DD202571A5 - PROCESS FOR THE PREPARATION OF 5,11-DIHYDRO-6H-PYRIDO (2,3-B) - (1,4) BENZODIAZEPINE-6-ONEN - Google Patents

Abstract

A new process for the preparation of 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-6-ones by reacting a 2-halo-3-aminopyridine with an anthranilic acid ester followed by Ring closure of the obtained 2-halo-3 (2-aminobenzoyl) aminopyridine. These compounds are starting materials for the preparation of pharmacologically valuable derivatives, such as pirenzepine.

Description

The invention relates to a novel process for the preparation of 5 »11-dihydro-6H-pyrido / 2,3-b7 / T, 47 ^tenzodiaze P ⁱⁿ -6-ones of the general formula

-UH-OX

(D,

in the

R represents a hydrogen or halogen atom or the methyl group

These compounds are valuable starting materials for the preparation of medicaments, for example for the preparation of pirenzepine (5,11-dihydro-11/1-methyl-1-piperazinyl) acetyl7-6H-pyrido / 2,3-b7- / T, , 47benzodiazepin-6-one dihydrochloride), a substance with a strong ulcer and gastric juice secretion-inhibiting action.

Characteristic of the known technical solutions

A process for the preparation of compounds of the formula I was already known from DE-PS 1 179 943. This known process is a 3-stage process in which initially a 2-halo-3-amino-pyridine of the formula II with a reactive ITitrobenzoesäurederivat, preferably its acid halide, reacted, the resulting nitro compound is reduced and the thus obtained compound of formula IV in the melt

-2FEB1983 * nefiai3

24 1 61 8 6 - ² -

or in the presence of a high boiling solvent such as paraffin or decalin, optionally in the presence of a basic catalyst or copper powder.

The yields obtained in the known process are not satisfactory. Another disadvantage of the known method is that the used 2-stitro-benzoyl chloride is a difficult to handle, dangerous reagent and the synthesis of the compounds of formula I must be carried out in a complicated 3-stage process.

Aim of the invention;

The aim of the invention is to provide an improved process for the preparation of 5,11-dihydro-6H-pyrido / 2,3-b7- / T, 4; 7benzodiazepin-6-ones, with which the desired products in a simple and economical manner in good yield can be produced.

Explanation of the essence of the invention

The invention has for its object to find suitable, readily available and inexpensive reactants for the preparation of 5,11-dihydro-6H-pyrido / 2,3-b7- / T, _j 47benzodiazepin-6-ones.

According to the invention, a 2-halo-3-aminopyridine of the general formula

1 61

60 880 11 1.2.83 '

(ID,

Hal

Hal is a halogen atom, preferably a chlorine atom, reacted with an anthranilic acid ester of the general formula

(III)

in which R is defined as above and R.sup.1 denotes an alkyl group having 1 to 3 carbon atoms, preferably the methyl group, in the presence of a basic condensing agent, wherein first a compound of the general formula

-HH - CO

Hal

(IV),

in which R and Hai have the meanings given, is formed, and subsequent ring closure of this compound in a neutral or acidic medium, preferably in the presence of sulfuric acid, at temperatures of 100 to 200 ⁰ C.

The novel process is particularly suitably carried out in the form of a one-pot process, whereby the formed compound of formula IV is not isolated, but the ring closure in the same reaction vessel after acidification of the reaction mixture to a pH of 7 or less is carried out.

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The reaction of a compound of formula II with an anthranilic acid ester of the formula III is carried out in the presence of an organic solvent and, as already mentioned, in the presence of a basic condensing agent at temperatures between 10 to 120 ° C. As basic condensing agents, compounds such as tetrabutylammonium hydroxide, sodium or The solvents used are, for example, ethanol, toluene, xylene, dimethylsulfoxide, sulfolane or trichlorobenzene, but it is also possible to use them as solvents Excess anthranilic acid alkyl ester can be used as solvent.

The ring closure of the resulting compound of formula IV, regardless of whether the compound of formula IV is isolated or the process is carried out as a one-pot reaction, at temperatures of 100 to 200 ⁰ C in a solvent, preferably trichlorobenzene and sulfolane, at neutral or acidic pH. When carried out as a one-pot reaction, the alkaline reaction mixture containing the compound IV is acidified, preferably with sulfuric acid, whereupon the ring closure is then carried out by heating to the temperatures mentioned.

