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WO2019211868A1 - Procédé amélioré pour la préparation de chlorhydrate de 9-éthyl-6,6-diméthyl-8-[4-(morpholin-4-yl) pipéridin-1-yl]-11-oxo-6,11-dihydro-5h-benzo[b]carbazole-3-carbonitrile - Google Patents

Procédé amélioré pour la préparation de chlorhydrate de 9-éthyl-6,6-diméthyl-8-[4-(morpholin-4-yl) pipéridin-1-yl]-11-oxo-6,11-dihydro-5h-benzo[b]carbazole-3-carbonitrile Download PDF

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WO2019211868A1
WO2019211868A1 PCT/IN2019/050347 IN2019050347W WO2019211868A1 WO 2019211868 A1 WO2019211868 A1 WO 2019211868A1 IN 2019050347 W IN2019050347 W IN 2019050347W WO 2019211868 A1 WO2019211868 A1 WO 2019211868A1
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formula
solvents
compound
alectinib
solvent
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Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Venkata Panakala Rao Gogulapati
Srinivas Reddy Gade
Bala Narsaiah Eppaturi
Malleswara Reddy Jakku
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel process for the preparation of Alectinib hydrochloride compound of formula- la, represented by the following structural formula:
  • the present invention provides an improved process for the preparation of tert-butyl- 4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate having the following structural formula which is useful in the preparation of Alectinib and its pharmaceutical acceptable salts.
  • Alectinib hydrochloride chemically known as 9-ethyl-6,6-dimethyl-8-[4-(morpholin- 4-yl)piperidin- 1 -yl] - 11 -oxo-6, 11 -dihydro-5H-benzo[b] carbazole-3-carbonitrile hydrochloride is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC).
  • Alectinib hydrochloride was approved by U.S. Food and Drug Administration in 2015 for the treatment of patients with metastatic non-small cell lung cancer.
  • ALESENSA has been approved by the Europe commission for the treatment of lung cancer.
  • ETS Patent No. 9126931 B2 first discloses Alectinib or its salts thereof and the process for its preparation.
  • WO2015/163447 Al discloses crystalline form-I, form-II and form-III of Alectinib hydrochloride.
  • Alectinib is purified by cumbersome, tedious workups and column chromatography which are not feasible on commercial scale.
  • the present inventors have developed simple process for the preparation of Alectinib hydrochloride which can be easily scalable on industrial level and provided Alectinib hydrochloride with high yield and purity..
  • First embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1 or salt thereof.
  • Second embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1 or salt thereof.
  • Third embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1 or salt thereof.
  • Fourth embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1 or salt thereof.
  • Fifth embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1 or salt thereof.
  • Sixth embodiment of the present invention provides novel intermediate compounds which are useful in the preparation of compound of formula- 1.
  • Seventh embodiment of the present invention provides an improved process for the preparation of 7-methoxy-3,4-dihydronaphthalen-2(lH)-one.
  • Eighth embodiment of the present invention provides an improved process for the preparation of 7-methoxy-3,4-dihydronaphthalen-2(lH)-one.
  • Ninth embodiment of the present invention provides an improved process for the preparation of 6-bromo-7-methoxy- 1 , 1 -dimethyl-3, 4-dihydronaphthalen-2(lH)-one.
  • Tenth embodiment of the present invention provides an improved process for the preparation of tert-butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate compound of formula-4.
  • Eleventh embodiment of the present invention provides a process for the preparation of tert-butyl 2-(4-cyano-2-nitrophenyl)-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate compound of formula-6.
  • Twelfth embodiment of the present invention provides a process for the preparation of pure Alectinib hydrochloride.
  • Figure 1 Illustrates the PXRD pattern of Alectinib.
  • Figure 2 Illustrates the PXRD pattern of Alectinib.
  • Figure 3 Illustrates the PXRD pattern of Alectinib.
  • Figure 4 Illustrates the PXRD pattern of Alectinib.
