WO2008136010A1 - A process for the preparation of highly pure imatinib base - Google Patents
A process for the preparation of highly pure imatinib base Download PDFInfo
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- WO2008136010A1 WO2008136010A1 PCT/IN2007/000178 IN2007000178W WO2008136010A1 WO 2008136010 A1 WO2008136010 A1 WO 2008136010A1 IN 2007000178 W IN2007000178 W IN 2007000178W WO 2008136010 A1 WO2008136010 A1 WO 2008136010A1
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- Prior art keywords
- imatinib
- chloroform
- base
- purity
- organic layer
- Prior art date
Links
- 239000005517 L01XE01 - Imatinib Substances 0.000 title claims abstract description 71
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960002411 imatinib Drugs 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 32
- 239000002585 base Substances 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 20
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 13
- 239000011976 maleic acid Substances 0.000 claims description 13
- 239000012044 organic layer Substances 0.000 claims description 13
- 239000010410 layer Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 9
- KNBRFZWWCBSGDU-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]benzoyl chloride Chemical compound C1CN(C)CCN1CC1=CC=C(C(Cl)=O)C=C1 KNBRFZWWCBSGDU-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 230000003472 neutralizing effect Effects 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000000047 product Substances 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QGAIPGVQJVGBIA-UHFFFAOYSA-N 4-methyl-3-n-(4-pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine Chemical compound CC1=CC=C(N)C=C1NC1=NC=CC(C=2C=NC=CC=2)=N1 QGAIPGVQJVGBIA-UHFFFAOYSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229960003685 imatinib mesylate Drugs 0.000 description 4
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 3
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002689 maleic acids Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 0 CN1CCN(*Cc2ccc(C(F)(F)F)cc2)CC1 Chemical compound CN1CCN(*Cc2ccc(C(F)(F)F)cc2)CC1 0.000 description 1
- CNENVUDERVIPTN-UHFFFAOYSA-N Cc(ccc(N)c1)c1C(c1nccc(-c2cnccc2)n1)=C Chemical compound Cc(ccc(N)c1)c1C(c1nccc(-c2cnccc2)n1)=C CNENVUDERVIPTN-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 150000004926 Imatinib derivatives Chemical class 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
- C07D401/14—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 three or more hetero rings
Definitions
- the present invention relates to an improved and novel process for the preparation of highly pure (>99.8) (Imatinib) of formula (I) and its pharmaceutically acceptable salts and process for preparation thereof Back ground of the invention :
- Imatinib mesylate which is the methane sulfonate salt of N- ⁇ 5-[4-(4-methylpiperazino- methyl)- benzoylamido]-2-methylphenyl ⁇ -4- (3-pyridyl) 2-pyrimidine-amine having the Formula I (a)
- I is approved under the trademark "Gleevec ®" by the US Food and Drug Administration for the treatment of Chronic Myelogenous Leukemia before and after the failure of interferon alpha. It has also been approved for the treatment of patients with kit (CDl 17) positive unresectable and / or metastatic malignant Gastro Intestinal Stromal Tumors (GISTs). It has also been approved for the treatment of pediatric patients with Philadelphia chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) in chronic phase.
- Imatinib mesylate I(a) The preparation of Imatinib mesylate I(a) and the use thereof especially as an antitumour agent is described in WO99/03854, ( Assignee : Novartis).
- This application describes two polymorphic forms of imatinib mesylate, the ⁇ -form and the ⁇ -form,
- WO 2005/075454 describes acid addition salts imatinib such as tartrate, citrate, malate, fumarate, etc., which are prepared by treatment of imatinib base with the corresponding acid.
- Imatinib base is the precursor of the salt forms of imatinib. As such, there is a need for imatinib base of high purity which may be conveniently used as a precursor in the preparation of highly pure imatinib mesylate for therapeutic application.
- the main object of the present invention is to provide an improved process for the preparation of highly pure (>99.8%) imatinib base and/or its pharmaceutically acceptable salts.
- Another object of the invention is to provide a process for preparation of highly pure (>99.8%) imatinib and/or its pharmaceutically acceptable salts using maleic acid salt of Imatinib.
