NO175057B - Process for the preparation of 3,3-disubstituted indolines - Google Patents

Description

The present invention relates to a process for the production of 3,3-disubstituted indolines, and in particular such processes for the production of 3,3-pyridine-substituted indolines which are useful as agents for treating perceptual or neurological dysfunction in a mammal.

There is a steadily increasing need for effective treatment of nervous system diseases that cause perceptual and neurological impairments. Many of these diseases, the signs of which generally increase with increasing age, are due to degenerative changes in the nervous system. Although certain systems in early stages of certain diseases are relatively specifically affected (for example cholinergic systems in Alzheimer's disease and Myasthenia Gravis, the dopaminergic system in Parkinson's disease etc.), there are multiple neurotransmitter system deficiencies (acetylcholine, dopamine, norepinephrine, serotonin) which are generally found in later stages of diseases and are assumed to exist in all stages of diseases such as senile dementia, multi-infarct dementia, Huntington's disease, mental retardation etc. This can explain the generally observed symptomatology which includes experiential, neurological and effective/ psychotic components (see Gottfries, Psychopharmacol. 86, 245, 1985). Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment

(see Francis et al., New England J. Med., 313, 7, 1985) while neurological deficits (eg Parkinson's symptoms) and visual/mental changes may be related to impairment of dopaminergic and serotonergic systems. Other neurological deficits (for example Myasthenia Gravis) are related to cholinergic impairments in the peripheral nervous system.

The treatment plans used so far include vasoactive drugs such as vincamine and pentoxofylline; "metabolic enhancers" such as ergoloid mesylates, piracetam and naftidrofuryl; neurotransmitter precursors such as 1-DOPA. choline and 5-hydroxytryptamine; transmitter metabolizing enzyme inhibitors such as physostigmine; and neuropeptides such as adrenocorticotropic hormone and vasopressin-related peptides. With the exception of 1-DOPA therapy in Parkinson's disease and cholinesterase inhibitor therapy in Myasthenia Gravis, these treatment regimens have generally failed to produce clinically significant improvements (Hollister, Drugs, 29, 483, 1985). Another strategy to treat these multiple symptoms is to increase the residual function of the affected systems by increasing the stimulus-induced release of neurotransmitters. Theoretically, such an increase could improve the "signal-to-sound" ratio during chemical transfer of information, thereby reducing deficits in processes related to perception, neurological function and mind regulation.

Compounds that increase the stimulus-induced release of neurotransmitters, specifically acetylcholine and additionally dopamine and serotonin in nervous tissue, and that improve processes involved in learning and remembering an active avoidance task,

is described in US patent application 944,953 filed January 5, 1987.

The process described there for the preparation of 3,3-disubstituted indolines uses the expensive picolyl chloride, and undergoes a strong exothermic reaction using aluminum chloride in the preparation of an intermediate of formula (I). There is thus a need to find a method for producing these compounds in a safe manner and in good yield using readily available raw materials.

According to the present invention, a method for the production of 3,3-disubstituted indolines of the formula is provided:

or a pharmaceutically acceptable salt thereof, wherein

p is 0 or 1;

R is alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, 2-, 3- or 4-pyridyl, or

V, W, X and Y are independently H, halogen, alkyl of 1-3 carbon atoms, OR<1>, NO2, CF3, CN or NR^; R<1> and R<2> are independently H or alkyl of 1-3 carbon atoms; Het and Het are independently 2- or 4-pyridyl, 2-, 4- or 6-pyrimidinyl or 2-pyrazinyl, optionally substituted with an alkyl group of 1-3 carbon atoms, which method is characterized in that (1) a compound of formula (II) in a solution at a temperature of 100°-150°C is brought into contact with at least one equivalent weight of Het^-CH^/ which compound of formula (II) has the formula: wherein X, Y, p and R are as defined above, for a sufficient time to obtain a compound of formula: (2) the compound of formula (III) prepared in step (1) is dehydrated to form a compound of formula: (3) the compound of formula (IV) is reduced in solution with a borohydride, or by catalytic hydrogenation under conditions such that no reduction of C=0 or of a double bond in Het<1> occurs, forming a compound of formula:

and

(4) the compound of formula (V) obtained in step (4) or a salt formed therefrom is contacted in a basic solution with a compound of formula:

wherein Het 2 is as defined above and D is a nucleophilic, displaceable group.

Preferred conditions

Step (1) - Acetic acid is the solvent of choice. The temperature is preferably in the range 100 - 150° C, preferably in the range 120 - 130° C. Other solvents and reaction conditions for carrying out step (1) will be described.

Step (2) - The dehydration is preferably completed with an acid anhydride (acetic anhydride preferred) at a temperature in the range 50 - 150° C, preferably 100 - 130° C. Other dehydration conditions

will be further described.

Step (3) - Sodium borohydride in methanol is the preferred reducing agent. Other applicable reducing agents and

conditions will be described.

