HU207327B - Process for producing new raceme and optically active 12-alkoxycarbonyl-5,6,8,9,10,10a,11,15- octahydro-1,2'-oxazino/5,6-i/indolo-/2,3-a/ quinolyzine derivatives and acid additional salts thereof - Google Patents

Abstract

12 - (alkoxy-carbonyl) - 5,6,8,9,10a,11,15 - octahydro - 1', 2'-oxazino (4,3i) indolo (2,3a) quinolizine-derivs. of formula (I) and their salts are prepd. as intermediary prods. for pharmaceutical prods. based on the eburene-structure. - In (I) formula R is 1-4 carbon alkoxy carbonyl-ethyl or cyano-ethyl gp.; and R1 is -4 carbon alkyl gp..

Description

The compounds of formula (I) according to the invention are valuable intermediates in the preparation of therapeutic compounds of eburnan skeleton.

The present invention relates to a novel racemic or optically active 12-alkoxycarbonyl-5,6,8,9,10,10a, 11,15-octahydro-1 ', 2'-oxazino [5, 6-i] indolo [2,3-a] quinolizine derivatives - wherein

R is C 1-4 alkyl, C 1-4 alkoxycarbonylethyl or cyanoethyl;

R ¹ is a C 1 -C 4 alkyl group and its acid addition salts of formula (Ia) wherein R is as defined above, X- is an acid residue, by preparation of a tetrahydroindolo [2,3-a] quinolizine of formula II a compound of formula (III) in which R ¹ is a C 1 -C 4 alkyl group and optionally the racemic compound of formula (I) is obtained; compound is resolved and / or converted to the acid addition salt of formula (Ia).

In the general formulas, R and R ^{1 as C} 1-4 alkyl are linear or branched alkyl groups such as methyl, ethyl, η-propyl, i-propyl, η-butyl, chair-butyl and tertiary-alkyl. but il group. The same C 1 -C 4 alkyl groups may be present in the presence of R (C 1 -C 4 alkoxy) carbonyl ethyl. X 'as an acid residue can be any inorganic or organic acid residue such as chloride, perchlorate or oxalate or tartrate.

The compounds of formula (I) obtained by the process of the present invention are novel and are valuable intermediates for pharmaceutically active compounds of the eburnan backbone, such as vincamine, vincamine and apovinc-amino acid esters, e.g. cavinton, a novel and known hydroxyimino-octahydroindolo [2,3-a] quinoline, a key element in the synthesis. isine derivatives.

The alkyl bromopyruvate 2-oxime of formula III is prepared by T. L. Gilchrist, J. Med. Chem. Soc. Chem. Comm. 1089, 45 (1979)] may be prepared by bromination of alkylpyruvate with elemental bromine followed by oxidation of the resulting alkylbromopyruvate with hydroxylamine.

Of the compounds of formula II, 50 having R 1 -C 4 alkyl are known [E. Wenkert, B. Wicker. J. Am. Chem. Soc.

87, 1580 (1965)].

Compounds of formula (II) wherein R is alkoxycarbonyl ethyl or cyanoethyl are new from 2,3,6,7-telrahydro-4H, 12H-indolo [2,3-55] quinolizine (RN Schut, TJ Leipzig Chem. 1966, 101) may be prepared by reaction with alkyl acrylate or acrylonitrile.

The preparation of the compounds of formula (I) is described in detail below

The reaction of the compounds of the formulas II and III can be carried out in two ways. The reaction may be carried out in the presence of a strong base and phase transfer agent in a water-immiscible organic solvent-aqueous biphasic system. Alternatively, the reaction may be carried out in the presence of a strong base in a water-miscible organic solvent.