- Imatinib and its pharmaceutically acceptable salts are prepared by i. preparing imatinib base by the condensation of N-(5-amino-2-methylphenyl)-4-(3- pyridyl)-2-pyrimidine amine of the formula (II) and 4-(4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) in presence of potassium hydroxide base and isolation of crude imatinib base
- preparation of Imatinib and its pharmaceutically acceptable salts comprise the following steps. i. condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine and 4- (4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) chloroform to yield Imatinib ii. Treatment of impure Imatinib with hydrochloric acid and again liberation of imatinib of purity 99.5% iii. Treating crude Imatinib with maleic acid yielding maleic acid addition salt of Imatinib iv. Converting Imatinib maleic acid addition salt to highly pure(>99.8)Imatinib
- the present invention provides a process for the preparation of Imatinib and its pharmaceutically acceptable salts, which involve
- the novel Imatinib maleic acid addition salt thus prepared is identified and characterized by chemical analysis, IR, NMR & Mass spectra. This acid addition salt is further converted to Imatinib by
- Example- 1 Process for the preparation highly pure imatinib of the formula (I)
- Step-1 Condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (II) and 4-(4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) :
- Imatinib (5kgs, purity 99.5%) is suspended in methanol (25L) at room temperature.
- Maleic Acid solution (1.1 kgs in 1OL methanol) is added to the above solution over 30 min at room temperature.
- Reaction mass temperature is raised to reflux and maintained for about 2-3 hrs.
- the reaction mass is slowly cooled to O 0 C and maintained for about 1 hr at O 0 C.
- the precipitated material is filtered and washed with 5 L of methanol.
- the product is dried at 60- 7O 0 C under vacuum to constant weight.
- Step - III Preparation of highly pure Imatinib from Imatinib maleate : Imatinib maleate (5.5kgs) is suspended in DM water(50L). Aqueous sodium hydroxide solution is added over a period of 30 min to a pH of 9-12 and extracted with chloroform(2x50L). Organic layer is washed with DM water and the solvent distilled off under vacuum to a residual volume of 5L . Ethyl acetate(50L) is charged to the residue and stirred for 30 mutes. The precipitated product is filtered and washed with ethyl acetate. The product is dried at temperature of 60-70 0 C till constant weight. Dry weight of Imatinib : 4.7 kgs Purity: 99.99% (by HPLC)
- the Imatinib is produced in more than 99.8% purity.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A novel process for the preparation of highly pure (>99.8%) imatinib base of Formula (I) is disclosed. Highly pure imatinib base of this invention is suitable for conversion to pharmaceutically acceptable salts.
Description
A PROCESS FOR THE PREPARATION OF HIGHLY PURE IMATINIB BASE
Field of the invention:
The present invention relates to an improved and novel process for the preparation of highly pure (>99.8) (Imatinib) of formula (I) and its pharmaceutically acceptable salts and process for preparation thereof Back ground of the invention :
(I)
Imatinib mesylate which is the methane sulfonate salt of N-{5-[4-(4-methylpiperazino- methyl)- benzoylamido]-2-methylphenyl}-4- (3-pyridyl) 2-pyrimidine-amine having the Formula I (a) I is approved under the trademark "Gleevec ®" by the US Food and Drug Administration for the treatment of Chronic Myelogenous Leukemia before and after the
failure of interferon alpha. It has also been approved for the treatment of patients with kit (CDl 17) positive unresectable and / or metastatic malignant Gastro Intestinal Stromal Tumors (GISTs). It has also been approved for the treatment of pediatric patients with Philadelphia chromosome positive (Ph+) Chronic Myeloid Leukemia (CML) in chronic phase.
The preparation of N-{5-[4-(4-methylpiperazino-methyl)- benzoylamido]-2-methylphenyl}- 4- (3-pyridyl) 2-pyrimidine-amine (Imatinib) of Formula (I) and the use thereof especially as an antitumour agent is described in EP0564 409, (Ciba-Geigy corp.) which was published on 6th Octoberl993 and in US 55211584 (Assignee : Ciba-Geigy corp; Title :
Pyrimidine derivatives and process for the preparation there of) which was published on 28th May 1996 and in equivalent applications in numerous other countries. However, the purity aspects of imatinib base are not discussed here.
