DE2851039A1 - Optically active alpha-substd. benzylamine derivs. racemisation - by liq. phase hydrogenation in presence of hydrogenation catalyst - Google Patents

Abstract

In a new process for the prodn. of racemic mixts. from optically active benzylamine derivs. of formula (I) (where R1 is alkyl2, aralkyl or opt. substd. aryl; and R is H, alkyl or alkoxy) the optically active (I) is treated with H2 in the presence of a hydrogenation catalyst at elevated temp. in the liq. phase. Optically active cpds. (I) are useful as intermediates and reagents, e.g. in the prodn. of optically active pharmaceuticals. The new process enables unwanted isomers of (I) to be converted into racemates from which further yields of the wanted isomer can be obtd. by optical resolution. In many cases the hydrogenation can be carried out at normal pressure.

Description

process for the racemization of optically active 1-arylamines

The invention relates to a method for producing racemic Mixtures of optically active 1-arylamines by treatment with hydrogen at increased Temperature in the presence of a hydrogenation catalyst.

The optically active l-arylamines of the general formula I. in which R1 is an alkyl, aralkyl or optionally substituted aryl radical and R2 is hydrogen, an alkyl or alkoxy radical, are valuable organic intermediates and auxiliaries, for example for the production of optically active pharmaceuticals.

For example, both stereoisomers of 1-phenylethylamine are in isolated form as a salt former to separate racemic mixtures from optical Active acids used because l-PhenylGthylamine can be synthesized and in simpler Way is cleavable in the antipodes. Compared to the naturally occurring alkaloids, which were previously used for this purpose, they have the advantage of being in any Quantity £ ur technical processes to be available.

When separating racemic mixtures, both are inevitably falling Antipodes (enantiomers) in equal amounts.

Usually, however, only one of the enantiomers is required, so that the other, whether one cannot or will not use it for other purposes, is worthless. There is therefore a need for a method to racemize the unnecessary enantiomer and to split the racemate again, i.e. to build up a circular process.

From Japanese laid-open specification 6911/76 it is known that optically active RW amino alcohols by treatment with hydrogen and ammonia in the presence a hydrogenation catalyst can be racemized and thus the recovery of the required optical enantiomers from the worthless in a circular process possible will. This process usually requires high pressure and temperatures have to act at 2000C for several hours; the mention of a process Ordinary pressure in the gas phase appears to be purely speculative, since there is such a Verifiably does not allow the procedure to be carried out.

For optically active l-arylamines that do not have a hydroxyl group in the 2-position have to the amino group, a corresponding racemization process is so far not been described.

The invention has therefore set itself the task for the inventive l-Arylamines indicate a technically useful racemization process, which according to Ability to dispense with the application of increased pressure.

As can be seen from the preceding claim, found that the optically active l-arylamines in the presence of a hydrogenation catalyst and hydrogen at atmospheric pressure under certain circumstances 'sate can, it being possible to work in the presence of solvents or without them. The use of ammonia is unnecessary, although of course ammonia in the corresponding Excess acts like a solvent and some pressure can be maintained would have to get the liquid phase. As solvents all come against hydrogenating Conditions of permanent connections in question; e.g. ethers, especially cyclic ones ethers such as tetrahydrofuran (THF) or 1,4-dioxane, alcohols and hydrocarbons.

The process can be carried out with the usual hydrogenation catalysts that are used in Reaction temperature do not cause hydrogenation of the phenyl group. Particularly suitable are e.g. Raney cobalt or Raney nickel as well as corresponding, Catalysts suitable for fixed arrangement in the reaction chamber. With these it can Procedures can easily be designed continuously.

A suitable reaction temperature can for example be between 80 and 250 ° C lie; i.a. a temperature below 2000C is sufficient. One turns accordingly the effective temperature a sufficient pressure to make the reaction mixture liquid to hold and in addition a hydrogen partial pressure of, for example, 0.5 to 250 bar. Pressures above 300 bar or even 500 bar are hardly required. In some Cases such as l-phenylethylamine, the tendency to racemization is so great, that can be carried out at atmospheric pressure, with a temperature of 1500C i.a. need not be exceeded.

