WO2011110199A1 - Procédé d'amidation de composés de carboxylate de pyrrole - Google Patents

Procédé d'amidation de composés de carboxylate de pyrrole Download PDF

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Publication number
WO2011110199A1
WO2011110199A1 PCT/EP2010/001609 EP2010001609W WO2011110199A1 WO 2011110199 A1 WO2011110199 A1 WO 2011110199A1 EP 2010001609 W EP2010001609 W EP 2010001609W WO 2011110199 A1 WO2011110199 A1 WO 2011110199A1
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Prior art keywords
formula
group
compound
process according
reaction
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Application number
PCT/EP2010/001609
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English (en)
Inventor
Jie Zhu
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Synthon B.V.
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 Synthon B.V. filed Critical Synthon B.V.
Priority to PCT/EP2010/001609 priority Critical patent/WO2011110199A1/fr
Priority to CN2010800662651A priority patent/CN102858739A/zh
Priority to EP10710795A priority patent/EP2545034A1/fr
Publication of WO2011110199A1 publication Critical patent/WO2011110199A1/fr

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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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • Certain pyrrole carboxamides are important pharmaceutical compounds.
  • sunitinib chemically (Z)-N-[2-(Diethylamino)ethyl]-5-(5-fluoro-2-oxo-2,3-dihydro-lH-indol- 3-ylidenemethyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide of formula (I)
  • Sunitinib molecule has one asymmetric double bond between the indole and pyrrole rings.
  • the compound is marketed with (Z) configuration on the double bond.
  • the compound may form acid addition salts, for instance sunitinib L-malate, which is the active ingredient in the medicinal products (sold, e.g., under brand name SUTENT by Pfizer).
  • the key step in the known processes of making sunitinib and structurally related pyrrole carboxamide compounds comprises, in the proper stage of the reaction sequence, amidation reaction of corresponding amine with proper pyrrole carboxylic acid, in which the carboxy-group may be optionally activated for the amidation reaction .
  • Activation of the pyrrole carbonyl group requires an extra reaction step (e.g. the compound (Ilia) is made from the corresponding acid (III) and carbonyldiimidazole), including isolation of the produced activated intermediate and removal of the rests of the reagents, which is not advantageous.
  • the formyl group of the compound (IV) may react in a side reaction with the activation agent and/or with the amine (II), which is also not desirable.
  • the present invention relates to a process of amidation of pyrrole carboxylate compounds, including indolone-substituted pyrrole carboxylate compounds, characterized by using a specific coupling agent for the amidation reaction, which is cheap, non-toxic and effective.
  • the invention provides a process of making a compound of general formula (1) wherein
  • R is a group comprising a straight, branched or cyclic hydrocarbon chain of 1 to 20 carbons, wherein the carbons on any place of the chain may be optionally replaced by one to four nitrogen, oxygen or sulfur atoms, and wherein any of the chain hydrogens may be optionally substituted by one to four amino-, hydroxyl- , oxo- , thio- thiono-, halo- groups,
  • Z is hydrogen or a — C ⁇ W group
  • W is hydrogen or a OR 3 group
  • Y is hydrogen or at least one halo-group, CI -CIO alkyl group, carboxy group, amino group and/or a sulfonamide group,
  • each of Ri,R 2 ,R3,R4,R5 is independently selected from the group consisting of hydrogen or CI -CIO alkyl group optionally containing one or more additional N,0 or S atom(s),
  • A is C1-C6 alkyl group, preferably n-propyl group.
  • the Z group represents a W group, wherein W is preferably
  • the group R is ⁇ , ⁇ -diethylaminoethyl- group and the amine of the formula (3) is ⁇ , ⁇ -diethylaminoethylamine of formula (3a)
  • the preferred compounds of formula (1) are accordingly compounds of formula (la) or (lb).
  • the compound (lb) corresponds to sunitinib
  • the reaction of the compound of formula (2) with the amine of formula (3) in the presence of the coupling agent of formula (4) proceeds in an inert solvent or in the amine (3) as the solvent, typically at ambient or close to ambient temperature.
  • reaction product is isolated from the reaction mixture and purified.
  • the compound of formula (la) may be converted to sunitinib (lb).
  • the invention provides a first process of making sunitinib of formula (l b) comprising the sequence of steps of
  • the invention provides a second process of making sunitinib of formula (lb) comprising the sequence of steps of
