CN105399709A - Preparation method of dronedarone hydrochloride key intermediate - Google Patents
Preparation method of dronedarone hydrochloride key intermediate Download PDFInfo
- Publication number
- CN105399709A CN105399709A CN201510958316.6A CN201510958316A CN105399709A CN 105399709 A CN105399709 A CN 105399709A CN 201510958316 A CN201510958316 A CN 201510958316A CN 105399709 A CN105399709 A CN 105399709A
- Authority
- CN
- China
- Prior art keywords
- preparation
- butyl
- key intermediate
- dronedarone
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of a dronedarone hydrochloride key intermediate. The preparation method comprises following steps: 1) 2-butyl-benzofuran-5-ylamine hydrochloride and phthalic anhydride are subjected to reflux reaction under alkaline conditions so as to protect amino groups; and 2) 4-[3-(dibutyl amino) propoxy] benzoic acid is added into Eaton's reagent for stirring reaction, an intermediate 1 is added, temperature is controlled for reaction, a free amine is obtained via treatment, and the free amine and oxalic acid are subjected to salt forming reaction so as to obtain compound IV 5-amino-2-n-butyl-3-[4-(3-n-dibutyl aminopropoxy) benzoyl]benzofuran oxalate. The dronedarone hydrochloride key intermediate is prepared by taking 2-butyl-benzofuran-5-ylamine hydrochloride as the starting raw material; production of the dronedarone free amino is high in selectivity, and high in yield; fewer steps are needed; so that the preparation method is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of key intermediate in dronedarone hydrochloride, belong to field of medicine preparing technology.
Background technology
Dronedarone hydrochloride (dronedaronehydrochloride); chemistry 2-normal-butyl-3-by name [4-(the amino propoxy-of 3-di-n-butyl) benzoyl]-5-methylsulfonyl amido cumarone hydrochloride; it is the polarization inhibitor developed by French Sanofi-Aventis company; in July, 2009, its chemical structural formula was as follows first in U.S.'s listing:
Clinical being mainly used in of dronedarone hydrochloride treats irregular pulse.This product effectively can reduce atrial fibrillation or atrial flutter patients's cardiovascular event and to be in hospital risk, and the rhythm of the heart being applicable to atrial fibrillation and atrial flutter patients controls, maintains sinus rhythm and the ventricular rhythm that slows down.Dronedarone and amiodarone (amiodarone) are all benzofuran derivative, have similar electro physiology effect, are the alternative more novel drugs of the latter, because eliminate atomic iodine, to reduce the organ toxicity of its propiodal; Add methylsulfonyl in cumarone side, reduce lipotropy, shorten the transformation period of medicine with this, and reduce the tissue accumulation effect of medicine, therefore both maintained the curative effect of amiodarone, and there is no the outer untoward reaction of the heart of amiodarone.Its fundamental characteristics and amiodarone similar, simultaneously also possess some new features.Exploitation Dronedarone has good market outlook to bring good economic benefit and social benefit.
At present, the intermediate of domestic and international published synthesis Dronedarone comprises:
1, US5223510 (patent families EP0471609A1, and WO03040120 FR266544), US2012108828, P2428511, CN102659726, US2012108828, EP2428511 and document ([J]. Chinese Journal of Pharmaceuticals, 2011, 42 (3), 161-164) with 2-butyl-5-nitrobenzofuran for starting raw material, with anisoyl chloride through Fu Ke acylation reaction, demethylating reaction, condensation reaction, catalytic hydrogenating reduction reaction has obtained 5-amino-2-normal-butyl-3-(4-(3-dibutyl amino) propoxy-) benzoyl) nitrobenzofuran, 5-amino-2-normal-butyl-3-(4-(3-dibutyl amino) propoxy-) benzoyl is obtained through metallic reducing agent PtO2 (or palladium/carbon) and high-pressure hydrogenation) aminobenzofur, concrete reaction is as follows:
This reacts the 2-butyl-5-nitrobenzofuran used and has strong carinogenicity, very large to operator's injury.Use expensive noble metal catalyzer cost during nitroreduction higher, and hydrogenation rear impurity is more, purifying is difficult to.
