CH627163A5 - Processes for the preparation of new indole derivatives - Google Patents

Description

627163

2

CLAIMS 1. Process for the preparation of a compound of formula

HN

/ \

year)

(VI)

Rs and the amide thus obtained of formula is reduced

(ch2) „- ch2-n

(h)

in which:

n is 1 or 2,

R2 represents a phenyl, isopropyl or methyl-1 cyclopropyl group,

R3 represents a hydrogen atom or an isopropyl or methylthio group, and

R4 and R5, which are identical or not, each represent a hydrogen atom or a methyl, ethyl or benzyl group, or alternatively, a pentamethylene, hexamethylene, oxidiethylene or N-methylaminodiethylene chain,

characterized in that a compound of formula is reacted

15

there is

(CH.) CON.

5

using mixed lithium / aluminum hydride.

"AT

The present invention relates to processes for the preparation of new indole derivatives corresponding to the formula:

-R.

Vm / "" 2

I

H

with sodium hydride, then the sodium derivative thus obtained is condensed with a halide of formula

(I)

(VI)

35

I R4

(CH2) n-CH2- * V

5

.Ri

X - (CH2) nCH2 - N

/ \

Rs

2. Process for the preparation of a compound of formula VI in which R3 is a hydrogen atom, characterized in that a compound of formula is reacted

(V)

in which:

n is 1 or 2

R2 represents a phenyl, isopropyl or methyl-1-cyclopropyl group,

R3 represents a hydrogen atom or an isopropyl or methylthio group, and

R4 and Rj, which are identical or not, each represent a hydrogen atom or a methyl, ethyl or benzyl group, or alternatively, a pentamethylene, hexamethylene, oxidiethylene or N-methylaminodiethylene chain.

The methods according to the invention are defined in claims 1 and 2.

The derivatives of formula I

a) with ethyl chloroacetate, or b) with acrylonitrile,

saponify the ester or the nitrile group, respectively react the acid of formula

55

(I)

✓S

(II)

in which R3 is an isopropyl or methylthio group, can be prepared by reacting a ketone of general formula:

W "" 2

(CH) —COOH 2 no.

II

R, - C - CH2 - R3

(IV)

obtained where n = 1 in the case of reaction a above, and n = 2 in the case of reaction b, with an amine of formula

65 with phenylhydrazine, then by cyclizing the phenylhydrazone obtained by means of a dehydrating agent or by thermolysis.

The derivative of formula I, in which R2 represents a phenyl radical and R3 a methylthio radical, can be prepared by making

3

627163

react 2-phenyl indole with tio-urea, in the presence of ethanol and water, then with dimethylsulfate.

The derivatives of formula II, in which n is 1, are prepared by reacting a derivative corresponding to the general formula:

AT-!

| (V)

XAnA "2

I

H

in which R2 takes the same values as in formula I, with ethyl chloroacetate, then by saponifying the ester obtained.

The derivatives of formula II, in which n is 2, are prepared by reacting a compound of formula V above with acrylonitrile, in the presence of N-ben2yltrimethylammonium hydroxide in dioxane, then by hydrolyzing to acidic medium the product obtained.

The indole derivatives of formula V are known or can be prepared by the general methods of Fischer or Bischlër.

The products prepared according to the invention have proved to be essentially useful as pharmacologically active indole derivatives; in particular, they have been found to be extremely useful as an antidepressant for the central nervous system.

The examples below illustrate, without limitation, the preparation methods according to the invention.

Example 1:

2-Phenyl-3-methylthio indole

Mixed in a flask of 21120.5 g (0.6 mol) of 2-phenyl indole, 95 g (1.25 mol) of thiourea, 11 of pure ethanol and 200 ml of water and added by small amounts 157.7 g (0.62 mol) of iodine in 45 min, the reaction medium being heated in a water bath to 50 ° C. It is allowed to return to room temperature and 100 g of sodium hydroxide are added in 30 min, then again 50 g of soda.

After dissolving the soda, 80 g of dimethyl sulphate are added at ambient temperature. The mixture is refluxed for 30 min, cooled and water is added until the final product precipitates. The latter is filtered and washed with water many times. After recrystallization from a hexane / benzene mixture, 2-phenyl-methylthio-3 indole is obtained with a yield of 87%. Melting point: 103 ° C.

Example 2:

Phenyl-2 isopropyl-3 indole

The phenylhydrazone is cyclized from 3-isopropyl acetophenone by heating at 135 ° C. for 10 min, in the presence of 3.5 parts of polyphosphoric acid, containing 4 parts of phosphoric anhydride and 5 parts of 85% phosphoric acid.

The product obtained is poured into water and the precipitate which forms is filtered and dried. After recrystallization from heptane, 2-phenyl-3-isopropyl-indole is obtained with a yield of 70%. Melting point: 115 ° C.

