DE1470065B2 - Process for the preparation of quinolizine derivatives - Google Patents

Description

where Ri denotes a hydrogen atom or an alkyl radical with I τ- 9 / C atoms, the benzoil rings can optionally be substituted by., Älkoxygruppeh ühd / öder, methylenedioxy groups and in 2,3-Stellühg, ·: a. Double bond ', (these compounds are called "la" in the following), ■; .-yx:; - . · <:; ■: ..-- ■■■■ ^ i ";:.;: Uh or, an Eihfachbinduhg (these connections- are called" Ib "in the following) ν. ■ · '■■' -ίί '^ -; -

The new procedure is characterized by the 'Reaktiohsscherna A': "'''''" ^: '"'

Reaction schemes ;; ■ ■ '"]''/"' ■ '.' ■. ■ '/ ^:

(H)

Ν — R ₂ - ;; ' ■ + C-MgX;

R ₁ ^ MiII) · ϊ

R ₂

'a) Addition and hydrolysis ^ "

: R ₂ = acetyl

,or.,,

'Π BenzoyK ^Yy

c) Halogenation with AHylümiagerung of IVa outgoing

(V)

d) Cyclization by elimination of HY

(Ia)

e) optionally hydrogenation

(Ib)

(IVa, b)

~ ..H ₂ c;.:;: D — Ri ^ r - ^^ i ^; ,,,,; Vj

HO ^ -C-- - ν '-' S ^Wh) l

CH ₂ b) saponification v / N ^ N- R ₂ -

■ The addictions have the following meaning: "-;" · ■ '·

Rj = ■ H, or an 'alkyl radical' with 1 .- ^ 9 carbon atoms, .. ,,. .R ₂ = - H, acetyl.pder benzpyl,; ~, - ν-ΐ ^ - \ '- ;. · ■■■■; w * ·.; '*: - .X = .chlor; Bromine or; iodine, _v .-- ■■ '■■ .si ^ ji .-' ^: ^ ".-> · '. ■ · ■■ *; ■!% ■ X,'. = Chlbr.qder- Bröm. ^, ... ^ / _.; V; _Λ .s ^ ' _νΛ ι-Η-χ ^

"The; in 'der Äüs'garigsverbihdüng I as well as in the intermediate products IV and Vündden end products'Iaütid Ib' vorharideheir Benzplkerhe"'köhhe'h"by; Ä.lköxygrüppeh ■' like 'Iviethox ^ gflippen; üWd / pdei'''' VletHylehdiöxygfüppen substitutes iein './^-''''-;"- ■. ~: ' ^{: y} ~ \ "" t ^: ■ - · As can be seen from the "Reaktiohsscherna ■; the new procedure consists of four or five reac'tiohs' stages:

^: a) 'Reaction of the cyclic β- aminoketone II with • ^/: a metal organischeri Vinylyerbindüng IH "züm tertiary j9-Amiribaikohol IVr ^'^vi;

b) saponification of an acetyl or benzoyl group which may be present in the 1-position tertiary amino alcohol (IVb - * IVa);

c) Conversion of the tertiary / I-amino alcohol IV with allyl rearrangement into the unsaturated halide V;

d) Cyclization of the unsaturated halide V by Elimination of hydrogen halide to form the 2-dehydroquinolizidine derivative Ia;

e) optionally hydrogenation of the quinolizine derivative Ia to the quinolizine compound Ib.

The individual reaction stages are explained below:

a) Addition and hydrolysis

15th

The reaction a) can be carried out particularly advantageously in such a way that the solution of the Grignard compound III and the j9-aminoketone II or its N-acetyl or benzoyl compound either dissolved in an inert solvent is added dropwise or in a finely powdered state with stirring enters. As a solvent, for. B. ether but preferably tetrahydrofuran can be used.

The work-up is carried out as usual, i. H. the reaction mixture is by adding water or dilute acids, e.g. B. hydrochloric acid or sulfuric acid, hydrolyzed and the base by adding ammonia and ammonium chloride solution set free. If the starting material used is the N-acetyl or Benzoyl compounds of II, the procedure is analogous, but the easiest way is by adding Ammonium chloride solution.

It is advisable to use an excess of organometallic compound, since in the case of conversion of the iS-aminoketone 1 mol of the organometallic compound is destroyed by the NH group, while when using the N-acetyl or benzoyl compounds of II see the organometallic compound Compound attaches to the acyl group in a complex manner and in some cases can also react with this, in particular when exposed to heat, with splitting off of the acyl group and liberation of an NH group. When working at temperatures below 50 ^° C., however, this reaction, which does not interfere with further processing, occurs only to a negligible extent.

b) Saponification of the N-acetyl or N-benzoyl group

Since it is advisable in those cases in which the aminoketone II is relatively unstable to carry out the addition after reaction a) using a more stable starting material of the formula II, where R2 is an acetyl or benzoyl group, it is in these cases necessary to saponify the N-acyl group again before replacing the hydroxyl group with halogen and splitting off hydrogen halide (reactions c) and d)). The saponification is usually carried out by treating with alkaline agents. Suitable as such are preferably alkali metal hydroxides in solvents which dissolve both the compound to be saponified and the alkali metal hydroxide, preferably higher-boiling alcohols such as n-butanol or benzyl alcohol. Since N-acyl compounds are generally hydrolysed relatively slow, it is expedient to approximately 140- it to heat for several hours to temperatures 160 ⁰ C. Working up is carried out in the usual way by distilling off the solvent, adding water to the residue and shaking out the base, which is insoluble in the excess alkali, with a suitable organic solvent, such as. B. ether or methylene chloride.