Step (4) - Aqueous sodium hydroxide is the preferred base in the basic solution. Preferred and other solvents, and reaction conditions will be described.

D is preferably halogen, methanesulfonate or p-toluenesulfonate.

The compounds of formula (I) (Reaction scheme I) are prepared by reacting a substituted isatin (II) with Het<1->CH^, e.g. an alkylpyridine such as 4-picoline, in acetic acid at 120 - 130° C, forming the aldol addition product (III). The reaction can also be carried out in 4-picoline itself as solvent. The product can be isolated via dilution with methylene chloride, followed by filtration and recrystallization of the product. Other high-boiling solvents such as hydrocarbons (xylenes or toluene) containing an excess of 4-picoline can also be used for this reaction. Substituted isatins (II) are well described in the literature. 1-phenyl-isatin is prepared from diphenylamine and oxalyl chloride as described in Ber., 46, 3915

(1914). Condensation of alkylpyridines with carbonyl compounds is described in E. Klingsberg, et al., Pyridines and Its Derivatives, Pt. II, 191-197 (1961).

Dehydration of (III) to form (IV) is preferably carried out bare or with acetic anhydride at a temperature of between 100 and 130° C. This reaction can also be carried out in the presence of acetic acid and other aprotic solvents such as toluene or xylene . Useful temperatures range from 50 to 150° C. Other dehydration methods well known to those skilled in the art include the use of zinc chloride, other acid hydrides, phosphorus pentoxide, potassium bisulfate and sulfuric acid as described in J. March, Advanced Organic Chemistry, 901-903

(1985). Dehydration of carbinols (III) resulting from the condensation of alkylpyridines with carbonyl compounds is described in E. Klingsberg, et al, Pyridine and Its Derivatives, Pt. II, 203 (1961).

Compounds of formula (IV) are preferably isolated before further processing for characterization. Isolation can be performed by any well-known isolation procedure known in the art. For example, the compounds can be filtered, the solvents evaporated etc.

The compounds of formula (V) are obtained via reduction

of the compounds (IV). Treatment of (IV) with sodium borohydride is the preferred method for converting (IV) to (V). This method is illustrated in J. Org. Chem., 31, 620 (1966). (V) kah is also obtained via transfer hydrogenation as described in Chem. Rev., 85, 129 - 170 (1985), or via catalytic hydrogenation in acetic acid or ethyl acetate under standard conditions well known in the art. Application of these reduction reactions will not reduce C=0 or a double bond in Het. Preferred temperatures range from 25 to 80° C. The preferred pressure for catalytic hydrogenation is 1 atm hydrogen.

The conversion of (V) to (I) is preferably carried out in a methanol-water mixture using sodium hydroxide as the preferred base, followed by reaction of the resulting anionic species with a compound of the formula D-CH2~Het 2 wherein D is preferably halogen, methanesulfonate or p-toluenesulfonate. Other alcohols such as ethanol, isopropanol, n-propanol can be used instead of methanol. Other bases such as potassium hydroxide, lithium hydroxide, and quaternary amines such as N-benzyltrimethylammonium hydroxide are also acceptable. Preparation of (I) from (V) can also be carried out under phase transfer catalysis using toluene-50% sodium hydroxide as solvents, and hexadecyltributylphosphonium bromide as catalyst.

The compounds according to the invention and their preparation are illustrated in more detail in the following examples in which all temperatures are in degrees Celsius and parts and percentages are by weight unless otherwise stated.

Example 1

Part A: 3-( 4- pyridinylmethylidene)- 1- phenylindolin- 2- one

A solution of 175 ml (254.6 g, 2.01 M) of oxalyl chloride was cooled to 5°, and a solution of 320 g (1.89 M) of diphenylamine in 580 ml of toluene was added over 8 minutes. The mixture was heated to 50-65° for 74 minutes. The mixture was then heated to 125° to distill off toluene and excess oxalyl chloride, and the total distillate collected was 630 ml. The solution was then refluxed at 125° + 2° for 20 hours. The mixture was cooled to 104° and a solution of 215 mL (205.7 g, 2.21 M) 4-picoline in 750 mL acetic acid was added over 17 minutes. The mixture was heated to 130° to remove excess toluene via acetic acid/toluene azeotrope. A further 750 ml of acetic acid was added during the distillation. A total of 875 ml of distillate containing 260 ml of toluene was collected. The mixture was cooled to 115° and 360 mL (389.5 g, 3.81M) of acetic anhydride was added over 10 minutes while heating to 120-130°. The mixture was stirred at 120 + 2° for 1.75 hours, and was then cooled to 76°. 530 ml of water was added over 7 minutes, followed by 430 ml of isopropanol while maintaining the temperature between 82 and 63°. The mixture was cooled to ambient temperature overnight, then to 0-5°. The impure product was collected by filtration, washed with 2.16 liters of isopropanol and 1.64 liters of water. Drying in a vacuum oven at 80-90° gave 422.6 g (75%) of the title compound as an orange crystalline solid. Melting point: 160.1 - 161.9°.

