WO2008001188A2 - An improved process for the preparation of substantially pure aripiprazole - Google Patents
An improved process for the preparation of substantially pure aripiprazole Download PDFInfo
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- WO2008001188A2 WO2008001188A2 PCT/IB2007/001732 IB2007001732W WO2008001188A2 WO 2008001188 A2 WO2008001188 A2 WO 2008001188A2 IB 2007001732 W IB2007001732 W IB 2007001732W WO 2008001188 A2 WO2008001188 A2 WO 2008001188A2
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- Prior art keywords
- aripiprazole
- substantially pure
- preparing substantially
- pure aripiprazole
- organic solvent
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- 0 *CCCCOc1ccc(CCC(N2)=O)c2c1 Chemical compound *CCCCOc1ccc(CCC(N2)=O)c2c1 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
Definitions
- WO 2006/038220A1 discloses novel intermediates useful for the preparation of aripiprazole and methods for the preparation of the novel intermediates and aripiprazole as per Schemc-(B): Scheme-(B)
- WO 2006/079549 discloses the acid addition salts of aripiprazole, a process for said acid addition salts and their use to prepare or purify aripiprazole in the form of a free base or in the form of a pharmaceutically acceptable salt.
- the invention further relates to preparation of aripiprazole which results in aripiprazole having dimeric impurity i.e. 7,7'- [letramelhylenebis(oxy)]bis(3,4-dihydroquinolin-2(lH)-one) in ⁇ 0.05 % (w/w).
- the prior ail processes suffers from various drawbacks like, having long reaction time, making use of chromatographic purification, using mixtures of solvents and multi- step extraction procedures and using hazardous reagent like sodium azide.
- the main object of the present invention is to develop the process for the preparation of aripiprazole without using chromatographic purification at any stage of the process.
- Another object of this invention is to provide a process for the synthesis of aripiprazole having shorter reaction times.
- Step-1 i.e. in the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril from 1,4-dibromobutane and 7-hydiOxy-3,4-dihydrocarbostyril [ 7-HQ] using a base
- the solvent used for this step is selected from : THF, 1,4-dioxane, acetonitrile, DMF, N,N-dimethyl acetamide, N- methylpyrrolidone, DMSO, Tetramethyl urea, sulfolane, chlorobenzene, or mixtures thereof;
- the preferred solvent is DMF.
- the temperature of the reaction depends on the solvent used and is from 10 to 140 0 C preferably from 20 to 10O 0 C more preferably from 25 to 45 0 C.
- Inorganic compounds which can be used as a base is selected from NaOH, KOIi, Ca(OH) 2 , LiOH, Na 2 CO 3 , K 2 CO 3 , Li 2 CO 3 , CaCO 3 and their like;
- the organic base is selected from a group of compounds such as triethyl amine, tripropylamine, pyridine, quinoline and their like.
- the preferred base is triethyl amine.
- the reaction is carried out at 0 to 140 0 C, preferably at 10 to 120 0 C, more preferably at 75 to 90 0 C. The progress of the reaction is monitored by TLC.
- the product of the reaction is isolated, after distillation of solvent followed by aqueous quenching and extractive workup.
- Step-3 i.e. in the preparation of aripiprazole salt formation and cleavage of salt, aripiprazole crude isolated in step-2 is dissolved in solvent selected from chloroform, methylene chloride, EDC , preferably chloroform.
- the organic acid is DL-tartaric acid.
- the solvent for dissolving DL tartaric acid is methanol.
- aripiprazole is reacted with a solution of DL- tartaric acid methanol at about ambient temperature to give aripiprazole DL- tartaric acid salt, which is filtered washed and dried.
- Aripiprazole obtained by salt formation and cleavage is crystallized from ethanol to give substantially pure aripiprazole having purity > 99.8 %.
- the present invention is illustrated with following non-limiting examples.
- Example-l Preparation of 7-(4-bromobutoxy)- 3,4- dihydro carbostyril [ BBQ]:
- the reaction mass was cooled to room temperature and dumped into 1500 ml of water.
- the reaction mass was stirred for 30 minutes and to it were added 500 ml of chloroform , layers were separated and aq. phase is further extracted with 500 ml of chloroform. Layers were separated and organic phases were combined and washed with 10 % NaOH solution. Layers were separated and chloroform layer was washed with 1500 ml water and organic phase was distilled out under vacuum.
- the traces were swapped with 2x250 ml of cyclohexane.
