Aripiprazole
7-[4-[4-(2,3-dichlorophenyl)-1- piperazinyl]butoxy]- 3,4-dihydro-2(1H)-quinolinone.
END AUG 2014
The US Food and Drug Administration (FDA) has received a new drug application (NDA) from Ireland-based Alkermes for its aripiprazole lauroxil to treat schizophrenia.
Aripiprazole lauroxil is an injectable atypical antipsychotic with one-month and two-month formulations, developed for the treatment of schizophrenia, which is a chronic, severe and disabling brain disorder.
The company has submitted the application based on positive results from the pivotal phase three study that assessed the efficacy and safety of aripiprazole lauroxil, where the drug demonstrated significant improvements in schizophrenia symptoms when compared to a placebo.
“We have designed aripiprazole lauroxil to be a differentiated treatment option for schizophrenia, with a ready-to-use format with multiple dosing options.”
Alkermes CEO Richard Pops said: “We have designed aripiprazole lauroxil to be a differentiated treatment option for schizophrenia, with a ready-to-use format with multiple dosing options, to help meet the individual needs of patients and their healthcare providers.
“These attributes, together with the robust clinical data observed in the pivotal study, position aripiprazole lauroxil to be a meaningful new entrant in the growing long-acting injectable antipsychotic market, and we look forward to working with the FDA to bring this important new medication to patients and physicians as quickly as possible.”
The study, in which both doses of aripiprazole lauroxil tested, including 441mg and 882mg, reached the primary endpoint with statistically significant and clinically meaningful reductions in positive and negative syndrome scale (PANSS) scores, according to the company.
In addition, it met all secondary endpoints and demonstrated significant improvements in schizophrenia symptoms against the placebo.
- ALKS 9070
- ALKS 9072
- Aripiprazole lauroxil
- RDC 3317
- RDC-3317
- UNII-B786J7A343
Aripiprazole lauroxil [USAN] CAS 1259305-29-7
Aripiprazole (/ˌɛərɨˈpɪprəzoʊl/ AIR-i-PIP-rə-zohl; brand names: Abilify, Aripiprex) is a partial dopamine agonist of the second generation (or atypical) class of antipsychotics that is primarily used in the treatment of schizophrenia, bipolar disorder, major depressive disorder (as an add on to other treatment), tic disorders, and irritability associated with autism.[5]
It was approved by the U.S. Food and Drug Administration (FDA) for schizophrenia on November 15, 2002 and the European Medicines Agency on 4 June 2004; for acute manic and mixed episodes associated with bipolar disorder on October 1, 2004; as an adjunct for major depressive disorder on November 20, 2007;[6] and to treat irritability in children with autism on 20 November 2009.[7] Likewise it was approved for use as a treatment for schizophrenia by the TGA of Australia in May 2003.[1]
Aripiprazole was developed by Otsuka in Japan, and in the United States, Otsuka America markets it jointly with Bristol-Myers Squibb.
Regulator status
In the United States, the FDA has approved aripiprazole for the treatment of schizophrenia in adults and adolescents (aged 13–17), of manic and mixed episodes associated with Bipolar I (One) Disorder with or without psychotic features in adults, children and adolescents (aged 10–17),[59] of irritability associated with autism in pediatric patients (aged 6–17),[60] and of depression when used along with antidepressants in adults.[61]
Aripiprazole has been approved by the FDA for the treatment of acute manic and mixed episodes, in both pediatric patients aged 10–17 and in adults.[62]
In 2007, aripiprazole was approved by the FDA for the treatment of unipolar depression when used adjunctively with an antidepressant medication.[63] It has not been FDA-approved for use as monotherapy in unipolar depression.
Patent status
Otsuka’s US patent on aripiprazole expires on October 20, 2014;[64] however, due to a pediatric extension, a generic will not become available until at least April 20, 2015.[62] Barr Laboratories (now Teva Pharmaceuticals) initiated a patent challenge under the Hatch-Waxman Act in March 2007.[65] On November 15, 2010, this challenge was rejected by a United States district court in New Jersey.[1][2]
Dosage forms
- Intramuscular injection, solution: 9.75 mg/mL (1.3 mL)
- Solution, oral: 1 mg/mL (150 mL) [contains propylene glycol, sucrose 400 mg/mL, and fructose 200 mg/mL; orange cream flavor]
- Tablet: 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
- Tablet, orally disintegrating: 10 mg [contains phenylalanine 1.12 mg; creme de vanilla flavor]; 15 mg [contains phenylalanine 1.68 mg; creme de vanilla flavor]
Synthesis
Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amine:[66]
- U.S. Patent No.4, 734, 416 and U.S. Patent No.5,006,528 discloses the Aripiprazole, 7-{4- [4- (2, 3-dichlorophenyl) -1-piperazinyl] butoxy}- 3,4-dihydro-2 (IH) -quinolinone or 7-{4-[4- (2, 3-dichlorophenyl) -1- piperazinyl] butoxy}-3, 4-dihydro carbostyril, is a typical antipsychotic agent useful for the treatment of Schizophrenia, having the formula as given below.
