EP2545034A1 - A process for amidation of pyrrole carboxylate compounds - Google Patents

A process for amidation of pyrrole carboxylate compounds

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Publication number
EP2545034A1
EP2545034A1 EP10710795A EP10710795A EP2545034A1 EP 2545034 A1 EP2545034 A1 EP 2545034A1 EP 10710795 A EP10710795 A EP 10710795A EP 10710795 A EP10710795 A EP 10710795A EP 2545034 A1 EP2545034 A1 EP 2545034A1
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Prior art keywords
formula
group
compound
process according
reaction
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German (de)
French (fr)
Inventor
Jie Zhu
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Synthon BV
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Synthon BV
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    • 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.

Abstract

The present invention relates to a process of amidation of pyrrole carboxylate compounds, including indolone-substituted pyrrole carboxylate compounds, characterized by using a cyclic alkyltriphosphonate anhydride coupling agent of formula (4) wherein A is C1-C6 alkyl group, preferably n-propyl group and to the use of the cyclic alkyltriphosphonate anhydride coupling agent of formula (4) in making pyrrole carboxamides.

Description

A PROCESS FOR AMIDATION OF PYRROLE CARBOXYLATE COMPOUNDS
Certain pyrrole carboxamides are important pharmaceutical compounds. For instance 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)
has been developed for a manufacture of a medicament for the treatment of gastrointestinal stromal cell tumors (GIST) and metastatic renal cell carcinoma. It has been disclosed , together with many structurally similar pyrrole carboxamides, in WO 01/60814 (EP 1255752, US 6573293). Other structurally similar pyrrole carboxamides with similar pharmaceutical activity have been disclosed, e.g., in WO 2004/76410, WO 2006/127961, WO 2007/81560, WO 2008/33562.
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 .
An example of such process leading to sunitinib may be found in WO 01/60814. The
5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (III)
reacts with N,N-diethylaminoethylamine (II)
in dimethylformamide in the presence of a base (triethylamine) under an action of a slight molar excess of a coupling agent, which is a mixture of l-ethyl-3-(3- dimethylaminopropyl)carbodiimide [EDCI] and l-hydroxybenztriazole [HBT]. The obtained product (IV)
then reacts with 5-fluoro-l ,3-dihydroindol-2-one (V)
in an inert solvent under presence of a base to yield the desired sunitinib.
An alternate reaction pathway was disclosed by Sun et al. in J.Med.Chem., 2003,46, 1 116-11 19. Herein, the 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid (III) first reacts with 5-fluoro-l ,3-dihydroindol-2-one (V) in ethanol and under the presence of piperidine base to yield the acid (VI)
which is then amidated by the amine (II) under action of EDCI and HBT coupling agents. As apparent from the Alternative Example 80 of WO 01/60814, the yield of the amidation reaction is very low (43%).
An improved amidation process has been disclosed in WO 03/070725 and in WO 05/023765, in which the carbonyl group on the pyrrole ring is activated for the amidation reaction by a covalently bond heterocyclic group, e.g. by a lH-imidazol-l-yl group. The activated intermediate, e.g. the compound (Ilia)
reacts, possibly in one step, with the amine (II) and the indolone (V) to yield the desired sunitinib (Exl of the WO' 725).
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. Furthermore, 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.
It would be desirable to have an alternate process of making sunitinib as well as other structurally related pyrrole-substituted indolone compounds having an amide substituent in the pyrrole ring, wherein the process does not exhibit the above disadvantages.
Brief description of the invention
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.
In a first aspect, 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,
X
II
Z is hydrogen or a— C~W group, W is hydrogen or a OR3 group,
C=X is C=0 group, C=N-R4 group, 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,R2,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),
the process comprising a step of reacting a compound of formula (2)
with an amine of formula (3)
NH2- R (3)
in the presence of a cyclic alkyltriphosphonate anhydride coupling agent of formula
(4)
wherein A is C1-C6 alkyl group, preferably n-propyl group.
X
II
In a specific aspect, the Z group represents a W group, wherein W is preferably
hydrogen and C=X is preferably C=0 group or group, and Ri,R2 are methyl groups. Thus, the preferred compounds of formula (2) are compounds of formula (2a) or formula (2b).
In yet specific aspect, the group R is Ν,Ν-diethylaminoethyl- group and the amine of the formula (3) is Ν,Ν-diethylaminoethylamine of formula (3a)
<
H2N (3a)
The preferred compounds of formula (1) are accordingly compounds of formula (la) or (lb).
As apparent, the compound (lb) corresponds to sunitinib In a yet specific aspect, 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.
Optionally, reaction product is isolated from the reaction mixture and purified.
