WO2008117298A1 - A novel method of preparation of imatinib - Google Patents
A novel method of preparation of imatinib Download PDFInfo
- Publication number
- WO2008117298A1 WO2008117298A1 PCT/IN2007/000122 IN2007000122W WO2008117298A1 WO 2008117298 A1 WO2008117298 A1 WO 2008117298A1 IN 2007000122 W IN2007000122 W IN 2007000122W WO 2008117298 A1 WO2008117298 A1 WO 2008117298A1
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- WO
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- Prior art keywords
- pyridyl
- preparation
- amino
- amine
- alcoholic
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- Imatinib base (I) is used in the treatment of Chronic Myeloid Leukemia in the form of its mesylate salt.
- the drug acts by inhibiting Tyrosine Kinase and is indicated for Philadelphia chromosome positive leukemia and also for malignant gastrointestinal stromal tumours
- the free base of the drug substance 'imatinib base' is usually prepared by condensation of N- (5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine (II) and 4-[(4-Methylpiperazin- 1-yl) methyljbenzoylchloride dihydrochloride (III).
- a novel, industrially feasible and environmentally friendly method of preparation of the intermediate amine N-(5-Amino-2- methyl phenyl)-4-(3-pyridyl)-2-pyrimidmeamine (II) and its condensation with the acid chloride (III) is described in the current invention.
- the amine intermediate N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine (II) is usually prepared from the corresponding nitro derivative N-(2-Methyl-5-nitrophenyl)-4-(3- pyridyl)-2-pyrimidineamine (IV).
- This conversion is effected by reduction of the nitro group by catalytic hydrogenation (Ha/Pd/C) as described in US 5522184 and EP 0564409.
- Ha/Pd/C catalytic hydrogenation
- the reduction of the nitrocompound (IV) may also be carried out in alkaline polysulphide solutions prepared by dissolving elemental sulphur in caustic alkali solutions like aq. NaOH, aq. KOH, alcoholic NaOH, alcoholic KOH or aq/alcoholic NaOH or aq. Alcoholic KOH.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
Imatinib base (I) is prepared by a novel method by reduction of N-(2-Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine (IV) employing sodium disulphide and condensing the resulting amine N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine (II) with the acid chloride 4-[(4-Methylpiperazin-1-yl) methyl]benzoylchloride dihydrochloride (III), in presence of potassium carbonate.
Description
A NOVEL METHOD OF PREPARATION OF IMATINIB
Imatinib base (I) is used in the treatment of Chronic Myeloid Leukemia in the form of its mesylate salt. The drug acts by inhibiting Tyrosine Kinase and is indicated for Philadelphia chromosome positive leukemia and also for malignant gastrointestinal stromal tumours
The free base of the drug substance 'imatinib base' is usually prepared by condensation of N- (5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine (II) and 4-[(4-Methylpiperazin- 1-yl) methyljbenzoylchloride dihydrochloride (III). A novel, industrially feasible and environmentally friendly method of preparation of the intermediate amine N-(5-Amino-2- methyl phenyl)-4-(3-pyridyl)-2-pyrimidmeamine (II) and its condensation with the acid chloride (III) is described in the current invention.
(I) Imatinib
The amine intermediate N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine (II) is usually prepared from the corresponding nitro derivative N-(2-Methyl-5-nitrophenyl)-4-(3-
pyridyl)-2-pyrimidineamine (IV). This conversion is effected by reduction of the nitro group by catalytic hydrogenation (Ha/Pd/C) as described in US 5522184 and EP 0564409. But this method suffers from the disadvantages like longer reaction times, inconsistency of product composition and requirement of large volume of solvent. In our hands in some batches the reduction did not proceed to yield the desired product.
Reducing agents like SnCl2 have been used successfully as described in the US patent 2004/0248918. These methods are beset with problems like use of heavy metal salts leading to problems in effluent streams rich in tin salts. Also purification of the resulting product free of heavy metal salts is rather difficult. In continuation of our Research & Development efforts to develop a simple method of preparation of the imatinib base and also useful amine intermediate (II) free of the disadvantages mentioned, we developed a simple method of reducing the nitro function of the intermediate (IV) by employing reagents like sodium disulphide or sodium polysulphide. The reduction of the nitrocompound (IV) may also be carried out in alkaline polysulphide solutions prepared by dissolving elemental sulphur in caustic alkali solutions like aq. NaOH, aq. KOH, alcoholic NaOH, alcoholic KOH or aq/alcoholic NaOH or aq. Alcoholic KOH.
