CN103288725B - Method for synthesising milrinone - Google Patents
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Abstract
The invention discloses a method for synthesising milrinone. The method comprises the following steps of: mixing 4-methylpyridine with acetylchloride in a solvent at a temperature below 10 DEG C; heating to react with or without a catalyst, and then adjusting the pH value of the reaction solution to 7-8 by sodium hydroxide aqueous solution; then directly adding saturated sodium hydrogen sulfite aqueous solution, and reacting; adjusting the pH value of the water layer obtained by the reaction by sodium hydroxide, and reacting to obtain a compound in formula (III); mixing the compound in formula (III) with glacial acetic acid, acetic anhydride and triethyl orthoformate, and then reacting at 50-100 DEG C to obtain a compound in formula (IV); cyclizing the compound in formula (IV) with alpha-cyanoacetamide in an alkaline condition to obtain a compound in formula (V). The process is more moderate in reaction conditions, simpler and more convenient to operate, and capable of greatly shortening the original reaction time, reducing cost and increasing yield simultaneously; the process is a preparation method for milrinone which is suitable for industrialized production.
Description
Technical field
The present invention relates to improving one's methods of a kind of milrinone (1,6-dihydro-2-methyl-6-oxygen-[the two pyridine of 3,4-]-5 formonitrile HCNs) preparation technology, belong to chemical industry and chemical and medicine industry field.
Background technology
Milrinone (Milrinone) is 1,6-dihydro-2-methyl-6-oxygen-[the two pyridine of 3,4-]-5 formonitrile HCN common names, molecular formula: C
12h
9n
3o, molecular weight: 211.22, its structural formula is:
Milrinone is developed successfully by Sterling company of the U.S. the earliest, within 1987, is ratified first in the U.S. by FDA, 1992 in United States Non-Provisional listing, subsequently in Britain, France, Germany, Holland and the national list marketing such as Belgian.
This product is phosphodiesterase inhibitor, and be the homology medicine of amrinone (Amrinone), the mechanism of action is identical with amrinone.Oral and quiet note is all effective, has positive inotropic action and vasorelaxation action concurrently.But it is strong 10 ~ 30 times that it acts on comparatively amrinone.Tolerance is better.This product positive inotropic action mainly by suppressing phosphodiesterase, makes cyclic monophosphate in myocardial cell (CAMP) concentration increase, and intracellular Ca2+ increases, and myocardial contraction is strengthened, and cardiac output increases.
At present multinational in U.S. etc., intravenous injection milrinone has been widely used in the heart function improving heart failure patient.Wherein, French Sai Nuofei-Sheng Delabao company milrinone sales volume in 2000 reaches 1.8 hundred million Euros.In China, the clinical application of milrinone is also increasing, and domestic milrinone in 2011 is sold and reached nearly 6,000 ten thousand yuan, 2012, and present the trend risen year by year, be mainly used for treatment congestive heart failure, pulmonary hypertension, postcardiac surgery Low output syndromes and myocardosis.
The synthesis technique of existing many sections of documents and patent report milrinone at present, but these documents all have shortcoming in various degree, and some reaction times is longer, and some desired raw materials are expensive, and operational hazards, some aftertreatments are loaded down with trivial details or yield is lower.
Existing technique is to be divided into two class methods on the whole: first kind method is for starting raw material with 4-picoline, prepare 1-(4-pyridyl)-2-acetone, then the method priority and triethyl orthoformate, the α-Malonamide nitrile that pass through " treating different things alike " are obtained by reacting milrinone crude product, then obtain the fine work milrinone of injection stage by recrystallization.These class methods are as reaction scheme I, its the first step can be realized by 2 paths, 1st paths needs to use n-Butyl Lithium, well-known butyllithium is met water chance oxygen and easily thermopositive reaction is occurred, at air easy firing, once expanded by heating easily causes blast, therefore more difficult in operation, price is relatively expensive simultaneously, is also unfavorable for suitability for industrialized production.2nd paths and Acetyl Chloride 98Min. at room temperature react 16 hours, although reaction conditions is gentleer, the reaction times is long.With saturated sodium carbonate regulation system pH value in aftertreatment simultaneously, find to need to consume the aqueous phase being greater than 10 times amount reaction volumes, cause operational difficulty, 3 extractions, concentrating under reduced pressure is used in whole post-reaction treatment, aftertreatment is more loaded down with trivial details, and the second step reaction times is longer, adds production cost.
