CN103980188B - The synthetic method of a kind of pyrrole Lun Panai and the synthetic method of intermediate and intermediate thereof - Google Patents
The synthetic method of a kind of pyrrole Lun Panai and the synthetic method of intermediate and intermediate thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Abstract
The present invention relates to pharmaceutical chemistry synthesis field, be specifically related to the synthetic method of a kind of pyrrole Lun Panai and the synthetic method of intermediate and intermediate thereof.The invention provides the synthetic method of a kind of pyrrole Lun Panai, comprise the steps: that formula V compound and formula VI compound carry out ring closure reaction and obtain formula VII compound:
wherein, R
1alkylamino, amino or alkoxyl group.Another object of the present invention is that the synthetic method the present invention of the intermediate providing a kind of pyrrole Lun Panai is in building-up process, introduce phenyl, cyano-phenyl and 2-pyridyl successively, compared with prior art, change and introduce substituent order, this avoid that to introduce the reaction yield that cyano-phenyl causes after first introducing 2-pyridyl low, by product is many, the problem that cannot remove again.Due to the change of route, final step reaction does not use the catalyzer containing Pd, thus decreases the residual of Pd, adds drug safety, and significantly improves reaction yield and product purity, be applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical chemistry synthesis field, be specifically related to the synthetic method of a kind of pyrrole Lun Panai and the synthetic method of intermediate and intermediate thereof.
Background technology
The chemical name of pyrrole Lun Panai (perampanel) is: 3-(2-cyano-phenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridine-2-ketone, and its structural formula is as follows:
Pyrrole Lun Panai (perampanel) is a kind of alpha-amino group-3-hydroxy-5-methyl base-4-different azoles propionic acid (AMPA) receptor antagonist, researched and developed by Eisai company, it reduces neurone be overexcited by suppressing postsynaptic AMPA receptors glutamate activity.This product ratifies listing on October 22nd, 2012 by U.S. food Drug Administration (FDA), its commodity are called Fycompa, for the assisting therapy of more than 12 years old epileptic's partial seizures, no matter whether patient is with Secondary cases full-blown.
Patent US20070142640 discloses a kind of method of synthesizing pyrrole Lun Panai on January 27th, 2007, and reaction process is as follows:
The defect of this route is: the tin reagent employing severe toxicity in reaction process; Final step reaction not exclusively, is difficult to remove raw material and impurity by the method for column chromatography or recrystallization; This step reaction is introduced containing Pd catalyzer, because there is Pd to remain, final product purity is not high, and yield is low, is not suitable as drug development.
Summary of the invention
The object of the present invention is to provide that a kind of toxicity is little, cost is low, yield is high, be applicable to the synthetic method of the pyrrole Lun Panai of drug development and suitability for industrialized production.
In order to realize this purpose, the invention provides the synthetic method of a kind of pyrrole Lun Panai, comprising the steps:
(1), formula V compound and formula VI compound carry out ring closure reaction and obtain formula VII compound:
Wherein, R
1alkylamino, amino or alkoxyl group.
Preferably, R
1methylamino, dimethylamino, amino, methoxy or ethoxy.
Preferably, R
1it is dimethylamino.
Preferably, described reaction exists at alkaline reagents, carries out under the condition of organic solvent.
Preferably, described reaction is carried out in potassium tert.-butoxide and THF system.
Preferably, described temperature of reaction is 90-100 DEG C, and the reaction times is 8-9 hour.
(2), formula IV compound and 2-cyanophenylboronic acid or its ester react acquisition formula V compound
Wherein, X
1it is halogen.
Preferably, X
1be bromine, described reaction exists at catalyzer, carries out under alkaline condition.
Preferably, in step (2), used catalyst is Pd (OAc)
2and PPh
3, alkaline condition is potassium tert.-butoxide, salt of wormwood, cesium carbonate, and described ester is 2-cyanophenylboronic acid dimethylene ester or 2-cyanophenylboronic acid-1,3-PD cyclic ester.
Preferred, described alkaline condition is salt of wormwood, and described ester is 2-cyanophenylboronic acid dimethylene ester.
