Process for preparing indolinone derivatives

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The present invention refers to a process for preparing indolinone derivatives of the general formula (VI) as defined in the specification and intermediates of that process.

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Description

This is a division of U.S. patent application Ser. No. 10/367,008, filed Feb. 14, 2003, which claims the benefit of U.S. Provisional Application No. 60/411,732, filed Sep. 18, 2002, and International Application No. PCT/US02/04407, filed Feb. 15, 2002, the disclosures of which are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention refers to a process for preparing indolinone derivatives and intermediates of that process.

BACKGROUND OF THE INVENTION

A number of indolinone derivatives have been found to exhibit pharmaceutical activity. Due to the ability to modulate the protein kinase activity, they have been suggested to treat an number of conditions such as various types of cancer, mastocytosis, allergy associated chronic rhinitis, diabetes, autoimmune disorders, restenosis, fibrosis, psoriasis, von Hippel-Lindau disease, osteoarthritis, rheumatoid arthritis, angiogensis, inflammatory disorders, immunological disorders, and cardiovascular disorders (WO 01/45689, WO 01/60814, WO 99/48868, U.S. Pat. No. 6,316,429, U.S. Pat. No. 6,316,635, U.S. Pat. No. 6,133,305, and U.S. Pat. No. 6,248,771).

Among the indolinone derivatives those having an amide group on a heterocyclic ring condensed with the indolinone have been of interest. These compounds modulate protein kinase activity and are thus useful in treating diseases relating to abnormal protein kinase activity. A process for preparing the amide derivatives is disclosed in WO 01/60814. An appropriate pyrrole is formylated and subsequently condensed with a 2-indolinone to give a respective 5-(2-oxo-1,2-dihydroindole-3-ylidenemethyl)-1H-pyrrole. If an amide derivative of the pyrrole is desired, a pyrrole having a carboxylic acid group is selected. The carboxylic acid group is reacted with the desired amine in the presence of dimethylformamide, 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide and 1-hydroxybenzotriazole. In example 129 a scale-up procedure is disclosed in which the amidation is conducted in the presence of dimethylformamide, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and triethylamine.

It is an object of the present invention to provide an improved process for preparing indolinone derivatives which have an amide group on a heterocyclic ring condensed with the indolinone.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing an indolinone of the general formula (VI)
wherein

  • R1, R2, R3, R4 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 alkoxy, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, C6-12 alkaryl, C6-12 alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO2NR′R″, —SO3R′, —SR′, —NO2, —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH2)nCO2R′, and —CONR′R″;
  • each R5 is independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 alkoxy, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, C6-12 alkaryl, C6-12 alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO2NR′R″, —SO3R′, —SR′, —NO2, —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH2)nCO2R′, and —CONR′R″; R6 is selected from —NR8(CH2)mR9 and —NR10R11, provided that optionally one to two of the CH2 groups may be substituted by —H or halogen; R8 is hydrogen or C1-12 alkyl;
  • R9 is selected from the group consisting of —NR10R11, —OH, —C(O)R2, C1-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, —N+(O)R10, and —NHC(O)R13;
  • R10 and R11 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, and C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O; or R10 and R11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and R11 may optionally be substituted by R′
  • R12 is selected from the group consisting of hydrogen, —OH, C1-12 alkoxy and C6-12 aryloxy;
  • R13 is selected from the group consisting of C1-12 alkyl, C-1-12 haloalkyl, and C1-12 aralkyl;
  • R′ and R″ are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group —NR′R″ the R′ and R″ substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R′ and R″ are bound;
  • The terms “halogen” and “halo” refer to substituents selected from the group consisting of F, Cl, Br, and I
  • J is selected from the group consisting of O, S, and NH;
  • one of K, L and M is C and the group —C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5, CR52, N, NRC, O and S;
  • n is 0, 1 or 2;
  • m is 1, 2, 3, or 4; and
  • p is 0, 1 or 2;
    comprising the steps of
  • (i) reacting a compound of general formula (I)
    wherein R5, J, K, L, M and p are as defined above,
  • Q is selected from the group consisting of
    with a compound of general formula (II)
    X2—R  (II)
    wherein:
  • (a) one of X1 and X2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, —O—C1-4 alkyl and —O-phenyl; and R is selected from the group consisting of —C(O)—C1-4 alkyl, —C(O)—O—(C1-4)alkyl, —C(O)—O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, —C(O)—O—CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, or
  • (b) X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
    or
  • (c) X1 is hydroxy, —O—C1-4 alkyl and —O-phenyl,
  • X2 is
    • and R is
  • to form a compound of the general formula (III)
    wherein R* is —O—R in case (a) of step (i) and —R in cases (b) and (c) of step (i);
  • (ii) reacting the compound of general formula (III) with a compound of general formula (IV)
    wherein R1, R2, R3, and R4 are as defined above,
  • and an amine of general formula (V)
    HR6  (V)
    wherein R6 is as defined above, to form the indolinone of the general formula (VI).

