NO143785B - PROCEDURE FOR HEAT EXTRACTION OF ALUMINUM ALLOYS WITH HIGH STRENGTH - Google Patents

Description

Process for the preparation of therapeutically active benzoquinolizines.

The present invention relates to

position of therapeutically active benzoquinolizine derivatives of the general formula

wherein R, means lower alkyl, trifluoromethyl,

phenyl, halophenyl, (lower alkyl)phenyl, (lower-

re alkoxy)phenyl, 3,4-methylenedioxyphenyl

or phenyl lower alkyl, R., means hydrogen

or lower alkyl, R:1 and R4 each means hyd-

rogen or lower alkoxy and together are

R., and R4 methylenedioxy as well as their acid addition salts and their quaternary ammonium compounds.

A large number of benzoquino-

lysines. Connections can be mentioned such as

manufactured according to the Austrian patent no.

195,928, which is represented by the gene-

real formula

in which R5 and R(i are hydrogen, hydroxyl- or

ler alkoxy groups or together an alkylenedioxy group, and R- means an alkyl, cycloalkyl, alkenyl or aralkyl group.

Furthermore, reference can be made to the bel-

German patent no. 554 816 which describes the

bonds with

in which R- and R,, are as defined in the preceding

walking and RH means an alkyl-, alkenyl-

or aralkyl group. If RH means an alkyl-

group, the hydrocarbon chain may be of-

broken with an oxygen atom.

Also the connection according to the Belgian

patent no. 565 824 can be mentioned, which rep-

resented by the formula

wherein R9, R10 and Rn each represents a hydrogen atom, an alkoxy group or an alkylenedioxy group, if any two of these radicals are taken together, R12 represents a hydrogen atom or a hydrocarbon group which is saturated in the p-position, R ,.( means a, hydrogen atom or a carboxyl group.,

The compound according to Belgian Patent No. 554,816 shows a very close resemblance to the compound according to Austrian Patent No. 206,441, which describes a process which is slightly different from that described in the said Belgian patent.

Furthermore, the compound according to the French patent no. 1,210,144 can be mentioned. These compounds are represented by the general formula

wherein Rl4 and Rl3 each represent a hydrogen atom, an alkoxy group or together represent an alkylenedioxy group, R1(i represents an alkyl, alkoxyalkyl, alkenyl or aralkyl radical, Rl7 is an ethynylidene, ethenylidene or ethylene group and R, 8 is a hydrogen atom, an alkoxy, alkyl or aryl group French Patent No. 1,221,027 describes compounds of the formula

in which the symbols R19 and R20 respectively mean an alkyl or aryl group and a hydrogen atom! or an alkyl group. If R2() means hydrogen, R19 can also be a hydrogen atom.

The benzene ring can also have substituents.

Several of the compounds described above are intended as intermediates in the production of emetine and similar compounds. In other cases, the compounds are also attributed with therapeutic properties.

The compounds produced according to the present invention are pharmacologically active substances that have adrenolytic and analgesic activity. In addition, the compounds have sedative activity and can therefore be used instead of known sedatives. In addition, a number of these have a vasodilatory effect, while some compounds lower the body temperature of the test animals.

The toxicity is low.

For use as therapeutic agents, the compounds are used either as such or in the form of their acid addition salts, in the usual pharmaceutical forms such as tablets, pills and capsules.

Among the suitable acid addition salts which are prepared according to the present invention can be mentioned the non-toxic acid addition salts, e.g. the salts with inorganic acids, such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), sulfuric acid, boric acid and phosphoric acid, and organic acids, such as acetic acid, oxalic acid, maleic acid, fumaric acid, citric acid, lactic acid, tartaric acid and pamoic acid.

The compounds obtained according to the present invention are produced by reduction of compounds with the formula

This reduction is preferably carried out using lithium aluminum hydride as reducing agent. The reaction is preferably carried out in a solvent. Ethers such as diethyl ether and tetrahydrofuran are very suitable if lithium aluminum hydride is used as the reducing agent.

Of primary importance are the properties of the compounds 9,10-dimethoxy-2-(4'-halophenyl)-1,3,4,6,7,1 lb-hexahydro-2H-benzo[a]quinolizine and especially 9,10- dimethoxy-2-(4'-chlorophenyl)-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine which has very good analgesic activity.

The following example may serve to illustrate the invention. A method for the production of the various intermediate products used in the synthesis of the starting products is included.

Preparation of 1,3,4,6,7,llb-hexahydro-2H-benzo[a]quinolizine.

Reduction of the quinolizones (lactams) to the corresponding quinolysines is usually carried out with lithium aluminum hydride, using at least y2 mol of hydride and often an excess per moles of lactam.

In the preparation of the lactams, as described below, an asymmetry center is introduced with the nitrogen atom, so that two isomers are formed.

