CN1235880C - Quinolinenone kind derivative and its accetable salt, its preparation method, application in preparation of alipyrazole and preparation of alipyrazole - Google Patents
Quinolinenone kind derivative and its accetable salt, its preparation method, application in preparation of alipyrazole and preparation of alipyrazole Download PDFInfo
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Abstract
The present invention relates to 7-[4-[4-(2, 3-dichlorophenyl)-1-piperazine]-2-butenoxy]-3, 4-dihydro-2-(1H)-quinoline-2-ketone, acceptable salt, a preparation method, application for preparing aripiprazole, and a preparation method of aripiprazole. The present invention adopts 1, 4-dibromo 2-butene which has high activity to replace 1, 4-dibromobutane. When the 1, 4-dibromo 2-butene and 7-hydroxyl-3, 4-dihydro-quinoline-2-ketone have a condensation reaction, the present invention has the characteristics that reaction conditions are moderate (the reaction temperature is 45 DEGC), side products are few, and the quality of an intermediate compound is easily controlled. When the aripiprazole is prepared, the present invention has the characteristics that reaction conditions are moderate (a reaction can be carried out under the room temperature), side products are few, and the yield rate is high. The present invention is good for industrialization of products.
Description
Technical field
The present invention relates to a kind of 7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2 (1H)-quinoline-2-one-and acceptable salt thereof, its preparation method and conduct preparation 7-[4-[4-(2, the 3-dichlorophenyl)-and the 1-piperazinyl] butoxy]-3,4-dihydro-2 (the 1H)-application of quinolinone (Aripiprazole) and a kind of preparation method of Aripiprazole.
Background technology
As everyone knows, Aripiprazole is a quinoline ketone derivative, and in invention in 1988, the Mei when back and the U.S. hundred-Shi Guibao company developed jointly by Japan big tomb company, obtained listing in 2002 through drugs approved by FDA, was used for the treatment of schizophrenia at present clinically.
About the preparation of Aripiprazole, 5 kinds of preparation methods that describe in the known EP367141 of the having patent.The specification sheets of this patent is set forth a kind of method for preparing Aripiprazole wherein, its synthetic route is with 7-hydroxyl-3,4-dihydro-quinoline-2-one-is a raw material, with 1, the 4-dibromobutane makes 7-bromine butoxy-3 after condensation reaction, 4-dihydro-quinoline-2-one-(I) (I) makes Aripiprazole with 1-(2, the 3-dichlorophenyl) piperazine again after condensation reaction.
When preparing Aripiprazole, need relate to the preparation of intermediate (I) with this synthetic route.When preparing compound (I) with regard to the method described in the EP367141 patent, under alkaline condition, water is cooked solvent and is made through back flow reaction.Because of 1, hydrolysis reaction will take place in the 4-dibromobutane in this reaction system, and makes this reaction have more side reaction; Intermediate (I) purifying is difficulty, its difficult quality guarantee.
The impurity that this intermediate (I) is introduced will influence next step reaction, and the impurity of being introduced also is difficult to adopt conventional methods such as recrystallization to be removed.Final product quality is difficult to guarantee that if need to obtain the Aripiprazole of " pharmaceutical grade " purity, then the crude product that need be obtained is repeatedly refining.Can reach 50% although obtain the total recovery of Aripiprazole crude product with this synthetic route, adopt repeatedly process for purification to obtain the Aripiprazole of " pharmaceutical grade " after, total recovery will reduce significantly, the Product industrialization production cost increases.
Four kinds of methods that prepare Aripiprazole in addition of describing in the claim of EP367141 patent because of relating to the preparation of piperazine ring, more are unfavorable for the industrialization of product; Because when carrying out the preparation of piperazine ring, temperature of reaction is higher than 220 ℃, and it is many to have a side reaction, aftertreatment difficulty, characteristics such as yield is extremely low.
Summary of the invention
The object of the present invention is to provide a kind of 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2 (1H)-quinoline-2-one-(A) and acceptable salt thereof.
Second purpose of the present invention is to provide 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3, the preparation method of 4-dihydro-2 (1H)-quinoline-2-one-(A) and acceptable salt thereof.