2, US Patent No. 6828448, WO03040120A1, CN102666522 etc. adopt intermediate 2-butyl-5-aminobenzofur and methylsulfonyl chloride to react and generate 2-butyl-5-methylsulfonyl amido cumarone, then carry out friedel-crafts reaction with 4-[3-bis-(fourth is amino) propoxy-] Benzoyl chloride, obtain Dronedarone.This method changes the order of reactions steps, and reduction step and formylation carry out when synthesizing and starting, and concrete reaction is as follows:
The defect of this method is that 2-butyl-5-aminobenzofur and methylsulfonyl chloride react the 2-butyl-5-methylsulfonyl amido cumarone generated and be not easy purifying, complicated operation, and friedel-crafts reaction is higher to ingredient requirement, the inevitable like this reduction causing yield, purity; Hydrogen in addition on methylsulfonyl amido and the easy complexing of louis catalyst, therefore need more catalysts and solvents, causes the raising of cost and more multicontaminated generation; Also have the reactive hydrogen on methylsulfonyl easily to react with 4-[3-bis-(fourth amino) propoxy-] Benzoyl chloride the difficulty causing generating by product and then increasing purifying, aftertreatment is loaded down with trivial details, is not suitable for suitability for industrialized production.
3, report according to document CN101993427; with 2-normal-butyl-5-kharophen benzo furans and 4-(3-chlorine propoxy-) Benzoyl chloride through friedel-crafts reaction; 2-normal-butyl-3-(4-(3-Di-n-Butyl Amine base propoxy-) benzoyl-5-kharophen benzo furans is obtained with Di-n-Butyl Amine condensation; again through hydrochloric acid hydrolysis; become with oxalic acid salt refining obtain 2-normal-butyl-3-(4-(3-Di-n-Butyl Amine base propoxy-) benzoyl-5-aminobenzofur dioxalic acid salt, synthetic route is as follows:
This method employs pays-Ke acylation reaction, and cause impurity in preparation process more because selectivity is poor, intermediate needs peroxidation aluminium chromatography, and the more difficult purifying of finished product, is unfavorable for suitability for industrialized production.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, provide a kind of preparation method of dronedarone hydrochloride intermediate, the method process is simple, good reaction selectivity, product yield are high, be easy to purifying, and products obtained therefrom is for the synthesis of the generation that can overcome by product during dronedarone hydrochloride, alleviate later-period purification process, reduce cost.
2-butyl-5-nitrobenzofuran is the raw material that synthesis Dronedarone is relatively commonly used, but owing to having strong carinogenicity, comparatively large to the injury of operator after considering later stage industrialization, so select with 2-butyl-5-aminobenzofur hydrochloride as raw material during research.Amino has 2 reactive hydrogens, be prepared Dronedarone can produce a lot of by products as direct with it, and purification difficult, yield is low, and therefore the generation how protecting the hydrogen on amino to stop by product is devoted in a lot of research, alleviates purifying difficulty.Patent US6828448, WO03040120A1, CN102666522, CN200880116389, WO2009044143, the method being carried out by the reactive hydrogen in amino protecting all is disclosed in CN101993427 etc., but have plenty of in these methods and only the substituting group (comprise methylsulfonyl) of one of them hydrogen with other is protected, have plenty of and two reactive hydrogens are all protected with different substituting groups, produce to overcome by product in reaction process, purification difficult, the problem of complicated operation, but these methods still also exist very large deficiency: only replace a hydrogen with methylsulfonyl, can reduce the later stage removes substituent process, but a remaining reactive hydrogen is still active, still by product can be produced in reaction process, increase the difficulty of purifying, and the consumption of solvent and catalyzer can be increased in Friedel-Crafts reaction process, increase cost, if replace the hydrogen on an amino with other substituting groups, not only there is above-mentioned deficiency, also need when the later stage prepares Dronedarone substituting group to remove, not only do not play the effect that protection is amino, also add operation steps, reduce productive rate.On amino two reactive hydrogen is replaced simultaneously, the generation of by product can be avoided, reduce the difficulty of purifying, but the substituent later stage removes difficulty and can not be all difference because of substituent.
