SAJJA ESWARAIAH (IN)
GOGULAPATI VENKATA PANAKALA RAO (IN)
GADE SRINIVAS REDDY (IN)
EPPATURI BALA NARSAIAH (IN)
JAKKU MALLESWARA REDDY (IN)
SRINIVASAN THIRUMALAI RAJAN (IN)
| WO2016074532A1 | 2016-05-19 | |||
| WO2010143664A1 | 2010-12-16 |
| US20160257667A1 | 2016-09-08 |
| We Claim: 1. A process for the preparation of Alectinib hydrochloride Formula- la comprising: a) Reacting 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid compound of formula-2 Formula-2 with 3-(tert-butoxy)-3-oxopropanoic acid compound of formula-27 Formula-27 in the presence of magnesium alkoxide, a coupling agent and a base in a solvent to provide tert-butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate compound of formula-28, Formula-28 b) converting the compound of formula-28 to Alectinib hydrochloride. 2. The process as claimed in claim 1 , wherein in step-a) the base is selected from organic or inorganic base. 3. The process as claimed in claim 1 wherein, the solvent used in step-a) 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; 4. The process as claimed in claim 1 wherein, the coupling agent used in step-a) is selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC. HC1), carbonyldiimidazole (CDI), 0-(7-aza-benzotriazole-l-yl)-N,N, N',N'-tetramethyluroniumhexafluoro phosphate (HATU), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenylphosphoroazidate (DPPA), thionyl chloride, pivalylchloride, oxalylchloride, phosphorousoxychloride, phosphorouspentachloride, 4-methyl-2-oxopentanoyl chloride (i- BuCOCOCl), benzotriazol-l-yl-oxytripyrrolidinophosphoniumhexafluoro phosphate (PyBOP), methanesulfonylchloride and the like; optionally in combination with l-hydroxy- 7-azatriazole (HOAt), 1 -hydroxybenzotriazole (HOBt), l-hydroxy-l-H-l,2,3-triazole-4- carboxylate (HOCt), 0-(henzotriazol-l-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4- dimethylaminopyridine (DMAP). 5. The process as claimed in claim 1 wherein, a process for the preparation of Alectinib hydrochloride, comprising: a) Reacting tert-butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoate compound of formula-28 Formula-28 with 4-chloro-3-nitrobenzonitrile compound of formula-29 Formula-29 in the presence of a base to provide tert-butyl 2-(4-cyano-2-nitrophenyl)-4-(4-ethyl-3- iodophenyl)-4-methyl-3-oxopentanoate compound of formula-30, Formula-30 b) converting compound of formula-30 to Alectinib hydrochloride. 6. The process as claimed in claim 5 wherein, the base used in step-a) is selected from 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. 7. The process as claimed in claim 5 wherein, a process for the preparation of pure Alectinib hydrochloride, comprising: a) treating tert-butyl 2-(4-cyano-2-nitrophenyl)-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxo pentanoate compound of frormula-30 with hydrose in a solvent to provide tert-butyl 6- cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-lH-indole-3-carboxylate compound of formula-31 , b) optionally purifying the compound of formula-31 by dissolving in a solvent selected from alcohol solvents, ester solvents, chloro solvents, nitrile solvents, ketone solvents, ether solvents and hydrocarbon solvents and precipitating by adding anti-solvent water to the solution to provide pure compound of formula-31, c) reacting the compound of formula-31 with 4-(piperidin-4-yl)morpholine compound of formula-7 in the presence of allylchloro[l,3-bis(2,6-di-i-propylphenyl)imidazol-2- ylidene]palladium (II) and sodium hexamethyldisilazane in a solvent to provide tert- butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin- 1 -yl)phenyl)propan-2-yl)- 1 H - indole-3 -carboxylate compound of formula-33, d) optionally converting compound of formula-33 into its hydrochloride salt compound of formula-33a by treating compound of formula-33 with a hydrochloric acid source in a solvent, e) treating compound of formula-33 or its hydrochloric acid salt compound of formula-33a with trimethylsilyl chloride in a solvent to provide 6-cyano-2-(2-(4-ethyl-3-(4- morpholinopiperidin- 1 -yl)phenyl)propan-2-yl)- lH-indole-3-carboxylic acid compound of formula-34, f) treating the compound of formula-34 with acetic anhydride in the presence of a base in a solvent to provide Alectinib, g) optionally purifying Alectinib free base using a solvent or mixture of solvents to provide pure Alectinib, h) treating the Alectinib with a hydrochloric acid source in a solvent to provide Alectinib hydrochloride. 8. The process as claimed in claim 7 wherein, 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. 