DE1108222B - Process for the preparation of 1-phenylaethyl-tetrahydroisoquinoline compounds and their salts - Google Patents

Description

GERMAN

PATENT OFFICE

H 37243 IVb / 12ρ

REGISTRATION DATE: AUG U S T 22, 1959

NOTICE
THE REGISTRATION
ANDOUTPUTE
EDITORIAL: JUNE 8, 1961

The invention relates to a process for the preparation of 1 - phenylethyl tetrahydroisoquinoline compounds the general formula

CHoO-

CH

N-CH,

CH-Ro

CH ₂

in which R _{1 is} fluorine, chlorine or bromine, R _{2 is} hydrogen or a straight or branched alkyl radical having 1 to 4 carbon atoms, η is the number 1, 2 or 3 and the undefined position of the radicals R ₁ means that they are in any position in the Benzene ring can have, as well as salts of these compounds.

The process according to the invention consists in that one l-alkanoyl-2- (ß-acylamino-ethyl) -4,5-dimethoxybenzene condensed with a halogen-substituted benzaldehyde, the styryl ketone formed to the corresponding 3,4-Dihydroisochmoline derivative cyclized, this reduced, the resulting substituted 1-phenethyl-l ^^^ - tetrahydroisoquinoline methylated on the nitrogen atom and the N-methyl derivative, if desired converted into a salt.

The acetophenone derivatives required as starting compounds can, according to the information in the German patent 1088986 can be produced.

In the first reaction stage, a 1-alkanoyl-2- (ß-acylamino-ethyl) -4,5-dimethoxy-benzene is used condensed with a halogen-substituted benzaldehyde. A suitable condensing agent is used alkaline agent, e.g. B. alkali amide, alkali alcoholate or aqueous alkali hydroxide. The reaction will expediently in a solvent, advantageously in a water-miscible solvent, such as Tetrahydrofuran, dioxane, or a lower alcohol such as methanol. The formed substituted Styryl ketones are mostly compounds that crystallize well.

In the next stage of the process, the styryl ketones are converted into the corresponding substituted 1-styryl-3,4-dihydroisoquinolines cyclized. The acyl radical on the nitrogen atom is split off and the substituted styryl- [2 - (^ - amino-ethyl) -phenyl] -ketone formed as an intermediate closed to form a ring with elimination of water. The cyclization is carried out by treatment with an acidic agent, if necessary carried out in the presence of a solvent. Suitable cyclizing agents are, for. B.

Method of manufacture

of l-phenylethyl-tetrahydroisoquinoline-

compounds and their salts

Applicant:

F. Hoffmann-La Roche & Co.

Corporation,

Basel, Switzerland)

Representative: Dr. G. Schmitt, lawyer,
Loerrach (Bad.), Friedrichstr. 3

Claimed priority:
Switzerland from September 4, 1958

Dr. Hedwig Besendorf, Basel,

Dr. Arnold Brossi, Riehen,

and Dr. Otto Schnider, Basel (Switzerland),

have been named as inventors

Solutions of mineral acids or phosphorus oxychloride in an inert organic solvent, like benzene. A preferred embodiment consists in that the styryl ketones with dilute hydrochloric acid refluxed in the presence of acetic acid. Usually the mineral acid salts crystallized the l-styryl-3,4-dihydroisochinoHne already exits when the reaction mixture cools down. Otherwise can crystallization is carried out by boiling the precipitate with a suitable solvent such as acetone reach. To obtain pure, crystalline l-styryl-3,4-dihydroisoquinolines one needs not to start from crystallized styryl ketones; one can directly contain the styryl ketones Use solution, acidifying and then boiling directly to the crystalline l-styryl-3,4-dihydroisoquinolines.

The corresponding substituted 1-phenethyl-1,2,3,4-tetrahydroisoquinolines are obtained by hydrogenation of the mineral acid salts of the l-styryl-3,4-dihydroisoquinoline compounds at room temperature and the prevailing atmospheric pressure in alcoholic solution in the presence of a metal catalyst, e.g. B.