From the data understood at present, also with Tetra hydro Phthalic anhydride, the method that amino is protected is not disclosed, find under study for action, Tetra hydro Phthalic anhydride is adopted to protect the amino in 2-butyl-5-nitrobenzofuran, due to phthalic acid is sterically hindered and with the conjugative effect of phenyl ring, make compound (II) selectivity when carrying out side chain docking very good, in reaction process, almost no coupling product produces, and reaction process step is simple, easy handling, equipment, solvent etc. require low, product yield is high, be easy to purifying, overcome in prior art and react loaded down with trivial details, cost is high, environmental pollution is serious, the bad purifying of intermediate, the problem that aftertreatment is loaded down with trivial details, greatly reduce the preparation difficulty of 5-amino-2-normal-butyl-3-[4-(the amino propoxy-of 3-di-n-butyl) benzoyl] cumarone oxalate.
The invention provides a kind of preparation method of dronedarone hydrochloride intermediate; it is a kind of method protecting amino reactive hydrogen; it is specially: to have the 2-butyl-5-aminobenzofur hydrochloride of structure formula I for starting raw material; under basic catalyst, organic solvent exist, carry out reaction generating structure formula II with Tetra hydro Phthalic anhydride.Under the effect of Eton reagent, 4-[3-(dibutylamino) propoxy-] phenylformic acid and structure formula II temperature control are obtained by reacting structure formula III, obtain the key intermediate structure formula IV of Dronedarone after structure formula III and oxalic acid salify.
Table 1. dronedarone hydrochloride intermediate structure formula
The route that the present invention prepares dronedarone hydrochloride key intermediate is as follows:
Embodiment:
Embodiment 1:
Prepared by 2-(2-butyl cumarone-5-base) isoindole-1,3-diketone:
Starting material 20.0g (0.0886mol) is slowly added to and stirs clearly molten in 15% sodium hydrogen carbonate solution of stirring, then add toluene 30mL, stir after 30 minutes, stratification, organic phase with 20mL washing once, organic phase retains.Tetra hydro Phthalic anhydride (13.2g, 0.0891mol) and triethylamine (0.9g, 0.0088mol) are slowly disposable to be added in organic phase, and temperature rising reflux water trap was except the water in dereaction 1.5 hours.Mixed reaction solution is cooled to 75 DEG C, after being down to temperature, adds 60.0mL hexanaphthene.Continue after adding hexanaphthene to be cooled to 20 DEG C, after reaction solution being continued be cooled to 20 DEG C, insulated and stirred crystallization 1 hour.Suction filtration, filter cake 20.0mL hexanaphthene drip washing.Dry title product at 50 DEG C, yield is: 93-98%.
LC-MS＝[M+H]
+＝319.12
Purity (HPLC): 97.8%
Embodiment 2:
The preparation of Eton solution:
Add P2O5 (27.8g0.196mol) under nitrogen protection in methanesulfonic (106mL) in batches.In reinforced process, temperature control is no more than 35 DEG C, has fed in raw material temperature control 25-35 DEG C and has stirred 30min, be prepared into Eton solution.
Embodiment 3:
5-amino-2-normal-butyl-3-[4-(the amino propoxy-of 3-di-n-butyl) benzoyl] cumarone preparation:
4-[3-(dibutylamino) propoxy-] phenylformic acid (17.6g0.0822mol) is added in the solution of Eton, add and stirred 15min, subsequently by JNDL-1 (25.0g, 0.0783mol) add in reaction solution the rear temperature control 35 DEG C that fed in raw material to stir 1 hour, after JNDL-1 has reacted, reaction solution is carried out cancellation by reaction solution at 15 DEG C, pour in the mixed solution of water (250ml) and methylene dichloride (50ml) slowly, stratification, organic layer is with 5% sodium hydrogen carbonate solution drip washing twice (total amount is 100ml), after using water wash (100ml) methylene dichloride evaporate to dryness subsequently again, obtain the title product of oily, yield is 90-95%.