- To the reaction mass were added 300 ml of cyclohexane and stirred for 3 hours.
- the solid material was filtered and washed with 200 ml of cyclohexane. T he material was dried in tray dryer at about 65-70 0 C for about 10 to 12 hours till loss on diying was less than 1 %
- reaction mass was heated up to 75 - 81 0 C and maintained at same temperature for 4 -5 hours. Acetonitrile was distilled out and reaction mass was dumped into 500 ml of water and extracted with 1400 ml of chloroform. The organic phase was separated and washed with 500 ml water. The chloroform layer was distilled under vacuum at 40-45 0 C 400 ml of methanol were added and chloroform (100 ml) were distilled out. The reaction mass was stirred at R.T. for 30 minutes filtered and washed with 100 ml of methanol. The material was dried under tray drier at 65 to 70 0 C for 10-12 hours till loss on diying is less than 1 %.
- the material was dried at 65 - 70 0 C for 10-12 hours till loss on drying is less than 1 %.
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an improved process for preparing substantially pure aripiprazole (HPLC >99.8 %), wherein 7,7'-[tetramethylenebis(oxy)]bis(3,4- dihydroquinolin-2(lH)-one) is present in pure aripiprazole in <0.01 % (w/w).
Description
TITLE ■ : AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE ARIPIPRAZOLE. FIELD OF INVENTION:
The present invention relates to a novel and commercially feasible method for preparation of substantially pure aripiprazole without involving chromatographic purification during synthesis. BACKGROUND OF INVENTION:
Aripiprazole,7-{4-[4-(2,3-dichlorophenyl)-l-piperazinyl]butoxy}-3,4-dihydro carbostyril or 7- {4-[4-(2,3 -dichlorophenyl)- 1 -piperazinyl]-butoxy} -3 ,4-dihydro-2( 1 H)- quinolinone, is atypical antipsychotic agent, used for the treatment of schizophrenia. The molecular structure of aripiprazole is represented by formula (1)
Formula-(l)
Aripiprazole as a carbostyril derivative is disclosed in US patent No. 4734416 and in US patent No. 5006528 for the treatment of schizophrenia.
US 5006528 describes the synthesis of aripiprazole (Reference example 6; Example- 1) wherein the process uses chromatography at the intermediate stage in the isolation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, which is time consuming, hence the process is commercially unattractive.
WO2004/063162 Al describes synthesis of aripiprazole by reacting a carbostyril of formula-(2) :
formula-(2)
Wherein X represents a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group , with a piperazine compound represented by formula-(3) :
This process also involves chromatographic separation which is not applicable on industrial scale.
WO2004/099152 describes the preparation of aripiprazole as per scheme-A as follows.
if n is 6 product is dehydroaripiprazole if n is 8 product is aripiprazole
The process suffers from following drawbacks.
Reaction of DCPP. HCl with 1,4 dibromobutane gives quaternary spiro compound which requires ~15 hours and the product gets contaminated with substantial quantity of inorganic salts. Purification requires mixed solvents for the isolation of quaternary spiro compound making the process of solvent recovery cost ineffective. The condensation of quaternary compound with 7-hydroxy 3,4 dihydrocarbostyril, requires 18 hours and mixture of solvents, involves multi-step extractive workup followed by purification.
WO 2006/038220A1 discloses novel intermediates useful for the preparation of aripiprazole and methods for the preparation of the novel intermediates and aripiprazole as per Schemc-(B):
Scheme-(B)
6-Hydroxy 1-indanone used as a starting material is a rare intermediate and requires separate preparation of this intermediate which adds to the number of steps required to get aripiprazole.
The use of sodium azide in presence of an acid generates hydrazoic acid, which even at 1 ppm level is considered veiy toxic. This makes the process commercially not feasible.
WO 2006/079549 discloses the acid addition salts of aripiprazole, a process for said acid addition salts and their use to prepare or purify aripiprazole in the form of a free base or in the form of a pharmaceutically acceptable salt. The invention further relates to preparation of aripiprazole which results in aripiprazole having dimeric impurity i.e. 7,7'- [letramelhylenebis(oxy)]bis(3,4-dihydroquinolin-2(lH)-one) in < 0.05 % (w/w).
The prior ail processes suffers from various drawbacks like, having long reaction time, making use of chromatographic purification, using mixtures of solvents and multi- step extraction procedures and using hazardous reagent like sodium azide.
