HU205056B - Process for racemization of phenyl alkyl amines - Google Patents

Abstract

Optically active aryl-alkyl-amines are racemised by halogenating them to N-halogen cpds. using a halogenating agent. Prods. are dehydro-halogenated to cpds. which in turn are reduced to racemic cpds.

Description

As is well known in pharmaceutical chemistry, many optically active phenylalkylamines are used partly as a drug and partly as an intermediate in some syntheses. A general characteristic of these applications is that only one of the optical isomers of each compound can be used for the desired purpose, while the other antipode isolated by resolution is a by-product of no practical use. The foregoing is well illustrated by, for example, Jumex (Selegiline hydrochloride, R - (-) - N-methyl-N-propynyl-2-phenyl-1-methylethylamine hydrochloride), where only R - (-) can be used. Therefore, the corresponding optically active intermediate, R - (-) - N-methyl-2-phenylmethylethylamine, is already used in the synthesis of the optically active article. The latter compound is prepared by diastereomeric salt formation (Hungarian Patents Nos. 154,655 and 169,845), whereby the same amount of the desired antipode, which is of no value for synthesis, is retained.

Although some attempts have been made to use the worthless stereoisomers formed in the above-mentioned syntheses, their general utility is only partially solved.

No. 2455914. According to the disclosure document of the Federal Republic of Germany, the worthless stereoisomer is broken down into an earlier intermediate of the synthesis series (the corresponding ketone) which no longer contains a chiral center and is used again as a starting material for the preparation of racemic products.

The use of a worthless stereoisomer is described in U.S. Patent No. 2,608,583. also patent specification. The disadvantage of this latter process is that it can only be carried out under vigorous reaction conditions for a long reaction time, which results in unwanted side reactions in the presence of Raney nickel.

It has been found that the optical antipodes of the compounds of formula I, wherein R, R ¹ and R ² independently of one another are hydrogen, C 1-5 straight or branched chain alkyl, are converted to the corresponding racemic compound if one is optically active. The compound of formula (I) is converted into a halogenating agent of formula (H) wherein X is chlorine or bromine, R, R ¹ and R ² are converted to the above N-halogen compounds and dehydrohalogenated to give the compound of formula (H1) , R ¹ and R ² are as defined above to form a Schiff base by reduction of the racemic formula (I) wherein R, R ¹ and R ² are as defined above. Although the reaction consists of several elementary steps, they may, if desired, be carried out in a single step without isolation of the intermediates and result in a product of the same chemical composition as the optically active compound of formula (I) used. The efficiency of the process is high, approximates, and in some cases achieves full racemization.

This ensures the conversion and recycling of the enantiomeric racemic compound, which has hitherto been considered worthless and polluting. The process provides full utilization of the racemic compounds of formula (I) in economically and environmentally satisfactory manner. This is the first such solution for compounds of formula (I) as evidenced in the literature.

Salts or esters of hypohalogenic acid (e.g., alkali hypochlorite, tert-butyl hypochlorite), N-haloacylamides and imides (e.g., N-chloroacetamide, N-chlorosuccinimide), N-halosulfonamides, for the preparation of N-halogen compounds. (e.g. Chloramine T). One preferred method involves the use of an alkali hypohalite and the reaction is carried out in aqueous solution. As the solvent, alcohols, ethers or other organic solvents (benzene, chloroform) may also be used if desired.

Although the compounds of formula (H) may be isolated if desired, it is preferred to convert them directly to the compounds of formula (ΓΠ).

Organic or inorganic bases (for example triethylamine, N-ethylpiperidine or alkaline or alkaline earth metal hydroxides, alkali metal alcoholates) may be used for dehydrohalogenation. This reaction is carried out in organic solvents or mixtures thereof (preferably alcohols or mixtures of alcohols and benzene).

The Schiff bases of formula (ΠΙ) are then converted to compounds of formula (I) in a manner known per se. The reduction can be effected catalytically, under normal pressure or under pressure, using nascent hydrogen (e.g., activated aluminum) or complex metal hydrides. Organic solvents or mixtures thereof (alcohols, alcohol-benzene, sometimes ethers) may be used as the solvent.

All three elementary steps of the process are characterized by very mild conditions (25-50 ° C) and good production.

The following examples illustrate the details of the process, but are not limited to these.

A) Examples for the preparation of N-halogen compounds of formula II

Example I

37.3 g (0.25 mol) of S - (+) - N-methyl-2-phenyl-1-methylethylamine [α] D = + 6.864 ° (abs. Alcohol, c = 5) 594 ml 9% sodium hypochlorite solution was added dropwise at 15 ° C. After stirring for two hours, the mixture was extracted with benzene, dried, filtered and concentrated in vacuo to below 50 ° C. A yellowish liquid is obtained with a mass corresponding to the theory.

Example 2

S - (+) - N-Methyl-2-phenyl-1-methylethylamine (37.3 g, 0.25 mol) was treated with Chloramine T trihydrate (70.67 g, 0.25 mol) in water (594 ml) for 4 hours at room temperature. The mixture was then partitioned between benzene, dried, filtered and concentrated in vacuo to below 50 ° C. The theoretical yield is a quantity of pale yellow liquid.

HU 205 056 Β

Example 3

S - (+) - N-Methyl-2-phenyl-1-methylethylamine (37.3 g, 0.25 mol) was added dropwise at 15 ° C to a mixture of 792 ml of methanol and 594 ml of aqueous 9% sodium hypochlorite. After stirring for 1 h, the mixture was removed in vacuo to remove methanol. The separated oil was collected by benzene extraction. Dry over sodium sulfate, filter. This solution is used for dehydrohalogenation.

