DESC:RELATED APPLICATION:
This application claims the benefit of the earlier filing date of Indian Provisional
Patent Application No. 201621036255 filed on Oct. 24, 2016; Indian Provisional
Patent Application No. 201721000753 filed on Jan. 09, 2017.
FIELD OF THE INVENTION
10 The present invention provides a novel crystalline solvate of Lenvatinib mesylate
and an improved process for preparation lenvatinib.
BACKGROUND OF THE INVENTION
Lenvatinib mesylate (LENVIMA) is a kinase inhibitor, indicated for the treatment
of patients with locally recurrent or metastatic, progressive, radioactive iodine15
refractory DTC (Differentiated Thyroid Cancer).
O N
H2N
O O
NH NH
O
Cl
CH3SO3H
Patent US7253286B2 discloses Lenvatinib and also its preparation method.
US7683172 patent discloses an improved process for preparation of Lenvatinib.
Patent US7612208 discloses crystalline forms of Lenvatinib mesylate Form-A, B,
20 C, F, I.
3
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have different arrangements and/or different configurations of the molecules". Different 5 polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and 10 commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and 15 Infrared spectrometry (IR). A solvate may be defined as a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute. Solvent medium and mode of isolation play very important role in obtaining a polymorphic form over the other.
The discovery of new polymorphic forms and solvates of a pharmaceutically useful 20 compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing.
SUMMARY OF THE INVENTION One aspect of the present invention provides a novel crystalline methyl isobutyl 25 ketone solvate form Al-1 of Lenvatinib mesylate represented by formula-I:
4
O N
H2N
O O
NH NH
O
Cl
formula-I
Another aspect of the invention relates to pharmaceutical compositions comprising
a crystalline methyl isobutyl ketone form Al-1 of Lenvatinib mesylate and at least
one pharmaceutically acceptable excipient.
5 Another aspect of the present invention provides a preparation process of
Lenvatinib of formula-I comprising:
a. reacting an ester compound of formula-II with a suitable reagent to obtain
Lenvatinib of formula-I;
N
O
O
O
O
Cl
NH NH
R O
formula-II
10 Wherein R represents alkyl, aryl, alkylaryl, heteroaryl, substituted alkyl, substituted
alkylaryl, substituted heteroaryl or substituted alkylheteroaryl.
Another aspect of the invention relates to preparation process of Lenvatinib of
formula-I: comprising steps I and II
I. preparing compound of formula-II, comprising steps of
a. reacting compound of formula-III, wherein R1 15 represents hydrogen, C1-
6 alkyl or C3-8 cycloalkyl; with a compound of formula-IV, wherein L is
leaving group to obtain compound of formula-II;
5
Cl
NH
HO
O
NH
R
1
formula-III
N
O
O
O
L
R
formula-IV
(or)
a. reacting compound of formula-IV with 4-amino-3-chlorophenol to obtain
compound of formula-V
N
O
O
O
L
R
formula-IV
N
O
O
O
O
Cl
NH2
R
formula-V
5
b. reacting compound of formula-V with carbamating reagent to obtain
compound of formula-VI;
N
O
O
O
O
Cl
NH O
R O
formula-VI
c. reacting compound of formula-VI without isolation or isolated compound
10 of formula-VI with cyclopropylamine to obtain compound of formula-II;
II. reacting an ester compound of formula-II with a suitable reagent to obtain
Lenvatinib of formula-I.
Another aspect of the invention relates to preparation process of Lenvatinib of
formula-I comprising:
6
a. reacting compound of formula-IV with 4-amino-3-chlorophenol to obtain
compound of formula-V
N
O
O
O
L
R
formula-IV
N
O
O
O
O
Cl
NH2
R
formula-V
b. converting compound of formula-V to a compound of formula-V(a)
N
O
O
O
NH2
Cl
NH2
formula-V(a)
5
c. reacting compound of formula V(a) with a carbamating reagent to obtain a
compound of formula VI(a)
N
O
O
O
Cl
NH O
O
NH2
formula-VI(a)
d. reacting compound of formula-VI(a) with cyclopropyl amine to obtain
10 Lenvatinib of formula-I.
BRIEF DESCRIPTION OF THE DRAWINGS
In the following description, reference(s) is made to the accompanying drawings, in
which
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of Lenvatinib
15 mesylate MIBK solvate form Al-1.