It is a long felt need of the industry to develop simpler process which is commercially attractive to give purity of the order of 99.8%. SUMMARY OF THE INVENTION:
The main object of the present invention is to develop the process for the preparation of aripiprazole without using chromatographic purification at any stage of the process.
Another object of this invention is to provide a process for the synthesis of aripiprazole having shorter reaction times.
Another object of this invention is to develop the process for the synthesis of aripiprazole without using hazardous reagent like sodium azide / hydrazoic acid.
Another object of this invention is to develop the process for the synthesis of aripiprazole having purity > 99.8 % by HPLC.
Another object of this invention is to provide a process for the preparation of aripiprazole having dimeric impurity i.e. 7,7'-[tetramethylenebis(oxy)]bis(3,4- dihydroquinolin-2(lH)-one) in < 0.01 % (w/w). DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides an industrially feasible process for the preparation of aripiprazole in substantially high purity (HPLC >99.8 %) without using chromatographic purification method at any stage of synthesis, having shorter reaction time and without using hazardous chemicals like sodium azide.
The present invention is described by Scheme-( C ) :
SCHEME - (C )
7-HYDROXY 3,4-DIHYDRO- 7-(4-BROMOBUTOXY)3,4-DI HYDRO- CARBOSTYRIL [ 7-HQ ] CARBOSTYRIL- [ BBQ 1
ARIPIPRAZOLE
CRYSTALLIZATION IN ETHANOL
ARIPIPRAZOLE PURE PURITY BY HPLC > 99.8
In Step-1 i.e. in the preparation of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril from 1,4-dibromobutane and 7-hydiOxy-3,4-dihydrocarbostyril [ 7-HQ] using a base, the solvent used for this step is selected from :
THF, 1,4-dioxane, acetonitrile, DMF, N,N-dimethyl acetamide, N- methylpyrrolidone, DMSO, Tetramethyl urea, sulfolane, chlorobenzene, or mixtures thereof; The preferred solvent is DMF.
The base used for the reaction is selected from NaOH, KOH, Ca(OH)2, LiOH, Na2CO3, K2CO3, Li2CO3, CaCO3 and their like; the preferred base being K2CO3.
The temperature of the reaction, depends on the solvent used and is from 10 to 140 0C preferably from 20 to 10O0C more preferably from 25 to 450C.
To minimize the byproduct formation, 1,4- dibromo butane is taken in excess. The product is isolated by an extractive workup after quenching in water.
In Step-2 i.e. in the preparation of aripiprazole crude from 7-(4-bromobutoxy)- 3,4-dihydrocarbostyril and l-(2,3-dichlorophenyl)-piperazine [DCPP] using a base, the solvent used for this step is selected from aromatic hydrocarbons such as benzene , toluene, xylene; alcohols such as Ci to C4 alcohols; ethers like THF,dioxane, l,2dimethoxyethane; polar aprotic solvents such as acetonitrile , DMF, N,N-dimethyl acetamide, N-methylpyrrolidone, DMSO, Tetramethyl urea, sulfolane, chlorobenzene, optionally mixtures thereof; Ketonic solvents such as MEK, MIBK , acetone and their like. The preferred solvent is acetonitrile.
The reaction can be carried out using basic compound which is organic or inorganic.
Inorganic compounds which can be used as a base is selected from NaOH, KOIi, Ca(OH)2, LiOH, Na2CO3, K2CO3, Li2CO3, CaCO3 and their like;
The organic base is selected from a group of compounds such as triethyl amine, tripropylamine, pyridine, quinoline and their like. The preferred base is triethyl amine.
The reaction is carried out at 0 to 1400C, preferably at 10 to 120 0C, more preferably at 75 to 900C. The progress of the reaction is monitored by TLC.
The product of the reaction is isolated, after distillation of solvent followed by aqueous quenching and extractive workup.
In Step-3 i.e. in the preparation of aripiprazole salt formation and cleavage of salt, aripiprazole crude isolated in step-2 is dissolved in solvent selected from chloroform, methylene chloride, EDC , preferably chloroform.
The organic acid is DL-tartaric acid. The solvent for dissolving DL tartaric acid is methanol.
The solution of aripiprazole is reacted with a solution of DL- tartaric acid methanol at about ambient temperature to give aripiprazole DL- tartaric acid salt, which is filtered washed and dried.
