WO2015198249A1 - Process for preparation of bosutinib - Google Patents
Process for preparation of bosutinib Download PDFInfo
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- WO2015198249A1 WO2015198249A1 PCT/IB2015/054758 IB2015054758W WO2015198249A1 WO 2015198249 A1 WO2015198249 A1 WO 2015198249A1 IB 2015054758 W IB2015054758 W IB 2015054758W WO 2015198249 A1 WO2015198249 A1 WO 2015198249A1
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- 0 CN1CCN(CCCOc(cc(*)c(C(O*)=O)c2)c2O*)CC1 Chemical compound CN1CCN(CCCOc(cc(*)c(C(O*)=O)c2)c2O*)CC1 0.000 description 3
- UBPYILGKFZZVDX-UHFFFAOYSA-N CN1CCN(CCCOc(c(OC)cc2c3Nc(cc(c(Cl)c4)OC)c4Cl)cc2ncc3C#N)CC1 Chemical compound CN1CCN(CCCOc(c(OC)cc2c3Nc(cc(c(Cl)c4)OC)c4Cl)cc2ncc3C#N)CC1 UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- XWIDFASHTPEYDZ-UHFFFAOYSA-N CN1CCN(CCCOc(cc(c(C2O)c3)N=CC2C#N)c3OC)CC1 Chemical compound CN1CCN(CCCOc(cc(c(C2O)c3)N=CC2C#N)c3OC)CC1 XWIDFASHTPEYDZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
Definitions
- the present invention relates to a process for preparation of compound of Formula (I).
- the present invention also relates to novel intermediates useful in the preparation of Bosutinib.
- the present invention also relates to a process for the preparation of novel Bosutinib intermediates.
- Bosutinib under the brand name BOSULIF ® is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. It was approved by USFDA in 2012.
- Bosutinib is a kinase inhibitor, chemically known as 4-[(2,4-dichloro-5- methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-Quinoline carbonitrile (I) and was marketed in the form of monohydrate.
- Bosutinib is a white to yellowish tan powder with the empirical formula C26H29CI2N5O3 and a molecular weight of 530.16. It acts as a highly soluble compound at below pH 5 and the solubility decreases with increase in pH.
- Bosutinib is a generically disclosed in US 6002008 and specifically disclosed in the Re-issue patent RE42376, wherein these patents disclosed processes for the preparation of Bosutinib.
- Bioorganic & Medicinal Chemistry Letters 10 (2000) 2477- 2480 & Journal of Medicinal Chemistry 2001, 44, 3965-3977 discloses a process for the preparation of Bosutinib which is as demostrated below:
- the main objective of the invention is to provide a process for the preparation of compound of Formula (I).
- Yet another objective of the invention is to provide a novel intermediates useful in the preparation of Bosutinib.
- Yet another objective of the invention is to provide a process for the preparation of novel Bosutinib intermediates.
- the main aspect of the present invention relates to a process for preparation of compound of Formula(I)
- X is halogen selected from F, CI, Br or I
- Another aspect of the present invention further relates to novel intermediate compounds of Formula
- R is same or different group selected from Ci -5 alkyl; R ⁇ is -NO 2 , NH 2 , NHCHCHCN; X is -OH, Halogen.
- Another aspect of the present invention also further relates to a process for preparation of compound of Formula(D)
- Another aspect of the present invention also further relates a process for preparation compound of Formula(E)
- Another aspect of the present invention also further relates a process for preparation of compound of Formula(F)
- Another aspect of the present invention also further relates a process for preparation of compound of Formula(B) wherein X is hydroxy; comprises cyclizing compound of Formula F
- Another aspect of the present invention also further relates a process for preparation of compound of Formula(B)
- the present invention relates to novel intermediates useful in the preparation of Bosutinib. DETAILED DESCRIPTION OF THE INVENTION
- the present invention relates to a process for preparation of Bosutinib of Formula(I) comprising the steps of reacting Methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate of Formula II with N-methyl piperazine in the presence of iodide salt selected from potassium iodide, sodium iodide, tetrabutylammonium iodide & tetrapropylammonium iodide optionally in the presence of base selected from organic base such as triethylamine,diisoproylethylamine, tributyl amine, ⁇ , ⁇ -dimethyl aniline, pyridine, DBN, DBU, N-methyl piperazine or inorganic base such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide; to give methyl 5-methoxy-4-(3-(4-methylpiperazin-l-y
- Reducing the compound of Formula III to give methyl 2-amino-5-methoxy-4-(3-(4- methylpiperazin-l-yl)propoxy)benzoate of Formula IV using a reducing agent selected from borane complexes, metals such as iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel in the presence of hydrogen or hydrogen source, selected from ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine in a solvent selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; ethers such as tetrahydrofuran; dioxane or mixture thereof at a temperature ranging from 5- 50°C , preferably at 25-30°C.
- a reducing agent selected from borane complexes, metals such as iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel in the presence
- 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quinolone-3-carbonitrile of Formula VI was also prepared by condensing 7-(3-chloropropoxy)-4-hydroxy-6- methoxyquinoline-3 -carbonitrile with N-methyl piperazine in the presence of iodide salt selected from sodium iodide, potassium iodide, tetrabutylammonium iodide & tetrapropylammonium iodide at 25-30°C. Stirred reaction mixture for 5 to 7 hrs at 80-85°C.
- iodide salt selected from sodium iodide, potassium iodide, tetrabutylammonium iodide & tetrapropylammonium iodide
- Reaction is monitored by HPLC for the % of 7-(3-chloropropoxy)-4-hydroxy-6- methoxyquinoline-3 -carbonitrile i.e. NMT 2.0%. Filtered the material and washed with acetonitrile to yield 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy) quinoline- 3 -carbonitrile.