According to the first process, the compound of formula II or an acid addition salt thereof is dissolved in a water-immiscible organic solvent, preferably a chlorinated aliphatic hydrocarbon solvent such as dichloromethane, dichloroethane, chloroform and the like. and a catalytic amount of a tetrasubstituted ammonium halide, such as triethylbenzylammonium chloride, tetrabutylammonium bromide, as the phase transfer agent. The resulting mixture was cooled to -10 ° C and at a temperature of -5 ° C to -10 ° C simultaneously with an aqueous solution of a strong base such as sodium hydroxide, potassium hydroxide and alkyl bromopyruvate 2-oxime, ethyl. a solution of bromopyruvate 2-oxime in one of the above chlorinated aliphatic hydrocarbon solvents. The reaction is carried out very rapidly, which is completed by stirring at room temperature, followed by TLC. At the end of the reaction, the organic and aqueous phases are separated and, if desired, the aqueous phase is extracted several times with the organic solvent used. After drying and filtration, the combined organic phases are distilled off by solvent distillation and the residue is crystallized from a suitable solvent such as ethanol. The compounds of formula (I) are obtained in very pure crystalline form.

According to the second process, the starting compound (II) is dissolved in a water-miscible organic solvent, preferably, for example, acetone, ethylene glycol. A solution of ethyl bromopyruvate 2-oxime in one of the above water-miscible organic solvents and an aqueous solution of a strong base, preferably an alkali metal hydroxide such as sodium hydroxide, are added simultaneously at -10 ° C. The reaction mixture is stirred at ambient temperature for 23 hours, and additional water is added to crystallize the compound of formula I, which is isolated by filtration.

The compounds of formula (I) may be converted, if desired, into an acid addition salt. In this case, the compound of formula (I) may be in an organic solvent or a mixture of organic solvents, e.g. in ethanol, dichloromethane or a mixture thereof2

To the data is added a solution of an equimolar amount of an organic or inorganic acid in one of the solvents mentioned above. The acid addition salts of the formula (Ia) formed are crystalline in a suitable solvent or mixture of solvents, and the crystals are isolated by filtration.

By the methods described above, racemic compounds of formula (I) are formed, resolving these compounds with an optically active acid or an acidic compound thereof to form optically active compounds of formula (I) containing the R group at the α or β position.

The resolution is carried out in a reaction-inert organic solvent, preferably a C 1 -C 4 alkanol such as ethanol or a non-polar organic solvent such as a chlorinated aliphatic or aromatic solvent such as dichloromethane or a mixture of these solvents, preferably with optically active tartaric acid. . The resulting 1- (2'-ethoxycarbonyl-2 -'-hydroxyiminoethyl) -1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5-ium tartrate base release provides the optically active compounds of formula (I) from which other acids may be used to form acid addition salts as described above.

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

Example 1 1- (Methoxycarbonyl-ethyl) -2,3,6,7-tetrahydro-4H, 12H-indolo [2,3-a] quinolizine (Π) g 2,3,6,7-tetrahydro-4H, 12H- Indolo [2,3-a] quinolizine was dissolved in 200 mL of absolute chloroform, 7.5 mL of methyl acrylate was added and allowed to stand at room temperature under nitrogen for 1 day. The reaction mixture was then stripped of solvent under vacuum and treated with isopropyl alcohol (40 mL). After cooling to 0 ° C, the precipitated title compound is filtered off and washed in two portions with a total of 20 ml of 5 ° C isopropyl alcohol.

Product weight: 22.1 g (80%). Melting point: 75-77 ° C. \

IR (KBr): 1715 cm ^-1 (ester C = O).

/

Example 2 1- (Cyanoethyl) -2,3,6,7-tetrahydro-4H, 12H-indolo [2,3-a] quinolizine (II) g 2,3,6,7-tetrahydro-4H, 12H, Indolo [2,3-a] quinolizine was dissolved in 180 ml of absolute dichloromethane, 9 ml of acrylonitrile was added and allowed to stand at room temperature under nitrogen for 1 day. The reaction mixture was then degassed under vacuum and the residue was treated with 40 mL of absolute methyl alcohol and stirred at room temperature for 1 hour. The title compound was filtered at room temperature and washed with two portions of a total of 20 mL of methanol.