9. The process as claimed in claim 7 wherein, a process for the purification of Alectinib comprising dissolving or suspending Alectinib in a solvent selected from polar aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP); ketone solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone and water or mixture thereof and isolating pure Alectinib. 10. The process as claimed in claim 9 wherein, a process for the purification of Alectinib, comprising dissolving or suspending Alectinib in a mixture of N-methylpyrrolidone and acetone and isolating pure Alectinib. 11. The process as claimed in claim 9 wherein, a process for the purification of Alectinib comprising dissolving or suspending Alectinib in a mixture of water and acetone and isolating pure Alectinib. 12. The process as claimed in claim 10 & 11 wherein, isolating Alectinib by 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. 13. Alectinib obtained according to any of the purification process claimed in claim 9 to 11 having amide impurity less than about 0.02% as measured by HPLC. 14. The process as claimed in claim 7 wherein, a process for purification of 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. 15. The process as claimed in claim 14 wherein, anti-solvent is water. 16. An improved process for the preparation of 6-bromo-7-methoxy- 1,1 -dimethyl-3, 4-dihydro naphthalen-2(lH)-one compound of formula-26, comprising: a) Reduction of 2,7-dimethoxynaphthalene compound of formula-22 aco. .oca Formula-22 with sodium silica gel in a solvent to provide 2, 7-dimethoxy-l, 4-dihydro naphthalene compound of formula-23, Formula-23 b) treating the compound of formula-23 with an acid in the presence of a solvent to provide 7-methoxy-3,4-dihydronaphthalen-2(lH)-one compound of formula- 24, Formula-24 c) converting compound of formula-24 to 6-bromo-7-methoxy-l,l-dimethyl-3, 4-dihydro naphthalen-2(lH)-one compound of formula-26. Formula-26 17. The process as claimed in claim 16 wherein, the 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; the acid in step-b) is hydrochloric acid. 18. The process as claimed in claim 16 wherein a process for the preparation of 6-bromo-7- methoxy-l,l-dimethyl-3,4-dihydronaphthalen-2(lH)-one compound of formula-26, comprising: a) Methylation 7-methoxy-3,4-dihydronaphthalen-2(lH)-one compound of formula-24 with methyl iodide in presence of tetrabutyl ammonium hydrogen sulfate in a base in a solvent to provide 7-methoxy- 1,1 -dimethyl-3, 4-dihydro naphthalen-2(lH)-one compound of formula-25, Formula-25 b) brominating the compound of formula-25 by treating it with a brominating agent in a solvent to provide 6-bromo-7-methoxy- 1,1 -dimethyl-3, 4-dihydronaphthalen-2(lH)-one compound of formula-26. Formula-26 19. The process according to claim 1 wherein, Alectinib hydrochloride is having purity greater than about 99.95% as measured by HPLC. 20. Alectinib hydrochloride obtained according to claim 1, having particle size distribution of D90 less than about 150 pm, preferably less than about 100 pm; more preferably less than about 50 pm. 21. Alectinib hydrochloride obtained according to the preceding claims is having impurities such as N-Oxide impurity; acid impurity; decarboxylate impurity; morpholine butyl ester impurity less than about 0.01% as measured by HPLC. 22. Alectinib hydrochloride obtained according to any of the preceding claims is useful for the preparation of pharmaceutical composition. 23. A pharmaceutical composition comprising Alectinib hydrochloride according to any of the preceding claims and a pharmaceutically acceptable carrier or diluent. 24. Crystalline Alectinib having PXRD pattern as depicted in figures- 1 to 4. 25. Use of crystalline Alectinib of claim 24 in the preparation of Alectinib hydrochloride. |
Related Applications:
This application claims the benefit of priority of our Indian patent application number 201841016280 filed on 30 th April 2018 which is incorporated herein by reference.
Field of the Invention:
The present invention relates to novel process for the preparation of Alectinib hydrochloride compound of formula- la, represented by the following structural formula:
Formula- la
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.
Background of the Invention:
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.
According to prior known process, Alectinib is purified by cumbersome, tedious workups and column chromatography which are not feasible on commercial scale.
In order to overcome the aforementioned problems, 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..
Brief description of the Invention:
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.
