FI114094B - Process for preparing substituted indolone derivatives - Google Patents

Description

114094

The present invention relates to an improved process for the preparation of substituted indolone derivatives. Such compounds are described in EP-113 964-B as useful in cardiovascular therapy and in EP 299 602-A as agents useful in the treatment of Parkinson's disease.

Methods for preparing substituted indolone derivatives are described in the art, e.g., in EP-113 964-B, EP-300 614-A1 and WO 91/16306.

It has now been found that substituted indolone derivatives can be prepared in high yields and pure by reducing the corresponding isatin precursor compounds. The process of high yields and purities, with a number of reaction steps, usually results in a more efficient and less expensive route to the final product.

The present invention is primarily directed to a process for the preparation of a compound of structure (I) or a pharmaceutically acceptable salt thereof: i:: i: (<™, NR 2!

: R

*: · 25 wherein: "'is 1-3; *, each R is independently hydrogen or C 1-4 alkyl; and R 1 is hydrogen, hydroxy or C 1-4 alkoxy; , h..1 wherein the compound of structure (II) is reduced in the presence of Raney nickel: 114094 2 (CH CHR NR, fr ~ f fννΛ (II)

I, H

R

wherein n, R and R 1 are as defined for structure (I), and optionally subsequently 5 - converting the compound of structure (I) into another compound of structure (I) - forming a salt.

The reduction is conveniently carried out using Raney nickel in a suitable solvent, for example C 1-4 alcohol, such as isopropanol, at a temperature between ambient temperature and the reflux temperature of the solvent used.

Preferably, Raney nickel is used in an excess relative to the compound of formula (II) and the mixture is heated under reflux in isopropanol as solvent.

Suitably one of R 2 is hydrogen and the other is hydrogen or C 1-4 alkyl; preferably both R groups are C 1-4 alkyl, especially n-propyl.

Suitably, n is 1 to 3; preferably n is 2.

Suitably, R 1 is hydrogen, hydroxy or C 1-4 alkoxy; 20 there methoxy; Preferably R 1 is hydrogen.

Preferred salts of the compounds of formula (I) are those described in EP-113,694-B, particularly preferred are acid addition salts such as the hydrochloride salt.

The above process is particularly useful for the preparation of compound 25 4- [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one hydrochloride salt (INN: ropinirole). *. a compound useful in the treatment of Parkinson's disease (EP 299 602 -A).

Certain compounds of structure (I) may be modified 30 therefore as compounds of structure (I). In particular, the structure (I)

·: *; compounds wherein both R groups are hydrogen or the other R is

is hydrogen and one is C 1-4 alkyl, can be converted to compounds of structure (I) 114094 3, wherein both R groups are C 1-4 alkyl, by conventional methods known in the art such as reductive alkylation with aldehydes, e.g. sodium cyanoborohydride or hydrogen sulfide as a reducing agent. Such methods are particularly useful in the preparation of 4- [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indol-2-one hydrochloride salt as described in the following examples.

Compounds of structure (II) may be prepared using standard procedures well known to those skilled in the art. For example, compounds of formula (II) may be prepared as shown in the following scheme: (CH 1) .x w · *

1NCS Ai-A

SfSm, El, N A °

Rl R

(V) 1. NBS

2 H2O. MeOH

• V

(CH 3) n N (R) 2 (CH 2) b X

: * ·;. · AA - A ° (RfcNH A-

;;; ·: i h 1 'H

(ID (III))

In the preceding scheme, R, R 1 and n are as defined for compounds of formula · · /: (I) and X is a leaving group or a group N (R) 2 wherein R is as defined in formula (I). Preferred leaving groups X are halogen, especially bromine and oxygen containing leaving groups such as * * p-toluenesulfonyloxy. It should be noted that when X is 114094 4 N (R) 2 / the compounds of formula (III) obtained are compounds of formula (II).