c) Halogenation with allyl rearrangement

The hydroxyl group of the tertiary alcohol of the formula IVa is replaced by chlorine or bromine according to methods known per se. Suitable halogenating agents are the halides of inorganic acids, preferably thionyl chloride or bromide or phosphorus trichloride or bromide. When using phosphorus trichloride or thionyl chloride, it is particularly advantageous to work in chloroform solution. The use of the bromides is possible, as mentioned, but it has no advantages, since in the allyl chlorides of the general formula V formed when the hydroxyl group is replaced by chlorine, the chlorine is already so reactive that the subsequent ring closure (stage d) ) takes place with the greatest of ease under the mildest conditions and in the shortest possible time. It is therefore not necessary to increase the reactivity of the halogen in V through the transition from chloride to bromide. ·; ■ .. ' ₍

Both the free bases of the formula IVa and their hydrohalides can be used. the Reaction with an excess of the chlorides of inorganic acids is usually after one to two hours Heating ended. Small amounts of a tertiary base such as pyridine can also be used in the reaction or trimethylamine can be added without, however, achieving any noticeable advantage.

d) Cyclization by evaporation of hydrogen halide

The elimination of hydrogen halide from an AlIyI halide of the formula V can be obtained by the action of any alkaline solution, such as sodium hydroxide solution, potassium hydroxide solution, potassium carbonate solution or from organic bases. It runs surprisingly smoothly and easily, like that that it is sufficient if the solution of an allyl halide of the formula V is made alkaline or its solution in an organic solvent, such as. B. chloroform, shaken briefly with aqueous alkali will.

It is not necessary for the cyclization to use the AUyI halide of the formula V first to be isolated in the form of a salt. Rather, it is expedient to carry out the halogenation a tertiary alcohol of the formula IVa obtained reaction solution after evaporation of the excess halogenating agent by simply * Alkalizing without isolating the allyl halide of Formula V directly into the desired quinolizine derivative to convert the formula Ia.

^{:: L} e) hydrogenation

The hydrogenation of the double bond in the quinolizine derivatives formed during the cyclization Formula Ia is made using the customary hydrogenation catalysts, such as palladium or platinum black or platinum oxide or palladium on barium sulfate or Raney nickel, smoothly possible if Ri means hydrogen If Ri is an alkyl radical with 1-9 carbon atoms, The hydrogenation requires particularly active catalysts, possibly also higher hydrogenation temperatures or a hydrogenation under pressure, since in this case the double bond between two quaternary carbon atoms.

For the catalytic hydrogenation, it is expedient not to use those which are not very stable to light and air

free bases of constitution Ia, but suitable salts, such as the hydrochloride or hydrobromide, which are stable in light and air. The hydrogenation takes place in a solution suitable for the base or salts Solvents, so in the hydrogenation of the base z. B. in lower alcohols or ethyl acetate, with hydrogenation the salts in lower alcohols, glacial acetic acid, water or else in dilute aqueous acids.

Output connections

The cyclic ^ aminoketones of the formula II used as starting material can be used either as free bases (R2 = H) or in the form of their N-acetyl (or benzoyl) derivatives (R ₂ = acetyl or benzoyl).

The ihdihi is a particularly important starting product

iy
lyl-l) acetone (meso- and racemic form) called. It is also possible, for example, to use the N-acetyl (or benzoyl) derivative of this compound.

In a vinyl compound of the formula III, Ri is Hydrogen or an alkyl radical with 1-9 carbon atoms.

Accordingly, for example, the following organometallic vinyl compounds are represented by the formula III, can be used as starting material: vinyl magnesium bromide, propenyl (2) magnesium chloride, Butene- (l) -yl- (2) -magnesium bromide etc.

A preferred embodiment of the process according to the invention is shown in reaction scheme B. In the reaction scheme, X and Y have the meanings given and R2 'means acetyl or Benzoyl.

Reaction scheme B

H ₃ CO

H ₃ CO

CH ₂ + C-MgX

/ \ / ^x NR ₂ ': C ₂ H ₅ ■ <

H ₃ CO

H ₂ C CC ₂ H ₅ HO-C

H ₃ CO

H ₃ CO

(IVb ')

b)

H, CO

H ₃ CO '

VAyNH

CH ₂

H ₂ C CC ₂ H ₅ HO-C

CH,

(IVa ')

H ₃ CO H ₃ CQ

V ¹

c)

H, CO, H, CO

H ₂ C CC ₂ H ₅

CH ₂

NH

(V)

H, CO χ

H ₃ CO '"H ₃ CO H ₃ CO

(Ia ')

909 545/1

QH ₅

H ₁ CO

H ₁ CO

(Ib ')

H ₃ CO

H ₃ CO

As can be seen from the reaction scheme, ", a'-Bis-O ^^ - tetrahydro ^ -acyl-oJ-dimethoxy-isoquinolyl-1) acetone (H ') grignarded in the first reaction stage with, for example, oc-ethyl-vinyl-magnesium bromide. After hydrolysis of the Grignardation product (IVb ') and saponification of the N-acyl groups the bis - [(1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolyl-1) methyl] - [1-butenyl-2] carbinol is obtained (IVa '). In the halogenation of the carbinol (IVa ') with thionyl chloride or bromide or phosphorus trichloride or bromide is obtained 1- [6,7-dimethoxy-1,2,3,4-tetrahyij ^ id

Chimica Acta, Volume 42 [1959], page 1515 ff.). The smooth course of the process according to the invention, however, is to be regarded as surprising, since, for example, it was known that Grignard compounds easily reduce sterically hindered carboxyl compounds, as used in the yoliegend process as starting products, and the acid amide group, as they are in the starting products of the process according to the invention in where R ₂ == acetyl or benzoyl is present, attacks, and that compounds with | 8-aminoketone structure, in particular double-sided /! - aminoketones, are easily cleaved. "■: ■..

