CN1249054C - Process for preparation of aripiprazole - Google Patents
Process for preparation of aripiprazole Download PDFInfo
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- CN1249054C CN1249054C CN 03135433 CN03135433A CN1249054C CN 1249054 C CN1249054 C CN 1249054C CN 03135433 CN03135433 CN 03135433 CN 03135433 A CN03135433 A CN 03135433A CN 1249054 C CN1249054 C CN 1249054C
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Abstract
The present invention relates to a preparation method of aripiprazole which is prepared from a compound in a general formula (A) by Friedel-Crafts alkylation reaction under the existence of a catalyst and under a molten state or the existence of solvent. When the present invention is adopted, a small quantity of aripiprazole isomers easily removed is concomitantly generated. The present invention has the advantages of easy control of the quality of intermediate bodies, stable quality of finished products, and mild reaction condition and small side effect of the rest steps except for low yield of the Friedel-Crafts alkylation reaction, and the total yield reaches 12%. An aripiprazole crude product obtained under the normal synthesis technology can be prepared into 'medicinal-stage ' aripiprazole without the need of multiple recrystallization.
Description
Technical field
What the present invention relates to is that a kind of Aripiprazole is 7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, the preparation method of 4-dihydro-2 (1H)-quinolinone.
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-(I) is a raw material, with 1, the 4-dibromobutane makes 7-bromine butoxy-3 after condensation reaction, 4-dihydro-quinoline-2-one-(II) (II) makes Aripiprazole with 1-(2, the 3-dichlorophenyl) piperazine again after condensation reaction.
As far back as Chem.Pharm.Bull.1961 (9): in 973, described 7-hydroxyl-3, the preparation method of 4-dihydro-quinoline-2-one-(I).(I) preparation is to be raw material with hydroxy phenyl between N--3-chlorine propionic acid amide, in the presence of Lewis acid, makes through Friedel-crafts reaction under molten state.Because the selectivity of this reaction is relatively poor, when preparation (I), will be with its a large amount of isomer 5-hydroxyl-3, the generation of 4-dihydro-quinoline-2-one-(III).
If (I) quality-guarantee is not, then when the preparation Aripiprazole, (I) isomer that is mixed with in (III) will participate in the back series reaction: (I) with 1, when 4 dibromobutanes generate (II) through condensation reaction, to generate with the isomer (IV) of (II), (IV) also will and 1-(2, the 3-dichlorophenyl) piperazine participate in condensation reaction, generate the isomer of Aripiprazole.
When the method for describing with the specification sheets of EP367141 patent prepares Aripiprazole, need relate to the preparation of intermediate (II).When preparing compound (II) 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, and intermediate (II) purifying is difficulty, its difficult quality guarantee.And the impurity that intermediate (II) is introduced will influence next step reaction, and the impurity of being introduced also be difficult to adopt conventional methods such as recrystallization to be removed, and final product quality is difficult to guarantee.
In view of the foregoing, during the Aripiprazole of the method preparation of describing with the specification sheets of EP367141 patent " pharmaceutical grade ", (I), the purifying of (II) and Aripiprazole will become the difficult point of this work.
Cause (I) and physico-chemical property difference (III) are little, want the recrystallization method by routine, remove difficulty with being mixed with a large amount of isomer (III) in (I).Under the uncontrollable situation of the quality of (I), the quality of intermediate (II) and Aripiprazole is also just uncontrollable.Seek out the Aripiprazole of " pharmaceutical grade ", can obtain after need adopting repeatedly the purification process of recrystallization (or column chromatography).Recrystallization repeatedly (or column chromatography) makes not only that its total recovery reduces significantly, the industrialization cost up, and operates loaded down with trivial detailsly, is unfavorable for the suitability for industrialized production of product.
This shows that the method for reporting in the EP367141 patent specification for preparing Aripiprazole will be subjected to certain restriction to the industrialization of product.And four kinds of methods that prepare Aripiprazole of only describing in the claims in addition 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 side reaction is many, yield is extremely low.
Summary of the invention
The object of the present invention is to provide a kind of reaction process to be easy to control, the preparation method of the Aripiprazole that cost of manufacture is low.
