A kind of synthetic method of polysubstituted tetrahydroisoquinoline derivatives

A technology of tetrahydroisoquinoline and a synthesis method, applied in the direction of organic chemistry and the like, can solve the problems of insufficient product structure diversity, narrow substrate applicability, harsh reaction conditions, etc., and achieves high atom economy, low cost, raw material easy-to-get effect

Inactive Publication Date: 2015-11-18
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The above-mentioned traditional method for synthesizing multi-substituted tetrahydroisoquinoline derivatives has great limitations: not only the complex precursor compound needs to be constructed first but also multi-step synthesis is required, the operation is cumbersome, the reaction conditions are harsh, and the substrate applicability is narrow , the product structure is not enough diversity and other shortcomings
So far there is no general method for the synthesis of polysubstituted tetrahydroisoquinoline derivatives with high diastereoselectivity and high optical purity

Method used

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  • A kind of synthetic method of polysubstituted tetrahydroisoquinoline derivatives
  • A kind of synthetic method of polysubstituted tetrahydroisoquinoline derivatives
  • A kind of synthetic method of polysubstituted tetrahydroisoquinoline derivatives

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Experimental program
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Effect test

Embodiment 1

[0035]

[0036] Weigh (E)-methyl-3-(2-formylphenyl) acrylate (0.22mmol), p-cymene dichloride ruthenium (0.004mmol), p-bromoaniline (0.2mmol), Molecular sieves (100mg), (S)-3,3'-phenyl substituted BINOL phosphoric acid (0.01mmmol), L-mandelic acid (0.02mmol) put them into a small test tube reactor, add redistilled 5.6 milliliters of 1,2-dichloroethane, stirred for one hour, then dropped to minus ten degrees Celsius, added benzyl carbamate (25.9 mg, 0.24 mmol), weighed methyl phenyldiazoacetate (0.24 mmol) and dissolved in 2.8ml of redistilled 1,2-dichloroethane, and injected into the reaction system through a peristaltic pump for 1 hour, after the injection was completed, potassium tert-butoxide (0.3mmol) was added and stirred for 1 hour, then filtered, and the filtrate was placed at 40°C The solvent is removed by rotary evaporation, and then separated by column chromatography (eluent: ethyl acetate: petroleum ether = 1: 10 ~ 1: 5) to obtain a multi-substituted tetrahydroiso...

Embodiment 2

[0039]

[0040] Weigh (E)-methyl-3-(2-formylphenyl) acrylate (0.22mmol), p-cymene dichloride ruthenium (0.004mmol), p-bromoaniline (0.2mmol), Molecular sieves (100mg), (S)-3,3'-naphthyl substituted BINOL phosphoric acid (0.01mmmol), L-mandelic acid (0.02mmol) put them into a small test tube reactor, add redistilled 5.6 milliliters of 1,2-dichloroethane, stirred for one hour, then dropped to minus ten degrees Celsius, added benzyl carbamate (25.9 mg, 0.24 mmol), weighed methyl phenyldiazoacetate (0.24 mmol) and dissolved in 2.8ml of redistilled 1,2-dichloroethane, and injected into the reaction system through a peristaltic pump for 1 hour, after the injection was completed, potassium tert-butoxide (0.3mmol) was added and stirred for 1 hour, then filtered, and the filtrate was placed at 40°C The solvent is removed by rotary evaporation, and then separated by column chromatography (eluent: ethyl acetate: petroleum ether = 1: 10 ~ 1: 5) to obtain a multi-substituted tetrahydro...

Embodiment 3

[0043]

[0044] Weigh (E)-methyl-3-(2-formylphenyl) acrylate (0.22mmol), p-cymene dichloride ruthenium (0.004mmol), p-bromoaniline (0.2mmol), Molecular sieves (100mg), (S)-3,3'-biphenyl substituted BINOL phosphoric acid (0.01mmmol), L-mandelic acid (0.02mmol) put them into a small test tube reactor, add redistilled 5.6 milliliters of 1,2-dichloroethane, stirred for one hour, then dropped to minus ten degrees Celsius, added benzyl carbamate (25.9 mg, 0.24 mmol), weighed methyl phenyldiazoacetate (0.24 mmol) In 2.8ml redistilled 1,2-dichloroethane, and injected into the reaction system by a peristaltic pump for 1 hour, after the injection was completed, potassium tert-butoxide (0.3mmol) was added and stirred for 1 hour, then filtered, and the filtrate was ℃ rotary evaporation to remove the solvent, and then separated by column chromatography (eluent: ethyl acetate: petroleum ether = 1: 10 ~ 1: 5) to obtain multi-substituted tetrahydroisocyanate with high diastereoselectivity...

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Abstract

The invention discloses a synthetic method of a polysubstituted tetrahydroisoquinoline derivative, which takes diazonium, oxygen alkyl amide, arylamine, o-acrylate benzaldehyde and potassium tert-butoxidea as raw materials, takes chiral phosphoric acid, an acid additive and dichloro(p-cymene) ruthenium as catalysts, takes an organic solvent as a solvent, and takes a molecular sieve as a water absorbing agent; the above materials are reacted, a solvent is removed to obtain crude product, after column chromatography, the high-diastereomeric selectivity high-optical purity tetrahydroisoquinoline derivative pure product can be obtained. The synthetic method has the advantages of easy and simple acquisition of raw materials, safe and easy operation, and the product has the advantages of high atom economy, high yield and high selectivity.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical synthesis chemistry and relates to a preparation method of polysubstituted tetrahydroisoquinoline derivatives. Background technique [0002] Multi-substituted tetrahydroisoquinolines are important intermediate skeleton structures of many natural products, and the natural products Ecteinascidin-743, CyanocyclineA, Bioxalomycinβ2, (-)-Lemonomycin and (-)-Cribrostatin4 all have similar highly substituted tetrahydro Structural fragment of isoquinoline. (Org.Lett.2003, 2095-2098; J.Org.Chem.2011, 5283-5294; J.Am.Chem.Soc.2007, 15460-25461; J.Am.Chem.Soc.2003, 15000-15001 ; J. Am. Chem. Soc. 1986, 2478-2479; Angew. Chem. Int. Ed. 2007, 1517-1520). The traditional chemical synthesis methods of multi-substituted tetrahydroisoquinoline derivatives include the multi-step synthesis of multi-substituted tetrahydroisoquinoline by quinoline and chiral amino acids or the construction of tetrahydroisoqui...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 胡文浩马晓初江俊郭震球史滔达
Owner EAST CHINA NORMAL UNIV
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