KR101059275B1 - Process for preparing improved 4- [2- (di-ene-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one - Google Patents

Abstract

The present invention relates to a novel preparation method and a novel intermediate for preparing 4- [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one, commonly known as ropinirole. It is about. The present invention provides an economical and easy method for producing rofinirol, which is relatively easy in the whole process without requiring a pressurized reaction facility or a dangerous process such as a hydrogenation reaction, and obtains a target compound in high yield and high purity.

Ropinirole, Dopamine, Parkinson's Disease

Description

An improved process for the preparation of 4- [2- (di-en-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one Di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one}

The present invention relates to a novel preparation method and a novel intermediate for the preparation of lopinirol, ie 4- [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one will be.

Ropinirole is a dopamine agonist represented by the following formula (i) and has a selective affinity for dopamine D2 like receptors, and has little or no affinity for brain receptors that are not activated with dopamine. Ropinillol is known in the art to be a useful drug for the treatment of Parkinson's disease.

    Formula i

Ropineniol was first reported by US Pat. No. 4,452,808. Ropineniol can be prepared, for example, according to the method described in US Pat. No. 4,452,808 or a modified method thereof. US Pat. No. 4,452,808 discloses 4-aminoalkyl-2 (3H) by two different methods, starting from 4-aminoalkyl-7-hydroxy-2 (3H) -indole or 2-methyl-3-nitrophenylacetic acid. It describes the preparation of indoleone. The manufacturing method starting from 2-methyl-3-nitrophenylacetic acid which can be more industrially implemented among the manufacturing methods in the said patent is shown by following Scheme 1.

 Scheme 1

In the above method, 2-methyl-3-nitrophenyl-N, N-di-n-propylacetamide (III) is prepared by subjecting 2-methyl-3-nitrophenylacetic acid (II) to chlorination and amine addition. do. The intermediate (III) produced is reduced to amide with borane / tetrahydrofuran to produce 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine (IV). The process further comprises treating the resulting intermediate (IV) with sodium metal, ethanol anhydride, diethyl oxalate, ethyl-6- (2-di-n-propylaminoethyl) -2-nitrophenyl pyruvate (V). Conversion to 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid hydrochloride (VI) by treatment with sodium hydroxide, hydrogen peroxide and hydrochloric acid. However, the known technique should be used for the reaction of sodium metal with a high explosive risk in the reaction in the preparation of the compound of formula (V), recovery of the starting material (IV) is not proceeded because the yield is low, that is, the reaction proceeds again Industrial manufacturing methods, such as recycling, are not appropriate. In addition, when recovering the starting material (IV) in which the reaction did not proceed and recycling it a total of 3 times to obtain ethyl-6- (2-di-n-propylaminoethyl) -2-nitrophenyl pyruvate (V) 3 The total recycle yield was only 43.1%, and the preparation of 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid hydrochloride (VI), which proceeds sequentially, also yielded 66.0% in two steps. The yield is 28.4%, which is very low from an industrial point of view. As described above, the above production method is very economical due to the low yield and is not easy on an industrial scale such as using sodium metal having a high explosive risk.

In addition, the resulting 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid hydrochloride (VI) was reduced using palladium / carbon as a hydrogenation catalyst to give rofinirol in a yield of 77.5%. To obtain hydrochloride (I), which also requires a separate pressurization reaction facility for the hydrogen reaction and is an uneconomical method of using an expensive palladium catalyst. And the use of heavy metal palladium, which is harmful to the human body at the final stage and not easy to remove completely, is not suitable for industrial production at the final stage of manufacture of pharmaceuticals.

Alternatively, there are a total of eight improved processes for preparing rofinirol, starting from Isochroman, as described in WO 91/16306, to obtain the final product, rofinirol hydrochloride, but with very expensive isochrom. It is a manufacturing method that requires multiple steps using bays and is not economical to apply to production on an industrial scale.

The inventors have repeatedly carried out examples of patents relating to the synthesis of US Pat. No. 4,452,808 and known ropinirole, and thus, the methods of preparing ropinirole in the prior art have very low yields and are flammable in the preparation of intermediates. It has been found to be difficult to manufacture, such as the use of dangerous borane / tetrahydrofuran and highly explosive sodium metal. In addition, the method of preparing rofinirol through the final hydrogen reaction requires a separate pressurization equipment and is not suitable for industrial mass production such as the use of an expensive heavy metal palladium catalyst, and also removes the heavy metal palladium used in the final synthesis step. It was confirmed that it is not easy.

