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WO2018104953A1 - Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate - Google Patents

Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate Download PDF

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WO2018104953A1
WO2018104953A1 PCT/IN2017/000138 IN2017000138W WO2018104953A1 WO 2018104953 A1 WO2018104953 A1 WO 2018104953A1 IN 2017000138 W IN2017000138 W IN 2017000138W WO 2018104953 A1 WO2018104953 A1 WO 2018104953A1
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compound
formula
reaction mixture
solvents
filtering
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French (fr)
Inventor
Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Jakku MALLESWARA REDDY
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • 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

Definitions

  • the present invention relates to an improved and novel process for the preparation of 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-I.-yl]butoxy ⁇ -2-0X0-3 ,4-dihydro-2H-quinolin- 1- yl)methyl dodecanoate compound of formula- 1 , which is represented by the following structural formula:
  • the first aspect of the present invention is to provide an improved process for the preparation of 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-l -yl]butoxy ⁇ -2-oxo-3,4-dihydro-2H- quinolin-l -yl) methyl dodecanoate compound of formula- 1.
  • the second aspect of the present invention is to provide an alternative process for the preparation of 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-l -yl]butoxy ⁇ -2-oxo-3,4-dihydro-2H- quinolin- l -yl)methyl dodecanoate compound of formula- 1 .
  • the third aspect of the present invention is to provide an alternative process for the preparation of the compound of formula-1.
  • the fourth aspect of the present invention is to provide novel process for the preparation of the compound of formula- 1.
  • the fifth aspect of the present invention is to provide a process for the preparation of the compound of general formula-10.
  • the sixth aspect of the present invention is to provide an alternative process for the preparation of the compound of general formula-10.
  • the seventh aspect of the present invention is to provide novel process for the preparation of the compound of formula-7.
  • the eighth aspect of the present invention is to provide the purification of lauric acid compound of formula-3.
  • Figure-1 Illustrates the powder X-ray diffraction of the compound of formula-7 obtained according to the present invention.
  • Figure-2 Illustrates the powder X-ray diffraction of the compound of formula- 1 obtained according to the present invention.
  • Figure-3 Illustrates the DSC thermogram of the compound of formula- 1 obtained according to the present invention. Detailed description of the Invention:
  • the present invention provides process for the preparation of 7- ⁇ 4-[4-(2,3-dichloro phenyl)-piperazin-l -yl]butoxy ⁇ -2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyi dodecanoate compound of formula- 1 .
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; "ether solvents” such as dimethoxymethane, tetrahydrofuran, 1 ,3-dioxane, 1 ,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1 ,2-dimethoxy ethane and the like; "ester solvents” such as methyl acetate,
  • suitable base refers to inorganic bases selected from “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the l ike; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkyl metals” such as n-butyl lithium and like; “metal hydrides” such as lithium hydride, sodium hydride, potassium hydride and the like; “alkali metal phosphates” such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and “organic bases” selected from but not limited to methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, trie
  • alkali metal carbonates such
  • the term "acid” used in the present invention refers to inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic acids such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; chiral acids such as S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D- maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)- (+)-camphor sulfonic acid, (lR)-(+)-bromocamphor- 10-sulfonic acid, (IS)-(-)-
  • condensing agent or coupling agent used in the present invention is selected form ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI), l -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCI), 0-(7-aza-benzotriazole- l -yl)-N,N,N',N'-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloro formate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pent
  • phase transfer catalyst used in the present invention is selected from but are not limited to quaternary ammonium salts, quaternary phosphonium salts, crown ethers, cryptands.
  • the suitable " N-protecting agent is selected such that it is capable of protecting the nitrogen atom with any of N-protecting groups known to the person skilled in the art.
  • the suitable hydroxy protecting agent is selected such that it is capable of protecting the oxygen atom with any of hydroxy protecting groups known to the person skilled in the art.
  • deprotecting agent used in the present invention is selected based on the protecting group employed.
  • the deprotecting agent is selected from but not limited to acids; bases; hydrogenating agents such as Pd/C, Pd(OH) 2 /C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni, tri(C 1 -C 6 )alkylsilanes, tri(C 1 -C 6 )alkylsilyl halides and the like.
  • the first aspect of the present invention provides an improved process for the preparation of the compound of formula- 1 , comprising of;
  • the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents, polar solvents or mixtures thereof;
  • the suitable base is selected from inorganic or organic bases;
  • the suitable catalyst is selected from alkali metal iodides such as sodium iodide, potassium iodide, lithium iodide; phase transfer catalyst.
  • step-a) to d) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) and c) the suitable base is same as defined in the first aspect of the present invention; in step-a) the suitable catalyst is same as defined in the first aspect of the present invention.
  • the third aspect of the. present invention provides an alternative process for the preparation of compound of formula-1 comprising of:
  • step-a) to c) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) the suitable base is same as defined in the first aspect of the present invention; in step-b) the suitable coupling agent is same as defined above.
  • Preferred embodiment of the present invention provides an alternative process for the preparation of compound of formula- 1 comprising:
  • Further aspect of the present invention provides a process for the preparation of 7- ⁇ 4- [4-(2,3-dichlorophenyl)-piperazin-l -yl]butoxy ⁇ -2-oxo-3,4-dihydro-2H-quinolin- 1 -y!methyl dodecanoate compound of formula- 1 having specific surface area less than 0.5 m 2 /g comprising the following step:
  • step-a) reacting the acid chloride obtained in step-a) in-situ with paraformaldehyde or formaldehyde in presence of with or without a catalyst and a base provide the compound of formula-4a,
  • the chlorinating agent (or) coupling agent is selected from thionyl chloride, oxalyl chloride, sulfuryl chloride, phosphorous oxychloride, carbon tetra chloride, phosphorous trichloride, phosphorous pentachloride, N-chlorosuccinamide (NCS);
  • the suitable catalyst is lewis acid, preferably Zinc chloride and base is selected from organic or inorganic bases;
  • step d) the suitable base is selected from organic or inorganic bases
  • the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents, polar solvents or mixtures thereof.
  • Preferred embodiment of the present invention provides a process for the preparation of 7- ⁇ 4-[4-(2,3-dichlorophenyI)-piperazin- l -yI]butoxy ⁇ -2-oxo-3,4-dihydro-2H-quinolin-l - yl)methyi dodecanoate compound of formula- 1 having specific surface area less than 0.5 m 2 /g comprising the following step:
  • the fourth aspect of the present invention provides novel process for the preparation of the compound of formula-1 , comprising of;
  • step-a) to c) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) and b) the suitable base is same as defined in the first aspect of the present invention.
  • the Fifth aspect of the present invention provides a process for the preparation of the compound of formula- 10, comprising of;
  • step-a) to c) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) the suitable base is same as defined in the first aspect of the present invention; in step-b) the suitable coupling agent is same as defined above.
  • the sixth aspect of the present invention provides an alternative process for the preparation of the compound of general formula- 10, comprising of;
  • step-a) to c) optionally purifying the compound of general formula- 10 using the suitable solvent.
  • the suitable solvent is same as defined in the first aspect of the present invention; in step-a) and b) the suitable base is same as defined in the first aspect of the present invention; in step-a) the suitable catalyst is same as defined in the first aspect of the present invention.
  • the seventh aspect of the present invention provides a novel process for the preparation of the compound of formula-7, comprising of;
  • step-a) to c) ' the suitable solvent is same as defined in the first aspect of the present invention; in step-a) & b) the suitable base is same as defined in the first aspect of the present invention.
  • the seventh aspect of the present invention is schematically represented as follows:
  • the eighth aspect of the present invention provides the purification of lauric acid compound of formula-3, comprising of;
  • the solvent is same as defined in the first aspect of the present invention; the suitable temperature is 30°C to reflux of the solvent used;
  • step-b) precipitating the compound optionally by adding an anti-solvent to the reaction mixture;
  • the suitable temperature is about -5°C to 30°C.
  • Preferred embodiment of the present invention provides the purification of lauric acid compound of formula-3, comprising;
  • Lauric acid compound of formula-3 prepared according to the present invention is most useful in the preparation of highly pure 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin- l - yl]butoxy ⁇ -2-oxo-3,4-dihydro-2H-quinolin- l-yl)methyl dodecanoate compound of formula- 1.
