The preparation method of the auspicious piperazine azoles of cloth and the compound for preparing the auspicious piperazine azoles of clothTechnical field
Compound the invention belongs to technical field of medicine synthesis there is provided a kind of preparation method of the auspicious piperazine azoles of cloth and for preparing the auspicious piperazine azoles of cloth.
Background technology
The auspicious piperazine azoles (Brexpiprazole) of cloth, chemical name：(4- (4- (benzo [b] thiophene -4- bases-piperazine -1- bases) butoxy) -1H- quinoline-2-one You Otsuka Pharmaceutical Co., Ltd researches and develops 7-, it is that a d2 dopamine receptor partial agonist (improves positive and negative symptoms, cognitive disorder and depressive symptom), 5-HT2A receptor antagonists (improve negative symptoms, cognition dysfunction, the symptom of depression, insomnia), Xl adrenoceptor antagonists (improve schizophrenia positive symptom), serotonin intake/reuptaking inhibitor (improvement depressive symptom)；Meanwhile, it is that 5-HT1A partial agonists (antianxiety and antidepressant activity) and 5-HT7 antagonists are made again.It obtains U.S. FDA in 20150711 and ratifies to be used for schizophrenia, the auxiliary treatment of major depressive disorder.The auspicious piperazine azoles of cloth has following structure：
There are many document patents also to disclose the synthetic method for reporting the auspicious piperazine azoles of cloth at present.Otsuka Pharmaceutical Co., Ltd discloses the syntheti c route of the auspicious piperazine azoles of cloth in PCT application WO2006112464A1, sees accompanying drawing 1.The difficult point of the route is that first step reaction generates the accessory substance being not readily separated, and is not easy to obtain the intermediate of high-purity by column chromatography, so as to have impact on the purity and yield of the auspicious piperazine azoles of final products cloth.
Then; Otsuka Pharmaceutical Co., Ltd discloses another preparation method of this step reaction in PCT application WO2013015456A1, see accompanying drawing 2, the route needs to use palladium compound and tertiary phosphine or palladium-carbene complex compound, these reagents are all costly, high cost, unfriendly to environment and unsuitable industrialized production.
WO2015054976A1 discloses key intermediate 1- (benzothiophene -4- bases)-piperazines and its preparation of salt of the auspicious piperazine azoles of cloth; see accompanying drawing 3; wherein R is acyl group class amino protecting group such as formoxyl, acetyl group etc., or alkoxy carbonyl group class amino protecting group such as tertbutyloxycarbonyl, benzyloxycarbonyl group etc..The route synthesizes 1- (benzothiophene -4- bases)-piperazine hydrochloride by raw material of the chloro- 6- fluorobenzaldehydes of 2- by 5 steps, although its is easy to operate, and reagent is easy to get, but route is relatively complicated causes the production cycle long, and yield is relatively low.
In view of the limitation that the existing auspicious piperazine azoles preparation method of cloth is present, it is therefore necessary to find an economic, practical, environmentally friendly variation route, to improve technology stability, cost is reduced, shortens the production cycle, improve product quality.
The content of the invention：
Compound it is an object of the invention to provide a kind of preparation method of the auspicious piperazine azoles of cloth and for preparing the auspicious piperazine azoles of cloth, to overcome the drawbacks described above that prior art is present.
Thus, according to an aspect of the present invention, the present invention provides the compound or its salt shown in a kind of formula IV,
Wherein, the one kind of the salt in hydrochloride, hydrobromate, sulfonate, mesylate, tosilate, oxalates, phosphate or maleate.
Inventor has surprisingly found that, the compound of formula IV when preparing the auspicious piperazine azoles of cloth using the compound of formula IV, can only need a step to can obtain the auspicious piperazine azoles of cloth as the key intermediate for preparing the auspicious piperazine azoles of cloth using the compound of formula IV, the auspicious piperazine azoles high income of cloth prepared by this method, and product purity is high.Technique in addition by the initiation material acquisition compound of formula IV is simple, and raw material is easy to get, suitable industrialized production.
According to another aspect of the present invention, the present invention provides a kind of preparation method of the compound of formula IV, comprises the following steps：
(1) in having solvent or without in the case of solvent, in the presence of alkaline matter, type I compound is reacted with the compound of formula VII, to obtain Formula II compound,
(2) compound of formula II is reacted to obtain the compound of formula III with the compound of formula VI (7- copper 8hydroxyquinolates),
(3) the compound Deprotection R of formula III to be to obtain the compound of formula IV,
Wherein, the R in formula I, Formula II, formula III compound is amino protecting group,
Optionally, the amino protecting group is one kind in acyl group, alkoxy carbonyl group,
Optionally, the one kind of the acyl group in formoxyl, acetyl group and propiono,
Optionally, one kind in the preferred methoxycarbonyl group of the alkoxy carbonyl group, carbethoxyl group, tertbutyloxycarbonyl and benzyloxycarbonyl group；
X in the compound of formula VII1、X2Respectively halogen, optionally, the halogen are at least one selected from fluorine, chlorine, bromine and iodine, preferably bromine, chlorine.