The 3rd purpose of the present invention is to provide a kind of (A) compound and acceptable salt thereof as preparation 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, the application of 4-dihydro-2 (1H)-quinolinone (being Aripiprazole).
The 4th purpose of the present invention is to provide a kind of preparation method of Aripiprazole.
A kind of 7-[4-[4-disclosed by the invention (2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3,4-hydrogen-2 (1H)-quinoline-2-one-(A) and acceptable salt thereof, available following formula is represented:
(A) the compound salt or the inorganic acid salt that can form, or organic acid salt; Wherein inorganic acid salt preferably salt hydrochlorate or vitriol, organic acid salt preferred or fumarate, acetate, tartrate, maleate, Citrate trianion, mesylate or succinate.
Second purpose of the present invention: (A) compound can be made after the condensation reaction of routine by a kind of compound of general formula (B) or a kind of compound of its salt that can form and general formula (C);
Wherein X represents that a halogen atom or one can be similar to the group of halogen atom generation nucleophilic substitution reaction such as sulfonyloxy, hydroxyl; R
1Be hydrogen atom or basic metal or alkaline-earth metal.
Salt or inorganic acid salt that the compound of above-mentioned general formula (B) can form, or organic acid salt.Its inorganic acid salt or hydrochloride or vitriol; The organic acid salt that the compound of general formula (B) can form or acetate or tartrate.Preferred inorganic acid salt is a hydrochloride.
The selected solvent of above-mentioned condensation reaction is tetrahydrofuran (THF), dioxane, glycol dimethyl ether, benzene, toluene, pyridine, dimethylbenzene, methylene dichloride, trichloromethane, ethylene dichloride, N, dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide or acetonitrile; Preferred solvent is acetonitrile, N, dinethylformamide.Selected alkaline reagents is potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate or Potassium ethanoate class mineral alkali, or triethylamine, Trimethylamine 99, pyridines organic bases; Excellent alkaline reagents is salt of wormwood or triethylamine.
The compound of general formula (B) can be made after conventional condensation reaction by a kind of compound and 1-(2, the 3-dichlorophenyl) piperazine (E) of general formula (F);
X=X wherein
1, X represents a halogen atom or group such as the sulfonyloxy or the hydroxyl that can be similar to halogen atom generation nucleophilic substitution reaction.
(A) compound also can be made after the condensation reaction of routine by a kind of compound and 1-(2, the 3-dichlorophenyl) piperazine (E) of general formula (D):
Wherein X represents a halogen atom or group such as the sulfonyloxy or the hydroxyl that can be similar to halogen atom generation nucleophilic substitution reaction.
The solvent that above-mentioned condensation reaction is selected for use is tetrahydrofuran (THF), dioxane, glycol dimethyl ether, benzene, toluene, pyridine, dimethylbenzene, methylene dichloride, trichloromethane, ethylene dichloride, N, dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide or acetonitrile; Selected alkaline reagents is potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate or Potassium ethanoate class mineral alkali, or triethylamine, Trimethylamine 99, pyridines organic bases.Wherein preferred solvent is acetonitrile, N, dinethylformamide; Preferred alkaline reagents is salt of wormwood, triethylamine.
The compound of above-mentioned general formula (D) can be made after conventional condensation reaction by a kind of compound and 1-(2, the 3-dichlorophenyl) piperazine (E) of general formula (F).
The 3rd purpose of the present invention: (A) compound and acceptable salt thereof are as preparation 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, the application of 4-dihydro-2 (1H)-quinolinone (Aripiprazole).
The 4th purpose of the present invention: a kind of preparation 7-[4-[4-(2, the 3-dichlorophenyl)-and the 1-piperazinyl] butoxy]-3, the method of 4-dihydro-2 (1H)-quinolinone (Aripiprazole), it is characterized in that: 7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2 (1H)-quinoline-2-one-(A) or its acceptable salt have catalyzer and hydrogen supply agent to exist down in solvent, prepare after reduction reaction.
Salt or inorganic acid salt that above-claimed cpd (A) can form, or organic acid salt.Inorganic acid salt or be hydrochloride or for vitriol; Organic acid salt or acetate or tartrate.Be preferably hydrochloride.