There is a major advantage of the new method in that the required output connections are easily accessible (in the, examples in individual executed) and that only. few reaction steps are required. When using an acylated jS-amino ketone of the formula II as well as in all In cases where it is expedient to dispense with the isolation of the unsaturated halide V, the entire process consists of only three reactions that proceed smoothly. The invention thus brings about an essential technical progress in the field of. Manufacture of quinolizine compounds. . ..

isochmolyl-l) methyl] -3-chloromethyl (or -3-bromomethyl) pentene- (2) (V). This unsaturated halide of formula V can be treated with alkaline Agents for S-ethyl-g.lO-dimethoxy-W.llbtetrahydro-2 - [( 1 ^, S ^ -tetrahydro-öy-dimethoxy-isoquinoline-1) -methyl] -4H-benzo [a] quinoIizine (Ia ') cyclize. If particularly active hydrogenation catalysts are used, it is possible to remove the one in the 2,3-position to hydrogenate isolated double bond to obtain the corresponding saturated quinolizine derivative Formula Ib '.

If the starting material used for this reaction is the meso form of the symmetrically substituted one j3-aminoketones of the formula IP, this is how you get that special strongly amoebicidal 2-dehydro-emetine, which corresponds to formula Ia '.

The process according to the invention represents a completely new route for the preparation of quinolizine derivatives, which is also not previously described analogously in the literature. It is known from the literature to convert ketones with Grignard compounds into tertiary alcohols and to saponify acid amides under alkaline conditions (Karrer, Textbook of Organic Chemistry, 13th edition (1959), pages 100/101 or 247), and allyl alcohol with inorganic acid halides with an AHyl rearrangement to convert into allyl halides (Liebig's Annalen der Chemie, Volume 479, 1930, page 21 1 ff.). It is also known that the chlorine atom in allyl chloride is very mobile and can easily be replaced by NH ₂ (Karrer, Textbook of Organic Chemistry, 11th Edition 1959, page 94), that cinnamyl chloride reacts with ethylaniline even in the cold (Liebig's Annalen der Chemie, 479 (1930), page 219) that by slightly heating d-chlorobutyl or y-chloropropyl-öJ-methoxy-S ^ -dehydro-isochino-Hn with ring closure, the corresponding benzo [a] -quinolizine derivative is formed (Journal of the Chemical Society 1931, page 36), and that the double bond in the 2,3-position can be catalytically hydrogenated in 1,6,7,1 lb-tetrahydro-4H-benzo [a] -quinolizines (cf. Helvetica

B is ρ ie le

1) In a from 16.5 g (0.122 MpI) of pure 2-bromobutene (l) and the equivalent amount (2.95 g) of magnesium in 80 ecm of tetrahydrofuran at 40 ⁰ C, cooled to room temperature solution of butene ( i) -yl- (2) -magnesium bromide (III; Ri = C ₂ H ₅ , X = Br) 19.8 g (0.03 mol) of finely powdered racemic form of the α, melting at 197-199 ° C., are added with stirring , Λ'-bis- (N-benzoyl-ej-dimethoxy-l ^^ - tetrahydro-isochino-IyI-1) -acetone registered, the temperature ^{rising to 50-6O 0} C and a clear solution results. The mixture is allowed to cool gradually and, after 5 hours, decomposed with ammonium chloride solution while cooling with ice. The tetrahydrofuran layer is separated off, extracted twice more with methylene chloride and the combined organic layers are evaporated after drying with sodium sulfate. The residue, which solidifies rapidly in crystalline form, gives, after trituration with 50 ecm of methanol and suction, 19.2 g (= 91% of theory) of bis - [(N-benzoyl-ej-dimethoxy-l ^^ - tetrahydro-isochino-lyl-l ) -methyl] -butene- (l) -yl- (2) -carbinol (IVb '; R ₂ ' = CO — C6H5), which already after recrystallization from dimethylformamide with the addition of

Ethanol constant melts at 225-227 ^0C. The dried at 100 ⁰ C in a high vacuum yields the substance for C43H4gN calculated ₂ O7 analysis values.

To split off the benzoyl residues, 25.0 g of this substance are dissolved in 250 ecm of butanol with 16 g of potassium hydroxide 5 hours reflux to the? Boiling heated. After cooling, it becomes of that during the saponification crystallized potassium benzoate (11.3 g = 99% d. Th.) Sucked off, the butanol under reduced pressure, finally with twice the addition of water

Feo distilled off, and the resinous base separated out with total of 250 ecm of ether recorded. From the only briefly dried ethereal solution crystallize during If 13.0 g (63% of theory) are already pure bis- [(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl-1) -methyl] -buten- (1) -yl at room temperature - (2) carbinol (IVa ') from melting point 126-128 ° C, which occurs during recrystallization from acetone no longer changes with the addition of water.