  • the invention provides a novel use of compound of formula (4), particularly the compound of formula (4a),
  • the invention relates to the use of the cyclic
  • alkyltriphosphonate anhydride coupling agent of formula (4) in making pyrrole carboxamides alkyltriphosphonate anhydride coupling agent of formula (4) in making pyrrole carboxamides.
  • the present invention deals with an improved amidation process for making pyrrole carboxamide compounds of general formula (1)
  • R is a group comprising a straight, branched or cyclic hydrocarbon chain of 1 to 20 carbons, wherein the carbons of any place of the chain may be optionally replaced by one to four nitrogen, oxygen or sulfur atoms and wherein any of the chain hydrogens may be optionally substituted by one to four amino-, hydroxyl-, oxo-, thio-, thiono-, halo- groups,
  • Z is hydrogen or a group
  • W is hydrogen or a OR 3 group
  • Ri,R 2 are methyl groups.
  • the preferred compounds of formula (1) are compounds of the formula (la) or (lb).
  • the compounds of general formula (1) are useful as pharmaceutically active compounds, for instance sunitinib and its analogues, or as intermediates in making them.
  • the industrial applicability thereof may be derived from the teaching of WO 01/60814, WO 03/070725, WO 05/023765, US appl. 2006/0009510 etc.
  • the compounds of formula (1) are, in general, known and they are preparable by various procedures.
  • the key synthetic pathway comprises a reaction step comprising an amidation reaction of a carboxylic acid of formula (2) by an amine of formula (3).
  • the amine of the formula (3) is ⁇ , ⁇ -diethylaminoethylamine of the formula (3a)
  • the goal of the present invention is an improvement in this respect.
  • amidation of a carboxylic acid with an amine generally requires a coupling agent, which is an agent that binds the water, which is produced by the amidation reaction :
  • carbodimide coupling agents such as EDCI are frequently used for the amidation reaction on the carboxy-group attached to the pyrrole ring.
  • Carbodiimides are toxic compounds, which give only moderate yields of amidation, and are difficult to be removed from the reaction mixture after terminating the amidation reaction. As shown above, the yield of carbodiimide-mediated amidation reaction in the process of making sunitinib is only 43 %.
  • the present invention improves the amidation reaction between the compounds of general formula (2) and (3) by using the coupling agent of formula (4), wherein A is C1-C6 alkyl group, preferably n-propyl group.
  • This compound is a cyclic phosphonic acid anhydride which reacts with the water liberated during the amidation reaction upon forming a linear triphosphate :
  • Both the cyclic and the linear triphosphates of the above scheme are well soluble in water and in various organic solvents and can thus be easily removed from the reaction product. They are non-toxic compounds, which may be handled by standard means.
  • the amidation reaction proceeds generally at ambient temperature, with almost a quantitative conversion.
  • the preferred compound of general formula (4) is the tris-n-propyl cyclic
  • triphosphonate anhydride 2,4,6-triprop- 1 -yl- 1 ,3,5-trioxa-2,4,6-triphosphinane-2,4,6-trioxide of formula (4a) ,
  • T3P which is commercially available and is herein denoted as T3P.
  • a suitable solvent e.g. ethyl acetate or N,N-dimethylformamide.
  • the present invention will now be illustrated, without limitation, on two processes of making sunitinib (lb), which are summarized on the following scheme.
  • the processes comprise the use of the coupling agent of formula (4a), as the preferred member of compounds of general formula (4).
  • the first process of the present invention comprises the sequence of steps of
  • the compound (2a) reacts with the amine (3a) in presence of the T3P coupling agent (4a) in an inert solvent.
  • the amine (3a) is a liquid, it may be used as the solvent for the reaction as well.
  • the amidation reaction may be carried out at room temperature
  • the reaction mixture basically represents a partition of the mixture between aqueous and organic phase (e.g. between water and a hydrocarbon or chlorinated hydrocarbon) and an isolation of the product from the organic layer.
  • aqueous and organic phase e.g. between water and a hydrocarbon or chlorinated hydrocarbon
  • the crude product may be further purified by a recrystallization or reprecipitation, optionally after an extraction of the rests of the used amine or rests of the T3P agent.
  • the desired product (la) may be obtained as a solid in a yield, which may exceed 90%.
  • the compound (la) may be isolated from the reaction mixture or from the purification solvent as a free base or in a form of an acid addition salt, e.g. as a hydrochloride.