The compounds of general formula II, general formula III and, the basic condensing agent are used in molar amounts, or there is an excess of the compound of formula III and / or the basic condensing agent used. The yields of the compounds of the formula IV are up to 98%, those of the end product of the formula I up to 87 %

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1 · 2 · 83

The process according to the invention has numerous advantages over the known process. Apart from the fact that the yields of the known process are lower, there is also used a poorly handled and dangerous 2-mtobenzoyl chloride, while the anthranilic acid ester is a particularly good starting material , In addition, it is a 3-stage process, while the process according to the invention, the compounds can be obtained in a one-pot reaction <> The ring closure can be in a neutral or acidic environment in the presence of the specified solvent perform much better and in higher yields than in the known process, which is usually carried out in a melt · The yields of ring closure are in the known method below those of the method according to the invention, with an overall yield of 87 % is achieved ·

It is also surprising that in the reaction of compounds of general formula II with compounds of general formula III in the presence of strong bases, the desired compounds of formula IV are obtained, since it is known that pyridines with halogen atoms in 2- or 4-position , in particular in the alkaline medium * are converted very rapidly into the corresponding pyridinols. It suffice for this purpose z. B, an alcoholic Hatriumhydrosidlösung or an aqueous potassium hydroxide solution and temperatures around 90 ⁰ C. Such reactions are otherwise known from the literature, for example, described by Schickh et al. in Ber. Dtsch · Chem. Ges. 1936 , Ur. 12, pp. 2594, 2600 and 2602, the reaction of 2-chloro-3-aminopyridine with a sodium methoxide solution to give 2-methoxy-3-aminopyridine. It was therefore particularly astonishing for the reasons given above that in

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1.2.83,

Not only the halogen atom of the compound of formula II is not exchanged for the anionic radical of the basic condensation agent of the erfindungsgeinäßen reaction, but that the compounds of formula IV and I are obtained in a very high yield.

The conversion of a compound of general formula I into the initially mentioned pirenzepine or into pirenzepine-like compounds is described in DE-PS 1 795 183.

Exemplary embodiment

The following examples are intended to explain the invention in more detail.

Examples of the preparation of 2-chloro-3- (2-aminobenzoyl) aminopyridine

example 1

51.4 g (0.4 mol) of 2-chloro-3-aminopyridine are suspended in 16O ml of xylene. To this is added 58.4 g (0.52 mol) of potassium tert-butoxide and, within about 25 minutes, 78.6 g (0.52 mol) of 2-aminobenzoic acid methyl ester. Then heated to reflux for 1 hour, the reaction mixture is cooled to about ⁰ · 20 C, adding 100 ml of water. The crystal suspension is adjusted with concentrated hydrochloric acid to pH 6, drained, washed with v / ater and dried at 80 ⁰ C in vacuum to constant weight. Yield: 94.3 g (95.2% of theory) Mp: 169-171 ⁰ C.

161

60 880 11 1.2.83

Further production possibilities under similar reaction conditions:

Solvent base

Temperature yield in % of theory

Dimethy1- Potassium tert · - 50 ⁰ G sulfoxide butoxide SuIfοlan Potassium tert 60 ⁰ C butoxide toluene KaIium tert - 90 ⁰ G butoxide Dimethy1- ETatrium- 50 ⁰ C sulfoxide isopropylate Example 2

98.0

97.4

91.9

98.0

12.85 g (0.1 mol) of 2-chloro-3-aminopyridine are dissolved in 65 ml of dimethylsulfoxide and, at room temperature, 10.9 g of 50% strength ITatriumamidsuspension in toluene (= 5.45 g Hatriumamid, 0.14 mol) was added , Then allowed to within 10 minutes 19.7 g (0.13 mol) of 2-aminobenzoic acid methylester flow added and stirred for 30 minutes at 50 ⁰ G. For working up, is cooled to 20 G, under nitrogen atmosphere, 100 ml of? / Ater and conc. Hydrochloric acid added to pH 6. The crystal suspension is filtered off, washed with water and dried at 50 ⁰ G to constant weight. Yield: 23.9 g (96.4 % of theory) Pp: 170-172 ⁰ G.

2k 1 6 1 8 6 " ⁸ " ^60B8011

1.2 · 83

Instead of sodium amide, ζ. B. also lithium amide can be used. Yield: 68.4 % of theory.