From the essential mother liquor let through Acidify with essential hydrochloric acid and rub the. Dihydrochloride with a little ethanol further kiengen.der base IVa 'in the form of the hydro-

, Chloride (3 ^ g = 17% of theory) vomSchmelzp. Isolate 250-252 ⁰ C, so that the. Total yield for this stage is 80% of theory / is, \,! , V ■ ... '

The: Base IVa 'is through a ίί, Ν'-bis-aeetyl compound, which can be prepared in the usual way, of melting point. iSSUrChkii / \

. ': .. The'. Analyzes' confirm the presence of the described; Connection.:■■·,!,:. '..-...
. '..' For, conversion into the l- £ 6iZ.T-dimethoxy-l ₍ 2,3,4-ter trahydro-isoquinolylT l] -2 - [(6,7-dimethoxy-Ϊ, 2,3,4 ^: tetra-, hydro-isqchinqlylrl) -methyl] _: 3-chloromethyl-pentene- (2) (V; Y = Cl), the solution of _; 5.0 g, of the dihydro-, chloride: of IVa 'in. 50 ecm alcohol-free chloroform with 50 ecm thionyl chloride heated to 50 ° C for 2 hours, the brownish. Discolored solution under reduced

- * Pruck evaporated to dryness, the residue triturated with ether, and dissolved in a little methanol, from which when stored at room temperature. 2.30 g (= 44% of theory); crystallize out of the bihydrochloride of V '(Y = Cl) with a melting point of 230-233 ° C. After the analysis of the. Resulting from Äthanol.umkristallisierten.Salzes drying under high vacuum at 8O ⁰ C, the ₂₉ Hj for the formula C ₉ CIN ₂ O ₄ · 2HCl calculated values. The cyclization to the quinolizine derivative of the constitution .Ia '(= racemic 2-dehydro-isoemetine) takes place by treating the aqueous solution of 2.0 g of the pihydrochloride of V (Y = C1) with excess 2N hydrate liquor at room temperature and shaking out the, doing, yourself. separating; Base Ia with Methyle.nchlqrid, which for purification by precipitating this solution with. ethereal hydrochloric acid, into which the chloride is converted (1.8 g = 82% of theory), which, after recrystallization from ethanol, with the addition of ether, melts at 241-243 ° C. /

It is not necessary, moreover, that before the cyclization, the; dihydrochloride described above of the chloride V. (Y = C1) isolated. Rather can one essential; easier to work like this; that one how above! obtained after distilling off the

.-., Chloroform / thionyl chloride mixture remaining, initially resinous residue after being rubbed with ether ;; in; excess. 2η sodium hydroxide solution: eintiänke, the precipitated base is taken up in methylene chloride and this is distilled off. If the remaining base is dissolved in a little 2 η-hydrochloric acid, then after a short time; standing 2.67 g (= 55%, d.Th.), Des / dihydrochlorideSifdes:; 2-De.hydfoMsoemetins (Ia ') from Rohschmelzp. 236 ° C, which rises to 241 to 243 ° C after recrystallizing once from alcohol with the addition of a little ether. The analysis of the ^{substance dried at 80 °} C. in a high vacuum gives the expected values. Ί -The: from the. aqueous solution of the Dihydröchjorids by addition of dilute sodium hydroxide solution in freedom set base melts after recrystallization from acetone with addition of water to turbidity at 93 ^ 95 ⁰ C. The photosensitive Basei contains after drying at 40 ?: under high vacuum ^ after analysis 1/2 mole of crystal water. The N-acetyl compound, which is usually prepared with acetic anhydride in pyridine, melts after recrystallization from acetone with the addition of water at 53-155 ° C; Its hydrochloride melts at 256-258 ° C, its iodine methylate at 208-210 ° C. - ■ ν '■■■ '

The 2-dehydro-isoemetin is already from A. Brossi and coworkers j H e! Y.Chim. Acta, Volume 42, page 785 (1959), presented in a more complicated manner and converted into the derivatives mentioned, whose melting points with the. match given above. There is only one exception: dihydrochloride, for the Brossi and co-workers: 223 _; specify up to 225 ° C; aljptrqpe modifications are likely to be present here, as in this one. _{-_.-.} /: - ^ series were observed several times ... ■ / ', ... ::; · .. ■,; · ■. ·;, ..; ·. . · : '.- ^ l'] -. ·; '· ,:' -yy: ·; · .'-. · :,

ίο; E) ie; Parstel ^ ng .. of the starting compound. ^! H '(R _2. = CO — όβΗδ) occurs through: condensation of 2 mol of the easily accessible 6,7-dimethoxy-3,4; -dihydroWsocliinqlins (representation: E. Späth and Y \. Epstein, Ben Dtsch. Chem. Ges., Vol. 59, Page 2796 (1926) and

E. Späth and NYPplgan Mh. Chem, Volume 51; Page 195 (1929)). with 1 _; MqL acetylene dicarboxylic acid; m ; same way as 3,4-dihydro-isqchinol.in with acetone dicarboxylic acid _:. condensed: was (G. Herberti; Dissertation Techn. Hochschule Darmstadt, 1956, pages 95 to 194).

