HU189012B - Process for production of optically active 3-ethil-2,6-dimethil-6,7,8,9-tetrahydro-4h-pirido /1,2-a/-piramidin-4-on enentiomers - Google Patents

Abstract

The optically active enantiomers of racemic 3-ethyl-2,6-dimethyl -6,7,8,9-tetrahydro-4H -pyrido-(1,2-a)-pyrimidin -4-one are sepd. by (a) reacting the racemic cpd. in an alcohol with 1-4 carbons, pref. in methanol, with (-)-dibenzoyl-tartaric-acid, liberating the enantiomer with the absolute configuration 6R-(-) from the crystalline ppte. of the diastereomeric salt with an inorganic base, pref. with ammonium-hydroxide, opt. evaporating the mother liquor with (-)-dibenzoyl-tartaric -acid in a 1:3 to 1:8 wt. ratio mixt. of water and a halogenated aliphatic satd. solvent, pref. chloroform and liberating the (+)-isomer from the pptd. crystalline salt with an inorganic base, pref. ammonium-hydroxide. This is followed by (b) reacting the racemic cpd. in a 1:3 to 1:8 wt. ratio mixt. of water and a satd. aliphatic chlorinated solvent, pref. chloroform, with (-)-dibenzoyl-tartaric-acid, the enantiomer with the absolute configuration 6S-(+) is liberated from the crystalline diastereomeric salt ppte. with an inorganic base, pref. ammonium-hydroxide, the (-)-isomer is opt. liberated from the mother liquor with an inorganic base, pref. ammonium -hydroxide, the resulting raw enantiomers are opt. purified. 888

Description

The present invention relates to a process for the preparation of a novel optically active 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro

- 4H-pyrido [1,2-a] pyrimidin-4-one enantiomers.

The racemic is 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro

Preparation of 4H-pyrido [1,2-a] pyrimidin-4-one

3 - ethyl formed by the condensation reaction of amino - 6 - methylpyridine with ethyl 2 - ethylacetoacetate

By catalytic hydrogenation of 2,6-dimethyl-4H-pyrido [1,2-a] pyrimidin-4-one (1979, J. Heterocycline Chem. 76, 457, 457). The resolution of the compound has not yet been resolved.

It has been found that separation of the various resolution agents (tartaric acid, camphorsulfonic acid, dibenzoyl tartaric acid, etc.) can be achieved with dibenzoyl tartaric acid. Various methods have been tried, of which the preferred ones are described below.

When resolved with a semi-equivalent amount of a resolving agent, using a combination of water and chloroform solvents, the mixture is bleached to form a precipitate which solidifies within a few days. However, crystallization takes only a few minutes with the seed crystal. The precipitated salt is the (-) - dibenzoyl-d-tartaric acid salt of the enantiomer of 6S- (+) - absolute configuration. Yield 56.7%, but 6S- (+) absolute configuration isomer ([?] D = + 54.9 °; (c: 1, methanol)) liberated from the salt with an inorganic base, indicating a neutral yield. and a sour salt precipitates. The crude 6R - (-) absolute configuration enantiomer ([α] D = -43 °; (c: 1, methanol)) isolated from the mother liquor was 98%.

The crude enantiomers can be recovered as a dense oil and then, upon standing at room temperature (25 ° C), some of them become crystalline which can be separated from the oily phase. Thus, for example, two thirds of the 6S (+) isomer of absolute configuration crystallizes out and has a rotation almost twice that of the crude enantiomer ([α]) / = + 106 °; (c: 1, methanol)).

Purification of the crude enantomers can also be accomplished by crystallization of the melt at room temperature. The crystalline portion is filtered to give the final product.

When the resolution is carried out in a methanolic medium, the dibenzoyl tartaric acid crystallizes with the 6R - (-) enantiomer of absolute configuration and. significantly higher yields are obtained and enantiomers with higher optical rotation are obtained. The crude enantiomers are obtained by evaporation after chloroform extraction, and some of the oily residue crystallizes out, with a higher optical purity. The method can also be used for cleaning. The diastereomeric salt ⁵ was found to be the clearest (Wd -109-111 °; (c: 1 methanol)) and the highest yield (82.3%) when * the resolution was performed so that the racemic compound methanol solution was first ₀ to 0.25 equivalents of (-) - dibenoil-d-tartaric acid, the resultant diastereomer salt is filtered and the mother liquor was again treated with the same quantity rezolválóágenssel. The diastereomeric salts thus obtained were isolated in 99% yield with high inorganic base ([α] θ = - 75 ', (c: 3.33, chloroform)) with an inorganic base. From the mother liquor · the (+) - isomer can be purely purified ([a] '= +93.5 (c: 0.25, chloroform)) by re-resolution after evaporation of θ after addition of water and chloroform according to the previous method (-) - dibenzoyl-d-tartaric acid. The optical purity of the resulting enantiomers was determined by 1 H NMR.