109 610/419

a platinum, palladium or nickel catalyst. Are «-alkylated l-styryl-3,4-dihydroisoquinolines to the corresponding α-alkylated 1-phenethyl-1,2,3,4-tetrahydroisoquinolines reduced, this creates a second center of asymmetry. There are thus two stereoisomeric racemates possible, their Separation, if necessary, can be done by fractional crystallization or chromatography.

In the last stage of the reaction, the substituted l-phenethyl-l ^ S ^ -tetrahydroisoquinoline compounds methylated on the secondary nitrogen atom. An expedient embodiment of the methylation consists in that the substituted 1-phenethyl-1,2,3,4-tetrahydroisoquinolines treated as free bases with aqueous formaldehyde solution and then catalytic, e.g. B. using Raney nickel, with hydrogen in the neutral or acidic Medium hydrogenated.

The substituted l-phenethyl-2-methyl-1,2,3,4-tetrahydroisoquinolines obtained are basic, mostly crystalline compounds that interact with common inorganic acids such as sulfuric acid, phosphoric acids, Hydrogen halides and common organic acids such as tartaric acid Formic acid, citric acid, fumaric acid, crystalline water-soluble salts.

Both the bases and their salts have valuable analgesic and spasmolytic properties. They can therefore be used as remedies or as intermediates in the manufacture of remedies be used.

example 1

81 g 2- _(j ß-acetylamino-ethyl) -4,5-dimethoxy-acetophenone and 42 g of p-chlorobenzaldehyde are dissolved in 250 cc of methanol under gentle heating and added with 30 cc of 3 N sodium hydroxide solution. After adding water to the solution until it becomes cloudy, it is allowed to stand for about 30 minutes. After filtration, washing with water and drying, 105 g of 2- (.beta.-acetylamino-ethyl) -4,5-dimethoxy- (4'-chlorobenzylidene) acetophenone of melting point 155 ⁰ C. The ultraviolet absorption maxima in ethanol are at 226 and 308 mn. (The extinction coefficient ε is 15800 and 25100.) The following were prepared in an analogous manner:

2- (j5-AcetyIamino-ethyl) -4,5-dimethoxy- (2'-chlorobenzylidene) -acetophenone of melting point 132 ° C; Ultraviolet absorption maxima in ethanol at 222 and 284ηιμ (ε = 14500 and 17900);

2 - ((3-acetamino-ethyl) -4,5-dimethoxy- (3 ', 4'-dichlorobenzylidene) acetophenone of melting point 160 ° C; Ultraviolet absorption maxima in ethanol at 234 and 299 ΐημ (ε = 16000 and 20400);

2- (β- acetamino-ethyl) -4,5-dimethoxy- (3'-chlorobenzylidene) -acetophenone with a melting point of 135 ° C .; Ultraviolet absorption maxima in ethanol at 232 and 294 ιημ (ε = 11100 and 15000);

2 - (^ - Acetamino-ethyl) -4,5-dimethoxy- (2 ', 4'-dichlorobenzylidene) -acetophenone of melting point 150 ° C; Ultraviolet absorption maxima in ethanol at 242 and 319 ηιμ (ε = 12100 and 14600).

105 g of 2- (18-acetamino-ethyl) -4,5-dimethoxy- (4'-chlorobenzylidene) acetophenone are dissolved in 100 ecm glacial acetic acid, 720 ecm gives 20% volume? weight-? aqueous Hydrochloric acid and refluxed for 1 hour. After cooling, the precipitate is sucked off, dried and then from a mixture of methanol and ether, which is 90% methanol contains, redissolved. 95 g of golden yellow crystals of 1- (4'-chlorostyryl) -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride are obtained with a melting point of 196 ° C. The ultraviolet absorption maxima in ethanol are at 236 and 340 πιμ (ε = 15600 and 17000).

The following were produced in an analogous manner:

1- (2 '-chlorostyryl) -6,7-dimethoxy -3,4-dihydro-isoquinoline hydrochloride of melting point 200 ° C; Ultraviolet absorption maxima in ethanol 241 and 331 πιμ (ε = 10100 and 17000);

isoquinoline hydrochloride with a melting point of 160 to 162 ° C; Ultraviolet absorption maxima in ethanol at 240 and 335 ΐημ (ε = 13 700 and 18 700);

1 - (3'-chloro - styryl) - 6,7-dimethoxy - 3,4 - dihydro - isoquinoline hydrochloride, melting point 200 ° C; Ultraviolet absorption maximum in ethanol at 325m _A u. (Ε = 17,000);

1- (2 ', 4'-dichlorostyryl) -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride of melting point 216 ° C; Ultraviolet absorption maxima in ethanol at 242 and 319 πιμ (ε = 12100 and 14600).