If the X moiety in the Z group of the compound of formula (1) or (2) , as defined above, does not correspond to the indolonylidene group
wherein Y is hydrogen or at least one halo-group, CI -CI O alky] group, carboxy group, amino group and/or a sulfonamide groupand typically is fluoro-group, (e.g. in case where W is hydrogen and C=X is C=0 group), then the process of the above may comprise a next step of converting the C=X moiety of the Z group into said indolonylidene group . In an example of such conversion, the compound of formula (la) may be converted to sunitinib (lb).
In a second aspect, the invention provides a first process of making sunitinib of formula (l b) comprising the sequence of steps of
-Amidation of the compound of formula (2a) by Ν,Ν-diethylaminoethylamine of formula (3) in the presence of cyclic propyltriphosphonate anhydride of formula (4a) and
-Reaction of the so obtained amide (la) with 5-fluoro-l,3-dihydroindol-2-one of formula (5) .
Furthermore, the invention provides a second process of making sunitinib of formula (lb) comprising the sequence of steps of
-Reaction of compound of formula (2a) with with 5-fJuoro-l ,3-dihydroindol-2-one (5) to yield the compound of formula (2b)
-Amidation of the compound of formula (2b) by N,N-diethylaminoethylamine of formula (3a) in the presence of cyclic propyltriphosphonate anhydride of formula (4a) In a third aspect, the invention provides a novel use of compound of formula (4), particularly the compound of formula (4a),
in a process for making compounds of general formula (1), typically for making the compound of formula (la) and/or (lb).
In a fourth aspect the invention relates to the use of the cyclic
alkyltriphosphonate anhydride coupling agent of formula (4) in making pyrrole carboxamides.
Detailed description of the invention
The present invention deals with an improved amidation process for making pyrrole carboxamide compounds 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 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 OR3 group,
C=X is C=0 group, group, Y is hydrogen or at least one halo-group, CI -CIO alkyl group, carboxy group, amino group and/or sulfonamide group, each of Ri,R2,R3,R 5R5,R6 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).
x
II
In a specific aspect, the Z group represents a— c~w group, wherein W is preferably hydrogen and C=X is preferably C=0 group or the
group, and Ri,R2 are methyl groups.
The preferred compounds of formula (1) are compounds of the formula (la) or (lb).
As apparent, the compound (lb) corresponds to sunitinib
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). In a typical example, the amine of the formula (3) is Ν,Ν-diethylaminoethylamine of the formula (3a) As the known amidation procedures in methods of making the compounds of formula (1) suffer from various disadvantages, particularly from a low yield, the goal of the present invention is an improvement in this respect.
The 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 :
-COOH + NH2-R -> -CONH-R + H-OH.
Binding the water switches the reaction equilibrium towards forming the amide.
In known processes of making sunitinib and its analogues and/or intermediates, generally having the formula (1), from acids of general formula (2), 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 %. Various other coupling agents may be used in theory for the amidation reaction, but none of them has been investigated for making sunitinib and its analogues except benzotriazole-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP) mentioned in the Example 129 of WO 01/60814 and in WO2007/034272. This coupling agent provides good yields of amidation, but BOP itself and its resulting by-products are highly toxic compounds requiring additional handling costs and safety measures, particularly in industrial scale.
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 :
(4)
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 compounds of formula (4) have been disclosed, e.g., in WO 2005/014604.
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) ,
which is commercially available and is herein denoted as T3P. In an advantageous mode, it is used in the process of the present invention within a solution in 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 starting material, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid of formula (2a), has been disclosed in WO 01/060814.
The first process of the present invention comprises the sequence of steps of
-Amidation of the compound of formula (2a) by Ν,Ν-diethylaminoethylamine of formula (3 a) in the presence of cyclic propyltriphosphonate anhydride of formula (4a) and
-Reaction of the so obtained amide of formula (la) with 5-fluoro-l ,3-dihydroindol-2- one of formula (5)
In the first step, the compound (2a) reacts with the amine (3a) in presence of the T3P coupling agent (4a) in an inert solvent. As 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 or close to room temperature ( e.g. in a range of 10-40°C, preferably at about 25°C) and is , in general, completed in a couple of hours. 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 workup of 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. If necessary, 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.