Fig 2 shows the X-ray powder diffractogram ("PXRD") pattern of Lenvatinib
7
mesylate propylene glycol solvate. Fig 3 shows the X-ray powder diffractogram ("PXRD") pattern of Lenvatinib mesylate DMSO solvate. Fig 4 shows the X-ray powder diffractogram ("PXRD") pattern of Lenvatinib mesylate DMF solvate. 5
DETAILED DESCRIPTION OF THE INVENTION
An aspect of the present invention relates to a preparation process of Lenvatinib of formula-I comprising: reacting an ester compound of formula-II with a suitable 10 reagent to obtain Lenvatinib of formula-I, wherein R represents alkyl, aryl, alkylaryl, heteroaryl, substituted alkyl, substituted alkylaryl, substituted heteroaryl or substituted alkylheteroaryl.
Another aspect of the invention relates to preparation process of Lenvatinib of formula-I, comprising steps I and II 15
I. preparing compound of formula-II, comprising steps of
a. reacting compound of formula-III, wherein R1 represents hydrogen, C1-6 alkyl or C3-8 cycloalkyl; with a compound of formula-IV, wherein L is leaving group to obtain compound of formula-II
(or) 20
a. reacting compound of formula-IV with 4-amino-3-chlorophenol to obtain compound of formula-V
In one embodiment in the above step a) involves reacting compound of formula-IV with 4-amino-3-chlorophenol in presence of a suitable base in a suitable solvent. 25
8
b. reacting compound of formula-V with carbamating reagent to obtain compound of formula-VI
c. reacting compound of formula-VI without isolation or isolated compound of formula-VI, with cyclopropylamine to obtain compound of formula-II.
In one embodiment the above step c) comprises reacting compound of formula-VI 5 without isolating with cyclopropylamine, i.e. cyclopropylamine is added to the reaction mixture comprising a compound of formula-VI obtained in step b).
In one embodiment the above step c) comprises reacting compound of formula-VI isolated after completion of reaction according to step b) with cyclopropylamine.
In one embodiment the above step c) is carried out in a suitable solvent. In another 10 embodiment the above step c) is optionally carried out in presence of a suitable base.
II. reacting an ester compound of formula-II with a suitable reagent to obtain lenvatinib of formula-I.
Another aspect of the invention relates to preparation process of Lenvatinib of 15 formula-I, comprising:
a. reacting compound of formula-IV with 4-amino-3-chlorophenol to obtain compound of formula-V;
b. converting compound of formula-V to a compound of formula-V(a) with a suitable reagent 20
c. reacting compound of formula V(a) with a carbamating reagent to obtain a compound of formula VI(a)
d. reacting compound of formula-VI(a) with cyclopropyl amine to obtain Lenvatinib of formula-I.
In an embodiment the above step d) is carried out in present of a suitable solvent. 25
9
In an embodiment the suitable reagent for conversion of ester to amide [i.e
formula-II to formula-I or formula V to formula V (a)] is a reagent which is
capable of converting ester to amide.
In one embodiment, the suitable reagent is source of nitrogen selected from source
5 of ammonia or amines. Source of ammonia is selected from ammonia gas, liquid
ammonia, aqueous ammonia, ammonium hydroxide, magnesium nitride and
formamide with base; more preferably ammonia gas.
In one embodiment the ester to amide conversion comprises reacting ester
compound of formula-II or formula-V with ammonia gas under suitable conditions.
10 The suitable conditions are using suitable solvent, pressure and temperature; the
ester to amide conversion comprises reacting ester compound of formula-II or
formula-V with ammonia solution in a suitable solvent and under suitable
conditions. The suitable conditions are using suitable solvent, and suitable
temperature.
15 In one embodiment the ester to amide conversion comprises reacting ester
compound of formula-II or formula-V with amine such as primary, secondary or
teritiary amines in a suitable solvent and under suitable conditions.
In one embodiment the carbamating reaction is carried out in presence of a
carbamating reagent in a suitable base and in a suitable solvent.
20 In one embodiment the carbamating reagent is selected from compounds of
formula O O
R1
O
R1 or Hal O
CH3
O
Wherein R1
is alkyl, alkenyl, aryl
group, aralkyl group and Hal is halogen.
In one embodiment the carbamating agent is selected from phenyl chloroformate,
methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, methoxyethyl
25 chloroformate, 1-chloroethyl chloroformate, isobutyl chloroformate, 2,2,2-
trichloroethyl chloroformate, 2-chloroethyl chloroformate, benzyl chloroformate,
10
4-chlorophenyl chloroformate, 4-nitrophenyl chloroformate; dimethyl carbonate, diethyl carbonate, triphosgene, carbonic acid bis(2-chloroethyl), diallyl carbonate, diphenyl/dibenzyl carbonate, ethylene carbonate.