A kind of preparation method of Aripiprazole is characterized in that: a kind of compound of general formula (A) or in molten state or in the presence of solvent has catalyzer to exist down and makes through the Fu Ke alkylated reaction.
When above-mentioned Fu Ke alkylated reaction reacts in the presence of solvent, the solvent of selecting for use be dioxane, oil of mirbane,
N, dinethylformamide, dimethyl sulfoxide (DMSO), Nitromethane 99Min. or ethylene dichloride, described catalyzer is a Lewis acid.
Above-mentioned catalyzer or aluminum chloride, zinc chloride, nickelous chloride, tin chloride, titanium chloride or boron trifluoride.
A kind of compound of general formula (A) is 3-[4-[4-(2, a 3-dichlorophenyl) piperazinyl] butoxy] aniline (B) in inert solvent, have alkali to exist down, make after acylation reaction with a kind of compound of general formula (C);
Wherein, X is defined as or bromine atoms or chlorine atom,
X1 is defined as or bromine atoms or chlorine atom.
The selected inert solvent of above-mentioned acylation reaction is tetrahydrofuran (THF), dioxane, glycol dimethyl ether, ethyl acetate, benzene, toluene, pyridine, dimethylbenzene, acetonitrile, acetic acid, methylene dichloride, trichloromethane or ethylene dichloride; Selected alkaline reagents is potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate, Potassium ethanoate class mineral alkali, triethylamine, Trimethylamine 99 or pyridines organic bases.
Compound 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] aniline (B) is by 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D) or its acceptable salt makes after reduction reaction in solvent.
Above-mentioned reduction reaction can be metallic reducing method or sulfide reduction method, catalytic hydrogenation method or multiple hydride reduction method, with compound 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D) is reduced into compound 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] aniline (B); Selected solvent is methyl alcohol, ethanol, Virahol or ether solvent such as ether, tetrahydrofuran (THF), dioxane in the reaction, or inert solvent such as benzene, toluene, methylene dichloride, trichloromethane, ethylene dichloride or or the mixed solvent formed of above organic solvent and water.
Compound 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D) be by a kind of compound with general formula (E) and 1-(2, the 3-dichlorophenyl) piperazine (F) in solvent, have alkaline reagents to exist down, after condensation reaction, make;
Wherein R is a halogen atom or is similar to the group that a halogen atom carries out substitution reaction, as sulfonyloxy, hydroxyl.
Selected solvent or ether solvent such as tetrahydrofuran (THF), dioxane, glycol dimethyl ether in the above-mentioned condensation reaction; Or aromatic hydrocarbon solvent such as benzene, toluene, pyridine, dimethylbenzene; Or alcoholic solvent such as methyl alcohol, ethanol, Virahol; Or polar aprotic solvent such as N, dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, acetonitrile; Methylene dichloride, trichloromethane, ethylene dichloride or N-Methyl pyrrolidone; Selected alkaline reagents is potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride class mineral alkali; Or sodium-acetate, Potassium ethanoate, triethylamine, Trimethylamine 99 or pyridines organic bases.
Make a general survey of the present invention; as can be seen: the preparation method of Aripiprazole of the present invention; be with 3-(4-bromine butoxy) oil of mirbane (E) and 1-(2; the 3-dichlorophenyl)-piperazine (F) takes place to make 3-[4-[4-(2 after the condensation reaction; the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D); (D) after reduction reaction, make 3-[4-[4-(2; the 3-dichlorophenyl) piperazinyl] butoxy] aniline (B); (B) and 3-chlorine (bromine) propionyl chloride (bromine) (C) after acylation reaction, make N-(3-chlorine propionyl)-3-[4-[4-(2; the 3-dichlorophenyl) piperazinyl] butoxy] aniline (A), (A) behind Friedel-crafts reaction, obtain Aripiprazole again.Synthetic route of the present invention is described as follows:
This synthetic method need not to prepare the intermediate (I) described in the EP367141 patent specification and (II), compares with the method for describing in the EP367141 patent specification for preparing Aripiprazole, and the advantage of this synthetic route is:
1, at the compound (as: N-(3-chlorine propionyl)-3-[4-[4-(2 of general formula (A); the 3-dichlorophenyl) piperazinyl] butoxy] aniline) in; because it is sterically hindered bigger; therefore when carrying out the Fu Ke alkylated reaction; the preferential 7-[4-[4-(2 that generates; the 3-dichlorophenyl)-and the 1-piperazinyl] butoxy]-3,4-dihydro-2 (1H)-quinolinone (Aripiprazole).Follow during reaction to generate a spot of Aripiprazole isomer, and a spot of Aripiprazole isomer can to adopt chloroform and tetrahydrofuran (THF) (5: 2) be recrystallization solvent, be easy to be removed.
