CS226745B2 - Method of preparing 5,11-dihydro-6h-pyrido(2,3-b)(1,4)-benzodiazepin-6-ones - Google Patents

Description

The above compounds are valuable starting materials for the preparation of medicaments, for example for the preparation of piernzepine, i.e. 5, H-dihydro-11-L (4-methyl-1-piperazinyl) acetyl-6H-pyrrolo4-bK1,4benzothiazepine-H-one-dihydrochloride , a substance with a strong anti-viral effect and an anti-gastric juice-inhibiting effect.

In accordance with the invention, the above-mentioned compounds of the formula I are prepared by the formation of a β-halo-3-3-aminopyridine of the formula II

226 745

(II) in which

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

(III) wherein

R is as defined above and represents an alkyl group having 1 to 3 carbon atoms, preferably a methyl group,

- 4 22В 745 in the presence of a basic condensing agent, - whereupon the resulting compound of formula IV is formed

(IV) wherein

R and Hal are as defined above, cyclized in a neutral or acidic environment, preferably in the presence of sulfuric acid, at a temperature of 100 to 200 ° C.

The novel process of the invention is particularly advantageously carried out in a single reaction vessel, wherein the resulting compound of formula IV is not isolated, but cyclization is carried out in the same reaction vessel after acidification of the reaction mixture to pH 7 or less.

The reaction of the compound of formula II and the anthrailic acid ester of formula III is carried out

22В 745 in the presence of an organic solvent and, as mentioned above, in the presence of a basic condensing agent. at a temperature between 10 and 120 ° C. As the basic condensing agents, for example, tetrabutylammonium hydroxide, sodium or potassium methoxide, sodium or potassium isopropoxide, sodium or potassium tert-butoxide, sodium hydride, lithium or sodium amide, or sodium hydroxide can be used. Examples include ethanol, toluene, xylene, dimethylsulphoxide, eulfolane or trichlorobenzene, with an excess of the starting alkyl ester of anti-furanilic acid being used as solvent.

The cyclization of the primary compound of formula (IV) is carried out whether the compound of formula (IV) is isolated or the process is carried out in a single reaction vessel, at a temperature between 100 and 2 ° C in a solvent, preferably trichlorobenzene or sulfolane, at neutral or acidic pH · When carrying out the reaction in a single reaction vessel, the alkaline reaction mixture in which the compound of formula (IV) has been prepared is acidified, preferably with sulfuric acid, followed by cyclization by heating to the above temperature.

Compounds of formula II, compounds of formula III and a basic condensing agent are reacted

The yields of the compounds of the formula IV are up to 98%, the yields of the final product of the formula I up to 87%.

The process for the preparation of the compounds of formula (I) is already known from German Patent Specification No. 1,179,943. This known process is a three-step reaction by first reacting the 2-halo-3-aminopyridine of the formula II with a reactive nitrobenzoic acid derivative, preferably the nitro compound formed is reduced and the compound of formula (IV) thus obtained is cyclized in the melt or in the presence of a boiling solvent such as paraffin or decalin, optionally in the presence of a basic catalyst or copper powder. Despite the fact that the yields of this process are lower than those of the process of the present invention, it uses hazardous 2-nitrobenzoyl chloride which is difficult to handle, while the anthranilic acid ester used as the starting material in the process of the present invention is very cheap. Furthermore, the prior art is a three-step process, while in accordance with the method of the invention, the compounds described can be obtained in a single

Also, cyclization can be carried out in a neutral or acidic medium and in the presence of the above solvent in a much easier and higher yield than in the known melt process. The cyclization yields in the known process are below the corresponding the yields obtained by the process according to the invention which achieve an overall yield of 87% ·

In addition, it is surprising that in the reaction of the compounds of formula II, In the presence of strong bases, the desired compounds of the formula IV are obtained, since it is known that pyridines containing 2 or 4 halogen atoms are converted very rapidly to the corresponding pyridinols, especially in an alkaline medium. sodium hydroxide solution or aqueous potassium hydroxide solution and a temperature of about 90 ° C. Reactions of this type are otherwise known in the literature. For example, 0 von Schickh et al. describe ▼ Ber. Dtsch. Chem. Ges. 1936. No. 12, p.