  • novel intermediate compounds obtained according to the present invention are useful in the preparation of the compound of formula- 1.
  • Further aspect of the present invention provides novel process for the preparation of the compound of formula-1 as represented by the following schemes: Further aspect of the present invention provides a process for preparation of pure 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy ⁇ -2-oxo-3,4-dihydro-2H-quinolin- l - yl)methyl dodecanoate compound of formula- 1 , comprising:
  • the suitable solvent is selected from alcohol solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents or mixtures thereof; preferably alcohol solvents, ketone solvents; the suitable temperature is 25°C to reflux temperature of the solvent used;
  • step-c) cooling the reaction mixture refers to the temperature range about - 10°C to 30°C
  • Preferred embodiment of the present invention provides a process for the preparation of pure 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy ⁇ -2-oxo-3,4-dihydro-2H- quin0lin- l -yl)methyl dodecanoate compound of formula-1 , comprising:
  • Another preferred embodiment of the present invention provides a process for the preparation of pure 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin- l -y!]butoxy ⁇ -2-oxo-3,4-dihydro- 2H-quinolin-l -yl)methy! dodecanoate compound of formula- 1 , comprising:
  • step f) optionally repeating the process from steps-a) to e) to get the compound of formula- 1 , g) recrystallizing the compound obtained in step-e) or step-f) using a second solvent to provide pure compound of formula- 1 .
  • the first solvent is selected from alcohol solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents or mixtures thereof; preferably alcohol solvents; in step-a) the suitable temperature is 25°C to reflux temperature of the solvent used;
  • step-c) cooling the reaction mixture refers to the temperature range about - 10°C to 30°C.
  • step-g) the second solvent is selected from ketone solvents, preferably acetone.
  • Preferred embodiment of the present invention provides a process for preparation of pure 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-l -yI]butoxy ⁇ -2-oxo-3,4-dihydro-2H-quinolin- l - yl)methyl dodecanoate compound of formula- 1 , comprising:
  • step-d) filtering the solid obtained in step-d) and washing with methanol, f) repeating the steps-a) to e) to get the compound of formula- 1 ,
  • step-e) recrystallizing the compound obtained in step-e) or step-f) using acetone to provide the pure compound of formula- 1 .
  • Further aspect of the present invention provides the compound of formula- 1 obtained according to the present invention having purity by HPLC >99%, preferably >99.5% which is having ⁇ 0.1 % of Aripiprazole & ⁇ 0. 1 % of N-Hydroxymethyl impurities.
  • Further aspect of the present invention provides particle size of 7- ⁇ 4-[4-(2,3- dichlorophenyl)-piperazin-l -yl]butoxy ⁇ -2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyl dodecanoate compound of formula- l obtained according to the present invention havjng D(90) ⁇ 150 ⁇ m, D(50) ⁇ 50 ⁇ m and D(10) ⁇ 15 ⁇ m..
  • the compound of formula- l obtained according to the present invention is designated as crystalline form-I and its PXRD pattern is illustrated in figure-2 and is further characterized by its powder X-Ray diffraction pattern having peaks at 6.9, 8.5, 1 1.9, 13.3, 13.9, 14.8, 15.2, 18.2, 20.1 , 20.8, 21 .6, 22.1 , 23.9 & 25.0 ⁇ 0.2 degrees of 2-theta. Further it is having the endotherm at 84oC ⁇ 3°C in its differential scanning calorimetric (DSC) thermogram as shown in figure-3.
  • DSC differential scanning calorimetric
  • the crystalline form-I of the compound of formula- ] obtained according to the present invention having purity by HPLC >99%, preferably >99.5%.
  • a gas chromatographic system is equipped with FID.
  • Chloromethyl laurate and its related substances were analyzed by GC with the following chromatographic conditions:
  • a gas chromatographic system is equipped with FID.
  • Column HP-5 Capillery column; Length: 30 mts; Injection- temperature: 280°C; Detector temperature: 260°C; Carrier gas: Helium; Carrier gas pressure: l Opsi; Hydrogen flow: 40 ml/min; Air flow: 400 ml/min; Make up (N2): 30ml/min; Injection volume: 1 ⁇ ; Diluent: Acetonitrile.
  • a liquid chromatograph is equipped with variable wavelength UV Detector.
  • Mobile phase-A Buffer (100%); Mobile phase-B: Acetonitrile:Buffer:Methanol [80: 10: 10 v/v/v]
  • PXRD analysis of compound of formula- 1 produced by the present invention was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu K ⁇ radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
  • DSC Differential scanning calorimetric
  • Example-1 Preparation of 7-(4-(4-(2,3-Dichlorophenyl)piperazin-l-yl)butoxy)-l- (hydroxymethyl)-3,4-dihydroquinolin-2(lH)-one compound of formula-7:
  • Aripiprazole 100 gm was added to the solution of chloromethyl laureate (416.1 1 gm) in 2500 ml of dichloromethane at 25-30°C and stirred the reaction mixture for 10 minutes.
  • Dimethylamino pyridine 13.4 gm
  • triethyl amine 93.2 ml was slowly added to the reaction mixture at 25-30°C and stirred for 22 hours at the same temperature.
  • Water was added to the reaction mixture at 25-30°C and stirred for 10 minutes. Separated the both aqueous and organic layers and the organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure and co- distilled with methanol. Recrystallized the obtained compound from methanol to get the title compound. Yield: 73 gm.
  • Example-11 Preparation of 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-l-yl] butoxy ⁇ -2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate:
  • Potassium tertiary butoxide (37.5 gm) was added to the mixture of Aripiprazole ( 100 gm) and tetrahydrofuran ( 1000 ml) at -5 to 0°C.
  • Chloromethyl laurate ( 138.7 gm) was slowly added to the reaction mixture at -5 to 0°C and stirred for 3 hours at the same temperature.
  • Water and ethyl acetate were added to the reaction mixture. Raised the temperature of reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and the obtained filtrate was stirred for 10 minutes at 25-30° C.
  • the other impurities i.e., Diamide Impurity, Tridecano Impurity, Tetradecano Impurity, Decano Impurity & Undecano Impurity are well below 0.05%.
  • Example-13 Purification of 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-l-yl]butoxy ⁇ -2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate compound of formula-1 using acetone:
  • Example-14 Purification of 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-l-yl] butoxy ⁇ -2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate using methanol :
  • Example-15 Purification of 7- ⁇ 4-[4-(2,3-dichlorophenyI)-piperazin-l-yl]butoxy ⁇ -2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate using ethyl acetate:
  • Example-16 Purification of 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-l-yl]butoxy ⁇ -2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate using isopropanol:
  • Example-17 Purification of 7- ⁇ 4-[4-(2,3-dichlorophenyl)-piperazin-l-yl]butoxy ⁇ -2-oxo- 3,4-dihydro-2H-quinoIin-l-yl)methyl dodecanoate using acetonitrile:

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Abstract

The present invention relates to improved process for the preparation of 7-{4-[4- (2,3-dichlorophenyl)-piperazin-1-yl]butoxy }-2 oxo-3,4-dihydro-2H-quinolin-1-yl)methyl dodecanoate compound of formula-1, which is represented by the following structural formula:

Description

Improved process for the preparation of 7-{4-|4-(2.3-dichlorophenv))-piperazin- l-Yllbutoxy)-2-oxo-3,4-dihvdro-2H-quinolin-l-yl)methyl dodecanoate
Related application:
This application claims the benefit of priority of our Indian patent application number 201641041 768 filed on 7th December 2016 which is incorporated herein by reference.
Field of the Invention:
The present invention relates to an improved and novel process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-I.-yl]butoxy} -2-0X0-3 ,4-dihydro-2H-quinolin- 1- yl)methyl dodecanoate compound of formula- 1 , which is represented by the following structural formula:
Figure imgf000002_0001
Formula-1
Background of the Invention:
7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]but6xy}-2-oxo-3,4-dihydro-2H-quinolin- l-yl)methyl dodecanoate is known as Aripiprazole Lauroxil. It is developed by Alkerms under the trade name Aristada® for the treatment of schizophernia.