Brief description of the Drawings:
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.
Detailed description of the Invention:
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, 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, 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, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone and the like;“nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like;“alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoro ethanol, 2,2,2-trifluoroethanol, ethylene glycol, propylene glycol, 2-methoxyethanol, 1,2- ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol and the like;“polar solvents” such as water or mixtures thereof.
The term“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.
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 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” such as disodium hydrogen phosphate, dipotassium hydrogen phosphate; ammonia and“organic bases” selected from but not limited to “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; methylamine, ethylamine, diisopropylamine, diisopropylethylamine (DIPEA), diisobutyl amine, tri ethylamine, tert.butylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), n-methylpyridine (NMP), l,8-diazabicyclo[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; or mixtures thereof.
The term“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(diisopropylphosphino) ethane, l,2-bis(dibutylphosphino)ethane, l,2-bis(dicyclohexylphosphino)ethane, 1,3 -bis (dicyclohexylphosphino)propane, 1 ,3 -bis(diiso-propylphosphino)propane, 1 ,4-bis(diisopropyl phosphino)-butane, 2,4-bis(dicyclohexylphosphino)pentane and 2-dicyclohexylphosphino-2', 4',6'-triisopropylbiphenyl (XPhos) and like.
The term “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.
The term“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.
The term“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.
The term“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.
The term“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:
Formula-9 Formula-1
The second 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:
Formula-1 Formula-9
The third 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:
Formula-9 Formula-8 X = Halogen
Alectinib Hydrochloride
Formula-la
The fourth 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:
Formula-18 Formula-17
Formula-14 Formula-13
R = C w straight or branched chail alkyl group
Formula-9 X = Halogen
The fifth 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:
Formula-8 Formula-19
Alectinib Hydrochloride
Formula-la x = Halogen
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:
Wherein 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, and 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-triisopropylphenyl) sulfonyloxy, (2,4,6-trimethylphenyl)sulfonyloxy, (4-tertbutylphenyl)sulfonyloxy, and (4- methoxyphenyl)sulfonyloxy.
The seventh embodiment of the present invention provides an improved process for the preparation of 7-methoxy-3,4-dihydronaphthalen-2(lH)-one, comprising:
a) Reduction of 2,7-dimethoxynaphthalene compound of formula-22
Formula-22
with sodium silica gel in a solvent to provide 2, 7-dimethoxy-l, 4-dihydro naphthalene compound of formula-23,
Formula-23
b) treating the compound of formula-23 in-situ with an acid in a solvent to provide 7- methoxy-3,4-dihydronaphthalen-2(lH)-one compound of formula-24.
Formula-24
Wherein, 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,
Formula-24
which comprises, reacting 2,7-dimethoxynaphthalene compound of formula-22 with Pd/C in the presence of hydrogen in a solvent to provide 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:
a) Reduction of 2,7-dimethoxynaphthalene compound of formula-22
Formula-22
with sodium silica gel in a solvent to provide 2, 7-dimethoxy-l, 4-dihydro naphthalene compound of formula-23,
Formula-23
b) treating the compound of formula-23 in-situ with an acid a solvent to provide 7- methoxy-3,4-dihydronaphthalen-2(lH)-one compound of formula-24,
Formula-24
c) methylation of the compound of formula-24 with methyl iodide in the presence of tetrabutyl ammonium hydrogen sulfate in a base in a solvent to provide 7-methoxy- 1,1 -dimethyl-3, 4-dihy dr onaphthalen-2(lH)-one compound of formula-25,
Formula-25
d) brominating the compound of formula-25 by treating it with a brominating agent in a solvent to provide 6-bromo-7-methoxy-l,l-dimethyl-3,4-dihydronaphthalen-2(lH)- one compound of formula-26.
Formula-26
Wherein, 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; in step-b) acid is hydrochloric acid and the brominating agent used in step-d) is selected from bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N-bromosuccinamide, carbontetrabromide, phosphorous tribromide.
In an embodiment of the present invention, converting 6-bromo-7-methoxy-l,l- dimethyl-3,4-dihydronaphthalen-2(lH)-one compound of formula-26 to Alectinib hydrochloride.
The tenth embodiment, 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.
DME, Mg alkoxide
Formula-2
In the process of the tenth embodiment, 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. In the process of the tenth embodiment, 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 (HATU), 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-l-H-l,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-l- yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate (TBTU), N-hydroxysuccinamide (HOSu), N-hydroxysulfosuccinimide (Sulfo-NHS), 4-dimethylamino pyridine (DMAP).
