CN104151277A - Preparation method of oxidation impurity dronedarone hydrochloride - Google Patents
Preparation method of oxidation impurity dronedarone hydrochloride Download PDFInfo
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- CN104151277A CN104151277A CN201410297935.0A CN201410297935A CN104151277A CN 104151277 A CN104151277 A CN 104151277A CN 201410297935 A CN201410297935 A CN 201410297935A CN 104151277 A CN104151277 A CN 104151277A
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- Prior art keywords
- reaction
- propoxy
- benzoyl
- butyl
- dronedarone hydrochloride
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- 0 C*C(CC*C(C1)N1I)C1OCC1 Chemical compound C*C(CC*C(C1)N1I)C1OCC1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
Abstract
The invention relates to a method for preparing one oxidation impurity dronedarone hydrochloride. Under a low temperature condition, N-(2-butyl-3-(4-(3-(dibutyl amino) propoxy)benzoyl)benzofuran-5-yl) methanesulfonamide reacts with an oxidizing agent so that N-(2-butyl-3-(4-(3-(dibutyl amino) propoxy)benzoyl)benzofuran-5-yl) methanesulfonamide is oxidized into a nitrogen oxide.
Description
Technical field
The invention belongs to pharmaceutical chemistry field, relate to the method for preparing an oxidation impurities of dronedarone hydrochloride.Its chemical structural formula is as follows:
。
Background technology
Dronedarone (Dronedarone) is a kind of new antiarrhythmic drug, and it is developed by French Sai Nuofei mono-Sanofi-Aventis, and proposes application for quotation in 2008 to each major country of the whole world, is that U.S. FDA is preferentially evaluated kind.Obtain FDA approval listing on July 1st, 2009, obtain again Canada's approval on August 12nd, 2009, in December, 2009 EMEA of 16Huo European Union approval.For studying its oxidation impurities, we have drafted the route of a synthetic hydrochloric acid Dronedarone oxynitride, and the method is simple to operate, and reaction conditions is gentle.
Summary of the invention
The invention provides a kind of preparation method of an oxidation impurities of dronedarone hydrochloride: under the condition of low temperature, will
n-(2-butyl-3-(4-(3-(dibutylamino) propoxy-) benzoyl) cumarone-5-yl) Toluidrin and oxidant reaction, be oxidized to oxynitride.This reaction conditions is gentle, is easy to control, and its syntheti c route is as follows.
Wherein in reaction process, add some mineral alkalis can promote the carrying out of reaction, mineral alkali alkali comprises sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus etc., wherein preferred sodium carbonate.In oxidizing reaction, selective reaction solvent is methylene dichloride and tetrahydrofuran (THF), wherein preferred methylene dichloride.Add oxidising agent in batches simultaneously, control temperature at 0 ° below C.
concrete embodiment
Following embodiment is to describe in detail the present invention, but should not be construed as limiting the invention.
Embodiment one
In 50 mL there-necked flasks, add 1.4 g
n-(2-butyl-3-(4-(3-(dibutylamino) propoxy-) benzoyl) cumarone-5-yl) Toluidrin and 10 mL methylene dichloride, stir and make it to dissolve.1.0 g metachloroperbenzoic acids are joined in reaction solution, and room temperature reaction spends the night.Column chromatography is purified and is obtained oxynitride, yield 40 ﹪.
Embodiment two
In 50 mL there-necked flasks, add 1.4 g
n-(2-butyl-3-(4-(3-(dibutylamino) propoxy-) benzoyl) cumarone-5-yl) Toluidrin and 10 mL methylene dichloride, stir and make it to dissolve.Control temperature and, 1.0 g metachloroperbenzoic acids are joined in reaction solution ° below C-10 ° of C-0 in batches, thin-layer chromatography monitoring reaction, reacts 10 hours, reacts complete.Column chromatography is purified and is obtained oxynitride, yield 50.5 ﹪.
Embodiment three
In 50 mL there-necked flasks, add 1.4 g
n-(2-butyl-3-(4-(3-(dibutylamino) propoxy-) benzoyl) cumarone-5-yl) Toluidrin and 10 mL methylene dichloride, stir and make it to dissolve.In reaction solution, add 0.6 g sodium carbonate, control temperature and, 1.0 g metachloroperbenzoic acids are joined in reaction solution ° below C-10 ° of C-0 in batches, thin-layer chromatography monitoring reaction, reacts 5.5 hours, reacts complete.Column chromatography is purified and is obtained oxynitride, yield 49.7 ﹪.