  • suitable solvent refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene, and the like;“ether solvents” such as dimethoxy methane, tetrahydrofuran, l,3-dioxane, l,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, l,2-dimethoxy ethane and the like;“ester solvents” such as methyl acetate,
  • salts used in the present invention refers to acid addition salts selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, citric acid etc., and like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
  • organic acids such as acetic acid, maleic acid, malic acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, citric acid etc., and like.
  • 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 like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like;“alkali metal amides” such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA), sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide (LiHMDS) 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
  • phosphine ligands used in the present invention refers to phosphine ligands selected from trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropyl phosphine, tributylphosphine, tricyclohexylphosphine, trimethylphosphite, triethylphosphite, tripropylphosphite, triisopropylphosphite, tributylphosphite, tricyclohexyl phosphite, 2,2'- bis(diphenylphosphino)-l,l '-binaphthyl (BINAP), l,2-bis(dimethylphosphino)ethane, l,2-bis (diethylphosphino)ethane, 1 ,2-bis(dipropylphosphino)ethane, 1 ,2-bis(diprop
  • palladium catalyst used in the present invention refers to palladium catalyst is selected from Pd/C, PdCl 2 , Pd(OAc) 2 , (CH3CN) 2 PdCl 2 , Pd 2 (dba)i, Pd(dba) 2 , Pd(PPh3) 4 , polymer supported Pd(0) etc., and like.
  • oxidizing agent used in the present invention refer to per acids such as m- chloroperbenzoic acid, peracetic acid, and the like; and an inorganic oxidizing agent such as manganesedioxide, sodiumperiodate, hydrogen peroxide, dinitrogentetroxide, hydroperoxide, iodobenzeneacetate, t-butylhypochlorite, sulfurylchloride, potassium peroxymonosulfate, sodium hypochlorite, DDQ in presence of TEMPO, DABCO, dess-martin reagent, oxaloyl chloride in DMSO and like.
  • per acids such as m- chloroperbenzoic acid, peracetic acid, and the like
  • an inorganic oxidizing agent such as manganesedioxide, sodiumperiodate, hydrogen peroxide, dinitrogentetroxide, hydroperoxide, iodobenzeneacetate, t-butylhypochlorite
  • reducing agent used in the present invention refers to DIBAL-H, lithium aluminium hydride, sodium borohydride, lithium borohydride, NaBHiCN, sodiumboro hydride /BF3-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride and sodium borohydride/iodine etc., and like.
  • chlorinating agents include but are not limited to chlorine, hydrochloric acid, oxalyl chloride, sulfuryl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, pivaloyl chloride, antimony pentachloride, iodine trichloride, sulfur dichloride, disulfur dichloride, manganese tetrachloride and the like.
  • the term“Lewis acid” used is selected from aluminium chloride (AICI 3 ), aluminium bromide (AlBr 3 ), boron trifluroide (BF 3 ), boron trichloride (BCI 3 ), ferric chloride (FeCli), tin(IV) chloride (SnCl 4 ), calcium chloride (CaCl 2 ) and calcium chloride dihydrate (CaCl 2 - 2H 2 0) and the like.
  • AICI 3 aluminium chloride
  • AlBr 3 aluminium bromide
  • BF 3 boron trifluroide
  • BCI 3 boron trichloride
  • FeCli ferric chloride
  • tin(IV) chloride SnCl 4
  • CaCl 2 calcium chloride
  • CaCl 2 - 2H 2 0 calcium chloride dihydrate
  • brominating agent used in the present invention refers to bromine, tetra alkyl ammonium tribromide, dioxane dibromide, N-bromosuccinamide, carbon tetrabromide, phosphoroustribromide.
  • the first embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1.
  • the process of the present invention is represented schematically as follow:
  • the second embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1.
  • the third embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1.
  • the fourth embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1.