Example 3:

(Methyl-1 'cyclopropyl) -2 indole

250 g of 85% phosphoric acid are introduced into a 500 ml reactor fitted with an agitator and a condenser surmounted by a desiccant guard, and 200 g of P205 are gradually added thereto, the medium being under an atmosphere of 'nitrogen.

The formation of polyphosphoric acid being very exothermic, the medium is cooled to 115 ° C. and phenylhydra-zone of the methyl (methyl-1 cyclopropyl) ketone sprayed is added, taking care that the temperature of the reaction medium does not exceed 125 ° C, the latter temperature being maintained for 20 min.

The reaction medium is then poured into ice water and the indole derivative is extracted with ether.

The organic phase is dried and concentrated under reduced pressure and the crude (methyl-1 'cyclopropyl) -2 indole is obtained, which is purified on a silica column, with a heptane / benzene mixture 50/50 as eluent. After recrystallization from heptane, the (methyl-1 'cyclopropyl) -2 indole is obtained with a yield of 65%. Melting point: 62 ° C.

By the above method, but starting from the appropriate starting material, 2,3-diisopropyl indole was prepared with a yield of 50%. Melting point: 138 ° C.

Example 4:

(2-Phenyl indol-1'yl) -3 N-methylpropionamide a) Preparation of (2-cyano-ethyl) -1 phenyl-2 indole

72 g (0.37 mol) of 2-phenyl indole in 200 ml of dioxane are added to 6 ml of N-benzyltrimethylammonium hydroxide, then 26 ml (0.6 mol) of acrylonitrile. The mixture is kept overnight at 60 ° C. by means of a thermostatted water bath, then the reaction medium is placed in a cooler until the final product crystallizes. After filtration and three recrystallizations from ethanol, the (2-cyano-ethyl) -1 phenyl-2 indole is obtained with a yield of 80%. Melting point: 90 ° C,

b) Preparation of (phenyl-2 'indol-1' yl) -3 propionic acid

The (cyano-2 'ethyl) -1 phenyl-2 indole is heated to reflux of hydrochloric acid at 36% and almost all of the acid precipitates from the hot medium. After filtration and purification via the sodium salt of the acid, recrystallization from ethanol and the acid (phenyl-2 'indol-1' yl) -3 propionic is obtained with a yield of 85%. Melting point: 129 ° C.

c) Preparation of (phenyl-2 'indol-1' yl) -3 N-methylpropionamide

26.5 g (0.1 mol) of (phenyl-2 'indol-1' yl) -3 propionic acid are stirred in 50 ml of anhydrous tetrahydrofuran and 14 ml of triethylamine are added. The temperature is maintained between -5 and -10 ° C by a mixture of dry ice and acetone, then poured onto the solution 10 ml of ethyl chloroformate in a little tetrahydrofuran, taking care that the temperature does not exceed not 0 ° C. It is left to stand for 30 min at -5 ° C. and methylamine previously cooled to -10 ° C. is added. The mixture is stirred for a few hours, then 600 ml of a cold aqueous solution are poured onto the reaction medium. 5% sodium hydroxide, while continuing to agitate. The oil which forms is extracted with ether which is then removed under reduced pressure. The amide obtained is recrystallized from isopropanol and the (phenyl-2 'indol-1' yl) -3 N-methylpropionamide is collected with a yield of 75%. Melting point: 126 ° C.

Example 5:

(2-Phenyl indol-1 yl) acetamide a) Preparation of (2-phenyl indol-1 yl) acetic acid

A solution of 20 g (0.105 mol) of 2-phenyl indole in 50 ml of dimethylformamide is added under a nitrogen atmosphere and with stirring to a suspension of 5.5 g (0.115 mol) of NaH in 100 ml. dimethylformamide, while monitoring the evolution of hydrogen. 16 g (0.13 mol) of ethyl chloroacetate are then added and the mixture is heated for 3 hours in a water bath at 70 ° C. The mixture is then poured into water containing a little acetic acid and extracted with ether. The ethereal phase is then washed several times with water and dried over magnesium sulfate. The ethyl (2-phenyl-indol-1 yl) acetate obtained is saponified using an alcoholic 20% potassium solution. The ethanol is evaporated, the residue is dissolved in water and the unreacted 2-phenyl indole is extracted with ether.

The aqueous phase is purified by boiling on activated charcoal and acidified with hydrochloric acid. The white precipitate which forms is recrystallized from ethanol.

b) Preparation of (2-phenyl indol-1 yl) acetamide

The procedure used is that of Example 4c, but starting with (2-phenyl-indol-1 yl) acetic acid and adding

5

10

15

20

25

30

35

40

45

50

55

60

65

627 163 4

liquid ammonia instead of methylamine, the reaction medium isopropanol, we obtain (2-phenyl-indol-1 yl) acetamide with a

being previously cooled to -20 ° C. After recrystallization in 95% yield. Melting point: 190 ° C.