The optically active l-arylamines can be given by the general formula (I), where the substituents R1 and R are those in the preceding claim have given meaning. Preferred are, for example, those in which one Methyl, ethyl, n- or iso-propyl, m- iso-, -tert-butyl group, amyl (pentyl) group, Hexyl or a similar optionally further substituted alkyl group with generally means fewer than ten carbon atoms; R1 can also be a cyclopentyl, Be cyclohexyl, cyclohexylmethyl, phenyl or a benzyl group, the phenyl or benzyl radical, optionally by one or more alkyl, fluorinated alkyl, Alkoxy or hydroxy radicals on the aromatic ring can be substituted. R2 means Hydrogen or an alkyl or alkoxy radical. R2 must together with the phenyl radical, which it substitutes, of course, be different from R1, since otherwise there is no optical Activity occurs.

Examples of corresponding optically active 1-arylamines are: 1-phenylethylamine, 1-phenyl-2- (p-tolyl) -ethylamine, 2-phenyl-1- (p-tolyl) -ethylamine.

The degree of optical purity of the starting compound is natural unimportant.

For example, to obtain (+) - 1-phenylethylamine one racemizes (-) - 1-Phenylethylamine according to the process of the invention, wherein D / L-1-phenylethylamine is formed. This is left in a known manner, for example in methanolic solution with dextrorotatory tartaric acid, easily or sparingly soluble diastereomeric salts form, and crystallizes fractionally. One wins from the fractions the (+) - and the (-) - enantiomer separates and subjects the undesired (-) - enantiomer again the racemization etc.

Example 1 In a glass stirring flask with a capacity of 250 ml 50 g optically active 1-phenylethylamine (degree of purity: 98.5%; optical rotation angle αD20 = 14.14 °) and 5 g of Raney cobalt, brought to 130 ° C., 4 liters of hydrogen stirred per hour at atmospheric pressure and 15 hours. Then with THF washed, this stripped off again under reduced pressure and the oily residue distilled between 35 and 450C at 0.1 mbar pressure.

39.2 g of racemic 1-phenylethylamine are obtained (degree of purity: 88.4 %, determined by gas chromatography by standardization with decanol; optical rotation angle .20 = -0.35 °).

The degree of recovery is 70.4%.

The degree of racemization results from α (product) (1 -) x 100 98.4% (αD20 = -12.69 °) corr.

α (raw material) where oC (product) or α (raw material) mean the (corrected) angle of rotation of the racemate or optically active starting material.

The achieved racemate yield is 68.6% of the mathematically possible. It is calculated according to the degree of recovery x degree of racemization (g) 100 example 2 As described in Example 1, 50 g of optically active 1-phenylethylamine (degree of purity: 99.0%, optical angle of rotation αD20 = -14.01 °) and 5 g of Raney cobalt under Ein-D 4.010) pass hydrogen at 1400C for 4 hours.

It is worked up and distilled as described.

39.4 g of racemic 1-phenylethylamine (degree of purity: 95.8) are obtained %; optical rotation angle αD20 = -2.07 °). The degree of recovery is 76.3 %, the degree of racemization 84.7% (αD20corr. = -13.56 °), the racemate yield is calculated at 64.6%.

Claims (2)

Patent claims 1. Process for the preparation of racemic mixtures from optically active 1-arylamines of the general formula I. in which R1 denotes an alkyl, aralkyl or optionally substituted aryl radical and R2 denotes hydrogen, an alkyl or alkoxy radical, characterized in that the optically active 1-arylamines are treated with hydrogen in the presence of a hydrogenation catalyst at elevated temperature in the liquid phase. 2. The method according to claim 1, characterized in that as Raney cobalt hydrogenation catalyst used.