Solvent that above-mentioned reduction reaction is selected or alcoholic solvent or ether solvent or N, dinethylformamide, ethyl acetate, acetic acid, water or alcohol/water mixed solvent and can with alcohol arbitrarily than miscible mixed solvent; Described reduction reaction is meant catalytic hydrogenation or hydroboration.
Above-mentioned alcoholic solvent or methyl alcohol, ethanol, (different) propyl alcohol or (just) butanols; Above-mentioned ether solvent or ether or tetrahydrofuran (THF).Preferred solvent is methyl alcohol, ethanol, (different) propyl alcohol or acetic acid.
During above-mentioned catalytic hydrogenation, in the presence of catalyzer, the hydrogenation that takes place when hydrogen supply agent is arranged; Described catalyzer or Raney's nickel, platinum, platinum oxide, palladium/carbon, nickel borides; Described hydrogen supply agent or hydrogen, tetrahydrobenzene, 1, borine or imide.Preferred catalyst or Raney's nickel or palladium/carbon; Preferred hydrogen supply agent is a hydrogen.
Make a general survey of the present invention, we are as can be seen: the 7-[4-[4-(2 that the present invention is alleged, the 3-dichlorophenyl)-and the 1-piperazinyl] butoxy]-3, the preparation method of 4-dihydro-2 (1H)-quinolinone (Aripiprazole), be with 1,4-dibromo 2-butylene (F) replaced describing in the EP367141 patent 1, the 4-dibromobutane, with 7-hydroxyl-3,4-dihydro-quinoline-2-one-makes 7-(4-bromo-2-butylene oxygen base)-3 after condensation reaction, 4 dihydros-2 (1H)-quinolinone (D), (D) and 1-(2, the 3-dichlorophenyl) piperazine (E) after condensation reaction, obtain 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2-(1H)-quinolinone (A) (A) makes Aripiprazole after catalytic hydrogenation.Synthetic route of the present invention is described as follows:
Compare with the preparation method of the Aripiprazole of describing in the EP367141 patent specification, though this synthetic route is than the many step chemical reactions of patent route; But the present invention adopts active high by 1,4-dibromo 2-butylene has replaced 1, the 4-dibromobutane, with 7-hydroxyl-3, when 4-dihydro-quinoline-2-one-carries out condensation reaction, have reaction conditions gentleness (45 ℃ of temperature of reaction), few, the easy characteristics of controlling of intermediate quality of by product.
Especially with 7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2-(1H)-quinolinone (A) is a raw material, when reduction reaction prepares Aripiprazole, not only has reaction conditions gentleness (reaction can be carried out at ambient temperature), by product is few, the characteristics that yield is high; And need not to obtain " pharmaceutical grade " Aripiprazole through recrystallization repeatedly.
Through a large amount of verification experimental verifications, quality controllable with the Aripiprazole that this synthetic route makes, stable yield (total recovery is up to more than 35%) is compared with the method for preparing Aripiprazole that the EP367141 patent is described, and then more helps the industrialization of product.
Description of drawings:
The infrared absorption spectrum of Fig. 1, the 7-that obtains produced according to the present invention (4-bromo-2-butylene oxygen base)-3,4 dihydro-2 (1H)-quinolinones
The proton nmr spectra absorption spectrum of Fig. 2, the 7-that obtains produced according to the present invention (4-bromo-2-butylene oxygen base)-3,4 dihydro-2 (1H)-quinolinones
The carbon-13 nmr spectra absorption spectrum of Fig. 3, the 7-that obtains produced according to the present invention (4-bromo-2-butylene oxygen base)-3,4 dihydro-2 (1H)-quinolinones
Fig. 4, the 7-[4-[4-that obtains produced according to the present invention (2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3, the infrared absorption spectrum of 4-dihydro-2-(1H)-quinolinone
Fig. 5, the 7-[4-[4-that obtains produced according to the present invention (2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3, the proton nmr spectra absorption spectrum of 4-dihydro-2-(1H)-quinolinone
Fig. 6, the 7-[4-[4-that obtains produced according to the present invention (2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3, the carbon-13 nmr spectra absorption spectrum of 4-dihydro-2-(1H)-quinolinone
The infrared absorption spectrum of Fig. 7, the Aripiprazole that obtains produced according to the present invention
The proton nmr spectra absorption spectrum of Fig. 8, the Aripiprazole that obtains produced according to the present invention
The carbon-13 nmr spectra absorption spectrum of Fig. 9, the Aripiprazole that obtains produced according to the present invention
Embodiment
The invention will be further described below in conjunction with embodiment, can make this area professional and technical personnel more fully understand the present invention, but not limit the present invention in any way.