7-{4-[4-(2,3-dichlorophenyl)-piperazin-l -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyl dodecanoate is an atypical antipsychotic agent.
7-{4-[4-(2,3-dichlorophenyl)-piperazin-l -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyl dodecanoate is first disclosed in US843 I 576. The said patent discloses the process for the preparation of the compound of formula- 1 which provides low yields with less purity.
There is a need for the development of the alternative process for the preparation of the compound of formula-1 with respect to higher yields and purity.
US8431576 patent describes PXR.D pattern of the crystalline form of compound of formula-1 . Herein after the said crystalline form is designated as crystalline form-I. Brief description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l -yl]butoxy}-2-oxo-3,4-dihydro-2H- quinolin-l -yl) methyl dodecanoate compound of formula- 1.
The second aspect of the present invention is to provide an alternative process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l -yl]butoxy}-2-oxo-3,4-dihydro-2H- quinolin- l -yl)methyl dodecanoate compound of formula- 1 .
The third aspect of the present invention is to provide an alternative process for the preparation of the compound of formula-1.
The fourth aspect of the present invention is to provide novel process for the preparation of the compound of formula- 1.
The fifth aspect of the present invention is to provide a process for the preparation of the compound of general formula-10.
The sixth aspect of the present invention is to provide an alternative process for the preparation of the compound of general formula-10.
The seventh aspect of the present invention is to provide novel process for the preparation of the compound of formula-7.
The eighth aspect of the present invention is to provide the purification of lauric acid compound of formula-3.
Brief description of the Drawings:
Figure-1 : Illustrates the powder X-ray diffraction of the compound of formula-7 obtained according to the present invention.
Figure-2: Illustrates the powder X-ray diffraction of the compound of formula- 1 obtained according to the present invention.
Figure-3: Illustrates the DSC thermogram of the compound of formula- 1 obtained according to the present invention. Detailed description of the Invention:
The present invention provides process for the preparation of 7-{4-[4-(2,3-dichloro phenyl)-piperazin-l -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyi dodecanoate compound of formula- 1 .
As used herein the term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; "ether solvents" such as dimethoxymethane, tetrahydrofuran, 1 ,3-dioxane, 1 ,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1 ,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbontetra chloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile; isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2- fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1 , 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexano!, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.
The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the l ike; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkyl metals" such as n-butyl lithium and like; "metal hydrides" such as lithium hydride, sodium hydride, potassium hydride and the like; "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and "organic bases" selected from but not limited to methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), n-methyl pyridine (NMP), l ,8-diazabicydo[5.4.0]undec-7-ene (DBU), l ,5-diazabicyclo[4.3.0]non-5-ene (DBN), l ,4-diazabicyclo[2.2.2]octane (DABCO), imidazole; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sod ium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysily!)amide (LiHMDS) and the like; or mixtures thereof.
The term "acid" used in the present invention refers to inorganic acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic acids such as acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid; chiral acids such as S-(+) mandelic acid, R-(-) mandelic acid, L-(+)tartaric acid, D-(-)tartaric acid, L-malic acid, D-malic acid, D- maleic acid, (-)-naproxen, (+)-naproxen, (lR)-(-)-camphor sulfonic acid, (IS)- (+)-camphor sulfonic acid, (lR)-(+)-bromocamphor- 10-sulfonic acid, (IS)-(-)- bromocamphor- 1 0-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-Dibenzoyl-L-tartaric acid monohydrate, (+)- Dibenzoyl-D-tartaric acid, (+)-Dibenzoyl-D-tartaric acid monohydrate, (+)-dipara-tolyl-D- tataric acid, (-)-dipara-tolyl-L-tataric acid, L(-)- pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid, L-lysine, D-lysine etc., and like.
The term "condensing agent or coupling agent" used in the present invention is selected form Ν,Ν'-dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIC), carbonyldiimidazole (CDI), l -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCI), 0-(7-aza-benzotriazole- l -yl)-N,N,N',N'-tetramethyl uronium hexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloro formate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2- oxopentanoyl chloride (i-BuCOCOCl), benzotriazol- l -yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like; optionally in combination with I -hydroxy-7-azatriazole (HO At), l -hydroxybenzotriazole (HOBt), I - hydroxy-l H-l ,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol- l -yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N- hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylaminopyridine (DMAP).
The term "phase transfer catalyst" used in the present invention is selected from but are not limited to quaternary ammonium salts, quaternary phosphonium salts, crown ethers, cryptands.
The suitable "N-protecting agent is selected such that it is capable of protecting the nitrogen atom with any of N-protecting groups known to the person skilled in the art.
The suitable hydroxy protecting agent is selected such that it is capable of protecting the oxygen atom with any of hydroxy protecting groups known to the person skilled in the art.
The term "deprotecting agent" used in the present invention is selected based on the protecting group employed. The deprotecting agent is selected from but not limited to acids; bases; hydrogenating agents such as Pd/C, Pd(OH)2/C (Pearlman's catalyst), palladium acetate, platinum oxide, platinum black, sodium borohydride, Na-liquid ammonia, Raney-Ni, tri(C1-C6)alkylsilanes, tri(C1-C6)alkylsilyl halides and the like.
The first aspect of the present invention provides an improved process for the preparation of the compound of formula- 1 , comprising of;
a) Reacting Aripiprazole compound of formula-2 with dihalomethane compound of general formula-5 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide the compound of general formula-6,
b) reacting the compound of general formula-6 with lauric acid compound of formula-3 in presence of a suitable base in a suitable. solvent to provide the compound of formula- 1 , c) optionally purifying the compound of formula- 1 using the suitable solvent.
Wherein in step-a) to c) the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents, polar solvents or mixtures thereof; in step-a) and step-b) the suitable base is selected from inorganic or organic bases; in step-a) the suitable catalyst is selected from alkali metal iodides such as sodium iodide, potassium iodide, lithium iodide; phase transfer catalyst. The second aspect of the present invention provides an alternative process for the preparation of the compound of formula- 1 , comprising of;
a) Reacting lauric acid compound of formula-3 with dihalomethane compound of general · formu!a-5 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide the compound of general formula-4,
b) optionally purifying the compound of general formula-4 using a suitable solvent, c) reacting the compound of general formula-4 with Aripiprazole compound of formu!a-2 in presence of a suitable base in a suitable solvent to provide the compound of formula- d) optionally purifying the compound of formula- 1 using the suitable solvent.
Wherein in step-a) to d) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) and c) the suitable base is same as defined in the first aspect of the present invention; in step-a) the suitable catalyst is same as defined in the first aspect of the present invention.
The third aspect of the. present invention provides an alternative process for the preparation of compound of formula-1 comprising of:
a) Reacting the compound of formula-2 with paraformaldehyde or formaldehyde in presence of a suitable base in a suitable solvent to provide the compound of formula-7, b) reacting the compound of formula-7 with lauric acid compound of formula-3 in presence of a suitable coupling agent in a suitable solvent to provide the compound of formula- 1 , c) optionally purifying the compound of formula- 1 using the suitable solvent.
Wherein in step-a) to c) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) the suitable base is same as defined in the first aspect of the present invention; in step-b) the suitable coupling agent is same as defined above.
Preferred embodiment of the present invention provides an alternative process for the preparation of compound of formula- 1 comprising:
a) reacting the compound of formula-2 with formaldehyde in presence of triethyl amine in dimethylformamide to provide the compound of formula-7, b) reacting the compound of formula-7 with lauric acid compound of formula-3 in presence of Ν,Ν'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane to provide the compound of formula- 1 ,
c) purifying the compound of formula- 1 using methanol.
Further aspect of the present invention provides a process for the preparation of 7-{4- [4-(2,3-dichlorophenyl)-piperazin-l -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- 1 -y!)methyl dodecanoate compound of formula- 1 having specific surface area less than 0.5 m2/g comprising the following step:
a) treating the lauric acid compound of formula-3 with chlorinating agent or coupling agent in a suitable solvent,
b) reacting the acid chloride obtained in step-a) in-situ with paraformaldehyde or formaldehyde in presence of with or without a catalyst and a base provide the compound of formula-4a,
Figure imgf000008_0001
c) optionally purifying the obtained compound using a suitable solvent,
d) reacting the compound of formula-4a with aripiprazole compound of formula-2 in presence of a suitable base in a suitable solvent to provide the compound of formula- 1 , e) optionally purifying the compound of formula- 1 using a suitable solvent.
