Patent Description:
Intedanib is a combined inhibitor of the vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR) that is used as a selective antagonist of the protein thyrosine kinase receptor. It is designed for the treatment of idiopathic pulmonary fibrosis (IPF) and in combination with other active ingredients also for the treatment of certain types of cancer. A combination of intedanib with docetaxel is designed for the treatment of non-small cell lung cancer (NSCLC).

Preparation of intedanib of formula <NUM> is first described by the <CIT> (Scheme <NUM>).

In this synthesis, methyl oxindole-<NUM>-carboxylate is converted to methyl (E)-<NUM>-acetyl-<NUM>-(ethoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula Et-<NUM> with the yield of <NUM>%. The compound Et-<NUM> subsequently reacts with N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide and then, without isolation of the intermediate, with piperidine, producing intedanib of formula <NUM>. The yield of this reaction step is not mentioned.

A modification of the above mentioned preparation of intedanib <NUM> was published in <NPL> (Scheme <NUM>).

There, methyl oxindole-<NUM>-carboxylate is first converted to methyl <NUM>-acetyl-oxindole-<NUM>-carboxylate of formula <NUM> with the yield of <NUM>%. Intermediate <NUM> is then converted to methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> without the yield being mentioned. Compound <NUM> subsequently reacts with N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide and then, without isolation of the intermediate, with piperidine, producing intedanib of formula <NUM>. The yield of this reaction step is <NUM>%. A weak point of the above mentioned synthesis is a relatively low yield of compound <NUM> in the first step. A significant drawback of the above mentioned synthesis is the use of the toxic dimethyl formamide as the solvent and of the toxic piperidine as the base in the last step.

A preparation method of intedanib of formula <NUM> suitable for industrial production is described in the <CIT> (Scheme <NUM>).

Methyl oxindole-<NUM>-carboxylate is first converted to methyl <NUM>-chloroacetyl-oxindole-<NUM>-carboxylate with the yield of <NUM>%. It is followed by a reaction of this compound with trimethyl orthobenzoate, producing methyl (E)-<NUM>-chloroacetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate with the yield of <NUM>%. Then, the chloroacetyl group is removed, producing methyl (E)-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate with the yield of <NUM>% and, finally, a reaction of this compound with N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide provides intedanib of formula <NUM> with the yield of <NUM>%. A weak point of the above mentioned synthesis is the use of the expensive chloroacetanhydride as the acylating agent in the first step. A considerable disadvantage of the above mentioned synthesis is the formation of the toxic methyl chloroacetate as a side product in the third step.

IPCOM000241006D (XP009191829, <NPL>) relates to a process for the preparation of indolinone compound.

<NPL> relates to design, synthesis and biological evaluation of deuterated nintedanib for improving pharmacokinetic properties. <CIT> relates to intedanib salts and solid state forms thereof.

The invention provides a method for preparing methyl (Z)-<NUM>-[[<NUM>-[methyl[<NUM>-(<NUM>-methyl-<NUM>-piperazinyl)acetyl]amino] phenyl]amino]phenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM>, comprising:
<CHM>
reacting (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> with N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide and subsequently reacting with a suitable base in a suitable solvent, characterized in that the reaction is carried out without isolation of the intermediate and the base is selected from an alkali hydroxide, potassium tert-butoxide and sodium ethoxide, and in that the solvent is selected from C1 to C4 aliphatic alcohols, and their mixtures.

Also provided is a method for preparing methyl (Z)-<NUM>-[[<NUM>-[methyl[<NUM>-(<NUM>-methyl-<NUM>-piperazinyl) acetyl]amino]phenyl]amino]phenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM>, comprising:
<CHM>.

Also provided is a method for preparing methyl (Z)-<NUM>-[[<NUM>-[methyl[<NUM>-(<NUM>-methyl-<NUM>-piperazinyl) acetyl]amino]phenyl]amino]phenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM>, characterized in that it comprises:
<CHM>.

In embodiments of the above method the alkali hydroxide is potassium hydroxide and the alkali alkoxide is potassium tert-butoxide or sodium ethoxide.

The invention provides a method for preparing intedanib of formula <NUM> from methyl oxindole-<NUM>-carboxylate, wherein methyl oxindole-<NUM>-carboxylate is first converted to methyl <NUM>-acetyl-oxindole-<NUM>-carboxylate of formula <NUM>, methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> is prepared from compound <NUM>, and, finally, compound <NUM> is converted to intedanib of formula <NUM> (Scheme <NUM>).