One, the compound of general formula (D) can be reacted in solvent by a kind of compound of general formula (C) and a kind of compound of general formula (F), and the temperature condition of reaction is 0 ℃ to 120 ℃, preferably 0-40 ℃, finishes this reaction in several hours to 48 hours.To react used solvent as for this can be following said solvent, and ether solvent is as tetrahydrofuran (THF), dioxane, glycol dimethyl ether; Aromatic hydrocarbon solvent is as benzene, toluene, pyridine, dimethylbenzene; Alcoholic solvent is as methyl alcohol, ethanol, Virahol; Polar aprotic solvent such as N, dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, acetonitrile.Use a kind of alkaline reagents to help the carrying out that reacts.Said basic cpd can be potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate, Potassium ethanoate class mineral alkali, also can be triethylamine, Trimethylamine 99, the pyridines organic bases.In the time of if necessary, can add a kind of alkali-metal iodide, as sodium iodide, potassiumiodide etc. as reaction promotor.At the feed ratio of above-mentioned reaction formula of (F) compound and general formula (C) compound mol ratio to 5 times molar weight such as is, the best is equimolar amount to 1.2 a times molar weight.
7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2-(1H)-quinolinone (A) can be by a kind of compound and the 1-(2 of general formula (D), the 3-dichlorophenyl) piperazine (E) is in solvent, have under the alkali existence and react, the temperature condition of reaction is a room temperature to 150 ℃, and preferably 35-80 ℃, this is reflected in several hours to 24 hours and finishes.To react used solvent as for this can be following said solvent, and ether solvent is as tetrahydrofuran (THF), dioxane, glycol dimethyl ether; Aromatic hydrocarbon solvent is as benzene, toluene, pyridine, dimethylbenzene; Alkane solvents is as methylene dichloride, trichloromethane, ethylene dichloride; Polar aprotic solvent such as N, N dimethyl formamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, acetonitrile.Said alkaline reagents can be potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate, Potassium ethanoate class mineral alkali, also can be triethylamine, Trimethylamine 99, pyridines organic bases.In the time of if necessary, can add a kind of alkali-metal iodide, as sodium iodide, potassiumiodide etc. as reaction promotor.At the compound of above-mentioned reaction formula of (D) and the feed ratio of 1-(2, the 3-dichlorophenyl) piperazine (E) is to wait mole to 5 times of molar weights, and the best is equimolar amount to 1.2 a times molar weight.
7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2-(1H)-quinolinone (A) or its salt that can form are having in the presence of the catalyzer, in solvent, carry out making after the catalytic hydrogenation, the temperature condition of this reaction is a room temperature to 120 ℃, preferably 20-55 ℃, be reflected in several hours to 24 hours and finish.This reaction can be reduced under pressurized conditions, also can reduce under normal pressure.Selected solvent can be alcoholic solvent such as methyl alcohol, ethanol, (different) propyl alcohol, (just) butanols class during this reaction, also can be ether solvent such as ether, tetrahydrofuran (THF), can also be N, dinethylformamide, ethyl acetate, acetic acid, water or alcohol/water mixed solvent and can with alcohol arbitrarily than miscible mixed solvent.Said reduction reaction is meant that the compound (A) that will have unsaturated link(age) generates a kind of arbitrarily method of reducing of the Aripiprazole with saturated bond after reacting.Method of reducing commonly used has catalytic hydrogenation, Hydroboronation process.When adopting catalytic hydrogenation, the catalyzer such as metal of being everlasting exists down, and the hydrogenation that takes place when hydrogen supply agent is arranged, concrete catalyzer can be Raney's nickel, platinum, platinum oxide, palladium/carbon, nickel borides, hydrogen supply agent specifically can be hydrogen, tetrahydrobenzene, 1, borine, imide etc.