Equations of The Second Kind method is as route 1, same with 4-picoline for starting raw material, prepare 1-(4-pyridyl)-2-acetone, and then with propane dinitrile and triethyl orthoformate for Ethoxy methylene malononitrile 99 prepared by raw material, finally 1-(4-pyridyl)-2-acetone and Ethoxy methylene malononitrile 99 reaction are prepared milrinone crude product, obtain fine work milrinone by recrystallization equally.This method needs 3 step reactions to prepare milrinone, and can not be realized by " treating different things alike " method, therefore route is longer comparatively speaking, and final step reaction yield is lower only has 34%, relative to other routes 70% yield for can say without any competitive edge.
Summary of the invention
The object of the invention is on the basis of existing technology, a kind of new milrinone preparation technology is provided.The time that this technological reaction condition milder, operation be easier, substantially reduce original reaction simultaneously, reduce costs raising yield, be suitable for the preparation method of the milrinone of suitability for industrialized production.
Object of the present invention can be reached by following measures:
Synthesize a method for milrinone, it comprises the steps:
(1) after 4-picoline and Acetyl Chloride 98Min. mix in less than 10 DEG C in a solvent, in the presence of a catalyst in 25 DEG C ~ 30 DEG C reactions 2 ~ 4 hours, or to be warming up to 35 DEG C ~ 45 DEG C reactions 2 ~ 4 hours under catalyzer not adding, then pH value to 7 ~ 8 of reaction solution are regulated with aqueous sodium hydroxide solution, directly add saturated aqueous solution of sodium bisulfite again to react, the water layer of reaction gained regulates pH13 ~ 14 to react with sodium hydroxide again, obtains formula (III) compound;
(2), after formula (III) compound mixes with glacial acetic acid, diacetyl oxide and triethyl orthoformate, react at 50 DEG C ~ 100 DEG C, obtain formula (IV) compound;
(3) formula (IV) compound and the cyclization in the basic conditions of α-Malonamide nitrile, obtain formula V compound;
Its reaction scheme is as follows:
Solvent is in step (1) the one in methylene dichloride, sherwood oil, normal hexane, normal heptane, toluene, hexanaphthene, methyl tertiary butyl ether; The mol ratio of 4-picoline and Acetyl Chloride 98Min. is 1:1.5 ~ 2.5, is preferably 1:1.8 ~ 2.2.Catalyzer can select Lewis acid (Lewis Acid): boron trifluoride diethyl etherate, Aluminum chloride anhydrous, iron(ic) chloride, zinc chloride, cuprous bromide, fluoroform sulphonate etc., when adopting catalyzer, temperature of reaction is 25 DEG C ~ 30 DEG C, as then having a strong impact on product yield and purity higher than this scope; When not adopting catalyzer, temperature of reaction is 35 DEG C ~ 45 DEG C.
Aqueous sodium hydroxide solution concentration in step (1) has a significant impact aqueous phase amount needed for regulation system PH, and then the operation difficulty of post-reaction treatment is had a strong impact on, its suitable concentration is 0.5 ~ 6mol/L, experiment confirms, can have a strong impact on yield and the purity of formula (III) compound higher or lower than this concentration; And after adding aqueous sodium hydroxide solution adjust ph, no longer need the steps such as static layering extraction, concentrating under reduced pressure, directly can add saturated aqueous solution of sodium bisulfite to react, temperature of reaction is 20 DEG C ~ 30 DEG C, reaction times is 2 ~ 4 hours, rear point water-yielding stratum, regulates PH to 13 ~ 14 to react with aqueous sodium hydroxide solution, obtains formula (III).
In step (2), the temperature of reaction of formula (III) compound and glacial acetic acid, diacetyl oxide and triethyl orthoformate is 50 DEG C ~ 100 DEG C, and the reaction times is 0.8 ~ 3.5 hour.The mol ratio of formula (III) compound and glacial acetic acid, diacetyl oxide and triethyl orthoformate is 1:2.5 ~ 5.0:2.0 ~ 3.0:1.0 ~ 2.5.
In step (3), the solvent of ring-closure reaction is preferably anhydrous methanol, and its alkaline condition can be provided by sodium methylate, and namely ring-closure reaction carries out under the existence of sodium methylate; The temperature of ring-closure reaction is 60 DEG C ~ 70 DEG C, preferred back flow reaction.
The mol ratio of formula (IV) compound, α-Malonamide nitrile and sodium methylate in step (3) is 1:1.0 ~ 2.0:4.5 ~ 8.0.
