CS236894B2 - Processing of 5,11-dihydro-11-(4-methyl-1-piperazinyl)acetyl)-6h-pyrido(2,3-b)-(1,4)benzodiazepine-6-one - 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

The present invention relates to a novel process for the preparation of 5,11-dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] (1,4) benzodiazepin-6-one (Pirenzepine) ) or a salt thereof with inorganic or organic acids, which has gained considerable therapeutic significance because of its excellent anticonvulsant effect.

The preparation of Pirenzepine is described in German Patent Specification 1 795 183 as a two-step process using 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one as starting material. The starting material is first converted by the action of a haloacetyl halide into the intermediate, i.e. 11-haloacetyl-5,11-dlhydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one, and then the intermediate is left with N-methylpiperazine to give the final product.

It has been repeatedly tried to introduce a side chain in a single step (cf., for example, EP-A-0 022 144 or D-A-31 09 769), but the procedures disclosed herein are practically impractical.

It has now been found that Pirenzepine can be obtained in good yields from a 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one of formula I in a simple manner in a simple manner if it is converted to the di-lithium salt of formula II and is then reacted with [4-methyl-1-piperazinyl) acetic acid ester of formula III to give Pirenzepine of formula IV according to the following reaction scheme:

In the (4-methyl-1-piperazinyl) acetic acid ester of the formula III, R represents an alkyl radical of 1 to 10 carbon atoms, preferably of 1 to 6 carbon atoms, or an aryl radical or an aralkyl radical. The aralkyl radical is preferably a phenylmethyl radical. a phenyl radical or a phenylpropyl radical and an aryl radical is preferably a phenyl radical.

The conversion of 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one of formula I to the lithium salt of formula II is effected by treatment with alkyllithium, in particular n-butyllithium, n-butyllithium in in the presence of tetramethylethylenediamine, tert-butyllithium, lithium diisopropylamide or lithium dicyclohexylamide or with aryllithium treatment, for example phenyllithium. Conversion to the lithium salt and further reaction to give Pirenzepine is carried out in an organic solvent at temperatures between -60 ° C and 0 ° C, but preferably at -10 ° C. C. Organic solvents are those which are useful for reactions with alkyllithium or aryllithium. Particular preference is given to using tetrahydrofuran or ethers, such as diethyl ether, aliphatic hydrocarbons, such as hexane or mixtures thereof, optionally also in the presence of hexamethylammonium phosphide as a co-solvent. Shortly after completion of the alkynithium or aryllithium addition, a stoichiometric amount or a slight excess of (4-methyl-1-piperazinyl) -acetic acid ester of formula III is added. and the reaction mixture is separated. it is allowed to react slowly to complete the reaction, for example within 2 hours, gradually raising the temperature to room temperature. The resulting Pirenzepine (IV) is isolated from the reaction mixture by conventional methods to give the free product. a compound which is then optionally converted into its salts.

Reaction of a compound of formula I with an alkyllithium or aryllithium to form a reaction. the lithium intermediate of formula II could not be expected, since it is known that the reaction of pyridines and fused pyridines with organometallic compounds preferably results in alkyl-substituted pyridine derivatives (cf. HW Scchwend and HR Rodriguez, Heteroatom-Facilitated Lithiations, Organic Reactions, 26, 27 (1979).

The following examples illustrate the invention but do not limit it in any way.

II

Example 1

5,11-Dihydro-11 - [(4-methyl-1-piperazinyl] acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

To a suspension of 21 g (0.1 mol) of 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one in 400 ml of tetrahydrofuran was slowly stirred at -10 ° C with stirring. drips

A 1.5 M solution of n-butyllithium in hexane. After the addition was complete, the mixture was further stirred at -10 ° C for 30 minutes. A solution of 20.4 g (0.11 mol) of (4-methyl-1-piperazinyl) acetic acid ethyl ester in 100 ml of absolute tetrahydrofuran was then added dropwise. The reaction mixture was allowed to warm to room temperature and then stirred for a further 2 hours. The reaction mixture was then diluted with ethyl acetate and 250 mL of 10% hydrochloric acid was added. The resulting precipitate was filtered off. After separation of the organic phase, the aqueous phase is made basic by addition of solid potassium carbonate and extracted several times with chloroform. The chloroform extract is filtered through charcoal and the filtrate is evaporated to dryness on a rotary evaporator. The crude product was purified by silica gel column chromatography using a 9: 1 by volume mixture of ethyl acetate and methanol as eluent. 21.1 g (60% of theory) of a colorless product are obtained which, after recrystallization from methanol, melts at 222 DEG-225 DEG C. and is identical with the compound described in German patent specification 1 795 according to thin-layer chromatogram, IR and NMR spectra. 183, example 7.