Two, the compound of general formula (B) can be by a kind of compound and the 1-(2 of general formula (F), the 3-dichlorophenyl) piperazine (E) has under the alkali existence and carries out in solvent, and temperature condition is 0 ℃ to 120 ℃, preferably 0-35 ℃, in several hours to 48 hours, finish this reaction.To react used solvent as for this can be following said solvent, and ether solvent is as tetrahydrofuran (THF), dioxane, glycol dimethyl ether; Aromatic hydrocarbon solvent is as benzene, toluene, pyridine, dimethylbenzene; Polar aprotic solvent such as N, dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, acetonitrile.Said alkaline reagents can be potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate, Potassium ethanoate class mineral alkali, also can be triethylamine, Trimethylamine 99, the pyridines organic bases.In the time of if necessary, can add a kind of alkali-metal iodide, as sodium iodide, potassiumiodide etc. as reaction promotor.The throwing of (2, the 3-dichlorophenyl) piperazine (E) of 1-in above-mentioned reaction and general formula (F) compound than mol ratio to 5 times molar weight such as being, the best is equimolar amount to 1.2 a times molar weight.
7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2-(1H)-quinolinone (A) can be by a kind of compound of a kind of compound of general formula (B) and general formula (C) in solvent, have under the alkali existence and react, the temperature condition of reaction is a room temperature to 150 ℃, preferably 35-80 ℃, this is reflected in several hours to 24 hours and finishes.To react used solvent as for this can be following said solvent, and ether solvent is as tetrahydrofuran (THF), dioxane, glycol dimethyl ether; Aromatic hydrocarbon solvent is as benzene, toluene, pyridine, dimethylbenzene; Alkane solvents is as methylene dichloride, trichloromethane, ethylene dichloride; Polar aprotic solvent such as N, dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, acetonitrile.Said alkaline reagents can be potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate, Potassium ethanoate class mineral alkali, also can be triethylamine, Trimethylamine 99, pyridines organic bases.In the time of if necessary, can add a kind of alkali-metal iodide, as sodium iodide, potassiumiodide etc. as reaction promotor.In this reaction, the feed ratio of the compound of the compound of general formula (B) and general formula (C) is to wait mole to 5 times of molar weights, and the best is equimolar amount to 1.2 a times molar weight.
Compound (A) and acceptable salt thereof prepare Aripiprazole after reduction reaction.
Embodiment 1:
The preparation of 7-(4-bromo-2-butylene oxygen base)-3,4 dihydros-2 (1H)-quinolinone (D)
In the 1000ml there-necked flask, drop into 5g (30mmol) 7-hydroxyl-3 successively, 4-dihydro-quinoline-2-one-, 7.9g (37mmol) 1,4-dibromo 2-butylene, 6.3g (45mmol) potassium hydroxide, 80ml acetonitrile, stir following 50 ℃ of reactions 3 hours, after reaction finishes, suction filtration, diafiltration, reclaim under reduced pressure part organic solvent, 20ml adds methylene chloride, distilled water 10ml, separate organic layer, water layer 10ml dichloromethane extraction three times merge organic layer, cause neutral approximately with the washing of semi-saturation salt solution, dry, suction filtration, reclaim under reduced pressure organic solvent, raffinate add ethanol 30ml, and be freezing, crystallization, suction filtration, obtain crude product, use the ethanol thermosol, obtain white crystals 6.2g (molecular formula: C
13H
14BrNO
2), mp:110-111 ℃, yield: 69.8%.
IR:3209 (v-NH), 1680 (v
O=C-N, acid amides I bands of a spectrum), 1517 (v
O=C-N, acid amides II bands of a spectrum), 1269 (v
O=C-NAcid amides III bands of a spectrum).