The isatin compounds of formula (III) (wherein X is a leaving group) may, using the methods described above, be reduced to indolones of formula (VI):

(Chax

VsAo (VI)

Il H R

wherein n and R 1 are as depicted for compounds of formula (III) and X is a leaving group. The resulting compounds of formula (VI) may then be reacted with an amine (R) 2 NH to give compounds of formula (I). Using the primary amine RNH2 where R is C 1-4 alkyl gives a compound of formula (I) wherein one group R is hydrogen and the other is C 1-4 alkyl. If desired, these compounds can then be subjected to reductive alkylation as described above: ·; ty, by adding another C 1-4 alkyl group. In particular, one can; employs a process for the preparation of compounds (I) wherein each group R is a different C 1-4 alkyl group.

Compounds of formula (VI) wherein X is halogen may be! is also treated with sodium azide followed by reduction of the resulting azidoindolone to give compounds of formula (I) wherein both R groups are hydrogen.

Compounds of formula (V) may be prepared using standard methods. For example, compounds of formula (V) wherein X is p-toluenesulfonyloxy may be prepared by treating the corresponding alcohol with p-toluenesulfonyl

• <· I

, ···, dyl and triethylamine.

• »

The following examples illustrate the present invention. Everybody! * ·· 30 temperatures are in degrees Celsius.

s 114094

Example 1 4- (2-Dipropylaminoethyl) -1,3-dihydro-2H-indol-2-one hydrochloride salt

A suspension of 2.74 g (10.0 mmol) of 4- (2-di-5 n-propylamino) ethylisatin in 70 mL of isopropanol was treated with 16.0 g (wet weight) Raney nickel / active catalyst (50% aqueous slurry, activity class ca. W-2). The resulting suspension was refluxed with stirring for 18 hours. After cooling, the reaction mixture of the ambient patient was washed with suction through a pad of silica using 100 mL more isopropanol to wash the filter cake. The isopropanol was evaporated to a volume of approx.

30 ml, followed by acidification with saturated gaseous HCl to give a cloudy solution. The mixture was stirred under cooling at 0 ° C for several hours before collecting the product by filtration. The product was dried under vacuum at 40 ° C to constant weight to give 2.40 g of the title compound, m.p. 228-229.5 ° C.

Example 2 4- (2-Dipropylaminoethyl) -1,3-dihydro-2H-indole-2-. one hydrochloride salt

A mixture of 4- (2-propylaminoethyl) -1,3-dihydro-2H-indol-2-one (30.0 g, 0.118 mol) in 10% platinum; Na / Carbon (3.0 g), propionaldehyde (65.8 g, 1.18 mol), 25, distilled water (300 mL) and methanol were charged into a Buchi? reactor and hydrogenated at 60 psi 75 minutes. The solutions were filtered through diatomaceous earth and the methanol and excess propionaldehyde removed in vacuo. The remaining aqueous phase was washed with dichloromethane (150 mL and, ···, 30 75 mL). The aqueous phase was basified with sodium hydroxide (6.0 g, 0.15 mol) in water (40 mL) and the product was extracted into dichloromethane (100 mL and 2 x 50 mL). The organic extracts were dried (MgSO 4) and concentrated to an oil in vacuo.

*. ·. The oil was recovered in isopropanol (315 mL) at 80 ° C and? 35 Hydrochloric acid (SG 1.18, 12 mL, 0.14 mol) was added.

The mixture was allowed to cool to 40 ° C and cooled at 040 ° C for 15 minutes. The resulting solid was filtered, washed with a small amount of isopropanol and then dried at 80 ° C for 24 hours to give the title compound as a light yellow solid (31.3 g, 90%).

Example 3 4- (2-Dipropylaminoethyl) -1,3-dihydro-2H-indol-2-one 4- (2-bromoethyl) -1,3-dihydro-2H-indol-2-one (0.12 mol) ) was added to propylamine (7 volumes) and the resulting mixture was refluxed under nitrogen for one hour. Excess propylamine was then removed by distillation, isopropanol was added, and isopropanol was removed by distillation in vacuo. The resulting product was treated with propionaldehyde (2 eq.) Followed by sodium cyanoborohydride (1.3 eq.) In methanol (15 volumes). After 1 hour, an additional portion of propionaldehyde (1 eq) and sodium cyanoborohydride (0.3 eq) was added to quench the reaction. The mixture was then acidified with concentrated HCl and methanol and excess propionaldehyde were removed in vacuo. The crude product was dissolved in water: methanol (4: 1, 15 vol) and extracted with ethyl acetate. The aqueous layer was basified to pH 9 with potassium hydroxide and the product was extracted into ethyl acetate. Solvent; was replaced with isopropanol, cooled to 0 ° C, and triturated in ethyl acetate to give the 4- (2-aminoethyl) -1,3-::: dihydro-2H-indol-2-one hydrochloride salt.