As the isomeric lactams are sometimes difficult to distinguish from each other, a mixture of the lactams is usually reduced. The amine fraction that is formed is isolated from the reaction mixture and subjected to fractional crystallization to separate the amines.

2.1 g of a mixture of isomeric 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2-(4'-methylphenyl)-2H-benzo[a]quinolizin-4-ones, melting range 164-174°C, mainly consisting of lactam with melting range 178-181°C', is dissolved in anhydrous tetrahydrofuran and 0.4 g of lithium aluminum hydride in 50 ml of tetrahydrofuran is added. The mixture is heated under reflux for 2 hours, after which excess lithium aluminum hydride is decomposed with a little water. The aluminum hydroxide that is formed is removed by filtration and washed with diethyl ether. The tetrahydrofuran is removed by distillation and the residue is treated with water and diethyl ether. The ethereal solution is dried and concentrated.

During this step, cis 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2-(4'-methylphenyl)-2H-benzo[a]quinolizine base (1.2 g = 60 pst.) in the form of long needle-shaped crystals.

After crystallization from petroleum ether with a boiling range of 60-80°C, the melting point is 117-118.5°C. Hydrochloride of the base prepared in the usual way in diethyl ether becomes crystalline on treatment with acetone and melts after crystallization from a mixture of alcohol and ethyl acetate at 245-247°C. The salt is easier to purify than the free base. By adding an ethereal hydrochloric acid solution to the mother liquor of the cis-base, the trans-hydrochloride can be isolated.

The yield is 40 percent. This salt can be crystallized from ethanol with a little water, melting point: 264-266°C.

The base liberated from this salt melts at 65-66° C, after crystallization from petroleum ether.

As a rule, the relative level of the melting points for quinolysines produced according to the present invention is as indicated above.

The free cis base has a higher melting point than the trans base, while the reverse appears to be the case for the hydrochloride.

Sometimes the differences found for the purified compounds are so small that too much emphasis should not be placed on this rule, especially when insufficiently purified reaction products are included. The infrared spectrum provides information regarding the spatial structure of the molecule.

The spectra for cis- and trans-isomers differ sufficiently to allow an unequivocal determination of the cis- or trans-configuration of the compounds in question. It has thus been found that all cis-compounds produced according to the present invention show absorption maxima at 2750 and 2805 cm-1", while the trans-compounds do not show these maxima.

This is in agreement with the finding of Bohlman, Berichte 91, 2157 (1958). The following table shows a summary of data for a number of quinolysines produced according to the present invention. With regard to the melting points of the salts, it should be noted that the salts melt during decomposition. Preparation of quaternary ammonium derivatives of 1, 3, 4, 6, 7, llb-hexahydro-2H-benzo [a] quinolizines.

The quinolizine bases produced according to the present invention can be converted into quaternary ammonium compounds in the usual way, e.g. dissolve 7.5 g in 1,3,4,6,7,1 lb-hexahydro-9,10-dimethoxy-2-(4-chlorophenyl)-2H-benzo[a]quinolizine base in a mixture of acetone and methyl alcohol. Excess of a solution of methyl iodide in acetone is added dropwise. After one minute, the 1,3,4,6;7,11b-hexahydro-9,10-di-Methioiodide is crystallized from a mixture of benzo [a] quinolizinium iodide begins to crystallize. The yield is 8.5 g, melting point 260°C. The metho iodide is crystallized from a mixture of methanol with a small amount of water. The yield is 5 g, melting point 274-276°C.

1,3,4,6,7,11b-hexahydro-2H-benzo [a]quinolizin-4-ones are used as starting reaction participants in the above reaction and can be prepared in the following way.

A. Preparation of glutaric anhydrides substituted in the 3-position.

The procedure is largely analogous to that described by W. F. Smith et al. in J. Am. Chem. Soc. 72, 1877

(1950).

120 g p-methylbenzaldehyde 260 g ethyl acetoacetate 50 ml ethanol and 20 ml pyridine are mixed.

After standing for several hours, 112 g of diethyl-2,4-diacetyl-3-(4-methylphenyl) glutarate, with a melting point of 133-133.5°C, have crystallized out. If the mixture stands for several weeks, another portion of the same ester can be obtained.

112 g of diethyl-2,4-diacetyl-3-(4-methyl-phenyl) glutarate, dissolved in 1500 ml of ethanol, is boiled with a reflux condenser with 1.8 kg of a 50% sodium hydroxide solution for 1 hour.

After removal of the alcohol by distillation and acidification, crystalline 3-(4-methylphenyl)glutaric acid is obtained by filtration. Extraction with ether and the mother liquor gives a further quantity of the product. The yield is 56 g (82 per cent), melting point 164-166°C.