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. As 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.
After several optimizations, 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.
The eleventh embodiment, 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-oxo pentanoate compound of formula-30.
Formula-28
Formula-30
In the process of the eleventh embodiment, 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 twelfth embodiment, the present invention provides a process for the preparation of pure Alectinib hydrochloride, comprising:
a) Treating tert-butyl 2-(4-cyano-2-nitrophenyl)-4-(4-ethyl-3-iodophenyl)-4-methyl- 3- oxopentanoate compound of formula-30 with hydrose in a solvent to provide tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-lH-indole-3- carboxylate compound of formula-31 ,
b) optionally purifying the compound of formula-31 using a solvent or mixture of solvents,
c) reacting the compound of formula-31 with 4-(piperidin-4-yl)morpholine compound of formula-7 in the presence of allylchloro[l,3-bis(2,6-di-i-propylphenyl)imidazol-2- ylidene]palladium (II) and sodium hexamethyldisilazane in a solvent to provide tert- butyl 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-l-yl)phenyl)p ropan-2-yl)-lH- indole-3-carboxylate compound of formula-33, d) optionally converting compound of formula-33 into its hydrochloride salt compound of formula-33a by treating compound of formula-33 with a hydrochloric acid source in a solvent,
e) treating compound of formula-33 or its hydrochloric acid salt compound of formula- 33a with trimethylsilyl chloride in a solvent to provide 6-cyano-2-(2-(4-ethyl-3-(4- morpholinopiperidin-l-yl)phenyl)propan-2-yl)-lH-indole-3-car boxylic acid compound of formula-34,
f) treating the compound of formula-34 with acetic anhydride in the presence of a base in a solvent to provide Alectinib,
g) optionally purifying Alectinib free base using a solvent or mixture of solvents to provide pure Alectinib,
h) treating Alectinib with a hydrochloric acid source in a solvent to provide Alectinib hydrochloride.
In the process of the twelfth embodiment, 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.
In the twelfth embodiment of the present invention the PXRD pattern of Alectinib obtained in step-f) is depicted in figure- 1 and figure-2.
In the process of the twelfth embodiment, 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.
In an embodiment of the present invention, wherein anti-solvent is water.
In the process of the twelfth embodiment, 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.
In the process of the twelfth embodiment, 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.
In the process of the twelfth embodiment, a process for the purification of Alectinib comprising: dissolving or suspending Alectinib in a mixture of N-methylpyrrolidone and acetone and isolating pure Alectinib.
In the process of the twelfth embodiment, the PXRD pattern of Alectinib obtained in step-g) is depicted in figure-3 and figure-4.
In an embodiment of the present invention, Alectinib obtained according to the present invention having“Amide impurity” less than 0.02% as measured by HPLC.
Amide impurity
In the process of the twelfth embodiment, dissolving or suspending Alectinib in a mixture of acetone and water.
In the process of the twelfth embodiment, 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.
In an embodiment, 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-morpholinopiperidin-l-yl)phenyl) propan-2-yl)-lH-indole-3-carboxylate hydrochloride [Morpholine butyl ester impurity] less than 0.02% as measured by HPLC.
In an embodiment, 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.
The invention also encompasses pharmaceutical compositions comprising compound of formula- 1 or salts thereof of the present invention. As used herein, the term "Pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
PSD method of Analysis:
Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument. The process of the presence invention is schematically represented as follows:
DIPEA, DMA
Acetic anhydride
NMP, Acetone, Water
HC1
Alectinib hydrochloride
P-XRD Method of Analysis:
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.
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 2,7-dimethoxy-l,4-dihydronaphthalene
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 ½ 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.
Example-2: Preparation of 7-methoxy-3,4-dihydronaphthalen-2(lH)-one
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.
Example-3: Preparation of 7-methoxy-l,l-dimethyl-3,4-dihydronaphthalen-2(lH)-one
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. Heated the reaction mixture to 55-60°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for stirred for 10 minutes at the same temperature. Water and methyl tertiary butyl ether was added to the reaction mixture at 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer using methyl tertiary butyl ether. Distilled off the solvent completely from the organic layer under reduced pressure. The obtained compound was purified by column chromatography using ethyl acetate and cyclohexane to get the title compound.
Yield: 0.6 gms.
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.