Product weight: 16.9 g (76%).

Melting point: 164-166 ° C.

IR (KBr): 2180 cm ^-1 (-CN).

Example 3 (±) 12-Ethoxycarbonyl-10a-ethyl-5,6,8,9,10,10a, 11,15-octahydro-1 ', 2'-oxazino [5,6-i] indolo [2,3- a] Quinolizine (I) Dissolve 1 g of ethyl-2,3,6,7-tetrahydro-4H, 12H-indolo [2,3-a] quinolizine (0.079 mol) in 40 ml of acetone and add to the solution at -10 ° C. a solution of ethyl bromopyruvate 2-oxime (21 g, 0.1 mol) in acetone (40 ml) and a solution of sodium hydroxide (4.8 g, 0.12 mol) in water (16 ml) were added in parallel, keeping the temperature above -5 ° C. do not rise. After stirring for 2 hours, ethyl alcohol (100 mL) and water (100 mL) were added slowly to the reaction mixture. The precipitated title compound was filtered, washed in two portions with a total of 50 ml of 50% aqueous alcohol, dried, weighing 24 g (80%).

Melting point: 200-204 ° C.

MS: 381 (M ⁺ ), 364,352,308,292,251,237,223 1 H-NMR (CDCl 3) δ: 0.47 (t, 3H, -CH ₂ -CH ₃ ); 1.28 (t,

3H, -CH ₂ -CH ₃ ); 2.57-2.74 (m, 2H, C); 7.16 (m,

2H, aromatic); 7.32-7.50 (2d, 2H, aromatic) \ \

IR (KBr): 3370 cm ^-1 (indole NH), 1720 (ester CO),

1691 cm <-1> C = N /

UV (nm, EtOH) max. 287 nm

Example 4 (±) 12-Ethoxycarbonyl) -10a-ethyl-5,6,8,9,10,10a, 11,15-octahydro-r, 2'-oxazino [5,6-i] indolo [2,3- a] Quinolizine g (0.04 mol) 1-ethyl-2,3,6,7-tetrahydro-4H, 12Hindolo [2,3-a] quinolizine was dissolved in 15 ml dichloromethane, 1 g (0.0044 mol) benzyl- triethylammonium chloride was added and a solution of 12.6 g (0.06 mol) of ethyl bromopyruvate 2-oxime in 25 ml of dichloromethane and 2.8 g (0.07 mol) was added at -10 to -5 ° C. a solution of sodium hydroxide in 26 ml of water was added. After stirring for a further half an hour, the organic layer was extracted with water (100 mL), dried, filtered and the solvent removed in vacuo. The residue is crystallized from 20 ml of ethyl alcohol, the crystals are filtered off, washed in two portions with a total of 5 ml of ethanol and dried. Weight: 11.4 g (75%).

Mp 202-204 ° C.

The spectroscopic data are the same as in Example 3.

Example J (+) - 1-Ethyl- (2'-ethoxycarbonyl-2 -'-hydroxyimino-ethyl) -1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizinium -chloride production (la)

3.8 g of the compound prepared in Example 3 are suspended in 10 ml of ethyl alcohol and acidified to pH 4 with hydrochloric acid in ethyl alcohol. The mixture was stirred for an additional two hours at room temperature and a

The title crystals are filtered off, washed in two portions each with 2 ml of ethyl alcohol, dried, weighing:

3.8 g (9l%).

Melting point: 214-218 ° C.