X in Formula II compound3For halogen or hydroxyl, optionally, the halogen is at least one selected from fluorine, chlorine, bromine and iodine, preferably bromine；X3Preferably bromine, hydroxyl.
According to another aspect of the present invention, the present invention provides a kind of preparation method by the compound of IV formula of formula V (the auspicious piperazine azoles of cloth), including the compound of formula IV further can react with the compound of formula VIII, to obtain the compound of formula V,
Wherein, the X in formula VIII4For halogen；
According to another aspect of the present invention, it is initiation material by formula I that the present invention, which is provided a kind of, and the method for formula V comprises the following steps：
(1) in having solvent or without in the case of solvent, in the presence of alkaline matter, type I compound is reacted with the compound of formula VII, to obtain Formula II compound,
(2) compound of formula II is reacted to obtain the compound of formula III with the compound of formula VI (7- copper 8hydroxyquinolates),
(3) the compound Deprotection R of formula III to be to obtain the compound of formula IV,
(4) compound of formula IV further can react with the compound of formula VIII, to obtain the compound of formula V,
Wherein, the X in formula VIII4For halogen；
Wherein, the R in formula I, Formula II, formula III compound is amino protecting group,
Optionally, the amino protecting group is one kind in acyl group, alkoxy carbonyl group,
Optionally, the one kind of the acyl group in formoxyl, acetyl group and propiono,
Optionally, one kind in the preferred methoxycarbonyl group of the alkoxy carbonyl group, carbethoxyl group, tertbutyloxycarbonyl and benzyloxycarbonyl group.
X1, X2 are respectively halogen in the compound of formula VII, optionally, and the halogen is at least one selected from fluorine, chlorine, bromine and iodine, preferably bromine, chlorine.
X in Formula II compound3For halogen or hydroxyl, optionally, the halogen is at least one selected from fluorine, chlorine, bromine and iodine, preferably bromine；X3Preferably bromine, hydroxyl.
According to another aspect of the present invention, the present invention provides compound or its salt shown in a kind of formula II, compound or its salt shown in formula III；
Wherein, R is amino protecting group,
Optionally, the amino protecting group is one kind in acyl group, alkoxy carbonyl group,
Optionally, the one kind of the acyl group in formoxyl, acetyl group and propiono,
Optionally, one kind in the preferred methoxycarbonyl group of the alkoxy carbonyl group, carbethoxyl group, tertbutyloxycarbonyl and benzyloxycarbonyl group；
X in Formula II compound3For halogen or hydroxyl, optionally, the halogen is at least one selected from fluorine, chlorine, bromine and iodine, preferably bromine；X3Preferably hydroxyl；
Optionally, the salt is at least one selected from hydrochloride, hydrobromate, sulfonate, mesylate, tosilate, oxalates, phosphate and maleate.
That is, offer of the present invention prepares the compound of the auspicious piperazine azoles of cloth (compound of formula V), compound or its salt shown in formula II, compound or its salt shown in formula III.Thus, based on these preparation of compounds of formula IV, and then the auspicious piperazine azoles of cloth is prepared.
Specific embodiment:
According to an aspect of the present invention, the present invention provides the compound or its salt shown in a kind of formula IV,
Wherein, the one kind of the salt in hydrochloride, hydrobromate, sulfonate, mesylate, tosilate, oxalates, phosphate or maleate.
According to an aspect of the present invention, the present invention provides a kind of preparation method of the compound of formula IV, is included in proton polar solvent, through under the special sour or inorganic base catalysis of Blang, the compound Deprotection R of formula III to obtain the compound of formula IV,
Wherein, the R in formula III compound is amino protecting group；
Optionally, the amino protecting group is one kind in acyl group, alkoxy carbonyl group；
Optionally, the one kind of the acyl group in formoxyl, acetyl group or propiono；
Optionally, one kind in the preferred methoxycarbonyl group of the alkoxy carbonyl group, carbethoxyl group, tertbutyloxycarbonyl and benzyloxycarbonyl group.