  • reaction mixture or the worked-up reaction mixture comprising the compound (la) may be used for the next reaction step without isolation of the compound (la). Both steps of the first process can then be performed in a "one-pot" arrangement.
  • the compound of the formula (la) is converted to sunitib (lb) by a conventional procedure, e.g. by the Method E disclosed in WO 01/060814.
  • a conventional procedure e.g. by the Method E disclosed in WO 01/060814.
  • equimolar amounts of the compound (la) and the 5-fluoro-l,3-dihydroindol-2-one (5) react, under presence of a base, in an inert solvent , for instance in an aliphatic alcohol, preferably at enhanced temperature.
  • the product may be isolated from the reaction mixture by
  • the second process of the present invention comprises essentially the reverse order of the amidation and condensation steps, particularly the sequence of steps of
  • the compound of formula (2a) and the 5-fluoro-l ,3-dihydroindol-2- one (5) react, in presence of an organic or inorganic base, in an inert solvent , for instance in an aliphatic alcohol, at an enhanced temperature.
  • the product is isolated from the reaction mixture by conventional procedures, for instance by a precipitation, and purified, if necessary.
  • the course of the reaction may be monitored by conventional analytical techniques, e.g. by TLC or HPLC, and the reaction may be terminated after the desired degree of conversion has been obtained.
  • the details of the synthetic procedure can be found in WO 2004/76410, WO 2006/127961 or in WO 2007/81560.
  • the compound of the formula (2b) is isolated in a solid, particularly crystalline, state, which is advantageous for storage and further handling. It may be optionally isolated as a salt with a base , e.g. as a sodium, potassium , magnesium, calcium or lithium salt.
  • the compound (2b) reacts with the amine (3a) in presence of the T3P coupling agent (4a) in an inert solvent.
  • the inert solvent is an organic solvent, typically a polar organic solvent and most preferably a dipolar aprotic solvent, e.g. N,N- dimethylformamide, acetonitrile or dimethylsulfoxide.
  • the reaction temperature is essentially room temperature or close to room temperature (10-40 C). Course of the reaction may be monitored by conventional analytical techniques, e.g. by TLC or HPLC.
  • the product is isolated from the reaction mixture. Typically, it may precipitate from the reaction mixture after diluting it with water.
  • the coupling agent stays entirely in the aqueous mother liquor.
  • the isolated product is washed and dried. If desired, it may be purified, e.g. by recrystallization, for instance form ethanol.
  • the desired sunitinib (lb) may be obtained as a solid in a yield, which may exceed
  • both steps may be performed in a one-pot arrangement.
  • the compound (lb) may be optionally isolated from reaction mixtures of any of the above processes (or subsequently converted to) as an acid addition salt with various inorganic or organic acids; examples of these acids are, without limitation, hydrochloric, hydrobromic, sulfuric, methane sulfonic, benzene sulfonic, p-toluene sulfonic, formic, acetic, maleic, fumaric, oxalic, citric , malic or succinic acid.
  • the compound of the formula (lb) and/or its acid addition salts are preferably useful in its isolated form, which yet preferably is a solid state form such as any crystalline or an amorphous form; the solid state forms also embraces solvates and hydrates. Due to the intended industrial application, compounds (lb) and salts thereof with more than 95% chemical purity, and particularly with more than 99% chemical purity, are preferred.
  • Particularly suitable acid addition salt of the compound (lb) is sunitinib-L-malate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention concerne un procédé d'amidation de composés de carboxylate de pyrrole, comprenant des composés de carboxylate de pyrrole substitués par une indolone, ledit procédé étant caractérisé par l'utilisation d'un agent de couplage de type anhydride d'alkyltriphosphonate cyclique de formule (4) ; et l'utilisation dudit agent de couplage d'alkyltriphosphonate cyclique de formule (4) pour préparer des carboxamides de pyrrole. Dans la formule (4), A est un groupe alkyle C1-C6, de préférence, un groupe n-propyle.
PCT/EP2010/001609 2010-03-10 2010-03-10 Procédé d'amidation de composés de carboxylate de pyrrole WO2011110199A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/EP2010/001609 WO2011110199A1 (fr) 2010-03-10 2010-03-10 Procédé d'amidation de composés de carboxylate de pyrrole
CN2010800662651A CN102858739A (zh) 2010-03-10 2010-03-10 酰胺化吡咯甲酸酯化合物的方法
EP10710795A EP2545034A1 (fr) 2010-03-10 2010-03-10 Procédé d'amidation de composés de carboxylate de pyrrole