1H-NMR：2.6(2H，t，CH
2CO)，2.9(2H，t，CH
2Ph)，4.0(2H，d，CH
2Br)，4.6(2H，d，CH
2O)，5.8-6.0(2H，m，CH＝CH)，6.3(1H，d，benzene-H)，6.5(1H，dd，benzene-H)，7.1(1H，d，benzene-H)。
13C-NMR：171(CON)；157.8，138.2，129.7，116.2，108.9，102.3(benzene-C)；128.8，128.7(C＝C)；63.3(C-O)，30.9(C-Ph)，26.1(C-Br)，24.5(C-CO)。
7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3, the preparation of 4-dihydro-2-(1H)-quinolinone (A)
In the 1000ml there-necked flask, drop into 5g (17mmol) 7-(4-bromo-2-butylene oxygen base)-3 successively, 4-dihydro-quinoline-2-one-, 4g (17mmol) 1-(2, the 3-dichlorophenyl)-piperazine, 3.6g (26mmol) potassium hydroxide, the 80ml acetonitrile, reflux stirs reaction down 10 hours, after reaction finishes, suction filtration, diafiltration, reclaim under reduced pressure part organic solvent, 20ml adds methylene chloride, distilled water 10ml, separate organic layer, water layer 10ml dichloromethane extraction three times merge organic layer, neutral extremely approximately with the washing of semi-saturation salt solution, dry, suction filtration, reclaim under reduced pressure organic solvent, raffinate add ethanol 3ml, and be freezing, crystallization, suction filtration, obtain crude product, use the ethanol thermosol, freezing, crystallization, suction filtration obtains white crystals 5.5g (molecular formula: C after the drying
23H
25ClN
3O
2), mp:164-165 ℃, yield: 71.9%.
IR:3028 (v
NH), 1679 (v
O=C-N, acid amides I bands of a spectrum), 1518 (v
O=C-N, acid amides II bands of a spectrum), 1242 (v
O=C-NAcid amides III bands of a spectrum), 732 (v
C-Cl).
1H-NMR：2.61(2H，t，CH
2CO)，2.64(4H，m，2×CH
2)，3.07(4H，m，2×CH
2)，3.17(2H，d，CH
2N)，4.60(2H，t，CH
2O)，5.77-5.91(2H，m，CH＝CH)，6.4(1H，d，benzene-H)，6.54(1H，dd，benzene-H)，6.94(1H，dd，benzene-H)，7.04(1H，d，benzene-H)，7.14(2H，t，benzene-H)。
13C-NMR:172.2 (CON); 158.6,151.2,138.1,133.9,127.4,115.6 (phenyl ring quaternary carbons); 128.5,127.4,124.5,118.5,108.6,102.2 (phenyl ring tertiary carbons); 130.6,128.6 (side chain C=C); 68.2 (C-O), 60.2 (C-N), 53.2,51.2 (4 * C-N); 30.9,24.5 (2 * CH2).
7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone (Aripiprazole)
In the there-necked flask of 1000ml, drop into 6g (m13mol) 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazine successively]-2-butylene oxygen base]-3,4-dihydro (1 hydrogen)-quinoline-2-one-, 50ml ethanol, 6.5gRaney Ni, displacement hydrogen 12 hours, reaction finishes, be chilled to room temperature, suction filtration, washing, decompression solvent, freezing and crystallizing is through column chromatography (methylene dichloride: obtain white crystals 4.5g (molecular formula: C methyl alcohol=20: 1)
20H
27C
12N
3O
2), mp:138-139 ℃ (literature value: 139.5-140.0 ℃), yield: 78.2%.
IR:Vmax (film)/cm
-1: 3410 (v
NH), 1677 (v
C=O), 1520 (δ
NH, v
CN), 1214 (acid amides III bands).
1H-NMR：δ：1.70-1.80(4H，m，2×CH
2)，2.47(2H，t，CH
2CO)，2.58(2H，t，CH
2)，2.63(4H，m，2×CH
2)，3.07(4H，m，2×CH
2)，3.95(2H，t，CH
2CO)，6.34(1H，d，Benzene-H)，6.52(1H，dd，Benzene-H)，6.94(1H，dd，Benzene-H)，7.04(1H，d，Benzene-H)，7.14(2H，t，Benzene-H)。
13C-NMR: δ: 172.2 (CON); 158.6,151.2,138.1,133.9,127.4,115.6 (phenyl ring quaternary carbons); 128.5,127.4,124.5,118.5,108.6,102.2 (phenyl ring tertiary carbons); 67.8,58.1,53.2,51.3,31.0,27.2,24.5,23.4 (the secondary carbon of phenyl ring); Wherein 53.2,51.3 is four carbon on the piperazine ring.