- a halogenating agent selected from Phosphorous oxy chloride, Oxalyl chloride, Phosphorous tri chloride, Phosphorous pentachloride, Thionyl chloride
- a solvent selected from Toluene, Xylene, Benzene & acetonitrile in the presence of a solvent selected from Toluene, Xylene, Benzene & acetonitrile.
- the reaction mixture was stirred at 80-85°C
- Reaction is monitored by HPLC for the % of 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy) quinoline-3-carbonitrile i.e. NMT 2.0%.
- Reaction mixture cooled to 0-5 °C and then water was added slowly water for 1 to 2 hrs.
- Methylene dichloride was added and extracted the material by dichloromethane. Washed organic layer with saturated sodium chloride solution followed drying over sodium sulphate. Filtered the organic layer and distilled out completely under vacuum below 45°C.
- Reaction mass cooled to 25-30°C, filtered and washed with n-heptane. The wet solid dried under vacuum to obtain 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy) quinoline-3-carbonitrile.
- crystallization of Bosutinib obtained from step (f) may be carried out using a suitable organic solvent or the mixture thereof to obtained pure Bosutinib, which is in crystalline nature.
- R is same or different group selected from Ci -5 alkyl; R, is -N0 2 , NH 2 , -NHCHCHCN;
- X is -OH, Halogen.
- the preset invention relates to process for the preparation of Bosutinib using compounds of Formula (A) and (B) is demonstrated in Scheme-II
- Bosutinib Complete synthesis of Bosutinib is extremely efficient with well conceived sequence of steps, which is feasible for commercial development.
- the present process involves the use of commercially viable rawmaterials/reagents and solvents
- the present invention relates to process for preparation of compound of Formula(D) comprises reacting alkyl-4-(3-halopropoxy)-5-alkoxy-2- nitrobenzoate (C) with N-methyl piperazine in the presence of in the presence of iodide salt selected from potassium iodide, sodium iodide, tetrabutylanimonium iodide & tetrapropylammonium iodide optionally in the presence of base selected from organic base such as triethylamine,diisoproylethylamine, tributyl amine, ⁇ , ⁇ -dimethyl aniline, pyridine, DBN, DBU, N-methyl piperazine or inorganic base such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide;, optionally in the base to provide alkyl- 5-alkoxy-4-(3-(4-methylpiperazin-l) with
- the present invention relates to process for preparation of compound of Formula(E) comprises reducing the compound of Formula (D) using a reducing agent selected from borane complexes, metals such as iron, tin, zinc; transition metals such as palladium-carbon,platinum oxide, Raney nickel in the presence of hydrogen or hydrogen source, selected from ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine in a solvent selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; ethers such as tetrahydrofuran; dioxane or mixture thereof at a temperature ranging from 5-50°C , preferably at 25-30°C to provide alkyl 5-alkoxy-4-(3-(4- methylpiperazin- 1 -yl)propoxy)-2-aminobenzoate(E)
- a reducing agent selected from borane complexes, metals such as iron, tin, zinc
- the present invention relates to process for preparation of compound of Formula(F) comprises condensing compound of Formula E with 3,3- Diethoxypropionitrile, in the presence of proton source selected from acetic acid, trifluoro acetic acid, methane sulfonic acid, para toluene sulfonic acid; and water at 25-30°C under nitrogen atmosphere. Stirred for 30 min to 45 min at 5 - 10 °C. Filter the solid and and dried to give a novel intermediate to provide alkyl-2-((2-cyanovinyl)amino)-5-alkoxy-4-(3-(4-methyl piperazin- 1 -yl)propoxy)benzoate (F);
- the present invention relates to process for preparation of compound of Formula(B), wherein X is hydroxy; comprises cyclizing compound of Formula F in the presence of base selected from inorganic base, such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide; in a solvent selected from alcohol such as methanol, ethanol, isopropanol, butanol, tert-butyl alcohol. Stirred reaction mixture for 4 hrs to 6 hrs at 25-30 °C. Reaction mass poured into water at 25-30 °C under stirring. Filtered the solid and dried to afford 4- hydroxy-6-alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy)quinolone-3-carbonitrile (B), wherein X is hydroxy.
- base selected from inorganic base, such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide
- the present invention relates to process for preparation of compound of Formula(B), wherein X is halogen; comprises cyclizing compound of Formula F in the presence of base to using the process as disclosed above to provide 4-hydroxy-6- alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy)quinolone-3-carbonitrile (B); wherein X is hydroxy; followed by reacting with a halogenating agent selected from Phosphorous oxy chloride, Oxalyl chloride, Phosphorous tri chloride, Phosphorous pentachloride, Thionyl chloride; in the presence of a solvent selected from Toluene, Xylene, Benzene.
- a halogenating agent selected from Phosphorous oxy chloride, Oxalyl chloride, Phosphorous tri chloride, Phosphorous pentachloride, Thionyl chloride
- purification of Bosutinib may be carried out by acid-base treatment for e.g. by using hydrochloric acid and sodium hydroxide. Purification may also be performed by treating with a suitable organic solvent or the mixture thereof. In one of the embodiment, Bosutinib obtained may be treated using a suitable organic solvent or the mixture thereof to obtained pure Bosutinib, which is in crystalline / noncrystalline nature ie, amorphous.
- the purification is carried out using a solvent selected from selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; ketones such as acetone, ethylmethyl ketone, methylisobutyl ketone; ethers such as tetrahydrofuran; non-polar solvents selected from Toluene, Xylene, Benzene; solvents like dioxane, acetonitrile or mixture thereof at a temperature ranging from 40-90°C , preferably at 25-30°C to yield Pure Bosutinib.