In the embodiment of the compound of formula IV, the one or more of described proton polar solvent in C1-C4 straight or brancheds alkanol, short chain fatty acids or water；One or more of the special acid of described Blang in hydrochloric acid, hydrogen chloride, hydrobromic acid, phosphoric acid, trifluoroacetic acid, one or more of the inorganic base in potassium carbonate, sodium carbonate, NaOH, potassium hydroxide or NaOH, the reaction is carried out at a temperature of 10 DEG C -90 DEG C, and the temperature is preferably 20 DEG C -60 DEG C.
Optionally, described C1-C4 straight or branched alkanols preferably are selected from the one or more in ethanol, propyl alcohol, isopropanol, n-butanol, isobutanol；Optionally, described short chain fatty acids preferably are selected from the one or more in formic acid, acetic acid, propionic acid, butyric acid.
In embodiment, acquisition is made by the steps in the compound of formula III：In organic solvent, in the presence of alkaline matter, the compound of formula II is reacted to obtain the compound of formula III with the compound of formula VI (7- copper 8hydroxyquinolates),
Wherein, the R in Formula II compound is amino protecting group,
Optionally, the amino protecting group is one kind in acyl group, alkoxy carbonyl group,
Optionally, the one kind of the acyl group in formoxyl, acetyl group and propiono,
Optionally, one kind in the preferred methoxycarbonyl group of the alkoxy carbonyl group, carbethoxyl group, tertbutyloxycarbonyl and benzyloxycarbonyl group；
X in Formula II compound3For halogen or hydroxyl, optionally, the halogen is at least one selected from fluorine, chlorine, bromine and iodine, preferably bromine；X3Preferably bromine, hydroxyl.
In specific embodiment prepared by the compound of formula III, organic solvent is the mixture of aprotic polar solvent or aprotic polar solvent and non-polar solven, described alkaline matter is selected from potassium carbonate, sodium carbonate, NaOH, potassium hydroxide, the preferably one or more in potassium carbonate, potassium hydroxide；One or more of the described aprotic polar solvent in dimethylformamide, dimethylacetylamide, tetrahydrofuran, methyltetrahydrofuran, acetone, acetonitrile, dimethyl sulfoxide (DMSO), hexamethyl phosphoramide, pyridine or picoline, the one or more of described non-polar solven in dimethylbenzene, 4-methyl-2 pentanone, toluene, ethylbenzene or isopropylbenzene；Reaction is carried out at a temperature of 20 DEG C -150 DEG C, and described temperature is preferably 100 DEG C -140 DEG C, more preferably 120 DEG C -125 DEG C.
In embodiment, acquisition is made by the steps in described Formula II compound：In having solvent or without in the case of solvent, in the presence of alkaline matter, type I compound is reacted with the compound of formula VII, to obtain Formula II compound,
Wherein, the R in type I compound is amino protecting group,
Optionally, the amino protecting group is one kind in acyl group, alkoxy carbonyl group,
Optionally, the one kind of the acyl group in formoxyl, acetyl group and propiono,
Optionally, one kind in the preferred methoxycarbonyl group of the alkoxy carbonyl group, carbethoxyl group, tertbutyloxycarbonyl and benzyloxycarbonyl group；
X1, X2 are respectively halogen in the compound of formula VII, and halogen is at least one selected from fluorine, chlorine, bromine and iodine, preferably bromine, chlorine.
In specific embodiment prepared by Formula II compound, the one or more of mixtures of described organic solvent in acetonitrile, acetone, butanone, ethanol, methanol, or one or more and the mixture of water in above-mentioned solvent；Alkaline matter one or more mixture in potassium carbonate, sodium carbonate, saleratus and sodium acid carbonate.
In embodiment, the further compound of formula V of the compound of formula IV is prepared as follows：When there is palladium compound and tertiary phosphine, in the presence of alkaline matter, in protonic solvent or without in the case of solvent, the compound of formula IV further can react with the compound of formula VIII, to obtain the compound of formula V,
Wherein, the X in formula VIII4For halogen；Optionally, the halogen is at least one selected from fluorine, chlorine, bromine and iodine；
In the specific embodiment of the compound of formula V, palladium compound is selected from palladium, palladium bichloride, described tertiary phosphine is selected from tri-tert tetraphenylboronic acid phosphorus, 2- dicyclohexyls phosphino- -2 ', 6 '-dimethoxy -1, 1 '-biphenyl, 2- (di-t-butyl phosphino-) -1, 1 '-biphenyl, 2- (di-t-butyl phosphino-) -2 '-methyl isophthalic acid, 1 '-biphenyl, 2- (di-t-butyl phosphino-) 1, 1 '-dinaphthalene, 2- dicyclohexyls phosphino- -2 ', 6 '-diisopropoxy -1, 1 '-biphenyl, one or more in N- phenyl -2- (di-t-butyl phosphino-) pyrroles and 1- phenyl -2- (di-t-butyl phosphino-) -1H- indenes；Alkaline matter can use the one or more in potassium carbonate, sodium carbonate, NaOH, potassium hydroxide, sodium acetate or potassium acetate；One or more of the protonic solvent in C1-C4 straight or brancheds alkanol, aromatic hydrocarbons, ethers, ketone, reaction temperature is 50 DEG C -140 DEG C, preferably 110 DEG C -135 DEG C；.