  • R C w straight or branched chail alkyl group
  • the fifth embodiment of the present invention provides a novel process for the preparation of Alectinib compound of formula- 1.
  • the sixth aspect of the present invention provides novel intermediate compounds which are useful in the preparation of compound of formula- 1 represented as follows:
  • Ri is selected from hydrogen, alkyl, hydroxyl or alkoxy groups, aryl, cycloalkyl, cyano, aminocarbonyl group, hydroxycarbonyl group, alkoxycarbonyl group, halogen, amino group and nitro group
  • R 2 is selected from aldehyde, aminocarbonyl group and alkyl halide
  • X is selected from leaving group such as halogens, alkyl boronate esters, cycloalkylboronate esters, mesyloxy, acyloxy, tosyloxy, benzyloxy, trifluoromethylsulfonyl oxy, nonafluorobutylsulfonyloxy, (4-bromophenyl)sulfonyloxy, (4-nitrophenyl)sulfonyloxy, (2-nitrophenyl)sulfonyloxy, (4-isopropylphenyl)sulfonyloxy, (2,4,6-triis
  • the seventh embodiment of the present invention provides an improved process for the preparation of 7-methoxy-3,4-dihydronaphthalen-2(lH)-one, comprising:
  • solvent used in step-a) & step-b) is selected from alcohol solvents, ester solvents, nitrile solvents, hydrocarbon solvents, ether solvents, ketone solvents, chloro solvents, polar aprotic solvents and polar solvents like water or mixtures thereof;
  • step-b) acid is selected from hydrochloric acid.
  • the eighth embodiment of the present invention provides an improved process for the preparation of 7-methoxy-3,4-dihydronaphthalen-2(lH)-one compound of formula-24,
  • the ninth embodiment of the present invention provides an improved process for the preparation of 6-bromo-7-methoxy-l , 1 -dimethyl-3, 4-dihydronaphthalen-2(lH)-one compound of formula-26, comprising:
  • solvent used in step-a) to step-d) is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
  • the base used in step-c) is selected from organic or inorganic base
  • acid is hydrochloric acid
  • the brominating agent used in step-d) is selected from bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N-bromosuccinamide, carbontetrabromide, phosphorous tribromide.
  • the present invention provides an improved process for the preparation of tert-butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate compound of formula-28, comprising reacting 3-(tert-butoxy)-3-oxopropanoic acid compound of formula- 27 with 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid compound of formula-2 in the presence of magnesium metal alkoxide, base and a coupling agent in a solvent to provide tert- butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate compound of formula-28.
  • the base is selected form organic or inorganic base;
  • the solvent is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
  • the coupling agent is selected from N,N'- dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), carbonyl diimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.
  • HC1 0-(7-aza- benzotriazole-l-yl)-N,N,N',N'-tetramethyluroniumhexafluoro phosphate
  • alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, pivalyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol- l-yl-oxytripyrrolidinophosphoniumhexafluorophosphate (PyBOP), methanesulfonylchloride and the like; optionally in combination with l-hydroxy-7-azatriazole (HO At), 1 -hydroxy benzotriazole (HOBt), l-hydroxy-aza
  • the magnesium alkoxide is selected from magnesium isopropoxide or magnesium isobutoxide or magnesium tert-butoxide.
  • US9440922 B2 discloses process for the preparation of compound of formula-28 by reacting compound of formula-2 with compound of formula-27 in the presence of magnesium chloride and CDI to provide compound of formula-28 with low yield and purity.
  • magnesium chloride is moisture sensitive and decreases the rate of the reaction by deactivating the CDI. This results in the incompletion of reaction and provides compound of formla-28 with low yield and hence the said process is not recommendable for commercial scale production.
  • inventors of the present invention have overcome the aforementioned problem by replacing magnesium chloride with magnesium alkoxide such as magnesium isopropoxide or magnesium tert-butoxide. By replacement of the reagent it is observed that rate of the reaction increased and completed in less span of time and provided compound of formula-28 with enhanced yield.