Aripiprazole
U.S. patent No.5,006,528 discloses preparation of Aripiprazole and its pharmaceutically acceptable acid-addition salts. The process for the preparation of acid salts involves reaction of Aripiprazole with a pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like; organic acids such as oxalic acid, maleic acid, fumaric acid, maleic acid, tartaric acid, citric acid, . benzoic acid and the like as per Scheme-1. Scheme- 1
a. K2CO3, Water K CH2CI2 c. Column chromatographic purification d. n-Hexane – Ethaπol
ARIPIPRAZOLE ACID SALT
The product Aripiprazole .obtained by the above process has melting point of 139.0° – 139.5°C.
The process involves purification of the intermediate, 7-(4- bromobutoxy) -3, 4-dihydrocarbostyril (III) by silica gel column chromatography to remove impurities formed during the reaction. The process further involves two recrystallizations of Aripiprazole from ethanol to obtain the pure Aripiprazole though compromising on yields by increasing the operational cost of the product. PCT publication WO 03/026659 discloses low hygroscopic forms of
Aripiprazole and the process for their preparation from the Aripiprazole hydrate Form SA’ . It further states that the anhydrous
Aripiprazole made by the Japanese patent publication No. 191256/1990, yields the Aripiprazole, which is significantly hygroscopic. As per PCT publication WO 03/026659 anhydrous crystals of Aripiprazole exist as type-I crystals and type-II crystals. Further discloses that the type-I crystals are prepared -by recrsytallization from ethanol solution of
Aripiprazole or by heating Aripiprazole hydrate at 800C and type-II crystals by heating type-I crystals at 130 to 1400C for 15 hrs.
PCT application Publication WO 03/026659 discloses process for the Aripiprazole polymorphic form-B by heating the Aripiprazole hydrate
‘A’ at 90 – 125°C for about 3 – 50 hrs. The process for Polymorphic
Form-C is by heating the Aripiprazole anhydrous to a temperature of 140
– 1500C. The process for Form-D is recrystallization from toluene; process for Form-E is heating with acetonitrile or by recrystallization from acetonitrile and the process for Form-F is by heating the suspension of anhydrous Aripiprazole in acetone. The polymorphic Form-G is by heating to 1700C for at least 2 weeks in a sealed tube, which is a glassy mass.
PCT publication WO 03/026659 further discloses the characterization data X-ray diffraction pattern; IR absorption and DSC of Form B, Form C, Form-D, Form-E, Form-F and Form-G.It further reported the melting point of Aripiprazole anhydrous Form B as 139.7°C-
Research
Perhaps owing to its mechanism of action relating to dopamine receptors, there is some evidence to suggest that aripiprazole blocks cocaine-seeking behavior in animal models without significantly affecting other rewarding behaviors (such as food self-administration).[67] Aripiprazole may be counter-therapeutic as treatment for methamphetamine dependency because it increased methamphetamine’s stimulant and euphoric effects, and increased the baseline level of desire for methamphetamine.[68]
http://www.google.com/patents/WO2006030446A1?cl=en
Scheme-3
Aripiprazole Acid addition salt
Form-A, B, C , D , E , F Type-I & Type-II Aripiprazole acid salts used for the preparation of polymorphs
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patent expiry
………………….patent…..approved….exp
| United States |
5006528 |
1994-10-20 |
2014-10-20 |
| United States |
7115587 |
2005-01-21 |
2025-01-21 |
Aripiprazole can be synthesized beginning with a dichloroaniline and bis(2-chloroethyl)amineU.S. Patent 5,006,528
Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro carbostyril or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2 (1H)-quinolinone, is an atypical antipsychotic agent useful for the treatment of schizophrenia (U.S. Pat. No. 4,74,416 and U.S. Pat. No. 5,006,528). Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and extensive withdrawal from others. Onset of schizophrenia typically occurs between the age of 16 and 25 and affects 1 in 100 individuals worldwide. It is more prevalent, than Alzheimer’s disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to significantly improved recovery and outcome. Moreover, early therapeutic intervention can avert costly hospitalization.
Aripiprazole (Aripiprazole) is an atypical antipsychotic, on 15 November 2002 by the U.S. FDA clearance to market, its efficacy is through the dopamine D2 receptor and serotonin 5HT1A receptor partial agonist activity and serotonin 5HT2A receptor antagonism activity mediated common. With its unique mechanism of action and safety assessment, aripiprazole known as third-generation antipsychotic drugs.
