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Preparation method of chiral 3, 4-dihydrobenzothiadiazine compound

A technology of dihydrobenzothiadiazine and compounds, which is applied in the field of preparation of chiral 3,4-dihydrobenzothiadiazine compounds, and can solve problems such as poor effect of aromatic aldehydes

Active Publication Date: 2021-01-19
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In summary, there are currently only two cases of asymmetric synthesis of 3,4-dihydrobenzothiadiazine (DHBDs), which have good catalytic effects on aliphatic aldehydes, but are less effective on aromatic aldehydes.

Method used

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  • Preparation method of chiral 3, 4-dihydrobenzothiadiazine compound
  • Preparation method of chiral 3, 4-dihydrobenzothiadiazine compound
  • Preparation method of chiral 3, 4-dihydrobenzothiadiazine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Chiral TADDOL type rare earth metal complex catalyzes the asymmetric ring amination reaction of anthranilamide and aldehyde:

[0064] Weigh 0.03mmol YH 3 L 1 3 , add 1.0mL hexane, add 60mg Spherical molecular sieves, after stirring at room temperature for 30 minutes, add 0.3 mmol of anthranilamide, after stirring for 30 minutes, add 0.36 mmol of cyclohexanal, and then add 1.0 mL of hexane solvent. Seal the bottle at 20°C and continue to stir for 18h, add ethyl acetate to terminate the reaction, and separate by column chromatography (EA:PE=1:2) to obtain a chiral cyclic amination product, and the enantioselectivity was determined by chiral HPLC. Yield 88%, ee 8%.

Embodiment 2

[0065] Example 2: Chiral TADDOL-type rare earth metal complex catalyzes the asymmetric ring amination reaction of anthranilamide and aldehyde:

[0066] Weigh 0.03mmol LaH 3 L 1 3 (THF), add 1.0mL hexane, add 60mg Spherical molecular sieves, after stirring at room temperature for 30 minutes, add 0.3 mmol of anthranilamide, after stirring for 30 minutes, add 0.36 mmol of cyclohexanal, and then add 1.0 mL of hexane solvent. Seal the bottle at 20°C and continue to stir for 18h, add ethyl acetate to terminate the reaction, and separate by column chromatography (EA:PE=1:2) to obtain a chiral cyclic amination product, and the enantioselectivity was determined by chiral HPLC. Yield 93%, ee 13%.

Embodiment 3

[0067] Example 3: Lithium chloride-complexed lanthanum silamide and chiral TADDOL ligand jointly catalyze the asymmetric ring amination reaction of anthranilamide and aldehyde:

[0068] Weigh 0.03mmol La[N(SiMe 3 ) 2 ] 3 (μ-Cl)Li(THF) 3 and 0.03 mmol of chiral TADDOL ligand H 2 L 2 , add 1.0mL hexane, add 60mg Spherical molecular sieves, after stirring at room temperature for 30 minutes, add 0.3 mmol of anthranilamide, after stirring for 30 minutes, add 0.36 mmol of cyclohexanal, and then add 1.0 mL of hexane solvent. Seal the bottle at 20°C and continue to stir for 18h, add ethyl acetate to terminate the reaction, and separate by column chromatography (EA:PE=1:2) to obtain a chiral cyclic amination product, and the enantioselectivity was determined by chiral HPLC. Product 4a was obtained in 98% yield with 93% ee.

[0069] The structure of product 4a is as follows:

[0070]

[0071] The product is a white solid, the yield is 98%, ee93%; [α] D 20 =56°(c0.32, in TH...

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Abstract

The invention relates to a preparation method of a chiral 3, 4-dihydrobenzothiadiazine compound, which comprises the following steps: under the conditions of no water, no oxygen and protective atmosphere, adding molecular sieves into compounds shown in a formula (1) and a formula (2) under the action of a catalyst, and reacting in an organic solvent at -40-40 DEG C to obtain the chiral 3, 4-dihydrobenzothiadiazine compound shown in a formula (4); the catalyst comprises a chiral TADDOL type rare earth metal complex or a combined catalyst of a chiral TADDOL ligand and a rare earth metal amide complexed with lithium chloride, the reaction route is as follows, in which R1 is selected from hydrogen, C1-C4 alkyl or halogen; R2 is selected from hydrogen, C1-C2 alkyl or phenyl; and R3 is selectedfrom a C1-C5 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a benzyl group, a phenylpropyl group, a C1-C4 alkyl substituted phenyl group, a C1-C4 alkoxy substituted phenyl group, a halogenatedphenyl group, a furyl group or a thienyl group.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of chiral 3,4-dihydrobenzothiadiazine compounds. Background technique [0002] Most pharmacological studies are performed using racemates, but stereoisomers of chiral drugs often exhibit different pharmacological activities. Therefore, the existing research methods are not rigorous enough, and it becomes very important to directly synthesize chiral drug molecules with pharmacological activity. 3,4-Dihydrobenzothiadiazines (DHBDs) are important nitrogen-containing heterocyclic compounds, which have a wide range of biological, medical and pharmacological properties. An ingredient in pain medications, antihistamines, antidepressants and vasodilators, among others. According to reports in the literature, there are many ways to obtain such compounds in racemic form, but it is still challenging to obtain optically pure and enriched products. At present, there ar...

Claims

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Application Information

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IPC IPC(8): C07D285/24B01J31/22
CPCC07D285/24B01J31/2213C07B2200/07B01J2531/37B01J2531/36
Inventor 赵蓓陆澄容单海文
Owner SUZHOU UNIV
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