The preparation of methyl <NUM>-acetyl-oxindole-<NUM>-carboxylate of formula <NUM> is carried out by the treatment with acetic anhydride of methyl oxindole-<NUM>-carboxylate. A high yield of methyl <NUM>-acetyl-oxindole-<NUM>-carboxylate of formula <NUM> has been observed (<NUM>%).

The preparation of compound <NUM> is carried out by the treatment with acetic anhydride and trimethyl orthobenzoate of methyl <NUM>-acetyl-oxindole-<NUM>-carboxylate of formula <NUM>. A high yield of methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> has been observed (<NUM> to <NUM>%).

The preparation of intedanib of formula <NUM> is carried out by the treatment with N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide of methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> and subsequent reaction with a suitable base in a suitable solvent without isolation of the intermediate.

It has been observed that the reaction provides the desired product of formula <NUM> in a surprisingly high yield (<NUM> to <NUM>%) and chemical purity (HPLC purity <NUM> to <NUM>%).

Bases that are suitable for the reaction are alkali hydroxides and alkali alkoxides. Advantageously, potassium hydroxide, potassium tert-butoxide or sodium ethoxide can be used. Solvents that are suitable for this reaction are C1 to C4 aliphatic alcohols, ethers, cyclohexane, toluene, xylene and their mixtures. Preferably, a solvent from the group of methanol, ethanol, tetrahydrofuran, tert-butyl methyl ether, dioxane, <NUM>,<NUM>-dimethoxyethane, bis(<NUM>-methoxyethyl)ether and their mixtures can be used.

A suitable temperature for carrying out the reaction is <NUM> to <NUM>.

An advantage of the process of synthesis of intedanib in accordance with the present invention is a high yield of the reaction and high chemical purity as compared to the preparation according to <NPL> (mentioning the yield of <NUM>%; without mentioning the purity of intedanib). A considerable weak point of the synthesis according to <NPL>, is the use of the toxic dimethyl formamide as the solvent and of the toxic piperidine as the base in the last step. In the process of synthesis in accordance with the present invention, the technologically more suitable methanol or ethanol is preferably used as the solvent and, in the last synthetic step, readily available and environment-friendly bases (alkali hydroxides, alkali alkoxides) are used instead of the toxic piperidine. Compared to <CIT>, the process of synthesis of intedanib in accordance with the present invention is one step shorter, while, instead of the toxic methyl chloroacetate, it provides the non-toxic methyl acetate as a side product. The synthesis is also convenient from the economic point of view as it avoids the use of the expensive chloroacetanhydride as the acylating agent.

The HPLC analyses of individual batches of intedanib of formula <NUM> were conducted with UV detection at <NUM>; column Acquity UPLC BEH C18 <NUM>; column length <NUM>; inner diameter of the column <NUM>; temperature <NUM>; flow rate <NUM>/min; mobile phase A: phosphate buffer (<NUM> (NH<NUM>)<NUM>HPO<NUM> dissolved in <NUM> of water, adjusted to pH <NUM> ± <NUM> with <NUM>% ammonia); mobile phase B: acetonitrile; gradient elution: <NUM>% A + <NUM>% B at the beginning and at <NUM>, <NUM>% A + <NUM>% B at <NUM>, <NUM>% A + <NUM>% B at <NUM> and <NUM>% A + <NUM>% B at <NUM> and <NUM>. The typical retention time of intedanib <NUM> under these conditions was <NUM>.

The starting methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate and N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide were prepared according to <NPL>).

A mixture of methyl oxindole-<NUM>-carboxylate (<NUM>) and acetanhydride (<NUM>) was stirred at the bath temperature of <NUM>; a clear red solution was produced within <NUM>. The reaction mixture was stirred at <NUM> for <NUM>, then left to stand at <NUM> for <NUM> and the crystallization of the product was completed in <NUM> at <NUM>. The product was filtered off, washed with petroleum ether and finally with glacial methanol. The yield was <NUM> (<NUM>%) of reddish crystals.

A mixture of methyl <NUM>-acetyl-oxindole-<NUM>-carboxylate of formula <NUM> (<NUM>), toluene (<NUM>) and acetanhydride (<NUM>) was stirred in a flask equipped with a small Vigreux column and a distillation adapter at <NUM> for <NUM>, producing a turbid orange-red solution. At the temperature of <NUM>, trimethyl orthobenzoate (<NUM>) was added dropwise to the reaction mixture, followed by toluene (<NUM>), by means of a syringe fitted with a needle reaching into the flask. The bath temperature was slowly increased to slowly distil the produced methyl acetate. After distilling for <NUM>, the bath temperature was <NUM> and the distillate volume was <NUM>.