The anhydride is obtained from the acid by boiling with a reflux condenser with twice the amount of acetic anhydride. If desired, acetic acid can be used as a solvent. The table below gives the data for the anhydrides, which are prepared in a similar way, replacing the corresponding aldehydes. It is rarely necessary to purify the intermediates mentioned above, and the syntheses can then proceed without interruption for purification.

20.4 g of 2-(3,4-methylenedioxyphenyl)ethylamine in 50 ml of benzene is slowly added to 23.5 g of 3-phenylglutaric anhydride in 250 ml of benzene. An exothermic reaction takes place, after which the amide immediately begins to crystallize. After cooling the reaction mixture, 40.7 g (92 percent) of 3-phenyl-glutaric acid homopiperonylamide is isolated. After several times of recrystallization from an acetone-water mixture, the compound melts at 136.5-137.5°C.

Suitable ethylamines which can be used as initial reactants in this process include: phenethylamine (lower alkoxy} substituted phenethylamines (e.g. p-methoxyphenethylamine, p-ethoxyphenethylamine, o-methoxyphenethylamine and m-methoxyphenethylamine); di(lower alkoxy)phenethylamines (eg m,p-dimethoxyphenethylamine) and m,p-methylenedioxyphenethylamine.

Suitable glutaric anhydrides that can be used as initial reaction participants in the method include: 3-substituted glutaric anhydrides, such as 3-(lower alkyl)-glutaric anhydrides (e.g. 3-methylglutaric anhydride, 3-ethylglutaric anhydride and 3-propylglutaric anhydride); 3-trifluoromethylglutaric anhydride; 3-phenylglutaric anhydride; 3-(halophenyl)-glutaric anhydrides (e.g. 3-p-chlorophenyl-j glutaric anhydride, 3-p-bromophenylglutaric anhydride, 3-p-fluorophenylglutaric anhydride, 3-o-chlorophenylglutaric anhydride and 3-m- chlorophenylglutaric anhydride); 3-(lower alkylphenyl)glutaric anhydrides (eg, 3-p-methylphenylglutaric anhydride);

3-(lower alkoxyphenyl)glutaric anhydrides (eg 3-p-methoxyphenylglutaric anhydride); 3,4-methylenedioxyphenylglutaric anhydride; 3-(phenyl lower alkyl)glutaric anhydrides (eg, 3-benzylglutaric anhydride and 3-phenethylglutaric anhydride);

3,3-di(lower alkyl)glutaric anhydrides (eg, 3,3-dimethylglutaric anhydride, 3-methyl-3-ethylglutaric anhydride, and 3,3-diethylglutaric anhydride); 3-(lower alkyl)-3-phenylglutaric anhydrides (eg, 3-methyl-3-phenylglutaric anhydride and 3-ethyl-3-phenylglutaric anhydride); 3-(lower alkyl)-3-(halophenyl)glutaric anhydrides (eg, 3-ethyl-3-p-chlorophenylglutaric anhydride); 3-(lower alkyl)-3-(lower alkylphenyl)glutaric anhydrides; 3-(Lower Alkyl)-3-(Lower Alkoxyphenyl) Glutaric Anhydrides; 3-(lower alkyl)-3-(phenyl lower alkyl) glutaric anhydrides.

Table III summarizes the data for a number of similar homoveratrylamides, and these compounds were prepared according to procedures analogous to the procedure described above.

For this conversion, Bischler-Napieralski isoquinoline synthesis can be used as described in Org. Reactions VI, 74-150. The cyclization, which is carried out under the influence of a condensing agent, such as freshly distilled phosphorus oxychloride, takes place without exception only when the free carboxyl group is esterified, e.g. with diazomethane.

A solution of diazomethane in ether is added slowly to 19 g of N-2-(3,4-dimethoxyphenyl)ethyl-3-(4-methoxyphenyl)-glutaric acid monoamide in 50 ml of diethyl ether and 5 ml of methanol. Nitrogen is evolved and the yellow diazomethane color disappears, while the formed ester dissolves in the reaction mixture. Diethyl ether is removed under reduced pressure and the oil-like residue is heated under reflux with 50 ml of freshly distilled phosphorus oxychloride and 50 ml of anhydrous benzene for 4-5 minutes, hydrogen chloride being evolved during the process. After removing benzene and excess phosphorus oxychloride by distillation under reduced pressure, the remaining phosphorus oxychloride is split with methanol while cooling.

The reaction mixture is made alkaline and extracted several times with diethyl ether. 5 g of oxalic acid in diethyl ether are added to the dried ethereal solution. The yield is 17.1 g of methyl 4-(3,4-dihydro-6,7-dimethoxy isoquinol-1-yl)-3-(4'-methoxyphenyl)-butyrate oxylate (73.2 percent), melting point 132— 134°C.

In a similar manner, the following methyl 4-[3,4-dihydro-(R3,R4-substituted)isoquinol-1-yl]-3-(R1,R2-substituted)butyrates can be obtained.

