WO2010041134A1 - Procédé pour la préparation d'un sel de malate de 2-indolinone substituée par pyrrole en position 3 - Google Patents

Procédé pour la préparation d'un sel de malate de 2-indolinone substituée par pyrrole en position 3 Download PDF

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Publication number
WO2010041134A1
WO2010041134A1 PCT/IB2009/007080 IB2009007080W WO2010041134A1 WO 2010041134 A1 WO2010041134 A1 WO 2010041134A1 IB 2009007080 W IB2009007080 W IB 2009007080W WO 2010041134 A1 WO2010041134 A1 WO 2010041134A1
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WO
WIPO (PCT)
Prior art keywords
acid
sunitinib
salt
malic
addition salt
Prior art date
Application number
PCT/IB2009/007080
Other languages
English (en)
Inventor
Bernardino Mangion
Original Assignee
Medichem, S.A.
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
Publication date
Application filed by Medichem, S.A. filed Critical Medichem, S.A.
Priority to EP09748141A priority Critical patent/EP2350056A1/fr
Priority to CN2009801405464A priority patent/CN102177155A/zh
Publication of WO2010041134A1 publication Critical patent/WO2010041134A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • Sunitinib (Compound I) is the international commonly accepted name for N- [2- (diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4- dimethyl-lH-pyrrole-3-carboxamide, and has an empirical formula Of C 22 H 27 FN 4 O 2 , and a molecular weight of 398.47 g/mol. Sunitinib is an active pharmaceutical substance indicated for the treatment of abnormal cell growth, such as cancer, in mammals, particularly in humans.
  • the malic acid salt of sunitinib has been selected for medical purpose and is commercially marketed under the trade name of SUTENTTM for the treatment of renal cell carcinoma and gastrointestinal stromal tumor.
  • Sunitinib base and its malate salt are described in U.S. Patent No. 6,573,293 ("the '293 patent"), which is incorporated herein by reference.
  • Example 80 of the '293 patent describes the preparation of sunitinib base via condensation of N- [2- (diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (compound II), and 5-fluoro-l,3-dihydro-2/f-indol-2-one (compound III) in the presence of ethanol as a solvent, as depicted herein in Scheme 1.
  • the sunitinib base obtained is filtered under vacuum, washed with ethanol, and subsequently dried under vacuum at 54 0 C for 130 hours.
  • Example 1 of U.S. Patent Application No. 20070191458A1 (“the '458 publication”) describes the preparation of sunitinib malate by reacting sunitinib base with malic acid in the presence of methanol as a solvent. However, no information about the preparation and isolation of the sunitinib base is provided.
  • the '458 publication is incorporated herein by reference.
  • the invention provides a process for preparing the malic acid salt of sunitinib comprising first forming an acid addition salt of sunitinib with an acid weaker than malic acid and then reacting the weaker acid addition salt with malic acid.
  • the invention also provides acid addition salts of sunitinib comprising an acid weaker than malic acid.
  • Figure 1 is an infrared spectrum of the acetic acid salt of sunitinib.
  • Figure 2 is an infrared spectrum of the malic acid salt of sunitinib. DETAILED DESCRIPTION OF THE INVENTION
  • Applicants have observed that acid addition salts of sunitinib wherein said salts are the salt of an acid weaker than malic acid, can be used for preparing the malic acid salt of sunitinib as an alternative to the processing of sunitinib base.
  • the acetic acid salt of sunitinib i.e., sunitinib acetate
  • the acetic acid salt of sunitinib can be used successfully for the direct preparation of sunitinib malate by means of treatment with an amount of malic acid sufficient to convert said acetic acid salt to said malic acid salt. Since the acetic acid salt of sunitinib can be prepared easily and rapidly from sunitinib base into the crude reaction solution, the isolation and processing of solid sunitinib base is avoided.
  • sunitinib acetate is a salt-type solid which crystallizes into the organic solvent of the reaction (e.g. n- butanol) and which hence is simple to filter and isolate, introducing thus an additional purification step. Therefore, processes of the invention avoid the isolation and processing of solid sunitinib base, and hence overcome the drawbacks associated with the difficult handling of said sunitinib base. Further, processes of the invention introduce an additional purification step, and so provide the malic acid salt of sunitinib with high purity and high yield. Consequently, processes of the invention are cost-effective and suitable for industrial implementation.
  • the organic solvent of the reaction e.g. n- butanol
  • the present invention provides a process for preparing the malic acid salt of sunitinib (malic acid salt of compound of Formula I),
  • step (i) comprising: (i) providing a solution comprising an acid addition salt of sunitinib in an organic solvent, wherein said salt is the salt of an acid weaker than malic acid; (ii) treating said solution of an acid addition salt of sunitinib with malic acid, to obtain a mixture comprising sunitinib malate; (iii) isolating sunitinib malate from the mixture; and (iv) optionally, purifying said sunitinib malate.
  • "Treating" in step (ii) includes contacting or reacting.