Example 6 (±) 12-Ethoxycarbonyl-10-Oa- (methoxycarbonylethyl) 5,6,8,9,10,10a, 11,15-oxahydro-1 ', 2'-oxazino [5,6i] indolo [2,3-a] cynolysin (I)

3.1 g of the compound of Example 1 are dissolved in 20 ml of dichloromethane and 0.3 g of trielylbenzylanunonium chloride are added. A solution of sodium hydroxide (0.75 g) in water (4 ml) and ethyl bromopyruvate 2-oxime (3.15 g) in dichloromethane (10 ml) was added in parallel over 15 minutes while maintaining the temperature between -5 and -10 ° C. After the addition, the mixture was stirred at room temperature for another half hour. The mixture was separated and the aqueous portion was extracted with dichloromethane (20 mL). The combined organic phases were extracted with 10 ml of saturated sodium chloride solution, dried in a desiccant, filtered from the desiccant and removed in vacuo. The oily residue was crystallized from ethanol (5 ml). The precipitated title compound was filtered and washed in two portions with a total of 2 mL of ethanol. Product weight: 3.5 g (80%). Mp 205-207 ° C.

\

IR (KBr): 3370 cm- ¹ (indole NH), 1720 and 1715 cm- ¹ (2 esters of CO) 1690 cm- ¹ (C = N).

/ /

MS (170 ° C): M ⁺ 439, 366, 350, 309, 221, 199, 167.

Example 7 (±) 12-Ethoxycarbonyl-10a-cinaoctyl-5,6,8,9,10,10a, 11,15-octahydro-1 ', 2'-oxazino [5,6i] indolo [2,3-a] ] quinolizine (1)

8.4 g of the compound described in Example 2 are quenched in 60 ml of dichloromethane and 0.9 g of triethylbenzylammonium chloride are added. Approx. A solution of 2.25 g of sodium hydroxide in 12 ml of water and 9.45 g of ethyl bromopyruvate 2-oxime in 20 ml of dichloromethane are added in parallel over half an hour at (-) 5 and (-) 10 ° C. After the addition, the mixture was stirred at room temperature for another half hour. The mixture was separated and the aqueous portion was extracted with dichloromethane (50 mL). The combined organic phases were extracted with a mixture of 10 ml of water and 10 ml of a saturated sodium chloride solution, dried on a desiccant, filtered off from the desiccant and removed in vacuo. The oily residue was crystallized from ethyl alcohol (18 mL). The precipitated title compound was filtered and washed in two portions with a total of 5 ml of ethyl alcohol.

Product weight: 9.7 g (79%).

Melting point: 218-220 ° C.

\

IR (KBr): 3370 cm- ¹ (indole NH), 2180 cm- ¹ (-CN), ' ^: / r' λ \

1720 cm ^-1 (ester CO), 1690 cm ^-1 (C = N).

/ /

MS (200); M ⁺ 406, 389, 366, 333, 317, 276, 221,

199, 167, 129.

Example 8

a) (±) -12-Ethoxycarbonyl-10a-ethyl-5,6,8,9,10,10a, 11,15-octahydro-1 ', 2'-oxazino- [5,6i] indolo [2,3- a] quinolizine (1), (R = position) g (0.026 mol) (± -12-ethoxycarbonyl-10a-ethyl5,6,8,9,10,10a, 11,15-octahydro-1 ', 2') -oxazino [5,6-i] indolo [2,3-a] quinolizine (I) was dissolved in a mixture of dichloromethane (66 ml) and ethyl alcohol (33 ml) and d-boronic acid (3.9 g, 0.026 mol) was added at room temperature. after stirring for 1 hour, the (+) - 1α-ethyl-1β- (2'-ethoxycarbonyl-1-2'-hydroxyiminoethyl) -1,2,3,4,6,7-hexahydro-12H-indolo Crystallization of [2,3-a] quinolysinium tartrate (Ia), which is filtered off and washed in two portions with a total of 10 ml of dichloromethane, dried weighs 4.8 g (70%). = 1, DMF), Melting point: 140-145 [deg.] C. The mother liquor is worked up as described in Example 9 (b) below. The (+) tartrate salt obtained above is dissolved in 100 ml of water to pH 9 cc. diluted with aqueous ammonia solution to give the title compound, which was filtered, washed with water to neutral, dried in a vacuum desiccator, 3.4 g (98%).