Purity (HPLC): 99.2%
LC-MS＝[M+H]
+＝478.32
Embodiment 4:
5-amino-2-normal-butyl-3-[4-(the amino propoxy-of 3-di-n-butyl) benzoyl] cumarone oxalate preparation:
Add Virahol (12.0L) stirring unlatching in the Dronedarone unhindered amina of oily after, add 40% aqueous methylamine solution (30ml), be warming up to 75 DEG C and stir 1 hour.Reaction solution concentrating under reduced pressure, steams debris getting Virahol (150ml) dispersed with stirring, adds oxalic acid (14.7g, 0.116mol), stirring reaction 30min at temperature control 65 DEG C.Reaction solution is cooled to 5 DEG C of stirring and crystallizing 1 hour.The solid suction filtration of separating out, acetone (30ml) drip washing is used in filter cake Virahol 30ml drip washing again, and filter cake is dry at 50 DEG C, and obtain title product, yield is 90-95%.
Purity (HPLC): 99.7%
LC-MS＝[M+H]
+＝568.31。
Claims (6)
1. the preparation method of a dronedarone hydrochloride key intermediate; it is characterized in that; described intermediate is 5-amino-2-normal-butyl-3-[4-(the amino propoxy-of 3-di-n-butyl) benzoyl] cumarone oxalate, and structural formula is as shown in formula IV, and step comprises:
1) with structure formula I for starting raw material, basic catalyst, organic solvent exist under, carry out reaction generating structure formula II with Tetra hydro Phthalic anhydride, reaction formula is as follows:
2) under the effect of Eton reagent, 4-[3-(dibutylamino) propoxy-] phenylformic acid and structure formula II temperature control are obtained by reacting structure formula III, obtain the key intermediate structure formula IV of Dronedarone after structure formula III and oxalic acid salify, reaction formula is as follows:
2. the preparation method of dronedarone hydrochloride key intermediate according to claim 1, step 1) it is characterized in that, described basic catalyst is selected from triethylamine, DIPEA, sodium carbonate; Described organic solvent is selected from tetrahydrofuran (THF), toluene, methylene dichloride, ether, sherwood oil.
3. the preparation method of dronedarone hydrochloride key intermediate according to claim 1, step 1) feature be, the mol ratio of basic catalyst and 2-butyl-5-aminobenzofur hydrochloride is 0.1:1 ~ 2:1; The mol ratio of Tetra hydro Phthalic anhydride and 2-butyl-5-aminobenzofur hydrochloride is 1:1 ~ 5:1.
4. the preparation method of dronedarone hydrochloride key intermediate according to claim 1, step 1) feature be, temperature of reaction is 60 DEG C ~ 130 DEG C.
5. the preparation method of dronedarone hydrochloride key intermediate according to claim 1, step 2) feature be, the mol ratio of 4-[3-(dibutylamino) propoxy-] phenylformic acid and structure formula III is 1:1 ~ 5:1.
