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US20050085495A1 - Process for preparing amino crotonyl compounds - Google Patents

Process for preparing amino crotonyl compounds Download PDF

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Publication number
US20050085495A1
US20050085495A1 US10/941,116 US94111604A US2005085495A1 US 20050085495 A1 US20050085495 A1 US 20050085495A1 US 94111604 A US94111604 A US 94111604A US 2005085495 A1 US2005085495 A1 US 2005085495A1
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US
United States
Prior art keywords
amino
chloro
tetrahydrofuran
yloxy
fluorophenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/941,116
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English (en)
Inventor
Rainer Soyka
Werner Rall
Juergen Schnaubelt
Peter Sieger
Christian Kulinna
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
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Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Priority to US10/941,116 priority Critical patent/US20050085495A1/en
Assigned to BOEHRINGER INGELHEIM INTERNATIONAL GMBH reassignment BOEHRINGER INGELHEIM INTERNATIONAL GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SCHNAUBELT, JUERGEN, KULINNA, CHRISTIAN, RALL, WERNER, SIEGER, PETER, SOYKA, RAINER
Publication of US20050085495A1 publication Critical patent/US20050085495A1/en
Priority to US11/457,622 priority patent/US8426586B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to an improved process for preparing aminocrotonyl compounds such as for example 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline and the physiologically acceptable salts thereof, particularly 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate, as well as 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-y
  • 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]-amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline has the following structure: and is already known from WO 02/50043, which describes compounds with valuable pharmacological properties, including in particular an inhibiting effect on signal transduction mediated by tyrosinekinases and an inhibitory effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R). Therefore, compounds of this type are suitable for the treatment of diseases, particularly for the treatment of tumoral diseases, diseases of the lungs and respiratory tract and diseases of the gastrointestinal tract and bile duct and gall bladder.
  • EGF-R Epidermal Growth Factor receptor
  • WO 02/50043 discloses a method of preparation wherein aminocrotonyl compounds (IV) such as for example 4-[(3-chloro4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline are prepared in a one-pot reaction from the corresponding aniline component (II), bromocrotonic acid (Ill), oxalyl chloride and a secondary amine (see Diagram 1).
  • Diagram 1 Diagram 1:
  • the aim of the present invention is to provide a process which allows the production of aminocrotonylarylamides, particularly 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, using highly pure starting materials which are readily available and without any great technical expenditure.
  • This new process should therefore also be suitable for synthesis on an industrial scale and hence for commercial application.
  • the corresponding aminoaryl compound (V) is reacted with a di-(C 1-4 -alkyl)-phosphonoacetic acid, preferably with diethylphos-phonoacetic acid, in suitable solvents, after corresponding activation, preferably with 1,1 -carbonyldiimidazole, 1,1 -carbonylditriazole or propanephosphonic anhydride, particularly preferably with 1,1-carbonyldiimidazole, according to Diagram 2.
  • the solvent used may be for example tetrahydrofuran (THF), dimethylformamide (DMF) or ethyl acetate.
  • the activation may be carried out by any possible method of amide linking, i.e. for example with 1,1-carbonyidiimidazole, 1,1-carbonylditriazole, DCC (N,N-dicyclohexylcarbodiimide), EDC (N′-(dimethylaminopropyl)-N-ethylcarbodiimide), TBTU O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate, thiazolidine-2-thione or by conversion into the corresponding acid chloride, possibly using thionyl chloride.
  • 1,1-carbonyidiimidazole 1,1-carbonylditriazole
  • DCC N,N-dicyclohexylcarbodiimide
  • EDC N′-(dimethylaminopropyl)-N-ethylcarbodiimide
  • TBTU O-
  • the activation may be carried out using organic bases such as triethylamine or pyridine, while DMAP (dimethylaminopyridine) may additionally be added.
  • Suitable solvents include DMF, THF, ethyl acetate, toluene, chlorinated hydrocarbons or mixtures thereof.