The resulting mixture of the racemic and meso form of ΙΓ (H for.R2 ') is converted into the mixture of dihydrobromides, which are based on: their;, different solubilities in, - methanol: or; Let the glacial acetic acid separate easily. The poorly soluble dihydrobrqmid from melting point. 204-2Q5 ° G is the racemic compound; oyster mother liquor by concentrating the jsqmere kristallösüngsmittelhaltige dihydrobromide the meso form of mp. 178-18Q ⁰ C preserving The dihydrobromide. the: Racem-Forrh, is. in the usual way either immediately or via, the: by; The free base with a melting point of 146-147 ° C, which is easily obtainable with aqueous sodium hydroxide solution, is broken down into the T-jibenzoyl compound which melts at 198 ° C and which; at 2Ql 'to 203 ° C melting diacetyl compound or the. at

J5 173 ⁰ C melting; di-ii-butyryl compound converted. The racemic base is also due to a hydrochloride that melts at 201 ° C and a hydrochloride that melts at 190-192 ° C. Methanesulfonate, a picronate that melts at 236 ^ 237 ⁰ C and a bis-phenylurea and bis-phenylthiourea with a melting point of 203-204 ° C or 176-17.7 ° .G ^f (unstable modification 154 ^ 155 ⁰ C) characterized.:.-·.·--.'·--..,·..;:;-;^)·;< 2-Bromo ^{i buteh- (1) i is} obtained by splitting off: 1: mol of hydrobromic acid from 1,2-dibromobutai: in the usual way, for example with alcoholic potassium hydroxide the stereoisomereriH-bromobut (; nen- (l) and the sought-after 2-bromine; -buten- (l) is the latter through fractional distillation ¹ in a column of at least 20 theoretical plates as the lowest, at 79.2- ^ 79.5 ° C ^ at 769 Torr: obtained boiling fraction of nf = 1.4511. Its purity can be checked not only by the refractive index but also by the IR spectrum: it can be 8.28; 9.83; 10.68, 13.20 and 13.41 μ no absorption bands e.g. own, -i

2) According to Example 1, the Carbinol IVa 'is first prepared. To convert the compound IVa ' into the chloride V' and its ring closure to Ia ', 5.0 g

öo dihydrochloride of the>. Racem form of IVa '^ of melting point 4250-252 ⁶ C ^r in ^; Suspended 50 ecm of chloroform and heated to boiling under reflux for 5 hours with 50 ecm of phosphorus trichloride. From the solution, which had temporarily become clear, some glassy, phosphorous acid has deposited on the flask, from which the colorless chlorine-form solution is decanted off. It is evaporated to dryness under reduced pressure, and the residue is triturated with ether

with pieces of ice and, after adding 100 ecm of methylene chloride, shake it for a few minutes with 2N sodium hydroxide solution. The alkaline layer is extracted twice with a little methylene chloride. After evaporation, the combined extracts leave 3.90 g (93% of theory) of a pale yellowish base, which is dissolved in acetone for complete purification and converted into the dihydrochloride by adding ethereal hydrochloric acid, which crystallizes on trituration with a little isopropyl alcohol ; is thus obtained 3.32 g of the hydrochloride of Ia '(= 74% d. Th.) of Rohschmelzpunkt 238-240 ⁰ C, which rises after a single recrystallization from alcohol with addition of some ether to the constant value 242-243 ° C . The compound is identical with that described elsewhere dihydrochloride of 2-dehydro-isoemetins the produced therefrom base melts after recrystallization from acetone / water at 93-95 ⁰ C.

3) According to Example 1, the free base IVa 'is first prepared. Then 2.0 g (0.004 mol) of the free base are heated

■ * Base of melting point 126 -128 ⁰ C with a mixture of 10 cc of chloroform and 10 cc of phosphorus trichloride reflux for 2 hours with exclusion of moisture to boil. It is evaporated to dryness and, without isolating the intermediate product V, closes the ring to give 2-dehydro-isoemetin Ia 'by shaking with 50 ecm 2 η-sodium hydroxide solution and methylene chloride. After the methylene chloride has evaporated, the base remains in quantitative yield. It is so pure that, despite its low melting point, it can be recrystallized immediately from acetone with the addition of water in the heat until it becomes cloudy. 1.40 g (70% of theory) of the base Ia 'containing 1/2 mol of water of crystallization after brief drying in a desiccator are obtained in colorless sticks; on repeated recrystallization in the same way the constant value of 93-95 ° C. is obtained.

4) In a cooled to room temperature, from 20.2 g (0.15 mol) of 2-bromo-butene (l) with a boiling point of 79.2 to 79.7 ° C at 762 Torr (ni ⁰ = 1.4511) in 100 cc tetrahydrofuran, and the equivalent amount of magnesium (3.61 g) at 40 ⁰ C solution prepared from 0.15 mol of butene- (l) -yl (2) -magnesium bromide with vigorous stirring 19.2 g (0, 0296 mol) finely powdered meso form of a, oc'-bis (N-benzoyl-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolyl-1) -acetone, melting at 197 ° C ( H '; RZ = CO-C ₆ H ₅ ), which with the racemic form of Example 2, which happens to melt at almost the same temperature (197-199 ° C), results in a strong lowering of the melting point, entered in proportions, the temperature to 40 -45 ° C rises. The clear solution is left to stand for 19 hours at room temperature with the exclusion of air and then decomposed by adding a little ice and saturated ammonium chloride solution. The tetrahydrofuran layer is separated off and the aqueous layer is extracted twice more with methylene chloride. The residue from the extracts is rubbed with 50 ecm of n-butanol, with 3.92 g (20.4% of the amount used) unchanged starting compound crystallizing out with a crude melting point of 194 ° C., which is fed to a new batch;