[0003] Aripiprazole is a quinolinone derivative, developed by the Japanese company Otsuka Pharmaceutical, the chemical name
Is: 7 – {4 – [4 – (2,3 – dichlorophenyl)-1_ piperazinyl] butoxy} -3,4 – dihydro-quinolone, the following structural formula:
[0004]
[0005] For the preparation of aripiprazole, Japanese OtsukaPharmaceutical’s patent EP 0367141A2, and related patents US4234585, CN89108934 preparation methods described in 5. In addition, the patent CN1450056A, CN1562973A, CN1784385A, CN1680328A, CN1576273A, etc. describe some of these five Preparation
Method is very similar way. These preparation methods are direct or indirect use of 7 – hydroxy -3,4 – dihydro – quinolin-2 – one (HCS) that the key to higher prices of raw materials, and some methods involve harsh reaction conditions, poor selectivity, low yield, but also increases the cost of industrial production of the product.
[0006] Chinese patent CN1304373C preparation method is not described in the 7 – hydroxy-3 ,4 _ dihydro-2_ (1H) – quinoline
Quinolone intermediates for their preparation of the core reaction is as follows:
[0007]
[0008] This reaction is Friedel-Crafts alkylation reaction, there is a harsh reaction conditions, the yield is low, the reaction selectivity is poor, the shortcomings of high emissions, is not conducive to industrial mass production. SUMMARY OF THE INVENTION
[0009] In order to solve the above problems, the present invention provides a simple, high selectivity, high yield, low cost, environmentally friendly, easy to prepare industrialization aripiprazole and intermediates thereof.
[0010] The technical solution of the present invention, the present invention provides in one aspect a process for preparingaripiprazole novel intermediates.
[0011] The present invention, on the other hand provides a method for the preparation of intermediates.
[0012] The present invention provides the use of the other intermediates for preparing aripiprazole two new preparation methods.
[0013] Specifically, the present invention relates to novel intermediates, compounds of formula ⑴:
[0014]
[0015] wherein, R is selected from methyl, ethyl, propyl, isopropyl, butyl, t-butyl, benzyl and other common alkyl groups in any one, and preferably is ethyl.
[0016] Compound of formula ⑴: 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate, is the following prepared by the procedure:
[0017] Step one, the acylation reaction: with 4 – methyl – 3 – nitro-phenol (VIII) and acetic anhydride as the raw material, DMAP as catalyst, to give 4 – methyl – 3 – nitrophenyl acetate ( VII).
[0018] wherein 4 – methyl – 3 – nitro-phenol (VIII), acetic anhydride, DMAP molar ratio is preferably 1: 1.0 to 1.4: 0.05, at room temperature, the reaction time is preferably 0.5 to 3 hours.
[0019] Step two, the bromination reaction: The resulting product, 4 to Step one – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide and benzoyl peroxide as a raw material , carbon tetrachloride solvent reflux, to give 4 – bromomethyl-3 – nitrophenyl acetate (VI).
[0020] wherein 4 – methyl – 3 – nitrophenyl acetate (VII), N-bromosuccinimide, benzoyl peroxide molar ratio is preferably 1: 1 to 1.2: 0.05, reaction time is preferably 4-18 hours.
[0021] Step three, instead of the reaction: in an appropriate solvent, adding an alkaline agent and diethyl malonate was stirred in an ice bath, was added dropwise step two the resulting product, 4 – bromomethyl-3 – nitrophenyl yl acetate (VI) solution after completion of the addition reaction of 1 to 3 hours to obtain a brown liquid product, 2 – (4_ acetoxy-2 – nitrobenzyl) malonate (V).
[0022], wherein the alkali agent is a common organic or inorganic base selected from sodium methoxide, sodium ethoxide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide, preferably sodium tert-butoxide; the solvent is selected from tetrahydrofuran, methanol, ethanol, butanol, tert-butanol, toluene or N, N-dimethylformamide; 4 – bromomethyl-3 – nitrophenyl acetate (VI), alkaline agent and lipid diethyl molar ratio is preferably 1: 1.0 to 1.8: 1.0 to 1.4.
[0023] Step 4 Hydrolysis decarboxylation: the product obtained in Step Three 2 – (4_ acetoxy-2 – nitro-benzyl)-malonic acid diethyl ester (V) was added concentrated hydrochloric acid and a suitable solvent, heating and stirring reflux, to give a yellow solid product 3 – (4_ hydroxy-2 – nitrophenyl) propionic acid (IV).
[0024] wherein the solvent is selected from water, methanol, ethanol or acetic acid, water soluble solvent, was heated with stirring under reflux time is preferably 3 to 18 hours. [0025] Step five, the esterification reaction: the product obtained in step 4, 3 – (4 – hydroxy-2 – nitrophenyl) propionic acid (IV) was added to an appropriate solvent, the mixture was stirred in an ice bath, was added dropwise thionyl sulfone, after completion of the addition reaction of 1 to 3 hours, to give a pale brown liquid product 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III).
[0026] wherein the solvent is selected from anhydrous methanol, ethanol, propanol, isopropanol, butanol, t-butanol, benzyl alcohol, alcohol and other common solvents.