Wherein in step a) the chlorinating agent (or) coupling agent is selected from thionyl chloride, oxalyl chloride, sulfuryl chloride, phosphorous oxychloride, carbon tetra chloride, phosphorous trichloride, phosphorous pentachloride, N-chlorosuccinamide (NCS);
In step b) the suitable catalyst is lewis acid, preferably Zinc chloride and base is selected from organic or inorganic bases;
In step d) the suitable base is selected from organic or inorganic bases;
In steps a) to e) the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents, polar solvents or mixtures thereof. Preferred embodiment of the present invention provides a process for the preparation of 7-{4-[4-(2,3-dichlorophenyI)-piperazin- l -yI]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-l - yl)methyi dodecanoate compound of formula- 1 having specific surface area less than 0.5 m2/g comprising the following step:
a) treating the Iauric acid compound of formula-3 with thionyl chloride in dichloromethane, b) reacting the acid chloride obtained in step-a) in-situ with paraformaldehyde in presence of zinc chloride provide chloromethyl laurate compound of formula-4a,
c) purifying the obtained compound using cyclohexane,
d) reacting the compound of formula-4a with aripiprazole compound of formula-2 in presence of potassium tertiary butoxide and 4-dimethylaminopyridine in tetrahydrofuran to provide the compound of formula- 1 ,
e) purifying the compound of formula- 1 using methanol,
f) optionally further recrystallizing the compound of formula- 1 in acetone to provide the compound of formula-1 having specific surface area less than 0.5 m2/g.
The first to third aspects of the present invention are schematically represented as follows:
Figure imgf000009_0001
The fourth aspect of the present invention provides novel process for the preparation of the compound of formula-1 , comprising of;
a) Reacting the compound of general formu!a-4 with the compound of general formula-8 in presence of a suitable base in a suitable solvent to provide the compound of general formula- 10,
b) reacting the compound of general formula- 10 with the compound, of formu!a- l l in presence of a suitable base in a suitable base to provide the compound of formula- 1 , c) . optionally purifying the compound of formula-1 using the suitable solvent.
Wherein in step-a) to c) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) and b) the suitable base is same as defined in the first aspect of the present invention.
The Fifth aspect of the present invention provides a process for the preparation of the compound of formula- 10, comprising of;
a) Reacting the compound of general formula-8 with paraformaldehyde or formaldehyde in presence of a suitable base in a suitable solvent to provide the compound of general formula- 12,
b) reacting the compound of general formula- 12 with the compound of formula-3 in presence of a suitable coupling agent in a suitable solvent to provide the compound of general formula- 10,
c) optionally purifying the compound of general formula-10 using a suitable solvent.
Wherein in step-a) to c) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) the suitable base is same as defined in the first aspect of the present invention; in step-b) the suitable coupling agent is same as defined above.
The sixth aspect of the present invention provides an alternative process for the preparation of the compound of general formula- 10, comprising of;
a) Reacting the compound of general formula-8 with dihalomethane compound of general formula-5 in presence of a suitable base in a suitable solvent optionally in presence of a suitable catalyst to provide the compound of general formula-9, b) reacting the compound of general formula-9 with lauric acid compound of formula-3 in presence of a suitable base in a suitable solvent to provide the compound of general formula- 10,
c) optionally purifying the compound of general formula- 10 using the suitable solvent. Wherein in step-a) to c) the suitable solvent is same as defined in the first aspect of the present invention; in step-a) and b) the suitable base is same as defined in the first aspect of the present invention; in step-a) the suitable catalyst is same as defined in the first aspect of the present invention.
The fourth to sixth aspects of the present invention are schematically represented as f llows:
Figure imgf000011_0001
The seventh aspect of the present invention provides a novel process for the preparation of the compound of formula-7, comprising of;
a) Reacting the compound of general formula-8 with paraformaldehyde or formaldehyde in presence of a suitable base in a suitable solvent to provide the compound of general formula- 12,
b) reacting the compound of general formula- 12 with the compound of formula- 1 1 in presence of a suitable base in a suitable solvent to provide the compound of formula-7, c) optionally purifying the compound of formula-7 using a suitable solvent.
Wherein in step-a) to c)' the suitable solvent is same as defined in the first aspect of the present invention; in step-a) & b) the suitable base is same as defined in the first aspect of the present invention.
The seventh aspect of the present invention is schematically represented as follows:
Scheme-III
Figure imgf000012_0001
The eighth aspect of the present invention provides the purification of lauric acid compound of formula-3, comprising of;
a) Dissolving lauric acid compound of formula-3 in a suitable solvent at a suitable temperature,
b) precipitating the compound by cooling the reaction mixture to a suitable temperature, c) filtering the precipitated solid to provide pure lauric acid compound of formula-3.
Wherein in step-a) the solvent is same as defined in the first aspect of the present invention; the suitable temperature is 30°C to reflux of the solvent used;
in step-b) precipitating the compound optionally by adding an anti-solvent to the reaction mixture; the suitable temperature is about -5°C to 30°C.
Preferred embodiment of the present invention provides the purification of lauric acid compound of formula-3, comprising;
a) dissolving lauric acid compound of formula-3 in aqueous acetone at 55 to 65°C, b) precipitating the compound by cooling the reaction mixture to 0-10°C,
c) filtering the precipitated solid to provide pure lauric acid compound of formula-3.
I I Commercially available lauric acid is not having the required purity. By utilizing the commercially available material impure compound of formula-1 is obtained. The purification of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1 -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l - yl)methyl dodecanoate compound of formula- 1 is highly impossible and also getting with low yield. The present inventors developed the process for the purification of lauric acid and proceed through highly pure lauric acid to get pure compound of formula-1 . The commercially available lauric acid is having the following impurities.
Figure imgf000013_0001
Laurie acid compound of formuta-3 obtained according to the present invention is having purity by GC >99%, preferably >99.5% and having any of other single impurity is not more than 0. 1 %.
Lauric acid compound of formula-3 prepared according to the present invention is most useful in the preparation of highly pure 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l - yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l-yl)methyl dodecanoate compound of formula- 1.
The novel intermediate compounds obtained according to the present invention are useful in the preparation of the compound of formula- 1.
Further aspect of the present invention provides novel process for the preparation of the compound of formula-1 as represented by the following schemes:
Figure imgf000014_0001
Further aspect of the present invention provides a process for preparation of pure 7- {4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l - yl)methyl dodecanoate compound of formula- 1 , comprising:
a) dissolving the compound of formula- 1 in a suitable solvent at a suitable temperature, b) optionally filtering the reaction mixture,
c) cooling the reaction mixture,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with a suitable solvent,
f) optionally repeating the process from steps-a) to e) to get the pure compound of formula- 1 .
Wherein in steps-a) and e) the suitable solvent is selected from alcohol solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents or mixtures thereof; preferably alcohol solvents, ketone solvents; the suitable temperature is 25°C to reflux temperature of the solvent used;
in step-c) cooling the reaction mixture refers to the temperature range about - 10°C to 30°C
Preferred embodiment of the present invention provides a process for the preparation of pure 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}-2-oxo-3,4-dihydro-2H- quin0lin- l -yl)methyl dodecanoate compound of formula-1 , comprising:
a) dissolving the compound of formula- 1 in methanol at 55°C to 65°C,
b) filtering the reaction mixture,
c) cooling the reaction mixture to 25-35°C,
d) stirring the reaction mixture,
e) filtering the solid to get the compound of formula- 1 ,
f) repeating the steps a) to e) to provide pure compound of formula- 1 .
Another preferred embodiment of the present invention provides a process for the preparation of pure 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -y!]butoxy}-2-oxo-3,4-dihydro- 2H-quinolin-l -yl)methy! dodecanoate compound of formula- 1 , comprising:
a) dissolving the compound of formula- 1 in acetone at 25°C to 65°C,
b) filtering the reaction mixture, c) cooling the reaction mixture to 0-25°C,
d) stirring the reaction mixture,
e) filtering the solid to provide the pure compound of formula- 1 .