In another aspect the present invention relates to preparation of a compound of formula-IV comprising 5
a. reacting 7-Methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid with thionyl chloride to obtain 7-Methoxy-4-chloroquinoline-6-carbonyl chloride
b. reacting 7-Methoxy-4-chloroquinoline-6-carbonyl chloride with or without isolation with compound of formula R2-OH to obtain compound formula-IV.
In an embodiment, R2 is selected from alkyl, aryl, or any hydrocarbon and R2-OH 10 is selected from alcohol such as methanol among others.
In one embodiment of the invention, preparation of a compound of formula-IV comprises reacting 7-Methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid with thionyl chloride to obtain 7-Methoxy-4-chloroquinoline-6-carbonyl chloride, to the reaction mixture comprising 7-Methoxy-4-chloroquinoline-6-carbonyl chloride, 15 R2-OH compound is added. In another embodiment of the invention, preparation of a compound of formula-IV comprises reacting 7-Methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid with thionyl chloride to obtain 7-Methoxy-4-chloroquinoline-6-carbonyl chloride. Isolated compound 7-Methoxy-4-chloroquinoline-6-carbonyl chloride is reacted with R2-OH. 20
Another aspect of the present invention relates to a novel crystalline methyl isobutyl ketone (MIBK) solvate form Al-1 of Lenvatinib mesylate of formula-I.
In an embodiment, the novel crystalline MIBK form Al-1 of Lenvatinib mesylate, has at least one PXRD peaks (2 theta) at 6.8 plus or minus 0.2° 2-theta.
In an embodiment, the novel crystalline MIBK form Al-1 of Lenvatinib mesylate, 25 has at least one PXRD peaks (2 theta) at 8.3 plus or minus 0.2° 2-theta.
11
In an embodiment, the novel crystalline MIBK form Al-1 of Lenvatinib mesylate, has at least two PXRD peaks (2 theta) at 6.8 and 8.3 plus or minus 0.2° 2-theta.
In an embodiment, the novel crystalline MIBK form Al-1 of Lenvatinib mesylate, has PXRD pattern as shown in fig.1.
In another aspect the present invention relates to preparation process of novel 5 crystalline MIBK form Al-1 of Lenvatinib mesylate comprising the steps of: a. providing lenvatinib mesylate in MIBK solvent; b. isolating Lenvatinib mesylate MIBK solvate form Al-1.
In an embodiment, the preparation process of novel crystalline MIBK form Al-1 comprises providing Lenvatinib mesylate in MIBK comprising adding Lenvatinib 10 mesylate in to MIBK solvent, heating, cooling, and optionally filtering the solvent solution to remove any extraneous matter; and finally, isolating Lenvatinib mesylate MIBK solvate form Al-1.
In an embodiment, the Lenvatinib mesylate used in step 1 of preparation of Lenvatinib mesylate MIBK solvate form Al-1 is Lenvatinib mesylate DMSO 15 solvate. The DMSO solvate used is either the one known in the art or novel Lenvatinib mesylate DMSO solvate prepared according to the present invention.
One aspect of the present invention relates to a novel crystalline propylene glycol solvate of Lenvatinib mesylate.
In an embodiment of the present invention relates to a novel crystalline propylene 20 glycol solvate of lenvatinib mesylate having one or more PXRD peaks (2 theta) at approximate positions: 7.08, 9.09, 13.48, 17.92, 19.61, 21.25 and 21.81 ± 0.2 degrees.
In an embodiment, the novel crystalline propylene glycol solvate of lenvatinib mesylate having one or more PXRD peaks (2 theta) approximately at: 7.08, 9.09, 25 10.86, 11.69, 12.22, 13.48, 14.87, 16.80, 17.92, 18.82, 19.61, 19.85, 21.25, 21.81,
12
22.49, 23.21, 23.74, 24.28, 25.40, 25.72, 26.35, 27.61, 27.97, 29.81, 31.77, 32.60, 33.58, 34.49, 35.66 and 37.26 ± 0.2 degrees.
In an embodiment, the novel crystalline propylene glycol solvate of lenvatinib mesylate has PXRD peaks as shown in fig-2.