[0027] Step VI substitution reaction: 1,4 – dibromobutane was added to an appropriate solvent and an alkaline reagent, heated to 50 ~ 100 ° C, the product obtained was added dropwise Step Five 3 – (4_ hydroxy – nitrophenyl) propionate (III) solution, after the addition was complete the reaction was kept 2 to 4 hours to obtain a brown liquid product 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II).
[0028] wherein the solvent is selected from methanol, 95% ethanol, ethanol, acetonitrile and N, N-dimethylformamide, and the like; said alkaline agent is a common organic or inorganic weak base, such as triethylamine, pyridine, potassium carbonate, sodium carbonate, etc..
[0029] Step 7 condensation reaction: the product obtained in Step Six 3 – (4 – (4 – bromo-butoxy)-2 – nitrophenyl) propionate (II) adding a suitable solvent, (2,3 – dichlorophenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, to obtain
The intermediate product 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl)-piperazin-1 – yl) butoxy)-2 – nitrophenyl) propionate ⑴.
[0030] Among them, 3 – (4 – (4 – (4 – (2,3 _-dichlorophenyl)-piperazinyl) butoxy) _2_ nitrophenyl) propionate (I), (2, 3 – dichloro-phenyl)-piperazine hydrochloride 1_, alkaline reagents and catalysts, the four molar ratio is preferably 1: 0.9 to 1.0: 2.0 to 2.2: 0.05 to 0.5. The solvent is selected from methanol, ethanol and N, N-dimethylformamide, acetonitrile and the like. Step six of the alkaline reagent and alkaline reagent used in the same, said catalyst is a common low-iodine salts, such as sodium iodide, potassium iodide.
[0031] The present invention provides two other hand, the use of a compound of formula ⑴ preparing aripiprazole new method.
[0032] Method one: ⑴ intermediate compound of formula in an appropriate solvent in the acid or salt or a base in the presence of a reducing agent under the action of restoring ring closure reaction to obtain aripiprazole.
[0033] Method one reductive cyclization of the reducing agent used is iron, zinc, sodium sulfide, stannous chloride, and preferably iron; reaction solvent is selected from water, methanol, ethanol, ethyl acetate or in one or more of the mixed solvent; said acid is a common organic or inorganic acid, preferably acetic acid or hydrochloric acid; said salt is a common inorganic or organic salts selected from chloride, ferrous chloride, , ammonium sulfate, calcium chloride, zinc chloride, sodium chloride, sodium bromide or sodium acetate and the like; common said base is an inorganic base selected from sodium hydroxide, potassium hydroxide or sodium bicarbonate; the reduction ring-closing reaction temperature range of 30 ~ 140 ° C, preferably about 80 ° C; reaction time ranges from about 0.5 to 8 hours, preferably 2 hours.
[0034] Method two: ⑴ intermediate compound of formula in an appropriate solvent in the first catalyst, the reduction reaction, and then carried out in a suitable solvent can be prepared by cyclization of aripiprazole.
[0035] The reduction reaction of the second approach, the reducing agent is hydrogen or a carboxylic acid; the catalyst is selected from molybdenum, molybdenum dioxide or Raney nickel, preferably Raney nickel; the solvent is selected from methanol, ethanol, ethyl acetate or acetic acid, preferably ethanol; said ring-closing reaction of the solvent is selected from N, N-dimethylformamide, trichlorobenzene or xylene; reaction temperature range of 50 ~ 180 ° C, preferably about 70 ~ 150 ° C; reaction time the range of about 1 to 8 hours.
[0036] In summary, the present invention is described for preparing aripiprazole method in 4– methyl – 3 – nitro-phenol (VIII) as a starting material, by acetylation protected hydroxy, radical instead of 4 – bromomethyl-3 – nitrophenyl acetate (VI), the diethyl malonate and a nucleophilic substitution reaction to obtain 2 – (4_ acetoxy-2 – nitrobenzyl ) malonic acid diethyl ester (V), which is decarboxylated by hydrolysis, esterification, to give 3 – (4 – hydroxy-2 – nitrophenyl) propionate (III), the reaction product with dibromobutane an ether compounds, and with (2,3 – dichlorophenyl)-piperazine hydrochloride 1_ condensation, to give 3 – (4 – (4 – (4 – (2,3 – dichlorophenyl) piperazine -1 – yl) butoxy) -2 – nitrophenyl) propionate (I), and then by reductive cyclization step, or first reduced and then ring-closing reaction of aripiprazole. The synthetic route of the present invention is as follows: [0037]
According to Example 1 of Japanese Unexamined Patent Publication No. 191256/1990, anhydrous aripiprazole crystals are manufactured for example by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril with 1-(2,3-dichlorophenylpiperadine and recrystallizing the resulting raw anhydrousaripiprazole with ethanol. Also, according to the Proceedings of the 4th Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996), anhydrousaripiprazole crystals are manufactured by heating aripiprazole hydrate at 80° C. However, the anhydrous aripiprazole crystals obtained by the aforementioned methods have the disadvantage of being significantly hygroscopic.