2594, 2600 and 2602 reacting 2-chloro-3-aminopyridine with sodium methoxide solution to form 2-methoxy-3-aminopyridine. For the above reasons, it is therefore particularly surprising to work with the method of the invention

226 745 not only does not exchange the halogen atom in the compound of formula II for an anionic residue of the basic condensing agent, but that compounds of the formulas IV and I are obtained in very high yields ·

The conversion of the compounds of the formula I into the aforementioned pisenzepine or pirenzepine analogs is described in German Patent Specification No. 1 795 183.

The invention is illustrated by the following non-limiting examples.

A · Examples of preparation of 2-chloro-3- (2-minobenzoyl) amino-pyridine

Example 1

51.4 g (0.4 mol) of 2-chloro-3-minopyridine are suspended in 160 ml of xylene and 58.4 g (0.52 mol) of potassium tert-butoxide are added first and then over about 25 minutes. 6 g (0.52 mol) of 2-aminobenzoic acid methyl ester · The mixture is heated at reflux for 1 hour, then cooled to about 20 ° C and 100 ml of water are added *

- 9 ·

226 745 The crystal suspension is acidified with concentrated hydrochloric acid to pH 6, the crystalline material is filtered off with suction, washed with water and dried to constant weight at 80 DEG C. in vacuo.

Yield: 94.3 g (95.2% of theory);

The following overview summarizes other preparation options under similar reaction conditions.

solvent base temperature yield (% of theory) dimethylsulfoxide terč.hutoxid Deň: 32 ° C 98.0 Potassium sulfolane terč.butoxid 60 ° C 97.4 Potassium toluene terč.butoxid 90 ° C 91.9 Potassium dimethylsulfoxld sodium isopropoxide Deň: 32 ° C 98.0

- 10 ·

Example 2

228 · 745

12.85 g (0.1 mole) of 2-chloro-3-amino-pyridine are dissolved in 65 ml of dimath31milfoxide and 10.9 g of a 50% suspension of sodium amide in toluene (5 ml) are added at room temperature. (45 g of sodium amide is 0.14 mol). 19.7 g (0.13 mol) of 2-aminobenzoic acid methyl ester are added to the mixture over 10 minutes, the resulting mixture is stirred at 50 ° C for 30 minutes, then cooled. 100 ml of water and concentrated hydrochloric acid are added to the mixture under nitrogen atmosphere to pH 6. The crystal suspension is filtered off with suction, the product is washed with water and dried to constant weight at 50 ° C.

M.p. 170 DEG-172 DEG C., yielding 23.9 g (96.4% of theory).

For example, lithium amide can also be used in addition to sodium amide, in which case the yield is

68.4% of theory.

- 11 226 745

25 g (0.2 mol) of 2-chloro-3-iminopyridine a

16.2 g (0.3 mol) of sodium methoxide are heated to boiling with 160 ml of toluene and 30 ml of solvent are distilled off from the mixture to 100 ° C. 30 ml of fresh toluene are added to the reaction mixture starting at 70 ° C. 39.6 g (0.26 mol) of 2-aminobenzoic acid methyl ester are added over 20 minutes. The resulting mixture is stirred at 90-95 ° C for 4 hours, after which a further 5.4 g is added. (0.1 mol) of sodium methoxide and the mixture is further reacted at 90-95 ° C.

After completion of the reaction, the mixture is cooled to about ° C, the product is filtered off with suction and washed with about 200 ml of petroleum ether. The filter residue, well suctioned to dryness, is suspended in 250 ml of water and adjusted to pH 6 with concentrated hydrochloric acid. The crystal suspension is filtered off with suction, washed with water and the residue on the filter is dried at 50 ° C until constant.

The yield of the product melting at 168-170 ° C is 37.7 g (76.1% of theory).