6. the preparation method of dronedarone hydrochloride key intermediate according to claim 1, step 2) feature be, the temperature of preparation structure (IV) is 10 DEG C ~ 45 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510958316.6A CN105399709A (en) | 2015-12-18 | 2015-12-18 | Preparation method of dronedarone hydrochloride key intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510958316.6A CN105399709A (en) | 2015-12-18 | 2015-12-18 | Preparation method of dronedarone hydrochloride key intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105399709A true CN105399709A (en) | 2016-03-16 |
Family
ID=55465511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510958316.6A Pending CN105399709A (en) | 2015-12-18 | 2015-12-18 | Preparation method of dronedarone hydrochloride key intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105399709A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880003A (en) * | 2016-09-30 | 2018-04-06 | 北京新领先医药科技发展有限公司 | A kind of new method of refined dronedarone hydrochloride |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050049302A1 (en) * | 2001-11-08 | 2005-03-03 | Arie Gutman | Process for the preparation of dronedarone |
| EP2371808A1 (en) * | 2010-03-08 | 2011-10-05 | Ratiopharm GmbH | Process for preparing dronedarone |
| CN102675267A (en) * | 2012-06-07 | 2012-09-19 | 济南富创医药科技有限公司 | Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride |
-
2015
- 2015-12-18 CN CN201510958316.6A patent/CN105399709A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050049302A1 (en) * | 2001-11-08 | 2005-03-03 | Arie Gutman | Process for the preparation of dronedarone |
| EP2371808A1 (en) * | 2010-03-08 | 2011-10-05 | Ratiopharm GmbH | Process for preparing dronedarone |
| CN102675267A (en) * | 2012-06-07 | 2012-09-19 | 济南富创医药科技有限公司 | Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| RAGHVENDRA R. HIVAREKAR等: "An Improved Scalable Route to Pure Dronedarone Hydrochloride", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
| RENU CHADHA等: "Identification and characterization of stress degradation products of dronedarone hydrochloride employing LC-UV/PDA, LC–MS/TOF and MSnstudies", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107880003A (en) * | 2016-09-30 | 2018-04-06 | 北京新领先医药科技发展有限公司 | A kind of new method of refined dronedarone hydrochloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4236926B2 (en) | Methanesulfonamide-benzofuran, its production method and use as a synthetic intermediate. | |
| EP2436669B1 (en) | Preparation of anticancer-active tricyclic compounds via alkyne coupling reaction | |
| CN102675267B (en) | Preparation method of dronedarone hydrochloride and intermediate of dronedarone hydrochloride | |
| CN105399709A (en) | Preparation method of dronedarone hydrochloride key intermediate | |
| CN109456253B (en) | Method for synthesizing (S) -3- (4-bromophenyl) -piperidine or salt thereof through chiral induction | |
| US4094987A (en) | 2-(3-m-hydroxy-phenyl-1-substituted-3-pyrrolidinyl)-ethanols | |
| CN105820174A (en) | Polysubstituted thienoindole derivative and preparation method thereof | |
| CN113004233B (en) | Compound for preparing PRC2 inhibitor, preparation method and application thereof | |
| CN110256451B (en) | Synthetic method of benzofuro [2,3-b ] quinoline derivative | |
| CN111303096B (en) | Synthesis method of polysubstituted 1, 3-dihydronaphtho [2,3-c ] furan derivative | |
| CN113429379A (en) | LH-1801 intermediate and preparation method and application thereof | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN110845410B (en) | Method for preparing 6, 7-dimethoxy-3, 4-dihydroisoquinoline hydrochloride by one-pot method | |
| CN107216300A (en) | The method of synthesis of chiral dihydropyran cyclics | |
| CN102336676A (en) | New preparation method of dopexamine hydrochloride by ArCHR protection strategy | |
| CN109232544B (en) | Preparation method of prucalopride | |
| CN111620788A (en) | Method for preparing (2S,3S) -3-amino-bicyclo [2.2.2] octane-2-formic ether | |
| CN113582953B (en) | Preparation method of key intermediate of amiodarone hydrochloride | |
| CN113461659B (en) | C-spirocyclic prostaglandin analogue intermediate and preparation method thereof | |
| CN102653530A (en) | Preparation method and application of benzofuran derivate | |
| CN116375570A (en) | Method for preparing dimethyl curcumin | |
| CN116813584A (en) | Preparation method of dronedarone hydrochloride intermediate | |
| Liu et al. | SmI2-mediated intermolecular addition–elimination of piperidine and pyrrolidine N-α-radicals with arylacetylene sulfones | |
| CN116410211A (en) | Benzofuran compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160316 |
|
| WD01 | Invention patent application deemed withdrawn after publication |