During the condensation of the N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2- pyrimidineamine (II) and 4-[(4-Methylρiperazin-l-yl) methyljbenzoylchloride dihydrochloride (III), organic bases like pyridine have been employed in prior art methods (EP0564409). Use of pyridine is not feasible for industrial scale operation and is now replaced with environmentally friendly potassium carbonate, sodium carbonate, dilute aq. NaOH or aq. KOH
M = Na, K R = Me, Et1 Pr -Sx = Polysulfide Example 1:
(A) Preparation of N-(5-Amino-2-methyIphenyl)-4-(3-pyridyl)-2-pyrimidineamine
To a solution of commercial sodium sulphide nonahydrate (Na2S.9H2O, 2Og) in ethanol (200ml) is charged sulphur (3g) and the mass refluxed for 2 hr. the resulting solution of sodium disulphide is treated with the nitro compound N-(2-Methyl-5- nitrophenyl)-4-(3-pyridyl)-2-ρyrimidineamine (12.5g) in one lot. The reaction mixture is refluxed for lhr and the solvent ethanol is distilled off under reduced pressure. The reaction mixture is diluted with water (100ml) and extracted with chloroform (2x100ml). The chloroform layer is washed with water (2x50ml), dried over anhy. Na2SO4 (2g) and the solvent distilled off. The cooled mass is crystallized from ethylacetate (40ml) to yield the intermediate amine N-(5-Amino-2-methyl phenyl)-4-(3-ρyridyl)-2-pyrimidineamine (II) (1Og). mp: 142 - 147°C
(B) Preparation of imatinib base (I): 4-[(4-Methylpiparazin-l-yl)methyl]benzoylchloride dihydrochloride (7.2g) is suspended in isopropanol (100ml), and anhy. potassium carbonate (5.3g) is added and the mixture stirred for 30 minutes at 25-30°C.
The resulting mixture is treated with N-(5-Amino-2-methylphenyl)-4-(3-pyridyl)-2- pyrimidineamine (5g) and the reaction slurry is refluxed for Ih when absence of the amine (IV) is observed by TLC. The reaction mixture is filtered and washed with hot isopropanol (30ml). The residual solid cake is suspended in water (100ml) extracted with chloroform (2x100ml). The chloroform layer is subjected to vacuum distilled and the residue treated with ethylacetate (50ml) and the slurry filtered and dried to get imatinib base (7.5g). mp.: 205 - 208°C
Advantage of the invention:
• Use of sodium disulphide / or sodium polysulfide for conversion of nitro intermediate (IV) is novel and is environmentally friendly and avoids the use of heavy metal like stannous chloride. • Considerable amount of time to the extent of 70% is saved in this conversion and the reduction is very fast and the entire procedure of reduction, work-up and isolation of the amine intermediate (II) is greatly simplified.
• Replacement of pyridine with environmentally friendly reagents like K2CO3 during the condensation of amine (II) and aroyl chloride (III) rendered the process of isolation of imatinib. Very elegant and operator friendly
• The total process of conversion of nitro compound to imatinib base is novel leading to an industrially feasible and economical manufacturing process for imatinib
Claims
We claim:
1) A novel high yielding method of reduction of the nitro compound, N-(2-Methyl-5- nitrophenyl)-4-(3-pyridyl)-2-pyrimidineamine (IV) employing sodium disulphide in an alkaline medium to get the pharmaceutically useful intermediate N-(5-Amino-2- methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine (II) in alcoholic or aqueous alcoholic media or aqueous media.
2) A novel high yielding method of preparation of the amine, N-(5-Amino-2- methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine from the nitro compound (II) N-(2- Methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine (IV) by employing sodium polysulphide in alcoholic or aq. alcoholic or aqueous media.
3) A method of preparation of the amine intermediate N-(5-Amino-2-methylphenyl)-4- (3-pyridyl)-2-pyrimidinamine (II) as in claim 1 and wherein the solvent is chosen from a lower alcohols like methanol, ethanol, isopropanol or n-butanol. 4) A method of preparation of the amine intermediate N-(5-Amino-2-methylphenyl)-4-
(3-pyridyl)-2-ρyrimidinamine (II) as in claim 2 wherein the alcoholic solvent is chosen from lower alcohols like methanol, ethanol, isopropanol or n-butanol.