- alcohols such as methanol, ethanol, isopropanol, tert-butyl alcohol
- ketones such as acetone, ethylmethyl ketone, methylisobutyl ketone
- ethers such as tetrahydrofuran
- non-polar solvents selected from Toluene, Xylene, Benzen
- the process related impurities that appear in the impurity profile of the Bosutinib may be substantially removed by the process of the present invention resulting in the formation pure Bosutinib.
- the merit of the process according to the present invention resides in that - product obtained after drying is directly obtained as pure Bosutinib. Said material is found to be adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.
- the Bosutinib obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
- the active product is mixed with one or more pharmaceutically acceptable excipients.
- the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
- compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
- a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
- These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
- the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
- compositions comprising Bosutinib obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like.
- diluents such as starch, pregelatinized starch,
- compositions derived from Bosutinib of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
- reaction mixture was cooled to 0-5°C followed addition of water (700 ml, 5.83 ml/g) for 1 to 2 hrs. Adjusted pH 8.0-8.5 by using aq ammonia solution. Material extracted by dichloromethane (1L x 3). Washed organic layer with saturated sodium chloride solution followed drying over sodium sulphate. Organic layer filtered and distilled out completely under vacuum below 45°C. n-heptane (1L) added to residue and stirred at 80-85°C for 2 hrs. Reaction mass cooled to 25-30°C, filtered and washed with n-heptane (240 ml). The wet solid dried under vacuum to obtain title compound.
- reaction mixture cooled to 5-10°C followed addition of water (840 ml) for 1 hr. Adjusted pH 8.0-8.5 by using IN HC1 solution. Stirred reaction mixture for 5 hrs at 25- 30°C. Reaction mass filtered, washed with purified water (70 ml) and dried under vacuum to obtain title compound.
Abstract
The present invention relates to a process for the preparation of compound of Formula (I). The present invention further relates to novel intermediates useful in the preparation of Bosutinib. The present invention also relates to a process for the preparation of novel Bosutinib intermediates.
Description
PROCESS FOR PREPARATION OF BOSUTINIB
FIELD OF THE INVENTION
The present invention relates to a process for preparation of compound of Formula (I).
The present invention also relates to novel intermediates useful in the preparation of Bosutinib.
The present invention also relates to a process for the preparation of novel Bosutinib intermediates.
BACKGROUND OF THE INVENTION
Bosutinib, under the brand name BOSULIF® is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. It was approved by USFDA in 2012.
Bosutinib is a kinase inhibitor, chemically known as 4-[(2,4-dichloro-5- methoxyphenyl) amino]-6-methoxy-7-[3-(4-methyl-l-piperazinyl)propoxy]-3-Quinoline carbonitrile (I) and was marketed in the form of monohydrate.
Bosutinib is a white to yellowish tan powder with the empirical formula C26H29CI2N5O3 and a molecular weight of 530.16. It acts as a highly soluble compound at below pH 5 and the solubility decreases with increase in pH.
Bosutinib is a generically disclosed in US 6002008 and specifically disclosed in the Re-issue patent RE42376, wherein these patents disclosed processes for the preparation of Bosutinib.
Bioorganic & Medicinal Chemistry Letters 10 (2000) 2477- 2480 & Journal of Medicinal Chemistry 2001, 44, 3965-3977 discloses a process for the preparation of Bosutinib which is as demostrated below:
Molecules (2010), 15, 4261-4266 and CN 101792416 dicloses similar process for the preparation of Bosutinib, which is as demonstrated below:
While reworking the above processes, the present inventors have found the following limitations , which often makes such processes not amenable to scaleup:
Formation of large number of impurities, which are exceeding the ICH compliance limit,
Tedious workup and multiple steps required for the removal of impurities resulting in exceptionally low yields.
Unwanted side reactions were observed during the condensation reaction and subsequent stages.
In view of the above and to overcome the existing prior-art problems, the present inventors have developed an improved process for the preparation of Bosutinib, using novel intermediates, which is not only industrially viable process, but also involves the use of environment friendly reagents and does not require tedious work up.
OBJECTIVE OF THE INVENTION
The main objective of the invention is to provide a process for the preparation of compound of Formula (I).
Yet another objective of the invention is to provide a novel intermediates useful in the preparation of Bosutinib.
Yet another objective of the invention is to provide a process for the preparation of novel Bosutinib intermediates.
SUMMARY OF THE INVENTION
The main aspect of the present invention relates to a process for preparation of compound of Formula(I)
comprising the steps of:
with N-methyl piperazine in the presence of iodide salt, optionally in the base to provide methyl 5-methoxy-4-(3-(4-methylpiperazin-l -yl)propoxy)-2- nitrobenzoate(III) ;
b) reducing the compound of Formula (III) to provide methyl 2-amino-5-methoxy-4-(3- (4-methy lpiperazin-l-yl)propoxy)benzoate ( IV);
c) condensing compound of Formula IV with 3,3-Diethoxypropionitrile, in the presence of proton source to provide methyl 2-((2-cyanovinyl)amino)-5-methoxy-4-(3-(4- methyl piperazin-l-yl)propoxy)benzoate (V);
d) preparation of 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l- yl)propoxy)quinolone-3 -carbonitrile (VI)
i. by cyclizing compound of Formula V in the presence of base ; or
with N-methyl piperazine in the presence of iodide salt, optionally in the base; e) reacting compound of formula (VI) with a halogenating agent to provide 4-halo-6- methoxy-7-(3-(4-methylpiperazin- 1 -yl)propoxy)quinolone-3-carbonitrile (VII); and
wherein X is halogen selected from F, CI, Br or I
f) condensing compound of Formula VII with 2,4-dichloro-5-methoxy aniline to provide compund of formula (I).