In the preferred embodiment of the compound of formula V, protonic solvent is in ethanol, propyl alcohol, isopropanol, n-butanol, isobutanol, toluene, dimethylbenzene, ethylbenzene, isopropylbenzene, from tetrahydrofuran, glycol dimethyl ether, 1, one or more in 4- dioxane, glycol monoethyl ether, ethylene glycol monoethyl ether, methyltetrahydrofuran, butanone, 4-methyl-2 pentanone, cyclohexanone or acetone, reaction temperature is 50 DEG C -140 DEG C, preferably 110 DEG C -135 DEG C；.
In embodiment, compound or its salt shown in formula II, compound or its salt shown in formula III；
Wherein, R is amino protecting group,
Optionally, the amino protecting group is one kind in acyl group, alkoxy carbonyl group,
Optionally, the one kind of the acyl group in formoxyl, acetyl group and propiono,
Optionally, one kind in the preferred methoxycarbonyl group of the alkoxy carbonyl group, carbethoxyl group, tertbutyloxycarbonyl and benzyloxycarbonyl group；
X in Formula II compound3For halogen or hydroxyl, optionally, the halogen is at least one selected from fluorine, chlorine, bromine and iodine, preferably bromine；X3Preferably hydroxyl.
Optionally, the salt is at least one selected from hydrochloride, hydrobromate, sulfonate, mesylate, tosilate, oxalates, phosphate and maleate.
General synthetic route：
Method disclosed by the invention is with type I compound and 1; 4- dihalos butane is the first synthesizing spiro class compound (compound of formula II) of raw material; Formula II compound and 7- oxyquinoline reactive ketone production III compounds; the compound of formula IV is obtained after formula III compound Deprotection, the last compound of formula IV obtains the auspicious piperazine azoles of target product cloth (compound of formula V) with the reaction of 4- halos benzothiophene.
Test route as follows：
Wherein, R, X in above-mentioned reaction scheme1、X2、X3、X4It is as defined above.
Beneficial effects of the present invention：
The present invention's prepares the auspicious piperazine azoles method of cloth, including preparing the auspicious piperazine azoles of cloth using cheap commercially available industrial chemicals and synthesis technique easy to operate, produce the auspicious piperazine azoles of cloth with being easy to economy of large scale, and the atom utilization of the chemical reaction of technique is high, the more conducively development of Green Chemistry.
Brief description of the drawings
Fig. 1 is to disclose the syntheti c route figure of the auspicious piperazine azoles of cloth in WO2006112464A1.
Another syntheti c route figure for the first step reaction that Fig. 2 is the WO2006112464A1 disclosed in WO2013015456A1.
Fig. 3：Key intermediate 1- (benzothiophene -4- the bases)-piperazines and its syntheti c route of salt of the auspicious piperazine azoles of cloth disclosed in WO2015054976A1.
The solution of the present invention is explained below in conjunction with embodiment.It will be understood to those of skill in the art that the following examples are merely to illustrate the present invention, and it should not be taken as limiting the scope of the invention.Unreceipted particular technique or condition in embodiment, are carried out according to the technology or condition described by document in the art or according to product description.Agents useful for same or the unreceipted production firm person of instrument, being can be by the conventional products of acquisition purchased in market.