Further aspect of the present invention provides a process for preparation of pure 7- {4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}-2 -oxo-3,4-dihydro-2H-Q,uino!in- 1 - yl)methyl dodecanoate compound of formula- 1 , comprising:
a) dissolving the compound of formula- 1 in a first solvent at a suitable temperature, b) optionally filtering the reaction mixture,
c) cooling the reaction mixture,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with a first solvent,
f) optionally repeating the process from steps-a) to e) to get the compound of formula- 1 , g) recrystallizing the compound obtained in step-e) or step-f) using a second solvent to provide pure compound of formula- 1 .
Wherein in steps-a) and e) the first solvent is selected from alcohol solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents or mixtures thereof; preferably alcohol solvents; in step-a) the suitable temperature is 25°C to reflux temperature of the solvent used;
in step-c) cooling the reaction mixture refers to the temperature range about - 10°C to 30°C. in step-g) the second solvent is selected from ketone solvents, preferably acetone.
Preferred embodiment of the present invention provides a process for preparation of pure 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l -yI]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l - yl)methyl dodecanoate compound of formula- 1 , comprising:
a) dissolving the compound of formula- 1 in methanol at 55-65°C,
b) filtering the reaction mixture,
c) cooling the reaction mixture to 20-30°C,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with methanol, f) repeating the steps-a) to e) to get the compound of formula- 1 ,
g) recrystallizing the compound obtained in step-e) or step-f) using acetone to provide the pure compound of formula- 1 .
Further aspect of the present invention provides the compound of formula- 1 obtained according to the present invention having purity by HPLC >99%, preferably >99.5% which is having <0.1 % of Aripiprazole & <0. 1 % of N-Hydroxymethyl impurities.
The following impurities are observed during the preparation of 7-{4-[4-(2,3- dichlorophenyl)-piperazin- l -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin-l -yl)methyl dodecanoate compound of formula-1 as per the present invention and these all impurities are well controlling in less than 0.1 5%, preferably less than 0.1% by HPLC.
Figure imgf000017_0001
Figure imgf000018_0001
Further aspect of the present invention , provides 7-{4-[4-(2,3-dichlorophenyl)- piperazin-l -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyl dodecanoate compound of formula- 1 having specific surface area less than 0.5m2/g.
Further aspect of the present invention provides particle size of 7-{4-[4-(2,3- dichlorophenyl)-piperazin-l -yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyl dodecanoate compound of formula- l obtained according to the present invention havjng D(90) < 150 μm, D(50) < 50 μm and D(10) < 15 μm..
Further aspect of the present invention the compound of formula- l obtained according to the present invention is designated as crystalline form-I and its PXRD pattern is illustrated in figure-2 and is further characterized by its powder X-Ray diffraction pattern having peaks at 6.9, 8.5, 1 1.9, 13.3, 13.9, 14.8, 15.2, 18.2, 20.1 , 20.8, 21 .6, 22.1 , 23.9 & 25.0 ± 0.2 degrees of 2-theta. Further it is having the endotherm at 84ºC±3°C in its differential scanning calorimetric (DSC) thermogram as shown in figure-3.
The crystalline form-I of the compound of formula- ] obtained according to the present invention having purity by HPLC >99%, preferably >99.5%.
Method of Analysis:
a) Laurie acid and its related substances were analyzed by GC with the following chromatographic conditions:
Apparatus: A gas chromatographic system is equipped with FID. Column: DB- I Capillery column; Length: 30 mts; Injection temperature: 250°C; Detector temperature: 260°C; Carrier gas: Helium; Carrier gas pressure: 4psi; Hydrogen flow: 40 ml/min; Air flow: 400 ml/min; Make up (N2): 30ml/min; Injection volume: 1 μm; Diluent: Acetonitrile. b) Chloromethyl laurate and its related substances were analyzed by GC with the following chromatographic conditions:
Apparatus: A gas chromatographic system is equipped with FID. Column: HP-5 Capillery column; Length: 30 mts; Injection- temperature: 280°C; Detector temperature: 260°C; Carrier gas: Helium; Carrier gas pressure: l Opsi; Hydrogen flow: 40 ml/min; Air flow: 400 ml/min; Make up (N2): 30ml/min; Injection volume: 1 μί; Diluent: Acetonitrile.
c) The compound of formula- 1 and its related substances were analyzed by HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatograph is equipped with variable wavelength UV Detector. Column: Zobrax Bonus RP, 250 x 4.6 mm, 5 μιτ» (or) Equivalent; Wavelength: 2 15 nm; Column temperature: 30°C; Injection volume: 5 μL ; Diluent: Acetonitrile:Methanol (50:50 v/v); Needle wash: Methanol; Elution: Gradient; Buffer: Weigh and transfer accurately 1 .0 gm of 1 -octane sulphonic acid sodium salt anhydrous in 1000mL of mi lli-Q-water, mix well and filter. Then add 2mL of perchloric acid, 1 ml triethyl amine and adjust pH:3.5 with aqueous sodium hydroxide solution & mix well.
Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile:Buffer:Methanol [80: 10: 10 v/v/v]
PXRD analysis of compound of formula- 1 produced by the present invention was carried out using BRUKER D8 ADVANCED/AXS X-Ray diffractometer using Cu Kα radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
Differential scanning calorimetric (DSC) analysis was performed on Q I 0 V9.9 Build 303 calorimeter (or) Q2000 V24.1 1 Build 124 calorimeter with aluminium pans, heating the samples from 40 to 120°C under closed conditions at a rate of 5.00°C/min.
Advantages of the present invention:
• Using of the pure of lauric acid in the preparation of the compound of formula- 1 gives pure compound of formula- 1 .
• Purification of the compound of formula- 1 as per the present invention provides ICH purity of compound of formula-] which is having less than 0.5% of total impurities.
• The compound of formula- 1 obtained according to the present invention is well suitable in the preparation of pharmaceutical composition. • The process is environment friendly, economically viable, good in quality and yield and scalable to industrial level.
The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples:
Example-1 : Preparation of 7-(4-(4-(2,3-Dichlorophenyl)piperazin-l-yl)butoxy)-l- (hydroxymethyl)-3,4-dihydroquinolin-2(lH)-one compound of formula-7:
500 ml of formaldehyde and triethyl amine (5 ml) were slowly added to the mixture of Aripiprazole (100 gm) and dimethylformamide (800 ml) at 25-30°C and stirred the reaction mixture for 10 minutes. Heated the reaction mixture to 85-90°C and stirred for 45 hours. Cooled the reaction mixture to 25-30°C. Water was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. The obtained compound was slurried in 500 ml of tetrahydrofuran at 25- 30°C for 3 hours. Filtered the compound, washed with tetrahydrofuran and dried to get the title compound. Yield: 76 gm. Purity by HPLC: 97.90%. PXRD of the obtained compound was depicted in figure- 1 .
Example-2: Purification of Laurie acid:
Dissolved 100 gms of lauric acid in 200 ml of 5% aqueous acetone at 55-60°C. Cooled the reaction mixture to 0-5°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with 5% aqueous acetone and dried to get the title compound. Yield: 45 gms; Purity by GC: 99.81 %. M.R. : 42-45°C.
Example-3: Preparation of the compound of formula-1:
83.6 gms of Lauric acid and 1 gm of DMAP were slowly added to the solution of 100 gms of the compound of formula-7 in 500 ml of dichloromethane at 25-30°C. The solution of DCC (86.1 gm) in 500 ml of dichloromethane was slowly added to the reaction mixture at 25-30°C and stirred for 8 hours at the same temperature. Filtered the reaction mixture and washed with dichloromethane. The filtrate was washed with water and distilled off the solvent completely under reduced pressure and co-distilled with methanol. The obtained compound was dissolved in 1000 ml of methanol at 55-60°C. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 85 gms. Purity by HPLC: 98.92%.