The preparation of Imatinib mesylate I(a) and the use thereof especially as an antitumour agent is described in WO99/03854, ( Assignee : Novartis). This application describes two polymorphic forms of imatinib mesylate, the α-form and the β-form, WO 2005/075454 describes acid addition salts imatinib such as tartrate, citrate, malate, fumarate, etc., which are prepared by treatment of imatinib base with the corresponding acid.
In EP 0564409 and in its equivalent US 55211584 the following route is described (Scheme- 1)
Scheme -I
(III)
(ID
3
(I)
A solution of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine of the formula (II) and 4-(4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) taken in pyridine are stirred under nitrogen at room temperature for 23 hours. The resulting reaction mixture is concentrated under high vacuum; water is added and the mixture is filtered. After drying at 8O0C under high vacuum, the crude product is made into slurry with methylene chloride & methanol and filtered to yield Imatinib of the formula (I). Chromatographic separation is used to obtain further crop of product.
After implementing the process described in the patent mentioned as per the scheme indicated, the following are the difficulties encountered and draw backs noticed.
i) the yield of compound of formula (I) is low (50%) making the process non economical and the purity of the product is only 97% ii) column chromatography is necessary to isolate product of formula (I) in pure form and column chromatography technique becomes unpractical on commercial scale. iii) usage of the obnoxious and foul smelling chemical pyridine as a solvent and its distillation for work-up makes this process to be abandoned on bulk scale.
Imatinib base is the precursor of the salt forms of imatinib. As such, there is a need for imatinib base of high purity which may be conveniently used as a precursor in the preparation of highly pure imatinib mesylate for therapeutic application.
It is observed that pharmaceutical salts of Imatinib, when prepared from imatinib of lower purity do not meet the pharmaceutically acceptable quality. There is therefore an unfulfilled need to provide industrially feasible process for the preparation of pharmaceutically acceptable salts of imatinib from less pure imatinib.
To overcome the problem, the inventors have tried to prepare high purity imatinib base through acid addition salts of imatinib of lower purity. When the base is liberated from the acid addition salts, imatinib of higher purity results.
It is surprisingly found by the inventors that when the impure imatinib is reacted with maleic acid it selectively forms the corresponding acid addition salt, leaving behind the other related substances and impurities which are otherwise difficult to remove by the conventional methods. The maleic acid salt of imatinib is further converted to highly pure imatinib base which in turn is converted into other pharmaceutically acceptable salts with high purity.
Summary of the invention:
The main object of the present invention is to provide an improved process for the preparation of highly pure (>99.8%) imatinib base and/or its pharmaceutically acceptable salts.
Another object of the invention is to provide a process for preparation of highly pure (>99.8%) imatinib and/or its pharmaceutically acceptable salts using maleic acid salt of Imatinib.
Accordingly in the present invention highly pure Imatinib and its pharmaceutically acceptable salts are prepared by i. preparing imatinib base by the condensation of N-(5-amino-2-methylphenyl)-4-(3- pyridyl)-2-pyrimidine amine of the formula (II) and 4-(4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) in presence of potassium hydroxide base and isolation of crude imatinib base
ii. Treatment of impure Imatinib with hydrochloric acid and again liberation of imatinib of purity g 99.5%
iii. Treating Imatinib with maleic acid yields maleic acid addition salt of Imatinib
iv) neutralizing maleic acid salts and isolating Imatinib of purity 99.99% and
v) converting highly pure Imatinib to other pharmaceutically acceptable salts
Detailed description of the invention:
Thus in accordance with the present invention preparation of Imatinib and its pharmaceutically acceptable salts comprise the following steps.
i. condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine and 4- (4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) chloroform to yield Imatinib ii. Treatment of impure Imatinib with hydrochloric acid and again liberation of imatinib of purity 99.5% iii. Treating crude Imatinib with maleic acid yielding maleic acid addition salt of Imatinib iv. Converting Imatinib maleic acid addition salt to highly pure(>99.8)Imatinib
hi a specific embodiment, the present invention provides a process for the preparation of Imatinib and its pharmaceutically acceptable salts, which involve
i. Cooling suspension of 4 -(4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) in chloroform at temperature of 5- 150C ii. Addition of 5-15 moles of potassium hydroxide flakes preferably 10-12 moles of potassium hydroxide flakes to the above suspension and stirring the mixture for 30-40 minutes iii. raising reaction mass temperature to 25-3O0C and addition of -(5-amino-2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (II) iv. Addition of 30% aqueous potassium hydroxide solution to the reaction mass over a period of 1 hour to 6 hours preferably over 3-4 hours
Separation of organic layer and washing of organic layer with water.
