WO2019016664A1 - An improved process for the preparation of lenvatinib - Google Patents
An improved process for the preparation of lenvatinib Download PDFInfo
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- WO2019016664A1 WO2019016664A1 PCT/IB2018/055229 IB2018055229W WO2019016664A1 WO 2019016664 A1 WO2019016664 A1 WO 2019016664A1 IB 2018055229 W IB2018055229 W IB 2018055229W WO 2019016664 A1 WO2019016664 A1 WO 2019016664A1
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- Prior art keywords
- lenvatinib
- base
- followed
- reaction mass
- monohydrate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- the present invention relates to an improved and economic industrial process for the preparation of Lenvatinib and salt thereof with the reduced processing steps and high yield.
- the present invention also relates to method and novel use of a reagent for preparing an amorphous form of Lenvatinib mesylate monohydrate.
- Lenvatinib is a nitrogenous aromatic -ring containing compound acting as a receptor tyrosine kinase (RTK) inhibitor.
- RTK receptor tyrosine kinase
- Lenvatinib is chemically known as 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7- methoxy-quinoline-6-carboxamide and is structurally represented as below:
- Lenvatinib mesylate is a white to pale reddish yellow powder and slightly soluble in water while practically insoluble in ethanol (dehydrated).
- the dissociation constant (pKa value) of Lenvatinib mesylate is 5.05 at 25°C.
- the partition co-efficient (log P value) is 3.30.
- Lenvatinib mesylate is indicated for the patients with progressive, locally recurrent or metastatic differentiated thyroid cancer (DTC) that can no longer be treated with radioactive iodine.
- DTC locally recurrent or metastatic differentiated thyroid cancer
- Thyroid cancer is a rare and representing less than 1% of all cancers.
- DTC a common thyroid cancer, arises from follicular epithelial cells and accounts around 90% to 95% of total thyroid cancer cases.
- Lenvatinib is also used in combination with Everolimus to treat adults with advanced renal cell carcinoma (RCC) type of kidney cancer.
- RRC renal cell carcinoma
- Lenvatinib is disclosed in PCT publication no. WO2002/032872 and is marketed by EISAI INC. as oral hypromellose hard capsules containing Lenvatinib as mesylate (methanesulfonate) salt in polymorphic 'Type C crystals. Initially, Lenvatinib is approved by USFDA during 2015 as LENVIMA ® capsule 4 mg and 10 mg. However, recommended daily dose of Lenvatinib is 24 mg once orally. LENVIMA ® capsule is reported to contain excipients like calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose and talc.
- WO2004/101526 discloses polymorphic 'Form A' and polymorphic 'Form B' of Lenvatinib, and process for preparation thereof.
- Part-3 by reacting l-(2-chloro-4-hydroxypenyl)-3-cyclopropylurea (II) with 7-methoxy-4- chloro-quinoline-6-carboxamide (III).
- l-(2-chloro-4- hydroxypenyl)-3-cyclopropylurea is prepared by Part-1 and 7-methoxy-4-chloro-quinoline-6- carboxamide is prepared by Part-2.
- WO2005/044788 discloses process for the preparation of Lenvatinib wherein the condensation reaction is performed between l-(2-chloro-4-hydroxypenyl)-3-cyclopropylurea (II) with 7- methoxy-4-chloro-quinoline-6-carboxamide (III) in dimethylsulfoxide, in the presence of cesium carbonate or potassium t-butoxide.
- WO2005/063713 discloses various crystalline forms like A, B and C of Lenvatinib mesylate. Further, a hydrate and an acetic acid solvate of Lenvatinib methanesulfonate are claimed as 'Form F' and 'Form ⁇ , respectively.
- Methanesulfonate salt of Lenvatinib is prepared by reacting Lenvatinib with methanesulfonic acid using methanol or acetic acid as solvent.
- WO2006/137474 discloses an amorphous form of Lenvatinib methanesulfonate and ethanesulfonate salt. Further, the said patent application also discloses preparation of these amorphous salts of Lenvatinib by dissolving their corresponding crystalline form salts in an alcohol and water followed by filtration and lyophilization.
- WO2014/098176 discloses an amorphous form of Lenvatinib.
- the said patent application also discloses preparation of an amorphous form of Lenvatinib by dissolving Lenvatinib crystals in solvents selected from the group consisting of water, an alcohol (C 1-6 ), an ether, acetonitrile or a combination thereof followed by freeze-drying of the said solution.
- WO2016/184436 discloses a new crystal form of Lenvatinib mesylate salt (Form M) and process for the preparation thereof.
- the said process of preparation involves crystallization of Lenvatinib 'Form M' crystals from Lenvatinib using solvent acetonitrile.
- WO2017/186197 claims salts of Lenvatinib with an acid in a solid form, wherein the acid is selected from the group consisting of phosphoric acid, tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid. Further, the above-mentioned patent application discloses method of preparing the said salts and their X-Ray diffraction (XRD) data along with melting points.
- XRD X-Ray diffraction
- WO2017/221215 claims salts of Lenvatinib with acetic acid, L-proline, maleic acid, citric acid, salicylic acid, succinic acid, and L-pyroglutamic acid, wherein the salt is either crystalline or amorphous. Further, the above-mentioned patent application discloses method of preparing the said salts and their X-Ray diffraction (XRD) data along with DSC data.
- XRD X-Ray diffraction
- the inventors of the present invention have developed an alternative improved process for the preparation of Lenvatinib with high yield.
- the present invention also entails an economical industrial process for the preparation of Lenvatinib with the reduced processing steps.
- the present invention comprises the novel use of a reagent in preparing Lenvatinib.
- Figure-1 illustrates a powder X-Ray diffraction pattern (PXRD) of Lenvatinib (I) base crude obtained at the end of step-c of below summary;
- Figure-2 illustrates a powder X-Ray diffraction pattern (PXRD) of Lenvatinib (I) base pure obtained at the end of step-d of below summary;
- Figure-3 illustrates a powder X-Ray diffraction pattern (PXRD) of an amorphous form of Lenvatinib mesylate (V) monohydrate obtained at the end of step-e of below summary.
- Figure-4 illustrates an infrared absorption pattern of an amorphous form of Lenvatinib mesylate (V) monohydrate obtained at the end of step-e of below summary.
- Figure-5 illustrates a DSC thermogram of an amorphous form of Lenvatinib mesylate (V) monohydrate obtained at the end of step-e of below summary.
- One aspect of the present invention relates to preparation of amorphous Lenvatinib mesylate (V) monohydrate comprising the reaction steps as below.
- Lenvatinib (I) base crude in a suitable solvent using activated charcoal e) reacting Lenvatinib (I) base pure obtained in step-d with methane sulphonic acid to obtain amorphous form of Lenvatinib mesylate (V) monohydrate.
- the present invention relates to an improved process for the preparation of Lenvatinib, wherein 4- (4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) in a suitable solvent, is reacted with cyclopropane isocyanate as a solution to yield Lenvatinib (I) base.
- Lenvatinib (I) base is eventually converted to yield Lenvatinib mesylate (V) monohydrate.
- One embodiment of the present invention relates to preparation of Lenvatinib (I) base crude comprising the steps as below.
- One embodiment of the present invention relates to purification of Lenvatinib (I) base crude comprising the steps as below.
- One embodiment of the present invention relates to preparation of amorphous form of Lenvatinib mesylate (V) monohydrate comprising the steps as below.
- PXRD X-Ray diffraction pattern
- V Lenvatinib mesylate
- %T transmittance
- V Lenvatinib mesylate
- V Lenvatinib mesylate
- Another embodiment of the present invention relates to method and novel use of cyclopropane isocyanate to prepare Lenvatinib (I) base by a shorter route.
- One embodiment of the present invention relates to preparation of cyclopropane isocyanate solution by diluting concentrated cyclopropane isocyanate with suitable solvent like DMF.
- Additional embodiment of the present invention relates to purification of Lenvatinib (I) base crude using suitable solvents and activated charcoal.
- Another embodiment of the present invention relates to preparation of hydrochloric acid solution by diluting concentrated hydrochloric acid with purified water.
- Another embodiment of the present invention relates to method of preparation of Lenvatinib mesylate (V) monohydrate by reacting Lenvatinib (I) base with methane sulfonic acid and suitable organic solvents accompanied by purified water.
- Another embodiment of the present invention relates to preparation of methane sulfonic acid solution by diluting concentrated methane sulfonic acid with methanol.
- Another aspect of the invention relates to pharmaceutical composition comprising Lenvatinib mesylate (V) prepared by using any of the process depicted in this specification, used for the treatment of cancer, especially thyroid cancer, for the treatment of patients with thyroid carcinoma histologically as differentiated (DTC), medullary and anaplastic.
- V Lenvatinib mesylate
- 4-chloro-7-methoxyquinoline-6-carboxamide (III) was reacted with 4-amino-3-chlorophenol in the presence of suitable solvent like dimethylsulfoxide to obtain 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV). Further, obtained 4-(4- amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) was reacted with isocyanate cyclopropane in a suitable solvent to obtain Lenvatinib (I) base crude. Lenvatinib (I) base crude was purified using suitable solvents and activated charcoal to obtain Lenvatinib (I) base pure.
- Lenvatinib (I) base pure was reacted with methane sulfonic acid to afford Lenvatinib mesylate (V) monohydrate in amorphous form.
- the obtained amorphous form of Lenvatinib mesylate (V) monohydrate complies purity norms as per ICH guidelines.
- EXAMPLE-6 Preparation of an amorphous form of Lenvatinib mesylate (V) monohydrate Methanol (300 ml) was added to Lenvatinib (I) base (30 g) pure obtained as per previous example- 5 at room temperature and stirred for 30 min. Solution of methane sulfonic acid (prepared by diluting 6.75 g MeS0 3 H in 60 ml methanol) (64.56 ml) was slowly added in to above reaction mass in 10-15 min at room temperature. The said reaction mass was stirred at room temperature for 4 h to obtain off white slurry followed by filtration. Obtained wet cake (29.8 g) was washed with methanol (30 ml, twice).
- the said wet cake (29.8 g) was charged in to glass assembly with purified water (596 ml) at room temperature and reaction mass was stirred for 2 h to get clear gummy mass. Ethanol (596 ml) was added to the obtained reaction mass for 2 h at room temperature to get yellow mass. The reaction mass was transferred in to buchi round bottom flask at room temperature. Under reduced pressure, solvent was distilled out in rota vapour below 35°C. The obtained material was dried in vacuum tray dryer below 35°C for 12 h to afford the title compound (34.1 g).
- Lenvatinib mesylate (V) monohydrate amorphous prepared by above example is having an endothermic melting peak at about 161 + 0.5°C.
- the said endothermic melting peak is having onset at about 148 + 0.5°C and end at about 169 + 0.5°C as shown in figure-5.
- Lenvatinib mesylate (V) monohydrate amorphous prepared by above example is having an infrared absorption spectrum (as shown in figure-4) with wave numbers of the absorption peak (cm 1 ) and transmittance (%T) at approximate positions as below.
- EXAMPLE-7 Oral formulation of an amorphous form of Lenvatinib mesylate (V) monohydrate
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Abstract
The present invention relates to an improved and economic industrial process for the preparation of Lenvatinib and salt thereof. The present invention also relates to method and novel use of a reagent for preparing an amorphous form of Lenvatinib mesylate (V) monohydrate..
Description
AN IMPROVED PROCESS FOR THE PREPARATION OF LENVATINIB
FIELD OF THE INVENTION:
The present invention relates to an improved and economic industrial process for the preparation of Lenvatinib and salt thereof with the reduced processing steps and high yield. The present invention also relates to method and novel use of a reagent for preparing an amorphous form of Lenvatinib mesylate monohydrate.
BACKGROUND OF THE INVENTION:
Lenvatinib is a nitrogenous aromatic -ring containing compound acting as a receptor tyrosine kinase (RTK) inhibitor.
Lenvatinib is chemically known as 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7- methoxy-quinoline-6-carboxamide and is structurally represented as below:
LENVATINIB
(I)
Lenvatinib mesylate is a white to pale reddish yellow powder and slightly soluble in water while practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of Lenvatinib mesylate is 5.05 at 25°C. The partition co-efficient (log P value) is 3.30. Lenvatinib mesylate is indicated for the patients with progressive, locally recurrent or metastatic differentiated thyroid cancer (DTC) that can no longer be treated with radioactive iodine. Thyroid cancer is a rare and representing less than 1% of all cancers. There are three main types of thyroid
carcinoma histologically as differentiated, medullary and anaplastic. Differentiated thyroid cancer
(DTC), a common thyroid cancer, arises from follicular epithelial cells and accounts around 90% to 95% of total thyroid cancer cases.
Lenvatinib is also used in combination with Everolimus to treat adults with advanced renal cell carcinoma (RCC) type of kidney cancer.
Lenvatinib is disclosed in PCT publication no. WO2002/032872 and is marketed by EISAI INC. as oral hypromellose hard capsules containing Lenvatinib as mesylate (methanesulfonate) salt in polymorphic 'Type C crystals. Initially, Lenvatinib is approved by USFDA during 2015 as LENVIMA® capsule 4 mg and 10 mg. However, recommended daily dose of Lenvatinib is 24 mg once orally. LENVIMA® capsule is reported to contain excipients like calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose and talc.
WO2004/101526 discloses polymorphic 'Form A' and polymorphic 'Form B' of Lenvatinib, and process for preparation thereof.
Part-l
4-amino-3-chlorophenol Phenyl (2-chloro-4- l-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea
hydroxyphenyl)carbamate
(Π)
Part-2
Ethyl 4-(((2,2-dimetbyl-4,6- ,4- 7-methoxy-4-oxo- 1 ,4- 4-chloro-7-methoxyquinoline- dioxo- 1 ,3 -dioxan-5- Ethyl 7-methoxy-4-oxo-l
ylidene)methyl)amino)-2- dihydroq inoline-6-carboxylate dihydroquinoline-6-carboxylic acid 6-carboxamide
(ΠΙ) methoxybenzoate
Lenvatinib
Scheme-1
The above-mentioned patent application discloses preparation of Lenvatinib crystalline polymorph
(Part-3) by reacting l-(2-chloro-4-hydroxypenyl)-3-cyclopropylurea (II) with 7-methoxy-4- chloro-quinoline-6-carboxamide (III). As per the said patent application, l-(2-chloro-4- hydroxypenyl)-3-cyclopropylurea is prepared by Part-1 and 7-methoxy-4-chloro-quinoline-6- carboxamide is prepared by Part-2. These processes are described herein as above (Scheme- 1).
WO2005/044788 discloses process for the preparation of Lenvatinib wherein the condensation reaction is performed between l-(2-chloro-4-hydroxypenyl)-3-cyclopropylurea (II) with 7- methoxy-4-chloro-quinoline-6-carboxamide (III) in dimethylsulfoxide, in the presence of cesium carbonate or potassium t-butoxide. WO2005/063713 discloses various crystalline forms like A, B and C of Lenvatinib mesylate. Further, a hydrate and an acetic acid solvate of Lenvatinib methanesulfonate are claimed as 'Form F' and 'Form Γ, respectively. In addition, crystals of Lenvatinib ethanesulfonate salt are disclosed as 'Form a' and 'Form β' . Methanesulfonate salt of Lenvatinib is prepared by reacting Lenvatinib with methanesulfonic acid using methanol or acetic acid as solvent. WO2006/137474 discloses an amorphous form of Lenvatinib methanesulfonate and ethanesulfonate salt. Further, the said patent application also discloses preparation of these amorphous salts of Lenvatinib by dissolving their corresponding crystalline form salts in an alcohol and water followed by filtration and lyophilization.
WO2014/098176 discloses an amorphous form of Lenvatinib. The said patent application also discloses preparation of an amorphous form of Lenvatinib by dissolving Lenvatinib crystals in solvents selected from the group consisting of water, an alcohol (C1-6), an ether, acetonitrile or a combination thereof followed by freeze-drying of the said solution.
WO2016/184436 discloses a new crystal form of Lenvatinib mesylate salt (Form M) and process for the preparation thereof. The said process of preparation involves crystallization of Lenvatinib 'Form M' crystals from Lenvatinib using solvent acetonitrile.
WO2017/186197 claims salts of Lenvatinib with an acid in a solid form, wherein the acid is selected from the group consisting of phosphoric acid, tartaric acid, citric acid, camphorsulfonic acid, isethionic acid and naphthalenedisulfonic acid. Further, the above-mentioned patent application discloses method of preparing the said salts and their X-Ray diffraction (XRD) data along with melting points.
WO2017/221215 claims salts of Lenvatinib with acetic acid, L-proline, maleic acid, citric acid, salicylic acid, succinic acid, and L-pyroglutamic acid, wherein the salt is either crystalline or
amorphous. Further, the above-mentioned patent application discloses method of preparing the said salts and their X-Ray diffraction (XRD) data along with DSC data.
V. Usharani et. al. (Asian Journal of Chemistry, Vol. 23(4), p. 1802, (2011)) disclose preparation of urea derivatives and use of theirs for the synthesis of various categories of active pharmaceutical ingredients including antineoplastic agent like sorafenib.
Dieqo Carnaroglio et. al. (Beilstein J Org. Chem. 2013, 9, 2378-2386) disclose preparation of alkyl urea derivatives.
The inventors of the present invention have developed an alternative improved process for the preparation of Lenvatinib with high yield. The present invention also entails an economical industrial process for the preparation of Lenvatinib with the reduced processing steps. Furthermore, the present invention comprises the novel use of a reagent in preparing Lenvatinib.
BRIEF DESCRIPTION OF THE DRAWINGS:
Figure-1: illustrates a powder X-Ray diffraction pattern (PXRD) of Lenvatinib (I) base crude obtained at the end of step-c of below summary;
Figure-2: illustrates a powder X-Ray diffraction pattern (PXRD) of Lenvatinib (I) base pure obtained at the end of step-d of below summary;
Figure-3: illustrates a powder X-Ray diffraction pattern (PXRD) of an amorphous form of Lenvatinib mesylate (V) monohydrate obtained at the end of step-e of below summary. Figure-4: illustrates an infrared absorption pattern of an amorphous form of Lenvatinib mesylate (V) monohydrate obtained at the end of step-e of below summary.
Figure-5: illustrates a DSC thermogram of an amorphous form of Lenvatinib mesylate (V) monohydrate obtained at the end of step-e of below summary.
SUMMARY OF THE INVENTION:
One aspect of the present invention relates to preparation of amorphous Lenvatinib mesylate (V) monohydrate comprising the reaction steps as below.
a) dissolving 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) in a suitable solvent,
b) preparing cyclopropane isocyanate solution in a suitable solvent,
c) reacting solution prepared in step-b with the reaction mass prepared in step-a to obtain
Lenvatinib (I) base crude,
d) purifying Lenvatinib (I) base crude in a suitable solvent using activated charcoal, e) reacting Lenvatinib (I) base pure obtained in step-d with methane sulphonic acid to obtain amorphous form of Lenvatinib mesylate (V) monohydrate.
The present invention is depicted as below.
4-amino-3 -chlorophenol methoxyquinoline- 4-(4-amino-3-chlorophenoxy)-7- 6-carboxamide methoxyquinoline-6-carboxamide (III) (IV) cyclopropane
isocyanate
Lenvatinib mesylate Lenvatinib (V) (I)
Scheme-2
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to an improved process for the preparation of Lenvatinib, wherein 4- (4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) in a suitable solvent, is reacted with cyclopropane isocyanate as a solution to yield Lenvatinib (I) base. Lenvatinib (I) base is eventually converted to yield Lenvatinib mesylate (V) monohydrate.
One embodiment of the present invention relates to preparation of Lenvatinib (I) base crude comprising the steps as below.
a) dissolving 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) in a suitable solvent,
b) preparing cyclopropane isocyanate solution,
c) reacting solution prepared in step-b with the reaction mass obtained in step-a to obtain Lenvatinib (I) base crude.
4-(4-amino-3-chlorophenoxy)-7- methoxyquinoline-6-carboxamide Lenvatinib base (I)
(IV) crude
In an embodiment of the present invention have a X-Ray diffraction pattern (PXRD) of Lenvatinib (I) base crude as shown in figure- 1.
In another embodiment of the present invention relates to Lenvatinib (I) base crude having one or more PXRD peaks (2 theta) at approximate positions: 4.06, 8.16, 9.66, 10.29, 12.33, 13.97, 16.47, 17.24, 18.46, 18.99, 19.97, 20.83, 21.63, 22.36, 23.20, 23.46, 24.22, 24.83, 25.35, 26.37, 27.97 and 29.37 + 0.5 degrees.
One embodiment of the present invention relates to purification of Lenvatinib (I) base crude comprising the steps as below.
a) dissolving Lenvatinib base (I) crude in a suitable solvent,
b) preparing hydrochloric acid solution,
c) reacting solution prepared in step-b with the reaction mass obtained in step-a followed by heating the same with activated charcoal to obtain yellowish clear filtrate,
d) preparing sodium carbonate solution,
e) reacting solution prepared in step-d with the reaction mass obtained in step-c to obtain Lenvatinib (I) base pure.
In an embodiment of the present invention have a X-Ray diffraction pattern (PXRD) of Lenvatinib (I) base pure as shown in figure-2.
In another embodiment of the present invention relates to Lenvatinib (I) base pure having one or more PXRD peaks (2 theta) at approximate positions: 4.21, 8.37, 10.43, 12.48, 14.08, 16.61, 19.15, 20.13, 21.00, 21.77, 23.53, 26.80, 28.20, 28.91, 29.47 + 0.5 degrees.
One embodiment of the present invention relates to preparation of amorphous form of Lenvatinib mesylate (V) monohydrate comprising the steps as below.
a) dissolving Lenvatinib base (I) pure in a suitable solvent,
b) preparing methane sulfonic acid solution,
c) reacting solution prepared in step-b with the reaction mass obtained in step-a with purified water to obtain clear gummy mass,
d) stirring reaction mass obtained in step-c with suitable solvent to afford amorphous form of Lenvatinib mesylate (V) monohydrate.
In an embodiment of the present invention have an infrared absorption spectrum of an amorphous form of Lenvatinib mesylate (V) monohydrate as shown in figure-4.
In another embodiment of the present invention relates to an amorphous form of Lenvatinib mesylate (V) monohydrate having wave numbers of the absorption peak (cm 1) and transmittance (%T) at approximate positions as below.
In an embodiment of the present invention have a DSC of an amorphous form of Lenvatinib mesylate (V) monohydrate as shown in figure-5.
In another embodiment of the present invention relates to an amorphous form of Lenvatinib mesylate (V) monohydrate having an endothermic melting peak at about 161 + 0.5°C. The said endothermic melting peak is having onset at about 148 + 0.5°C and end at about 169 + 0.5°C.
In another embodiment of the present invention relates to an amorphous form of Lenvatinib mesylate (V) monohydrate having the ^-NMR chemical shift values as below:
!H-NMR Spectrum (DMSO-d6) 5(ppm): 0.207 (2H,S), 0.428-0.442 (2H,d), 2.188 (3H,S), 2.271- 2.355 (2H,S), 3.857 (3H,S), 6.717-6.734 (lH,d), 7.057 (1H,S), 7.119-7.147 (lH,dd), 7.407-7.412 (lH,d), 7.471 (1H,S), 7.688 (1H,S), 7.752 (1H,S), 7.860 (1H,S), 8.112-8.135 (lH,d), 8.489 (1H,S), 8.747-8.757 (lH,d).
Other embodiment of the present invention relates to method and novel use of cyclopropane isocyanate to prepare Lenvatinib (I) base by a shorter route. One embodiment of the present invention relates to preparation of cyclopropane isocyanate solution by diluting concentrated cyclopropane isocyanate with suitable solvent like DMF.
Additional embodiment of the present invention relates to purification of Lenvatinib (I) base crude using suitable solvents and activated charcoal.
In yet another embodiment of the present invention relates to use of hydrochloric acid solution during purification of Lenvatinib (I) base crude.
Another embodiment of the present invention relates to preparation of hydrochloric acid solution by diluting concentrated hydrochloric acid with purified water.
In yet another embodiment of the present invention relates to use of sodium carbonate solution during purification of Lenvatinib (I) base crude. Another embodiment of the present invention relates to preparation of sodium carbonate solution by dissolving sodium carbonate in purified water.
Another embodiment of the present invention relates to method of preparation of Lenvatinib mesylate (V) monohydrate by reacting Lenvatinib (I) base with methane sulfonic acid and suitable organic solvents accompanied by purified water.
Another embodiment of the present invention relates to preparation of methane sulfonic acid solution by diluting concentrated methane sulfonic acid with methanol. Another aspect of the invention relates to pharmaceutical composition comprising Lenvatinib mesylate (V) prepared by using any of the process depicted in this specification, used for the treatment of cancer, especially thyroid cancer, for the treatment of patients with thyroid carcinoma histologically as differentiated (DTC), medullary and anaplastic.
According to the present invention, 4-chloro-7-methoxyquinoline-6-carboxamide (III) was reacted with 4-amino-3-chlorophenol in the presence of suitable solvent like dimethylsulfoxide to obtain 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV). Further, obtained 4-(4- amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) was reacted with isocyanate cyclopropane in a suitable solvent to obtain Lenvatinib (I) base crude. Lenvatinib (I) base crude was purified using suitable solvents and activated charcoal to obtain Lenvatinib (I) base pure. Lenvatinib (I) base pure was reacted with methane sulfonic acid to afford Lenvatinib mesylate (V) monohydrate in amorphous form. The obtained amorphous form of Lenvatinib mesylate (V) monohydrate complies purity norms as per ICH guidelines.
The scope of invention is not only limited to above-mentioned specific embodiments, but also shall be read in conjunction with the disclosures done in the complete specification together with the information and knowledge which are known to the person skilled in the art. The invention is further exemplified by the following examples, which are illustrative representation of the preferred modes of carrying out the invention. However, these examples are in no way limitative to the scope of the present invention.
EXAMPLE- 1: Preparation of 4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6- carboxamide (IV)
4-amino-3-chlorophenol (1.213 g) was dissolved in dimethylsulfoxide (10 ml) followed by charging of sodium hydride (0.290 g) and reaction mixture was stirred for 30 min at room temperature. 4-chloro-7-methoxyquinoline-6-carboxamide (III) (1.0 g) was gradually added into the said reaction mass at room temperature and the resulted mixture was heated at 100°C for 2 h under stirring. In-process conversion was monitored by TLC until completion of the reaction. After completion of the reaction, purified water (100 ml) and ethyl acetate (50 ml) were added to the reaction mixture at room temperature. The obtained product contained an organic layer that was washed with purified water (50 ml) followed by brine solution. Solvent was distilled out to obtain the title compound (1.216 g).
Yield: 83.7 %
EXAMPLE-2: Preparation of Lenvatinib base (I) crude
4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) (50 g) was added in methylene dichloride (350 ml) followed by cooling of the reaction mass. Cyclopropane isocyanate solution (12 g in 50 ml of MDC) (56 ml) was gradually added in 15-20 min to above reaction mass at room temperature. The resulting mixture was stirred at room temperature for 22 h and in-process conversion was monitored by TLC until completion of the reaction. Solvent was distilled out after completion of the reaction to afford the title compound. (54.6 g).
Yield: 88.0 %; Purity: 96.00 %
EXAMPLE-3: Preparation of Lenvatinib base (I) crude
4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) (50 g) was added in acetone (300 ml) followed by stirring of the reaction mass at room temperature. Cyclopropane isocyanate solution (12 g in 36 ml acetone) (42 ml) was added in 15-20 min to above reaction mass at room temperature. The resulting mixture was stirred at room temperature for 20 h and in-process conversion was monitored by TLC until completion of the reaction. Solvent was distilled out by reducing pressure after completion of the reaction to afford the title compound. Lenvatinib base (crude) was recrystallized in acetone: water (1:2) and dried at 50-55°C to afford the title compound (57.66 g).
Yield: 93.0 %; Purity: 96.20 %
EXAMPLE-4: Preparation of Lenvatinib base (I) crude
4-(4-amino-3-chlorophenoxy)-7-methoxyquinoline-6-carboxamide (IV) (50 g) was added in dimethylformamide (100 ml). Cyclopropane isocyanate solution (12 g in 25 ml DMF) (31 ml) was added in 15-20 min to above reaction mass at room temperature. The resulting mixture was stirred at room temperature for 2-3 h and in-process conversion was monitored by TLC till completion of the reaction. Purified water (1700 ml) was charged into another assembly at room temperature followed by cooling at 5-10°C. The above cooled reaction mass was slowly added into pre-chilled water for 30-45 min under stirring at 5-10°C. The said reaction mass was stirred for 1 h at 10-20°C and filtered. Obtained solid material is washed with purified water (100 ml) and sucked to get wet cake (90-100 g). Wet cake was dried under vacuum at 40-45°C until the moisture content of the product reaches not more than 1.0% to afford the title compound (58.67 g).
Yield: 94.5 %; Purity: 97.85 %
EXAMPLE-5: Preparation of Lenvatinib base (I) pure
Methanol (6000 ml) was added to Lenvatinib (I) base (100 g) crude obtained as per previous examples at room temperature. Hydrochloric acid solution (prepared by 34.2 g of 28-30% HC1 diluted with 34.2 ml purified water) (64 ml) was added to the said reaction mass and stirred for 10-15 followed by heating the same at 35-40°C. Activated charcoal (5 g) was added in to the above reaction mass at 35-40°C followed by filtration through celite hyflo bed. The said hyflo bed was washed with methanol (twice with 100 ml) to obtain yellowish clear filtrate and cool the reaction mass to room temperature. Sodium carbonate solution (prepared by dissolving 19 g sodium carbonate in 170 ml of purified water) (180 ml) was added to the said reaction mass at room temperature to obtain white thick slurry. Purified water (1000 ml) was added at the room temperature to the reaction mass to obtain stirrable slurry followed by filtration through cotton cloth and whatman filter paper. The obtained solid material was washed with purified water (100 ml, four times) and sucked dry to get wet cake (250-280 g). Wet cake was dried under vacuum at 40-45°C until the moisture content of the product reaches not more than 1.0% to afford the title compound (92 g).
