CN102690249B - Preparation method of dronedarone - Google Patents
Preparation method of dronedarone Download PDFInfo
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- CN102690249B CN102690249B CN201110069597.1A CN201110069597A CN102690249B CN 102690249 B CN102690249 B CN 102690249B CN 201110069597 A CN201110069597 A CN 201110069597A CN 102690249 B CN102690249 B CN 102690249B
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Abstract
The invention relates to the field of chemical synthesis, and discloses a preparation method of dronedarone. The preparation method takes inorganic base as an acid binding agent, and brings 5-amino-3-[4-(3-di-n-butylamino-propoxy)benzoyl]-2-n-butylbenzofuran or its salt and methanesulfonyl chloride into a mesylation reaction so as to obtain dronedarone. The preparation method prepared in the invention effectively reduces disulfonylation byproduct generation and improves the yield of dronedarone.
Description
Technical field
The present invention relates to the field of chemical synthesis, particularly a kind of preparation method of Dronedarone.
Background technology
Irregular pulse (cardiacarrhythmia) refers to that abnormal symptom appears in the rhythm of the heart origin position, cardiac frequency and the rhythm and pace of moving things and conduction of impulse etc.Atrial fibrillation is called for short " atrial fibrillation ", that cardiac muscle has been lost normal regular easypro contracting activity, and replace fast inharmonic faint wriggling, cause atrium to lose normal effectively contraction, it is a kind of common cardiac arrhythmia, sickness rate is up to 10% in the elderly for atrial fibrillation, and its danger is only second to premature beat, in numerous cardiovascular disordeies, occupies second.
Cardiovascular agent amiodarone (amiodarone) belongs to III class anti-arrhythmic, not only can serve as slight noncompetitive α and beta-2 adrenoceptor retarding agent, and have the character of slight I and IV class anti-arrhythmic.The electric physiological effect of amiodarone is mainly manifested in: 1, extend action potential and the effective refractory period of Ge Bu cardiac muscular tissue, be conducive to eliminate reciprocal excitation; 2, the fast sodium ion inflow that suppresses atrium and myocardiac conductive fibers, conduction of velocity slows down; 3, lower sinus-node self-activity, atrial fibrillation is had to good result for the treatment of.Although amiodarone can effectively be treated cardiac arrhythmia, the untoward reaction of patient's long-term taking amiodarone is more, wherein taking thyroid disease, retinal damage and lung's toxicity as main.Studies confirm that, the iodine in above-mentioned untoward reaction and amiodarone structure is in close relations.Dronedarone (Dronedarone) is a kind of derivative of cumarone, chemical name is: N-{2-butyl-3-[4-(3-dibutylamino propyl alcohol) benzoyl] cumarone-5-yl } methylsulfonamides (IUPAC), structurally similar to amiodarone, there is no iodine substituting group, it is a kind of hyperchannel retarding agent, pharmaceutical research shows, the electrophysiology of Dronedarone is similar to amiodarone with blood dynamics characteristic.In animal model, show, Dronedarone can prevent atrial fibrillation, recover sinus rhythm, prevention ventricular tachycardia and ventricular fibrillation.Given this, using close with amiodarone structure and containing the Dronedarone (structure is suc as formula shown in II) of iodine, as the alternative medicine Cardiovarscular of amiodarone, security is not higher.
Formula II
European patent EP 471609 discloses a kind of preparation method of Dronedarone; the method is taking triethylamine as acid binding agent; in methylene dichloride, 5-amino-3-[4-(3-di-n-butyl amino propoxy-) benzoyl]-2-normal-butyl benzo furans (structure is suc as formula shown in I) reacts generation Dronedarone with methylsulfonyl chloride.
Formula I
But the method, taking triethylamine as acid binding agent, easily produces a large amount of disulfonyl by products (structure is as shown in formula III), the yield of the product Dronedarone making by the method is only 61.6%.Separately there are some researches show, if condition control is improper, almost all generate disulfonyl by product.And acid binding agent triethylamine and product separation difficulty, need column chromatography to carry out purifying, complicated operation.Therefore, provide a kind of new method to prepare Dronedarone, significant.