2, prepare Aripiprazole with this synthetic route, except that Fu Ke alkylated reaction yield was on the low side, all the other respectively went on foot the reaction conditions gentleness, side reaction is few, and the intermediate quality is controlled easily, and final product quality is stable, and total recovery reaches 12%.Under normal synthesis technique, the Aripiprazole crude product that is obtained need not repeatedly recrystallization and can make " pharmaceutical grade " Aripiprazole.
Description of drawings
Fig. 1,3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl that makes according to the present invention] butoxy] infrared absorpting light spectra of oil of mirbane (D);
Fig. 2,3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl that makes according to the present invention] butoxy] the proton nmr spectra abosrption spectrogram of oil of mirbane (D);
Fig. 3,3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl that makes according to the present invention] butoxy] infrared absorpting light spectra of aniline (B);
Fig. 4,3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl that makes according to the present invention] butoxy] the proton nmr spectra abosrption spectrogram of aniline (B);
Fig. 5, N-(3-chlorine propionyl)-3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl that makes according to the present invention] butoxy] infrared absorpting light spectra of aniline (A);
Fig. 6, N-(3-chlorine propionyl)-3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl that makes according to the present invention] butoxy] the proton nmr spectra abosrption spectrogram of aniline (A);
The infrared absorpting light spectra of Fig. 7, the Aripiprazole that makes according to the present invention;
The proton nmr spectra abosrption spectrogram of Fig. 8, the Aripiprazole that makes 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 preparation of compound (D)
3-(4-bromine butoxy) oil of mirbane (E) and 1-(2, the 3-dichlorophenyl)-piperazine (F) or the salt that (F) can form make 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl after condensation reaction in the presence of solvent] butoxy] oil of mirbane (D).The temperature condition of its reaction is a room temperature to 150 ℃, and preferably 60-120 ℃, this is reflected in several hours to 60 hours and finishes.Reacting used solvent as for this can be ether solvent such as tetrahydrofuran (THF), dioxane, glycol dimethyl ether; Aromatic hydrocarbon solvent such as benzene, toluene, pyridine, dimethylbenzene; Alcoholic solvent such as methyl alcohol, ethanol, Virahol; Also can be aprotic, polar such as N, dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, acetonitrile.Use a kind of alkaline reagents to help the carrying out that reacts, said alkaline reagents can be potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride 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 as reaction promotor.In above-mentioned reaction, the feed ratio of 3-(4-bromine butoxy) oil of mirbane (D) and 3-(4-bromine butoxy) oil of mirbane (E) is equimolar amount to 5 a times molar weight, and the best is equimolar amount to 1.5 a times molar weight.
Two, the preparation of compound (B)
3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D) or its salt that can form in the presence of solvent, after reduction reaction, make 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] aniline (B).Said reduction reaction can be taked conventional method of reducing, and said method of reducing has: metallic reducing, hydrogen sulfide reduction, catalytic hydrogenation, multiple hydride reduction method.The temperature of reaction condition is a room temperature to 150 ℃, preferably 45-80 ℃, finishes this reaction in several hours to 12 hours.Reaction can be alcoholic solvent such as methyl alcohol, ethanol, Virahol with solvent; Ether solvent such as ether, tetrahydrofuran (THF), dioxane; Inert solvent such as benzene, toluene, methylene dichloride, trichloromethane, ethylene dichloride; Or the mixed solvent of above organic solvent and water composition.When carrying out this reaction, 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] feed ratio of oil of mirbane (D) and reductive agent is equimolar amount to 7 times molar weight, the best is 1.5 times of molar weight to 2.5 times molar weights.