Aripiprazole DL- tartaric acid salt is taken up in water and same organic solvent which is used for dissolving aripiprazole in the salt formation step, and treated with a base to liberate aripiprazole. Separating organic layer, washing with w ater and removing solvent gives an oily mass. Methanol is added to it and part of it is distilled to remove traces of other solvent used, and finally the material is separated from reaction mass, washed with methanol and dried to give pure aripiprazole. Step-4
Aripiprazole obtained by salt formation and cleavage is crystallized from ethanol to give substantially pure aripiprazole having purity > 99.8 %. The present invention is illustrated with following non-limiting examples. Example-l
Preparation of 7-(4-bromobutoxy)- 3,4- dihydro carbostyril [ BBQ]:
In a 3 -Liter capacity multi necked flask equipped with mechanical stirrer, condenser, thermometer, were charged 100 gm of 7 - HQ, 397.5 gm of 1,4- dibromobutane, 42.33 gm of potassium carbonate and 300 ml of N,N-dimethyl formamide at RT (30 - 35°C).The reaction mass was heated up to 40-45 0C and maintained for 1 hour at 40 - 450C. After that second lot of potassium carbonate (42.33 gm) was added. The reaction mass was further maintained for 1 hour. After that third lot of potassium carbonate (42.33 gm) was added and further maintained at 40 - 450C for 4 - 5 hours. The reaction mass was cooled to room temperature and dumped into 1500 ml of water. The reaction mass was stirred for 30 minutes and to it were added 500 ml of chloroform , layers were separated and aq. phase is further extracted with 500 ml of chloroform. Layers were separated and organic phases were combined and washed with 10 % NaOH solution. Layers were separated and chloroform layer was washed with 1500 ml water and organic phase was distilled out under vacuum. The traces were swapped with 2x250 ml of cyclohexane. To the reaction mass were added 300 ml of cyclohexane and stirred for 3 hours. The solid material was filtered and washed with 200 ml of cyclohexane. T he material was dried in tray dryer at about 65-700C for about 10 to 12 hours till loss on diying was less than 1 %
Weight of product: 148 gms Yield is 80.95%; Purity 86.09 % by HPLC Example-2
Preparation of pure aripiprazole: (a) Preparation of crude aripiprazole
In 2 Liter capacity multi necked flask equipped with mechanical stirrer, thermometer, condenser, were charged 68.29 gm of l-(2,3-dichlorophenyl)-piperazine [DCPP], 29.95 ml of triethyl amine and 1 Liter of acetonitrile and stirred for 15 minutes at R.T. To it were charged 100 gm of 7-(4-bromobutoxy)- 3,4- dihydro carbostyril [ BBQ] at R.T. ( 30-350C ) . The reaction mass was heated up to 75 - 810C and maintained at same temperature for 4 -5 hours. Acetonitrile was distilled out and reaction mass was dumped into 500 ml of water and extracted with 1400 ml of chloroform. The organic phase was separated and washed with 500 ml water. The chloroform layer was distilled under vacuum at 40-450C 400 ml of methanol were added and chloroform (100 ml) were distilled out. The reaction mass was stirred at R.T. for 30 minutes filtered and washed with 100 ml of methanol. The material was dried under tray drier at 65 to 70 0C for 10-12 hours till loss on diying is less than 1 %.
Weight: 125 gm [Aripiprazole Crude] Yie Id 83.15 % Purity 92.22 % by HPLC (b) Preparation of aripiprazole -DL-lartaric acid salt:
In 2-Liter capacity multi necked flask equipped with mechanical stirrer, thermometer, dropping funnel , condenser were charged 800 ml of chloroform and 100 gm of crude aripiprazole. The reaction mass was stirred for 15 minutes at 30- 350C. A solution of 33.48 gm of DL- tartaric acid in 400 ml of methanol was added to the stirred reaction mass at room temperature during 15 minutes and stirred for 1 hour. The salt was filtered at R.T. and washed with 200 ml (1:1) mixture of chloroform-methanol. The material was dried in tray dryer at 65 to 700C for 7-8 hours. Weight: 125 gm;
Yield: 93.65 %;
Purity 99.35 % by HPLC
(c) Preparation of aipiprazole from aripiprazole DL-tailaric acid salt:
In 2-Liter capacity multinecked flask equipped with ' mechanical stirrer, thermometer, dropping funnel , condenser were charged 100 gm of aripiprazole-DL tartaric acid salt, 500 ml water and 1200 ml of chloroform. The stirred r eaction mass was basified with 200 ml of 25 % aq. ammonia maintaining 30 - 350C and stirred for 20 minutes. Layers were separated and organic layer was washed with 250 ml water and organic phase was separated and distilled to give oily mass .To it were char g e d 400 ml of methanol and about 100 ml of methanol were distilled to remove traces of chloroform. The reaction mass was stirred for 25 - 30 minutes and filtered and washed with 100 ml of methanol.
