CN103980188A - Synthetic method of perampanel, intermediate of perampanel and synthetic method of intermediate - Google Patents

Synthetic method of perampanel, intermediate of perampanel and synthetic method of intermediate Download PDF

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CN103980188A
CN103980188A CN201410240827.XA CN201410240827A CN103980188A CN 103980188 A CN103980188 A CN 103980188A CN 201410240827 A CN201410240827 A CN 201410240827A CN 103980188 A CN103980188 A CN 103980188A
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CN103980188B (en
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叶天健
郁光亮
马苏旺
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Zhejiang Yongning Pharmaceutical Co Ltd
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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

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention relates to the field of medicinal chemical synthesis and in particular relates to a synthetic method of perampanel, an intermediate of the perampanel and a synthetic method of the intermediate. The provided synthetic method of the perampanel comprises the following steps: carrying out a cyclization reaction on a compound shown in a formula V and a compound shown in a formula VI, so that a compound shown in a formula VII is obtained, wherein the formulas V, VI and VII are described in the specification, and R1 is alkyl amino, amino or alkoxy. The invention also aims at providing a synthetic method of an intermediate of the perampanel. In a synthetic process, phenyl, cyano phenyl and 2-pyridyl are sequentially introduced, compared with the prior art, a sequence of introducing substituent groups is changed, so that the problems that reaction yield is low and byproducts are many and can not be removed as 2-pyridyl is firstly introduced and then cyano phenyl is introduced can be solved; a route is changed, and a Pd containing catalyst is not used in reaction of the last step, so that Pd residue is reduced, drug safety is improved, and reaction yield and product purity are greatly improved, so that the synthetic method of the perampanel is applicable to industrial production.