Three, the preparation of compound (A)
3-[4-[4-(2; the 3-dichlorophenyl) piperazinyl] butoxy] aniline (B) and 3-chlorpromazine chloride (C) be under nitrogen protection; after acylation reaction, make N-(3-chlorine propionyl)-3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl when having solvent and alkaline reagents to exist] butoxy] aniline (A).The temperature condition of this reaction is 0 ℃ to 100 ℃, preferably 10-50 ℃, finishes this reaction in several hours to 12 hours.This reacts used solvent tetrahydrofuran (THF), dioxane, glycol dimethyl ether, ethyl acetate, benzene, toluene, pyridine, dimethylbenzene, acetonitrile, acetic acid, methylene dichloride, trichloromethane, ethylene dichloride.Use a kind of alkaline reagents to help the carrying out that reacts.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.3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl in this reaction] butoxy] feed ratio of aniline (B) and 3-chlorpromazine chloride (C) mol ratio to 5 times molar weight such as is, the best is equimolar amount to 1.1 a times molar weight.
Four, the preparation of Aripiprazole
N-(3-chlorine propionyl)-3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] aniline (A) or its salt that can form in the presence of Lewis acid, solvent is arranged or makes Aripiprazole through Friedel-crafts reaction when solvent-free.The temperature of reaction condition is 75-170 ℃, and preferably 90-150 ℃, this is reflected in several hours to 12 hours and finishes.Said solvent has dioxane, oil of mirbane, N, dinethylformamide, dimethyl sulfoxide (DMSO), Nitromethane 99Min., ethylene dichloride.Said Lewis acid has aluminum chloride, zinc chloride, nickelous chloride, tin chloride, titanium chloride, boron trifluoride.N-in above-mentioned reaction (3-chlorine propionyl)-3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] aniline (A) and lewis acidic feed ratio be catalytic amount to 5 times molar weight, the best is equimolar amount to 2.5 a times molar weight.
The specific embodiment of this synthetic route is as follows:
Example 1:
3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] preparation of oil of mirbane (D)
In reaction flask, drop into 1-(2, the 3-dichlorophenyl) piperazine (F) 5.80g (25mmol), 3-(4-bromine butoxy) oil of mirbane (E) 6.89g (25mmol) successively, salt of wormwood 4.15g (30mmol), acetonitrile 25ml, potassiumiodide a little, stirred down heating reflux reaction 48 hours.Reaction finishes, and suction filtration is removed inorganics, and wash filtrate concentrates filtrate the recovery part organic solvent then.The 30ml that in enriched material, adds methylene chloride, distilled water 10ml separates organic layer, and water layer merges organic layer with 20ml dichloromethane extraction three times, is washed with water to neutrality.The organic layer anhydrous sodium sulfate drying, suction filtration filtering siccative, the reclaim under reduced pressure organic solvent, adding sherwood oil and ethyl acetate 12ml (v/v=7: 3) crystallization, suction filtration, drying obtains faint yellow crystallization 5.8g (molecular formula: C
20H
23C
L2N
3O
3), mp:86.5-87.5 ℃, yield: 54.4%.
IR(KBr)/cm
-1：
2949，2814.7，1617，1580，1482.4，1351，1309，1286.5，1240，1141，1028，947.9，875.3，8068，773.6，741.6，707.6。See Fig. 1
1H-NMR(CDCl
3)：
δ(ppm)：
1.70-1.77(2H，m，-CH
2-)，1.85-1.92(2H，m，-CH
2-)，2.49-2.53(2H，t，-CH
2-)，2.67(4H，m，2×CH
2)，3.08(4H，m，2×CH
2)，4.07-4.13(2H，t，-CH
2-O)，6.93-6.98(1H，d，Benzene-H)，7.14-7.17(2H，dd，Benzene-H)，7.20-7.26(1H，dd，Benzene-H)，7.40-7.44(1H，d，Benzene-H)，7.72-7.73(1H，t，Benzene-H)，7.79-7.82(1H，m，Benzene-H)。See Fig. 2.
Get the 1g product and be dissolved in the 5ml ethyl acetate, ice bath is chilled to 0 ℃, and slowly the dripping hydrochloric acid ethanolic soln makes pH=5, and freezing crystallization obtains hydrochloride 0.96g, and mp:192-194 ℃, yield: 88.4%.
