DE1227461B - Process for the production of new thioxanthene derivatives - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. CL:

C07d

German class: 12 ρ -1/01

Number: 1227461

File number: S 73704IV d / 12 ρ

Filing date: April 27, 1961

Opening day: October 27, 1966

The present invention relates to a process for the preparation of new thioxanthene derivatives of the general formula I.

Method of making new
Thioxanthene derivatives

and their acid addition salts, in which R represents a lower alkyl group.

According to the invention, the new compounds are obtained by adding a thioxanthenol derivative of the general formula II

II

Applicant:

SANDOZ A. G., Basel (Switzerland)

Representative:

Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg

and Dr. V. Schmied-Kowarzik, patent attorneys,

Frankfurt / M., Große Eschenheimer Str. 39

Named as inventor:

Dr. Jany Renz,

Dr. Jean-Pierre Bourquin,

Dr. Rudolf Griot, Basel;

Gustav Schwarb, Neuallschwil;

Leo Ruesch, Basel (Switzerland)

Claimed priority:
Switzerland of April 29, 1960 (4965, 4966),
dated July 21, 1960 (8345, 8347)

H ₂ C

wherein R has the above meaning, treated with dehydrating agents and the obtained Compounds, if appropriate in a manner known per se, by reaction with acids into their addition salts caught.

The process is carried out, for example, by using a thioxanthenol derivative of the formula II with dehydrating agents, such as phosphorus oxychloride, reacted at elevated temperature. To the Isolation of the product is the reaction solution, if necessary after removing excess dehydrating agent in vacuo, poured onto ice, alkaline with an alkali hydroxide solution made, and the thioxanthene derivative with a water-immiscible organic solvent, preferably chloroform, extracted. After removing the solvent the product becomes isolated and purified by known methods and optionally converted into acid addition salts.

The elimination of water from the thioxanthenol (9) derivative can advantageously also be carried out with concentrated Hydrochloric acid can be run at room temperature.

The thioxanthene derivatives prepared according to the invention are crystalline, basic at room temperature Compounds which, with acids, form stable salts which crystallize at room temperature.

609 708/396

The previously unknown thioxanthene derivatives produced by the present process are due to their excellent pharmdkodynamic properties for use as Remedies highly suitable. They have an anesthetic and sedative effect. Above all, draw they are characterized by histamine-inhibiting effects.

The thioxanthenol derivatives of the formula II used as starting materials are, for example, as follows made: ro

Activated magnesium chips are covered with an anhydrous open-chain or cyclic one Ether, e.g. B. tetrahydrofuran, and leaves N-methyl-4-chloro-piperidine or N-isopropyl-4-chloropiperidine drip.

The activation of the magnesium takes place according to known methods, e.g. B. with iodine, bromine or HgCk. Instead of pure magnesium, a magnesium-copper alloy (according to G i 1 m a n) be used.

The so prepared Grignard solution is then mixed with thioxanthone and the reaction mixture heated for several hours. The solvent is removed under reduced pressure and treating the organometallic complex with aqueous ammonium chloride solution. The thioxanthenol (9) derivative is isolated and purified by known methods and optionally converted into an acid addition salt.

The production of starting materials is not part of the subject matter of the invention.

All are done in the following examples, which illustrate how the process is carried out Temperatures in degrees Celsius. The melting points are not corrected.

example 1

9- (N-methyl-piperidylidene-4 ') -thioxanthene a) 9- (N-methyl-piperidyl-4') -thioxanthene- (9)

For the production of the starting material, thioxanthones), (Mp 207 °) o-chlorobenzoic acid is condensed with thiophenol and the reaction product cyclized with thionyl chloride and aluminum chloride.

In a well-dried apparatus, 8.77 g of magnesium turnings are covered with tetrahydrofuran and etched with an iodine crystal and a few drops of ethyl bromide. Then one lets 48 g of N-methyl-4-chloropiperidine are added dropwise in such a way that the reaction always continues. After finished The addition is heated to boiling under reflux for 10 hours, during which the magnesium is almost completely implements. 16.4 g of thioxanthone are added by means of an attached extraction apparatus and the mixture is then heated 20 hours at reflux to the boil. The solvent is now removed in vacuo and the remaining Treated organomagnesium compound with an ammonium chloride solution, whereby the 9- (N-methyl-piperidyl-4 ') -thioxanthenol- (9) precipitates. It is crystallized from ethanol. F. 187.5 to 188.5 °.