Alternately, the reaction mixture or the worked-up reaction mixture comprising the compound (la) (e.g. a solution of the compound (la) in the amine (3a) or in an organic solvent) 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.
In the second step, 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. In general, 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
conventional procedures, and purified, if necessary.
The second process of the present invention comprises essentially the reverse order of the amidation and condensation steps, particularly the sequence of steps of
-Reaction of the compound of formula (2a) with 5-fluoro-l ,3-dihydroindol-2-one (5) to yield the compound of formula (2b)
-Amidation of the compound of formula (2b) by N,N-diethylaminoethylamine of formula (3 a) in the presence of cyclic propyltriphosphonate anhydride of formula (4a)
In the first step, 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.
Typically, 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.
In the second step, 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. After the desired conversion is reached, 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
90%.
As in the preceded process, the 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.
Other compounds of the general formula (1) may be prepared in an essentially similar way. For instance, the process of the present invention may be used for making the compound of the formula (lc)
and pharmaceutically acceptable salts thereof, which has been disclosed in WO
2004/76410 and WO 2007/34272.
The present invention will be further illustrated by way of the following Examples. These examples are non-limiting and do not restrict the scope of the invention. Examples
Example 1 - Conversion of (2a) to (la)
To a solution of acid derivative (2a) (835 mg, ~5mmol) in N-diethylethylene-diamine (10 ml), with stirring at room temperature, propane phosphoric acid anhydride (T3P) (10 ml, 50% EtOAc solution) was added dropwise and completed in 1.5 hours. The resulting reaction mixture was stirred further over night. Water (25 ml) and dichloromethane (25 ml) were added, and the mixture was stirred for 25 minutes. The dichloromethane layer was separated and concentrated in vacuo to give an oily material. The oil was mixed with ethyl acetate (50 ml) and sodium carbonate solution (4%, 25 ml), and stirred at 70°C for 30 minutes. After cooling, the ethyl acetate layer was separated and washed with water (10 ml), dried ( a2S04) and concentrated to give a yellow solid (la) (1.35 g).
Example 2 - Conversion of (2a) to (la)
To a solution of acid derivative (2a) (835 mg, ~5mmol) in N,N-diethylaminoethylamine (10 ml), with stirring at room temperature, propane phosphoric acid anhydride (T3P) (6 ml, 50% EtOAc solution) was added dropwise (using an addition equipment) and completed in 1.5 hours. Water (25 ml) and dichloromethane (50 ml) were added, and the resulting mixture was stirred for 20 minutes. The dichloromethane layer was separated, washed with water (20 ml) and concentrated in vacuo to give an oily material. The oil was mixed with ethyl acetate (50 ml) and HCl solution (1 M, 12 ml), and stirred at rt for 30 minutes. Then, the mixture was basified to pH~10. The ethyl acetate layer was separated, washed with water (10 ml), and concentrated in vacuo to give a yellow solid (la) (1.3 g). Example 3 - Conversion of (la) to (lb)
(l a) (lb)
To a mixture of 150 mg of 5-fluoro-l,3-dihydroindol-2-one of formula (5) and 450 mg of the aldehyde derivative (la) in 10 ml of ethanol, -0.5 ml of pyrrolidine (10 drops) was added. The mixture was heated to reflux for 3 hours. After cooling to room temperature, the formed solid sunitinib (lb) was filtered off. The filtrate was concentrated and the residue was dissolved in 2 ml of ethanol. The clear solution was stored at room temperature over night to generate 2 crop of solid sunitinib.
In total, 310 mg desired solid sunitinib was obtained after drying at 40 °C over night in vacuo, (yield: 77%)
Example 4 - Conversion of (2a) to (2b)
To a mixture of 200 mg of 5-fluoro oxindole (5) and 266 mg of aldehyde (2a) in 6 ml of ethanol, -0.5 ml of piperidine (10 drops) was added and the mixture was heated to 60 °C over night. After cooling to RT the solid was filtered off and washed twice with 5 ml of 1 M HCL solution. The solid was dried over night at 40 °C under vacuum. 390 mg desired product (2b) was obtained. Example 5 - Conversion of (2b) to sunitinib (lb)
To 150 mg of (2b) in 3 ml of DMF, 1.5 ml of Ν,Ν-diethylaminoethylamine was added to form a solution. Then 0.6 ml of a 50 % solution of propane phosphonic acid cyclic anhydride in DMF was added in 1.5 hours at ambient temperature using a syringe pump. Stirring was continued over night at room temperature. Then 0.1 ml of 50 % solution of propane phosphonic acid anhydride in DMF was added and stirring at RT was continued for 2 hours. 50 ml of water was added and formed suspension was filtered. The solid was washed twice with water. Approx. 150 mg solid sunitinib was obtained after dring at 40 °C under vacuum for 3 hours. Analytical sample was obtained by recrystallization in ethanol.
The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