Example 2

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

A suspension of 21 g (0.1 mol) of 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzrdiazepin-6-one in 400 ml of tetrahydrofuran was cooled to -60 ° C under a nitrogen atmosphere and then added dropwise to a solution of 200 ml of lithium diisopropylamide, which was also cooled to -60 DEG C., prepared from 20.2 g of diisopropylamine and 153.8 ml of a 1.3 M solution of n-butyllithium in hexane and 50 ml of hexamethylammonium phosphate. . After stirring at the same temperature for 30 minutes, a solution of 24.7 g (0.10 mol) of (4-methyl-1-piperazinyl) -acetic acid benzyl ester in 100 ml of tetrahydrofuran was added dropwise, stirring was continued for 2 hours and the temperature was allowed to rise. Treatment of the reaction mixture was carried out in an analogous manner to that described in Example 1. Purification of the crude product was carried out by chromatography on silica gel using a 3: 1 mixture of ethyl acetate and methanol as a colorless product. and NMR spectra identical to those described in Example 1.

Yield: 21.8 g (62% of theory).

Example 3

5.11-Dihydro-11 - [(4-methyl-1-

-piperazinyl) acetyl] -6H-pyridine-2,3-b] [1,4] benzodiazepin-6-one

Using an analogous procedure to that described in Example 1, using 17.2 g (0.10 med) of 4-methyl-1-piperazinylacetic acid methyl ester, 20.2 g (57% of theory) of the title compound are obtained.

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

Example 4

5,11] dihydrr-11 - [(4-methyl-1-piperazinylacetyl) -6H-pyridoph 2,3-b] [1,4] benzodiazepin-6-one

In an analogous manner to that described in Example 1, 21 - g (0.1 mol) of 5,11-dihydrl-6H-pyido-2,3-b - [1,4] benzrdiazepin] 6-one is reacted with 36 g. (0.15 mol) of (4-methyl-1-piperazinyl) -acetic acid hexyl ester. After purification by chromatography on a silica gel column, 11.9 g (34.7% of theory) of a colorless product are obtained which, after recrystallization, is recrystallized from ethyl acetate. the crystallization from methanol melts at 222-224 cc and, according to spectroscopic data, is identical to the compound described in Example 1.

Example 5

5.11-Dihydro-11- (4-methyl-1-piperazinyl) acetyl '-1H-pyrido (2,3-b] [1,4] benzodiazepin-6-one

In an analogous manner to that described in Example 1, 21 g (0.1 mol) was reacted.

5.11-Dihydrr-6H-pyridine [2,3-b [1,4] benzodiazepin-5-one with 41.4 g (0.15 mol) of (4-methyl-1-piperazinyl) acetic acid 3-phenylpropyl ester acid. Chromatographic purification on a silica gel column gives 14.5 g (41.4% of theory) of a colorless product which, after recrystallization from methanol, melts at 222 DEG-225 DEG C. and is identical with the compound described in Example 1 according to spectroscopic data.

Example 1 a d 6

5.11-Dihydro-11 - [(4-methyl-1-piperazinyl) acetyl] -6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one

To a suspension of 21 g (0.1 mol) of 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzrdiazepin-6-one in 400 ml of tetrahydrofuran was stirred at -10 ° C under stirring. 150 ml of an approximately 2M solution of phenyllithium in a mixture of benzene and ether (75:25) is slowly added dropwise. After the addition was complete, the mixture was further stirred at -10 ° C for 30 minutes. The solution is then added dropwise

20.4 g (0.11 mol) of (4-methyl-1-piperazinyl) -acetic acid ethyl ester in 100 ml of absolute tetrahydrofuran The reaction mixture was allowed to warm to room temperature and stirred for a further 2 hours. 1. 11.3 g (32.2% of theory) of a colorless product are obtained, which according to the spectroscopic data is identical with the compound obtained according to Example 1.

Example 7

Advantageously, other organic solvents or solvent mixtures which are suitable for reaction with alkyllithium or aryllithium can also be used in the process of Example 1 instead of tetrahydrofuran.

Some examples are given in the following table (the weight data given in Example 1 applies):

solvent

Claims (4)

Subject A process for the production of 5,11-dihydro-11- [4-methyl-1-piperazinyl] acetyl-1 H -pyridof2.Sb] (1,4) benzodiazepin-6-one and its salts with inorganic or organic acids, characterized in that: The process of claim 5, wherein the 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one of formula I is reacted in an organic solvent with at least two equivalents of alkyl lithium or aryl lithium at temperatures between -60 and 0. C and then with an ester of (4-methyl-piperazinyl) acetic acid of formula III ^CH 3 ^{F O, 'or} I ^ ^0R invention in which R represents an alkyl group, an aryl group or an aralkyl group, and the desired compound is isolated and optionally converted into its salts with inorganic or organic acids. 2. The process according to claim 1, wherein the reaction is carried out at a temperature of -10 ° C. 3. A process according to claim 1, wherein n-butyllithium, optionally in the presence of tetramethylethylenediamine, tert-butyllithium, lithium diisopropylamide, lithium dicyclohexylamide or phenyllithium is used as alkyllithium or aryllithium and ethers such as diethyl ether are used as solvents. aliphatic hydrocarbons, such as hexane, mixtures of these solvents and optionally hexamethylammonium phosphide as a co-solvent. 4. The process according to claim 1, 2 or 3, wherein the esters are compounds of the formula III in which R is C1-C6alkyl or phenylmethyl, phenylethyl or phenylpropyl.