CN105712930A - Aripiprazole and aripiprazole intermediate synthesis method - Google Patents
Aripiprazole and aripiprazole intermediate synthesis method Download PDFInfo
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Abstract
The present invention relates to an aripiprazole and aripiprazole intermediate synthesis method, 1,4-butanediol and 7-hydroxy-3,4-dihydro-2 (1H)-quinolinone as raw materials are first reacted under the effect of a catalyst into an ether, the obtained ether compound is reacted with a sulfonyl chloride or sulfonic anhydride in the presence of a base to obtain a sulfonate, and finally the sulfonate is reacted with 1-(2,3-dichlorophenyl) piperazine in the presence of a base to obtain aripiprazole. The method has the advantages of mild reaction conditions, cheap and readily available raw materials, and simple post-treatment.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of method synthesizing Aripiprazole and intermediate thereof.
Background technology
Aripiprazole is a kind of pharmaceutically active substance, has the structure of formula 1, its chemistry 7-{4-[4-(2,3-Dichlorobenzene base)-1-piperazinyl] butoxy by name }-3,4-dihydro-2 (1H)-quinolinones.
[formula 1]
Aripiprazole is the first dopamine system stabilizer, schizophrenia is positive and negative symptoms all has significant curative effect, this schizoid symptom can be significantly improved, and some side effect that other antipsychotic drug are common will not be caused, such as body weight increases and nonautonomy musculation etc., but may result in the symptoms such as headache, anxiety and insomnia.
The synthetic route of current Aripiprazole mainly has following four classes:
First kind synthetic route is as shown in scheme 1 (referring to CN1590377；J.Med.Chem., the 1998, the 41st volume, 658-667 page).The advantage of the method is in that: technical maturity, and step is simple, and raw material is easily bought.
[scheme 1]
But main disadvantage is that of the method: use dihalo butane to make raw material, reaction easily generates the dimer impurity (compound of formula 2, content about 10%), this impurity not easily passs through recrystallization method and removes, silica gel column chromatography can only be used to remove, but this processing method is difficult to be applied in industrial amplification production.In addition, owing to quinolinone compounds is completely insoluble in water, therefore in aqueous phase, reaction may affect its yield (in the embodiment of former patent CN1590377, reaction yield is 92.8%, but the repetition yield set forth of other patent such as US77770391 only about 60%).
[formula 2]
Equations of The Second Kind synthetic route is as shown in scheme 2 (referring to US5006528), including four kinds of methods synthesizing Aripiprazole.
[scheme 2]
This type of method uses sodium iodide or potassium iodide as catalyst, utilizes the ring closure reaction of N, N-dihaloethane compounds and ammoniac compounds to prepare the compound with piperazine ring structure.But, owing to employing chloroform in this type of method, thus environment friendly is poor.Additionally, N, N-dihaloethane compounds is difficult to obtain, and relatively costly.
3rd class synthetic route is as shown in Scheme 3.
[scheme 3]
2004, Delmar Chemicals Inc. of Canada disclosed a kind of by forming the method that quaternary ammonium salt intermediate prepares Aripiprazole.The method is by dichlorophenylpiperazine or its acid-addition salts and Formula X-C4H8-Y or X-C4H6The compound reaction of-Y (X, Y can be each halogen or sulfo group independently of one another), produces novel quaternary spiro ammonium salt intermediate.This quaternary spiro ammonium salt intermediate reacts with 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone can obtain Aripiprazole.The great advantage of the method is in that: can prepare the quaternary spiro ammonium salt intermediate (referring to CN1784385) of a kind of novel easily separated purification；Its shortcoming is in that equally: be easily formed dimer impurity (compound of formula 3).
[formula 3]
Shown in 4th class synthetic route such as scheme 4 and scheme 5.
Scheme 4 is recorded in CN1618791.Concretely comprising the following steps of the method: by 1-(2,3-Dichlorobenzene base) piperazine and 4-halo n-butyl alcohol or 4-halo n-butyric acie ester dissolve in organic solvent, under inorganic base or organic base exist, it is made to react generation 1-(4-hydroxy-n-butyl)-4-(2,3-Dichlorobenzene base) piperazine intermediate, add 7-hydroxyl-3 afterwards, 4-dihydro-2 (1H)-quinolinone, under the existence of the dehydrants such as concentrated sulphuric acid, p-methyl benzenesulfonic acid or titanium tetrachloride, reaction generates Aripiprazole.The advantage of the method is in that: decrease the content of dimer impurity in above-mentioned first kind method；It has drawbacks in that including alcohol and phenol is dehydrated into the reactions steps of ether in acid condition, and this step typically requires and carries out under relatively violent reaction condition, and therefore the productivity of target product Aripiprazole is relatively low.