The following overview lists the additional potency under similar reaction conditions:

solvent base temperature yield note (% theory)

226 745 0 ►, SM «0 ^r 0 d O Li 0 O O O Ό rH «0 O and O £ and ► O 0 O WITH O © φ • Л »Я φ ÍH 00 and> 00 P £ P

0 3 O O > ► O O ΛΙ Д4 M M ^r d <0 O O 0 ⁰ 0 9 O M 0 If 0 O O O O rH «0 rH X! O xt O O p- O ► 0 O 0 O O 0 O and 0 Φ q φ • H > « • H >> N rH ⁴ 0 ГН Φ Й Φ If Φ ra 00 n £ P £ P

Λ «Φ \O M · LA E • · » r <D C- Ol Ol 00 t * · cn t- LA <0

O O O O O O O O O O LA O LA O LA b- what M r- 0-

Ϊ AND 3 5 O O O O O 00 m <0 00 m • 0 • 0 O «0 • 0 no «Rl • rl • d • d TO TO M M O O O O O xl xt XL XL X0 • P -P + » • P • P Φ Φ Φ Φ Φ WITH Θ E 6 WITH

0 rH 0 00 H £ 9 rH M £ 0 rd О h φ -Ρ го φ rd ⁴ Φ Й Д -P O H д Η rd Ф Ф τ! O cjj xf Λ Φ rd with M r4 ω xl Ρ • Ρ 00 P> • Я O 0 да Ή φ 0 Р? К <0 00 0 Φ 6 0 XI

potassium dimethyl sulfide methoxide 50 ° C 52.0 precipitated with water and foxide hydrochloric acid

- 1 * Example 4

226 745

51.4 g (0.4 mol) of 2-chloro-3-minopyridine are dissolved in 160 ml of dimethylsulfoxide and 24.0 g (0.6 mol) of powdered sodium hydroxide are added. The mixture was heated to about 80 ° C under a vacuum pump for 1 hour, with very little distillate being distilled. Cool the contents of the flask to 50 ° C, add over about 30 minutes

2-Aminobenzoic acid methyl ester (78.6 g, 0.52 mol) was added and the mixture was stirred at 50 ° C for 30 min. An additional 11.7 g (0.077 mol) of the ester was added. After another reaction. After 2.5 hours, 11.7 g (0.077 mol) of 2-aminobenzoic acid methyl ester and 5.0 g (0.125 mol) of sodium hydroxide powder are added again, the mixture is stirred at the above temperature for 30 minutes, then cooled. to about 20 ° C, 190 ml of water and concentrated hydrochloric acid are added to pH 6. The suspension of crystals. The product is filtered off with suction, washed with water and dried at 50 DEG C. to constant hmoon.

Yield of the product, m.p. 170 ° C is 30.7 ((310% of theory)).

·

Bros. 5

226 745

25.7 g (0.2 mol) of 2-chloro-3-mlnopyridinium are suspended in 160 ml of toluene and 11.2 g of a ca 60% suspension of sodium hydride (0.28 mol) and 39.6 g (0.1 M) are added. 26 mol) of 2-aminobenzoic acid methyl ester * The reaction mixture is stirred at 90 ° C for 4 hours, then cooled to room temperature and 100 ml of water are added under nitrogen. 6. Aspirate, filter residue is washed with water and dried to constant weight at 50 ° C.

The yield of the product melting at 168-170 DEG C. is 36.8 g (74.3% of theory).

Example '6

25.95 g (0.1 mol) of tetramylphenone monoxide hydroxide (obtained by evaporation of a commercial solution of tetrabutylmmonium hydroxide) was dissolved in 30 ml of dimethylsulfoxide and 9.2 g (0.072 mol) of 2-chloro-3-amino-pyridine was added. Starting at about 30 ° C, 14.0 g (0.092 mol) of 2-lmio-benzoic acid meehhyester are added over about 20 minutes while operating under vacuum.