95 g of 1- (4'-chlorostyryl) -6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride are dissolved in 3500 ecm of 80 percent by volume aqueous methanol and hydrogenated in the presence of 500 mg of platinum oxide. The amount of hydrogen calculated for 2 moles is taken up. After filtering off the catalyst, the solution is concentrated and boiled with acetone. Man receives 72 g of l- (4'-chloro-phenethyl) -6,7-dimethoxy-1, 2, 3, 4 - tetrahydroisoquinoline - hydrochloride from Melting point 238 ° C. The ultraviolet absorption maximum in ethanol is 283 πιμ (ε = 3,800). the crystallized from the aqueous solution of the hydrochloride by the addition of soda solution base after standing for some time. After dissolving from isopropyl ether, it melts at 69 to 70 ° C.

The following were produced in an analogous manner:

1 - (2'-chloro-phenethyl) - öj-dimethoxy-l ^^^ - tetrahydroisoquinoline hydrochloride of melting point 189 ° C;

1 - (3 ', 4'-dichloro-phenethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride of melting point 230 ° C;

hydroisoquinoline hydrochloride with a melting point of 203 to 205 ° C;

1- (2 ', 4'-dichlorophenethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride of melting point 250 ° C;

1- (4'-Bromo-phenethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride from melting point 233 to 235 ° C;

1- (4'-Fluoro-phenethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride from melting point 227 to 229 ° C;

60 g of 1- (4'-chlorophenethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline are dissolved in 250 ecm of methanol dissolved and mixed with 20 ecm of a 38 weight percent aqueous formaldehyde solution. After 2 hours If the solution is at room temperature, it becomes with the addition of 10 g of Raney nickel catalyst hydrogenated. 7500 N-ccm of hydrogen are absorbed. After filtering off the catalyst the solution is concentrated and the crystalline residue is redissolved from methanol-water. You get 54 g of l- (4'-chlorophenethyl) -2-methyl-6,7-dimethoxy-

1,2,3,4-tetrahydroisoquinoline as colorless flakes that melt at 110 to 111 ° C. The hydrochloride prepared in acetone solution of the base by adding alcoholic hydrochloric acid crystallizes after the addition of ether; Melting point 105 to 106 ⁰ C; the ultraviolet absorption maxima in ethanol are 283 and 287 τημ (ε = 3830). Melting point of the picrate 151 ⁰ C.

The following were produced in an analogous manner:

1- (2'-Chloro-phenethyl) -2-methyl-6,7-dimethoxy-1,2, S ^ -tetrahydroisoquinoline hydrobromide of melting point 164 ° C;

l- (3 ', 4'-dichloro-phenethyl) -2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with a melting point of 94 ⁰ C; Melting point of the hydrochloride 120 ⁰ C;

1- (3'-chlorophenethyl) -2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride with a melting point of 112 ^° C .;

l- (2 ', 4'-dichloro-phenethyl) -2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with a melting point of 108 ⁰ C;

1 - (4'-Bromo-phenethyl) -2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, melting point 116 ° C;

1 - (4'-fluoro-phenethyl) -2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with a melting point of 127 to 129 ^° C .; Melting point of the hydrochloride 109 ⁰ C.

Example 2

7.2 g of the l- (4'-chlorostyryl) - 6,7 - dimethoxy - 3,4 - dihydroisoquinoline - hydrochloride prepared according to Example 1 are dissolved in 300 ecm of 90% aqueous methanol in the heat and then partially with a total of 2 g of sodium borohydride are added. The initially orange-red solution is discolored. After it has been concentrated, it is mixed with water and left to stand. The crystalline base obtained in this way is redissolved from methanol-water. 4.5 g of 1- (4'-chlorostyryl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline with a melting point of 144 ° C. are obtained. This is prepared from the acetone solution of the base by adding alcoholic hydrochloric acid Hydrochloride crystallizes after the addition of ether; Mp 243 ⁰ C. The ultraviolet absorption maximum of the base in ethanol is 260 ηιμ (e = 29000).

