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Optically pure alpha-difluoromethylamine and method of highly stereo-seective preparation

A difluoromethylamine, optical technology, applied in the field of preparation of high stereoselectivity, can solve the problems that have not been reported, and achieve the effect of short reaction time, high yield and easy separation

Inactive Publication Date: 2006-01-25
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, using difluoromethylphenyl sulfone (PhSO 2 CF 2 H) The preparation of α-difluoromethylamine has never been reported

Method used

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  • Optically pure alpha-difluoromethylamine and method of highly stereo-seective preparation
  • Optically pure alpha-difluoromethylamine and method of highly stereo-seective preparation
  • Optically pure alpha-difluoromethylamine and method of highly stereo-seective preparation

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Typical preparation methods: in ether, toluene, dichloromethane, acetonitrile or tetrahydrofuran organic solvents. 2 mmol of phenyldifluoromethyl sulfone and 2 mmol of imine 2a were placed in the reaction flask. Under a dry ice-acetone bath, 2.2 mmol LHMDS was added. Stirring at this temperature for 30 min, the temperature was slowly raised to room temperature, quenched with saturated brine, and extracted with ethyl acetate (20 ml). After drying with anhydrous magnesium sulfate and spin-drying the solvent, the pure product 3a (763 mg) was obtained. Yield 95%. The characterization data of compound 3a are as follows: white solid, melting point 144-146°C; optical rotation [α] D 25 =-27.4 (c=0.8, CHCl 3). Infrared spectrum (coating method): 3066, 2962, 1584, 1449, 1349, 1158, 1087cm -1 . NMR Spectrum: 1 H NMR: δ7.89(d, J=7.5Hz, 2H), 7.70-7.75(m, 1H), 7.60(t, J=7.5Hz, 2H), 7.37-7.44(m, 5H), 5.24-5.36 (m, 1H), 4.04(d, J=7.8Hz, 1H), 1.29(s, 9H). 19 F NMR: δ-102.51 (dd...

Embodiment 2

[0036] Preparation method: 2mmol phenyl difluoromethyl sulfone and 2mmol imine 2b were placed in a reaction flask. Under a dry ice-acetone bath, 2.2 mmol LHMDS was added. Stirring at this temperature for 30 min, the temperature was slowly raised to room temperature, quenched with saturated brine, and extracted with ethyl acetate (20 ml). After drying with anhydrous magnesium sulfate and spinning to dry the solvent, the pure product 3 was obtained with a yield of 96%. The characterization data of compound 3b are as follows: white solid, melting point 108-110°C. Optical rotation [α] D 25 =-20.7 (c=0.7, CHCl 3 ). Infrared spectrum (coating method): 2961, 1612, 1585, 1516, 1158cm -1 . NMR Spectrum: 1 H NMR: δ7.88(d, J=7.5Hz, 2H), 7.68-7.73(m, 1H), 7.55(t, J=7.5Hz, 2H), 7.35(d, J=8.7Hz, 2H), 6.88(d, J=8.7Hz, 2H), 5.18-5.29(m, 1H), 3.95(d, J=8.4Hz, 1H), 3.79(s, 3H), 1.27(s, 9H). 19 FNMR: δ-102.84 (dd, J=236.3, 11.0Hz, 1F), -108.10 (dd, J=236.3, 15.8Hz, 1F). 13 C NMR: δ160.44...

Embodiment 3

[0039] The preparation method is the same as in Examples 1 and 2. The characterization data of compound 3c are as follows: white solid. Mp135-137°C. Optical rotation [α] D 25 =-17.8 (c=0.6, CHCl 3 ). Infrared spectrum (film): 2962, 1584, 1494, 1448, 1349, 1158cm -1 . NMR Spectrum: 1 H NMR: δ7.90(d, J=7.8Hz, 2H), 7.74(t, J=7.5Hz, 1H), 7.59(t, J=7.8Hz, 2H), 7.34-7.41(m, 4H), 5.22-5.34(m, 1H), 4.06(d, J=8.7Hz, 1H), 1.29(s, 9H). 19 F NMR: δ-102.49 (dd, J=238.0, 9.6Hz, 1F), -108.88 (dd, J=238.0, 18.0Hz, 1F). 13 C NMR: δ135.68, 135.39, 133.08, 131.74, 130.40, 130.07, 129.27, 129.06, 120.71 (t, J=292.5Hz), 60.12 (dd, J=24.2, 19.7Hz), 57.42, 22.29. Mass Spectrum: ( ESI, m / z): 436 (M + +1). Elemental analysis: theoretical value C 18 h 20 CIF 2 NO 3 S 2 : C, 49.59; H, 4.62; N, 3.21; Experimental values: C, 49.57; H, 4.72; N, 3.04.

[0040] The characterization data of compound 4c are as follows: white solid. Optical rotation: [α] D 25 =24.9 (c=0.5, CH 3 OH). Infrared sp...

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Abstract

The invention provides a process for preparing optical purity alpha-difluoro methyl amine and its derivative with high stereo-selectivity and its use, the compounds have a structural formula I, wherein R is C1-12 alkyl, C4-12 aryl, C1-C6 alkoxy aryl, halogenated aryl, furyl, the aryl can be phenyl, naphthyl, R1 is H or SO2Ph, R2 is H or formula II, III or IV. The preparing process has the advantages of low cost and good repeatability, the optical purity of the end product can reach an ee value of over 99%.

Description

technical field [0001] The invention relates to an optically pure α-difluoromethylamine and its derivatives, and a preparation method thereof with high stereoselectivity. The chiral compound is a potential drug synthesis building block, and the method of the invention is a preparation method with high stereoselectivity. Background technique [0002] Fluorinated amines are very important building blocks in drug synthesis. Since difluoromethyl (CF 2 H) can be regarded as the isoelectric and isopolar body of the methylene hydroxyl group (-CH2OH), and can also act as a lipophilic hydrogen bond donor, so α-difluoromethylamine (1) has received extensive attention focus on. [0003] [0004] (R, R' = alkyl, aryl, H, etc) [0005] Although □-difluoromethylamine is expected to have important application prospects in medicine and life sciences, there are few methods for preparing □-difluoromethylamine. In particular, there is no report on the efficient synthesis of optically p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/52C07C209/00C07C209/68C07C233/66
Inventor 胡金波李亚
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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