Yield: 92.0 %; Purity: 99.81 %
EXAMPLE-6: Preparation of an amorphous form of Lenvatinib mesylate (V) monohydrate Methanol (300 ml) was added to Lenvatinib (I) base (30 g) pure obtained as per previous example- 5 at room temperature and stirred for 30 min. Solution of methane sulfonic acid (prepared by diluting 6.75 g MeS03H in 60 ml methanol) (64.56 ml) was slowly added in to above reaction mass in 10-15 min at room temperature. The said reaction mass was stirred at room temperature for 4 h to obtain off white slurry followed by filtration. Obtained wet cake (29.8 g) was washed with methanol (30 ml, twice). The said wet cake (29.8 g) was charged in to glass assembly with purified water (596 ml) at room temperature and reaction mass was stirred for 2 h to get clear gummy mass. Ethanol (596 ml) was added to the obtained reaction mass for 2 h at room temperature to get yellow mass. The reaction mass was transferred in to buchi round bottom flask at room temperature. Under reduced pressure, solvent was distilled out in rota vapour below 35°C. The obtained material was dried in vacuum tray dryer below 35°C for 12 h to afford the title compound (34.1 g).
Yield: 92.9 %; Purity: 99.58 %
Lenvatinib mesylate (V) monohydrate amorphous prepared by above example is having the Ή- NMR chemical shift values as below:
Ή-ΝΜΡν Spectrum (DMSO-d6) 5(ppm): 0.207 (2H,S), 0.428-0.442 (2H,d), 2.188 (3H,S), 2.271- 2.355 (2H,S), 3.857 (3H,S), 6.717-6.734 (lH,d), 7.057 (1H,S), 7.119-7.147 (lH,dd), 7.407-7.412 (lH,d), 7.471 (1H,S), 7.688 (1H,S), 7.752 (1H,S), 7.860 (1H,S), 8.112-8.135 (lH,d), 8.489 (1H,S), 8.747-8.757 (lH,d).
Lenvatinib mesylate (V) monohydrate amorphous prepared by above example is having an endothermic melting peak at about 161 + 0.5°C. The said endothermic melting peak is having onset at about 148 + 0.5°C and end at about 169 + 0.5°C as shown in figure-5.
Lenvatinib mesylate (V) monohydrate amorphous prepared by above example is having an infrared absorption spectrum (as shown in figure-4) with wave numbers of the absorption peak (cm 1) and transmittance (%T) at approximate positions as below.
EXAMPLE-7: Oral formulation of an amorphous form of Lenvatinib mesylate (V) monohydrate
An amorphous form of Lenvatinib mesylate (V) monohydrate as prepared by preceding examples was geometrically mixed with calcium carbonate, mannitol and microcrystalline cellulose to prepare blend A. Hydorxypropylcellulose (HPC) was dissolved into an organic solvents to prepare a binder solution. Prepared binder solution was sprayed or poured into blend A to from granules
using fluid bed processor or rapid mixer granulator, respectively. The prepared granules were dried and size-controlled using mesh of an appropriate size. These size-controlled granules were lubricated using talc. These granules were filled in hard capsules or compressed to form tablets. The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasized in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
Claims
1. A process for preparation of Lenvatinib mesylate (V) monohydrate comprising:
(a) reacting 4-(4-amino-3-chlorophenoxy)7-methoxyquinoline-6-carboxamide (IV) in a suitable solvent at 25-30°C,
(b) preparing cyclopropane isocyanate solution in a suitable solvent,
(c) reacting solution prepared in step- 1(b) with the reaction mass prepared in step- 1(a) at °C,
(d) purifying Lenvatinib (I) base crude obtained in step- 1(c) in a suitable solvent using activated charcoal at 35-40°C followed by reacting with sodium carbonate solution a °C,
(e) reacting Lenvatinib (I) base pure obtained in step- 1(d) in a suitable solvent with methane sulphonic acid followed by addition of purified water with a suitable solvent at 25-30°C to obtain Lenvatinib mes late V monoh drate.
2. The process for preparation of Lenvatinib mesylate (V) monohydrate as claimed in claim
1, wherein obtained Lenvatinib mesylate (V) monohydrate is in amorphous state,
(a) having an endothermic melting peak at about 161 + 0.5°C;
(b) having the ^-NMR chemical shift values at the approximate positions:
!pi-NMR Spectrum (DMSO-d6) 5(ppm): 0.207 (2H,S), 0.428-0.442 (2H,d), 2.188 (3H,S), 2.271-2.355 (2H,S), 3.857 (3H,S), 6.717-6.734 (lH,d), 7.057 (1H,S), 7.119- 7.147 (lH,dd), 7.407-7.412 (lH,d), 7.471 (1H,S), 7.688 (1H,S), 7.752 (1H,S), 7.860 (1H,S), 8.112-8.135 (lH,d), 8.489 (1H,S), 8.747-8.757 (lH,d) and;
(c) having an infrared absorption spectrum showing wave numbers of the absorption peak (cm 1) and transmittance (%T) at approximate positions as depicted below:
3. The process for preparation of Lenvatinib mesylate (V) monohydrate as claimed in claim 1, wherein a suitable solvent is selected as dimethylformamide (DMF) in step- 1(a) to step- lib) and methanol or ethanol in step- 1(d) to step- 1(e).