Another aspect of the invention relates to preparation process of novel crystalline 5 propylene glycol solvate of Lenvatinib mesylate.
A wide variety of solvents may be employed in the preparation of the solvates of lenvatinib mesylate. Preferred solvents include, for example, polar solvents, including polar protic and polar aprotic solvents.
In one embodiment of the invention, the process for preparation of Lenvatinib 10 mesylate propylene glycol solvate which has PXRD pattern as shown in fig 2, comprising a. contacting Lenvatinib mesylate with propylene glycol; b. crystallizing the propylene glycol solvate of Lenvatinib mesylate; c. isolating the solvate.
In another embodiment of the invention, there is provided a process for preparation 15 of lenvatinib mesylate propylene glycol solvate, the process comprising: a. contacting lenvatinib free base with propylene glycol in solution or suspension; b. treating the resulting solution of step-a with methanesulfonic acid; c. crystallizing the propylene glycol solvate of lenvatinib mesylate; d. isolating the solvate. 20
Another aspect of the invention relates to a novel crystalline DMSO solvate of lenvatinib mesylate of formula-I.
In an embodiment the novel crystalline DMSO solvate of Lenvatinib mesylate has PXRD pattern as shown in fig.3.
Still another aspect of the invention relates to preparation of Lenvatinib mesylate 25 DMSO solvate of Lenvatinib mesylate comprises providing a solution of
13
Lenvatinib mesylate in DMSO solvent, and isolating the Lenvatinib mesylate DMSO solvate.
Another aspect of the invention relates to a novel crystalline DMF solvate of Lenvatinib mesylate of formula-I. In an embodiment the novel crystalline DMF solvate of Lenvatinib mesylate has PXRD pattern as shown in fig.4. 5
Still another aspect of the invention relates to preparation of Lenvatinib mesylate DMF solvate of Lenvatinib mesylate comprises providing a solution of Lenvatinib mesylate in DMF solvent, and isolating the Lenvatinib mesylate DMF solvate.
The crystalline solvates of the present invention may have advantages relative to other known forms of Lenvatinib mesylate, including chemical stability, 10 polymorphic stability and/or varying solubility.
Another aspect of the invention relates to pharmaceutical compositions comprising a substantially pure Lenvatinib mesylate MIBK solvate form Al-1 or Lenvatinib mesylate propylene glycol solvate or Lenvatinib mesylate DMSO solvate or Lenvatinib mesylate DMF solvate and at least one pharmaceutically acceptable 15 excipient.
Another aspect of the invention relates to pharmaceutical composition comprising Lenvatinib mesylate MIBK solvate form Al-1 or Lenvatinib mesylate propylene glycol solvate or Lenvatinib mesylate DMSO solvate or Lenvatinib mesylate DMF solvate used for the treatment of cancer, especially thyroid cancer, for the treatment 20 of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only 25 but should be read in conjunction with what is disclosed anywhere else in the
14
specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples Example-1a Preparation of methyl 4-chloro-7-methoxyquinoline-6-carboxylate 5 A suspension of methyl 4-amino-2-methoxybenzoate (26.5 g) in isopropanol (500 ml) was stirred and heated to 50°C. 2,2-dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (methoxymethylene Meldrum's Acid, 25.6 g) was added and the resultant suspension was warmed to 80°C with stirring. The reaction mixture was allowed to cool to ambient temperature and the white precipitate was isolated to 10 obtain 2,2-dimethyl-5-(3-methoxy-4-methoxycarbonyl-anilinomethylene)-1,3-dioxane-4,6-dione (40.5 g) of which a portion (25 g) of the material was heated to 240°C in a mixture of diphenyl ether (225 ml) and biphenyl (75 ml). After cooling the resultant precipitate was isolated and washed with diethyl ether to obtain methyl 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylate (14 g). A mixture of 15 a portion (3.9 g) of the material so obtained, thionyl chloride (50 ml) and DMF (a few drops) were heated to reflux for 2 hours. There was thus obtained methyl 4-chloro-7-methoxyquinoline-6-carboxylate.