Embodiment 2-6:
7-hydroxyl-3,4-dihydro-quinoline-2-one--1, the preparation of 4-two bromo-2-butylene (D)
With 7-hydroxyl-3,4-dihydro-quinoline-2-one-(C), 1,4-dibromo 2-butylene (F) is dissolved in the following solvent, adopts corresponding disacidify agent respectively, the heat tracing reaction, reaction finishes, and obtains product (D) behind aftertreatment, recrystallization.See Table 1:
Example solvent disacidify agent temperature (℃) time (h) yield (%)
2 tetrahydrofuran (THF) potassium hydroxide 60 4 61.5
3 ethanol triethylamines 11 0 166
4 propyl carbinol sodium bicarbonates 50 6 44.3
5 N, dinethylformamide sodium hydride 45 3.5 68
6 dimethyl sulfoxide (DMSO) salt of wormwood 75 6 54.8
Embodiment 7-11:
7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3, the preparation of 4-dihydro-2-(1H)-quinolinone (A)
With raw material 7-(4-bromo-2-butylene oxygen base)-3,4-dihydro-quinoline-2-one-(D), 1-(2, the 3-dichlorophenyl)-piperazine (E) are dissolved in the following solvent, adopt corresponding disacidify agent respectively, the heat tracing reaction, reaction finishes, and obtains product (A) behind aftertreatment, recrystallization.See Table 2:
Example solvent disacidify agent temperature (℃) time (h) yield (%)
7 dioxane potassium hydroxide 120 8 72.3
8 toluene triethylamines 110 12 70.8
9 Virahol potassium hydroxide 70 10 61.6
10 N, dinethylformamide salt of wormwood 120 6 73.5
11 dimethyl sulfoxide (DMSO) sodium hydrides 70 6 75.4
Embodiment 12-16:
7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone (Aripiprazole)
With raw material 7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro (1H)-quinoline-2-one-(A) is dissolved in the following solvent, adopts following catalyst hydrogenation replacement(metathesis)reaction respectively, reaction finishes, and obtains product behind aftertreatment, recrystallization.See Table 3:
Example solvent catalyst temperature (℃) time (h) yield (%)
12 tetrahydrofuran (THF) Pa/C 60 10 75.5
13 ethyl acetate Raney Ni 55 9 71.1
14 Virahol Raney Ni 25 12 78.3
15 N, dinethylformamide Pa/C 45 8 78.6
16 acetic acid Pa/C 25 10 85.6
Embodiment 17:
7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3, the preparation of 4-dihydro-2-(1H)-quinolinone hydrochloride
With 1g (2.24mmol) 7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2-(1H)-quinolinone (A) is dissolved in the 10ml methyl alcohol, stirs down, and slowly the dripping hydrochloric acid ethanolic soln makes pH=4, freezing and crystallizing, suction filtration, drying obtains white crystals 0.93g, yield: 86%, mp:141-151 ℃ (decomposition).
With the hydrochloride reference example 1 described method for preparing Aripiprazole of above-mentioned (A) that obtains, after reduction reaction (strengthening in case of necessity, the amount of solvent) finishes, reaction solution is concentrated, alkalizes, extracts, dry, concentrated, freezing, crystallization makes Aripiprazole after suction filtration, the drying.
Embodiment 18:
7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazine]-2-butylene oxygen base]-3, the preparation of 4-dihydro-2-(1H)-quinolinone maleate
With 1g (2.24mmol) 7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2-(1H)-quinolinone (A) is dissolved in the 10ml methyl alcohol, stirs down, slowly drips the toxilic acid methanol solution and makes pH=4, freezing and crystallizing, suction filtration, drying obtains white crystals 1.1g, yield: 87.3%, mp:124-131 ℃ (decomposition).
The maleate of above-mentioned (A) that obtains is made Aripiprazole according to the embodiment 17 described methods that prepare Aripiprazole.
Claims (16)
1, following (A) compound:
Chemical name is 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl]-2-butylene oxygen base]-3,4-dihydro-2 (1H)-quinoline-2-one-, and acceptable salt.
2, according to claim 1, (A) the compound salt or the inorganic acid salt that can form, or organic acid salt.