(3), formula III compound carries out substitution reaction acquisition formula IV compound:
Wherein, X
1it is halogen.
Preferably, X
1be bromine, described substitution reaction is carried out in NBS.
(4), formula II compound and phenylo boric acid or its ester react acquisition formula III compound under metal catalyst alkaline condition:
Preferably, described metal catalyst is salt or the complex compound of copper or palladium, and alkaline condition is triethylamine or pyridine, and formula II compound and phenylo boric acid react.
Preferred, described metal catalyst is mantoquita, and alkaline condition is triethylamine, and the ratio of formula II compound and triethylamine is 1:1.5,1:1.7,1:3.
Most preferred, the ratio of formula II compound and triethylamine is 1:1.7.
(5), type I compound hydrolysis acquisition formula II compound:
Wherein, X
2halogen or alkoxyl group.
Preferably, X
2be chlorine, bromine, iodine, methoxy or ethoxy, described hydrolysis is carried out in acid condition.
Preferred, X
2be chlorine, described hydrolysis is carried out under hydrochloric acid or Hydrogen bromide condition.
Another object of the present invention is to the intermediate that a kind of pyrrole Lun Panai is provided, as follows:
Another object of the present invention is the synthetic method of the intermediate providing a kind of pyrrole Lun Panai, comprises the steps:
Formula IV compound and 2-cyanophenylboronic acid or its ester react acquisition formula V compound
Wherein, X
1it is halogen.
Preferably, X
1be bromine, described reaction exists at catalyzer, carries out under alkaline condition.
Preferably, used catalyst is Pd (OAc)
2and PPh
3, alkaline condition is potassium tert.-butoxide, salt of wormwood, cesium carbonate, and described ester is 2-cyanophenylboronic acid dimethylene ester or 2-cyanophenylboronic acid-1,3-PD cyclic ester.
Preferred, described alkaline condition is salt of wormwood, and described ester is 2-cyanophenylboronic acid dimethylene ester.
Formula III compound carries out substitution reaction and obtains formula IV compound:
Wherein, X
1it is halogen.
Preferably, X
1be bromine, described substitution reaction uses NBS to carry out.
Formula II compound and phenylo boric acid or its ester react acquisition formula III compound in the basic conditions:
Preferably, described metal catalyst is salt or the complex compound of copper or palladium, and alkaline condition is triethylamine or pyridine, and formula II compound and phenylo boric acid react.
Preferred, described metal catalyst is mantoquita, and alkaline condition is triethylamine, and the ratio of formula II compound and triethylamine is 1:1.5,1:1.7,1:3.
Most preferred, the ratio of formula II compound and triethylamine is 1: 1.7.
Type I compound hydrolysis acquisition formula II compound:
Wherein, X
2halogen or alkoxyl group.
Preferably, X
2be chlorine, bromine, iodine, methoxy or ethoxy, described hydrolysis is carried out in acid condition.
Preferred, X
2be chlorine, described hydrolysis is carried out under hydrochloric acid or Hydrogen bromide condition.
The present invention, in building-up process, introduces phenyl, cyano-phenyl and 2-pyridyl, compared with prior art successively, change and introduce substituent order, this avoid that to introduce the reaction yield that cyano-phenyl causes after first introducing 2-pyridyl low, by product is many, the problem that cannot remove again.Due to the change of route, final step reaction does not use the catalyzer containing Pd, thus decreases the residual of Pd, adds drug safety, and significantly improves reaction yield and product purity, be applicable to suitability for industrialized production.
Specific embodiment
Below in conjunction with embodiment, the invention will be further described, but protection content of the present invention is not limited only to these embodiments.
In the following example, method therefor if no special instructions, is ordinary method.Material required in following examples or reagent, be market if no special instructions and buy.
Embodiment 1:
The synthesis of 5-ethanoyl-1,2-dihydropyridine-2-ketone
The hydrochloric acid soln of 63ml35% is added, 100 DEG C of back flow reaction in the chloro-5-acetylpyridine of 155g2-.After reacting completely, regulate reaction solution pH to 7 to 8 with solution of potassium carbonate, under stirring, add 935mlTHF and 32g salt solution simultaneously.After solution layering, aqueous phase 935mlTHF and the water washing of 32g salt, merge organic phase, and concentrating under reduced pressure obtains crude product.Crude product is dissolved in ethyl acetate, is cooled to 0-5 DEG C of crystallization.Filtration, drying, obtain 130.1g target compound (yield 95%, purity 99.7%).
