NO833474L - PROCEDURE FOR PREPARING PIRENZEPINE - Google Patents

Abstract

1. Process for preparing 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H- -pyrido[2,3-b][1,4]-benzodiazepin-6-one or the salts thereof with inorganic or organic acids, characterised in that 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one of formula I see diagramm : EP0104566,P8,F1 is reacted in a solvent conventionally used for lithiation reactions first with at least two equivalents of a lithium alkyl or lithium aryl at temperatures of between -60 and 0 degrees C and subsequently with a (4-methyl-1-piperazinyl)-acetate of general formula III see diagramm : EP0104566,P8,F2 wherein R represents an alkyl group with 1 to 10 carbon atoms, a phenyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, and the compound thus obtained is isolated and, if desired, converted into the salts thereof with inorganic or organic acids.

Description

This invention relates to a new process for the production of 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,43benzodiazepine-6-one (Pirenzepine ) and salts thereof with inorganic or organic acids. Due to its outstanding anti-ulcer effect, this compound has

gained great therapeutic importance.

Production of Pirenzepine is described in DE-PS 1 795 183 as a two-stage process starting from 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one. Here, the starting compound is first transferred with a haloacetyl halide to an intermediate product, 11-haloacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one, and then this intermediate is reacted with N-methylpiperazine to the final product.

There have previously been repeated attempts to introduce the side chain in one step (see for example EP-A-0 022 144 or DE-A-31 09 769), but the method postulated there is however completely impracticable in practice.

It has now been found that Pirenzepine can be prepared from 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one (I) in good yields in a simple way by a one-step reaction, when one first transfers it to the dilithium salt (II) and then reacts the latter with a (4-methyl-1-piperazinyl)-acetic acid ester (III) according to the following reaction scheme to Pirenzepine (IV):

In the (4-methyl-1-piperazinyl)-acetic acid ester of the general formula III, R means an alkyl radical with 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, or an aryl or aralkyl radical. A phenylmethyl, phenylethyl or phenylpropyl radical is preferably taken into account as an aralkyl radical, and a phenyl group is preferably taken into account as an aryl radical.

The transfer of 5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepine-6-one (formula I) to the lithium salt of formula II is achieved with lithium alkyl compounds, in particular with n-butyllithium , n-butyllithium in the presence of tetramethylethylenediamine, tertiary-butyllithium, lithium diisopropylamide or lithium dicyclohexylamide or with lithium aryl compounds, for example with lithium phenyl. The transfer to the lithium salt and the further conversion to Pirenzepine is carried out in an organic solvent at temperatures between -60 and 0°C, preferably at -10°C. As organic solvents, those that are applicable for reaction with lithium alkyl or lithium aryl compounds are used, and particularly advantageous is the use of tetrahydrofuran or ethers such as diethyl ether, aliphatic hydrocarbons such as hexane or mixtures thereof, optionally also in the presence of hexamethylphosphoramide as co-solvent . Shortly after the addition of the lithium alkyl or -aryl compound is added, the stoichiometric amount or a small excess of the (4-methyl-1-piperazinyl)-acetic acid ester of the general formula III is added and the reaction mixture is allowed to come slowly to room temperature, for example in within 2 hours, to achieve complete turnover. The formed Pirenzepine of formula IV can be isolated from the reaction mixture by usual methods, and the free compound is obtained which can then optionally be transferred to its salts.

The course of the reaction between the compound of formula I

and the lithium alkyl or -aryl compound of the lithium intermediate compound of formula II could not be predicted, as it is known that the reaction of pyridines and condensed pyridines with organometallic compounds preferentially leads to alkyl-substituted pyridine derivatives (see H. W. Gschwend and H. R. Rodriguez, Heteroatom-Facilitated Lithiations, Organic Reactions, 26, 27 (1979)).

The following examples shall further illustrate the invention.

Example 1

5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]6H-pyrido-[2,3-b][1,4]benzodiazepine-6-one

To a suspension of 21 g (0.1 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one in 400 ml of tetrahydrofuran is slowly added dropwise with stirring at -10 °C, 200 ml of a 1.5 molar solution of n-butyllithium in hexane. After the addition has been completed, the mixture is stirred further for 30 minutes at -10°C. A solution of 20.4 g is then added dropwise

(0.11 mol) (4-methyl-1-piperazinyl)-acetic acid ethyl ester in 100 ml of absolute tetrahydrofuran. The reaction mixture is allowed to come to room temperature and stirred for a further 2 hours. The reaction mixture is then diluted with acetic acid ethyl ester and 250 ml of 10% hydrochloric acid is added. The precipitate formed is suctioned off. After separation of the organic phase, the aqueous phase is made alkaline by the addition of solid potassium carbonate and extracted several times with chloroform. It is filtered over activated charcoal and evaporated to dryness on a rotary evaporator. The crude product is purified by column chromatography on silica gel using ethyl acetate/methanol in a volume ratio of 9:1. You get 21.1 g (60% of the theoretical) of a colorless product which, after recrystallization from methanol, melts at 222-225°C and according to thin layer chromatogram, IR and NMR spectra is completely identical to the compound described in DE-PS

1,795,183, example 7.