Embodiment
Embodiment 1 8-BOC-5,8- diaza spiro [4,5] decane (compound of formula II, R=-Boc, X3=-OH) preparation
By N-Boc piperazines (37.2g, 0.2mol), 1,4- dibromobutanes (43.2g, 0.2mol), potassium carbonate (55.2g, 0.4mol), acetonitrile (225g) and water (16g) are put into 1L there-necked flasks successively, are warming up to backflow (76-78 DEG C).Reaction process is monitored by gas-chromatography after 20h, if vapor detection N-Boc piperazine contents it is relatively low and no longer change when stop reaction, filter while hot, concentration acetonitrile after use recrystallisation from isopropanol, obtain the 32.3g of white solid II, yield 72.8%.Products obtained therefrom is compound ii (R=-Boc, X by mass spectrum, nuclear-magnetism, infrared carry out structural confirmation3=-OH).MS:Rt=0.37min, [M-H]=257.2, [M-OH]=241.1；
1HNMR(400MHz,MeOD),1.51(s,9H)；2.26(s,4H)；3.51-3.54(m,4H)；3.69-3.72 (t, J=6.0Hz, 4H), 3.81 (s, 4H) .IR:2978.66cm-1(C-H(CH3))；1701.01cm-1(C=O)；1145.79cm-1(C-O-C)。
Embodiment 2 8-BOC-5,8- diaza spiro [4,5] decane (compound of formula II, R=-Boc, X3=-OH) preparation
By N-Boc piperazines (37.2g, 0.2mol), 1,4- dichloroetane (25.4g, 0.2mol), sodium acid carbonate (35g), ethanol (110g) and water (16g) are put into 1L there-necked flasks successively, are warming up to backflow.Reaction process is monitored by gas-chromatography after 20h, if vapor detection N-Boc piperazine contents it is relatively low and no longer change when stop reaction, filter while hot, concentration remove solvent after use recrystallisation from isopropanol, obtain the 32.3g of white solid II, yield 72.8%.Products obtained therefrom is compound ii (R=-Boc, X by mass spectrum, nuclear-magnetism, infrared carry out structural confirmation3=-OH).MS:Rt=0.37min, [M-H]=257.2, [M-OH]=241.1；1HNMR(400MHz,MeOD),1.51(s,9H)；2.26(s,4H)；3.51-3.54(m,4H)；3.69-3.72 (t, J=6.0Hz, 4H), 3.81 (s, 4H) .IR:2978.66cm-1(C-H(CH3))；1701.01cm-1(C=O)；1145.79cm-1(C-O-C)。
Embodiment 3 8- carbethoxyl groups -5,8- diaza spiro [4,5] decane spiro-compound (compound of formula II, R=-COOCH2CH3, X3=-OH) preparation
By N- ethoxycarbonylpiperazines (31.64g, 0.2mol), the bromo- 4- chlorobutanes (34.3g of 1-, 0.2mol), potassium carbonate (55.2g, 0.4mol), acetonitrile (225g) and water (16g) are put into 1L there-necked flasks successively, are warming up to backflow (76-78 DEG C).Reaction process is monitored by gas-chromatography, if vapor detection N-Boc piperazine contents are relatively low and (22h or so) stops reaction when no longer changing, reaction is filtered while hot after stopping, and recrystallisation from isopropanol is used after concentration acetonitrile, obtain white solid 26.8g (II, R=-COOCH2CH3, X3=-OH), yield 58.2%.
The preparation of the 7- of embodiment 4 [4- (4-BOC-1- piperazines) butoxy] -2 (1H)-quinolinones (compound of formula III, R=-Boc)
By (the R=-Boc of 1 gained loop coil of embodiment II, X3=-OH) (7.7g (after conversion purity), 0.024mol), 7- copper 8hydroxyquinolates (3.2g, 0.02mol), potassium carbonate (5.5g, 0.04mol), 4-methyl-2 pentanone (MIBK 75.7g) and dimethylacetylamide (DMAc, 11.4g) add in 250mL there-necked flasks, be warming up to micro- backflow, about 116-118 DEG C of interior temperature.The detection of 20h or so thin-layer chromatography is reacted, when the less and content of 7- copper 8hydroxyquinolates residue no longer changes, stops reaction, first boils off solvent, then add water stirring, is extracted with dichloromethane, the washing of 5% sodium hydroxide solution, washing, solvent is sloughed, faint yellow solid 8.9g, yield 77.9% is obtained.Products obtained therefrom is III (R=-Boc) by mass spectrum, nuclear-magnetism, infrared carry out structural confirmation.MS:Rt=1.697min, [M+H]=402.2.
1HNMR(400MHz,MeOD),1.47(s,9H)；1.71-1.78(m,2H)；1.84-1.90(m,2H)；2.45-2.49(m,6H)；3.45(s,4H)；4.10-4.13 (t, J=6.1Hz, 2H)；6.44-6.46 (d, J=9.4Hz, 1H)；6.85-6.90(m,2H)；7.55-7.58 (d, J=8.7Hz, 1H)；7.88-7.90 (d, J=9.4Hz, 1H)
IR:3381.22cm-1(N-H)；2825.28cm-1[C-H(CH3)]；1652.34cm-1,1626.06cm-1(C=O)；
1220.73cm-1,1137.02cm-1(C-O-C).