The visible following formula of a kind of detailed reaction process of this technique:
The technique that the present invention be directed to existing milrinone syntheti c route is improved, overcoming 3 step reactions in original synthetic route has 2 step reaction required times oversize, need to use a large amount of saturated sodium carbonates in post-reaction treatment and carry out regulation system pH value, extract concentrating under reduced pressure number of times too many simultaneously, complex operation, is unfavorable for the problems such as its suitability for industrialized production.The first step reaction can be shortened to 2 ~ 4hr by this technique, and second step reaction shortens to 0.8 ~ 2hr; Aqueous phase needed for regulation system pH value reduces the aqueous phase of 1.5 ~ 3 times amount reaction volumes; The system PH of adjustment directly adds sodium bisulfite reaction, decreases extraction concentrating under reduced pressure number of times etc.Technique of the present invention saves labor cost and raw materials cost, improves efficiency, simultaneously easy operational difficulty, and does not reduce purity and the yield of target product, easily can must realize suitability for industrialized production.
Embodiment
Embodiment one:
In 100mL three-necked bottle, add 4-picoline 7.95mL (81mmol), methylene dichloride 30mL and 20mg Aluminum chloride anhydrous, ice bath is cooled to 0 DEG C and drips Acetyl Chloride 98Min. 11.7mL (165mmol), in controlling in dropping process, temperature is below 10 DEG C, 25 DEG C are warming up to, reaction 2.5hr after dropwising.In system, drip 0.5mol/L aqueous sodium hydroxide solution under ice bath cooling and regulate pH to 7 ~ 8, then add the saturated sodium sulfite solution of 19.5mL, stirring at room temperature 2.5hr.Organic layer is merged, anhydrous sodium sulfate drying with dichloromethane extraction (50mL × 2).After recycling design, 65 ~ 67 DEG C/2.7kPa cut 3.84g is collected in underpressure distillation, and this is the complete 4-picoline of unreacted.Water layer 6.25molL-1 sodium hydroxide solution adjust pH is 13.25, reacts 2hr under room temperature.Add 24mL water, with methylene dichloride (20mL × 2) extraction, anhydrous sodium sulfate drying.Underpressure distillation after recycling design, collects 100 ~ 102 DEG C/217kPa cut 3.62g, HPLC:97.73%, yield 67.38%.
1-(4-pyridyl)-2-acetone 3.0g (22.2m mol) is added in 50mL round-bottomed flask, under stirring, 5.4mL (33mmol) triethyl orthoformate, 5.7mL (60mmol) diacetyl oxide and 5.55mL (102mmol) glacial acetic acid are joined in reaction flask, 50 DEG C of stirring reactions, after TLC tracing detection 3.5hr, raw material reaction is complete.60 DEG C of concentrating under reduced pressure except desolventizing, after add dehydrated alcohol and take high boiling solvent out of, obtain dark red oil, do not need purifying to be directly used in next step reaction.Sodium methylate 15g (content >=50%, >=139mmol), α-Malonamide nitrile 2.4g (28.5m mol) and product obtained in the previous step is added, 60 DEG C of reaction 2hr in 60mL anhydrous methanol.Cold filtration, solids with methanol washes twice, then dissolves by suitable quantity of water, activated carbon decolorizing.Filtrate adjusts pH6.5 ~ 7.0 to separate out solid with Glacial acetic acid, filters and obtains milrinone crude product.Solid, with DMF-ethyl alcohol recrystallization, obtains 3.39g light yellow crystal, HPLC:99.90%, yield 72.25%.
Embodiment two:
In 1000mL three-necked bottle, add 4-picoline 63.6mL (0.648mol), normal hexane 240mL, ice bath cooling is lower drips Acetyl Chloride 98Min. 66.9mL (0.972mol), in controlling in dropping process, temperature is below 10 DEG C, 40 DEG C of back flow reaction are warming up to, reaction 3hr after dropwising.In system, 6molL is dripped under ice bath cooling
-1aqueous sodium hydroxide solution regulates pH to 7 ~ 8, then adds the saturated sodium sulfite solution of 156mL, stirring at room temperature 2.5hr.Organic layer is merged, anhydrous sodium sulfate drying with n-hexane extraction (150mL × 2).After recycling design, 65 ~ 67 DEG C/2.7kPa cut 31.6g is collected in underpressure distillation, and this is the complete 4-picoline of unreacted.Water layer 6.25molL-1 sodium hydroxide solution adjust pH is 13.08, reacts 2hr under room temperature.Add 192mL water, with normal hexane (160mL × 2) extraction, anhydrous sodium sulfate drying.Underpressure distillation after recycling design, collects 100 ~ 102 DEG C/217kPa cut 28.3g, HPLC:97.97%, yield 66.82%.