  • the arylamide (VI) thus obtained in a high yield and high purity is reacted with the corresponding 2-aminoacetaldehyde using suitable organic or inorganic bases in the sense of a Wittig-Horner-Emmons reaction (Diagram 3).
  • This reaction may be carried out directly or after isolation of the compound (VI), for example by precipitation by the addition of tert-butylmethyl ether, for example.
  • Suitable bases include for example DBU (1,5-diazabicyclo[4.3.0]non-5-ene), sodium hydroxide and potassium hydroxide, of which sodium hydroxide and potassium hydroxide are preferred and potassium hydroxide is particularly preferred.
  • a corresponding equivalent e.g. a hydrate or acetal, may be used, from which the aldehyde is released (beforehand or in situ).
  • the acetals used may be for example compounds of the following general type: wherein R 2 to R 5 in each case represent a straight-chain or branched C 1-4 -alkyl group, while the groups may be identical or different.
  • aminocrotonylarylamide of formula (VII) for example 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline of formula (I), may then be converted into the salts thereof, particularly the physiologically acceptable salts thereof, by methods known per se. Preferably they are converted into fumarates, tartrates or maleates.
  • the compound (I) is dissolved in a suitable solvent, such as for example methanol, isopropanol, n-butanol or ethanol, optionally with the addition of water, preferably ethanol, and combined with crystalline maleic acid or a maleic acid solution, with heating.
  • a suitable solvent such as for example methanol, isopropanol, n-butanol or ethanol
  • water preferably ethanol
  • crystalline maleic acid or a maleic acid solution with heating.
  • ethanol ethanol
  • the reaction conditions are preferably selected so that the desired salt crystallises out as quickly as possible.
  • Preferably approx. 2 equivalents of maleic acid are used.
  • the starting compound of formula (V) may for example be prepared as follows in accordance with methods known from the literature.
  • the invention also relates to 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate.
  • This salt is particularly suitable for pharmaceutical use as it exists in only one crystalline modification, which is moreover anhydrous and very stable.
  • an active substance not only has to exhibit the desired activity, but must also conform to additional requirements in order to be allowed to be used as a pharmaceutical composition. These parameters are to a large extent connected with the physicochemical nature of the active substance.
  • examples of these parameters are the stability of effect of the starting material under various environmental conditions, stability during production of the pharmaceutical formulation and stability in the final medicament compositions.
  • the pharmaceutically active substance used for preparing the pharmaceutical compositions should therefore have a high stability which must be guaranteed even under various environmental conditions. This is absolutely essential to prevent the use of pharmaceutical compositions which contain, in addition to the actual active substance, breakdown products thereof, for example. In such cases the content of active substance in pharmaceutical formulations might be less than that specified.
  • the absorption of moisture reduces the content of pharmaceutically active substance on account of the weight gain caused by the uptake of water.
  • Pharmaceutical compositions with a tendency to absorb moisture have to be protected from damp during storage, e.g. by the addition of suitable drying agents or by storing the medicament in a damp-proof environment.
  • the uptake of moisture can reduce the content of pharmaceutically active substance during manufacture if the medicament is exposed to the environment without being protected from damp in any way.
  • a pharmaceutically active substance should therefore have only limited hygroscopicity.
  • the solubility of the active substance Another criterion which may be of exceptional importance under certain circumstances depending on the choice of formulation or the choice of manufacturing process is the solubility of the active substance. If for example pharmaceutical solutions are prepared (e.g. for infusions) it is essential that the active substance should be sufficiently soluble in physiologically acceptable solvents. It is also very important for drugs which are to be taken orally that the active substance should be sufficiently soluble.
  • the problem of the present invention is to provide a pharmaceutically active substance which not only is characterised by high pharmacological potency but also satisfies the above-mentioned physicochemical requirements as far as possible.