3, as described in the claim 2, (A) the compound inorganic acid salt that can form is hydrochloride, vitriol; Organic acid salt is fumarate, acetate, tartrate, maleate, Citrate trianion, mesylate or succinate.
4, as the preparation method of claim 1,2 or 3 described (A) compound, it is characterized in that: after conventional condensation reaction, make by a kind of compound of general formula (B) and a kind of compound of acceptable salt and general formula (C) thereof;
Wherein X represents a halogen atom or the group that can be similar to halogen atom generation nucleophilic substitution reaction; R1 is hydrogen atom or basic metal or alkaline-earth metal.
5, preparation method as claimed in claim 4, X is a sulfonyloxy.
6, preparation method as claimed in claim 4, the compound of its formula of (B) can be made after conventional condensation reaction by a kind of compound of 1-(2, the 3-dichlorophenyl) piperazine (E) and general formula (F);
X=X1 wherein, the X definition is described with claim 4.
7, preparation method as claimed in claim 5, the compound of its formula of (B) can be made after conventional condensation reaction by a kind of compound of 1-(2, the 3-dichlorophenyl) piperazine (E) and general formula (F);
X=X1 wherein, the X definition is described with claim 5.
8, as the preparation method of (A) compound as described in the claim 1,2 or 3, it is characterized in that: by a kind of compound of general formula (D) and 1-(2,3-
Dichlorophenyl) piperazine (E) makes after conventional condensation reaction;
Wherein the X definition is described with claim 4.
9, preparation method as claimed in claim 8, the compound of its formula of (D) is made after conventional condensation reaction by a kind of compound of general formula (C) and a kind of compound of general formula (F);
X1=X wherein, X, R1 definition is described with claim 4.
10, preparation method as claimed in claim 9 is characterized in that: X is a sulfonyloxy.
11, as claim 1,2 or 3 described (A) compounds and acceptable salt thereof as the preparation 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, the application of 4-dihydro-2 (1H)-quinolinone.
12, a kind of preparation 7-[4-[4-(2, the 3-dichlorophenyl)-and the 1-piperazinyl] butoxy]-3, the method of 4-dihydro-2 (1H)-quinolinone, it is characterized in that: 7-[4-[4-(2, the 3-dichlorophenyl)-the 1-piperazine]-2-butylene oxygen base]-3,4-dihydro-2 (1H)-quinoline-2-one-(A) or its acceptable salt have catalyzer and hydrogen supply agent to exist down in solvent, make after conventional reduction reaction.
13, preparation method as claimed in claim 12, solvent that wherein said reduction reaction is selected or alcoholic solvent or ether solvent or N, dinethylformamide, ethyl acetate, acetic acid, water or alcohol/water mixed solvent and can with alcohol arbitrarily than miscible mixed solvent; Described reduction reaction is meant catalytic hydrogenation or hydroboration.
14, preparation method as claimed in claim 13, wherein said alcoholic solvent or methyl alcohol, ethanol, Virahol or propyl carbinol; Described ether solvent or ether or tetrahydrofuran (THF).
When 15, preparation method as claimed in claim 12, wherein said catalytic hydrogenation, in the presence of catalyzer, the hydrogenation that takes place when hydrogen supply agent is arranged; Described catalyzer is Raney's nickel, platinum, platinum oxide, palladium/carbon or nickel borides; Described hydrogen supply agent or hydrogen, tetrahydrobenzene, 1, borine or imide.
16, as claim 13,14 or 15 described preparation methods, wherein said solvent or methyl alcohol or ethanol; Catalyzer or Raney's nickel or palladium/carbon; Described hydrogen supply agent is a hydrogen.
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| CN 03135329 CN1235880C (en) | 2003-06-30 | 2003-06-30 | Quinolinenone kind derivative and its accetable salt, its preparation method, application in preparation of alipyrazole and preparation of alipyrazole |
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| CN109776408B (en) * | 2017-11-14 | 2022-12-20 | 上海医药工业研究院 | Preparation method of 7-hydroxy-2-quinolinone |
| CN108218771A (en) * | 2018-03-12 | 2018-06-29 | 钦州学院 | Deuterated Aripiprazole and its preparation method and application |
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