The dashed lines in the heterocyclic ring system mean that two double bonds are present but their position is not specified.

A further embodiment the present invention relates to a process for preparing a compound of the general formula (III)
wherein

  • R5, J, K, L, M, and p are as defined above;
    comprising the steps of
  • (i) reacting a compound of general formula (I)
  • R5, J, K, L, M, and p are as defined above;
  • with a compound of general formula (II)
    X2—R  (II)
  • (a) wherein one of X1 and X2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, —O—C1-4 alkyl and —O-phenyl; and R is selected from the group consisting of —C(O)—C1-4 alkyl, —C(O)O—(C1-4)alkyl, —C(O)—O-phenyl, —C(O)—O—CH2-phenyl, wherein the phenyl can optionally be substituted by 1 to 3 halogen atoms;
  • (b) wherein X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
    or
  • (c) wherein X1 is hydroxy, —O—C1-4 alkyl and —O-phenyl, and X2 is
    • and R is
  • to form a compound of the general formula (III)
    wherein R* is —O—R in case (a) of step (i) and —R in cases (b) and (c) of step (i).
  • (ii) reacting the compound of general formula (III) with a compound of general formula (IV)
    wherein R1, R2, R3, and R4 are as defined above,
  • and an amine of general formula (V)
    HR6  (V)
    wherein R6 is as defined above, to form the indolinone of the general formula (VI).

The present invention also refers to a process for preparing an indolinone of the general formula (VI)
wherein

  • R1, R2, R3, R4, R5, R6, J, K, L, M, and p are as defined above;
    comprising the steps of
  • reacting a compound of the general formula (III)
  • R5, J, K, L, M, and p are as defined above;
  • wherein R* is selected from the group consisting of —O—C(O)—O—C1-4alkyl, —O—C(O)—O—(C1-4)alkyl, —O—C(O)—O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, —O—C(O)—O—CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
  • with a compound of general formula (IV)
  • R1, R2, R3, and R4 are as defined above;
  • and an amine of general formula (V)
    HR6  (V)
    wherein R6 is as defined above, to form the indolinone of the general formula (VI).

In yet another embodiment compounds of the general formula (III):
wherein R5, J, K, L, M, and p are as defined above and R* is selected from the group consisting of —O—C(O)—C1-4 alkyl, —O—C(O)—O—(C1-4)alkyl, —O—C(O)—O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, —O—C(O)—O—CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
are disclosed. Preferably R* is

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparing indolinone derivatives of general formula (VI). The compounds can modulate the activity of protein kinases and the compounds themselves, their pharmaceutically acceptable salts and derivatives are useful in a wide range of medical applications. Preferred compounds having the formula (VI), pharmaceutical compositions containing such compounds and the medical utility of these compounds have been described, e.g. in WO 01/45689, WO 01/60814, WO 99/48868, U.S. Pat. No. 6,316,429, U.S. Pat. No. 6,316,635,6,133,305, and U.S. Pat. No. 6,248,771, all of which are incorporated herein by reference in the entirety. Particularly preferred compounds are described in WO 01/45689 (e.g. compounds 15 and 16) and WO 01/60814 (e.g. in the examples and in Table 1).

The indolinone compounds have the general formula (VI)
R1, R2, R3, R4 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 alkoxy, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, C6-12 alkaryl, C6-12 alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO2NR′R″, —SO3R′, —SR′, —NO2, —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH2)nCO2R′, and —CONR′R″. Preferably R1 is hydrogen or C1-4 alkyl; more preferably R1 is hydrogen.

