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Preparation method of 2,3-dihydro-1H-benzo[f] chromane-2-amine derivative

A derivative, benzo technology, applied in the field of drug synthesis, can solve the problems of high production cost, difficult purification, low yield, etc.

Active Publication Date: 2019-09-17
SHANDONG BIOPOLAR DICHANG PHARM CO LTD
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  • Abstract
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  • Claims
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Problems solved by technology

[0005]However, the existing (2S,3R)-2-amino-3-(2,4,5-trifluorophenyl)-9-methoxy The preparation method of -2,3-dihydro-1H-benzo[f]chroman-8-substituted derivatives has the problems of low yield, difficult purification and high production cost

Method used

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  • Preparation method of 2,3-dihydro-1H-benzo[f] chromane-2-amine derivative
  • Preparation method of 2,3-dihydro-1H-benzo[f] chromane-2-amine derivative
  • Preparation method of 2,3-dihydro-1H-benzo[f] chromane-2-amine derivative

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preparation example Construction

[0077] Specifically, (2S,3R)-2-amino-3-(2,4,5-trifluorophenyl)-9-methoxy-2,3-dihydro-1H represented by formula I of the present invention -The preparation method of benzo [f] chroman-8-position substituted derivative comprises the following steps:

[0078] (1) The 3,6-dimethoxynaphthalene substituted by R adopts the following method to form an aldehyde group: CHCl 3 / NaOH, DMF / POCl 3 , 1,1-dichloromethyl methyl ether / TiCl 4 Reaction was carried out in an organic solvent, quenched with hydrochloric acid, extracted, spin-dried, washed, and dried to obtain 6-substituted-2,7-dimethoxyl-1-naphthaldehyde ( Intermediate 1 );

[0079]

[0080] (2) Will Intermediate 1 use BBr 3 / DCM, CH 3 ONa / CH 3 OH / DMSO, anhydrous aluminum trichloride, anhydrous aluminum trichloride / potassium iodide for selective demethylation, hydrochloric acid quenching, suction filtration, washing, and drying to obtain 6-substituted-2-hydroxyl-7-methoxy Base-1-naphthaldehyde ( Intermediate 2 );

[0081...

Embodiment 1

[0158] Example 1. (2S,3R)-2-amino-3-(2,4,5-trifluorophenyl)-9-methoxy-2,3 dihydro-1H-benzo[f]chroman - Preparation of 8-carbonitrile

[0159] (1) Preparation of 6-cyano-2,7-dimethoxy-1-naphthaldehyde

[0160] Weigh 1,1-dichloromethyl methyl ether (4.80g, 42.24mmol) in a 500mL eggplant-shaped bottle, add 30mL of dichloromethane to dissolve it, and add TiCl4 (14.00g, 70.40mmol), stirred at 0°C for 15min; weighed 3,6-dimethoxynaphthalenenitrile (4.00g, 28.16mmol) and dissolved it completely in an appropriate amount of dichloromethane, and added it dropwise to the above reaction solution, Stir at room temperature for 36 hours, monitor with TLC plate, add appropriate amount of 1N hydrochloric acid solution after the reaction to adjust the acidity of the reaction solution, extract with dichloromethane, wash with saturated saline, dry with anhydrous sodium sulfate, and wash with ethanol to obtain 4.275g of white product, product The rate is 94.5%.

[0161] (2) Preparation of 6-cya...

Embodiment 2

[0180] Example 2. (2S,3R)-2-amino-3-(2,4,5-trifluorophenyl)-9-methoxy-2,3 dihydro-1H-benzo[f]chroman - Preparation of 8-carbonitrile

[0181] (1) Obtain (E)-1-(2,4,5-trifluorophenyl)-2-nitroene and 6-cyano-2-hydroxyl-7-methoxyl- 1-naphthaldehyde;

[0182]

[0183] (2) As shown in the above reaction formula, the 6-cyano-2-hydroxyl-7-methoxy-1-naphthaldehyde (100.0g, 0.44mol) obtained above and (E)-1-(2, 4,5-trifluorophenyl)-2-nitroene (98.3g, 0.48mol) was condensed under the combined action of catalyst L-2-piperidinecarboxylic acid (11.5g, 89mmol) and DABCO (4.9g) , Refluxed water in toluene for 24-48h. After the reaction, the reaction solution was cooled and filtered to obtain 2-nitro-3-(2,4,5-trifluorophenyl)-9-methoxy-3H-benzo[f]chroman-8-carbonitrile. The yield is 70-85%;

[0184] or,

[0185] 6-cyano-2-hydroxy-7-methoxy-1-naphthaldehyde (100.0g, 0.44mol) and (E)-1-(2,4,5-trifluorophenyl)-2-nitrate Alkene (98.3g, 0.48mol) was condensed under the action of catalyst...

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Abstract

The invention provides a preparation method of a (2S, 3R)-2-amidogen-3-(2,4,5-trifluorophenyl)-9-methoxyl-2,3-dihydro-1H-benzo[f] chromane-8 bit substitutive derivative shown as a formula I shown in the accompanying drawing, wherein R is selected from H, OCH3, CN, SO2CH3 and NHSO2CH3. The method has the advantages that the yield is high; the purification is convenient; the cost is low, and the like.

Description

technical field [0001] The invention relates to the field of drug synthesis. Specifically, the present invention relates to a process for the preparation of 2,3-dihydro-1H-benzo[f]chroman-2-amine derivatives. Background technique [0002] (2S,3R)-2-Amino-3-(2,4,5-trifluorophenyl)-9-methoxy-2,3-dihydro-1H-benzo[f]chroman-8 Substituted derivatives are a newly discovered DPP-4 inhibitor. These compounds are incretin-based hypoglycemic agents that act on pancreatic β-cells in an indirect manner by inhibiting the target DPP-4 and increasing the amount of endogenous active incretins GLP-1 and GIP, Promote insulin secretion to achieve the effect of stabilizing blood sugar. [0003] (2S,3R)-2-Amino-3-(2,4,5-trifluorophenyl)-9-methoxy-2,3-dihydro-1H-benzo[f]chroman-8 The discovery, preparation and application of substituted derivatives have been reported (J.Med.Chem.2016,59,6772-6790), and the synthesis process is as follows: [0004] [0005] However, the existing (2S,3R)-2-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/92
CPCC07D311/92C07B2200/07Y02P20/55
Inventor 李静雅赵文娟赵振江李丹
Owner SHANDONG BIOPOLAR DICHANG PHARM CO LTD
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