Formula III
Summary of the invention
In view of this, the present invention proposes a kind of preparation method of Dronedarone.Preparation method provided by the invention, has effectively reduced the generation of disulfonyl by product, has improved the yield of Dronedarone.
In order to realize foregoing invention object, the invention provides following technical scheme:
The invention provides the preparation method of a kind of structure suc as formula the Dronedarone of compound shown in II, taking mineral alkali as acid binding agent, compound or its salt shown in formula I reacts with methylsulfonyl chloride generation methylsulfonyl, generates Dronedarone.
Formula I
Formula II
The chemical name of compound shown in formula I is 5-amino-3-[4-(the amino propoxy-of 3-di-n-butyl) benzoyl]-2-normal-butyl benzo furans, can be buied by market, also can prepare voluntarily.The present invention adopts the method for recording in patent EP471609, taking 4-nitrophenol as compound shown in raw material synthesis type I.
Consider that shown in formula I, compound contains aniline structure, unstable and be unfavorable for store, be made into salt, can strengthen its stability.Therefore, the present invention also adopts the salt of compound shown in formula I to carry out compound Dronedarone shown in preparation formula II as raw material.Salt to compound shown in formula I also has no special requirements, as long as can salify.Wherein preferably salt hydrochlorate, vitriol, nitrate, phosphoric acid salt in inorganic salt, preferred oxalate, Citrate trianion in organic salt.In preparation method provided by the invention, the salt of compound shown in formula I can be selected from hydrochloride, vitriol, nitrate, phosphoric acid salt, oxalate, Citrate trianion.Preferably, the present invention adopts the oxalate of compound shown in formula I as compound Dronedarone shown in raw material preparation formula II.
In methylsulfonyl process, the HCl generating when acidylate can generate salt with free amine, thereby reduces the speed of main reaction; therefore can add in acid binding agent and HCl, make medium keep neutrality or weakly alkaline, and make amine keep unbound state; impel reaction to carry out to the right, to improve the yield of acylation reaction.
Acid binding agent, refers to the sour alkaline matter generating in can absorption reaction system, conventional acid binding agent: organic bases is as triethylamine, pyridine etc., and mineral alkali is as sodium carbonate, sodium hydroxide, salt of wormwood, saleratus etc.
In producing at present mainly with triethylamine as acid binding agent; react with methylsulfonyl chloride and generate a large amount of disulfonyl by products at compound shown in methylene dichloride Chinese style I; the yield of Dronedarone is lower; and triethylamine and product separation difficulty, need column chromatography to carry out purifying, complicated operation to product; consider that again triethylamine has strong impulse to respiratory tract; after suction, can cause that pulmonary edema is even dead, eye and skin contact can cause chemical burn, easily operator's health are worked the mischief.The alkalescence of mineral alkali is weaker than triethylamine, can make amino reactive behavior reduce, and effectively reduces the generation of disulfonyl by product, and easy and product separation, and security is good, and therefore, the present invention selects mineral alkali as acid binding agent.As preferably, mineral alkali can be a kind of or both the above mixtures in sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.Preferably, select sodium bicarbonate as acid binding agent.
As preferably, in preparation method provided by the invention, the mol ratio of compound or its salt shown in formula I and mineral alkali is 1: 2～6.Preferably, the mol ratio of compound or its salt and mineral alkali shown in formula I is 1: 4.
As preferably, the solvent of methylsulfonylization reaction is selected organic solvent, and organic solvent can be DMF, toluene or methylene dichloride.Preferably, the solvent of methylsulfonylization reaction is methylene dichloride.
As preferably, in preparation method provided by the invention, the condition of methylsulfonylization reaction is to react 7～30h at 20～50 DEG C.Preferably, in preparation method provided by the invention, the condition of methylsulfonylization reaction is 40 DEG C of reaction 20h.