In a preferred embodiment R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, —O—C1-4 alkyl, phenyl, —COOH, —CN, —C(O)CH3, —SO2NH2 and —SO2N(CH3)2; more preferably R2 is selected from the group consisting of hydrogen, fluorine, chlorine, C1-4 alkyl, —O—C1-4 alkyl, —CN, —SO2NH2 and —SO2N(CH3)2 and even more preferably R2 is hydrogen, fluorine, chlorine, and C1-4 alkyl. Most preferably R2 is fluorine.

In a preferred embodiment R3 is selected from the group consisting of hydrogen, C1-4 alkyl, phenyl, C1-4 alkoxy and —COOH; more preferably R3 is hydrogen or C1-4 alkyl; most preferably R3 is hydrogen.

It is preferred that R4 is hydrogen.

Each R5 is independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 alkoxy, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, C6-12 alkaryl, C6-12 alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO2NR′R″, —SO3R′, —SR′, —NO2, —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH2)nCO2R′, and —CONR′R″. Preferably R5 is hydrogen or a C1-4 alkyl.

R6 is is selected from —NR8(CH2)mR9 and —NR10R11, provided that optionally one to two of the CH2 groups may be substituted by —OH or halogen. Preferably R6 is —NR8(CH2)mR9. In a preferred embodiment the CH2 groups are unsubstituted or one of the CH2 groups is substituted by —OH.

R8 is hydrogen or C1-12 alkyl. Preferably R8 is hydrogen or C1-4 alkyl, and more preferably R8 is hydrogen.

R9 is selected from the group consisting of —NR10R11, —OH, —C(O)R12, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, —N+(O−)R10, and —NHC(O)R13. In one embodiment R9 is preferably —NR10R11. In a second embodiment R9 is preferably a C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O. Preferably the heterocyclic group is a five- to seven-membered heterocyclic group bonded to the (CH2)m group via a nitrogen atom and optionally containing a further heteroatom selected from N, O, and S. Examples of the heterocyclic group are, but are not limited to

Preferably the heterocyclic group is

R10 and R11 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, and C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O; or R10 and R11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and R11 may optionally be substituted by R′. Preferably R10 and R11 are hydrogen or C1-4 alkyl. More preferably R10 and R11 are H.

R12 is selected from the group consisting of hydrogen, —OH, C1-12 alkoxy and C6-12 aryloxy. Preferably R12 is a C1-4 alkyl.

R13 is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, and C6-12 aralkyl. Preferably R13 is a C1-4 alkyl.

R′ and R″ are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group —NR′R″ the R′ and R″ substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R′ and R″ are bound. Preferably R′ and R″ are independently a C1-4 alkyl.

J is selected from the group consisting of O, S, and NH, preferably J is NH.

one of K, L and M is C and the group —C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5, CR52, N, NR5, O and S. Preferred heterocyclic groups
are

Particularly preferred as the heterocyclic group is

  • n is 0, 1 or 2.
  • m is 1, 2, 3, or 4; preferably m is 2 or 3.
  • p is 0, 1 or 2.

Preferred compounds are shown wherein X is a halogen

In the first step of the process of the present invention, a compound of general formula (I)
wherein R5, R6, J, K, L, M and p are as defined above, is reacted with a compound of general formula (II)
X2—R  (II)

  • (a) wherein one of X1 and X2 is chlorine, or bromine; and the other is selected from the group consisting of hydroxy, —O—C1-4 alkyl and —O-phenyl; and R is selected from the group consisting of —C(O)—C1-4 alkyl, —C(O)—O—(C1-4)alkyl, —C(O)—O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, —C(O)—O—CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms,
  • (b) wherein X1 is chlorine or bromine, X2 is hydrogen and R is selected from the group consisting of
    or
  • (c) wherein X1 is hydroxy, —O—C1-4 alkyl and —O-phenyl, and X2 is
  • and R is
  • to form a compound of the general formula (III)
    wherein R* is OR in case (a) of step (1) and —R in cases (b) and (c) of first step. In first step, option (c) is preferred.

The compounds of general formulae (I) and (II) are either commercially available or can be prepared by methods well known in the art. For example, heterocycles having a formyl group can be obtained by slowly adding POCl3 to dimethylformamide followed by addition of the appropriate heterocycle, which is also dissolved in dimethylformamide. This reaction is described in more detail and exemplified e.g. in WO 01/60814, which is incorporated herein by reference.