The preparation of the 7- of embodiment 5 [4- (4-BOC-1- piperazines) butoxy] -2 (1H)-quinolinones (compound of formula III, R=-Boc)
By (the R=-Boc of 1 gained loop coil of embodiment II, X3=-OH) (7.7g (after conversion purity), 0.024mol), 7- copper 8hydroxyquinolates (3.2g, 0.02mol), potassium hydroxide (2.24g, 0.04mol), 4-methyl-2 pentanone (75.7g) and tetrahydrofuran (5g) are added in 250mL there-necked flasks, it is warming up to micro- backflow, about 116-118 DEG C of interior temperature.The detection of 20h or so thin-layer chromatography is reacted, when the less and content of 7- copper 8hydroxyquinolates residue no longer changes, stops reaction, first boils off solvent, then add water stirring, is extracted with dichloromethane, the washing of 5% sodium hydroxide solution, washing, solvent is sloughed, faint yellow solid 8.9g, yield 77.9% is obtained.Products obtained therefrom is III (R=-Boc) by mass spectrum, nuclear-magnetism, infrared carry out structural confirmation.MS:Rt=1.697min, [M+H]=402.2.1HNMR(400MHz,MeOD),1.47(s,9H)；1.71-1.78(m,2H)；1.84-1.90(m,2H)；2.45-2.49(m,6H)；3.45(s,4H)；4.10-4.13 (t, J=6.1Hz, 2H)；6.44-6.46 (d, J=9.4Hz, 1H)；6.85-6.90(m,2H)；7.55-7.58 (d, J=8.7Hz, 1H)；7.88-7.90 (d, J=9.4Hz, 1H)
IR:3381.22cm-1(N-H)；2825.28cm-1[C-H(CH3)]；1652.34cm-1,1626.06cm-1(C=O)；
1220.73cm-1,1137.02cm-1(C-O-C).
The preparation of the 7- of embodiment 6 [4- (4-BOC-1- piperazines) butoxy] -2 (1H)-quinolinones (compound of formula III, R=-Boc)
By N-Boc piperazines (37.2g, 0.2mol), Isosorbide-5-Nitrae-dibromobutane (43.2g, 0.2mol), potassium carbonate (55.2g, 0.4mol), ethanol (225g) is put into 1L there-necked flasks successively, is warming up to backflow (76-78 DEG C).Reaction process is monitored by gas-chromatography after 20h, if vapor detection N-Boc piperazine contents it is relatively low and no longer change when stop reaction, filter while hot, concentration ethanol after.7- copper 8hydroxyquinolates (16g, 0.1mol), MIBK (375.7g) and DMAc (55.4g) are added, micro- backflow, about 116-118 DEG C of interior temperature is warming up to.React the detection of 20h or so thin-layer chromatography, when the less and content of 7- copper 8hydroxyquinolates residue no longer changes, stop reaction, first boil off solvent, then add water stirring, extracted with dichloromethane, the washing of 5% sodium hydroxide solution, washing, slough solvent, obtain faint yellow solid (III, R=-Boc) 41g, yield 72%.
The 7- of embodiment 7 [4- (4- carbethoxyl group -1- piperazines) butoxy] -2 (1H)-quinolinone (III, R=-COOCH2CH3) preparation by N- ethoxycarbonylpiperazines (4.24g, 0.025mol), 1,4- dibromobutanes (5.3g, 0.025mol), potassium carbonate (6.2g, 0.05mol), acetone (25g) and water (1.6g) are put into 1L there-necked flasks successively, are warming up to backflow.Reaction process is monitored by gas-chromatography, if vapor detection N- ethoxycarbonylpiperazine contents are relatively low and (22h or so) stops reaction when no longer changing, filtering and concentrating is done while hot after reaction stopping, add 7- copper 8hydroxyquinolates (4.0g, 0.025mol), potassium carbonate (8.5g, 0.04mol) MIBK (75.7g) and DMAc (11.4g), is warming up to micro- backflow, about 116-118 DEG C of interior temperature.The detection of 20h or so thin-layer chromatography is reacted, when the less and content of 7- copper 8hydroxyquinolates residue no longer changes, stops reaction, first boils off solvent, then add water stirring, is extracted with dichloromethane, the washing of 5% sodium hydroxide solution, washing, solvent is sloughed, faint yellow solid (III, R=-COOCH is obtained2CH3) 5.1g, yield 69.1%.
The 7- of embodiment 8 [4- (4- carbethoxyl group -1- piperazines) butoxy] -2 (1H)-quinolinone (III, R=-COOCH2CH3) preparation
By (the R=-COOCH of 3 gained loop coil of embodiment II2CH3, X3=-OH) (after conversion purity) (5.5g, 0.024mol), 7- copper 8hydroxyquinolates (3.2g, 0.02mol), potassium carbonate (5.5g, 0.04mol) MIBK (75.7g) and DMAc (11.4g) is added in 250mL there-necked flasks, it is warming up to micro- backflow, about 116-118 DEG C of interior temperature.The detection of 20h or so thin-layer chromatography is reacted, when the less and content of 7- copper 8hydroxyquinolates residue no longer changes, stops reaction, first boils off solvent, then add water stirring, is extracted with dichloromethane, the washing of 5% sodium hydroxide solution, washing, solvent is sloughed, faint yellow solid (III, R=-COOCH is obtained2CH3) 5.0g, yield 67.3%.