The present in the butanol mother liquor reaction product of the constitution IVb '(R _2' = CO-QH ₅₎ is used for cleavage of the benzoyl residues after addition of 12 g of potassium hydroxide and 50 cc further butanol 6 hours in oil bath at 140 ⁰ C for Boiling heated. It is evaporated to dryness in vacuo, finally with twice the addition of water, and the base which separates out is taken up in methylene chloride. The base that remains after evaporation and which also contains, as a neutral body, some of the bis (buten- (1) -yl- (2)) -phenyl-carbinol formed by the cleavage of some benzoyl residues by the organometallic compound is a Mixture of the two diastereoisomeric alcohols of the constitution theoretically possible when using the meso form of II 'as starting material

ίο IVa '. To separate the main isomer, the crude product is dissolved in 50 ecm of methyl ethyl ketone and this solution is precipitated with ethereal hydrobromic acid, 13.6 g (= 70% of theory) of an amorphous dihydrobromide being obtained, which after trituration with 50 ecm hot water after cooling gives 7.8 g (= 36% of theory, since it contains 9% water of crystallization) of pure dihydrobromide of the one stereoisomeric alcohol IVa '; The melting point is vaguely 180-190 ° C; when heated at 200-220 ⁰ C, the melt foams. The quantitative conversion into the crystallized dibenzoyl compound (IVb '; R ₂ ' = CO — C ₆ H ₅ ), which ^{melts sharply at 204 to 206 ° C., proves that the compound is uniform.} The free base corresponding to the hydrobromide melts after recrystallization from tetrahydrofuran at 139 ° C; the dihydrochloride produced therefrom in the usual way after recrystallization from ethanol at 199 to 20 ° C.

Leaves from the aqueous mother liquor of the dihydrobromide of melting point 180-190 ⁰ C over the free base by the benzoylation with benzoyl chloride in pyridine a second at 204 -206 ⁰ C melting dibenzoyl compound isolate, with the above stereoisomeric, - the randomly at at the same temperature melting dibenzoyl compound gives a strong lowering of the melting point. After the analysis, she presents the second. in the meso series possible stereoisomers of constitution IVb '(R2' = CO-C ₆ H ₅ ).

To carry out the ring closure 5.6 g of the hydrochloride of melting point 199-201 ⁰ C with a mixture of 100 cc of chloroform and 45 g of phosphorus trichloride with the addition of a few drops of pyridine

8 hours under reflux with exclusion of moisture heated to boiling, whereby the initially suspended hydrochloride goes into solution and adheres to the glass wall separates some phosphorous acid.

After cooling, it is decanted off, evaporated to dryness in a vacuum, the amorphous residue is dissolved in 70 ecm of water and shaken vigorously for a few minutes with 250 ecm 2 N sodium hydroxide solution and a lot of ether. After drying and evaporation, the ether leaves behind 3.20 g (= 71.5% of theory) initially still amorphous, but already largely pure 2-dehydro-emetine (Ia '); a sample gives 86% of theory on acetylation with acetic anhydride in pyridine. N-acetyl-2-dehydro-emetine with a melting point of 197-198 ° C. To purify the base, 2.0 g of the crude base are converted into the dihydrochloride with ethereal hydrochloric acid (1.58 g = 68.6% of theory). i which melts ^{at 248-25O 0} C after rubbing with isopropyl alcohol. The 2-dehydroemetine (Ia ') liberated from it with alkali melts after recrystallization from acetone with the addition of water at 112-114 ° C. It contains 1 mol of crystal water which is still held by the analysis also on drying at 7O ⁰ C under high vacuum. The compound turns into one when boiled with acetone

194-195 ° C melting modification, very sparingly soluble in acetone. It is identical to that of A. Brossi and coworkers, HeIv. Chim. Acta, Volume 42, Page 785 (1959), 2-dehydro-emetin presented in a different, much more complicated way.

The starting compound, the meso form of the a, a'-bis- (N-benzoyl-6,7-dimethoxy-l, 2,3,4-tetrahydroisoquinolyl- (l)) acetone (ΙΓ; Ry = CO-C ₆ H ₅₎ is derived from the more readily soluble hydrobromide of melting point 178-180 ⁰ C (H '; H for R _2') by benzoylation with benzoyl chloride in pyridine or benzoyl chloride. obtained in chloroform and soda solution in quantitative yield. _{For their representation, one can also start from the quaternary:} salts formed from 6,7-dimethoxy-3,4-dihydro-isoquinoline by heating with benzyl chloride or bromide in: quantitative yield, these with acetone dicarboxylic acid to a, a ' -Bis- (N-ben lO))

condense acetone (11 '! C ₆ H ₅ -CH ₂ for R ₂ '), which in this case is obtained as a uniform meso form, '* and from this by catalytic hydrogenation of the hydrochloride in glacial acetic acid with palladium hydroxide on barium -> · sulfate split off the two benzyl residues as toluene. Man

(::) thus obtains the sterically uniform meso compound II '

(H for R ₂ '), which melts at 144-145 ⁰ C as the base. In addition to the dibenzoyl compound already mentioned at the beginning, which melts at 197.degree. C., the diacetyl compound with a melting point of 191-192.degree. C. (unstable modification 174-176.degree. C.), the di-n- butyryl-compound, melting at 193-195 ⁰ C dihydrochloride, which melts at 173-174 ° C methanesulfonate, which melts at 234-235 ° C Pikrolonat and characterized by the bis-phenylthiourea melting point of 195-197 ⁰ C.