(A) (B)
wherein R is same or different group selected from Ci-5 alkyl; R\ is -NO2, NH2, NHCHCHCN; X is -OH, Halogen.
Another aspect of the present invention also further relates to a process for preparation of compound of Formula(D)
with N-methyl piperazine in the presence of iodide salt, optionally in the base to provide alkyl 5-alkoxy-4-(3 -(4-methylpiperazin- 1 -yl)propoxy)-2-nitrobenzoate(D)
Another aspect of the present invention also further relates a process for preparation compound of Formula(E)
comprises reducing the compound of Formula (D)
Another aspect of the present invention also further relates a process for preparation of compound of Formula(F)
comprises condensing compound of Formula E
with 3,3-Diethoxypropionitrile, in the presence of proton source to provide methyl 2-((2- cyanovinyl)amino)-5-alkoxy-4-(3-(4-methyl piperazin-l-yl)propoxy)benzoate (F);
Another aspect of the present invention also further relates a process for preparation of compound of Formula(B)
wherein X is hydroxy; comprises cyclizing compound of Formula F
in the presence of base to provide 4-hydroxy-6-alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy)quinolone-3-carbonitrile (B), wherein X is hydroxy. Another aspect of the present invention also further relates a process for preparation of compound of Formula(B)
wherein X is halogen; comprises cyclizing compound of Formula F
in the presence of base to provide 4-hydroxy-6-alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy)quinolone-3-carbonitrile (B); wherein X is hydroxy; followed by reacting with a halogenating agent to provide 4-halo-6-alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy) quinolone-3-carbonitrile (B)
In another aspect the present invention relates to novel intermediates useful in the preparation of Bosutinib. DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for preparation of Bosutinib of Formula(I) comprising the steps of reacting Methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate of Formula II with N-methyl piperazine in the presence of iodide salt selected from potassium iodide, sodium iodide, tetrabutylammonium iodide & tetrapropylammonium iodide optionally in the presence of base selected from organic base such as triethylamine,diisoproylethylamine, tributyl amine, Ν,Ν-dimethyl aniline, pyridine, DBN, DBU, N-methyl piperazine or inorganic base such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide; to give methyl 5-methoxy-4-(3-(4-methylpiperazin-l-yl)propoxy)-2-nitrobenzoate of Formula III
Reducing the compound of Formula III to give methyl 2-amino-5-methoxy-4-(3-(4- methylpiperazin-l-yl)propoxy)benzoate of Formula IV, using a reducing agent selected from borane complexes, metals such as iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel in the presence of hydrogen or hydrogen source, selected from
ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine in a solvent selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; ethers such as tetrahydrofuran; dioxane or mixture thereof at a temperature ranging from 5- 50°C , preferably at 25-30°C.
Condensing 2-amino-5-methoxy-4-(3-(4-methyl piperazin-l-yl)propoxy)benzoate with 3,3-Diethoxypropionitrile, in the presence of proton source selected from acetic acid, trifluoro acetic acid, methane sulfonic acid, para toluene sulfonic acid; and water at 25-30°C under nitrogen atmosphere. Stirred for 30 min to 45 min at 5-10 °C. Filter the solid and and dried to give a novel intermediate methyl 2-((2-cyanovinyl)amino)-5-mefhoxy-4-(3-(4- methyl piperazin-l-yl)propoxy)benzoate of Formula V.
Cyclizing methyl 2-((2-cyanovinyl)amino)-5-methoxy-4-(3-(4-methyl piperazin-1- yl)propoxy)benzoate in the presence of base, selected from inorganic base, such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide; in a solvent selected from alcohol such as methanol, ethanol, isopropanol, butanol, tert-butyl alcohol. Stirred reaction mixture for 4 hrs to 6 hrs at 25-30 °C. Reaction mass poured into water at 25-30 °C under stirring. Filtered the solid and dried to afford 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quinolone-3- carbonitrile of Formula VI .
4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quinolone-3-carbonitrile of Formula VI was also prepared by condensing 7-(3-chloropropoxy)-4-hydroxy-6- methoxyquinoline-3 -carbonitrile with N-methyl piperazine in the presence of iodide salt selected from sodium iodide, potassium iodide, tetrabutylammonium iodide & tetrapropylammonium iodide at 25-30°C. Stirred reaction mixture for 5 to 7 hrs at 80-85°C. Reaction is monitored by HPLC for the % of 7-(3-chloropropoxy)-4-hydroxy-6- methoxyquinoline-3 -carbonitrile i.e. NMT 2.0%. Filtered the material and washed with acetonitrile to yield 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy) quinoline- 3 -carbonitrile.
Halogenating 4-hydroxy-6-methoxy-7-(3 -(4-methylpiperazin- 1 -yl)propoxy) quinoline -3 -carbonitrile with a halogenating agent selected from Phosphorous oxy chloride, Oxalyl chloride, Phosphorous tri chloride, Phosphorous pentachloride, Thionyl chloride; in the
presence of a solvent selected from Toluene, Xylene, Benzene & acetonitrile. The reaction mixture was stirred at 80-85°C for 6 hrs to 8 hrs. Reaction is monitored by HPLC for the % of 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy) quinoline-3-carbonitrile i.e. NMT 2.0%. Reaction mixture cooled to 0-5 °C and then water was added slowly water for 1 to 2 hrs. Methylene dichloride was added and extracted the material by dichloromethane. Washed organic layer with saturated sodium chloride solution followed drying over sodium sulphate. Filtered the organic layer and distilled out completely under vacuum below 45°C. Reaction mass cooled to 25-30°C, filtered and washed with n-heptane. The wet solid dried under vacuum to obtain 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy) quinoline-3-carbonitrile.