The material was dried at 65 - 700C for 10-12 hours till loss on drying is less than 1 %. Weight: 70 gm Yield: 93.43 % Purity: 99.80 % by HPLC.
(d) Crystallization of aripiprazole to give pure aripiprazole:
In 2-Liter capacity multinecked flask equipped with mechanical stirrer, thermometer, condenser were charged ethanol (1000 ml ) and 100 gm of Aripiprazole, stirred up to reflux temperature (75-780C). Filtered and transferred in another 2 L capacity flask. Again heated up to reflux temp to get clear solution and gradually cooled to about 350C, filtered at 350C and washed with 100 ml ethanol. Wet cake: 93 gms [Dry Wl: 82 gm]
Thus obtained 93 gm wet cake was re-dissolved in 930 nil of ethanol by heating to reflux and again gradually cooled to 350C, filtered at 350C and washed with 93 ml of ethanol .This wet cake was dried in a tray dryer at 100 to 1050C for 10-12 hours till loss on drying is less than 0.5 %. Weight: 77 gm Yield: 77.00 % Purity: 99.95 % by HPLC
Claims
1. A process for preparing substantially pure aripiprazole (HPLC >99.8 %) comprising, a. reacting 7-hydroxy-tetrahydiOquiniline (7-HQ) with 1,4-dibromobutane (1,4- DBB), using at least one organic solvent and a base to give 7-(4- bromobutoxy)3 , 4-dihy drocarb ostyril (BB Q), b. reacting of BBQ with 1 ,2-dichlorophenyl piperazine (DCPP) and a base in an organic solvent at elevated temperature to give crude aripiprazole, c. reacting crude aripiprazole in organic solvent with DL tartaric acid acid in water miscible alcohol at ambient temperature to give aripiprazole salt, d. isolating aripiprazole base , followed by extracting in organic solvent, removing solvent, to give a residue, e. adding alcohol to the residue to get aripiprazole, f. crystallizing aripiprazole from ethanol to give substantially pure aripiprazole in HPLC purity > 99.8 %.
2. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein the mole ratio of 7-HQ to 1,4-DBB in step-a is 1:1 to 1:10.
3. A process for preparing substantially pure aripiprazole as claimed in claim 2, wherein the preferred mole ratio of 7-HQ to 1,4-DBB is 1:3.
4. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein the organic solvent in step-a, is selected from DMF, DMA.
5. A process for preparing substantially pure aripiprazole as claimed in claim 4, wherein the preferred organic solvent is DMF.
6. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein the base in step-a, is selected from anhydrous K2CO3, anhydrous Na2CO3, KOH, NaOH.
7. A process for preparing substantially pure aripiprazole as claimed in claim 6 wherein the preferred base is anhydrous K2CO3
8. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein the reaction in step-a, is earned out at about 40-45 0C.
9. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein the organic solvent in step-b, is selected from EtOH, IPA, Butanol, acetonitrile, THF or mixture thereof.
10. A process for preparing substantially pure aripiprazole as claimed in claim- 9 wherein the organic solvent is acetonitrile.
11. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein the reaction in step-b, is carried out at about 50 0C to boiling point of the solvent.
12. A process for preparing substantially pure aripiprazole as claimed in claim 11, wherein the reaction is preferably carried out at reflux temperature of the solvent.
13. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein the base in step-b, is selected from triethyl amine, t-butyl amine, dimethyl aniline.
14. A process for preparing substantially pure aripiprazole as claimed in claim 13, wherein the preferred base is triethyl amine.
15. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein crude aripiprazole in step-c, is dissolved in organic solvent selected from water immiscible solvents such as chloroform, methylene chloride, EDC.
16. A process for preparing substantially pure aripiprazole as claimed in claim 15, wherein the preferred water immiscible solvent is chloroform.
17. A process for preparing substantially pure aripiprazole as claimed in claim 1, wherein, in step-c, wherein, DL tartaric acid is dissolved in water miscible alcohols such as from methanol, ethanol, propanol, isopropanol.
18. A process for preparing substantially pure aripiprazole as claimed in claim 17, wherein DL tartaric acid is dissolved methanol.