      Accordingly, in the present invention, in order to solve the problems of the conventional method such as the low yield and the dangerous production method that is not easy to industrial production, it is easy to apply when manufacturing on an industrial scale, that is 4- [2 A novel production method and a novel intermediate for preparing-(di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one have been developed to solve the conventional problems.

      The production process according to the present invention provides the preparation of ropineni from 2-methyl-3-nitrophenyl-N, N-di-n-propylacetamide (III) which is used as an intermediate of ropinirole production in the known art. To provide economical and easy technology.

      The present invention is directed to reducing 2-methyl-3-nitrophenyl-N, N-di-n-propylacetamide (III) with an alkali metal borohydride in the presence of iodine, a novel process for preparing 2- A method for preparing methyl-3-nitrophenylethyl-N, N-di-n-propylamine (IV) in high yield. In contrast, Borane / Tetrahydrofuran, used in the preparation of 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine (IV) in US Pat. No. 4,452,808, is highly flammable for industrial use. This is a high and dangerous handling method. Accordingly, the present invention improves these disadvantages and proceeds with a reduction reaction with an alkali metal borohydride in the presence of iodine to facilitate the industrial application and to minimize the risk of the production method on an industrial scale. To provide.

      In addition, 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine (IV) was reacted with paraformaldehyde in the presence of a catalytic amount of base to form a novel intermediate, hydroxyethyl derivative, 2 of lopinirol. -(2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol (VII) or a salt compound thereof is conveniently obtained in high yield.

     A novel intermediate, 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol (VII) or a salt compound thereof, is subjected to oxidation using sodium nitrite under organic acid solvent conditions such as trifluoroacetic acid. Is converted to high yield with a salt compound, such as 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid or its hydrochloride (VI), which is the main intermediate of ropinirole. In the present invention, 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine (IV) is 2-nitro-6- (2-di-n) in a yield of about 70% over a total of two steps. -Propylaminoethyl) phenylacetic acid hydrochloride (VI) is prepared, which is known from US Pat. No. 4,452,808 to 2-methyl-3-nitrophenylethyl-N, N-di-n-propyl amine (IV). Recirculation three times yielded ethyl-6- (2-di-n-propylaminoethyl) -2-nitrophenyl pyruvate (V) in a yield of 43.1%, followed by 2-nitro-6- (2-di- n-propylaminoethyl) phenylacetic acid hydrochloride (VI) was prepared in a yield of 66.1%, yielding a surprisingly improved yield compared to the known method with a total yield of 28.5% in two steps. In addition, the preparation method using a novel intermediate of the present invention, hydroxyethyl derivative, 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol (VII) or a salt compound thereof is described in US Pat. No. 4,452,808 It is an improved novel manufacturing method that does not use the high explosive risk sodium metal used in the arc.

     Further, in the present invention, a salt compound such as 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid or its hydrochloride (VI) is reduced by using iron under acidic conditions to prepare rofinirol. do. Rofinirol is purified to a hydrochloride compound such as hydrochloride through addition of an acid such as hydrochloric acid. In the present invention, in the known US Patent No. 4,452,808, without using palladium / carbon, which is the hydrogenation catalyst used in the above reaction, the reductive cyclization reaction was performed under mild conditions using inexpensive iron. It is a new manufacturing method that is not used for roll production, which secures economics in the final manufacturing process of rofinirol and remarkably improves the problems due to the use of heavy metals. A representative process for preparing ropinirole hydrochloride according to the present invention is disclosed in Scheme 2 below.

Schematic 2

The present invention provides an improved process for producing ropinirole with industrially easy to produce, non-hazardous, stable and improved yields and high purity.

First, the novel ropinirole manufacturing method according to the present invention was surprisingly improved in yield using a novel intermediate without using a known low yielding ropinirole intermediate, and the production method is easily known. It has the effect of surprisingly improving the low yield and the manufacturing process which is not easy to apply industrially.

In addition, the novel production method according to the present invention improves the reductive cyclization reaction through a hydrogen reaction required in the known production method to a reaction using low-cost iron, does not require a separate pressurization equipment, and also expensive palladium hydrogenation There is an effect of surprisingly improving the economics of the production of rofinirol because no catalyst is used. In addition, by using iron instead of heavy metal that is harmful to the human body, which is difficult to remove, it provides an environmentally friendly manufacturing method.