4-chloro-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quinoline-3-carbonitrile was condensed with 2,4-dichloro-5-methoxy aniline. The reaction was carried out at 25-30°C for 5 to 6 hrs. Reaction is monitored by HPLC for the completionof the reaction. Reaction mixture was cooled to 5-10°C followed addition of water for 1 hr. Adjusted pH 8.0-8.5 by using IN HCl solution. Material extracted by dichloromethane. Again, stirred the reaction mixture for 5 hrs to 6 hrs at 25-30°C. Reaction mass filtered, washed with water and dried under vacuum to yield Bosutinib of Formula I. In prior art the condensation reaction mentioned between 7-(3-chloropropoxy)-4- chloro-6-methoxy-quinoline-3-carbonitrile with 2,4-dichloro-5-methoxy aniline in 2-ethoxy ethanol using as a solvent at temp. 130-135°C afford very poor yield due to formation of 7- (3-chloropropoxy)-4-hydroxy-6-methoxy-quinoline-3-carbonitrile. Our process avoids such type of impurity formation.
A synthetic process for the preparation of Bosutinib, obtained as per the present invention is demonstrated in Scheme-I
In one of the embodiment, crystallization of Bosutinib obtained from step (f) may be carried out using a suitable organic solvent or the mixture thereof to obtained pure Bosutinib, which is in crystalline nature.
In another embodiment the present invention relates to a process for the preparation of Bosutinib using novel intermediates of formula
(A)
wherein R is same or different group selected from Ci-5 alkyl;
R, is -N02, NH2, -NHCHCHCN;
X is -OH, Halogen.
In another embodiment the intermediates disclosed above are used in the preparation of Bosutinib.The compounds listed below were synthesized according to the general methods shown below, and the more detailed exemplar procedures. Some of the compounds of formula (A) and (B)
In another embodiment the preset invention relates to process for the preparation of Bosutinib using compounds of Formula (A) and (B) is demonstrated in Scheme-II
Advantages of this process:
Complete synthesis of Bosutinib is extremely efficient with well conceived sequence of steps, which is feasible for commercial development.
The present process involves the use of commercially viable rawmaterials/reagents and solvents
In another embodiment the present invention relates to process for preparation of compound of Formula(D) comprises reacting alkyl-4-(3-halopropoxy)-5-alkoxy-2- nitrobenzoate (C) with N-methyl piperazine in the presence of in the presence of iodide salt selected from potassium iodide, sodium iodide, tetrabutylanimonium iodide & tetrapropylammonium iodide optionally in the presence of base selected from organic base such as triethylamine,diisoproylethylamine, tributyl amine, Ν,Ν-dimethyl aniline, pyridine, DBN, DBU, N-methyl piperazine or inorganic base such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide;, optionally in the base to provide alkyl- 5-alkoxy-4-(3-(4-methylpiperazin-l- yl)propoxy)-2-nitrobenzoate(D).
In another embodiement the present invention relates to process for preparation of compound of Formula(E) comprises reducing the compound of Formula (D) using a reducing agent selected from borane complexes, metals such as iron, tin, zinc; transition metals such as palladium-carbon,platinum oxide, Raney nickel in the presence of hydrogen or hydrogen source, selected from ammonium formate, ammonium chloride, sodium dihydrogen phosphate, hydrazine in a solvent selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; ethers such as tetrahydrofuran; dioxane or mixture thereof at a temperature ranging from 5-50°C , preferably at 25-30°C to provide alkyl 5-alkoxy-4-(3-(4- methylpiperazin- 1 -yl)propoxy)-2-aminobenzoate(E)
In another embodiment the present invention relates to process for preparation of compound of Formula(F) comprises condensing compound of Formula E with 3,3- Diethoxypropionitrile, in the presence of proton source selected from acetic acid, trifluoro acetic acid, methane sulfonic acid, para toluene sulfonic acid; and water at 25-30°C under nitrogen atmosphere. Stirred for 30 min to 45 min at 5 - 10 °C. Filter the solid and and dried to give a novel intermediate to provide alkyl-2-((2-cyanovinyl)amino)-5-alkoxy-4-(3-(4-methyl piperazin- 1 -yl)propoxy)benzoate (F);
In another embodiment the present invention relates to process for preparation of compound of Formula(B), wherein X is hydroxy; comprises cyclizing compound of Formula F in the presence of base selected from inorganic base, such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide; in a solvent selected from alcohol such as methanol, ethanol, isopropanol, butanol, tert-butyl alcohol. Stirred reaction mixture for 4 hrs to 6 hrs at 25-30 °C. Reaction mass poured into water at 25-30 °C under stirring. Filtered the solid and dried to afford 4- hydroxy-6-alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy)quinolone-3-carbonitrile (B), wherein X is hydroxy.
In another embodiment the present invention relates to process for preparation of compound of Formula(B), wherein X is halogen; comprises cyclizing compound of Formula F in the presence of base to using the process as disclosed above to provide 4-hydroxy-6- alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy)quinolone-3-carbonitrile (B); wherein X is hydroxy; followed by reacting with a halogenating agent selected from Phosphorous oxy chloride, Oxalyl chloride, Phosphorous tri chloride, Phosphorous pentachloride, Thionyl
chloride; in the presence of a solvent selected from Toluene, Xylene, Benzene. The reaction mixture was stirred at 80-85°C for 6 hrs to 8 hrs to provide 4-halo-6-alkoxy-7-(3-(4- methylpiperazin-l-yl)propoxy) quinolone-3-carbonitrile (B). The obtained compound was condensed with 2,4-dichloro-5-methoxy aniline to yield Bosutinib of Formula I.