Carbon treatment of the chloroform layer vii. Suspension of chloroform layer into DM water and adjusting PH to 3.0 to 4.0 with diluted hydrochloric acid . viii. Washing the reaction mass with Chloroform ix. Adjusting the aqueous layer PH to 9.0 to 12.0 and extraction with chloroform . x. Concentration of the organic layer and addition of ethyl acetate. xi. Isolation of the precipitated imatinib base of purity 99.5%
Further reacting the resultant base of of Imatinib with maleic acid by
i. Suspension of the imatinib base in a short chain alcohol such as methanol, ethanol, propanol or mixture thereof, ii. Adding maleic acid directly or as a solution in short chain alcohol, Maintaining the reaction mixture at room temperature of the solvent for about 30 min to 2 hrs iii. Removal of the alcohol under vacuum and triturating the syrup with acetone iv. Isolating the precipitated product and drying the product at 40 to 6O0C, preferably at 50 to 6O0C affording pure Imatinib as an acid addition salt of maleic acid.
The novel Imatinib maleic acid addition salt thus prepared is identified and characterized by chemical analysis, IR, NMR & Mass spectra. This acid addition salt is further converted to Imatinib by
i) Neutralizing Imatinib maleate with a base such as organic amines, alkali hydroxides, alkali carbonates, alkali bicarbonates and ammonia, in a mixture of water and water immiscible solvent ii) Separating the layers,
iii) Washing the organic layer with water,
iv) Concentrating the organic layer under vacuum affording Imatinib of purity 99.99% by HPLC
The required N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine and 4-(4- methyl-piperazinomethyl)benzoyl chloride of the formula (III) can be prepared by the prior art processes
The details of the inventions are given in the Examples which are provided for illustration only and therefore the Examples should not be construed to limit the scope of the invention.
EXAMPLES
Example- 1 : Process for the preparation highly pure imatinib of the formula (I) Step-1 : Condensation of N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (II) and 4-(4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) :
Into the reactor a suspension of 5OL of chloroform and 13.0 Kgs of 4-(4-methyl- piperazinomethyl)benzoyl chloride(III) is charged and cooled to 5-1O0C. 50 kgs of potassium hydroxide pellets are charged slowly during 1-2 hours. It is stirred for 30 minutes and 25 Kg of amine of formula (II) is charged to the reaction mass. Aqueous 30% solution of potassium hydroxide (500L) is added slowly during four hours at 25-350C. Organic layer is separated from the reaction mass and is washed with 3 x 400 L DM water .. Carbon treatment is given to the chloroform layer and is suspended in 350L DM water and dilute Hydrochloric acid is added slowly during 30 minutes to a pH of 3-4. Aqueous layer is washed with 3x10OL of chloroform. Aqueous layer is basified with sodium hydroxide solution to a pH of 9-12 and extracted with 1x35 OL chloroform. Organic layer is dried over anhydrous sodium sulfate and the solvent distilled off under vacuum to a residual volume of 7-lOL . 25L of Ethyl acetate is charged and stirred for 15 minutes at 25-35°C. The product of the formula (I) is centrifuged and washed with 10 L Ethyl Acetate. It is dried in oven at 60-700C Dry wt. : 35 Kg Purity by HPLC : 99.5% Step - II : Preparation of Imatinib maleate :
Imatinib (5kgs, purity 99.5%) is suspended in methanol (25L) at room temperature. Maleic Acid solution (1.1 kgs in 1OL methanol) is added to the above solution over 30 min at room temperature. Reaction mass temperature is raised to reflux and maintained for about 2-3 hrs. The reaction mass is slowly cooled to O0C and maintained for about 1 hr at O0C. The precipitated material is filtered and washed with 5 L of methanol. The product is dried at 60- 7O0C under vacuum to constant weight. Dry weight : 5.5 kg melting point : 166- 1700C
Step - III : Preparation of highly pure Imatinib from Imatinib maleate : Imatinib maleate (5.5kgs) is suspended in DM water(50L). Aqueous sodium hydroxide solution is added over a period of 30 min to a pH of 9-12 and extracted with chloroform(2x50L). Organic layer is washed with DM water and the solvent distilled off under vacuum to a residual volume of 5L . Ethyl acetate(50L) is charged to the residue and stirred for 30 mutes. The precipitated product is filtered and washed with ethyl acetate. The product is dried at temperature of 60-700C till constant weight. Dry weight of Imatinib : 4.7 kgs Purity: 99.99% (by HPLC)
Advantages of the invention:
1) The Imatinib is produced in more than 99.8% purity.
