HU191927B - Process for production of amino-cis-2,6-lupeditin - Google Patents

Abstract

The prod. is prepd. by the nitrosylation of cis-2,6-lupetidine and the hydrogenation of the resulting nitroso-lupetidine in the presence of a palladium catalyst poisoned with ferro-salts, in an aq. ammonia medium at a pressure of 1-10 bar.

Description

The present invention relates to a new and improved process for the preparation of aminocis-2,6-lupetidine. Amino-cis-2,6-lupetidine is a valuable pharmaceutical intermediate useful in the preparation of, inter alia, 4-chloro-N- (cis-2,6-dimethylpiperidino) -3-sulfamoyl-benzamide. The latter compound is a known pharmacologically active substance.

It is known that N-amino dialkyl compounds, also known as dialkylhydrazo compounds, can be prepared by nitrosation of the corresponding amine followed by selective reduction of the resulting nitroso compound (HoubenWeyl, Meth. Org. Chem. 10 / 2,38- 43). Nitrosation is carried out in a solution of the amino compound in hydrochloric acid with sodium nitrite under cooling (0-5 ° C) or heating (70-80 ° C). The nitroso compound formed is insoluble in water and can thus be separated.

The Helv. Chim. Acta 45, 7, 2316 (1962), lupetidine is nitrosated in an aqueous medium in the presence of sulfuric acid at a temperature of 0-3 ° C. The reaction mixture is worked up several times with ether extraction and the extracts are evaporated, dried and then distilled. The publication does not disclose extraction data. The disadvantage of this process is that the industrial-scale extraction of ether is explosive. In addition, in our own experiments, it was found that hydrogenation of nitrosolupetidine obtained by nitrosation of sulfuric acid without purification by vacuum distillation afforded only the desired amino-cis-2,6-lupetidine in moderate yield.

The nitrosolupetidine thus obtained is purified by distillation before reduction

Several methods are known in the art for reducing the resulting nitrosolupetidine. The Beilstein: Handbuch hoarfrost org. Chemie TV. However, the process is unsuitable and uneconomical for industrial use (cost of electricity use, safety measures, etc.), according to the procedure described on page 109 of the current edition of N-nitroso-2,6-lupetidine in 50-60% sulfuric acid. .).

Other reports indicate that nitrosol-lupetidine is converted to amino-cis-2,6-lupetidine by chemical reduction. 77, 4100 (1955) J. Am. Chem. Soc., 1955, lithium aluminum hydride is subjected to reduction of nitroso-2,6-dimethylpiperidine. However, the process has several disadvantages. Lithium aluminum hydride is a special and costly reducing agent which is avoided on an industrial scale due to the risk of stapling. J. Org. Chem. 22, 858 (1957). Reduction of Nitrosolupetidine with Sodium Dithionite The disadvantage of the process is that the reducing agent used is expensive, the reaction mixture is difficult to process and, due to its high volume requirements, it is unsuitable for industrial use. The Helv. Chim. Acta 45,7,2316 (1962) states that nitrosolupetidine is reduced with zinc in an acetic acid medium, but the process can be carried out only in moderate yields, while the zinc used in the reaction is expensive and circular.

927 B 2 causes environmental problems (zinc sludge). A further disadvantage is the high volume requirement of the process.

No. 2979505. U.S. Pat. No. 4,123,198 discloses the reduction of nitrosolupetidine by catalytic hydrogenation in the presence of a palladium catalyst poisoned with iron (II) sulfate.

The patent does not actually exemplify hydrogenation of nitrosolupetidine. It is described, inter alia, the reduction of aliphatic N-nitrosodimethylamine and N-nitrosopiperidine; the latter compound is unsubstituted at the α-positions relative to nitrogen. Both spatially strongly inhibited nitrosolupetidine substituted at both α-positions relative to nitrogen exhibit reduced reactivity to hydrogenation. According to U.S. Patent No. 5,779,505, the hydrogenation of nitrosolupetidine is carried out in a homogeneous solution of aqueous or ethanol. Hydrogenation as described in US patent yields only 65% yield of aminocis-2,6-lupetidine (see Example 14 of this application). It is further noted that the process selectivity is only moderate - 60-70% - because of the significant amount of cis-2,6-lupetidine produced by over-hydrogenation. It is an object of the present invention to development of a process for the preparation of amino-cis-2,6-lupetidine.

The present invention relates to a process for the preparation of amino-cis-2,6-lupetidine by nitrosation of cis-2,6-lupetidine in an acidic medium and hydrogenation of the resulting nitrosolupetidine in the presence of a palladium catalyst poisoned with iron (H) salt. chloride ions; cis-2,6-lupetidine is nitrosated in the presence of acetic acid at 40 ° C to 55 ° C and hydrogenation of nitrosolupetidine is carried out in an aqueous ammonia medium at 110 bar.

The present invention is based on the discovery that chloride ions inhibit the selective reduction of nitrosolupetidine in the presence of palladium catalyst poisoned with iron (H) salts. Hydrogenation is therefore reported to be carried out under high pressure (30-40 bar) in the literature, and in addition to the desired amino cis-2,6-lupetidine, cis-2,6-lupetidine is also produced in significant amounts.

The objects of the present invention are achieved on the basis of the above recognition by providing a chlorine-free environment in the preparation of amino-cis-2,6-lupetidine. chloride ions are excluded.

