PROCESS FOR THE PREPARATION OF 3,4-DIHYDROISOQUINOLINE

Abstract: Process for the preparation of 3,4-dihydroisoquinoline by dehydrogenation of the 1,2,3,4-tetrahydroisoquinoline with elementar sulphur.

Description: PROCESS FOR THE PREPARATION OF 3,4-DIHYDR0IS0- QUIHOLHE The invention relates to a new process for the preparation of 3,4-dihydroisoquinoline. The isoquinoline derivatives, which are unsubstituted in 1-position, are very important starting materials as well as intermediates in the synthesis of different substituted and condensed isoquinolinea By using the Reissert compounds obtained from the 3,4-dihydroisoquinolines many substituted iso- quinolines may be prepared (J. Org. Ghem. 3 3119 /1970/). The 3,4-dihydroisoquinolines are suitable also for the preparation of the condensed isoquino- lines occuring also in the nature (Chem. Ber. 2 > 557 /1965/). The above mentioned synthesis were, however, performed only with 6,7-dialkosy derivatives since the 3,4-dihydroisoquinolines, which contain an electron donor substituent in 6-position, may be prepared easily by the Bischler-Napieralsky synthe¬ sis. The compound of the invention may be prepared by the Bischler-Napieralsky synthesis only in a very low yield since the starting material, the N-formyl-2-phenylethylamin does not contain an electron donor substituent in para-position and during the reaction mainly the non-wanted by¬ products are formed (Ann. 382, 3β9 /1911/). Therefore those synthesis routes were mainly studied for the preparation of the 3,4-dihydroiso¬ quinoline which are based on the partially dehyro- genation of the easily available 1,2,3,4-tetrahydo- isoquinoline. This reaction cannot be stopped, however, at a partial dehydrogenation degree while using oxidizing agent and so isoquinoline will be formed (Arch. Pharm. 274, 153 A936/). Therefore this method is suitable only for the preparation of the F-substituted derivatives where due to the partial dehydrogenation quaternary 3,4-dihydroiso- quinolinium salts are formed (<J. Am. Chem. Soc. 71, "3 08 /1949/) * In the newest literature some oxidation methods are described whereby 3,4-dihydo- isoquinoline may be obtained, in these processes special oxidizing agents and catalysts (e.g. ruthenium ■+- tertv-buthylhydroperoxyd) are, however, needed by which the widespread use of this process will be restricted (J. Chem. Soc. Chem. Comm. 1985 , 615) * Also isoquinolines are formed in the dehydro¬ genation reaction performed in the presence of noble metal catalysts (Chem. Ber. 60, 2602, /1927/). An improved process for the preparation of the compound of the invention is described in our earlier application according ' to which the 3,4-di¬ hydroisoquinolines were prepared by Bischler-Napi- eralsky synthesis in the presence of Lewis-acids (published Hungarian patent application Nr. T25,548i Although by this process the 3,4-dihydroisoquinoli¬ nes substituted in 1-position could be obtained in very high yield, in case of 3,4-dihydroisoquinoline unsubstituted in 1-position the corresponding hexa- chlorostannate is formed only in a 62 yield, from which the base may be set free v/ith some additional loss. Our invention, by which the selective dehydro¬ genation of 1,2,3,4-tetrahydroisoquinoline is reali- zed, eliminates the disadvantages of the known processes and gives a method for the preparation of 3,4-dihydroisoquinoline in large amounts and high purity which is more simple and can be carried out easier than the processes known in the art. It has been found that the 1,2,3,4-tetrahydroisoquinoline ma be selective dehydrogenated to 3,4-dihydroisoquinoline with elementar sulphur in a solvent at 50 to 150 C. In the reaction the end product is obtained in very high yield, in high purity. As solvents alcohols, 5 aromatic hydrocarbons, ethers, etc. may be