Example-4: Preparation of the compound of formula-1:
65 gms of thionyl chloride was slowly added to the mixture of lauric acid (83.6 gm), dichloromethane (500 ml) and dimethylformamide ( 1 ml) at 25-30°C and stirred the reaction mixture for 2 hours. Distilled off the solvent completely from the reaction mixture. The obtained lauroyi chloride was diluted with 1500 ml of dichloromethane at 25-30°C. This solution was slowly added to the mixture of the compound of formula-7 (100 gm), triethylamine ( 105.7 gm) and dichloromethane ( 100 ml) at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Water was added to the reaction mixture at 25- 30°C and stirred for 1 5 minutes. Separated both the organic and aqueous layers and washed the organic layer with water. Distilled off the solvent completely from the organic layer and co-distilled with methanol. The obtained compound was dissolved in 1000 ml of methanol at 55-60°C. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 83 gms, HPLC purity: 98.44%.
Example-5: Preparation of the compound of formula-1 :
The mixture of the compound of formula-7 (100 gm), Laurie anhydride (121.56 gm) and tetrahydrofuran (500 ml) was heated to 60-65°C and stirred the reaction mixture for 1 hour at the same temperature. 2.74 gms of triethylmaine was added to the reaction mixture at 60- 65°C and stirred the reaction mixture for 30 hours at the same temperature. Cooled the reaction mixture to 25-30°C and ethyl acetate, n-heptane and followed by 5% sodium bicarbonate solution were added to the reaction mixture at 25-30°C and stirred the reaction for 10 minutes. Separated both the organic and aqueous layers. Aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with aqueous sodium bicarbonate solution. Distilled off the solvent completely from the organic layer. The obtained compound was purified by the column chromatography using 40% ethyl acetate in cyclohexane as eluents. The obtained compound was dissolved in isopropyl acetate (120 ml) at 60-65°C, n-heptane (200 ml) was added to the reaction mixture at 60-65°C and stirred the reaction mixture for 30 minutes at the same temperature. Cooled the reaction mixture to 10- 15°C and stirred for 3 hours at same temperature. Filtered the precipitated sol id, washed with n-heptane and dried to get the title compound. Yield: 38 gms. Purity by HPLC: 98.44%, Example-6: Purification of the compound of form u la- 1:
1 10 gms of the compound of formula- 1 was dissolved in 330 ml of ethyl acetate at 55-60°C. To this solution 1 1 gms of carbon was added at 60-65°C and stirred the reaction mixture for 15 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with ethyl acetate. Distilled off the solvent from the filtrate under reduced pressure and co-distilled with methanol. Dissolved the obtained compound in 550 ml of methanol at 65-70°C. Cooled to the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 98 gms. Purity by HPLC purity: 99.67%.
Example-7: Preparation of chloromethyl laurate:
71 .3 gms of thtonyt chloride was slowly added to the mixture of Laurie acid ( 100 gm), dichloromethane ( 1000 ml) and dimethylformamide ( 1 ml) at 25-30°C and stirred the reaction mixture for 2 hours. Distilled off the solvent completely from the reaction mixture. The mixture of paraformaldehyde ( 14.99 gm) and anhydrous zinc chloride (1 .36 gm) was cooled to 0-5°C. The above obtained acid chloride was add to the reaction mixture at 0-5°C and stirred for 60 minutes at the same temperature. Raised the temperature of the reaction mixture to 25-30°C, followed by heating to 90-95°C and stirred for 16 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours. Filtered the reaction mixture and distilled off the solvent completely from the filtrate under reduced pressure. Purified the obtained compound by column chromatography using cyclohexane as eluent. Yield: 73 gms.
Example-8: Preparation of the compound of formula-1 :
Aripiprazole ( 100 gm) was added to the solution of chloromethyl laureate (416.1 1 gm) in 2500 ml of dichloromethane at 25-30°C and stirred the reaction mixture for 10 minutes. Dimethylamino pyridine ( 13.4 gm) and triethyl amine (93.2 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 22 hours at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 10 minutes. Separated the both aqueous and organic layers and the organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent from the organic layer under reduced pressure and co- distilled with methanol. Recrystallized the obtained compound from methanol to get the title compound. Yield: 73 gm.
Example-9: Purification of Laurie acid
Laurie acid (30 kgs) was dissolved in 5% aqueous acetone (57 Its of acetone and 3 Its of water) at 55-60°C. Cooled the reaction mixture to 5- 10°C and stirred for 3 hours. Filtered the precipitated solid, washed with chilled aqueous acetone and dried to get the pure Laurie acid. Yield: 15.20 kg. Purity by GC: 99.94%.
Figure imgf000023_0001
Example-10: Preparation of chloromethyl laurate:
Thionyl chloride (10.7 kgs) was slowly added to a mixture of Laurie acid ( 15 kgs), dichloromethane (75 Lts) and dirnethylformamide. (0. 14 kgs) at 25-30°C and stirred for 2 hours at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. The above obtained acid chloride was cooled to 25-30°C and added to the mixture of paraformaldehyde (2.3 kgs) and anhydrous zinc chloride (0.2 kgs) at the same temperature. Heated the reaction mixture to 90-95°C and stirred for 12 hours at the same temperature. Cooled the reaction mixture to 25-30°C, ethyl acetate followed by aqueous sodium carbonate solution was added to the reaction mixture and stirred for 45 minutes at the same temperature. Filtered the reaction mixture. Both the aqueous and organic layers were separated from the obtained filtrate. Organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with cyclohexane. The obtained residue was purified by column chromatography using cyclohexane as eluent. Yield: 7. 1 kg. Purity by GC: 97.72%. Example-11 : Preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l-yl] butoxy}-2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate:
4-Dimethylamino pyridine (0.68 kgs) and potassium tertiary butoxide (1.88 kgs) were added to the mixture of Aripiprazole (5 kgs) and tetrahydrofuran (50 l iters) at -5 to 0°C. Chloromethyl laurate (6.94 kg) was slowly added to the reaction mixture at -5 to 0°C and stirred for 3 hours at the same temperature. Water and ethyl acetate were added to the reaction mixture. Raised the temperature of reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflo bed and the obtained filtrate was stirred for 10 minutes at 25-30° C. Both the aqueous and organic layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and dried over anhydrous sodium sulphate. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methanol. Slurried the obtained compound in methanol at 25-30°C. Dissolved the obtained compound in methanol (75 lits) at 60-65°C. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed methanol. Again recrystallization the obtained compound in methanol. The obtained compound was dissolved in acetone ( 15 lits) at 55-60°C. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound.
Yield: 2.9 kg. Purity by HPLC: 99.65%, Aripiprazole impurity: 0.03%, N-Hydroxy methyl impurity: 0.05%, total impurities: 0.35%. SSA of the obtained compound: 0.344 m2/g Example-12: Preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l-yl] butoxy}-2-oxo- 3,4-dihydro-2H-quinolin-l-yI)methyl dodecanoate:
Potassium tertiary butoxide (37.5 gm) was added to the mixture of Aripiprazole ( 100 gm) and tetrahydrofuran ( 1000 ml) at -5 to 0°C. Chloromethyl laurate ( 138.7 gm) was slowly added to the reaction mixture at -5 to 0°C and stirred for 3 hours at the same temperature. Water and ethyl acetate were added to the reaction mixture. Raised the temperature of reaction mixture to 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and the obtained filtrate was stirred for 10 minutes at 25-30° C. Both the aqueous and organic layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and dried over anhydrous sodium sulphate. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with methanol. Slurried the obtained compound in methanol at 25-30°C.
Purity of the obtained compound by HPLC: 96.66%.
Figure imgf000025_0001
1st Purification: Dissolved the obtained compound in methanol ( 1500 ml) at 60-65°C. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed methanol.
Purity of the obtained compound by HPLC: 97.15%.
Figure imgf000025_0002
2" Purification: Again recrystallization the obtained compound using methanol. Purity of the obtained compound by HPLC: 99.31 %.
Figure imgf000025_0003
3rd Purification: The obtained compound was dissolved in acetone (300 ml) at 55-60°C. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 56 gm. Particle Size of the obtained compound: D( I 0): 5.59 μπι, D(50): 1 9.7 μηι & D(90): 50.6 μm. SSA of the obtained compound: 0.40 m2/g.
Purity by HPLC: 99.69%.
Figure imgf000026_0001
The other impurities i.e., Diamide Impurity, Tridecano Impurity, Tetradecano Impurity, Decano Impurity & Undecano Impurity are well below 0.05%.
