WO2008136010A1 - A process for the preparation of highly pure imatinib base - Google Patents

A process for the preparation of highly pure imatinib base Download PDF

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Publication number
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
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PCT/IN2007/000178
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French (fr)
Inventor
Amala Kompella
Sreenivas Rachakonda
Bhujanga Rao Adibhatla Kali Satya
Nannapaneni Venkaiah Chowdary
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Natco Pharma Limited
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Priority to PCT/IN2007/000178 priority Critical patent/WO2008136010A1/en
Publication of WO2008136010A1 publication Critical patent/WO2008136010A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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

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 :

Figure imgf000002_0001

(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

Figure imgf000004_0001

(III)

(ID

3

Figure imgf000004_0002

(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 .
PCT/IN2007/000178 2007-05-07 2007-05-07 A process for the preparation of highly pure imatinib base WO2008136010A1 (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
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

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0564409A1 (en) * 1992-04-03 1993-10-06 Ciba-Geigy Ag Pyrimidin derivatives and process for their preparation
WO1999003854A1 (en) * 1997-07-18 1999-01-28 Novartis Ag Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use
WO2005075454A2 (en) * 2004-02-04 2005-08-18 Novartis Ag SALT FORMS OF 4-(4-METHYLPIPERAZIN-1-YLMETHYL)-n-[4-METHYL-3-(4-PYRIDIN-3-YL)PYRIMIDIN-2-YLAMINO)PHENYL]-BENZAMIDE
US20060149061A1 (en) * 2004-12-30 2006-07-06 Huang Anli Novel process for preparing Imatinib
EP1857454A1 (en) * 2006-05-15 2007-11-21 Chemagis Ltd. Crystalline imatinib base and production process therefor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0564409A1 (en) * 1992-04-03 1993-10-06 Ciba-Geigy Ag Pyrimidin derivatives and process for their preparation
WO1999003854A1 (en) * 1997-07-18 1999-01-28 Novartis Ag Crystal modification of a n-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use
WO2005075454A2 (en) * 2004-02-04 2005-08-18 Novartis Ag SALT FORMS OF 4-(4-METHYLPIPERAZIN-1-YLMETHYL)-n-[4-METHYL-3-(4-PYRIDIN-3-YL)PYRIMIDIN-2-YLAMINO)PHENYL]-BENZAMIDE
US20060149061A1 (en) * 2004-12-30 2006-07-06 Huang Anli Novel process for preparing Imatinib
EP1857454A1 (en) * 2006-05-15 2007-11-21 Chemagis Ltd. Crystalline imatinib base and production process therefor

Cited By (13)

* Cited by examiner, † Cited by third party
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
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
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

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