1-(4-pyridyl)-2-acetone 20.0g (0.148mol) is added in 200mL round-bottomed flask, under stirring, 24.2mL (0.148mol) triethyl orthoformate, 28.1mL (0.296mol) diacetyl oxide and 20.1mL (0.37mol) glacial acetic acid are joined in reaction flask, 75 DEG C of stirring reactions, after TLC tracing detection is about 2hr, raw material reaction is complete.60 DEG C of concentrating under reduced pressure except desolventizing, after add dehydrated alcohol and take high boiling solvent out of, obtain dark red oil, do not need purifying to be directly used in next step reaction.Sodium methylate 71.9g (content >=50%, >=0.666mol), α-Malonamide nitrile 12.5g (0.148mol) and product obtained in the previous step is added, 70 DEG C of reaction 1.5hr in 400mL anhydrous methanol.Cold filtration, solids with methanol washes twice, then dissolves by suitable quantity of water, activated carbon decolorizing.Filtrate adjusts pH6.5 ~ 7.0 to separate out solid with Glacial acetic acid, filters and obtains milrinone crude product.Solid, with DMF-ethyl alcohol recrystallization, obtains 22.0g light yellow crystal, HPLC:99.90%, yield 70.4%.
Embodiment three:
In 2000mL three-necked bottle, add 4-picoline 200mL (2.038mol), hexanaphthene 800mL and 1mL copper trifluoromethanesulfcomposite, ice bath cooling is lower drips Acetyl Chloride 98Min. 361.3mL (5.092mol), in controlling in dropping process, temperature is below 10 DEG C, is warming up to 30 DEG C of reaction 3.5hr after dropwising.In system, drip 4molL-1 aqueous sodium hydroxide solution under ice bath cooling and regulate pH to 7 ~ 8, then add the saturated sodium sulfite solution of 491mL, stirring at room temperature 2.5hr.Organic layer is merged, anhydrous sodium sulfate drying with hexanaphthene extraction (400mL × 2).After recycling design, 65 ~ 67 DEG C/2.7kPa cut 93.95g is collected in underpressure distillation, and this is the complete 4-picoline of unreacted.Water layer 6.25m olL-1 sodium hydroxide solution adjust pH is 13.18, reacts 2hr under room temperature.Add 600mL water, with hexanaphthene (500mL × 2) extraction, anhydrous sodium sulfate drying.Underpressure distillation after recycling design, collects 100 ~ 102 DEG C/217kPa cut 100.3g, HPLC:94.51%, yield 71.15%.
1-(4-pyridyl)-2-acetone 50.0g (0.37mol) is added in 500mL round-bottomed flask, under stirring, 151.4mL (0.925mol) triethyl orthoformate, 105.5mL (1.11mol) diacetyl oxide and 100.7mL (1.85mol) glacial acetic acid are joined in reaction flask, 100 DEG C of stirring reactions, after TLC tracing detection 0.8hr, raw material reaction is complete.60 DEG C of concentrating under reduced pressure except desolventizing, after add dehydrated alcohol and take high boiling solvent out of, obtain dark red oil, do not need purifying to be directly used in next step reaction.Sodium methylate 320g (content >=50%, >=2.96mol), α-Malonamide nitrile 62.3g (0.74mol) and product obtained in the previous step is added, back flow reaction 1.5hr in 1000mL anhydrous methanol.Cold filtration, solids with methanol washes twice, then dissolves by suitable quantity of water, activated carbon decolorizing.Filtrate adjusts pH6.5 ~ 7.0 to separate out solid with Glacial acetic acid, filters and obtains milrinone crude product.Solid, with DMF-ethyl alcohol recrystallization, obtains 58.3g light yellow crystal, HPLC:99.93%, yield 74.6%.
Comparative example:
In 1000mL three-necked bottle, add 4-picoline 63.6mL (0.648mol), methylene dichloride 240mL, ice bath cooling is lower drips Acetyl Chloride 98Min. 93.6mL (1.32mol), in controlling in dropping process, temperature is below 10 DEG C, 40 DEG C of back flow reaction are warming up to, reaction 3hr after dropwising.In system, drip 8molL-1 aqueous sodium hydroxide solution under ice bath cooling and regulate pH to 7 ~ 8, then add the saturated sodium sulfite solution of 156mL, stirring at room temperature 2.5hr.Organic layer is merged, anhydrous sodium sulfate drying with dichloromethane extraction (150mL × 2).After recycling design, 65 ~ 67 DEG C/2.7kPa cut 31.6g is collected in underpressure distillation, and this is the complete 4-picoline of unreacted.Water layer 6.25molL-1 sodium hydroxide solution adjust pH is 13.20, reacts 2hr under room temperature.Add 192mL water, with methylene dichloride (160mL × 2) extraction, anhydrous sodium sulfate drying.Underpressure distillation after recycling design, collects 100 ~ 102 DEG C/217kPa cut 22.5g, HPLC:89.24%, yield 53.13%.Regulate pH to 7 ~ 8 and embodiment two to contrast with concentration 8molL-1 aqueous sodium hydroxide solution, formula (III) compound yield reduces to 53.13% from original 66.82%, and HPLC purity also reduced nearly 10%, and product purity is lower, and color becomes tawny from faint yellow.