Example-1b Preparation of methyl 4-chloro-7-methoxyquinoline-6-carboxylate 20 A suspension of 3-Methoxy-4-methoxycarbonylaniline (14.15g) in isopropanol was heated at 50°C. 2,2-dimethyl-5-methoxymethylene-1,3-dioxane-4.6-dione (14.8 g, 80 mmol), was then added and the mixture was heated at reflux for 30 minutes and then left to cool to ambient temperature overnight. The precipitate formed was collected by filtration to give 5-((3-methoxy-4-25 methoxycarbonylanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.2g). 5-((3-Methoxy-4-methoxycarbonylanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g) was suspended in DOWTHERM A, (trade mark of Fluka Chemie AG), (125ml) and heated to 180-190°C over 30 minutes. Upon reaching 40°C ether was added and the mixture was stirred for 30 minutes. The solid was collected by 30
15
filtration to give 7-methoxy-6-methoxycarbonyl-1,4-dihydroquinolin-4-one (5.56g). A mixture of 7-methoxy-6-methoxycarbonyl-1,4-dihydroquinoIin-4-one (5.4g), DMF (0.4ml) and thionyl chloride (75ml) was heated at reflux and then stirred at ambient temperature to give 4-chloro-7-methoxy-6-methoxycarbonylquinoline (4.06g). 5 Example-1c Preparation of methyl 4-chloro-7-methoxyquinoline-6-carboxylate 4-Amino-2-chlorobenzonitrile (3 g) was dissolved in 1-methyl-2-pyrrolidone (10 ml), and then sodium methoxide (2.12 g) was added and the mixture was heated at 100° C to obtain an aniline compound (1.26 g). The aniline compound (1.26 g) was 10 heated to reflux in ethanol together with ethoxymethylene-Meldrum acid (1.7 g) to obtain 4-[(2,2-Dimethyl-4,6-dioxo[1,3]dioxane-5-ylidenemethyl)-amino]-2-methoxybenzonitrile (1.9 g). After adding Dowtherm A (160 ml) to 4-[(2,2-Dimethyl-4,6-dioxo[1,3]dioxane-5-ylidenemethyl)amino]-2-methoxybenzonitrile (1.9 g), the mixture was stirred at 200° C for 1 hour. Upon cooling to room 15 temperature, the precipitated crystals were filtered to get a solid (7.19 g). Glycerol (20 ml) and potassium hydroxide (3.0 g) were added to the 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carbonitrile (2 g) and after heating at 160° C for 3 hours, water (40 ml) was added and the mixture was heated at 80° C for 30 minutes. After cooling, 2N hydrochloric acid was added to acidity and the precipitated insoluble 20 portion was filtered out to obtain the 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (1.6 g) to which thionyl chloride (10 ml) and a small amount of dimethylformamide (DMF) were added and the mixture was heated to reflux for 2 hours to obtain the 7-methoxy-4-chloroquinoline-6-carbonyl chloride (2.7 g) which on reaction with methanol gave methyl 4-chloro-7-methoxyquinoline-6-25 carboxylate. Example-2a Preparation of Lenvatinib After dissolving 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea in dimethylsulfoxide (50 ml), sodium acetate was gradually added at room temperature and the mixture was stirred for 30 minutes. Thereafter, methyl 4-30
16
chloro-7-methoxyquinoline-6-carboxylate was added, and the mixture was heated at 100° C to obtain methyl 4-(3-chloro-4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate which is converted to the corresponding amide by reaction with ammonia gas under suitable conditions to give the title compound. 5 Example-2b Preparation of Lenvatinib After dissolving 4-amino-3-chlorophenol (1.213 g) in dimethylsulfoxide (10 ml), sodium acetate was gradually added at room temperature and the mixture was stirred for 30 minutes. To this 4-chloro-7-methoxy-6-methoxycarbonylquinoline (3.70 g) was added, and the mixture was heated at 100° C for 3 hours to give 10 methyl 4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxylate. The methyl 4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxylate obtained was dissolved in dimethylformamide (35 ml) under a nitrogen atmosphere, and then the solution was cooled in an ice water bath, pyridine (2.43 ml) and phenyl chloroformate (1.38 ml) were added in that order, and the mixture was stirred at 15 room temperature for 3 hours to obtain the compound phenyl N-(2-chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate. Phenyl N-(2-chloro-4-(7-methoxy-6-methoxycarbonyl-4-quinolyl)oxyphenyl)carbamate was dissolved in dimethylsulfoxide and then cyclopropylamine was added and the mixture was heated at 85° C for 3 hours while stirring to obtain methyl 4-(3-chloro-20 4-(((cyclopropylamino)carbonyl)amino)phenoxy)-7-methoxy-6-quinolinecarboxylate which was converted to the corresponding amide by reaction with ammonia gas under suitable conditions to give the title compound. Example-2c Preparation of Lenvatinib After dissolving 4-amino-3-chlorophenol (1.213 g) in dimethylsulfoxide (10 ml), 25 sodium acetate was gradually added at room temperature and the mixture was stirred for 30 minutes. To this 4-chloro-7-methoxy-6-methoxycarbonylquinoline (3.70 g) was added, and the mixture was heated at 100° C for 3 hours to give methyl 4-(4-amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxylate which was converted to the corresponding amide 4-(4-Amino-3-chlorophenoxy)-7-30