[scheme 4]
Scheme 5 is recorded in CN103214415.The method adopted is: at N, in dinethylformamide, 7-hydroxyl-3, there is alkylated reaction in a heated condition in 4-dihydro-2 (1H)-quinolinone and 4-bromo n-butyl alcohol, subsequently the reaction intermediate obtained and sulfonic acid chloride are carried out esterification, obtain sulfonate compound, finally it is reacted with diethylenediamine compound, obtain target product Aripiprazole.Scheme 5 utilizes the reaction of bromide and phenolic hydroxyl group to prepare ether, is then sulphonic acid ester by the conversion of hydroxyl of this intermediate, finally reacts to prepare target product by itself and amino.From the angle of synthesis, the method is easier to realize, and productivity is high, be simple to operate and friendly to environment, and the appearance of dimer impurity (compound of formula 2) main in scheme before can avoiding.But the method have drawbacks in that 4-bromo n-butyl alcohol price is higher, cause that industrial production cost is higher；It addition, the more difficult removing of organic solvent DMF used.
[scheme 5]
Therefore, in order to reduce the production cost of Aripiprazole, its production method has been improved by inventor, the method cost after improvement is low, reaction condition is gentle, simple to operate, be prone to purification, be suitable for large-scale industrial production.
Summary of the invention
It is an object of the invention to provide that a kind of cost is low, productivity is high, be simple to operate and friendly to environment, suitable in the method for synthesis Aripiprazole of large-scale industrial production.
The present invention provides a kind of improved method synthesizing Aripiprazole, prepares Aripiprazole for raw material by three-step reaction including with BDO, and synthetic route is as follows:
Wherein,
" RCl " represents sulfonic acid chloride, it is preferred to mesyl chloride, trifluoromethanesulfchloride chloride or paratoluensulfonyl chloride etc., more preferably mesyl chloride.
“R2O " represent sulphonic acid anhydride, it is preferred to methanesulfonic acid acid anhydride or trifluoromethanesulfanhydride anhydride etc., more preferably methanesulfonic acid acid anhydride.
Concretely comprise the following steps:
Step one: 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone reacts under azodicarboxylate and phosphonate reagent exist with BDO, prepares the compound of formula (I)；
Step 2: the compound of formula (I) and sulfonic acid chloride (RCl) or sulphonic acid anhydride (R2O) react in the presence of a base, prepare the compound of formula (II),
Wherein " R " represents sulfonyl, it is preferred to mesyl, trifyl or p-toluenesulfonyl etc., more preferably mesyl；
Step 3: the compound of formula (II) and 1-(2,3-Dichlorobenzene base) piperazine react in the presence of a base, prepares Aripiprazole.
The present invention also provides for the method that one prepares formula (I) compound:
React under the existence of azodicarboxylate and phosphonate reagent including making 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and 1,4-butanediol.
The improved method reaction condition of synthesis Aripiprazole provided by the invention is gentle, cheaper starting materials is easy to get, post processing is simple.
Detailed description of the invention
The present invention provides a kind of improved method synthesizing Aripiprazole, prepares Aripiprazole for raw material by three-step reaction including with BDO, and synthetic route is as follows:
Wherein,
" RCl " represents sulfonic acid chloride, it is preferred to mesyl chloride, trifluoromethanesulfchloride chloride or paratoluensulfonyl chloride etc., more preferably mesyl chloride.
“R2O " represent sulphonic acid anhydride, it is preferred to methanesulfonic acid acid anhydride or trifluoromethanesulfanhydride anhydride etc., more preferably methanesulfonic acid acid anhydride.
Concretely comprise the following steps:
Step one: 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone reacts under azodicarboxylate and phosphonate reagent exist with BDO, prepares the compound of formula (I)；
Step 2: the compound of formula (I) and sulfonic acid chloride (RCl) or sulphonic acid anhydride (R2O) react in the presence of a base, prepare the compound of formula (II),
Wherein " R " represents sulfonyl, it is preferred to mesyl, trifyl or p-toluenesulfonyl etc., more preferably mesyl；
Step 3: the compound of formula (II) and 1-(2,3-Dichlorobenzene base) piperazine react in the presence of a base, prepares Aripiprazole.
