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Heterocyclic compound, intermediate, preparation method and application thereof

A technology of heterocyclic compounds, applied in the field of heterocyclic compounds

Active Publication Date: 2020-07-07
WUHAN LL SCI & TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are currently no marketed drugs that inhibit the P2X3 pathway for the treatment of many conditions including chronic cough

Method used

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  • Heterocyclic compound, intermediate, preparation method and application thereof
  • Heterocyclic compound, intermediate, preparation method and application thereof
  • Heterocyclic compound, intermediate, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0558]

[0559] Step (1) Preparation of (R)-2-formyl-morpholine-4-formic acid tert-butyl ester

[0560]

[0561] Compound 1-1 (10g, 460mmol), TEMPO (0.073g, 0.44mmol), sodium bromide aqueous solution (0.5M, 10mL, 41mmol) and dichloromethane (100mL) were cooled to a temperature of 0°C-5°C, Sodium bicarbonate (2.3g, 23mmol) was added to the sodium hypochlorite (1.5M, 34ml, 58mmol) solution to adjust the pH of the solution to 9.3, and the solution was slowly dropped into the reaction system over 30 minutes, and the stirring was continued for half an hour after the addition was completed , heated to 20° C. and added water (50 mL), and added dichloromethane to extract the aqueous phase. After multiple extractions, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and column chromatography obtained compound 1-2. Orange-yellow oily liquid (6g, 60%). LC-MS: [M+H] + = 216.4.

[0562] Step (2) Preparation of (...

Embodiment 2

[0591]

[0592] Step (1) Preparation of 2,6-difluoro-4-bromobenzaldehyde

[0593]

[0594] Get 3,5-difluorobromobenzene (10g, 51.8mmol) and dissolve in anhydrous THF (80mL), N 2 Under protection, add LDA (31mL, 62.5mmol) dropwise at -78°C, continue stirring for 1h after the dropwise addition is complete, add DMF (4mL, 51.9mmol), stir for 30min, then add the reaction solution into NH 4 Cl solution, and extracted with ethyl acetate, the organic phase was washed with NaCl, dried over anhydrous magnesium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the concentrated crude product was obtained by column chromatography to obtain compound 2-2, a yellow solid (8g, yield 70% ).

[0595] Step (2) (S)-2-((2-(2,6-difluoro-4-bromophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methanol base) the preparation of morpholine-4-formic acid tert-butyl ester

[0596]

[0597] Take compound 2-2 (200mg, 0.9mmol), 2-amino-4-picoline (100mg, 0.9mmol), compound 1-4...

Embodiment 3

[0609]

[0610] Step (1) (S)-2-((2-(2,6-difluoro-4-aminophenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)-methanol base) the preparation of morpholine-4-formic acid methyl ester

[0611]

[0612] At room temperature, hydrochloric acid (1.5 mL) was added to a solution of compound 2 (145 mg, 0.32 mmol) in ethanol (3 mL), and the reaction solution was reacted for 1 h at 100 ° C. After the reaction was complete, it was cooled to room temperature and washed with 1 N NaHCO 3 The solution was quenched, extracted with DCM (5 mL×3), washed with saturated sodium chloride solution (5 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a yellow oily liquid (90 mg). LC-MS: [M+H] + = 417.3.

[0613] Step (2) (S)-2-((2-(2,6-difluoro-4-(methoxycarbonylamino)phenyl)-7-methylimidazo[1,2-a]pyridine- Preparation of 3-yl)-methyl)morpholine-4-carboxylic acid methyl ester

[0614]

[0615] At 0°C, to a solution of Intermediate 3-1 (70mg, 0.17mmol) and...

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PUM

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Abstract

The invention discloses a heterocyclic compound, an intermediate, and a preparation method and application thereof. The invention provides a heterocyclic compound shown as a formula I, and a stereoisomer, a geometrical isomer, a tautomer or a pharmaceutically acceptable salt thereof. The heterocyclic compound has high P2X3 antagonistic activity, good selectivity, low toxicity, good metabolic stability and small influence on taste.

Description

technical field [0001] The present invention relates to a heterocyclic compound, an intermediate, its preparation method and application. Background technique [0002] ATP receptors are classified into two major families, P2Y- and P2X-purinergic receptors, based on molecular structure, transduction mechanism, and pharmacological properties. P2X-purinergic receptors are a family of ATP-gated cation channels of which several subtypes have been cloned, including: six homomeric receptors, P2X1; P2X2; P2X3; P2X4; P2X5; and P2X7; and three heteromeric receptors Receptors P2X2 / 3, P2X4 / 6, P2X1 / 5. The study found that P2X3 receptors are specifically expressed in the primary afferent nerve fibers of "hollow viscera", such as the lower urinary tract and respiratory tract. [0003] Cough is the main symptom of respiratory diseases. In the outpatient department of respiratory department, 70% to 80% of patients have cough symptoms. With the increasing prevalence of COPD, IPF, etc., and...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D413/06C07D487/04C07D491/048C07D265/30C07D317/26C07C233/15C07C233/65C07C69/76A61P29/00A61P13/00A61P11/00A61P25/04A61P25/06A61P13/10A61P13/02A61P11/06A61P11/14A61K31/5377A61K31/496A61K31/444A61K31/4545
CPCC07D471/04C07D413/06C07D487/04C07D491/048C07D265/30C07D317/26C07C233/15C07C233/65C07C69/76A61P29/00A61P13/00A61P11/00A61P25/04A61P25/06A61P13/10A61P13/02A61P11/06A61P11/14A61K31/5377C07D209/18C07F5/04
Inventor 娄军陈永凯刘军华张轶涵郭晓丹柳力钱丽娜王朝东
Owner WUHAN LL SCI & TECH DEV
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