The catalytic hydrogenation of the base or the hydrochloride provides that described in Example 1 l - ^ '- Chlor-phenäthyty-oJ-dimethoxy-1,2,3,4-tetrahydroisoquinoline.

Example 3

40 g of 2 - (/ 3-acetamino-ethyl) -4,5-dimethoxy-propiophenone are condensed according to Example 1 with 20 g of p-chlorobenzaldehyde. 2 - (β- acetamino-ethyl) -4,5-dimethoxy-α- (4'-chlorobenzylidene) -propiophenone with a melting point of 126 ° C. is obtained in quantitative yield. Its cyclization in an acetic acid-hydrochloric acid mixture according to Example 1 results in l- (4'-chloro-methyl-styryl) -6,7-dimethoxy-3,4-dihydroisoquinoline as an oily hydrochloride, which is catalytically hydrogenated in alcoholic solution according to Example 1, the l- (4'-chlorine - «- methyl-phenethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride is obtained. If the aqueous solution of the hydrochloride is made alkaline and the precipitated base is taken up in benzene, one of the two possible racemates with a melting point of 138 ° C. is obtained after evaporation of the benzene and recrystallization of the residue from isopropyl ether with a melting point of 138 ° C. The base obtained from the acetone solution introducing prepared by hydrogen chloride gas hydrochloride melts after recrystallising from alcohol-ether at 203-204 ⁰ C. the methylation of the secondary amine of example 1 yields l- (4'-Chlora-methyl-phenethyl) -2-methyl-6,7- dimethoxy-1,2,3,4-tetrahydroisoquinoline as one of the two possible racemates. Melting point of the hydrobromide: 194 ⁰ C. The ultraviolet absorption maximum in ethanol is 283 πιμ (ε = 3830).

The propiophenone required as a starting material can be produced as follows:

21 g of 1-ethyl-6,7-dimethoxy-3,4-dihydroisoquinoline (E. Späth et al., Monatshefte der Chemie, 51. [1929], p. 199) are dissolved in 50 ecm of absolute pyridine. 25 ecm of acetic anhydride are added and the mixture is heated on the water bath for one hour. Which is recrystallized from Essigester-petroleum ether (melting point 99 ⁰ C) according to the concentration of the solution crystallized l-acetyl-Äthyüden ^ o ^ dimethoxy-l ^ S ^ -tetrahydroisochinolin out. The product obtained is then dissolved in 100 ecm 3 η-hydrochloric acid with gentle heating. Afterwards it sets saturated sodium carbonate solution to phenolphthaleinalkalischen to the reaction to give 2- _(J ö-acetamido-ethyl) -4,5-dimethoxy-propiophenone fails, which melts, after filtration, drying, and redissolution of Essigester-petroleum ether at 118 ⁰ C.

Claims (2)

PATENT CLAIMS:
1. Process for the preparation of 1-phenylethyltetrahydroisoquinoline compounds of the general formula CH ₅ O -
CH ₃ O- ' , N-CH, CH-R ₂ and their salts, in which R _{1 is} fluorine, chlorine or bromine, R _{2 is} hydrogen or a straight or branched alkyl radical having 1 to 4 carbon atoms, η is the number 1, 2 or 3 and the undefined position of the radicals R ₁ means that these can have any position in the benzene ring, characterized in that an l-alkanoyl-2 - ((S-acylamino-ethyl) -4,5-dimethoxybenzene is condensed with a halogen-substituted benzaldehyde, the styryl ketone formed in the presence of acidic condensing agents to 3 , 4-Dihydroisoquinoline compound cyclized, this reduced in a manner known per se, the resulting substituted l-phenylethyl-l ^^^ - tetrahydroisoquinoline in a manner known per se methylated on the nitrogen atom and the N-methyl compound, if necessary, converted into a salt. 2. The method according to claim 1, characterized in that the substituted styryl ketone in Presence of a mineral acid as a condensing agent, preferably in the presence of acetic acid, cyclized. © 109 610/419 5.61