Preparation method provided by the invention is using mineral alkali as acid binding agent, and compound or its salt shown in formula I reacts with methylsulfonyl chloride generation methylsulfonyl, makes Dronedarone.Test-results shows, preparation method provided by the invention has effectively reduced the generation of disulfonyl by product, and the content of disulfonyl by product is reduced to 0～0.58% by 81.07%; Improved the yield of Dronedarone, yield is that 75.8～77.2%, HPLC analysis Dronedarone purity is 98.7～99.2%.From above technical scheme, preparation method of the present invention can effectively reduce the generation of disulfonyl by product, and the yield of gained Dronedarone is higher, and preparation method is simple, and agents useful for same safety, is beneficial to industrial production.
Brief description of the drawings
Fig. 1 shows in embodiment 1, taking sodium bicarbonate as acid binding agent, carries out the HPLC figure of methylsulfonylization reaction after product, wherein, and HPLC condition: phenomenex prodigy C18 post (250 × 4.6mm, 5 μ are m); Moving phase: methyl alcohol and buffering salt (10mmol/L KH
2pO
4solution, pH=7.0) volume ratio be 90: 10; Flow velocity: 1mL/min; Ultraviolet detection wavelength: 220nm; Column temperature: 40 DEG C; The peak 3 of retention time 10.59min is Dronedarone, and all the other peaks are impurity peaks, generates without disulfonyl by product.
Embodiment
The invention discloses a kind of preparation method of Dronedarone, those skilled in the art can use for reference content herein, suitably improve processing parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the middle of the present invention.Method of the present invention and application are described by preferred embodiment, related personnel obviously can change methods and applications as herein described in content of the present invention, spirit and scope or suitably change and combination not departing from, and realizes and apply the technology of the present invention.
The invention provides the preparation method of a kind of structure suc as formula the Dronedarone of compound shown in II, taking mineral alkali as acid binding agent, compound or its salt shown in formula I reacts with methylsulfonyl chloride generation methylsulfonyl, makes Dronedarone.
Formula I
Formula II
The chemical name of compound shown in formula I is 5-amino-3-[4-(the amino propoxy-of 3-di-n-butyl) benzoyl]-2-normal-butyl benzo furans; can be according to recording in EP471609 patent application document, compound shown in through type IV (2-butyl-5-nitrobenzofuran) makes compound shown in formula I for raw material through friedel-crafts reaction, demethylating reaction, O-hydrocarbylation, hydro-reduction.
Formula IV
Synthetic route is as follows:
Compound shown in formula I can also be by compound shown in formula IV (2-butyl-5-nitrobenzofuran)
For raw material, with chemical name be that shown in the formula V of 4-(3-dibutylamino propoxy-) benzoyl chloride hydrochloride salt, compound obtains compound shown in formula VI through friedel-crafts reaction, then make through hydro-reduction.
Formula V formula VI
Synthetic route is as follows:
The present invention adopts the method for recording in patent EP471609, and taking 4-nitrophenol as compound shown in raw material synthesis type I, synthetic route is as follows:
The present invention also adopts the salt of compound shown in formula I to carry out compound Dronedarone shown in preparation formula II as raw material.The salt of compound shown in formula I can be selected from hydrochloride, vitriol, nitrate, phosphoric acid salt, oxalate, Citrate trianion.Preferably, the present invention adopts the oxalate of compound shown in formula I to prepare Dronedarone as raw material.
Preparation method provided by the invention, methylsulfonylization reaction selects mineral alkali as acid binding agent.As preferably, mineral alkali can be a kind of or both the above mixtures in sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus.Preferably, select sodium bicarbonate as acid binding agent.
As preferably, in preparation method provided by the invention, the mol ratio of compound or its salt shown in formula I and mineral alkali is 1: 2～6.Preferably, the mol ratio of compound or its salt and mineral alkali shown in formula I is 1: 4.
Preparation method provided by the invention, methylsulfonylization reaction is carried out in solvent, preferably organic solvent, organic solvent can be DMF, toluene or methylene dichloride.Preferably, organic solvent is methylene dichloride.