Example 4

S - (+) - N-Methyl-2-phenyl-1-methylethylamine (37.3 g, 0.25 mol) was dissolved in ether (910 mL) and N-chloro (33.8 g, 0.25 mol) was added under nitrogen. -succinimide is added. Stir for 1 hour at 20 ° C. Water (192 mL) was added. After extraction with ether, the organic phase is dried and filtered. The resulting ether solution is used for dehydrohalogenation.

Example 5

S - (+) - N-Methyl-2-phenyl-1-methylethylamine (37.3 g, 0.25 mol) was dissolved in benzene (750 ml) and N-bromosuccinimide (46.75 g, 0.26 mol) was added. we add 20 'Con. After stirring for two hours, the precipitated succinimide is filtered off. The filtrate was used for the dehydrohalogenation step.

B) Examples for the preparation of Schiff bases of formula (III) by dehydrohalogenation

Example 6

1-5. The N-halogen compound prepared according to any one of Examples 1 to 4 or its solution is poured into a solution of sodium methylate (5.75 g, 0.25 mol) in sodium and 395 ml of methanol at 25 ° C. The mixture was heated to 35 ° C. After stirring for 4 hours, the sodium halide precipitated from the mixture is filtered off. The resulting solution is reduced according to any one of the examples in (C).

Example 7

The N-halo compound or a solution thereof obtained according to any of the examples described in A) is reacted with 13% methanolic solution of potassium hydroxide (15.4 g, 0.275 mol) at 25 ° C for 4 hours. The solution obtained after filtration is reduced according to any of the examples in (C).

Example 8

1-2. The N-halogen compounds prepared according to Examples 1 to 5 are dissolved in 300 ml of methanol; using the solution obtained according to the examples. To the solutions was added 50.5 g (0.5 mol) of triethylamine. Heat to 35 'C and stir for an additional two hours. Any of the solutions thus obtained can be used as starting material for the reduction steps described in (C).

C) Examples for the preparation of racemic compounds of formula (I) by reduction

Example 9

To the solution containing Schiff's base prepared in any of the examples in B) is added 20 g (0.528 mol) of sodium borohydride under ice-water cooling. Allow to stand overnight at 25 ° C. It is then decomposed by pouring into 10% hydrochloric acid. The aqueous portion was extracted with benzene. The aqueous phase was made basic and the separated oil was collected with benzene. The benzene phase was dried, filtered, concentrated and distilled. The product obtained weighs 24.2-27.9 g and boils at 86-92'C at 1 kPa, n = 1, 5130, [.alpha.] D @ 20 = + 2,210 DEG (abs. Alcohol, c = 5).

Example 10

To the solution of Schiff base prepared in any of the examples in B) is added 17 g of palladium on charcoal and hydrogenation at 104 MPa at 25 ° C for 4 hours. After filtration of the catalyst, the filtrate was evaporated. The residue was taken up in 100 ml of 10% hydrochloric acid and extracted with benzene. The aqueous portion was made basic and the resulting oil was extracted with benzene. The solution is dried, filtered, concentrated and distilled. The product obtained weighs 25-27 g, boiling point 86-90 'C, ηθ-1.5120 at 1 kPa, [α] D = + 1.992 ° (abs. Alcohol, c = 5).

Example 11

To the Schiff base solution obtained in any of the examples in B) is added 8.66 g of mercury (II) chloride-activated aluminum foil. The mixture was stirred for 3 hours at 25 'C and then for 5 hours at 45' C. The reaction mixture is filtered, the filtrate is evaporated and the residue is distilled off. The product weighs 24-26 g and boils at 86 kPa at 86-90 ° C, n = 1.5556, [α] D = + 2.051 ° (abs. Alcohol, c = 5).

Claims (8)

PATENT CLAIMS A process for the preparation of an optically active compound of formula I wherein R ¹ , R ¹ and R ² are each independently hydrogen, for the racemization of straight or branched C 1 -C 5 alkyl compounds, characterized in that an optically active compound of formula (I) is a halogenating agent of formula (II) wherein X is chlorine - or my bromine, R, R ^l and R ² are converted to the N-halo compound as defined above, followed by dehydrohalogenation and the resulting (III): - wherein R, R ¹ and R ² are as defined above Schiff base reduction of racemic formula (I) where R, R ¹ and R ² are as defined above. Process according to claim 1, characterized in that the halogenating agent for the halogenation is N-haloacylamides and imides, preferably N-halosuccinimides, N-haloacetamides, N-halosulfonamides, preferably N-chlorotoluenesulfonamide. sodium, hypochlorous acid salts or esters, preferably calcium or sodium hypochlorite or tert-butyl hypochlorite. The process of claim 2, wherein The halogenation is carried out with an aqueous solution of sodium hypochlorite. The process according to claim 1, wherein the base for the dehydrohalogenation is an organic or inorganic base, preferably triethylamine, N-ethylpiperidine or alkali or alkaline earth metal hydroxides, alkali metal alcoholates. 5. The process of claim 4 wherein the base is sodium methylate. Process according to claim 1, characterized in that the Schiff base of formula (ΠΙ) is characterized by nascent hydrogen, preferably activated aluminum, catalytic hydrogenation, preferably in the presence of Raney nickel or palladium-on-carbon, or complex metal hydrides, preferably sodium. borohydride, Sodium cyanoborohydride 5 is reduced. 7. Process according to any one of claims 1 to 3, characterized in that the reaction is carried out in one step without isolation of the intermediates, or the desired intermediate is carried out after isolation 10 next steps.