Embodiment 2:
The synthesis of 5-ethanoyl-1,2-dihydropyridine-2-ketone
The hydrochloric acid soln of 32ml35% is added, 100 DEG C of back flow reaction in 75.6g2-methoxyl group-5-acetylpyridine.After reacting completely, regulate reaction solution pH to 7 to 8 with solution of potassium carbonate, under stirring, add 468mlTHF and 16g salt solution simultaneously.After solution layering, aqueous phase 468mlTHF and the water washing of 16g salt, merge organic phase, and concentrating under reduced pressure obtains crude product.Crude product is dissolved in ethyl acetate, is cooled to 0-5 DEG C of crystallization.Filtration, drying, obtain 56.2g target compound (yield 82%, purity 99.0%).
Embodiment 3:
The synthesis of 5-ethanoyl-1,2-dihydropyridine-2-ketone
The hydrobromic acid solution of 63ml35% is added, 100 DEG C of back flow reaction in the chloro-5-acetylpyridine of 155g2-.After reacting completely, regulate reaction solution pH to 7 to 8 with solution of potassium carbonate, under stirring, add 935mlTHF and 32g salt solution simultaneously.After solution layering, aqueous phase 935mlTHF and the water washing of 32g salt, merge organic phase, and concentrating under reduced pressure obtains crude product.Crude product is dissolved in ethyl acetate, is cooled to 0-5 DEG C of crystallization.Filtration, drying, obtain 117.8g target compound (yield 86%, purity 99.3%).
Embodiment 4:
The synthesis of 1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone
Get 120g5-ethanoyl-1,2-dihydropyridine-2-ketone to be dissolved in DCM, and add Cu (OAc) successively in this solution
232g, phenyl-boron dihydroxide 215g and triethylamine 208ml (1.7 equivalent), stirred at room temperature 24h.In reaction solution, add strong aqua, separatory is washed, and solvent removed by evaporation at reduced pressure, obtains target compound 152.9g (yield 82%, purity 99.6%).
1H-NMR(400MHz,DMSO-d
6)δ：2.63(s，3H)，7.33(m，1H)，7.52-7.59(m，5H)，7.87(m，1H)，8.01(m，1H)
Embodiment 5:
The synthesis of 1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone
Get 54.8g5-ethanoyl-1,2-dihydropyridine-2-ketone to be dissolved in DCM, and add Cu (OAc) successively in this solution
214.6g, phenyl-boron dihydroxide 98.2g and triethylamine 84ml (1.5 equivalent), stirred at room temperature 24h.In reaction solution, add strong aqua, separatory is washed, and solvent removed by evaporation at reduced pressure, obtains target compound 63.9g (yield 75%, purity 99.3%).
Embodiment 6:
The synthesis of 1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone
Get 54.8g (0.4mol) 5-ethanoyl-1,2-dihydropyridine-2-ketone to be dissolved in DCM, and add Cu (OAc) successively in this solution
214.6g, phenyl-boron dihydroxide 98.2g and triethylamine 168ml (3 equivalent), stirred at room temperature 24h.Strong aqua is added in reaction solution.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product, through column chromatography purification, obtains target compound 53.0g (yield 62.2%, purity 99.5%).
Embodiment 7:
The synthesis of 1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone
Get 120g5-ethanoyl-1,2-dihydropyridine-2-ketone to be dissolved in DCM, and add Cu (OAc) successively in this solution
232g, phenyl-boron dihydroxide 215g and pyridine 120ml, stirred at room temperature 24h.Strong aqua is added in reaction solution.Solvent removed by evaporation at reduced pressure, obtains crude product.Crude product, through column chromatography purification, obtains target compound 85.8g (yield 46%, purity 99.0%).