  • magnesium alkoxide such as magnesium isopropoxide or magnesium tert-butoxide.
  • the present invention provides a process for the preparation of tert-butyl 2-(4-cyano-2-nitrophenyl)-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate compound of formula-30, comprising of reacting tert-butyl-4-(4-ethyl-3-iodophenyl)-4- methyl-3-oxopentanoate compound of formula-28 with 4-chloro-3-nitrobenzonitrile compound of formula-29 in the presence of a base in a solvent to provide tert-butyl 2-(4- cyano-2-nitrophenyl)-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate compound of formula-30.
  • base is selected from organic or inorganic base
  • solvent is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
  • the present invention provides a process for the preparation of pure Alectinib hydrochloride, comprising:
  • base used in step-f) is selected from organic or inorganic base
  • solvent used in step-a) to step-h) is selected from alcohol solvents, ether solvents, chloro solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar aprotic solvents and polar solvents like water or mixture thereof.
  • purifying compound of formula-31 comprising dissolving compound of formula-31 in a solvent selected from alcohol solvents, ester solvents, chloro solvents, nitrile solvents, ketone solvents, ether solvents and hydrocarbon solvents and adding anti-solvent to a solution of compound of formula-31 and isolating pure compound of formula-31.
  • anti-solvent is water
  • a process for the purification of Alectinib comprising dissolving or suspending Alectinib in a solvent selected from polar aprotic solvents, ketone solvent and water or mixture thereof and isolating pure Alectinib.
  • a process for the purification of Alectinib comprising dissolving or suspending Alectinib in a mixture of solvents selected from polar aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and ketone solvents such as acetone, methyl ethyl ketone, methyl isobutylketone and isolating pure Alectinib.
  • polar aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP) and ketone solvents such as acetone, methyl ethyl ketone, methyl isobutylketone and isolating pure Alectinib.
  • solvents selected from polar aprotic solvents such as dimethyl acetamide (DMA), di
  • a process for the purification of Alectinib comprising: dissolving or suspending Alectinib in a mixture of N-methylpyrrolidone and acetone and isolating pure Alectinib.
  • step-g the PXRD pattern of Alectinib obtained in step-g) is depicted in figure-3 and figure-4.
  • Alectinib obtained according to the present invention having“Amide impurity” less than 0.02% as measured by HPLC.
  • isolating Alectinib can be carried out by any methods known in the art or can be isolated by employing any of the techniques, but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • the present invention provides Alectinib hydrochloride having purity at least about 95%; preferably of at least about 98%; more preferably of at least about 99%; most preferably of at least about 99.9% as measured by HPLC.
  • Alectinib hydrochloride obtained according to the present invention having 6-cyano-2- (2-(4-ethyl-3-(4-morpholinopiperidin- 1 -yl)phenyl)propan-2-yl)- lH-indole-3-carboxylic acid [acid impurity] ; 4-( 1 -(3-cyano-9-ethyl-6, 6-dimethyl- 11 -oxo-6, 11 -dihydro-5H-benzo[b] carbazol-8-yl)piperidin-4-yl)morpholine 4-oxide [N-Oxide impurity]; 2-(2-(4-ethyl-3-(4- morpholinopiperidin- 1 -yl)phenyl)propan-2-yl)- 1 H-indole-6-carbonitrile [de-carboxylate impurity]; and tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morph
  • the present invention provides Alectinib hydrochloride having particle size distribution of D 90 less than about 150 pm, preferably less than about 100 pm; more preferably less than about 50 pm.
  • Alectinib hydrochloride prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • compositions comprising compound of formula- 1 or salts thereof of the present invention.
  • pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.