The present invention also provides for the method that one prepares formula (I) compound:
React under the existence of azodicarboxylate and phosphonate reagent including making 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and 1,4-butanediol.
Can be seen that from the composition of the present invention, the method of preparation formula (I) compound is equivalent to the first step that the present invention synthesizes the method for Aripiprazole, therefore, hereinafter, for simplicity, method for preparing formula (I) compound does not do other explanation, and its details are referred to the first step that the present invention synthesizes the method for Aripiprazole, i.e. step one.
In a preferred embodiment of the inventive method, the phosphonate reagent used in step one can be triaryl phosphine such as triphenylphosphine, or trialkyl phosphine such as tri-butyl phosphine or tricyclohexyl phosphine, it is preferred to triphenylphosphine.
In a preferred embodiment of the inventive method, the azodicarboxylate used in step one can be diethyl azodiformate, diisopropyl azodiformate or azo acid dimethyl ester etc., it is preferred to diethyl azodiformate.
In a preferred embodiment of the inventive method, the solvent used in step one can be oxolane, dichloromethane, Isosorbide-5-Nitrae-dioxane, ether or chloroform etc., it is preferred to oxolane.
In a preferred embodiment of the inventive method, in step one, reaction temperature can be 0-50 DEG C, it is preferred to 0-45 DEG C, it is most preferred that for 15-35 DEG C.
In a preferred embodiment of the inventive method, in step, 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone, 1, the mol ratio of 4-butanediol, azodicarboxylate and phosphonate reagent can be 1:1:1:1-1:10:10:10, it is preferably 1:1.05:1.05:1.05-1:5:5:5, more preferably 1:1.1:1.1:1.1-1:1.5:1.5:1.5.
In a preferred embodiment of the inventive method, the alkali used in step 2 can be triethylamine, trimethylamine, diisopropyl ethyl amine, DMAP, potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate etc., it is preferred to triethylamine.
In a preferred embodiment of the inventive method, the solvent used in step 2 can be dichloromethane, oxolane, Isosorbide-5-Nitrae-dioxane, ether or chloroform etc., it is preferred to dichloromethane, oxolane.
In a preferred embodiment of the inventive method, in step 2, reaction temperature can be-10 DEG C to 50 DEG C, it is preferred to 5-25 DEG C.
In a preferred embodiment of the inventive method, in step 2, the mol ratio of compound (I), sulfonic acid chloride or sulphonic acid anhydride, alkali can be 1:1:1-1:10:10, it is preferred to 1:1.05:1.05-1:5:5, more preferably 1:1.1:1.1-1:1.5:1.5.
In a preferred embodiment of the inventive method, the alkali used in the step 3 of the inventive method can be triethylamine, trimethylamine, diisopropyl ethyl amine, DMAP, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate or potassium bicarbonate etc., it is preferred to potassium carbonate, cesium carbonate.
In a preferred embodiment of the inventive method, the solvent used in the step 3 of the inventive method can be DMF, Isosorbide-5-Nitrae-dioxane, oxolane or dimethyl sulfoxide etc., it is preferred to dimethyl sulfoxide.
In a preferred embodiment of the inventive method, in the step 3 of the inventive method, compound (II), 1-(2,3-Dichlorobenzene base) mol ratio of piperazine and alkali can be 1:1:1-1:5:5, it is preferably 1:1.05:1.05-1:3:3, more preferably 1:1.1:1.1-1:1.5:1.5.
Each step of the inventive method is generally implemented at ambient pressure, and the response time is generally 0.5-24 hour.
After each step of the inventive method terminates, it is possible to adopt the conventional method of prior art to do post processing, including separating, for instance by distilling, being separated, the method such as recrystallization.
Reagent used by the present invention and raw material are all commercially.
Wide in range, preferred, preferred and most preferred definition and scope in the present invention can be mutually combined.
The exemplary illustration present invention by the following examples, but the present invention should not be limited by the examples.