Example-5: Preparation of tert-butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxo pentanoate:
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. 3-(tert-butoxy)-3-oxopropanoic acid (80 gms) was added to the reaction mixture. Triethyl amine (219 ml) was slowly added to the reaction mixture and stirred the reaction mixture 5 hours at 25-30°C (reaction mixture 1). 1 ,2-dimethoxyethane (300 ml) was added to 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid (100 gms) at 25- 30°C and stirred for 15 minutes at the same temperature. Carbonyldiimidazole (56.03 gms) 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 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. Aqueous acetic acid was added to the reaction mixture and stirred for 30 minutes at 25-30°C. Both the organic and aqueous layers were separated. Organic layer was washed with 15% sodium chloride solution. Distilled off the solvent completely under reduced pressure and co-distilled with isopropanol. To the obtained compound, isopropanol was added at 25-30°C and stirred for 2 hours at the same temperature. Filtered the reaction mixture, washed with isopropanol and dried to get the title compound. Yield 95 gms; M R: l 56-l6l°C.
Example-7: Preparation of tert-butyl 6-cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)- lH-indole-3-carboxylate:
Sodium hydrosulfite (154.78 gms) was added to a mixture of tert-butyl 2-(4-cyano-2- nitrophenyl)-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxopentanoa te (100 gms), tetrahydrofuran (600 ml) and water (700 ml) 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. Both the organic and aqueous layers were separated and extracted the aqueous layer using ethyl acetate. Combined the organic layers and washed with 15% aqueous sodium chloride solution. 10% aqueous hydrochloric acid solution was added to organic layer and stirred for 1 hour at 25-30°C. 4% aqueous sodium hydroxide was added to the reaction mixture. Both the organic and aqueous layers were separated. Distilled off the solvent from the organic layer under reduced pressure and co-distilled with isopropanol. To the obtained compound, isopropanol (210 ml) was added at 25-30°C and stirred for 10 minutes at the same temperature. Water (90 ml) was added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with a mixture of isopropanol and water and dried to get the title compound.
Yield: 90 gms; M R: l25-l35°C.
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. 1 ,2-dimethoxyethane (500 ml) was added to the reaction mixture at 25-30°C and stirred for 15 minutes tert-butyl 6- cyano-2-(2-(4-ethyl-3-iodophenyl)propan-2-yl)-lH-indole-3-ca rboxylate (100 gms) was added to the reaction mixture. Allylchloro[l,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene ] palladium(II) (4.0 gms) and then sodium hexamethyldisilazane (500 ml) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 5 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Isopropyl acetate (500 ml) and then 20% ammonium chloride solution was added to the reaction mixture. Both the organic and aqueous layers were separated and washed the organic layer with 10% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. 1 ,2-dimethoxyethane (500 ml) and water (10 ml) was added to the obtained compound. N-acetyl cysteine (3.15 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 1 hour at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the obtained filtrate under reduced pressure. Acetone (1000 ml) was added to the obtained compound at 25-30°C and stirred for 1 hour the same temperature. Pyridinium chloride solution was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 80 gms; M.R: 215-225°C.
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) was added to the reaction mixture. 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)p ropan-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. Methanol (700 ml) was added to the reaction mixture at 25-30°C. Cooled the reaction mixture to l0-l5°C. Water (1200 ml) was added at 10-15°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed with mixture of methanol and water. Yield: 110 gms.
Purity by HPLC: 98.39%; Amide impurity: 0.15%.
Example-11: Purification of Alectinib:
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.
Purity by HPLC: 99.70%; Amide impurity: Not detected.
Example-12: Purification of Alectinib:
Water (500 ml) and acetone (500 ml) was added to Alectinib obtained in example-l l 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: 65.0 gms.
Melting range: >250°C; Purity by HPLC: 99.74%.
The PXRD pattern of the obtained compound is matching with the PXRD pattern of Alectinib disclosed in Figure-l of IPCOM000250294 D.
Example-13: Preparation of Alectinib hydrochloride:
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.
Yield: 85 gms; Purity by HPLC: 99.97%.
Before micronization: Particle size distribution: D 90 : 35.73 pm; D 50 : 14.29 pm; Dio: 5.57 pm. After micronization: Particle size distribution: D 90 : 6.08 pm; D 50 : 2.99 pm; Dio: 1.21 pm.