Embodiment four
In 50 mL there-necked flasks, add 1.4 g
n-(2-butyl-3-(4-(3-(dibutylamino) propoxy-) benzoyl) cumarone-5-yl) Toluidrin and 10 mL tetrahydrofuran (THF)s, stir and make it to dissolve.Control temperature and, 1.0 g metachloroperbenzoic acids are joined in reaction solution ° below C-10 ° of C-0 in batches, control temperature of reaction at 0 ° below C, thin-layer chromatography monitoring reaction, reacts 14 hours, reacts complete.Column chromatography is purified and is obtained oxynitride, yield 38.6 ﹪.
Embodiment five
In 50 mL there-necked flasks, add 1.4 g
n-(2-butyl-3-(4-(3-(dibutylamino) propoxy-) benzoyl) cumarone-5-yl) Toluidrin and 10 mL tetrahydrofuran (THF)s, stir and make it to dissolve.In reaction solution, add 0.6 g sodium carbonate again.Control temperature and, 1.0 g metachloroperbenzoic acids are joined in reaction solution ° below C-10 ° of C-0 in batches, thin-layer chromatography monitoring reaction, reacts 12 hours, reacts complete.Column chromatography is purified and is obtained oxynitride, yield 36.9 ﹪.
Claims (5)
1. a method of preparing dronedarone hydrochloride oxidation impurities, is characterized in that under cold condition, will
n-(2-butyl-3-(4-(3-(dibutylamino) propoxy-) benzoyl) cumarone-5-yl) Toluidrin mixes with oxygenant, in certain solvent, is oxidized to oxynitride.
2. according to the method for claim 1, oxidising agent is metachloroperbenzoic acid or hydrogen peroxide.
3. according to the method for claim 1, low temperature refers to temperature of reaction and controls 0 ° below C.
4. according to claim 1,2,3 method, metachloroperbenzoic acid or hydrogen peroxide add in batches.
5. according to the method for claim 1, certain solvent refers to methylene dichloride or tetrahydrofuran (THF), wherein preferred methylene dichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410297935.0A CN104151277A (en) | 2014-06-30 | 2014-06-30 | Preparation method of oxidation impurity dronedarone hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410297935.0A CN104151277A (en) | 2014-06-30 | 2014-06-30 | Preparation method of oxidation impurity dronedarone hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104151277A true CN104151277A (en) | 2014-11-19 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410297935.0A Pending CN104151277A (en) | 2014-06-30 | 2014-06-30 | Preparation method of oxidation impurity dronedarone hydrochloride |
Country Status (1)
| Country | Link |
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| CN (1) | CN104151277A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999031100A1 (en) * | 1997-12-17 | 1999-06-24 | Astrazeneca Ab | Novel bispidine antiarrhythmic compounds |
| CN1348442A (en) * | 1999-02-26 | 2002-05-08 | 默克公司 | Novel sulfonamide compounds and uses thereof |
| WO2006078619A1 (en) * | 2005-01-18 | 2006-07-27 | Bayer Cropscience Ag | Insecticidal heterocyclic 1,4-disubstituted benzene n-oxides |
-
2014
- 2014-06-30 CN CN201410297935.0A patent/CN104151277A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999031100A1 (en) * | 1997-12-17 | 1999-06-24 | Astrazeneca Ab | Novel bispidine antiarrhythmic compounds |
| CN1348442A (en) * | 1999-02-26 | 2002-05-08 | 默克公司 | Novel sulfonamide compounds and uses thereof |
| WO2006078619A1 (en) * | 2005-01-18 | 2006-07-27 | Bayer Cropscience Ag | Insecticidal heterocyclic 1,4-disubstituted benzene n-oxides |
Non-Patent Citations (1)
| Title |
|---|
| SHASHIKANT B. LANDGE 等: "Stability Indicating RP-HPLC Method for the Determination of Dronedarone Hydrochloride and Its Potential Process-Related Impurities in Bulk Drug and Pharmaceutical Dosage Form", 《AMERICAN JOURNAL OF ANALYTICAL CHEMISTRY》 * |
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| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20141119 |