SU135083A1 - The method of dehydrogenation of 3,4-dihydroisoquinoline and its derivatives - Google Patents

Description

Methods are known for the dehydrogenation of 3,4-dihydroquinolines, including 3H-dihydropapaverine, using platinum or palladium catalysts, as well as René nickel. However, palladium and platinum are suitable for use only on a laboratory scale, the use of these catalysts in industry is difficult due to their belonging to the discharge of precious, expensive, their products and the difficulty of regenerating spent catalysts. The use of Rene nickel in industrial conditions makes the production particularly explosive due to the pyrophoricity of the catalyst and abundant release, either by the dehydrogenation reaction of hydrogen acclimated by nickel during its manufacture, and also due to the fact that in most cases the dehydrogenation is carried out in a medium combustible organic solvents (tetralin, decalin, xylene, etc.).

The proposed method for the dehydrogenation of 3,4-dihydroisoquinoline and its derivatives in the presence of a nenirphore nickel catalyst has several advantages over the known ones (lower cost and safety of the used catalyst, as well as high yields of the target products). The method consists in that the dehydrogenation is carried out in the presence of a non-pyrophoric nickel catalyst, and the reaction can be carried out both in a solvent, for example, in decalin, or without it. The non-pyrophoric nickel catalyst is prepared by decomposing nickel formate under a layer of paraffin. The catalyst is non-flammable, does not require special storage conditions, stands in the air, does not contain accredited hydrogen and is suitable for dehydrogenating various derivatives of 3,4-dihydroisoquinoline, which is of particular importance for the production of papaverine - a drug that is one of the best antispasmodic agents .

In order to carry out the process, the dehydrogenating substance and the catalyst are heated in a stream of carbon dioxide for several hours. After the visible termination of the hydrogen evolution, the catalyst is filtered off.

jNb 135083-2 Filtration, depending on the nature of the compound to be obtained, is treated by known methods to obtain a purified final product.

Example 1. And 3 o X and n o l and i. 3.2 g (0.0265 mol) of 3,4-dihydroisoquinoline and 0.32 g of catalyst are heated in a stream of carbon dioxide for 4 hours at 200-210 °. Upon the termination of the visible evolution of hydrogen, 20 ml of benzene was added to the reaction mass, and the catalyst was filtered off. From the benzene solution, the reaction product is extracted with 10% hydrochloric acid, the acidic extract is alkalinized with sodium hydroxide, and the isoquinoline released is extracted with benzene1M. After removal of benzene, the residue is distilled in vacuo. 2.2 g of isoquinoline are obtained. Yield 69%. T. pl. picrate 225-227.

Example 2. And 3 o X and n o l and n. 5.15 g (0.042 mol) of 3,4-dihydroisoquioline is dissolved in 15–1 l of decalin, 1.25 g of catalyst are added, and the mixture is heated in a stream of carbon dioxide for 4 hours at 210–220 ° (ban). After treatment as described in the previous example, 4.7 g of isoquinoline is obtained, which corresponds to a yield of 91.3%. T. pl. picrate 225 °.

Example 3. 1-f en n and l and 3 o X and n o l and n. 5.5 g (0.0268 mol) of β-phenyl-3, 4-dihydroisoquinoline, 25 ml of decalin and 0.55 g of catalyst are heated on an oil bath at 190–200 ° in a stream of carbon dioxide for 7 hours. The catalyst is filtered off, and the reaction product from the decalin solution is extracted with 5% hydrochloric acid. From the acidic solution, 1-phenylisoquinoline is isolated by neutralization with ammonia. The purification product was recrystallized three times with aqueous alcohol. 4 g of 1-phenylisoquinoline are obtained, or 73%. T. pl. picrate 165-166 °.

Example 4. 1-6 e of i and 3 o X inol and n .. 4.1 g (0.0185 mol) of 1-benzyl-3, 4-dihydro-isohy 1olina is dissolved in 15 ml of decalin, added 0.41 g of catalyst and the mixture is heated at 180-190 ° in a stream of carbon dioxide. Hydrogen evolution ceases after 6 hours. 1-benzylisoquinoline was isolated as in Example 3. Yield 3.1 g, or 76%. T. pl. picrate 182-184 °.

Example 5. Papaverine (base). 5 g (0,0146 mol) of 3,4-dihydropapaverine and 1 g of catalyst are heated in a stream of carbon dioxide for 3/2 hours, during which time the visible evolution of hydrogen ceases. After cooling, 20 ml of alcohol is added to the reaction mass, the mixture is heated and filtered from the catalyst. When cooling the alcoholic solution, the main (3.8 g) amount of papaverine base is separated, and an additional 1 g of papaverip base is separated from the mother liquor by partial steaming. The total yield of 4.8 g, or 96% of theoretical. T. pl. 142-144 °

The base of papaverine is converted into hydrochloride, which, after recrystallization from water, has a mp. 219 °, which meets the requirements of Gosparmakopep.

Example 6. PaPa aver and n (base). 7.7 g (0.02 mol) of 3,4-dihydropapaverine-3-carboxylic acid with m.p. 132-134 ° is shifted from 25 ml of decalin and the mixture is heated at 150-160 ° until carbon dioxide evolution ceases. Then, 2.2 2 catalysts are added to the reaction mass and the mixture is heated in a stream of carbon dioxide for 7 hours with a gradual rise in temperature from 150 to 200. During this time, an amount of hydrogen that is close to theoretical is released. The reaction mass at 100-110 ° C is filtered off from the catalyst, and when cooled, the base oil, first released as oil, solidifies into a crystalline mass. The yield of papaverine base is 5.9 g, or 86.7%. After recrystallization from methanol