The reaction is generally carried out in a polar aprotic solvent. An aprotic solvent is any solvent that, under normal reaction conditions, does not donate a proton to a solute. Polar solvents are those which have a non-uniform distribution of charge. Generally they include 1 to 3 atoms selected from heteroatom such as N, S or O. Examples of polar aprotic solvents that can be used in the invention are ethers such as tetrahydrofuran, diethylether, methyl tert-butyl ether; nitrile solvents such as acetonitrile; and amide solvents such as dimethylformamide. Preferably the reaction solvent is an ether, more preferably the solvent is tetrahydrofuran. Mixtures of the solvents may also be employed. The aprotic, polar solvent preferably has a boiling point from 30° C. to 130° C., more preferably from 50° C. to 80° C. Both components of the reaction are introduced into a reaction vessel together with the solvent. The reactants may be added in any order, although it is preferred to add compound I to a stirred suspension of compound II in a suitable solvent, at room temperature (18-25° C.). A reactant concentration of 0.3 to 0.5 moles/liter is preferred, although the person of skill in the art will appreciate that the reaction may be conducted at different concentrations. The reaction may be conducted at a temperature of 0° C. up to the reflux temperature of the solvent. However, it is preferred to conduct the reaction at a temperature of 25° C. to 80° C. with mechanical stirring. The progress of the reaction may be monitored by a suitable analytical method, such as HPLC. Upon completion of the reaction the reaction mixture is cooled and the intermediate compound III crystallizes. It is preferred to cool the reaction mixture to a temperature below room temperature and 0° C. is most preferred. The intermediate compound III may be separated from the reaction mixture by methods known to those skilled in the art, such as centrifuging, and filtration. Intermediate III is a crystalline solid that is non-hygroscopic and is stable in air at room temperature.

The compound of general formula (III) is then reacted in a second step with a compound of general formula (IV)
wherein R1, R2, R3, R4 are as defined above

  • and an amine of general formula (V)
    HR6  (V)
    wherein R6 is as defined above to form the indolinone of the general formula (VI). The reaction can be carried out in solution, using the same solvents used in the first reaction step. The reaction may be carried out sequentially by reacting compound III with either compound compound IV or compound V and then adding the other compound. However, it is preferred that compounds II, IV and V are introduced into a reaction vessel together with the solvent. The reactants may be added in any order, although it is preferred to add compound III to a stirred suspension of compound IV and the amine V in a suitable solvent, at room temperature (18-25 IC). A reactant concentration of 0.3 to 0.5 moles/liter is preferred, although the person of skill in the art will appreciate that the reaction may be conducted at different concentrations. The reaction may be conducted at a temperature of 50° C. up to the reflux temperature of the solvent. However, it is preferred to conduct the reaction at a temperature of 50° C. to 80° C. with mechanical stirring. The progress of the reaction may be monitored by a suitable analytical method, such as HPLC. Upon completion of the reaction, the reaction mixture is cooled and compound VI crystallizes. It is preferred to cool the reaction mixture to a temperature below room temperature and 0° C. is most preferred. Compound VI may be separated from the reaction mixture by methods known to those skilled in the art, such as centrifuging, and filtration. Although Compound VI obtained from the process above is often of sufficient purity for medical use, if desired, compound VI may be further purified by methods known to those skilled in the art, such as recrystallization.

If desired the indolinone compounds of general formula (VI) can be further reacted to their pharmaceutically acceptable salts or derivatives according to conventional processes.

The present invention provides a process for preparing indolinone derivatives, which is more convenient than the prior art processes. Generally the intermediates are easier to handle. Furthermore, product isolation is facilitated.

The following examples serve to illustrate the invention and should not be construed as limiting. Unless otherwise specified all percentages, parts, and amounts are based on weight.

EXAMPLES Example 1 N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (14.0 g), N,N-diethylethylenediamine (15.0 g), 5-fluorooxindole (9.86 g), triethylamine (27 ml), and acetonitrile (250 ml) were mixed and heated to 60° C. The black slurry was stirred for 18 h at 60° C. (needs mechanical stirrer). The resulting yellow slurry was cooled to room temperature, diluted with 100 ml acetonitrile, and filtered. The cake was washed with 3×100 ml acetonitrile and dried overnight at 50° C. under house vacuum. N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (21.7 g) was obtained with 85% yield.

