Preparation method of fluorine-containing polysubstituted pyrrolidine derivative

A technology of fluorine-containing iodoalkane and pyrrolidine, which is applied in the field of preparation of fluorine-containing multi-substituted pyrrolidine derivatives, can solve the problems of many synthesis steps, high cost, and low yield, and achieve simple reaction operation and mild reaction conditions Effect

Active Publication Date: 2018-01-05
JIANGNAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The traditional multi-substituted pyrrolidine synthesis method has problems such as many synthesis steps, low yield and high cost

Method used

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  • Preparation method of fluorine-containing polysubstituted pyrrolidine derivative
  • Preparation method of fluorine-containing polysubstituted pyrrolidine derivative
  • Preparation method of fluorine-containing polysubstituted pyrrolidine derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The preparation method of (E)-4-benzylidene-3-methyl-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-1-tosylpyrrolidine, its synthetic route is as follows:

[0022]

[0023] Embodiment one:

[0024] (E)-4-benzylidene-3-methyl-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-1-tosylpyrrolidine is prepared according to the following steps:

[0025] In an inert gas environment, add p-toluenesulfonamide enyne derivative 1a (1.0mmol, 339mg), perfluoroiodobutane (2.0mmol, 692mg), CuBr 2 (20%, 45mg), zinc powder (3.0mmol, 192mg), acetic acid (3.0mmol, 180mg), then add 10mL of dichloromethane, and react the reaction system in 40-50°C oil bath for 24 hours; The evaporator was rotated to remove the solvent, and the crude product was subjected to column chromatography to obtain 386 mg of fluorine-containing pyrrolidine compound, with a yield of 69%. The obtained compound has a melting point of 112-113.5°C, NMR 1 H NMR (400MHz, CDCl 3 ):7.74(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),7.25-7.27(m,3H),7.0...

Embodiment 2

[0027] The preparation method of (E)-4-benzylidene-3-(2,2,3,3,4,4,4-heptafluorobutyl)-3-methyl-1-tosylpyrrolidine, its synthetic route is as follows:

[0028]

[0029] Embodiment two:

[0030] The preparation method of (E)-4-benzylidene-3-(2,2,3,3,4,4,4-heptafluorobutyl)-3-methyl-1-tosylpyrrolidine is carried out as follows:

[0031] In an inert gas environment, add p-toluenesulfonamide enyne derivative 1a (1.0mmol, 339mg), perfluoroiodopropane (2.0mmol, 592mg), CuBr 2 (20%, 45mg), zinc powder (3.0mmol, 192mg), acetic acid (3.0mmol, 180mg), then add 10mL of dichloromethane, and react the reaction system in 40-50°C oil bath for 24 hours; The evaporator was rotated to remove the solvent, and the crude product was subjected to column chromatography to obtain 356 mg of fluorine-containing pyrrolidine compound, with a yield of 70%. The obtained compound has a melting point of 94-95°C, NMR 1 H NMR (400MHz, CDCl 3 ):7.74(d,J=8.0Hz,2H),2.37(d,J=8.0Hz,2H),7.26-7.28(m,3H),7.08(d,...

Embodiment 3

[0033] (E)-3-methyl-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-4-(thiophen-2-ylmethylene)-1-tos ylpyrrolidine preparation method, Its synthetic route is as follows:

[0034]

[0035] Embodiment three:

[0036] (E)-3-methyl-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-4-(thiophen-2-ylmethylene)-1-tos ylpyrrolidine preparation method, Proceed as follows:

[0037] In an inert gas environment, add p-toluenesulfonamide enyne derivative 2a (1.0mmol, 345mg), perfluoroiodobutane (2.0mmol, 692mg), CuBr 2 (20%, 45mg), zinc powder (3.0mmol, 192mg), acetic acid (3.0mmol, 180mg), then add 10mL of dichloromethane, and react the reaction system in 40-50°C oil bath for 24 hours; The evaporator was rotated to remove the solvent, and the crude product was subjected to column chromatography to obtain 424 mg of fluorine-containing pyrrolidine compound with a yield of 75%. The resulting compound has a melting point of 100-102°C, and NMR 1 H NMR (400MHz, CDCl 3 ):7.73(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),...

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Abstract

The invention discloses a preparation method of a fluorine-containing polysubstituted pyrrolidine derivative. The compound has the structure shown in the formula (I). The preparation method includes the following steps that in an inert gas environment, p-toluenesulfonamide-substitued 1,6-eneyne 1, fluorine-containing alkyl iodides, a copper catalyst, a reduction agent, an activating agent and a solvent are added in a reaction vessel, and reaction is conducted for 12-24 hours at 40-50 DEG C; after reaction is over, a rotary evaporator is used for evaporating the solvent through rotation, and acrude product is subjected to recrystallization or column chromatography to obtain the pyrrolidine derivative 2. The formula can be seen in the description.

Description

technical field [0001] The invention relates to a preparation method of a drug molecule or an intermediate, in particular to a preparation method of a fluorine-containing polysubstituted pyrrolidine derivative. Background technique [0002] Pyrrolidine derivatives are widely used in biology, pesticides, medicine and other research fields, and are key intermediates for the synthesis of quinolone antibacterial drugs, blood pressure lowering drugs, hypoglycemic drugs and antitumor drugs. The synthesis of its skeleton has always been one of the hotspots in drug synthesis and organic synthesis. The traditional synthesis method of multi-substituted pyrrolidine has problems such as many synthesis steps, low yield and high cost. Introducing fluorine-containing cutting blocks in drug molecules can significantly improve the fat solubility, metabolic stability and biopharmaceutical efficiency of organic compound molecules (Biomedicinal Aspects of Fluorine Chemistry; R.Filler, Y.Kobaya...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D409/06C07D207/48
Inventor 夏晓峰王大伟
Owner JIANGNAN UNIV
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