Embodiment 8:
The synthesis of the bromo-1-phenyl of 3--5-ethanoyl-1,2-dihydropyridine-2-ketone
100g1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone is dissolved in 530mlN, and in dinethylformamide, low temperature adds N-bromine succinimide 83.7g under stirring.After adding, stirred at ambient temperature 2 hours.Reaction solution dilute with water, then extraction into ethyl acetate.The organic layer obtained uses water and saturated common salt water washing respectively, through anhydrous sodium sulfate drying.Solvent removed by evaporation at reduced pressure, obtains target compound 117.4g (yield 86%, purity 99.4%)
1H-NMR(400MHz,DMSO-d
6)δ：2.69(s，3H)，7.51(m，1H)，7.58-7.67(m，5H)，7.93(m，1H)
Embodiment 9:
The synthesis of 3-(2-cyano-phenyl)-1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone
Stir in downhill reaction device and add the bromo-1-phenyl of 116.4g3--5-ethanoyl-1,2-dihydropyridine-2-ketone, 90g2-cyanophenylboronic acid dimethylene ester, 75.9g salt of wormwood and 1900ml dimethyl formamide successively.Then 21.8gPd (OAc) is added wherein
2and 25.5gPPh
3, be stirred at 60 DEG C and react completely.After reaction terminates, add water in reaction solution, and be extracted with ethyl acetate.Organic layer uses water and salt water washing respectively, then uses anhydrous sodium sulfate drying.Rotary evaporation except desolventizing, adds ethyl acetate and heptane recrystallization obtains target compound 89.2g (yield 71%, purity 99.1%).
1H-NMR(400MHz,DMSO-d
6)δ：2.73(s，3H)，7.39(m，1H)，7.59-7.60(m，6H)，7.65(m，1H)，7.76(d，1H)，8.09(d，1H)，8.27(d，1H)
Embodiment 10:
The synthesis of 3-(2-cyano-phenyl)-1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone
Stir in downhill reaction device and add the bromo-1-phenyl of 116.4g3--5-ethanoyl-1,2-dihydropyridine-2-ketone, 90g2-cyanophenylboronic acid dimethylene ester, 61.7g potassium tert.-butoxide and 1900ml dimethyl formamide successively.Then 21.8gPd (OAc) is added wherein
2and 25.5gPPh
3, be stirred at 60 DEG C and react completely.After reaction terminates, add water in reaction solution, and be extracted with ethyl acetate.Organic layer uses water and salt water washing respectively, then uses anhydrous sodium sulfate drying.Rotary evaporation is except desolventizing, and gained crude product, by column chromatography purification (petrol ether/ethyl acetate system), obtains target compound 72.8g (yield 58%, purity 98.3%).
Embodiment 11:
The synthesis of 3-(2-cyano-phenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridine-2-ketone
By 62.8g3-(2-cyano-phenyl)-1-phenyl-5-ethanoyl-1; 2-dihydropyridine-2-ketone and 20.8g (2E)-3-(dimethylamino)-2-propenal are dissolved in 160mlTHF; be cooled to 0 DEG C; in reaction solution, add 27.0g potassium tert.-butoxide, then stir 1 hour at 30 DEG C.Subsequently, add 80ml acetic acid and 93.3g ammonium acetate, be warming up to 100 DEG C of reactions 5 hours.Cool the temperature to 50 DEG C, add 3.6g (2E)-3-(dimethylamino)-2-propenal, react at continuing 100 DEG C.After having reacted, in reaction solution, add 1000ml toluene, add 25% sodium hydroxide solution extraction.Organic layer with concentrated after water and 10% salt water washing, obtains target compound 62.8g respectively.(yield 90%, purity 99.7%)
1H-NMR(400MHz,DMSO-d
6)δ：7.32(m，1H)，7.52-7.62(m，6H)，7.72-7.85(m，3H)，7.93(dd，1H)，8.01(d，1H)，8.48(d，1H)，8.53(d，1H)，8.59(d，1H)
Embodiment 12:
The synthesis of 3-(2-cyano-phenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridine-2-ketone