By the same method, but starting from the appropriate starting materials, we also prepared:

Compounds

Melting point (° C)

Yield (%)

(2-Phenyl indol-1 yl) N-methylacetamide

190 (isopropanol)

35

N - [(2-phenyl-indol-1 yl) acetyl] morpholine

235 (toluene)

60

N - [(2-phenyl indol-1 yl) acetyl] N-methypiperazine

175 (cyclohexane / ethanol)

45

(2-Phenyl indol-1 yl) N, N-dimethylacetamide

161 (cyclohexane)

70

(2-Phenyl indòl-1 yl) N, N-diethylacetamide

128 (cyclohexane)

72

N - [(2-phenyl indol-1 yl) acetyl] pyrrolidine

184 (benzene)

37

N - [(2-phenyl-indol-1 yl) acetyl] cyclohexylene-imide

147 (ethyl acetate)

65

Example 6:

(N-methylamino-3 'propyl) -! 2-phenol indole

At room temperature, 5.56 g (0.02 mol) of (2-phenyl-indol-1 'yl) -3-N-methylpropionamide, prepared as in Example 4, are poured in solution in a minimum of tetrahydrofuran , on a mixture of 2.66 g (0.02 mol) of aluminum chloride, 3.05 g (0.08 mol) of LiAlH4 and 100 ml of tetrahydrofuran, all with stirring. After the addition, the mixture is heated at reflux for 5 h, then allowed to cool and hydrolyzed slowly, under a nitrogen atmosphere and with small pieces of ice.

The gel formed is vigorously stirred with ether, then filtered and washed several times with ether. The ethereal phases are combined and evaporated, without going dry. The product is taken up in ether, washed with water and dried over magnesium sulfate. Melting point of the hydrochloride: 187 ° C.

By the above method, but starting from the appropriate starting materials, we also prepared:

Compounds

Fusion point

(° C)

(Methylamino-2 'ethyl) hydrochloride-1

197

2-phenyl indole

(isopropanol)

(2 'Morpholino ethyl) -1 phenyl-2 indole

80

(hexane)

(2-Diethylamino-ethyl) -l acid oxalate

180

2-phenyl indole

(ethanol)

(N-methylpiperazinyl-2 ') hydrochloride

180

ethyl) -1 phenyl-2 indole

(isopropanol)

(2-amino-1 'ethyl-1-phenyl-2 hydrochloride)

222

indole

(isopropanol)

Acid fumarate (2 'cyclohexylene-imino)

212

ethyl) -1 phenyl-2 indole

(ethanol)

(3-Amino-propyl) -1 phenyl-2 hydrochloride

222

indole

(isopropanol)

Example 7:

(Dimethylamino-3 'propyl) -1 phenyl-2 isopropyl-3 indole

In an atmosphere of dry nitrogen, 23.5 g (0.1 mol) of 2-phenylisopropyl-3 indole, prepared as in Example 2, are mixed with stirring, dissolved in 25 ml of dry dimethylformamide, with a suspension. 2.9 g (0.12 mol) of NaH in 50 ml of dry dimethylformamide, the temperature of the mixture being maintained between 10 and 35 ° C. The addition time is determined by the intensity of the evolution of hydrogen and is about 15 min. The mixture is allowed to return to ambient temperature and 14 g (0.1 mol) of 1-chloro-3-dimethylamino propane are added, which is left to react for 10 h at ambient temperature, or for 4 h at 50 ° C.

When the reaction is complete, the reaction medium is poured into a solution of ice-cold hydrochloric acid and washed with ether to remove the non-alkylated 2-phenyl-isopropyl-3 indole.

The base is regenerated from its hydrochloride, using a 20% sodium hydroxide solution, extracted with ether and the ethereal solution 45 is washed with water, then dried over magnesium sulfate and evaporates the solvent.

After recrystallization from a mixture of dimethylformamide and water, 3-dimethylamino-propyl) -1 phenyl-2-isopropyl-3 indole is obtained with a yield of 72%. Melting point: 166 ° C. 50 By the above method, but starting from the appropriate starting materials, we also prepared:

55

Compounds

Fusion point

(° C)

Acid fumarate (3'-dimethylamino)

191

propyl) -1 (methyl-1 'cyclopropyl) -2 indole

(methanol)

(3-Dimethylamino-propyl) hydrochloride -1

190

2-phenyl-3-pentanoyl indole

(isopropanol).

Acid fumarate (3'-dimethylamino)

173-175

propyl) -l 2,3-diisopropyl indole

(methanol)

(3'-Dimethylamino-propyl) hydrochloride-1

90

2-phenyl-3-methylthio indole

(Piperidino-3 'propyl) hydrochloride -1

240

2-phenyl indole

(isopropanol)

R