As preferably, in preparation method provided by the invention, the condition of methylsulfonylization reaction is to react 7～30h at 20～50 DEG C.Preferably, in preparation method provided by the invention, the condition of methylsulfonylization reaction for to react 20h at 40 DEG C.
In preparation method provided by the invention, also comprise the step of product being carried out to purifying.Particularly, comprise to product wash, be dried, the step of crystallization.
Below in conjunction with embodiment, further set forth the present invention:
The selection of embodiment 1 acid binding agent
Taking compound shown in formula I as raw material, respectively with triethylamine, N, N-diisopropyl ethyl amine, DMAP, salt of wormwood, sodium bicarbonate are acid binding agent, and methylene dichloride is solvent, carries out methylsulfonyl reaction, and HPLC analyzes, and result is as table 1:
Table 1 is taking compound shown in formula I as the suitable acid binding agent of raw material screening
Wherein, HPLC condition: phenomenex prodigy C18 post (250 × 4.6mm, 5 μ are m); Moving phase: methyl alcohol and buffering salt (10mmol/L KH
2pO
4solution, pH=7.0) volume ratio be 90: 10; Flow velocity: 1mL/min; Ultraviolet detection wavelength: 220nm; Column temperature: 40 DEG C; Retention time 10.36min is Dronedarone, and retention time 11.41min is disulfonyl by product.
Table 1 data presentation, is reacted with methylsulfonyl chloride under the effect of acid binding agent triethylamine by compound shown in formula I, easily produces a large amount of disulfonyl by products, and content is 81.07%; Adopt organic bases N, N-diisopropyl ethyl amine or DMAP are acid binding agent, can produce content and be 77.89～84.51% disulfonyl by product.Adopting mineral alkali salt of wormwood, sodium bicarbonate is acid binding agent, and the content of disulfonyl by product is only 0.24～0.58%, has effectively reduced the generation of disulfonyl by product.
Reacted with methylsulfonyl chloride under the effect of acid binding agent triethylamine by compound shown in formula I, in product, the content of Dronedarone is only 7.31%; Adopt organic bases N, N-diisopropyl ethyl amine or DMAP, in product, the content of Dronedarone is 7.62～19.43%.Adopting mineral alkali salt of wormwood, sodium bicarbonate is acid binding agent, and in product, the content of Dronedarone is increased to 94.57～94.88%, has effectively improved the yield of Dronedarone.Adopt mineral alkali as acid binding agent, avoided the separation and purification of triethylamine and product, easy and simple to handle, avoided the residual harm that may cause of triethylamine, not only environmental protection but also economy simultaneously.
The selection of embodiment 2 acid binding agents
Taking the oxalate of compound shown in formula I as raw material, respectively taking triethylamine, diisopropyl ethyl amine, DMAP, pyridine, salt of wormwood, sodium bicarbonate as acid binding agent, methylene dichloride is solvent, carries out methylsulfonyl reaction, and HPLC analyzes, and result is as table 2:
Table 2 is taking the oxalate of compound shown in formula I as the suitable acid binding agent of raw material screening
Wherein, HPLC condition: phenomenex prodigy C18 post (250 × 4.6mm, 5 μ are m); Moving phase: methyl alcohol and buffering salt (10mmol/L KH
2pO
4solution, pH=7.0) volume ratio be 90: 10; Flow velocity: 1mL/min; Ultraviolet detection wavelength: 220nm; Column temperature: 40 DEG C; Retention time 10.40min is Dronedarone, and retention time 11.25min is disulfonyl by product.
Table 2 data presentation, is reacted with methylsulfonyl chloride under the effect of acid binding agent triethylamine by the oxalate of compound shown in formula I, and the output that the content of disulfonyl by product generates disulfonyl by product than compound shown in formula I as raw material is few, and content is 0.36%; Adopt organic bases N, N-diisopropyl ethyl amine or DMAP are as acid binding agent, and the content of disulfonyl by product is 0.15～0.37%.Adopting mineral alkali salt of wormwood, sodium bicarbonate is acid binding agent, does not produce disulfonyl by product, has effectively avoided the generation of disulfonyl by product.
