]

[0038] At room temperature, (S)-2-oxo-3-tritylazolidine-4-carbaldehyde (500g, 1.27mol) was dissolved in DCM (10L), and under the protection of an inert gas, the reaction solution was cooled and controlled The reaction temperature does not exceed 10°C, slowly inject DAST (253ml, 1.9mol), after the addition is complete, rise to 30-35°C for reaction, and monitor the reaction by color development of phosphomolybdic acid on a silica gel plate. After the reaction was completed, the reaction solution was slowly poured into ice-saturated aqueous sodium bicarbonate solution (8L), the drop rate was controlled, and the internal temperature was controlled to be less than 40°C. After the quenching was complete, the mixture was stirred and layered, and dichloromethane (3L× 3) Extraction, combined organic phases, washed with saturated sodium chloride (2.5×2L), dried over anhydrous sodium sulfate, co...

Embodiment 2

[0043] Step (1): Preparation of (R)-4-(difluoromethyl)-3-trityloxazolidin-2-one

[0044]

[0045] At room temperature, (R)-2-oxo-3-tritylazolidine-4-carbaldehyde (2g, 5.59mmol) was dissolved in toluene (20ml), under the protection of an inert gas, the reaction liquid was cooled, controlled The reaction temperature did not exceed 10°C, and BAST (2.5ml, 13.98mmol) was slowly injected. After the addition, it was raised to 35°C for reaction, and the reaction was monitored by phosphomolybdic acid color development on a silica gel plate. After the reaction was completed, a white solid (R)-4-(difluoromethyl)-3-trityloxazolidin-2-one (1.91g, yield 90% , ESI / MS: m / z=381 (M+H) + ).

[0046] Step (2): Preparation of (R)-4-(difluoromethyl)oxazolidin-2-one

[0047]

[0048] At room temperature, (R)-4-(difluoromethyl)-3-trityloxazolidin-2-one (1.9g, 5.00mmol) was dissolved in dichloromethane (20ml), and hydrochloric acid was added Gas, continue to stir until the reaction is comple...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to a synthetic method of difluoromethyl substituted oxane-2-one. The synthetic method uses compound III as a raw material to prepare compound I via fluorination and deprotectiontwo-step reaction; the synthetic method is simple to perform, the reaction is easy to monitor, the synthetic cycle is short, the yield is high, the risk is low, the cost is low, and the synthetic method is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of difluoromethyl-substituted oxan-2-one, which belongs to the field of organic synthesis. Background technique [0002] 4,4-(Difluoromethyl)oxazolidin-2-one as an intermediate for the preparation of benzoxazepin oxazolidinone compounds with phosphoinositide-3 kinase modulating activity or function, disclosed in WO2017001645A1 and WO2017001658A1 The synthesis method of 4,4-(difluoromethyl)oxazolidin-2-one, as shown in the following formula, needs to use compound 1 as a raw material to go through oxidation, fluorination, deprotection, two-step selective protection, and stacking Prepared by 9 steps of sodium nitride substitution, reduction, deprotection and ring formation. The inventors found that compound 2 is unstable and highly volatile, and can only be stored stably for 4-5 days under the condition of -20°C filled with argon; and the purity of compound 2 has a great influence on the fluorination reaction. ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D263/20C07D265/10
CPCC07D263/20C07D265/10
Inventor 郑保富付小旦张宏伟周治国高强
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD