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WO2024157170A1 - Procédé de préparation de tivozanib ou d'un sel de celui-ci - Google Patents

Procédé de préparation de tivozanib ou d'un sel de celui-ci Download PDF

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Publication number
WO2024157170A1
WO2024157170A1 PCT/IB2024/050628 IB2024050628W WO2024157170A1 WO 2024157170 A1 WO2024157170 A1 WO 2024157170A1 IB 2024050628 W IB2024050628 W IB 2024050628W WO 2024157170 A1 WO2024157170 A1 WO 2024157170A1
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Prior art keywords
compound
tivozanib
impurity
formula
iii
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PCT/IB2024/050628
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English (en)
Inventor
Venkata Raghavendra Acharyulu Palle
Pratik Patel
Raj Mahendra SHANMUGHASAMY
Premkumar Ramraj YADAV
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Glenmark Life Sciences Limited
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Publication of WO2024157170A1 publication Critical patent/WO2024157170A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4

Definitions

  • the present invention relates to a process for the preparation of tivozanib or a pharmaceutically acceptable salt or a hydrate thereof. Particularly, the present invention relates to a process for the preparation of tivozanib hydrochloride or a hydrate thereof.
  • the present invention also provides a process for the purification of tivozanib or a pharmaceutically acceptable salt thereof.
  • the chemical name of tivozanib hydrochloride is 1- ⁇ 2-chloro-4-[(6,7- dimethoxyquinolin-4-yl)oxy]phenyl ⁇ -3-(5-methylisoxazol-3-yl)urea hydrochloride, which is represented by the compound of formula I (the compound I).
  • the free base, tivozanib represented by the compound of formula II (the compound II) is described in U.S. Pat. No.6,821,987.
  • Tivozanib hydrochloride (the compound I) is indicated for the treatment of advanced renal cell carcinoma (RCC), and is marketed in the USA as FOTIVDA ® in capsule dosage form for oral administration.
  • RRC advanced renal cell carcinoma
  • FOTIVDA ® in capsule dosage form for oral administration.
  • Various processes for the preparation of tivozanib hydrochloride are reported in the art.
  • 6,821,987 discloses a process for the preparation of tivozanib free base (referred to herein as a compound of formula II or the compound II), wherein 2- chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline is treated with triphosgene in chloroform in the presence of triethylamine followed by treatment with 3-amino-5- methylisoxazole to obtain tivozanib (the compound II).
  • 2- chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline is treated with triphosgene in chloroform in the presence of triethylamine followed by treatment with 3-amino-5- methylisoxazole to obtain tivozanib (the compound II).
  • 7,166,722 discloses a process for the preparation of tivozanib (the compound II) wherein 3-amino-5-methylisoxazole is treated with phenyl chloroformate in N,N-dimethylacetamide in the presence of pyridine resulting in the formation of phenyl(5-methylisoxazol-3-yl)carbamate, which without isolation is treated with 2- chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline to obtain tivozanib (the compound II).
  • the present invention provides a process for the preparation of tivozanib (the compound II) or a pharmaceutically acceptable salt thereof represented by the following formula IA (the compound IA) or a hydrate thereof; TIVO-2024 IA wherein X is selected from the group consisting of HCl, HBr, HF, H 2 SO 4 , and H 3 PO 4 ; comprising the steps of: (a) reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III); III with an isolated 5-methylisoxazol-3-yl carbamate compound represented by the compound of formula IV (the compound IV); IV wherein R 1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or
  • the present invention provides a process for the preparation of tivozanib represented by the compound of formula II (the compound II); comprising: reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III); III with an isolated 5-methylisoxazol-3-yl carbamate compound represented by the compound of formula IV (the compound IV); IV wherein R 1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl; wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F; in a solvent, and at a temperature ranging from about 25°C to about 140°C to obtain tivozanib (the compound II); and TIVO-2024 wherein
  • the present invention also provides a process for the preparation of 2-chloro-4- ((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III); TIVO-2024 [0014]
  • the present invention further provides tivozanib (the compound II), or a pharmaceutically acceptable salt (the compound IA) or a hydrate thereof, having chemical purity of at least 99% wherein the content of each of the compound of formulae A, B, C and D (as described herein) is from about 0.01% to about 0.5% w/w as measured by HPLC (High performance liquid chromatography).
  • the present invention relates to a compound selected from the group consisting of the compounds of formulae A, B and C (as described herein).
  • DETAILED DESCRIPTION OF THE INVENTION [0016] The present invention provides a process for the preparation of tivozanib (the compound II) or a pharmaceutically acceptable salt represented by the compound of formula IA (the compound IA) or a hydrate thereof; IX wherein X is selected from the group consisting of HCl, HBr, HF, H 2 SO 4 , and H 3 PO 4 ; comprising the steps of: a) reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III); III with an isolated 5-methylisoxazol-3-ylcarbamate compound represented by the compound of formula IV (the compound IV); TIVO-2024 IV wherein R 1 is methyl, ethyl, 2,2,2-trichloroethy
  • the present invention provides a process for the preparation of tivozanib represented by the compound of formula II (the compound II); comprising: reacting 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline represented by the compound of formula III (the compound III); TIVO-2024 III with an isolated 5-methylisoxazol-3-yl carbamate compound represented by the compound of formula IV (the compound IV); IV wherein R1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F; in a solvent, and at a temperature ranging from about 25°C to about 140°C to obtain tivozanib (the compound II); and wherein
  • the term “isolated” as used herein in reference to 5-methylisoxazol-3-yl carbamate compound (the compound IV) means that the 5-methylisoxazol-3-yl carbamate compound is physically separated from the reaction mixture wherein it is formed.
  • the term “substantially free” as used herein, unless otherwise defined, indicates presence of the impurities selected from Impurity A, Impurity B, Impurity C or Impurity D in a range from about 0.01% to about 0.5% w/w (as measured by HPLC) in the target TIVO-2024 compound (e.g. tivozanib, pharmaceutically acceptable salt of tivozanib, the compound III etc.).
  • tivozanib the compound II
  • the statement, “wherein tivozanib (the compound II) is substantially free of the dimer impurity C” means that the content of dimer impurity C in tivozanib (the compound II) obtained by the present invention is in a range from about 0.01% to about 0.5% w/w.
  • the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.
  • the solvent used in the reaction of the compound III with the isolated compound IV is selected from a hydrocarbon solvent, a chlorinated solvent, a nitrile solvent, an ester solvent, an ether, a ketone, a polar aprotic solvent, an alcohol, or a mixture thereof
  • the hydrocarbon solvent is selected from toluene, xylene, benzene, chlorobenzene, cyclohexane, or a mixture thereof
  • the chlorinated solvent is selected from dichloromethane, dichloroethane, chloroform, or a mixture thereof
  • the nitrile solvent is selected from acetonitrile, propionitrile, butyronitrile, or a mixture thereof
  • the ester solvent is selected from ethyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, or a mixture thereof
  • the ether is selected from diethyl ether, methyl ter
  • the solvent used in the reaction of the compound III with the isolated compound IV is a hydrocarbon solvent selected from toluene, xylene, benzene, chlorobenzene, cyclohexane; or a mixture thereof.
  • the reaction of the compound III with the isolated compound IV is carried out at a temperature ranging from about 40°C to about 110°C.
  • the compound of formula III (the compound III) is a key intermediate in the preparation of tivozanib (the compound II) and its pharmaceutically acceptable salts (the compound IA) or hydrate thereof.
  • the compound of formula III (the compound III); TIVO-2024 III is prepared by a process comprising: reacting 4-chloro-6,7-dimethoxy quinoline represented by a compound of formula VII (the compound VII); VII with 4-amino-3-chlorophenol represented by a compound of formula VIII (the compound VIII); VIII in a solvent and in the presence of a base; and wherein the base is used in a molar equivalent of about 0.8 to about 1.8 with respect to the compound VII, to provide 2- chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (the compound III); wherein the compound III is substantially free of an impurity represented by the compound of formula A (the Impurity A);
  • the solvent used is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N- methylpyrrolidinone, dimethylsulfoxide, cyclopen
  • the base in the reaction of the compound VII with the compound VIII, is used in a molar equivalent of about 1.2 to about 1.7 with respect to the compound VII.
  • the base used in the reaction of the compound VII with the compound VIII in the preparation of the compound III, is selected from potassium tertiary butoxide, sodium tertiary butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or sodamide.
  • the base used in the reaction of the compound VII with the compound VIII is selected from potassium tertiary butoxide or sodium tertiary butoxide.
  • the reaction of the compound VII with the compound VIII is carried out at a temperature ranging from about 50°C to about 150°C.
  • the compound of formula IV (the compound IV) used in the preparation of tivozanib (the compound II); IV wherein R 1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted with Cl, Br or F; is prepared by reacting 5-methylisoxazol-3-amine represented by the compound of formula V (the compound V) with a haloformate represented by the compound of formula VI (the compound VI); V VI wherein in the compound of formula VI, X is Cl, Br, I or F, and R 1 is as
  • the compound VI is selected from group consisting of phenyl chloroformate, chlorophenyl chloroformate, bromophenyl chloroformate, fluorophenyl chloroformate, benzyl chloroformate, methyl chloroformate, ethyl chloroformate, 2,2,2- trichloroethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, n-butyl chloroformate, isobutyl chloroformate, tertiary butyl chloroformate, methyl fluoroformate, and ethyl fluoroformate.
  • the compound VI is selected from phenyl chloroformate, methyl chloroformate, or ethyl chloroformate.
  • the reaction of the compound V with the compound VI is carried out in the presence of an organic base selected from pyridine, lutidine, N,N-dimethylaniline, trimethylamine, triethylamine, N- ethyldiisopropylamine, piperidine, 4-N,N-dimethylaminopyridine, N,N-dimethylaniline, imidazole, or N-methyl imidazole.
  • lutidine encompasses 2,3-lutidine, 2,4-lutidine, 2,5- lutidine, 2,6-lutidine, 3,4-lutidine and 3,5-lutidine.
  • the isolated 5-methylisoxazol-3-yl carbamate (the compound IV) is used in an amount of about 6.5 to about 7.5 molar equivalent with respect to 2-chloro-4-((6,7- dimethoxyquinolin-4-yl)oxy)aniline (the compound III).
  • the present invention further provides a process for the preparation of a pharmaceutically acceptable salt of tivozanib represented by the following formula IA (the compound IA) or a hydrate thereof; IA wherein X is selected from the group consisting of HCl, HBr, HF, H 2 SO 4 , and H 3 PO 4 ; TIVO-2024 comprising the step of treating tivozanib (the compound II) with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, and phosphoric acid, in a polar aprotic solvent to provide the corresponding pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate; and wherein the pharmaceutically acceptable salt of tivozanib
  • pharmaceutically acceptable salt as used herein may be used interchangeably with the term “salt”, and includes the salts selected from the group consisting of hydrochloride, hydrobromide, hydrofluoride, hydrogen sulfate and phosphate salts of tivozanib.
  • the polar aprotic solvent used in the process for the preparation of the pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate is selected from N,N-dimethylformamide or N,N-dimethylacetamide.
  • the acid in the process for the preparation of the pharmaceutically acceptable salt of tivozanib (the compound IA) or its hydrate, is used in the form of an aqueous solution or in the form of a solution in an organic solvent selected from methanol, ethanol, isopropyl alcohol or n-butanol.
  • the preparation of the compound IA or its hydrate is carried out at a temperature ranging from about 25°C to about 80°C.
  • the present invention relates to a process for the preparation of tivozanib hydrochloride represented by the compound of formula I (the compound I); comprising treating tivozanib (the compound II) with hydrochloric acid in a polar aprotic solvent to provide tivozanib hydrochloride (the compound I) or its hydrate; and wherein the tivozanib hydrochloride (the compound I) or its hydrate is substantially free of the dimer impurity (the Impurity C).
  • the polar aprotic solvent used in the process for the preparation of the tivozanib hydrochloride (the compound I) is as described supra.
  • the hydrochloric acid is used in the form of an aqueous solution or in the form of a solution in an organic solvent selected from methanol, ethanol, isopropyl alcohol or n-butanol.
  • the present invention relates to a process for the preparation of tivozanib (the compound II); comprising the steps of: A.
  • the base is used in a molar equivalent of about 1.2 to about 1.7 with respect to the compound VII.
  • the solvent and the base used in the reaction step (A) are as described supra in reference to the process for the preparation of the compound III.
  • the reaction in the step (A) is carried out at a temperature ranging from about 50°C to about 150°C.
  • the solvent and the organic base used in the reaction step (B) are as described supra in reference to the process for the preparation of the compound IV.
  • the solvent used the step (C) is as described supra in reference to the process for the preparation of tivozanib (the compound II).
  • the reaction of the compound III with the isolated compound IV is carried out at a temperature ranging from about 40°C to about 110°C.
  • the present invention provides a process for the purification of tivozanib (compound II) comprising treating tivozanib with a solvent selected from an alcohol, an ester solvent, or a hydrocarbon solvent.
  • the solvent used for purification is selected from an alcohol, which is selected from methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, sec- butyl alcohol, tert-butyl alcohol, and isobutyl alcohol; an ester, which is selected from ethyl acetate, butyl acetate, isopropyl acetate, and isobutyl acetate; or a hydrocarbon solvent, which is selected from benzene, toluene, xylene, cyclohexane and a mixture thereof.
  • the present invention provides a process for the purification of tivozanib (the compound II) comprising the steps of: (i) treating tivozanib (the compound II) with an aqueous solution of a metal sulfate or a metal halide in a solvent; and (ii) isolating the pure tivozanib (the compound II) as obtained in the step (i).
  • the tivozanib free base (the compound II) used in the process for the purification of the present invention can be obtained by any process for its preparation known in the art. For instance, tivozanib base prepared by following the process described in U.S. Pat.
  • No.6,821,987 can be purified using the purification process of the present invention.
  • the pure tivozanib (the compound II) obtained by the purification process of the present invention is optionally converted to its corresponding pharmaceutically acceptable salt (the compound IA) or a hydrate thereof as per the process described herein above.
  • the term “pure”, unless otherwise defined, means that tivazanib (the compound II) or its pharmaceutically acceptable salt (the compound IA) has purity of at least 99%.
  • the solvent used in the step (i) of the process for the purification of tivozanib (compound II) is an alcohol selected from methanol, ethanol, propanol, isopropyl alcohol, n-butanol, sec-butyl alcohol, tert-butyl alcohol, or isobutyl alcohol; or a hydrocarbon solvent selected from benzene, toluene, xylene, cyclohexane or a mixture thereof.
  • tivozanib (compound II) is treated with the aqueous solution of metal sulfate or a metal halide, which is prepared without using any organic solvent, at a temperature ranging from about 200C to about 1000C.
  • the metal sulfate used in step (i) of the purification process is selected from copper sulfate pentahydrate or zinc sulfate heptahydrate.
  • the metal halide used in step (i) of the purification process is selected from zinc chloride, zinc bromide, zinc iodide, copper chloride, copper bromide or copper iodide.
  • the metal halide is selected from zinc chloride, zinc bromide or zinc iodide.
  • the present invention relates to a compound selected from the group consisting of the compounds of formulae A, B, and C; wherein, R 1 is methyl, ethyl, 2,2,2-trichloroethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, benzyl or phenyl, wherein the benzyl and phenyl are unsubstituted or substituted [0066]
  • the inventors of the present invention have identified the compounds of formulae A, B and C as three major impurities that are formed in the process for the preparation of tivozanib (the compound II) or pharmaceutically acceptable salt (the compound IA) or a hydrate thereof.
  • the inventors of the present invention have also identified the following compound of formula D, which is also formed as an impurity in the process for the preparation of tivozanib (the compound II) or pharmaceutically acceptable salt (the compound IA) or a hydrate thereof.
  • TIVO-2024 D The compounds of formulae A, B, C and D that are formed as impurities in the process for the preparation of tivozanib (the compound II) or a pharmaceutically acceptable salt (the compound IA) or a hydrate thereof are designated as Impurity A, Impurity B, Impurity C and Impurity D respectively.
  • the Impurity B is a compound represented by the compound of formula B, wherein R 1 is phenyl, which is unsubstituted or substituted with Cl, Br or F.
  • the present invention provides tivozanib (compound II) or its pharmaceutically acceptable salt (the compound IA) or a hydrate thereof having chemical purity of at least 99% as measured by HPLC.
  • the present invention provides tivozanib (compound II) or its pharmaceutically acceptable salt (the compound IA) or a hydrate thereof having chemical purity of at least 99.5% wherein the content of each of the Impurity A, B, C and D ranges from about 0.01% to about 0.5 % w/w as measured by HPLC.
  • the present invention provides tivozanib (compound II) or its pharmaceutically acceptable salt (the compound IA) or a hydrate thereof obtained by the process of the present invention, wherein the having chemical purity of at least 99.5% wherein the content of each of the Impurity A, B, C and D ranges from about 0.01% to about 0.5 % w/w as measured by HPLC.
  • the present invention provides a process for the preparation of tivozanib hydrochloride (the compound I) or a hydrate thereof; having chemical purity of at least 99% wherein the content of each of the Impurity A, B, C and D ranges from about 0.01% to about 0.5% w/w as measured by HPLC.
  • the present invention provides a process for the preparation of hydrochloride salt of tivozanib i.e. tivozanib hydrochloride (the compound I) or a hydrate thereof; having chemical purity of about 99.5% wherein the content of TIVO-2024 each of the Impurity A, B, C and D ranges from about 0.01% to about 0.3 % w/w as measured by HPLC.
  • the present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
  • HPLC method High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chemical purity: Column: Zorbax Eclipse XDB C8, 150 x 4.6mm, 5 ⁇ m Column Temperature: 35°C Mobile phase: Mobile Phase A: Buffer: Methanol (95:5 v/v) Mobile Phase B: Methanol: ACN: Water (55:35:10, v/v) Time (min) % Mobile Phase A % Mobile Phase B 0.01 100 00 05 100 00 20 50 50 30 20 80 45 20 80 45.1 100 00 50 100 00 Diluent: 0.1% O-Phosphoric acid: Methanol (70:30, v/v) Flow Rate: 1.0 mL/minute Detection: UV 225 nm Injection Volume: 10 ⁇ L [0077] Example 1: Preparation of 2-chloro-4-((6,7-dimethoxyquinolin-4- yl)oxy)aniline (HPLC) was performed with the conditions described below for detecting chemical purity:
  • reaction mass was warmed to a temperature of 20-35 0C, and stirred for 2 hours.
  • the reaction mass was filtered and washed with water (50 ml).
  • water 650 ml
  • Wet material was dried in vacuum oven at a temperature of 45-50°C.
  • reaction mass was stirred for 2 hours at a temperature of 0-10°C.
  • 4-chloro-6,7-dimethoxyquinoline (compound VII, 93.46 g) was added to the reaction mass.
  • the reaction mass was heated to 110-115°C, and stirred for 4 hours at the same temperature. Cooled the reaction mass to a temperature of 0-15°C.
  • Reaction mass was warmed to a temperature of 20-30 0C, and stirred for 3 hours.
  • the reaction mass was filtered and washed thrice with water (300 ml). Wet material was dried in vacuum oven at a temperature of 50-55°C.
  • Example 3 Preparation of Phenyl carbamate of 5-methyl-1,2-oxazol-3- amine (Compound IV): In a clean and dry flask, 5-methyl-1,2-oxazol-3-amine (compound V, 50 g) was added with N,N-dimethyl acetamide (500ml) and pyridine (164.2 g). The reaction mass was cooled to 0-10°C.
  • Phenyl chloroformate (Compound VI, 65.86 g) was added to the reaction mass over a period of 30 minutes. The reaction mass was stirred for 30 minutes at a temperature of 0-10°C. Reaction mass was warmed to a temperature of 20-25°C and stirred for 4 hours. Reaction mass was cooled to a temperature of 0-10°C and water (1.0 Lit) was added slowly. Reaction mass was warmed to a temperature of 20-30°C and stirred for 2 hours. The solid obtained was filtered and dried in vacuum oven at a temperature of 45-50°C to get crude phenyl (5-methylisoxazol-3-yl)carbamate. To the crude material obtained was added with 10% aq.
  • Example 4 Preparation of Phenyl carbamate of 5-methyl-1,2-oxazol-3- amine (Compound IV): In a clean and dry flask, 5-methyl-1,2-oxazol-3-amine (compound V, 100g) was added with N,N-dimethyl acetamide (700ml) and pyridine (322.41 g). The reaction mass was cooled to 0-10°C. Phenyl chloroformate (Compound VI, 175.5 g) was added to the TIVO-2024 reaction mass over a period of 30 minutes. The reaction mass was stirred for 30 minutes at a temperature of 0-10°C.
  • Reaction mass was warmed to a temperature of 20-25°C and stirred for 4 hours. Reaction mass was cooled to a temperature of 0-10°C and water (1.4 Lit) was added slowly. Reaction mass was warmed to a temperature of 20-30°C and stirred for 2 hours. The solid obtained was filtered, washed thrice with water (200 ml) and dried in vacuum oven at a temperature of 50-55°C to get crude phenyl (5-methylisoxazol- 3-yl)carbamate. To the crude material obtained was added with 3 N aqueous Hydrochloric acid solution (1200 ml). Reaction mass was filtered & washed thrice with water (300ml).
  • Example 5 Preparation 1-(2-chloro-4-((6,7-dimethoxyquinolin-4- yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl)urea (Tivozanib, compound II) In a clean and dry flask, 2-chloro-4-((6,7-dimethoxyquinolin-4-yl)oxy)aniline (compound III, 5 g) was added with toluene (100 ml).
  • Phenyl carbamate of 5-methyl-1,2- oxazol-3amine (compound IV, 22.98 g) was added to the reaction mass and reaction mass was heated to 75-80°C. Reaction mass was stirred for 12-14 hours at 75-80°C. Reaction mass was cooled to 20-25°C and was filtered to obtain the wet material. The wet material was dried in vacuum oven at 45-50°C to obtain crude 1-(2-chloro-4-((6,7- dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl) urea (Tivozanib, compound II).
  • Phenyl carbamate of 5-methyl- 1,2-oxazol-3amine (compound IV, 461.88 g) was added to the reaction mass and reaction mass was heated to 75-80°C. Reaction mass was stirred for 10-14 hours at 75-80°C. Reaction mass was cooled to 20-25°C and was filtered to obtain the wet material. The wet material was dried in vacuum oven at 60-65°C to obtain crude 1-(2-chloro-4-((6,7- dimethoxyquinolin-4-yl)oxy)phenyl)-3-(5-methylisoxazol-3-yl) urea (Tivozanib, compound II).
  • Phenyl carbamate of 5-methyl-1,2-oxazol-3amine (compound IV, 16.4 g), having pH 8.4, was added to the reaction mass. Reaction mass was stirred for 10-14 hours at 20- 30°C. Reaction mass was added with another two lots of Phenyl carbamate of 5-methyl- 1,2-oxazol-3amine (compound IV, 1.64 g), having pH 8.4. Reaction mass was stirred for 2 hours at 20-30°C. Reaction mass was added with water (200 ml) and methanol (100 ml) and was stirred for 30 minutes. Reaction mass was filtered and washed with water (50 ml) to obtain the wet material.
  • Reaction mass was maintained at 60°C for 2 hours.
  • the Reaction mass was cooled to 20-25°C and added with concentrated Hydrochloric acid (0.6ml) followed by addition of ethanol (16.8 ml) and water (1.68 ml) under stirring.
  • the reaction mass was stirred for 30 minutes at 20-30°C and was further cooled to 0-5°C.
  • Reaction mass was stirred for 12 hours at 0-5°C.
  • the solid obtained was filtered and dried under vacuum at 45-50°C.
  • Example 8 Preparation of Tivozanib hydrochloride monohydrate (compound I): In a clean flask, solution of Tivozanib (compound II, 100 g) in N,N-dimethylformamide (2400 ml) was heated to 60°C. Reaction mass was maintained at 60°C for 2 hours. The Reaction mass was cooled to 20-30°C and added with concentrated hydrochloric acid (100 ml) followed by ethanol (8600 ml) and water (864 ml) under stirring.
  • Example 9 Purification of Tivozanib (Compound II) TIVO-2024 In a clean flask solution of copper sulfate pentahydrate (0.55g) in water (12 ml) was added with crude Tivozanib (compound II, 1 g). Reaction mass was stirred at 20-30°C for 30 minutes. Reaction mass was added with ethanol (12ml) and was stirred at 75-80°C for 3 hours. The Reaction mass was cooled to 20-25°C. The solid obtained was filtered and dried under vacuum at 45-50°C for 12 hours.
  • Example 10 Purification of Tivozanib (Compound II) In a clean flask, a solution of Zinc sulfate heptahydrate (0.65g) in water (12 ml) was added to crude tivozanib (compound II, 1 g). The resulting reaction mass was stirred at a temperature of 20-30°C for 30 minutes. To the reaction mass, was added ethanol (12ml) and stirred at a temperature of 75-80°C for 3hours. The reaction mass was cooled to 20- 25°C.
  • Example: 11 The stability data of the Tivozanib hydrochloride monohydrate Tivozanib hydrochloride monohydrate prepared by the process of present invention was subjected to stability studies at 25°C ⁇ 2°C/ 60% ⁇ 5% RH and at 40°C ⁇ 2°C/ 75% ⁇ 5% RH respectively for 3 months. Results of the stability studies are presented in the following Table 1.

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Abstract

La présente invention concerne un procédé de préparation de tivozanib ou d'un sel pharmaceutiquement acceptable ou d'un hydrate de celui-ci. La présente invention concerne en particulier un procédé de préparation de chlorhydrate de tivozanib ou d'un hydrate de celui-ci. La présente invention concerne également un procédé de purification de tivozanib ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/IB2024/050628 2023-01-25 2024-01-23 Procédé de préparation de tivozanib ou d'un sel de celui-ci WO2024157170A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532116A (zh) * 2011-08-09 2012-07-04 武汉迈德森医药科技有限公司 抗肿瘤靶向治疗药物tivozanib的合成方法
CN104072492A (zh) * 2013-11-27 2014-10-01 苏州摩尔医药有限公司 一种抗肿瘤靶向治疗药物Tivozanib的合成方法
CN106967058A (zh) * 2017-04-05 2017-07-21 泰力特医药（湖北）有限公司 一种替沃扎尼的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102532116A (zh) * 2011-08-09 2012-07-04 武汉迈德森医药科技有限公司 抗肿瘤靶向治疗药物tivozanib的合成方法
CN104072492A (zh) * 2013-11-27 2014-10-01 苏州摩尔医药有限公司 一种抗肿瘤靶向治疗药物Tivozanib的合成方法
CN106967058A (zh) * 2017-04-05 2017-07-21 泰力特医药（湖北）有限公司 一种替沃扎尼的制备方法

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