Description

The synthetic method of the synthetic method of a kind of pyrrole Lun Panai and intermediate thereof and intermediate
Technical field
The present invention relates to the synthetic field of pharmaceutical chemistry, 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, and 2-dihydropyridine-2-ketone, its structural formula is as follows:
Pyrrole Lun Panai (perampanel) is a kind of alpha-amino group-3-hydroxy-5-methyl different azoles propionic acid of base-4-(AMPA) receptor antagonist, researched and developed by Eisai company, it,, by suppressing postsynaptic ampa receptor glutamate activity, reduces neurone and is overexcited.This product was gone on the market by U.S. food Drug Administration (FDA) approval on October 22nd, 2012, its commodity are called Fycompa, for the assisting therapy of more than 12 years old epileptic partial seizures, no matter whether patient shows effect with Secondary cases comprehensively.
Patent US20070142640 discloses the method for synthetic pyrrole Lun Panai a kind of on January 27th, 2007, reaction process is as follows:
The defect of this route is: in reaction process, used hypertoxic tin reagent; 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 residual, 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, comprise 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, under the condition of organic solvent, carries out.
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 reacts acquisition formula V compound with 2-cyanophenylboronic acid or its ester
Wherein, X 1it is halogen.
Preferably, X 1be bromine, described reaction exists at catalyzer, under alkaline condition, carries out.
Preferably, in step (2), used catalyst is Pd (OAc) 2and PPh 3, alkaline condition is potassium tert.-butoxide, salt of wormwood, cesium carbonate, 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 reacts acquisition formula III compound with phenylo boric acid or its ester 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 reacts with phenylo boric acid.
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), formula I compound hydrolysis obtains formula II compound:
Wherein, X 2halogen or alkoxyl group.
Preferably, X 2be chlorine, bromine, iodine, methoxy or ethoxy, described hydrolysis is carried out under acidic conditions.
Preferred, X 2be chlorine, described hydrolysis is carried out under hydrochloric acid or Hydrogen bromide condition.
Another object of the present invention is to provide the intermediate of a kind of pyrrole Lun Panai, as follows:
Another object of the present invention is the synthetic method of the intermediate that a kind of pyrrole Lun Panai is provided, and comprises the steps:
Formula IV compound reacts acquisition formula V compound with 2-cyanophenylboronic acid or its ester
Wherein, X 1it is halogen.
Preferably, X 1be bromine, described reaction exists at catalyzer, under alkaline condition, carries out.
Preferably, used catalyst is Pd (OAc) 2and PPh 3, alkaline condition is potassium tert.-butoxide, salt of wormwood, cesium carbonate, 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 is used NBS to carry out.
Formula II compound reacts acquisition formula III compound with phenylo boric acid or its ester under 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 reacts with phenylo boric acid.
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.
Formula I compound hydrolysis obtains formula II compound:
Wherein, X 2halogen or alkoxyl group.
Preferably, X 2be chlorine, bromine, iodine, methoxy or ethoxy, described hydrolysis is carried out under acidic conditions.
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 introduced substituent order, avoided so first introducing that to introduce the reaction yield that cyano-phenyl causes after 2-pyridyl low, by product is many, the problem that cannot remove again.Due to the change of route, final step reaction is not used the catalyzer containing Pd, thereby has reduced the residual of Pd, has increased drug safety, and has significantly improved reaction yield and product purity, is 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 embodiment.
In the following example, method therefor if no special instructions, is ordinary method.Needed material or reagent in following examples, be if no special instructions market and buy.
Embodiment 1:
5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
To the hydrochloric acid soln that adds 63ml35% in the chloro-5-acetylpyridine of 155g2-, 100 DEG C of back flow reaction.After reacting completely, to 8, under stirring, add 935ml THF and 32g salt solution with solution of potassium carbonate adjusting reaction solution pH to 7 simultaneously.After solution layering, 935ml THF and the water washing of 32g salt for water, 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.Filter, be dried, obtain 130.1g target compound (yield 95%, purity 99.7%).
Embodiment 2:
5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
To the hydrochloric acid soln that adds 32ml35% in 75.6g2-methoxyl group-5-acetylpyridine, 100 DEG C of back flow reaction.After reacting completely, to 8, under stirring, add 468mlTHF and 16g salt solution with solution of potassium carbonate adjusting reaction solution pH to 7 simultaneously.After solution layering, 468ml THF and the water washing of 16g salt for water, 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.Filter, be dried, obtain 56.2g target compound (yield 82%, purity 99.0%).
Embodiment 3:
5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
To the hydrobromic acid solution that adds 63ml35% in the chloro-5-acetylpyridine of 155g2-, 100 DEG C of back flow reaction.After reacting completely, to 8, under stirring, add 935ml THF and 32g salt solution with solution of potassium carbonate adjusting reaction solution pH to 7 simultaneously.After solution layering, 935ml THF and the water washing of 32g salt for water, 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.Filter, be dried, obtain 117.8g target compound (yield 86%, purity 99.3%).
Embodiment 4:
1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
Get 120g5-ethanoyl-1,2-dihydropyridine-2-ketone is dissolved in DCM, and adds successively Cu (OAc) in this solution 232g, phenyl-boron dihydroxide 215g and triethylamine 208ml (1.7 equivalent), 24h stirs the mixture under room temperature.In reaction solution, add strong aqua, separatory washing, 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:
1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
Get 54.8g5-ethanoyl-1,2-dihydropyridine-2-ketone is dissolved in DCM, and adds successively Cu (OAc) in this solution 214.6g, phenyl-boron dihydroxide 98.2g and triethylamine 84ml (1.5 equivalent), 24h stirs the mixture under room temperature.In reaction solution, add strong aqua, separatory washing, solvent removed by evaporation at reduced pressure, obtains target compound 63.9g (yield 75%, purity 99.3%).
Embodiment 6:
1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
Get 54.8g (0.4mol) 5-ethanoyl-1,2-dihydropyridine-2-ketone is dissolved in DCM, and adds successively Cu (OAc) in this solution 214.6g, phenyl-boron dihydroxide 98.2g and triethylamine 168ml (3 equivalent), 24h stirs the mixture under room temperature.In reaction solution, add strong aqua.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:
1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
Get 120g5-ethanoyl-1,2-dihydropyridine-2-ketone is dissolved in DCM, and adds successively Cu (OAc) in this solution 232g, phenyl-boron dihydroxide 215g and pyridine 120ml, 24h stirs the mixture under room temperature.In reaction solution, add strong aqua.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 bromo-1-phenyl-5-of 3-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
By 100g1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone is dissolved in 530ml DMF, and low temperature adds N-bromine succinimide 83.7g under stirring.After adding, under room temperature, stir 2 hours.Reaction solution dilute with water, then ethyl acetate extraction.The organic layer obtaining is 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:
3-(2-cyano-phenyl)-1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
Stir in downhill reaction device and add successively the bromo-1-phenyl-5-of 116.4g3-ethanoyl-1,2-dihydropyridine-2-ketone, 90g2-cyanophenylboronic acid dimethylene ester, 75.9g salt of wormwood and 1900ml dimethyl formamide.Then add wherein 21.8g Pd (OAc) 2with 25.5g PPh 3, be stirred at 60 DEG C and react completely.After reaction finishes, in reaction solution, add water, and be extracted with ethyl acetate.Organic layer is water and salt water washing respectively, then uses anhydrous sodium sulfate drying.Rotary evaporation, except desolventizing, adds ethyl acetate and heptane recrystallization to obtain 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:
3-(2-cyano-phenyl)-1-phenyl-5-ethanoyl-1,2-dihydropyridine-2-ketone synthetic
Stir in downhill reaction device and add successively the bromo-1-phenyl-5-of 116.4g3-ethanoyl-1,2-dihydropyridine-2-ketone, 90g2-cyanophenylboronic acid dimethylene ester, 61.7g potassium tert.-butoxide and 1900ml dimethyl formamide.Then add wherein 21.8g Pd (OAc) 2with 25.5g PPh 3, be stirred at 60 DEG C and react completely.After reaction finishes, in reaction solution, add water, and be extracted with ethyl acetate.Organic layer is 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:
3-(2-cyano-phenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridine-2-ketone synthetic
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 160ml THF; 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, continue 100 DEG C at reaction.After having reacted, in reaction solution, add 1000ml toluene, add 25% sodium hydroxide solution extraction.Concentrated after organic layer difference water and 10% salt water washing, obtain target compound 62.8g.(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:
3-(2-cyano-phenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridine-2-ketone synthetic
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 160ml THF; 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, continue 100 DEG C at reaction.After having reacted, in reaction solution, add 1000ml toluene, add 25% sodium hydroxide solution extraction.Concentrated after organic layer difference water and 10% salt water washing, obtain target compound 50.9g.(yield 73%, purity 98.9%)
Embodiment 13:
According to synthetic 3-(2-the cyano-phenyl)-1-phenyl-5-(2-pyridyl)-1 of the method for embodiment 11,2-dihydropyridine-2-ketone, 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. a method of synthetic pyrrole Lun Panai, 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. a method of synthetic pyrrole Lun Panai, 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 synthetic pyrrole Lun Panai according to claim 1 and 2, is characterized in that, described formula V compound is that through type IV compound reacts acquisition with 2-cyanophenylboronic acid or its ester:
Wherein, X 1it is halogen.
4. the intermediate suc as formula the pyrrole Lun Panai shown in V:
5. the synthetic method of formula V compound claimed in claim 4, is characterized in that, described formula V compound is that through type IV compound reacts acquisition with 2-cyanophenylboronic acid or its ester:
Wherein, X 1it is halogen.
6. according to the synthetic method of the pyrrole Lun Panai described in claim 1 or 2 or 3 or 5 or its intermediate formula V compound, it is characterized in that, it is to carry out under catalyzer condition taking Pd (OAc) 2 and PPh3 that formula IV compound reacts with 2-cyanophenylboronic acid or its ester.
7. according to the synthetic method of the pyrrole Lun Panai described in claim 1 or 2 or 3 or 5 or its intermediate formula V compound, 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 reacts acquisition with phenylo boric acid or its ester under metal catalyst alkaline condition:
9. the synthetic method of synthetic 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. synthetic pyrrole Lun Panai according to claim 8 or claim 9 or the synthetic method of its intermediate formula V compound, is characterized in that, formula II compound is that through type I compound is hydrolyzed acquisition under acidic conditions:
Wherein, X 2halogen or alkoxyl group.
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CN104356056A (en) * 2014-11-19 2015-02-18 南京华威医药科技开发有限公司 Preparation method of perampanel intermediate
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