Particle Size of the obtained compound: D( 10): 5.59 μηι, D(50): 19.7 μm & D(90): 50.6 μτη. SSA of the obtained compound: 0.4 m2/g.
Example-13: Purification of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l-yl]butoxy}-2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate compound of formula-1 using acetone:
Dissolved 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}-2-oxo-3,4-dihydro-2H- quinolin- l -yl)methyl dodecanoate (2.5 kgs) in acetone (22.5 liters) at 35-40°C. Filtered the reaction mixture on hyflow bed and washed with acetone. The obtained filtrate was stirred for 30 minutes at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get pure the title compound.
Yield: 2. 1 kg. Purity by HPLC: 99.64%, Aripiprazole impurity: 0.04%, N-Hydroxy methyl impurity: 0.03%, total impurities: 0.36%. SSA of the obtained compound: 0.34 m2/g.
Example-14: Purification of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l-yl] butoxy}-2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate using methanol :
Dissolved . 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}-2-oxo-3,4-dihydro-2H- quinolin- l -yl)methyl dodecanoate (100 gms) in methanol (1500 ml) at 60-65°C. Filtered the reaction mixture. The obtained filtrate was cooled to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound.
Yield: 85 gm. Purity by HPLC: 99.73%, Aripiprazole impurity: 0.04%, N-Hydroxy methyl impurity: 0.06%, HIUI : 0.03%. Particle Size of the obtained compound: D( I 0): 3.04 μτη, D(50): 21 .16 μm & D(90): 75.53 μm. SSA of the obtained compound: 0.36 m2/g. PXRD of the obtained compound is shown in figure-2 & DSC histogram is shown in figure-3.
Example-15: Purification of 7-{4-[4-(2,3-dichlorophenyI)-piperazin-l-yl]butoxy}-2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate using ethyl acetate:
Dissolved 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}-2-oxo-3,4-dihydro-2H- quinolin- l -yl)methyl dodecanoate (5 gms) in ethyl acetate ( 150 ml) at 60-65°C. Filtered the reaction mixture through hyflow bed. The obtained filtrate was cooled to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 4.1 gm. Purity by HPLC: 99.67%, Aripiprazole impurity: 0.07%, N-Hydroxy methyl impurity: 0.05%, HIUI : 0.04%.
Example-16: Purification of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l-yl]butoxy}-2-oxo- 3,4-dihydro-2H-quinolin-l-yl)methyl dodecanoate using isopropanol:
Dissolved 7-{4-[4-(2,3-dichlorophenyl)-piperazin- 1 -yl]butoxy}-2-oxo-3,4-dihydro-2H- quinolin- l -yl)methyl dodecanoate (5 gms) in isopropanol (750 ml) at 65-70°C. Filtered the reaction mixture through hyflow bed. The obtained filtrate was cooled to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 4.2 gm. Purity by HPLC: 99.57%, Aripiprazole impurity: 0.05%, N-Hydroxy methyl impurity: 0.07%, HIUI: 0.05%.
Example-17: Purification of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-l-yl]butoxy}-2-oxo- 3,4-dihydro-2H-quinoIin-l-yl)methyl dodecanoate using acetonitrile:
Dissolved 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}-2-oxo-3,4-dihydro-2H- quinolin- l -yl)methyl dodecanoate ( 10 gms) in acetonitrile ( 1 50 ml) at 60-65°C. Filtered the reaction mixture through hyflow bed. The obtained filtrate was cooled to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound.
Yield: 5.8 gm. Purity by HPLC: 99.71 %, Aripiprazole impurity: 0.02%, N-Hydroxy methyl impurity: 0.03%, HIUI: 0.12%.

Claims

We Claims:
1 . A process for the preparation of pure 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l - yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyl dodecanoate compound of formula- 1
Figure imgf000028_0001
comprising the following steps:
a) dissolving the compound of formula- 1 in a suitable solvent at a suitable temperature, b) optionally filtering the reaction mixture,
c) cooling the reaction mixture,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and optionally washing with solvent,
f) optionally repeating the steps-a) to e) to provide the pure compound of formula- 1 .
2.
The process according to claim 1 , wherein in step-a) the suitable solvent is selected from alcohol solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents or mixtures thereof; preferably alcohol solvents, ketone solvents; the suitable temperature is 25°C to reflux temperature of the solvent used;
in step-c) cooling the reaction mixture refers to the temperature range about - 10°C to 30°C. 3. A process for the preparation of pure 7-{4-[4-(2,
3-dichlorophenyl)-piperazin- l - yl]butoxy}-2-oxo-3,4-dihydro-2H-quinolin- l -yl)methyl dodecanoate compound of formula- 1 comprising the following steps:
a) dissolving the compound of formula- 1 in methanol at 55-65°C,
b) filtering the reaction mixture,
c) cooling the reaction mixture,
d) stirring the reaction mixture, e) filtering the solid obtained in step-d) and washing the solid with methanol to provide the pure compound of formula- l .
4. A process for the preparation of pure compound of formula- l comprising the following steps:
a) dissolving the compound of formula- l in acetone at 55-65°C,
b) filtering the reaction mixture,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with acetone to provide the pure compound of formula- l .
5. A process for the preparation of pure compound of formula- l comprising the following steps:
a) dissolving the compound of formula- l in acetone at 35-45°C,
b) optionally filtering the reaction mixture,
c) cooling the reaction mixture to 0-5°C,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with acetone to provide the pure compound of formula- l .
6. A process for the preparation of pure compound of formula-l comprising the following steps:
a) dissolving the compound of formula- l in acetonirile at 55-65°C,
b) optionally filtering the reaction mixture,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with acetonirile to provide the pure compound of formula- 1 .
7. A process for the preparation of pure compound of formula- 1 comprising the following steps:
a) dissolving the compound of formula- 1 in isopropanol at 55-65°C,
b) optionally filtering the reaction mixture,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with isopropanol to provide the pure compound of formula- 1 ,
8. A process for the preparation of pure compound of formula-1 comprising the following steps:
a) dissolving the compound of formula- 1 in ethyl acetate at 55-65°C,
b) optionally filtering the reaction mixture,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with ethyl acetate to provide the pure compound of formula- 1.
9. A process for preparation of pure 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}- 2-oxo-3,4-dihydro-2H-quinolin- ] -yl)methyl dodecanoate compound of formula- 1 ,
. comprising:
a) dissolving the compound of formula- 1 in a first solvent at a suitable temperature, b) optionally filtering the reaction mixture,
c) cooling the reaction mixture,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with a first solvent,
f) optionally repeating the process from steps-a) to e) to get the compound of formula- 1 , g) recrystallizing the compound obtained in step-e) or step-f) using a second solvent to provide pure compound of formula- 1 .
10. The process according to claim 9, wherein in steps-a) and e) the first solvent is selected from alcohol solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents or mixtures thereof; preferably alcohol solvents; in step-a) the suitable temperature is 25°C to reflux temperature of the solvent used;
in step-c) cooling the reaction mixture refers to the temperature range about - 10°C to 30°C;
in step-g) the second solvent is selected from ketone solvents, preferably acetone.
1 1. A process for preparation of pure 7-{4-[4-(2,3.-dichlorophenyl)-piperazin- l -yl]butoxy}- 2-oxo-3,4-dihydro-2H-quinolin-l -yl)methyl dodecanoate compound of formula- ! , comprising:
a) dissolving the compound of formula- 1 in methanol at 55-65°C,
b) filtering the reaction mixture,
c) cooling the reaction mixture to 25-30°C,
d) stirring the reaction mixture,
e) filtering the solid obtained in step-d) and washing with methanol,
f) repeating the process from steps-a) to e) to get the compound of formula- 1 , g) recrystallizing the compound obtained in step-f) using acetone to provide pure compound of formula- 1.
12. A process for the preparation of the compound of formula- 1 having specific surface area less than 0.5 m2/g
Figure imgf000031_0001
comprising the following step:
a) treating the lauric acid compound of formula-3 with chlorinating agent in a suitable solvent,
Figure imgf000032_0003
b) reacting the acid chloride obtained in step-a) in-situ with paraformaldehyde in presence of a catalyst or base provide the compound of formu!a-4a,
Figure imgf000032_0001
c) optionally purifying the obtained compound using a suitable solvent,
d) reacting the compound of formula-4a with aripiprazole compound of formula-2
Figure imgf000032_0002
in presence of a suitable base in a suitable solvent to provide the compound of formula- 1 ,
e) optionally purifying the compound of formula- 1 using a suitable solvent.