Racemic and optically active 3 - ethyl - 2,6 - dimethyl

- 6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine

- 4 - ones antiserotonin activity determined Konzett-test (Konzett H., Rossler R., Arch Exp Path, Pharm 1940, 195, 71st...) On guinea pigs ^U needles. The results are shown in Table 1:

Table 1 Test compound Rotation capacity (c = 1, methanol) Inhibition of 5-hydroxytryptamine-induced convulsions _ID50 : pmol / kg Racemic 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one - 21.6 65-3-Ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one (+) Π3.8 50.0 6R-3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4/7-pyrido [1,2-a] pyrimidin-4-one (-) 104.5 15.9 * theophylline anisate (known) - 14.0

* = lasting effect

-2189 012

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as beneficial bronchodilators.

(I) wherein a low toxicity, oral administration in rats and mice LD _S0 is above the value of 500 mg / kg.

The compounds of formula (I) may be used in medicine in the form of formulations containing the active ingredient and inert solid or liquid organic or inorganic carriers. The formulations are prepared by methods well known in the art of pharmaceutical manufacture.

The compositions may be formulated for oral or parenteral administration or administration by injection, for example in the form of tablets, dragees, capsules, lozenges, powders, aerosol sprays, aqueous suspensions or solutions, or injectable solutions or syrups. The compositions may contain suitable solid diluents or carriers, sterile aqueous diluents or non-toxic organic solvents. Sweetening or flavoring agents may be added to the compositions for oral administration.

For oral administration, suitable tablets may contain, for example, lactose, sodium citrate, calcium carbonate, disintegrating agents (e.g., starch, alginic acid) lubricating agents (e.g., talc, sodium lauryl sulfate, magnesium stearate). The carrier for the capsules may be lactose and polyethylene glycol. Aqueous suspensions may contain emulsifying or suspending agents. The organic solvent slurry diluent is ethanol, glycerol, chloroform, and the like. may.

Formulations for parenteral administration and inhalation are solutions or suspensions of the active ingredient in a suitable medium (for example, peanut oil, sesame oil, polypropylene glycol or water). Injection formulations may be administered intramuscularly or intravenously or subcutaneously. Injectable solutions are preferably formulated in an aqueous medium and the pH is adjusted to a suitable level. The solutions may be prepared in isotonic saline or glucose solution if necessary.

The active ingredient content of the pharmaceutical compositions may vary within wide limits and may range from 0.005% to 90%.

The daily dose of active ingredient may vary within wide limits and will depend on the severity, age, weight, form of the condition and activity of the patient. In the case of oral administration, the daily dose is generally 0.05 to 15 mg / kg, whereas in the case of inhalation or intravenous administration, it is usually 0.001 to 5 mg / kg in single or multiple daily doses. The above information is for guidance purposes only and may vary both upwards and downwards depending on the requirements of the case and the physician's instructions.

The following examples further illustrate the process without limiting the invention to the examples.

L.A. example

20.6 g (0.1 mol) of racemic 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one are dissolved in 50 ml of methanol and (-) - Dibenzoylboronic acid (9.5 g, 0.025 mol) in methanol (1 ml) was added. The resulting solution was inoculated with pure diastereomeric salt, allowed to stand overnight, filtered, and washed twice with 3 ml of methanol (mother liquor I). The resulting diastereomeric salt weighed 12.7 g (45.1%), m.p. 122-128 ° C. [α] D = -109; (c: 1; methanol). To the mother liquor I was added (-) - dibenzoylboronic acid (9.5 g, 0.025 mol) in methanol (30 ml) again, seeded overnight, filtered and washed twice with 3 ml of methanol (mother liquor II). Said diastereomeric salt weighed 10.5 g (37.2%), m.p .: 124-130 ° C, [uj ² D = -107 ° (c 1, MeOH).

L.B. example

10.3 g (0.05 mol) of racemic. 3-Ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one was dissolved in 40 ml of chloroform. The solution was reacted with (-) - dibenzoyl tartaric acid (4.7 g, 0.0125 mol) in chloroform (40 ml) and water (10 ml). The reaction mixture was inoculated with neutral dibenzoyl tartrate of 6S - (+) - 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidine and after vigorous stirring, After 5 hours of external ice cooling, the precipitate was filtered and washed twice with 5 ml of chloroform (mother liquor III). The resulting diastereomeric salt mixture weighed 5.4 g (56.7%), m.p. 128-130 ° C.