  • 4-[(3-chloro-4-fluorophenyl)amino]-6- ⁇ [4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]-amino ⁇ -7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate has a melting point of 178° C. (cf. the thermoanalysis shown in FIG. 2 ).
  • solution A 58 kg of 1,1-carbonyldiimidazole (22.16 mol) are placed in 12.8 litres of tetrahydrofuran and at 40° C. combined with 4.52 kg (22.16 mol) of diethylphosphonoacetic acid dissolved in 6.5 litres of tetrahydrofuran. The mixture is stirred for 30 minutes at 40° C. The resulting solution is referred to as solution A.
  • solution B 5.6 litres of 30% hydrochloric acid (53.17 mol) are added to 4.4 litres of water. Then 4.28 kg of 95% (dimethylamino)-acetaldehyde-diethylacetal (26.59 mol) are added dropwise within 20 minutes at 30° C. The reaction solution is stirred for 8 hours at 35° C. stirred, cooled to 5° C. and stored under argon. This solution is referred to as solution B.
  • solution C 4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 litres of water and cooled to ⁇ 5° C. This solution is referred to as solution C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US10/941,116 2003-10-17 2004-09-15 Process for preparing amino crotonyl compounds Abandoned US20050085495A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US10/941,116 US20050085495A1 (en) 2003-10-17 2004-09-15 Process for preparing amino crotonyl compounds
US11/457,622 US8426586B2 (en) 2003-10-17 2006-07-14 Process for preparing amino crotonyl compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10349113 2003-10-17
DE10349113A DE10349113A1 (de) 2003-10-17 2003-10-17 Verfahren zur Herstellung von Aminocrotonylverbindungen
US51777703P 2003-11-06 2003-11-06
US10/941,116 US20050085495A1 (en) 2003-10-17 2004-09-15 Process for preparing amino crotonyl compounds

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US (2) US20050085495A1 (fr)
EP (2) EP2508521B2 (fr)
JP (2) JP4594317B2 (fr)
KR (2) KR101282812B1 (fr)
CN (2) CN1867564B (fr)
AR (1) AR046118A1 (fr)
AU (2) AU2004281938B2 (fr)
BR (2) BRPI0415424B8 (fr)
CA (2) CA2759063C (fr)
CY (2) CY1114866T1 (fr)
DE (1) DE10349113A1 (fr)
DK (2) DK1678165T3 (fr)
EA (1) EA016624B1 (fr)
EC (1) ECSP066509A (fr)
ES (2) ES2440466T3 (fr)
HR (2) HRP20160246T4 (fr)
HU (1) HUE028254T2 (fr)
IL (2) IL174951A (fr)
ME (1) ME00341B (fr)
MX (2) MXPA06004076A (fr)
MY (2) MY149921A (fr)
NO (2) NO333971B1 (fr)
NZ (2) NZ547154A (fr)
PE (2) PE20050965A1 (fr)
PL (2) PL1678165T3 (fr)
PT (2) PT1678165E (fr)
RS (3) RS20060260A (fr)
SG (1) SG139743A1 (fr)
SI (2) SI2508521T2 (fr)
TW (2) TWI373470B (fr)
UA (2) UA91006C2 (fr)
UY (2) UY28559A1 (fr)
WO (1) WO2005037824A2 (fr)
ZA (1) ZA200602234B (fr)

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US20070027170A1 (en) * 2003-10-17 2007-02-01 Rainer Soyka Process for preparing amino crotonyl compounds
US20080254040A1 (en) * 2003-04-29 2008-10-16 Boehringer Ingelheim International Gmbh Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis
US20080318950A1 (en) * 2005-11-08 2008-12-25 Hanmi Pharm. Co., Ltd Quinazoline Derivatives as a Multiplex Inhibitor and Method For the Preparation Thereof
US20090306378A1 (en) * 2006-01-26 2009-12-10 Juergen Schroeder Process for preparing aminocrotonylamino-substituted quinazoline derivatives
US20090306044A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Quinazoline derivatives for the treatment of cancer diseases
US20090306101A1 (en) * 2005-11-11 2009-12-10 Flavio Solca Combination treatment of cancer comprising egfr/her2 inhibitors