used. According to a preferred embodiment of our invention the reaction is performed in toluene or butanol at the boiling point of the solvent. In the reaction l-mercapto-l,2,3,4-tetrahydroisoquino- 10 line is formed as intermediate, which cannot be isolated and by hydrogen sulfide elimination it will be spontaneously transformed to 3,4-dihydroisoquino¬ line. In the dehydrogenation reaction 1 to 10 moles of sulphur is used pro 1 mole of the tetrahydroiso- 15 quinoline. In a preferred embodiment of the inven¬ tion the sulphur is used i excess for the complete reaction and is removed by filtration from the reaction mixture after the reaction has been finis¬ hed. The partial dehydrogenation may be carried out 20 during 4 to 20 hours depending on the solvent applied and the reaction temperature. After cooling the reaction mixture, filtering the excess of the sulphur and evaporation of the solvent the product is obtained as an oil which may be further purified or by distillation in vacuo, if desired. The product may be purified also by salt formation or aqueous acidic extraction. In the reaction the 3,4-dihydro¬ isoquinoline is obtained in a 90 to 95 % yield. The process of the invention is shown by the 0 following non-limiting Examples. Example 1 30.0 g of 1,2,3,4-tetrahydoisoquinoline and 15.0 g of sulphur powder in 200 ml of toluene are refluxed for 6 hours. After cooling the precipita- 5 ting sulphur is filtered off, the filtrate is extracted with 200 ml of 5 hydrochloric acid. The aqueous solution is made alkaline with 40 % sodium hydroxide to pH=10, then extracted with 250 ml of chloroform. The chloro orm extract is dried with sodium sulfate and evaporated in vacua. As residue 28.5 g of 3,4-dihydroisoquinoline are obtained. Example 2 30.0 g of 1,2,3,4-tetrahydroisoquinoline and 0 15.0 g of sulphur powder in 200 ml of toluene are refluxed for 7 hours. After cooling the sulphur is filtered off, the filtrate is evaporated in vacuo. The resulting thick oily residue is distilled in vacuo. 27.5 g of 3,4-dihydroisoquinoline are obtai¬ s ned, bp. 64-67 °C at 0.6 mmHg. Example 3 6.0 g of 1,2,3,4-tetrahydoisoquinoline and 3.0 g of sulphur powder in 40 ml of n-butanol are refluxed for 7 hours. After cooling the sulphur is 0 filtered off, the filtrate is evaporated in vacuo. The residing oily product is converted with satura¬ ted alcoholic picric acid to the picrate. 12.0 g of 3,4-dihydroisoquinoline-picrate are obtained, mp. 176-177 °C. literature mp. 176-177 °C (J. A. Chem. Soc. 72, 2962 /1950/). 5 Example 4 β.O g of 1,2,3,4-tetrahydroisoquinoline and 3.0 g of sulphur powder in 40 ml of dioxane are refluxed for 20 hours. The reaction mixture is 0 evaporated, to the residue 60 ml of ether are added, the precipitated sulphur is filtered off and the filtrate is evaporated. 5.7 g of 3,4-dihydro¬ isoquinoline are obtained. 5

Claims: Claims 1. Process for the preparation of 3,4-dihydro¬ isoquinoline which comprises dehydrogenation of the 1,2,3,4-tetrahydroisoquinoline with elementar 5 sulphur. 2. The process of claim 1 which comprises performing the dehydrogenation in a solvent medium at 50 to 150 °C, preferably at the boiling point of the solvent. Q 3. The process of claim 2 which comprises using alcohols, aromatic hydrocarbons, ethers as solvent, 4. The process of claim 1 which comprises using 1 to 10 moles of sulphur calculated on 1 mole of 1,2,3,4-tetrahydroisoquinoline.

Inventors: AJZERT ILONA K, ECSERINE PUSKAS MARIANN, FLEISCHER JUDIT, MARMAROSI TAMASNE, RIMAI JOZSEF, TAKACS KALMAN, AJZERT, ILONA, K., ECSERINE PUSKAS, MARIANN, FLEISCHER, JUDIT, MARMAROSI, TAMASNE, RIMAI, JOZSEF, TAKACS, KALMAN
Applicants: CHINOIN GYOGYSZER ES VEGYESZET, CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT.
Application year: 1987
Main classification: C07D217
IPC codes: B01J27, C07D217