  • the treating can be in any suitable order, i.e., the malic acid can be added to the solution of sunitinib salt or the solution of sunitinib salt can be added to malic acid, as desired.
  • the organic solvent in accordance with processes of the invention preferably comprises at least one C 1 -C 5 alcohol solvent, and more preferably comprises at least n- butanol.
  • the malic acid salt of compound (I) obtained according to an embodiment process of the invention has a purity higher than 99.7% as measured by HPLC.
  • the invention provides an acid addition salt of sunitinib, wherein said salt is the salt of an acid weaker than malic acid.
  • the acid addition salt of the invention is the acetic acid salt of sunitinib (acetic acid salt of compound of formula I).
  • the acid addition salt of sunitinib is a salt other than sunitinib malate.
  • the present invention provides a process for preparing an acid addition salt of sunitinib of the invention, said process comprising: (i) providing a solution of sunitinib base in an organic solvent; (ii) treating said solution of sunitinib base with an acid weaker than malic acid, to obtain a mixture comprising the acid addition salt of sunitinib; (iii) optionally, isolating the acid addition salt of sunitinib from the mixture; and (iv) optionally, purifying said acid addition salt of sunitinib.
  • Treating in step (ii) includes contacting or reacting.
  • the treating can be in any suitable order, i.e., the solution of sunitinib base can be added to the weak acid or the weak acid can be added to the sunitinib base solution, as desired.
  • the crude reaction solution obtained after synthesizing sunitinib base is used directly in step (i) of the process of the invention above.
  • the acid addition salt of sunitinib of the invention can be prepared easily and rapidly in situ from the crude reaction solution containing the sunitinib base, thereby avoiding the isolation of the sunitinib base.
  • the synthesis of sunitinib base can be carried out according to any of the methods known in the art.
  • the sunitinib base can be synthesized by reacting JV-[2-(diethylamino)ethyl]-5- formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (compound II) with 5-fluoro-l,3-dihydro- 2//-indol-2-one (compound III) in an organic solvent.
  • the acid weaker than malic acid is preferably an organic acid capable of forming a salt with sunitinib having a pKa greater than the pKa of malic acid, that is, having a pKa greater than 3.40 OpKa 1 ).
  • the acid weaker than malic acid has a pKa of from about 3.5 to about 6.5, or from about 4 to about 6, or from about 4 to about 5.
  • the pKa of acetic acid is about 4.76.
  • Illustrative organic acids suitable for use in the practice of the invention include acetic acid (pKa about 4.76), formic acid (pKa about 3.75), propanoic acid (pKa about 4.86), 3-hydroxypropanoic acid (pKa about 4.51), succinic acid (pKa about 4.16), butanoic acid (pKa about 4.83), 2 methylpropanoic or isobutyric acid (pKa about 4.88), 3-hydroxybutanoic acid (pKa about 4.70), 4-hydroxybutanoic acid (pKa about 4.72), uric acid (pKa about 3.89), glutaric acid (pKa about 4.31), methylsuccinic acid (pKa about 4.13), pentanoic acid (pKa about 4.84), trimethylacetic acid (pKa about 5.03), ascorbic acid (pKa about 4.10), hexanoic or caproic acid (pKa about 4.85), 4-methylpentanoic acid (pK
  • the acid weaker than malic acid of step (ii) of the process of the invention is acetic acid.
  • the solvent of the process above preferably comprises at least one C 1 -C 5 alcohol solvent, and more preferably comprises at least ⁇ -butanol.
  • Isolating the acid addition salt of sunitinib from the mixture of step (iii) of the invention preferably comprises: (i) precipitating said acid addition salt of sunitinib from the mixture thereby obtaining a suspension of said acid addition salt of sunitinib in an organic solvent; and (ii) filtering the suspension.
  • the present invention provides a process for preparing the malic acid salt of sunitinib (malic acid salt of compound of Formula I), said process comprising reacting the acid addition salt of sunitinib of the invention with malic acid.
  • the present invention relates to the use of the acid addition salt of sunitinib of the invention for preparing the malic acid salt of sunitinib.
  • FTIR Fourier transform IR
  • DSC Differential scanning calorimetry
  • High performance liquid chromatography (HPLC) analyses were conducted using a Shimadzu Prominence LC-20 system with the following parameters: column: XTerra MS C18, 5 ⁇ m, 4.6 x 150 mm; flow rate: 1 niL/min; detector: UV monitoring 265 nni; mobile phase A: 99.8:0.2 10 mM ammonium bicarbonate, pH 7.5 : triethylamine; mobile phase B: acetonitrile; gradient: 85% A (0 min) - 85% A (6 min) - 70% A (21 min) - 70% A (50 min) - 85% A (55 min) - 85% A (65 min); temperature: ambient; sample: 1.5 mg / mL in 25:75 mobile phase A : mobile phase B; injection volume: 10 ⁇ L.
  • This example illustrates a process for preparing the acetic acid salt of sunitinib (acetic acid salt of compound of Formula I) without isolating sunitinib base in accordance with an embodiment of the invention.
  • This example illustrates a process for preparing the acetic acid salt of sunitinib (acetic acid salt of compound of Formula I) in accordance with an embodiment of the invention.
  • This example illustrates a process for preparing the malic acid salt of sunitinib (malic acid salt of compound of Formula I) from the acetic acid salt of sunitinib in accordance with an embodiment of the invention.