For catalytic hydrogenation, a solution of 3.0 g of dihydrochloride of the 2-Dehydroemetins in 100 cc of methanol, after addition of 1.5 g is a 10% palladium hydroxide-barium sulfate catalyst in a stirred autoclave at 100 atmospheres hydrogen and 100- 110 ⁰ C for 10 hours long stirred. After the catalyst has been filtered off and the methanol has been evaporated off, the hydrochloride which remains is dissolved in a little hot isopropyl alcohol. On cooling, 66% of the theory crystallize. Th., \ .-, dihydrochloride a dihydro compound, the constant melts after recrystallization from methanol -J at 253 to 255 ⁰ C and dihydrochloride Äusgangs-by is a strong decrease of melting point. The base released from this is amorphous; It is characterized not only by the dihydrochloride but also by the crystallized phenylurea with a melting point of 122-125 ° C. (from ethyl acetate) obtainable in quantitative yield with phenyl isocyanate. This connection has already been described by A. Grüssner, E. Jaeger, J. Hellerbach and O. Schnider, HeIv. Chim. Acta 42, 2434, 2439 (1959) obtained by other routes and characterized as an isomer of emetine.

5) 10.5 g (0.020 mol) ^{melting at 191-192 0} C meso form of a, «'- bis (N-acetyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl -l) -acetons (H '; R _2' = CO-CH ₃ be) with stirring in an as prepared in example 1, at +10 ⁰ C cooled solution of 0.122 mol of butene- (l) -yl (2) Magnesium bromide added to 80 ecm of tetrahydrofuran with stirring so that the internal temperature does not rise above 25 ° C. The acetyl compound dissolves and a small amount of other crystals separates out. After decomposition with pieces of ice and 120 ecm 20% ammonium chloride solution, the crude reaction product is heated to boiling for 5 hours in an oil bath at 145 ° C without waiting for crystallization to split off the acetyl residue with 8 g of potassium hydroxide in 100 ecm of butanol, and the butanol in a vacuum finally evaporated with twice the addition of water and the residue taken up with methylene chloride. When the methylene chloride extracts are evaporated off, 8.70 g of crude reaction product IX still contaminated with neutral bodies formed by partial cleavage of the acetyl residues during Grignardation are obtained. For its purification, the dihydrochloride is precipitated from a solution of the crude product in a little acetone with alcoholic hydrochloric acid (6.23 g = 71.4% of theory), which as crude product at 193 ° C, after recrystallization from ethanol constant at 199 -201 ⁰ C melts: '^; -. · ■ ■ ; '■ -' ■■■ ' ^v hr-: ■■■■' ■: ■.,: .. ·: · ·. ■■. ■■■ ■ ■ · ■. ■: ■ :: The further conversion of this hydrochloride to 2-dehydroemetine (Ia ') takes place as indicated in Example 4

give. ^ -! -.- X, :: - .:.: -. ■:,. ■ ·. ' : ■ -.-. : ■■■■ ■ : ·.;. · ■ "■■■■ '■ ." ■■

6) To a solution of vinyl magnesium bromide prepared from 8.5 g of magnesium and 38.5 g of freshly distilled vinyl bromide under nitrogen at about 40 ° C. in 150 ecm of tetrahydrofuran, 10.0 g of finely powdered dihydrobromide des oi, <x'-bis - (6,7-methylenedioxy-1,2,3, 4-tetrahydroisoquinolyl-l) -acetons added mp 246 to 248 ⁰ C with stirring and heating to about 5O ⁰ C, wherein the salt immediately went into solution.. Mari is stirred for a further 5 hours with heating under reflux in a nitrogen atmosphere, cools, decomposes with ammonium chloride solution and works up as in Example 1. The resulting bis- (6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolyl- (l) rmethyl) vinyl carbinol is a slightly brownish colored resin, which is characterized by a crystallized picrolonate. The picrolonate crystallizes from dimethylformamide with the addition of methanol in flakes with a melting point of 242-245 ° C and gives a sharp decrease in the melting point with the picrolonate of the starting material. It crystallizes with 1 mol of crystal methanol; the analysis proves the presence of the substance sought. By flowing a solution of the picrolonate in an acetone / water mixture (mixing ratio 8: 3) through an anion exchanger in the Cl ° form, the hydrochloride of the tertiary alcohol is obtained as an amorphous, solid substance after evaporation.

For conversion into the chloride and for ring closure, treatment is carried out as in Example 2 in succession with phosphorus trichloride in chloroform and alkali. When the methylene chloride extracts are evaporated, the compound sought is obtained as a barely colored, foamy mass. It is characterized by a crystallized hydrobromide, perchlorate and a crystallized from a dimethyl formamide / methanol crystallizes with 1 mole of crystal methanol Pikrolonat of mp. 223-225 ⁰ C.

The obtained g.lO-methylenedioxy-l.ej.llb-tetrahydro-2- [1,2,3,4-tetrahydro-6,7-methylenedioxy-isoquinoline-1) methyl] -4H-benzo [a] - quinolizine can be hydrogenated analogously to the preceding examples to give the corresponding 2,3-saturated quinolizine derivative.