In one of the embodiment, purification of Bosutinib may be carried out by acid-base treatment for e.g. by using hydrochloric acid and sodium hydroxide. Purification may also be performed by treating with a suitable organic solvent or the mixture thereof. In one of the embodiment, Bosutinib obtained may be treated using a suitable organic solvent or the mixture thereof to obtained pure Bosutinib, which is in crystalline / noncrystalline nature ie, amorphous.
In another embodibemnet the purification is carried out using a solvent selected from selected from alcohols, such as methanol, ethanol, isopropanol, tert-butyl alcohol; ketones such as acetone, ethylmethyl ketone, methylisobutyl ketone; ethers such as tetrahydrofuran; non-polar solvents selected from Toluene, Xylene, Benzene; solvents like dioxane, acetonitrile or mixture thereof at a temperature ranging from 40-90°C , preferably at 25-30°C to yield Pure Bosutinib.
The process related impurities that appear in the impurity profile of the Bosutinib may be substantially removed by the process of the present invention resulting in the formation pure Bosutinib. The merit of the process according to the present invention resides in that - product obtained after drying is directly obtained as pure Bosutinib. Said material is found to be adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.
In another embodiment, the Bosutinib obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions,
syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerine, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Bosutinib obtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived from Bosutinib of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
EXAMPLES
Example 1
Preparation of Methyl-5-methoxy-4-(3-(4-methylpiperazin-l-yf)propoxy)-2-nitro benzoate
Methyl 4-(3-chloropropoxy)-5-methoxy-2-nitrobenzoate (0.3 gm), N-methyl piperazine (3.63 ml), Sodium iodide (0.148 g, 0.9873 mmol, 1.00 eq) are charged in to a round bottom flask at 20-25°C. Reaction mixture is stirred for 5 minutes and then heated to 80-85°C. Stirred the reaction mass for 4 hours and continued stirring if required till the content of methyl 4-(3- chloropropoxy)-5-methoxy-2-nitrobenzoate was below 5%. Distilled off the solvent completely under vacuum, to the obtained residue ethylacetate ( 10 ml) was added and then washed with sodium bicarbonate solution (5 ml). Dried the organic layer over Sodium sulphate and removed the Ethyl acetate from the filtrate under vacuum completely at below 45°C to get thick brownish yellow coloured mass of the title compound.
Yield: 100 mg. (Mass complies)
Exmaple 2
Preparation of Methyl-2-amino-5-methoxy-4-(3-(4-methylpiperazin-l-yI)propoxy) benzoate
Powdered iron (0.450 g) and Ammonium chloride (0.678 g, 0.0126 mol) are added in to the reaction flask containing Methanol (6.85 ml) and Water (2.94 ml) at 25-30°C. Resulting reaction mixture was heated to reflux and stirred for 10 minutes. Methyl 5-methoxy-4-(3-(4- methylpiperazin-l-yl)propoxy)-2-nitrobenzoate (0.890 0 g, 0.0024 mol) in heated Methanol (9.80 ml) was added dropwise to the above prepared reaction mixture at 65 °C under stirring. The obtained reaction mixture was stirred for 4 hours at reflux and then filtered the material. Distilled of the solvent completely under vacuum and air dried the residue to obtained the title product
Yield: 0.817 gm (Mass complies) Example 3
Preparation of (E)-methyl 2-((2-cyanovinyl)amino)-5-methoxy-4-(3-(4-methylpiperazin- 1 -yl)propoxy)benzoate
Charged 3,3-diethoxypropionitrile (20 ml, 19.08 g, 0.1332 mol, 2.25 eq), trifmoroacetic acid (40 ml, 59.56 g, 0.5223 mol, 8.82 eq) and water (10 ml) to the reaction flask at 25-30°C under nitrogen atmosphere. Stirred for 6 h at 5-10 °C under nitrogen atmosphere. Added
dropwise a solution of methyl 2-amino-5-methoxy-4-(3-(4-methyl piperazin-1- yl)propoxy)benzoate in 80 ml ethylacetate within 30-45 min. Stirred the mixture for 10 min. Check the reaction by TLC. Filtered the solid and air dried to afford the title product as light yellow solid.
Yield: 19.40 g
Example 4
Preparation of 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy) quinoline- 3-carbonitriIe
Process-i)
Charged ethyl alcohol (200 ml) and (E)-methyl 2-((2-cyanovinyl)amino)-5-methoxy-4-(3-(4- methylpiperazin-l-yl) propoxy)benzoate to reaction flask at 25-30°C under stirring. Adjust pH 12-13 with sodium hydroxide. Stirred reaction mixture for 6 h at 25-30 °C. Reaction mass poured into purified water (1000 ml) at 25-30 °C under stirring. Filtered the solid and dried to afford title compound as light yellow solid.
Yield: 11.80 g
Process-ii)
Charged acetonitrile, 7-(3-chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile (100.0 g, 0.3416 mol, 1.00 eq), N-methyl piperazine (257.36 g, 2.5694 mol, 7.52 eq), Sodium iodide (76.8 g, 0.5124 mol, 1.50 eq) in reactionn flask flask at 25-30°C. Stirred reaction mixture for 6 to 7 hrs at 80-85°C. Reaction is monitored by HPLC for completion. Reaction mixture filtered through celite bed followed washing with acetonitrile (100 ml). Filtered reaction mixture containing the title product.