17
methoxy-6-quinolinecarboxamide by reaction with ammonia gas under suitable conditions. The 4-(4-Amino-3-chlorophenoxy)-7-methoxy-6-quinolinecarboxamide was dissolved in dimethylformamide (35 ml) under a nitrogen atmosphere, and then the solution was cooled in an ice water bath, pyridine (2.43 ml, 30.0 mmol) and phenyl chloroformate (1.38 ml, 11.0 mmol) were added in that order, and the 5 mixture was stirred at room temperature for 3 hours. Water (40 ml) was added to the reaction solution and the precipitated crystals were filtered out to get Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate which was dissolved in dimethylsulfoxide (1 ml), and then cyclopropylamine was added and the mixture was heated at 85° C to get the title compound. 10
Example 3: Preparation of lenvatinib mesylate methyl isobutyl ketone (MIBK) solvate A solution of Methyl isobutyl ketone (25 mL) and methanesulfonic acid (6.65 gm, 70 mmol) was added to the suspension of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide 15 (25.00 g, 58 mmol) in Methyl isobutyl ketone (250 ml) at 60° C. After completion of addition add Methyl isobutyl ketone (250 ml) to the reaction mixture, and the reaction mixture was stirred for 1.5 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled Compound (36 g).
Example 4: Preparation of lenvatinib mesylate propylene glycol solvate 20 Propylene glycol (35 ml) and lenvatinib Mesylate (5.0 gm) are charged in a reaction vessel and reaction mass was heated at 69±2°C. The reaction mass was stirred for 10-15 min at 69±2°C. Then methanol (250 ml) is charged and again the reaction mass is stirred for 25-30 min at 69±2°C. Solvent is distilled out and above residue is charged to diethyl ether (350 ml). The reaction mass is stirred for 55-60 25 min and then filtered and washed with ether. The wet cake was dried under vacuum at 50±2°C to obtain 4.5 g lenvatinib mesylate crystalline solvate with PXRD as shown in fig-2
18
Example 5: Preparation of lenvatinib mesylate propylene glycol solvate Propylene glycol (35 ml) and lenvatinib free base (5 gm) are charged in a reaction vessel and reaction mass was heated at 50±2°C. Methanol (100 ml) is charged to the reaction mass and methane sulfonic acid (1.35 gm) is slowly added. Then reaction mass is heated and stirred for 25-30 min. Methanol is distilled out 5 completely. Then the above residue is charged to Methyl tert-butyl ether (250 ml) and reaction mass is stirred for 55-60 min. The reaction mass is filtered and washed with Ether. The wet cake is dried under vacuum at 50±2°C to obtain 4.0 g lenvatinib mesylate crystalline solvate with PXRD as shown in fig-2. Example 6: Preparation of lenvatinib mesylate Propiophenone Solvate 10 A solution of Propiopphenone (20 mL) and methanesulfonic acid (5.4 gm, 56 mmol) was added to the suspension of 4-(3-chloro- 4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide (20.00 g, 46 mmol) in Propiophenone (200 ml) at 60° C. After completion of addition add Propiophenone (200 ml) to the reaction mixture, and the reaction mixture was 15 stirred for 1.5 hours. Precipitated crystals were filtered off and dried at 60° C. to give the titled Compound (29 g). Example 7: Preparation of lenvatinib mesylate DMSO Solvate A methanesulfonic acid (1.35 gm, 14 mmol) was added to the suspension of 4-(3-chloro- 4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinoline 20 carboxamide (5.00 g, 11.7 mmol) in DMSO (50 ml) at 60° C. Ethyl acetate (10 mL) and seed crystals of a Crystalline form of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (Form A) (10 mg) were added in this order to the reaction mixture, after that add slowly Ethyl acetate (40 ml) to the reaction mixture .Stir the reaction mass 15-20 25 minutes at 60° C and gradually cool the reaction mass at room temperature and stir it for 18-20 hours and Precipitated crystals were filtered off and dried at 60° C. to give the titled Compound (5.3 g) with PXRD as shown in fig-3.