Embodiment 1
The synthesis (step one) of 7-(4-hydroxybutoxy)-3,4-dihydro-2 (the 1H)-quinolinone of intermediate formula (I)
By 7-hydroxyl-3, 4-dihydro-2 (1H)-quinolinone (16.3 grams, 100 mMs) join in 200 milliliters of oxolanes, then diethyl azodiformate (20.88 grams it is sequentially added into, 120 mMs) and triphenylphosphine (31.56 grams, 120 mMs), after mixture being stirred at room temperature 60 minutes, by 1, 4-butanediol (9.0 grams, 100 mMs) join in reaction system, continue to be stirred at room temperature 4 hours, utilize thin layer chromatography (TLC) detection reaction, until after reaction raw materials consumes completely, 100 milliliters of saturated aqueous common salts are added in reactant mixture, continue stirring gained mixed solution 30 minutes, separatory afterwards, aqueous layer with ethyl acetate (100 milliliters) extracts once, merge tetrahydrofuran solution and extract, decompression is distilled off solvent, then in residue, add 200 milliliters of ethyl acetate, carefully separate the water of residual, organic facies anhydrous sodium sulfate dries 2 hours, last low-pressure distillation removes solvent, obtain anhydrous grease 23.5 grams, crude yield is 92.9%, HPLC purity 93.5%.The thick product of gained is not further purified, and is directly used in next step reaction.
Or in order to obtain the sterling of formula (I) compound, use ethanol that the thick product of gained is carried out recrystallization, obtain off-white color solid 20.1 grams, HPLC yield 99.1%, yield 79.5%.
1HNMR(CDCl3,400MHz): 1.50 (2H, m), 1.73 (2H, m), 2.59 (2H, m), 2.86 (2H, t), 3.55 (2H, m), 3.93 (2H, m), 6.47 (1H, d), 6.89 (1H, d), 7.11 (1H, s), 7.99 (1H, s).
Embodiment 2
The synthesis (step one) of 7-(4-hydroxybutoxy)-3,4-dihydro-2 (the 1H)-quinolinone of intermediate formula (I)
By 7-hydroxyl-3, 4-dihydro-2 (1H)-quinolinone (16.3 grams, 100 mMs) join in 200 milliliters of dichloromethane, then diisopropyl azodiformate (24.24 grams it is sequentially added into, 120 mMs) and triphenylphosphine (31.56 grams, 120 mMs), after mixture being stirred at room temperature 60 minutes, by 1, 4-butanediol (9.0 grams, 100 mMs) join in reaction system, continue to be stirred at room temperature 4 hours, TLC detects reaction, until after reaction raw materials consumes completely, 100 milliliters of saturated aqueous common salts are added in reactant mixture, continue stirring gained mixed solution 30 minutes, separatory afterwards, organic facies anhydrous sodium sulfate dries 2 hours, last low-pressure distillation removes solvent, obtain anhydrous grease 21.1 grams, productivity is 83.4%.The thick product of gained is not further purified, and is directly used in next step reaction.
Characterize data such as embodiment 1.
Embodiment 3
The synthesis (step 2) of methanesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) butyl ester of intermediate formula (II)
By 7-(4-hydroxybutoxy)-3,4-dihydro-2 (1H)-quinolinone (20 grams, 85.1 mM) join in 200 milliliters of dichloromethane, it is subsequently adding triethylamine (15 grams, 150 mMs), utilize ice-water bath that mixture is cooled to 5 DEG C, be slowly added dropwise the dichloromethane solution (50 milliliters) of mesyl chloride (9.75 grams, 85.1 mMs) subsequently.Dropwising follow-up continuous insulation reaction 12 hours, TLC detects reaction, after consumption of raw materials is complete, adds 100 milliliters of water, continues stirring 30 minutes, separatory afterwards, organic over anhydrous dried over sodium sulfate 2 hours.Finally decompression is distilled off solvent, obtains colorless oil 27.3 grams, crude yield about 100%.
Crude product is put into vacuum drying oven reduced pressure at room temperature 12 hours, obtain off-white color solid 25.9 grams, yield 94.9%, HPLC purity 94.8%.
1HNMR(CDCl3,400MHz): 1.51 (2H, m), 1.72 (2H, m), 2.60 (2H, m), 2.89 (2H, t), 3.01 (3H, t), 3.59 (2H, m), 3.90 (2H, m), 6.43 (1H, d), 6.80 (1H, d), 7.19 (1H, s), 8.05 (1H, s).
