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Methanamide compound, preparation method of intermediate of methanamide compound, and applications of the intermediate

A formamide compound and compound technology, which is applied in the preparation of organic compounds, amino hydroxyl compounds, carboxylic acid amides, etc., can solve the problems such as no report on the synthesis of formamide compound 6

Inactive Publication Date: 2014-07-02
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] At present, many patents have disclosed the preparation method of formoterol, but there is no report on the synthesis of formamide compound 6, one of the impurities in the detection process

Method used

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  • Methanamide compound, preparation method of intermediate of methanamide compound, and applications of the intermediate
  • Methanamide compound, preparation method of intermediate of methanamide compound, and applications of the intermediate
  • Methanamide compound, preparation method of intermediate of methanamide compound, and applications of the intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0169] 2-[N-Benzyl-N-[1-methyl-2-(4-methoxy-3-chloromethylphenyl)]ethyl]amino-1-(4-benzyloxy-3- Preparation of nitrophenyl)ethanone (compound 2, * in the structural formula represents the achiral central carbon atom, that is, compound 2 is a racemate)

[0170] In a 25mL four-neck flask, add 1g of compound 1 (compound 1, * in the structural formula represents the achiral central carbon atom, that is, compound 1 is a racemate, CAS: 43229-66-9), 10mL of anhydrous acetic acid, and stir After complete dissolution, add 2mL of 35% formaldehyde aqueous solution, 4mL of concentrated hydrochloric acid and 0.05g of anhydrous zinc chloride at one time, react at 90°C for 0.5h, and TLC detects that the raw material point disappears.

[0171] Under ice-water bath cooling, use 5mol / L NaOH aqueous solution to adjust the pH of the reaction solution to 9-11, extract three times with 20mL ethyl acetate, separate the organic layer, wash once with 30mL water, wash three times with 20mL saturated sa...

Embodiment 2

[0174] 2-[N-Benzyl-N-[1-methyl-2-(4-methoxy-3-chloromethylphenyl)]ethyl]amino-1-(4-benzyloxy-3- Preparation of nitrophenyl)ethanone (compound 2, * in the structural formula represents the achiral central carbon atom, that is, compound 2 is a racemate)

[0175] In a 100mL four-neck flask, add 4g of compound 1, 40mL of anhydrous acetic acid, stir to dissolve completely, add 8mL of 35% formaldehyde solution, 16mL of concentrated hydrochloric acid and 0.4g of anhydrous zinc chloride at one time, and react at 85°C for 1h. TLC detects that the raw material spot disappears.

[0176] Under ice-water bath cooling, use 5mol / L NaOH aqueous solution to adjust the pH of the reaction solution to 9-11, extract three times with 100mL ethyl acetate, separate the organic layer, wash once with 100mL water, wash three times with 200mL saturated saline, and anhydrous Dry over sodium sulfate and concentrate to give 4.3 g of crude solid. Recrystallized with ethanol / acetone to obtain 1.7 g of compo...

Embodiment 3

[0178] 2-[N-Benzyl-N-[1-methyl-2-(4-methoxy-3-chloromethylphenyl)]ethyl]amino-1-(4-benzyloxy-3- Preparation of nitrophenyl)ethanone (compound 2, * in the structural formula represents the achiral central carbon atom, that is, compound 2 is a racemate)

[0179] In a 500mL four-neck flask, add 18g of compound 1, 180mL of anhydrous acetic acid, stir to dissolve completely, add 36mL of 35% formaldehyde solution, 72mL of concentrated hydrochloric acid and 3.6g of anhydrous zinc chloride at one time, and react at 60°C for 2 hours. TLC detects that the raw material spot disappears.

[0180] Under ice-water bath cooling, use 5mol / L NaOH aqueous solution to adjust the pH of the reaction solution to 9-11, extract three times with 400mL ethyl acetate, separate the organic layer, wash once with 400mL water, wash three times with 300mL saturated saline, anhydrous Dry over sodium sulfate and concentrate to obtain 20.1 g of crude solid. Recrystallized with ethanol / ethyl acetate = 10 / 1 to o...

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Abstract

The invention discloses a methanamide compound, a preparation method of an intermediate of the methanamide compound, and applications of the intermediate. The invention provides a preparation method of a methanamide compound 6. The preparation method comprises the following steps: (1) subjecting a compound 4 to carry out carbamylation reactions with a formylating agent in a solvent so as to obtain a compound 5; (2) subjecting the compound 5 obtained in the step (1) to carry out reactions with hydrogen gas in the presence of a palladium-carbon catalyst to remove the hydroxy protecting groups so as to obtain the compound 6. The synthesis method has the advantages of mild conditions, high conversion rate, high product yield, and high purity. The synthesized compound 6 can be taken as an impurity standard sample in the inspection of formoterol.

Description

technical field [0001] The present invention relates to formamide compound, its intermediate preparation method and its application. Background technique [0002] The formamide compound shown in formula 6 is one of the impurities that may be contained or produced and need to be controlled during the production and normal storage of the antiasthmatic drug formoterol shown in formula 7, and is also regulated by the Pharmacopoeia One of the related substances that must be checked, the European Pharmacopoeia (EP7.0 version) and the United States Pharmacopoeia (USP2010 version) limit the impurity to 0.1%. [0003] [0004] Formoterol, chemical name N-[2-hydroxy-5-[1-hydroxy-2-[[2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl] Phenyl]formamide is a long-acting beta 2 - Adrenergic receptor agonists for the treatment of chronic bronchial asthma, nocturnal asthma, exercise-induced asthma, chronic embolism pneumonia, and non-asthmatic respiratory diseases in children. The formoter...

Claims

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Application Information

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IPC IPC(8): C07C233/43C07C231/12C07C221/00C07C225/16C07C217/70C07C213/00G01N33/15
CPCY02P20/55
Inventor 陈超叶小珍潘竞胡翔蔡正艳周伟澄李智
Owner SHANGHAI INST OF PHARMA IND
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