Example 3

25.7 g (0.2 mol) of 2-chloro-3-aminopyridine and 16.2 g (o, 3 mol) of sodium bicarbonate are heated in 160 ml of toluene to boiling and distilled off 30 ml of solvent to a temperature of 100 ⁰ C. , One 30 ml of fresh toluene to the reaction mixture and allowed starting at 70 ⁰ G within 20 minutes 39.6 g (0.26 mole) was added 2-amino-benzoic flow. Thereafter, the mixture is stirred at 90 to 95 ⁰ O for 4 hours. Optionally, after this time, another 5.4 g (0.1 mol) of sodium methylate is added and allowed to react at 90 to 95 ⁰ C.

After completion of the reaction, the mixture is cooled to about 15 ⁰ C, filtered off with suction and washed with about 200 ml of petroleum ether after · The well-dried filter residue is suspended in 250 ml of water and acidified with conc. Hydrochloric acid adjusted to pH 6. The crystal. Porridge is filtered off, washed with water and dried at 50 ⁰ C to constant weight

Yield: 37.7 g (76.1% of theory) Pp: 168-170 ⁰ C.

Further production possibilities under similar reaction conditions.

Solvent base xylene

dimethyl sulfoxide

SuIfοlan

Sodium methylate, sodium methylate

Uatriuramethylat

Ethanol abs. Itfatrium methylate 75 C

Anthranilic acid sodium methylate 75 ⁰ C methyl ester

Dimethyl potassium methylate, Bulfoxide

Temperature ⁰ o Yield in % of theory Remarks water 90 ⁰ C 76.3 water 45 ⁰ C 97.4 Precipitation by means of hydrochloric acid water 70 ⁰ C 72.6 Precipitation by means of hydrochloric acid water 75 ⁰ C 52.4 Precipitation by means of hydrochloric acid 75 68.5 Precipitation by means of hydrochloric acid

52.0

Precipitation by means of water and hydrochloric acid

• O ro

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Example 4

51.4 g (0.4 mol) of 2-chloro-3-aminopyridine are dissolved in 16 ml of dime of thyisulfoside and 24.0 g (0.6 mol) of sodium hydroxide are added. The mixture is heated under application of a water-jet vacuum for 1 hour to about 80 ⁰ C, with small amounts distilling over · The contents of the flask is then cooled to 50 ⁰ G. Within about 30 minutes left

78.6 g (0.52 mol) of 2-aminobenzoic acid methyl ester, stirred for 30 minutes at 50 ⁰ C and adds another 11.7 g (0.077 mol) of ester added. Subject another 2 1/2 hours again

11.7 g of 2-aminobenzoic acid methyl ester (0.077 mol) and 5.0 g of powdered sodium hydroxide (0.125 mol) were added to the reaction mixture and stirred for 30 minutes at the indicated temperature. It is cooled to about 20 ⁰ C, 190 ml of water and conc. Hydrochloric acid to pH 6 added. The crystal slurry is filtered off, washed with water and dried at 50 ⁰ C to constant weight.

Yield: 30.7 g (31.0% of theory) Mp: 168-170 ⁰ C.

Example 5

25.7 g (0.2 mol) of 2-chloro-3-aminopyridine are suspended in 16O ml of toluene, 11.2 g of sodium hydride suspension (about 60%, 0.28 mol) and 39.6 g (0.26 Mol) 2-aminobenzoic acid methyl ester added. The mixture is then stirred for 4 hours at 90 ⁰ C, cooled to room temperature and allowed to stand under nitrogen atmosphere. Add 100 ml of V / asser. The crystal pulp is made by conc. Hydrochloric acid adjusted to pH 6, filtered off, washed with water and dried at 50 ⁰ C to constant weight.

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Yield: 36.8 g (74.3% of theory) Mp: 168-170 ⁰ C.

Example 6

25.95 g (0.1 mole) of tetrabutylammonium hydroxide (obtained by evaporation of commercially available tetrabutylammonium hydroxide solution) are dissolved in 30 ml of dimethyl sulfoxide and 9.2 g (0.072 mole) of 2-chloro-3-aminopyridine are added. Beginning within about 20 minutes, 14.0 g (0.092 mol) of 2-amino-benzoic at about 30 ⁰ C are added, the process being carried under application of water-jet vacuum, supplied while the addition, the mixture is stirred first for 50 minutes at 50 ⁰ C and after 30 minutes at 70 ⁰ C. After cooling to room temperature, 30 ml of water and conc. Hydrochloric acid added to pH 6. The crystal slurry is filtered off, washed with water and dried at 50 ⁰ G to constant weight. Yield: 10.3 g (58.1% of theory) Pp: 168-170 ⁰ C.

