DE1253271B - Process for the preparation of 2-oxo-1, 2, 3, 4, 6, 7-hexahydro-11bH-benzo [a] quinolizines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07d

German class: 12 ρ - 5

Number: 1253 271

File number: M 52128 IV d / 12 ρ

Filing date: March 14, 1962

Open date: November 2, 1967

It is known that numerous natural alkaloids (ζ. Β. Berberine, Emetine, Yonimbine, Rauwolfia alkaloids) as well as some structurally with the named ones related synthetic products contain quinolizine ring systems in their molecule. To the synthetic Establishing such connections are so far only complicated in the literature, from many steps Existing and poor yields are described processes in which the ring closure of the quinolizine ring system mostly through a Dieckmann condensation of the corresponding Dicarboxylic acid ester takes place ("Journal of the Chemical Society", London 1935, p. 1743; "Experientia", Vol. 5, 1949, p. 115; Journal of the Chemical Society, London 1952, p. 650).

2-Oxo-1,2,3,4,6,7-hexahydrollbH-benzo [a] quinolizines were used again also produced by the reaction of substituted isoquinolines with methyl vinyl ketone ("Helvetica Chimica Acta", vol. 43, 1960, p. 583), but in this way the desired quinolizine derivatives can only be achieved with very poor results Yield can be obtained; the tests have shown that in such cases as the main product the reaction produces an addition product made up of 2 moles of substituted isoquinoline and 1 mole of methyl vinyl ketone with a structure that has not yet been clarified.

It has been found that 2-oxo-1,2,3,4,6,7-hexahydro-IIbH-benzo [a] quinolizine of the general formula I.

Ri

ι CH ₂ R ₅ Λ / '\
CH ₂ N
>. / \ / R ₆ τ CH CC R ₄ \ R ₇ CH CH R ₈ / \ / \ C ^χ

where Ri to R4 are hydrogen or halogen atoms, alkyl or alkoxy groups or where R2 and R3 together can also form a methylenedioxy group and where R ₅ to R _{8 are} hydrogen atoms, alkyl groups with straight or branched carbon chains with 1 to 10 carbon atoms, aryl - Or aralkyl groups, in a one-step reaction and with good yield ge-method for the production

of 2-oxo-1,2,3,4,6,7-hexahydro-

11 bH-benzo [a] quinolizines

Applicant:

Magyar Tudomänyos Akademia, Budapest

Representative:

Dr. G. W. Lotterhos

and Dr.-Ing. H. W. Lotterhos, patent attorneys,

Frankfurt / M., Annastr. 19th

Named as inventor:

Dipl.-Ing. Chem. Dr. Denes Beke,

Dipl.-Ing. Chem. Dr. Csaba Szäntay, Budapest

Claimed priority:

Hungary of March 28, 1961 (1026)

are obtained if you quaternary 3,4-dihydroisoquinolinium salts of the general formula II

Χ ^θ

Ν® - C - R ₆

CH-R ₇

R ₈ - CH ₂ - C

wherein Ri to Rs have the meaning given above own and X for the anion of a strong acid, e.g. B. for a halide or a sulfate anion, exposed to the action of bases in aqueous solution.

It was not foreseeable that quinolizine derivatives of the formula I would be able to produce good yields in this way can be obtained, since the compounds of formula II the possibility not only for a ring-closing intramolecular condensation, but also for an intermolecular condensation consists.

709 680/418

The quaternary 3,4-dihydroisoquinolinium salts of the general formula used as starting materials II can in an unclaimed manner with extremely good yield by implementing 3,4-dihydroisoquinoline salts of the general formula III

Ri

N-HX

III

IO

at elevated temperature with methyl vinyl ketones of the general formula IV

R ₅ N

Re'

> C =

C —CH ₂ R ₈

IV

I Il

R ₇ O

can be obtained.

The 3,4-dihydroisoquinolinium quaternary salts of the general formula prepared in this way II-containing reaction mixture can optionally also directly without isolation of the Starting material II treated with bases and thus converted into the desired product.

It has already been proposed (German Auslegeschrift 1 134 678), quinolizine derivatives by implementation of 3,4-dihydroisoquinolines with alkyl vinyl ketones to manufacture. In this process, the substances used as starting materials must be substituted 3,4-Dihydroisoquinolines are reacted in a basic medium with the alkyl vinyl ketones. Under such conditions, however, undesired side reactions occur, which reduce the yields greatly reduced and the reaction mixture contaminated.

The quinolizine derivatives prepared according to the invention, on the other hand, have a very good yield obtain.

The further details of the process according to the invention are illustrated in the following examples b) explained.

example 1

a) 2.27 g of o ^ -dimethoxy-S ^ -dihydroisoquinoline hydrochloride are with 5 ml of methyl vinyl ketone

Heated on the water bath for 1 hour and then evaporated to dryness.

b) That obtained with quantitative yield

2 - (ß - acetoethyl) - 6,7 - dimethoxy - 3,4 - dihydroisoquinolinium chloride, which crystallizes from water with 2 mol of water of crystallization and ^{melts at 142 to 143 0} C, is dissolved in 20 ml of water and the solution with 5% Sodium carbonate solution made alkaline. In this way, 2.1 g of 2-0x0-9,10-dimethoxy-1,2,3,4,6,7-hexahydrollbH-benzo [a] quinolizine (80.5% of theory) are obtained in crystalline form. Mp. 154-155 ⁰ C.