Yield: 121.76 g
Example 5
Preparation of 4-chIoro-6-methoxy-7-(3-(4-methyIpiperazin-l-yl)propoxy)quinoline-3- carbonitrile
Charged acetonitrile filtrate containing 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l- yl)propoxy) quinoline-3-carbonitrile (120.0 g, 0.3367 mol, 1.00 eq) obtained as per example- 4 to reaction flask at 25-30°C. Added phosphorous oxychloride (372.9 g, 2.4320 mol, 7.22 eq) slowly to reaction mixture for 1 hr at 25-30°C under stirring. Stirred reaction mixture for 8 hrs at 80-85°C. Reaction is monitored by HPLC. After completion of the reaction the reaction mixture was cooled to 0-5°C followed addition of water (700 ml, 5.83 ml/g) for 1 to
2 hrs. Adjusted pH 8.0-8.5 by using aq ammonia solution. Material extracted by dichloromethane (1L x 3). Washed organic layer with saturated sodium chloride solution followed drying over sodium sulphate. Organic layer filtered and distilled out completely under vacuum below 45°C. n-heptane (1L) added to residue and stirred at 80-85°C for 2 hrs. Reaction mass cooled to 25-30°C, filtered and washed with n-heptane (240 ml). The wet solid dried under vacuum to obtain title compound.
Yield: 70.00 g
Example 6
Preparation of Bosutinib
Charged dimethylsulfoxide (560 ml) and potassium tert. Butoxide (42.0 g, 0.3743 mol, 2.00 eq) to reaction flask at 25-30°C. Stired for 15 min followed further charging of 2,4-dichloro- 5-methoxy aniline (39.2 g, 0.2041 mol, 1.09 eq) and 4-chloro-6-methoxy-7-(3-(4-methyl piperazin-l-yl)propoxy) quinoline-3-carbonitrile (70.0 g, 0.1867 mol, 1.00 eq). Stirred reaction mixture for 5 to 6 hrs at 25-30°C. Reaction is monitored by HPLC. After completion of the reaction the reaction mixture cooled to 5-10°C followed addition of water (840 ml) for 1 hr. Adjusted pH 8.0-8.5 by using IN HC1 solution. Stirred reaction mixture for 5 hrs at 25- 30°C. Reaction mass filtered, washed with purified water (70 ml) and dried under vacuum to obtain title compound.
Yield: 56.56 g
Example 7
Purification of Bosutinib
Charged isopropyl alcohol (5.67 ml), water (2.33 ml) and 4-(2,4-dichloro-5-methoxybenzyl)- 6-methoxy-7-(3-(4-methyl piperazin -l-yl)piOpoxy)quinoline-3-carbonitrile (1.0 g) to reaction flask at 25-30°C. Stired for 15 min. Reaction mass dissolved at 70-75°C under stirring. Filtered the clear solution at 70-75°C. Filtrate maintained at 70-75°C for 45 min under stirring followed further over night cooling to 25-30°C. Filtered the solid and washed with isopropyl alcohol (1.33 ml) & water (0.66 ml, total 2.0 ml). Suck dried for 15 min. Solid dried under vacuum to obtain 4-(2,4-dichloro-5-methoxybenzyl)-6-methoxy-7-(3-(4- methylpiperazin-l-yl)propoxy)quinoline-3-carbonitrile.
Yield: 0.7 g
Chromatographic Purity (By HPLC): 99.71%.
Example 8
Purification of Bosutinib
Charged acetone (10 ml) and 4-(2,4-dichloro-5-methoxybenzyl)-6-methoxy-7-(3-(4-methyl piperazin -l-yl)propoxy)quinoline-3-carbonitrile (1.0 g) to reaction flask at 25-30°C. Reaction mass dissolved at 25-30°C under stirring. Filtered clear solution. Hptane (20 ml) added to filtrate at 25-30°C under stirring and maintained for 1 hr followed further cooled to 5-10°C and maintained for 2 hrs. Filtered the solid and washed with n-heptane (2 ml). Suck dried for 15 min. Solid dried under vacuum to obtain 4-(2,4-dichloro-5-methoxybenzyl)-6- methoxy-7-(3 -(4-methylpiperazin- 1 -yl)propoxy)quinoline-3 -carbonitrile.
Yield: 0.5 g
Chromatographic Purity (By HPLC): 99.68%.
Example 9
Purification of Bosutinib
Charged acetonitrile (6 ml) and 4-(2,4-dichloro-5-methoxybenzyl)-6-methoxy-7-(3-(4-methyl piperazin -l-yl)propoxy)quinoline-3 -carbonitrile (1.0 g) to reaction flask at 25-30°C. Reaction mass dissolved at 70-75°C under stirring. Filtered clear solution at 70-75°C. Filtrate cooled to 25-30°C for lhr under stining followed further cooling to 5-10°C and maintained for 2 hrs. Filtered the solid and washed with acetonitrile (1 ml). Suck dried for 15 min. Solid dried under vacuum to obtain 4-(2,4-dichloro-5-methoxybenzyl)-6-methoxy-7-(3-(4- methylpiperazin- 1 -yl)propoxy)quinoline-3 -carbonitrile.
Yield: 0.75 g
While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the description and examples are illustrative only of the principles of the invention and not limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.