The preparation of the 7- of embodiment 9 [4- (piperazine -1) butoxy] -2 (1H)-quinolinones (IV)
To compound III (R=-Boc) (after conversion purity) (4.0g, 0.01mol) in add 40mL ethanol, 10mL concentrated hydrochloric acids, then mixed liquor be stirred at 20 DEG C, thin-layer chromatography is detected after 30mins, stops reaction if reaction completely.Neutralized with 50% sodium hydroxide solution, boil off ethanol, then use 20ml dichloromethane every time, extraction 3 times, drying is concentrated to give yellow solid 2.85g, is 95% through HPLC detection purity, yield 95%, product is compounds Ⅳ by mass spectrum, nuclear-magnetism, infrared carry out structural confirmation.
MS:Rt=0.883min, [M+H]=302.2.
1HNMR (400MHz, MeOD), 1.75-1.77 (d, J=6.8Hz, 2H)；1.87-1.88 (d, J=6.8Hz, 2H)；2.50-2.54(m,2H)；2.62(s,4H)；3.04(s,4H)；4.11-4.14(t,2H)；6.44-6.46 (d, J=9.4Hz, 1H)；6.88-6.90 (d, J=9.0Hz, 2H)；7.58-7.60 (d, J=8.3Hz, 1H)；7.90-7.92 (d, J=9.4Hz, 1H)
IR:2946.16cm-1(N-H)；1639.60cm-1(C=O)；1221.29cm-11(C-O-C).
The preparation of the 7- of embodiment 10 [4- (piperazine -1) butoxy] -2 (1H)-quinolinones (IV)
At room temperature to compound III (R=-COOCH2CH3) mixture of 5.5 grams of NaOH and 42mL methanol is added in (3.7g, 0.01mol), reactant mixture reacts the 12h, (R=-COOCH of HPLC detection compounds III at reflux2CH3) after content is less than 0.5%, concentration removes methanol, adds 20 milliliters of water, then use 20ml dichloromethane every time, extracts 3 times, and sodium chloride solution elution is molten to obtain yellow solid (IV) 2.52g, yield 84%.Product is compounds Ⅳ by mass spectrum, nuclear-magnetism, infrared carry out structural confirmation.
MS:Rt=0.883min, [M+H]=302.2.
1HNMR (400MHz, MeOD), 1.75-1.77 (d, J=6.8Hz, 2H)；1.87-1.88 (d, J=6.8Hz, 2H)；2.50-2.54(m,2H)；2.62(s,4H)；3.04(s,4H)；4.11-4.14(t,2H)；6.44-6.46 (d, J=9.4Hz, 1H)；6.88-6.90 (d, J=9.0Hz, 2H)；7.58-7.60 (d, J=8.3Hz, 1H)；7.90-7.92 (d, J=9.4Hz, 1H)
IR:2946.16cm-1(N-H)；1639.60cm-1(C=O)；1221.29cm-11(C-O-C).
The preparation of the 7- of embodiment 11 [4- (piperazine -1) butoxy] -2 (1H)-quinolinones (IV)
At room temperature to compound III (R=-COOCH2CH3) (3.7g, the mixture of 5.5 grams of NaOH and 25mL 80% ethanol is added in 0.01mol), reactant mixture reacts 12h at 10 DEG C, it is concentrated in vacuo and removes ethanol, then 20ml dichloromethane is used every time, is extracted 3 times, and sodium chloride solution elution is molten to obtain yellow solid (IV) 2.58g, yield 86%, HPLC detection purity 99.1%.Product is compounds Ⅳ by mass spectrum, nuclear-magnetism, infrared carry out structural confirmation.
MS:Rt=0.883min, [M+H]=302.2.
1HNMR (400MHz, MeOD), 1.75-1.77 (d, J=6.8Hz, 2H)；1.87-1.88 (d, J=6.8Hz, 2H)；2.50-2.54(m,2H)；2.62(s,4H)；3.04(s,4H)；4.11-4.14(t,2H)；6.44-6.46 (d, J=9.4Hz, 1H)；6.88-6.90 (d, J=9.0Hz, 2H)；7.58-7.60 (d, J=8.3Hz, 1H)；7.90-7.92 (d, J=9.4Hz, 1H)
IR:2946.16cm-1(N-H)；1639.60cm-1(C=O)；1221.29cm-11(C-O-C).