The hygroscopicity of these crystals makes them difficult to handle since costly and burdensome measures must be taken in order ensure they are not exposed to moisture during process and formulation. Exposed to moisture, the anhydrous form can take on water and convert to a hydrous form. This presents several disadvantages. First, the hydrous forms of aripiprazole have the disadvantage of being less bioavailable and less dissoluble than the anhydrous forms ofaripiprazole. Second, the variation in the amount of hydrous versus anhydrousaripiprazole drug substance from batch to batch could fail to meet specifications set by drug regulatory agencies. Third, the milling may cause the drug substance, Conventional Anhydrous Aripiprazole, to adhere so manufacturing equipment which may further result in processing delay, increased operator involvement, increased cost, increased maintenance, and lower production yield. Fourth, in addition to problems caused by introduction of moisture during the processing of these hygroscopic crystals, the potential for absorbance of moisture during storage and handling would adversely affect the dissolubility of aripiprazole drug substance. Thus shelf-life of the product could be significantly decreased and/or packaging costs could be significantly increased. It would be highly desirable to discover a form of aripiprazole that possessed low hygroscopicity thereby facilitating pharmaceutical processing and formulation operations required for producing dosage units of an aripiprazole medicinal product having improved shelf-life, suitable dissolubility and suitable bioavailability.
Also, Proceedings of the 4 the Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996) state that, anhydrous aripiprazole crystals exist as type-I crystals and type-II crystals; the type-I crystals of anhydrous aripiprazolecan be prepared by recrystallizing from an ethanol solution of aripiprazole, or by heating aripiprazole hydrate at 80° C.; and the type-II crystals of anhydrousaripiprazole can be prepared by heating the type-I crystals of anhydrousaripiprazole at 130 to 140° C. for 15 hours.
By the aforementioned methods, anhydrous aripiprazole type-II crystals having high purity can not be easily prepared in an industrial scale with good repeatability.
Chemical Synthesis of Aripiprazole (active ingredient for Abilify)
Experimental Procedures for the preparation of Aripiprazole (Abilify, aripiprazole)
US 5,006,528 discloses process for the preparation of Aripiprazole in two steps The first step comprises synthesis of 7 -. (4-bromobutoxy) -3,4-dihydrocarbostyril (7-BBQ) by alkylating the hydroxy group of 7-hydroxy-3, 4 -dihydrocarbostyril (7-HQ) with 1 ,4-dibromobutane using potassium carbonate in water at reflux temperature for 3 hours to obtain 7-BBQ in 68% yield The resulting 7-BBQ is further reacted with 1 -. (2,3 – dichlorophenyl)-piperazine to obtain Aripiprazole.
Preparation of 7 – (4-Bromobutoxy) 3 ,4-dihydro-2 (1H) quinolinon ( 7 – (4-Bromobutoxy) 3 ,4-dihydrocarbostyril; 7-BBQ)
7-Hydroxy-3 ,4-dihydro-2 (1H)-quinolinone (aka 7-Hydroxy-3 ,4-dihydrocarbostyril, 60gm) and potassium carbonate (76.3 gm) were taken in acetonitrile (1200ml) at room temperature. To this tetra butyl ammonium iodide (13.7 gm) and 1 ,4-dibromobutane (238.5gm) were added and heated at 40 – 45 ° C for 24 hours Reaction mass was cooled upto room temperature and was filtered off The resulting filtrate was distilled off.. under vacuum. The resultant mass was cooled to 25-30 ° C and cyclohexane (300 ml) was added under stirring. The resulting solid was filtered off and was dried. The resulting solid was taken in water and was stirred for few minutes. The . solid was filtered and dried under vacuum at 55-60 ° C for 20 hours to obtain title compound mp 110.5-111 ° C; 1H NMR (DMSO-d6) ä 1.81 (2H, m,-CH2-), 1.95 (2H , m,-CH2-), 2.41 (2H, t, J) 7 Hz,-CH2CO-), 2.78 (2H, t, J) 7 Hz,-CH2-C-CO-), 3.60 (2H, t, J) 6 Hz,-CH2Br), 3.93 (2H, t, J) 6 Hz, O-CH2-), 6.43 (1H, d, J) 2.5 Hz), 6.49 (1H, dd, J) 2.5, 8 Hz ), 7.04 (1H, d, J) 8 Hz), 9.98 (1H, s, NHCO). Anal. (C13H16NO2Br) C, H, N.