Part B: 3, 3- bis( 4- pyridinylmethyl)- 1- phenylindolin- 2- one

A slurry of 80 g (0.268 M) 3-(4-pyridinyl-methylidene)-1-phenylindolin-2-one in 600 ml methanol was cooled to 6°. Sodium borohydride pellets (0.2 g each, 3.19 g total, 0.084 M) were added over 20 min with gentle cooling. The mixture was stirred for 50 minutes, was cooled to 7°, and 64 mL (0.64 M) of 10N sodium hydroxide was added over 11 minutes. A solution of 4.85 g (0.296 M) of 4-picolyl chloride hydrochloride in 160 mL of water was then added over 28 minutes while maintaining the temperature at

10 - 15°. The cooling was then removed and 80 ml (0.8 M)

10 N sodium hydroxide was added over 10 minutes. The mixture was stirred for 2 hours, after which 580 ml of water was added over 45 minutes. The slurry was cooled to 10-15°, stirred for 10 minutes and the solid collected by filtration. The solid was then reslurried in 450 ml of water, filtered and washed with water. Drying in a vacuum oven at 85-95° gave 89.4 g (85%) of the impure title compound. This crude product (85 g) was recrystallized from isopropanol and water to give 77.3 g of the title compound (90% recovery). Melting point: = 186 - 188°.

Example 2

3-(4-pyridinylmethyl)-1-phenyl lindolin-2-one hydrochloride

A mixture of 1211 g (4.06 M) 3-(4-pyridinylmethylidene)-1-phenylindolin-2-one, 260 ml (317 g, 6.89 M) formic acid, 6.5 liters of isopropanol and 180 g of 5% palladium-on-carbon catalyst was heated to 70°. An additional 1000 ml (1220 g, 26.50 M) of formic acid was added over 125 minutes while heating to 82° C. The mixture was heated under reflux for 70 minutes and was cooled to 75°. The catalyst was removed by filtration and was washed with 300 ml of isopropanol. The solution was heated to 51°, and 530 ml (6.4 M) of concentrated hydrochloric acid was added over 75 minutes. The resulting slurry was cooled to 15°, the title compound was isolated by filtration and was washed with 2 liters of isopropanol. The solid was then reslurried in 3.5 liters of isopropanol, filtered and dried in a hot vacuum oven. The title product yield was 1126 g (82%) of a brown crystalline solid. Melting point: 244 - 248° (decomposition). % chloride: 10.64% (theoretical: 10.5%). % H 2 O: 0.06%.

The compounds according to examples 1 and 2 are shown in Table I.

Claims (7)

1. Process for the preparation of 3,3-disubstituted indolines of the formula: or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1; R is alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, 2-, 3- or 4-pyridyl, or V, W, X and Y are independently H, halogen, alkyl of 1-3 carbon atoms, OR<1>, NO2, CF3, CN or NR^; 1 2 R and R are independently H or alkyl of 1-3 carbon atoms; Het 1 and Het 2 are independently 2- or 4-pyridyl, 2-, 4- or 6-pyrimidinyl or 2-pyrazinyl, optionally substituted with an alkyl group with 1-3 carbon atoms, characterized in that (1) a compound of formula (II) in solution at a temperature of 100°-150°C is contacted with at least one equivalent weight of Het^-CH^, which compound of formula (II) has the formula: wherein X, Y, p and R are as defined above, for a sufficient period of time to obtain a compound of formula: (2) the compound of formula (III) prepared in step (1) is dehydrated to form a compound of formula: (3) the compound of formula (IV) is reduced in solution with a borohydride, or by catalytic hydrogenation under conditions such that no reduction of C=0 or of a double bond in Het takes place, forming a compound of formula: and (4) the compound of formula (V) obtained in step (4) or a salt formed therefrom is contacted in a basic solution with a compound of formula: wherein Het<2> is as defined above and D is a nucleophilic displaceable group. 2. Method according to claim 1, characterized in that step (2) is carried out in acetic anhydride at a temperature in the range 50 - 150° C. 3. Method according to claim 1, characterized in that the compound of formula (IV) in step (3) is brought into contact with sodium borohydride in methanol. 4. Method according to claim 1, characterized in that the basic solution in step (4) is aqueous sodium hydroxide and D is halogen, methanesulfonate or p-toluenesulfonate. 5. Method according to claim 1, characterized in that the compound of formula (IV) is isolated before it is reduced. 6. Method according to claim 1, characterized in that (a) step (1) is carried out in acetic acid at a temperature in the range 120 - 130° C; (b) step (2) is carried out in acetic anhydride at a temperature in the range 10 0 - 130° C; (c) in step (3) sodium borohydride in methanol is used as reducing agent; and (d) in step (4), the basic solution is aqueous sodium hydroxide and D is halogen, methanesulfonate or p-toluenesulfonate. 7. Method according to claim 6, characterized in that the compound of formula (IV) is isolated before it is reduced