5) A method of condensation of the amine intermediate 4-[(4-Methylpiperazin-l-yl) methyl]benzoylchloride dihydrochloride (III) wherein the acid scavenging agent is potassium carbonate and the solvent is a lower alcohol like methanol, ethanol, isopropanol or n-butanol.
6) A method of preparation of the amine N-(5-Amino-2-methyrphenyl)-4-(3-pyridyl)-2- pyrimidinamine (II) essentially as described in the example cited above.
7) A method of preparation of imatinib base (I) essentially as described in example cited above.
Priority Applications (1)
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PCT/IN2007/000122 WO2008117298A1 (en) | 2007-03-26 | 2007-03-26 | A novel method of preparation of imatinib |
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PCT/IN2007/000122 WO2008117298A1 (en) | 2007-03-26 | 2007-03-26 | A novel method of preparation of imatinib |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011070588A1 (en) | 2009-12-10 | 2011-06-16 | Arch Pharmalabs Limited | Process for the preparation of imatinib and salts thereof |
WO2011114337A1 (en) * | 2010-03-15 | 2011-09-22 | Natco Pharma Limited | Process for the preparation of highly pure crystalline imatinib base |
WO2011130918A1 (en) * | 2010-04-23 | 2011-10-27 | 上海百灵医药科技有限公司 | Process for synthesizing imatinib |
WO2012131711A1 (en) * | 2011-03-31 | 2012-10-04 | Ind-Swift Laboratories Limited | Improved process for preparation of imatinib and its mesylate salt |
WO2013035102A1 (en) * | 2011-09-05 | 2013-03-14 | Natco Pharma Limited | Processes for the preparation of imatinib base and intermediates thereof |
KR101558960B1 (en) | 2013-07-18 | 2015-10-08 | 하나제약 주식회사 | Novel method for manufacturing of N-(5-[4-[4-methyl-piperazino-methyl]benzolamido)-2-methylphenyl-4-[3-pyridyl]-2-pyrimidin-amine |
CN107089969A (en) * | 2017-04-26 | 2017-08-25 | 黑龙江鑫创生物科技开发有限公司 | A kind of method for synthesizing imatinib intermediate |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0564409B1 (en) * | 1992-04-03 | 2000-01-19 | Novartis AG | Pyrimidin derivatives and process for their preparation |
WO2004108699A1 (en) * | 2003-06-06 | 2004-12-16 | Natco Pharma Limited | Process for the preparation of the anti-cancer drug imatinib and its analogues |
-
2007
- 2007-03-26 WO PCT/IN2007/000122 patent/WO2008117298A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0564409B1 (en) * | 1992-04-03 | 2000-01-19 | Novartis AG | Pyrimidin derivatives and process for their preparation |
WO2004108699A1 (en) * | 2003-06-06 | 2004-12-16 | Natco Pharma Limited | Process for the preparation of the anti-cancer drug imatinib and its analogues |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011070588A1 (en) | 2009-12-10 | 2011-06-16 | Arch Pharmalabs Limited | Process for the preparation of imatinib and salts thereof |
WO2011114337A1 (en) * | 2010-03-15 | 2011-09-22 | Natco Pharma Limited | Process for the preparation of highly pure crystalline imatinib base |
WO2011130918A1 (en) * | 2010-04-23 | 2011-10-27 | 上海百灵医药科技有限公司 | Process for synthesizing imatinib |
WO2012131711A1 (en) * | 2011-03-31 | 2012-10-04 | Ind-Swift Laboratories Limited | Improved process for preparation of imatinib and its mesylate salt |
US8912325B2 (en) | 2011-03-31 | 2014-12-16 | Ind-Swift Laboratories Limited | Process for preparation of imatinib and its mesylate salt |
WO2013035102A1 (en) * | 2011-09-05 | 2013-03-14 | Natco Pharma Limited | Processes for the preparation of imatinib base and intermediates thereof |
KR101558960B1 (en) | 2013-07-18 | 2015-10-08 | 하나제약 주식회사 | Novel method for manufacturing of N-(5-[4-[4-methyl-piperazino-methyl]benzolamido)-2-methylphenyl-4-[3-pyridyl]-2-pyrimidin-amine |
CN107089969A (en) * | 2017-04-26 | 2017-08-25 | 黑龙江鑫创生物科技开发有限公司 | A kind of method for synthesizing imatinib intermediate |
CN107089969B (en) * | 2017-04-26 | 2020-04-24 | 黑龙江鑫创生物科技开发有限公司 | Method for synthesizing imatinib intermediate |
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