2) The process can be used for commercial preparation of Imatinib salts of pharmaceutical grade.
Claims
WE CLAIM :
1) Novel process for the preparation of Imatinib base comprising i. Cooling suspension of 4 -(4-methyl-piperazinomethyl)benzoyl chloride of the formula (III) in chloroform at temperature of 5- 150C ii. Addition of 5-15 moles of potassium hydroxide flakes preferably 10-12 moles of potassium hydroxide flakes to the above suspension and stirring this at for 30-40 minutes iii. raising reaction mass temperature to 25-3O0C and addition of -(5-amino-2- methylphenyl)-4-(3-pyridyl)-2-pyrimidine amine of the formula (II) iv. Addition of 30% aqueous potassium hydroxide solution to the reaction mass over a period of 1 hour to 6 hours preferably over 3-4 hours
Separation of organic layer and washing of organic layer with water.
Carbon treatment of the chloroform layer vii. Suspension of chloroform layer into DM water and adjusting PH to 3.0 to 4.0 with diluted hydrochloric acid . viii. Washing the reaction mass with Chloroform ix. Adjusting the aqueous layer PH to 9.0 to 12.0 and extraction with chloroform . x. Concentration of the organic layer and addition of ethyl acetate. xi. Isolation of the precipitated imatinib base of purity 99.5%
2) Novel process for the preparation of highly pure (>99.8) Imatinib and its pharmaceutically acceptable acid addition salts comprising of the following steps i. Suspension of the imatinib base of purity 99.5% in a short chain alcohol such as methanol, ethanol, propanol or mixture thereof, ii. Adding maleic acid directly or as a solution in short chain alcohol, Maintaining the reaction mixture at room temperature for about 30 min to 2 hrs iii. Removal of the alcohol under vacuum and triturating the syrup with acetone iv. Isolating the precipitated product and drying the product at 40 to 60 0C, preferably at 50 to
6O0C affording the pure Imatinib as an acid addition salt of maleic acid v. Neutralizing Imatinib maleate with a base such as organic amines, alkali hydroxides, alkali carbonates, alkali bicarbonates and ammonia, in a mixture of water and water immiscible solvent
Separating the layers, vi. Washing the organic layer with water vii. Concentration of the organic layer and addition of ethyl acetate, viii. Isolation of the precipitated imatinib base of purity 99.99%