The starting material for this example is obtained by mixing a solution of 7.3 g of acetone dicarboxylic acid in 400 ecm of water with the solution of 17.5 g of ey-methylenedioxy-S ^ -dihydro-isoquinoline in a mixture of 60 ecm of methanol and combine 20 ecm of water at room temperature. _{Strong CO 2} evolution occurs in the clear solution; after

909 545/1

The α, oi'-bis (6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinolyI-1) -acetone begins to crystallize out for 15 minutes, and one of the possible stereoisomers of the raw material is obtained after standing for 5 hours at room temperature. 142-148 ° C (sintering from 127 °). To convert it into the hydrobromide, 48% hydrobromic acid is added to the crude base in a mixture of chloroform / methanol until an acidic reaction occurs. The hydrobromide melts after boiling with methanol at 248 ⁰ -25o C. The resulting compound in free base melts after recrystallization from methanol at 170-172 ° C, which Pikrolonat at 232-234 ° C.

From the "aqueous methanolic mother liquor of the condensation of acetone dicarboxylic acid with the 6,7-Methylenedioxy-3,4-dihydro-isoquinoline crystallizes after a further 43 hours, a second at 152-158 ° C melting fraction from which the hydrobromide already mentioned could also be obtained.

7) In a solution of vinyl magnesium bromide in tetrahydrofuran prepared as in the previous example 8.0 g <x, a'-bis (2-acetyl-6,7-methylenedioxy-1,2,3,4-tetrahydro-isoquinolyl-1) acetone

Melting point 228-230 ^c C registered and heated and worked up as there. vinyl carbinol, which apparently has already lost some of the acetyl radicals according to the IR spectrum, is saponified with KOH in butanol like the analogous benzoyl compound of Example 1. The same picrolonate with a melting point of 242-245 ° C. that was obtained in the example provided by reacting the non-acetylated starting material can be prepared in good yield from the saponification product. The further reaction takes place as in the previous example. '■; ■: ■'';'■"■' ■ '-

To prepare the bis (2-acetyl-6,7-methyIenedioxy-l, 2,3,4-tetrahydroisoquinolyl- (l) -acetone used as the starting product, the dihydrobromide of aA'-bis-6,7 is used in the usual way -methylenedioxy-l, 2,3,4-tetrahydro-isoquinolyl-l) -acetone in pyridine with acetic anhydride for 5 hours at room temperature and worked up as usual. After recrystallization from dimethylformamide / methanol, the diacetyl compound melts at 228-230 ⁰ C.

Claims (2)

14 70ÖÖ5 Patent claims: i. Process for the preparation of quinolizine derivatives the general formula IO 20th wherein Ri is a hydrogen atom or an alkyl radical with 1-9 carbon atoms denotes the benzene rings, optionally through alkoxy groups and / or methylenedioxy groups can be substituted and a single or double bond in the 2,3-position is present, characterized in that one 1,3-bis- (1,2,3,4-tetrahydro-isoquinolyl-1) -acetori derivative the general formula 25th 30th 35 40 45 50 wherein R ₂ denotes H or the acetyl or benzoyl group and the benzene rings as indicated in formula I can be substituted with an organometallic vinyl compound of the general formula (II) (III) MgX in which X is a chlorine, bromine or iodine atom and Ri has the above meaning, the addition _{product is hydrolyzed in a manner known per se, if R 2 stands} for the acetyl or benzoyl radical, it splits off hydrolytically in a manner known per se, the obtained tertiary alcohol the b0 65 general H ₂ CGR | Ho-c where Ri has the meaning given above, and the benzene rings can be substituted as indicated in formula I, with an inorganic acid chloride or -bromide converts, and that with AHyl rearrangement obtained unsaturated halide of the general formula in which Y is chlorine or bromine and; Ri is as defined above, .hat and the benzene rings can be substituted as indicated in formula I, ■ ■ · · -'- ^'c *' ■ '■ -' - '' ■ '^""'; 'alkaline by treatment with Agents cyclized and optionally: in the dehydroquinolizine derivatives of the above formula I in which there is a double bond in the 2,3-position, this double bond is catalytically hydrogenated in a manner known per se. 2. The method according to claim 1, characterized in that one a, a'-bis- (l, 2,3,4-tetrahydro-2-acetyl (or. -benzoyl-e ^ -dimethoxy-isoquinolyl-1) acetone, preferably its mesoform, grignarded with Λ-ethyl-vinyI-magnesium bromide, the obtained Grignardation product hydrolyzed as usual, the N-acetyl (or Benzoylj group saponified, then the hydroxyl group of the so produced Bis - [(1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolyl) methyl] - [1-butenyl-2] carbinoIs replaced by chlorine by treatment with thionyl chloride or phosphorus trichloride and from this under allyl rearrangement obtained l- [6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl-1 ] -2 - [(6,7-dimethoxy-1,2,3,4-tetra- hydro-isoquinolyl-1) methyl] -3-chloromethyl-pentene (2) HCl is split off by treatment with alkaline agents, as well as, if appropriate, those in the 2,3-position located isolated double bond; of the .S- ^ tn ^ r ^ i ^ dimethöxy-iÄZit ib-teträhydrö-2-ifl ^^^ - Mräh ^ rp ^^ inethdxy ^ ifeöchihoiyi-1 ) -. ■ melhy \ i-4H -behzö ^ ä |; hinöiiz! ns hydrogenated. ... -The. Invention. concerns ... fine new _; only from; woe Stages. bW see 'ride's,:, ^ C.hmQlizlndeHvä'teh.üer äligemeineüi- ^FornVel; . .-.