[alpha] $: + 486 ° (C = 1, CHC1 _3).

Melting point: 165-170 ° C (from petroleum ether).

b) (-) - 12-Ethoxycarbonyl-10α-3-ethyl-5,6,8,9,10,10a, 11,154-octadihydro-1 ', 2'-oxazino [5,6-i] indolo [2,3-a] cinnolizine (I), (at position R = β)

The resolution mother liquor obtained in (a) was allowed to stand overnight, from which (-) - 1 β-ethyl-1 α- (2'-ethoxycarbonyl-2'-hydroxyiminoethyl) -1,2,3,4,6, 7-Hexahydro-12H-indolo [2,3-a] quinolizine-5-lumar tartrate crystallizes. The crystals were filtered off, washed in two portions with dichloromethane (5 mL each), dried, 4.3 g (63%). [A] g: -228 (C = 1, DMF).

The (-) - tartrate salt thus obtained was dissolved in 100 ml of water to pH 9 cc. diluted with aqueous ammonia, the precipitated title compound was washed neutral with water, dried in a vacuum desiccator, 3.0 g (97%), [α] D = -488 °. (C = 1, CHCl 3).

130-133 ° C.

Example 9

a) (+) - 12-Ethoxycarbonyl-10aa- (methoxycarbonyl) -5,6,8,9,10,10a, 11,15-octahydro-1 ', 2'-oxazino [5,6-i] indolo [2,3-a] quinolizine (I), (R = position)

65.85 g (0.15 mol) of (±) -12-ethoxycarbonyl-10α-methoxycarbonyl-1-ethyl-5,6,8,9,10,10a, 11,15-octahydro-1 ', 2'-oxazino [ 5,6-i] Indolo [2,3-a] quinolizine (I) was dissolved in 300 ml of dichloromethane, treated with hot ethanolic solution of tartaric acid (22.5 g, 0.15 mol) and cooled to room temperature over 1 hour. The precipitated (+) - la (methoxycarbonyl-ethyl) -1- (2'-ethoxycarbonyl-2'-hydroxy)

EN 207 327 (iminoethyl) -1,2,3,4,6,7-hexahydro-1H-indolo [2,3-a] quinolizine-5-lumium tartrate (Ia) is filtered off and treated in two portions for a total of 50 ml. washed with ethanol (ml), dried, weight: 44 g (99.6%), [α] g: + 256.4 ° (C = 1, DMF). The mother liquor was further worked up as described in Example 10 (b). The (+) - tartrate salt thus obtained was dissolved in 1000 ml of water and cc. basified to pH 9 by addition of aqueous ammonia. The precipitated title compound was filtered, washed with water to neutral, dried, 32.5 g (99%), [α] D = + 446.7 ° (C = 1, CHCl ₃ ). 115-120 ° C.

b) (-) - 12-Ethoxycarbonyl-10α-methoxycarbonylethyl-5,6,8,9,10,10a, 11,15-octahydro-1,2,4-oxazino [5,6-i] indole [2 3-a] quinolizine (I) at position R = p

The resolution mother liquor obtained in (a) is freed of solvent in vacuo to give a crystalline foam which is (-) - 1β-methoxycarbonylethyl-la- (2'-ethoxycarbonyl-2'-hydroxyiminoethyl) -1,2,3 , 4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-lumium tartrate (Ib) was dissolved in 1000 mL of water and c.c. basified by addition of aqueous ammonia. The precipitated title compound was filtered, washed with water and dried, weight: 32 g (97%), [a] D: -460 ° (c = 1, CHC1 _3). Melting point: 110-115 ° C.