Abstract

L'invention porte sur un procédé pour la préparation du sel de l'acide malique du sunitinib comprenant la réaction d'acide malique avec un sel d'addition d'acide du sunitinib, lequel est un agent de traitement anticancéreux, le sel d'addition d'acide du sunitinib étant un acide plus faible que l'acide malique. L'invention porte également sur des sels d'addition d'acide du sunitinib, l'acide étant un acide plus faible que l'acide malique.
PCT/IB2009/007080 2008-10-10 2009-10-09 Procédé pour la préparation d'un sel de malate de 2-indolinone substituée par pyrrole en position 3 WO2010041134A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP09748141A EP2350056A1 (fr) 2008-10-10 2009-10-09 Procédé pour la préparation d'un sel de malate de 2-indolinone substituée par pyrrole en position 3
CN2009801405464A CN102177155A (zh) 2008-10-10 2009-10-09 一种3-吡咯取代的2-吲哚酮苹果酸盐的制备工艺

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10434408P 2008-10-10 2008-10-10
US61/104,344 2008-10-10

Publications (1)

Publication Number Publication Date
WO2010041134A1 true WO2010041134A1 (fr) 2010-04-15

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EP (1) EP2350056A1 (fr)
CN (1) CN102177155A (fr)
AR (1) AR073807A1 (fr)
WO (1) WO2010041134A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011033472A1 (fr) * 2009-09-16 2011-03-24 Ranbaxy Laboratories Limited Sels de sunitinib
WO2013140232A1 (fr) 2012-03-23 2013-09-26 Laurus Labs Private Limited Procédé perfectionné pour la préparation de sunitinib et de ses sels d'addition avec un acide
US8618309B2 (en) 2008-07-24 2013-12-31 Teva Pharmaceutical Industries Ltd. Sunitinib and salts thereof and their polymorphs
WO2014167436A3 (fr) * 2013-04-10 2015-02-19 Shilpa Medicare Limited Sel glucuronate de sunitinib et procédé pour sa préparation
WO2015056247A1 (fr) * 2013-10-18 2015-04-23 Ranbaxy Laboratories Limited Forme cristalline ii pure de sel d'acide l-malique du sunitinib et procédés pour sa préparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050176802A1 (en) * 2000-02-15 2005-08-11 Sugen, Inc. & Pharmacia & Upjohn Co. Pyrrole substituted 2-indolinone protein kinase inhibitors
US20070191458A1 (en) * 2001-08-15 2007-08-16 Pharmacia & Upjohn Company Crystals Including a Malic Acid Salt of a 3-Pyrrole Substituted 2-Indolinone, and Compositions Thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110036588A (ko) * 2008-07-24 2011-04-07 테바 파마슈티컬 인더스트리즈 리미티드 수니티닙 아세테이트 및 이의 다형을 통한 수니티닙 말레이트의 제조 방법

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050176802A1 (en) * 2000-02-15 2005-08-11 Sugen, Inc. & Pharmacia & Upjohn Co. Pyrrole substituted 2-indolinone protein kinase inhibitors
US20070191458A1 (en) * 2001-08-15 2007-08-16 Pharmacia & Upjohn Company Crystals Including a Malic Acid Salt of a 3-Pyrrole Substituted 2-Indolinone, and Compositions Thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LIDE (ED.): "CRC Handbook of Chemistry and Physics, 73rd ed.", 1992, CRC PRESS, BOCA RATON, XP002562645 *
See also references of EP2350056A1 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8618309B2 (en) 2008-07-24 2013-12-31 Teva Pharmaceutical Industries Ltd. Sunitinib and salts thereof and their polymorphs
US9067915B2 (en) 2008-07-24 2015-06-30 Teva Pharmaceutical Industries Ltd. Sunitinib and salts thereof and their polymorphs
WO2011033472A1 (fr) * 2009-09-16 2011-03-24 Ranbaxy Laboratories Limited Sels de sunitinib
WO2013140232A1 (fr) 2012-03-23 2013-09-26 Laurus Labs Private Limited Procédé perfectionné pour la préparation de sunitinib et de ses sels d'addition avec un acide
US9206163B2 (en) 2012-03-23 2015-12-08 Laurus Labs Private Ltd. Process for the preparation of sunitinib and its acid addition salts thereof
WO2014167436A3 (fr) * 2013-04-10 2015-02-19 Shilpa Medicare Limited Sel glucuronate de sunitinib et procédé pour sa préparation
WO2015056247A1 (fr) * 2013-10-18 2015-04-23 Ranbaxy Laboratories Limited Forme cristalline ii pure de sel d'acide l-malique du sunitinib et procédés pour sa préparation
US9604968B2 (en) 2013-10-18 2017-03-28 Sun Pharmaceutical Industries Limited Pure crystalline Form II of L-malic acid salt of sunitinib and processes for its preparation

Also Published As

Publication number Publication date
EP2350056A1 (fr) 2011-08-03
AR073807A1 (es) 2010-12-01
CN102177155A (zh) 2011-09-07

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