Example 2

5,11-dihydro-11[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido-[ 2,3-b][1,4]benzodiazepine-6-one

A suspension of 21 g (0.1 mol) of 5,1l-dihydro-eH-pyrido-^^-b] [1,4]benzodiazepine-6-one in 400 ml of tetrahydrofuran is cooled to -60°C under nitrogen and is then added dropwise to a similarly cooled to -60°C solution of 200 ml of lithium diisopropylamide, prepared from 20.2 g of diisopropylamine and 153.8 ml of a 1.3 molar solution of n-butyllithium in hexane, and 50 ml of hexamethylphosphoramide. After 30 minutes of stirring at the same temperature, a solution of 24.7 g (0.10 mol) (4-methyl-1-piperazinyl)-acetic acid benzyl ester in 100 ml of tetrahydrofuran is added dropwise. Stirring is continued for a further 2 hours and the reaction mixture is then allowed to come to room temperature. Processing of the reaction mixture takes place analogously to the method described in example 1. Purification of the crude product takes place by chromatography on silica gel using acetic acid ethyl ester/methanol in a volume ratio of 3:1. According to thin-layer chromatogram, IR and NMR spectra, the resulting colorless product is completely identical to the compound described in example 1. Yield: 21.8 g (62% of theory).

Example 3

5,11-dihydro-11[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-one

Analogous to example 1, using 17.2 g (0.10 mol) of 4-methyl-1-piperazinylacetic acid methyl ester, 20.2 g (57% of the theoretical) of the desired compound is obtained.

Comparable results are obtained by using (4-methyl-1-piperazinyl)-acetic acid-n-propyl- or -2-phenyl-ethyl ester.

Example 4

5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido-[2,3-b][1,4]benzodiazepine-6-one

Analogous to example 1, 21 g (0.1 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one are reacted with 36 g (0.15 mol) (4 -methyl-1-piperazinyl)-acetic acid hexyl ester. After column chromatographic purification, 11.9 g (34.7% of the theoretical) is obtained of a colorless product, which after recrystallization from methanol melts at 222-224°C and, according to the spectroscopic data, is completely identical to the compound described in example 1 .

Example 5

5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido-[ 2, 3-b][ 1, 4] benzodiazepine- 6-one

Analogous to example 1, 21 g (0.1 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one are reacted with 41.4 g (0.15 mol) (4-Methyl-1-piperazinyl)-acetic acid 3-phenylpropyl ester. After column chromatographic purification, 14.5 g (41.4% of the theoretical) is obtained of a colorless product which, after recrystallization from methanol, melts at 222-225°C and, according to the spectroscopic data, is completely identical to the compound described in example 1.

Example 6

5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido-[ 2, 3-b][ 1, 4] benzodiazepine- 6-one

To a suspension of 21 g (0.1 mol) 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one in 400 ml of tetrahydrofuran is slowly added dropwise with stirring at -10 °C 150 ml of an approx. 2 molar solution of phenyllithium in a mixture of benzene and ether (75/25). After completion of the addition, the mixture is stirred for 30 minutes at -10°C. A solution of 20.4 g (0.11 mol) of (4-methyl-1-piperazinyl)-acetic acid ethyl ester in 100 ml of absolute tetrahydrofuran is then added dropwise. The reaction mixture is allowed to come to room temperature and stirred for a further 2 hours. The work-up takes place analogously to example 1. One obtains 11.3 g (32.2% of the theoretical) of a colorless product which, according to the spectroscopic data, is completely identical to the compound obtained in example 1.

Example 7

Advantageously, instead of tetrahydrofuran in example 1, other organic solvents or solvent mixtures that are suitable for reaction could also be used

with lithium alkyl or lithium aryl compounds.

Some examples are given in the following table (this refers to the weight specifications given in example 1):

Claims (4)

1. Process for the production of 5,11-dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzo-diazepin-6-one or salts thereof with inorganic or organic acids, characterized in that 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepine-6-one of formula I is reacted in an organic solvent first with at least two equivalents of a lithium alkyl or lithium aryl compound at temperatures between -60 and 0°C and then with a (4-methyl-1-piperazinyl)-acetic acid ester of the general formula where R means an alkyl residue, an aryl or aralkyl residue, and the desired compound is isolated and optionally transferred to its salts with inorganic or organic acids. 2. Method according to claim 1, characterized in that the reaction is carried out at -10°C. 3. Method according to claims 1 and 2, characterized in that n-butyllithium is used as the lithium alkyl or -aryl compound, optionally in the presence of tetramethylethylenediamine, tertiary butyllithium, lithium diisopropylamide, lithium dicyclohexylamide or lithium phenyl, and ethers are used as the solvent, such as diethyl ether, tetrahydrofuran, aliphatic hydrocarbons such as hexane, mixtures of these solvents and optionally as a co-solvent hexamethylphosphoramide. 4. Process according to claims 1, 2 and 3, characterized in that the ester used is one with the general formula III, where R means an alkyl group with 1 to 6 carbon atoms or a phenylmethyl, phenylethyl or phenylpropyl group.