Example 10 (-) - 12-Ethoxycarbonyl-10α-cyanoethyl-5,6,8,9,10,10a, 11,15-octahydro-1 ', 2'-oxazino [5,6i] indolo [2,3-a] ] quinolizine (I), (at position R-β) g (0.042 mol) of (+) - 12-ethoxycarbonyl-10α-cyanoethyl-5,6,8,9,10,10a, 11,15-octahydro-2 '-oxazino- [5,6i] indolo [2,3-a] quinolizine (I) is suspended in 90 ml of dichloromethane and a hot solution of 6.3 g (0.042 mol) of d-tartaric acid in 90 ml of ethanol is added. After pouring, a homogeneous solution is obtained which is cooled to room temperature with (-) - 13-cyanoethyl-la- (2'-ethoxycarbonyl-2'-hydroxyiminoethyl) -1,2,3,4,6,7-hexahydro-12H-indolo [2 , 3-a] quinolizine-5-lumium tartrate (Ib) crystallises out which is filtered and washed with 10 ml of ethanol in two portions, dried, weighing 13 g. The product was boiled in water (50 mL), filtered, dried, weighing 10 g (85%), [α] g: -322.8 ° (C = 1, CHCl ₃ ).

Melting point: 215-217 ° C.

The resolution mother liquor was further worked up as described in Example 10 (b). The (-) - tartrate salt thus obtained is dissolved in 100 ml of hot water and cc. basified to pH 9 with aqueous ammonia, the precipitated title solution was filtered from the cooled to room temperature, washed with water to neutral, dried, 7.2 g (98%), [α] D = 445.8 ° (Cl, CHCl ₃ ). M.p. 115-120 ° C.

b) (+) - 12-Ethoxycarbonyl-10a-cyanoethyl-5,6,8,9,10,10a, 11,15-octahydro-1 ', 2'-oxazino- [5,6i] indolo [2,3-a] ] quinolizine (I), (R = position)

The resolution mother liquor obtained in (a) is de-solvented in vacuo and the resulting residue is boiled in 20 ml of water, cooled to room temperature and the (+) - la-cyanoethyl - (2'-ethoxycarbonyl-2-hydroxyiminoethyl) -123i4,6,7- hexahydro-12H-indolo [2,3-a] quinolizine-5-lumium tartrate (Ia) was filtered, washed in two portions with a total of 10 ml of water, dried, 7.5 g (64%). [α] D: + 310.4 ° (C = 1, DMF). Melting point: 210-215 ° C. The (+) - tartrate salt thus obtained was dissolved in 100 ml of water warm and cc. basified to pH 9 with aqueous ammonia, the precipitated title product was filtered, washed with water to neutral, dried, 5.4 g (98%). [α] D: + 440 ° (C = 1, CHCl ₃ ). Melting point: 113118 ° C.

Claims (4)

PATENT CLAIMS A process for the preparation of a novel racemic and optically active 12-alkoxycarbonyl-5,6,8,9,10,10a, 11,15-octahydro-r, 2'-oxazino [5,6-i] indolo [I]. 2,3-a] quinolizine derivatives - wherein R is C1-C4 alkyl, (C1-C4 alkoxy) carbonyl ethyl, or cyanoethyl ^R1 is C1-4 alkyl and (Ia) can be acid addition salts thereof - wherein R is as defined above and X ^- preparation, characterized in that some (II) tetrahydro-indolo [2,3-a] of the formula - is an acid residue a quinolizine derivative wherein R is as defined above or an acid addition salt thereof in the presence of a base with an alkyl bromopyruvate 2-oxime of the formula III wherein R ¹ is C1-C4 alkyl and, if desired, resolving the resulting racemic compound of formula (I) and / or converting it into an acid addition salt of formula (Ia). Process according to claim 1, characterized in that the reaction is carried out in an organic solvent in the presence of an aqueous solution of an alkali metal hydroxide and optionally a phase transfer agent. The process according to claim 2, wherein the reaction is carried out in a water-immiscible organic solvent-water biphasic system in the presence of an alkali metal hydroxide and tetrasubstituted ammonium halide as the phase transfer agent. Process according to claim 2, characterized in that the reaction is carried out in the presence of an alkali metal hydroxide in a water-miscible organic solvent.