Example 2 5-[(Z)-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

A 0.1 L flask fitted with a thermometer, condenser, heating mantle, nitrogen inlet and magnetic stirring was charged with; 3.0 g 5-Bromooxindole, 3.03 g 4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde, 3.24 g N,N-Diethylethylene diamine, 4.23 g Triethylamine and 30 ml Tetrahydrofuran. The mixture was heated to 60-65° C. for 8 hours, then cooled to ambient temperature. 10 ml Tetrahydrofuran was added to aid stirring and the reaction mixture was filtered. Drying provided 3.7 g (57.7%) first crop of 5-[(Z)-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethylamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. The mother liquors are cooled to −10° C. for 6 h for an additional 1.9 g (29.6%). 1HNMR (DMSO): δ 8.08 (1H,s); 7.75 (1H,s); 7.41 (1H,s); 7.24 (1H,d); 6.81 (1H,d); 3.31 (4H,bs); 2.46 (14H,bm); 0.96 (6H,t).

Example 3 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

A 0.25 L flask fitted with a thermometer, condenser, magnetic stirring, and nitrogen inlet was charged with 4.92 g 5-Fluorooxindole, 7.0 g 4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl- 1H-pyrrole-2-carbaldehyde, 15.5 g (R)-1-Amino-3-(4-morpholinyl)-2-propanol, 9.78 g Triethylamine and 88 ml Tetrahydrofuran. The mixture was heated to 60° C. for 16.5 hours. The reaction was cooled to ambient temperature and filtered. The solids obtained were slurried (3) three successive times in acetonitrile at 11 ml/g, dried in vacuo to produce a yield of 3.6 g (25.25%) of 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.

1HNMR (DMSO): δ 10.86 (1H,bs); 7.75 (1H,d); 7.70 (1H,s); 7.50 (1H,m); 6.88 (2H,m); 4.72 (1H,bs); 3.78 (1H,bs); 3.56 (4H,m); 3.32 (6H, m); 3.15 (1H,m); 2.43 (8H,bm).

Example 4 5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (6.8 g, 31.3 mmol), (2S)-1-amino-3-morpholin-4-ylpropan-2-ol (10.0 g, 62.5 mmol), 5-chlorooxindole (5.3 g, 31.6 mmol), and THF (100 ml) were mixed and heated to 60° C. After stirring for 68 h at 60° C., triethylamine (14 ml) was added and stirred for 5 h at 60° C. Added 4.6 g of (2S)-1-amino-3-morpholin-4-ylpropan-2-ol, and stirred for 20 h at 60° C. The yellow slurry was cooled to room temperature and filtered. The cake was washed with 2×50 ml THF and dried overnight at 50° C. under house vacuum. 5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (5.48 g) was obtained with 38% yield.

Example 5 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide

A mixture of 4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (4.1 Kg), THF (70.8 Kg), and water (4.7 L) were heated at 40-50° C. until the solids were dissolved. The resulting solution was filtered, and then distilled to 40-50. The mixture was subsequently cooled to 25-30° C. A solution of 1-(2-aminoethyl) pyrrolidine (2.8 Kg) in THF (2.1 L) was added. A solution of 5-Fluorooxindole (2.9 Kg) in THF (18.8 Kg) was also added. The mixture was then heated to 45-50° C. for 17 h. The mixture was cooled, filtered, washed with THF (28 Kg), and dried at 45-50° C. to afford 5.53 Kg (73%) of 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide. 1H NMR (DMSO-d6) δ 2.48 (d, J=8 Hz, 6H), 2.55 (m, 7H), 2.62 (t, J=8 Hz, 1H), 3.37 (m, 6H), 6.90 (m,1H), 7.00 (m, 1H), 7.57 (t, J=4 Hz, 1H), 7.80 (m, 2H).

Example 6 5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (7.0 g, 32.3 mmol), (2R)-1-amino-3-morpholin-4-ylpropan-2-ol (15.5 g, 96.9 mmol), 5-chlorooxindole (5.48 g, 32.6 mmol), triethylamine (14 ml), and THF (88 ml) were mixed and heated to 60° C. A red solution formed. After stirring for 16 h at 60° C., the yellow slurry was cooled to room temperature and filtered. The cake was washed with 2×50 ml of THF and dried overnight at 50° C. under house vacuum. 5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (4.36 g) was obtained in 29% yield.

