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Preparation of benzofurans and use thereof as synthetic intermediates

A technology of furan and compound, applied in the field of preparation of benzofuran

Inactive Publication Date: 2012-10-24
MAPI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] For the method for preparing dronedarone or a pharmaceutically acceptable salt thereof, and / or a dronedarone intermediate (the method can be realized on an industrial scale using readily available and inexpensive intermediates, the method is significantly significantly reduce or inhibit the side reactions in the final stage of dronedarone preparation) there is an unmet need

Method used

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  • Preparation of benzofurans and use thereof as synthetic intermediates
  • Preparation of benzofurans and use thereof as synthetic intermediates
  • Preparation of benzofurans and use thereof as synthetic intermediates

Examples

Experimental program
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preparation example Construction

[0083] Preparation of compound (7):

[0084] Ortho formylation of phenol (6) can be achieved by different methods described in the literature (eg, Houben-Weyl E3, 4th edition). It is also possible to use a known direct process for the preparation of hydroxybenzaldehydes by carbonylation of the corresponding phenols.

[0085] In one embodiment, the present invention provides an improved process for the preparation of aldehyde (7) involving the reaction of phenol (6) with paraformaldehyde (paraformaldehyde) in organic solvents in the presence of magnesium or tin salts according to known methods Perform the reaction [Tetrahedron Letters 50 (2009) 5823-5826; J.CHEM.SOC., PERKIN TRANS.1, 1994, 1823; Organic Syntheses, Vol.82, p.64 (2005), the contents of each of which are by reference incorporated here]. In another embodiment, the present invention provides a method for the preparation of aldehyde (7) based on the improved Duff reaction, involving the reaction of phenol (6) wit...

Embodiment 1-4

[0184] Examples 1-4: Method A

Embodiment 1

[0186] A typical procedure for the synthesis of 5-substituted-2-hydroxybenzaldehydes from 4-substituted phenols:

[0187] Dry paraformaldehyde (paraformaldehyde) (3.5 g) was added in multiple portions to 4-substituted phenol (30 mmol), triethylamine (90 mmol), and anhydrous MgCl in acetonitrile (300 mL) 2 (100mmol) in the mixture. The mixture was refluxed for 6-8h under TCL or HPLC control. When the reaction was complete, the mixture was cooled to room temperature, acidified with 3N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. Removal of solvent yielded crude material that was pure enough for the next stage. If necessary, the compound can be purified by crystallization, distillation, or by column chromatography using an appropriate solvent or solvent mixture.

[0188] To prepare 5-chloro-2-hydroxy-benzaldehyde a modified procedure is used:

[0189] a) at N 2 Anhydrous SnCl 4 (651.2mg, 2...

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Abstract

The present invention provides several synthetic methods for preparing N-(2-butylbenzofuran-5-yl)-N-(methylsulfonyl) methanesulfonamide, a compound of formula (3), an intermediate in the preparation of Dronedarone. The present invention further provides a process for preparing Dronedarone, comprising the steps of converting 2-butyl-5-bis(methanesulfon)-amidobenzofuran of formula (3) to Dronedarone, wherein the 2-butyl-5-bis(methanesulfon)-amidobenzofuran of formula (3) is prepared by the processes of the present invention.

Description

technical field [0001] The present invention relates to a process for the preparation of benzofurans and their use as synthetic intermediates. More specifically, the present invention provides for the preparation of N-(2-butylbenzofuran-5-yl)-N-(methylsulfonyl)methanesulfonamide, in the preparation of 2-butyl-3-(4- [3-(Dibutylamino)propoxy]-benzoyl)-5-(methanesulfonamide)benzofuran (Dronedarone) and its pharmaceutically acceptable salts are an intermediate Several alternatives to bodies. Background technique [0002] Dronedarone hydrochloride (also known as SR33589 or Multaq) is a drug mainly used for arrhythmia (irregular heartbeat) indications. It was approved by the FDA on July 1, 2009 to help maintain a normal heart rate in patients with a history of atrial fibrillation or atrial flutter (a heart rhythm disorder). The drug is intended for use in patients whose hearts have returned to normal frequency or in patients taking medication or undergoing electroconvulsive the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N43/08
CPCC07C311/48C07D307/80C07D307/79
Inventor 埃胡德·马罗姆迈克尔·米治里特斯基塞·鲁比诺夫
Owner MAPI PHARMA