Yield: 73-75%; Purity: 93-95%
Preparation of Aripiprazole (7 – {4 – [4 – (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One)
7 – (4-Bromobutoxy)-l ,2,3,4-tetrahydroquinolin-2-one (50 gm) was taken in acetonitrile (500 ml) at 25-30 ° C. To this potassium carbonate (67.2 gm) and l – (2,3 – dichlorophenyl). piperazine hydrochloride (44.9gm) were added under stirring The reaction mixture was refluxed at 80-85 ° C for 8 hours The reaction mass was cooled to room temperature, filtered and the resulting solid was washed. with acetonitrile. To the resulting solid, water was added and was stirred. The solid was filtered off, washed with water and dried under vacuum at 75-80 ° C for 15 hrs. The resulting crude aripiprazole was crystallized from isopropyl alcohol and water to . obtain title compound Yield: 75-80%; Dimer Impurity: <0.1% 1H NMR:. DMSO-d6 d 9.96 [1H, s, NH]; 7.29 [2H, m, Ar]; 7.13 [1H, q, Ar ]; 7.04 [1H, d, Ar]; 6.49 [1H, dd, Ar]; 6.45 [1H, d, Ar]; 3.92 [2H, t,-CH2-O-]; 2.97 [4H, bb, 2 ( -CH2-)]; 2.78 [2H, t,-CH2-N2-)]; 2.39 [4H, m, 2 (-CH2-)]; 1.73 [2H, m, – CH2-]; 1.58 [2H, m .,-CH2-] IR: cm-1 3193; 2939; 2804; 1680; 1627; 1579; 1520; 1449; 1375; 1270; 1245; 1192; 1169; 1045; 965; 649; 869; 780; 712; 588 .
Preparation of aripiprazole anhydrous Type I using isopropyl alcohol and water
Crude aripiprazole (30 g) was taken in isopropyl alcohol (600 ml) and was heated to 80-85 ° C. Water (90 ml) was added at the same temperature. Activated carbon was added and the mixture was stirred for 30 minutes at the same temperature. The resulting hot solution was filtered and the bed was washed with hot isopropyl alcohol. The resulting filtrate was cooled to 25-30 ° C for 4 hours. The resulting solid was filtered, washed with isopropyl alcohol and dried under suction for 1 hour. The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 6 hours to obtain title compound.
Yield: 87-89% HPLC Purity: 99.89
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle Size Distribution: d 10 = 15.83 m, d 50 = 60.12 m, d 90 = 144.99 m
Preparation of aripiprazole anhydrous Type I using ethanol and water
Crude aripiprazole (15 g) was taken in ethanol (300 ml) and water (45 ml) and was heated to 80-85 ° C for 1-2 hours. The resulting mixture was cooled to 25-30 ° C within 4 hours and . stirred for 3 hours The resulting solid was filtered and dried under suction for 1 hour The resulting wet solid was dried in preheated oven maintained at 100-105 ° C for 3 hours to obtain title compound Yield:.. 90% HPLC Purity: 99.9 %
Anhydrous crystal D: Below detectable limit (BDL) at limit of detection 1%.
Hydrate A: Below detectable limit (BDL) at limit of detection 1%.
Particle Size Distribution: d 10 = 22.01 m, d 50 = 105.10 m, d 90 = 232.97 m
For the Process of references Aripiprazole (Abilify, Japanese: Oh, Bldg re phi, Ann reピplastic AKZO have suitable; Chinese: Ann-law who, aripiprazole)
Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi, Tatsuyoshi Tanaka, Tetsuro Kikuchi, Katsura Tottori, Yasufumi Uwahodo, and Takao Nishi; Novel Antipsychotic Agents with Dopamine autoreceptor Agonist Properties: Synthesis and Pharmacology of 7 – [4 – (4-Phenyl-1- piperazinyl) butoxy] – 3,4-dihydro-2 (1H)-quinolinone Derivatives ; J. Med Chem. 1998, 41, 658-667.
Yasuo Oshiro, Seiji Sato, Nobuyuki Kurahashi; Carbostyril Derivatives , Otsuka Pharmaceutical Co., Ltd.;. U.S. Patent 5006528 ; Issue Date: Apr 9, 1991
BANDO, Takuji, YANO, Katsuhiko, FUKANA, Makoto, AOKI, Satoshi; Method for producing fine particles of aripiprazole anhydride crystals b; OTSUKA PHARMACEUTICAL CO, LTD, WO 2013002420 A1..