19. A process for preparing substantially pure aripiprazole as claimed in claim 1 wherein the reaction in step-c is carried out at about 25-35 0C.
20. A process for preparing substantially pure aripiprazole as claimed in claim 1 wherein base in step-d is selected from aqueous ammonia, NaOH, KOH, Na2CO3 preferably aqueous ammonia.
21. A process1 for preparing substantially pure aripiprazole as claimed in claim 1 wherein organic solvent in step-d is selected from methylene chloride, EDC, chloroform, ethyl acetate, isopropyl acetate, butyl acetate.
22. A process for preparing substantially pure aripiprazole as claimed in claim 21, wherein organic solvent is chloroform.
23. A process for preparing substantially pure aripiprazole as claimed in claim 1 wherein alcohol in slep-e, is selected from Cj-C4 alcohol.
24. A process for preparing substantially pure aripiprazole as claimed in claim-23 wherein the alcohol is methanol.
25. A process for preparing substantially pure aripiprazole as claimed in claim- 1 wherein 7,7 '-[tetramethylenebis(oxy)]bis(3 ,4-dihydroquinolin-2( 1 H)-one) is present in pure aripiprazole in <0.01 % (w/w).
26. A process of preparing aripiprazole, wherein the purity of aripiprazole is > 99.8 % by HPLC.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1038/MUM/2006 | 2006-06-29 | ||
| IN1038MU2006 | 2006-06-29 |
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| WO2008001188A2 true WO2008001188A2 (en) | 2008-01-03 |
| WO2008001188A8 WO2008001188A8 (en) | 2008-05-02 |
| WO2008001188A3 WO2008001188A3 (en) | 2009-04-23 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7714129B2 (en) | 2003-12-16 | 2010-05-11 | Teva Pharmaceutical Industries Ltd. | Methods of preparing anhydrous aripiprazole form II |
| WO2011030213A1 (en) * | 2009-09-14 | 2011-03-17 | Jubilant Organosys Limited | Improved process for the preparation of 7.(4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole |
| CN101781246B (en) * | 2009-01-15 | 2012-02-29 | 成都康弘药业集团股份有限公司 | Improved method for synthesizing Aripiprazole |
| WO2012131451A1 (en) * | 2011-03-30 | 2012-10-04 | Jubilant Life Sciences Limited | Process for producing aripiprazole in anhydrous type i crystals |
| CN102863377A (en) * | 2012-08-17 | 2013-01-09 | 南京正大天晴制药有限公司 | Method for preparing high-purity aripiprazole |
| CN105037264A (en) * | 2015-08-17 | 2015-11-11 | 苏州统华药品有限公司 | Purifying method of aripiprazole |
| KR20190027472A (en) * | 2017-09-07 | 2019-03-15 | 주식회사 엘지화학 | Reactor for manufacturing nano particle |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5006528A (en) * | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
-
2007
- 2007-06-26 WO PCT/IB2007/001732 patent/WO2008001188A2/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5006528A (en) * | 1988-10-31 | 1991-04-09 | Otsuka Pharmaceutical Co., Ltd. | Carbostyril derivatives |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7714129B2 (en) | 2003-12-16 | 2010-05-11 | Teva Pharmaceutical Industries Ltd. | Methods of preparing anhydrous aripiprazole form II |
| CN101781246B (en) * | 2009-01-15 | 2012-02-29 | 成都康弘药业集团股份有限公司 | Improved method for synthesizing Aripiprazole |
| WO2011030213A1 (en) * | 2009-09-14 | 2011-03-17 | Jubilant Organosys Limited | Improved process for the preparation of 7.(4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole |
| WO2012131451A1 (en) * | 2011-03-30 | 2012-10-04 | Jubilant Life Sciences Limited | Process for producing aripiprazole in anhydrous type i crystals |
| CN102863377A (en) * | 2012-08-17 | 2013-01-09 | 南京正大天晴制药有限公司 | Method for preparing high-purity aripiprazole |
| CN105037264A (en) * | 2015-08-17 | 2015-11-11 | 苏州统华药品有限公司 | Purifying method of aripiprazole |
| KR20190027472A (en) * | 2017-09-07 | 2019-03-15 | 주식회사 엘지화학 | Reactor for manufacturing nano particle |
| KR102176234B1 (en) | 2017-09-07 | 2020-11-09 | 주식회사 엘지화학 | Reactor for manufacturing nano particle |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008001188A8 (en) | 2008-05-02 |
| WO2008001188A3 (en) | 2009-04-23 |
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