  • the process of the presence invention is schematically represented as follows:
  • PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
  • 2,7-dimethoxynaphthalene (5.0 gms) was added to a mixture of sodium silica gel (8.55 gms) and t-butanol (150 ml) at 25-30°C under nitrogen atmosphere and stirred for 2 1 ⁇ 2 hours at the same temperature. Cooled the reaction mixture to 0-5°C. Chilled water (50 ml) was slowly added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C. Ethyl acetate (25 ml) was added to reaction mixture at 25-30°C. Filtered the reaction mixture through hyflow bed and washed the bed with ethyl acetate. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Distilled off the solvent from the organic layer under reduced pressure to get the title compound.
  • Acetone (5 ml) was added to 2,7-dimethoxy-l,4-dihydronaphthalene (0.5 gms) at 25- 30°C and stirred for 10 minutes at the same temperature.
  • 5% aqueous hydrochloric acid was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature.
  • Water and dichloromethane were added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer using dichloromethane. Distilled off the solvent from the organic layer under reduced pressure to get the title compound. Yield: 0.42 gms.
  • Methyl iodide (6.02 gms) and tetrabutyl ammonium hydrogen sulfate (0.65 gm) were added to a mixture of 7-methoxy-3,4-dihydronaphthalen-2(lH)-one (3.4 gm) and tetrahydrofuran (10.2 ml) at 25-30°C.
  • Aqueous potassium hydroxide solution was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 10 minutes at the same temperature.
  • Methyl iodide was added to the reaction mixture at 25-30°C.
  • Example-4 Preparation of 6-bromo-7-methoxy-l,l-dimethyl-3,4-dihydronaphthalen- 2(lH)-one N-bromosuccinamide (0.38 gms) was slowly added to 7-methoxy-l,l-dimethyl-3,4- dihydronaphthalen-2(lH)-one (0.4 gms) and acetonitrile (8.0 ml) at 25-30°C and stirred for 2 hours at the same temperature. Distilled off the solvent from the reaction mixture under reduced pressure. Petroleum ether (20 ml) was added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the solid, washed with petroleum ether and dried to get the title compound. Yield: 0.4 gms.
  • Magnesium chloride (32.9 gms) was added to the mixture of toluene (1000 ml) and isopropanol (1000 ml) at 25-30°C. Heated the reaction mixture to 80-85°C and distilled off the solvent azeotropically. Further, raised the temperature to l05-H0°C and distilled off the solvent completely azeotropically. Cooled the reaction mixture to 60-65 °C and co-distilled with toluene. Further cooled the reaction mixture to 25-30°C. 1 ,2-dimethoxyethane (400 ml) was added to the reaction mixture.
  • Reaction mixture 2 was added to reaction mixture 1 at 25- 30°C. Heated the reaction mixture to 65-70°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 20-25°C. Isopropyl acetate (300 ml) and n-Heptane (300 ml) were added to the reaction mixture. 20% aqueous hydrochloric acid solution and stirred for 45 minutes at 25-30°C. Both the organic and aqueous layers were separated. Organic layer was washed with 4% sodium hydroxide solution and then with 15% sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 100 gms.
  • Example-6 Preparation of tert-butyl 2-(4-cyano-2-nitrophenyl)-4-(4-ethyl-3-iodo phenyl)-4-methyl-3-oxopentanoate
  • Dimethylformamide 400 ml was added to tert-butyl-4-(4-ethyl-3-iodophenyl)-4- methyl-3 -oxopentanoate obtained according to example-5 at 25-30°C.
  • Cesium carbonate 234.5 gms was added to the reaction mixture at 25-30°C.
  • 4-chloro-3-nitrobenzonitrile 53.93 gms in dimethylformamide (150 ml) was added to the reaction mixture. Heated the reaction mixture to 45-50°C and stirred for 8 hours at the same temperature. Tetrahydrofuran and ethyl acetate was added to the reaction mixture.
  • Example-7 Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)- lH-indole-3-carboxylate:
  • Example-8 Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-l- yl)phenyl)propan-2-yl)-lH-indole-3-carboxylate hydrochloride: Toluene (700) was added to 4-(piperidin-4-yl)morpholine (66.0 gms) at 25-30°C. Distilled off the solvent from the reaction mixture azeotropically.