In addition, the present invention provides the effect of easily obtaining a high-purity rofinirol by limiting the production of rofinirol flexible material which is not easy to remove.

The present invention provides a novel preparation method and a novel intermediate for the preparation of lopinirol, ie 4- [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one. do.

The present invention provides 2-methyl-3-nitro by reducing 2-methyl-3-nitrophenyl-N, N-di-n-propylacetamide (III) in the presence of iodine with an alkali metal borohydride. Preparing phenylethyl-N, N-di-n-propylamine (IV). The boron hydride alkali metal used in the reaction step is sodium borohydride, potassium borohydride, lithium borohydride, or the like, preferably sodium borohydride. In the reaction step, a solvent such as tetrahydrofuran may be used.

The present invention reacts 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine (IV) with paraformaldehyde in the presence of a catalytic amount of base to form a novel hydroxyethyl derivative, 2- (2- Obtaining (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol (VII) or a salt compound thereof. Use a suitable solvent and base for a smooth reaction. Suitable solvents in this reaction step are dimethyl sulfoxide, N, N-dimethylformamide and the like, preferably dimethyl sulfoxide. The base used in the reaction step may be selected from sodium methoxide (alkali metal alkoxide), sodium ethoxide, potassium tert-butoxide or sodium hydroxide (alkali metal hydroxide), potassium hydroxide and the like. . Preferred bases are sodium methoxide, potassium hydroxide and most preferably sodium methoxide. 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol (VII) prepared by the present reaction was easily purified through the crystallization process by chloride by using an organic acid such as hydrochloric acid. It is possible.

In the present invention, sodium nitrite is dissolved in 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol (VII), which is a hydroxyethyl derivative, or a salt compound thereof under organic acid solvent conditions such as trifluoroacetic acid. It proceeds the oxidation reaction using to prepare a salt compound, such as 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid or its hydrochloride (VI). The solvent used in the reaction step may be trifluoroacetic acid, acetic acid or a mixture thereof. Most preferred solvent is trifluoroacetic acid.

In the present invention, a salt compound such as 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid or its hydrochloride (VI) is reduced with iron under acidic conditions to reduce ropinirole, that is, 4- Preparing [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one. The resulting rofinirol is chlorinated in the presence of an acid such as hydrochloric acid and purified into a hydrochloride compound such as ropinol hydrochloride (I). Acids used in the reaction step are hydrochloric acid, acetic acid, formic acid, sulfuric acid and the like, and preferred acids are hydrochloric acid, acetic acid and most preferably hydrochloric acid. The solvent used in the reaction step is a lower aliphatic alcohol, such as methanol, ethanol, propanol, isopropanol, n-butanol, iso-butanol, t-butanol or a mixture thereof. Preferred solvents are methanol, ethanol, isopropanol and most preferred solvents are ethanol.

Hereinafter, the present invention will be described in more detail with reference to Examples.

The following examples illustrate the novel process for preparing ropinillol and novel intermediates in the present invention, but do not limit the scope of the present invention.

Example 1 Preparation of 2-Methyl-3-nitrophenylethyl-N, N-di-n-propylamine (IV)

200 ml of tetrahydrofuran is added to 50.0 g of 2-methyl-3-nitrophenyl-N, N-di-n-propylacetamide, and 16.3 g of sodium borohydride is gradually added while stirring. 47.9 g of iodine dissolved in 200 ml of tetrahydrofuran are added slowly with the temperature of the reaction solution at 40 ° C. or lower and stirred under reflux until the reaction is complete. After the reaction is completed, the reaction solution is cooled, and then 50 ml of methanol is slowly added, and the reaction solution is concentrated under reduced pressure. 200 ml of 3N hydrochloric acid solution was added to the reaction solution, and the mixture was stirred under reflux at 85 to 95 ° C for 1 hour. To separate. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 38.9 g of 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine as a yellow oil. (Yield: 82% ) ¹ H-NMR (400 MHz, CDCl ₃ ): 7.58 (1H, d, J = 8.0 Hz), 7.37 (1H, d, J = 7.6 Hz), 7.24 (1H, t, J = 7.8 Hz), 2.84 ( 2H, m) 2.63 (2H, m), 2.46 (4H, m), 2.42 (3H, s), 1.47 (4H, m), 0.91 (6H, t, J = 7.2 Hz)

Example 2 Preparation of 2- (2- (2-Di-propylamino-ethyl) -6-nitrophenyl) ethanol (VII)