13. The process according to claim 12, wherein in step a) the chlorinating agent is selected from thionyl chloride, oxalyl chloride, sulfuryl chloride, phosphorous oxychloride, carbon tetra chloride, phosphorous trichloride, phosphorous pentachloride, N- chlorosuccinamide (NCS);
In step b) the suitable catalyst is lewis acid, preferably Zinc chloride and base is selected from organic or inorganic bases;
In step d) the suitable base is selected from organic or inorganic bases;
In steps a) to e) the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents, polar solvents or mixtures thereof.
14. A process for the preparation of the compound of formula- 1 having specific surface area less than 0.5 m2/g comprising the following step: a) treating the lauric acid compound of formula-3 with thionyl chloride in dichloromethane,
b) reacting the acid chloride obtained in step-a) in-situ with paraformaldehyde in presence of zinc chloride provide chloromethyl laurate compound of formula-4a, c) purifying the obtained compound using cyclohexane,
d) reacting the compound of formula-4a with aripiprazole compound of formula-2 in presence of potassium tertiary butoxide and dimethylaminopyridine in tetrahydrofuran to provide the compound of formula- 1 ,
e) purifying the compound of formula- 1 using methanol,
f) optionally further recrystallizing the compound in acetone to provide the compound of formula- 1 having specific surface area less than 0.5 m2/g.
15. A process for the preparation of the compound of formula- 1 comprising the follow step:
a) reacting aripiprazole c mpound of formula-2
Figure imgf000033_0001
with formaldehyde or paraformaldehyde in presence of base in a suitable solvent to provide the compound of formula-7,
Figure imgf000033_0002
b) reacting the compound of formula-7 with lauric acid compound of formula-3 presence of a suitable coupling agent in a suitable solvent to provide the compound formula- 1 ,
c) optionally purifying the compound of formula- 1 using a suitable solvent.
16. The process according to claim 15, wherein in step a) the suitable base is selected from organic or inorganic bases;
In step b) the suitable coupling agent is selected form Ν,Ν'-dicyclohexylcarbodiimide, Ν,Ν'-diisopropylcarbodiimide, carbonyldiimidazole, I -ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, 0-(7-aza-benzotriazole-l -yl)- Ν,Ν,Ν',Ν'-tetramethyl uronium hexafluoro phosphate, alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate, thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride, benzotriazol- l -yl-oxytripyrrolidino phosphonium hexafluorophosphate, methane sulfonyl chloride and the like; optionally in combination with l -hydroxy-7-azatriazole, l -hydroxybenzotriazole, 1 -hydroxy- 1 H- l ,2,3-triazole-4-carboxylate, 0-(benzotriazol- l -yl)-N,N,N\NMetramethyluronium tetrafluoroborate, · N-hydroxysuccinamide, N-hydroxysulfosuccinimide, 4- dimethylarninopyridine.
In steps a) to c) the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents, polar solvents or mixtures thereof.
17. A process for the preparation of the compound of formula- 1 comprising the following step:
a) reacting aripiprazole compound of formula-2 with formaldehyde in presence of triethyl amine in dimethyl formamide to provide the compound of formula-7, b) reacting the compound of formula-7 with lauric acid compound of formula-3 in presence of a Ν,Ν'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane to provide the compound of formula- 1 ,
c) purifying the compound of formula-1 using methanol.
18. The process according to any of preceding claims, the compound of formula- 1 having purity by HPLC greater than 99%, preferably 99.5%.
19. The process according to any of preceding claims, the compound of formula- 1 having Aripiprazole impurity less than 0.1 %, preferably less than 0.05% by HPLC.
20. The process according to any of preceding claims, the compound of formula- 1 having N- Hydroxymethyl impurity less than 0.15%, preferably less than 0.1 % by HPLC.
21. The crystalline 7-{4-[4-(2,3-dichlorophenyl)-piperazin- l -yl]butoxy}-2-oxo-3,4-dihydro- 2H-quinolin- l -yl)methyl dodecanoate compound of formula-1 having specific surface area less than 0.5 m2/g.
22. The compound of formula- 1 obtained according to any of preceding claims having particle size D(90) < 150 μm.
23. A process for the purification of lauric acid compound of formula-3 comprising the following steps:
a) dissolving lauric acid compound of formula-3 in a suitable solvent at a suitable temperature,
b) cooling the reaction mixture to a suitable temperature,
c) filtering the precipitated solid to provide pure lauric acid compound of formula-3, Wherein in step-a) the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvent, chloro solvents, polar aprotic solvents, ketone solvents, polar solvents or mixtures thereof.
in step-b) the suitable temperature is about -5°C to 30°C.
24. A process for the purification of lauric acid compound of formula-3 comprising the following steps:
a) dissolving lauric acid compound of formula-3 in aqueous acetone at 55-65°C, b) cooling the reaction mixture to -5°C to 30°C,
c) filtering the obtained solid to provide pure lauric acid compound of formula-3.
25. The process according to any of preceding claims, lauric acid compound of formula-3 having purity by GC greater than 99%, preferably 99.5%.
26. The compound of formula- 1 obtained according to any of preceding claims is characterized by its powder X-Ray diffraction pattern having substantially in accordance with that shown in figure-2.
27. The compound of formula-] of claim 26, is further characterized by its powder X-Ray diffraction pattern having peaks at 6.9, 13.9, 14.8, 15.2, 18.2, 20.1 , 21 ,6, 22.1 , 23.9 & 25.0 ± 0.2 degrees of 2-theta.
28. The compound of formula-1 according to any of preceding claims is having the endotherm at 84°C±3°C in its differential scanning calorimetric (DSC) thermogram.
29. Use of the compound of formula- 1 obtained according to any of preceding claims in the preparation of pharmaceutical composition.
****** ***
PCT/IN2017/000138 2016-12-07 2017-12-06 Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate Ceased WO2018104953A1 (en)

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CN110790704A (en) * 2018-08-01 2020-02-14 北京万全德众医药生物技术有限公司 Preparation method of lauroyl aripiprazole
CN110790703A (en) * 2018-08-01 2020-02-14 北京万全德众医药生物技术有限公司 Preparation method of lauroyl aripiprazole
WO2021009087A1 (en) 2019-07-12 2021-01-21 Interquim, S.A. Process for the preparation of aripiprazole lauroxil
CN114685367A (en) * 2020-12-30 2022-07-01 上海现代药物制剂工程研究中心有限公司 Preparation method of lauroyloxymethyl aripiprazole
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CN111315722A (en) * 2017-07-28 2020-06-19 因特奎姆私人控股公司 Process for preparing lauroyl aripiprazole
WO2019020821A1 (en) * 2017-07-28 2019-01-31 Interquim, S.A. Process for the preparation of aripiprazole lauroxil
US12172979B2 (en) 2017-07-28 2024-12-24 Interquim, S.A. Process for the preparation of aripiprazole lauroxil
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CN110790704A (en) * 2018-08-01 2020-02-14 北京万全德众医药生物技术有限公司 Preparation method of lauroyl aripiprazole
CN109096249B (en) * 2018-08-13 2021-04-09 中国科学院兰州化学物理研究所 A kind of synthetic method of aripiprazole
CN109096249A (en) * 2018-08-13 2018-12-28 中国科学院兰州化学物理研究所 A kind of synthetic method of Aripiprazole
WO2021009087A1 (en) 2019-07-12 2021-01-21 Interquim, S.A. Process for the preparation of aripiprazole lauroxil
JP2022543990A (en) * 2019-07-12 2022-10-17 インタークイム，エス．エー． Process for the preparation of aripiprazole lauroxyl
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CN114685367B (en) * 2020-12-30 2024-03-01 上海现代药物制剂工程研究中心有限公司 Preparation method of lauroyl oxymethyl aripiprazole
CN120481419A (en) * 2025-07-15 2025-08-15 群力塑胶有限公司 BOPP film with low-temperature heat sealing performance and preparation method thereof

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