The reaction mixture was left to stand at <NUM> for <NUM> and the crystallization of the product was completed in <NUM> at <NUM>. The product was filtered off, washed with toluene and finally with a mixture of toluene and ethyl acetate (<NUM> : <NUM>). The yield was <NUM> (<NUM>%) of a beige powder.

A mixture of methyl <NUM>-acetyl-oxindole-<NUM>-carboxylate of formula <NUM> (<NUM>), toluene (<NUM>) and acetanhydride (<NUM>) was stirred in a flask equipped with a small Vigreux column and a distillation adapter at <NUM> for <NUM>, producing a turbid orange-red solution. At the temperature of <NUM>, trimethyl orthobenzoate (<NUM>) was added dropwise to the reaction mixture, followed by toluene (<NUM>), by means of a syringe fitted with a needle reaching into the flask. The bath temperature was slowly increased to slowly distil the produced methyl acetate. After distilling for <NUM>, the bath temperature was <NUM> and the distillate volume was <NUM>. The reaction mixture was left to stand at <NUM> for <NUM> and the crystallization of the product was completed in <NUM> at <NUM>. The product was filtered off, washed with toluene and finally with a mixture of toluene and ethyl acetate (<NUM> : <NUM>). The yield was <NUM> (<NUM>%) of a beige powder.

A mixture of methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> (<NUM>), N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide (<NUM>) and methanol (<NUM>) was stirred under reflux for <NUM>. The bath temperature was reduced to <NUM> and, at this temperature, a solution of KOH (containing <NUM>% of KOH; <NUM>) in methanol (<NUM>) was added dropwise. After adding of <NUM> of KOH solution the addition was stopped. The reaction mixture was stirred at <NUM> to <NUM> for <NUM>, then it was left to stand at <NUM> for <NUM> and the crystallization of the product was completed in <NUM> at <NUM>. The product was filtered off, washed with glacial methanol twice and air-dried. The yield was <NUM> (<NUM>%) of a yellow powder. HPLC purity <NUM>%.

A mixture of methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> (<NUM>), N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide (<NUM>) and methanol (<NUM>) was stirred under reflux for <NUM>. The bath temperature was reduced to <NUM> and, at this temperature, a solution of KOH (containing <NUM>% of KOH; <NUM>) in methanol (<NUM>) was added dropwise. The reaction mixture was stirred at <NUM> to <NUM> for <NUM>, then it was left to stand at <NUM> for <NUM> and the crystallization of the product was completed in <NUM> at <NUM>. The product was filtered off, washed with glacial methanol twice and air-dried. The yield was <NUM> (<NUM>%) of a yellow powder. HPLC purity <NUM>%.

A mixture of methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> (<NUM>), N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide (<NUM>) and methanol (<NUM>,<NUM>) was stirred under reflux conditions for <NUM>. The bath temperature was reduced to <NUM> and at this temperature a solution of KOtBu (<NUM>) in methanol (<NUM>) was added dropwise. After adding of <NUM> of KOtBu solution the addition was stopped. The reaction mixture was stirred at <NUM> to <NUM> for <NUM>, then it was left to stand at <NUM> for <NUM> and the crystallization of the product was completed in <NUM> at <NUM>. The product was filtered off, washed with glacial methanol twice and air-dried. The yield was <NUM> (<NUM>%) of a yellow powder. HPLC purity <NUM>%.

Claim 1:
A method for preparing methyl (Z)-<NUM>-[[<NUM>-[methyl[<NUM>-(<NUM>-methyl-<NUM>-piperazinyl)acetyl]amino] phenyl]amino]phenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM>, comprising:
<CHM>
reacting methyl (E)-<NUM>-acetyl-<NUM>-(methoxyphenylmethylene)-oxindole-<NUM>-carboxylate of formula <NUM> with N-(<NUM>-aminophenyl)-N,<NUM>-dimethyl-<NUM>-piperazine acetamide and subsequently reacting with a suitable base in a suitable solvent, characterized in that the reaction is carried out without isolation of the intermediate and the base is selected from an alkali hydroxide, potassium tert-butoxide and sodium ethoxide, and in that the solvent is selected from C1 to C4 aliphatic alcohols, and their mixtures.