Example-14: Preparation of tert-butyl 2-(4-cyano-2-nitrophenyl)-4-(4-ethyl-3-iodo phenyl)-4-methyl-3-oxopentanoate
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. 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. n-Heptane (135 lts) and isopropyl acetate (135 lts) to the reaction mixture at 20-25°C. Aqueous hydrochloric acid was slowly added to the reaction mixture at 20-25 °C and stirred for 45 minutes at the same temperature. Both the organic and aqueous layers were separated and extracted the organic layer using water. Aqueous sodium hydroxide solution 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. 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. A mixture of tetrahydrofuran and ethyl acetate was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Aqueous acetic acid solution was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Both the organic and aqueous layers were separated. Aqueous sodium chloride was added to the organic layer at 25-30°C and stirred for 20 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 and then co-distilled with isopropanol. To the obtained compound, isopropanol (67.5 lts) was added 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 to get the title compound. Yield: 58.49 kgs.
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-oxopentanoa te (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. Water (49.5 lts) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with a mixture of isopropanol and water and dried to get the title compound. Yield: 42.78 kgs.
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. Allylchloro[l,3- bis(2,6-di-i-propylphenyl)imidazol-2-ylidene]palladium (II) (1.60 kgs) and sodium hexamethyldisilazane (200 lts) was added to the reaction mixture at 25-30°C. Raised the temperature of the reaction mixture to 45-50°C and stirred for 5 hours at the same temperature. Isopropyl acetate (200 lts) was added to the reaction mixture at 25-30°C. Aqueous ammonium chloride solution was slowly 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. 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) and 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-carboxyla te 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. 10% aqueous dipotassium hydrogen phosphate was slowly added to the reaction mixture and stirred for 2 hours at 0-5°C. Filtered the precipitated solid, washed with a mixture of acetone and water and dried to get the title compound. Yield: 21.78 kgs.
Example-18: Preparation of Alectinib
Dimethylacetamide (360 lts) to 6-cyano-2-(2-(4-ethyl-3-(4-morpholinopiperidin-l-yl) phenyl)propan-2-yl)-lHindole-3 -carboxylic acid (20 kgs) at 25-30°C and stirred for 10 minutes at the same temperature. Acetic anhydride (11.60 kgs) and disiopropylethylamine (34.0 kgs) was added to the reaction mixture at 25-30°C. Raised the temperature of the reaction mixture to 85-90°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Methanol was added to the reaction mixture. Cooled the reaction mixture to 5-l0°C. Water was added to the reaction mixture and stirred for 3 hours at 5-l0°C. Filtered the precipitated solid and washed with a mixture of methanol and water. Acetone (100 lts) and N-methyl-2-pyrrolidone (100 lts) was added to the obtained compound at 25-30°C and stirred for 2 hours at the same temperature. Filtered the solid and washed with acetone. To the obtained compound, water (140 lts) and hydrose (0.10 kgs) was added at 25-30°C and stirred for 2 hours at the same temperature. Acetone was added to the reaction mixture and stirred for 45 minutes at 25-30°C. Filtered the solid, washed with acetone and dried to get the title compound. Yield: 12.47 kgs.
Example-19: Preparation of Alectinib hydrochloride
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.
Purity by HPLC: 99.99%; N-Oxide impurity: Not detected; Acid impurity: Not detected; Decarboxylate impurity: Not detected; Morpholine butyl ester impurity: Not detected.
Before micronization: Particle size distribution: D 90 : 43.22 pm; D 50 : 16.91 pm; Dio: 6.00 pm. After micronization: Particle size distribution: D 90 : 6.19 pm; D 50 : 3.02 pm; Dio: 1.25 pm.
Example-20: Preparation of tert-butyl-4-(4-ethyl-3-iodophenyl)-4-methyl-3-oxo pentanoate:
1 ,2-Dimethoxyethane (400 ml) was added to 3-(tert-butoxy)-3-oxopropanoic acid (80 gms) and stirred the reaction mixture. Anhydrous magnesium tert-butoxide (58.96 gms) was added to above reaction mixture. Triethyl amine (219 ml) was slowly added to the reaction mixture and stirred the reaction mixture 5 hours at 25-30°C (reaction mixture 1). 1,2- dimethoxyethane (300 ml) was added to 2-(4-ethyl-3-iodophenyl)-2-methylpropanoic acid (100 gms) at 25-30°C and stirred for 15 minutes at the same temperature. Carbonyldiimidazole (56.03 gms) 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 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: 90 gms.