3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] preparation of aniline (B)
In three mouthfuls of reaction flasks of 50ml, drop into 3-[4-[4-(2 successively, the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D) 8.5g (20mmol), 80% ethanol 30ml, zinc powder 2.0g (30.6mmol), be heated with stirring to 45 ℃, drip Glacial acetic acid 2.2g (36.6mmol), dropwise, be heated to back flow reaction 2 hours.Reaction finishes, and the reclaim under reduced pressure partial solvent is with the KOH aqueous solution neutralization of 5mol/L, make pH=9, with 30ml dichloromethane extraction three times, merge organic layer, after organic layer water 20ml collection is washed, with dried over sodium sulfate, suction filtration, filtering siccative, reclaim under reduced pressure organic solvent add sherwood oil and ethyl acetate 20ml (v/v=8: 3) crystallization, suction filtration, drying obtains light yellow amorphous powder 6.2g (molecular formula: C
20H
25Cl
2N
3O), mp:99.5-100.5 ℃, yield: 78.5%.
IR(KBr)/cm
-1：
3400.9，3354.2，2948.5，2667.5，2581.9，1619.4，1605，1578.8，1497.6，1400.6，1195.7，1171.9，1054.8，939.9，787.9，683.7。See Fig. 3
1H-NMR(CDCl
3)：
δ(ppm)：1.66-1.72(2H，m，-CH
2-)，1.77-2.16(2H，m，-CH
2-)，2.46-2.53(2H，t，-CH
2-)，2.65(4H，m，2×CH
2)，3.07(4H，m，2×CH
2)，3.70(2H，s，-NH
2)，3.93-3.96(2H，t，-CH
2-O)，6.23-6.33(1H，d，Benzene-H)，6.93-6.98(2H，dd，Benzene-H)，7.20-7.26(1H，dd，Benzene-H)，7.40-7.44(1H，d，Benzene-H)，7.73-7.72(1H，t，Benzene-H)，7.79-7.82(1H，t，Benzene-H)。See Fig. 4.
Get the 1g product and be dissolved in the 5ml acetone, ice bath is chilled to 0 ℃, and slowly the dripping hydrochloric acid ethanolic soln makes pH=5, and freezing crystallization obtains hydrochloride 0.87g, and mp:221-223 ℃, yield: 79.6%.
N-(3-chlorine propionyl)-3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] preparation of aniline (A)
In three mouthfuls of reaction flasks of 100ml, drop into 3-[4-[4-(2 successively; the 3-dichlorophenyl) piperazinyl] butoxy] aniline (B) 3.95g (10mmol); benzene 10ml; triethylamine 1.7ml (12mmol); slowly dripped 3-chlorpromazine chloride (C) 1ml (11mmol) room temperature reaction under the nitrogen protection 4 hours; reaction finishes; filter, benzene is washed, and collects filtrate; wash organic layer with 0.5mol/LKOH aqueous solution 20ml collection; tell organic layer, the salt solution washed twice with 20%, organic layer dried over sodium sulfate; the filtering siccative, the reclaim under reduced pressure organic solvent.Obtain off-white color needle 3.2g (molecular formula: C
23H
28Cl
3N
3O
2), mp:102-104 ℃, yield: 65.9%.
IR(KBr)/cm
-1：
3413.4，2947.7，2512.7，2444.7，1689.2，1602.5，1541.9，1446.9，1290.0，1214.9，1153.4，1051.2，953.3，782.8。See Fig. 5.
1H-NMR(CDCl
3)：
δ(ppm)：1.50-2.00(4H，m，2×CH
2)；2.48，3.87(2H，t，-CH
2CO)；2.62，3.07(8H，m，4×CH
2-)，2.80(2H，t，CH
2N)；3.85，5.75(2H，t，CH
2Cl)；3.99(2H，t，CH
2O)；6.19-7.23(7H，m，Benzene-H)，8.41(1H，s，N-H)。See Fig. 6.