Claims (7)
1. synthesize a method for milrinone, it is characterized in that comprising the steps:
(1) after 4-picoline and Acetyl Chloride 98Min. mix in less than 10 DEG C in a solvent, in 25 DEG C ~ 30 DEG C reactions 2 ~ 4 hours under catalyzer copper trifluoromethanesulfcomposite exists, then pH value to 7 ~ 8 of reaction solution are regulated with 0.5 ~ 6mol/L aqueous sodium hydroxide solution, directly add saturated aqueous solution of sodium bisulfite again to react 2 ~ 4 hours at 20 DEG C ~ 30 DEG C, then water-yielding stratum is divided, pH to 13 ~ 14 are regulated again with 0.5 ~ 6mol/L sodium hydroxide, react 2 ~ 3 hours, obtain formula (III) compound;
(2), after formula (III) compound mixes with glacial acetic acid, diacetyl oxide and triethyl orthoformate, react at 50 DEG C ~ 100 DEG C, obtain formula (IV) compound;
(3) formula (IV) compound and the cyclization in the basic conditions of α-Malonamide nitrile, obtain formula (V) compound;
Its reaction scheme is as follows:
2. the method for synthesis milrinone according to claim 1, is characterized in that the solvent in step (1) is methylene dichloride, sherwood oil, normal hexane, normal heptane, toluene, hexanaphthene or methyl tertiary butyl ether; The mol ratio of 4-picoline and Acetyl Chloride 98Min. is 1:1.5 ~ 2.5.
3. the method for synthesis milrinone according to claim 1, the temperature of reaction that it is characterized in that formula (III) compound in step (2) and glacial acetic acid, diacetyl oxide and triethyl orthoformate is 50 DEG C ~ 100 DEG C, and the reaction times is 0.8 ~ 3.5 hour.
4. the method for synthesis milrinone according to claim 1, is characterized in that the mol ratio of formula (III) compound in step (2) and glacial acetic acid, diacetyl oxide and triethyl orthoformate is 1:2.5 ~ 5.0:2.0 ~ 3.0:1.0 ~ 2.5.
5. the method for synthesis milrinone according to claim 1, is characterized in that in step (3), and the solvent of ring-closure reaction is anhydrous methanol, and ring-closure reaction carries out under the existence of sodium methylate.
6. the method for synthesis milrinone according to claim 1, is characterized in that in step (3), and the temperature of ring-closure reaction is 60 DEG C ~ 70 DEG C.
7. the method for synthesis milrinone according to claim 5, is characterized in that the mol ratio of formula (IV) compound, α-Malonamide nitrile and the sodium methylate in step (3) is 1:1.0 ~ 2.0:4.5 ~ 8.0.
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| CN103965101B (en) * | 2014-05-21 | 2016-07-06 | 合肥久诺医药科技有限公司 | A kind of preparation method of milrinone |
| CN104387320B (en) * | 2014-09-28 | 2018-01-26 | 湖州展望药业股份有限公司 | A kind of preparation method of high-purity milrinone |
| CN104326975A (en) * | 2014-10-20 | 2015-02-04 | 郑州四环医药用品有限公司 | Preparation method of high-purity milrinone |
| CN105777626A (en) * | 2014-12-18 | 2016-07-20 | 扬子江药业集团上海海尼药业有限公司 | Preparation method of milrinone |
| CN104744357A (en) * | 2015-03-30 | 2015-07-01 | 浙江中维药业有限公司 | Recrystallization purification method of milrinone |
| CN105037261B (en) * | 2015-07-03 | 2017-11-24 | 湖南赛隆药业有限公司 | A kind of method for synthesizing milrinone |
| CN106243032A (en) * | 2016-07-20 | 2016-12-21 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of preparation method of milrinone |
| CN106632025A (en) * | 2016-11-30 | 2017-05-10 | 湖州恒远生物化学技术有限公司 | Method for preparing milrinone |
| CN108440395A (en) * | 2018-04-04 | 2018-08-24 | 梯尔希（南京）药物研发有限公司 | A kind of preparation method of milrinone impurity |
| CN111484450A (en) * | 2019-01-28 | 2020-08-04 | 上海隆盛化工有限公司 | Preparation method of medical intermediate milrinone |
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