Maleate: 1.19 g of the base obtained and 0.45 g of maleic acid are dissolved in 30 ecm of absolute ethanol solved. On cooling, the maleate precipitates in crystalline form; it is recrystallized from absolute ethanol. F. 194 to 195 °.

b) 9- (N-methyl-piperidylidene-4 ') -thioxanthene

4.0 g of 9- (N-methyl-piperidyl-4 ') -thioxanthenol- (9) (mp. 187.5 to 188.5 °) are mixed with 24 ecm of phosphorus oxychloride heated to boiling under reflux for 5 hours. Any excess is then removed Phosphorus oxychloride in vacuo and dissolve the residue in 40 ecm ice water. From the 20 ecm concentrated aqueous solution alkaline sodium hydroxide solution, the compound is extracted with Chloroform. After evaporation of the solvent, the 9- (N-methyl-piperidylidene-4 ') -thioxanthene crystallizes from ligroin. F. 120 to 120.5 °.

Maleate: 1.10 g of the base obtained and 0.44 g of maleic acid are dissolved in 30 ecm of absolute ethanol solved. On cooling, the maleate of 9- (N-methyl-piperidylidene-4 ') -thioxanthen falls in crystalline form the end. After recrystallization from absolute ethanol, the analytically pure maleate melts at 183 to 184 °.

Hydrochloride: M.p. 162 to 165 ° from water.
Tartrate: F. 192 to 194 ° from ethanol.
Acetate: m.p. 103 to 105 ° from ether.

Example 2
9- (N-isopropyl-piperidylidene-4 ') -thioxanthene

a) 9- (N-Isopropyl-piperidyl-4 ') -thioxanthenol- (9)

3.2 g of magnesium shavings activated with iodine are added to a well-dried apparatus 10 ecm of tetrahydrofuran overlaid. One etches with a few drops of ethyl bromide and leaves inside about 1 hour 22.0 g of N-isopropyl-4-chloropiperidine add dropwise in 30 ecm of tetrahydrofuran. The mixture is refluxed for 3 hours heated, whereby the magnesium practically completely dissolves. The so prepared Grignard solution becomes Reacted on an extractor with 6.0 g of thioxanthone (mp 207 °) and then Heated to the boil for 14 hours.

After removing the solvent in vacuo, the remaining organomagnesium compound becomes treated with an ammonium chloride solution and the reaction product with chloroform moved out.

After evaporation of the solvent, the residue is chromatographed on aluminum oxide, the 9- (N-isopropyl-piperidyl-4 ') -thioxanthenol- (9) with chloroform as a light yellow, viscous oil is eluted.

b) 9- (N-isopropyl-piperidylidene-4 ') -thioxanthene

The solution of 9- (N-isopropyl-piperidyl-4 ') -thioxanthenol- (9) in 10 ecm of chloroform is three times extracted with 30 ecm concentrated hydrochloric acid. The deep red hydrochloric acid solution becomes after 1 hour Stand diluted, made alkaline with sodium carbonate solution and extracted with chloroform. To After standing for several days, the analytically pure 9- (N-isopropyl) is obtained after recrystallization from methanol - piperidylidene - 4 ') - thioxanthene from 109 to 110 °.

Maleat: F. 190 to 102 °.

Claims (1)

Claim: Process for the preparation of new thioxanthene derivatives of the general formula I. H ₂ C H ₂ C CH ₂ CH ₂ IO and their acid addition salts, in which R is a lower alkyl group, characterized in that that a thioxanthenol 20 derivative of the general formula II wherein R has the above meaning, treated with dehydrating agents and the obtained If appropriate, compounds are converted into their addition salts in a known manner by reaction with acids. Publications considered: Austrian patent specification No. 201 591. 609 708/396 10.66 O Bundesdruckerei Berlin