19
Example 8: Preparation of lenvatinib mesylate DMF Solvate A methane sulfonic acid (0.54 gm, 5.6 mmol) was added to the suspension of 4-(3-chloro- 4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinoline carboxamide (2.00 g, 4.6 mmol) in DMF (20 ml) at 60° C. Stir the reaction mass 60 minutes at 60°C and gradually cool the reaction mass at room temperature and 5 stir it for 90-120 minutes and Precipitated crystals were filtered off and dried at 60° C. to give the titled Compound (1.63 g) with PXRD as shown in fig-4. Example 9: Preparation of lenvatinib mesylate (Amorphous Form) To THF (20 mL), Methyl isobutyl ketone solvate of the methanesulfonate of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinoline 10 carboxamide (1.00 g) was added and heated to 65° C. and then the reaction mixture was stirred at the same temperature for 2-3 hours. Cool the reaction mass and precipitated crystals were filtered off and dried at 60° C. to give the titled crystals (0.77 g).
Example 10: Preparation of 4-(4-Amino-3-chlorophenoxy)-6-15 methoxyquinoline-7-carboxamide. To Dimethyl sulfoxide (8.0 L), 4-Amino-3-chlorophenol (0.91 Kg) was added at 27±3°C, and stirred. To this reaction mixture sodium-t-butoxide (0.61 Kg) was added, stirred the reaction mixture at 35±5°C. To this reaction mixture 4-Chloro-6-methoxyquinoline-7-carboxamide (1.0 Kg) was added, heated to 60±2°C, stirred 20 for 120-240 min, cooled the reaction mixture to 25±3°C chilled process water (5.0 L) was slowly added, cooled to 27±3°C, stirred , filtered and dried. The obtained wet cake is added to a solution of water and DMSO, stirred, filtered, washed and dried for 12 hrs in vacuum tray dryer or fluid bed dryer at 60±2°C. This dried product is added to dimethylsulphoxide (5.5 l), heated to 78±3°C, stirred, cooled to 25 22±2°C , stirred, filtered and dried to obtain title compound.
Example 11: Preparation of phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl) carbamate To Dimethylformamide (10.00L), added 4-(4-amino-3-chlorophenoxy)-6-
20
methoxyquinoline-7-carboxamide (Stage-I, 1.0 Kg), stirred, cooled to -12±2°C. Pyridine (0.396 Kg) was added to the reaction mixture, then 0.683 Kg of phenyl chloroformate was slowly added at -12±2°C, and stirred. 5.5 L of process water was slowly added at -12±2°C, temperature was raised to 27±3°C, stirred, filtered, washed and dried. Obtained product is added to dimethylformamide (5.0 L), 5 heating the reaction mixture to 62±3°C, stirred. Ethyl acetate (12.0 L) was added at 62±3°C, stirred, cooled to 27±3°C, stirred, filtered, washed and dried to obtain title compound.
Example 12: Preparation of 4-{3-chloro-4-[(cyclopropylcarbamoyl)amino]phenoxy}-6-methoxyquinoline-7-carboxamide 10 Cyclopropylamine (0.246 Kg) was added to DMSO (10 L), Phenyl N-(4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-chlorophenyl)carbamate (1.0 Kg) was added at 20±2°C (in lots), stirred the reaction mixture. Temperature was raised to to 35±3°C, stirred, filtered, washed with DMSO. acetone: water mixture (5.5 Lit) (0.33 L Acetone + 0.67 L Water) was slowly added, stirred, filtered, and dried. 15 The obtained wet material was added to dimethyl sulphoxide (8.25 Lit), heated to 45±3°C, stirred, acetone: water mixture (4.20 Lit) (0.33 L Acetone + 0.67 L Water) was slowly added, stirred, filtered, washed and dried to obtain title compound.