226 745 water pump * At the end of the addition, the reaction mixture is stirred for 50 minutes at 50 ° C and then for 30 minutes at 70 ° C, cooled to room temperature and 30 ml of water and concentrated hydrochloric acid are added. pH 6. The crystal suspension is filtered off with suction, the residue on the filter is washed with water and at room temperature. Dry at constant 50 ° C ·

Yield: 10.3 g (58.1% of theory);

B. Examples of Preparation of 5,11-iydydro-6H-pyrido [2,3-b] [11,4] benzodiazepio-6-oou

51.4 g (0.4 mol) of 2-chloro-3-ethoxy pyridine are suspended in 160 ml of 1,2,4-trichloride, and 58.4 g (0.52 mol) are added to the suspension. Potassium tert-butoxide · Add 78.6 g (0.52 mol) of 2-amino acid methyl ester in 30 minutes, stir at 50 ° C for 1 hour, then dilute the reaction with 220 ml · 1 It is added to it

22.8 ml of concentrated sulfuric acid and tert-butanol were removed by distillation under vacuum.

226 745 hours at 115 ° C - and then 2 hours at 160 ° C · For working-up, the reaction mixture is cooled to room temperature, the crystal suspension is filtered off with suction and the residue on the filter is washed with 300 ml of petroleum ether. is suspended in 670 ml of 50% aqueous acetone at about 50 DEG C., 60 ml of concentrated ammonia are added. The mixture is stirred at about 50 DEG C. for 1 hour, filtered off with suction, washed with water and overnight. was dried at 80 - ^C · Jhrodukt .se pulverized, slurried in 5 ⁰⁰ ml of petroleum ether, filtered off with suction and washed with patroletherem · Z - well sucked dry filter cake is then water-deionisovmou vymmjí chloride and sulfate ions - and - the material is dried at a temperature of 80 ° C to a constant tanoonosi

Melting point: 279-281 ° C (dec.) Yields 58.7 g (69.5% of theory).

For example, a salt of 1,2,4-trifluorobenzene may also be used as a solvent, in which case the yield is 87.4% of theory.

Example 8

226 745

100 g (0.4 mol) of 2-chloro-3- (2-aminobenzoylaminopyridine) are suspended in 400 ml of 1,2,4-trichlorobenzene, 1 ml of concentrated aioic acid is added and the mixture is stirred at 160 DEG C. for 22 hours. C. After cooling to room temperature, the reaction mixture is filtered off with suction, the filter residue is washed with 200 ml of petoohetheum and the well-dried filter cake is suspended in 670 ml of 50% aqueous acetone, 40 ml of concentrated ammonia are added to the suspension. 50 ° C, then suction filtered, the residue on the filter was freed of chloride ions by washing with water and dried at 80 ° C to constant weight.

Yield of the product melting from ozone at

279 DEG -280 DEG C., 65.7 g (77.0% of theory).

Claims (4)

- 18 BACKGROUND OF THE INVENTION 226 745 A process for the preparation of 5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepin-6-ones of the general formula I H (I) wherein R represents a hydrogen atom, a halogen atom or a methyl group, characterized in that the 2-halo-3-fiminopyridine of the general formula II in which: 226 745 Hal is a halogen atom, reacted with an anthranilic acid ester of formula III (III) in which: R is as defined above and R 1 represents an alkyl group having 1 to 3 carbon atoms, in an organic solvent in the presence of a basic condensing agent, at a temperature between 10 and 120 ° C, 20 and the resulting compound of formula IV 220 745 (IV) wherein R and Hal are as defined above, then cyclized at pH 7 and below, at a temperature between 100 and 200 ° C. 2. A process according to claim 1, characterized in that the resulting compound of formula (IV) without isolation, after addition of a mineral acid, preferably sulfuric acid, is added to the reaction mixture to a pH of 7 or lower at 100 to 200 ° C. a compound of formula I. - 21 226 745 3. A process according to claim 1, wherein the basic condensation agent is tetrabutylanionium hydroxide, sodium or potassium methoxide, sodium or potassium ionopropoxide, sodium or potassium tert-butoxide, sodium hydride, lithium amide, potassium amide, sodium amide or sodium amide. sodium hydroxide· Process according to Claims 1 to 3, characterized in that molar amounts of the compounds of the formulas II and III and of the basic condensation agent or an excess of the compound of the formula III and / or of the basic condensation agent are used for the reaction.