Sometimes a slightly deviating method is used, whereby the (3-substituted glutaric anhydrides produced according to step A are first converted to the monomethyl esters by treatment with methanol. The esters crystallize from the methanol solution on cooling and can be isolated by filtration.

These monoesters are then reacted with thionyl chloride, so that the corresponding rionoacyl chloride of the monoester is formed.

Excess thionyl chloride is distilled off, leaving behind a yellow syrupy mass which is then reacted without prior purification with an equivalent amount of the desired (3-arylethylamine in an excess of pyridine. The reaction is carried out at a temperature of 80-85° C. Benzene is used as a solvent. After cooling, the mixture is extracted with water. The benzene layer is dried with sodium sulfate and filtered. The benzene is distilled off, leaving a solid residue that can be purified by recrystallization from a suitable solvent. Some of the compounds mentioned in the above table are prepared using these procedures.

As the last method is less cumbersome, as time and material-consuming cleaning operations are mostly avoided, this method is usually preferred. D. Preparation of methyl 4-[1,2,3,4-tetrahydro-(R3,R1-substituted)isoquinol-1-yl]'-3-(R1,R2-substituted)butyrates.

Reaction scheme IV

Hydrogenation of the hydroisoquinoline derivatives for which purpose platinum has proved a valuable catalyst usually proceeds smoothly, the theoretical amount of hydrogen being absorbed.

As a result of this reaction, another asymmetric center is formed, so that two isomers can be expected. It is often difficult to separate the two isomers, and the inherent problems are exacerbated as the amino acid esters present tend to spontaneously convert to the corresponding lactam. Because these lactams, although not formed spontaneously, are obtained during the next step, the tetrahydroisoquinoline derivatives are usually not isolated, but are submitted directly to the next reaction step.

Instead of the esters, the corresponding acids can also be used as starting products for reduction.

5.5 g of methyl 4-(3,4-dihydro-6,7-methylenedioxyisoquinol-1-yl)-3-phenylbutyrate, as the oxalic acid salt, dissolved in 150 ml of methanol with a portion of water, shaken with hydrogen in the presence of 25 mg platinum oxide (Adam's catalyst) 325 ml 'hydrogen is absorbed in

.2y2 itime. After removal of the catalyst by filtration, the solution of the oxalate is concentrated under pre-reduced pressure. Treatment of the residue with acetone yields 2.7 g

of -an isomer of -methyl-4-(1,2,3;4-tetrahydro-6,7-methylenedioxyisoquinol-1-yl)-3-phenylbutyrate, as its oxalate. The isomers are called cc isomers. After evaporation

of acetone and treatment of the residue with ethyl acetate, 2.2 g of crystalline fHisomer-e are obtained.

E. Manufacturing . of 1, 3, 4, 6, 7', llb- hexa-hy dr o- 2H- benzo [a] quinolizin- 4-ones.

Reaction scheme V

The cyclization of the amino esters to lactams (quinolizinones) sometimes goes less smoothly if the salts of the amino esters are used as starting material. On the other hand, liberation of amino ester from the salt in some cases presents difficulties, and it should therefore be found out in practice which starting product, either the free amino ester or its salt, is to be preferred for reaction. 4.5 g of methyl 4-(1,2,3,4-tetrahydro-6,7-methylenedioxy-isoquinol-1-yl)-3-phenylbutyrate in the form of its oxalate is heated under reflux in xylene for 1 hour. Oxalic acid crystallizes on cooling.

The xylene is evaporated and the residue crystallized from a methanol-diethyl ether mixture. Two isomeric forms of the product were obtained. An isomer of 1,3,4,6,7,1 lb-hexahydro-9,10-methylenedioxy-2-phenyl-2H-benzo [a]quinolizin-4-one with melting point 162-163°C is obtained in 1 g dividend. A quantity of 1.5 g is obtained from the second isomer which melts at 121-126°C.

Instead of the ester, the corresponding acid can be used as starting product for the ring closure.

1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizin-4-ones listed in the following table can be prepared in a similar manner.

Claims (1)

Process for the preparation of therapeutically active benzoquinolizines with the general formula wherein R, means lower alkyl, trifluoromethyl, phenyl, halophenyl, (lower alkyl)phenyl, (lower alkoxy)phenyl, 3,4-methylenedioxyphenyl or phenyl lower alkyl, R, means hydrogen or lower alkyl, R3 and R., means each hydrogen or lower alkoxy, and together are Rs and R4 methylenedioxy, as well as their acid addition salts and their quaternary ammonium compounds, characterized in that compounds with the formula wherein R 1 , R 2 and R 4 have the above meaning, are reduced and, if desired, the compounds thus formed are converted into their acid addition salts or their quaternary ammonium compounds.