3. The acid addition salt 'Imatinib maleate' as a novel pharmaceutically acceptable salt of imatinb.
4. Imatinib base of high purity (> 99.8%)
5. A novel method of preparing highly pure (> 99.8%) Imatinib essentially as herein described with reference to example 1 .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2007/000178 WO2008136010A1 (en) | 2007-05-07 | 2007-05-07 | A process for the preparation of highly pure imatinib base |
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| Application Number | Priority Date | Filing Date | Title |
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| PCT/IN2007/000178 WO2008136010A1 (en) | 2007-05-07 | 2007-05-07 | A process for the preparation of highly pure imatinib base |
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| WO2008136010A1 true WO2008136010A1 (en) | 2008-11-13 |
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| PCT/IN2007/000178 WO2008136010A1 (en) | 2007-05-07 | 2007-05-07 | A process for the preparation of highly pure imatinib base |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010133976A3 (en) * | 2009-05-22 | 2011-01-27 | Actavis Group Ptc Ehf | Substantially pure imatinib or a pharmaceutically acceptable salt thereof |
| 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 |
| WO2011157450A1 (en) * | 2010-06-18 | 2011-12-22 | Krka, D. D., Novo Mesto | New polymorphic form of imatinib base and preparation of salts thereof |
| WO2012026897A1 (en) * | 2010-08-23 | 2012-03-01 | MUSTAFA NEVZAT iLAÇ SANAYU A.Ş. | A process for the preparation of imatinib base |
| WO2012090221A1 (en) | 2010-12-29 | 2012-07-05 | Cadila Healthcare Limited | Novel salts of imatinib |
| WO2012131711A1 (en) * | 2011-03-31 | 2012-10-04 | Ind-Swift Laboratories Limited | Improved process for preparation of imatinib and its mesylate salt |
| EP2927223A1 (en) | 2014-04-04 | 2015-10-07 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Process for preparing imatinib and salts thereof, free of genotoxic impurity f |
| 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 |
| US11229650B2 (en) | 2019-05-16 | 2022-01-25 | Aerovate Therapeutics, Inc. | Inhalable imatinib formulations, manufacture, and uses thereof |
| US11464776B2 (en) | 2019-05-16 | 2022-10-11 | Aerovate Therapeutics, Inc. | Inhalable imatinib formulations, manufacture, and uses thereof |
| US11980689B2 (en) | 2013-07-31 | 2024-05-14 | Avalyn Pharma Inc. | Inhaled imatinib for treatment of pulmonary arterial hypertension (PAH) |
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|---|---|---|---|---|
| WO2010133976A3 (en) * | 2009-05-22 | 2011-01-27 | Actavis Group Ptc Ehf | Substantially pure imatinib or a pharmaceutically acceptable salt thereof |
| 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 |
| US20130060030A1 (en) * | 2010-03-15 | 2013-03-07 | Natco Pharma Limited | Process for the preparation of highly pure crystalline imatinib base |
| WO2011157450A1 (en) * | 2010-06-18 | 2011-12-22 | Krka, D. D., Novo Mesto | New polymorphic form of imatinib base and preparation of salts thereof |
| EA024088B1 (en) * | 2010-06-18 | 2016-08-31 | КРКА, д.д., НОВО МЕСТО | Alpha-form of imatinib mesylate, processes for preparation thereof and pharmaceutical composition comprising the same |
| WO2012026897A1 (en) * | 2010-08-23 | 2012-03-01 | MUSTAFA NEVZAT iLAÇ SANAYU A.Ş. | A process for the preparation of imatinib base |
| WO2012090221A1 (en) | 2010-12-29 | 2012-07-05 | Cadila Healthcare Limited | Novel salts of 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 |
| 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 |
| US11980689B2 (en) | 2013-07-31 | 2024-05-14 | Avalyn Pharma Inc. | Inhaled imatinib for treatment of pulmonary arterial hypertension (PAH) |
| EP2927223A1 (en) | 2014-04-04 | 2015-10-07 | F.I.S.- Fabbrica Italiana Sintetici S.p.A. | Process for preparing imatinib and salts thereof, free of genotoxic impurity f |
| US9630944B2 (en) | 2014-04-04 | 2017-04-25 | F.I.S.—Fabbrica Italiana Sintetici S.p.A. | Process for preparing Imatinib and salts thereof, free of genotoxic impurity F |
| US11229650B2 (en) | 2019-05-16 | 2022-01-25 | Aerovate Therapeutics, Inc. | Inhalable imatinib formulations, manufacture, and uses thereof |
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| US11413289B2 (en) | 2019-05-16 | 2022-08-16 | Aerovate Therapeutics, Inc. | Inhalable imatinib formulations, manufacture, and uses thereof |
| US11464776B2 (en) | 2019-05-16 | 2022-10-11 | Aerovate Therapeutics, Inc. | Inhalable imatinib formulations, manufacture, and uses thereof |
| US11806349B2 (en) | 2019-05-16 | 2023-11-07 | Aerovate Therapeutics, Inc. | Inhalable imatinib formulations, manufacture, and uses thereof |
| US11813263B2 (en) | 2019-05-16 | 2023-11-14 | Aerovate Therapeutics, Inc. | Inhalable imatinib formulations, manufacture, and uses thereof |
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