  • Example-9 Preparation of 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-l-yl) phenyl)propan-2-yl)-lH-indole-3-carboxylic acid:
  • Trimethylsilyl chloride (36.62 gms) was added to a pre-cooled mixture of trifluoro ethanol (500 ml) and tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-l-yl)phenyl) propan-2-yl)-lH-indole-3-carboxylate hydrochloride (100 gms) at 0-5°C and stirred for 6 hours at the same temperature.
  • Acetone 400 ml
  • 4% aqueous sodium hydroxide solution and followed by 10% dipotassium hydrogen phosphate solution was added to the reaction mixture at 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetone and water and dried to get the title compound. Yield: 77 gms; M.R: l 80-l 85°C
  • Example-10 Preparation of Alectinib: A mixture of 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-l-yl)phenyl)propan-2- yl)-lH-indole-3-carboxylic acid (100 gms) and dimethyl acetamide (1800 ml) were stirred for 15 minutes at 25-30°C. Acetic anhydride (53.22 ml) and diisopropylethylamine (233.7 ml) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 85-90°C and stirred for 5 hours. Cooled the reaction mixture to 25-30°C.
  • Alectinib obtained in example-lO was added to N-methylpyrrolidone (500 ml) and acetone (500 ml) at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filtered the solid to provide the title compound. Yield: 100 gms.
  • the PXRD pattern of the obtained compound is matching with the PXRD pattern of Alectinib disclosed in Figure-l of IPCOM000250294 D.
  • Alectinib 100 gms was added to methyl ethyl ketone (1000 ml) and stirred at 25-30°C for 10 minutes. Hydrose solution (hydrose (0.5 gms) and water (400 ml)) and followed by acetic acid (300 ml) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with methyl ethyl ketone. The obtained filtrate was heated to 55-60°C.
  • Ethanolic hydrochloride solution (hydrochloric acid (40 ml), water (160 ml) and ethanol (2200 ml)) was added to the reaction mixture at 55-60°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours. Filtered the precipitated solid, washed with ethanol and dried to get the title compound.
  • a mixture of toluene (450 lts), isopropanol (450 lts) and magnesium chloride (14.85 kgs) were heated to 85-90°C and stirred for 45 minutes at the same temperature under nitrogen atmosphere. Distilled off the solvent from the reaction mixture. Further raised the temperature of the reaction mixture to H0-ll5°C and distilled off the solvent from the reaction mixture and then co-distilled with toluene. Cooled the reaction mixture to 25-30°C. l,2-Dimethoxy ethane (180 lts) and 3-(tert-butoxy)-3-oxopropanoic acid (36.0 kgs) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature.
  • Triethyl amine (98.6 lts) was slowly added to the reaction mixture at 25-30°C and stirred for 5 hours at the same temperature (reaction mixture 1).
  • l,2-Dimethoxyethane (135 lts) was added to 2-(4- ethyl-3-iodophenyl)-2-methylpropanoic acid (45.0 kgs) at 25-30°C and stirred for 15 minutes at the same temperature.
  • Carbonyldiimidazole (25.26 kgs) was added in three lots to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature (reaction mixture 2).
  • Reaction mixture 2 was slowly added to the reaction mixture 1 at 25-30°C.
  • Aqueous sodium chloride was added to the organic layer at 20-25°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure. Dimethylformamide (180 lts) and caesium carbonate (105.75 kgs) was added to the obtained compound at 25-30°C. Dimethylformamide (67.5 lts) and 4-chloro-3-nitrobenzonitrile (24.30 kgs) was added to the reaction mixture at 25-30°C. Raised the temperature of the reaction mixture to 40-45°C and stirred for 8 hours at the same temperature. Cooled the reaction mixture to 25-30°C.