3. Examples for the production of

5,11-dihydro-6H-pyrido / 2,3-B7 / T, 47benzodiazepin-6-one

Example 7

51.4 g (0.4 mol) of 2-chloro-3-aminopyridine are suspended in 16O ml of 1,2,4-trichlorobenzene and added 58.4 g (0.52 mol) of potassium tert-butoxide. Within 30 minutes, allowed to 78.6 g (0.52 mol) was added dropwise 2-aminobenzoate and stirred for 1 hour at 50 ⁰ G. Subsequently,

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the reaction mixture diluted with 220 ml 1 ^^ - trichlorobenzene, 22.8 ml conc. Sulfuric acid is added and distilled under the application of vacuum, the tert-butanol is stirred for 24 hours at 115 ⁰ C and then for 2 hours at ΐβθ ⁰ C. For workup is cooled to room temperature, the crystal suspension is filtered off with suction and washed with 300 ml of petroleum ether · The good dry-filtered filter cake is suspended in 670 ml of 50% aqueous acetone of about 50 ^° C., 60 ml of conc. Ammonia added and stirred for 1 hour at about 50 ⁰ C. It is then filtered off, washed with water and dried overnight at 80 ⁰ C. The substance is comminuted, stirred into 500 ml of petroleum ether, filtered off with suction and washed with petroleum ether · The well sucked dry filter cake is finally washed with deionized Y / ater chloride and sulfate-free and dried at 80 ⁰ C until constant weight. · Yield: 58.7 g (69.5% of theory) Pp: 279-281 ⁰ C dec,

Instead of 1,2,4-trichlorobenzene z _o B, also sufolin can be used as a solvent. Yield: 87 »4 % of theory.

Example 8

100 g (0.4 mol) of 2-chloro-3- (2-aminobenzoyl) aminopyridine are suspended in 400 ml of 1,2,4-trichlorobenzene, 1 ml of concentrated "sulfuric acid added and the mixture stirred at 16O ⁰ C for 22 hours , After cooling to room temperature is filtered off with suction, washed with 200 ml of petroleum ether and the well-dried filter cake suspended in 670 ml of 50% aqueous acetone · It adds 40 ml of conc. Ammonia, stirred for 15 minutes at ca, 50 ⁰ C, then sucks, washed with

1 81

60 880 11 1.2.83

Water free of chloride and dried at 80 C to constant weight.

Yield: 65.7 g (77.0 % of theory)

Mp 279-280 ⁰ C dec.

Claims (2)

241 61 60 880'11 1.2.83 Invented wigs ansόγ uch 1. A process for the preparation of 5,11-dihydro-6H-pyrido- / 2% 3-jb7- / T, 4 _: 7benzodiazepin-6-ones of the general formula (D, in the R is a hydrogen or halogen atom or the methyl group, characterized in that a 2-halogen-3 aminopyridine of the general formula (ID, in the Hal represents a halogen atom with an anthranilic acid ester of the general formula (III) - 15 - 60 380 11 1.2.83. in the R is as defined above and R _- . represents an alkyl group 'having 1 to 3 carbon atoms, reacted in an organic solvent in the presence of a basic condensing agent at temperatures between 10 and 120 ⁰ C and the resulting compound of formula IV in the R and shark have the meanings given, at a pH of 7 and below at temperatures between 100 and 200 ⁰ C is cyclized. A method according to item 1, characterized in that the resulting compound of formula IV without isolation after addition of a mineral acid, preferably sulfuric acid, to the reaction mixture to a pH of 7 and below, at 100 to 200 ⁰ C in the compound of formula I is convicted. Process according to items 1 and 2, characterized in that tetrabutylammonium hydroxide, sodium or potassium methylate, ITatrium or potassium isopropylate, sodium or potassium t-butylate, sodium hydride, lithium amide, potassium amide, sodium amide or sodium hydroxide is used as the basic condensation agent. " 1618 δ " ¹⁶ ~ 60 880 11 1,2.83 Process according to points 1 to 3j, characterized in that molar amounts of the compounds of the formula II and III and of the basic condensing agent or an excess of the compound of the formula III and / or of the basic condensing agent are used.