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A method of a catalytic asymmetric molecule internal amine synthetic sulfa

An asymmetric, palladium-catalyzed technology, applied in the direction of organic chemistry, etc., to achieve the effect of simple and practical reaction operation, complete reaction and convenient separation

Active Publication Date: 2019-06-04
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Simple alkyl or aryl amines are usually used as nitrogen nucleophiles in asymmetric reductive amination reactions, and the use of sulfonamides as nitrogen nucleophiles for reductive amination reactions to synthesize chiral sulfonamides has not been reported.

Method used

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  • A method of a catalytic asymmetric molecule internal amine synthetic sulfa
  • A method of a catalytic asymmetric molecule internal amine synthetic sulfa
  • A method of a catalytic asymmetric molecule internal amine synthetic sulfa

Examples

Experimental program
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Effect test

Embodiment 1

[0031] Embodiment 1: optimization of conditions

[0032] Drop into palladium trifluoroacetate (3mol% of substrate consumption in formula 1) and chiral phosphine ligand (S, S)-f-binaphane (3.3mol% of substrate consumption in formula 1) in reaction flask, nitrogen displacement Then 1 ml of acetone was added and stirred at room temperature for 1 hour. Concentrate in vacuo then, add 3 milliliters of trifluoroethanol under nitrogen, this solution is transferred to the reaction kettle that has put substrate 1a (51.8 mg, 0.2 mmol) and camphorsulfonic acid (100mol% of substrate consumption in formula 1) in advance , 600 psi of hydrogen was passed through, and the reaction was carried out at 50° C. for 24 hours. Slowly release hydrogen, remove the solvent, and directly separate the pure product by column chromatography. The reaction formula and ligand structure are as follows:

[0033]

[0034] The yield is the separation yield, and the enantiomeric excess of the product is determ...

Embodiment 2

[0038] Example 2: Synthesis of various chiral sulfonamides by palladium-catalyzed asymmetric reductive amination 2

[0039] Put palladium trifluoroacetate (3 mol% of the amount of substrate in formula 1) and (S, S,)-f-Binaphane (3.3 mol% of the amount of substrate in formula 1) in the reaction bottle, add 1 ml after nitrogen replacement Acetone, stirred at room temperature for 1 hour. Concentrate in vacuo then, add 3 milliliters of trifluoroethanol under nitrogen, this solution is transferred to the reaction kettle that has substrate (0.2 mmol) and D-CSA (100mol% of substrate consumption in formula 1) in advance, feeds Hydrogen to 600psi, react at 50°C for 15-24 hours, release hydrogen slowly. After removing solvent, direct column chromatography separates and obtains pure product, and reaction formula is as follows:

[0040]

[0041] The yield is the separation yield, and the enantiomeric excess of the product is determined by chiral liquid chromatography, see Table 2.

...

Embodiment 3

[0046] Example 3: Synthesis of various chiral sulfonamides by palladium-catalyzed asymmetric reductive amination

[0047] Put palladium trifluoroacetate (3 mol% of the amount of substrate in formula 1) and (S, S,)-f-Binaphane (3.3 mol% of the amount of substrate in formula 1) in the reaction bottle, add 1 ml after nitrogen replacement Acetone, stirred at room temperature for 1 hour. Concentrate in vacuo then, add 3 milliliters of trifluoroethanol under nitrogen, this solution is transferred to the reaction kettle that has substrate (0.2 mmol) and D-CSA (100mol% of substrate consumption in formula 1) in advance, feeds Hydrogen to 600psi, react at 50°C for 15-24 hours, release hydrogen slowly. After removing solvent, direct column chromatography separates and obtains pure product, and reaction formula is as follows:

[0048]

[0049] The yield is the isolated yield, and the enantiomeric excess of the product is determined by chiral liquid chromatography, see Table 3.

[00...

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Abstract

The invention discloses a palladium-catalyzed asymmetric intramolecular reductive amination method for synthesizing chiral sulfonamides. The catalytic system used is palladium chiral bisphosphine complexes. Reductive amination of a simple and readily available ketoamine substrate yields the corresponding chiral sulfonamide with an enantiomeric excess of 99%. The invention is simple and practical in operation, easy to obtain raw materials, commercially available catalyst, and mild reaction conditions. In addition, chiral sulfonamides were synthesized by asymmetric reductive amination with high enantioselectivity, good yield and environmental friendliness.

Description

technical field [0001] The invention relates to a method for synthesizing chiral sulfonamide by highly enantioselective catalytic reductive amination using palladium homogeneous system. Background technique [0002] Chiral sulfonamides are a class of very important molecules, which are not only important skeletons of many bioactive molecules, but also important intermediates for the synthesis of many drugs (references 1: (a) Wells, G.J.; Tao, M.; Josef, K.A. ; Bihovsky, R.J.Med.Chem.2001, 44, 3488. (b) Cherney, R.J.; Mo, R.; ; Wasserman, Z.R.; Christ, D.D.; Trzaskos, J.M.; Newton, R.C.; Org. Chem. 2008, 5254.). Although many methods for the synthesis of sulfonamides have been developed, there are few examples of chiral sulfonamides synthesized by catalytic asymmetric methods. An early method for the synthesis of chiral sulfonamides was the asymmetric hydrogenation of cyclic sulfonimides using ruthenium catalysts. Afterwards, people have developed a series of ruthenium or...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D275/02C07D279/02C07D281/02
CPCC07D275/02C07D279/02C07D281/02
Inventor 周永贵宋波余长斌孙蕾
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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