  • Example-15 Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)- lH-indole-3-carboxylate
  • Tetrahydrofuran (330 lts) and water (385 lts) was added to tert-butyl 2-(4-cyano-2- nitrophenyl)-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate (55.0 kgs) at 25-30°C and stirred for 10 minutes at the same temperature.
  • Sodium hydrosulfite (85.25 kgs) in five lots was added to the reaction mixture at 25-30°C and stirred for 5 hours at the same temperature.
  • Ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature.
  • Both the organic and aqueous layers were separated and extracted the aqueous layer using ethyl acetate. Combined the organic layer and washed with aqueous sodium chloride solution. Aqueous hydrochloric acid solution was added to the organic layer at 25-30°C and stirred for 1 hour at the same temperature. Aqueous sodium hydroxide solution was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent from the organic layer under reduced pressure and then co-distilled with isopropanol. To the obtained compound, isopropanol (115.5 lts) was added at 25-30°C and stirred for 10 minutes at the same temperature.
  • Example-16 Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin- l-yl)phenyl)propan-2-yl)-lH-indole-3-carboxylate hydrochloride
  • Toluene (280 lts) was added to 4-(piperidin-4-yl)morpholine (26.40 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to H0-l l5°C and collect the water azeotropically and distilled off the solvent under reduced pressure. Dimethoxyethane (200 lts) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature.
  • Tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodo phenyl)propan-2- yl)-lH-indole-3-carboxylate (40.0 kgs) was added to the reaction mixture.
  • Aqueous sodium chloride solution was added to the organic layer and stirred for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated. Distilled off the solvent completely from the organic layer under reduced pressure. Dimethoxyethane (200 lts) and water (4.0 lts) was added to the obtained compound at 25-30°C and stirred for 15 minutes at the same temperature. N-acetyl cysteine (1.28 kgs) was added to the reaction mixture. Raised the temperature of the reaction mixture to 45-50°C and stirred for 1 hour at the same temperature. Filtered the reaction mixture through hyflow bed and washed the bed with dimethoxyethane. Distilled off the solvent from the filtrate under reduced pressure.
  • Acetone 400 lts was added to the obtained compound.
  • Pyridine 5.0 kgs was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to l0-l5°C.
  • Hydrochloric acid 5.0 lts was added to the reaction mixture at 10-15°C and stirred for 20 minutes at the same temperature.
  • Ethanol 8.0 lts
  • acetone 80 lts was added to the reaction mixture at l0-l5°C and stirred for 10 minutes at the same temperature. Filtered the solid and pyridine was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid, washed with acetone and dried to get the title compound. Yield 35.20 kgs.
  • Example-17 Preparation of 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-l-yl) phenyl)propan-2-yl)-lH-indole-3-carboxylic acid
  • Trifluoroethanol 150 lts is added to tert-butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpho linopiperidin-l-yl)phenyl)propan-2-yl)-lH-indole-3-carboxylate hydrochloride (30 kgs) at 25- 30°C and stirred for 10 minutes at the same temperature. Cooled the reaction mixture to 0- 5°C. Trimethylsilylchloride (11.10 kgs) was slowly added to the reaction mixture at 0-5°C and stirred for 5 hours at the same temperature. Acetone was added to the reaction mixture. Aqueous sodium hydroxide solution was slowly added to the reaction mixture.
  • Methyl ethyl ketone (110 lts) was added to Alectinib (11.50 kgs) at 25-30°C and stirred for 10 minutes at the same temperature.
  • Aqueous hydrose solution was added to the reaction mixture.
  • Acetic acid (34.5 lts) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture. Heated the obtained filtrate to 55-60°C.
  • a mixture of water (18.4 lts), ethanol (253 lts) and hydrochloric acid (4.6 lts) was slowly added to the reaction mixture at 55-60°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with ethanol and dried to get the title compound. Yield: 10.75 kgs.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau procédé de préparation du composé de chlorhydrate de 9-éthyl-6,6-diméthyl-8-[4-(morpholin-4-yl)pipéridin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile de formule-1a, représenté par la formule structurale suivante : La présente invention concerne également un procédé amélioré pour la préparation de tert-butyl-4-(4-éthyl-3-iodophényl)-4-méthyl-3-oxopentanoate ayant la formule structurale suivante qui est utile dans la préparation d'alectinib et de ses sels pharmaceutiquement acceptables.