Example 4 4- (2-Dipropylaminoethyl) -1,3-dihydro-2H-indol-2-one hydrochloride salt,? · 30, 30 A. 4- (2-Azidoethyl) -1,3-dihydro-2H-indol-2 -one '1' 4- (2'-bromoethyl) -1,3-dihydro-2H-indol-2-one, (12.02 g, 50 mmol), degassed water with nitrogen, (100ml), sodium azide (16.26g, 250mmol) and ethyl deglycoled ethylene glycol (50ml) were heated at 95-98 ° C with stirring under nitrogen.

* I

At 80 ° C absolute ethanol (8-10 ml) was added to dissolve the starting material. The resulting solid was filtered, washed with recycled mother liquor and twice with water (40 mL). The product was dried at 40 ° C to give the title compound as a tan solid (9.2 g, 91%), m.p. 114-151 ° C.

B. 4- (2-Aminoethyl) -1,3-dihydro-2H-indol-2-one hydrochloride A 500 mL Parr pressure bottle was charged with 50% water-wetted 5% Pd / C ( 2.0 g), 4- (2-10 azidoethyl) -1,3-dihydro-2 H -indol-2-one (8.0 g, 39.6 mmol) and anhydrous methanol (300 mL). The reaction mixture was then hydrogenated at 60-65 psir for three hours. After filtering the catalyst, the solution was acidified with excess gaseous HCl and about 2/3 of the solvent was removed in vacuo. The resulting solid was filtered, washed with recycled filtrate and then dried at 40 ° C to give a white solid. Recrystallization from ethanol / water 2: 1 gave the title compound as a tan solid (5.5 g, 65%) m.p. 300 ° C dec.

C. 4- (2-Dipropylaminoethyl) -1,3-dihydro-2H-indol-2-one hydrochloride salt A 250 ml Parr pressure bottle was charged at 50%. * with 5% Pd / C (300 mg) moistened with water, 4- (2- • aminoethyl) -1,3-dihydro-2H-indol-2-one hydrochloride 25 (1.4 g, 5 mmol). , glacial acetic acid (50 mL) and propionaldehyde (1.5 mL, 20 mmol). The mixture was hydrogenated at 68 ° C and 70 ° C for 5 hours. The catalyst was filtered and the filtrate removed in vacuo. The resulting orange oil concentrate was dissolved in refluxed ethanol and the Liu-30 os saturated with HCl. Upon cooling, the solid crystallized from the solution, which was filtered, washed with ether and then dried to give the title compound as a yellow solid (1.07 g, 68%), m.p. 240-243 ° C.

i * · t '· · * »* *

Claims (3)

114094 A process for the preparation of a compound of structure (I) 5 (PUNK * Sv * R wherein n is 1-3; each R is independently hydrogen or C 1-4 alkyl; and R 1 is hydrogen, hydroxy or C 1-4 alkoxy , characterized in that, in the presence of Raney nickel, a compound of structure (II) is reduced: (OUNRiT? (II> .15 rI · · 1.) wherein n, R and R1 are as defined for structure (I), * * * and thereafter optionally · '' - converting compound of structure (I) to another compound of structure (I) - forming a salt. The method of claim 1, wherein it is stated that both R groups are C 1-4 alkyl and n is 2. • » A process according to claim 1, characterized in that the compound of structure (I) prepared is: 4- [2- (di-n-propylamino) ethyl] -1,3-dihydro-2H-indole. 2-one hydrochloride (INN: ropinirole). 11409 ^