By 62.8g3-(2-cyano-phenyl)-1-phenyl-5-ethanoyl-1; 2-dihydropyridine-2-ketone and 18.1g (2E)-3-methoxyl group-2-propenal are dissolved in 160mlTHF; be cooled to 0 DEG C, in reaction solution, add 27.0g potassium tert.-butoxide, then stir 1 hour at 30 DEG C.Subsequently, add 80ml acetic acid and 93.3g ammonium acetate, be warming up to 100 DEG C of reactions 5 hours.Cool the temperature to 50 DEG C, add 3.1g (2E)-3-methoxyl group-2-propenal, react at continuing 100 DEG C.After having reacted, in reaction solution, add 1000ml toluene, add 25% sodium hydroxide solution extraction.Organic layer with concentrated after water and 10% salt water washing, obtains target compound 50.9g respectively.(yield 73%, purity 98.9%)
Embodiment 13:
According to method synthesis 3-(2-cyano-phenyl)-1-phenyl-5-(2-pyridyl)-1, the 2-dihydropyridine-2-ketone of embodiment 11, as shown in the following chart, acquired results also sees the following form alkaline reagents used:
| Alkaline reagents | Productive rate (%) | Purity (%) |
| Cesium carbonate | 75.0 | 98.5 |
| Salt of wormwood | 79.2 | 99.0 |
| Triethylamine | 52.1 | 98.0 |
Claims (10)
1. synthesize a method of pyrrole Lun Panai, it is characterized in that, this reaction scheme carries out successively by reaction formula (1)-(5):
Wherein, R
1alkylamino, amino or alkoxyl group; X
1it is halogen; X
2halogen or alkoxyl group.
2. synthesize a method of pyrrole Lun Panai, it is characterized in that, the method comprises the steps: that formula V compound and formula VI compound carry out ring closure reaction and obtain formula VII compound pyrrole Lun Panai:
Wherein, R
1alkylamino, amino or alkoxyl group.
3. the method for synthesis pyrrole Lun Panai according to claim 1 and 2, is characterized in that, described formula V compound is that through type IV compound and 2-cyanophenylboronic acid or its ester react and obtain:
Wherein, X
1it is halogen.
4. the intermediate such as formula the pyrrole Lun Panai shown in V:
5. the synthetic method of formula V compound according to claim 4, is characterized in that, described formula V compound is that through type IV compound and 2-cyanophenylboronic acid or its ester react and obtain:
Wherein, X
1it is halogen.
6. the synthetic method of pyrrole Lun Panai or its intermediate formula V compound according to claim 1 or 5, is characterized in that, it is carry out under being catalysts conditions with Pd (OAc) 2 and PPh3 that formula IV compound and 2-cyanophenylboronic acid or its ester react.
7. the synthetic method of pyrrole Lun Panai or its intermediate formula V compound according to claim 1 or 5, it is characterized in that, described formula IV compound is that through type III compound carries out substitution reaction acquisition:
Wherein, X
1it is halogen.
8. the synthetic method of pyrrole Lun Panai according to claim 7 or its intermediate formula V compound, is characterized in that, described formula III compound is that through type II compound and phenylo boric acid or its ester react and obtain under metal catalyst alkaline condition:
9. the synthetic method of synthesis pyrrole Lun Panai according to claim 8 or its intermediate formula V compound, is characterized in that, described metal catalyst is salt or the complex compound of copper or palladium, and alkaline condition is triethylamine or pyridine.
10. the synthetic method of synthesis pyrrole Lun Panai according to claim 8 or claim 9 or its intermediate formula V compound, it is characterized in that, formula II compound is hydrolyzed acquisition in acid condition by type I compound:
Wherein, X
2halogen or alkoxyl group.
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| CN104356056B (en) * | 2014-11-19 | 2017-04-05 | 南京华威医药科技开发有限公司 | The preparation method of pyrrole Lun Panai intermediate |
| WO2016132343A1 (en) * | 2015-02-17 | 2016-08-25 | Mapi Pharma Ltd. | Process and intermediates for the preparation of perampanel |
| CN110028442B (en) * | 2018-01-11 | 2020-07-17 | 新发药业有限公司 | Simple preparation method of Perampanel |
| CN114605286B (en) * | 2022-04-21 | 2023-09-08 | 山东达因海洋生物制药股份有限公司 | Preparation method and application of pirenzepine intermediate |
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