Oxalate by compound shown in formula I reacts with methylsulfonyl chloride under the effect of acid binding agent triethylamine, and in product, the content of Dronedarone is 94.56%, and the product yield making as raw material than compound shown in formula I is high; Adopt organic bases N, N-diisopropyl ethyl amine or DMAP are as acid binding agent, and in product, the content of Dronedarone is 96.12～96.23%.Adopting mineral alkali salt of wormwood, sodium bicarbonate is acid binding agent, and in product, the content of Dronedarone is increased to 96.82～97.98%, has improved the yield of Dronedarone.Adopt mineral alkali as acid binding agent, avoided the separation and purification of triethylamine and product, easy and simple to handle, avoided the residual harm that may cause of triethylamine, not only environmental protection but also economy simultaneously.
The preparation of embodiment 3 Dronedarones
Get 50mL reaction flask, add 5-amino-3-[4-(3-di-n-butyl amino propoxy-) benzoyl] the hydrochloride 1.0g of-2-normal-butyl benzo furans, methylene dichloride 10mL, sodium bicarbonate 0.61g.Room temperature drips methylsulfonyl chloride 0.42g/ methylene dichloride 10mL solution.Drip and finish, 20 DEG C of reaction 20h.Suction filtration, collect filtrate, filter cake washed with dichloromethane, collect washings, after merging filtrate and washings through wash, anhydrous magnesium sulfate drying, evaporate to dryness, crystallization, obtains Dronedarone 0.76g, yield 76.0%.HPLC purity is 99.1%.
Wherein, HPLC condition: phenomenex prodigy C18 post (250 × 4.6mm, 5 μ are m); Moving phase: methyl alcohol and buffering salt (10mmol/L KH
2pO
4solution, pH=7.0) volume ratio be 90: 10; Flow velocity: 1mL/min; Ultraviolet detection wavelength: 220nm; Column temperature: 40 DEG C; Fig. 1 is shown in by collection of illustrative plates, and the peak 3 that retention time is 10.59min is Dronedarone, and all the other peaks are impurity peaks, generate without disulfonyl by product.
The preparation of embodiment 4 Dronedarones
Get 250mL reaction flask, add 5-amino-3-[4-(3-di-n-butyl amino propoxy-) benzoyl] the oxalate 5.0g of-2-normal-butyl benzo furans, toluene 60mL, adds saleratus 3.04g.Room temperature drips methylsulfonyl chloride 1.74g/ toluene 40mL solution.Drip and finish, 40 DEG C of reaction 30h.Suction filtration, collect filtrate, filter cake toluene wash, collect washings, after merging filtrate and washings through wash, anhydrous magnesium sulfate drying, evaporate to dryness, crystallization, obtains Dronedarone 3.22g, yield 77.2%.HPLC purity is 99.2%.
The preparation of embodiment 5 Dronedarones
Get 50mL reaction flask, add 5-amino-3-[4-(the amino propoxy-of 3-di-n-butyl) benzoyl]-2-normal-butyl benzo furans 1.0g, DMF 10mL, adds salt of wormwood 0.58g.Room temperature drips methylsulfonyl chloride 0.35g/N, dinethylformamide 10mL solution.Drip and finish, 25 DEG C of reaction 7h.Suction filtration, collect filtrate, filter cake washs with DMF, collect washings, after merging filtrate and washings through washing, anhydrous magnesium sulfate drying, evaporate to dryness, crystallization, obtains Dronedarone 0.88g, yield 75.8%.HPLC purity is 98.7%.
The preparation of embodiment 6 Dronedarones
Get 250mL reaction flask, add 5-amino-3-[4-(3-di-n-butyl amino propoxy-) benzoyl] the vitriol 5.12g of-2-normal-butyl benzo furans, methylene dichloride 60mL, adds sodium carbonate 2.52g.Room temperature drips methylsulfonyl chloride 1.74g/ methylene dichloride 40mL solution.Drip and finish, 50 DEG C of reaction 25h.Suction filtration, collect filtrate, filter cake washed with dichloromethane, collect washings, after merging filtrate and washings through wash, anhydrous magnesium sulfate drying, evaporate to dryness, crystallization, obtains Dronedarone 3.18g, yield 76.3%.HPLC purity is 98.9%.