Example 7 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (7.0 g, 32.3 mmol), (2S)-1-amino-3-morpholin-4-ylpropan-2-ol (15.0 g, 64.6 mmol), 5-fluorooxindole (4.93 g, 32.6 mmol), triethylamine (9.79 g, 96.9 mmol), and THF (88 ml) were mixed and heated to 60° C. After stirring for 24 h at 60° C., the mixture was cooled to rt and filtered. The cake was washed with 80 ml THF and dried overnight at 50° C. under house vacuum. A brown solid (23.2 g) was obtained. The solid was slurried in 350 ml water for 5 h at room temperature and filtered. The cake was washed with 100 ml water and dried at 50° C. under house vacuum overnight. 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (8.31 g) was obtained in 56% yield.

Example 8 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-morpholin-4-ylethyl)-1H-pyrrole-3-carboxamide

4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (5.0 g, 23.0 mmol), 4-(2-aminoethyl)morpholine (4.5 g, 34.6 mmol), 5-fluorooxindole (3.47 g, 23.0 mmol), and THF (80 ml) were mixed and heated to 65° C. After stirring for 24 h at 65° C., the mixture was cooled to room temperature and filtered. The cake was washed with 40 ml THF and dried overnight at 50° C. under house vacuum. 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-N-(2-morpholin-4-ylethyl)-1H-pyrrole-3-carboxamide (8.28 g) was obtained in 87% yield.

Example 9 (3Z)-3-({3,5-dimethyl-4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-5-fluoro-1,3-dihydro-2H-indol-2-one

4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (11.3 g, 51.9 mmol), 4-morpholinopiperidine (15.0 g, 88.2 mmol), 5-fluorooxindole (7.84 g, 51.9 mmol), and THF (126 ml) were mixed and heated to 66° C. After stirring for 68 h at 66° C., the mixture was cooled to room temperature and filtered. The cake was washed with 4×20 ml THF and dried overnight at 70° C. under house vacuum. (3Z)-3-({3,5-dimethyl-4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl]-1H-pyrrol-2-yl}methylene)-5-fluoro-1,3-dihydro-2H-indol-2-one 16.09 g was obtained in 68% yield.

Claims

1. A process for preparing an indolinone of the general formula (VI) wherein

R1, R2, R3, R4 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C-1-12 alkoxy, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, C6-12 alkaryl, C6-12 alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO2NR′R″, —SO3R′, —SR′, —NO2, —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH2)nCO2R′, and —CONR′R″;
each R5 is independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 alkoxy, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, C6-12 aryloxy, C6-12 alkaryl, C6-12 alkaryloxy, halogen, trihalomethyl, hydroxy, —S(O)R′, —SO2NR′R″, —SO3R′, —SR′, —NO2, —NR′R″, —OH, —CN, —C(O)R′, —OC(O)R′, —NHC(O)R′, —(CH2)nCO2R′, and —CONR′R″;
R6 is —NR8(CH2)mR9 or —NR10R11;
R8 is hydrogen or C1-12 alkyl;
R9 is selected from the group consisting of —NR10R11, —OH, —C(O)R12, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, —N+(O−)R10, and —NHC(O)R13;
R10 and R11 are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, and C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O; or R10 and R11 may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R10 and R11 are bound, provided that the heterocyclic group formed by R10 and R11 may optionally be substituted by R′;
R12 is selected from the group consisting of hydrogen, —OH, C1-12 alkoxy and C6-12 aryloxy;
R13 is selected from the group consisting of C1-12 alkyl, C1-12 haloalkyl, and C6-12 aralkyl;
R′ and R″ are independently selected from the group consisting of hydrogen, C1-12 alkyl, C1-12 cyanoalkyl, C5-12 cycloalkyl, C6-12 aryl, C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O, provided that the heterocyclic group may be partially unsaturated, but not aromatic, or in the group —NR′R″ the R′ and R″ substituents may be combined to form a five- or six-membered heterocyclic group optionally containing 1 to 3 atoms selected from N, O, or S in addition to the nitrogen atom to which R′ and R″ are bound;
J is selected from the group consisting of O, S, and NH;
one of K, L and M is C and the group —C(O)R6 is bound thereto, the others of the group of K, L and M are independently selected from the group consisting of CR5, CR52, N, NR5, O and S;
n is 0, 1 or 2;
m is 1, 2, 3, or 4; and
p is 0, 1 or 2;
the process comprising the steps of
reacting a compound of the general formula (III)
wherein R* is selected from the group consisting of —O—C(O)—C1-4 alkyl, —O—C(O)—O—(C1-4)alkyl, —O—C(O)—O-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms, —O—C(O)—O—CH2-phenyl, provided that the phenyl may optionally be substituted by 1 to 3 halogen atoms;
with a compound of general formula (IV)
and an amine of general formula (V)
HR6  (V)
to form the indolinone of the general formula (VI).