PCT/IN2019/050347 2018-04-30 2019-04-30 Procédé amélioré pour la préparation de chlorhydrate de 9-éthyl-6,6-diméthyl-8-[4-(morpholin-4-yl) pipéridin-1-yl]-11-oxo-6,11-dihydro-5h-benzo[b]carbazole-3-carbonitrile Ceased WO2019211868A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112028874A (zh) * 2020-09-10 2020-12-04 苏州富德兆丰生化科技有限公司 艾立替尼的合成方法
US11014919B2 (en) 2018-12-07 2021-05-25 Fresenius Kabi Ipsum S.R.L. Process for the preparation of alectinib
US11098037B2 (en) 2017-07-05 2021-08-24 Fresenius Kabi Oncology Ltd. Process for preparing alectinib or a pharmaceutically acceptable salt thereof
CN115677659A (zh) * 2022-10-11 2023-02-03 枣庄市润安制药新材料有限公司 一种阿雷替尼的制备方法
CN117024410A (zh) * 2023-08-15 2023-11-10 上海药坦药物研究开发有限公司 一种艾乐替尼中间体及其制备方法
WO2025067412A1 (fr) * 2023-09-28 2025-04-03 重庆博腾制药科技股份有限公司 Procédé de préparation d'un intermédiaire de médicament antitumoral

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WO2010143664A1 (fr) * 2009-06-10 2010-12-16 中外製薬株式会社 Composé tétracyclique
WO2016074532A1 (fr) * 2014-11-12 2016-05-19 苏州明锐医药科技有限公司 Procédé de préparation d'alectinib
US20160257667A1 (en) * 2015-03-02 2016-09-08 Yong Xu Synthesis of intermediates in the preparation of alk inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010143664A1 (fr) * 2009-06-10 2010-12-16 中外製薬株式会社 Composé tétracyclique
WO2016074532A1 (fr) * 2014-11-12 2016-05-19 苏州明锐医药科技有限公司 Procédé de préparation d'alectinib
US20160257667A1 (en) * 2015-03-02 2016-09-08 Yong Xu Synthesis of intermediates in the preparation of alk inhibitor

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11098037B2 (en) 2017-07-05 2021-08-24 Fresenius Kabi Oncology Ltd. Process for preparing alectinib or a pharmaceutically acceptable salt thereof
US11465999B2 (en) 2017-07-05 2022-10-11 Fresenius Kabi Oncology Ltd. Process for preparing Alectinib or a pharmaceutically acceptable salt thereof
US11014919B2 (en) 2018-12-07 2021-05-25 Fresenius Kabi Ipsum S.R.L. Process for the preparation of alectinib
CN112028874A (zh) * 2020-09-10 2020-12-04 苏州富德兆丰生化科技有限公司 艾立替尼的合成方法
CN112028874B (zh) * 2020-09-10 2021-12-24 苏州富德兆丰生化科技有限公司 艾立替尼的合成方法
CN115677659A (zh) * 2022-10-11 2023-02-03 枣庄市润安制药新材料有限公司 一种阿雷替尼的制备方法
CN115677659B (zh) * 2022-10-11 2024-03-22 枣庄市润安制药新材料有限公司 一种阿雷替尼的制备方法
CN117024410A (zh) * 2023-08-15 2023-11-10 上海药坦药物研究开发有限公司 一种艾乐替尼中间体及其制备方法
WO2025067412A1 (fr) * 2023-09-28 2025-04-03 重庆博腾制药科技股份有限公司 Procédé de préparation d'un intermédiaire de médicament antitumoral

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