Applications Claiming Priority (1)

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PCT/EP2010/001609 WO2011110199A1 (fr) 2010-03-10 2010-03-10 Procédé d'amidation de composés de carboxylate de pyrrole

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2828251A4 (fr) * 2012-03-23 2015-12-09 Laurus Labs Private Ltd Procédé perfectionné pour la préparation de sunitinib et de ses sels d'addition avec un acide

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109485639B (zh) * 2018-12-20 2020-04-07 石药集团中奇制药技术（石家庄）有限公司 一种舒尼替尼制备方法

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WO2001060814A2 (fr) 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
WO2003070725A2 (fr) 2002-02-15 2003-08-28 Pharmacia & Upjohn Company Procede de preparation de derives de l'indolinone
WO2004076410A2 (fr) 2003-02-24 2004-09-10 Pharmacia & Upjohn Company Polymorphes d'inhibiteurs de compose de proteine kinase 2-indolinone a substitution de pyrrole
WO2005014604A2 (fr) 2003-07-21 2005-02-17 Clariant Produkte (Deutschland) Gmbh Procede de production d'anhydrides d'acide phosphonique cycliques
WO2005023765A1 (fr) 2003-09-11 2005-03-17 Pharmacia & Upjohn Company Llc Methode de catalyse de reactions d'amidation au moyen de co2
US20060009510A1 (en) 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
WO2006127961A1 (fr) 2005-05-26 2006-11-30 The Scripps Research Institute Inhibiteurs de la proteine kinase a base d'indolinone amelioree
WO2007034272A1 (fr) 2005-09-19 2007-03-29 Pfizer Products Inc. Sels solides de 2-indolinone a substitution pyrrole
WO2007081560A2 (fr) 2005-12-29 2007-07-19 The Scripps Research Institute Inhibiteurs de proteines kinases a base de derives d'acides amines d'indolinone
WO2008033562A2 (fr) 2006-09-15 2008-03-20 Xcovery, Inc. Composés inhibiteurs de kinases

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WO2001060814A2 (fr) 2000-02-15 2001-08-23 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
EP1255752A2 (fr) 2000-02-15 2002-11-13 Sugen, Inc. Inhibiteurs de la proteine kinase 2-indolinone a substitution pyrrole
US6573293B2 (en) 2000-02-15 2003-06-03 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
WO2003070725A2 (fr) 2002-02-15 2003-08-28 Pharmacia & Upjohn Company Procede de preparation de derives de l'indolinone
WO2004076410A2 (fr) 2003-02-24 2004-09-10 Pharmacia & Upjohn Company Polymorphes d'inhibiteurs de compose de proteine kinase 2-indolinone a substitution de pyrrole
WO2005014604A2 (fr) 2003-07-21 2005-02-17 Clariant Produkte (Deutschland) Gmbh Procede de production d'anhydrides d'acide phosphonique cycliques
WO2005023765A1 (fr) 2003-09-11 2005-03-17 Pharmacia & Upjohn Company Llc Methode de catalyse de reactions d'amidation au moyen de co2
US20060009510A1 (en) 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
WO2006127961A1 (fr) 2005-05-26 2006-11-30 The Scripps Research Institute Inhibiteurs de la proteine kinase a base d'indolinone amelioree
WO2007034272A1 (fr) 2005-09-19 2007-03-29 Pfizer Products Inc. Sels solides de 2-indolinone a substitution pyrrole
WO2007081560A2 (fr) 2005-12-29 2007-07-19 The Scripps Research Institute Inhibiteurs de proteines kinases a base de derives d'acides amines d'indolinone
WO2008033562A2 (fr) 2006-09-15 2008-03-20 Xcovery, Inc. Composés inhibiteurs de kinases

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ARCHIMICA: "Coupling Agent ®T3P-The Water Scavenger", 2006, pages 1-20, XP002598930, Retrieved from the Internet <URL:http://www.archimica.com/PDF/ARCHIMICA_T3P_Brochure.pdf> [retrieved on 20100902] *
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SUN L ET AL: "Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl] 2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)ami de, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, US LNKD- DOI:10.1021/JM0204183, vol. 46, no. 7, 27 March 2003 (2003-03-27), pages 1116 - 1119, XP009070151, ISSN: 0022-2623 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2828251A4 (fr) * 2012-03-23 2015-12-09 Laurus Labs Private Ltd Procédé perfectionné pour la préparation de sunitinib et de ses sels d'addition avec un acide

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EP2545034A1 (fr) 2013-01-16
CN102858739A (zh) 2013-01-02

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