4. A process for preparation of Lenvatinib base (I) crude comprising:
(a) reacting 4-(4-amino-3-chlorophenoxy)7-methoxyquinoline-6-carboxamide (IV) in DMF at 25-30°C,
(b) adding cyclopropane isocyanate solution to the reaction mass obtained in step-4 (a) at 25-30°C followed by stirring for 2-3 h,
(c) adding purified water into the reaction mass obtained in step-4 (b) and cooling the same to 5-10°C,
(d) adding the reaction mass obtained in step-4 (c) into pre-chilled water followed by stirring the same for 1 h at 10-20°C,
(e) washing of solid material obtained in step-4 (d) with purified water followed by sucked drying to get wet cake,
(f) drying of the wet cake obtained in step-4 (e) at 40-45°C to afford Lenvatinib base (I) crude. 5. The process for preparation of Lenvatinib base (I) crude as claimed in claim 4, wherein obtained Lenvatinib base (I) crude is having one or more PXRD peaks (2 theta) at approximate positions of 4.06, 8.16, 9.66, 10.29, 12.33, 13.97, 16.47, 17.24, 18.46, 18.99, 19.97, 20.83, 21.63, 22.36, 23.20, 23.46, 24.22, 24.83, 25.35, 26.37, 27.97 and 29.37 + 0.
5 degrees.
6. A process for purifying Lenvatinib base (I) crude comprising:
(a) dissolving Lenvatinib base (I) crude in methanol at 25-30°C,
(b) adding hydrochloric acid solution to the reaction mass obtained in step-5 (a) at 25- 30°C followed by stirring for 10-15 min,
(c) adding activated charcoal into the reaction mass obtained in step-5 (b) and heating the same to 35-40°C for 1 h followed by cooling to 25-30°C,
(d) adding sodium carbonate solution into the reaction mass obtained in step-5 (c) followed by stirring the same for 1 h at 25-30°C,
(e) washing of solid material obtained in step-5 (d) with purified water followed by sucked drying to get wet cake,
(f) drying of the wet cake obtained in step-5 (e) at 40-45°C to afford Lenvatinib base (I) pure.
7. The process for purifying Lenvatinib base (I) crude as claimed in claim 6, wherein obtained Lenvatinib base (I) pure is having one or more PXRD peaks (2 theta) at approximate positions of 4.21, 8.37, 10.43, 12.48, 14.08, 16.61, 19.15, 20.13, 21.00, 21.77, 23.53, 26.80, 28.20, 28.91, 29.47 + 0.5 degrees.
8. A process for preparation of amorphous form of Lenvatinib mesylate (V) monohydrate comprising:
(a) dissolving Lenvatinib base (I) pure in methanol at 25-30°C,
(b) adding methane sulfonic acid solution to the reaction mass obtained in step-6 (a) followed by stirring for 4 h at 25-30°C,
(c) adding purified water into the wet cake obtained in step-6 (b) followed by stirring the reaction mass for 2 h at 25-30°C,
(d) adding ethanol into clear gummy mass obtained in step-6 (c) followed by stirring the same for 2 h at 25-30°C,
(e) distilling solvents from clear yellow mass obtained in step-6 (d) under reduced pressure in rota vapour below 35°C,
(f) drying of the reaction mass obtained in step-6(e) below 35°C for 12 h to afford amorphous form of Lenvatinib mesylate (V) monohydrate.
9. An oral pharmaceutical composition comprising of an amorphous form of Lenvatinib mesylate (V) monohydrate and pharmaceutically acceptable excipients.
10. An amorphous form of Lenvatinib mesylate monohydrate.
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| CN112654603A (en) * | 2018-09-07 | 2021-04-13 | 因德纳有限公司 | Preparation method of lenvatinib |
| CN113087666A (en) * | 2020-01-09 | 2021-07-09 | 南京正大天晴制药有限公司 | Process for the preparation of amorphous quinoline carboxamide derivatives |
| CN113372270A (en) * | 2021-06-24 | 2021-09-10 | 江西国药有限责任公司 | Lunvatinib and preparation method thereof |
| CN113831283A (en) * | 2021-11-04 | 2021-12-24 | 南京科默生物医药有限公司 | Preparation method of amorphous matter of Ranuncutinib salt |
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| CN112654603A (en) * | 2018-09-07 | 2021-04-13 | 因德纳有限公司 | Preparation method of lenvatinib |
| CN112654603B (en) * | 2018-09-07 | 2024-05-03 | 意迪那有限公司 | Preparation method of lenvatinib |
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| CN113831283A (en) * | 2021-11-04 | 2021-12-24 | 南京科默生物医药有限公司 | Preparation method of amorphous matter of Ranuncutinib salt |
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