The preparation of the 7- of embodiment 12 [4- (piperazine -1) butoxy] -2 (1H)-quinolinones (IV)
To compound III (R=-Boc) (after conversion purity) (4.0g, 0.01mol) in add 30ml glacial acetic acids, 5 milliliters of concentrated hydrochloric acids, then mixed liquor be stirred at 20 DEG C, thin-layer chromatography is detected after 30mins, stops reaction if reaction completely.Neutralized with 50% sodium hydroxide solution, 20ml dichloromethane is then used every time, extracted 3 times, drying is concentrated to give yellow solid 2.85g, be 95% through HPLC detection purity, yield 95%, product is compounds Ⅳ by mass spectrum, nuclear-magnetism, infrared carry out structural confirmation.
MS:Rt=0.883min, [M+H]=302.2.
1HNMR (400MHz, MeOD), 1.75-1.77 (d, J=6.8Hz, 2H)；1.87-1.88 (d, J=6.8Hz, 2H)；2.50-2.54(m,2H)；2.62(s,4H)；3.04(s,4H)；4.11-4.14(t,2H)；6.44-6.46 (d, J=9.4Hz, 1H)；6.88-6.90 (d, J=9.0Hz, 2H)；7.58-7.60 (d, J=8.3Hz, 1H)；7.90-7.92 (d, J=9.4Hz, 1H)
IR:2946.16cm-1(N-H)；1639.60cm-1(C=O)；1221.29cm-11(C-O-C).
The preparation of the 7- of embodiment 13 [4- (4- chlorobenzenes simultaneously [b] thiophene) -4- piperazines -1) butoxy] -2 (1H)-quinolinones (compound of formula V) hydrochloride
By 4- chlorobenzenes simultaneously [b] thiophene (32.8mmol at 120-130 DEG C, 5.5g), (the 30.3mmol of diethylenediamine compound IV, 9.0g), palladium (0.012mmol, 2.7mg), tri-tert tetraphenylboronic acid phosphorus (0.012mol, 6.2mg), potassium carbonate (88.95mmol, 12.3g) 5h is stirred with dimethylbenzene (70mL), after detecting that diethylenediamine compound IV disappears substantially, reaction solution is cooled to after room temperature, add water thereto, separation, diformazan benzene layer is washed with water, then washed with sodium chloride solution, plus activated carbon, it is stirred at room temperature after 30mins and filters, enriching hydrochloric acid in filtrate, 30mins is stirred to obtained mixture at room temperature, filtration drying obtains hydrochloride, yellow solid 11.6g, yield 81%, HPLC detects purity 99.5%.
The preparation of the 7- of embodiment 14 [4- (4- chlorobenzenes simultaneously [b] thiophene) -4- piperazines -1) butoxy] -2 (1H)-quinolinones
7- [4- (4- chlorobenzenes simultaneously [b] thiophene) -4- piperazines -1) butoxy] -2 (1H)-quinolinones (compound of formula V) 10 grams of hydrochloride is added in 90 milliliters of dichloromethane, plus 15 grams of potassium carbonate, 45 milliliters of water, stirring 2 hours, separate dichloromethane layer, water layer is extracted once with 20 milliliters of dichloromethane, combined dichloromethane layer, it is washed with water twice, 30 milliliters every time, dichloromethane layer concentration removes dichloromethane, obtains slightly yellow solid 8.8g, yield 96%, HPLC detection purity 99.6%.
The preparation of the 7- of embodiment 15 [4- (4- chlorobenzenes simultaneously [b] thiophene) -4- piperazines -1) butoxy] -2 (1H)-quinolinones (compound of formula V) hydrochloride
By 4- chlorobenzenes simultaneously [b] thiophene (32.8mmol at 65-70 DEG C, 5.5g), (the 30.3mmol of diethylenediamine compound IV, 9.0g), palladium (5.6mg), 2- dicyclohexyls phosphino- -2 ', 6 '-diisopropoxy -1, 1 '-biphenyl (69mg), potassium carbonate (88.95mmol, 12.3g) 5h is stirred with tetrahydrofuran (80mL), after detecting that diethylenediamine compound IV disappears substantially, it is cooled to after reacting liquid filtering is concentrated after room temperature, thereto plus 80 milliliters of dimethylbenzene, 30 grams of water are stirred 30 minutes, separate diformazan benzene layer, diformazan benzene layer is washed with water, then washed with sodium chloride solution, plus activated carbon, it is stirred at room temperature after 30mins and filters, enriching hydrochloric acid in filtrate, 30mins is stirred to obtained mixture at room temperature, filtration drying obtains hydrochloride, yellow solid 11.9g, yield 83%, HPLC detects purity 99.3%.