7-[4-[4-(2, the 3-dichlorophenyl)-1-piperazinyl] butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone (Aripiprazole)
In three mouthfuls of reaction flasks of 100ml, drop into N-(3-chlorine propionyl)-3-[4-[4-(2 successively; the 3-dichlorophenyl) piperazinyl] butoxy] aniline (A) 4.9g (10mmol), N, dinethylformamide 10ml; zinc chloride 2.1g (15.4mmol) was heated to back flow reaction 1 hour under the nitrogen protection.Reaction finishes, be cooled to room temperature, add water 30ml, use 25ml dichloromethane extraction three times, merge organic layer, wash organic layer with 20ml water collection, tell organic layer, use dried over sodium sulfate, the filtering siccative, the reclaim under reduced pressure organic solvent adds the mixed solvent 10ml of chloroform and tetrahydrofuran (THF) (5: 2) in residue, obtain crude product.Crude product is with 95% ethanol 5ml recrystallization, and freezing, crystallization, suction filtration, drying obtain white needle 0.87g (molecular formula: C
23H
27Cl
2N
3O
2), mp:137.5-138.5 ℃, yield: 19.2%.
IR:V
Max(KBr)/cm
-13410 (v
NH), 1677 (v
C=O), 1520 (δ
NH, V
CN), 1214 (acid amides III bands).See Fig. 7.
1H-NMR(CDCl
3)：
δ(ppm)：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)。See Fig. 8.
Example 2-6 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] preparation of oil of mirbane (D)
Raw material 1-(2, the 3-dichlorophenyl) piperazine (F), 3-(4-bromine butoxy) oil of mirbane (E) are dissolved in the following solvent, adopt different disacidify agent respectively, the heat tracing reaction, reaction finishes, and obtains product behind aftertreatment, recrystallization, sees Table 1:
Example solvent disacidify agent temperature (℃) time (h) yield (%)
2 tetrahydrofuran (THF) potassium hydroxide 60 46 86.2
3 toluene triethylamines 110 22 79.5
4 Virahol sodium bicarbonates 75 60 54.6
5 N, dinethylformamide pyridine 80 42 83.4
6 dimethyl sulfoxide (DMSO) salt of wormwood 70 27 51.3
Example 7-11 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] preparation of aniline (B)
With raw material 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D) is dissolved in the following solvent, and listed reductive agent and reaction conditions reacts in the employing table respectively, and question response finishes, and obtains product behind aftertreatment, recrystallization, sees Table 2:
Example solvent reductive agent temperature (℃) time (h) yield (%)
7 ethanol/water Fe/HCl 75 2.5 75.2
8 benzene/water Zn/HCl 70 2 76.7
9 ethanol/water Na
2S
2O
435 0.5 71.4
10 water Na
2S
280 4 63.0
11 isopropanol Na
2S/NH
4Cl 85 1.5 65
Example 12-16 N-(3-chlorine propionyl)-3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] preparation of aniline (A)
With raw material 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] aniline (B) and 3-chlorpromazine chloride (C) be dissolved in the following solvent, and listed reaction conditions reacts in the employing table respectively, and question response finishes, behind aftertreatment, recrystallization, obtain product, see Table 3:
Example solvent disacidify agent temperature (℃) time (h) yield (%)
12 pyridines/55 3 87.3
13 acetonitrile salt of wormwood 60 2 45.9
14 trichloromethane triethylamines 35 4 88.6
15 acetic acid sodium-acetates 60 1.5 63.0
16 tetrahydrofuran (THF) triethylamines 45 3 70
The preparation of example 17-21 Aripiprazole
With raw material N-(3-chlorine propionyl)-3-[4-[4-(2; the 3-dichlorophenyl) piperazinyl] butoxy] aniline (A) is dissolved in the following solvent, and listed reaction conditions reacts in the employing table respectively, and question response finishes; behind aftertreatment, recrystallization, obtain product, see Table 3:
Example solvent catalyst temperature (℃) time (h) yield (%)
17 dioxane AlCl
3120 1 22
18 dimethyl sulfoxide (DMSO) SnCl
4150 0.5 17.6
19 / AlCl
3 100 1.5 18.4
20 Nitromethane 99Min. AlCl
3100 1 15.3
21 N, dinethylformamide BF
3100 1.5 12.7
Claims (9)
1, a kind of preparation method of Aripiprazole is characterized in that: have catalyzer to exist down, a kind of compound of general formula (A) is in molten state or in the presence of solvent, makes through the Fu Ke alkylated reaction;
Wherein X is defined as or bromine atoms or chlorine atom; Described catalyzer is a Lewis acid.