Yuanqiu Hui, Chen Hongwen, Qian Wen, firewood rain column, Xu Dan, Yang Zhimin, Tian Zhoushan; method for preparing high purity of aripiprazole; NJCTT Pharmaceutical Co., Ltd.; application number: 201210292382.0; Publication Number: CN102863377A; Publication date: 2013.01.09 After (The invention relates to the field of medicine and chemical industry, in particular to a method for preparing high purity of aripiprazole would join aripiprazole A solvent is heated, filtered, and the filtrate was added to a solvent B, low temperature mixing, filtration, the filter cake is suspended in water, adjusted to alkaline pH of the aqueous solution, filtration, high temperature vacuum dried to obtain a high-purity refined product Aripiprazole This method is simple, high purity, suitable for the industrial the large-scale application)
ZHENG Siji, LIU Xiaoyi, FU Linyong, TAN Bo, ZHOU Min:.. ARIPIPRAZOLE MEDICAMENT FORMULATION AND PREPARATION METHOD THEREFOR / FORMULATION DE MÉDICAMENT ARIPIPRAZOLE ET SON PROCÉDÉ DE PRÉPARATION / a aripiprazole pharmaceutical formulation and preparation method SHANGHAI ZHONGXI. PHARMACEUTICAL January 2013: WO 2013/000391
Zheng Si Ji, Liu Xiaoyi, Fulin Yong, Tan Bo, Zhou Min: A aripiprazole pharmaceutical formulation and preparation method; Shanghai Pharmaceutical Co., Ltd. and Western; Publication date: 2013.01.02: Application Number: CN 201210235157.3; Publication Number: CN102846543A (the invention provides a method for preparing aripiprazole pharmaceutical formulation, comprising the steps of: an acidic solution containing aripiprazole is dissolved in the acidulant, to obtain an acidic solution containing the drug; Thereafter, the resulting drug-containing acidic solution alkalizing agents and materials prepared by wet granulation or suspension to give aripiprazole pharmaceutical formulation; said excipients include antioxidants)
Zheng Si Ji; Tan wave; Fulin Yong; Liu Xiaoyi; Yuanshao Qing; Cao Zhihui; aripiprazole Ⅰ type microcrystalline, aripiprazole solid preparation and preparation methods; application number: 201110180032.0; Publication Number: CN102850268A; Publication Date: 2013.01.02
Cai Fu Bo, Qin Xinrong, Du Xiaochun, Li Ling; kind of aripiprazole improved method of synthesis; Chengdu Nakasone Pharmaceutical Group Co., Ltd.; Application Number: 200910058148.X; Publication Number: CN101781246A; Publication date: 2010.07.21 (the invention provides a method of synthesis of aripiprazole improved method according to the modified method of the present invention, aripiprazole into the etherification reaction and condensation reaction of two-step synthesis, by an etherification reaction in the quinolone compound and at least 6-fold molar equivalents of 1,4 – dihalo-butane reacted with a non-polar solvent ether aripiprazole precipitate, and recovering 1,4 – dihalo-butane recycling; azeotropic condensation reaction of a ketone to be / water mixture as solvent, aripiprazole etherified with a piperazine compound or a salt thereof in the presence of a base under reflux and alkaline metal iodide compound conditions, the amount of water added to the end of the reaction, cooling crystallization, filtration, and dried to give aripiprazole. improved high yield synthesis of high purity, step simple, low cost, suitable for industrial production.)
GUPTA, Vijay Shankar, KUMAR, Pramod, VIR, Dharam; Process for producing aripiprazole in anhydrous type i crystals; JUBILANT LIFE SCIENCES LIMITED; WO 2012131451 A1
SRIVASTAVA JAYANT GUPTA Vijay Shankar;. Improved process for the preparation of 7 (4-bromobutoxy) 3,4-dihydrocarbostyril, a precursor of aripiprazole; wo2011030213 A1
No Generic Abilify in the US until April 2015
On May 7, 2012, The US Court of Appeals for the Federal Circuit ruled in favor of Otsuka Pharmaceutical Co., Ltd. In its patent litigation against several companies including Israel-based Teva and Weston, Ontario-based Apotex seeking FDA approval to market generic copies of Abilify ®.. The Federal Circuit Affirmed a Decision of the U.S. District Court for the District of New Jersey Holding that the asserted claims ofU.S. Patent No. 5,006,528 Covering aripiprazole, the active Ingredient in Abilify ®, are Valid, THUS Maintaining Patent and Regulatory Protection for Abilify ® in the U.S. until at least April 20, 2015 . The Case is Otsuka Pharma Co.. V. sand Inc.., 2011-1126 and 2011-1127, US Court of Appeals for the Federal Circuit (Washington). The lower court case is Otsuka Pharmaceutical Co. v. Sandoz Inc., 07cv1000, US District Court for the District of New Jersey (Trenton).
Chemical Name for Aripiprazole (Abilify for active Ingredient): 7 – {4 – [4 – (2,3-Dichlorophenyl) piperazin-1-yl] butoxy} 3 ,4-dihydroquinolin-2 (1H)-One
CAS Number 129722 -12-9
aripiprazole chemical name 7 – [4 – [4 – (2,3 – dichlorophenyl) -1 – piperazinyl] butoxy] -3,4 – dihydro-2 ( 1H) – quinolinone
Aripiprazole (, Aripiprazole, Abilify) is an atypical antipsychotic medication for the quinoline derivatives, aripiprazole is a dopamine system stabilizer first, positive and schizophrenia negative symptoms have a significant effect. For the treatment of schizophrenia, the development of Otsuka Pharmaceutical Co., Ltd., in November 15, 2002 by the U.S. Food and Drug Administration (FDA) approval in the U.S., domestic aripiprazole has (Booz clear (brisking, manufacturers : Chengdu Nakasone Pharmaceutical), Austrian (Manufacturer: Shanghai Pharmaceutical Co., Ltd. and Western)) have been approved by the listing in China. On sale in the United States where the law by Bristol-Myers Squibb is responsible. An law where the main patent protection in the United States, and more than three-quarters of its sales from the U.S., patent will expire in April 2015.