42.0 g of 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine and 5.3 g of paraformaldehyde were added to 126 ml of dimethyl sulfoxide while stirring, and 4.0 g of sodium methoxide was added thereto. Next, the reaction is carried out by stirring at room temperature, and when the reaction is completed, a constant is added to the reaction solution, 420 ml of acetic acid is added to the reaction solution, and the organic layer is separated after stirring. The separated organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain 40.2 g of 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol as a brown oil. Yield: 86%) ¹ H-NMR (400 MHz, CDCl ₃ ): 7.60 (1H, d, J = 9.2 Hz), 7.44 (1H, d, J = 8.8 Hz), 7.29 (1H, t, J = 7.8 Hz ), 3.84 (2H, t, J = 6.8 Hz), 3.11 (4H, m), 2.87 (2H, t, J = 7.8 Hz), 2.68 (4H, m), 1.60 (4H, m), 0.93 (6H , t, J = 7.4 Hz)

Example 3: Preparation of 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid hydrochloride (VI)

402 mL of trifluoroacetic acid was added to 40.2 g of 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol, and then cooled to -5 to 0 ° C, followed by 18.8 g of Sodium nitrite is added and stirred at -5 to 0 DEG C to send the reaction, and when the reaction is completed, the reaction solution is concentrated under reduced pressure. 1443 ml of 1N sodium hydroxide solution was added to the reaction solution, 50 ml of dichloromethane was added thereto, followed by stirring. Then, the organic layer was removed. 96 ml of 6N hydrochloric acid solution was slowly added to the aqueous layer. The organic layer was separated and the organic layer was concentrated under reduced pressure to give 38.1 g of 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid hydrochloride as a solid. (Yield: 81%) ¹ H-NMR (400 MHz , D ₂ 0): 7.99 (1H, d, J = 9.2 Hz), 7.71 (1H, d, J = 8.8 Hz), 7.57 (1H, t, J = 8.0 Hz), 4.04 (2H, s), 3.39 (2H, m), 3.23 (6H, m), 1.77 (4H, m), 1.00 (6H, t, J = 7.4 Hz)

Example 4 Preparation of 4- [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one hydrochloride (rofiniro hydrochloride) (I)

810 ml of ethanol was added to 40.5 g of 2-nitro-6- (2-di-n-propylaminoethyl) phenylacetic acid hydrochloride, 25.5 ml of hydrochloric acid and 16.4 g of iron were added, and the mixture was stirred under reflux to give a reaction. Upon completion of this, the reaction solution is filtered under reduced pressure and the filtrate is concentrated under reduced pressure. 324 ml of 2N aqueous sodium hydroxide solution was slowly added to the reaction mixture, followed by stirring with 810 ml of ethyl acetate, followed by stirring. The organic layer was separated, and concentrated under reduced pressure, 4- [2- (di-n-propylamino) ethyl]- Obtain 1,3-dihydro-2H-indol-2-one. 405.0 mL of isopropyl alcohol was added to the obtained 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one, 10.2 mL of hydrochloric acid was added thereto, followed by stirring at room temperature. Cool to ˜10 ° C. to filter the crystals. 4- [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one hydrochloride as a yellowish white crystalline solid, dried at 65 ° C. or lower for at least 6 hours. (Ropinyrrole hydrochloride) is obtained.

Purity by HPLC is 99.0% or more. (Yield: 84%) ¹ H-NMR (400 MHz, DMSO- d ₆ ): 10.48 (1H, s), 7.14 (1H, t, J = 7.8 Hz), 6.86 ( 1H, d, J = 7.6 Hz, 6.74 (1H, d, J = 7.6 Hz), 3.56 (2H, s), 3.19 (2H, m), 3.02 (6H, m), 1.73 (4H, m), 0.94 (6H, t, J = 7.4 Hz)

Claims (8)

delete 2-methyl-3-nitrophenylethyl-N, N-di-n-propylamine is reacted with paraformaldehyde to give 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol or Method for preparing the salt compound thereof. 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol or its salt compound was subjected to oxidation with sodium nitrite in trifluoroacetic acid solvent to give 2-nitro-6- (2- Di-n-propylaminoethyl) phenylacetic acid or a salt compound thereof. delete 2- (2- (2-di-propylamino-ethyl) -6-nitrophenyl) ethanol represented by the following formula (VII) or a salt compound thereof     Formula VII

delete The process according to claim 2, wherein the reaction is carried out in the presence of a base selected from sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydroxide or potassium hydroxide. delete