The nitrosation of cis-2,6-lupetidine according to the invention is carried out in the presence of acetic acid, excluding chloride ions. The reaction is carried out under heating at 4055 ° C, preferably 50 ° C. The reaction medium is aqueous acetic acid. The nitrating agent used is an alkali metal nitrite such as sodium or potassium nitrite, preferably sodium nitrite. The reaction is carried out easily and quickly in aqueous acetic acid.

HU 191 927 B

The reaction mixture can be processed very simply. The reaction mixture is basified and the nitrosolupetidine is separated from the aqueous phase. Contrary to the known methods, it is not necessary to distil the resulting nitrosolupetidine and this, on the one hand, saves energy and, on the other hand, eliminates further losses.

The thus obtained nitroso-lupetidine is hydrogenated directly without purification in the presence of a poisoned palladium catalyst on a support. Palladium on activated carbon is preferably used as the catalyst. The catalyst may be poisoned with 1 to 20% by weight of iron (H) sulphate.

Hydrogenation is already low in the chloride-free medium provided by the process of the present invention

Performs very selectively at a pressure of 1-10 bar Preferably, a pressure of 3-6 bar is used. The hydrogenation is carried out at 40-65 ° C. Hydrogenation is selectively carried out within a few hours and, under the mild conditions employed, no side reactions (such as cis-2,6-lupetidine formation) occur.

The hydrogenation can be carried out in an aqueous medium in an aqueous solution of ammonium hydroxide. The reaction mixture is very simple to process; amino-cis-2,6-lupetidine is readily recovered from the aqueous solution.

It has been found that hydrogenation in an aqueous solution of ammonium hydroxide in a heterogeneous phase is excellent and easy to carry out. Nitrosolupetidine will not dissolve in aqueous ammonium hydroxide medium and, as the reaction proceeds, will be phase-phased and isolated in a very simple manner due to the excellent water solubility of the resulting amino-cis-2,6-lupetidine.

The advantages of the process of the present invention are summarized below:

- the crude nitrosolupetidine produced by nitrosation can be directly hydrogenated without distillation;

hydrogenation of nitrosolupetidine can be carried out at lower pressures with better selectivity;

- hydrogenation is carried out in a short time;

hydrogenation can be carried out in an aqueous medium, which is advantageous on the one hand from the safety point of view and on the other hand allows the easy recovery of the amino-lupetidine from the aqueous solution;

- using our process, the poisoned catalyst can be used several times in successive reactions.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

120 g of cis-2,6-lupetidine, 120 ml of water and 115 g of acetic acid are charged into a apparatus equipped with stirrer, heating, reflux condenser and thermometer. In another flask was dissolved 100 g of sodium nitrite in 100 ml of water under heating. The temperature of the apparatus was raised to 50 ° C with stirring and the sodium nitrite solution was heated to ca. Add in 15 minutes. The reaction mixture was kept at this temperature for 2 hours, then made basic and the nitrosolupetidine was separated from the aqueous phase.

100 ml of distilled water was charged to a pressure-hydrogenated apparatus and 5 g of palladium on charcoal containing 10% palladium on carbon was added. A solution of 0.5 g of iron (H) sulfate in 10 ml of water is then added with stirring. To the suspension of catalyst is added 50 ml of 25% aqueous ammonium hydroxide solution with stirring, followed by the addition of the nitrosolupetidine prepared according to the preceding paragraph. The autoclave was sealed, purged with nitrogen and hydrogen, the hydrogen pressure was adjusted to 6 bar and the temperature was raised to 50 ° C. The hydrogenation was carried out for 5 hours and the reaction mixture was subjected to gas chromatography; according to this, the content of nitrosolupetidine is 3%, the content of amino-lupetidine is 89% and the content of lupetidine is 8%.

The apparatus was cooled, purged with nitrogen, the catalyst filtered and washed with water (2 x 50 mL). To the combined filtrates were added 150 g of potassium hydroxide or 120 g of sodium hydroxide, and the organic phase was separated and subjected to vacuum fractionation. 97 g of pure cis-2,6-amino-lupetidine are thus obtained. Yield: 83% based on starting cis-2,6-lupetidine. Boiling point: 165-170 ° C / 1013 mbar, d ₂ o 0.89.

2-9. example

The procedure described in Example 1 was carried out with the modification that the amounts of starting materials and parameters indicated in the following table were used. 7-9. example is comparative; according to this, nitrosation is carried out in the presence of chloride ions. hydrogenation is carried out using sodium hydroxide in a medium.

From the results of the table it can be seen that the process according to the invention provides a much better yield than the prior art method. Hydrogenation in the presence of sodium hydroxide can only be carried out under high pressure - 40 bar

See table on next page.

Claims (2)

PATENT CLAIMS CLAIMS 1. A process for the preparation of aminocis-2,6-lupetidine by nitrosating cis-2,6-lupetidine in an acidic medium and hydrogenating the resultant nitrosolupetidine in the presence of an iron (II) salt poisoned catalyst, characterized in that exclusion; cis-2,6-lupetidint presence of acetic acid at 40 ° C and 55 C, and ^this temperature of between nitrosation of nitroso-lupetidin hydrogenation is carried out in aqueous ammonia medium, 1-10 bar. Process according to claim 1, characterized in that the nitrosolupetidine obtained after nitrosation in the presence of acetic acid, after elimination of chloride ions, is directly subjected to hydrogenation without distillation.