Embodiment 4
The synthesis (step 2) of p-methyl benzenesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) butyl ester of intermediate formula (II)
By 7-(4-hydroxybutoxy)-3,4-dihydro-2 (1H)-quinolinone (10 grams, 42.6 mM) join in 100 milliliters of dichloromethane, it is subsequently adding triethylamine (7.5 grams, 75 mMs), utilize ice-water bath that mixture is cooled to 5 DEG C, be slowly added dropwise the dichloromethane solution (50 milliliters) of paratoluensulfonyl chloride (9.75 grams, 85.1 mMs) subsequently.Dropwising follow-up continuous insulation reaction 12 hours, TLC detects reaction, after consumption of raw materials is complete, adds 40 milliliters of water, continues stirring 30 minutes, separatory afterwards, organic over anhydrous dried over sodium sulfate 2 hours.Finally decompression is distilled off solvent, obtains colorless oil 14.3 grams, crude yield about 86.1%.
Crude product is put into vacuum drying oven reduced pressure at room temperature 12 hours, obtain off-white color solid 13.9 grams, yield 83.7%, HPLC purity 97.2%.
1HNMR(CDCl3,400MHz): 1.55 (2H, m), 1.73 (2H, m), 2.64 (2H, m), 2.91 (2H, t), 3.42 (3H, t), 3.60 (2H, m), 3.91 (2H, m), 6.48 (1H, d), 6.82 (1H, d), 7.25 (1H, s), 7.51 (2H, d), 7.94 (2H, d), 8.23 (1H, s).
Embodiment 5
The synthesis (step 3) of target product Aripiprazole
By methanesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) butyl ester (the preparing product of embodiment 3) (9.4 grams, 30 mMs) joins in 50 milliliters of dimethyl sulfoxide, is subsequently adding cesium carbonate (19.5 grams, 60 mMs) and 1-(2,3-Dichlorobenzene base) piperazine (7.62 grams, 33 mMs), heat the mixture to 100 DEG C afterwards and react 3 hours.TLC detects reaction, treat methanesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) after butyl ester consumption completely, reactant liquor is poured in 250 milliliters of frozen water, and with ethyl acetate (200 milliliters) extraction, gained extract is with saturated common salt water washing (50 milliliters × 3), and dries 2 hours with anhydrous sodium sulfate.Decompression obtains thick product after solvent is distilled off, and is purified finally by column chromatography (ethyl acetate: normal heptane=1:1), obtains off-white color solid 8.5 grams, productivity 63.2%.
1HNMR(CDCl3,400MHz): 1.76 (2H, m), 1.97 (2H, m), 2.51 (2H, m), 2.63 (2H, t), 2.76 (4H, m), 2.88 (2H, m), 2.93 (4H, m), 4.15 (2H, t), 6.77 (2H, m), 6.87 (1H, d), 7.11 (2H, d), 7.51 (1H, d), 11.50 (1H, s).
Embodiment 6
The synthesis (step 3) of target product Aripiprazole
By p-methyl benzenesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) butyl ester (the preparing product of embodiment 4) (11.69 grams, 30 mMs) joins in 50 milliliters of dimethyl sulfoxide, is subsequently adding cesium carbonate (19.5 grams, 60 mMs) and 1-(2,3-Dichlorobenzene base) piperazine (7.62 grams, 33 mMs), heat the mixture to 110 DEG C afterwards and react 2.5 hours.TLC detects reaction, treat p-methyl benzenesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) after butyl ester consumption completely, reactant liquor is poured in 250 milliliters of frozen water, and with ethyl acetate (200 milliliters) extraction, gained extract is with saturated common salt water washing (50 milliliters × 3), and dries 2 hours with anhydrous sodium sulfate.Decompression obtains crude product after solvent is distilled off, and is purified finally by column chromatography (ethyl acetate: normal heptane=1:1), obtains off-white color solid 7.1 grams, productivity 52.4%.
Characterize data such as embodiment 5.
Embodiment 7
The synthesis (step 3) of target product Aripiprazole
By methanesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) butyl ester (the preparing product of embodiment 3) (9.4 grams, 30 mMs) joins in 50 milliliters of dimethyl sulfoxide, is subsequently adding potassium carbonate (8.3 grams, 60 mMs) and 1-(2,3-Dichlorobenzene base) piperazine (7.62 grams, 33 mMs), heat the mixture to 100 DEG C afterwards and react 3 hours.TLC detects reaction, treat methanesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) after butyl ester consumption completely, reactant liquor is poured in 250 milliliters of frozen water, and with ethyl acetate (200 milliliters) extraction, gained extract is with saturated common salt water washing (50 milliliters × 3), and dries 2 hours with anhydrous sodium sulfate.Decompression obtains thick product after solvent is distilled off, and is purified finally by column chromatography (ethyl acetate: normal heptane=1:1), obtains off-white color solid 7.8 grams, productivity 57.5%.