2. The process of claim 1, wherein is selected from the group consisting of

3. The process of claim 1, wherein

4. The process of claim 1, wherein R1 is hydrogen or C1— alkyl.

5. The process of claim 1, wherein R1 is hydrogen.

6. The process of claim 1, wherein R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C1-4 alkyl, —O—C1-4 alkyl, phenyl, —COOH, —CN, —C(O)CH3, —SO2NH2 and —SO2N(CH3)2.

7. The process of claim 1, wherein R2 is fluorine.

8. The process of claim 1, wherein R3 is selected from the group consisting of hydrogen, C1-4 alkyl, phenyl, —O—C1-4 alkyl and —COOH.

9. The process of claim 1, wherein R3 is hydrogen or C1-4 alkyl.

10. The process of claim 1, wherein R4 is hydrogen.

11. The process of claim 1, wherein R5 is selected from the group consisting of hydrogen, C1-4 alkyl, —C(O)—C1-4 alkyl, —C(O)phenyl, and phenyl.

12. The process of claim 1, wherein R5 is hydrogen, or C1-4 alkyl.

13. The process of claim 1, wherein R6 is —NR8(CH2)mR9, provided that one or two of the CH2 groups can optionally be substituted by —OH or halogen.

14. The process of claim 1, wherein R8 is hydrogen or C1-4 alkyl.

15. The process of claim 1, wherein m is 2 or 3.

16. The process of claim 1, wherein R9 is —NR10R11.

17. The process of claim 16, wherein R10 and R11 are hydrogen or C1-4 alkyl.

18. The process of claim 1, wherein R9 is a C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O.

19. The process of claim 18, wherein the heterocyclic group is a five- to seven-membered heterocyclic group bonded to the (CH2)m group via a nitrogen atom and optionally containing a further heteroatom selected from N, O, and S.

20. The process of claim 19, wherein the heterocyclic group is selected from the group consisting of

21. The process of claim 20, wherein the heterocyclic group is selected from the group consisting of

22. The process of claim 13, wherein R8 is hydrogen or C1-4 alkyl, m is 2 or 3 and R9 is —NR10R11.

23. The process of claim 22, wherein R10 and R11 are hydrogen or C1-4 alkyl.

24. The process of claim 13, wherein R9 is a C5-12 heterocyclic group containing 1 to 3 atoms selected from N, S or O.

25. The process of claim 24, wherein the heterocyclic group is a five- or six-membered heterocyclic group bonded to the (CH2)m group via a nitrogen atom and optionally containing a further heteroatom selected from N, O, and S.

26. The process of claim 25, wherein the heterocyclic group is selected from the group consisting of

27. The process of claim 26, wherein the heterocyclic group is selected from the group consisting of

28. The process of claim 1, wherein the compound of general formula (VI) is selected from the group consisting of: wherein X is selected from the group consisting of hydrogen, fluorine, chlorine and bromine.

29. The process of claim 28, wherein X is fluorine.

30. The process of claim 1, wherein the compound of general formula (VI) is selected from the group consisting of:

Patent History
Publication number: 20050171357
Type: Application
Filed: Mar 30, 2005
Publication Date: Aug 4, 2005
Applicant:
Inventors: Qingwu Jin (Kalamazoo, MI), Michael Mauragis (Scotts, MI), Paul May (Kalamazoo, MI)
Application Number: 11/095,433
Classifications
Current U.S. Class: 548/181.000; 548/229.000; 548/311.100; 548/465.000