The preparation of embodiment 7 Dronedarones
Get 50mL reaction flask, add 5-amino-3-[4-(3-di-n-butyl amino propoxy-) benzoyl] the Citrate trianion 1.0g of-2-normal-butyl benzo furans, DMF 10mL, adds salt of wormwood 1.23g.Room temperature drips methylsulfonyl chloride 0.35g/N, dinethylformamide 10mL solution.Drip and finish, 32 DEG C of reaction 14h.Suction filtration, collect filtrate, filter cake washs with DMF, collect washings, after merging filtrate and washings through washing, anhydrous magnesium sulfate drying, evaporate to dryness, crystallization, obtains Dronedarone 0.64g, yield 76.2%.HPLC purity is 98.9%.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (6)
1. a preparation method for Dronedarone, is characterized in that, taking mineral alkali as acid binding agent, compound or its salt shown in formula I reacts with methylsulfonyl chloride generation methylsulfonyl, generates Dronedarone; Described mineral alkali is one or more the mixture in sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus; Shown in described formula I, the salt of compound is selected from its hydrochloride, vitriol, nitrate, phosphoric acid salt, oxalate, Citrate trianion; The condition of described methylsulfonylization reaction is to react 7～30h at 20～50 DEG C;
2. preparation method as claimed in claim 1, is characterized in that, shown in described formula I, the salt of compound is oxalate.
3. preparation method as claimed in claim 1, is characterized in that, shown in described formula I, the mol ratio of compound or its salt and described mineral alkali is 1: 2～6.
4. preparation method as claimed in claim 3, is characterized in that, shown in described formula I, the mol ratio of compound or its salt and described mineral alkali is 1: 4.
5. preparation method as claimed in claim 1, is characterized in that, the solvent of described methylsulfonylization reaction is selected from DMF, toluene or methylene dichloride.
6. preparation method as claimed in claim 1, is characterized in that, the condition of described methylsulfonylization reaction for to react 20h at 40 DEG C.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW199095B (en) * | 1990-08-06 | 1993-02-01 | Sanofi Co | |
| WO2003040120A1 (en) * | 2001-11-08 | 2003-05-15 | Isp Investments Inc. | Process for the preparation of dronedarone |
| CN1479706A (en) * | 2000-12-11 | 2004-03-03 | ʥŵ��-�ϳ�ʵ���ҹ�˾ | 2-butyl-3-(4-[3-(dibutylamino) propoxy] benzoyl)-5-nitro-benzofuran hydrochloride and preparation thereof |
| CN101429156A (en) * | 2008-10-15 | 2009-05-13 | 河北百灵威超精细材料有限公司 | Novel methods for producing 1,2,3,4-tetrahydrochysene-4,4-dimethyl quinoline and its derivant |
-
2011
- 2011-03-22 CN CN201110069597.1A patent/CN102690249B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW199095B (en) * | 1990-08-06 | 1993-02-01 | Sanofi Co | |
| CN1479706A (en) * | 2000-12-11 | 2004-03-03 | ʥŵ��-�ϳ�ʵ���ҹ�˾ | 2-butyl-3-(4-[3-(dibutylamino) propoxy] benzoyl)-5-nitro-benzofuran hydrochloride and preparation thereof |
| WO2003040120A1 (en) * | 2001-11-08 | 2003-05-15 | Isp Investments Inc. | Process for the preparation of dronedarone |
| CN101429156A (en) * | 2008-10-15 | 2009-05-13 | 河北百灵威超精细材料有限公司 | Novel methods for producing 1,2,3,4-tetrahydrochysene-4,4-dimethyl quinoline and its derivant |
Non-Patent Citations (1)
| Title |
|---|
| 何晓清，等.盐酸决奈达隆合成路线图解.《中国医药工业杂志》.2010,第41卷(第2期),全文. * |
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