2a example

A-l l.a. Example II. The mother liquor was evaporated, water (10 ml) was added, and (-) - dibenzoyl tartaric acid (11.4 g, 0.0245 mol), previously dissolved in chloroform (30 ml), was added. Hardly filtered curd precipitate is obtained which is removed by filtration (mother liquor IV). Weight: 15.1 g (53.5%), m.p. 138-141 ° C, [α] D = -39 ° (c: 1, methanol). The resulting diastereomeric salt (15.1 g) was suspended in water (26 ml), concentrated ammonium hydroxide (18 ml) and extracted with chloroform (3 x 30 ml). The combined extracts were dried over anhydrous sodium sulfate and evaporated. The residue was 6.3- (+) -3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a] pyrimidin-4-one. Weight: 6.25 g (60.7%). [α] D = + 93.3 ° (c: 6.25, chloroform).

2 b example

The l.b. The two solvent-phase mother liquors (mother liquor III) obtained in Example 1B are basified to pH 11 with concentrated ammonium hydroxide.

The organic phase was washed with water, dried and evaporated. The residue was 6R - (-) - 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4/7-pyridofl, 2-apyrimidin-4-one, weighing 5.1 g (98%). ), [α] D = -43 ° (c: 1, methanol).

3.a. example

The diastereomeric salts of Example 1a (12.7 g and 10.5 g, 82.3% yield) were suspended in 38 ml of water, basified with 50 ml of concentrated ammonium hydroxide, extracted three times with 110 ml of chloroform each, and the combined extracts were dried over anhydrous sodium sulfate. dried and evaporated. The residue is 6R- (-) - 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4/7-pyridofl, 2-a] pyrimidin-4-one. Weight: 10.2 g (99%), [j (= ₃ ° -95 ° (c 1.33, chloroform).

3b example

The l.b. The diastereomeric salt obtained according to Example 1 a

3.a. disassembled according to example. The residue is 6S - (+) 3-ethyl-2,6-dimethyl-6,7,8,9-terrahydro-4/7 pyrido [1,2-a] pyrimidin-4-one. Weight: 3.4 g (66%), Md ^{= +} 54.9 ° (c: 1; methyl alcohol).

Example 4

3.b. The crude (+) enantiomer ([g]) (Example 5) ([?] (= 54.9 ° (c: 1; methanol))) was heated to 50 ° C and allowed to stand at 25 ° C. heavily drained weight: 1.09 g, [a] /, ⁰ - + 95 ° (c 3.33, chloroform) of the filtrate.. 2.2 g, [α] θ = + 32.4 ° ( c: 3; chloroform).

Example 5

2.a. IV. The mother liquor is evaporated to dryness, mixed with 15 ml of concentrated ammonium hydroxide, extracted with 3 times 15 ml of chloroform, and the combined extracts are dried over anhydrous sodium sulfate and concentrated. The residue was 3.2 g (91.7%), 6S - (+) - 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]. pyrimidine at O 4 -, [α] D 20 = + 20 ° (c: 3.33; chloroform).

Claims (2)

Claims A process for the separation of the enantiomers of racemic 3-ethyl-2,6-dimethyl-6,7,8,9-tetrahydro-4/7-pyridofl, 2-a] pyrimidin-4-one characterized in that: a) reacting the racemic compound in a (1-4C) alkanol, preferably methanol, with (-) - dibenzoyl tartaric acid, liberating the 6R- (-) absolute enantiomer of the crystalline excellent diastereomeric salt with an inorganic base, preferably ammonium hydroxide, and optionally water and a halogenated saturated aliphatic solvent, preferably chloroform, in a ratio of 1: 3 to 1: 8 with (-) - dibenzoyl tartaric acid and liberating the (+) isomer from the crystalline salt with an inorganic base, preferably ammonium hydroxide. b) reacting the racemic compound with (-) - dibenzoyl tartaric acid in a 1: 3 to 1: 8 ratio of water and a halogenated saturated aliphatic solvent, preferably chloroform, to the 6S- (+) absolute configuration enantiomer of the crystalline excellent diastereomeric salt; preferably liberating ammonium hydroxide and, if desired, liberating the (-) - isomer from the mother liquor with an inorganic base, preferably ammonium hydroxide, and purifying the resulting crude enantiomers, if desired. 2. The l. The process of claim 1, wherein the purification of the crude enantiomers is carried out, if desired, by crystallizing the melt at room temperature and isolating by filtration.