Claims

1. 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 at 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,
X
II
Z is hydrogen or a w group,
W is hydrogen or a OR3 group,
C=X is C=0 group, group,
Y is hydrogen or at least one halo-group, CI -CI O alkyl group, carboxy group, amino group and/or a sulfonamide group,
each of Ri,R2,R3,R4,R5,R6 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),
the process comprising a step of reacting a compound of formula (2)
with an amine of formula (3)
NH2- R (3) n the presence of a cyclic alkyltriphosphonate anhydride coupling agent of formula (4)
whereinA is C1-C6 alkyl group.
2. The process according to claim 1 , wherein A in the formula (4) is n-propyl group.
3. The process according to claim 1 or 2, wherein
X
II
the Z group represents a C~W group, wherein W is preferably hydrogen and C=X is
preferably C=0 group or group,
and Ri and R2 are methyl groups.
4. The process according to claim 1-3, wherein the compound of formula (2) is the compound of formula (2a) or formula (2b).
5. The process according to claim 1-4, wherein the group R is N,N-diethylaminoethyl group and the amine of formula (3) is Ν,Ν-diethylaminoethylamine of formula (3a)
6. The process according to claims 1-5, wherein the compound of formula (1) is compound of formula (la) or (lb).
7. The process according to claims 1-6, wherein 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.
8. The process according to claim 7, wherein the reaction proceeds at ambient or close to ambient temperature.
9. The process according to claims 1-8, wherein the reaction product of formula (1) isolated from the reaction mixture and, optionally purified.
10. The process according to claims 1-9 , wherein the Z group of the compound of formula (1) or (2) does not correspond to the indolonylidene group
wherein Y is hydrogen or at least one halo-group, CI -CIO alkyl group, carboxy group, amino group and/or a sulfonamide group,
said process further comprising a step of converting the C=X moiety of the Z group into said indolonylidene group.
1 1. The process according to claim 10, wherein W is hydrogen , C=X is C=0 group, R is hydrogen or N,N-diethylaminoethyl- group , Ri and R2 are methyl groups, and Y is a fluoro-group.
12. A process for making the compound of formula (lb)
comprising the sequence of steps of
-Amidation of the compound of formula (2a)
-diethylaminoethylamine of formula (3a)
in the presence of cyclic n-propyltriphosphonate anhydride of formula (4a) and
(4a)
Reaction of the so obtained amide
with 5-fluoro-l ,3-dihydroindol-2-one of formula (5)
13. A process for making the compound of formula (lb) comprising the sequence of steps of
- Reaction of compound of formula (2a) with 5-fluoro-l ,3-dihydroindol-2-one (5) to yield the compound of formula (2b)
-Amidation of the compound of formula (2b) by Ν,Ν-diethylaminoethylamine of formula (3a) in the presence of cyclic propyltriphosphonate anhydride of formula (4a).
14. The process according to claims 12 or 13, wherein the compound (l b) is isolated from the reaction mixture.
15. The process according to claim 14, wherein the compound (lb) is obtained as is or converted to an acid addition salt, and preferably the acid addition salt is sunitinib L- malate.
16. Use of a compound of formula (4),
wherein A is C1-C6 alkyl group, preferably n-propyl,
in a process for making compounds of general formula (1).
17. The use according to claim 16, wherein the compound of the general formula (1) is the compound of formula (la) and/or (lb).
EP10710795A 2010-03-10 2010-03-10 A process for amidation of pyrrole carboxylate compounds Withdrawn EP2545034A1 (en)

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CN104114550A (en) * 2012-03-23 2014-10-22 劳拉斯实验室私人有限公司 An improved process for the preparation of sunitinib and its acid addition salts
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PT1255752E (en) 2000-02-15 2007-10-17 Pharmacia & Upjohn Co Llc Pyrrole substituted 2-indolinone protein kinase inhibitors
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US7452913B2 (en) 2003-02-24 2008-11-18 Pharmacia & Upjohn Company Polymorphs of pyrrole substituted 2-indolinone protein kinase inhibitors
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WO2005023765A1 (en) 2003-09-11 2005-03-17 Pharmacia & Upjohn Company Llc Method for catalyzing amidation reactions by the presence of co2
US20060009510A1 (en) 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
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MX2008002415A (en) 2005-09-19 2008-03-27 Pfizer Prod Inc Solid salt forms of a pyrrole substituted 2-indolinone.
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