Aripiprazole synthetic route
7 – hydroxy-3 ,4. Dihydro -2 (1H) – quinolinone as a starting material, 1,4. Dibromobutane ether to give 7 – (4 – Bromo-butoxy) -3,4 – dihydro – 2 (1H) quinolinone, and then with 1 – (2,3 – dichlorophenyl) piperazine acid condensation aripiprazole (7 – [4 – [4 – (2,3 – dichlorophenyl) -1 – piperazinyl] butoxy] -3,4 – dihydro -2 (1H) – quinolinone)
Aripiprazole preparation method
7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone
A reaction flask was added 7 – hydroxy – 3,4 – dihydro -2 (1H) – quinolone 32.6 g (0.2mol), 1,4 – dibromo butane 129.5g (0.6mol), 11.2% KOH solution 250ml (0.5mol) and DMF975ml, was heated to 60 º C for 2h diluted with 1L water, the aqueous layer with ethyl acetate. acetate (300ml × 2) and the combined organic layers were washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to recover the solvent, the residue was recrystallized from isopropanol, to give 7 – (4 – Bromo-butoxy) – 3,4 – dihydro -2 (1H) – quinolone 38.7g, yield 68%, mp108 ~ 110 º C.
Synthesis of aripiprazole
in the reaction flask was added 7 – (4 – Bromo-butoxy) -3,4 – dihydro -2 (1H) – quinolone, 29.8g (0.1mol), KI25g (0.15mol) 95% Ethanol 596ml, stirred and heated to 60 º C, was added N-2 30min after 3 – dichlorophenyl piperazine 23.1g (0.1mol) and triethylamine 20ml (0.15mol), stirred for 8h at 60 º C the mixture is filtered. crystallization filtrate was cooled, filtered and the filter cake was recrystallized twice from ethanol and dried to obtain aripiprazole 25.6g, yield 57%, mp138.9 ~ 139.6 º C.
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External links
| WO2006079548A1 * |
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Sandoz Ag |
Organic compounds |
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Sandoz Ag |
Salts of aripiprazole |
| WO2014060324A1 |
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Sanovel Ilac Sanayi Ve Ticaret A.S |
Aripiprazole formulations |
| EP1844036A1 * |
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Sandoz AG |
Salts of aripiprazole |
| EP2093217A1 * |
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Sandoz AG |
Polymorph and solvates of aripiprazole |
| EP2233471A1 * |
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Adamed Sp. z o.o. |
A salt of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4.dihydro-2(1h)-quinolinone with 5-sulfosalicylic acid and its preparation process |
| EP2359816A1 |
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Sanovel Ilac Sanayi ve Ticaret A.S. |
Aripiprazole formulations |
| US7504504 |
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Teva Pharmaceutical Industries Ltd. |
Methods of preparing aripiprazole crystalline forms |
| US7714129 |
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Teva Pharmaceutical Industries Ltd. |
Methods of preparing anhydrous aripiprazole form II |
| US8008490 |
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Polymorphic forms of aripiprazole and method |
| US8188076 |
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Reviva Pharmaceuticals, Inc. |
Compositions, synthesis, and methods of utilizing arylpiperazine derivatives |
| US8207163 |
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Compositions, synthesis, and methods of using piperazine based antipsychotic agents |
| US8247420 |
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Compositions, synthesis, and methods of using quinolinone based atypical antipsychotic agents |
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Methods of utilizing arylpiperazine derivatives |
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Reviva Pharmaceuticals, Inc. |
Methods of utilizing arylpiperazine derivatives |
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Reviva Pharmaceuticals, Inc. |
Compositions, synthesis, and methods of utilizing quinazolinedione derivatives |
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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space groups, respectively. The improved solubility of telmisartan–saccharin (TEL–SAC) (nine-fold) and telmisartan–glutaric acid (two-fold) cocrystals in comparison with the free drug has been demonstrated in solubility experiments in phosphate buffer, pH 7.5. The TEL–SAC cocrystal remained stable in the aqueous medium for 6 hours as confirmed by PXRD. The AUC0–24 of TEL–SAC and TEL–GA was found to be 2-fold and 1.4-fold increased in terms of bioavailability than pure TEL, respectively. The in vivo antihypertensive activity of TEL–SAC in DOCA salt-induced hypertensive rats showed two-fold improved efficacy, while acute toxicity studies revealed no signs of toxicity in rats even at doses of 2000 mg kg−1 of body weight (BW). The new solid phase of telmisartan with saccharin represents a promising and viable opportunity for the manufacture of a drug product with improved therapeutic outcomes.
O, O–H
New Drug Approvals 