US20090318480A1 (en) * 2006-09-18 2009-12-24 Boehringer Ingelheim International Gmbh Method for treating cancer harboring egfr mutations
US20100069414A1 (en) * 1999-06-21 2010-03-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
US20100144639A1 (en) * 2002-05-11 2010-06-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of inhibitors of the egfr-mediated signal transduction for the treatment of benign prostatic hyperplasia (bph) / prostatic hypertrophy
WO2010104406A1 (fr) 2009-03-11 2010-09-16 Auckland Uniservices Limited Formes promédicaments d'inhibiteurs de kinase et leur utilisation en thérapie
WO2011003853A2 (fr) 2009-07-06 2011-01-13 Boehringer Ingelheim International Gmbh Procédé de séchage du bibw2992, de ses sels et des préparations pharmaceutiques solides contenant ce principe actif
US20110142929A1 (en) * 2008-06-06 2011-06-16 Boehringer Ingelheim International Gmbh Solid pharmaceutical formulations comprising bibw 2992
US20120107304A1 (en) * 2010-04-27 2012-05-03 Boehringer Ingelheim International Gmbh Combination therapy in treatment of oncological and fibrotic diseases
WO2013052157A1 (fr) 2011-10-06 2013-04-11 Ratiopharm Gmbh Formes cristallines de di-maléate d'afatinib
US8828391B2 (en) 2011-05-17 2014-09-09 Boehringer Ingelheim International Gmbh Method for EGFR directed combination treatment of non-small cell lung cancer
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
WO2016051380A1 (fr) * 2014-10-01 2016-04-07 Sun Pharmaceutical Industries Limited Forme cristalline de dimaléate d'afatinib
US9309228B2 (en) 2012-07-19 2016-04-12 Boehringer Ingelheim International Gmbh Fumaric acid salt of 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one, its use as a medicament and the preparation thereof
US20160122329A1 (en) * 2014-01-02 2016-05-05 IVAX International GmbH Crystalline forms of afatinib di-maleate
US20160207907A1 (en) * 2015-01-15 2016-07-21 Hangzhou Pushai Pharmaceutical Technology Co., Ltd. Crystalline Forms of Afatinib Monomaleate, Preparation Methods and Pharmaceutical Compositions Thereof
WO2016199076A3 (fr) * 2015-06-12 2017-03-09 Fresenius Kabi Oncology Ltd. Formes polymorphes de base libre d'afatinib et de dimaléate d'afatinib
US9725439B2 (en) 2013-09-28 2017-08-08 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Quinazoline derivative and preparation method therefor
US10231973B2 (en) 2015-03-20 2019-03-19 Chai Tai Tianqing Pharmaceutical Group Co., Ltd. Salts of quinazoline derivative and method for preparing the same
US10525059B2 (en) 2015-08-21 2020-01-07 Fresenius Kabi Oncology, Ltd. Pharmaceutical compositions comprising Afatinib
US11136314B2 (en) 2017-04-06 2021-10-05 Johnson Matthey Public Limited Company Forms of afatinib dimaleate
US11446302B2 (en) 2016-11-17 2022-09-20 Board Of Regents, The University Of Texas System Compounds with anti-tumor activity against cancer cells bearing EGFR or HER2 exon 20 mutations

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JP2012515184A (ja) 2009-01-14 2012-07-05 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 大腸がんの治療方法
WO2010130757A1 (fr) 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh Nouvelle polytherapie destinee a traiter les maladies oncologiques et fibrotiques
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US20150368230A1 (en) 2013-02-01 2015-12-24 Boehringer Ingelheim International Gmbh Radiolabeled quinazoline derivatives
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