Example 13: Preparation of lenvatinib mesylate methyl isobutyl ketone (MIBK) solvate 20
To dimethylsulfoxide (10.0L), Lenvatinib free base was added at 27±3°C. The reaction mixture was heated to 30±2°C. Methanesulphonicacid (0.23 Kg) was slowly added to reaction mixture at 30±2°C, stirred to get clear solution. Seeding with Lenvatinib DMSO solvate (0.02 kg), the reaction mixture was stirred. Ethyl 25 acetate (10.0 L) was added slowly at 27±3°C, stirred, filtered, washed and dried. Adding the obtained product to methyl isobutyl ketone (MIBK) (30.0 L), heating the reaction mixture to 50±2°C, stirred for 7-9 hours at 50±2 °C, cooled to 27±3°C,
21
stirred for 15-17 hours, filtered, washed with MIBK and dried to obtain the title compound with PXRD as shown in fig-1. ,CLAIMS:We claim:
1. A preparation process of Lenvatinib of formula-I comprising:
a. reacting an ester compound of formula-II with a suitable reagent to obtain
Lenvatinib of Formula-I;
N
O
O
O
O
Cl
NH NH
R O
formula-II
5
wherein R represents alkyl, aryl, alkylaryl, heteroaryl, substituted alkyl,
substituted alkylaryl, substituted heteroaryl or substituted alkylheteroaryl.
2. A preparation process of Lenvatinib of formula-I, comprising steps I and II
I. preparing compound of formula-II, comprising steps of
a. reacting compound of formula-III, wherein R1 10 represents hydrogen, C1-
6 alkyl or C3-8 cycloalkyl; with a compound of formula-IV, wherein L is
leaving group to obtain compound of Formula-II;
Cl
NH
HO
O
NH
R
1
formula-III
N
O
O
O
L
R
formula-IV
(or)
15 a. reacting compound of formula-IV with 4-amino-3-chlorophenol to obtain
compound of formula-V , wherein L is leaving group.
23
N
O
O
O
L
R
formula-IV
N
O
O
O
O
Cl
NH2
R
formula-V
b. reacting compound of formula-V with carbamating reagent to obtain
compound of formula-VI;
N
O
O
O
O
Cl
NH O
R O
formula-VI
5 c. reacting compound of formula-VI without isolation or isolated compound
of formula-VI with cyclopropylamine to obtain compound of Formula-II;
II. reacting an ester compound of Formula-II with a suitable reagent to obtain
Lenvatinib of formula-I.
3. A preparation process of Lenvatinib of formula-I comprising the steps of
10 a. reacting compound of formula-IV with 4-amino-3-chlorophenol to obtain
compound of formula-V
N
O
O
O
L
R
formula-IV
N
O
O
O
O
Cl
NH2
R
formula-V
b. converting compound of Formula-V to a compound of Formula-V(a)
24
N
O
O
O
NH2
Cl
NH2
formula-V(a)
c. reacting compound of formula-V(a) with a carbamating reagent to obtain a
compound of formula-VI(a)
N
O
O
O
Cl
NH O
O
NH2
formula-VI(a)
d. reacting 5 compound of formula-VI(a) with cyclopropyl amine to obtain
Lenvatinib of formula-I
4. The process as claimed in claims 1 and 3, the suitable reagent for conversion of
ester to amide [formula-II to formula-I or formula V to formula V(a)] is a
reagent which is capable of converting ester to amide, the reagent selected from
10 NH3, ammonium hydroxide, or amines such as primary, secondary or tertiary
amines or mixture thereof.
5. The process as claimed in claims 2 and 3, wherein the carbamating agent is
O O
R1
O
R1 or Hal O
CH3
O
, where R1
is alkyl, alkenyl, aryl group,
aralkyl group and Hal is halogen.
15 6. A process for preparation of Lenvatinib mesylate MIBK solvate, comprising a.
providing Lenvatinib mesylate in MIBK solvent; b. isolating Lenvatinib
mesylate MIBK solvate form Al-1.
25
7. The process as claimed in claim 6, wherein the Lenvatinib mesylate MIBK solvate has PXRD pattern with at least one peak selected from 6.8 and 8.3 plus or minus 0.2° 2-theta.
8. A process for preparation of Lenvatinib mesylate propylene glycol solvate which has PXRD pattern as shown in fig 2, comprising a. contacting Lenvatinib 5 mesylate with propylene glycol; b. crystallizing the propylene glycol solvate of Lenvatinib mesylate; c. isolating the solvate.
9. A process for preparation of Lenvatinib mesylate DMSO solvate which has PXRD pattern as shown in fig 3, comprising a. providing a solution of Lenvatinib mesylate in DMSO solvent; b. isolating Lenvatinib mesylate DMSO 10 solvate.
10. A process for preparation of Lenvatinib mesylate DMF solvate which has PXRD pattern as shown in fig 4, comprising a. providing a solution of Lenvatinib mesylate in DMF solvent; b. isolating Lenvatinib mesylate DMF solvate