WO2014170910A1 - Process for the preparation of lapatinib - Google Patents
Process for the preparation of lapatinib Download PDFInfo
- Publication number
- WO2014170910A1 WO2014170910A1 PCT/IN2014/000210 IN2014000210W WO2014170910A1 WO 2014170910 A1 WO2014170910 A1 WO 2014170910A1 IN 2014000210 W IN2014000210 W IN 2014000210W WO 2014170910 A1 WO2014170910 A1 WO 2014170910A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- improved process
- chloride
- compound
- solvent
- Prior art date
Links
- 0 CS(CCN(*)Cc1ccc(-c(cc2)cc3c2ncnc3O)[o]1)(=O)=O Chemical compound CS(CCN(*)Cc1ccc(-c(cc2)cc3c2ncnc3O)[o]1)(=O)=O 0.000 description 2
- SAOUQBGFYWYISS-UHFFFAOYSA-N CN(C(c1c2)NC(CC3)=CC(Cl)=C3OCc3cccc(F)c3)C=Nc1ccc2-c1ccc(CNCCS(C)(=O)=O)[o]1 Chemical compound CN(C(c1c2)NC(CC3)=CC(Cl)=C3OCc3cccc(F)c3)C=Nc1ccc2-c1ccc(CNCCS(C)(=O)=O)[o]1 SAOUQBGFYWYISS-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- Present invention relates to a novel process for the preparation of lapatinib of formula-I having chemical name N- ⁇ 3-Chloro-4-[(3-fluorobenzyloxy]phenyI ⁇ -6-[5- ( ⁇ [2-(methanesulfonyl)ethyl]-amino ⁇ methyl]-2-furyl]-4-quinazolinamine and its pharmaceutically acce table salts.
- Lapatinib ditosylate of formula-II is currently marked in the United States under the trade name TYKERB by GlaxoSmithKline. It was approved by the US FDA as a drug for use in patients with advanced metastatic breast cancer.
- Lapatinib of formula-I is reported for the first time by M.C. Carter et.al in PCT International Publication No. : WO 99/35146 (1999 to Glaxo). Its equivalent US Patent is US 6727256 (2004 to SmithKline Beecham). Process for the preparation of Lapatinib of formula-I, disclosed in WO 99/35146, is given in Scheme-I.
- 4-chloro-6-iodo-quinazoline of formula-Ill is reacted with 3-chloro-4- (3 1 -fluoro-benzyloxy)aniline to get N-[3-chloro-4- ⁇ (3'-fluoro-benzyloxy)phenyl ⁇ ]-6- iodo-quinazoline of formula-IV.
- the main objective of the present invention is to provide an improved process for the preparation of Lapatinib of formula-I, which is simple, economical and commercially applicable.
- the present invention is to provide an improved process for the preparation of Lapatinib of formula-I, which involves readily and cheaply available raw materials.
- Yet another objective of the present invention is to provide an improved process for the preparation of lapatinib of formula-I which avoids the usage of costly boronic acid intermediates and palladium reagents.
- 6-aminoquinazoline derivatives are considered as potential precursors for diazonium intermediates.
- 2-amino-5- nitrobenzonitrile of formula- VIII could be a suitable starting material.
- the chloro compound is reacted with 3-chloro-4-(3- fluorobenzyloxy)aniline at an elevated temperature to get the N-aryl derivative of formula-XVII.
- the N-protected group of compound of formula-XVII is removed under acidic or basic conditions to get lapatinib base of formula-I.
- the crude base is converted into tosylate salt by using p-toluenesulfonic acid monohydrate to get technical lapatinib ditosylate salt of formula-II.
- the crude salt is crystallized from aqueous isopropyl alcohol to get high purity lapatinib ditosylate monohydrate salt.
- the present invention provides an improved process for the preparation of Lapatinib of formula-I.
- R C1-C6 alkyl, perfluoroalkyl, C1-C6 alkoxy, etc.
- X CI, Br, I, OS0 2 CH 3 , OS0 2 CF 3 , OTs, OBs, etc.
- R C1-C6 alkyl, perfluoroalkyl, C 1 -C6 alkoxy, etc.
- metal catalyst used in step (i) is selected from iron, zinc, nickel, etc., preferably iron powder.
- Alcoholic solvent used in step (i) is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, t- butanol, etc., preferably isopropanol.
- Acid medium used in diazotization step (ii) is selected from dilute hydrochloric acid, sulfuric acid, preferably hydrochloric acid.
- Copper catalyst used in step (ii) is selected from copper (II) chloride, copper (II) acetate, etc., preferably copper (II) chloride.
- solvent used in step (iii) is selected from alcoholic solvents such as methanol, ethanol, isopropanol, ethers like tetrahydrofuran, diisopropyl ether, 1,4-dioxane, nitriles like acetonitrile, amides like dimethylformamide, etc. preferably methanol or tetrahydrofuran, more preferably methanol.
- Salt of 2-(methylsulfonyl)ethylamine used in step (iii) is selected from hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, etc., preferably hydrochloride.
- Temperature of the reaction in step (iii) is the boiling point of the solvent or 50-70°C.
- neutralizing reagents such as triethylamine or other non-reactive bases are used to neutralize acid part.
- Reducing agent used in step (iv) is selected from a borohydride reagent such lithium boroh dride, sodium borohydride, sodium tri(acetoxy)borohydride, vitride, lithium aluminum hydride, catalytic reduction in the presence of metal such as Nickel, palladium, rhodium, platinum, etc., preferably 5-10% of 50% wet palladium-on- carbon.
- Solvent used in step (iv) is selected from methanol, isopropanol, THF, dimethylformamide or a combination thereof.
- Acylating agent used in step (v) is selected from C1-C6 alkanoyl/perfluoroalkanoyl halide or C1-C6 alkanoic/perfluoroalkanoic anhydride, Boc anhydride, t- butyldimethylsilyl chloride.
- Solvent used in step (v) is selected from tetrahydrofuran, ethyl acetate, methylene chloride, etc.
- Suitable reagent used in step (vi) is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p- toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, etc., preferably oxalyl chloride or thionyl chloride.
- Suitable solvent used in step (vi) is selected from tetrahydrofuran, chloroform, acetonitrile, toluene, preferably tetrahydrofuran or chloroform. Temperature of the reaction in step (vi) is ambient to reflux temperature of the solvent preferably 50-60°C.
- Amount of 3-chloro 4-(3-fluorobenzyloxy)aniline used in step (vii) is 1.0-2.2 molar equivalents to the compound of formula-XVII. Temperature of the reaction in step (vii) is the boiling point of the solvent employed in the reaction.
- Product isolated in step (vii) is a hydrochloride salt when the leaving group is a chloride. This hydrochloride salt can be neutralized with a suitable base to get N-acylated compound of formula-XIX.
- Acid used in step (viii) is selected from dilute hydrochloric acid, sulfuric acid, nitric acid, etc., preferably dilute sulfuric acid.
- Base used in step (viii) is selected from sodium/potassium hydroxide or carbonate, preferably sodium hydroxide.
- Solvent employed in step (viii) aqueous alcohols or ethers.
- Solvent used in salt formation step (ix) can be aqueous alcoholic solvent as disclosed in WO2011039759 or WO2010061400.
- Method 1 Into a 5 L, four-necked, RB flask was charged isopropyl alcohol (2 L), water (1 L), iron powder (248 g), and ammonium chloride (13 g). The reaction mass was heated to 70-75 °C and added 6-nitroquinazolin-4-ol (100 g) in 3-4 lots keeping the mass under reflux temperature. After the addition of final lot reaction mass was maintained at reflux for 1.5 h and monitored the progress of reaction by TLC. Reaction mass was cooled to 50-60 °C, and filtered through Buchner funnel and flask. The filtrate was transferred into a single-necked RB flask and distilled off solvent partially under reduced pressure keeping the temperature below 60 °C.
- Method-2 Into a 250 ml, four-necked, RJB flask was charged 5.0 g of 6- nitroquinazolin-4-ol and 100 ml of ⁇ , ⁇ -dimethylformamide. The reaction mass was heated to 50-60 °C and maintained for 30 minutes to dissolve the solid. The solution was transferred into a 1 L stainless steel hydrogenation kettle. Raney nickel (5.0 g, wet) was charged into the reaction mass. The kettle was connected to hydrogenation set up and shaken at 50-60 psi hydrogen pressure. After completion of hydrogen consumption the kettle was removed from the hydrogenation set up and filtered. DMF was distilled of from the filtrate under reduced pressure.
- Step-I Preparation of (E/Z)-6-(5-((2-(methylsulfonyl)ethylimino)methyl)furan- 2-yl)quinazoIin-4-ol (XV)
- Method 1 Into a 2 L, four-necked, RB flask was charged 875 ml of N,N- dimethylformamide and the above wet solid compound. Palladium-on-carbon (10%, 10.0 g, 50% wet) was added to the reaction mass under nitrogen atmosphere. Hydrogen gas was bubbled into the reaction mass at 25-30 °C under stirring. After completion of the reaction, mass was filtered and concentrated under reduced pressure to get crude compound. Methanol (400 ml) was added to the residual mass and stirred for 30 min. The solid thus formed was filtered and dried at 60-65 °C to get 49.0 g of title compound as a greenish yellow powder. HPLC purity is 95.1%. !
- IR (KBr, cm “1 ): 3339.7, 2928.0, 2362.4, 1637.3, 1608.6, 1593.4, 1572.1, 1539.1, 1497.9, 1445.9, 1425.6, 1394.3, 1371.0, 1330.5, 1294.8, 1216.9, 1 198.2, 1171.6, 1 123.8, 1061.4, 1026.5, 956.6, 927.8, 888.3, 868.1, 839.9, 789.7, 748.5, 679.9, 643.2, 628.7, 544.4, 517.6, and 501.5.
- reaction mass was cooled to 50° C and distilled of solvent under reduced pressure. Finally, 2 x 50 ml of toluene was added and distilled under reduced pressure to remove traces of thionyl chloride to get the crude title compound. It was directly used in next step.
Abstract
Present process relates to an improved and commercial process for the preparation of lapatinib of formula-I or its pharmaceutically acceptable p-toluenesulfonate salt involving novel intermediates of formulae-XVII, XVIII, and XIX. Present process utilizes Meerwein reaction as a key step in the aryl C-C bond formation step avoiding costly boronate coupling chemistry used in the conventional synthesis of lapatinib.
Description
PROCESS FOR THE PREPARATION OF LAPATINIB
FIELD OF INVENTION:
Present invention relates to a novel process for the preparation of lapatinib of formula-I having chemical name N-{3-Chloro-4-[(3-fluorobenzyloxy]phenyI}-6-[5- ({[2-(methanesulfonyl)ethyl]-amino}methyl]-2-furyl]-4-quinazolinamine and its pharmaceutically acce table salts.
II: ditosylate
Lapatinib ditosylate of formula-II is currently marked in the United States under the trade name TYKERB by GlaxoSmithKline. It was approved by the US FDA as a drug for use in patients with advanced metastatic breast cancer.
BACKGROUND OF INVENTION:
Lapatinib of formula-I is reported for the first time by M.C. Carter et.al in PCT International Publication No. : WO 99/35146 (1999 to Glaxo). Its equivalent US Patent is US 6727256 (2004 to SmithKline Beecham). Process for the preparation of Lapatinib of formula-I, disclosed in WO 99/35146, is given in Scheme-I. Accordingly, 4-chloro-6-iodo-quinazoline of formula-Ill, is reacted with 3-chloro-4- (31-fluoro-benzyloxy)aniline to get N-[3-chloro-4-{(3'-fluoro-benzyloxy)phenyl}]-6- iodo-quinazoline of formula-IV. Compound of formula-TV is reacted with (1,3- dioxolan-2-yl)-2-(tributylstannyl)furan to get the compound of formula-V which on reaction with HC1, gave 5-(4-{3-chloro-4-(3-fluoro-benzyloxy)anilino}-6-
quinazolinyl)-furan-2-carbaldehyde of formula- VI. The compound of formula- VI is reacted with 2-methanesulfonylethylamine, followed by reduction to give the required compound Lapatinib of formula-I as an organic residue. The crude labatinib is purified by column chromatography.
Scheme-I
In the subsequent PCT international publication No. WO 02/02552 (Glaxo) and its equivalent US7157466; the preparation of ditosylate salt of Lapatinib of formula-II is disclosed as shown in Scheme-II.
Subsequently processes for the preparation of Lapatinib and its ditosylate are described in PCT applications WO 2002/056912, WO 2003/086467, WO 2005/046678, WO 2006/002422, WO 2006/089150, WO 2006/1 13649, WO 2007/121279, WO 2007/143483, WO 2008/063853, WO 2008/067144, WO 2008/154469, WO 2009/079547, WO 2009/079541, WO 2009/140144, WO
2010/017387, WO 2010/061400, WO 2010/120387, WO 2010/148163, WO 2011/035540, WO 2011/039759, WO 2011/1 16634, WO 201 1/160594, WO 2012083440, and WO 2012/017448. Process for the preparation of lapatinib is also disclosed in EP 2468745 and EP 2489661. In these disclosed processes key reaction is based on the coupling of one arylboronic acid with one haloaryl moiety in the presence of a palladium reagent.
VII
Scheme-II Main drawbacks in these processes are the involvement of costly intermediates having boronic acid functionality and the palladium catalysts.
SUMMARY OF THE INVENTION:
Keeping in view of the difficulties in the above mentioned prior art processes for the preparation of Lapatinib on a commercial scale, we aimed to develop a simple, economical and commercially viable process for the preparation of Lapatinib, of formula-I.
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of Lapatinib of formula-I, which is simple, economical and commercially applicable. According to another objective of the present invention is to provide an improved process for the preparation of Lapatinib of formula-I, which involves readily and cheaply available raw materials.
Yet another objective of the present invention is to provide an improved process for the preparation of lapatinib of formula-I which avoids the usage of costly boronic acid intermediates and palladium reagents.
During our sustained research in developing a process for the preparation of Lapatinib of formula-I on a commercially viable scale, we observed that Meerwein reaction between an aryl diazonium salt and furfuraldehyde would provide the required aryl C-C coupled product. Such process would eliminate the need of aryl boronic acid and palladium catalysts. According to Meerwein reaction furfuraldehyde would react exclusively on 5-position with a diazonium salt in the presence of a metal catalyst (Scheme-Ill).
VIII IX X
Scheme-Ill
Accordingly, 6-aminoquinazoline derivatives are considered as potential precursors for diazonium intermediates. Commercially and readily available 2-amino-5- nitrobenzonitrile of formula- VIII could be a suitable starting material.
DETAILED DESCRIPTION OF THE INVENTION:
Process of the present invention is given in below Scheme-IV. Commercially available 2-amino-5-nitrobenzonitrile of formula-XI is reacted with formic acid/sulfuric acid under known conditions (Bertrand Jacques Jean-Claude, et al, J. Med. Chem. 2006, 49, 3544-3552) to get 6-nitro-quinazolin-4-ol of the formula-XII. The compound of formula-XII is reduced with iron powder and catalytic quantity of ammonium chloride in the presence of aqueous isopropyl alcohol to get 6-amino- quinazolin-4-ol of formula-XIII. The amino compound of formula-XIII is diazotized with sodium nitrite in hydrochloric acid medium and coupled with 2-furfuraldehyde in the presence of cupric chloride to get the coupled aldehyde compound of formula- XIV.
The key intermediate of formula-XIV was reacted with 2-methanesulfonylethylamine or its salt in the presence of triethylamine in an alcoholic solvent at reflux temperature to give the corresponding, imine compound of formula-XV, which was reduced to get the amine compound of formula-XV. The amine compound of formula-XV is selectively protected on H group with trifluoroacetic anhydride to get the corresponding trifluoroacetyl derivative of formula-XVI. Compound of formula-XVI is reacted with excess thionyl chloride or oxalyl chloride to get the chloro compound. The chloro compound is reacted with 3-chloro-4-(3- fluorobenzyloxy)aniline at an elevated temperature to get the N-aryl derivative of formula-XVII. The N-protected group of compound of formula-XVII is removed under acidic or basic conditions to get lapatinib base of formula-I. The crude base is converted into tosylate salt by using p-toluenesulfonic acid monohydrate to get technical lapatinib ditosylate salt of formula-II. The crude salt is crystallized from aqueous isopropyl alcohol to get high purity lapatinib ditosylate monohydrate salt.
Scheme-IV
In one embodiment, the present invention provides an improved process for the preparation of Lapatinib of formula-I.
and its pharmaceutically acceptable salts,
which comprises:
(i) Reduction of 6-nitroquinazolin-4-ol of formula-XII
XII
with a metal catalyst and a catalytic quantity of ammonium chloride in the presence of aqueous alcohols at reflux temperature to get the amino compound of formula-XIII,
XIII
Diazotization of compound of formula-XIII with sodium/potassium nitrite in the presence of an acid and coupling with furfural in the presence of a copper catalyst to get the coupled roduct of formula-XIV,
XIV
(iii) Reaction of compound of formula-XIV with 2-methanesulfonylethylamine or its salt in a solvent medium at elevated temperature to get an imine derivative of formula-XV,
XV
(iv) Reduction of compound of formula-XV in a solvent medium to get the amine compound of formula-XVI,
XVI
Selective protection of the amino group of the compound of formula-XVI with a suitable protecting group to get the compound of formula-XVII,
Wherein R = C1-C6 alkyl, perfluoroalkyl, C1-C6 alkoxy, etc.
(vi) Conversion of hydroxyl group present in XVII into a leaving group with a
suitable reagent to get the compound of formula-XVIII,
XVIII
Wherein X = CI, Br, I, OS02CH3, OS02CF3, OTs, OBs, etc., R = C1-C6 alkyl, perfluoroalkyl, C 1 -C6 alkoxy, etc.
(vii) Reacting the compound of the formula-XVIII with 3-chloro 4-(3- fluorobenzyloxy)aniline in a solvent medium at an elevated temperature to get the amine protected lapatinib base of formula-XIX,
Wherein R = as defined above
(viii) Removal of amine protection group in compound of formula-XIX using a base or acid to get lapatinib base of formula-I,
(ix) Conversion of lapatinib base into pharmaceutically acceptable p-tolunesulfonate salt in a solvent medium to get lapatinib di-tosylate of formula-II as its monohydrate,
II
In a preferred embodiment of the present invention metal catalyst used in step (i) is selected from iron, zinc, nickel, etc., preferably iron powder. Alcoholic solvent used
in step (i) is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, t- butanol, etc., preferably isopropanol. Acid medium used in diazotization step (ii) is selected from dilute hydrochloric acid, sulfuric acid, preferably hydrochloric acid. Copper catalyst used in step (ii) is selected from copper (II) chloride, copper (II) acetate, etc., preferably copper (II) chloride.
In a preferred embodiment of the present invention solvent used in step (iii) is selected from alcoholic solvents such as methanol, ethanol, isopropanol, ethers like tetrahydrofuran, diisopropyl ether, 1,4-dioxane, nitriles like acetonitrile, amides like dimethylformamide, etc. preferably methanol or tetrahydrofuran, more preferably methanol. Salt of 2-(methylsulfonyl)ethylamine used in step (iii) is selected from hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, etc., preferably hydrochloride. Temperature of the reaction in step (iii) is the boiling point of the solvent or 50-70°C. When slat is used in the reaction neutralizing reagents such as triethylamine or other non-reactive bases are used to neutralize acid part.
Reducing agent used in step (iv) is selected from a borohydride reagent such lithium boroh dride, sodium borohydride, sodium tri(acetoxy)borohydride, vitride, lithium aluminum hydride, catalytic reduction in the presence of metal such as Nickel, palladium, rhodium, platinum, etc., preferably 5-10% of 50% wet palladium-on- carbon. Solvent used in step (iv) is selected from methanol, isopropanol, THF, dimethylformamide or a combination thereof.
Acylating agent used in step (v) is selected from C1-C6 alkanoyl/perfluoroalkanoyl halide or C1-C6 alkanoic/perfluoroalkanoic anhydride, Boc anhydride, t- butyldimethylsilyl chloride. Solvent used in step (v) is selected from tetrahydrofuran, ethyl acetate, methylene chloride, etc.
Suitable reagent used in step (vi) is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p- toluenesulfonyl chloride, p-bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, etc., preferably oxalyl chloride or thionyl chloride. Suitable solvent used in step (vi) is selected from tetrahydrofuran, chloroform, acetonitrile, toluene, preferably tetrahydrofuran or chloroform. Temperature of the reaction in step (vi) is ambient to reflux temperature of the solvent preferably 50-60°C.
Amount of 3-chloro 4-(3-fluorobenzyloxy)aniline used in step (vii) is 1.0-2.2 molar equivalents to the compound of formula-XVII. Temperature of the reaction in step (vii) is the boiling point of the solvent employed in the reaction. Product isolated in step (vii) is a hydrochloride salt when the leaving group is a chloride. This hydrochloride salt can be neutralized with a suitable base to get N-acylated compound of formula-XIX.
Acid used in step (viii) is selected from dilute hydrochloric acid, sulfuric acid, nitric acid, etc., preferably dilute sulfuric acid. Base used in step (viii) is selected from sodium/potassium hydroxide or carbonate, preferably sodium hydroxide. Solvent employed in step (viii) aqueous alcohols or ethers.
Solvent used in salt formation step (ix) can be aqueous alcoholic solvent as disclosed in WO2011039759 or WO2010061400.
Present process involves the usage of novel compounds of formulae-XVII, XVIII, and XIX.
EXAMPLES:
The details of the invention are given in the Examples given below which are provided to illustrate the invention only and therefore should not be construed to limit the scope of present invention.
Example 1
Preparation of 6-nitroquinazolin-4-ol (XII)
Formic acid (500 ml, 85%) was charged into a 2 L, four-necked, RB flask and cooled to 15-20 °C. Cone, sulfuric acid (60 ml) was added to the mass and stirred for 15min at 15-20 °C. The reaction mass was heated to reflux temperature. Slurry of 2-amino- 5-nitrobenzonitrile (200 g) in 200 ml of 85% formic acid was added to the above reaction mass over a period of 10-15 minutes at reflux temperature. The reaction mass was maintained for lhr at reflux temperature. Reaction mass was cooled to 50- 60 °C and poured into ice-cold water. The reaction mass was stirred for 1 h at 25-30 °C, filtered, washed with water, and dried at 65-70 °C to get 217 g of yellow colored powder. HPLC purity is 98.9%.
Example 2
Preparation of 6-aminoquinazoIin-4-ol (XIII)
Method 1: Into a 5 L, four-necked, RB flask was charged isopropyl alcohol (2 L), water (1 L), iron powder (248 g), and ammonium chloride (13 g). The reaction mass was heated to 70-75 °C and added 6-nitroquinazolin-4-ol (100 g) in 3-4 lots keeping the mass under reflux temperature. After the addition of final lot reaction mass was maintained at reflux for 1.5 h and monitored the progress of reaction by TLC. Reaction mass was cooled to 50-60 °C, and filtered through Buchner funnel and flask. The filtrate was transferred into a single-necked RB flask and distilled off solvent partially under reduced pressure keeping the temperature below 60 °C. The product was filtered and dried in the oven at 60-65 °C to get 70 g of 6- aminoquinazolin-4-ol as a brown colored powder. HPLC purity is 99.25%. ^H-NMR
(400 MHz, DMSO-D6): δ 5.61 (s, 2H), 7.05-7.07 (m, 1H), 7.17-7.18 (d, 1H), 7.36- 7.38 (d, 1H), 7.75 (s, 1H), and 11.80 (s, 1H).
Method-2: Into a 250 ml, four-necked, RJB flask was charged 5.0 g of 6- nitroquinazolin-4-ol and 100 ml of Ν,Ν-dimethylformamide. The reaction mass was heated to 50-60 °C and maintained for 30 minutes to dissolve the solid. The solution was transferred into a 1 L stainless steel hydrogenation kettle. Raney nickel (5.0 g, wet) was charged into the reaction mass. The kettle was connected to hydrogenation set up and shaken at 50-60 psi hydrogen pressure. After completion of hydrogen consumption the kettle was removed from the hydrogenation set up and filtered. DMF was distilled of from the filtrate under reduced pressure. Ethyl acetate (20 ml) was added to the residue, filtered the solid and dried in a oven at 60-65 °C to get 4.0 g of 6-aminoquinazolin-4-ol as a yellow colored powder. HPLC purity is 93.0%.
Example 3
Preparation of 5-(4-hydroxyquinazolin-6-yl)furan-2-carbaxaldehyde (XIV) Method 1: Into a 250 ml, four-necked, RB flask was charged cone, hydrochloric acid (32.7 ml), water (20 ml), and 6-aminoquinazolin-4-ol (10 g). The reaction mass was cooled to 0-5 °C and added a solution of sodium nitrite (4.2 g) in water (24 ml) at below 5 °C. After maintaining for 30 minutes at 0-5 °C, a solution of furfural (6.6 g) in acetone (15 ml) was added to the reaction mass over a period of 30 minutes at 0-5 °C followed by a solution of cupric chloride (1.06 g) in water (30 ml). The reaction mass was maintained for 1.5 h at 0-5 °C and allowed to reach 10-15 °C and maintained for 4.0 h at that temperature. The reaction mass was filtered, washed the wet cake with water. The wet solid was taken into a flask and purified through its bisulphite adduct to get 6.5g of 5-(4-hydroxyquinazolin-6-yl)furan-2-carbaxaldehyde.
Purity by HPLC is 96.55%. 'H-NMR (400 MHz, DMSO-D6): δ 7.45-7.46 (d, 1H), 7.68-7.75 (dd, 2 H), 8.16 (s, lH), 8.24-8.26 (d, 1H), 8.53 (s, 1H), 9.64 (s, 1H), and 12.77 (s, 1H). Example 4
Preparation of 6-(5-((2-(methyIsulfonyl)ethylamino)methyl)furan-2- yl)quinazolin-4-oI (XVI)
Step-I: Preparation of (E/Z)-6-(5-((2-(methylsulfonyl)ethylimino)methyl)furan- 2-yl)quinazoIin-4-ol (XV)
Into a 1 L, four-necked, RB flask was charged 500 ml of methanol and 50.0 g of 5-(4- hydroxyquinazolin-6-yl)furan-2-carbaxaldehyde. 2-(Methylsulfonyl)ethylamine hydrochloride (50.0 g) was added to the reaction mass under stirring. Triethylamine (51.0 g) was added to the reaction at 25-30 °C, heated to reflux temperature, and maintained for 7.0 h. The reaction mass was cooled to 25-35 °C and filtered under suction to get 67g of the title compound as wet solid. The wet solid was directly used in the next step.
Step-II: Preparation of 6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2- yl)quinazolin-4-ol (XVI)
Method 1: Into a 2 L, four-necked, RB flask was charged 875 ml of N,N- dimethylformamide and the above wet solid compound. Palladium-on-carbon (10%, 10.0 g, 50% wet) was added to the reaction mass under nitrogen atmosphere. Hydrogen gas was bubbled into the reaction mass at 25-30 °C under stirring. After completion of the reaction, mass was filtered and concentrated under reduced pressure to get crude compound. Methanol (400 ml) was added to the residual mass and stirred for 30 min. The solid thus formed was filtered and dried at 60-65 °C to get 49.0 g of title compound as a greenish yellow powder. HPLC purity is 95.1%. !H- NMR (400 MHz, DMSO-D6): δ 2.96 (broad s, 2H), 3.02 (s, 3H), 3.24-3.27 (t, 2H),
3.80 (broad s, 2H), 6.43-6.44 (d, 1H), 7.05-7.06 (d, 1H), 7.68-7.70 (d, 1H), 8.08- 8.13 (t, 2H), 8.33 (s, 1H), and 12.29 (s, 1H).
Method 2: Reduction with sodium borohydride
Into 3 L, 4-necked RB flask was charged 55 g of (E/Z)-6-(5-((2- (methylsulfonyl)ethylimino)-methyl)furan-2-yl)quinazolin-4-ol, 1 L THF, and 250 ml of methanol. The reaction mass was cooled to 0-5 °C and added solid sodium borohydride (17 g) in lots. Reaction mass was maintained at RT for overnight. Solvent was distilled of from the reaction mass under reduced pressure at 45-50 °C. To the residue water (250 ml) was added, extracted the product into ethyl acetate, dried and distilled of solvent under reduced pressure to get 48 g of title compound as beige color solid. Ή NMR supported the structure of compound.
Example 5
Preparation of 2,2,2-trifluoro-N-((5-(4-hydroxyquinazolin-6-yl)furan-2- yl)methyl)-N-(2-(methylsulfonyI)ethyl)acetamide (XVII, R=CF3)
Into a 250 ml, four-necked, RB flask was charged 120 ml of tetrahydrofuran and 24.0 g of 6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-ol under nitrogen atmosphere. 4-Dimethylaminopyridine (0.85 g) was added to the reaction mass. Trifluoroacetic anhydride (29.0 g diluted with 20.0 ml of tetrahydrofuran) was added to the reaction mass over a period of 1 h at 25-30 °C. After the addition, reaction mass was maintained for 1.5 h at 25-30 °C. The reaction mass was filtered and the wet solid dried at 60-65 °C to get 23.0 g of title compound as brown colored solid. HPLC purity is 99.0%. Ή-NMR spectrum showed a mixture two tautomers at 7:3 ratio in DMSO-d6 solvent. IR (KBr, cm"1): 3339.7, 2928.0, 2362.4, 1637.3, 1608.6, 1593.4, 1572.1, 1539.1, 1497.9, 1445.9, 1425.6, 1394.3, 1371.0, 1330.5, 1294.8, 1216.9, 1 198.2, 1171.6, 1 123.8, 1061.4, 1026.5, 956.6, 927.8, 888.3, 868.1, 839.9, 789.7, 748.5, 679.9, 643.2, 628.7, 544.4, 517.6, and 501.5. 'H-NMR (400 MHz, DMSO-D6): 3.05 (s, 3H), 3.44 (t, 2H), 3.81 (t, 2H), 4.84 (s, 2H), 6.71 (d, 1H)
7.17 (d, 1H), 7.72 (d, 1H), 8.12 (dd, 1H), 8.19 (br. s, 1H), 8.35 (triplet, 1H), 12.3 (br. s, 1H).
Example 6
Preparation of N-((5-(4-chIoroquinazolin-6-yl)furan-2-yl)methyl)-2,2,2-trifluoro- N-(2-(methyIsulfonyl)ethyl)acetamide (XVIII, R=CF3)
Into a 250 ml, four-necked, RB flask was charged 125 ml of chloroform and 5.0 g of 2,2,2-trifluoro-N-((5-(4-hydroxyquinazolin-6-yl)furan-2-yl)methyl)-N-(2- (methylsulfonyl)ethyl)aceta-mide under N2 atmosphere. N,N-dimethylformamide (0.5 ml) was added to the reaction mass and heated to reflex temperature. Thionyl chloride (16.0 ml) was added to the reaction mass over a period of 30-45 minutes. After the addition, the reaction mass was maintained at reflux for 5 h. The reaction mass was cooled to 50° C and distilled of solvent under reduced pressure. Finally, 2 x 50 ml of toluene was added and distilled under reduced pressure to remove traces of thionyl chloride to get the crude title compound. It was directly used in next step.
Example 7
Preparation of N-((5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin- 6-yl)furan-2-yl)methyl)-2,2,2-trifluoro-N-(2-(methylsulfonyl)ethyl)acetamide (XIX, R=CF3)
Into a 250 ml, four-necked, RB flask was charged the above crude and 100 ml of tetrahydrofuran under nitrogen atmosphere. 3-Chloro-4-(3-fluorobenzyloxy)aniline (4.22 g) was added to the reaction mass. The reaction mass was heated to 60-65 °C, and maintained for 4 h at 60-65 °C. Reaction mass was cooled to 25-30 °C and maintained for 2-3 h at 25-30 °C. The reaction mass was filtered and dried the wet material in oven at 60-65 °C to get 10.1 g of title compound as yellow solid. HPLC purity is 87.36% containing 3-chloro-4-(3-fluorobenzyloxy)aniline 4.39%. 'H-NMR
(400 MHz,CDCl3): δ 2.99 (s, 3H), 3.38-3.42 (m, 2H), 4.22-4.26 (t, 2H), 4.77 (s, 2H), 5.17 (s, 2H), 6.51-6.52 (d,lH), 6.75-6.78 (m, 2H), 6.99-7.02 (m, 3H), 7.19-7.24 (t, 2H), 7.34-7.39 (m, 2H), 7.72-775 (dd, 1H), 7.89-7.90 (m,2H), 7.94-7.97(dd, 1H), 8.41-8.44 (d, 2H), and 8.71 (s, 1H).
Example 8
Preparation of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2- (methylsulfonyl)ethyl-amino)methyl)furan-2-yl)quinazolin-4-amine
Into a 500 ml, four-necked, RB flask was charged 180 ml of methanol and 9.0 g of N- ((5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2- yl)methyl)-2,2,2-trifluoro-N-(2-(methylsulfonyl)ethyl)acetamide under stirring. Aqueous sodium hydroxide (2.52 g of sodium hydroxide dissolved in 22.5 ml of water) was added to the reaction mass at 25-30 °C. The reaction mass was stirred for 2 h at 25-30 °C. Solvent was evaporated under reduced pressure. Water (75 ml) was added to the residue and the product extracted into ethyl acetate. The organic layer was treated with carbon and distilled of solvent partially under reduced pressure. Residual mass was cooled to 25-30 °C, stirred for 30 minutes, and filtered. The wet solid was dried in oven at 60 °C to get 4.2 g of title compound. HPLC purity is 98.85%.
Example 9
Preparation of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2- (methyIsuIfonyl)ethyI-amino)methyI)furan-2-yl)quinazolin-4-amine ditosylate salt
Into a 100 ml, four-necked, RB flask was charged methanol (60 ml) and 2.0 g of lapatinib base. The reaction mass was heated to reflex temperature and maintained for 30 minutes. The reaction mass was cooled to 45-50 °C and added a solution of p- toluenesulfonic acid monohydrate (1.4 g dissolved in 10 ml of methanol). Reaction
mass was maintained at reflux for 3 h, cooled to 25-30 °C, filtered the mass, and dried at 60 °C to get 2.5 g of lapatinib ditosylate. HPLC purity is 99.87%.
Example 10
Preparation of N-(3-chloro-4-(3-fIuorobenzyloxy)phenyl)-6-(5-((2-
(methyIsulfonyl)ethyI-amino)methyl)furan-2-yl)quinazolin-4-amine ditosylate salt monohydrate 1(c):
Into a 100 ml, four-necked, flask was charged 80 ml of 70% aq. IPA and 2.0 g of lapatinib ditosylate salt under stirring. The reaction mass was heated to 75-80 °C to dissolve the solids. The solution was clarified by carbon treatment and filtered. The filtrate was cooled to 30-35 °C under stirring. The product was filtered and dried at 70-75 °C under vacuum, till water content was around 2% w/w to get 1.8 g of yellow colored lapatinib ditosylate monohydrate. HPLC purity is 99.94%.
Example 11
Preparation of N-((5-(4-hydroxyquinazolin-6-yl)furan-2-yI)methyI)-N-(2- (methylsulfonyI)-ethyl)acetamide (XVII, R=CH3)
Into a 3 L, four-necked, RB flask was charged 1.5 L of methylene chloride, 5.0 g of 6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-ol, 4.7g of triethylamine, 0.3g of 4-dimethylaminopyridine and 4.3g of acetic anhydride. Reaction mass was heated to reflex temperature and maintained for 5 h. Methanol (150 ml) was added to the reaction mass and maintained for 1 h at reflex temperature. Solvent was distilled of up to 95% under vacuum. The mass was cooled to 25-30 °C, added 30 ml of diisopropyl ether. After stirring for 30 min at RT mass was filtered, and the wet solid dried at 55-60 °C to get 5.1 g of title compound as brown colored
crystalline solid. HPLC purity is 93.7%. IR (KBr, cm"1): 3445.1, 3024.1, 2828.7, 2344.6, 1681.2, 1645.6, 1610.7, 1545.2, 1473.2, 1420.4, 1365.2, 1342.2, 1328.2, 1285.2, 1246.1, 1214.2, 1 132.0, 1027.2, 971.8, 919.0, 835.5, 795.2, 663.5, 624.1. ¾ NMR (400MHz, CDC13): δ 2.35 (s, 3H), 2.99 (s, 3H) 3.32-3.35 (t, 2H), 3.86-3.90 (t, 2H), 4.66 (s, 2H), 6.44-6.45 (d, 1H), 6.80-6.81(d, 1H), 7.78-7.81 (d, 1H); 8.03-8.06 (m, 2H), 8.51 (s, 1H), 9.22 (broad s, 1H). El-Mass: 389.2.
Example 12
Preparation of N-((5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazoIin- 6-yl)furan-2-yl)methyl)-N-(2-(methylsulfonyI)ethyl)acetamide (XIX, R=CH3)
Into a 1 L, four-necked, RB flask was charged 300 ml of chloroform, 1.0 g of N-((5- (4-hydroxyquinazolin-6-yl)furan-2-yl)methyl)-N-(2-(methylsulfonyl)- ethyl)acetamide (XVII, R = CH3), 200ml of acetonitrile and 0.1 ml of DMF under N2 atmosphere. Reaction mass was heated to reflex temperature. Thionyl chloride (1.6 ml) was added to the reaction mass over a period of 30-45 minutes. Reaction mass was maintained at reflux for 5 h, cooled to 50 °C and distilled of solvent under reduced pressure. To the residue charged 2 x 40 ml of chloroform and distilled under vacuum. Finally, 40 ml of acetonitrile is charged and distilled under vacuum. To the residual solid acetonitrile (120ml) and 3-chloro-4-(3-fluorobenzyloxy)aniline (1.7g) were added and heated to reflux temperature. Reaction was maintained at reflux for 6h, cooled to RT and filtered the solids. The wet cake was washed with acetonitrile and dried to get 1.1 g of title compound as solid. Ή NMR (400MHz, CDC13): δ 2.25 (s, 3H), 2.94 (s, 3H), 3.45 (t, 2H), 4.08 (t, 2H), 4.60 (s, 2H), 5.16 (s, 2H), 6.43 (d, 1H), 6.74 (d, 1H), 7.00 (t, 2H), 7.23 (t, 2H), 7.35 (t, 1H), 7.69 (dd, 1H), 7.90 (dt, 3H), 8.40 (s, 1H), 1.00 (s, 1H), and 8.69 (s, 1H).
Example 13
Preparation of tert-butyl (5-(4-hydroxyquinazolin-6-yl)furan-2-yl)methyl(2- (methylsulfo-nyl)ethyl)carbamate (XVII, R=t-BuO)
Into a 50ml, three-necked RB flask was charged 0.5 g of 6-(5-((2- (methylsulfonyl)ethylamino)-methyl)furan-2-yl)quinazolin-4-ol, 10 ml of THF, 0.82g of Boc anhydride, 0.32g of TEA and 0.04g of DMAP. Reaction was stirred at RT for 3h, distilled of solvent under vacuum. To the residue 5ml of ethyl acetate and 5ml of IPE were added and filtered to get 0.5 g of title compound as a brown colored solid. Ή-NMR (400 MHz, CDC13): δ 1.53 (s, 9H), 2.95 (s, 3H), 3.34 (broad s, 2Η), 3.78- 3.81 (t, 2H), 4.54 (s, 2H), 6.37(broad s, IH), 6.76-6.77(d, IH), 7.76-7.78 (d, IH), 8.03-8.06 (m, IH), 8.1 l(s, IH), 8.50 (s, IH), and 1 1.45 (broad s, IH exchangeable with D20).
ADVANTAGES OF PRESENT PROCESS:
1. Purity of lapatinib and its pharmaceutically acceptable ditosylate salt obtained by this process is high (>99.6%).
2. Present process does not require any chromatographic purification.
3. All the raw materials used in the present process are commercially readily available and cheap.
4. Present process does not require costly reagents like 5-formyl-furanboronic acid or (5-(l,3-dioxolan-2-yl)furan-2-yl)tributylstannane, or any other boronic acid derivative.
Claims
1. An improved process for the preparation of Lapatinib of formula-I,
and its pharmaceutically acceptable salts,
which comprises:
(i) Reduction of 6-nitroquinazolin-4-ol of formula-XII
XII
with a metal catalyst in the presence of a solvent medium at elevated temperature to get the amino compound of formula-XIII,
XIII
Diazotization of compound of formula-XIII with sodium/potassium nitrite in the presence of an acid and coupling with furfural in the presence of a copper catalyst to get the coupled product of formula-XIV,
(iii) Reaction of compound of formula-XIV with 2-methanesulfonylethylamine or its salt in a solvent medium at elevated temperature to get an imine derivative of formula-XV,
XV
(iv) Reduction of compound of formula-XV in a solvent medium to get the amine compound of formula-XVI,
XVI
Selective protection of the amino group of the compound of formula-XVI with a suitable protecting group to get the compound of formula-XVII,
XVII
Wherein R = C1-C6 alkyl, perfluoroalkyl, C1-C6 alkoxy, etc.
(vi) Conversion of hydroxyl group present in XVII into a leaving group with a
suitable reagent to get the compound of formula-XVIII,
Wherein X = CI, Br, I, OS02CH3, OS02CF3, OTs, OBs, etc., R = C1-C6 alkyl, perfluoroalkyl, C1-C6 alkoxy, etc
(vii) Reacting the compound of the formula-XVIII with 3-chloro 4-(3- fluorobenzyloxy)aniline in a solvent medium at an elevated temperature to get the amine protected lapatinib base of formula-XIX,
Wherein R = as defined above
(viii) Removal of amine protection group in compound of formula-XIX using a base or acid to get lapatinib base of formula-I,
(ix) Conversion of lapatinib base into pharmaceutically acceptable p-tolunesulfonate salt in a solvent medium to get lapatinib di-tosylate of formula-II as its dihydrate,
II
2. An improved process as claimed in claim 1 wherein the metal catalyst used in step (i) is selected from iron, zinc, Raney nickel, palladium, etc., preferably Raney nickel or iron powder.
3. An improved process as claimed in claims 1 and 2 wherein the solvent used in step (i) is selected from Ν,Ν-dimethylformamide, methanol, ethanol, isopropanol, n- propanol, n-butanol, t-butanol, water, etc., preferably Ν,Ν-dimethylformamide or isopropanol.
4. An improved process as claimed in claims 1-3 wherein the acid medium used in diazotization step (ii) is selected from dilute hydrochloric acid, sulfuric acid, preferably hydrochloric acid.
5. An improved process as claimed in claims 1-4 wherein the copper catalyst used in step (ii) is selected from copper (II) chloride, copper (II) acetate, copper (II) bromide, etc., preferably copper (II) chloride.
6. An improved process as claimed in claims 1-5 wherein the solvent used in step (iii) is selected from alcoholic solvents such as methanol, ethanol, isopropanol, ethers like tetrahydrofuran, diisopropyl ether, 1,4-dioxane, nitriles like acetonitrile, amides like
Ν,Ν-dimethylformamide, etc. preferably methanol or tetrahydrofuran, more preferably methanol.
7. An improved process as claimed in claims 1-6 wherein the salt of 2- methanesulfonylethylamine used in step (iii) is selected from hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, etc., preferably hydrochloride.
8. An improved process as claimed in claims 1-7 wherein the temperature of the reaction in step (iii) is the boiling point of the solvent or 50-70°C.
9. An improved process as claimed in claims 1-8 wherein the neutralizing reagent used in step (iii) is selected from trialkylamine such as triethylamine.
10. An improved process as claimed in claims 1-9 wherein the reducing agent used in step (iv) is selected from a borohydride reagent such as lithium borohydride, sodium borohydride, sodium tri(acetoxy)borohydride, vitride, lithium aluminum hydride, a metal catalyst such as such as Raney nickel, palladium, rhodium, platinum, etc.,, in the presence of hydrogen gas, preferably sodium borohydride or 5-10% of 50% wet palladium-on-carbon.
1 1. An improved process as claimed in claims 1-10 wherein the solvent used in step (iv) is selected from methanol, isopropanol, THF, Ν,Ν-dimethylformamide or a combination thereof.
12. An improved process as claimed in claims 1-1 1 wherein the acylating agent used in step (v) is selected from C1-C6 alkanoyl/perfluoroalkanoyl halide or C1-C6 alkanoic/perfluoroalkanoic anhydride, Boc anhydride, t-butyldimethylsilyl chloride, preferably acetic anhydride or trifluoroacetic anhydride.
13. An improved process as claimed in claims 1-12 wherein the solvent used in step (v) is selected from tetrahydrofuran, ethyl acetate, methylene chloride, etc.
14. An improved process as claimed in claims 1-13 wherein the suitable reagent used in step (vi) is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p-toluenesulfonyl chloride, p- bromobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, etc., preferably oxalyl chloride or thionyl chloride. Suitable solvent used in step (vi) is selected from tetrahydrofuran, chloroform, acetonitrile, toluene, preferably tetrahydrofuran or chloroform.
15. An improved process as claimed in claims 1-14 wherein the temperature of the reaction in step (vi) is ambient to reflux temperature of the solvent, preferably 50-
60°C.
16. An improved process as claimed in claims 1-15 wherein the temperature of the reaction in step (vii) is the boiling point of the solvent employed in the reaction.
17. An improved process as claimed in claims 1-16 wherein the acid used in step (viii) is selected from dilute hydrochloric acid, sulfuric acid, nitric acid, etc., preferably dilute sulfuric acid.
18. An improved process as claimed in claims 1-17 wherein the base used in step (viii) is selected from sodium/potassium hydroxide or carbonate, preferably sodium hydroxide.
19. An improved process as claimed in claims 1-18 wherein the solvent employed in step (viii) is aqueous alcohols or ethers, preferably aqueous IPA.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1542/CHE/2013 | 2013-04-04 | ||
IN1542CH2013 | 2013-04-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014170910A1 true WO2014170910A1 (en) | 2014-10-23 |
Family
ID=51263452
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2014/000210 WO2014170910A1 (en) | 2013-04-04 | 2014-04-03 | Process for the preparation of lapatinib |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2014170910A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9024023B2 (en) | 2013-01-14 | 2015-05-05 | F.I.S.—Fabbrica Italiana Sintetici S.p.A. | Efficient process for the preparation of lapatinib and salts thereof by means of new intermediates |
CN106432206A (en) * | 2016-08-30 | 2017-02-22 | 成都美睿科生物科技有限公司 | Method for synthesizing lapatinib or intermediate 5-(4-hydroxy quinazoline)-furan-2-formaldehyde of lapatinib |
CN106432205A (en) * | 2016-08-30 | 2017-02-22 | 成都美睿科生物科技有限公司 | Method for synthesizing lapatinib or intermediate thereof |
Citations (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999035146A1 (en) | 1998-01-12 | 1999-07-15 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
WO2002002552A1 (en) | 2000-06-30 | 2002-01-10 | Glaxo Group Limited | Quinazoline ditosylate salt compounds |
WO2002056912A2 (en) | 2001-01-16 | 2002-07-25 | Glaxo Group Limited | Pharmaceutical combination for the treatment of cancer containing a 4-quinazolineamine and another anti-neoplastic agent |
WO2003086467A1 (en) | 2002-04-08 | 2003-10-23 | Smithkline Beecham Corporation | Cancer treatment method comprising administering an erb-family inhibitor and a raf and/or ras inhibitor |
WO2005046678A1 (en) | 2003-11-07 | 2005-05-26 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
WO2006002422A2 (en) | 2004-06-24 | 2006-01-05 | Novartis Vaccines And Diagnostics Inc. | Compounds for immunopotentiation |
WO2006089150A2 (en) | 2005-02-18 | 2006-08-24 | Novartis Vaccines And Diagnostics Inc. | Antiangiogenic agents with aldesleukin |
WO2006113649A1 (en) | 2005-04-19 | 2006-10-26 | Smithkline Beecham [Cork] Limited | Pharmaceutical composition |
WO2007121279A2 (en) | 2006-04-13 | 2007-10-25 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
WO2007143483A2 (en) | 2006-06-01 | 2007-12-13 | Smithkline Beecham Corporation | Combination of pazopanib and lapatinib for treating cancer |
WO2008063853A2 (en) | 2006-11-21 | 2008-05-29 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
WO2008067144A2 (en) | 2006-11-28 | 2008-06-05 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
WO2008154469A1 (en) | 2007-06-11 | 2008-12-18 | Smithkline Beecham (Cork) Limited | Quinazoline salt compounds |
WO2009079541A1 (en) | 2007-12-18 | 2009-06-25 | Smithkline Beecham (Cork) Limited | Quinazoline ditosylate anhydrate forms |
WO2009079547A1 (en) | 2007-12-18 | 2009-06-25 | Smithkline Beecham (Cork) Limited | Quinazoline anhydrate forms |
WO2009140144A1 (en) | 2008-05-15 | 2009-11-19 | Teva Pharmaceutical Industries Ltd. | Forms of crystalline lapatinib and processes for preparation thereof |
WO2010017387A2 (en) | 2008-08-06 | 2010-02-11 | Teva Pharmaceutical Industries Ltd. | Lapatinib intermediates |
WO2010061400A1 (en) | 2008-11-03 | 2010-06-03 | Natco Pharma Limited | A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts |
WO2010120387A1 (en) | 2009-04-17 | 2010-10-21 | Nektar Therapeutics | Oligomer-protein tyrosine kinase inhibitor conjugates |
WO2010148163A1 (en) | 2009-06-18 | 2010-12-23 | University Of Utah Research Foundation | Radiation enhanced macromolecular delivery of therapeutic agents for chemotherapy |
WO2011035540A1 (en) | 2009-09-28 | 2011-03-31 | 齐鲁制药有限公司 | 4-(substituted anilino)quinazoline derivatives as tyrosine kinase inhibitors |
WO2011039759A1 (en) | 2009-09-29 | 2011-04-07 | Natco Pharma Limited | A new process for the preparation of lapatinib and its pharmaceutically acceptable salts |
WO2011116634A1 (en) | 2010-03-23 | 2011-09-29 | Scinopharm Taiwan Ltd. | Process and intermediates for preparing lapatinib |
WO2011160594A1 (en) | 2010-06-24 | 2011-12-29 | 齐鲁制药有限公司 | New preparation method of lapatinib |
WO2012017448A2 (en) | 2010-08-03 | 2012-02-09 | Hetero Research Foundation | Salts of lapatinib |
EP2468745A1 (en) | 2011-03-25 | 2012-06-27 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Process for the preparation of lapatinib and the salts thereof |
WO2012083440A1 (en) | 2010-12-23 | 2012-06-28 | Apotex Pharmachem Inc | A process for the preparation of lapatinib and its ditosylate salt |
EP2489661A1 (en) | 2011-05-20 | 2012-08-22 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Impurity of lapatinib and salts thereof |
-
2014
- 2014-04-03 WO PCT/IN2014/000210 patent/WO2014170910A1/en active Application Filing
Patent Citations (30)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999035146A1 (en) | 1998-01-12 | 1999-07-15 | Glaxo Group Limited | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
US6727256B1 (en) | 1998-01-12 | 2004-04-27 | Smithkline Beecham Corporation | Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
US7157466B2 (en) | 2000-06-30 | 2007-01-02 | Smithkline Beecham (Cork) Limited | Quinazoline ditosylate salt compounds |
WO2002002552A1 (en) | 2000-06-30 | 2002-01-10 | Glaxo Group Limited | Quinazoline ditosylate salt compounds |
WO2002056912A2 (en) | 2001-01-16 | 2002-07-25 | Glaxo Group Limited | Pharmaceutical combination for the treatment of cancer containing a 4-quinazolineamine and another anti-neoplastic agent |
WO2003086467A1 (en) | 2002-04-08 | 2003-10-23 | Smithkline Beecham Corporation | Cancer treatment method comprising administering an erb-family inhibitor and a raf and/or ras inhibitor |
WO2005046678A1 (en) | 2003-11-07 | 2005-05-26 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
WO2006002422A2 (en) | 2004-06-24 | 2006-01-05 | Novartis Vaccines And Diagnostics Inc. | Compounds for immunopotentiation |
WO2006089150A2 (en) | 2005-02-18 | 2006-08-24 | Novartis Vaccines And Diagnostics Inc. | Antiangiogenic agents with aldesleukin |
WO2006113649A1 (en) | 2005-04-19 | 2006-10-26 | Smithkline Beecham [Cork] Limited | Pharmaceutical composition |
WO2007121279A2 (en) | 2006-04-13 | 2007-10-25 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
WO2007143483A2 (en) | 2006-06-01 | 2007-12-13 | Smithkline Beecham Corporation | Combination of pazopanib and lapatinib for treating cancer |
WO2008063853A2 (en) | 2006-11-21 | 2008-05-29 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
WO2008067144A2 (en) | 2006-11-28 | 2008-06-05 | Smithkline Beecham (Cork) Limited | Cancer treatment method |
WO2008154469A1 (en) | 2007-06-11 | 2008-12-18 | Smithkline Beecham (Cork) Limited | Quinazoline salt compounds |
WO2009079541A1 (en) | 2007-12-18 | 2009-06-25 | Smithkline Beecham (Cork) Limited | Quinazoline ditosylate anhydrate forms |
WO2009079547A1 (en) | 2007-12-18 | 2009-06-25 | Smithkline Beecham (Cork) Limited | Quinazoline anhydrate forms |
WO2009140144A1 (en) | 2008-05-15 | 2009-11-19 | Teva Pharmaceutical Industries Ltd. | Forms of crystalline lapatinib and processes for preparation thereof |
WO2010017387A2 (en) | 2008-08-06 | 2010-02-11 | Teva Pharmaceutical Industries Ltd. | Lapatinib intermediates |
WO2010061400A1 (en) | 2008-11-03 | 2010-06-03 | Natco Pharma Limited | A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts |
WO2010120387A1 (en) | 2009-04-17 | 2010-10-21 | Nektar Therapeutics | Oligomer-protein tyrosine kinase inhibitor conjugates |
WO2010148163A1 (en) | 2009-06-18 | 2010-12-23 | University Of Utah Research Foundation | Radiation enhanced macromolecular delivery of therapeutic agents for chemotherapy |
WO2011035540A1 (en) | 2009-09-28 | 2011-03-31 | 齐鲁制药有限公司 | 4-(substituted anilino)quinazoline derivatives as tyrosine kinase inhibitors |
WO2011039759A1 (en) | 2009-09-29 | 2011-04-07 | Natco Pharma Limited | A new process for the preparation of lapatinib and its pharmaceutically acceptable salts |
WO2011116634A1 (en) | 2010-03-23 | 2011-09-29 | Scinopharm Taiwan Ltd. | Process and intermediates for preparing lapatinib |
WO2011160594A1 (en) | 2010-06-24 | 2011-12-29 | 齐鲁制药有限公司 | New preparation method of lapatinib |
WO2012017448A2 (en) | 2010-08-03 | 2012-02-09 | Hetero Research Foundation | Salts of lapatinib |
WO2012083440A1 (en) | 2010-12-23 | 2012-06-28 | Apotex Pharmachem Inc | A process for the preparation of lapatinib and its ditosylate salt |
EP2468745A1 (en) | 2011-03-25 | 2012-06-27 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Process for the preparation of lapatinib and the salts thereof |
EP2489661A1 (en) | 2011-05-20 | 2012-08-22 | F.I.S. Fabbrica Italiana Sintetici S.p.A. | Impurity of lapatinib and salts thereof |
Non-Patent Citations (2)
Title |
---|
BERTRAND JACQUES JEAN-CLAUDE ET AL., J. MED. CHEM., vol. 49, 2006, pages 3544 - 3552 |
PAIZS C ET AL: "Preparation of novel phenylfuran-based cyanohydrin esters: lipase-catalysed kinetic and dynamic resolution", TETRAHEDRON ASYMMETRY, PERGAMON PRESS LTD, OXFORD, GB, vol. 14, no. 13, 4 July 2003 (2003-07-04), pages 1895 - 1904, XP004432049, ISSN: 0957-4166, DOI: 10.1016/S0957-4166(03)00286-6 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9024023B2 (en) | 2013-01-14 | 2015-05-05 | F.I.S.—Fabbrica Italiana Sintetici S.p.A. | Efficient process for the preparation of lapatinib and salts thereof by means of new intermediates |
US9169236B2 (en) | 2013-01-14 | 2015-10-27 | F.I.S.-Fabbrica Italiana Sintetiei S.p.A. | Efficient process for the preparation of lapatinib and salts thereof by means of new intermediates |
US9359333B2 (en) | 2013-01-14 | 2016-06-07 | F.I.S.—Fabbrica Italiana Sintetiei | Efficient process for the preparation of Lapatinib and salts thereof by means of new intermediates |
CN106432206A (en) * | 2016-08-30 | 2017-02-22 | 成都美睿科生物科技有限公司 | Method for synthesizing lapatinib or intermediate 5-(4-hydroxy quinazoline)-furan-2-formaldehyde of lapatinib |
CN106432205A (en) * | 2016-08-30 | 2017-02-22 | 成都美睿科生物科技有限公司 | Method for synthesizing lapatinib or intermediate thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US8563719B2 (en) | Process and intermediates for preparing lapatinib | |
KR101342241B1 (en) | Processes for the preparation of 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione compounds | |
CN102030654B (en) | Method for producing aminothiazole derivative and production intermediate | |
CN102356063B (en) | A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and synthetic intermediates thereof | |
CN101993407B (en) | Indoline compound for preparing silodosin and preparation method thereof | |
CN107176955B (en) | A kind of Ba Rui replaces the preparation method of Buddhist nun | |
WO2014170910A1 (en) | Process for the preparation of lapatinib | |
WO2017071419A1 (en) | Method for preparing rociletinib | |
CN110498771B (en) | Method for preparing intermediate of pergolide | |
CN103664959B (en) | Preparation method of five-membered bicyclic guanidine compounds | |
CN105884747B (en) | Preparation method for preparing Bruton's Tyrosine Kinase (BTK) kinase inhibitor | |
WO2005070909A1 (en) | An improved process for the preparation of gefitinib | |
CN105377820B (en) | Process for producing quinazoline derivative | |
US8093384B2 (en) | Processes for the preparation of alfuzosin | |
RU2409555C1 (en) | Method for synthesis of 4-(3,4-diaminophenoxy)benzoic acid esters | |
US20150225376A1 (en) | Efficient Process for the Preparation of Lapatinib and Salts thereof by Means of New Intermediates | |
RU2409554C1 (en) | Method for synthesis of 4-(3,4-diaminophenoxy)benzoic acid | |
KR101130717B1 (en) | Process for the Preparation of a Chiral Intermediate for the Preparation of HMG-CoA Reductase Inhibitors | |
EP1431278A1 (en) | Process for producing (2-nitrophenyl)acetonitrile derivative and intermediate therefor | |
CZ304887B6 (en) | Process for preparing arylethanoldiamines | |
US8710221B2 (en) | Process and intermediates for preparing lapatinib | |
CN108658931A (en) | A kind of preparation method of Raltitrexed key intermediate | |
EP3609875B1 (en) | An improved process for the preparation of n-(3-ethynylphenyl)-7-methoxy-6-(3-morpholinopropoxy) quinazolin -4-amine dihydrochloride | |
US8124790B2 (en) | Preparation process useful in synthesis of atorvastatin | |
WO2014045294A1 (en) | A novel process for the preparation of rosuvastatin calcium using novel intermediates |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14747150 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14747150 Country of ref document: EP Kind code of ref document: A1 |