Claims
We Claim:
1 ) A process for preparation of compound of Formula(I)
comprising the steps of:
with N-methyl piperazine in the presence of iodide salt, optionally in the base to provide methyl 5-methoxy-4-(3-(4-methylpiperazin-l-yl)propoxy)-2-nitrobenzoate(III);
b) reducing the compound of Formula (III) to provide methyl 2-amino-5-methoxy-4-(3-(4- methyl piperazin-l-yl)propoxy)benzoate ( IV);
c) condensing compound of Formula IV with 3,3-Diethoxypropionitrile, in the presence of proton source to provide methyl 2-((2-cyanovinyI)amino)-5-methoxy-4-(3-(4-methyl piperazin- 1 -yl)propoxy)benzoate (V);
d) preparation of 4-hydroxy-6-methoxy-7-(3-(4-methylpiperazin-l-yl)propoxy)quinolone- 3-carbonitrile (VI)
ni. by cyclizing compound of Formula V in the presence of base ; or
by reacting 7-(3-chloropropoxy)-4-hydroxy-6-methoxyquinoline-3-carbonitrile
with N-methyl piperazine in the presence of iodide salt, optionally in the base; e) reacting compound of formula (VI) with a halogenating agent to provide 4-halo-6- methoxy-7-(3-(4-methylpiperazin- 1 -yl)propoxy)quinolone-3-carbonitrile (VII); and
wherein X is halogen selected from F, CI, Br or I
f) condensing compound of Formula VII with 2,4-dichloro-5-methoxy aniline to provide compound of formula (I).
2) A process for preparation of Bosutinib, according to claim-1, wherein the iodide salt used is selected from sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrapropylammonium iodide.
3) A process for preparation of Bosutinib, according to claim-1, wherein the reduction in step b) is carried out using a reducing agent selected from borane complexes; metals such as
iron, tin, zinc; transition metals such as palladium-carbon, platinum oxide, Raney nickel; in the presence of hydrogen or hydrogen source, selected from ammonium formate, ammonium chloride, sodium dihydrogen phosphate and hydrazine. 4) A process for preparation of Bosutinib, according to claim-1, wherein the condensation in step c) is carried out using a proton source selected from acetic acid, trifluoroacetic acid, methane sulfonic acid, para toluene sulfonic acid.
5) A process for preparation of Bosutinib, according to claim-1, wherein the base used is selected from organic base such as triethylamine,diisoproylethylamine, tributyl amine, Ν,Ν-dimethyl aniline, pyridine, DBN, DBU, N-methyl piperazine or inorganic base such as sodium bicarbonate, potassium bicarbonate, ammonium hydroxide, sodium hydroxide, potassium hydroxide and lithium hydroxide. 6) A process for preparation of Bosutinib, according to claim-1, wherein the halogenating agent is selected from Phosphorous oxy chloride, Oxalyl chloride, Phosphorous tri chloride, Phosphorous pentachloride and Thionyl chloride.
7) Novel intermediate compounds of Formula
(A) (B) wherein R is same or different group, selected from C] -5 alkyl; Ri is -N02, N¾, - NHCHCHCN; X is -OH, Halogen.
8) A process for preparation of compound of Formula(D)
with N-methyl piperazine in the presence of iodide salt, optionally in the base to provide alkyl- 5-alkoxy-4-(3-(4-methylpiperazin-l-yl)propoxy)-2-nitrobenzoate(D).
9) A process for preparation of compound of Formula(E)
comprises reducing the compound of Formula (D)
to provide alkyl 5-alkoxy-4-(3-(4-methylpiperazin-l-yl)propoxy)-2-aminobenzoate(E)
10) A process for preparation of compound of Formula(F)
comprises condensing compound of Formula (E)
with 3,3-Diethoxypropionitrile, in the presence of proton source to provide alkyl-2-((2- cyanovinyl)amino)-5-alkoxy-4-(3-(4-methyl piperazin- 1 -yl)propoxy)benzoate (F);
1) A process for preparation of compound of Formula(B)
wherein X is hydroxy; comprises cyclizing compound of Formula F
in the presence of base to provide 4-hydroxy-6-alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy)quinolone-3-carbonitrile (B), wherein X is hydroxy. process for preparation of compound of Formula(B)
wherein X is halogen; comprises cyclizing compound of Formula F
in the presence of base to provide 4-hydroxy-6-alkoxy-7-(3-(4-methylpiperazin-l-yl) propoxy)quinolone-3-carbonitrile (B); wherein X is hydroxyl; followed by reacting with a halogenating agent to provide 4-halo-6-alkoxy-7-(3-(4-methylpiperazin-l-yl)propoxy) quinolone-3-carbonitrile (B)
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CN110204490A (en) * | 2018-02-28 | 2019-09-06 | 新发药业有限公司 | A kind of two replace the preparation method of 4- chloroquinoline -3- 6-carbonitrile derivatives and Bosutinib |
CN110317168A (en) * | 2018-03-30 | 2019-10-11 | 正大天晴药业集团股份有限公司 | A kind of purification process of bosutinib |
CN111646940A (en) * | 2019-03-04 | 2020-09-11 | 鲁南制药集团股份有限公司 | Preparation method of bosutinib intermediate |
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CN103265482A (en) * | 2013-06-14 | 2013-08-28 | 苏州明锐医药科技有限公司 | Preparation method of bosutinib |
CN104447541A (en) * | 2013-09-16 | 2015-03-25 | 天津市汉康医药生物技术有限公司 | Bosutinib compound |
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CN110204490A (en) * | 2018-02-28 | 2019-09-06 | 新发药业有限公司 | A kind of two replace the preparation method of 4- chloroquinoline -3- 6-carbonitrile derivatives and Bosutinib |
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CN111646940B (en) * | 2019-03-04 | 2024-01-30 | 鲁南制药集团股份有限公司 | Preparation method of bosutinib intermediate |
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