2, preparation method as claimed in claim 1, it is characterized in that: when described Fu Ke alkylated reaction reacts in the presence of solvent, the solvent of selecting for use is dioxane, oil of mirbane, N, dinethylformamide, dimethyl sulfoxide (DMSO), Nitromethane 99Min. or ethylene dichloride.
3, preparation method as claimed in claim 1 or 2 is characterized in that: described catalyzer or aluminum chloride, zinc chloride, nickelous chloride, tin chloride, titanium chloride or boron trifluoride.
4, preparation method as claimed in claim 1 is characterized in that: the compound of general formula (A) is 3-[4-[4-(2, a 3-dichlorophenyl) piperazinyl] butoxy] aniline (B) is in inert solvent, and there have alkaline reagents to exist to be following, with logical
A kind of compound of formula (C) makes after acylation reaction;
Wherein, X is defined as or bromine atoms or chlorine atom,
X
1Be defined as or bromine atoms or chlorine atom.
5, preparation method as claimed in claim 4 is characterized in that: the selected inert solvent of described acylation reaction is tetrahydrofuran (THF), ethyl acetate, benzene, toluene, pyridine, dimethylbenzene, acetonitrile, acetic acid, methylene dichloride, trichloromethane or ethylene dichloride; Selected alkaline reagents is potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate, Potassium ethanoate, triethylamine, Trimethylamine 99 or pyridine.
6, preparation method as claimed in claim 4 is characterized in that: compound (B) is by 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D) or its acceptable salt makes after reduction reaction in solvent;
7, preparation method as claimed in claim 6, it is characterized in that: described reduction reaction is metallic reducing method, sulfide reduction method, catalytic hydrogenation method or multiple hydride reduction method, with compound 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] oil of mirbane (D) is reduced into compound 3-[4-[4-(2, the 3-dichlorophenyl) piperazinyl] butoxy] aniline (B); Selected solvent is methyl alcohol, ethanol, Virahol, ether, tetrahydrofuran (THF), dioxane in the reaction, the mixed solvent that benzene, toluene, methylene dichloride, trichloromethane, ethylene dichloride or above organic solvent and water are formed.
8, preparation method as claimed in claim 6 is characterized in that: described compound (D) in solvent, has alkaline reagents to exist down, through condensation by a kind of compound with general formula (E) and 1-(2, the 3-dichlorophenyl) piperazine (F)
Make after the reaction;
Wherein R is a halogen atom or sulfonyloxy or hydroxyl.
9, preparation method as claimed in claim 8, it is characterized in that: selected solvent is tetrahydrofuran (THF), dioxane, glycol dimethyl ether, benzene, toluene, pyridine, dimethylbenzene, methylene dichloride, trichloromethane, ethylene dichloride, N in the described condensation reaction, dinethylformamide, dimethyl sulfoxide (DMSO), hexamethylphosphoramide, acetonitrile or N-Methyl pyrrolidone; Selected alkaline reagents is potassium hydroxide, salt of wormwood, sodium hydroxide, yellow soda ash, sodium bicarbonate, sodium amide, sodium hydride, sodium-acetate, Potassium ethanoate, triethylamine, Trimethylamine 99 or pyridine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 03135433 CN1249054C (en) | 2003-07-15 | 2003-07-15 | Process for preparation of aripiprazole |
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|---|---|---|---|
| CN 03135433 CN1249054C (en) | 2003-07-15 | 2003-07-15 | Process for preparation of aripiprazole |
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| CN1249054C true CN1249054C (en) | 2006-04-05 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP6345651B2 (en) * | 2012-05-09 | 2018-06-20 | サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． | Heteroaryl compounds and methods of use thereof |
| CN103214415A (en) * | 2013-05-09 | 2013-07-24 | 江苏万全特创医药生物技术有限公司 | Preparation method of aripiprazole and key intermediate of aripiprazole |
| CN111826677B (en) * | 2020-01-17 | 2021-06-04 | 浙江大学 | Electro-reduction preparation method of aripiprazole intermediate |
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