Characterize data such as embodiment 5.
Embodiment 8
The synthesis (step 3) of target product Aripiprazole
By methanesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen bases) butyl ester (the preparing product of embodiment 3) (9.4 grams, 30 mMs) joins 50 milliliter 1, in 4-dioxane, it is subsequently adding potassium carbonate (8.3 grams, 60 mMs) and 1-(2,3-Dichlorobenzene base) piperazine (7.62 grams, 33 mMs), heat the mixture to 110 DEG C afterwards and react 5 hours.TLC detects reaction, treat methanesulfonic acid 4-(2-oxo-1,2,3,4-tetrahydrochysene quinolizidine morpholine-7-oxygen base) after butyl ester consumption completely, reactant liquor is poured in 250 milliliters of frozen water, and with ethyl acetate (200 milliliters) extraction, gained extract is with saturated common salt water washing (50 milliliters × 3), and dries 2 hours with anhydrous sodium sulfate.Decompression obtains thick product after solvent is distilled off, and is purified finally by column chromatography (ethyl acetate: normal heptane=1:1), obtains off-white color solid 5.2 grams, productivity 38.4%.
Characterize data such as embodiment 5.
Except as otherwise noted, above example carries out all at ambient pressure.
Claims (10)
1. the method synthesizing Aripiprazole, comprises the following steps:
Step one: 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone reacts under azodicarboxylate and phosphonate reagent exist with BDO, prepares the compound of formula (I)；
Step 2: the compound of formula (I) and sulfonic acid chloride (RCl) or sulphonic acid anhydride (R2O) react in the presence of a base, prepare the compound of formula (II),
Wherein " R " represents sulfonyl；
Step 3: the compound of formula (II) and 1-(2,3-Dichlorobenzene base) piperazine react in the presence of a base, prepares Aripiprazole.
2. method according to claim 1, it is characterised in that the phosphonate reagent used in described step one is triaryl phosphine or trialkyl phosphine.
3. method according to claim 1, it is characterised in that the azodicarboxylate used in described step one is selected from diethyl azodiformate, diisopropyl azodiformate and azo acid dimethyl ester.
4. method according to claim 1, it is characterised in that reaction temperature is 0-50 DEG C in described step one.
5. method according to claim 1, it is characterised in that in described step one, 7-hydroxyl-3, the mol ratio of 4-dihydro-2 (1H)-quinolinone, BDO, azodicarboxylate and phosphonate reagent is 1:1:1:1-1:10:10:10.
6. method according to claim 1, it is characterized in that, the alkali used in described step 2 and step 3 is selected from triethylamine, trimethylamine, diisopropyl ethyl amine, DMAP, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate.
7. method according to claim 1, it is characterised in that reaction temperature is-10 DEG C to 50 DEG C in described step 2.
8. method according to claim 1, it is characterised in that in described step 2, the mol ratio of compound (I), sulfonic acid chloride or sulphonic acid anhydride, alkali is 1:1:1-1:10:10.
9. method according to claim 1, it is characterised in that in described step 3, the mol ratio of compound (II), 1-(2,3-Dichlorobenzene base) piperazine and alkali is 1:1:1-1:5:5.
10. the method preparing formula (I) compound:
React under the existence of azodicarboxylate and phosphonate reagent including making 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and 1,4-butanediol.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1680328A (en) * | 2005-01-11 | 2005-10-12 | 中国人民解放军第二军医大学 | Preparation of Alipioxazole |
| EP2423204A1 (en) * | 2009-04-20 | 2012-02-29 | SBI Biotech Co., Ltd. | Thiazolidinone derivative |
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2014
- 2014-12-02 CN CN201410720807.2A patent/CN105712930A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1680328A (en) * | 2005-01-11 | 2005-10-12 | 中国人民解放军第二军医大学 | Preparation of Alipioxazole |
| EP2423204A1 (en) * | 2009-04-20 | 2012-02-29 | SBI Biotech Co., Ltd. | Thiazolidinone derivative |
Non-Patent Citations (1)
| Title |
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| LÁSZLÓ KÜRTI等: "《有机合成战略性应用》", 31 December 2005 * |
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