B is ρ ie 1 2 _6j

a) 1.65 g of 3,4-dihydroisoquinoline hydrochloride become warmed with 3 ml of methyl vinyl ketone on a water bath for 1 hour. The reaction mixture is then evaporated to dryness in vacuo and the residue recrystallized from acetone.

b) The thus obtained 2 g of colorless, crystalline 2 -. (/ S-Acetoäthyl) -3,4-dihydroisochinoliniumchlorids (yield 85%, mp 220 ⁰ C) is dissolved in water and the solution with aqueous ammonia to alkaline reaction added; 1.5 g of 2-oxo-1,2,3,4,6,7-hexahydrollbH-benzo [a] quinolizine (75% of theory) are obtained. M.p. 78 to 79 ⁰ C.

Example 3

a) 2.11 g of 6,7-methylenedioxy-8-methoxy-3,4-dihydroisoquinoline are dissolved in 2 ml of ethanol with warming and the solution with an equivalent Amount of ethanolic hydrochloric acid, then mixed with 4 ml of methyl vinyl ketone. The mixture will Heated on the water bath for 1 hour, then evaporated in vacuo.

b) The residue is dissolved in water and aqueous sodium carbonate solution is added to the solution until it has an alkaline reaction. By recrystallizing the resulting crystalline precipitate from aqueous ethanol, 2 g of 2-oxo-9,10-methylenedioxy-11-methoxy-1,2,3,4,6,7-hexahydro-11 b H-benzo [a] quinolizine ( 70% of theory). Mp. 133 to 134 ⁰ C.

Example 4

a) 2.27 g of o ^ -dimethoxy-S ^ -dihydroisoquinoline hydrochloride are with 5 ml of 2-ethyl-l-buten-3-one and 4 ml of absolute ethanol for 1 hour on the water bath heated to reflux. The reaction mixture is then evaporated to dryness in vacuo.

b) The residue is dissolved in water and mixed with 5% sodium carbonate solution until an alkaline reaction occurs. In this way, 2.34 g of 2-oxo-3-ethyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydrollbH-benzo [a] quinolizine (81% of theory) are crystalline Form "obtained; m.p. 110 to 112 ⁰ C.

Example 5

a) 5.61 g of oJ-dimethoxy-S ^ -dihydroisoquinoline hydrochloride (crystalline form, with 3 mol of water of crystallization) are heated with 6 ml of absolute ethanol and 10 ml of 2-isobutyl-l-buten-3-one on a water bath for 5 hours. The reaction mixture is then evaporated to dryness and the residue is recrystallized from water. 5 g 2 - (/? - acetyl - /? - isobutyl - ethyl) - 6,7 - dimethoxy 3,4 - dihydroisochinoliniumchlorid (72% of theory, mp 208-209 ⁰ C.) Can be obtained.

b) The salt obtained according to a) is dissolved in water and aqueous sodium carbonate solution is added to the solution until an alkaline reaction occurs. 4 g of 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-IIbH-benzo [a] quinolizine (89% of theory) are obtained in crystalline form. M.p. 125 ⁰ C.

c) That which is required for the production of the starting material according to a) and which has not yet been described in the literature 2-Isobutyl-1-buten-3-one is prepared from 2-methylhexan-5-one as follows in a manner not claimed :

The Mannich base obtained with formaldehyde and dimethylamine is reacted in ethyl acetate with methyl iodide to give the corresponding quaternary salt (mp. 180-181 ⁰ C) and then through

Treatment with dilute sodium hydroxide solution converted into the desired unsaturated ketone; The 2-isobutyl-l-buten-3-one boils under a pressure of 13 mm of mercury at 53 to 55 ° C. ² g = 1.4356; Melting point of the semicarbazone 168 to 169 ⁰ C.

Example 6

a) 5.61 g of oJ-dimethoxy-B ^ dihydroisoquinoline hydrochloride (crystalline form, with 3 mol of water of crystallization) with 10 ml of mesityl oxide for 2 hours warmed on the water bath. The reaction mixture is evaporated to dryness in vacuo and the Residue dissolved in water.

b) Aqueous sodium carbonate solution is added to the solution until it has an alkaline reaction the 2-oxo-4,4'-dimethyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-IIbH-benzo [a] quinoIizine precipitated in this way isolated. M.p. 145 ° C.

Claims (1)

Claim: Process for the preparation of 2-0x0-1,2,3,4, 6,7-hexahydro-IIbH-benzo [a] quinolizines of the general Formula I. IO 20th I. 35 where Ri to R4 represent hydrogen or halogen atoms, Alkyl or alkoxy groups or where R2 and R3 together are also a methylenedioxy group can form and where Rs to Rs Hydrogen atoms, alkyl groups with straight or branched carbon chains with 1 to 10 carbon atoms, aryl or aralkyl groups, characterized in that either a) quaternary 3,4-dihydroisoquinolinium salts of the general formula II Rt R ₂ ^ CH ₂ / R ₅ Xe R ₃ -I, CR ₆ "CH CH
/ - R -CH ₂ - /
C. T T
R ₄ R ₈ wherein X stands for the anion of a strong acid, or b) a by reaction of 3,4-dihydroisoquinolinium salts of the general formula III N-HX III with methyl vinyl ketones of the general formula IV ) C = C-C-CH ₂ • R ₈ IV Re' R ₇ O reaction mixture obtained at elevated temperature in aqueous solution of the action of Exposing bases. Considered publications:
German patent specification No. 1 134 678. 709 680/418 10.67 θ Bundesdruckerei Berlin